Synthesis of 3-Cyano-1H-indoles and Their 2′-Deoxyribonucleoside Derivatives through One-Pot Cascade Reactions

Article abstract of DOI:10.1021/acs.joc.6b01612

An efficient and economical synthetic approach toward 3-cyano-1H-indoles through the reactions of 2-(2-bromophenyl)acetonitriles with aldehydes and aqueous ammonia is presented. Mechanically, this novel protocol involves a one-pot cascade procedure consisting of an aldol-type condensation, a copper-catalyzed amination by using aqueous ammonia as a cheap and safe nitrogen source, and an intramolecular Michael addition followed by a dehydrogenative aromatization. Interestingly, the indole products thus obtained were found to be ready substrates for the preparation of indole 2′-deoxyribonucleosides through an unprecedented and highly practical glycosylation procedure in which the required C-N bond formation and toluoyl protecting group removal were accomplished efficiently in one pot.

Full text of DOI:10.1021/acs.joc.6b01612

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pubs.acs.org/joc
Synthesis of 3‑Cyano‑1H‑indoles and Their 2′-Deoxyribonucleoside
Derivatives through One-Pot Cascade Reactions
Bin Li, Beibei Zhang, Xinying Zhang,* and Xuesen Fan*
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Environment, School of
Chemistry and Chemical Engineering, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan
Normal University, Xinxiang, Henan 453007, China
S
* Supporting Information
ABSTRACT: An efficient and economical synthetic approach toward 3-cyano-1H-indoles through the reactions of 2-(2-
bromophenyl)acetonitriles with aldehydes and aqueous ammonia is presented. Mechanically, this novel protocol involves a one-
pot cascade procedure consisting of an aldol-type condensation, a copper-catalyzed amination by using aqueous ammonia as a
cheap and safe nitrogen source, and an intramolecular Michael addition followed by a dehydrogenative aromatization.
Interestingly, the indole products thus obtained were found to be ready substrates for the preparation of indole 2′-
deoxyribonucleosides through an unprecedented and highly practical glycosylation procedure in which the required C−N bond
formation and toluoyl protecting group removal were accomplished efficiently in one pot.
Cascade reactions in which two or more transformations are
well accomplished in one pot to afford complex products from
simple starting materials are rapidly gaining popularity. In
comparison with step-by-step operations, cascade reactions
have the advantages of obviated isolation and purification of
intermediates and minimized generation of waste chemicals. In
addition, copper-catalyzed C−N bond formation is a powerful
and economical tool for the construction of N-heterocycles.2c,10
In this regard, our recent study has focused on the synthesis of
fused N-heterocycles through copper-catalyzed amination by
using aqueous ammonia as a cheap and safe nitrogen source.11
As a continuation of our interest in this aspect, we have studied
the one-pot, three-component cascade reaction of the
commercially available 2-(2-bromophenyl)acetonitriles with
aldehydes and aqueous ammonia. From this reaction, a series
of diversely substituted N-unprotected 3-cyanoindoles were
obtained in good to excellent yields through an easy-to-perform
one-pot procedure. Herein, we report our results in this regard.
INTRODUCTION
■
Indole derivatives have attracted much attention due to their
diverse medicinal activities, ubiquitous occurrence in nature,
and multiple uses in organic synthesis.1,2 In particular, 3-cyano-
substituted indoles are key building units embedded in lead
compounds currently being developed as estrogen receptor
ligands, hepatitis C virus inhibitors, or therapeutic agents for
cardiovascular diseases.3,4 Moreover, 3-cyanoindoles are also
indispensable intermediates for the preparation of a broad
range of fine chemicals.5 Because of their importance, a number
of synthetic methods leading to 3-cyanoindoles have been
developed. Based on the structural characteristics of the
substrates used therein, the existing synthetic methods might
be roughly classified into the following three categories: (1)
functional group transformation or structural manipulation of
3-carbonyl-, oximido-, hydroxymethyl-, or halide-substituted
indoles;5a,6 (2) direct C(sp2)−H cyanation on the 3-position of
indoles without prefunctionalization;5b,7,8 and (3) cyclization of
nonindole substrates such as functionalized benzenes.9 While
these literature synthetic strategies are generally efficient and
reliable, the first and the third methods usually necessitate
multiple synthetic steps if commercial reagents are used as the
starting materials. Meanwhile, the C−H cyanation protocol
often employs noble metal catalysts and/or toxic cyano sources
which many cases are only suitable for N-protected indoles. As
a result, new synthetic approaches toward 3-cyanoindoles with
a free −NH unit through simple procedures by directly using
commercially available, inexpensive, and safe reagents are still
urgently needed.
RESULTS AND DISCUSSION
■
Initially, a mixture of 2-(2-bromophenyl)acetonitrile (1a),
benzaldehyde (2a), and aqueous ammonia (3) was treated
with CuI and K2CO3 in DMF at 100 °C under air for 20 h.
From this reaction, the desired 2-phenyl-1H-indole-3-carbon-
itrile (4a) was obtained in a yield of 32% (Table 1, entry 1). To
improve the efficiency, different copper salts such as CuCl,
Received: July 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b01612
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a
carbaldehyde, or isonicotinaldehyde, the corresponding reac-
tions took place smoothly to give 4l, 4m, or 4n in 87%, 66%, or
57% yield, respectively. Promisingly, in addition to aromatic
aldehydes, alkyl aldehydes were also found to be suitable for
this reaction to provide products 4o−r in generally good yields.
Next, the scope of the 2-(2-bromophenyl)acetonitrile
substrate (1) was studied. The results listed in Table 3 showed
that 1 bearing either a strong electron-withdrawing trifluor-
omethyl group or two electron-donating methoxy groups
reacted smoothly with various aldehydes (2) and aqueous
ammonia (3) to give diversely substituted 3-cyanoindoles (4s−
z) in yields ranging from 63% to 89%.
On the basis of the above results and previous studies, a
plausible pathway for the formation of 2-phenyl-1H-indole-3-
carbonitrile (4a) is proposed in Scheme 1. Initially, an aldol-
type condensation between 1a and 2a affords an α,β-
unsaturated nitrile as intermediate A.12 Next, a Cu(I)-catalyzed
and ligand-assisted aryl amination of A with aqueous ammonia
(3) as the nitrogen source affords intermediate D, most likely
via intermediates B and C. Then, D undergoes an intra-
molecular Michael addition to give intermediate E. Finally, a
dehydrogenative aromatization occurs with E to afford 4a. It is
worth noting that under the catalysis of copper compound13 air
could act as an efficient and sustainable terminal oxidant for the
aromatization of the in situ formed indoline to give the
corresponding indole product.
