doi.org/10.26434/chemrxiv.12370574.v1

Scandium and Dimethylaminopyridine Catalyzed Dehydrative Couplingof Secondary Benzylic and Primary Alcohols to SynthesizeUnsymmetrical EthersJulia Duncan, Lun Li, Vahid Mohammadrezaei, Laina Geary

Submitted date: 26/05/2020 • Posted date: 27/05/2020Licence: CC BY-NC-ND 4.0Citation information: Duncan, Julia; Li, Lun; Mohammadrezaei, Vahid; Geary, Laina (2020): Scandium andDimethylaminopyridine Catalyzed Dehydrative Coupling of Secondary Benzylic and Primary Alcohols toSynthesize Unsymmetrical Ethers. ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.12370574.v1

We developed a direct catalytic condensation of benzylic alcohols and primary alcohols to synthesizeunsymmetrical ethers in one step, catalyzed by scandium triflate and p-dimethylaminopyridine (DMAP).Preliminary experiments give some insight into the mechanism of the reaction, though suggest that theprocess is quite complex. We suspect the rapid formation of a dimer from a secondary benzylic alcohol via acarbocation intermediate precedes unsymmetrical ether formation. Full experimental details andspectroscopic data are provided as supplementary information.

File list (2)

download fileview on ChemRxivSecOH.pdf (288.08 KiB)

download fileview on ChemRxivSecOH_SI.pdf (4.18 MiB)

Scandium and dimethylaminopyridine catalyzed dehydrative coupling of secondary benzylic and primary alcohols to synthesize unsymmetrical ethers Julia M. Duncan,1† Lun Li,1,2† Vahid Mohammadrezaei,1 and Laina M. Geary1*

Abstract: We developed a direct catalytic condensation of benzylic alcohols and primary alcohols to synthesize

unsymmetrical ethers in one step, catalyzed by scandium triflate and p-dimethylaminopyridine (DMAP). Preliminary

experiments give some insight into the mechanism of the reaction, though suggest that the process is quite complex.

We suspect the rapid formation of a dimer from a secondary benzylic alcohol via a carbocation intermediate precedes

unsymmetrical ether formation.

Introduction The direct modification of functional groups is an ongoing challenge in synthetic organic chemistry. Alcohols are

abundant and easily accessible via a variety of transformations and are thus attractive substrates for further

modification. However, alcohols typically require derivatization or preactivation to enable their use in coupling or

substitution reactions. The desire for chemoselective, direct transformation of alcohols into alternate functional

groups has been identified as a key goal in the pharmaceutical industry.1 While there are now a number of protocols

to do so,2 direct condensation of two symmetrical alcohols to form ethers represents a significant challenge. Recent

work in the syntheses of unsymmetrical ethers have relied on gold catalysts,3 solid-phase thiazolium salts,4 ruthenium

catalysts,5 and boronic acid activation.6

We discovered that when 3-hydroxydihydrobenzofuran 1a was exposed to a Lewis acid catalyst and primary alcohol,

direct substitution to the unsymmetrical ethers occurred. We report application of this chemistry to a variety of

secondary and tertiary benzylic alcohols, as well as some preliminary mechanistic investigations (Scheme 1).

1 University of Nevada, Reno Department of Chemistry; Reno Nevada USA 2 Westlake University Department of Chemistry; Hangzhou China † These authors contributed equally to this work

Scheme 1. The synthesis of unsymmetrical ethers via a direct catalytic substitution.

13 examples14-88% yields

DCE (0.25 M)0 °C-rt, 24 h

R2 Sc(OTf)3 (10 mol%)

DMAP (10 mol%)HO

R1

OH

R1

O R2

Results and Discussion Initial screening studies used 3-hydroxydihydrobenzofuran 1a as substrate for reactions with prenol. Scandium triflate

is a well-known Lewis acid catalyst for dehydrogenation of alcohols in a variety of applications.7 Appling catalytic

amounts of scandium triflate led to full consumption of 1a at room temperature in acetonitrile after 30 minutes;

however, only trace amounts of the desired ether substitution product was detected, along with significant amounts

of benzofuran from competing elimination chemistry. Copper,8 ytterbium,9 and bismuth triflates10 all led to

incomplete consumption of 1a under otherwise identical conditions, and yielded only trace amounts of the

substitution product, despite precedence for their ability to enable direct ionization of alcohols. Both zinc triflate, able

to catalyze the direct cyanation of benzylic alcohols at 100 °C,11 and zinc chloride, known for dehydration of alcohols

to form ethers at room temperature,12 were unreactive towards 1a at room temperature. Similarly, copper catalysts

known to ionize allylic alcohols at room13 or elevated temperatures14 were ineffective at this dehydrogenative benzylic

ether formation from 1a.

As the preliminary reactions performed using scandium triflate as the catalyst led to the complete consumption of

the 1a, albeit with low selectivity for ether formation, we then screened various reaction conditions in the coupling of

3a with neopentyl alcohol 2a to optimize for formation of the desired ether. Ultimately, we found that performing the

reaction in the polar aprotic dichloroethane (DCE) and initiating the reaction at 0 °C was optimal as increasing the

temperature led to complete formation of benzofuran 4, and keeping the reaction at lower temperatures slowed the

reaction down substantially. However, in the absence of an exogenous ligand, that was at the expense of formation

of ether 3a (Table 1, entry 1). We examined amino acids as ligands, which are an inexpensive source of diverse

functionality, with 1a and neopentyl alcohol 2a as substrates (Table 1, entries 2-7). Heteroaromatic L-histidine led to

full consumption of 1a and a modest yield of the desired 3a. Applying basic amino acids L-lysine and L-arginine as

ligands improved the relative conversion to 3a, though the isolated yield was slightly diminished (entry 3, 4). Other

aromatic amino acid ligands, L-tryptophan and L-phenylalanine performed poorly, and incomplete consumption of 1a

was observed (entry 5, 6). Although use of glycine as ligand gave comparable product ratios to L-histidine, the yield

was poor. We were interested in identifying the particular chemical motif of L-histidine that allowed it to function as

an effective ligand for selective direct substitution of a benzylic alcohol. Imidazole as a ligand led to poor conversion

and selectivity for 3a (entry 8). N-Substitution at the 1 or 3 position of the imidazole ring of L-histidine improved

selectivity for 3a and modestly improved yield, but did not give full conversion of 1a (entries 9, 10). Converting the

carboxylic acid of L-histidine to the methyl ester resulted in an improvement in isolated yield of 3a relative to the

parent amino acid (entry 11 vs 2), but the yield was still only moderate at 44%.

Table 1. Selected optimization experiments in the dehydrative coupling of 3-hydroxydihydrobenzofuran 1a to neopentylalcohol 2a.a

123456789

101112

0:0:trace0:1.5:12:8.5:10:3:11:0:0

1.5:1.3:10:1:1

1.6:1.5:16:11:11:6:1

1:6:1.50:2:1

Entry 1a:3a:4 Yield% (3a)a

DCE (0.25 M)0 °C - rt, 24 h 3a2a

(1.5 equiv)1a

(1 equiv)

Sc(OTf)3 (10 mol%)

Ligand (10 mol%)HO

Me

0b

272225NR6133235424458c

Ligand-

L-histidineL-lysine

L-arginineL-tryptophan

L-phenylalanineglycine

imidazole1-methyl-L-histidine3-methyl-L-histidine

L-histidine methyl ester4-(dimethylamino)pyridine

O

OMeMe

O

OH MeMe Me

4O

a Isolated yields of analytically pure material. bIntractable mixture. cThe isolated yieldwas reduced to 40% if left to run for 48 hours. We rationalized that the Lewis basic ligands were modulating the relative Lewis acidity of the scandium catalyst, and

were pleased to find that employing 4-dimethylaminopyridine in conjunction with Sc(OTf)3 led to the formation of 3a

in 58% isolated yield (entry 12). Increasing catalyst loading to 20 mol% did not result in a significant increase in isolated

yield of 3a, and decreasing the loading to 5 mol% only slowed the reaction down, and did not improve selectivity for

3a over 4.

The unusual success of DMAP in combination with Sc(OTf)315 promoted us to evaluate other nitrogen bases, both

mono- and bidentate (Table 2). Guanidine·HCl and guanidine derivatives led to exclusive production of benzofuran 4,

unless functionalized with an electron donating group (entries 1-3 versus entries 4-6). Bidentate ligands slowed the

consumption of 1a substantially, consistent with decreased reactivity with excess DMAP (vide infra). While the catalyst

derived from bipyridines L7 and L8 were able to successfully generate some ether 3a, the catalysts derived from

phenanthrolines L9 and L10 led only to formation of benzofuran 4, perhaps due to the increased basicity of the

phenanthrolines relative to bypyridines.16 Most reactions that employed pyridine-derived ligands produced moderate

amounts of ether 3a, with the exception of 2,6-lutidine L16 and 2,6-ditertbutylpyridine L17, which only produced

benzofuran 4.17 DMAP L13, 2-phenylpyridine L18, and 2,6-bis(diethylamino)pyridine L20 were equally effective, and

DMAP L13 was selected for further studies as it is inexpensive, easily handled, and not as susceptible to decomposition

as L20.18

Table 2. Screening of Lewis basic ligand in conjunction with scandium triflate.

123456

0:10:10:1

1:0.671:0.721:0.3

Entry 3a:4 Yield% (3a)a

DCE (0.25 M)0 °C - rt, 24 h 3a2a

(1.5 equiv)1a

(1 equiv)

Sc(OTf)3 (10 mol%)

Ligand (10 mol%)HO

Me

000

47%43%41%

LigandL1L2L3L4L5L6

O

OMeMe

O

OH MeMe Me

4O

aIsolated yield of 3a. bUsed as the HCl salt. cBoc = t-butyl carbonate. dTMEDA = tetramethylethylenediamine.

eDABCO = 1,4-diazabicyclo[2.2.2]octane. fR=H unless otherwise indicated. gN.D.=not determined.

N N

NR1

R2 R3

H H

L1, R1=R2=R3=Hb

L2, R1=H, R2=R3=Bocc

L3, R1=Tf,c R2=R3=Boc

L4, R1=R2=Boc, R3=BnL5, R1=R2=Boc, R3=pyrrolidineL6, R1=H, R2=R3=Ph

789101112

1.3:11:20:10:10:1

0.4:1

Entry 3a:4 Yield% (3a)a

39%29%

000

18%

LigandL7L8L9

L10L11L12

(B) N2

L7, bipyridine (bipy)L8, 4,4'-(tBu)2-bipyL9, phenanthroline

L10, neocuproineL11, TMEDAd

L12, DABCOeN N

aryl

alkyl

1314151617181920

2:1N.D.gN.D.0:10:1

1.2:11:0.6N.D

Entry 3a:4 Yield% (3a)a

58%48%58%

00

40%42%57%

LigandL13L14L15L16L17L18L19L20

(C)f

N

L13, R4=NMe2, DMAPL14, R3=OMe, R5=ClL15, R2=PhL16, R2=R6=Me

L17, R2=R6=tBu

L18, R2=R4=Me, R6=NH2L19, R2=R6=NH2L20, R2=R6=NEt2NR2 R6

R3 R5R4

(A)

We then finally looked at the effect of DMAP loading relative to scandium (Scheme 2); unsurprisingly, we found that

increasing DMAP to 20 mol% (2 equiv. relative to scandium), the reaction between either 1a or 1i and neopentyl

alcohol 2a was slowed, and the isolated yields of ethers 3a and 3i were reduced. Further increasing the loading of

DMAP to 30 mol% (reaction with 1a) or 50 mol% (reaction with 1l), the reaction was shut down entirely, and no ether

or elimination product could be detected. These results are consistent with the reduced ability of catalysts derived

from bidentate ligands to promote the reaction, and further supports that the DMAP ligand is tuning the Lewis acidity

of scandium to control the reaction and favor substitution reactions.

DCE (0.25 M)0 °C - rt, 24 h

3ax=10 mol%, 58% yield x=20 mol%, 37% yield

x=30 mol%, no reaction

(1.5 equiv)1a

(1 equiv)

Sc(OTf)3 (10 mol%)

DMAP (x mol%)

O

O

O

OH MeMe Me

DCE (0.25 M)0 °C-rt, 24 h

1i(1 equiv)

Sc(OTf)3 (10 mol%)

DMAP (x mol%)

Me

OH

Me

O

MeOMeO

2a

(1.5 equiv)

2a

3ix=10 mol%, 86% yield x=20 mol%, 41% yield

x=50 mol%, no reaction

Me

MeMe

Scheme 2. Effect of DMAP loading on conversion to 3a and 3i.

With optimized conditions in hand, we evaluated the scope of the reaction with respect to the nature of the benzylic

alcohol component (Table 3). While the reaction between 2a and 1a gave ether 3a in 58% yield, an analogous 3-

hydroxy-5-methoxydihydrobenzofuran 1b substrate was unreactive under identical conditions. However, 5-bromo-3-

hydroxydihydrobenzofuran 1c as substrate gave a modest 37% yield of the corresponding ether 3c with incomplete

consumption of 1c. One could predict that a carbocation generated from 1b would be more stabilized and therefore

less reactive than a carbocation generated from either 1a or 1c;19 given that we have evidence of the possibility of

carbocation intermediates (vide infra), that could justify the lack of reactivity of 1b. The reaction of indanol 1d with 2a

gave 50% yield of ether 3d as estimated by the crude 1H NMR spectrum of the reaction mixture, which could not be

separated cleanly from the competing elimination product, indene 4d.

We then evaluated the direct substitution of dihydrochromenols and tetrahydronapthalenols in the presence of

scandium and DMAP. Dihydrochromenols 1e and 1f were suitable substrates, and ethers 3e and 3f were formed in

40% and 70% yield, respectively, in high conversion and selectivity. However, tetrahydronaphalenol 3g was produced

in only 26% yield and reaction with the quaternary 1h led gave exclusive elimination to dihydronaphthalene 4h.

58% yield;a 3a

O

OtBu

NF; 3bO

OtBu

37% yield;a,b 3cO

OtBu

50% yield;b,c 3d

40% yield;a,b 3e

OtBu

70% yield;a 3f 0% yield;b

3h

MeO Br

O

O tBu O tBu

O

O tBu Me

26% yield;b,c 3g

O tBuMe

aIsolated yields of pure material. bSubstantial amounts of corresponding elminationbyproduct 4

detected by analysis of crude 1H NMR spectra. cYield determined by analysis of crude 1H NMR spectra. fAverage of two runs. NF=not formed.

