Oxidative cyclization of 2-aryl-3-arylamino-2-alkenenitriles to N-arylindole-3-carbonitriles mediated by NXS/Zn(OAc)2

Article abstract of DOI:10.1021/jo2012187

A variety of 2-aryl-3-arylamino-2-alkenenitriles were converted to N-arylindole-3-carbonitriles in a one-pot manner through NBS- or NCS-mediated halogenation followed by Zn(OAc)₂-catalyzed intramolecular cyclization. It is postulated that the p

Full text of DOI:10.1021/jo2012187

ARTICLE
pubs.acs.org/joc
Oxidative Cyclization of 2-Aryl-3-arylamino-2-alkenenitriles to
N-Arylindole-3-carbonitriles Mediated by NXS/Zn(OAc)2
Qiao Yan, Ji Luo, Daisy Zhang-Negrerie, Hui Li, Xiuxiang Qi,* and Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072, P. R. China
S Supporting Information
b
ABSTRACT: A variety of 2-aryl-3-arylamino-2-alkenenitriles
were converted to N-arylindole-3-carbonitriles in a one-pot
manner through NBS- or NCS-mediated halogenation followed
by Zn(OAc)2-catalyzed intramolecular cyclization. It is postu-
lated that the process involves the formation of arylnitrenium
ion intermediates, which undergo the electrophilic aromatic
substitution to give the cyclized N-arylindole product.
’ INTRODUCTION
The N-arylindole skeleton is an important heterocyclic motif
due to its presence in many synthetically challenging1 and
pharmaceutically active compounds.2 Although a great many
methods have been developed for the synthesis of various
substituted indoles, the strategic approaches to the N-arylated
pattern of indole compounds are limited. Generally, these
methodologies can be categorized into the following types: (1)
Fischer cyclization of N,N-diarylhydrazones (path a, Figure 1);3
(2) connecting an indole compound to a functionalized arene
under various coupling conditions, which is considered as the
predominant strategy of the N-arylindole synthesis (path b,
Figure 1);4 (3) tandem amination and cyclization approach using
o-alkynylhaloarenes or o-alkenylhaloarenes and substituted ani-
lines as the starting materials (path c and d, Figure 1);5 (4)
joining the N-atom on the side chain in an enamine substrate to
the benzene ring via palladium-mediated cyclization (W = I)6 or
Figure 1. General strategies for the construction of the N-arylindole
skeleton.
direct oxidative annulation (W = H) (path e, Figure 1);7 (5)
reduction of indolin-2-ones or desulfurization of indoline-2-
structure than 2a0. The structure of compound 2a was deter-
thiones (path f, Figure 1).8 In addition, the synthesis of N-
mined by the NMR spectroscopic data of the crude reaction
arylindole may also be achieved by the reaction of a diarylamine
with triethanolamine mediated by a ruthenium catalyst.9 Herein
mixture (see the Supporting Information). An attempt to isolate
the pure 2a through silica gel column chromatography was not
we report an alternative one-pot route to N-arylindole-3-carbo-
successful since the rearranged enamine 4a was isolated in 95%
yield instead during this purification process. Fortunately, both
nitriles via halogenation of 2-aryl-3-arylamino-2-alkenenitriles
followed by Zn(OAc)2-mediated intramolecular cyclization.
the benzylic brominated intermediate 2a and allylic brominated
intermediate 4a, upon treatment with Zn(OAc)2 in DCE,12 can
efficiently provide the desired indole 3a (Scheme 1).
’ RESULTS AND DISCUSSION
Considering that both compound 2a and 4a were unstable
intermediates, a one-pot procedure of adding Zn(OAc)2 directly
to the crude reaction mixture to promote the intramolecular
cyclization was investigated. The screening of the reaction
conditions using 2-phenyl-3-(phenylamino)-2-butenenitrile 1a
We began our work by assuming that the treatment of
enamine substrate 1a with NBS would afford the reactive N-bromo
intermediate 2a0,10 which could be taken as a nitrenium ion11
intermediate and undergo Lewis acid mediated intramolec-
ular cyclization to give the cyclized indole product 3a. However,
we found the reaction of substrate 1a with NBS in dichloro-
methane (DCM) nearly quantitatively led to the benzylic
bromination product 2a, a theoretically more reasonable
Received: June 10, 2011
Published: September 20, 2011
r
2011 American Chemical Society
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Scheme 1. Unexpected Formation of N-Phenylindole-3-car-
bonitrile 3a via Bromination of 1a Followed by Lewis Acid
Mediated Intramolecular Cyclization
Scheme 2. Study of N-Alkylenamine 5 under Identical
Conditions
Figure 2. Other models that failed to afford the desired N-arylindoles.
In addition, we were disappointed to find that this approach
was not successful for the synthesis of the corresponding
N-alkylindole-3-carbonitriles. Subjecting 2-phenyl-3-(propylamino)-
2-butenenitrile 5 to NBS at room temperature in DCE afforded
benzylic brominated imine 6, which is stable enough for column
chromatography and was isolated in excellent yield of 97%. However,
the subsequent treatment of imine 6 with Zn(OAc)2 under identical
conditions only led to the rearranged enamine 7, which is a stable
compound even at reflux temperature in the presence of Zn(OAc)2
(Scheme 2). This result clearly indicates that N-aryl substituents are
essential for the Lewis acid assisted cyclization process.
Disappointingly, similar substrates 8ꢀ10 (Figure 2), differing
from 1a with only the benzylic cyano group being replaced by an
ethoxycarbonyl (ester) or acyl group, yielded none of the
expected cyclized product via this one-pot procedure in each
case. This intriguing result implies that the benzylic cyano group
plays some important role in the course of this reaction.
A plausible mechanism for the above halogenationꢀcyclization
process, taking substrate 1a as an example, is shown in Scheme 3.13
Initially, the reaction of enamine 1a with NBS provides
the brominated imine 2a. In view of the fact that imine 2a
converts to enamine 4a in the presence of silica gel and both 2a
and 4a can undergo Zn(OAc)2-mediated cyclization to give
indole product 3a, we propose that compound 2a adopts a
rearrangement to give enamine A, imine B and then tautomerize
into 4a before the intramolecular cyclization mediated by Zn-
(OAc)2 occurs. Assisted by the Lewis acid, the bromide anion
will be eliminated from B to give the nitrenium ion intermediate
C, which can be stabilized to a great extent by an aromatic ring.15
The electrophilic attack on the nitrenium ion by the benzene ring
will give the cyclized intermediate D. With the loss of a proton,
the Wheland intermediate D will be converted to E, which can
undergo tautomerization and aromatization to furnish the title
N-arylindole-3-carbonitrile 3. We tentatively propose that the
unsuccessful cyclization of N-alkylenamine 5 could be attributed
to the failure of the formation of the nitrenium ion11 similar to
C since an alkyl substituent on the N-atom cannot stabilize
this highly reactive species.
as a model substrate showed that the best result could be
achieved when 1a was treated with 1.2 equiv of NBS in DCE,
with the subsequent introduction of 0.8 equiv of Zn(OAc)2 while
keeping the reaction mixture at reflux for 1 h (see the Supporting
Information for details).
