draft - university of toronto t-space · draft 4 and 4-aminobenzaldehydes are too expensive and...

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Synthesis of 2-(Aminoaryl)adenine Derivatives: a Simple Protocol using the Classical Iron Powder/Acetic Acid

Reduction Methodology

Journal: Canadian Journal of Chemistry

Manuscript ID cjc-2019-0270.R1

Manuscript Type: Article

Date Submitted by the Author: 26-Nov-2019

Complete List of Authors: Rocha, Ashly; Universidade do Minho, ChemistryProenca, M. Fernanda; Universidade do Minho, ChemistryCarvalho, Maria Alice; Universidade do Minho, Chemistry

Is the invited manuscript for consideration in a Special

Issue?:Not applicable (regular submission)

Keyword: 2-(aminophenyl)adenine derivatives, nitro reduction, chemoselectivity, purine derivatives, 2-aryladenine derivatives

https://mc06.manuscriptcentral.com/cjc-pubs

Canadian Journal of Chemistry

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Synthesis of 2-(Aminophenyl)adenine Derivatives: a Simple Protocol using the

Classical Iron Powder/Acetic Acid Reduction Methodology

Ashly Rocha, M. F. Proença, M. Alice Carvalho*

Center of Chemistry, Universidade do Minho, Campus de Gualtar, 4710-057 Braga.

[email protected]

Telf: +351 253 604 386

Fax: +351 253 604 382

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mailto:[email protected]

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Synthesis of 2-(Aminophenyl)adenine Derivatives: a Simple Protocol using the

Classical Iron Powder/Acetic Acid Reduction Methodology

Ashly Rocha, M. F. Proença, M. Alice Carvalho

Abstract

2-(Nitrophenyl)adenine derivatives were isolated from the reaction of 5-amino-4-

amidino-imidazoles with nitro-benzaldehydes. The conversion of the nitro derivatives to

2-(aminophenyl)adenine derivatives was performed using iron/acetic acid as reducing

agent, in 70% aqueous ethanol. The products were isolated in good yield and the isolation

protocol involves simple filtration and extraction procedures. This methodology is

compatible with the presence of functional groups such as amines, ethers, halofluorides

and halochlorides.

Key words

2-(aminophenyl)adenine derivatives, nitro reduction, chemoselectivity, purine

derivatives, 2-aryladenine derivatives

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Introduction

A broad scientific community remains interested in nucleobases, in particular purine

derivatives, as these compounds exhibit a diverse biological activity that is closely related

to the substituents in the central nucleus of the molecule.1 In particular purine derivatives

with a hydrogen atom or an alkyl group on N9 of the purine nucleus have received special

attention. In recent years, our research group designed and prepared new 9-aryl and 9-

alkylpurine derivatives that showed high activity against Mycobacterium tuberculosis2

and potential antipsychotic activity,3 respectively and this boosted a new drug

development program.

Many synthetic methodologies have been reported to incorporate several functional

groups in the purine core4 however, most of these methods use reagents that are typically

expensive and/or environmentally hazardous. Our research group developed a mild,

simple and inexpensive synthetic approach to purine derivatives having different

substituents in N9, C2 and C6 and several alkyl and aryl groups, including phenolic

groups, were regioselectively incorporated in N9 and C2.2,5 To the best of our knowledge,

a simple, efficient, inexpensive, non-toxic synthetic route to obtain 2-(aminoaryl)-purines

4 has not yet been reported. Considering that arylamines are key intermediates and

fundamental precursors in the synthesis of numerous pharmaceuticals, dyes, agricultural

chemicals and polymers6 these new hetero-arylamines may be of interest for a large

research community.

In order to generate the target compounds 4 using the synthetic approach designed

previously by our group, the reaction of the imidazole derivative 1 with the desired

amino-arylaldehyde would lead directly to the compounds 4 (Scheme 1). However, 2-

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and 4-aminobenzaldehydes are too expensive and 3-aminobenzaldehyde is not even

commercially available.

Scheme 1. Synthetic approaches to prepare 2-(aminophenyl)adenine derivatives 4 from

imidazoles 1.

To overcome these obstacles we considered using nitrobenzaldehydes 2, as an efficient

and economically feasible approach to obtain 2-(aminophenyl)purines 4 upon reduction

of the corresponding nitro derivative.

The literature reports different methodologies to perform nitro group reduction such as

hydrogenations, metal dissolving and hydride transfer reductions, catalytic transfer

hydrogenations and metal-free reductions.7 However some shortcomings associated to

these methodologies are the lack of chemoselectivity, the need for special high-pressure

equipment, the use of flammable hydrogen gas, hazardous reagents, expensive metal

complexes, extensive reaction times or laborious work up procedures. So, the use of

simple and ecofriendly methods to perform this reduction in molecules with other groups

susceptible to reduction, are always desired. As far as we know, the synthesis and

reduction of 2-(nitroaryl)adenine derivatives 3 was never reported.

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Herein we report the synthesis of novel 2-nitroaryladenine derivatives 3, from the reaction

of 5-amino-4-amidino-imidazoles 1 with the selected nitrobenzaldehydes 2, and their

conversion to the corresponding amino derivatives 4 using the classical iron

powder/acetic acid methodology in a greener and simplified protocol.

Results and discussion

Previous work on the synthesis of adenine derivatives2, 5j-k showed that the success of the

condensation between imidazole 1 and carbon electrophiles mainly depends on the carbon

electrophile and on the catalyst. In the present case the activation of imidazole with base

catalysis was considered the most promising approach and DBU and triethylamine were

selected for this purpose (Scheme 2, Table 1).

Scheme 2. Synthesis of novel 2-(nitrophenyl)adenine derivatives 3.

When the reaction of 1b with 2a was performed in DMSO, under DBU catalysis, after

21h at temperature between 19 - 21 oC, the major component in the reaction mixture was

identified as 1b. The temperature was raised to 40oC and after 26 days compound 3c was

the major component in the isolated solid product. However, extensive degradation of the

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reaction mixture occurred (table 1, entry 1). The reaction was repeated using

triethylamine as base (table 1, entry 4) and was performed using the minimum amount of

DMSO and an excess of triethylamine, at 80oC. After 17.5 h, the product 3c was isolated

in 62% yield. These reaction conditions were applied to the other derivatives 1a, 1c-1j

and the corresponding products were isolated in moderate to excellent yield after 2 to 22

hours (table 1).