Table 1. Optimization Study on the Formation of 4a
c
b
entry
catalyst
CuI
base
ligand
solvent
yield (%)
1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
K3PO4
tBuOK
DMF
32
16
2
CuCl
CuBr
CuCl2
Cu(OAc)2
Cu(OTf)2
CuI
DMF
3
DMF
18
4
DMF
15
5
DMF
22
6
DMF
trace
75
7
L-proline
DMEDA
TMEDA
1,10-Phen
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
DMF
8
CuI
DMF
45
9
CuI
DMF
51
10
11
12
13
14
15
16
17
18
19
20
CuI
DMF
60
CuI
DMSO
NMP
88
21
CuI
CuI
iPrOH
PEG-400
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
20
CuI
64
CuI
65
CuI
67
CuI
62
CuI
68
CuI
57
To verify the proposed reaction mechanism, some control
experiments were carried out. First, 1a was treated with 2a
under standard reaction conditions for 2 h, from which 2-(2-
bromophenyl)-3-phenylacrylonitrile, the proposed intermediate
A as described in Scheme 1, was obtained in a yield of 90%
(Scheme 2, eq 1). Second, a mixture of 1a, 2a, and 3 in DMSO
was treated with CuI, L-proline and K2CO3 at 100 °C under a
nitrogen atmosphere for 18 h. From this reaction, 2-
phenylindoline-3-carbonitrile, the proposed intermediate E,
was obtained in a yield of 83% (eq 2). Third, A was treated with
3 under standard reaction conditions for 15 h, from which 4a
was obtained in a yield of 91% (eq 3). Fourth, when E was
subjected to standard reaction conditions for 1 h, 4a could be
obtained in a yield of 97% (eq 4). Fifth, E was stirred in DMSO
under air but in the absence of all other reagents at 100 °C for 4
h. Under this circumstance, the formation of 4a was not
observed (eq 5). This result suggested that air alone could not
promote the transformation of indoline (E) toward indole (4a).
Taking all of the related results (Scheme 2, eqs 2, 4 and 5) into
account and based on previous reports,13 it is reasonable to
suggest that in the oxidative transformation of E toward 4a, air
is most likely acting as a terminal oxidant while the copper
compound should have acted as a catalyst to promote this
oxidation process.
Meanwhile, it is well-known that many indole nucleoside
analogues possess significant biological activities.14 In particular,
Townsend et al. reported that 3-substituted indole 2′-
deoxyribonucleosides (IDNs) are highly effective against
human cytomegalovirus (HCMV).15 Moreover, IDNs have
also been used in the extension of the genetic alphabet since the
indole unit represents an important artificial DNA base owing
to its structural similarity to guanine and adenine. For example,
a substituted IDN has been designed and used as a nonpolar
isostere of syn-8-oxoguanine to act as a probe for the
recognition and repair of oxidative DNA damage and to
study the syn−anti conformational effect.16 In view of the
importance of IDNs and as a continuation of our ongoing
K2CO3
a
Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), 3 (26%, 0.5
mL), catalyst (0.05 mmol), ligand (0.1 mmol), base (0.5 mmol),
b
solvent (2 mL), 100 °C, sealed tube, air, 20 h. Isolated yield.
c
DMEDA for N,N′-dimethylethylenediamine, TMEDA for N,N,N′,N′-
tetramethylethylenediamine, 1,10-Phen for 1,10-phenanthroline.
CuBr, CuCl2, Cu(OAc)2, and Cu(OTf)2 were tried as possible
catalysts. However, they were found to be less effective than
CuI in promoting this reaction (entries 2−6). On the other
hand, the yield of 4a increased significantly in the presence of
ligand, especially L-proline (entries 7−10). Next, DMSO, 1-
i
methyl-2-pyrrolidinone (NMP), PrOH, or PEG-400 was used
as the reaction medium (entries 11−14). Among them, DMSO
turned out to be the most efficient, affording 4a in a yield of
88% (entry 11). Subsequent studies on the effect of different
t
bases showed that Na2CO3, Cs2CO3, K3PO4, and BuOK were
less efficient than K2CO3 in promoting this cascade reaction
(entries 15−18 vs 11). Next, control experiments showed that
the yield of 4a decreased in the absence of a base (entry 19),
and the formation of 4a was not observed without a copper
catalyst (entry 20).
With the optimized reaction conditions in hand, we then
examined a series of substrates to determine the influence of
steric and electronic parameters on the efficiency of this cascade
procedure. First, with 1a and 3 as model substrates, the scope
of aldehyde (2) was explored. The results listed in Table 2
showed that phenyl aldehydes with either electron-donating
alkyl and alkoxyl groups or electron-withdrawing cyano and
trifluoromethyl groups attached on the phenyl ring underwent
this cascade process smoothly to give the corresponding
products 4a−k in good to excellent yields. Notably, various
functional groups were well tolerated under the reaction
conditions without showing obvious electronic and steric
effects. Halogenated aromatic moieties survived the reaction
conditions well, allowing for subsequent structural elaboration
of the products. Next, with 1-naphthaldehyde, thiophene-2-
B
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a,b
Table 2. Substrate Scope for the Synthesis of 3-Cyanoindole Derivatives I
a
Reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), 3 (26%, 0.5 mL), CuI (0.05 mmol), L-proline (0.1 mmol), K2CO3 (0.5 mmol), DMSO (2
b
mL), 100 °C, sealed tube, air, 20 h. Isolated yield.
a,b
Table 3. Substrate Scope for the Synthesis of 3-Cyanoindoles II
a
Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), 3 (26%, 0.5 mL), CuI (0.05 mmol), L-proline (0.1 mmol), K2CO3 (0.5 mmol), DMSO (2 mL),
b
100 °C, sealed tube, air, 20 h. Isolated yield.
interest in the synthesis and biological activity of nucleoside
analogues,17 we set out to synthesize some novel IDNs by using
the indole derivatives obtained above as the nucleobases. We
noticed that in previous studies IDNs were obtained through
two separate synthetic steps:15,16 (1) glycosylation of the -NH
free indoles with Hoffer’s chlorosugar (1-chloro-2-deoxy-3,5-di-
O-p-toluoyl-α-D-erythro-pentofuranose) in dry acetonitrile
under the promotion of sodium hydride affording toluoyl-
C
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accomplished in one pot to give the desired IDN 6a with free
hydroxyl groups in a total yield of 70% (Scheme 3).
Scheme 1. Proposed Reaction Mechanism for the Formation
of 4a
In addition, our following studies showed that this novel
nucleoside formation protocol was well suitable for indole
substrates with either electron-donating or electron-with-
drawing groups attached on the indole scaffold or the 2-phenyl
unit to give a series of diversely substituted IDNs (6a−g) in
reasonably good yields (Table 4).
In summary, we have developed an efficient and sustainable
synthetic approach toward 3-cyano-1H-indoles via copper-
catalyzed one-pot cascade reaction of the commercially
available 2-(2-bromophenyl)acetonitriles, aldehydes, and aque-
ous ammonia. Substrate generality studies showed that this
novel process provided a facile access toward diversely
substituted −NH-free 3-cyanoindoles with good efficiency.