DCE (0.25 M)0 °C-rt, 24 h

2a(1.5 equiv)

1a-1t(1 equiv)

Sc(OTf)3 (10 mol%)

DMAP (10 mol%)HOMe

MeMe

3a-3t

R

OH

R

OMe

MeMe

4

R

88% yield;a,f 3l

Me

MeO

O tBu

Me

O tBu

40% yield;a 3m

tBu

MeO

O tBu

25% yield;a 3n

20% yield;a 3i

O tBu

F

O tBu

14% yield;a 3j

F

OMe

MeO

O tBu

99% yield;a 3k

OMe

Me

O2N

O tBu

Me

O tBu

tBu

Br

O tBu

NF, 3o NF, 3p NF, 3qF

NMe

O tBu

Me

O tBu O tBu

NF, 3r NF, 3s NF, 3t

NHTs

Cl Cl

NHTs

F

Table 3. Scandium catalyzed substitutions of benzylic alcohols 1a-1t with neopentyl

alcohol 2a.

We next evaluated the utility of acyclic benzhydrols and secondary benzylic alcohols in the substitution chemistry. The

parent benzyhydrol, as well as the di-p-fluorosubstituted variant were only moderately good substrates, and ethers

3i and 3j were produced in relatively low yields. In contrast, the bis(p-methoxyphenyl)methanol was an excellent

substrate, and ether 3k was produced in nearly quantitative yield. With those data in hand, we evaluated several

secondary benzylic alcohols with one aryl and one alkyl ligand (substrates 1l-1t). Unfortunately, but unsurprisingly,

only substrates with a methoxy group were reactive (1l-1n). The reaction was most successful when the methoxy

group was in the para position, and ether 3l was isolated in 86% yield; the more sterically encumbered ethers 3m and

3n were isolated in lower yields. Benzylic alcohols with electron withdrawing groups were entirely unreactive under

the optimized conditions, consistent with the necessity for generating a cationic intermediate.

As ether 3l was produced in high yield, we next examined the scope of the reaction of 1l with various primary alcohol

nucleophiles (Table 4). Most alcohols examined gave moderate to high yields of the unsymmetrical ether (5b-5j).

Simply primary and allylic alcohols were effective coupling partners (2b-2d) to yield ethers 5b-5d, as were alcohols

containing β–substitution (2e and 2f to give 5e and 5f). Notably, furfural alcohol 2g and highly activated benzylic

alcohol 2h could also be employed, and the unsymmetrical ethers 5g and 5h were isolated in high yields, with no

detection of byproducts arising from ionization of 2g or 2h.

We then sought to employ amino alcohols as coupling partners for direct ether formation. Though unprotected amino

alcohols were unreactive in this process, N-tosyl-3-aminopropanol 2i and N-tosyl-(S)-valinol 2j were both able to

couple with benzylic alcohol 1i, and ethers 5i and 5j were isolated in high yields, albeit with no diastereoselectivity in

the case of 5j (1:1 dr). An analogous reaction with N-Boc valinol was unsuccessful; the consumption of 1i was

incomplete, and the only identifiable products were p-methoxystryene and dimer 6.

Table 4. Scandium catalyzed substitution of 4-methoxylphenyl-1-ethanol 1i with alcohols 2a-1i.a

76% yield;a 5b

Me

MeO

OMe

74% yield;a 5c

Me

MeO

O Me

79% yield;a 5f

Me

MeO90% yield;a

5e

Me

MeO

O

79% yield;a 5i

MeO

O

90% yield;a 5d

Me

MeO

O

83% yield;a 5h

MeO

O

83% yield;a 5g

Me

MeO

O

DCE (0.25 M)0 °C-rt, 24 h

5b-5j

R

2b-2i(1.5 equiv)

1l(1 equiv)

Sc(OTf)3 (10 mol%)

DMAP (10 mol%)HO

Me

OH

Me

O R

MeOMeO

2b, R = H2e, R = c-hexyl2h, R = 3,4,5-(OMe)3C6H2

2c, R = Me2f, R = adamantyl2i, Nu = CH2CH2NHTs

2d, R = CH2CH=CH22g, R = 2-furyl2j, Nu = (S)-N-Ts-valinol

O

NHTs

Me

O

MeOMe

OMe

OMe

aIsolated yields of pure material.

86% yield;a 5j

1:1 dr

MeO

O MeNHTs

Me

Me

In most experiments in Table 4, we couldn’t detect any significant amount of elimination product to p-methoxystyrene

or the product of homodimerization of 1l. However, when the primary alcohol was omitted from the reaction,

homodimer 6 was isolated in high yields and moderate diasteroselectivity (Scheme 3, equation a). p-Methoxybenzyl

alcohol 1k was unreactive under the standard reaction conditions (equation b). Those results suggested that we

should have been able to selectively couple an activated benzylic alcohol with an unprotected diol, and thus we

evaluated several diol coupling partners with benzylic alcohol 1l under our optimized conditions (Scheme 3, equations

c-e). We found that both 1,2-propane diol (Scheme 3c) and 1,3-butanediol (Scheme 3d) were unreactive under

optimized conditions, nor were styrene of dimer 6 detected. We hypothesized that the lack of reactivity was due to

the diol chelating the Lewis acid catalyst, rendering it unable to promote any reaction.20 We reasoned that a longer

chain between the secondary and primary alcohols would be less likely to form a chelate with scandium, and exposed

1i to 1,4-pentanediol under optimized conditions (Scheme 3e). Unlike reactions with primary alcohols that generally

went to completion within 20 hours (Table 3), the reaction with 1,4-pentanediol was very slow, and reasonable

conversion was observed only after 3 days. We attribute this to some amount of scandium-diol chelate forming;

however, this would form a 7-membered chelate, which wasn’t as stable as the 5- and 6-membered chelates that

would have formed from 1,2-propane and 1,3-butanediols and scandium, respectively. Thus, some active catalyst was

present in solution and could promote the reaction between 1l and pentanediol, yielding 51% yield of a 2.6:1 mixture

of 7a and 7b as 1:1 mixtures of diastereomers.

To further probe that hypothesis, we employed methoxyethanol as a substrate, and ether 8 was isolated in 43% yield

(Scheme 3f). This supports our hypothesis above, and protecting one of the alcohols makes the deoxygenated

substrate a poorer ligand for scandium, enabling the catalytic dehydrogenative coupling.

Scheme 3. Selectivity for reaction of benzylic alcohol with primary versus secondary alcohols.

standardconditions

1i

Ar Me

O

OHMe

Ar Me

O

OH

Me

Me

OHOH

7a 7b

Me

OHOH

no reaction(2l, 1.5 equiv)

standardconditions

1i

Me

OH

no reaction(2m, 1.5 equiv)

OH

standardconditions

3 days

1i(2n, 1.5 equiv)

51% yield2.6:11:1 dr

(c)

(d)

(e)

683% yield

3:1 dr

Me

MeO

O

1i

Me

MeO

OH Me

OMe

(a)

Ar Me

OMe Me

OH

9standard

conditions

1i(2o, 1.5 equiv)

52% yield

(g)Me

Me

7% yield

Me Me

OH

6

standardconditions

1i(1.5 equiv each)

(h) Me

OH

Ar Me

O

Ar

Me

Ar Me

O

929% yield

Me

Me

7% yield6

Ar Me

O

Ar

Me

Ar Me

O

5c59% yield

Me

1kMeO

OH(b)no reaction

standardconditions

standardconditions

standardconditions

1i

OHOMe

(2l, 1.5 equiv)(f)

Ar Me

O

843% yield

OMe

An exogenous secondary aliphatic alcohol was able to selectively react with alcohol 1l, and ether 9 was formed in 52%

yield, with only 7% of the benzylic dimer 6 isolated (Scheme 3g). This could be due to decreased steric encumbrance

about isopropanol relative to benzylic alcohol 1l, increased nucleophilicity of the aliphatic alcohol, or a combination

of both factors.

In the intramolecular competition experiment between primary and secondary alcohols, the primary alcohol out

competed the secondary alcohol in a 2.6:1 ratio (Scheme 3e); a similar result was observed in an intermolecular

competition reaction with alcohol 1l and an equimolar mixture of ethanol and isopropanol; ether 5c was favored over

ether 9 in a 2:1 ratio, with only a small amount of benzylic dimer isolated (Scheme 3g).

Scheme 4. Control reactions to help elucidate the mechanism

standard conditions

(R)-1d

[α]D = -17.2

(1 equiv)

H2O (1.5 equiv)

(±)-1d

[α]D = -0.18

OH OH(a)

standard conditions

2a (1.5 equiv)

3i

32% yield

(b)

PMP Me

O

PMP

Me

PMP Me

O tBu

standard conditions

2a (1.5 equiv)(f)PMP no reaction

6

standard conditions

1i (1.5 equiv)(c)

PMP Me

O tBu

3i

6

30% yield

H2O (1.5 equiv)

standard conditions

H2O (1.5 equiv)(d)

PMP Me

O tBu

3i

1i

25% yield

(e) Ar Ar

O

Ar

Ar

10a

Ar=4-OMe-C6H4

+Ar' Ar'

O

Ar'

Ar'

10a

Ar'=4-F-C6H4

1:1standard

conditions

no

reaction

For further mechanistic insight, we subjected enantiopure (R)-indanol to the standard reaction conditions in the

presence of water as a nucleophile. After approximately 20 hours, the observed optical rotation went from [α]D20

= -

17.2 to [α]D20

= -0.18 (Scheme 4, equation a), suggestive of a carbocation intermediate. We next subjected both the

dimer 6 and elimination product to standard reaction conditions to evaluate their role within the catalytic cycle. We

found that the dimer 6 was consumed under standard reaction conditions, and was slowly converted into the

unsymmetrical ether 3l in the presence of neopentyl alcohol 1l (equation b). Hall21 and Gunanathan22 recently made

similar observations, where the catalytic activation of benzylic alcohols rapidly formed a dimer, which was slowly

converted to arylated species via Friedel-Crafts-type reactivity. When ether 3l was exposed to benzyl alcohol 1l, the

dimer 6 could be isolated in 30% yield (equation c); similarly, when ether 3l was exposed to water, benzyl alcohol was

isolated in 25% yield (equation d). However, when a mixture of dimers of benzhydrol derivatives were combined in

the absence of an alcohol or water nucleophile under otherwise standard reaction conditions, no reaction was

observed (equation e), consistent with the necessity of an alcohol or water nucleophile to initiate ionization of the

ethers. Similarly, the styrene elimination product was unreactive under the standard reaction conditions (equation f).

Thus, we have derived a preliminary mechanistic scenario (Figure 1). The target ether 3 is clearly accessible from

dimeric ether 6, though it is difficult to assess relative rates of formation of 3 from 1 and 6 (k1 vs k3) due to the

complexity of the reaction. Hydrolysis to starting alcohol 1 occurs from both 3 and 6 (k-1 and k-2, respectively), though

those relative rates do not appear to weigh significantly on the overall rate to formation of 3. The rate of formation

of dimer 6 is much faster than direct formation of 3 from 1 (k2 >> k1). Competing elimination appears to only occur

from the starting alcohol 1, and formation of the styrene is irreversible and off cycle, as it is not reactive under the

reaction conditions.

Figure 1. Preliminary relative rates of the competing reactions.

6

Ar Me

O Me

Ar Me

O

3

Ar Me

OH

Ar

1

R

k1

k-1

k2

k-2

k3

k-3

H2O2

1

H2O

1

2

Finally, we were also able to demonstrate that this chemistry may employ aromatic nucleophiles in a Friedel-Crafts

type alkylation (Scheme 5).23 The reaction between 1a and indole produced 38% yield of alkylated indole 11. Further

examination of aromatic nucleophiles showed promising results towards development of catalytic electrophilic

aromatic substitution chemistry, results for which are forthcoming.

Scheme 5. Reaction of indole with a benzylic alcohol via a Friedel-Crafts-like reaction.

DCE (0.25 M)0 °C-rt, 24 h

(1.5 equiv)1i

(1 equiv)

Sc(OTf)3 (10 mol%)

DMAP (10 mol%)

1138% yield

Me

OH

MeO

HN

Me

MeO

HN

Conclusions In summary, we have developed a simple and selective method for producing unsymmetrical ethers via catalytic

substitution of benzylic alcohols with primary alcohols. Preliminary mechanistic investigations suggest that the

reaction is more SN1-like than SN2-like due to racemization of enantiopure starting alcohols, but the dynamics are

complex. The relative rates of formation of dimer 6 and ether 3 are k2 > k1 >> k3, where dimer formation occurs

faster than unsymmetrical ether from the alcohol 1, and the dimer is much more slowly converted to the ether 3;

the overall process has complex kinetics due to competing and reversible side reactions. Further detailed

mechanistic studies are warranted to understand both the nature of the catalyst and the origin of selectivity, and

will be reported in due course.

Acknowledgements Acknowledgements The University of Nevada, Reno, and the National Institute of General Medicine of the National

Institutes of Health, Grant R15GM120738 are acknowledged for partial support of this research.