With optimal conditions in hand, the scope and limitations of
this one-pot methodology have been investigated. As shown in
Table 1, when R is H and R2 is H, an electron-withdrawing
bromo group or electron-donating methoxy group, the reaction
can give the desired N-arylindole product in 72%, 69%, and 62%
yields, respectively (Table 1, entries 1ꢀ3). A range of varying aryl
groups on the enamine with the N-substituents being phenyl or
p-tolyl groups, as shown in entries 4ꢀ7, tolerate both electron-
deficient as well as electron-rich groups and give the correspond-
ing indoles in good to excellent yields. It is worth noting that for
substrates with R being a methoxy group, the reaction with NBS
under standard conditions gave a complex mixture. We assume
that bromination processes on the electron-rich aromatic rings
occurred as competitive side reactions. The replacement of NBS
with NCS led to clean formation of the corresponding chlori-
nated intermediate.14 Subsequent treatment of the less reactive
chloroimino nitriles with Zn(OAc)2 under similar conditions
facilitated the intramolecular cyclization at slightly lower tem-
perature to afford the desired products (Table 1, entries 4ꢀ6).
More interestingly, when the aryl groups are more compli-
cated aromatic or heteroaromatic rings, the desired indole-3-
carbonitriles were also successfully prepared in good yields
(entries 8 and 9). A number of additional examples have also
demonstrated to be efficient when a series of electron-rich and
electron-deficient aryl groups were employed. The meta-substi-
tuted enamine 3j afforded a 3:1 mixture of 5- and 7-substituted
indoles as inseparable regioisomers, determined by 1H NMR of
the crude reaction mixture. However, for entries 5 and 6, only
single products 3e and 3f were observed, respectively, in each
case. Finally, diversity studies focused on the R1 groups have
proved that the substrates bearing primary alkyl group can be
successfully converted into 2-alkyl-substituted indoles in mod-
erate to good yields (Table 1, entries 14ꢀ16).
Previously, we described an alternative synthesis route for the
indole compounds from the reactions of the same enamine
substrates with phenyliodine bis(trifluoroacetate) (PIFA) via in-
tramolecular cyclization.7 With that method, substrates other than
the N-arylenamine ones as described herein, such as 5 and 8, can
also undergo oxidative annulation to give the corresponding
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Table 1. Synthesis of N-Arylindole-3-carbonitriles via Halogenation Followed by Zn(OAc)2-Mediated Intramolecular
Cyclizationa
a Reaction conditions: (1) substrate 1 (2.0 mmol), NBS (1.2 equiv), DCE (15 mL); (2) Zn(OAc)2 (0.8 equiv), reflux, unless otherwise noted. b The
reaction was operated at 50 °C after the addition of Zn(OAc)2. c NCS (1.5 equiv) instead of NBS was used. d Overall yield of the two isomers. e Yields
after silica gel chromatography.
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N-substituted indole products. Disappointingly, the substrate scope
in our current study is confined to only N-aryl-2-aryl-3-amino-2-
alkenenitrile substrates. However, we have found that by avoiding
applying stoichiometric amout of PIFA, the combination of the
inexpensive halogenation reagent (NXS) and the readily available
Zn(OAc)2 also give the corresponding N-arylindole-3-carbonitriles
with equally good yields via a unique ring-closure process.13,15
Scheme 3. Proposed Mechanism
’ CONCLUSION
In summary, we have demonstrated herein an alternative
method for the formation of N-arylindole-3-nitriles, the process
of which involves an unprecedented halogenation of 2-aryl-3-
arylamino-2-alkenenitriles followed by a Lewis acid mediated
cyclization. This route features simple procedures, inexpensive
reagents, and good to excellent yields, which can be utilized for
the synthesis of a variety of substituted N-arylindole-3-nitriles.
Further mechanistic studies are currently in progress within the
research group.
133.3, 131.4, 129.5, 128.6, 127.5, 127.2, 122.2, 114.5, 82.6, 55.5, 18.5;
minor isomer (cis) δ 158.1, 157.1, 134.3, 131.4, 129.6, 128.6, 127.5,
126.6, 122.2, 114.5, 82.6, 55.5, 16.7. HRMS (ESI): m/z calcd for
C17H16N2NaO+ [M + Na+] 287.1155, found 287.1156.
’ EXPERIMENTAL SECTION
General Information. 1H and 13C NMR spectra were recorded on
a 400 MHz spectrometer at 25 °C. Chemical shifts values are given in
ppm and referred as the internal standard to TMS: 0.00 ppm. The peak
patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q,
quadruplet; sxt, sextuplet; m, multiplet and dd, doublet of doublets. The
coupling constants J are reported in hertz (Hz). Low-resolution mass
spectrometry (ESI) was performed on an ion-trap spectrometer. High-
resolution mass spectra (HRMS) were obtained on a Q-TOF micro
spectrometer. Melting points were determined with a national micro-
melting point apparatus without corrections. TLC plates were visualized
by exposure to ultraviolet light. THF, DCE, and toluene were dried by
CaH2 before use. Other reagents and solvents were purchased from
commercial suppliers as reagent grade and were used without further
purification. Flash column chromatography was performed over silica
gel 200ꢀ300 mesh, and the eluent was a mixture of petroleum ether
(PE) and ethyl acetate (EtOAc). Rf values of 2-aryl-3-arylamino-2-
alkenenitrile are given for the major isomer.
2-(4-Methoxyphenyl)-3-(phenylamino)-2-butenenitrile, 1d. Yellow
solid. Yield: 82% (cis/trans = 1:5.9). Mp: 117ꢀ119 °C. 1H NMR (400
MHz, CDCl3): major isomer (trans) δ 7.37ꢀ7.29 (m, 4H), 7.24ꢀ7.14
(m, 1H), 6.98ꢀ6.92 (m, 4H), 6.59 (s, 1H), 3.81 (s, 3H), 2.30 (s, 3H);
minor isomer (cis) δ 7.37ꢀ7.29 (m, 2H), 7.24ꢀ7.14 (m, 3H), 7.09 (d,
J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 6.59 (s, 1H), 3.81 (s, 3H), 1.99
(s, 3H). 13C NMR (100 MHz, CDCl3): major isomer (trans) δ 159.0,
153.3, 138.9, 130.4, 129.3, 125.3, 124.9, 124.6, 124.2, 114.9, 84.2, 55.3,
18.4; minor isomer (cis) δ 159.0, 153.3, 138.9, 130.9, 129.3, 125.4, 124.9,
124.6, 121.9, 114.0, 84.2, 55.3, 16.8. HRMS (ESI): m/z calcd for
C17H16N2NaO+ [M + Na+] 287.1155, found 287.1159.
2-[4-(Benzyloxy)-3-methoxyphenyl]-3-(phenylamino)-2-buteneni-
trile, 1e. White solid. Yield: 89% (cis/trans = 1:12.5). Mp: 190ꢀ192 °C.
