template for electronic submission to acs...

Template for Electronic Submission to ACS Journals

A transition-metal-free access to heteroaromatic-fused 4-tetralones by the oxidative ring expansion of the cyclobutanol moiety

Philipp Natho, Lewis A. T. Allen, Andrew J. P. White & Philip J. Parsons*

Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, W12 0BZ, London, U.K.

ABSTRACT: Advances in the transition-metal-free cyclobutanol ring expansion to 4-tetralones under NBS-mediation are described. We have expanded the scope of this ring expansion methodology and investigated the effect substituents on the aromatic ring, and the cyclobutanol moiety, have on the outcome of the reaction. Limitations with certain substituents on the cyclobutanol moiety are also described. Further experimental evidence to support our mechanistic understanding is disclosed and we now preclude the suggested involvement of a primary radical for this transformation.

PAGE 2

Introduction

The benzofuran motif fused to a 4-tetralone ring system can have significant biological importance; for example members of the Ribisin family, Karnatakafurans A and B and Fortuneanoside K have shown activity in tyrosinase inhibition, stimulation of neurite outgrowth of NGF-mediated PC12-cells, antimalarial and antibacterial properties (Figure 1).1-3 The 4-tetralone motif, when fused to an indole ring can also show significant biological activity. The drug Alectinib, used to treat non-small-cell lung cancer, is an example of this framework.4

Figure 1. Natural products and pharmaceutically important molecules containing the 4-tetralone motif.

The 3,4-dihydrodibenzo[b,d]furan-1(2H)one motif (1) can be synthesized through an intramolecular Friedel-Crafts cyclization of an acid chloride containing chain onto the benzofuran core. Alternatively, the synthesis of the aforementioned core 1 can be achieved by means of a tandem cross-coupling/cyclization sequence of two cyclic fragments (Scheme 1).

Scheme 1. Previously developed methodologies for the construction of 3,4-dihydrodibenzo[b,d]furan-1(2H)ones.

The most prominent route for the first class of 4-tetralone preparations is the Haworth protocol, which includes a series of Friedel-Crafts acylation and reduction steps and can yield 1-tetralones or 4-tetralones, depending on the regioselectivity of the first acylation.5 It has been demonstrated by Aubé and co-workers, that the intramolecular acylation of acyl chlorides 2 can be achieved without the use of metal-based Lewis acids. Instead, the reaction can be promoted by 1,1,1,3,3,3-hexafluoro-2-propanol.6

The development of protocols utilizing a tandem cross-coupling/cyclization approach for the synthesis of heteroaromatic tetralones is more prevalent. In 2000, Hendrickson et al. demonstrated a two-component reaction between a sulfoxide-substituted cyclohexenone and a phenol to generate benzofurans, without the use of transition metals.7 The 4-tetralone could further be accessed from 1,3-cyclohexanediones and a dihalobenzene under copper catalysis (Beifuss, 2012) or the same 1,3-diketone and an O-arylhydroxylamine under gold/silver dual catalysis (Liu, 2010).8,9 Both of these transition metal-catalyzed processes, however, appear to be limited to the formation of tetralones fused to benzofurans. 4-Tetralone 1 can also be formed in low yield (25%) with iodonium ylides in the presence of cesium fluoride (Li, 2008).10 Ma (2005) has utilized a copper-catalyzed cross-coupling, followed by an intramolecular Heck-reaction to yield the desired tetralone structure 1 in 49% over two steps.11 Furthermore, most recently Shang et al. have developed a protocol to access substituted 4-tetralone structures under rhodium/silver dual catalysis from the corresponding 2-diazo-1,3-diketones.12

A similar cross-coupling/cyclization approach has not yet been utilized for the synthesis of the regioisomeric 1-tetralones 6 or 8 (Scheme 2). These motifs can be accessed by Friedel-Crafts acylation sequences or through the oxidative cyclobutanol ring expansion of 5 and 7 respectively. In 2001, Uemura first described the palladium-catalyzed oxidative expansion of tertiary cyclobutanol moieties onto aromatic rings under an oxygen atmosphere (Scheme 2).13

Zhu’s extension of this methodology was also shown to be effective for various heteroaromatic rings using substoichiometric quantities of silver nitrate and potassium persulphate as the co-oxidant (Scheme 2).14 Peng et al. observed 1-tetralones 6 and 8 in up to 49% yield when the corresponding cyclobutanols (5 & 7) were treated with hypervalent iodine and trimethylsilyl trifluoromethanesulfonate.15

In 2018, Gong’s group further improved on Zhu’s procedure, generating similar 1-tetralones in as little as 30 seconds reaction time with the use of an excess of ceric ammonium nitrate (Scheme 2).16

Scheme 2. Oxidative ring expansion of cyclobutanols to 1-tetralones.

In contrast to the previously described oxidative ring expansions to 1-tetralones, our group has recently shown that the regioisomeric 4-tetralones fused to heteroaromatics can be accessed regioselectively through oxidative expansion of the same cyclobutanol starting materials. We had demonstrated that treatment of heteroaromatic-substituted cyclobutanols with N-bromosuccinimide (NBS) in acetonitrile yielded the desired 4-tetralones (Scheme 3).17

Scheme 3. Oxidative ring expansion of cyclobutanols to 4-tetralones developed in our group.

We would now like to describe advances in the scope and limitations of our methodology to convert cyclobutanols to 4-tetralones, as well as supply additional information on the mechanism of this transformation.

Results and Discussion

After optimization of the reaction conditions and demonstration of a small set of examples in our previous communication, we have now turned our attention to more complex fused and substituted tetralones, containing synthetic handles for further synthetic manipulation, which could act as building blocks with pharmaceutical application.17

An extension to the example scope is presented in Table 1.

Table 1. Scope evaluation of the NBS-mediated cyclobutanol ring expansion.a

entry

cyclobutanol

tetralone

reaction time

yield %

Unsubstituted tetralone examples

1

3 hrs

63b

2

30 min

13

3

4 hrs

49c

4

10 min

52

5

5 min

40

6

10 min

20

7

5 min

23

8

10 min

37

9

10 min

29

10

3 min

30

11

3.5 hrs

48

Monosubstituted tetralone examples

12

15 min

40

13

15 min

25

14

15 min

38

15

2 min

29

16

2 min

20

17

--

--

--

Disubstituted tetralone examples

18

10 min

39

19

10 min

43

20

2 min

46

21

2 min

35

22

2 hrs

12

23

30 min

19

24

30 min

29

25

--

--

--

Trisubstituted tetralone example

26

1.5 hrs

21

a Conditions: cyclobutanol (1.0 equiv.), NBS (1.15 equiv.), MeCN (0.05 – 0.1 M), 0 °C to rt. bUpon repeats on larger scales reduced yields of 46% were observed for this transformation in our hands cThis reaction was also performed at a 1.5 mmol scale to yield the tetralone in 53% yield.

We began our studies with the preparation of cyclobutanols 13 to 23 containing various substituents on the aromatic ring to investigate the effect these would have on the outcome and rate of the reaction. The indole ring system was chosen for this study due to the commercial availability of a wide range of substituted indoles, as well as their importance to the chemical industry.

Indole derivatives containing weakly activating alkyl groups (Table 1, Entry 5) 13 expand rapidly and with yields comparable to the unsubstituted example (Table 1, Entry 4). Strongly activating groups, such as methoxy 15 and benzyloxy 17 substituents (Table 1, Entry 6 & 7) appear to hinder the progress of the reaction to the desired tetralones 16 and 18 and reduce the observed yields drastically compared to the unsubstituted example. The tetralone is the major isolable compound in these reactions and in the case of indole 15, the 4-brominated product was isolated in a yield of 4%, together with large amounts of decomposition. The extremely rapid expansion rates, however, enable a high throughput of material. The same retarding effect was also observed on the 5-methoxy benzofuran derivative 9 (Table 1, Entry 2), for which the yield of the tetralone 10 was reduced to 13%. It is likely that strongly activating groups activate the ortho-positions of the substituent on the aromatic ring, hindering the initiation of the reaction. Despite the low yields, full consumption of the starting material is observed in each case and the regioisomeric 1-tetralone is not formed.

Additionally, we noted that when one or more halogen substituents were added to the indole unit bearing the cyclobutanol moiety (Table 1, Entry 8, 9 & 10), a very rapid ring expansion was observed as well. Successful ring expansion of substituent-containing indoles provides tetralones with useful handles for further synthetic manipulation. The structure of monofluorinated 4-tetralone 20 was confirmed by X-ray crystallography (see Supporting Information).

Further to the addition of substituents on the aromatic ring, we have decided to extend this work to examples with larger rings fused to the four-membered ring (Table 1, Entry 20 & 21). Due to the presence of 6,6,5,6-fused tetracycles in some steroid skeleta (c.f. veratramine and cyclopamine), we prepared the bicyclo4.2.0octan-7-one and the appropriate cyclobutanols 42 and 44.18 These expanded as expected under NBS-mediation to the desired ,-substituted fused tetralones 43 and 45 in 46% and 35% yield. This provides access to the skeleton of heteroaromatic derivatives of the aforementioned steroids in a short and efficient synthetic sequence.

Finally, we elected to prepare heteroatom-substituted cyclobutanol derivative 52. 2,3-Diethoxycyclobutanone was prepared by a procedure by Scheeren and co-workers.19 The corresponding alcohol 52 was treated with NBS in acetonitrile (Table 1, Entry 25). However, to our surprise, none of the expected 4-tetralone was formed. Instead the -keto ester 55, resulting from a fragmentation reaction, was isolated as the major product (Scheme 4).

Scheme 4. NBS-Mediated fragmentation of cyclobutanol 52 to -keto ester 55

Intrigued by the outcome of this reaction, 3-ethoxy substituted cyclobutanol 37 was prepared through the addition of lithiated benzofuran. Upon treatment of this example with NBS, however, no conversion was detected, even after prolonged reaction times (Table 1, Entry 17). It is suggested that the ethoxy group on the 3-position of the cyclobutanol inhibits the reaction.

During review of our previous communication, a mechanism was suggested to us based upon previously published mechanisms by Zhu et al. for related oxidative transformations of cyclobutanol rings.14,20,21 Key intermediates in this suggested mechanism are the hypobromite 56, as well as the primary radical 58, eventually rearranging to the 4-tetralone through a spirocyclic intermediate 59 (Scheme 5).

Scheme 5. Previously proposed mechanism based on published mechanisms.

The formation of the hypobromite intermediate 56 would require the free tertiary alcohol. It was therefore suggested that protection of the tertiary alcohol as a silyl ether 61 should prevent the rearrangement to the 4-tetralone, since the alcohol is not available for the formation of the hypobromite. Silyl protection of the alcohol as the TES-ether 61 was achieved in 77% yield, which was then subjected to our ring expansion conditions (Scheme 6). To our delight we found that the TES-ether 61 rearranged to the tetralone 6 in 46% isolated yield. The free alcohol was not observed on TLC or the 1H-NMR of the crude material. Further to the experimental evidence, hypohalite esters of alcohols have previously only been formed through mercury- or silver-salt mediation.22-27 Due to the absence of transition metals in our ring-expansion reaction and the successful conversion to the desired 4-tetralone with the TES-ether we deduce that the formation of the hypobromite ester as a reactive intermediate is unlikely.

Scheme 6. NBS-mediated oxidative ring expansion of TES-ether 61.

Zhu and Gong propose the intermediacy of the primary radical 58 for their known metal-catalyzed cyclobutanol ring expansions to 1-tetralones.14,16 This primary radical was subsequently suggested to be present as an intermediate in our NBS-mediated ring expansion. In order to test this hypothesis, we aimed to generate the primary radical 58 from the alkyl bromide 65 using tributyltin hydride (Scheme 7). The known route to 65 by oxidation and halogenation of cyclobutanol 5 is very low-yielding and a more scalable synthesis was required.28

Synthesis of alkyl bromide 65 through lithiation or Friedel-Crafts acylation conditions with 4-bromobutyroyl chloride and benzofuran proved to be fruitless. A successful three-step route shown in Scheme 8 was devised instead. Commercially available ester 62 was reduced with DIBAL-H and the obtained aldehyde 63 added to lithiated 2,3-benzofuran to obtain alcohol 64 in 57% yield over two steps. Oxidation of the alcohol with Dess-Martin periodinane yielded the desired ketone 65 in 81% yield on a gram scale.

Bromoketone 65 was subsequently treated with tributyltin hydride and AIBN in benzene heated to reflux (Scheme 7). Instead of intramolecular cyclisation, however, a clean conversion to the reduced ketone 66 was observed even at high dilution. Whilst this confirmed the successful generation of the primary radical, no traces of tetralone 6 were observed. This was determined by comparison of the 1H-NMR of the crude material (1H-NMR in the Supplementary Information) with those of previously synthesized 1- and 4-tetralones. Based on this finding it is unlikely that the primary radical is an intermediate in the mechanism, as the extent of intramolecular cyclisation should be appreciable at high dilution, compared to intermolecular hydrogen abstraction.

Scheme 7. Synthesis of bromoketone 65 and generation of primary radical.