Keywords: scandium • catalysis • dehydration • chemoselective • ethers

References

1. Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Key Green Chemistry Research Areas-a Perspective from Pharmaceutical Manufacturers. Green Chem. 2007, 9, 411-420. 2. Dryzhakov, M.; Richmond, E.; Moran, J. Recent Advances in Direct Catalytic Dehydrative Substitution of Alcohols. Synthesis 2016, 48, 935-959. 3. Liu, Y.; Wang, X.; Wang, Y.; Du, C.; Shi, H.; Jin, S.; Jiang, C.; Xiao, J.; Cheng, M. Gold(I)-Catalyzed Synthesis of Unsymmetrical Ethers Using Alcohols as Alkylating Reagents. Adv. Synth. Catal. 2015, 357, 1029-1036. 4. Bivona, L. A.; Quertinmont, F.; Beejapur, H. A.; Giacalone, F.; Buaki-Sogo, M.; Gruttadauria, M.; Aprile, C. Thiazolium-Based Catalysts for the Etherification of Benzylic Alcohols under Solvent-Free Conditions. Adv. Synth. Catal. 2015, 357, 800-810. 5. Kim, J.; Lee, D.-H.; Kalutharage, N.; Yi, C. S. Selective Catalytic Synthesis of Unsymmetrical Ethers from the Dehydrative Etherification of Two Different Alcohols. ACS Catal. 2014, 4, 3881-3885. 6. Estopiñá-Durán, S.; Donnelly, L. J.; Mclean, E. B.; Hockin, B. M.; Slawin, A. M. Z.; Taylor, J. E. Aryl Boronic Acid Catalysed Dehydrative Substitution of Benzylic Alcohols for C−O Bond Formation. Chem. Eur. J. 2019, 25, 3950-3956. 7. (a) Matsui, M.; Karibe, N.; Hayashi, K.; Yamamoto, H. Synthesis of Α-Tocopherol: Scandium(III) Trifluoromethanesulfonate as an Efficient Catalyst in the Reaction of Hydroquinone with Allylic Alcohol. Bull. Chem. Soc. Jap. 1995, 68, 3569-3571; (b) Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S.-i. Scandium(III) Triflate Catalyzed Friedel-Crafts Alkylation with Benzyl and Allyl Alcohols. Synlett 1996, 557-559; (c) El Gihani, M. T.; Heaney, H.; Shuhaibar, K. F. Scandium and Copper Triflate-Catalyzed Acylaminoalkylation and Friedel-Crafts Alkylation Reactions. Synlett 1996, 871-872; (d) Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S.-i. Scandium(III) Triflate-Catalyzed Friedel−Crafts Alkylation Reactions. J. Org. Chem. 1997, 62, 6997-7005; (e) Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima, H.; Ishii, K. Secondary Benzylation Using Benzyl Alcohols Catalyzed by Lanthanoid, Scandium, and Hafnium Triflate. J. Org. Chem. 2003, 68, 9340-9347; (f) Wenz, D. R.; Read de Alaniz, J. Aza-Piancatelli Rearrangement Initiated by Ring Opening of Donor-Acceptor Cyclopropanes. Org. Lett. 2013, 15, 3250-3253. 8. Yadav, J. S.; Reddy, B. V. S.; Rao, T. S.; Rao, K. V. R. Copper(II)-Catalyzed Allylation of Propargylic and Allylic Alcohols by Allylsilanes: A Facile Synthesis of 1,5-Enynes. Tetrahedron Lett. 2008, 49, 614-618. 9. Sharma, G. V. M.; Mahalingam, A. K. A Facile Conversion of Alcohols into P-Methoxybenzyl Ethers (Pmb-Ethers) Using P-Methoxybenzyl Alcohol−Yb(Otf)3. J. Org. Chem. 1999, 64, 8943-8944. 10. (a) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Bismuth-Catalyzed Direct Substitution of the Hydroxy Group in Alcohols with Sulfonamides, Carbamates, and Carboxamides. Angew. Chem., Int. Ed. 2007, 46, 409-413; (b) Zhan, Z.-P.; Yang, W.-Z.; Yang, R.-F.; Yu, J.-L.; Li, J.-P.; Liu, H.-J. BiCl3-Catalyzed Propargylic Substitution Reaction of Propargylic Alcohols with C-, O-, S- and N-Centered Nucleophiles. Chem. Commun. 2006, 3352-3354; (c) Rubenbauer,

P.; Herdtweck, E.; Strassner, T.; Bach, T. Bi(OTf)3-Catalyzed Diastereoselective SN1-Type Reactions of Chiral Propargylic Acetates. Angew. Chem., Int. Ed. 2008, 47, 10106-10109. 11. Theerthagiri, P.; Lalitha, A. Zn(OTf)2—Catalyzed Direct Cyanation of Benzylic Alcohols—a Novel Synthesis of Α-Aryl Nitriles. Tetrahedron Lett. 2012, 53, 5535-5538. 12. Kim, S.; Chung, K. N.; Yang, S. Direct Synthesis of Ethers Via Zinc Chloride-Mediated Etherification of Alcohols in Dichloroethane. J. Org. Chem. 1987, 52, 3917-3919. 13. Rokade, B. V.; Gadde, K.; Prabhu, K. R. Copper-Catalyzed Direct Transformation of Secondary Allylic and Benzylic Alcohols into Azides and Amides: An Efficient Utility of Azide as a Nitrogen Source. Eur. J. Org. Chem. 2015, 2015, 2706-2717. 14. Chen, K.; Chen, H. J.; Wong, J.; Yang, J.; Pullarkat, S. A. Copper(Ii) Triflate Catalyzed Allylic Arylation of Allylic Alcohols: Direct and Selective Access to C-Allylanilines. ChemCatChem 2013, 5, 3882-3888. 15. DMAP and Scandium are most often used in in acylation reactions; for an example, see: Greenwald, R. B.; Pendri, A.; Zhao, H. Tetrahedron: Aysmm. 1998, 9, 915-918 16. Kulkari, B., S.; Mishra, D.; Pal, S. Role of Substituents on the Reactivity and Electron Density Profile of Diimine Ligands: A Density Functional Theory Based Study. J. Chem. Sci. 2013, 125, 1247-1258. 17. This could be a steric effect; if the bulkier ligands render the catalyst unable to pi-pi stack, elimination could out compete reaction with an alcohol to form the ether. 18. Both L19 and L20 must be recrystallized immediately before use. 19. Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. Reference Scales for the Characterization of Cationic Electrophiles and Neutral Nucleophiles. J. Am. Chem. Soc. 2001, 123, 9500-9512. 20. It is also possible that the diols were forming intramolecular hydrogen bonds, rendering them unreactive under standard conditions. 21. Ang, H. T.; Rygus, J. P. G.; Hall, D. G. Two-Component Boronic Acid Catalysis for Increased Reactivity in Challenging Friedel–Crafts Alkylations with Deactivated Benzylic Alcohols. Org. Biomol. Chem. 2019, 17, 6007-6014. 22. Sahoo, P. K.; Gawali, S. S.; Gunanathan, C. Iron-Catalyzed Selective Etherification and Transetherification Reactions Using Alcohols. ACS Omega 2018, 3, 124-136. 23. (a) McCubbin, J. A.; Krokhin, O. V. Organocatalyzed Friedel–Crafts Arylation of Benzylic Alcohols. Tetrahedron Letters 2010, 51, 2447-2449; (b) McCubbin, J. A.; Hosseini, H.; Krokhin, O. V. Boronic Acid Catalyzed Friedel-Crafts Reactions of Allylic Alcohols with Electron-Rich Arenes and Heteroarenes. J. Org. Chem. 2010; (c) Wilcke, D.; Herdtweck, E.; Bach, T. Enantioselective Brønsted Acid Catalysis in the Friedel-Crafts Reaction of Indoles with Secondary Ortho-Hydroxybenzylic Alcohols. Synlett 2011, 2011, 1235-1238; (d) Wang, W.; Xiong, W.; Wang, J.; Wang, Q.-A.; Yang, W. Brønsted Acid-Catalyzed Asymmetric Friedel–Crafts Alkylation of Indoles with Benzothiazole-Bearing Trifluoromethyl Ketone Hydrates. J. Org. Chem. 2020, 85, 4398-4407.

download fileview on ChemRxivSecOH.pdf (288.08 KiB)

Scandium and dimethylaminopyridine catalyzed dehydrative coupling of secondary benzylic and primary alcohols to synthesize unsymmetrical ethers Julia M. Duncan,[a] Lun Li,[a],[b] Vahid Mohammadrezaei,[a] and Laina M. Geary*[a] Supplementary Information

Table of Contents General information.............................................................................................................................................................. 4 Synthesis of Starting Materials for Table 3 .......................................................................................................................... 5

(1a) 2,3-dihydro-1-benzofuran-3-ol .......................................................................................................... 5

(1b) 6-methoxy-2,3-dihydro-1-benzofuran-3-ol ....................................................................................... 5

(1c) 6-bromo-2,3-dihydro-1-benzofuran-3-ol ........................................................................................... 5

(1e) 3,4-dihydro-2H-chromen-4-ol ........................................................................................................... 6

(1f) 4-methyl-3,4-dihydro-2H-chromen-4-ol ............................................................................................ 6

(1g) 1,2,3,4-tetrahydronaphthalen-1-ol ................................................................................................... 7

(1h) 1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol.................................................................................... 7

(1l) 1-(4-methoxyphenyl)ethanol .............................................................................................................. 7

(1n) 1-(4-methoxyphenyl)-2,2-dimethylpropan-1-ol ................................................................................ 8

(1r) 1-(4-Pyridinyl)ethanol ........................................................................................................................ 8

General procedure for protection of amine ............................................................................................. 9

(1s) N-[4-chloro-2-(1-hydroxyethyl) phenyl]-4-methylbenzene-1-sulfonamide....................................... 9

(1t) N-{4-chloro-2-[(2-fluorophenyl) (hydroxy)methyl]phenyl}-4-methylbenzene-1-sulfonamide. ......... 9

General procedure for synthesis of benzyl ethers ............................................................................................................ 10 Characterization Data for Products of Table 3 (3a-3t) ...................................................................................................... 10

(3a) 3-(2,2-dimethylpropoxy)-2,3-dihydro-1-benzofuran ....................................................................... 10

(3c) 6-bromo-3-(2,2-dimethylpropoxy)-2,3-dihydro-1-benzofuran........................................................ 10

(3d) 2,3-dihydro-1H-inden-1-yl 2,2-dimethylpropyl ether ..................................................................... 10

(3e) 4-(2,2-dimethylpropoxy)-3,4-dihydro-2H-chromene ...................................................................... 11

(3f) 4-(2,2-dimethylpropoxy)-4-methyl-3,4-dihydro-2H-chromene ....................................................... 11

(3i) [(2,2-dimethylpropoxy)(phenyl)methyl]benzene. ............................................................................ 11

(3j) 1-[(2,2-dimethylpropoxy)(4-fluorophenyl)methyl]-4-fluorobenzene. ............................................. 11

(3k) 1-[(2,2-dimethylpropoxy)(4-methoxyphenyl)methyl]-4-methoxybenzene. .................................... 12

(3l) 1-[1-(2,2-dimethylpropoxy)ethyl]-4-methoxybenzene .................................................................... 12

(3m) 1-[1-(2,2-dimethylpropoxy)ethyl]-2-methoxybenzene .................................................................. 12

(3n) 1-[1-(2,2-dimethylpropoxy)-2,2-dimethylpropyl]-4-methoxybenzene ........................................... 12

Characterization Data for Products of Table 4 .................................................................................................................. 13

(5b) 1-methoxy-4-(1-methoxyethyl)benzene ......................................................................................... 13

(5c) 1-(1-ethoxyethyl)-4-methoxybenzene ............................................................................................. 13

(5d) 1-methoxy-4-[1-(prop-2-en-1-yloxy)ethyl]benzene ........................................................................ 13

(5e) 1-[1-(cyclohexylmethoxy)ethyl]-4-methoxybenzene ...................................................................... 14

(5f) 1-{[1-(4-methoxyphenyl)ethoxy]methyl}tricyclo[3.3.1.13,7]decane ................................................. 14

(5g) 2-{[1-(4-methoxyphenyl)ethoxy]methyl}furan ................................................................................ 14

(5h) 1,2,3-trimethoxy-5-{[1-(4-methoxyphenyl)ethoxy]methyl}benzene .............................................. 14

(5i) 1-[1-(4-methoxyphenyl)ethoxy]-3-methylbutan-2-tosylamine ........................................................ 15

(5j) (2S)-1-[1-(4-methoxyphenyl)ethoxy]-3-methylbutan-2-tosylamine ................................................ 15

Characterization Data for the Products of Scheme 3........................................................................................................ 15

(6) (2S)-1-[1-(4-methoxyphenyl)ethoxy]-3-methylbutan-2-tosylamine ................................................. 15

(7a) (2S)-1-[1-(4-methoxyphenyl)ethoxy]-3-methylbutan-2-tosylamine and (7b) ................................. 16

(8) 1-methoxy-4-[1-(2-methoxyethoxy)ethyl]benzene ........................................................................... 16

Synthesis of Dimers for Cross Over Experiment (Scheme 4, equation e) ........................................................................ 16

(10a) 1-{[bis(4-methoxyphenyl)methoxy](4-methoxyphenyl)methyl}-4-methoxybenzene ................... 16

(10b) 1-{[bis(4-fluorophenyl) methoxy](4-fluorophenyl)methyl}-4-fluorobenzene ............................... 17

(11) 3-[1-(4-methoxyphenyl)ethyl]-1H-indole ........................................................................................ 17

NMR SPECTRA ..................................................................................................................................................................... 18

(1a) 2,3-dihydro-1-benzofuran-3-ol ........................................................................................................ 19

(1b) 6-methoxy-2,3-dihydro-1-benzofuran-3-ol ..................................................................................... 21

(1c) 6-bromo-2,3-dihydro-1-benzofuran-3-ol ......................................................................................... 23

(1e) 3,4-dihydro-2H-chromen-4-ol ......................................................................................................... 25

(1f) 4-methyl-3,4-dihydro-2H-chromen-4-ol .......................................................................................... 27

(1g) 1,2,3,4-tetrahydronaphthalen-1-ol ................................................................................................. 29

(1h) 1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol.................................................................................. 30

(1l) 1-(4-methoxyphenyl)ethanol ............................................................................................................ 32

(1n’) 1-(4-methoxyphenyl)-2,2-dimethylpropan-1-one .......................................................................... 34

(1n) 1-(4-methoxyphenyl)-2,2-dimethylpropan-1-ol .......................................................................... 36

(1r) 1-(4-Pyridinyl)ethanol ...................................................................................................................... 38

(1s) N-[4-chloro-2-(1-hydroxyethyl) phenyl]-4-methylbenzene-1-sulfonamide..................................... 40

(1t) N-{4-chloro-2-[(2-fluorophenyl) (hydroxy)methyl]phenyl}-4-methylbenzene-1-sulfonamide. ....... 42

(3a) 3-(2,2-Dimethylpropoxy)2,3-dihydro-1-benzofuran .................................................................... 44

(3c) 6-Bromo-3-(2,2-dimethylpropoxy)-2,3-dihydro-1-benzofuran ................................................... 46

(3d) 2,3-Dihydro-1H-inden-1-yl-2,2-dimethylpropyl ether ................................................................. 48

(3e) 4-(2,2-Dimethylpropoxy)-3,4-dihydro-2H-chromene .................................................................. 50

(3f) 4-(2,2-Dimethypropoxy)-4-methyl-3,4-dihydro-2H-chromene .................................................... 52

(3i) [(2,2-dimethylpropoxy)(phenyl)methyl]benzene. ............................................................................ 54