1H NMR (400 MHz, CDCl3): major isomer (trans) δ 7.44ꢀ7.28 (m,
7H), 7.21ꢀ7.08 (m, 1H), 6.97ꢀ6.85 (m, 5H), 6.70 (s, 1H), 5.15 (s, 2H),
3.87 (s, 3H), 2.28 (s, 3H); minor isomer (cis) δ 7.44ꢀ7.28 (m, 5H),
7.21ꢀ7.08 (m, 3H), 6.97ꢀ6.85 (m, 3H), 6.77 (d, J = 8.0 Hz, 2H), 6.70
(s, 1H), 5.15 (s, 2H), 3.89 (s, 3H), 1.99 (s, 3H). 13C NMR (100 MHz,
CDCl3): major isomer (trans) δ 153.5, 150.4, 147.7, 138.9, 136.8, 129.2,
128.6, 127.9, 127.2, 125.8, 125.4, 124.7, 124.3, 121.4, 114.5, 112.8,
84.2, 71.0, 56.1, 18.4. The 13C NMR data of the cis isomer was not col-
lected due to its low concentration. HRMS (ESI): m/z calcd for
C24H22N2NaO2+ [M + Na+] 393.1573, found 393.1577.
Preparation of Substrates. 1. General Procedure for the Synth-
esis of 2-Aryl-3-substituted-2-alkenenitriles 1, 5, and 8ꢀ107. The
desired substrate 1 was prepared following the general procedure
described in the previous paper.7 The ratio of the trans and cis isomers
1
of 2-aryl-3-substituted-2-alkenenitrile 1 was determined from the H
NMR spectral data. Compounds 1a, 1h, 1i, 1l, and 1o have been
prepared and characterized in our previous paper;7 the new compounds
thus obtained were characterized as follows:
2-[3,4-Bis(benzyloxy)phenyl]-3-(phenylamino)-2-butenenitrile, 1f.
1
3-[(4-Bromophenyl)amino]-2-phenyl-2-butenenitrile, 1b.
White solid. Yield: 80% (cis/trans = 1:4.5). Mp: 115ꢀ117 °C. 1H NMR
(400 MHz, CDCl3): major isomer (trans) δ 7.40ꢀ7.24 (m, 7H), 6.85 (d,
J = 8.0 Hz, 2H), 6.65 (s, 1H), 2.29 (s, 3H); minor isomer (cis) δ 7.47 (d,
J = 8.0 Hz, 2H), 7.42ꢀ7.24 (m, 5H), 6.98 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H),
2.01 (s, 3H). 13C NMR (100 MHz, CDCl3): major isomer (trans) δ
153.1, 137.9, 132.8, 132.4, 129.6, 129.0, 127.9, 125.8, 121.5, 118.6, 85.7,
18.7; minor isomer (cis) δ 155.1, 137.9, 133.7, 132.4, 129.6, 128.7,
127.1, 126.2, 120.1, 118.8, 85.7, 17.0. HRMS (ESI): m/z calcd for
C16H1379BrN2Na+ [M + Na+] 335.0154, found 335.0157.
3-[(4-Methoxyphenyl)amino]-2-phenyl-2-butenenitrile, 1c. White
solid. Yield: 65% (cis/trans = 1:4.5). Mp: 117ꢀ119 °C. 1H NMR (400
MHz, CDCl3): major isomer (trans) δ 7.46ꢀ7.20 (m, 5H), 6.95 (dd, J =
8.5, 2.0 Hz, 2H), 6.84 (dd, J = 8.5, 2.0 Hz, 2H), 6.68 (s, 1H), 3.79 (s, 3H),
2.20 (s, 3H); minor isomer (cis) δ 7.46ꢀ7.20 (m, 5H), 7.07 (dd, J = 8.5,
2.0 Hz, 2H), 6.89 (dd, J = 8.5, 2.0 Hz, 3H), 3.81 (s, 3H), 1.93 (s, 3H).
13C NMR (100 MHz, CDCl3): major isomer (trans) δ 158.0, 155.0,
White solid. Yield: 90% (cis/trans = 1:14.3). Mp: 116ꢀ118 °C. H
NMR (400 MHz, CDCl3): major isomer (trans) δ 7.45ꢀ7.34 (m, 6H),
7.31ꢀ7.27 (m, 3H), 7.19ꢀ7.14 (m, 4H), 6.98ꢀ6.80 (m, 5H), 6.51 (s,
1H), 5.16 (d, J = 8.0 Hz, 4H), 2.23 (s, 3H); minor isomer (cis) δ
7.45ꢀ7.34 (m, 10H), 7.31ꢀ7.27 (m, 1H), 7.06 (d, J = 8.0 Hz, 2H),
6.98ꢀ6.80 (m, 5H), 6.51 (s, 1H), 5.16 (d, J = 4.0 Hz, 4H), 1.85 (s, 3H).
13C NMR (100 MHz, CDCl3): major isomer (trans) δ 153.4, 149.3,
148.4, 138.8, 137.0, 136.9, 129.2, 128.6, 128.5, 127.9, 127.8, 127.2, 126.0,
125.4, 124.6, 124.5, 122.3, 121.8, 115.8, 115.7, 84.0, 71.3, 71.3, 18.5. The
13C NMR data of the cis isomer was not collected due to its low
concentration. HRMS (ESI): m/z calcd for C30H26N2NaO2+ [M + Na+]
469.1887, found 469.1891.
2-(4-Fluorophenyl)-3-(p-tolylamino)-2-butenenitrile, 1g. White sol-
id. Yield: 76% (cis/trans = 1:4). Mp: 122ꢀ124 °C. 1H NMR (400 MHz,
CDCl3): major isomer (trans) δ 7.42 (dd, J = 8.5, 5.0 Hz, 2H),
7.18ꢀ7.00 (m, 4H), 6.92ꢀ6.88 (m, 2H), 6.52 (s, 1H), 2.33 (s, 3H),
2.25 (s, 3H); minor isomer (cis) δ 7.18ꢀ7.00 (m, 7H), 6.92ꢀ6.88
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(m, 1H), 6.52 (s, 1H), 2.35 (s, 3H), 1.94 (s, 3H). 13C NMR (100 MHz,
CDCl3): major isomer (trans) δ 161.9 (d, JCꢀF = 246.0 Hz), 154.6,
135.9 (d, JCꢀF = 4.0 Hz), 131.4 (d, JCꢀF = 8.0 Hz), 131.0 (d, JCꢀF = 8.0
Hz), 129.9, 125.3, 124.9, 116.5 (d, JCꢀF = 21.5 Hz), 115.5 (d, JCꢀF = 21.5
Hz), 82.5, 20.9, 18.5. The 13C NMR data of the cis isomer was not
collected due to its low concentration. HRMS (ESI): m/z calcd for
C17H15FN2Na+ [M + Na+] 289.1111, found 289.1117.
111.7 (d, JCꢀF = 21.0 Hz), 110.6 (d, JCꢀF = 23.5 Hz), 87.7, 33.2, 21.6,
21.2, 13.5. The 13C NMR data of the cis isomer was not collected due
to its low concentration. HRMS (ESI): m/z calcd for C19H19FN2Na+
[M + Na+] 317.1424, found 317.1425.