To further probe the involvement of a radical at the chain terminal we decided to install a cyclopropyl group on the cyclobutanone as a radical probe.29-31 The required cyclobutanone was synthesized through a Johnson-Corey-Chaykovsky epoxidation and subsequent acid-catalyzed rearrangement to the 2-substituted cyclobutanone.32 Addition of lithiated benzofuran to the aforementioned cyclobutanone yielded the desired alcohol 33 in 67% yield. Upon treatment of alcohol 33 with NBS in acetonitrile, formation of the radical at the terminal containing the cyclopropyl substituent should be observed according to the mechanism shown in Scheme 9. Radical formation at this position to yield intermediate 68 could reversibly open the three-membered ring to yield alkenes 69 and 70 as a consequence of the relief of ring-strain (Scheme 8).33 Due to the high rate constants (108 s-1 at 37 °C)30 the radical-mediated ring opening of cyclopropylalkyl derivatives should supersede the rate of rearrangement to the observed tetralones. Formation of alkenes 69 and 70 would confirm the intermediacy of radical 68.

Scheme 8. Proposed cyclopropyl-ring opening upon formation of the secondary radical.

Alkenes 69 & 70 were prepared as analytical standards by addition of 2-lithiated benzofuran to the respective aldehyde, followed by oxidation of the resulting alcohol with Dess-Martin periodinane. Cyclobutanol 33 (Table 1, Entry 15) was exposed to our known ring expansion conditions and the crude material was subsequently compared to analytically pure samples of alkenes 69 and 70 by 1H-NMR. Neither alkene could be identified in the crude material. The desired 4-tetralone was formed as expected in 29% yield. Analogous to this example, the benzothiophene equivalent 35 expanded in 20% yield (Table 1, Entry 16). Based on this experimental evidence we believe it is unlikely that the radical at the chain terminal is a major intermediate in the prevailing pathway for this rearrangement.

As an alternative initiation step we had previously suggested that an iminyl radical, formed through reaction of bromine radical with acetonitrile, could add to the 3-position of benzofuran. This was suggested to account for the specificity of this reaction for nitrile-containing solvents. Following single electron transfer (SET) to the succinimide radical a tertiary carbocation is formed, which initiates the migration of the carbon with the highest migratory aptitude to a spirocycle. Formation and subsequent migration of the acyl group would then displace the acetonitrile and bromide anion, forming the 4-tetralone after aromatization.17

In order to evaluate the initiation step, we reacted benzofuran with NBS in acetonitrile, which gave quantitative recovery of starting material even after 12 hrs, which we attributed to the highly reversible nature of radical addition of bromine radicals to the double bond in the furan unit (Scheme 9). We then further reacted NBS in acetonitrile with 2-methylbenzofuran which afforded a 5:1 mixture of the 3-brominated material and starting material after 3 hrs. The methyl group will stabilize a neighboring radical, and hence after electron transfer, the resulting cation will cause loss of the neighboring proton to afford the 3-brominated material. This we ascribe to the longer lifetime of the tertiary radical over the secondary radical formed in the first case.

Scheme 9. Bromination of benzofuran and 2-methylbenzofuran in the NBS/MeCN system.

When the tertiary alcohol 71 was reacted with NBS in acetonitrile we isolated a 1:1 mixture of the 3-brominated material 72, together with the highly unstable intermediate of a Ritter reaction 73 (Scheme 10) (1H-NMR and 13C-NMR spectra of the mixture can be found in the Supplementary Information), which decomposed upon treatment with silica gel in CDCl3. Products of this type were previously suggested by Bellucci et al. when alkenes are treated with NBS in acetonitrile and have been subject to further synthetic investigation.34-36 This nicely demonstrated that in acetonitrile the tertiary cation between oxygen and the alcohol moiety is stabilized by the formation of an acetonitrile adduct, which we now also suggest as part of our ring expansion reaction. This observation also offers an explanation for the observation that our recently discovered ring expansion only occurs successfully in nitrile-containing solvents.

Scheme 10. Formation of Ritter adduct as a stabilizing intermediate in the bromination of 71.

It now appears instead of an iminyl radical attacking the benzofuran unit it is the bromine radical, which attacks the benzofuran unit (React-IR showed no presence of an iminyl radical when NBS was added to acetonitrile). Furthermore, we found that the reaction is inhibited by TEMPO, indicating a radical mechanism. We can also rule out a comment made by another referee, that this reaction involves the migration of a ketone hydrate. We have conducted the reaction under strictly anhydrous conditions and obtained exactly the same product 6. When the reaction was conducted in the presence of various amounts of water, the desired product was not formed, but instead a multicomponent mixture was obtained.

Based on these data, our revised mechanism is shown in Scheme 11. We believe the reaction is initiated by attack of a bromine radical to the benzofuran, forming a stabilized radical 75. This will undergo single-electron transfer to the succinimide radical to form the cation 76, which is stabilized by the formation of the Ritter adduct 77. This allows the migration of the carbon with the highest migratory aptitude to the spirocycle 78, in which the carbonyl group has the necessary anti-relationship to the bromine to allow further migration, eventually leading to the 4-tetralone 79 after aromatization.

Scheme 11. Revised proposed mechanism for the formation of 4-tetralones from cyclobutanols.

The suggested sequence of initial migration of the carbon with the highest migratory aptitude, followed by migration of the carbonyl group, was supported with the trisubstituted cyclobutanone 7-phenylbicyclo[3.2.0]heptan-6-one, which was synthesized according to Ghosez’s procedure.18 The cyclobutanol 53 was prepared by addition of lithiated benzofuran to the ketone in 51% yield (Table 1, Entry 26). The carbon containing the phenyl group now possesses the highest migratory aptitude and should migrate first to form the spirocyclic intermediate, followed by 1,2-migration of the carbonyl group to yield the ,-fused 4-tetralone with the phenyl substituent in the -position. This proposal was confirmed experimentally with the expected product 54 being isolated in 21% combined yield as scrambling of the stereochemistry at the doubly benzylic position was observed. The substitution pattern was confirmed through HMBC analysis. This is in contrast to the expected ,-fused tetracycles obtained when R1=H, as the carbon containing the alkyl group has a larger migratory aptitude than the methylene group (Table 1, Entry 18 – 21).

Conclusion

We have developed a useful and efficient synthesis of 4-tetralones, achieved through the NBS-mediated ring expansion reactions of cyclobutanols. This work has provided a more direct approach to the target molecules than has existed hitherto. We have also laid the foundation stone for further work in this area, which includes the synthesis of the biologically important molecules Ribisin A, Karnatakafurans A and B and Fortuneanoside K.

Experimental Section

General methods

Reagents were acquired from commercial suppliers and dry solvents obtained from Acros Organics® and used without further purification, unless otherwise stated. Reactions were performed under an N2-atmosphere and in oven-dried glassware equipped with a magnetic follower, which were dried at 130 °C for 12 hrs prior to use. The concentration of n-butyllithium was determined by titration against diphenylacetic acid before use. Progress of reactions was followed by Thin Layer Chromatography (TLC) on aluminium backed silica-gel-coated plates, precoated with fluorescent indicator (60 F254 Merck). TLC plates were visualized using a Mineralight lamp Multiband UV 254/365 nm and stained with acidic vanillin solution. Flash column chromatography was performed using silica gel 60 Å (VWR, particle size 40 – 63 m) using head pressure achieved by the use of head bellows. All 1H and 13C NMR spectra were recorded at 400 MHz and 101 MHz respectively on a Bruker AV-400 at ambient temperature in deuterated chloroform. The acquired NMR spectra were referenced to the residual solvent peak (CDCl3: δ = 7.26 for 1H NMR and δ = 77.0 for 13C NMR). Chemical shifts are reported in parts per million (ppm) and to two decimal places for 1H NMR and to one decimal place for 13C NMR. Spectral peak splittings are assigned as singlet (s), doublet (d), triplet (t), quartet (q), pentet (p) or multiplet (m) or a combination thereof. Coupling constants (J) are reported in Hz to the nearest 0.1 Hz. IR spectra were recorded on an Agilent Cary 630 Fourier Transform Infrared Spectrometer and reported in cm-1. Mass spectra were measured by the Imperial College Mass Spectrometry service using Micromass AutoSpec Premier, Magnetic Sector or Waters LCT Premier TOF instruments. Samples were ionized by means of electrospray ionization (ES) or electron ionization (EI). Melting points are uncorrected and were measured using a Gallenkamp melting point apparatus. X-Ray diffraction data was obtained from the Imperial College X-ray crystallography facility.

Synthesis of cyclobutanols

General procedures

1) Tosyl protection of indole derivatives

Following a procedure by Wang and co-workers.37 To a solution of indole derivative (1 equiv.) in acetonitrile (0.2 M) at 0 °C was added sodium hydride (60% dispersion in mineral oil, 1.4 equiv.) and the resulting suspension was stirred for 10 mins. 4-Toluenesulfonyl chloride (1.1 equiv.) was added in one portion and the reaction mixture was allowed to warm to room temperature and stirred overnight before it was quenched by the slow addition of saturated aqueous ammonium chloride solution (15 mL). The aqueous layer was separated and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with 10% aqueous sodium hydroxide solution (3 x 15 mL), saturated aqueous sodium chloride solution (15 mL), dried over MgSO4 and concentrated to yield the tosyl-protected indole which was used without further purification.

2) Synthesis of cyclobutanols with benzofuran

To a solution of 2,3-benzofuran (1.2 equiv.) in Et2O (0.2 M) cooled to 78 °C was added n-butyllithium solution (1.2 equiv.) as drops at a rate to maintain the internal temperature below 70 °C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hrs, before it was again cooled down to 78 °C. A solution of desired cyclobutanone (1 equiv.) in Et2O (0.25 M) was added as drops and the reaction mixture was stirred at 78 °C until completion of the reaction was observed by TLC (allowing the reaction to slowly warm to room temperature). The reaction was quenched by addition of saturated ammonium chloride solution (15 mL) at 0 °C and the aqueous phase was separated and extracted with diethyl ether (3 x 30 mL). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over MgSO4 and concentrated. Purification through flash column chromatography (Et2O/pentane) yielded the desired alcohols.

3) Synthesis of cyclobutanols with tosylated indole derivatives

To a solution of tosylated indole derivative (1.5 equiv.) in THF (0.2 – 0.25 M) cooled to 78 °C was added n-butyllithium solution (1.5 equiv.). The reaction mixture was stirred at 78 °C for 1 hr and 15 mins, before cyclobutanone (1 equiv.) was added as drops at 78 °C and the reaction stirred at the same temperature until completion of the reaction was observed by TLC. The reaction was quenched by addition with saturated aqueous ammonium chloride solution (15 mL) at 0 °C and the aqueous phase extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (15 mL), dried over MgSO4 and purified through flash column chromatography (Et2O/pentane) to yield the pure cyclobutanols.

4) Synthesis of cyclobutanols with benzothiophene

To a solution of thiophene (1.2 equiv.) in THF (0.2 – 0.25 M) cooled to 78 °C was added n-butyllithium solution (1.2 equiv.). The reaction mixture was stirred at 78 °C for 20 mins, before being allowed to warm to room temperature and stirred for a further 1 hr at the same temperature. Cyclobutanone (1 equiv.) was then added as drops at 78 °C and the reaction stirred at the same temperature until completion of the reaction was observed by TLC. The reaction was quenched by addition with saturated aqueous ammonium chloride solution (15 mL) at 78 °C and then allowed to warm to room temperature. The aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (15 mL), dried over MgSO4 and purified through flash column chromatography (Et2O/pentane) to yield the pure cyclobutanols.

1-(Benzofuran-2-yl)cyclobutan-1-ol, 5

For a detailed synthetic procedure, see our initial communication.17

White solid (1.62 g, 8.61 mmol, 78%); purified through flash column chromatography (20% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.56 (1H, d, J = 8.3 Hz), 7.48 (1H, dq, J = 8.3, 0.9 Hz), 7.34 – 7.18 (2H, m), 6.68 (1H, d, J=0.9 Hz), 2.72 – 2.56 (2H, tdd, J = 8.6, 4.2, 3.0 Hz), 2.44 (1H, s), 2.52 – 2.30 (2H, m), 1.96 (1H, dtt, J = 11.3, 9.8, 4.2 Hz), 1.79 (1H, dp, J = 11.3, 8.7 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 160.5, 154.9, 128.0, 124.0, 122.6, 120.9, 111.1, 101.3, 72.5, 35.4, 12.7; IR (neat, v cm-1) = 3325, 2941, 2872, 1454, 1249; HRMS (FTMS + p) m/z calculated for C12H11O (M-OH)+ 171.0804, found 171.0805; Melting point 53.2 – 54.4 °C. Data in accordance with previous reports.15

1-(5-Methoxybenzofuran-2-yl)cyclobutan-1-ol, 9

Synthesized through General procedure (2)

White solid (600 mg, 2.75 mmol, 82%); purified through flash column chromatography (30% Et2O/pentane to 40% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.35 (1H, dd, J=8.9, 0.8 Hz), 7.01 (1H, d, J=2.6 Hz), 6.87 (1H, dd, J=8.9, 2.6 Hz), 6.61 (1H, d, J=0.9 Hz), 3.84 (3H, s), 2.61 (2H, m), 2.40 (3H, m), 1.96 (1H, ddt, J=11.4, 9.7, 4.2 Hz), 1.78 (1H, dp, J=11.2, 8.7 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 161.6, 156.0, 150.0, 128.8, 112.8, 111.6, 103.7, 101.6, 72.8, 56.0, 35.6, 12.8; IR (neat, v cm-1) = 3374, 2992, 2942, 2833, 1615, 1600, 1474, 1448, 1203; HRMS (ES+) m/z calculated for C13H13O2 (M-OH)+ 201.0916, found 201.0916; Melting point 59.7 – 61.7 °C