In order to establish the methodology to perform the nitro reduction, we selected

compound 3a and different reaction conditions were tested (Table 2). The reactions were

monitored by TLC.

When compound 3a was treated with pentahydrate CuSO4 (1.5 equiv.) and NaBH4 (2.5

equiv.), either in a mixture of EtOH: EtOAc (2:1) or in DCM, at temperature between 19

- 21 oC, no reaction was observed (Table 2, entries 1, 2). The reduction was then

performed with tin (II) chloride (4.0 equiv.), combined with aqueous hydrochloric acid,

in ethanol, at 65oC, for 14.5h, following an experimental procedure previously described

in the literature.8

The product 4a was isolated but in very low yield (Table 2, entry 3). Iron powder was

then considered for the reduction. In the first attempt (Table 2, entry 4) compound 3a was

treated with iron powder in ethanol, at temperature between 19 - 21 oC. After 5h, the 1H

NMR on the solid isolated showed that product 4a was the major component in a complex

mixture. The reaction was repeated but acetic acid was added to the reaction mixture in a

70% aqueous ethanol solution. The mixture was refluxed and after 3.5 h the product 4a

was isolated in 55% yield. In order to improve the experimental conditions, the reaction

was repeated using 8 equiv. of iron powder and the reflux was maintained for 4.5h, until

TLC showed absence of starting reagent. The product 4a was isolated in low yield (Table

2, entry 6). The reaction was repeated once again but using a volume of solvent enough

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to solubilize the starting purine (Table 2, entry 7). After 4h under reflux the product 4a

was isolated in 87% yield. These results seem to indicate that the volume of solvent is

critical for the success of the reaction. A detailed analysis of the reactions showed that a

better yield was obtained when the reagent 3 was in solution. These reaction conditions

were applied to the derivatives 3b – 3j and the corresponding products 4 were isolated in

very good to excellent yield after simple filtration and extraction procedures (Scheme 3,

Table 3).

Scheme 3. Selected method for the reduction of 2-(nitrophenyl)adenine derivatives 3 to

the amine counterpart 4.

Conclusions

In summary, we have successfully synthesized novel 2-(aminophenyl)adenine derivatives

4, from the corresponding 2-(nitrophenyl)adenine derivatives 3 using reaction conditions

that avoid the use of flammable hydrogen gas or high-pressure equipment. The method is

compatible with the presence of functional groups such as amines, ethers, halofluorides

and halochlorides but hasn't been evaluated for bromo or iodo derivatives. Our protocol

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involves predominantly ecofriendly reagents and solvents, simple procedures for the

isolation of products and short reaction times. The products are generally isolated in high

yields. The reported compounds are fundamental precursors for the generation of new

adenine derivatives with biological activity that will be reported elsewhere.

Experimental

Melting points (mp, ˚C) were determined in a Gallenkamp apparatus and are uncorrected.

1H and 13C NMR spectra, including HMQC and HMBC were recorded on a Bruker

Avance III at 400 and 100.6 MHz, respectively. Chemical shifts (δ) are given in parts per

million (ppm), downfield from tetramethylsilane (TMS), and coupling constants (J) in

hertz (Hz). Elemental analysis was performed on a LECO CHNS 932 elemental analyzer.

Reactions were monitored by thin layer chromatography (TLC), using pre-coated TLC-

sheets Alugram Xtra SIL G/UV254, with revelation under UV light (254 nm). Infrared

spectra were recorded with a FT-IR Bomem MB 104 using Nujol mulls and NaCl cells.

General procedure for the synthesis of compounds 3

The nitrobenzalaldehyde 2 (1.1 equiv) and Et3N (15 equiv.) were added to a suspension

of 5-amino-4-amidino-imidazoles 1 in DMSO. The reaction was carried out at 80 ˚C

under efficient magnetic stirring and was carefully monitored by TLC. When the starting

reagent was absent the reaction was cooled to r.t. and distilled water was added to the

suspension. The solid was filtered and washed with distilled water followed by cold

ethanol and cold diethyl ether and identified as compound 3. Analytical pure samples

were obtained by recrystallization of the isolated solids from ethanol.

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4-(2-(3-nitrophenyl)-9-phenyl-9H-purin-6-yl)morpholine (3a)

Compound 3a (0.75 g, 1.79 mmol, 93%) was obtained as a light-yellow solid from

compound 1a (0.52 g, 1.93 mmol) with 1.1. equiv of 2a after 2h. Mp 185-187˚C. IR

(nujol): v = 3356, 3288, 3121, 1591, 1572, 1515 cm-1.1H NMR (400 MHz, DMSO-d6): δ

= 8.94 (t, J = 1.6 Hz, 1 H, ArH), 8.67 (d, J = 8.0 Hz, 1 H, ArH), 8.61 (s, 1 H, 8-H), 8.24

(dd, J4 = 1.6 Hz, J3 = 8.0 Hz, 1H, ArH), 7.90 (d, J = 7.6 Hz, 2 H, ArH), 7.71(t, J = 8.0

Hz, 1 H, ArH), 7.63 (t, J = 7.6 Hz, 2 H, ArH), 7.50 (t, J = 7.6 Hz, 1 H, ArH), 4.29 (br s,

4 H, CH2), 3.78 (t, J = 4.8 Hz, 4 H, CH2). 13C NMR (100 MHz, DMSO-d6): δ = 155.2,

153.1, 151.0, 148.0, 139.8 (8-C), 139.6, 134.8, 133.8, 130.0, 129.6, 127.8, 124.3, 123.4,

121.7, 119.1, 66.2, 45.5. Anal. Calcd for C21H18N6O3: C, 62.68; H, 4.50; N, 20.89; Found:

C, 62.57; H, 4.51; N, 20.87.