(3j) 1-[(2,2-dimethylpropoxy)(4-fluorophenyl)methyl]-4-fluorobenzene. ............................................. 56

(3k) 1-[(2,2-dimethylpropoxy)(4-methoxyphenyl)methyl]-4-methoxybenzene. .................................... 58

(3l) 1-[1-(2,2-Dimethylpropoxy)ethyl]-4-methoxybenzene ................................................................ 60

(3m) 1-[1-(2,2-dimethylpropoxy)ethyl]-2-methoxybenzene .................................................................. 62

(3n) 1-[1-(2,2-Dimethylpropoxy)-2,2-dimethylpropyl]-4-methoxybenzene ....................................... 64

(5b) 1-Methoxy-4-(1-methoxyethyl)benzene ..................................................................................... 66

(5c) 1-(1-Ethoxyethyl)-4-methoxybenzene ......................................................................................... 68

(5d) 1-Methoxy-4-[1-(prop-2-en-1-yloxy)ethyl]benzene .................................................................... 70

(5e) 1-[1-(Cyclohexylmethoxy)ethyl]-4-methoxybenzene ...................................................................... 72

(5f) 1-{[1-(4-Methoxyphenyl)ethoxy]methyl}tricyclo[3.3.1.13,7]-decane ........................................... 74

(5g) 2-{[1-(4-Methoxyphenyl)ethoxy]methyl}furan ............................................................................ 76

(5h) 1,2,3-Trimethoxy-5-{[1-(4-methoxyphenyl)ethoxy]methyl}benzene .......................................... 78

(5i) 1-[1-(4-Methoxyphenyl)ethoxy]3-methylbutan-2-tosylamine ..................................................... 80

(5j) (2S)-1-[1-(4-Methoxyphenyl)ethoxy]-3-methylbutan-2-tosylamine ............................................ 82

(6) 1,1’-(Oxydiethylidene)bis[4-methoxybenzene] ............................................................................. 84

5-[1-(4-methoxyphenyl)ethoxy]pentan-2-ol (7a) and 4-[1-(4-methoxyphenyl)ethoxy]pentan-1-ol (7b) ...................................................................................................................................................... 86

(8) 1-methoxy-4-[1-(2-methoxyethoxy)ethyl]benzene ........................................................................... 88

(9) 3-[1-(4-Methoxyphenyl)ethyl]-1H-indole ...................................................................................... 90

(10a) 1-{[bis(4-methoxyphenyl)methoxy](4-methoxyphenyl)methyl}-4-methoxybenzene ................... 91

(10b) 1-{[bis(4-fluorophenyl) methoxy](4-fluorophenyl)methyl}-4-fluorobenzene ............................... 93

General information NMR: 1H and 13C NMR spectra were obtained on a 500 MHz Varian VNMRS or a 400 MHz Varian VNMRS instrument in CDCl3 referenced to tetramethylsilane (TMS) internal standard. All chemical shifts for 1H and 13C NMR spectra are reported in parts per million (ppm) downfield from TMS. Mass Spectrometry: High resolution mass spectra were obtained on Agilent model G6230A TOF-Mass Spectrometer. Low resolution mass spectra were obtained on an Agilent 7890A gas chromatograph coupled to a 5975C quadrupole mass spectrometer. Solvents: Anhydrous dichloroethane and anhydrous methanol were purchased and used without further purification. All other solvents used were degassed prior to use and obtained over dual purifying alumina columns (101mm OD x 635 mm L) under nitrogen pressure. Glassware: All glassware used was either oven dried or flame dried and flushed with nitrogen prior to use. All reactions were performed under nitrogen atmosphere unless otherwise noted. Reagents: All chemicals were purchased from chemical suppliers and used without further purification unless otherwise noted. Chromatography: 40-63 mm (230-400 mesh) silica gel was used for purification via column chromatography with reagent grade eluent. Aluminum backed TLC silica gel 60 F254 analytical plates was used for thin layer chromatography to monitor reaction progress and in tandem with column chromatography.

Synthesis of Starting Materials for Table 3

(1a) 2,3-dihydro-1-benzofuran-3-ol

O

OH

NaH(1.5 equiv.), DMSOSO(CH3)3I (1 equiv.)

5 oC - RT O

OH

1a This compound was prepared under standard Corey-Chaykovsky reaction conditions.1 NaH (3.6 g, 60% dispersion in mineral oil, 90 mmol, 1.5 equiv.) was suspended in anhydrous DMSO (40 ml) and cooled to 5 °C on a salt ice bath. Trimethylsulfoxonium iodide (13.2 g, 60 mmol, 1 equiv.) was added portionwise and the mixture stirred for 2 hours at 5 °C. Salicylaldehyde (6.4 ml, 60 mmol, 1 equiv.) was added dropwise and the reaction stirred overnight allowing it to come to ambient room temperature. The reaction was quenched by the slow addition of water (100 ml). The organics were extracted into EtOAc (3 x 100 ml), washed with brine (3 x 50 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was isolated via column chromatography over silica gel (20% EtOAc/Hex) as a white solid (1.2871 g, 31% yield). 1H NMR data were consistent with literature values.2 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.24 (m, 1H), 7.18 (tdd, J = 8.0, 1.5, 0.9 Hz, 1H), 6.91 – 6.82 (m, 1H), 6.77 (dt, J = 8.1, 0.8 Hz, 1H), 5.03 (tt, J = 5.7, 2.4 Hz, 1H), 4.29 (dd, J = 10.7, 6.6 Hz, 1H), 4.17 (dd, J = 10.7, 2.6 Hz, 1H), 3.74 (d, J = 5.4 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 159.9, 130.5, 128.1, 125.5, 120.9, 110.3, 78.8, 71.6 ppm.

(1b) 6-methoxy-2,3-dihydro-1-benzofuran-3-ol

This compound was prepared via the same method as 1a at a 30 mmol scale. The product was isolated via column chromatography over silica gel (2.5% EtOH/DCM) to gain a pale yellow solid (1.5264 g, 30% yield). 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.3 Hz, 1H), 6.50 (dd, J = 8.2, 2.2 Hz, 1H), 6.43 (d, J = 1.9 Hz, 1H), 5.28 (broad t, J = 5.1, 1H), 4.55 (dd, J = 10.6, 6.3 Hz, 1H),

4.46 (dd, J = 10.6, 2.3 Hz, 1H), 3.78 (s, 3H), 1.86 (d, J = 5.2 Hz, 1H) ppm. 13C NMR (101 MHz CDCl3) δ 162.4, 161.9, 125.7, 120.6, 107.5, 96.2, 80.3, 71.9, 55.5 ppm. HRMS (ESI) m/z (%): calcd. for C9H11O3 [(M+H)+] 167.0708 ; found 167.0728, 147.0596 [(M+H)-(H2O)].

(1c) 6-bromo-2,3-dihydro-1-benzofuran-3-ol

This compound was prepared via the same method as 1a at a 20 mmol scale. The product was isolated via recrystallization from toluene to gain a yellow solid (1.5185 g, 35% yield).

1 Holt, B.; Lowe, P. A. Tetrahedron Lett. 1966, 7, 683-686. 2 Ghosh, S.; Datta, I.; Chakraborty, R.; Das, T. K.; Sengupta, J.; Sarkar, D. C. Tetrahedron 1989, 45, 1441-1446.

O

OH

MeO1b

O

OH

Br1c

1H NMR (400 MHz, CDCl3) δ 7.27 (dt, J = 7.9, 0.6 Hz, 1H), 7.08 (dd, J = 7.9, 1.7 Hz, 1H), 7.05 (dt, J = 1.7, 0.5 Hz, 1H), 5.32 (td, J = 7.1, 2.6 Hz, 1H), 4.57 (dd, J = 10.7, 6.5 Hz, 1H), 4.46 (dd, J = 10.8, 2.6 Hz, 1H), 1.93 (d, J = 7.6 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 161.2, 127.5, 126.4, 124.2, 124.1, 114.2, 79.9, 71.6 ppm. HRMS (APCI) m/z (%): calcd. for C8H6OBr [(M+H)-(H2O)+] 196.9602; found 196.9597.

(1e) 3,4-dihydro-2H-chromen-4-ol O

O

NaBH4 (1.2 equiv.)

MeOH, 0 oC O

OH

1e This compound was prepared via standard sodium borohydride reduction conditions.3 4-chromanone (370.4 mg, 2.5 mmol, 1 equiv.) was dissolved in anhydrous MeOH (5 ml) and cooled to 0 °C on an ice bath. NaBH4 (113.5 mg, 3 mmol, 1.2 equiv.) was added portionwise. The reaction was monitored via TLC (30% EtOAc/Hex). After completion (20 minutes), water (5 ml) was slowly added to quench. The organics were extracted into EtOAc (3 x 5 ml), washed with water (5 ml), 3 M HCl (3 ml), and brine (3 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was isolated via column chromatography over silica gel (30% EtOAc/Hex) to gain a clear oil (354.6 mg, 94 % yield). 1H and 13C NMR data were consistent with literature values.4 1H NMR (400 MHz, CDCl3) δ 7.32 (ddd, J = 7.7, 1.8, 0.5 Hz, 1H), 7.21 (ddd, J = 8.2, 7.3, 1.7 Hz, 1H), 6.93 (td, J = 7.4, 1.2 Hz, 1H), 6.85 (dd, J = 8.3, 1.3 Hz, 1H), 4.80 (q, J = 4.3 Hz, 1H), 4.30 – 4.25 (m, 2H), 2.19 – 1.98 (m, 2H), 1.78 (d, J = 4.7 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 154.7, 129.8, 129.8, 124.4, 120.7, 117.2, 63.3, 62.0, 30.9 ppm.

(1f) 4-methyl-3,4-dihydro-2H-chromen-4-ol

O

O

O

OH1. Mg0, I2, MeI

Et2O, 0 oC - RT2. H3O+

1f This compound was prepared from 4-chromanone in a similar fashion reported in literature.5

To a flame dried round bottom flask under nitrogen, Mg0 turnings (364.7 mg, 15 mmol, 1.5 equiv.) and Iodine (2 pieces) were added followed by anhydrous diethyl ether (7 ml) over an ice bath. Iodomethane (6.9 ml, 11 mmol, 1.1 equiv.) in diethyl ether (5 ml) was added dropwise via syringe. The ice bath was removed and the mixture allowed to reflux for 30 minutes. The mixture was cooled to 0 °C and a solution of 4-chromanone (1.4816 g, 10 mmol, 1 equiv.) in diethyl ether (3 ml) was added dropwise via syringe. The reaction was stirred overnight allowing it to come to ambient room temperature, then hydrolyzed by the addition of saturated ammonium chloride (10 ml) followed by 1 M HCl (2 ml) and stirred for 30 minutes. The organics were extracted into Et2O

3 Gladkowski, W.; Skrobiszewski, A.; Mazur, M.; Siepka, M.; Pawlak, A.; Obminska-Mrukowicz, B.; Bialonska, A.; Poradowski, D.; Drynda, A.; Urbaniak, M. Tetrahedron 2013, 69, 10414-10423. 4 Dieskau, A. P.; Begouin, J.-M.; Plietker, B. Eur. J. Org. Chem. 2011, 5291-5296. 5 Ozdemirhan, D.; Sezer, S.; Sonmez, Y. Tetrahedron: Asym. 2008, 19, 2717-2720.

(3 x 30 ml), washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was recrystallized from hexanes to gain a white solid (545 mg, 33% yield). 1H and 13C NMR data were consistent with literature values. 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 7.8, 1.6 Hz, 1H), 7.18 (ddd, J = 8.2, 7.2, 1.7 Hz, 1H), 6.94 (ddd, J = 7.8, 7.2, 1.3 Hz, 1H), 6.82 (ddd, J = 8.2, 1.3, 0.4 Hz, 1H), 4.34 – 4.18 (m, 2H), 2.09 – 2.06 (m, 2H), 1.91 (s, 1H), 1.63 (s, 3H) ppm.6 13C NMR (101 MHz, CDCl3) δ 154.0, 129.3, 128.6, 126.5, 120.9, 117.3, 66.5, 63.5, 38.2, 29.7 ppm.

(1g) 1,2,3,4-tetrahydronaphthalen-1-ol

This compound was prepared via the same method as 1e at a 10 mmol scale. The product was isolated via column chromatography over silica gel (30% EtOAc/Hex) to gain a white solid (280.2 mg, 19 % yield). 1H and 13C NMR data were consistent with literature values.4

1H NMR (400 MHz, CDCl3) δ 7.49 – 7.38 (m, 1H), 7.24 – 7.15 (m, 2H), 7.14 – 7.04 (m, 1H), 4.78 (d, J = 4.8 Hz, 1H), 2.83 (dt, J = 16.6, 5.5 Hz, 1H), 2.72 (dt, J = 16.5, 5.9 Hz, 1H), 2.08 – 1.85 (m, 3H), 1.85 – 1.73 (m, 1H), 1.70 (d, J = 4.5 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 138.9, 137.3, 129.2, 128.8, 127.7, 126.3, 68.3, 32.4, 29.4, 18.9 ppm.

(1h) 1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol

This compound was prepared via the same method as 1f at a 10 mmol scale. Recrystallization from hexanes yielded a white solid (728 mg, 45% yield). 1H NMR data were consistent with literature values.6 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 1H), 7.21 (tdd, J = 7.3, 1.8, 0.9 Hz, 1H),

7.16 (tt, J = 7.2, 1.4 Hz, 1H), 7.10 – 7.03 (m, 1H), 2.87 – 2.70 (m, 2H), 2.04 – 1.88 (m, 3H), 1.87 – 1.77 (m, 1H), 1.74 (s, 1H), 1.56 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 143.0, 136.4, 129.0, 127.3, 126.5, 126.4, 70.8, 40.0, 30.9, 30.1, 20.6 ppm.

(1l) 1-(4-methoxyphenyl)ethanol

This compound was prepared from 4-methoxyacetophenone via the same method as 1e at a 10 mmol scale. The product was isolated via column chromatography over silica gel (30% EtOAc/Hex) to gain a colorless oil (1.2605 g, 82 % yield). 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.84

(q, J = 6.5 Hz, 1H), 3.80 (s, 3H), 1.47 (d, J = 6.4 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 159.1, 138.1, 126.8, 114.0, 70.1, 55.4, 25.1 ppm.