Control experiments indicated that air actually acted as an
oxidant for this cascade procedure. As a further aspect, the
indole products thus obtained were found to be ready
substrates for the preparation of indole 2′-deoxyribonucleosides
via an unprecedented glycosylation procedure, in which the
required C−N bond formation and the toluoyl protecting
group removal were efficiently accomplished in one pot.
Compared with literature procedures, the synthetic protocols
developed herein showed advantages such as commercially
available and nontoxic starting materials, broad substrate scope
with a wide range of functional group tolerance, and obviation
of tedious step by step operations. With these notable features,
they are expected to find applications in synthetic and
medicinal chemistry.
protected IDNs; (2) treatment of the toluoyl-protected IDNs
with a solution of sodium methoxide in methanol to remove
the toluoyl protecting groups giving the target IDNs with free
hydroxyl units. Bearing in mind the advantages of one-pot
cascade reactions, we were interested in developing a one-pot
cascade procedure for the preparation of IDNs directly from
indoles and Hoffer’s chlorosugar. For this purpose, different
bases as the reaction promoter and various solvents as the
reaction medium were screened by using 4a and Hoffer’s
chlorosugar (5) as model substrates. After much trial and error,
we were pleased to find that by first treating 4a with Hoffer’s
chlorosugar (5) in the presence of 5 equiv of sodium hydride in
anhydrous acetonitrile at room temperature for 3 h followed by
adding 5 equiv of water and stirring the resulting mixture at
room temperature for 10 h, the required C−N bond formation
and toluoyl protecting group removal could be efficiently
EXPERIMENTAL SECTION
1. General Methods. Reagents and solvents were purchased from
commercial suppliers and used without further purification. The H
■
1
and 13C NMR spectra were recorded at 400 or 600 MHz and 100 or
150 MHz, respectively. Chemical shifts were referenced to
tetramethylsilane in CDCl3 or DMSO-d6. Multiplicity was indicated
Scheme 2. Control Experiments in Supporting the Proposed Reaction Mechanism
D
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Scheme 3. One-Pot Cascade Reaction Leading to IDN 6a
a,b
Table 4. One-Pot Synthesis of Indole 2′-Deoxyribonucleosides
a
b
Reaction conditions: 4 (0.3 mmol), 5 (0.33 mmol), NaH (1.5 mmol), CH3CN (3 mL), rt, 3 h; then, H2O (27 μL), rt, 10 h. Isolated yield.
as follows: s (singlet); d (doublet); t (triplet); m (multiplet); dd
(doublet of doublets); td (triplet of doublets); br s (broad singlet), etc.
Coupling constants are given in hertz. High-resolution mass spectra
(HRMS) were obtained via ESI mode by using a MicrOTOF mass
spectrometer. The conversion of starting materials was monitored by
thin-layer chromatography (TLC) using silica gel plates (silica gel 60
F254 0.25 mm), and components were visualized by observation
under UV light (254 and 365 nm).
12.62 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 81.4, 112.6, 116.4
2
4
(d, JC−F = 22.5 Hz), 116.9, 118.3, 122.1, 123.9, 125.9 (d, JC−F = 2.8
3
1
Hz), 128.2, 129.3 (d, JC−F = 8.7 Hz), 135.5, 143.8, 162.8 (d, JC−F
=
246.4 Hz). HRMS calcd for C15H10FN2: 237.0823 [M + H]+, found
237.0828.
2-(4-Chlorophenyl)-1H-indole-3-carbonitrile (4c). Eluent: petro-
leum ether−ethyl acetate (5:1). White solid (105 mg, 83%). Mp: 291−
292 °C (lit.11d 287−289 °C). 1H NMR (400 MHz, DMSO-d6) δ: 7.26
(t, J = 7.2 Hz, 1H), 7.30−7.34 (m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.64
(d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H),
12.67 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 82.2, 113.2, 117.2,
118.9, 122.6, 124.6, 128.66, 128.69, 129.1, 129.9, 135.1, 136.0, 143.8.
MS: m/z 253 [M + H]+.
2-(4-Bromophenyl)-1H-indole-3-carbonitrile (4d). Eluent: petro-
leum ether−ethyl acetate (5:1). White solid (75 mg, 51%). Mp: 299−
301 °C (lit.11d mp 301−302 °C). 1H NMR (600 MHz, DMSO-d6) δ:
7.29 (d, J = 7.2 Hz, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz,
1H), 7.67 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4
Hz, 2H), 12.68 (s, 1H). 13C NMR (150 MHz, DMSO-d6) δ: 82.3,
113.2, 117.3, 118.9, 122.7, 123.8, 124.6, 128.7, 129.0, 129.3, 132.8,
136.1, 143.9. MS: m/z 297 [M + H]+.
2. Typical Procedure for the Preparation of 2-Phenyl-1H-
indole-3-carbonitrile (4a). To a tube containing a solution of 2-(2-
bromophenyl)acetonitrile (1a, 98 mg, 0.5 mmol) in DMSO (2 mL)
were added CuI (9.5 mg, 0.05 mmol), L-proline (11.5 mg, 0.1 mmol),
K2CO3 (69 mg, 0.5 mmol), benzaldehyde (2a, 80 mg, 0.75 mmol),
and aqueous ammonia (3, 26%, 0.5 mL). The tube was then sealed,
and the mixture was stirred at 100 °C under an air atmosphere for 20
h. After being cooled to room temperature, the mixture was quenched
with water and extracted with ethyl acetate (10 mL × 3). The
combined organic phases were washed with brine, dried over
anhydrous Na2SO4, and concentrated under vacuum. The residue
was purified by column chromatography on silica gel using petroleum
ether−ethyl acetate (5:1) as the eluent to give 4a (96 mg, 88%). Other
3-cyanoindole derivatives (4b−z) were obtained in a similar manner.
2-Phenyl-1H-indole-3-carbonitrile (4a). Eluent: petroleum ether−
ethyl acetate (5:1). White solid (96 mg, 88%). Mp: 230−231 °C
2-(4-(Trifluoromethyl)phenyl)-1H-indole-3-carbonitrile (4e). Elu-
ent: petroleum ether−ethyl acetate (5:1). White solid (116 mg, 81%).
Mp: 267−268 °C (lit.11d mp 260−262 °C). H NMR (400 MHz,
1
(lit.11d mp 233−234 °C). H NMR (400 MHz, DMSO-d6) δ: 7.24−
1
DMSO-d6) δ: 7.30 (t, J = 7.2 Hz, 1H), 7.36−7.39 (m, 1H), 7.61 (d, J =
8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 8.20
(d, J = 8.0 Hz, 2H), 12.82 (s, 1H). 13C NMR (150 MHz, DMSO-d6)
δ: 83.2, 113.4, 117.0, 119.1, 122.8, 124.4 (q, 1JC−F = 271.05 Hz), 125.0,
7.34 (m, 2H), 7.52−7.58 (m, 2H), 7.60−7.66 (m, 3H), 7.99 (d, J = 7.6
Hz, 2H), 12.62 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 81.3,
112.6, 117.0, 118.4, 122.0, 123.9, 127.0, 128.3, 129.30, 129.33, 129.9,
135.5, 144.7. MS: m/z 219 [M + H]+.