4-(2-(4-nitrophenyl)-9-phenyl-9H-purin-6-yl)morpholine (3b)

Compound 3b (0.44 g, 1.08 mmol, 65%) was obtained as a yellow solid from compound

1a (0.45 g, 1.67 mmol) and 1.1 equiv of 2b after 16h. Mp 237-239 ˚C. IR (nujol): v =

3359, 3295, 3123, 3036, 1594, 1573, 1518 cm-1. 1H NMR (400 MHz, DMSO-d6): δ =

8.68 (s, 1 H, 8-H), 8.55 (d, J = 8.8 Hz, 2 H, ArH), 8.29 (d, J = 8.8 Hz, 2 H, ArH), 7.93

(d, J = 7.6 Hz, 2 H, ArH), 7.64 (t, J = 7.6 Hz, 2 H, ArH), 7.51 (t, J = 7.6 Hz, 1 H, ArH),

4.35 (br s, 4 H, CH2), 3.80 (t, J = 4.8 Hz, 4 H, CH2). 13C NMR (100 MHz, DMSO-d6): δ

= 155.4, 153.2, 151.1, 148.2, 144.0, 140.2 (8-C), 134.8, 129.6, 128.7, 127.8, 123.6, 123.5,

119.2, 66.2, 45.3. Anal. Calcd for C21H18N6O3: C, 62.68; H, 4.50; N, 20.89. Found: C,

62.57; H, 4.51; N, 20.81.

4-(9-(4-fluorophenyl)-2-(3-nitrophenyl)-9H-purin-6-yl)morpholine (3c)

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Compound 3c (0.47 g, 1.10 mmol, 62%) was obtained as a very light-yellow solid from

compound 1b (0.52 g, 1.78 mmol) and 1.1 equiv of 2a after 17.5h. Mp 215-217 ˚C. IR

(nujol): v = 3315, 3121, 3049, 1591, 1574, 1509 cm-1.1H NMR (400 MHz, DMSO-d6): δ

= 9.01 (t, 2.0 Hz, 1 H, ArH), 8.74 (dt, J4 = 2.4 Hz, J3 = 8.0 Hz, 1 H, ArH), 8.62 (s, 1 H,

8-H), 8.29 (ddd, J4 = 2.0 Hz, J4 = 2.4 Hz, J3 = 8.0 Hz, 1 H, ArH), 7.93 (dd, J4 = 4.8Hz,

J3 = 9.2 Hz, 2 H, ArH), 7.64 (t, J = 8.0 Hz, 1 H, ArH), 7.51 (t, J = 9.2 Hz, 2 H, ArH),


= 161.2 (d, J1 = 244.0 Hz), 155.4, 153.3, 151.2, 148.2, 140.1, 139.7 (8-C), 133.9, 131.2

(d, J4 = 2.0 Hz), 130.1, 126.0 (d, J3 = 9.0 Hz), 124.5, 121.9, 119.0, 116.4 (d, J2 = 23.0

Hz), 66.3, 45.3. Anal. Calcd for C21H17FN6O3: C, 60.00; H, 4.08; N, 19.99. Found: C,

60.05; H, 4.09; N, 19.89.

4-(9-(3-fluorophenyl)-2-(3-nitrophenyl)-9H-purin-6-yl)morpholine (3d)

Compound 3d (0.49 g, 1.08 mmol, 92%) was obtained as a light-yellow solid from

compound 1c (0.34 g, 1.17 mmol) and 1.1 equiv of 2a after 22h. Mp 204-206 ˚C. IR

(nujol): v = 3317, 3119, 3046, 1592, 1571, 1513 cm-1. 1H NMR (400 MHz, DMSO-d6): δ

= 8.96 (t, J4 = 2.0 Hz, 1 H, ArH), 8.67-8.70 (m, 2H, 8-H + ArH), 8.26 (dd, J4 = 2.0 Hz,

J3 = 8.0 Hz, 1 H, ArH), 7.92 (dt, J4 = 3.2 Hz, J3 = 8.4 Hz, 1 H, ArH), 7.85 (dd, J4 = 3.2

Hz, J3 = 8.4 Hz, 1 H, ArH), 7.73 (t, J = 8.0 Hz, 1 H, ArH), 7.66 (td, J4 = 3.2 Hz, 1 H,

ArH), 7.33 (dt, J4 = 3.2 Hz, J3 = 8.0 Hz, 1 H, ArH), 4.31 (br s, 4 H, CH2), 3.78 (t, J = 4.8

Hz, 4 H, CH2). 13C NMR (100 MHz, DMSO-d6): δ = 161.2 (d, J1 = 243.0 Hz), 155.3,

153.1, 150.9, 148.0, 139.6 (8-C), 139.5, 136.3 (d, J3 = 10.0 Hz), 133.8, 131.3 (d, J3 = 9.0

Hz), 130.0, 124.0, 121.8, 119.0 (d, J3 = 4 Hz), 118.9, 114.4 (d, J2 = 21.0 Hz), 110.4 (d,

J2 = 26.0 Hz), 66.2, 45.6. Anal. Calcd for C21H17FN6O3: C, 60.00; H, 4.07; N, 19.99.

Found: C, 60.22; H, 4.05; N 19.98.

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4-(9-(4-chlorophenyl)-2-(3-nitrophenyl)-9H-purin-6-yl)morpholine (3e)

Compound 3e (0.46 g, 1.04 mmol, 59%) was obtained as a yellow solid from compound

1d (0.54 g, 1.76 mmol) and 1.1 equiv of 2a after 18.5h. Mp 246-248˚C. IR (nujol): v =

3387, 3115, 3086, 1594, 1572, 1520 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 9.01 (t,

J4 = 2.4 Hz, 1 H, ArH), 8.75 (dt, J4 = 2.4 Hz, J3 = 8.0 Hz, 1 H, ArH), 8.66 (s, 1 H, 8-H),

8.29 (dd, J4 = 2.4 Hz, J3 = 8.0 Hz, 1 H, ArH), 7.98 (d, J = 8.8 Hz, 2 H, ArH), 7.76 (t, J =

8.0 Hz, 1 H, ArH), 7.71 (d, J = 8.8 Hz, 2 H, ArH), 4.34 (br s, 4 H, CH2), 3.80 (t, J = 4.8

Hz, 4 H, CH2). 13C NMR (100 MHz, DMSO-d6): δ = 155.5, 153.3, 151.1, 148.2, 139.9

(8-C), 139.7, 134.0, 133.7, 132.3, 131.2, 130.2, 129.6, 125.3, 124.6, 121.9, 119.1, 66.3,

45.4. Anal. Calcd for C21H17ClN6O3: C, 57.74; H, 4.92; N, 19.24. Found: C, 57.63; H,

3.90; N, 19.18.