6 Kelley, B. T.; Walters, J. C.; Wengryniuk, S. E. Org. Lett. 2016, 18, 1896-1899.

OH

1g

OH

1h

OH

MeO1l

(1n) 1-(4-methoxyphenyl)-2,2-dimethylpropan-1-ol

MeOCl

OAlCl3

, PhMe

70 oCMeO

O

This compound was prepared according to literature procedures.7

1-(4-methoxyphenyl)-2,2-dimethylpropan-1-one: Anisole (2.16 g, 20 mmol, 2 equiv.) and pivaloyl chloride (1.21 g, 10 mmol, 1 equiv.) were dissolved in toluene (6 ml) and AlCl3 (1.33 g, 20 mmol, 2 equiv.) was added. The mixture was stirred at 70 °C under nitrogen for 40 minutes. After cooling on an ice bath, 1 M HCl was added to quench. The organics were extracted into Et2O (3 x 10 ml), washed with saturated NaHCO3 (aq.) (30 ml) , dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification via column chromatography (10% EtOAc/Hex) gave a clear oil (1.1824 g, 61% yield). 1H NMR data were consistent with literature values.8 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J = 9.1, 1.0 Hz, 1H), 6.90 (dd, J = 9.1, 0.9 Hz, 1H), 3.85 (s, 3H), 1.37 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3) δ 206.4, 162.1, 131.1, 130.2, 113.4, 55.5, 44.0, 28.5 ppm.

MeO

OLiAlH4

(0.12 equiv)

THF, RTMeO

OH

1n 1-(4-methoxyphenyl)-2,2-dimethylpropan-1-ol: A solution of 1-(4-methoxyphenyl)-2,2-dimethylpropan-1-one (0.9613 g, 5 mmol, 1 equiv.) in dry THF (3 ml) was added dropwise to a slurry of LiAlH4 (23 mg, 0.6 mmol, 0.12 equiv.) in THF (7 ml) at room temperature under nitrogen. The mixture was heated to reflux for 24 hours. After completion, the reaction was quenched by the slow addition of water (10 ml) followed by 15% NaOH (aq.) (5 ml). The organics were extracted into Et2O (3 x 10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel gave a clear oil (237 mg, 24% yield). 1H NMR data were consistent with literature values.9 1H NMR (500 MHz, CDCl3) δ 7.22 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.35 (d, J = 2.7 Hz, 1H), 3.80 (s, 3H), 1.82 (d, J = 2.8 Hz, 1H), 0.91 (s, 9H) ppm. 13C NMR (126 MHz, CDCl3) δ 158.8, 134.4, 128.6, 112.9, 82.0, 55.2, 35.7, 25.9 ppm.

(1r) 1-(4-Pyridinyl)ethanol

N

OH

N

OH3BO3

, NaBH4

15 min, RT 1r According to a literature procedure,10 in a mixture of boric acid (0.1854 g, 3mmol, 3 equiv.) and sodium borohydride (0.1135 g, 3mmol, 3 equiv.), 4-actyl pyridine (0.1211 g, 1mmol, 1 equiv.) was added and the final mixture was ground using mortar and pestle for 15 mins at room temperature. 7 (a) Lechner, R.; König, B. Synthesis, 2010, 1712-1718. (b) Collins, D.J.; Jacobs, H.A. Aus. J. C. 1986, 39, 2095-2110. 8 Weiberth, F. J.; Hall, S. S. J. Org. Chem. 1987, 52, 3901-3904. 9 Fujihara, T.; Semba, K.; Terao, J.; Tsuji, Y. Angew. Chem., Int. Ed. 2010, 49, 1472-1476. 10 Cho, B. T.; Kang, S. K.; Kim, M. S.; Ryu, S. R.; An, D. K. Tetrahedron. 2006, 62, 8164–8168.

The reaction was quenched with 1M HCl. The product was isolated via column chromatography over silica gel (0.1218 g, 99%). 1H NMR Data were consistent with literature values.10 1H NMR (400 MHz, CDCl3) δ 8.3 (d, J = 6.48 2H), 7.4 (d, J = 6.61, 2H), 4.92 (q, J = 6.59,6.58, 1H), 1.40 (d, J = 6.63, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 159.24, 147.02, 122.12, 68.03, 24.79 ppm.

General procedure for protection of amine

R2

OHNH2 TsCl (1.05 equiv)

Pyr (0.8M), 105 °C, 30 minR1 R2

OHTsHN

R1

The protection of the amine group was carried out according to the literature.11 The amine compound (1mmol, 1equiv.) was added portionwise to a solution of tosyl chloride (0.2 g, 1.05 mmol, 1.05 equiv) and pyridine (0.8 M) at 105 ˚C for 30 minutes under argon. After completion, the resulting mixture was diluted with ethyl acetate then washed with 3M HCl and brine, dried over sodium sulfate. The product was isolated via column chromatography over silica gel.

(1s) N-[4-chloro-2-(1-hydroxyethyl) phenyl]-4-methylbenzene-1-sulfonamide

1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.59-7.65 (m, 2H), 7.33(d, J = 8.27, 1H), 7.20-7.25 (m, 1H), 712 (dd, J = 8.53, 2.45, 1H), 7.05 (d, J = 2.54, 1H), 4.72-4.82 (m, 1H), 2.82-2.87 (m, 1H), 2.35 (s, 3H), 1.26 (d, J = 6.59, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 144.2, 136.4, 136.5, 134.2, 130.3, 129.9, 128.4, 127.2, 123.5, 69.2, 22.9, 21.7 ppm.

HRMS (ESI) m/z (%): calcd. for C15H16ClNO3S [(M+H)-(H2O)+] 308.0512; found 308.0502. Rf = 0.35, Hexane/EtOAc (2:1), white solid, 90%, 144 mg.

(1t) N-{4-chloro-2-[(2-fluorophenyl) (hydroxy)methyl]phenyl}-4-methylbenzene-1-sulfonamide.

1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 6.63-7.69 (m, 10H), 5.86 (s, 1H), 5.28 (s, 1H), 3.33 (s, 1H), 2.38 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) 161.0, 158.6, 144.3, 136.2, 135.6, 134.0, 131.1, 129.9, 129.0, 128.6, 127.9, 127.2, 124,9, 115.7, 110.1, 68.1, 24.8, 21.6 ppm. HRMS (ESI) m/z (%): calcd. for C20H17ClFNO3S [(M+H)-(H2O)+] 388.0574; found

388.0584. Rf = 0.58, Hexane/EtOAc (2:1), yellow solid, 64%, 0.52 g.

11 Song, W.; Li, M.; He, J.; Li, J.; Dong, K.; Zheng, Y. Org. Biomol. Chem. 2019, 17, 2663–2669.

OHNHTs

ClF

1t

NHTs

Cl

OH

1s

General procedure for synthesis of benzyl ethers Sc(OTf)3 (12.3 mg, 0.025 mmol) and DMAP (3.1 mg, 0.025 mmol) were stirred in anhydrous DCE (0.5 ml) for 30 minutes at room temperature, then cooled to 0°C on an ice bath. A solution of benzylic alcohol (0.25 mmol, 1 equiv.) and primary alcohol (0.375 mmol) in DCE (0.5 ml) was added dropwise via syringe. The reaction was stirred for 24 hours allowing it to slowly come to ambient room temperature. The crude mixture was filtered through a short pad of celite, the filtrate concentrated under reduced pressure and the residue purified via column chromatography on silica gel (30-50% DCM/Hexanes).

Characterization Data for Products of Table 3 (3a-3t)

(3a) 3-(2,2-dimethylpropoxy)-2,3-dihydro-1-benzofuran

1H NMR (400 MHz, CDCl3) δ 7.38 (ddt, J = 7.4, 1.1, 0.6 Hz, 1H), 7.29 – 7.20 (m, 1H), 6.91 (tt, J = 7.4, 1.0 Hz, 1H), 6.86 (ddt, J = 8.1, 1.1, 0.5 Hz, 1H), 5.09 (dd, J = 6.4, 2.7 Hz, 1H), 4.51 (dd, J = 10.5, 2.9 Hz, 1H), 4.46 (dd, J = 10.5, 6.5 Hz, 1H), 3.19 (d, J = 8.4 Hz, 1H), 3.04 (d, J = 8.4 Hz, 1H), 0.87 (s, 9H) ppm.

13C NMR (101 MHz, CDCl3) δ 160.7, 130.3, 126.3, 126.1, 120.4, 110.4, 79.1, 78.0, 76.3, 31.9, 26.7 ppm. HRMS (APCI) m/z (%): calcd. for C13H18O2Na+ ([M+Na]+) 229.1199; found 229.1172, 119.0509 ([M-C5H11O]+).

(3c) 6-bromo-3-(2,2-dimethylpropoxy)-2,3-dihydro-1-benzofuran

1H NMR (400 MHz, CDCl3) δ 7.24 (ddd, J = 7.6, 1.8, 0.7 Hz, 1H), 7.06 (td, J = 1.7, 0.6 Hz, 1H), 7.04 (dd, J = 1.7, 0.7 Hz, 1H), 5.07 – 5.00 (m, 1H), 4.56 – 4.45 (m, 2H), 3.16 (dd, J = 8.4, 2.4 Hz, 1H), 3.03 (dd, J = 8.4, 2.3 Hz, 1H), 0.88 (s, 9H) ppm.

13C NMR (101 MHz, CDCl3) δ 161.8, 127.2, 125.8, 123.9, 123.8, 114.2, 78.6, 78.3, 77.3, 32.1, 26.8 ppm. HRMS (APCI) m/z (%): calcd. for C13H17BrO2 ([M]+) 284.0412; found 284.0417, 196.9597 ([M-C5H11O]+).

(3d) 2,3-dihydro-1H-inden-1-yl 2,2-dimethylpropyl ether

1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 7.3, 0.9 Hz, 1H), 7.26 – 7.17 (m, 3H), 4.90 (t, J = 6.1 Hz, 1H), 3.23 (d, J = 8.6 Hz, 1H), 3.18 (d, J = 8.8 Hz, 1H), 3.03 (ddd, J = 15.9, 8.7, 4.8 Hz, 1H), 2.87 – 2.73 (m, 1H), 2.43 – 2.31 (m, 1H), 2.06 – 1.95 (m, 1H), 0.93 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3) δ 143.5, 127.9, 126.2, 124.9, 124.7, 110.0, 83.7, 79.2,

32.3, 32.1, 30.1, 26.8 ppm. HRMS (APCI) m/z (%): calcd. for C14H21O+ ([M+H]+) 205.1587; found 205.1278, 117.0705 ([M-C5H11O]+).

O

O

3a

O

O

Br3c

O

3d

(3e) 4-(2,2-dimethylpropoxy)-3,4-dihydro-2H-chromene

1H NMR (400 MHz, CDCl3) δ 7.30 – 7.23 (m, 1H), 7.21 – 7.15 (m, 1H), 6.88 (td, J = 7.4, 1.3 Hz, 1H), 6.82 (ddd, J = 8.3, 1.2, 0.6 Hz, 1H), 4.33 (t, J = 4.1 Hz, 1H), 4.28 (dd, J = 10.3, 3.2 Hz, 1H), 4.22 (dddt, J = 10.7, 4.4, 3.9, 0.7 Hz, 1H), 3.26 (d, J = 8.3 Hz, 1H), 3.18 (d, J = 8.3 Hz, 1H), 2.16 – 1.96 (m, 2H), 0.92 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3) δ 154.9, 130.6, 129.4, 122.8, 120.0, 116.9, 79.0, 71.0,

62.6, 32.3, 27.9, 26.9 ppm. HRMS (APCI) m/z (%): calcd. for C14H21O2 ([M+H]+) 221.1536; found 221.147, 133.0650 ([M-C5H11O]+).

(3f) 4-(2,2-dimethylpropoxy)-4-methyl-3,4-dihydro-2H-chromene

1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 7.9, 1.7 Hz, 1H), 7.14 (ddd, J = 8.2, 7.2, 1.7 Hz, 1H), 6.92 – 6.82 (m, 1H), 6.79 (dd, J = 8.2, 0.9 Hz, 1H), 4.36 (ddd, J = 11.0, 8.8, 3.3 Hz, 1H), 4.17 (ddd, J = 11.0, 6.8, 3.4 Hz, 1H), 2.89 (d, J = 8.1 Hz, 1H), 2.85 (d, J = 8.1 Hz, 1H), 2.21 (ddd, J = 13.7, 6.8, 3.3 Hz, 1H), 1.85 (ddd, J = 13.7, 8.7, 3.5 Hz, 1H), 1.52 (s, 3H), 0.83 (s, 9H) ppm.

13C NMR (101 MHz, CDCl3) δ 154.7, 128.7, 127.7, 125.8, 119.7, 116.8, 71.9, 69.7, 63.5, 34.3, 31.7, 26.8, 26.5 ppm. HRMS (APCI) m/z (%): calcd. for C15H23O2 ([M+H]+) 235.1672; found 235.169, 147.0808 ([M-C5H11O]+).

(3i) [(2,2-dimethylpropoxy)(phenyl)methyl]benzene.

1H NMR (400 MHz, CDCl3) δ 7.21-7.38 (m, 10H), 5.30 (s, 1H), 3.10 (s, 2H), 0.97 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3) δ 143.1, 128.4, 127.3, 127.0, 83.8, 79.5, 32.4, 27.1 ppm. HRMS (ESI) m/z (%): calcd. for 2 C18H22O [(M+H)+] 254.1671; found 254.0471.

HRMS (ESI) m/z (%): calcd. for C18H22O [(M+H)+] 255.1749; found , 255.1739, 167.0849 ([M-C5H11O]+). Rf = 0.85, Hexane/DCM (3:1), colorless liquid, 20%, 50 mg

(3j) 1-[(2,2-dimethylpropoxy)(4-fluorophenyl)methyl]-4-fluorobenzene.

1H NMR (400 MHz, CDCl3) δ 7.24-7.30 (m, 4H), 6.96-7.04 (m, 4H), 5.24 (s, 1H), 3.05 (s, 2H), 0.94 (s, 9H) ppm. 13C NMR (100 MHz, CDCl3) δ 162.2 (s), 138.7 (d), 128.6 (d), 115.3 (d), 82.5, 79.5, 32.3, 27.0.