2
126.8 (q, 3JC−F = 3.45 Hz), 128.2, 128.7, 130.2 (q, JC−F = 31.35 Hz),
2-(4-Fluorophenyl)-1H-indole-3-carbonitrile (4b). Eluent: petro-
133.7, 136.3, 143.1. MS: m/z 287 [M + H]+.
leum ether−ethyl acetate (5:1). White solid (99 mg, 84%). Mp: 240−
1
2-(4-Cyanophenyl)-1H-indole-3-carbonitrile (4f). Eluent: petrole-
um ether−ethyl acetate (5:1). White solid (73 mg, 60%). Mp: >300
°C. 1H NMR (400 MHz, DMSO-d6) δ: 7.30 (t, J = 8.0 Hz, 1H), 7.36−
241 °C. H NMR (400 MHz, DMSO-d6) δ: 7.26 (t, J = 7.2 Hz, 1H),
7.32 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 8.8 Hz, 2H), 7.55 (d, J = 8.4 Hz,
1H), 7.64 (d, J = 7.6 Hz, 1H), 8.02 (dd, J1 = 8.4 Hz, J2 = 5.2 Hz, 2H),
E
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7.40 (m, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 8.11
(d, J = 8.0 Hz, 2H), 8.16 (d, J = 8.4 Hz, 2H), 12.83 (s, 1H). 13C NMR
(100 MHz, DMSO-d6) δ: 83.0, 112.0, 112.9, 116.5, 118.4, 118.7,
122.4, 124.7, 127.5, 128.2, 133.2, 133.5, 135.8, 142.2. HRMS calcd for
C16H10N3: 244.0869 [M + H]+, found 244.0868.
2-Cyclohexyl-1H-indole-3-carbonitrile (4o). Eluent: petroleum
ether−ethyl acetate (5:1). White solid (81 mg, 72%). Mp: 166−167
1
°C; H NMR (400 MHz, CDCl3) δ: 1.25−1.35 (m, 1H), 1.39−1.50
(m, 2H), 1.56−1.66 (m, 2H), 1.78−1.82 (m, 1H), 1.87−1.92 (m, 2H),
2.06−2.10 (m, 2H), 3.01−3.09 (m, 1H), 7.22−7.26 (m, 2H), 7.27−
7.40 (m, 1H), 7.66−7.68 (m, 1H), 8.64 (br s, 1H). 13C NMR (100
MHz, CDCl3) δ: 25.7, 26.2, 32.4, 37.6, 83.2, 111.4, 116.6, 119.0, 122.0,
123.4, 127.8, 134.2, 153.6. HRMS calcd for C15H16N2Na: 247.1206 [M
+ Na]+, found 247.1176.
2-Propyl-1H-indole-3-carbonitrile (4p). Eluent: petroleum ether−
ethyl acetate (5:1). White solid (60 mg, 65%). Mp: 116−117 °C
(lit.11d mp 115−117 °C). 1H NMR (600 MHz, DMSO-d6) δ: 0.94 (t, J
= 7.2 Hz, 3H), 1.74−1.80 (m, 2H), 2.87 (t, J = 7.2 Hz, 2H), 7.17−7.23
(m, 2H), 7.45 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 12.07 (s,
1H). 13C NMR (150 MHz, CDCl3) δ: 13.7, 22.5, 29.5, 84.8, 111.5,
116.7, 118.9, 122.0, 123.4, 127.7, 134.7, 149.3. MS: m/z 185 [M +
H]+.
2-Isobutyl-1H-indole-3-carbonitrile (4q). Eluent: petroleum
ether−ethyl acetate (5:1). White solid (74 mg, 75%). Mp: 116−117
°C (lit.11d mp 116−117 °C). 1H NMR (400 MHz, CDCl3) δ: 1.00 (s,
3H), 1.02 (s, 3H), 2.09−2.20 (m, 1H), 2.82 (d, J = 7.2 Hz, 2H), 7.22−
7.28 (m, 2H), 7.39−7.42 (m, 1H), 7.65−7.68 (m, 1H), 8.83 (br s,
1H). 13C NMR (100 MHz, CDCl3) δ: 22.4, 29.3, 36.6, 85.5, 111.5,
116.7, 119.0, 122.0, 123.4, 127.6, 134.6, 148.5. MS: m/z 199 [M +
H]+.
2-Phenethyl-1H-indole-3-carbonitrile (4r). Eluent: petroleum
ether−ethyl acetate (5:1). White solid (103 mg, 84%). Mp: 128−
129 °C (lit.11d mp 125−126 °C). 1H NMR (600 MHz, DMSO-d6) δ:
3.09 (t, J = 7.8 Hz, 2H), 3.21 (t, J = 7.8 Hz, 2H), 7.17−7.23 (m, 5H),
7.28 (t, J = 7.8 Hz, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.8 Hz,
1H), 12.17 (s, 1H). 13C NMR (150 MHz, DMSO-d6) δ: 29.2, 34.7,
83.2, 112.7, 116.8, 118.3, 121.9, 123.3, 126.7, 127.6, 128.6, 128.9,
135.3, 140.6, 149.4. MS: m/z 247 [M + H]+.
2-(p-Tolyl)-1H-indole-3-carbonitrile (4g). Eluent: petroleum
ether−ethyl acetate (5:1). White solid (94 mg, 81%). Mp: 289−290
°C (lit.11d mp 287−288 °C). 1H NMR (400 MHz, DMSO-d6) δ: 2.39
(s, 3H), 7.22−7.28 (m, 1H), 7.31 (dd, J1 = 7.2 Hz, J2 = 1.2 Hz, 1H),
7.42 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.6 Hz,
1H), 7.88 (d, J = 8.4 Hz, 2H), 12.54 (s, 1H). 13C NMR (100 MHz,
DMSO-d6) δ: 20.9, 80.9, 112.5, 117.1, 118.2, 121.9, 123.7, 126.6,
126.8, 128.3, 129.8, 135.4, 139.8, 144.9. MS: m/z 233 [M + H]+.
2-(4-Methoxyphenyl)-1H-indole-3-carbonitrile (4h). Eluent: petro-
leum ether−ethyl acetate (5:1). White solid (110 mg, 89%). Mp: 283−
284 °C (lit.11d mp 280−282 °C). 1H NMR (400 MHz, DMSO-d6) δ:
3.85 (s, 3H), 7.19 (d, J = 8.8 Hz, 2H), 7.23 (t, J = 8.0 Hz, 1H), 7.26−
7.30 (m, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.94
(d, J = 9.2 Hz, 2H), 12.47 (s, 1H). 13C NMR (100 MHz, DMSO-d6)
δ: 55.4, 80.2, 112.4, 114.8, 117.3, 118.1, 121.7, 121.8, 123.5, 128.3,
128.4, 135.4, 144.9, 160.5. MS: m/z 249 [M + H]+.