1-(Benzo[b]thiophen-2-yl)cyclobutan-1-ol, 7


White crystalline solid (750 mg, 3.67 mmol, 98%); purified through flash column chromatography (20% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.81 (1H, d, J = 7.7 Hz), 7.73 (1H, d, J = 7.7 Hz), 7.38-7.28 (3H, m), 2.62 (2H, tdd, J = 8.6, 4.4, 2.2 Hz), 2.48 (2H, tdd, J = 9.6, 8.4, 2.9 Hz), 2.39 (1H, s), 1.99 (1H, dtt, J = 11.3, 9.4, 4.4 Hz), 1.82 (1H, dp, J = 11.2, 8.5 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 152.5, 140.1, 124.8, 124.7, 123.9, 122.9, 119.6, 75.7, 38.6, 13.3; IR (neat, v cm-1) = 3249, 2982, 2934, 1435, 1248; HRMS (EI +) m/z calculated for C12H12OS (M)+ 204.0609, found 204.0613; Melting point 47.0 – 49.5 °C. Data in accordance with previous reports.15,28

1-(1-Tosyl-1H-indol-2-yl)cyclobutan-1-ol, 11



1H NMR (400 MHz, CDCl3): δH 7.88 (1H, d, J = 7.6 Hz), 7.67 (2H, m), 7.48 (1H, m), 7.20 (4H, m), 6.74 (1H, d, J=0.8 Hz), 4.43 (1H, s), 2.67 (2H, dtd, J = 12.1, 5.7, 2.7 Hz), 2.52 (2H, ddd, J = 12.5, 9.3, 6.9 Hz), 2.32 (3H, s), 2.10 (1H, dtt, J = 11.2, 9.3, 5.8 Hz), 1.74 (1H, dtt, J = 11.0, 8.8, 7.0 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 145.7, 144.9, 137.4, 135.8, 129.8, 128.7, 126.5, 125.0, 123.8, 121.2, 114.7, 109.9, 73.1, 36.4, 21.6, 14.3; IR (neat, v cm-1) = 3398, 2986, 2939, 1597, 1451, 1327; HRMS (ES+) m/z calculated for C19H20NO3S (M+H)+ 342.1164, found 342.1148; Melting point 113.7 – 116.0 °C

1-(4-Methyl-1-tosyl-1H-indol-2-yl)cyclobutan-1-ol, 13



1H NMR (400 MHz, CDCl3): δH 7.68 (3H, m), 7.17 (2H, m), 7.12 (1H, dd, J=8.4, 7.3 Hz), 6.99 (1H, dt, J=7.3, 0.9 Hz), 6.75 (1H, d, J=0.8 Hz), 4.44 (1H, s), 2.69 (2H, dddd, J=12.3, 6.6, 5.7, 2.8 Hz), 2.53 (2H, m), 2.46 (3H, d, J=0.8 Hz), 2.32 (3H, s), 2.11 (1H, dtt, J=11.3, 9.2, 5.7 Hz), 1.75 (1H, dtt, J=11.0, 8.8, 7.0 Hz); 13C{1H} NMR (125 MHz, CDCl3): δC 145.1, 144.8, 137.2, 135.9, 130.7, 129.8, 128.1, 126.5, 125.0, 124.2, 112.2, 108.1, 73.1, 36.4, 21.5, 18.3, 14.3; IR (neat, v cm-1) = 3542, 2990, 2948, 1596, 1368, 1334, 1179, 1164, 1096; HRMS (ES –) m/z calculated for C20H20NO3S (M–H)– 354.1164, found 354.1170; Melting point 136.8 – 143.9 °C

1-(5-Methoxy-1-tosyl-1H-indol-2-yl)cyclobutan-1-ol, 15


Off-white solid (322 mg in crop 1, 80 mg in crop 2; 1.08 mmol, 76%); purified through crystallization from pentane.

1H NMR (400 MHz, CDCl3): δH 7.78 (1H, dt, J=9.1, 0.6 Hz), 7.64 (2H, m), 7.16 (2H, m), 6.92 (1H, dd, J=2.6, 0.5 Hz), 6.83 (1H, dd, J=9.1, 2.6 Hz), 6.67 (1H, d, J=0.7 Hz), 4.42 (1H, s), 3.79 (3H, s), 2.65 (2H, m), 2.50 (2H, m), 2.32 (3H, s), 2.10 (1H, dtt, J=11.5, 9.4, 5.8), 1.73 (1H, dtt, J=11.0, 8.8, 6.9 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 156.6, 146.5, 144.8, 135.8, 132.0, 129.8, 129.7, 126.4, 115.6, 113.7, 110.1, 103.6, 73.1, 55.6, 36.3, 21.6, 14.3; IR (neat, v cm-1) = 3539, 2993, 2949, 1471, 1213, 1171; HRMS (ES–) m/z calculated for C20H20NO4S (M-H)– 370.1113, found 370.1120; Melting point 134.7 – 138.0 °C

1-(5-(Benzyloxy)-1-tosyl-1H-indol-2-yl)cyclobutan-1-ol, 17



1H NMR (400 MHz, CDCl3): δH 7.79 (1H, d, J=9.1 Hz), 7.65 (2H, m), 7.39 (5H, m), 7.17 (2H, d, J=8.1 Hz), 7.00 (1H, d, J=2.6 Hz), 6.92 (1H, dd, J=9.1, 2.6 Hz), 6.66 (1H, s), 5.04 (2H, s), 4.42 (1H, s), 2.65 (2H, dtd, J=12.1, 5.5, 2.7 Hz), 2.50 (2H, dtd, J=12.4, 6.8, 2.9 Hz), 2.32 (3H, s), 2.10 (1H, dtt, J=11.2, 9.1, 5.7 Hz), 1.72 (1H, dtt, J=11.0, 8.8, 6.9 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 155.8, 146.5, 144.8, 136.9, 135.8, 132.1, 129.8, 129.7, 128.6, 128.0, 127.5, 126.5, 115.7, 114.5, 110.1, 104.9, 73.1, 70.5, 36.3, 21.6, 14.3; IR (neat, v cm-1) = 3537, 2985, 2945, 2868, 1595, 1451, 1367, 1332, 1150; HRMS (ES –) m/z calculated for C26H24NO4S (M–H) – 446.1426, found 446.1432

1-(4-Fluoro-1-tosyl-1H-indol-2-yl)cyclobutan-1-ol, 19


Brown solid (472 mg, 1.31 mmol, 93%); purified through crystallization from pentane.

1H NMR (400 MHz, CDCl3): δH 7.67 (1H, s), 7.65 (2H, d, J=8.6 Hz), 7.19 (3H, m), 6.88 (1H, ddd, J=8.9, 8.1, 0.6 Hz), 6.83 (1H, d, J=0.8 Hz), 4.35 (1H, s), 2.68 (2H, dddd, J=9.7, 8.7, 5.9, 2.8 Hz), 2.52 (2H, m), 2.34 (3H, s), 2.12 (1H, dtt, J=11.3, 9.2, 5.7 Hz), 1.75 (1H, dtt, J=11.1, 8.8, 7.0 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 155.9 (d, J=249.2 Hz), 146.0, 145.3, 139.5 (d, J=10 Hz), 135.6, 130.0, 126.6, 125.8 (d, J=7.3 Hz), 117.6 (d, J=22.6 Hz), 110.8 (d, J=4.2 Hz), 109.2 (d, J=18.3 Hz), 105.0, 73.1, 36.4, 21.6, 14.3; 19F NMR (377 MHz, CDCl3): δF –121.49; IR (neat, v cm-1) = 3555, 2986, 2950, 2937, 1591, 1485, 1367; HRMS (ES –) m/z calculated for C19H17NO3SF (M-H)– 358.0913, found 358.0904; Melting point 119.1 – 127.2 °C

1-(5-Chloro-1-tosyl-1H-indol-2-yl)cyclobutan-1-ol, 21


Colourless oil (200 mg, 0.53 mmol, 48%); purified through flash column chromatography (20% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.80 (1H, d, J=8.9 Hz), 7.66 (2H, m), 7.44 (1H, d, J=2.0 Hz), 7.18 (3H, ddd, J=8.9, 3.5, 1.5 Hz), 6.67 (1H, d, J=0.8 Hz), 4.35 (1H, s), 2.66 (2H, dddd, J=9.6, 8.6, 5.9, 2.2 Hz), 2.52 (2H, m), 2.33 (3H, s), 2.12 (1H, dtt, J=11.5, 9.3, 5.8 Hz), 1.74 (1H, dtt, J=11.1, 8.8, 6.9 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 147.2, 145.2, 135.7, 135.5, 129.9, 129.5, 126.8, 126.5, 125.1, 120.8, 115.8, 109.0, 73.0, 36.3, 21.6, 14.3; IR (neat, v cm-1) = 3545, 2988, 2948, 1595, 1444, 1369, 1336, 1165; HRMS (ES –) m/z calculated for C19H17NO3SCl (M-H)– 374.0618, found 374.0622

1-(4,6-Difluoro-1-tosyl-1H-indol-2-yl)cyclobutan-1-ol, 23


Yellow solid (340 mg, 0.90 mmol, 83%); purified through flash column chromatography (20% Et2O/pentane). Sample for X-ray crystallography was recrystallized from chloroform.

1H NMR (400 MHz, CDCl3): δH 7.69 (2H, m), 7.45 (1H, ddt, J=9.8, 1.9, 0.8 Hz), 7.23 (2H, m), 6.77 (1H, d, J=0.8 Hz), 6.70 (1H, td, J=9.4, 2.0 Hz), 4.25 (1H, s), 2.65 (2H, m), 2.51 (2H, m), 2.36 (3H, s), 2.11 (1H, dtt, J=11.5, 9.3, 5.8 Hz), 1.74 (1H, dtt, J=11.1, 8.8, 7.0 Hz); 13C{1H} NMR (125 MHz, CDCl3): δC 160.8 (dd, J=243.6, 11.4 Hz), 155.4 (dd, J=251.4, 14.5 Hz), 146.3 (d, J=4.1 Hz), 145.6, 138.9 (dd, J=14.4, 11.2 Hz), 135.4, 130.2, 126.8, 114.2 (d, J=22.0 Hz), 104.7, 99.4 (dd, J=28.2, 22.7 Hz), 98.7 (dd, J=29.4, 4.4 Hz), 73.1, 36.5, 21.8, 14.4; 19F NMR (377 MHz, CDCl3): δF –112.6 (m), –118.0 (dd, J=9.2, 4.7 Hz); IR (neat, v cm-1) = 3546, 2994, 2952, 1635, 1595, 1489, 1428, 1167, 1101; HRMS (ES –) m/z calculated for C19H16NO3SF2 (M–H) – 376.0819, found 376.0804

1,1'-(Thiophene-2,5-diyl)bis(cyclobutan-1-ol), 25

n-Butyllithium solution (1.8 M in hexanes, 14.4 mL, 26 mmol) was added as drops to a solution of freshly distilled TMEDA (3.9 mL, 26 mmol) in hexane (45 mL) at room temperature. The resulting solution stirred for 10 mins, before thiophene (1.0 mL, 13 mmol) was added as drops and the reaction mixture heated to reflux for 1 hr, before it was cooled to 0 °C and a solution of cyclobutanone (2.1 mL, 28 mmol) in THF (30 mL) was added as drops. After complete addition the reaction mixture was allowed to warm to room temperature and stirred for further 15 mins, before it was quenched by the careful addition of saturated aqueous ammonium chloride solution (40 mL) at 0 °C. The aqueous layer was separated and extracted with diethyl ether (3 x 20 mL) and the combined organic layers were sequentially washed with deionized water (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over MgSO4 and concentrated. The crude material was purified by recrystallisation from boiling dichloromethane to yield the diol 25 (815 mg, 3.63 mmol, 28%) as a brown crystalline solid.

1H NMR (400 MHz, CDCl3): δH 6.92 (2H, s), 2.53 (4H, m), 2.42 (4H, m), 2.24 (2H, s), 1.94 (2H, m), 1.74 (2H, dp, J = 11.2, 8.5 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 150.8, 122.4, 74.9, 38.4, 12.7; IR (neat, v cm-1) = 3418, 2982, 2941, 2865, 1443, 1243; HRMS (ES +) m/z calculated for C12H15OS (M-OH)+ 207.0844, found 207.0835; Melting point 112.1 – 113.1 °C

1-(Benzofuran-2-yl)-3-phenylcyclobutan-1-ol, 27


Pale yellow solid (492 mg, 1.86 mmol, 68%); purified through flash column chromatography (30% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.60 (1H, m), 7.52 (1H, dq, J = 8.3, 1.0 Hz), 7.39 – 7.28 (6H, m), 7.24 (1H, m), 6.80 (1H, d, J = 0.9 Hz), 3.29 (1H, qd, J = 9.9, 8.0 Hz), 3.09 (2H, ddt, J = 11.8, 8.0, 2.6 Hz), 2.60 (3H, ddt, J = 12.1, 9.4, 2.5 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 160.3, 155.2, 144.2, 128.5, 128.1, 126.7, 126.3, 124.4, 122.9, 121.2, 111.4, 102.1, 68.6, 43.3, 30.5; IR (neat, v cm-1) = 3234, 3023, 2984, 2935, 1450, 1239; HRMS (ES +) m/z calculated for C18H15O (M-OH)+ 247.1123, found 247.1134; Melting point 81.1 – 82.6 °C

1-(Benzo[b]thiophen-2-yl)-3-phenylcyclobutan-1-ol, 29


Faint yellow solid (553 mg, 1.97 mmol, 72%); crude material obtained as solid and washed with pentane.