4-(9-(3,4-dichlorophenyl)-2-(3-nitrophenyl)-9H-purin-6-yl)morpholine (3f)

Compound 3f (0.56 g, 1.18 mmol, 80%) was obtained as a yellow solid from compound

1e (0.51 g, 1.49 mmol) and 1.1 equiv of 2a after 18.5h. Mp 258-260 ˚C; IR (nujol) v =

3357, 3130, 3097, 1591, 1575, 1525 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 9.02 (br

s, 1 H, ArH), 8.71 (dd, J4 = 1.6 Hz, J3 = 8.0 Hz, 1H, ArH), 8.67 (s, 1 H, 8-H), 8.36 (d, J4

= 2.4 Hz, 1H, ArH), 8.27 (dd, J4 = 1.6 Hz, J3 = 8.0 Hz, 1 H, ArH), 8.02 (dd, J4 = 2.4 Hz,

J3 = 8.8 Hz, 1 H, ArH), 7.86 (d, J = 8.8 Hz, 1H, ArH), 7.75 (t, J = 8.0 Hz, 1 H, ArH),


= 155.3, 153.1, 150.8, 148.0, 139.4, 139.0 (8-C), 134.4, 134.0, 131.7, 131.0, 129.9, 129.7,

124.5, 124.0, 122.8, 121.6, 118.9, 65.9, 45.2. Anal. Calcd for C21H16Cl2N6O3: C, 53.52;

H, 3.42; N, 17.83. Found: C, 53.50; H, 3.43; N, 17.79.

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4-(9-benzyl-2-(3-nitrophenyl)-9H-purin-6-yl)morpholine (3g)

Compound 3g (0.25 g, 0.60 mmol, 72%) was obtained as a light-beige solid from

compound 1f (0.24 g, 0.83 mmol) and 1.1 equiv of 2a after 5h. Mp 202-204˚C; IR (nujol):

v = 3357, 3294, 3096, 1593, 1574, 1532, 1517cm-1. 1H NMR (400 MHz, DMSO-d6): δ =

9.02 (t, J4 = 2.0 Hz, 1 H, ArH), 8.73 (dd, J4 = 2.0 Hz, J3 = 8.0 Hz, 1H, ArH), 8.67 (s, 1

H, 8-H), 8.73 (dd, J4 = 2.0 Hz, J3 = 8.0 Hz, 1 H, ArH), 8.33 (s, 1 H, H8), 8.24 (dd, J4 =

2.0 Hz, J3 = 8.0 Hz, 1 H, ArH), 7.72 (t, J = 8.0 Hz, 1 H, ArH), 7.38 (d, J = 7.2 Hz, 2 H,

ArH), 7.33 (t, J = 7.2 Hz, 2 H, ArH), 7.26 (t, J = 7.2 Hz, 1 H, ArH), 5.44 (s, 2 H, CH2),

4.28 (br s, 4 H, CH2), 3.73(t, J = 4.8Hz, 4 H, CH2). 13C NMR (100 MHz, DMSO-d6): δ

= 155.1, 153.3, 151.7, 148.4, 141.3 (8-C), 140.1, 137.1, 134.1, 130.4, 129.0, 128.2, 128.1,

124.6, 122.0, 118.8, 66.5, 46.7, 45.6. Anal. Calcd for C22H20N6O3 : C, 63.45; H, 4.84; N,

20.18; Found: C, 63.28; H, 4.82; N, 20.09.

4-(2-(3-nitrophenyl)-9H-purin-6-yl)morpholine (3h)

Compound 3h (0.13 g, 0.38 mmol, 73%) was obtained as a tanned yellow solid from

compound 1g (0.10 g, 0.52 mmol) and 1.1 equiv of 2a after 20h. Mp 258-260˚C. IR

(nujol): v = 3400, 3145, 3094, 1590, 1568, 1526, 1514cm-1. 1H NMR (400 MHz, DMSO-

d6): δ = 13.24 (br s, 1 H, 9-NH), 9.08 (t, J4 = 1.6 Hz, 1 H, ArH), 8.76 (d, J = 8.0 Hz, 1 H,

ArH), 8.28 (dd, J4 = 1.6 Hz, J3 = 8.0 Hz, 1 H, ArH), 8.21 (s, 1 H, 8-H), 7.76 (t, J = 8.0

Hz, 1 H, ArH), 4.31 (br s, 4 H, CH2), 3.77 (t, J = 4.8 Hz, 4 H, CH2).13C NMR (100 MHz,

DMSO-d6): δ = 154.7, 153.0, 152.4, 148.1, 140.1 (8-C), 139.4, 133.7, 130.1, 124.1, 121.7,

118.4, 66.2, 45.2. Anal. Calcd for C15H14N6O3: C, 55.21; H, 4.32; N, 25.76. Found: C,

55.03; H, 4.02; N, 25.82.

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4-(9-methyl-2-(3-nitrophenyl)-9H-purin-6-yl)morpholine (3i)

Compound 3i (0.28 g, 0.81 mmol, 60%) was obtained as a yellow solid from compound

1h (0.28 g, 1.35 mmol) and 1.1 equiv of 2a after 17h. Mp 148-150 ˚C. IR (nujol): v =


J4 = 2.4 Hz, 1 H, ArH), 8.77 (dt, J4 = 2.4 Hz, J3 = 8.0 Hz, 1 H, ArH), 8.27 (dd, J4 = 2.4

Hz, J3 = 8.0 Hz, 1 H, ArH), 8.19 (s, 1 H, 8-H), 7.75 (t, J = 8.0 Hz, 1 H, ArH), 4.28 (br s,

4 H, CH2), 3.80 (s, 3 H, 9-CH3), 3.76 (t, J = 4.8 Hz, 4 H, CH2). 13C NMR (100 MHz,

DMSO-d6): δ = 154.6, 153.0, 151.8, 148.1, 141.7 (8-C), 139.9, 133.8, 130.0, 124.2, 121.7,

118.6, 66.2, 45.2, 29.6. Anal. Calcd for C16H16N6O3: C, 56.47; H, 4.73; N, 24.79. Found:

C, 56.51; H, 4.70; N, 24.73.

