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org/joc

Copper-Mediated Cyclization-Halogenation and

Cyclization-Cyanation Reactions of β-Hydroxyalkynes and
o-Alkynylphenols and Anilines
Nalivela Kumara Swamy, Arife Yazici, and Stephen G. Pyne*
School of Chemistry, University of Wollongong, Wollongong, New South Wales 2522, Australia

[email protected]
Received March 18, 2010

The CuX (X = I, Br, Cl, CN)-mediated cyclization-halogenation and cyclization-cyanation reactions

of β-hydroxyalkynes and o-alkynylphenol and -aniline derivatives give rise to 3-halo- and 3-cyanofuro-
[3,2-b]pyrroles, 3-iodo-, 3-bromo-, and 3-cyanobenzofurans, and 3-cyanoindoles, respectively.

Introduction alkaloids.3 We recently reported an efficient synthesis of this

latter heterocyclic class of compounds, for example, 2 (R =
The benzofuran and indole ring structures are common to
H, Ph, Scheme 1), via metal-catalyzed cycloisomerization of
many bioactive and natural product molecules, and there-
4,5-cis-hydroxyalkynylpyrrolidin-2-ones 1 using Agþ, Auþ,
fore efficient methods for the synthesis of substituted deri-
or Pd2þ/Cuþ as catalyst.4 Related cycloisomerization reac-
vatives are highly desirable.1,2 The less common furo[3,2-
tions have been developed to prepare benzofurans and
b]pyrrole heterocyclic system is a key structural feature
indoles.5 This type of transformation would be made more
of the bioactive fungal metabolite lucilactaene and related
valuable if the initially formed cyclized organometallic inter-
(1) McCallion, G. D. Curr. Org. Chem. 1999, 3, 67–76.
mediate A could be utilized to introduce further useful
(2) ROMPP Encylopedia Natural Products; Steglich, W., Fugmann, B., functional groups into the cyclized products and provide,
Lang-Fugmann, S., Eds.; Thieme Verlag: Stuttgart, 2000; pp 314-316. for example, 3-functionalized furo[3,2-b]pyrroles, like 3
(3) Bashyal, B. P.; Faeth, S. H.; Gunatilaka, A. A. L. Nat. Prod. Commun.
2007, 2, 547-550 and references cited therein. (Scheme 1). Such useful functional groups could include
(4) Jury, J. C.; Swamy, N. K.; Yazici, A.; Willis, A.; Pyne, S. G. J. Org. halogen and cyano that have well-documented utility in
Chem. 2009, 74, 5523–5527. organic synthesis for the formation of new C-Y bonds (Y =
(5) For reviews on metal-catalyzed cyclization reactions, see: Nakamura,
I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127–2198. Zeni, G.; Larock, R. C. C, N, S and O) and the preparation of other key functional
Chem. Rev. 2006, 106, 4644–4680. Hashmi, A. S. K.; Hutchings, G. J. Angew. groups (e.g., keto, formyl, CH2NH2, and CH2OH groups),
Chem., Int. Ed. 2006, 45, 7896–7936. Hashmi, A. S. K. Chem. Rev. 2007, 107, respectively.6
3180–3211. Fuerstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
3410–3449. Shen, H. C. Tetrahedron 2008, 64, 3885–3903. Shen, H. C. The organometallic intermediates formed in the cyclo-
Tetrahedron 2008, 64, 7847–7870. Alvarez-Corral, M.; Munoz-Dorado, isomerization reactions of related o-alkynylphenols and
M.; Roderiguez-Garcia, I. Chem. Rev. 2008, 108, 3174–3198. Patil, N. T.;
Yamamoto, Y. Chem. Rev. 2008, 108, 3395–3442. Gorin, D. J.; Sherry, B. D.; anilines have been shown to undergo further metal-mediated
Toste, F. D. Chem. Rev. 2008, 108, 3351–3378. Arcadi, A. Chem. Rev. 2008,
108, 3266–3325. Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239–
3265. Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T. Chem. Commun. (6) Comprehensive Organic Transformations, 2nd ed.; Larock, R. C., Ed.;
2009, 5075–5087. Wiley: New York, 1999.