1H NMR (400 MHz, CDCl3): δH 7.85 (1H, ddd, J = 7.5, 1.6, 0.7 Hz), 7.78 (1H, m), 7.43-7.20 (8H, m), 3.30 (1H, tt, J = 10.0, 8.0 Hz), 3.09 (2H, ddt, J = 11.9, 8.1, 2.6 Hz), 2.66 (2H, m), 2.49 (1H, s); 13C{1H} NMR (101 MHz, CDCl3): δC 151.5, 144.1, 139.8, 139.5, 128.5, 126.7, 126.5, 126.3, 124.5, 123.6, 122.5, 119.8, 70.9, 45.6, 30.4; IR (neat, v cm-1) = 3305, 3052, 3023, 2973, 2891, 1493, 1457, 1232; HRMS (ES +) m/z calculated for C18H15S (M-OH)+ 263.0894, found 263.0891; Melting point 90.7 – 92.0 °C

3-Phenyl-1-(1-tosyl-1H-indol-2-yl)cyclobutan-1-ol, 31


White solid (606 mg, 1.45 mmol, 53%); purified through flash column chromatography (20% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.87 (1H, m), 7.71 (2H, m), 7.53 (1H, m), 7.37-7.12 (8H, m), 6.92 (1H, d, J = 0.8 Hz), 4.68 (1H, s), 3.23 (2H, m), 3.13 (1H, m), 2.68 (2H, m), 2.33 (3H, s); 13C{1H} NMR (101 MHz, CDCl3): δC 145.2, 145.0, 144.3, 137.5, 135.8, 129.9, 128.6, 128.4, 126.7, 126.5, 126.2, 125.2, 123.9, 121.3, 114.7, 110.3, 68.8, 44.3, 31.4, 21.6; IR (neat, v cm-1) = 3547, 3055, 2991, 2947, 2916, 1597, 1446, 1362, 1170; HRMS (ES +) m/z calculated for C25H24NO3S (M+H)+ 418.1477, found 418.1483; Melting point 121.1 – 124.0 °C

1-(Benzofuran-2-yl)-2-cyclopropylcyclobutan-1-ol, 33


Yellow oil (450 mg, 1.97 mmol, 68%); purified through flash column chromatography (20% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.53 (1H, m), 7.45 (1H, dq, J=8.4, 0.9 Hz), 7.23 (2H, m), 6.61 (1H, d, J=0.9 Hz), 2.68 (1H, s), 2.55 (1H, dddd, J=12.3, 9.1, 8.0, 1.4 Hz), 2.24 (2H, m), 2.04 (1H, dtd, J=11.3, 8.7, 4.8 Hz), 1.91 (1H, m), 1.00 (1H, qt, J=8.3, 4.9 Hz), 0.53 (2H, m), 0.25 (1H, m), 0.10 (1H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 161.6, 154.9, 128.5, 123.9, 122.7, 120.9, 111.2, 101.0, 74.9, 49.1, 32.3, 20.3, 9.2, 2.6, 2.2; IR (neat, v cm-1) = 3563, 3433, 3075, 2992, 2943, 1452, 1254; HRMS (ES+ ) m/z calculated for C15H17O2 (M+H)+ 229.1229, found 229.1224

1-(Benzo[b]thiophen-2-yl)-2-cyclopropylcyclobutan-1-ol, 35



1H NMR (400 MHz, CDCl3): δH 7.80 (1H, d, J=8.3 Hz), 7.71 (1H, m), 7.31 (2H, m), 7.19 (1H, d, J=0.8 Hz), 2.72 (1H, d, J=0.7 Hz), 2.46 (1H, m), 2.38-2.18 (2H, m), 2.03 (1H, dtd, J=11.3, 8.6, 4.7 Hz), 1.91 (1H, ddt, J=11.3, 9.4, 8.0 Hz), 1.00 (1H, qt, J=8.2, 5.0 Hz), 0.54 (2H, m), 0.26 (1H, m), 0.15 (1H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 153.1, 139.9, 139.4, 124.2, 123.9, 123.4, 122.4, 118.5, 77.2, 51.9, 35.3, 20.1, 9.2, 2.5, 2.3; IR (neat, v cm-1) = 3567, 3547, 3430, 3072, 2981, 2941, 2863, 1457, 1436, 1118; HRMS (FTMS + p) m/z calculated for C15H15S (M–OH)+ 227.0889, found 227.0879

1-(Benzofuran-2-yl)-3-ethoxycyclobutan-1-ol, 37


Yellow solid (660 mg, 2.84 mmol, 65%); purified through flash column chromatography (35% Et2O/pentane to 50% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.54 (1H, ddd, J=7.5, 1.5, 0.7 Hz), 7.46 (1H, dq, J=8.2, 0.9 Hz), 7.25 (2H, m), 6.65 (1H, d, J=0.9 Hz), 3.85 (1H, p, J=6.9 Hz), 3.46 (2H, m), 3.00 (2H, m), 2.43 (2H, dddd, J=10.3, 7.0, 3.3, 2.1 Hz), 1.22 (3H, t, J=7.0 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 161.0, 155.5, 128.6, 124.8, 123.4, 121.6, 111.7, 102.2, 66.6, 65.5, 64.2, 44.7, 15.8; IR (neat, v cm-1) = 3362, 3006, 2982, 2973, 2932, 2877, 1593, 1456, 1249, 1169; HRMS (FTMS+p) m/z calculated for C14H15O2 (M-OH+H)+ 215.1067, found 215.1064; Melting point: 46.8 – 52.5 °C

6-(Benzofuran-2-yl)bicyclo[3.2.0]heptan-6-ol, 38


Brown solid (310 mg, 1.36 mmol, 62%); purified through flash column chromatography (10% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.55 (1H, m), 7.47 (1H, dq, J = 8.3, 0.9 Hz), 7.25 (2H, m), 6.64 (1H, d, J = 0.9 Hz), 3.08 (1H, m), 2.77 (1H, ddd, J = 13.0, 8.7, 3.1 Hz), 2.66 (1H, m), 2.14 (1H, m), 1.89 (3H, m), 1.58 (3H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 162.7, 155.0, 128.3, 124.0, 122.7, 121.0, 111.2, 100.7, 69.3, 48.5, 38.7, 32.6, 31.3, 26.1, 25.8; IR (neat, v cm-1) = 3400, 2947, 2868, 2851, 1452, 1251; HRMS (ES +) m/z calculated for C17H20NO2 (M+MeCN+H)+ 270.1494, found 270.1506

6-(Benzo[b]thiophen-2-yl)bicyclo[3.2.0]heptan-6-ol, 40


Light brown solid (330 mg, 1.35 mmol, 60%); purified through flash column chromatography (10% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.80 (1H, m), 7.72 (1H, dt, J = 8.1, 0.9 Hz), 7.39 – 7.23 (3H, m), 3.11 (1H, td, J = 8.6, 7.8, 3.2 Hz), 2.73 (2H, m), 2.13 (1H, m), 1.92 (3H, m), 1.59 (4H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 155.1, 139.9, 139.4, 124.3, 124.0, 123.4, 122.4, 118.1, 71.7, 51.5, 41.9, 32.5, 30.9, 26.4, 25.7; IR (neat, v cm-1) = 3391, 3056, 2943, 2850; HRMS (ES +) m/z calculated for C15H17OS (M+H)+ 245.1000, found 245.1009; Melting point 85.5 – 86.8 °C

Bicyclo4.2.0octan-7-one

Adapted procedure by Ghosez et al.18

To a solution of dimethylacetamide (1.1 mL, 12 mmol) in dichloroethane (20 mL) cooled to –30 °C was added freshly distilled trifluoromethanesulfonic anhydride (2.4 mL, 13 mmol) as drops. The resulting suspension was allowed to stir at –30 °C for 30 mins before a solution of 2,4,6-collidine (1.9 mL, 13 mmol) and freshly distilled cyclohexene (12.4 mL, 121 mmol) in dichloroethane (10 mL) was added as drops. After complete addition the reaction mixture was heated to reflux and stirred at the same temperature overnight. The solution was then allowed to cool to room temperature, concentrated and the residue washed with Et2O (2 x 20 mL). The remaining residue was dissolved in dichloromethane (20 mL) and deionized water (20 mL) and heated to reflux for 3 hrs. The biphasic mixture was allowed to cool to room temperature and the aqueous phase extracted with dichloromethane (3 x 30 mL). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over MgSO4 and concentrated. The crude material was purified through flash column chromatography (10% Et2O/pentane) to yield the title compound (582 mg, 4.09 mmol, 34%) as a colourless oil. 1H NMR (400 MHz, CDCl3): δH 3.29 (1H, tt, J=8.9, 2.6 Hz), 3.15 (1H, ddd, J=15.9, 8.9, 2.5 Hz), 2.50 (2H, m), 2.17 (1H, ddd, J=15.3, 6.6, 2.8 Hz), 1.98 (1H, m), 1.58 – 1.45 (3H, m), 1.34 – 1.08 (3H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 210.1, 55.7, 52.2, 29.5, 22.6, 22.5, 22.4, 21.3. Data in accordance with previous reports.38

7-(Benzofuran-2-yl)bicyclo[4.2.0]octan-7-ol, 42


Yellow solid (340 mg, 1.40 mmol, 44%); purified through flash column chromatography (15% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.55 (1H, ddd, J=7.5, 1.5, 0.7 Hz), 7.47 (1H, dq, J=8.1, 0.9 Hz), 7.25 (2H, m), 6.69 (1H, d, J=0.9 Hz), 2.72 (1H, m), 2.49 (1H, ddd, J=11.1, 7.9, 4.2 Hz), 2.36 (1H, m), 2.24 (2H, m), 1.92-1.72 (3H, m), 1.59-1.38 (4H, m), 1.17 (1H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 161.5, 155.0, 128.2, 124.1, 122.7, 121.0, 111.2, 101.7, 71.1, 42.0, 36.7, 26.0, 24.5, 22.6, 21.7, 21.5; IR (neat, v cm-1) = 3521, 3426, 2924, 2850, 1446, 1227, 1156; HRMS (ES +) m/z calculated for C16H19O2 (M+H)+ 243.1385, found 243.1390; Melting point 80.8 – 81.5 °C

7-(Benzo[b]thiophen-2-yl)bicyclo[4.2.0]octan-7-ol, 44


Yellow solid (330 mg, 1.28 mmol, 79%); purified through flash column chromatography (10% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.81 (1H, m), 7.72 (1H, m), 7.32 (3H, m), 2.75 (1H, qd, J=8.4, 4.0 Hz), 2.53-2.36 (2H, m), 2.27 (1H, ddddd, J=9.9, 7.8, 5.5, 3.9, 1.9 Hz), 2.20 (1H, s), 1.94-1.68 (3H, m), 1.63-1.39 (4H, m), 1.19 (1H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 153.0, 139.6, 124.3, 124.2, 123.5, 122.4, 119.4, 73.5, 44.5, 39.3, 26.0, 24.5, 22.6, 21.9, 21.8; IR (neat, v cm-1) = 3381, 3055, 2969, 2919, 2845, 1457, 1435, 1145; HRMS (ES +) m/z calculated for C16H17S (M-OH)+ 241.1051, found 241.1047; Melting point 72.1 – 75.8 °C

trans-1-(Benzofuran-2-yl)-3-((benzyloxy)methyl)-2-phenylcyclobutan-1-ol, 46



1H NMR (400 MHz, CDCl3): δH Some peaks are doubled due to the presence of minor quantities of the cis-diastereomer. 7.53 (2H, m), 7.41-7.17 (12H, m), 6.62 and 6.61 (1H, d, J = 0.9 Hz), 4.58 and 4.52 (2H, s), 4.00 (1H, d, J = 9.7 Hz), 3.72 and 3.69 (2H, dd, J = 5.8, 1.8 Hz), 3.33 (1H, tdt, J = 9.4, 8.3, 5.7 Hz), 2.60 (1H, ddd, J = 12.0, 9.3, 1.4 Hz), 2.41 (1H, ddd, J =11.9, 8.4, 0.7 Hz), 2.05 and 2.04 (1H, d, J = 1.4 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 160.6, 155.0, 138.5, 136.3, 128.6, 128.5, 128.3, 128.3, 127.5, 127.4, 127.2, 123.9, 122.8, 121.0, 111.2, 101.8, 73.6, 73.0, 72.9, 52.0, 35.2, 34.0; IR (neat, v cm-1) = 3531, 3437, 2856, 1496, 1454, 1253; HRMS (ES +) m/z calculated for C26H25O3 (M+H)+ 385.1804, found 385.1800

trans-1-(Benzo[b]thiophen-2-yl)-3-((benzyloxy)methyl)-2-phenylcyclobutan-1-ol, 48