2-(3-nitrophenyl)-9-phenyl-6-(piperidin-1-yl)-9H-purine (3j)

Compound 3j (0.44 g, 1.10 mmol, 52%) was obtained as a yellow solid from compound

1i (0.57 g, 2.11 mmol) and 1.1 equiv of 2a after 17.5h. Mp 179-181 ˚C. IR (nujol): v =


J4 = 2.0 Hz, 1 H, ArH), 8.68 (d, J = 8.0 Hz, 1 H, ArH), 8.47 (s, 1 H, 8-H), 8.22 (dd, J4 =

2.0 Hz, J3 = 8.0 Hz, 1 H, ArH), 7.90 (d, J = 7.6 Hz, 2 H, ArH), 7.71 (t, J = 8.0 Hz, 1 H,

ArH), 7.61 (t, J = 7.6 Hz, 2 H, ArH), 7.48 (t, J = 7.6 Hz, 1 H, ArH), 4.30 (brs, 4 H, CH2),

1.67-1.72 (m, 6 H, CH2).13C NMR (100 MHz, DMSO-d6): δ = 155.3, 153.2, 151.0, 148.1,

140.0, 138.9 (8-C), 134.8, 133.4, 129.6, 129.3, 127.5, 123.8, 123.3, 121.6, 118.9, 45.7,

25.4, 23.9. Anal. Calcd for C22H20N6O2: C, 65.99; H, 5.03; N, 20.99. Found: C, 65.79; H,

5.01; N, 20.91.

General procedure for the reduction of 2-(nitrophenyl)adenine derivatives 3

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2-(Nitrophenyl)adenine derivative 3 was combined, in a round bottom flask, with Fe

powder (8 equiv.) and acetic acid (20 equiv.) in 70% aqueous ethanol solution. The

reaction mixture, under nitrogen atmosphere, was submitted to reflux and the reaction

was monitored by TLC. When the TLC showed absence of starting material, the

suspension was cooled to approximately 20 oC. A 25% aqueous ammonia solution was

added to the suspension until pH=10. The residue in suspension was filtered through a

diatomaceous earth column (1.0 cm) and the aqueous layer was extracted using DCM

(70mL). The organic yellow solution was dried over anhydrous sodium sulfate and

concentrated using the rotary evaporator. The suspension was cooled to 5˚C, filtered and

the solid was washed successively with cold ethanol and diethyl ether and identified as

compound of structure 4. Analytical pure samples were obtained by recrystallization of

the isolated solids from dichloromethane.

3-(6-morpholino-9-phenyl-9H-purin-2-yl)aniline (4a)

Compound 4a (0.42 g, 1.09 mmol, 87%) was obtained as a beige solid from compound

3a (0.52 g, 1.25 mmol) after 4h. Mp 184-185˚C. IR (nujol): v = 3459, 3360, 3240, 3118,

1629, 1594, 1588, 1566, 1518 cm-1.

1H NMR (400 MHz, DMSO-d6): δ = 8.58 (s, 1 H, 8-

H), 7.95 (d, J = 7.6 Hz, 2 H, ArH), 7.60-7.65 (m, 3 H, ArH), 7.53 (d, J = 8.0 Hz, 1 H,

ArH), 7.48 (t, J = 7.6 Hz, 1H, ArH), 7.08 (t, J = 8.0 Hz, 1 H, ArH), 6.63 (dd, J4 = 1.6

Hz, J3 = 8.0 Hz, 1 H, ArH), 5.13 (br s, 2 H, ArNH2), 4.33 (br s, 4 H, CH2), 3.78 (t, J =

4.8 Hz, 4 H, CH2). 13C NMR (100 MHz, DMSO-d6): δ = 158.5, 153.2, 151.4, 148.6, 139.3

(8-C), 138.7, 135.1, 129.6, 128.6, 127.6, 123.3, 118.6, 115.8, 115.6, 113.5, 66.3, 45.3.

Anal. Calcd for C21H20N6O: C, 67.73; H, 5.41; N, 22.57. Found: C, 67.64; H, 5.39; N,

22,51.

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4-(6-morpholino-9-phenyl-9H-purin-2-yl)aniline (4b)

Compound 4b (0.31 g, 0.80 mmol, 83%) was obtained as a tanned yellow solid from

compound 3b (0.40 g, 0.96 mmol) after 2.5h. Mp 254 -256 ̊ C. IR (nujol): v = 3450, 3362,

3223, 3115, 1632, 1597, 1580, 1561, 1515 cm-1. 1H NMR (400 MHz, DMSO-d6): δ =

8.51 (s, 1 H, 8-H), 8.06 (d, J = 8.8 Hz, 2 H, ArH), 7.95 (d, J = 7.6 Hz, 2 H, ArH), 7.63

(t, J = 7.6 Hz, 2 H, ArH), 7.46 (t, J = 7.6 Hz, 1 H, ArH), 6.59 (d, J = 8.8 Hz, 2 H, ArH),

5.48 (br s, 2 H, ArNH2), 4.30 (br s, 4 H, CH2), 3.77 (t, J = 4.8 Hz, 4 H, CH2). 13C NMR

(100 MHz, DMSO-d6): δ = 158.5, 153.2, 151.6, 150.7, 138.4 (8-C), 135.3, 129.5, 129.1,

127.3, 125.4, 123.1, 117.8, 113.1, 66.3, 45.2. Anal. Calcd for C21H20N6O: C, 67.73; H,

5.41; N, 22.57. Found: C, 67.75; H, 5.42; N, 22.51.

3-(9-(4-fluorophenyl)-6-morpholino-9H-purin-2-yl)aniline (4c)

Compound 4c (0.29 g, 0.74 mmol, 77%) was obtained as an ivory solid from compound

3c (0.41 g, 0.97 mmol) after 1.5h. Mp 145-147˚C. IR (nujol): v = 3405, 3329, 3230, 3125,

1630, 1570, 1520 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 8.55 (s, 1 H, 8-H), 7.98 (dd,

J4 = 4.4 Hz, J3 = 8.8 Hz, 2 H, ArH), 7.60 (t, J4 = 2.0 Hz, 1 H, ArH), 7.53 (d, J = 8.0 Hz,

1 H, ArH), 7.48 (t, J = 8.8 Hz, 2H, ArH), 7.08 (t, J4 = 2.0 Hz, 1 H, ArH), 6.63 (dd, J4 =

2.0 Hz, J3 = 8.0 Hz, 1 H, ArH), 5.13 (br s, 2 H, ArNH2), 4.33 (br s, 4 H, CH2), 3.78 (t, J

= 4.8 Hz, 4 H, CH2). 13C NMR (100 MHz, DMSO-d6): δ = 161.0 (d, J1 = 243.0 Hz),

158.3, 153.1, 151.4, 148.5, 139.3 (8-C), 131.5 (d, J4 = 3.0 Hz), 128.6, 125.6 (d, J3 = 8.0

Hz), 118.4, 116.4 (d, J2 = 23.0 Hz), 115.8, 115.6, 113.5, 66.3, 45.3. Anal. Calcd for

C21H19FN6O: C, 64.61; H, 4.90; N, 21.53. Found: C, 64.49; H, 4.89; N, 21.49.