2-Phenyl-3-(propylamino)-2-butenenitrile, 5. Yellow liquid. Yield:
1
87% (cis/trans = 1:5). H NMR (400 MHz, CDCl3): major isomer
(trans) δ 7.39ꢀ7.30 (m, 4H), 7.23ꢀ7.16 (m, 1H), 5.14 (s, 1H),
3.11ꢀ3.06 (m, 2H), 2.26 (s, 3H), 1.51ꢀ1.42 (m, 2H), 0.88 (t, J = 7.5
Hz, 3H); minor isomer (cis) δ 7.39ꢀ7.30 (m, 2H), 7.23ꢀ7.16 (m, 3H),
5.14 (s, 1H), 3.25ꢀ3.21 (m, 2H), 1.99 (s, 3H), 1.63ꢀ1.58 (m, 2H), 0.98
(t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): major isomer (trans)
δ 156.7, 133.8, 129.3, 128.9, 126.9, 123.1, 78.6, 45.4, 23.7, 17.5, 11.1;
minor isomer (cis) δ 158.7, 134.9, 129.6, 128.4, 126.1, 121.4, 78.6, 45.5,
23.7, 15.6, 11.2. HRMS (ESI): m/z calcd for C13H16N2Na+ [M + Na+]
223.1206, found 223.1206.
Ethyl 2-Phenyl-3-(propylamino)-2-butenoate, 8. Light yellow liquid.
Yield: 82%. 1H NMR (400 MHz, CDCl3): δ 11.32 (s, 1H), 7.36ꢀ7.13
(m, 10H), 4.16ꢀ4.13 (m, 2H), 1.82 (d, J = 3.0 Hz, 3H), 1.18ꢀ1.15 (m,
3H). ESI-MS: m/z 584.4.
2-(3-Chlorophenyl)-3-[(4-methoxyphenyl)amino]-2-butenenitrile,
1
1j. White solid. Yield: 91% (cis/trans = 1:3.5). Mp: 106ꢀ108 °C. H
NMR (400 MHz, CDCl3): major isomer (trans) δ 7.44 (s, 1H), 7.33 (d,
J = 8.0 Hz, 2H), 7.29ꢀ7.17 (m, 1H), 6.97 (d, J = 9.0 Hz, 2H), 6.85 (d, J =
9.0 Hz, 2H), 6.69 (s, 1H), 3.80 (s, 3H), 2.19 (s, 3H); minor isomer (cis)
δ 7.29ꢀ7.17 (m, 4H), 7.08 (d, J = 9.0 Hz, 2H), 6.98ꢀ6.95 (m, 1H), 6.90
(d, J = 9.0 Hz, 2H), 3.82 (s, 3H), 1.94 (s, 3H). 13C NMR (100 MHz,
CDCl3): major isomer (trans) δ 158.2, 155.7, 135.2, 131.0, 130.6, 129.0,
127.5, 127.3, 127.1, 121.8, 121.7, 114.5, 81.3, 55.5, 18.6; minor isomer
(cis) δ 158.3, 157.8, 136.2, 134.2, 129.7, 129.4, 127.6, 127.7, 127.6,
126.6, 120.2, 120.2, 114.9, 79.8, 16.7. HRMS (ESI): m/z calcd for
C17H1535ClN2NaO+ [M + Na+] 321.0765, found 321.0768.
2. General Procedure for the Synthesis of 9. 3-Phenyl-
4-(propylamino)-3-penten-2-one, 9. To a solution of 3-phenylpen-
tane-2,4-dione (1.0 mmol) in toluene (10 mL) was added aniline (1.5
mmol). The reaction mixture was stirred at reflux until TLC indicated
the total consumption of 3-arylpentane-2,4-dione. The mixture was
evaporated to partially remove the solvent. EtOAc (15 mL ꢁ 3) was
used to extract the mixture, and the combined organic phase, after being
dried with anhydrous Na2SO4, was evaporated to remove the solvent.
White solid. Yield: 87%. Mp: 105ꢀ107 °C. 1H NMR (400 MHz,
CDCl3): δ 13.58 (s, 1H), 7.39ꢀ7.27 (m, 5H), 7.23ꢀ7.18 (m, 3H),
7.14 (d, J = 7.5 Hz, 2H), 1.90 (s, 3H), 1.74 (s, 3H). ESI-MS: m/z 274.0.
3. General Procedure for the Synthesis of 10. 2-Phenyl-
3-(phenylamino)-2-cyclohexenone, 10. 2-Phenylcyclohexane-1,3-dione
(3 mmol) was dissolved in neat aniline (5 mL). The solution was stirred
at 140 °C until TLC indicated the completion of the reaction. White
2-(4-Methoxyphenyl)-3-[(4-nitrophenyl)amino]-2-butenenitrile,
1k. Yellow solid. Yield: 91% (cis/trans = 1:3.3). Mp: 171ꢀ173 °C. 1H
NMR (400 MHz, CDCl3): major isomer (trans) δ 8.15 (d, J = 9.0 Hz,
2H), 7.33ꢀ7.25 (m, 2H), 6.96ꢀ6.93 (m, 4H), 6.70 (s, 1H), 3.82 (s, 3H),
2.49 (s, 3H); minor isomer (cis) δ 8.22 (d, J = 9.0 Hz, 2H), 7.33ꢀ7.25
(m, 2H), 7.14ꢀ7.08 (m, 2H), 6.96ꢀ6.93 (m, 2H), 6.71 (s, 1H), 3.84 (s,
3H), 2.18 (s, 3H). 13C NMR (100 MHz, CDCl3): major isomer (trans)
δ 149.7, 145.3, 130.8, 130.3, 125.5, 125.4, 123.9, 120.4, 120.1, 115.1,
114.3, 55.4, 19.2. The 13C NMR data of the cis isomer was not collected due
+
to its low concentration. HRMS (ESI): m/z calcd for C17H15N3NaO3
[M + Na+] 332.1006, found 332.1011.
3-[(4-Ethoxyphenyl)amino]-2-o-tolyl-2-butenenitrile, 1m. White
1
solid. Yield: 68% (cis/trans = 1:7.7). Mp: 92ꢀ94 °C. H NMR (400
MHz, CDCl3): major isomer (trans) δ 7.33ꢀ7.17 (m, 4H), 6.92ꢀ6.80
(m, 4H), 5.98 (s, 1H), 4.05ꢀ3.97 (m, 2H), 2.39 (s, 3H), 2.21 (s, 3H),
1.40 (t, J = 7.0 Hz, 3H); minor isomer (cis) δ 7.33ꢀ7.17 (m, 4H), 7.06
(d, J = 9.0 Hz, 2H), 6.92ꢀ6.80 (m, 3H), 4.05ꢀ3.97 (m, 2H), 2.35 (s,
3H), 1.69 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): major isomer (trans) δ 157.3, 155.5, 138.4, 131.9, 131.2, 131.1,
130.4, 128.7, 127.3, 126.9, 121.6, 114.9, 81.1, 63.7, 19.7, 17.7, 14.8;
minor isomer (cis) δ 157.3, 155.5, 138.4, 131.9, 131.4, 131.3, 130.4,
128.0, 127.4, 126.1, 121.6, 115, 81.1, 63.7, 19.7, 17.7, 14.8. HRMS (ESI):
m/z calcd for C19H20N2NaO+ [M + Na+] 315.1468, found 315.1470.
2-(4-Chlorophenyl)-4-phenyl-3-(p-tolylamino)-2-butenenitrile, 1n.