Colourless oil (402 mg, 1.00 mmol, 45%); purified through flash column chromatography (15% Et2O/pentane to 30% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.81 (1H, dd, J = 8.0, 1.1 Hz), 7.72 (1H, m), 7.38-7.22 (13H, m), 4.57 (2H, s), 3.95 (1H, d, J = 9.6 Hz), 3.68 (2H, dd, J = 5.2, 1.5 Hz), 3.28 (1H, m), 2.51 (2H, qd, J = 12.0, 8.8 Hz), 2.12 (1H, d, J = 1.2 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 152.8, 140.2, 139.7, 138.7, 136.5, 128.9, 128.5, 127.7, 127.6, 127.5, 124.5, 124.2, 123.6, 122.5, 119.3, 75.8, 73.3, 72.6, 55.0, 38.9, 34.1; IR (neat, v cm-1) = 3537, 3415, 3059, 3027, 2853, 1495; HRMS (ES +) m/z calculated for C26H25O2S (M+H)+ 401.1575, found 401.1582

trans-3-((Benzyloxy)methyl)-2-phenyl-1-(1-tosyl-1H-indol-2-yl)cyclobutan-1-ol, 50



1H NMR (400 MHz, CDCl3): Some peaks are doubled due to the presence of minor quantities of the cis-diastereomer. δH 7.94 (1H, m), 7.68 (2H, m), 7.56 and 7.52 (2H, m), 7.47 (1H, m), 7.38 (2H, m), 7.32 – 7.27 (4H, m), 7.26 – 7.14 (6H, m), 6.82 and 6.79 (1H, d, J = 0.8 Hz), 4.51 and 4.45 (2H, s), 4.07 (1H, s), 3.99 (1H, d, J = 9.5 Hz), 3.61 (2H, dd, J = 5.4, 3.6 Hz), 3.25 (1H, m), 2.79 (1H, dd, J = 12.0, 8.3 Hz), 2.38 (1H, m), 2.31 and 2.29 (3H, s); 13C{1H} NMR (101 MHz, CDCl3): Some peaks are doubled due to the presence of minor quantities of the cis-diastereomer. δC 146.3, 144.8, 138.6, 138.2, 137.2, 135.6, 129.7, 129.2, 128.8 and 128.7, 128.4 and 128.3, 128.2, 127.5, 127.4, 126.9, 126.7, 125.0, 123.8, 121.2, 114.9, 110.3, 73.3, 73.0, 72.6, 51.4, 38.8, 36.8, 21.6; IR (neat, v cm-1) = 3529, 3058, 3025, 2941, 2848, 1450, 1167, 1087; HRMS (ES –) m/z calculated for C33H30NO4S (M–H)– 536.1896, found 536.1904; Melting point 53.2 – 55.0 °C

1-(Benzofuran-2-yl)-trans-2,3-diethoxycyclobutan-1-ol, 52



1H NMR (400 MHz, CDCl3): δH 7.54 (1H, ddd, J=7.4, 1.5, 0.7 Hz), 7.47 (1H, dq, J=8.2, 0.9 Hz), 7.24 (2H, m), 6.78 (1H, d, J=1.0 Hz), 4.09 (1H, dt, J=6.4, 1.0 Hz), 3.77 (2H, m), 3.57 (3H, m), 3.13 (1H, s), 2.80 (1H, ddd, J=11.8, 8.0, 1.0 Hz), 1.91 (1H, ddd, J=11.8, 8.3, 1.0 Hz), 1.23 (3H, t, J=7.0 Hz), 1.11 (3H, t, J=7.0 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 157.5, 155.1, 128.2, 124.3, 122.9, 121.2, 111.3, 103.7, 89.0, 71.8, 71.5, 65.8, 64.9, 36.4, 15.5, 15.3; IR (neat, v cm-1) = 3422, 2975, 2875, 1454, 1253, 1112; HRMS (FTMS+p) m/z calculated for C16H19O3 (M-OH)+ 259.1329, found 259.1323

trans-6-(Benzofuran-2-yl)-7-phenylbicyclo[3.2.0]heptan-6-ol, 53


1H NMR (400 MHz, CDCl3): δH 7.57 (1H, m), 7.51 (1H, dq, J=8.2, 0.9 Hz), 7.39-7.20 (7H, m), 6.71 (1H, d, J=0.9 Hz), 3.82 (1H, d, J=7.5 Hz), 3.38 (1H, q, J=7.2 Hz), 2.95 (1H, ddd, J=9.9, 7.3, 2.2 Hz), 2.04 (1H, m), 1.97 – 1.74 (2H, m), 1.60 (3H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 159.5, 155.1, 137.2, 128.7, 128.6, 128.2, 127.0, 124.0, 122.8, 121.0, 111.4, 103.4, 75.4, 49.7, 49.3, 39.5, 31.8, 27.5, 26.1; IR (neat, v cm-1) = 3507, 3105, 2958, 2942, 2928, 1497, 1452, 1170; HRMS (ES+) m/z calculated for C21H21O2 (M+H)+ 305.1542, found 305.1550; Melting point 122.4 – 124.0 °C

Ethyl 4-(benzofuran-2-yl)-4-oxobutanoate, 55

To a solution of alcohol 52 (20 mg, 0.07 mmol) in acetonitrile (2 mL) at 0 °C was added N-bromosuccinimide (15.5 mg) in one portion. The reaction mixture was allowed to stir at 0 °C before it was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched by addition into saturated aqueous sodium thiosulphate solution, and the aqueous phase separated and extracted with Et2O (3 x 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), dried over MgSO4 and concentrated. Purification through flash column chromatography (15% Et2O/pentane) yielded the ester 55 (5.0 mg, 0.020 mmol, 29%) a brown oil.

1H NMR (400 MHz, CDCl3): δH 7.71 (1H, dt, J=7.9, 1.0 Hz), 7.57 (2H, m), 7.48 (1H, ddd, J=8.4, 7.2, 1.3 Hz), 7.31 (1H, ddd, J=8.0, 7.2, 1.0 Hz), 4.17 (2H, q, J=7.1 Hz), 3.32 (2H, t, J=6.8 Hz), 2.79 (2H, t, J=6.8 Hz), 1.27 (3H, t, J=7.1 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 189.5, 172.7, 155.8, 152.5, 128.4, 127.2, 124.1, 123.5, 112.8, 112.6, 60.9, 33.8, 28.1, 14.3; IR (neat, v cm-1) = 2983, 1731, 1684, 1559, 1265, 1156, 1138; HRMS (FTMS+p) m/z calculated for C14H15O4 (M+H)+ 247.0965, found 247.0962

Data in accordance with previous reports.39

(1-(Benzofuran-2-yl)cyclobutoxy)triethylsilane, 61

To a solution of cyclobutanol 5 (500 mg, 2.66 mmol) and triethylamine (0.55 mL, 0.40 g, 3.97 mmol) in dichloromethane (6 mL) cooled to 0 °C, was added triethylsilyl trifluoromethanesulfonate (0.70 mL, 0.82 g, 3.1 mmol). The reaction mixture was allowed to stir for 3 hrs, before it was diluted with dichloromethane and carefully quenched into saturated aqueous ammonium chloride solution (10 mL). The aqueous phase was separated and extracted with dichloromethane (2 x 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (15 mL), dried over MgSO4 and concentrated. The crude material was purified through flash column chromatography (1:19 Et2O/pentane) to yield the title compound 61 (617 mg, 2.04 mmol, 77%) as a yellow oil.

1H NMR (400 MHz, CDCl3): δH 7.56 (1H, ddd, J=7.5, 1.5, 0.7 Hz), 7.47 (1H, dq, J=8.2, 0.9 Hz), 7.25 (2H, m), 6.66 (1H, d, J=1.0 Hz), 2.59 (2H, ddt, J=9.3, 8.3, 2.7 Hz), 2.44 (2H, m), 1.81 (1H, dtt, J=11.1, 9.7, 2.8 Hz), 1.66 (1H, m), 0.88 (9H, t, J=7.9 Hz), 0.51 (6H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 161.3, 154.9, 128.3, 124.0, 122.6, 120.9, 111.2, 101.9, 73.0, 36.9, 12.9, 6.8, 5.6; IR (neat, v cm-1) = 2988, 2950, 2909, 2874, 1452, 1293, 1249, 1140; HRMS (ES+) m/z calculated for C18H26O2NaSi (M+Na)+ 325.1600, found 325.1615

Synthesis of 4-tetralones

5) General procedure for the synthesis of 4-tetralones from cyclobutanols

To a solution of cyclobutanol derivative (1 equiv.) in acetonitrile was added NBS (1.15 equiv.) at 0 °C before the reaction was allowed to stir at room temperature until complete conversion of the starting material was observed by TLC. The reaction was diluted with Et2O (10 mL), and quenched into saturated aqueous sodium thiosulphate solution (10 mL). The aqueous layer was separated and extracted with Et2O (3 x 10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), dried over MgSO4 and concentrated. Crude materials were purified through flash column chromatography.

3,4-Dihydrodibenzo[b,d]furan-1(2H)-one, 6

Synthesized through General procedure (5)17


Off-white solid (450 mg, 2.42 mmol, 46%) on a 5.3 mmol scale. Purified through flash column chromatography (15% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 8.06 (1H, m), 7.47 (1H, m), 7.32 (2H, m), 3.04 (2H, td, J = 6.3, 1.2 Hz), 2.61 (2H, td, J = 6.4, 1.0 Hz), 2.28 (2H, p, J = 6.4 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 195.2, 171.2, 155.0, 125.4, 124.9, 124.2, 122.3, 117.0, 111.5, 38.3, 24.3, 23.0; IR (neat, v cm-1) = 2950, 1672, 1590, 1481, 1450, 1404, 1167; HRMS (EI +) m/z calculated for C12H10O2 (M)+ 186.0681, found 186.0690; Melting point 57.3 – 59.3 °C


8-Methoxy-3,4-dihydrodibenzo[b,d]furan-1(2H)-one, 10


White solid (6.9 mg, 0.032 mmol, 13%); purified through flash column chromatography (15% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.53 (1H, d, J=2.7 Hz), 7.35 (1H, d, J=8.9 Hz), 6.89 (1H, dd, J=9.0, 2.7 Hz), 3.87 (3H, s), 3.02 (2H, t, J=6.3 Hz), 2.60 (2H, dd, J=7.3, 5.7 Hz), 2.27 (2H, p, J=6.4 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 194.8, 171.4, 157.3, 149.3, 124.4, 116.7, 113.9, 111.6, 103.9, 56.0, 37.9, 23.9, 22.5; IR (neat, v cm-1) = 3000, 2960, 2843, 1669, 1459, 1398; HRMS (ES+ ) m/z calculated for C13H13O3 (M+H)+ 217.0865, found 217.0866

3,4-Dihydrodibenzo[b,d]thiophen-1(2H)-one, 8



White solid (162 mg, 0.801 mmol, 53%) on a 1.50 mmol scale. Purified through flash column chromatography (15% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 8.67 (1H, dt, J = 8.1, 0.9 Hz), 7.77 (1H, dt, J = 8.0, 1.0 Hz), 7.45 (1H, ddd, J = 8.2, 7.2, 1.2 Hz), 7.36 (1H, ddd, J = 8.4, 7.2, 1.3 Hz), 3.14 (2H, t, J = 6.1 Hz), 2.67 (2H, m), 2.29 (2H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 193.4, 159.9, 137.1, 136.3, 129.7, 125.6, 124.9, 124.8, 121.5, 38.6, 26.3, 24.1; IR (neat, v cm-1) = 3076, 2952, 2924, 1655, 1463, 1381; HRMS (EI +) m/z calculated for C12H10OS (M)+ 202.0452, found 202.0460


9-Tosyl-1,2,3,9-tetrahydro-4H-carbazol-4-one, 12



1H NMR (400 MHz, CDCl3): δH 8.27 (1H, m), 8.18 (1H, m), 7.79 (2H, m), 7.37 (2H, m), 7.30 (2H, m), 3.36 (2H, t, J = 6.2 Hz), 2.59 (2H, m), 2.40 (3H, s), 2.25 (2H, dq, J = 7.9, 6.3 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 195.5, 151.4, 146.3, 136.4, 136.0, 130.7, 127.1, 126.2, 125.8, 125.4, 122.3, 118.4, 114.3, 38.3, 25.0, 23.7, 22.1; IR (neat, v cm-1) = 2953, 2950, 1666, 1372, 1170; HRMS (ES +) m/z calculated for C19H18NO3S (M+H)+ 340.1007, found 340.1005; Melting point 150.9 – 152.3 °C. Data in accordance with previous reports.41

5-Methyl-9-tosyl-1,2,3,9-tetrahydro-4H-carbazol-4-one, 14



1H NMR (400 MHz, CDCl3): δH 8.05 (1H, d, J=8.5 Hz), 7.73 (2H, m), 7.27-7.21 (3H, m), 7.09 (1H, dt, J=7.4, 1.0 Hz), 3.35 (2H, t, J=6.2 Hz), 2.81 (3H, s), 2.57 (2H, m), 2.37 (3H, s), 2.17 (2H, p, J=6.4 Hz); 13C{1H} NMR (125 MHz, CDCl3): δC 193.6, 151.1, 145.7, 136.7, 135.5, 133.2, 130.2, 127.2, 126.6, 125.3, 125.0, 119.9, 111.3, 39.0, 25.2, 23.5, 22.7, 21.6; IR (neat, v cm-1) = 3096, 3067, 2947, 1670, 1381, 1372, 1189, 1176; HRMS (ES– ) m/z calculated for C20H18NO3S (M–H) – 352.1007, found 352.0994

6-Methoxy-9-tosyl-1,2,3,9-tetrahydro-4H-carbazol-4-one, 16



1H NMR (400 MHz, CDCl3): δH 8.04 (1H, d, J=9.1 Hz), 7.73 (3H, dd, J=8.3, 2.0 Hz), 7.27 (2H, m), 6.95 (1H, dd, J=9.2, 2.7 Hz), 3.86 (3H, s), 3.31 (2H, t, J=6.2 Hz), 2.55 (2H, dd, J=7.4, 5.7 Hz), 2.38 (3H, s), 2.21 (2H, p, J=6.3 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 195.0, 157.6, 151.3, 145.7, 135.5, 130.3, 130.2, 126.9, 126.6, 114.8, 114.6, 103.7, 55.8, 37.9, 24.6, 23.2, 21.7; IR (neat, v cm-1) = 2951, 1664, 1478, 1459, 1400; HRMS (ES+) m/z calculated for C20H20NO4S (M+H)+ 370.1113, found 370.1100. Data in accordance with previous reports.42

1-(4-Bromo-5-methoxy-1-tosyl-1H-indol-2-yl)cyclobutan-1-ol

Isolated as by-product from the reaction of 15 with NBS.