19FNMR (376 MHz, CDCl3) δ -113.07 ppm HRMS (ESI) m/z (%): calcd. for C18H20F2O [(M+H)+] 291.1560; found 291.1543, 204.0747 ([M-C5H11O]+). Rf = 0.52, Hexane/DCM (2:1), colorless liquid, 14%, 39 mg

O

O

3e

O

O

3f

O tBu

3i

F

O tBu

F3j

(3k) 1-[(2,2-dimethylpropoxy)(4-methoxyphenyl)methyl]-4-methoxybenzene.

1H NMR (400 MHz, CDCl3) δ 7.33 (td, J =8.76, 2.87, 4H), 6.93 (dt, J = 6.91, 3.14, 4H), 5.29 (s, 1H) , 3.83 (s, 6H), 3.15 (s, 2H), 1.04 (s, 9H) ppm. 13C NMR (400 MHz, CDCl3) δ 158.8, 135.6, 128.2, 113.7, 82.9, 79.2, 55.2, 32.3, 27.0 ppm.

HRMS (ESI) m/z (%): calcd. for C20H26O3 [(M+H)+] 315.1960; found 350.2013, 227.1156([M-C5H11O]+). Rf = 0.44, Hexane/EtOAc (2:1), colorless liquid, 99%, 0.34 g

(3l) 1-[1-(2,2-dimethylpropoxy)ethyl]-4-methoxybenzene

1H NMR (400 MHz, CDCl3) δ 7.22 (dd, J = 8.5, 1.4 Hz, 2H), 6.86 (dd, J = 8.6, 1.6 Hz, 2H), 4.29 (q, J = 6.4 Hz, 1H), 3.80 (s, 3H), 2.94 (d, J = 8.7 Hz, 1H), 2.91 (d, J = 8.7 Hz, 1H), 1.39 (d, J = 6.5 Hz, 2H), 0.89 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3) δ 158.8, 137.0, 127.4, 113.8, 79.1, 77.9, 55.4, 32.1,

26.9, 24.3 ppm. HRMS (APCI) m/z (%): calcd. for C14H23O2 ([M+H]+) 223.1693; found 223.1668, 135.0808 ([M-C5H11O]+).

(3m) 1-[1-(2,2-dimethylpropoxy)ethyl]-2-methoxybenzene

1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J =5.73, 1.83, Hz, 1H), 7.23-7.27 (m, 1H), 7.01 (dtd, J = 7.48, J =1.1, 0.43 Hz, 1H), 6.88 (dd, J = 8.23, 1.14, 1H), 4.80 (q, J = 6.39 Hz, 1H), 3.84 (s, 3H), 3.08 (d, J = 8.64, 1H), 2.99 (d, J = 8.8 Hz, 1H), 1.39 (d, J = 6.52 Hz, 3H), 0.96 (s, 9H) ppm.

13C NMR (400 MHz, CDCl3) δ 156.55, 133.33, 127.71, 126.22, 120.82, 110.21, 79.54, 72.22, 55.36, 32.22, 26.97, 22.91 ppm. HRMS (ESI) m/z (%): calcd. for C14H22O2 [(M+H)+] 223.1698; found 223.1663, 136.0846 ([M-C5H11O]+). Rf = 0.55, Hexane/DCM (2:1), colorless liquid, 40%, 90 mg

(3n) 1-[1-(2,2-dimethylpropoxy)-2,2-dimethylpropyl]-4-methoxybenzene

1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H), 3.76 (s, 1H), 2.94 (d, J = 8.3 Hz, 1H), 2.76 (d, J = 8.3 Hz, 1H), 0.91 (s, 9H), 0.87 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3) δ 158.7, 132.5, 129.5, 112.8, 89.8, 79.8, 55.3, 36.2,

32.5, 27.0, 26.4 ppm. HRMS (APCI) m/z (%): calcd. for C12H17O ([M-C5H11O]+) 177.1279; found 177.1276.

O

MeO 3l

tBu

MeO

O

3n

O tBu

OMeMeO 3k

Me

O tBuOMe

3m

Characterization Data for Products of Table 4 All of these were synthesized according to the general procedure.

(5b) 1-methoxy-4-(1-methoxyethyl)benzene

1H and 13C NMR data are consistent with literature reports.12 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.23 (q, J = 6.5 Hz, 1H), 3.79 (s, 3H), 3.18 (s, 3H), 1.41 (d, J = 6.5 Hz, 1H) ppm. 13C NMR (101 MHz, CDCl3) δ 158.9, 135.4, 127.4, 113.8, 79.1, 56.1, 55.2, 23.7 ppm. GC-MS (EI): calcd. for C10H14O2 ([M]+) 166.0994; found 166.1.

HRMS (APCI) m/z (%): calcd. for C9H11O ([M-CH3O]+) 135.0810; found 135.0824 ([M-CH3O]+).

(5c) 1-(1-ethoxyethyl)-4-methoxybenzene

1H and 13C NMR data are consistent with literature reports.13 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.34 (d, J = 6.5 Hz, 1H), 3.78 (s, 3H), 3.31 (q, J = 7.0 Hz, 2H), 1.41 (d, J = 6.5 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 158.8, 136.2, 127.3, 113.7, 77.2, 63.6, 55.2, 24.1, 15.4 ppm.

GC-MS (EI): calcd. for C11H16O2 ([M]+) 180.1150; found 180.1. HRMS (APCI) m/z (%): calcd. for C9H11O ([M-C2H5O]+) 135.0810; found 135.0843 ([M-C2H5O]+).

(5d) 1-methoxy-4-[1-(prop-2-en-1-yloxy)ethyl]benzene

1H and 13C NMR data are consistent with literature reports.14

1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.94-5.84 (m, 1H), 5.25-5.19 (m, 1H), 5.15 – 5.13 (m, 1H), 4.41 (q, J = 6.5 Hz, 1H), 3.89-3.74 (m, 2H), 3.79 (s, 3H), 1.43 (d, J = 6.5 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 158.9, 135.7, 135.1, 127.4, 116.5, 113.8, 76.7, 69.2, 55.2, 24.0 ppm.

GC-MS (EI): calcd. for C12H16O2 ([M]+) 192.1150; 192.1. HRMS (APCI) m/z (%): calcd. for C9H11O ([M-C3H5O]+) 135.0810; found 135.0812 ([M-C3H5O]+).

12 Ke, F.; Li, Z.; Xiang, H.; Zhou, X. Tetrahedron Lett. 2011, 52, 318-320. 13 Das, R. N.; Sarma, K.; Pathak, M.; Goswami, A. Synlett 2010, 2908-2912. 14 Talluir, S. K.; Sudalai, A. Org. Lett. 2005, 7, 855-857.

MeO

O

5b

MeO

O

5c

MeO

O

5d

(5e) 1-[1-(cyclohexylmethoxy)ethyl]-4-methoxybenzene

1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.30 (q, J = 6.5 Hz, 1H), 3.79 (s, 3H), 3.06 (d, J = 6.3 Hz, 2H), 1.81-1.51 (m, 6H), 1.40 (d, J = 6.5 Hz, 3H), 1.29-1.10 (m, 3H), 0.92-0.78 (m, 2H) ppm. 13C NMR (101 MHz, CDCl3) δ 158.8, 136.5, 127.3, 113.6, 77.4, 74.4, 55.2, 38.2, 30.3, 30.1, 26.7, 25.9, 25.8, 24.2 ppm.

GC-MS (EI): calcd. for C16H24O2 ([M]+) 248.1776; found 248.2. HRMS (APCI) m/z (%): calcd. for C9H11O ([M-C7H13O]+) 248.1776; found 135.0814 ([M-C7H13O]+).

(5f) 1-{[1-(4-methoxyphenyl)ethoxy]methyl}tricyclo[3.3.1.13,7]decane

1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.26 (q, J = 6.4 Hz, 1H), 3.80 (s, 3H), 2.85 (q, J = 8.9 Hz, 2H), 1.95 (s, 3H), 1.73-1.63 (m, 6H), 1.53 (s, 6H), 1.38 (d, J = 6.4 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 158.7, 136.9, 127.2, 113.6, 79.4, 77.7, 55.2, 39.8, 37.3, 34.0, 28.3, 24.2 ppm.

GC-MS (EI): calcd. for C20H28O2 ([M]+) 300.2089; found 300.1. HRMS (APCI) m/z (%): calcd. for C9H11O ([M-C11H17O]+) 135.0810; found 135.0811 ([M-C11H17O]+).

(5g) 2-{[1-(4-methoxyphenyl)ethoxy]methyl}furan

1H NMR (400 MHz, CDCl3) δ 7.39 -7.38(m, 1H), 7.28 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.32-6.31 (m, 1H), 6.23-6.22 (m, 1H), 4.46 (q, J = 6.5 Hz, 1H), 4.35-4.20 (m, 2H), 3.81 (s, 3H), 1.44 (d, J = 6.5 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 159.1, 152.1, 142.6, 135.2, 127.6, 113.9, 110.2, 108.9, 76.5, 62.1, 55.2, 24.0 ppm.

GC-MS (EI): C14H16O3 ([M]+) 232.1099; found 232.1. HRMS (APCI) m/z (%): calcd. for C9H11O ([M-C5H5O2]+) 135.0810; found 135.0814 ([M-C5H5O2]+).

(5h) 1,2,3-trimethoxy-5-{[1-(4-methoxyphenyl)ethoxy]methyl}benzene

1H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.54 (s, 2H), 4.47 (q, J = 6.5 Hz, 1H), 4.38-4.22 (m, 2H), 3.86 (s, 6H), 3.84 (s, 3H), 3.83 (s, 3H), 1.49 (d, J = 6.5 Hz, 3H) ppm. 13C NMR (126 MHz, CDCl3) δ 159.1, 153.2, 137.3, 135.6, 134.4, 127.6, 113.9, 104.7, 76.8, 70.3, 60.8, 56.0, 55.2, 24.1 ppm.

GC-MS (EI): calcd. for C19H24O5 ([M]+) 332.1624; found 332.2. HRMS (APCI) m/z (%): calcd. for C9H11O ([M-C10H13O4]+) 135.0810; found 135.0811 ([M-C10H13O4]+).

MeO

O

5e

MeO

O

5f

MeO

O

5g

O

MeO

O

5h

OMe

OMeOMe

(5i) 1-[1-(4-methoxyphenyl)ethoxy]-3-methylbutan-2-tosylamine

1H NMR (400 MHz, CDCl3) δ 7.80 – 7.65 (m, 2H), 7.37 – 7.24 (m, 2H), 7.20 – 7.06 (m, 2H), 6.92 – 6.77 (m, 2H), 5.27 (t, J = 5.8 Hz, 1H), 4.26 (q, J = 6.4 Hz, 1H), 3.79 (s, 3H), 3.35 – 3.20 (m, 2H), 3.12 – 2.94 (m, 2H), 2.43 (s, 3H), 1.75 – 1.56 (m, 2H), 1.38 (d, J = 6.5 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 159.1, 143.2, 137.1, 135.3, 129.7, 127.3, 127.1, 113.9, 77.9, 67.0, 55.3, 42.1, 28.9, 23.9, 21.6 ppm.

GC-MS (EI): 363.1. HRMS (APCI) m/z (%): calcd. for C19H25NO4S ([M]+) 363.1504; found 363.1478 ([M- C19H25NO4S]+)

(5j) (2S)-1-[1-(4-methoxyphenyl)ethoxy]-3-methylbutan-2-tosylamine

Mixture (dr 1:1) 1H NMR (400 MHz, CDCl3) δ 7.73 (7.61) (d, J = 8.2 Hz, 2H), 7.25 (7,14) (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 4.94 (4.88) (d, J = 8.8 Hz, 1H), 4.12 (4.00) (q, J = 6.4 Hz, 1H), 3.79 ( 3.76) (s, 3H), 3.17 (3.11) (dd, J = 9.5, 3.6 Hz, 1H), 3.03-2.97 (m, 1H), 2.93-2.84 (m, 1H), 2.40

(2.35) (s, 3H), 1.98-1.75 (m, 1H), 1.28 (1.27) (d, J = 6.4, 3H), 0.87-0.68 (m, 6H) ppm. 13C NMR (101 MHz, CDCl3) δ 159.0, 143.0, 142.8, 138.4, 138.1, 135.2, 135.2, 129.5, 129.4, 127.3, 127.2, 127.0, 127.0, 113.8, 113.7, 78.1, 77.9, 67.3, 67.2, 59.0, 58.8, 55.2, 55.2, 29.8, 29.8, 23.6, 23.5, 21.5, 21.4, 19.1, 19.0, 18.7, 18.3 ppm. GC-MS (EI): calcd. for C21H29NO4S ([M]+) 391.1817; found 391.2. HRMS (APCI) m/z (%): calcd. for C9H11O ([M-C12H18NO3S]+) 135.0810; found 135.0813 ([M-C12H18NO3S]+)

Characterization Data for the Products of Scheme 3

(6) (2S)-1-[1-(4-methoxyphenyl)ethoxy]-3-methylbutan-2-tosylamine

Mixture (3:1 dr). 1H and 13C NMR data were consistent with literature values.15 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.17 (m, 5H), 6.92 – 6.86 (6.85 – 6.80) (m, 3H), 4.18 (4.46) (q, J = 6.5 Hz, 2H), 3.81 (3.78) (s, 3H), 1.35 (1.43) (d, J = 6.5 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 158.9, 158.7, 136.4, 136.2, 127.5, 127.4, 113.8, 113.6, 73.7, 73.7, 55.2, 55.2, 24.7, 22.8 ppm. GC-MS (EI): 286.1

15 Noji, M.; Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72, 5161-5167.

MeO

O

5j

NHTs

MeO

O

6

OMe

MeO

O

5i

NHTs

(7a) (2S)-1-[1-(4-methoxyphenyl)ethoxy]-3-methylbutan-2-tosylamine and (7b)

Mixture (2.6:1); each regioisomer dr 1:1

1H NMR (400 MHz, CDCl3) δ 7.25 – 7.20 (m, 2H), 6.91 – 6.84 (m, 2H), 4.36 (q, J =

6.5 Hz, 1H), (4.36) [(4.51) (4.48)], 3.80 (s, 3H), 3.77 (m, 1H), (3.69 – 3.60), 3.36 – 3.23 (m, 2H), 2.88 (s, 1H) (2.75), 1.69 – 1.61 (m, 2H), 1.61 – 1.45 (m, 3H), 1.43 (d, J = 6.5, 0.7 Hz, 3H) (1.41), 1.18 (d, J = 6.2, 3H), 1.14 (d, J = 6.1 Hz, 3H), (1.03) ppm. 13C NMR (101 MHz, CDCl3) δ 158.9, 135.6, 127.7, 127.3, 113.7, 113.6, 77.7, 75.1, 73.9, 72.6, 71.0, 68.7, 68.5, 67.8, 67.6, 63.0, 62.9, 55.2, 36.9, 36.7, 34.1, 32.5, 28.6, 28.3, 26.7, 26.4, 24.4, 24.0, 23.9, 23.8, 23.4, 20.5, 18.8 ppm. GC-MS (EI): 238.1 HRMS (APCI) m/z (%): calcd. for C14H21O3 ([M-H]-) 237.1491; found 237.1504

(8) 1-methoxy-4-[1-(2-methoxyethoxy)ethyl]benzene

1H NMR (400 MHz, CDCl3) δ 7.22-7.27 (m, 2H), 6.85-6.90 (m, 2H), 4.40 (q, J = 6.46 Hz, 1H), 3.80 (s, 3H), 3.46-3.52 (m, 2H), 3.39-3.45 (m, 2H), 3.36 (s, 3H), 1.43 (d, J = 6.48 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 159.1, 135.8, 127.53, 113.87, 78.1, 72.2, 67.6,

59.1, 53.3, 24.1 ppm.