2-(3-Chlorophenyl)-1H-indole-3-carbonitrile (4i). Eluent: petrole-
um ether−ethyl acetate (5:1). White solid (109 mg, 86%). Mp: 267−
268 °C. 1H NMR (400 MHz, DMSO-d6) δ: 7.25- 7.31 (m, 1H), 7.32−
7.35 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.63−
7.67 (m, 2H), 7.96 (d, J = 7.6 Hz, 1H), 8.02 (s, 1H), 12.71 (s, 1H).
13C NMR (100 MHz, DMSO-d6) δ: 82.1, 112.8, 116.7, 118.5, 122.2,
124.3, 125.5, 126.5, 128.1, 129.6, 131.2, 131.3, 134.0, 135.5, 142.7.
HRMS calcd for C15H10ClN2: 253.0527 [M + H]+, found 253.0526.
2-(m-Tolyl)-1H-indole-3-carbonitrile (4j). Eluent: petroleum
ether−ethyl acetate (5:1). White solid (92 mg, 79%). Mp: 245−246
°C (lit.11d mp 248−250 °C). 1H NMR (400 MHz, DMSO-d6) δ: 2.42
(s, 3H), 7.25 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 7.2 Hz, 1H), 7.33−7.36
(m, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.64 (d, J =
7.6 Hz, 1H), 7.78−7.80 (m, 2H), 12.58 (s, 1H). 13C NMR (100 MHz,
DMSO-d6) δ: 21.0, 81.2, 112.6, 117.0, 118.3, 122.0, 123.8, 124.1,
127.4, 128.3, 129.2, 129.3, 130.6, 135.5, 138.6, 144.8. MS: m/z 233 [M
+ H]+.
2-(o-Tolyl)-1H-indole-3-carbonitrile (4k). Eluent: petroleum
ether−ethyl acetate (5:1). White solid (94 mg, 81%). Mp: 182−183
°C (lit.11d mp 181−183 °C). 1H NMR (600 MHz, DMSO-d6) δ: 2.37
(s, 3H), 7.28 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.40 (t, J =
7.2 Hz, 1H), 7.45−7.50 (m, 2H), 7.52 (d, J = 7.2 Hz, 1H), 7.54 (d, J =
7.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H). 13C NMR (150 MHz, CDCl3)
δ: 20.2, 86.8, 111.7, 116.3, 119.5, 122.4, 124.2, 126.3, 128.0, 129.2,
130.2, 131.1, 134.8, 137.0, 145.9. MS: m/z 233 [M + H]+.
2-(Naphthalen-1-yl)-1H-indole-3-carbonitrile (4l). Eluent: petro-
leum ether−ethyl acetate (5:1). White solid (117 mg, 87%). Mp: 266−
268 °C (lit.11d mp 266−268 °C). 1H NMR (400 MHz, DMSO-d6) δ:
7.29−7.38 (m, 2H), 7.58−7.64 (m, 3H), 7.69−7.73 (m, 2H), 7.79−
7.81 (m, 1H), 7.86- 7.89 (m, 1H), 8.08−8.10 (m, 1H), 8.16 (d, J = 8.4
Hz, 1H), 12.71 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 85.6,
113.2, 116.8, 118.9, 122.5, 124.2, 125.5, 125.9, 127.1, 127.8, 127.9,
128.1, 129.1, 129.4, 130.8, 131.2, 133.8, 136.0, 145.4. MS: m/z 269 [M
+ H]+.
2-Phenyl-5-(trifluoromethyl)-1H-indole-3-carbonitrile (4s). Elu-
ent: petroleum ether−ethyl acetate (5:1). White solid (110 mg,
77%). Mp: > 310 °C (lit.11d 321−323 °C). H NMR (400 MHz,
1
DMSO-d6) δ: 7.58−7.69 (m, 4H), 7.76 (d, J = 8.4 Hz, 1H), 7.97 (s,
1H), 8.01 (d, J = 7.2 Hz, 2H), 13.03 (s, 1H). 13C NMR (150 MHz,
3
DMSO-d6) δ: 82.9, 114.2, 116.3 (q, JC−F = 4.5 Hz), 116.5, 120.8 (q,
3JC−F = 3.75 Hz), 123.3 (q, 2JC−F = 31.65 Hz), 125.3 (q, 1JC−F = 270.3
Hz), 127.7, 128.1, 129.2, 129.9, 131.0, 137.7, 147.5. MS: m/z 287 [M
+ H]+.
2-(4-Fluorophenyl)-5-(trifluoromethyl)-1H-indole-3-carbonitrile
(4t). Eluent: petroleum ether−ethyl acetate (5:1). White solid (109
mg, 72%). Mp: 278−279 °C. 1H NMR (400 MHz, DMSO-d6) δ: 7.51
(t, J = 8.8 Hz, 2H), 7.60 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H), 7.73 (d, J =
8.4 Hz, 1H), 7.92 (s, 1H), 8.02−8.06 (m, 2H), 13.00 (s, 1H). 13C
NMR (100 MHz, DMSO-d6) δ: 82.4, 113.5, 115.7 (q, 3JC−F = 4.3 Hz),
115.9, 116.4 (d, 2JC−F = 21.4 Hz), 120.3 (q, 3JC−F = 2.6 Hz), 122.8 (q,
1
4
2JC−F = 31.7 Hz), 124.8 (q, JC−F = 269.7 Hz), 125.2 (d, JC−F = 4.0
3
1
Hz), 127.5, 129.5 (d, JC−F = 8.7 Hz), 137.1, 145.9, 163.1 (d, JC−F
=
247.7 Hz). HRMS calcd for C16H9F4N2: 305.0697 [M + H]+, found
305.0689.
2-(4-Methoxyphenyl)-5-(trifluoromethyl)-1H-indole-3-carboni-
trile (4u). Eluent: petroleum ether−ethyl acetate (5:1). White solid
(130 mg, 82%). Mp: 231−233 °C. 1H NMR (400 MHz, DMSO-d6) δ:
3.88 (s, 3H), 7.22 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.8 Hz, 1H), 7.72
(d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 12.89 (s,
1H). 13C NMR (100 MHz, DMSO-d6) δ: 55.4, 81.2, 113.3, 114.8,
2-(Thiophene-2-yl)-1H-indole-3-carbonitrile (4m). Eluent: petro-
leum ether−ethyl acetate (5:1). White solid (74 mg, 66%). Mp: 207−
209 °C (lit.11d 206−208 °C). 1H NMR (400 MHz, DMSO-d6) δ: 7.25
(t, J = 7.2 Hz, 1H), 7.27−7.34 (m, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.61
(d, J = 8.0 Hz, 1H), 7.85−7.86 (m, 2H), 12.65 (s, 1H). 13C NMR (100
MHz, DMSO-d6) δ: 80.7, 112.4, 116.5, 118.2, 122.1, 124.1, 127.7,
127.9, 128.3, 129.0, 131.1, 135.4, 139.2. MS: m/z 225 [M + H]+.