3412 J. Org. Chem. 2010, 75, 3412–3419 Published on Web 04/21/2010 DOI: 10.1021/jo1005119
r 2010 American Chemical Society
Swamy et al.
JOC Article
SCHEME 1. Synthesis of Furo[3,2-b]pyrroles 2 and 3 In principle, compounds 3 could be prepared from reduc-
tive elimination of the cyclization intermediate A (X =
halogen or CN) (Scheme 1). In fact, Ma has demonstrated
that CuCl2 and CuBr2 are effective reagents for the halo-
lactonization of 2,3-allenoic acids.12 Presumably, these reac-
tions occur via a reductive elimination pathway of a RCu-
(II)X (X = Cl or Br) intermediate. This type of reaction
has been further developed employing Pd/Cu catalysis, using
PdX2 (5 mol %) and CuX2 (3 equiv) [X = Cl, Br or I], for the
cyclization-halogenation reactions of o-alkynylphenols and
N-acetyl-o-alkynylanilines to give 3-halo-2-substituted benzo-
furans and indoles, respectively.13 These reactions, however,
often gave mixtures of 3-unsubstituted-2-substituted benzo-
furans and indoles (cycloisomerization products) and
3-halo-2-substituted benzofurans and indoles (cyclization-
halogenation products). We report here a novel and direct
method for the synthesis of 3-halo- and 3-cyanofuro[3,2-
b]pyrroles, 3-iodo, 3-bromo-, and 3-cyanobenzofurans, and
3-cyanoindoles from the CuX (X = I, Br, Cl, CN)-promoted
sequential cyclization-reductive elimination reactions of
the cis-4-hydroxy-5-phenylethynylpyrrolidinones 1 (R =
Ph, n-Pent) and O- and N-protected o-alkynylphenols and
-anilines, respectively.
reactions with alkenes or CO/MeOH, or reductive elimina-
tion when the cyclization catalyst is RPd(II), to provide Results and Discussion
3-substituted benzofurans and indoles through subsequent
Under the Ma conditions,12 the reaction of 1 (R = Ph)
C-C bond-forming reactions.5 Further, methods that in-
with CuBr2 (2 equiv) in acetone/water at 70 °C resulted in
volve migration of the initial O- or N-substituent of the
only recovered 1, while the same reaction with 6 equiv of
phenol and aniline precursors, respectively, to the C-3 posi-
CuBr2 in DMF with heating at 70 °C for 12 h gave the 1,2-
tion during the cyclization process have also been reported.7
dibromo derivative 4 (X = Br) in 67% yield (Scheme 1).
Metal-catalyzed procedures for the direct cyclization-
When 1 (R = Ph) was treated with CuI (1.5 equiv) in DMF at
cyanation reaction of these and related substrates, however,
rt, no reaction occurred; however, when the mixture was
have not been reported.8
heated at 80 °C under a nitrogen atmosphere for 16 h, a 68:32
While the synthesis of 2-substituted 3-iodobenzofurans
mixture of 3 and 2 (R = Ph) was obtained from which 3 (R =
and indoles has been achieved from the cyclization reactions
Ph, X = I) could be isolated after column chromatography
of o-alkynylphenols9 (or their O-protected derivatives)10 and
in 46% yield (Table 1, entry 1). We assumed that intermedi-
anilines11 with electrophilic iodine reagents, the synthesis of
ate A (M = Cu(I), m = 0) was formed initially and under-
the valuable nitrile products in a direct process requires a