Yellow oil (10 mg, 0.022 mmol, 4%); purified through flash column chromatography (20% to 60% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 7.79 (1H, dd, J=9.1, 0.7 Hz), 7.65 (2H, m), 7.19 (2H, m), 6.85 (1H, d, J=9.1 Hz), 6.76 (1H, d, J=0.7 Hz), 4.33 (1H, br. s), 3.89 (3H, s), 2.69 (2H, dddd, J=9.7, 8.7, 4.4, 2.1 Hz), 2.51 (2H, dddd, J=11.9, 7.6, 6.6, 2.8 Hz), 2.33 (3H, s), 2.13 (1H, m), 1.76 (1H, dtt, J=11.1, 8.9, 6.7 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 152.7, 147.5, 145.1, 135.6, 132.1, 130.9, 129.9, 126.5, 114.2, 110.1, 109.8, 103.0, 73.1, 57.0, 36.3, 21.6, 14.4; IR (neat, v cm-1) = 3543, 2995, 2948, 1596, 1166; HRMS (FTMS+p) m/z calculated for C20H19NO3SBr (M-OH)+ 432.0264, found 432.0264.

6-(Benzyloxy)-9-tosyl-1,2,3,9-tetrahydro-4H-carbazol-4-one, 18



1H NMR (400 MHz, CDCl3): δH 8.05 (1H, d, J=9.1 Hz), 7.83 (1H, d, J=2.6 Hz), 7.73 (2H, m), 7.47 (2H, m), 7.39 (2H, m), 7.33 (1H, m), 7.27 (2H, d, J=7.1 Hz), 7.03 (1H, dd, J=9.2, 2.7 Hz), 5.11 (2H, s), 3.31 (2H, t, J=6.2 Hz), 2.55 (2H, dd, J=7.4, 5.7 Hz), 2.38 (3H, s), 2.22 (2H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 195.2, 156.8, 151.3, 145.8, 137.0, 135.5, 130.5, 130.2, 128.6, 128.0, 127.7, 126.8, 126.6, 117.9, 115.2, 114.8, 105.0, 70.5, 37.9, 24.6, 23.2, 21.7; IR (neat, v cm-1) = 3062, 3030, 2949, 1662, 1450, 1399, 1374, 1157; HRMS (ES+ ) m/z calculated for C26H24NO4S (M+H)+ 446.1426, found 446.1417; Melting point 58.6 – 65.3 °C

5-Fluoro-9-tosyl-1,2,3,9-tetrahydro-4H-carbazol-4-one, 20


White solid (27 mg, 0.076 mmol, 40%); purified through flash column chromatography (50% Et2O/pentane). Sample for X-ray crystallography recrystallized from Chloroform/Et2O.

1H NMR (400 MHz, CDCl3): δH 8.00 (1H, m), 7.74 (2H, m), 7.29 (3H, m), 7.03 (1H, ddd, J=10.1, 8.1, 0.8 Hz), 3.33 (2H, t, J=6.2 Hz), 2.59 (2H, m), 2.39 (3H, s), 2.20 (2H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 192.1, 155.9 (d, J=255.3 Hz), 151.1, 146.1, 138.3 (d, J=9.7 Hz), 135.2, 130.3, 126.6, 126.4 (d, J=7.5 Hz), 117.7 (d, J=6.9 Hz), 114.0 (d, J=22.3 Hz), 111.4 (d, J=20.9 Hz), 109.9 (d, J=4.3 Hz), 38.4, 24.8, 22.9, 21.7; 19F NMR (377 MHz, CDCl3): δF 107.01 (m); IR (neat, v cm-1) = 2951, 1683, 1491, 1394, 1093; HRMS (ES+) m/z calculated for C19H17NO3SF (M+H)+ 358.0913, found 358.0928

6-Chloro-9-tosyl-1,2,3,9-tetrahydro-4H-carbazol-4-one, 22



1H NMR (400 MHz, CDCl3): δH 8.23 (1H, d, J=2.2 Hz), 8.08 (1H, d, J=8.9 Hz), 7.74 (2H, m), 7.30 (3H, m), 3.31 (2H, t, J=6.2 Hz), 2.55 (2H, dd, J=7.4, 5.7 Hz), 2.39 (3H, s), 2.22 (2H, p, J=6.3 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 194.7, 151.9, 146.1, 135.2, 134.3, 130.9, 130.4, 127.0, 126.6, 125.6, 121.5, 117.3, 114.9, 37.7, 24.5, 23.1, 21.7; IR (neat, v cm-1) = 2851, 1666, 1592, 1440, 1392; HRMS (ES –) m/z calculated for C19H15NO3SCl (M-H)– 372.0461, found 372.0457

5,7-Difluoro-9-tosyl-1,2,3,9-tetrahydro-4H-carbazol-4-one, 24



1H NMR (400 MHz, CDCl3): δH 7.79 (1H, ddd, J=9.6, 2.2, 0.8 Hz), 7.74 (2H, m), 7.32 (2H, m), 6.83 (1H, td, J=9.7, 2.2 Hz), 3.30 (2H, t, J=6.2 Hz), 2.57 (2H, m), 2.41 (3H, s), 2.19 (2H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 192.0, 161.5 (dd, J=244, 11.1 Hz), 155.3 (dd, J=256.0, 14.4 Hz) 151.4, 146.5, 138.0 (dd, J=14.5, 12 Hz), 135.1, 130.6, 126.8, 117.6 (d, J=7.4 Hz), 110.7 (d, J=22.5 Hz), 101.2 (dd, J=27.0, 24.0 Hz), 98.0 (dd, J=29.0, 4.0 Hz), 38.4, 24.9, 22.8, 21.7; 19F NMR (377 MHz, CDCl3): δF –103.18 (dd, J=9.9, 6.5 Hz), –112.40 (m); IR (neat, v cm-1) = 3137, 3091, 3067, 2957, 1683, 1627, 1591, 1555, 1157; HRMS (ES+) m/z calculated for C19H16NO3SF2 (M+H)+ 376.0819, found 376.0804

2-(1-Hydroxycyclobutyl)-6,7-dihydrobenzo[b]thiophen-4(5H)-one, 26


Yellow solid (70 mg, 0.32 mmol, 48%); purified through flash column chromatography (5% EtOAc/pentane to 30% EtOAc/pentane).

1H NMR (400 MHz, CDCl3): δH 7.35 (1H, s), 3.03 (2H, t, J=6.1 Hz), 2.55 (4H, m), 2.43 (2H, m), 2.24 (2H, tt, J=6.5, 5.6 Hz), 1.95 (1H, m), 1.76 (1H, dp, J=11.4, 8.6 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 193.5, 156.0, 149.4, 136.7, 119.6, 74.7, 38.2, 37.7, 25.6, 24.5, 12.5; IR (neat, v cm-1) = 3383, 2936, 1655, 1404, 1225; HRMS (ES+) m/z calculated for C12H15O2S (M+H)+ 223.0793, found 223.0801

3-Phenyl-3,4-dihydrodibenzo[b,d]furan-1(2H)-one, 28



1H NMR (400 MHz, CDCl3): δH 8.09 (1H, m), 7.50 (1H, m), 7.41-7.29 (7H, m), 3.68 (1H, tt, J = 10.8, 5.7 Hz), 3.28 (2H, m), 2.89 (2H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 193.3, 169.9, 154.9, 142.3, 129.0, 127.4, 126.8, 125.2, 124.6, 123.5, 121.8, 116.5, 111.2, 45.2, 41.2, 31.6; IR (neat, v cm-1) = 3062, 3025, 2947, 1655, 1586, 1402, 1044; HRMS (ES +) m/z calculated for C18H15O2 (M)+ 263.1072, found 263.1074; Melting point 113.2 – 117.4 °C. Data in accordance with previous reports.8

3-Phenyl-3,4-dihydrodibenzo[b,d]thiophen-1(2H)-one, 30



1H NMR (400 MHz, CDCl3): δH 8.70 (1H, dt, J=8.1, 1.0 Hz), 7.79 (1H, dt, J = 8.0, 1.0 Hz), 7.48 (1H, ddd, J = 8.2, 7.2, 1.2 Hz), 7.43-7.27 (6H, m), 3.67 (1H, dddd, J=11.2, 9.3, 7.5, 4.6 Hz), 3.37 (2H, m), 2.95 (2H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 192.6, 159.1, 142.5, 137.6, 136.3, 129.8, 128.9, 127.3, 126.8, 125.9, 125.3, 125.0, 121.8, 45.8, 42.5, 34.1; IR (neat, v cm-1) = 3053, 3029, 2915, 1651, 1459, 1426, 1379; HRMS (ES+) m/z calculated for C18H15OS (M)+ 279.0844, found 279.0853; Melting point 146.5 – 148.2 °C

2-Phenyl-9-tosyl-1,2,3,9-tetrahydro-4H-carbazol-4-one, 32


White solid (30 mg, 0.072 mmol, 38%); purified through flash column chromatography.

1H NMR (400 MHz, CDCl3): δH 8.27 (1H, m), 8.17 (1H, m), 7.73 (2H, m), 7.47 – 7.16 (10H, m), 3.84 (1H, dd, J = 18.1, 4.7 Hz), 3.58 (1H, tt, J = 10.5, 5.1 Hz), 3.33 (1H, dd, J = 18.1, 10.5 Hz), 2.87 (2H, m), 2.38 (3H, s); 13C{1H} NMR (101 MHz, CDCl3): δC 193.8, 149.9, 145.9, 142.5, 136.3, 135.5, 130.3, 128.9, 127.3, 126.9, 126.6, 125.6, 125.5, 125.0, 121.9, 117.9, 114.0, 44.8, 41.5, 32.2, 21.7; IR (neat, v cm-1) = 3107, 3056, 2960, 1670, 1380, 1173; HRMS (ES+) m/z calculated for C25H22NO3S (M+H)+ 416.1320, found 416.1302; Melting point 159.0 – 159.4 °C

4-Cyclopropyl-3,4-dihydrodibenzo[b,d]furan-1(2H)-one, 34



1H NMR (400 MHz, CDCl3): δH 8.08 (1H, m), 7.51 (1H, m), 7.33 (2H, m), 2.76 (1H, m), 2.56 (1H, m), 2.41 (2H, m), 2.17 (1H, m), 1.05 (1H, m), 0.76 (1H, m), 0.62 (2H, m), 0.34 (1H, dddd, J=8.8, 7.4, 5.7, 3.5 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 195.0, 172.9, 154.7, 125.0, 124.4, 123.7, 121.9, 115.7, 111.2, 39.9, 36.7, 29.3, 13.5, 4.6, 3.0; IR (neat, v cm-1) = 3077, 3001, 2947, 2866, 1670, 1584, 1481, 1449, 1405; HRMS (ES+) m/z calculated for C15H15O2 (M+H)+ 227.1072, found 227.1074

4-Cyclopropyl-3,4-dihydrodibenzo[b,d]thiophen-1(2H)-one, 36



1H NMR (400 MHz, CDCl3): δH 8.69 (1H, dt, J=8.1, 1.0 Hz), 7.80 (1H, dt, J=8.0, 0.9 Hz), 7.45 (1H, ddd, J=8.2, 7.2, 1.2 Hz), 7.36 (1H, ddd, J=8.3, 7.2, 1.3 Hz), 2.78 (1H, dt, J=16.9, 4.4 Hz), 2.61 (1H, ddd, J=17.0, 12.3, 4.7 Hz), 2.42 (1H, dq, J=12.9, 4.6 Hz), 2.32 (1H, td, J=9.8, 4.4 Hz), 2.14 (1H, tdd, J=12.5, 9.9, 4.2 Hz), 1.08 (1H, dtt, J=9.7, 8.0, 4.9 Hz), 0.82 (1H, dddd, J=9.1, 7.9, 5.8, 4.4 Hz), 0.69 (1H, dddd, J=9.0, 8.0, 5.5, 4.5 Hz), 0.58 (1H, ddd, J=10.2, 9.3, 4.9 Hz), 0.41 (1H, ddt, J=9.4, 5.7, 4.7 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 193.7, 165.8, 137.8, 136.6, 129.1, 125.7, 125.1, 125.0, 121.7, 43.7, 38.5, 30.8, 17.3, 5.6, 4.2; IR (neat, v cm-1) = 3070, 2995, 2939, 2928, 2866, 1645, 1462, 1374; HRMS (FTMS + p) m/z calculated for C15H15OS (M+H)+ 243.0838, found 243.0829