White solid. Yield: 79% (cis/trans = 1:8.3). Mp: 107ꢀ109 °C. 1H NMR
(400 MHz, CDCl3): major isomer (trans) δ 7.37ꢀ7.18 (m, 7H), 7.10
(d, J = 7.0 Hz, 2H), 7.02ꢀ6.91 (m, 2H), 6.68 (d, J = 9.0 Hz, 2H), 6.41 (s,
1H), 4.01 (s, 2H), 2.28 (s, 3H); minor isomer (cis) δ 7.37ꢀ7.18 (m,
6H), 7.02ꢀ6.91 (m, 5H), 6.82 (m, 3H), 3.72 (s, 2H), 2.29 (s, 3H). 13C
NMR (100 MHz, CDCl3): major isomer (trans) δ 156.4, 136.3, 135.9,
135.8, 133.3, 131.7, 130.3, 129.6, 129.4, 128.9, 128.6, 128.4, 127.0, 125.0,
84.6, 37.6, 20.9; minor isomer (cis) δ 156.4, 136.5, 135.9, 135.8, 133.3,
131.7, 130.8, 129.7, 129.5, 128.9, 128.7, 128.0, 126.8, 125.3, 84.6, 36.7,
34.2. HRMS (ESI): m/z calcd for C23H1935ClN2Na+ [M + Na+]
381.1129, found 381.1133.
1
solid. Yield: 67%. Mp: 127ꢀ130 °C. H NMR (400 MHz, CDCl3):
δ 7.43 (t, J = 8.0 Hz, 2H), 7.33ꢀ7.26 (m, 5H), 7.18 (t, J = 8.0 Hz, 1H),
7.00 (d, J = 8.0 Hz, 2H), 6.52 (s, 1H), 2.60 (t, J = 8.0 Hz, 2H), 2.54 (t, J =
8.0 Hz, 2H), 2.06ꢀ2.00 (m, 2H). ESI-MS: m/z 549.2.
General Procedure for the Synthesis of Imine 2 and 6. To a
solution of substrate 1 (4.0 mmol) in dried dichloromethane (20 mL)
was added NBS (4.8 mmol) or NCS (6 mmol) (when R was methoxy or
benzyloxy) in one portion with stirring at room temperature, and the
process of the reaction was monitored by TLC analysis. After the
consumption of substrate 1, the mixture was evaporated to dryness.
The selected crude compounds thus obtained were characterized as follows:
(E)-2-Bromo-2-phenyl-3-(phenylimino)butanenitrile, 2a. 1H NMR
(400 MHz, CDCl3): δ 7.76 (d, J = 7.0 Hz, 2H), 7.49ꢀ7.41 (m, 3H), 7.34
(t, J = 8.0 Hz, 2H), 7.12 (t, J = 7.0 Hz, 1H), 6.77 (d, J = 7.5 Hz, 2H), 1.87
(s, 3H); 13C NMR (100 MHz, CDCl3): δ 163.6, 148.8, 133.9, 130.1,
129.3, 129.1, 127.5, 124.6, 118.7, 117.3, 56.0, 15.5. HRMS (ESI): m/z
calcd for C16H13BrN2Na+ [M + Na+] 335.0154, found 335.0155.
(E)-2-Chloro-2-(4-methoxyphenyl)-3-(phenylimino)butanenitrile,
2d. 1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.0 Hz, 2H), 7.34 (t, J =
7.5 Hz, 2H), 7.12 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.78 (d, J =
7.5 Hz, 2H), 3.84 (s, 3H), 1.81 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
171.3, 164.1, 160.8, 148.7, 129.1, 128.0, 124.6, 118.8, 117.0, 114.6, 66.6,
55.5, 14.7. HRMS (ESI): m/z calcd for C17H1535ClN2NaO+ [M + Na+]
321.0765, found 321.0767.
3-[(3-Fluorophenyl)amino]-2-p-tolyl-2-hexenenitrile, 1p. White solid.
Yield: 83% (cis/trans = 1:11.1). Mp: 101ꢀ104 °C. 1H NMR (400 MHz,
CDCl3): major isomer (trans) δ 7.33ꢀ7.29 (m, 2H), 7.23ꢀ7.16 (m,
3H), 6.89ꢀ6.79 (m, 3H), 6.40 (s, 1H), 2.73 (t, J = 8.0 Hz, 2H), 2.33 (s,
3H), 1.63ꢀ1.54 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H); minor isomer (cis) δ
7.33ꢀ7.25 (m, 2H), 7.23ꢀ7.16 (m, 3H), 6.89ꢀ6.79 (m, 3H), 6.40
(s, 1H), 2.43 (t, J = 8.0 Hz, 2H), 2.36 (s, 3H), 1.33ꢀ1.25 (m, 2H), 0.70
(t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3): major isomer (trans)
δ 163.0 (d, JCꢀF = 245.5 Hz), 156.5, 141.0 (d, JCꢀF = 10.5 Hz), 137.8,
130.3 (d, JCꢀF = 9.5 Hz), 130.1, 129.7, 128.7, 121.2, 118.9 (d, JCꢀF =3.0Hz),
(E)-2-Bromo-2-(4-bromophenyl)-3-[(2-methoxyphenyl)imino]-
butanenitrile, 2l. 1H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 8.5 Hz,
2H), 7.60 (d, J = 9.0 Hz, 2H), 7.10 (t, J = 7.0 Hz, 1H), 6.98ꢀ6.90
(m, 2H), 6.79 (d, J = 7.0 Hz, 1H), 3.78 (s, 3H), 1.83 (s, 3H). HRMS
(ESI): m/z calcd for C17H1479Br2N2NaO+ [M + Na+] 442.9365, found
442.9369.
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ARTICLE
(E)-2-Bromo-2-(4-chlorophenyl)-3-(p-tolylimino)hexanenitrile, 2o.
1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5
Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 8.0 Hz, 2H), 2.39ꢀ2.32
(m, 5H), 1.30ꢀ1.02 (m, 2H), 0.60 (t, J = 7.0 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 165.9, 146.0, 136.2, 133.8, 132.9, 129.6, 129.2, 129.1,
118.0, 117.3, 54.6, 32.1, 21.0, 20.8, 14.2. HRMS (ESI): m/z calcd for
C19H1879BrClN2Na+ [M + Na+] 411.0234, found 411.0237.
(E)-2-Bromo-2-phenyl-3-(propylimino)butanenitrile, 6. 1H NMR
(400 MHz, CDCl3): δ 7.64 (d, J = 7.5 Hz, 2H), 7.56ꢀ7.48 (m, 3H),
3.37 (q, J = 7.0 Hz, 2H), 1.88 (s, 3H), 1.67 (sxt, J = 7.0 Hz, 2H), 0.95 (t,
J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 162.2, 134.5, 130.4,
129.8, 127.7, 118.2, 57.5, 53.5, 23.4, 14.3, 12.2. HRMS (ESI): m/z calcd
for C13H1579BrN2Na+ [M + Na+] 301.0311, found 301.0317.
Conversion of Substrate Imine 2 to Enamine 4. Compound 2
was passed through silica gel (100 g) chromatography for purification,
enanitriles 4 were fully characterized, and the corresponding analytical
data are described in a later section.