2-(Pyridin-4-yl)-1H-indole-3-carbonitrile (4n). Eluent: petroleum
ether−ethyl acetate (5:1). White solid (62 mg, 57%). Mp: 274−275
°C. 1H NMR (400 MHz, DMSO-d6) δ: 7.32 (t, J = 7.2 Hz, 1H), 7.40
(t, J = 7.2 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H),
7.97 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 2H), 8.84 (d, J = 6.4 Hz, 2H), 12.96
(s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 83.3, 113.0, 116.3, 118.7,
120.5, 122.4, 124.8, 128.1, 135.8, 136.2, 141.0, 150.7. HRMS calcd for
C14H10N3: 220.0869 [M + H]+, found 220.0875.
3
3
115.4 (q, JC−F = 4.6 Hz), 116.4, 120.0 (q, JC−F = 3.1 Hz), 121.0,
122.6 (q, 2JC−F = 31.4 Hz), 124.9 (q, JC−F = 269.7 Hz), 127.8, 128.7,
1
137.1, 147.1, 160.9. HRMS calcd for C17H12F3N2O: 317.0896 [M +
H]+, found 317.0888.
2-Propyl-5-(trifluoromethyl)-1H-indole-3-carbonitrile (4v). Elu-
ent: petroleum ether−ethyl acetate (5:1). White solid (79 mg, 63%).
Mp: 168−169 °C (lit.11d mp 171−173 °C). H NMR (600 MHz,
1
DMSO-d6) δ: 0.96 (t, J = 7.2 Hz, 3H), 1.77−1.83 (m, 2H), 2.92 (t, J =
7.2 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.87 (s,
1H), 12.54 (br s, 1H). 13C NMR (100 MHz, CDCl3) δ: 13.6, 22.4,
29.5, 85.7, 112.0, 115.7, 116.6 (q, 3JC−F = 4.7 Hz), 120.3 (q, 3JC−F = 4.2
F
DOI: 10.1021/acs.joc.6b01612
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
2
1
Hz), 124.6 (q, JC−F = 32.2 Hz), 124.7 (q, JC−F = 271 Hz), 127.1,
136.2. 151.2. MS: m/z 253 [M + H]+.
70.0, 85.7, 85.8, 87.1, 114.8, 115.8, 118.6, 122.7, 123.8, 125.4, 127.3,
129.6, 129.7, 133.8, 140.2, 148.0. HRMS calcd for C21H20N2O3Na:
20
371.1366 [M + Na]+, found 371.1368. [α]D = +7.8 (c = 0.36,
5,6-Dimethoxy-2-phenyl-1H-indole-3-carbonitrile (4w). Eluent:
petroleum ether−ethyl acetate (5:1). White solid (124 mg, 89%).
Mp: 266−267 °C (lit.9a mp 263−264 °C). 1H NMR (400 MHz,
DMSO-d6) δ: 3.84 (s, 3H), 3.85 (s, 3H), 7.02 (s, 1H), 7.08 (s, 1H),
7.50 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 2H), 7.93 (d, J = 7.2 Hz,
2H), 12.31 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 55.66, 55.72,
81.2, 95.4, 99.8, 117.4, 121.2, 126.3, 129.2, 129.7, 129.8, 142.5, 146.6,
148.1. MS: m/z 279 [M + H]+.
MeOH).
1-((2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-
yl)-2-(4-methoxyphenyl)-1H-indole-3-carbonitrile (6c). Eluent: di-
chloromethane−methanol (10:1). White solid (78 mg, 71%). Mp:
1
147−148 °C; H NMR (600 MHz, CDCl3) δ: 2.11−2.15 (m, 1H),
2.26 (br s, 2H), 2.88−2.93 (m, 1H), 3.83−3.97 (m, 6H), 4.67 (t, J =
3.6 Hz, 1H), 6.18 (t, J = 7.2 Hz, 1H), 7.04 (d, J = 7.8 Hz, 2H), 7.29−
7.30 (m, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.65−7.66 (m, 1H), 7.72−7.73
(m, 1H). 13C NMR (150 MHz, CDCl3) δ: 38.7, 55.5, 61.9, 70.8, 85.2,
85.4, 87.3, 113.1, 114.7, 116.3, 119.9, 120.7, 122.8, 124.0, 128.4, 131.2,
133.9, 148.4, 161.1. HRMS calcd for C21H20N2O4Na: 387.1315 [M +
2-(4-Fluorophenyl)-5,6-dimethoxy-1H-indole-3-carbonitrile (4x).
Eluent: petroleum ether−ethyl acetate (5:1). White solid (119 mg,
1
80%). Mp: 237−238 °C. H NMR (400 MHz, DMSO-d6) δ: 3.84 (s,
3H), 3.85 (s, 3H), 7.00 (s, 1H), 7.08 (s, 1H), 7.45−7.49 (m, 2H),
20
Na]+, found 387.1316. [α]D = +2.5 (c = 0.40, MeOH).
7.94−7.98 (m, 2H), 12.33 (s, 1H). 13C NMR (100 MHz, DMSO-d6)
2
1-((2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-
yl)-5,6-dimethoxy-2-phenyl-1H-indole-3-carbonitrile (6d). Eluent:
dichloromethane−methanol (10:1). White solid (79 mg, 67%). Mp:
δ: 55.67, 55.71, 81.2, 95.4, 99.8, 116.3 (d, JC−F = 21.8 Hz), 117.3,
4
3
121.1, 126.4 (d, JC−F = 3.1 Hz), 128.6 (d, JC−F = 9.2 Hz), 129.8,
1
141.5, 146.7, 148.1, 162.4 (d, JC−F = 246.0 Hz). HRMS calcd for
1
C17H14FN2O2: 297.1034 [M + H]+, found 297.1031.
175−176 °C. H NMR (400 MHz, CDCl3) δ: 2.01−2.13 (m, 1H),
2.35 (br s, 1H), 2.60 (br s, 1H), 2.78−2.85 (m, 1H), 3.81−4.01 (m,
9H), 4.71 (t, J = 4.0 Hz, 1H), 6.14 (t, J = 8.0 Hz, 1H), 7.10 (s, 1H),
7.31 (s, 1H), 7.46−7.50 (m, 5H). 13C NMR (100 MHz, CDCl3) δ:
39.0, 56.2, 56.4, 61.4, 70.5, 85.3, 85.5, 87.0, 96.8, 100.7, 116.6, 121.5,
128.3, 128.8, 129.1, 129.7, 129.9, 146.2, 147.2, 148.0. HRMS calcd for
C22H22N2O5Na: 417.1421 [M + Na]+, found 417.1409. [α]D20 = +15.7
(c = 0.49, MeOH).
5,6-Dimethoxy-2-(p-tolyl)-1H-indole-3-carbonitrile (4y). Eluent:
petroleum ether−ethyl acetate (5:1). White solid (120 mg, 82%).