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3-(9-(3-fluorophenyl)-6-morpholino-9H-purin-2-yl)aniline (4d)

Compound 4d (0.29 g, 0.74 mmol, 68%) was obtained as an ivory solid from compound

3d (0.41 g, 0.97 mmol) after 2.5h. Mp 183-185˚C. IR (nujol): v = 3102, 1589, 1574 cm-

1. 1H NMR (400 MHz, DMSO-d6): δ = 8.66 (s, 1 H, 8-H), 7.96 (t, J4 = 2.0 Hz, 1 H, ArH),

7.92 (dt, J4 = 2.0 Hz, J3 = 7.6 Hz, 2 H, ArH), 7.66 (t, J4 = 2.0 Hz, 1 H, ArH), 7.60 (t, J4

= 2.0 Hz, 1H, ArH), 7.53 (dt, J4 = 2.0 Hz, J3 = 8.0 Hz, 1 H, ArH), 7.33 (td, J4 = 2.0 Hz,

J3 = 7.6 Hz, 1H, ArH), 7.10 (t, J = 8.0 Hz, 1 H, ArH), 6.64 (dd, J4 = 2.0 Hz, J3 = 8.0 Hz,

1 H, ArH), 5.13 (br s, 2 H, ArNH2), 4.33 (br s, 4 H, CH2), 3.76 (t, J = 4.8 Hz, 4 H, CH2).

13C NMR (100 MHz, DMSO-d6): δ = 162.24 (d, J1 = 243.0 Hz), 158.40, 153.11, 151.35,

148.57, 139.02 (8-C), 138.59 (2-C), 136.53 (d, J3 = 9.0 Hz), 131.30 (d, J3 = 9.0 Hz),

128.66, 118.93 (d, J4 = 3.0 Hz), 118.56, 115.75, 115.68, 114.2(d, J2 = 21.0 Hz), 113.4,

110.3 (d, J2 = 24.0 Hz), 66.2, 45.2. Anal. Calcd for C21H19FN6O: C, 64.61; H, 4.90; N,

21.53. Found: C, 64.73; H, 4.87; N, 21.47.

3-(9-(4-chlorophenyl)-6-morpholino-9H-purin-2-yl)aniline (4e)

Compound 4e (0.34 g, 0.82 mmol, 86%) was obtained as a beige solid from compound

3e (0.46 g, 1.05 mmol) after 4.5h. Mp 206-208˚C. IR (nujol): v = 3462, 3265, 3230, 3112,

1634, 1572, 1510 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 8.60 (s, 1 H, ArH), 8.01 (d,

J = 8.8 Hz, 2 H, ArH), 7.70 (d, J = 8.8 Hz, 2 H, ArH), 7.61 (t, J4 = 2.0 Hz, 1 H, ArH),

7.53 (d, J = 7.6 Hz, 1 H, ArH), 7.08 (t, J = 7.6 Hz, 1 H, ArH), 6.64 (dq, J4 = 2.0 Hz, J3

= 7.6 Hz, 1 H, ArH), 5.13 (br s, 2 H, ArNH2), 4.33 (br s, 4 H, CH2), 3.78 (t, J = 4.8 Hz,

4 H, CH2). 13C NMR (100 MHz, DMSO-d6): δ = 158.4, 153.2, 151.4, 148.6, 139.0 (8-C),

138.6, 134.0, 131.83, 129.51, 128.65, 118.49, 115.83, 115.68, 113.47, 66.26, 45.21. Anal.

Calcd for C21H19ClN6O: C, 61.99; H, 4.70; N, 20.66. Found: C, 61.83; H, 4.71; N, 20.59.

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3-(9-(3,4-dichlorophenyl)-6-morpholino-9H-purin-2-yl)aniline (4f)

Compound 4f (0.35 g, 0.78 mmol, 87%) was obtained as a light-yellow solid from

compound 3f (0.42 g, 0.89 mmol) after 11h. Mp 163-165˚C. IR (nujol): v = 3442, 3362,

3233, 3092, 1572, 1514 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 8.64 (s, 1 H, 8-H),

8.34 (d, J4 = 2.4 Hz, 1 H, ArH), 8.09 (d, J4 = 2.4 Hz, J3 = 8.8 Hz, 1 H, ArH), 7.87 (d, J

= 8.8 Hz, 1 H, ArH), 7.60 (t, J4 = 2.0 Hz, 1 H, ArH), 7.52 (d, J = 7.6 Hz, 1 H, ArH), 7.09

(t, J= 7.6 Hz, 1 H, ArH), 6.65 (dd, J4 = 2.0 Hz, J3 = 7.6 Hz, 1 H, ArH), 5.13 (br s, 2 H,

ArNH2), 4.30 (br s, 4 H, CH2), 3.77 (t, J = 4.8 Hz, 4 H, CH2). 13C NMR (100 MHz,

DMSO-d6): δ = 158.4, 153.1, 151.3, 148.7, 138.8 (8-C), 138.5, 135.0, 131.9, 131.3, 129.7,

128.7, 124.53, 123.0, 118.5, 115.8, 115.8, 113.5, 66.3, 45.1. Anal. Calcd for

C21H18Cl2N6O: C, 57.15; H, 4.11; N, 19.04. Found: C, 57.32; H, 4.04; N, 18.87.