4-Bromo-2-phenyl-3-(phenylamino)-2-butenenitrile, 4a. White sol-
id (cis/trans = 1:4). 1H NMR (400 MHz, CDCl3): major isomer (trans)
δ 7.51ꢀ7.27 (m, 8H), 7.08 (d, J = 8.0 Hz, 2H), 6.52 (s, 1H), 4.39 (s,
2H); minor isomer (cis) δ 7.51ꢀ7.27 (m, 5H), 7.24ꢀ7.17 (m, 5H), 6.66
(s, 1H), 4.07 (s, 2H). HRMS (ESI): m/z calcd for C16H1379BrN2Na+
[M + Na+] 335.0154, found 335.0159.
4-Bromo-2-(4-bromophenyl)-3-[(2-methoxyphenyl)amino]-2-bu-
tenenitrile, 4l. White solid (cis/trans = 1:4). Mp: 25ꢀ26 °C. 1H NMR
(400 MHz, CDCl3): major isomer (trans) δ 7.53ꢀ7.30 (m, 4H),
7.16ꢀ7.09 (m, 2H), 6.86 (t, J = 8.0 Hz, 2H), 6.52 (s, 1H), 4.35 (s,
2H), 3.83 (s, 3H); minor isomer (cis) δ 7.53ꢀ7.30 (m, 5H), 7.16ꢀ7.09
(m, 1H), 7.02ꢀ6.94 (m, 2H), 6.68 (s, 1H), 4.02 (s, 2H), 3.88 (s, 3H).
HRMS (ESI): m/z calcd for C17H1479Br2N2NaO+ [M + Na+], 442.9365;
Found 442.9369.
reduced to 50 °C). After completion of the reaction, the reaction mixture
was evaporated in vacuum to remove the solvent. The residue was
purified by silica gel chromatography using a mixture of PE and EA as
eluent to give the desired products.
2-Methyl-1-phenyl-1H-indole-3-carbonitrile, 3a. White solid. Yield:
72%. Mp: 105ꢀ106 °C. This compound was consistent with the one we
have synthesized in our previous work.7
1-(4-Bromophenyl)-2-methyl-1H-indole-3-carbonitrile, 3b. White
solid. Yield: 69%. Mp: 191ꢀ192 °C. 1H NMR (400 MHz, CDCl3): δ
7.73 (d, J = 9.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.29ꢀ7.20 (m, 2H),
7.22 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1H), 2.45 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 145.7, 137.1, 135.0, 133.3, 129.4, 126.9, 123.8,
123.3, 122.7, 119.1, 116.0, 110.8, 87.0, 12.6. HRMS (ESI): m/z calcd for
C16H1179BrN2Na+ [M + Na+] 332.9998, found 333.0002.
1-(4-Methoxyphenyl)-2-methyl-1H-indole-3-carbonitrile, 3c. White
solid. Yield: 62%. Mp; 144ꢀ145 °C. 1H NMR (400 MHz, CDCl3): δ
7.70 (d, J = 7.5 Hz, 1H), 7.27ꢀ7.17 (m, 4H), 7.06 (t, J = 9.0 Hz, 3H),
3.90 (s, 3H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 160.0, 146.4,
137.6, 128.9, 128.5, 126.8, 123.3, 122.3, 118.9, 116.4, 115.1, 111.1, 86.0,
55.7, 12.6. HRMS (ESI): m/z calcd for C17H14N2NaO+ [M + Na+]
285.0998, found 285.1004.
6-Methoxy-2-methyl-1-phenyl-1H-indole-3-carbonitrile, 3d. White
solid. Yield: 74%. Mp: 159ꢀ156 °C. 1H NMR (400 MHz, CDCl3): δ
7.62ꢀ7.53 (m, 4H), 7.33 (d, J = 8.0 Hz, 2H), 6.92 (dd, J = 8.5, 2.0 Hz,
1H), 6.53 (d, J = 2.0 Hz, 1H), 3.74 (s, 3H), 2.41 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 157.4, 145.2, 138.1, 136.1, 130.0, 129.2, 127.7, 120.7,
119.5, 116.4, 111.7, 94.9, 86.2, 55.7, 12.6. HRMS (ESI): m/z calcd for
C17H14N2NaO+ [M + Na+] 285.0998, found 285.1002.
6-(Benzyloxy)-5-methoxy-2-methyl-1-phenyl-1H-indole-3-carboni-
1
trile, 3e. White solid. Yield: 92%. Mp: 200ꢀ201 °C. H NMR (400
MHz, CDCl3): δ 7.60ꢀ7.53 (m, 3H), 7.39ꢀ7.28 (m, 5H), 7.24 (dd, J =
8.0, 2.0 Hz, 2H), 7.17 (s, 1H), 6.61 (s, 1H), 5.05 (s, 2H), 3.98 (s, 3H),
2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 147.9, 146.6, 144.1,
136.9, 136.2, 131.2, 129.9, 129.0, 128.5, 127.9, 127.6, 127.5, 120.5, 116.6,
100.9, 98.1, 86.1, 71.8, 56.5, 12.6. HRMS (ESI): m/z calcd for
C24H20N2NaO2+ [M + Na+] 391.1417, found 391.1418.
4-Bromo-2-(4-chlorophenyl)-3-(p-tolylamino)-2-hexenenitrile, 4o.
1
Light yellow solid (cis/trans = 1:2.2). Mp: 28ꢀ30 °C. H NMR (400
MHz, CDCl3): major isomer (trans) δ 7.73 (d, J = 8.0 Hz, 2H), 7.42 (d,
J = 8.0 Hz, 2H), 7.13 (d, J = 7.5 Hz, 2H), 6.65 (d, J = 7.5 Hz, 2H), 6.38 (s,
1H), 2.37ꢀ2.29 (m, 5H), 1.15 (t, J = 7.0 Hz, 1H), 0.60 (t, J = 7.0 Hz,
3H); minor isomer (cis) δ 7.42 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 7.5 Hz,
1H), 7.01ꢀ6.94 (m, 3H), 6.77 (d, J = 8.0 Hz, 2H), 6.50 (d, J = 8.0 Hz, 1H),
6.38 (s, 1H), 2.37ꢀ2.29 (m, 1H), 2.26ꢀ2.19 (m, 2H), 2.15 (s, 3H), 0.87 (t,
J = 7.0 Hz, 3H). HRMS (ESI): m/z calcd for C19H1879Br35ClN2Na+ [M +
Na+] 411.0234, found 411.0237.
5,6-Bis(benzyloxy)-2-methyl-1-phenyl-1H-indole-3-carbonitrile, 3f.
White solid. Yield: 77%. Mp: 147ꢀ148 °C. 1H NMR (400 MHz,
CDCl3): δ 7.59ꢀ7.53 (m, 3H), 7.50 (d, J = 8.0 Hz, 2H), 7.39ꢀ7.28
(m, 8H), 7.25ꢀ7.23 (m, 3H), 6.62 (s, 1H), 5.20 (s, 2H), 5.02 (s, 2H),
2.39 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 147.4, 147.0, 144.4,
137.1, 137.0, 136.1, 131.8, 129.9, 129.0, 128.4, 128.3, 127.84, 127.82,
127.6, 127.5, 127.4, 120.7, 116.5, 104.1, 98.9, 86.1, 72.2, 71.9, 12.6.