Synthesis of Dimers for Cross Over Experiment (Scheme 4, equation e)

(10a) 1-{[bis(4-methoxyphenyl)methoxy](4-methoxyphenyl)methyl}-4-methoxybenzene

1H NMR (400 MHz, CDCl3) δ 7.24 (d, J= 8.66, 2H), 6.82 (d, J= 8.66, 2H), 4.40 (s, 1H), 3.69 (s, 3H), ppm. 13C NMR (100 MHz, CDCl3) δ 158.92, 134.92, 128.54, 113.83, 79.06, 55.25 ppm.16

16 Jereb, M.; Vražič, D. Iodine-Catalyzed Disproportionation of Aryl-Substituted Ethers under Solvent-Free Reaction

Conditions. Org. Biomol. Chem. 2013, 11, 1978–1999.

MeO

O

7aOH MeO

O

7b

OH

Me

MeO

O OMe

8

MeO

O

OMe

OMe

OMe

10a

(10b) 1-{[bis(4-fluorophenyl) methoxy](4-fluorophenyl)methyl}-4-fluorobenzene

1H NMR (400 MHz, CDCl3) δ 7.24-7.33 (m, 2H), 6.94-7.03 (m, 2H), 5.33 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 163.53, 161.06, 137.47,.128.83, 115.35, 78.91 ppm.17

(11) 3-[1-(4-methoxyphenyl)ethyl]-1H-indole

1H and 13C NMR data are consistent with literature reports.18 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.33 (dd, J = 19.1, 7.7 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 7.13 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 6.99 (ddt, J = 8.0, 7.0, 0.8 Hz, 1H), 6.96 (dd, J = 2.4, 1.0 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 4.32 (q, J = 7.1 Hz, 1H), 3.76 (s, 3H), 1.67 (d, J = 7.1 Hz, 3H) ppm.

13C NMR (101 MHz, CDCl3) δ 157.9, 139.1, 136.8, 128.4, 127.0, 122.1, 122.0, 121.1, 119.9, 119.3, 113.8, 111.1, 55.4, 36.2, 22.7 ppm. HRMS (ESI) m/z (%): calcd. for C17H18NO ([M+H]+) 252.1388; found 252.1402.

17 Brahmachari, G.; Banerjee, B. Facile Synthesis of Symmetrical Bis(Benzhydryl)Ethers Using p-Toluenesulfonyl Chloride under Solvent-Free Conditions. Org. Med. Chem. Lett. 2013, 3, 1. 18 Wang, M.-Z.; Wong, M.-K.; Che, C.-M. Chem. Eur. J. 2008, 14, 8353-8364.

MeO 11

HN

F

O

F

F

F

10b

NMR SPECTRA

(1a) 2,3-dihydro-1-benzofuran-3-ol

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0

f1 (ppm)

1.06

1.04

1.06

1.00

0.91

0.96

0.95

0.92

3.72

93.

742

4.15

64.

162

4.18

24.

187

4.18

94.

266

4.28

34.

293

4.31

0

5.00

75.

013

5.02

15.

025

5.03

05.

037

5.04

3

6.76

16.

763

6.76

56.

781

6.78

36.

785

6.84

36.

846

6.86

06.

862

6.86

46.

879

6.88

16.

883

7.15

57.

156

7.15

87.

160

7.17

57.

177

7.17

87.

180

7.18

17.

194

7.19

57.

199

7.25

97.

261

7.26

37.

277

7.27

9

O

OH

1a

0102030405060708090100110120130140150160170180f1 (ppm)

71.5

73

78.7

75

110.

321

120.

880

125.

546

128.

113

130.

501

159.

939

(1b) 6-methoxy-2,3-dihydro-1-benzofuran-3-ol

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0

f1 (ppm)

1.03

3.24

1.13

1.11

1.00

1.07

1.03

0.92

1.85

31.

866

3.78

54.

441

4.44

24.

446

4.44

74.

467

4.46

84.

473

4.47

44.

527

4.52

84.

543

4.54

44.

553

4.55

44.

569

4.57

04.

775

5.28

25.

289

5.29

45.

295

6.42

76.

429

6.43

36.

434

6.48

36.

484

6.48

96.

504

6.51

0

7.28

27.

283

7.30

27.

304

O

OH

MeO1b

-100102030405060708090100110120130140150160170180190

f1 (ppm)55

.516

71.8

59

80.3

11

96.2

20

107.

521

120.

557

125.

693

161.

860

162.

407

(1c) 6-bromo-2,3-dihydro-1-benzofuran-3-ol

-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0

f1 (ppm)

1.06

2.26

1.00

0.73

0.75

0.99

1.92

21.

941

4.43

94.

446

4.46

64.

473

4.54

44.

561

4.57

14.

587

5.29

85.

304

5.31

25.

314

5.31

55.

316

5.31

85.

321

5.32

35.

333

5.34

07.

046

7.04

77.

048

7.05

07.

051

7.05

37.

067

7.07

17.

087

7.09

17.

257

7.25

87.

259

7.26

17.

277

7.27

87.

280

O

OH

Br1c

-100102030405060708090100110120130140150160170180190

f1 (ppm)

71.6

18

79.8

80

114.

218

124.

138

124.

206

126.

418

127.

468

161.

172

(1e) 3,4-dihydro-2H-chromen-4-ol

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0

f1 (ppm)

0.95

1.28

1.21

2.03

1.00

0.92

0.98

0.96

0.96

1.77

71.

789

2.01

02.

018

2.02

12.

024

2.02

82.

031

2.03

82.

043

2.04

62.

051

2.05

52.

061

2.06

42.

065

2.07

02.

074

2.09

32.

103

2.10

82.

115

2.11

92.

124

2.12

92.

140

2.14

32.

151

2.15

42.

160

2.16

52.

175

4.25

84.

261

4.27

14.

276

4.27

74.

284

4.28

64.

287

4.29

24.

782

4.79

34.

804

4.81

4

6.83

56.

837

6.83

96.

855

6.85

66.

858

6.85

96.

906

6.90

96.

925

6.92

86.

943

6.94

77.

189

7.19

37.

207

7.21

07.

211

7.21

27.

214

7.22

87.

304

7.30

57.

306

7.30

87.

310

7.32

37.

324

7.32

77.

329

O

OH

1e

-100102030405060708090100110120130140150160170180190f1 (ppm)

30.9

22

62.0

2863

.310

117.

163

120.

680

124.

425

129.

783

129.

804

154.

675

(1f) 4-methyl-3,4-dihydro-2H-chromen-4-ol

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0

f1 (ppm)

3.36

0.81

1.77

2.31

0.90

1.03

1.04

1.00

1.63

41.

859

2.06

32.

066

2.07

52.

077

2.08

52.

089

4.20

34.

214

4.21

74.

228

4.23

14.

242

4.24

44.

256

4.26

24.

274

4.28

04.

290

4.29

24.

301

4.30

94.

320

6.81

06.

813

6.81

46.

831

6.83

46.

835

6.91

56.

918

6.93

36.

935

6.93

76.

938

6.95

36.

956

7.15

47.

159

7.17

17.

172

7.17

47.

175

7.17

77.

179

7.19

37.

197

7.47

77.

482

7.49

77.

501

O

OH

1f

-100102030405060708090100110120130140150160170180190

f1 (ppm)

29.6

53

38.2

20

63.4

7866

.546

117.

282

120.

942

126.

508

128.

566

129.

331

153.

997

(1g) 1,2,3,4-tetrahydronaphthalen-1-ol

-1.-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0

f1 (ppm)

5.71

2.18

1.00

0.86

1.58

0.81

169

91.

710

1.75

61.

770

1.77

51.

783

1.79

01.

798

1.89

21.

897

1.90

31.

910

1.91

81.

923

1.93

71.

946

1.95

21.

959

1.96

71.

970

1.98

01.

983

1.99

32.

000

2.00

62.

010

2.01

32.

018

2.68

62.

702

2.72

12.

728

2.74

22.

748

2.76

22.

797

2.80

92.

823

2.83

82.

851

2.86

6

4.77

64.

788

7.09

07.

101

7.11

37.

189

7.19

57.

200

7.20

47.

206

7.21

17.

418

7.43

07.

441

OH

1g

(1h) 1-methyl-1,2,3,4-tetrahydronaphthalen-1-ol

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

2.98

0.99

2.83

2.00

0.73

1.64

0.73

1.56

11.

563

1.73

31.

736

1.77

81.

790

1.79

31.

795

1.79

81.

800

1.80

21.

813

1.81

71.

819

1.82

21.

824

1.82

61.

829

1.83

21.

834

1.83

61.

838

1.84

11.

844

1.85

81.

860

1.86

31.

893

1.89

71.

901

1.90

41.

909

1.91

21.

915

1.91

81.

921

1.92

31.

925

1.92

81.

931

1.93

51.

938

1.94

51.

948

1.95

21.

961

1.96

41.

967

1.96

92.

733

2.74

82.

776

2.78

92.

799

2.80

52.

818

2.83

52.

846

7.05

87.

061

7.07

57.

078

7.08

07.

082

7.14

17.

144

7.14

77.

159

7.16

27.

166

7.17

77.

180

7.18

47.

191

7.19

47.

196

7.19

87.

210

7.21

27.

214

7.21

57.

217

7.23

07.

232

7.23

47.

579

7.59

9

OH

1h

0102030405060708090100110120130140150160f1 (ppm)

20.5

70

30.0

8130

.894

39.9

86

70.7

65

126.

425

126.

512

127.

266

128.

988

136.

409

142.

987

(1l) 1-(4-methoxyphenyl)ethanol

OH

MeO1l

-100102030405060708090100110120130140150160170180190f1 (ppm)

25.1

38

55.4

10

70.0

79

113.

956

126.

779

138.

133

159.

078

(1n’) 1-(4-methoxyphenyl)-2,2-dimethylpropan-1-one

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

9.13

3.12

2.00

1.89

1.37

1

3.85

1

6.88

66.

908

7.83

87.

861

MeO

O

(1n) 1-(4-methoxyphenyl)-2,2-dimethylpropan-1-ol

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

9.31

0.88

2.94

1.00

1.91

1.97

0.90

6

1.81

71.

822

3.80

1

4.34

74.

352

6.83

96.

857

7.21

37.

230

MeO

OH

1n

(1r) 1-(4-Pyridinyl)ethanol

N

OH

1r

(1s) N-[4-chloro-2-(1-hydroxyethyl) phenyl]-4-methylbenzene-1-sulfonamide

NHTs

Cl

OH

1s

(1t) N-{4-chloro-2-[(2-fluorophenyl) (hydroxy)methyl]phenyl}-4-methylbenzene-1-sulfonamide.

OHNHTs

ClF

1t

(3a) 3-(2,2-Dimethylpropoxy)2,3-dihydro-1-benzofuran

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

9.05

1.06

1.13

2.31

1.00

1.97

1.09

1.02

0.87

5

3.03

23.

053

3.17

83.

199

4.43

84.

454

4.46

44.

480

4.49

54.

502

4.52

14.

528

5.08

05.

087

5.09

65.

103

6.85

16.

853

6.85

46.

855

6.87

26.

873

6.87

46.

876

6.88

66.

889

6.89

16.

905

6.90

76.

909

6.92

36.

926

6.92

87.

223

7.22

47.

227

7.24

17.

244

7.24

67.

247

7.36

97.

370

7.37

27.

374

7.37

57.

387

7.38

97.

390

7.39

27.

394

O

O

3a

(3c) 6-Bromo-3-(2,2-dimethylpropoxy)-2,3-dihydro-1-benzofuran

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

9.48

1.15

1.14

2.37

1.00

1.92

1.05

0.87

93.

020

3.02

53.

041

3.04

63.

152

3.15

73.

172

3.17

84.

465

4.46

74.

469

4.47

14.

481

4.48

34.

485

4.48

74.

491

4.49

34.

496

4.49

74.

502

4.50

74.

509

4.51

34.

519

4.52

04.

522

4.52

54.

526

4.53

94.

541

4.54

54.

547

4.54

94.

551

4.55

35.

025

5.02

75.

029

5.03

15.

032

5.03

75.

038

5.04

05.

042

5.04

55.

047

5.04

85.

052

5.05

47.

034

7.03

57.

038

7.04

07.

053

7.05

57.

058

7.05

97.

063

7.22

47.

225

7.22

87.

230

7.24

37.

244

7.24

77.

249

O

O

Br3c

(3d) 2,3-Dihydro-1H-inden-1-yl-2,2-dimethylpropyl ether

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

8.63

1.01

1.01

1.00

1.01

1.88

1.03

2.70

1.00

0.92

91.

965

1.97

81.

981

1.98

61.

990

1.99

61.

998

2.00

02.

003

2.00

62.

011

2.01

42.

017

2.01

92.

022

2.02

82.

032

2.03

62.

039

2.04

92.

052

2.32

62.

327

2.32

92.

338

2.33

92.

341

2.34

32.

347

2.35

02.

355

2.35

62.

359

2.36

22.

364

2.36

52.

367

2.37

12.

371

2.37

42.

376

2.37

92.

383

2.38

82.

388

2.39

12.

395

2.39

72.

400

2.40

82.

412

2.75

32.

773

2.79

22.

812

2.83

12.

997

3.00

93.