went oxidation by a redox reaction with CuI to the
different synthetic strategy. Further, these iodonium ion
corresponding Cu(II), or possibly Cu(III),14 intermediate A
induced cyclization reactions are sometimes complicated
(M = Cu(II), m = 1), which then gave the desired product 3
due to competing 1,2-addition reactions to the triple bond
(R = Ph). Consistent with this hypothesis was the fact that
of the starting substrates.11b Indeed, treatment of 1 (R = Ph)
increasing the amount of CuI to 3 and 6 equiv gave higher
with I2/NaHCO3/CH2Cl2 gave a complex mixture of pro-
ratios of 3:2, the latter modification giving only 3 (R = Ph,
ducts while the reaction of 1 (R = Ph) with NIS/CH2Cl2
X = I) in 71% isolated yield (Table 1, entries 2 and 3, res-
resulted in an 81:19 mixture of 3 (R = Ph, X = I, 71%
pectively). The addition of base (Et3N) resulted in formation
isolated yield) and the 1,2-diiodo addition product 4 (X=I,
of only the cyclized product 2 (R = Ph). The amount of CuI
13% isolated yield), Scheme 1.
could be reduced to 1.1 equiv if the reaction was performed
(7) See, for example: Cacchi, S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998,
under an oxygen atmosphere (balloon) providing iodide 3
63, 1001–1011. Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. (R = Ph, X = I) in 85% yield (Table 1, entry 4). The reac-
Soc. 2004, 126, 10546–10547. tions under an oxygen atmosphere required heating at 100 °C
(8) For some recent methods to prepare 3-cyanofurans and indoles using
strategies different from that described here, see: Shi, Z.; Zhang, C.; Li, S.; to ensure complete conversion in 16 h. Similar results were
Pan, D.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 4572– obtained using 1 (R = Ph) and 1.1 equiv of CuBr or CuCl
4576. Li, X.; Du, Y.; Liang, Z.; Li, X.; Pan, Y.; Zhao, K. Org. Lett. 2009, 11, under an oxygen atmosphere (Table 1, entries 5 and 6)
2643–2646. Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417–2420. Huang,
X.-C.; Liu, Y.-L.; Liang, Y.; Pi, S.-F.; Wang, F.; Li, J.-H. Org. Lett. 2008, 10, providing the corresponding 3-bromo- and 3-chloro-cyclized
1525–1528. Wacker, D. A.; Kasireddy, P. Tetrahedron Lett. 2002, 43, 5189– products. The cyano derivative 3 (R = Ph, X = CN) was ob-
5191. Chen, C.-y.; Domer, P. G. J. Org. Chem. 2005, 70, 6964–6967.
(9) Arcardi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett
tained in 76% yield when the amount of CuCN was increased
1999, 1432–1434.
(10) (a) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292– (12) Ma, S.; Wu, S. J. Org. Chem. 1999, 64, 9314–9317.
10296. (b) Okitsu, T.; Nakazawa, D.; Taniguchi, R.; Wada, A. Org. Lett. (13) (a) Liang, Y.; Tang, S.; Zhang, X.-D.; Mao, L.-Q.; Xie, Y.-X.; Lie,
2008, 10, 4967–4970. J.-H. Org. Lett. 2006, 8, 3017–3020. (b) Tang, S.; Xie, Y.-X.; Li, J.-H.; Wang,
(11) (a) Barluenga, J.; Trincado, M.; Rubino, E.; Gonzalez, J. M. Angew. N.-X. Synthesis 2007, 1841–1847.
Chem., Int. Ed. 2003, 42, 2406–2409. (b) Yue, D.; Yao, T.; Larock, R. C. (14) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–
J. Org. Chem. 2006, 71, 62–69. 5449.