HRMS (ESI): m/z calcd for C30H24N2NaO+ [M + Na+] 467.1730,
found 467.1737.
Procedure for the Conversion of Compound 6 to 7. To a
solution of substrate 6 (4.0 mmol) in dried DCE (20 mL) was added
Zn(OAc)2 2H2O (3.2 mmol) in one portion, and then the mixture was
3
stirred at reflux temperature. The process of the reaction was monitored
by TLC analysis. After the total consumption of compound 6, the
reaction mixture was evaporated in vacuum to remove the solvent. The
residue was purified by silica gel chromatography using a mixture of PE
and EA as eluent to give the product 7.
6-Fluoro-2-methyl-1-(p-tolyl)-1H-indole-3-carbonitrile, 3g. White
solid. Yield: 92%. Mp: 134ꢀ136 °C. 1H NMR (400 MHz, CDCl3): δ
7.61 (dd, J = 8.5, 5.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.5 Hz,
2H), 7.01 (t, J = 9.0 Hz, 1H), 6.75 (dd, J = 9.0, 1.5 Hz, 1H), 2.48 (s, 3H),
2.42 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 160.4 (d, JCꢀF = 239.5
Hz), 146.7 (d, JCꢀF = 2.0 Hz), 139.7, 137.5 (d, JCꢀF = 12.0 Hz), 132.9,
4-Bromo-2-phenyl-3-(propylamino)-2-butenenitrile, 7. Yellow sol-
id. Yield: 80% (cis/trans = 1:2.5). Mp: 74ꢀ75 °C. 1H NMR (400 MHz,
CDCl3): major isomer (trans) δ 7.42ꢀ7.35 (m, 5H), 4.96 (s, 1H), 4.33
(s, 2H), 3.20 (q, J = 7.0 Hz, 2H), 1.54 (sxt, J = 7.0 Hz, 2H), 0.91 (t, J = 7.5
Hz, 3H); minor isomer (cis) δ 7.42ꢀ7.35 (m, 2H), 7.29ꢀ7.26 (m, 3H),
4.96 (s, 1H), 3.97 (s, 2H), 3.37 (q, J = 7.0 Hz, 2H), 1.68 (sxt, J = 7.0 Hz,
2H), 1.03 (t, J = 7.5 Hz, 3H). HRMS (ESI): m/z calcd for
C13H1579BrN2Na+ [M + Na+] 301.0311, found 301.0312.
130.7, 127.3, 123.0, 119.7 (d, JCꢀF = 10.0 Hz), 116.0, 110.9 (d, JCꢀF
=
24.0 Hz), 97.9 (d, JCꢀF = 27.0 Hz), 86.2, 21.2, 12.6. HRMS (ESI): m/z
calcd for C17H13FN2Na+ [M + Na+] 287.0955, found 287.0956.
2-Methyl-3-(p-tolyl)-3H-benzo[e]indole-1-carbonitrile, 3h. White
solid. Yield: 90%. Mp: 204ꢀ206 °C. This compound was consistent
with the one we have synthesized in our previous work.7
2,8-Dimethyl-1-phenyl-1,8-dihydropyrrolo[2,3-b]indole-3-carboni-
trile, 3i. Light yellow solid. Yield: 67%. Mp: 164ꢀ166 °C. This
compound was consistent with the one we have synthesized in our
previous work.7
General One-Pot Procedure for the Synthesis of N-Aryl-
indole-3-carbonitrile Derivatives 3. To a solution of 2-phenyl-
3-(phenylamino)but-2-enenitrile 1a (4 mmol) in DCE (20 mL) was
added NBS in one portion. The reaction was stirred at room temperature
until the total consumption of 1a. Then Zn(OAc)2 2H2O (3.2 mmol)
was added in one potion. The reaction temperature was gradually raised
to reflux (when R was methoxyl or benzyloxyl, the temperature was
5-Chloro- and 7-Chloro-1-(4-methoxyphenyl)-2-methyl-1H-indole-
3-carbonitrile, 3j. White solid. Yield: 50% (5-Cl/7-Cl = 3:1). Mp:
150ꢀ151 °C. 1H NMR (400 MHz, CDCl3): major isomer (5-Cl) δ 7.63
3
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The Journal of Organic Chemistry
ARTICLE
(d, J = 2.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.13 (dd, J = 8.0, 2.0 Hz,
1H), 7.08 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 2.42
(s, 3H); minor isomer (7-Cl) δ 7.74 (s, 1H), 7.28 (d, J = 8.5 Hz, 2H),
7.23ꢀ7.18 (m, 2H), 7.12ꢀ7.07 (m, 1H), 7.00 (dd, J = 8.5, 6.0 Hz, 1H),
3.92 (s, 3H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3): major isomer
(5-Cl) δ 160.2, 147.5, 136.0, 128.8, 128.2, 128.0, 127.7, 123.7, 118.3,
115.8, 115.2, 112.1, 85.6, 55.6, 12.6; minor isomer (cis) δ 160.4, 148.3,
136.6, 130.0, 128.7, 128.3, 127.4, 125.7, 119.6, 115.6, 115.4, 114.3, 85.7,
55.7, 12.7. HRMS (ESI): m/z calcd for C17H1335ClN2NaO+ [M + Na+]
319.0609, found 319.0612.
’ ACKNOWLEDGMENT
X.Q. acknowledges the project supported by the China
Postdoctoral Science Foundation (200904507610).
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S. P. J. Org. Chem. 2001, 66, 7729. (g) Taillefer, M.; Xia, N.; Ouali, A.
Angew. Chem., Int. Ed. 2007, 46, 934. (h) Nandurkar, N. S.; Bhanushali,
M. J.; Bhor, M. D.; Bhanage, B. M. Tetrahedron Lett. 2007, 48, 6573.
(i) Wang, H. F.; Li, Y.; Sun, F.; Feng, Y.; Jin, K.; Wang, X. N. J. Org.
Chem. 2008, 73, 8639. (j) Smith, C. J.; Tsang, M. W. S.; Holmes,
A. B.; Danheiserd, R. L.; Testerd, J. W. Org. Biomol. Chem. 2005,
3, 3767.
6-Methoxy-2-methyl-1-(4-nitrophenyl)-1H-indole-3-carbonitrile,
3k. Yellow solid. Yield: 90%. Mp: 144ꢀ145 °C. 1H NMR (400 MHz,
CDCl3): δ 8.48 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 3H), 6.95 (dd,
J = 9.0, 2.0 Hz, 1H), 6.56 (d, J = 1.5 Hz, 1H), 3.76 (s, 3H), 2.46 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 158.0, 147.7, 144.0, 141.8, 137.6,
128.6, 125.5, 120.8, 120.0, 115.6, 112.3, 94.7, 88.3, 55.8, 12.8. HRMS
+
(ESI): m/z calcd for C17H13N3NaO3 [M + Na+] 330.0849, found
330.0854.
6-Bromo-1-(2-methoxyphenyl)-2-methyl-1H-indole-3-carbonitrile,
3l. Light yellow solid. Yield: 66%. Mp: 165ꢀ166 °C. This com-
pound was consistent with the one we have synthesized in our previous
work.7
1-(4-Ethoxyphenyl)-2,4-dimethyl-1H-indole-3-carbonitrile, 3m.