1,2,3,3a,4,10b-Hexahydro-5H-indeno[4,5-b]benzofuran-5-one, 39


Brown crystalline solid (34 mg, 0.15 mmol, 39%); purified through flash column chromatography (15% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 8.06 (1H, m), 7.47 (1H, m), 7.32 (2H, m), 3.49 (1H, td, J = 7.0, 5.7 Hz), 2.91 – 2.61 (3H, m), 2.20 (2H, m), 1.95 (1H, m), 1.74 (2H, m), 1.53 (1H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 194.4, 172.2, 154.9, 124.9, 124.4, 123.7, 121.9, 115.4, 111.1, 41.0, 39.4, 38.3, 30.6, 30.0, 24.3; IR (neat, v cm-1) = 2958, 2939, 2908, 2871, 1661, 1586, 1404; HRMS (ES+) m/z calculated for C15H15O2 (M+H)+ 227.1072, found 227.1083; Melting point 80.9 – 84.5 °C

1,2,3,3a,4,10b-Hexahydro-5H-benzo[b]indeno[5,4-d]thiophen-5-one, 41


Brown crystalline solid (39 mg, 0.16 mmol, 43%); purified through flash column chromatography (10% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 8.66 (1H, dt, J = 8.1, 1.0 Hz), 7.78 (1H, dt, J = 8.0, 1.0 Hz), 7.44 (1H, ddd, J = 8.2, 7.1, 1.2 Hz), 7.35 (1H, ddd, J = 8.3, 7.2, 1.3 Hz), 3.57 (1H, dt, J = 7.5, 5.8 Hz), 2.89 – 2.62 (3H, m), 2.24 (1H, m), 2.07 (1H, ddt, J = 13.5, 8.2, 5.6 Hz), 1.97 (1H, m), 1.78 (2H, tddd, J = 7.9, 6.5, 5.1, 2.1 Hz), 1.56 (1H, ddt, J = 13.1, 8.8, 6.8 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 193.3, 163.8, 137.7, 136.5, 129.0, 125.7, 125.0, 121.8, 41.4, 41.2, 40.2, 34.5, 30.1, 23.9; IR (neat, v cm-1) = 2948, 2938, 2866, 1661, 1457, 1378, 1194; HRMS (ES+) m/z calculated for C15H15OS (M+H)+ 243.0844, found 243.0850; Melting point 72.2 – 75.8 °C

1,3,4,4a,5,11b-Hexahydronaphtho[1,2-b]benzofuran-6(2H)-one, 43



1H NMR (400 MHz, CDCl3): δH 8.06 (1H, m), 7.48 (1H, m), 7.32 (2H, m), 3.27 (1H, dt, J=7.4, 4.7 Hz), 2.69 (1H, dd, J=17.4, 9.2 Hz), 2.56 (2H, m), 2.09 (1H, br. s), 1.91 (1H, ddt, J=13.0, 8.7, 4.5 Hz), 1.72-1.41 (6H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 195.0, 173.4, 154.8, 124.8, 124.4, 123.9, 121.8, 115.4, 111.2, 42.6, 35.9, 35.5, 28.8, 26.9, 23.6, 22.9; IR (neat, v cm-1) = 2924, 2852, 1667, 1584, 1480, 1447, 1159; HRMS (ES+) m/z calculated for C16H17O2 (M+H)+ 241.1229, found 241.1231

1,3,4,4a,5,11b-Hexahydrobenzo[b]naphtho[2,1-d]thiophen-6(2H)-one, 45


Colourless film (30 mg, 0.12 mmol, 35%); purified through flash column chromatography (10% Et2O/pentane).

1H NMR (400 MHz, CDCl3): δH 8.68 (1H, dt, J=8.1, 1.0 Hz), 7.79 (1H, dt, J=8.0, 0.9 Hz), 7.45 (1H, ddd, J=8.2, 7.1, 1.2 Hz), 7.36 (1H, ddd, J=8.3, 7.2, 1.3 Hz), 3.40 (1H, dt, J=6.9, 4.7 Hz), 2.82 – 2.60 (2H, m), 2.54 (1H, ddt, J=12.5, 9.3, 3.9 Hz), 2.12 – 1.86 (2H, ddd, J=18.5, 14.8, 8.0 Hz), 1.79 – 1.25 (6H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 193.7, 164.8, 137.6, 136.8, 129.1, 125.7, 125.0, 124.9, 121.8, 43.0, 38.3, 36.6, 31.0, 28.6, 23.4, 23.0; IR (neat, v cm-1) = 3056, 2924, 2852, 1663, 1461, 1379, 1198; HRMS (ES +) m/z calculated for C16H17OS (M+H)+ 257.1000, found 257.0999

trans-3-((Benzyloxy)methyl)-4-phenyl-3,4-dihydrodibenzo[b,d]furan-1(2H)-one, 47



1H NMR (400 MHz, CDCl3): δH 8.12 (1H, dt, J = 7.5, 1.1 Hz), 7.45-7.28 (11H, m), 7.16 (2H, dt, J = 7.3, 1.5 Hz), 4.55 (1H, d, J = 8.5 Hz), 4.49 (2H, d, J = 1.4 Hz), 3.43 (2H, dd, J=4.3, 1.1 Hz), 2.85 (2H, m), 2.68 (1H, ttd, J = 8.5, 4.4, 2.2); 13C{1H} NMR (101 MHz, CDCl3): δC 194.0, 170.6, 155.1, 138.3, 138.0, 128.9, 128.6, 128.4, 127.7, 127.7, 127.6, 125.2, 124.5, 123.5, 121.9, 111.4, 73.2, 70.0, 44.7, 44.3, 41.0; IR (neat, v cm-1) = 3029, 2860, 1676, 1587, 1483, 1450; HRMS (ES+) m/z calculated for C26H23O3 (M+H)+ 383.1647, found 383.1650

trans-3-((Benzyloxy)methyl)-4-phenyl-3,4-dihydrodibenzo[b,d]thiophen-1(2H)-one, 49



1H NMR (400 MHz, CDCl3): δH 8.72 (1H, dt, J = 8.2, 1.0), 7.68 (1H, dt, J = 8.1, 1.0), 7.46 (1H, ddd, J = 8.2, 7.1, 1.2 Hz), 7.39-7.24 (11H, m), 4.55 (1H, d, J = 9.6 Hz), 4.44 (2H, d, J = 2.2 Hz), 3.36 (2H, m), 2.90 (2H, m), 2.77 (1H, dddd, J = 15.7, 9.7, 7.9, 4.1 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 193.1, 164.6, 141.1, 138.5, 138.1, 136.3, 130.1, 128.8, 128.8, 128.4, 127.9, 127.7, 127.5, 125.8, 125.2, 125.1, 121.7, 73.3, 70.6, 46.1, 44.8, 42.0; IR (neat, v cm-1) = 3067, 3030, 2856, 1666, 1463, 1103; HRMS (ES+) m/z calculated for C26H23O2S (M+H)+ 399.1419, found 399.1423

trans-2-((Benzyloxy)methyl)-1-phenyl-9-tosyl-1,2,3,9-tetrahydro-4H-carbazol-4-one, 51



1H NMR (400 MHz, CDCl3): Some peaks are doubled due to the presence of minor quantities of the cis-diastereomer. δH 8.35 (1H, m), 8.16 and 8.03 (1H, m), 7.40 (2H, m), 7.36 – 7.26 (7H, m), 7.27 – 7.18 (3H, m), 7.09 (2H, m), 6.90 (2H, m), 5.54 and 5.48 (1H, d, J = 1.5 Hz), 4.52 and 4.44 (2H, d, J = 1.7 Hz), 3.55 (2H, m), 2.76 (2H, m), 2.35 (1H, m), 2.43 and 2.25 (3H, s); 13C{1H} NMR (101 MHz, CDCl3): Some peaks are doubled due to the presence of minor quantities of the cis-diastereomer. δC 194.1, 149.3, 145.4, 140.3, 138.1, 136.3, 135.1, 129.8, 129.5, 129.0, 128.8, 128.6, 128.5, 128.3, 127.8, 127.8, 127.6, 127.4, 127.1, 127.1, 125.7, 125.5, 125.1, 122.3, 118.2, 114.3, 73.2, 72.2 and 70.3, 45.2 and 44.8, 42.4 and 41.2, 36.4, 21.7; IR (neat, v cm-1) = 3058, 3028, 2857, 1668, 1450, 1404, 1375; HRMS (ES–) m/z calculated for C33H28NO4S (M–H)– 534.1739, found 534.1727

4-Phenyl-1,2,3,3a,4,10a-hexahydro-10H-indeno[5,6-b]benzofuran-10-one, 54 (Pure isomer)


White solid (7.8 mg, 0.026 mmol, 13%); purified through flash column chromatography (2% CH2Cl2, 2% Et2O, 96% pentane).

1H NMR (400 MHz, CDCl3): δH 8.16 (1H, m), 7.41-7.29 (6H, m), 7.20 (2H, m), 4.30 (1H, d, J=4.3 Hz), 2.96 (1H, dt, J=8.3, 5.8 Hz), 2.77 (1H, m), 2.32 (1H, ddt, J=13.5, 9.2, 5.6 Hz), 1.96 (2H, dddd, J=15.8, 8.3, 4.9, 1.7 Hz), 1.72 (3H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 196.6, 169.1, 155.2, 140.4, 129.0, 127.9, 127.5, 125.2, 124.5, 123.8, 122.1, 115.9, 111.4, 49.2, 43.4, 30.6, 27.7, 22.4; IR (neat, v cm-1) = 3059, 3026, 2947, 2871, 1661, 1596, 1588, 1480, 1448, 1407; HRMS (ES+) m/z calculated for C21H19O2 (M+H)+ 303.1385, found 303.1376

Synthesis of compounds for mechanism studies

1-(Benzofuran-2-yl)-4-bromobutan-1-ol, 64

Reduction according to a procedure by Chamberlin et al.43

To a solution of 4-bromoethylbutanoate 68 (1.98 mL, 2.70 g, 13.8 mmol) in dichloromethane (25 mL) cooled to –78 °C was added a solution of DIBAL-H (1.2 M in toluene, 13.0 mL, 15 mmol) as drops and the reaction mixture stirred for 30 mins, before it was quenched into an ice-cold aqueous 10% HCl solution (50 mL). The biphasic mixture was stirred at 0 °C for 30 mins before the aqueous phase was separated and extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over MgSO4 and concentrated to yield the crude aldehyde 63 (2.00 g) as a colourless oil, which was used in the next step without further purification.

To a solution of 2,3-benzofuran (1.40 mL, 1.50 g, 12.7 mmol) in Et2O (40 mL) cooled to 0 °C was added n-butyllithium solution (1.9 M in hexanes, 6.8 mL, 13 mmol) as drops. The reaction mixture was allowed to warm to room temperature and stirred for 3 hrs, before it was cooled to –78 °C. A solution of aldehyde 63 (1.60 g, 10.4 mmol) in Et2O (5 mL) was added as drops and the reaction mixture stirred for 2 hrs, before it was quenched by the slow addition of saturated aqueous ammonium chloride solution (10 mL). The biphasic mixture was then allowed to warm to room temperature, the aqueous phase separated and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over MgSO4 and concentrated. The crude material was purified through flash column chromatography (1:4 EtOAc/pentane) to yield the desired alcohol 64 (1.71 g, 6.28 mmol, 57% over two steps) as a brown oil.

1H NMR (400 MHz, CDCl3): δH 7.55 (1H, ddd, J=7.5, 1.5, 0.7 Hz), 7.46 (1H, dq, J=8.1, 1.0 Hz), 7.26 (2H, m), 6.64 (1H, t, J=0.9 Hz), 4.87 (1H, br. s), 3.48 (2H, m), 2.18-1.92 (4H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 158.7, 154.8, 128.0, 124.3, 122.9, 121.1, 111.3, 102.8, 67.6, 34.0, 33.5, 28.7; IR (neat, v cm-1) = 3421, 3056, 2929, 2867, 1451, 1251; HRMS (FTMS+ p) m/z calculated for C12H12O2Br (M-H)+ 267.0015, found 267.0013

1-(Benzofuran-2-yl)-4-bromobutan-1-one, 65

To a solution of alcohol 64 (1.50 g, 5.57 mmol) in dichloromethane (50 mL) at room temperature was added Dess-Martin periodinane (3.50 g, 8.36 mmol). The resulting black suspension was allowed to stir at room temperature for 1 hr, before it was directly loaded onto a flash column and eluted with 1:4 Et2O/pentane to yield the ketone 65 (1.2 g, 4.5 mmol, 81%) as a yellow solid.

1H NMR (400 MHz, CDCl3): δH 7.72 (1H, ddd, J=7.9, 1.3, 0.7 Hz), 7.59 (1H, dq, J=8.4, 0.9 Hz), 7.56 (1H, d, J=1.0 Hz), 7.49 (1H, ddd, J=8.4, 7.2, 1.3 Hz), 7.32 (1H, ddd, J=8.0, 7.2, 1.0 Hz), 3.56 (2H, t, J=6.3 Hz), 3.19 (2H, t, J=7.0 Hz), 2.35 (2H, m); 13C{1H} NMR (101 MHz, CDCl3): δC 189.9, 155.7, 152.4, 128.4, 127.0, 124.0, 123.4, 112.9, 112.5, 36.9, 33.2, 26.7 ; IR (neat, v cm-1) = 3107, 3077, 2957, 2932, 1665, 1549, 1161; HRMS (FTMS+p) m/z calculated for C12H12BrO2 (M+H)+ 267.0015, found 267.0017; Melting point 77.8 – 84.3 °C. Data in accordance with previous reports.44

1-(Benzofuran-2-yl)butan-1-one, 66

To a solution of ketone 65 (70 mg, 0.26 mmol) in benzene (7 mL) heated to reflux was added a solution of tributyltin hydride (70 µL, 0.26 mmol) and AIBN (43 mg, 0.26 mmol) in benzene (5 mL) in 4 portions as drops over 3.25 hrs. The resulting reaction mixture was remained at reflux overnight and then concentrated. The crude material was purified through flash column chromatography (1:19 Et2O/pentane) to yield the ketone 66 (30 mg) as a white solid. Remaining tin residues were removed by further flash column chromatography on 1:9 KF/silica (1:19 Et2O/pentane) to yield the ketone 66 (15 mg, 0.080 mmol, 31%) as a white solid.