J. Org. Chem. Vol. 75, No. 10, 2010 3413

JOC Article Swamy et al.

TABLE 1. Synthesis of Furo[3,2-b]pyrroles 3a,b TABLE 2. Synthesis of 3-Substituted Benzofurans 7a

entry 1 (R) CuX (equiv) atm ratio 2:3 yield (%) of 3

1 Ph CuI (1.5) N2 32:68 46
2 Ph CuI (3.0) N2 25:75 50
3 Ph CuI (6.0) N2 0:100 71
4 Ph CuI (1.1) O2 0:100 85
5 Ph CuBr (1.1) O2 0:100 87
6 Ph CuCl (1.1) O2 0:100 77c
7 Ph CuCN (2.2)d O2 7:93 76
8 n-Pent CuI (1.1) O2 0:100 72
9 n-Pent CuCN (2.2) O2 0:100 79
a
Reactions under N2 were performed in DMF at 80 °C for 16 h.
b
Reactions under O2 were performed in DMF at 100 °C for 16 h. cThis
product was obtained in approximately 90% purity. dWhen 1.1 equiv
was used the ratio of 2:3 was 28:72 and the yield of 3 was 50%.

to 2.2 equiv (Table 1, entry 7). Quenching of the CuCl reaction a

Reactions were performed under O2 in DMF at 135-140 °C for 16 h.
mixture with water after 2 h at 80 °C afforded only the product The ratio of 7:8 was 100:0, except entry 4 (93:7) and entry 9 (92:8).
b
2 (R=Ph). This result suggested that cyclization of 1 (R = A complex mixture of products was obtained that included 7f, which
Ph) to a Cu(I) intermediate A (M = Cu(I), m = 0) was could not be obtained pure. cReaction performed at 100 °C for 16 h.
relatively fast and that its further oxidation by O2 to A (M =
Cu(II), m = 1) and/or reductive elimination to give 3 was a products. The reactions of substrates 6 having electron-
much slower process. The nonaromatic substrate 1 (R = withdrawing (Table 2, entries 5 and 7) and electron-donating
n-Pent) reacted with CuI and CuCN to provide the iodinated (Table 2, entry 4) substituents work equally well in their
and cyanated derivatives 3 (R = n-Pent, X = I or CN) in reactions with CuCN as did the parent compound 6 (R = H,
respective yields of 72% and 79% (Table 1, entries 8 and 9). R1 =Ph). The methoxy derivative 6 (R=OMe, R1 = Ph),
In order to further examine the scope of these CuX- however, produced a complex mixture of products. The
mediated reactions, the related o-alkynylphenols and 1-alkylalkynyl substrate 6 (R = H, R1 = n-Pent) also reacted
-anilines were examined as substrates. The o-alkynylphenol 5 efficiently with CuI and CuCN to give the respective benzo-
(R = H, R1 = Ph) underwent similar CuI- and CuCN- furan products 7h and 7i in 76% and 69% yields, respectively
mediated reactions to provide mixtures of 7a or 7c and the (Table 2, entries 8 and 9).
cycloisomerization product 8 (R = H, R1 = Ph). Often, the An attempt to perform the cyclization-iodination reac-
products 7 and 8 were difficult to separate. For example, tion on 6 (R = H, R1 = Ph) using CuI in a catalytic amount
treatment of 5 (R = H, R1 = Ph) with CuI (1.1 equiv) under (0.1 equiv) in the presence of LiI (3 equiv) and TMEDA (1
an oxygen atmosphere as described above gave an insepar- equiv) under an oxygen atmosphere gave an inseparable
able 86:14 mixture of 7a and the benzofuran 8 (R = H, R1 = 49:51 mixture of 7a and 8 (R = H, R1 = Ph) in a combined
Ph) in a combined yield of 82%. The starting o-alkynyl- yield of 73%.
phenol 5 (R = H, R1 = Ph) was, as previously noted,10a an The N-Ts and N-TFA o-alkynylanilines 9 (R = H, R1 =
unstable substrate and underwent cyclization to benzofuran Ph) underwent CuCN-mediated cyclization-cyanation re-
8 (R = H, R1 = Ph) on storage and had to be prepared or actions upon heating at 100 °C for 16 h to provide the
purified fresh before each reaction. 3-cyano, N-Ts, and N-unsubstituted indoles 10a and 10b in
Because of these difficulties, attention was focused on the yields of 74% and 80%, respectively (Table 3, entries 1 and 2)