White solid. Yield: 78%. Mp: 164ꢀ166 °C. 1H NMR (400 MHz,
CDCl3): δ 7.19 (d, J = 9.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H), 7.04 (d, J =
9.0 Hz, 2H), 6.98 (d, J = 7.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.11 (q,
J = 6.8 Hz, 2H), 2.78 (s, 3H), 2.42 (s, 3H), 1.48 (t, J = 7.0 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 159.4, 146.7, 137.6, 130.1, 128.9, 128.5,
125.2, 123.3, 123.2, 118.1, 115.5, 108.9, 85.2, 63.9, 18.5, 14.8, 12.4.
HRMS (ESI): m/z calcd for C19H18N2NaO+ [M + Na+] 313.1311,
found 313.1313.
2-Benzyl-6-chloro-1-(p-tolyl)-1H-indole-3-carbonitrile, 3n. White
1
solid. Yield: 64%. Mp: 141ꢀ142 °C. H NMR (400 MHz, CDCl3): δ
7.64 (d, J = 9.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.22 (dd, J = 8.5 1.5 Hz,
1H), 7.18ꢀ7.12 (m, 3H), 7.15 (s, 1H), 6.98ꢀ6.94 (m, 3H), 6.88 (dd, J =
7.0, 3.5 Hz, 2H), 4.14 (s, 2H), 2.45 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 149.1, 139.9, 138.2, 136.3, 132.6, 130.5, 129.8, 128.6, 128.5, 127.9, 126.9,
125.3, 123.2, 120.1, 115.8, 111.4, 87.0, 32.4, 21.3. HRMS (ESI): m/z calcd
for C23H1735ClN2Na+ [M + Na+] 379.0972, found 379.0975.
(5) (a) Willis, M. C.; Brace, G. N.; Findlay, T. J. K.; Holmes, I. P. Adv.
Synth. Catal. 2006, 348, 851. (b) Beller, M.; Breindl, C.; Riermeier, T. H.;
Tillack, A. J. Org. Chem. 2001, 66, 1403. (c) Hodgkinson, R. C.; Schulzb,
J.; Willis, M. C. Org. Biomol. Chem. 2009, 7, 432. (d) Ackermann, L. Org.
Lett. 2005, 7, 439.
(6) Brown, J. A. Tetrahedron Lett. 2000, 41, 1623.
6-Chloro-2-propyl-1-(p-tolyl)-1H-indole-3-carbonitrile, 3o. White
solid. Yield: 91%. Mp: 106ꢀ107 °C. This compound was consistent
with the one we have synthesized in our previous work.7
(7) Du, Y. F.; Liu, R. H.; Linn, G.; Zhao, K. Org. Lett. 2006, 8, 5919.
(8) (a) Nishio, T.; Okuda, N.; Kashima, C. Helv. Chim. Acta 1990,
73, 1719. (b) Nishio, T. J. Org. Chem. 1988, 53, 1323. (c) Nishio, T.;
Okuda, N.; Kashima, C. J. Chem. Soc., Perkin Trans. 1 1992, 899.
(9) Shim, S. C.; Youn, Y. Z.; Lee, D. Y.; Kim, T. J. Synth. Commun.
1996, 26, 1349.
(10) For a similar N-bromination of enamines using NBS, see: (a)
Kurasawa, Y.; Moritaki, Y.; Ebukuro, T.; Takada, A. Chem. Pharm. Bull.
1983, 31, 3897.(b) Yang, J.; Feng, K.-C.; Li, Y.-S.; Zang, H.-M.; Wang,
H.; Chou, C.-H.; Liang, R.-C. WO 2005017046, 2005.
(11) (a) Falvey, D. E. J. Phys. Org. Chem. 1999, 12, 589. (b) Liard, A.;
Nguyen, T. H.; Smir, A. I. D.; Vaultier, M.; Derdour, A.; Mortier, J.
Chem.—Eur. J. 2003, 9, 1000. (c) Boche, G.; Andrews, P.; Harms, K.;
Marsch, M.; Rangappa, K. S.; Schimeczek, M.; Willeke, C. J. Am. Chem.
Soc. 1996, 118, 4925. (d) Chiapperino, D.; McIlroy, S.; Falvey, D. E.
J. Am. Chem. Soc. 2002, 124, 3567.
1-(3-Fluorophenyl)-6-methyl-2-propyl-1H-indole-3-carbonitrile,
3p. Light yellow liquid. Yield: 74%. 1H NMR (400 MHz, CDCl3): δ
7.61ꢀ7.55 (m, 2H), 7.30ꢀ7.24 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H),
7.11ꢀ7.06 (m, 2H), 6.83 (s, 1H), 2.80 (t, J = 8.0 Hz, 2H), 2.39 (s, 3H),
1.61ꢀ1.51 (m, 2H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 163.2 (d, JCꢀF = 249.0 Hz), 149.2, 137.6 (d, JCꢀF = 3.0 Hz),
137.5 (d, JCꢀF = 9.0 Hz), 133.9, 131.3 (d, JCꢀF = 9.0 Hz), 124.7, 124.3,
124.0 (d, JCꢀF = 2.0 Hz), 118.7, 116.5 (d, JCꢀF = 21.0 Hz), 116.3,
115.7 (d, JCꢀF = 23.0 Hz), 110.8, 86.5, 28.2, 22.3, 21.7, 13.6. HRMS
(ESI): m/z calcd for C19H17FN2Na+ [M + Na+] 315.1268, found
315.1270.
’ ASSOCIATED CONTENT
(12) (a) Some other Lewis acids were also tested but were not as
efficient as Zn(OAc)2 2H2O: (1) AlCl3 (1 equiv), DCE, reflux, 0.5 h,
10%; (2) FeCl3 (1 equiv), DCE, reflux, 0.5 h, 5%; (3) ZnCl2 (1.0 equiv),
S
Supporting Information. Spectral data for all synthe-
3
b
sized compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
DCE, reflux, 0.5 h, 20%; (4) BF3 Et2O (1 equiv), DCE, reflux, 0.5 h, 8%.
3
(b) Anhydrous Zn(OAc)2 did not give a better result than Zn(OAc)2
2H2O.
3
(13) We thank one of the reviewers for putting forward an alter-
native mechanistic pathway, which includes the following: (i) formation
of a CꢀN bond via intramolecular electrophilic aromatic substitution of
2a; (ii) formation of the title N-arylindole-3-carbonitrile 3 from the
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: qxx@zzu.edu.cn; combinology@yahoo.com.
8696
dx.doi.org/10.1021/jo2012187 |J. Org. Chem. 2011, 76, 8690–8697

The Journal of Organic Chemistry
ARTICLE
intermediate arenium ion F via rearomatization through the loss of a
proton.
(14) Imine 2d also rearranged to enamine compound after silica gel
column chromatography.
(15) For a similar indole synthesis describing the formation of
nitrenium ion intermediate that is stablized by a methoxy group, see:
Creary, X.; Burtch, E. A.; Jiang, Z. J. Org. Chem. 2003, 68, 1117.
8697
dx.doi.org/10.1021/jo2012187 |J. Org. Chem. 2011, 76, 8690–8697