1
Mp: 225−226 °C; H NMR (400 MHz, DMSO-d6) δ: 2.39 (s, 3H),
3.84 (s, 3H), 3.85 (s, 3H), 7.00 (s, 1H), 7.07 (s, 1H), 7.40 (d, J = 8.0
Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H), 12.24 (s, 1H). 13C NMR (100
MHz, DMSO-d6) δ: 20.9, 55.67, 55.72, 80.7, 95.4, 99.8, 117.5, 121.2,
126.2, 127.0, 129.7, 129.8, 139.0, 142.7, 146.6, 147.9. HRMS calcd for
C18H17N2O2: 293.1285 [M + H]+, found 293.1283.
2-(4-Fluorophenyl)-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)-
tetrahydrofuran-2-yl)-5,6-dimethoxy-1H-indole-3-carbonitrile (6e).
Eluent: dichloromethane−methanol (10:1). White solid (85 mg,
5,6-Dimethoxy-2-phenethyl-1H-indole-3-carbonitrile (4z). Eluent:
petroleum ether−ethyl acetate (5:1). White solid (121 mg, 79%). Mp:
1
1
69%). Mp: 202−203 °C. H NMR (600 MHz, CDCl3) δ: 2.04 (br s,
188−189 °C. H NMR (400 MHz, DMSO-d6) δ: 3.05 (t, J = 7.2 Hz,
2H), 2.11−2.15 (m, 1H), 2.86−2.91 (m, 1H), 3.88−4.06 (m, 9H),
4.76 (t, J = 3.6 Hz, 1H), 6.11 (t, J = 7.2 Hz, 1H), 7.14 (s, 1H), 7.23−
7.26 (m, 2H), 7.30 (s, 1H), 7.52−7.54 (m, 2H). 13C NMR (150 MHz,
CDCl3) δ: 39.0, 56.3, 56.4, 61.5, 70.7, 85.3, 85.4, 87.6, 96.7, 100.8,
2H), 3.14 (t, J = 7.2 Hz, 2H), 3.80 (s, 6H), 6.97 (s, 1H), 6.98 (s, 1H),
7.18−7.22 (m, 3H), 7.28 (t, J = 7.2 Hz, 2H), 11.85 (s, 1H). 13C NMR
(100 MHz, DMSO-d6) δ: 28.7, 34.4, 55.7, 82.4, 95.7, 100.0, 116.7,
119.8, 126.2, 128.1, 128.4, 128.8, 140.0, 146.1, 146.6, 147.1. HRMS
calcd for C19H19N2O2: 307.1441 [M + H]+, found 307.1438.
4
116.4 (d, 2JC−F = 22.95 Hz), 121.4, 124.9 (d, JC−F = 2.85 Hz), 128.3,
131.8 (d, 3JC−F = 8.1 Hz), 145.0, 147.3, 148.1, 163.6 (d, 1JC−F = 250.5
3. Typical Procedure for the Preparation of 1-((2R,4S,5R)-4-
Hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-phenyl-
1H-indole-3-carbonitrile (6a). To a flask containing 4a (65 mg, 0.3
mmol) were added acetonitrile (3 mL) and sodium hydride (60% w/w
dispersion in mineral oil, 60 mg, 1.5 mmol). After the mixture was
stirred at room temperature for 5 min, Hoffer’s chlorosugar (130 mg,
0.33 mmol) was added, and the stirring was continued at room
temperature for 3 h. Then, water (27 μL, 1.5 mmol) was added, and
the resulting mixture was stirred at room temperature for 10 h. Upon
completion, the mixture was neutralized with diluted hydrochloric
acid, and extracted with ethyl acetate (10 mL × 3). The combined
organic phases were washed with brine, dried over anhydrous Na2SO4,
and concentrated under vacuum. The residue was purified by column
chromatography on silica gel using dichloromethane-methanol (10:1)
as the eluent to give 6a (70 mg, 70%). Other indole 2′-
deoxyribonucleosides (6b−g) were obtained in a similar manner.
1-((2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-
yl)-2-phenyl-1H-indole-3-carbonitrile (6a). Eluent: dichlorome-
thane−methanol (10:1). White solid (70 mg, 70%). Mp: 210−212
Hz). HRMS calcd for C22H21FN2O5Na: 435.1327 [M + Na]+, found
20
435.1326. [α]D = +5.8 (c = 0.38, MeOH).
1-((2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-
yl)-2-phenyl-5-(trifluoromethyl)-1H-indole-3-carbonitrile (6f). Elu-
ent: dichloromethane−methanol (10:1). White solid (82 mg, 68%).
1
Mp: 207−208 °C. H NMR (600 MHz, CDCl3) δ: 2.16−2.20 (m,
1H), 2.53 (br s, 2H), 2.81−2.86 (m, 1H), 3.86−3.98 (m, 3H), 4.70 (t,
J = 3.6 Hz, 1H), 6.19 (t, J = 7.2 Hz, 1H), 7.55 (s, 6H), 7.91 (d, J = 8.4
Hz, 1H), 8.03 (s, 1H). 13C NMR (150 MHz, CDCl3) δ: 39.2, 61.7,
70.7, 85.6, 88.4, 114.1, 115.2, 117.3 (q, 3JC−F = 3.9 Hz), 120.9 (q, 3JC−F
1
2
= 3.0 Hz), 124.5 (q, JC−F = 271.35 Hz), 125.4 (q, JC−F = 32.1 Hz),
127.8, 127.9, 129.3, 129.7, 130.7, 135.6, 149.8. HRMS calcd for
20
C21H18F3N2O3: 403.1264 [M + H]+, found 403.1255. [α]D = +49.7
(c = 0.35, MeOH).
1-((2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-
yl)-2-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-indole-3-carboni-
trile (6g). Eluent: dichloromethane−methanol (10:1). White solid (87
1
mg, 67%). Mp: 195−196 °C. H NMR (600 MHz, CDCl3) δ: 2.17−
1
2.20 (m, 1H), 2.47 (br s, 2H), 2.84−2.89 (m, 1H), 3.88 (s, 3H), 3.92−
4.00 (m, 3H), 4.72 (t, J = 10.2 Hz, 1H), 6.21 (t, J = 7.2 Hz, 1H), 7.07
(d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1H),
7.88 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H). 13C NMR (150 MHz, CDCl3)
δ: 39.2, 55.5, 61.8, 70.8, 85.6, 88.0, 113.9, 114.78, 114.83, 115.4, 117.3
°C. H NMR (400 MHz, DMSO-d6) δ: 2.09−2.14 (m, 1H), 2.71−
2.78 (m, 1H), 3.71−7.78 (m, 3H), 4.40−4.42 (m, 1H), 5.23 (br s,
2H), 6.07−6.11 (m, 1H), 7.34−7.38 (m, 2H), 7.63−7.72 (m, 6H),
8.12−8.14 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 61.0, 70.0,
85.7, 86.1, 87.1, 114.8, 115.8, 118.7, 122.8, 123.9, 127.3, 128.4, 129.1,
129.7, 130.3, 133.8, 147.8. HRMS calcd for C20H18N2O3Na: 357.1210
4
(q, 3JC−F = 4.8 Hz), 120.0, 120.7 (q, JC−F = 2.85 Hz), 124.5 (q, 1JC−F
= 270.0 Hz), 125.3 (q, 2JC−F = 33.6 Hz), 127.9, 131.19, 131.23, 150.0,
20
[M + Na]+, found 357.1218. [α]D = +4.7 (c = 0.30, MeOH).