3-(6-morpholino-9H-purin-2-yl)aniline (4g)

Compound 4g (0.16 g, 0.54 mmol, 82%) was obtained as a brownish solid from

compound 3g (0.22 g, 0.66 mmol) after 3.5h. Mp 274-276˚C. IR (nujol): v =3447, 3350,

3223, 1688, 1597, 1570 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 12.96 (br s, 1 H, 9-

NH), 8.11 (s, 1 H, 8-H), 7.60 (t, J4 = 3.6 Hz, 1 H, ArH), 7.52 (dt, J4 = 3.6 Hz, J3 = 8.0

Hz, 1 H, ArH), 7.07 (t, J = 8.0 Hz, 1 H, ArH), 6.61 (dd, J4 = 3.6 Hz, J3 = 8.0 Hz, 1 H,

ArH), 5.11 (br s, 2 H, ArNH2), 4.28 (br s, 4 H, CH2), 3.75 (t, J = 4.8 Hz, 4 H, CH2). 13C

NMR (100 MHz, DMSO-d6): δ = 157.6, 152.9, 152.7, 148.5, 139.1, 138.7 (8-C), 128.6,

117.8, 115.6, 115.3, 113.3, 66.3, 45.1. Anal. Calcd for C22H22N6O: C, 68.38; H, 5.73; N,

21.75. Found: C, 68.15; H, 5.71; N, 21.78.

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3-(9-methyl-6-morpholino-9H-purin-2-yl)aniline (4h)

Compound 4h (0.31 g, 1.00 mmol, 78%) was obtained as a tanned yellow solid from

compound 3h (0.44 g, 1.28 mmol) after 1.5h. Mp 201-203˚C. IR (nujol): v = 3428, 3123,

3090, 1592, 1574, 1531 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 8.12 (s, 1 H, 8-H),

7.65 (t, J4 = 2.0 Hz, 1 H, ArH), 7.57 (dt, J4 = 2.0 Hz, J3 = 8.0 Hz, 1 H, ArH), 7.08 (t, J =

8.0 Hz, 1 H, ArH), 6.62 (dd, J4 = 2.0 Hz, J3 = 8.0 Hz, 1 H, ArH), 5.12 (br s, 2 H, ArNH2),

4.22 (br s, 4 H, CH2), 3.76 (t, J = 4.8 Hz, 4 H, CH2), 3.75 (s, 3 H, 9-CH3). 13C NMR (100

MHz, DMSO-d6): δ = 157.9, 152.9, 152.1, 148.5, 141.1 (8-C), 139.0, 128.6, 118.0, 115.9,

115.5, 113.4, 66.3, 45.2, 29.4. Anal. Calcd for C15H16N6O: C, 60.80; H, 5.44; N, 28.36.

Found: C, 60.65; H 5.41; N 28.28.

3-(9-benzyl-6-morpholino-9H-purin-2-yl)aniline (4i)

Compound 4i (0.34 g, 0.88 mmol, 78%) was obtained as a light brown solid from

compound 3i (0.47 g, 1.12 mmol) after 2h. Mp 122-124˚C. IR (nujol): v = 3105, 1587,

1573, 1519 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 8.29 (s, 1 H, 8-H), 7.66 (t, J4 = 1.6

Hz, 1 H, ArH), 7.58 (d, J = 7.6 Hz, 1 H, ArH), 7.38 (d, J = 7.2 Hz, 2 H, ArH), 7.34 (t, J

= 7.2 Hz, 2 H, ArH), 7.27 (t, J = 7.2 Hz, 1 H, ArH), 7.09 (t, J = 7.6 Hz, 1 H, ArH), 6.62

(dd, J4 = 1.6 Hz, J3 = 7.6 Hz, 1 H, ArH), 5.44 (s, 2 H, CH2), 5.13 (br s, 2 H, ArNH2), 4.22

(br s, 4 H, CH2), 3.75 (t, J = 4.8 Hz, 4 H, CH2). 13C NMR (100 MHz, DMSO-d6): δ =

157.7, 152.9, 152.7, 148.5, 140.3 (8-C), 138.9, 137.2, 128.7, 128.6, 127.8, 127.7, 118.0,

115.8, 115.5, 113.4, 66.2, 46.1, 45.1. Anal. Calcd for C16H18N6O: C, 61.92; H, 5.84; N,

27.08. Found: C, 61.76; H, 5.82; N, 27.13.

3-(9-phenyl-6-(piperidin-1-yl)-9H-purin-2-yl)aniline (4j)

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Compound 4j (0.19 g, 0.52 mmol, 66%) was obtained as an ivory solid from compound

3j (0.31 g, 0.78 mmol) after 2h. Mp 193-195 ˚C. IR (nujol): v = 3457, 3358, 3224, 3108,

1572, 1515 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 8.53 (s, 1 H, 8-H), 7.93 (d, J = 7.2

Hz, 2 H, ArH), 7.59-7.65 (m, 3 H, ArH), 7.52 (d, J = 7.6 Hz, 1 H, ArH), 7.47 (t, J = 7.2

Hz, 1 H, ArH), 7.07 (t, J = 7.6 Hz, 1 H, ArH), 6.63 (dd, J4 = 3.6 Hz, J3 = 7.6 Hz, 1 H,

ArH), 5.13 (br s, 2 H, ArNH2), 4.31 (br s, 4 H, CH2), 1.71 (d, J = 3.6 Hz, 2 H, CH2), 1.64

(d, J = 3.6 Hz, 4 H, CH2). 13C NMR (100 MHz, DMSO-d6): δ = 158.3, 153.1, 151.4,

148.5, 139.0, 138.7 (8-C), 135.3, 129.6, 128.6, 127.5, 118.4, 115.9, 115.7, 113.5, 45.8,

25.8, 24.4. Anal. Calcd for C22H22N6: C, 71.33; H, 5.98; N, 22.69. Found: C, 71.15; H,

5.95; N, 22.73.

Supplementary material

1H NMR and 13C NMR data of all new compounds are available with the article through the journal Web site.

Acknowledgements

Thanks are due to the University of Minho and Fundaҫão para a Ciência e Tecnologia

(FCT) for financial support [project n°F-COMP-01-0124-FEDER-022716 (ref. FCT

PEst-/QUI/UI0686/2011) FEDER-COMPETE, FCT-Portugal, a PhD Grant awarded to

Ashly Rocha (SFRH/BD/85937/2012). The NMR spectrometer (Bruker 400 Avance III)

is part of the National NMR network, supported with funds from FCT.

References

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(1) (a) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987. (b) Asati,

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Trans. 1 1992, 913. (b) Booth, B. L.; Dias, A. M.; Proença, M. F. J. Chem. Soc.,

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Heterocycl. Chem. 1994, 31, 345. (d) Booth, B. L.; Coster, R. D.; Proença, M. F.

Synthesis 1988, 389. (e) Alves, M. J.; Booth, B. L.; Carvalho, M. A.; Pritchard, R.

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L.; Carpenter, R. A.; Carvalho, M. A.; Marrelec, E.; Pritchard, R. G.; Proença, M.F.

J. Chem. Soc., Perkin Trans. 1 2001, 2532. (g) Booth, B.L.; Cabral, I. M.; Dias, A.

M.; Freitas, A. P.; Matos-Beja, A. M.; Proença, M. F.; Ramos-Silva, M. J. Chem.