019

3.03

03.

036

3.04

83.

058

3.07

03.

169

3.19

03.

216

3.23

84.

889

4.90

54.

919

7.19

37.

195

7.20

47.

206

7.21

07.

212

7.22

27.

226

7.22

97.

238

7.24

07.

243

7.38

97.

392

7.40

8

O

3d

0102030405060708090100110120130140150160f1 (ppm)

26.7

9430

.054

32.1

3532

.350

79.1

75

83.6

89

109.

988

124.

695

124.

910

126.

162

127.

947

143.

535

(3e) 4-(2,2-Dimethylpropoxy)-3,4-dihydro-2H-chromene

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

9.00

2.34

1.16

1.12

1.12

0.95

1.25

0.89

1.13

1.00

0.92

0.91

9

3.16

53.

186

3.24

63.

267

4.19

54.

196

4.20

44.

206

4.21

64.

218

4.22

24.

232

4.24

34.

266

4.27

34.

292

4.29

94.

316

4.32

54.

335

6.81

16.

813

6.83

16.

834

6.86

56.

868

6.88

36.

886

6.90

26.

905

7.16

27.

166

7.18

17.

183

7.18

47.

185

7.18

67.

200

7.20

57.

254

7.25

87.

259

7.27

37.

274

7.27

77.

278

O

O

3e

(3f) 4-(2,2-Dimethypropoxy)-4-methyl-3,4-dihydro-2H-chromene

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

8.91

3.21

1.16

1.11

1.00

1.03

1.09

1.10

0.87

0.99

0.96

1.00

0.82

61.

519

1.82

01.

829

1.84

21.

851

1.85

51.

863

1.87

71.

885

2.18

32.

191

2.20

02.

208

2.21

82.

226

2.23

52.

243

2.83

52.

855

2.87

72.

897

4.14

04.

148

4.15

74.

165

4.16

64.

175

4.18

44.

192

4.33

34.

341

4.35

54.

360

4.36

34.

369

4.38

24.

390

6.78

16.

784

6.80

26.

804

6.85

16.

855

6.87

06.

871

6.87

26.

874

6.88

96.

892

7.11

97.

123

7.13

77.

139

7.14

17.

144

7.15

87.

162

7.31

67.

320

7.33

67.

340

O

O

3f

-100102030405060708090100110120130140150160170180190f1 (ppm)

26.5

1726

.783

31.6

8234

.283

63.4

72

69.7

2671

.940

116.

768

119.

687

125.

788

127.

699

128.

679

154.

653

(3i) [(2,2-dimethylpropoxy)(phenyl)methyl]benzene.

(3j) 1-[(2,2-dimethylpropoxy)(4-fluorophenyl)methyl]-4-fluorobenzene.

F

O tBu

F3j

(3k) 1-[(2,2-dimethylpropoxy)(4-methoxyphenyl)methyl]-4-methoxybenzene.

O tBu

OMeMeO 3k

(3l) 1-[1-(2,2-Dimethylpropoxy)ethyl]-4-methoxybenzene

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

8.53

2.93

2.01

2.81

1.00

1.79

1.87

0.88

7

1.37

91.

395

2.89

52.

917

2.93

32.

954

3.79

9

4.26

14.

277

4.29

34.

309

6.85

56.

877

7.20

77.

229

O

MeO 3l

-100102030405060708090100110120130140150160170180190f1 (ppm)

24.3

2226

.944

32.1

30

55.3

65

77.9

2679

.106

113.

752

127.

367

136.

991

158.

839

(3m) 1-[1-(2,2-dimethylpropoxy)ethyl]-2-methoxybenzene

OMe

Me

O tBu

3m

(3n) 1-[1-(2,2-Dimethylpropoxy)-2,2-dimethylpropyl]-4-methoxybenzene

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

9.37

9.30

1.12

1.13

3.17

1.92

2.00

0.87

50.

907

2.75

42.

774

2.93

12.

952

3.80

7

6.82

96.

851

7.13

17.

153

tBu

MeO

O

3n

-100102030405060708090100110120130140150160170180190f1 (ppm)

Z:/nmr400/data/Geary/juliad/b3p1.10_13C.fid/fid

26.4

1927

.036

32.4

62

36.2

01

55.3

06

79.7

68

89.7

55

112.

844

129.

537

132.

525

158.

702

(5b) 1-Methoxy-4-(1-methoxyethyl)benzene

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

3.00

2.82

3.28

0.92

1.91

1.94

1.39

81.

414

3.17

9

3.78

8

4.21

04.

226

4.24

24.

258

6.86

06.

882

7.20

67.

227

MeO

O

5b

(5c) 1-(1-Ethoxyethyl)-4-methoxybenzene

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

2.97

3.10

2.01

3.00

1.06

1.95

1.99

1.13

81.

156

1.17

31.

398

1.41

4

3.28

83.

305

3.32

33.

340

3.78

5

4.31

94.

332

4.34

84.

364

6.85

26.

874

7.21

17.

233

MeO

O

5c

-100102030405060708090100110120130140150160170180190f1 (ppm)

15.3

68

24.1

31

55.1

95

63.6

03

77.1

88

113.

695

127.

253

136.

217

158.

812

(5d) 1-Methoxy-4-[1-(prop-2-en-1-yloxy)ethyl]benzene

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

3.00

0.87

3.12

1.14

1.11

1.02

1.03

1.03

1.90

1.88

1.42

11.

437

3.73

73.

741

3.75

63.

772

3.78

43.

792

3.83

23.

836

3.84

03.

849

3.86

43.

872

3.88

13.

885

4.38

64.

403

4.41

94.

435

5.11

35.

117

5.12

15.

139

5.14

25.

147

5.19

45.

198

5.20

25.

207

5.23

75.

241

5.24

55.

250

5.84

25.

857

5.86

85.

881

5.89

85.

911

5.92

45.

939

6.86

16.

883

7.22

27.

243

MeO

O

5d

(5e) 1-[1-(Cyclohexylmethoxy)ethyl]-4-methoxybenzene

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

2.17

3.15

3.00

6.14

1.91

3.00

1.07

1.74

1.81

0.80

00.

827

0.85

00.

878

0.88

50.

909

1.09

51.

156

1.19

01.

206

1.23

71.

276

1.38

81.

404

1.52

61.

591

1.65

51.

657

1.69

81.

764

1.79

6

3.05

23.

068

3.79

1

4.27

44.

290

4.30

64.

322

6.85

56.

877

7.20

67.

227

MeO

O

5e

-100102030405060708090100110120130140150160170180190f1 (ppm)

24.1

6725

.845

25.9

0726

.654

30.1

4330

.255

38.1

72

55.1

79

74.3

9177

.435

113.

645

127.

252

136.

448

158.

771

(5f) 1-{[1-(4-Methoxyphenyl)ethoxy]methyl}tricyclo[3.3.1.13,7]-decane

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

3.00

6.17

6.08

3.17

2.20

2.78

1.12

1.90

2.06

1.37

71.

393

1.53

21.

632

1.66

01.

696

1.72

61.

950

2.81

82.

840

2.85

42.

876

3.80

1

4.23

54.

252

4.26

84.

284

6.86

26.

884

7.20

77.

229

MeO

O

5f

-100102030405060708090100110120130140150160170180190f1 (ppm)

24.1

8528

.338

33.9

7237

.277

39.7

65

55.1

70

77.6

9679

.411

113.

576

127.

199

136.

857

158.

657

(5g) 2-{[1-(4-Methoxyphenyl)ethoxy]methyl}furan

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

2.76

3.00

1.09

0.98

0.97

0.81

0.81

1.98

1.82

0.78

1.43

41.

450

3.80

64.

199

4.23

14.

322

4.35

44.

438

4.45

44.

470

4.48

6

6.22

56.

233

6.30

66.

311

6.31

36.

319

6.89

26.

914

7.26

77.

289

7.38

67.

388

7.39

17.

393

MeO

O

5g

O

-100102030405060708090100110120130140150160170180190f1 (ppm)

24.0

20

55.2

26

62.0

54

76.5

32

108.

912

110.

145

113.

861

127.

614

135.

227

142.

619

152.

118

159.

078

(5h) 1,2,3-Trimethoxy-5-{[1-(4-methoxyphenyl)ethoxy]methyl}benzene

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

3.00

2.86

2.79

5.82

1.09

1.09

1.08

1.91

1.89

2.06

1.48

81.

501

3.82

63.

842

3.85

64.

218

4.24

14.

352

4.37

54.

451

4.46

44.

477

4.49

0

6.54

0

6.91

36.

931

7.28

97.

307

MeO

O

5h

OMe

OMeOMe

(5i) 1-[1-(4-Methoxyphenyl)ethoxy]3-methylbutan-2-tosylamine

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

2.98

2.12

2.86

2.08

2.01

3.00

1.09

1.03

2.00

1.96

2.04

1.89

1.37

51.

391

1.64

21.

646

1.65

51.

659

1.67

22.

430

3.00

33.

012

3.01

73.

020

3.02

13.

026

3.03

13.

035

3.04

13.

043

3.04

93.

058

3.24

33.

255

3.26

13.

273

3.28

53.

287

3.29

13.

302

3.79

14.

247

4.26

45.

260

5.27

45.

289

6.83

16.

836

6.84

86.

853

7.11

47.

115

7.11

77.

121

7.13

27.

136

7.13

77.

286

7.28

87.

289

7.29

17.

293

7.29

47.

296

7.30

47.

306

7.30

87.

309

7.31

17.

312

7.71

97.

724

7.73

57.

740

MeO

O

5i

NHTs

-100102030405060708090100110120130140150160170180190f1 (ppm)

21.5

6623

.904

28.9

05

42.1

13

55.2

97

66.9

68

77.9

38

113.

902

127.

141

127.

326

129.

698

135.

340

137.

080

143.

233

159.

088

(5j) (2S)-1-[1-(4-Methoxyphenyl)ethoxy]-3-methylbutan-2-tosylamine

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

6.30

3.00

1.51

3.23

1.14

1.14

1.20

3.23

1.46

1.25

2.01

2.05

1.08

1.14

1.08

1.10

0.70

70.

724

0.80

80.

813

0.81

90.

825

0.83

00.

836

1.25

51.

266

1.27

11.

282

1.78

41.

814

1.83

11.

848

1.86

51.

887

1.90

41.

920

1.93

72.

355

2.39

72.

858

2.87

12.

881

2.89

22.

904

2.91

52.

971

2.98

22.

989

2.99

53.

002

3.01

03.

019

3.09

33.

102

3.11

73.

126

3.15

43.

164

3.17

83.

187

3.75

93.

786

3.99

44.

011

4.10

04.

116

4.13

24.

864

4.88

64.

929

4.95

16.

796

6.80

36.

818

6.82

47.

031

7.03

47.

052

7.05

67.

134

7.15

67.

239

7.24

07.

260

7.59

77.

617

7.72

47.

745

MeO

O

5j

NHTs

-100102030405060708090100110120130140150160170180190f1 (ppm)

18.3

2918

.728

18.9

8119

.105

21.4

3021

.470

23.5

2323

.630

29.7

6829

.806

55.1

9755

.223

58.7

7958

.993

67.2

3767

.296

77.8

8878

.067

113.

732

113.

752

126.

970

127.

027

127.

238

127.

271

129.

391

129.

456

135.

162

135.

175

138.

063

138.

407

142.

820

143.

021

159.

018

(6) 1,1’-(Oxydiethylidene)bis[4-methoxybenzene]

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

5.78

1.85

1.68

5.67

2.00

0.70

1.20

3.64

4.80

1.33

81.

354

1.42

11.

437

3.77

83.

812

4.15

64.

172

4.18

84.

205

4.43

84.

454

4.47

04.

486

6.81

46.

816

6.83

66.

838

6.87

76.

880

6.89

96.

902

7.17

97.

181

7.18

47.

185

7.18

77.

187

7.19

07.

201

7.20

37.

206

7.20

77.

208

7.20

9

MeO

O

6

OMe

-100102030405060708090100110120130140150160170180190f1 (ppm)

22.7

7024

.661

55.2

1455

.224

73.6

9373

.739

113.

589

113.

778

127.

434

127.

494

136.

154

136.

425

158.

715

158.

903

5-[1-(4-methoxyphenyl)ethoxy]pentan-2-ol (7a) and 4-[1-(4-methoxyphenyl)ethoxy]pentan-1-ol (7b)

-1.0-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)

0.37

0.52

2.43

0.75

2.95

2.89

2.09

0.73

0.66

2.07

0.24

0.35

0.41

0.90

3.17

0.57

1.00

0.38

2.16

1.88

1.02

51.

041

1.13

21.

148

1.16

81.

184

1.39

31.

404

1.40

91.

417

1.41

91.

420

1.43

31.

435

1.43

71.

450

1.45

81.

468

1.47

41.

476

1.47

81.

483

1.48

51.

495

1.56

31.

573

1.58

11.

587

1.59

11.

596

1.60

11.

611

1.62

11.

635

1.63

91.

652

1.65

71.

669

3.27

93.

280

3.28

33.

295

3.29

83.

310

3.31

23.

325

3.76

33.

778

3.77

93.

782

3.80

04.

347

4.35

34.

363

4.36

96.

867

6.87

26.

884

6.88

87.

214

7.23

57.

237

MeO

O

7aOH

MeO

O

7b

OH

0102030405060708090100110120130140150160170180f1 (ppm)

18.8

4020

.491

23.3

5523

.799

23.8

9523

.962

24.3

8126

.389

26.6

9028

.298

28.6

0032

.468

34.0

9836

.652

36.9

35

55.1

8562

.905

62.9

7767

.630

67.7

8468

.479

68.6

7670

.977

72.6

0973

.948

75.1

4877

.729

113.

646

113.

734

127.

327

127.

673

135.

587

158.

932

(8) 1-methoxy-4-[1-(2-methoxyethoxy)ethyl]benzene

O OMe

MeO 8

(9) 3-[1-(4-Methoxyphenyl)ethyl]-1H-indole

MeO 11

HN

(10a) 1-{[bis(4-methoxyphenyl)methoxy](4-methoxyphenyl)methyl}-4-methoxybenzene

MeO

O

OMe

OMe

OMe

10a

(10b) 1-{[bis(4-fluorophenyl) methoxy](4-fluorophenyl)methyl}-4-fluorobenzene

F

O

F

F

F

10b

download fileview on ChemRxivSecOH_SI.pdf (4.18 MiB)