161.4. HRMS calcd for C22H20F3N2O4: 433.1370 [M + H]+, found
1-((2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-
yl)-2-(p-tolyl)-1H-indole-3-carbonitrile (6b). Eluent: dichlorome-
thane−methanol (10:1). White solid (71 mg, 68%). Mp: 211−212
20
433.1366. [α]D = +32.0 (c = 0.35, MeOH).
4. Procedure for the Preparation of 2-(2-Bromophenyl)-3-
phenylacrylonitrile (A). To a tube containing a solution of 2-(2-
bromophenyl)acetonitrile (1a, 98 mg, 0.5 mmol) in DMSO (2 mL)
were added CuI (9.5 mg, 0.05 mmol), K2CO3 (69 mg, 0.5 mmol), L-
proline (11.5 mg, 0.1 mmol), and benzaldehyde (2a, 80 mg, 0.75
mmol). Then the tube was sealed, and the mixture was stirred at 100
°C under an air atmosphere for 2 h. Upon completion, it was
1
°C. H NMR (400 MHz, DMSO-d6) δ: 2.05−2.10 (m, 1H), 2.45 (s,
3H), 2.68−2.76 (m, 1H), 3.68−3.77 (m, 3H), 4.39 (d, J = 3.6 Hz,
1H), 5.12 (t, J = 5.2 Hz, 1H), 5.29 (d, J = 4.8 Hz, 1H), 6.05−6.08 (m,
1H), 7.32−7.36 (m, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz,
2H), 7.68 (dd, J1 = 6.4 Hz, J2 = 3.2 Hz, 1H), 8.10 (dd, J1 = 6.4 Hz, J2 =
3.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ: 21.0, 38.6, 61.0,
G
DOI: 10.1021/acs.joc.6b01612
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
quenched with water and extracted with ethyl acetate (8 mL × 3). The
combined organic phases were washed with brine, dried over
anhydrous Na2SO4, and concentrated under vacuum. The residue
was purified by column chromatography on silica gel using petroleum
ether−ethyl acetate (100:1) as the eluent to give 2-(2-bromophenyl)-
3-phenylacrylonitrile (A, 128 mg, 90%).
AUTHOR INFORMATION
Corresponding Authors
*E-mail: xuesen.fan@htu.cn.
*E-mail: xinyingzhang@htu.cn.
■
Notes
2-(2-Bromophenyl)-3-phenylacrylonitrile (A). Eluent: petroleum
ether−ethyl acetate (100:1). White solid (128 mg, 90%). Mp: 80−82
°C. 1H NMR (600 MHz, CDCl3) δ: 7.09 (s, 1H), 7.13 (td, J1 = 7.8 Hz,
J2 = 1.2 Hz, 1H), 7.24−7.26 (m, 1H), 7.27−7.30 (m, 1H), 7.34−7.36
(m, 3H), 7.53 (d, J = 6.6 Hz, 1H), 7.77−7.79 (m, 2H). 13C NMR (150
MHz, CDCl3) δ: 110.7, 117.3, 122.8, 128.1, 129.1, 129.4, 130.6, 131.0,
131.1, 133.2, 133.7, 136.4, 148.3. HRMS calcd for C15H11BrN:
284.0069 [M + H]+, found 284.0077.
5. Procedure for the Preparation of 2-Phenylindoline-3-
carbonitrile (E). To a tube containing a solution of 2-(2-
bromophenyl)acetonitrile (1a, 98 mg, 0.5 mmol) in DMSO (2 mL)
were added CuI (9.5 mg, 0.05 mmol), K2CO3 (69 mg, 0.5 mmol), L-
proline (11.5 mg, 0.1 mmol), benzaldehyde (2a, 80 mg, 0.75 mmol),
and aqueous ammonia (3, 26%, 0.5 mL). After being flushed with
nitrogen, the tube was sealed, and the mixture was stirred at 100 °C
under a nitrogen atmosphere for 18 h. Upon completion, it was
quenched with water and extracted with ethyl acetate (8 mL × 3). The
combined organic phases were washed with brine, dried over
anhydrous Na2SO4, and concentrated under vacuum. The residue
was purified by column chromatography on silica gel using petroleum
ether−ethyl acetate (20:1) as the eluent to give 2-phenylindoline-3-
carbonitrile (E, 91 mg, 83%).
2-Phenylindoline-3-carbonitrile (E). Eluent: dichloromethane−
methanol (20:1). Colorless liquid (99 mg, 90%). 1H NMR (400
MHz, CDCl3) δ: 4.03 (d, J = 10.8 Hz, 1H), 4.24 (d, J = 2.8 Hz, 1H),
5.10 (dd, J1 = 10.4 Hz, J2 = 3.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.84
(t, J = 7.6 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.23−7.28 (m, 1H), 7.36−
7.42 (m, 3H), 7.53 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 2H). 13C NMR (100
MHz, CDCl3) δ: 42.3, 68.8, 110.1, 119.1, 120.0, 122.5, 124.5, 126.6,
128.9, 129.1, 130.0, 139.9, 149.8. HRMS calcd for C15H13N2: 221.1073
[M + H]+, found 221.1062.
6. Preparation of 4a from Intermediate A. To a tube
containing a solution of 2-(2-bromophenyl)-3-phenylacrylonitrile (A,
128 mg, 0.45 mmol) in DMSO (2 mL) were added CuI (8.6 mg, 0.045
mmol), K2CO3 (62 mg, 0.45 mmol), L-proline (10.4 mg, 0.09 mmol),
and aqueous ammonia (3, 26%, 0.5 mL). Then the tube was sealed,
and the mixture was stirred at 100 °C under an air atmosphere for 15
h. After being cooled to room temperature, it was quenched with
water, and extracted with ethyl acetate (8 mL × 3). The combined
organic phases were washed with brine, dried over anhydrous Na2SO4,
and concentrated under vacuum. The residue was purified by column
chromatography on silica gel using petroleum ether−ethyl acetate
(5:1) as the eluent to give 2-phenyl-1H-indole-3-carbonitrile (4a, 89
mg, 91%).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (NSFC) (Grant Nos. 21272058 and 21572047),
Program for Innovative Research Team in Science and
Technology in Universities of Henan Province
(15IRTSTHN003), Program for Science and Technology
Innovation Talents in Universities of Henan Province
(15HASTIT005), and PCSIRT (IRT 1061) for financial
support.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01612.
1H and 13C NMR spectra (PDF)
H
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