Soc., Perkin Trans. 1 2001, 1241. (h) Carvalho, M. A.; Esteves, T. M.; Proença, M.

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https://www.ncbi.nlm.nih.gov/pubmed/?term=Lougiakis%20N%5BAuthor%5D&cauthor=true&cauthor_uid=27720327

https://www.ncbi.nlm.nih.gov/pubmed/?term=Gavriil%20ES%5BAuthor%5D&cauthor=true&cauthor_uid=27720327

https://www.ncbi.nlm.nih.gov/pubmed/?term=Kairis%20M%5BAuthor%5D&cauthor=true&cauthor_uid=27720327

https://www.ncbi.nlm.nih.gov/pubmed/?term=Benaki%20D%5BAuthor%5D&cauthor=true&cauthor_uid=27720327

https://www.ncbi.nlm.nih.gov/pubmed/?term=Mikros%20E%5BAuthor%5D&cauthor=true&cauthor_uid=27720327

https://www.ncbi.nlm.nih.gov/pubmed/?term=Marakos%20P%5BAuthor%5D&cauthor=true&cauthor_uid=27720327

https://www.ncbi.nlm.nih.gov/pubmed/?term=Pouli%20N%5BAuthor%5D&cauthor=true&cauthor_uid=27720327

https://www.ncbi.nlm.nih.gov/pubmed/?term=Diallinas%20G%5BAuthor%5D&cauthor=true&cauthor_uid=27720327

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C.; Morán, J. R. Tetrahedron, 1996, 52, 12323.

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List of table captions

Table 1. Synthesis of novel 2-(nitrophenyl)adenine derivatives 3, as represented in

scheme 2.

Table 2. Attempts to perform the reduction of 2-(nitrophenyl)adenine derivative 3a.

Table 3. Selected method for the reduction of 2-(nitrophenyl)adenine derivatives 3 to

the amine counterpart 4, according to scheme 3.

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Graphical abstract

NH

NH2N

N

R1

R

R= H, alkyl, arylR1= morpholinyl, piperidinyl;

1

DMSO, Et3N, 80 oC

+

R2 = 4-NO2C6H4R2 = 3-NO2C6H4

N

NN

N

R1

R

3

NO2

N

NN

N

R1

R

4

NH2

Fe powder, HOAc,70% aq. EtOH,

2R2

O

H

3

10 new compoundsup to 93% yield

10 new2-(aminoaryl)adenine

derivativesUp to 87% yield

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Table 1. Synthesis of novel 2-(nitrophenyl)adenine derivatives 3, as represented in

scheme 2.

Entry Imidazole

1

Aldehyde

2

Reaction Conditions (i) Product 3 Yield

(%)

1 1b 2a i) a) 1b (0.17 g), 2a (1.1

equiv), DMSO, DBU

(cat.), 19-21oC, 21h; b)

40℃, 26d

3c a

2 1a 2a i) 1a (0.52 g), 2a (1.1

equiv), DMSO, Et3N (15

equiv), 80℃, 2h

3a 93

3 1a 2b i) 1a (0.45 g), 2b (1.1

equiv), DMSO, Et3N

(15 equiv), 80℃, 16h

3b 65

4 1b 2a i) 1d (0.52 g), 2a (1.1


equiv), 80℃, 17.5h

3c 62

5 1c 2a i) 1e (0.34 g), 2a (1.1


equiv), 80℃, 22h

3d 92

6 1d 2a i) 1f (0.54 g), 2a (1.1


equiv), 80℃, 18.5h

3e 59

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7 1e 2a i) 1g (0.51 g), 2a (1.1


equiv), 80℃, 18.5h

3f 80

8 1f 2a i) 1h (0.24 g), 2a (1.1


equiv), 80℃, 5h

3g 72

9 1g 2a i) 1i (0.10 g), 2a (1.1


equiv), 80℃, 20h

3h 73

10 1h 2a i) 1j (0.28 g), 2a (1.1


equiv), 80℃, 17h

3i 60

11 1i 2a i) 1k (0.57 g), 2a (1.1


equiv), 80℃, 17.5h

3j 52

a Product 3c identified as the major component by 1H NMR.

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Table 2. Attempts to perform the reduction of 2-(nitrophenyl)adenine derivative 3a.

Entry Catalyst H2 Source Solvent

(mL)

Time

(h)

T (oC) Yield

(%)

1 CuSO4 5H2O,

1.5 equiv.

NaBH4, 2.5

equiv.

EtOH:EtOAc

(2:1), 24

19 19-21 a

2 CuSO4 5H2O,

1.5 equiv.

NaBH4, 2.5

equiv.

DCM, 12 80 19-21 a

3 SnCl2, 4.0

equiv.

aq. HCl, 30

mL

EtOH, 30 14.5 65 9

4 Fe powder,

10 equiv.

no source EtOH, 20 5 19-21 b

5 Fe powder,

10 equiv.

HOAC,

20 equiv.

70% aq.

EtOH, 13

3.5 reflux 55

6 Fe powder,

8 equiv.

HOAC,

20 equiv.

70% aq.

EtOH, 15

4.5 reflux 25

7 Fe powder,

8 equiv.

HOAC,

20 equiv.

70% aq.

EtOH, 50

4 reflux 87

a No reaction.b Compound 4a identified as major component in a complex mixture.

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Table 3. Selected method for the reduction of 2-(nitrophenyl)adenine derivatives 3 to

the amine counterpart 4, according to scheme 3.

Entry Substrate 3

(mmol)

70% aq.

EtOH (mL)

Time

(h)

Product 4 Yield

(%)

1 3a (1.25) 50 4 4a 87

2 3b (0.96) 50 2.5 4b 83

3 3c (0.96) 80 1.5 4c 77

4 3d (1.26) 80 2.5 4d 68

5 3e (0.95) 80 4.5 4e 86

6 3f (0.89) 80 4 4f a

7 3f (1.17) 150 14.5 4f b

8 3f (0.89) 250 11 4f 87

9 3g (0.60) 60 3.5 4g 82

10 3h (1.28) 65 1.5 4h 78

11 3i (1.13) 80 2 4i 78

12 3j (0.79) 70 2 4j 66

a Isolated as a mixture of 3f and 4f in a 1:2 molar ratio by 1H NMR.

b Isolated as a mixture of 3f and 4f in a 1:4 molar ratio by 1H NMR.

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