1H NMR (400 MHz, CDCl3): δH 7.71 (1H, dt, J=7.8, 1.0 Hz), 7.58 (1H, dq, J=8.5, 0.9 Hz), 7.50 (1H, d, J=1.0 Hz), 7.47 (1H, m), 7.31 (1H, ddd, J=8.1, 7.2, 1.0 Hz), 2.94 (2H, t, J=7.4 Hz), 1.82 (2H, h, J=7.4 Hz), 1.03 (3H, t, J=7.4 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 191.6, 155.6, 152.7, 128.1, 127.1, 123.9, 123.2, 112.6, 112.5, 40.9, 17.8, 13.9; IR (neat, v cm-1) = 2961, 2933, 2872, 1676, 1554, 1159, 1140; HRMS (ES+) m/z calculated for C12H13O2 (M+H)+ 189.0916, found 189.0909. Data in accordance with previous reports.45

(Z)-1-(Benzofuran-2-yl)hept-4-en-1-ol

To a solution of 2,3-benzofuran (1.2 mL, 1.3 g, 11 mmol) in Et2O (20 mL) cooled to –78 °C was added n-butyllithium solution (2.0 M in hexanes, 5.4 mL, 11 mmol) as drops. The resulting reaction mixture was allowed to stir at –78 °C for 45 mins, before it was allowed to warm to room temperature and stirred for further 3 hrs. The solution was then cooled to –78 °C and (Z)-4-heptenal (1.20 mL,1.02 g, 9.01 mmol) was added as drops and the reaction mixture allowed to stir for 1.5 hrs, before it was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL) at 0 °C. The aqueous layer was separated and extracted with Et2O (3 x 15 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution (15 mL), dried over MgSO4 and concentrated. The crude material was purified through flash column chromatography (1:3 Et2O/pentane) to yield the alcohol (Z)-1-(benzofuran-2-yl)hept-4-en-1-ol (1.72 g, 7.47 mmol, 84%) as a yellow oil.

1H NMR (400 MHz, CDCl3): δH 7.55 (1H, m), 7.46 (1H, dt, J=8.1, 1.1 Hz), 7.25 (2H, m), 6.62 (1H, d, J=0.9 Hz), 5.41 (2H, m), 4.84 (1H, dt, J=7.4, 5.6 Hz), 2.21 (2H, m), 2.04 (5H, m), 0.96 (3H, t, J=7.5 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 159.3, 154.8, 133.0, 128.1, 127.7, 124.1, 122.8, 121.0, 111.2, 102.6, 67.9, 35.5, 23.2, 20.6, 14.3; IR (neat, v cm-1) = 3376, 3004, 2960, 2932, 2870, 1452, 1252; HRMS (EI+) m/z calculated for C15H18O2 (M)+ 230.1307, found 230.1299

(Z)-1-(Benzofuran-2-yl)hept-4-en-1-one, 69

To a solution of (Z)-1-(benzofuran-2-yl)hept-4-en-1-ol (505 mg, 2.19 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (1.37 g, 3.23 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 2.5 hrs before it was directly loaded onto a flash column and eluted with 1:4 Et2O/pentane to yield ketone 69 (370 mg, 1.62 mmol, 75%) as a white solid.

1H NMR (400 MHz, CDCl3): δH 7.71 (1H, ddd, J=7.9, 1.3, 0.7 Hz), 7.58 (1H, dq, J=8.5, 1.0 Hz), 7.51 (1H, d, J=1.0 Hz), 7.48 (1H, ddd, J=8.5, 7.2, 1.3 Hz), 7.31 (1H, ddd, J=8.0, 7.2, 1.0 Hz), 5.42 (2H, m), 3.01 (2H, dd, J=8.0, 7.1 Hz), 2.52 (2H, m), 2.09 (2H, m), 0.97 (3H, t, J=7.5 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 190.9, 155.6, 152.6, 133.3, 128.2, 127.1, 126.9, 123.9, 123.3, 112.6, 112.5, 39.0, 21.9, 20.6, 14.3; IR (neat, v cm-1) = 2999, 2961, 2931, 2898, 2872, 1678, 1559, 1404, 1367; HRMS (ES+) m/z calculated for C15H17O2 (M+H)+ 229.1229, found 229.1223; Melting point 52.4 – 55.4 °C

Ethyl (E)-hept-4-enoate

According to a procedure by Shakhmaev et al.46

To a solution of 1-penten-3-ol (5.1 mL, 4.3 g, 50 mmol) in triethyl orthoacetate (27.0 mL, 25.0 g, 150 mmol) was added acetic acid (0.1 mL) and the reaction mixture heated to 150 °C (hotplate temperature). The formed ethanol was separated through a Dean-Stark trap. A second portion of acetic acid (0.1 mL) was added after 2 hrs and the reaction mixture heated at 150 °C for another 4 hrs, at which point 5.0 mL of ethanol were collected. The solution was allowed to cool to room temperature, diluted with Et2O (50 mL) and washed sequentially with saturated aqueous sodium bicarbonate solution (2 x 30 mL) and saturated aqueous sodium chloride solution (30 mL). The combined organic phases were dried over MgSO4, and carefully concentrated. The majority of residual triethyl orthoacetate was removed by vacuum distillation, and the crude material purified further by flash column chromatography (5% Et2O/pentane) to yield ethyl (E)-hept-4-enoate (2.30 g, 14.7 mmol, 29%) as a colourless oil.

1H NMR (400 MHz, CDCl3): δH 5.50 (1H, m), 5.39 (1H, m), 4.13 (2H, q, J=7.1 Hz), 2.33 (4H, m), 2.00 (2H, m), 1.25 (3H, t, J=7.1 Hz), 0.95 (3H, t, J=7.4 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 173.3, 133.3, 127.0, 60.2, 34.4, 27.9, 25.5, 14.3, 13.8; IR (neat, v cm-1) = 2963, 2933, 2873, 2850, 1734, 1444, 1161; HRMS (ES+) m/z calculated for C9H17O2 (M+H)+ 157.1229, found 157.1223. Data in accordance with previous reports.46

(E)-1-(Benzofuran-2-yl)hept-4-en-1-ol

To a solution of ethyl (E)-hept-4-enoate (800 mg, 5.12 mmol) in dichloromethane (10 mL) cooled to –78 °C was added a solution of DIBAL-H (1.0 M in hexane, 5.2 mL, 5.2 mmol) as drops. The reaction was allowed to stir for 30 mins before it was quenched into an ice-cold aqueous 10% HCl solution and stirred for 40 mins at 0 °C. The aqueous phase was separated and extracted with dichloromethane (3 x 15 mL). The combined organic phases were washed with saturated aqueous sodium chloride solution (15 mL), dried over MgSO4 and concentrated. Traces of residual ester were removed by elution through a silica plug (2% Et2O/pentane) to yield the aldehyde (E)-hept-4-enal (200 mg) as a colourless oil which was used without further purification.

To a solution of 2,3-benzofuran (0.24 mL, 0.25 g, 2.1 mmol) in Et2O (10 mL) cooled to –78 °C was added n-butyllithium solution (2.0 M, 1.1 mL, 2.2 mmol) as drops at a rate to maintain the internal temperature below –70 °C. The solution was stirred at –70 °C for 15 min, before it was allowed to warm to room temperature and stirred for further 3 hrs. The reaction mixture was then cooled to –70 °C and a solution of (E)-hept-4-enal (200 mg, 1.78 mmol) in Et2O (2 mL) was added as drops. The resulting reaction mixture was stirred for further 1.5 hrs at –70 °C, before it was allowed to warm to 0 °C and quenched by the slow addition of saturated aqueous ammonium chloride solution (10 mL). The aqueous phase was separated and extracted with Et2O (3 x 10 mL) and the combined organic phases washed with saturated aqueous sodium chloride solution (15 mL), dried over MgSO4 and concentrated. The crude material was purified through flash column chromatography (1:9 Et2O/pentane to 1:4 Et2O/pentane) to yield (E)-1-(benzofuran-2-yl)hept-4-en-1-ol (140 mg, 0.608 mmol, 12% over two steps) as a yellow oil.

1H NMR (400 MHz, CDCl3): δH 7.54 (1H, m), 7.46 (1H, dq, J=8.2, 1.0 Hz), 7.25 (2H, m), 6.62 (1H, t, J=0.9 Hz), 5.52 (1H, m), 5.43 (1H, ddt, J=15.2, 6.5, 1.2 Hz), 4.85 (1H, dt, J=7.6, 5.6 Hz), 2.19-1.96 (6H, m), 0.97 (3H, t, J=7.5 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 159.3, 154.8, 133.2, 128.1, 127.9, 124.1, 122.8, 121.0, 111.2, 102.6, 67.9, 35.3, 28.5, 25.6, 13.9; IR (neat, v cm-1) = 3368, 2959, 2930, 2870, 2848, 1453, 1252; HRMS (ES+) m/z calculated for C15H19O2 (M+H)+ 231.1385, found 231.1379

(E)-1-(Benzofuran-2-yl)hept-4-en-1-one, 70

To a solution of (E)-1-(benzofuran-2-yl)hept-4-en-1-ol (120 mg, 0.521 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane (342 mg, 0.806 mmol) at room temperature. The reaction was allowed to stir at room temperature for 2 hrs, before it was directly loaded onto a flash column and eluted with 1:4 Et2O/pentane to yield the ketone 70 (83 mg, 0.36 mmol, 70%) as a white solid.

1H NMR (400 MHz, CDCl3): δH 7.71 (1H, ddd, J=7.9, 1.3, 0.7 Hz), 7.58 (1H, dq, J=8.4, 0.9 Hz), 7.51 (1H, d, J=1.0 Hz), 7.47 (1H, ddd, J=8.4, 7.2, 1.3 Hz), 7.31 (1H, ddd, J=8.0, 7.1, 1.0 Hz), 5.52 (2H, m), 3.03 (2H, dd, J=8.0, 7.0 Hz), 2.47 (2H, tdt, J=7.3, 5.3, 1.2 Hz), 1.99 (2H, m), 0.95 (3H, t, J=7.4 Hz); 13C{1H} NMR (101 MHz, CDCl3): δC 191.0, 155.6, 152.6, 133.5, 128.2, 127.1, 123.9, 123.3, 112.6, 112.5, 39.0, 27.1, 25.5, 13.8; IR (neat, v cm-1) = 2961, 2925, 2897, 2845, 1678, 1559, 1368; HRMS (ES+) m/z calculated for C15H17O2 (M+H)+ 229.1229, found 229.1228; Melting point 42.2 – 43.8 °C

2-(Benzofuran-2-yl)propan-2-ol, 71

Synthesized according to a procedure by Speybroeck et al.47

Yellow solid (955 mg, 5.42 mmol, 64%)

1H NMR (400 MHz, CDCl3): δH 7.54 (1H, ddd, J=7.4, 1.6, 0.7 Hz), 7.47 (1H, dq, J=8.2, 0.9 Hz), 7.25 (2H, m), 6.58 (1H, d, J=1.0 Hz), 2.36 (1H, s), 1.68 (6H, s); 13C{1H} NMR (101 MHz, CDCl3): δC 163.0, 154.7, 128.3, 124.0, 122.7, 121.0, 111.2, 100.4, 69.4, 28.8; IR (neat, v cm-1) = 3274, 2982, 1452, 1252, 1151, ; HRMS (ES+) m/z calculated for C11H11O (M-OH)+ 159.0810, found 159.0815. Data in accordance with previous reports.47

2-(3-Bromobenzofuran-2-yl)propan-2-ol, 72


Yellow oil (25 mg, 0.10 mmol, 18%). Purified through flash column chromatography (25% Et2O/pentane)

1H NMR (400 MHz, CDCl3): δH 7.50 (1H, dt, J=7.7, 1.3 Hz), 7.44 (1H, m), 7.25 (2H, m), 2.51 (1H, s), 1.76 (6H, s); 13C{1H} NMR (101 MHz, CDCl3): δC 156.7, 152.5, 128.9, 125.3, 123.4, 119.7, 111.3, 91.7, 71.0, 29.0; IR (neat, v cm-1) = 3370, 2978, 2932, 1646, 1599, 1452, 1249; HRMS (ES+) m/z calculated for C11H10OBr (M-OH)+ 236.9915, found 236.9923

ASSOCIATED CONTENT

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website.

1H-NMR, 13C-NMR and 19F-NMR spectra (PDF)

X-Ray crystal structures of 20 and 23 (PDF, CIF)

AUTHOR INFORMATION

Corresponding Author

* E-Mail: [email protected]

ORCID

Philip J. Parsons: 0000-0002-9158-4034

template for electronic submission to acs...

Documents