more stable O-acetyl derivatives 6. These substrates required when 3.0 equiv.of CuCN was used. The aforementioned
higher reaction temperatures (135-140 °C) than 5 in their reaction also produced a small amount (3%) of the less
reactions with CuX but provided much higher ratios of 7:8 substituted indole 11 (R = H, R1 = Ph, R2 = Ts), while the
(usually 7:8 = 100:0, see Table 2, footnote a) and allowed reaction of the latter substrate resulted in clean formation of
for the isolation of pure products 7 (Table 2). We found that the N-unprotected indole product 10b with efficient loss of
2.2 equiv of CuX was required in these cases to ensure the N-TFA group. Attempts to cyclize the N-unprotected
good conversions to 7 in 16 h. The parent compound 6 (R = compound 9 (P = H, R = H, R1 = Ph) resulted in a complex
H, R1 = Ph) gave the desired 3-substituted benzofurans mixture of products, while the reaction of its N-Cbz analo-
7a-c exclusively and in good yields (Table 2, entries 1-3), gue 9 (P = Cbz, R = H, R1 = Ph) returned only unreacted
while its reaction with CuCl gave a complex mixtures of starting material. These results may suggest that only the
3414 J. Org. Chem. Vol. 75, No. 10, 2010
Swamy et al.
JOC Article
TABLE 3. Synthesis of 3-Cyanoindoles 10a cyanation reactions of cis-4-hydroxy-5-phenylethynylpyrro-
lidinones 1 and O- and N-protected o-alkynylphenols 6 and
-anilines 9, respectively. Although cyclization-halogenation
reactions of similar substrates have been reported using
electrophilic halogenation reagents,10,11 the CuX (X = I,
Br, Cl) method reported here will be useful in cases where
the aforementioned reagents give poor yields of cyclized
products due to competing intermolecular addition reactions
of the alkyne moiety or halogenation of the aromatic ring.
While the cyanation reactions of alkynes are known,16 the
sequential cyclization-cyanation reactions of these sub-
strates has not been reported. Furthermore, this method
allows for the synthesis of 3-cyanobenzofurans and indoles
in a one-step process that otherwise would require two
sequential steps from the same starting substrates, that is,
iodonium ion induced cyclization followed by a classical
Rosenmund-von Braun reaction with CuCN17 or its more
recent and milder Pd-catalyzed versions,18 on the resulting
3-iodobenzofurans or 3-iodoindoles.10,11 As a comparison,
the 3-cyanobenzofuran 7c was obtained in 65% overall yield
from the two-step method, which employed in the second
step a Pd-catalyzed Rosenmund-von Braun reaction which
required heating at 120 °C for 36 h,13a while this compound
was obtained in 78% yield using this new method at a similar
reaction temperature (135 °C) in 16 h. The majority of
reactions that provided the 3-cyanoindoles 10, using this
new one-step process, however, proceeded efficiently under
much milder conditions at 100 °C. Further, this new method
a
Reactions were performed under O2 in DMF at 100 °C for 16 h. The is also more cost-effective when one compares the relatively
ratio of 7:8 was 100:0, except entry 1 (98:2), entry 6 (30:70), and entry 9 higher costs per mole of iodine and NIS with the less
(70:30). bCompound 11 was also isolated in 3% yield. cAt 130 °C for 16 h.
d expensive CuCN.
Compound 11 was also isolated in 38% yield. eCompound 11 was also
isolated in 24% yield. While the exact mechanism of these reactions is not
known, the difference in the results of the reaction of 1
softer amine nucleophiles (NHTFA and NHTS compared (R = Ph) with CuBr2 (alkyne dibromination) and CuBr
to NH2) were suitable for cyclization with the relatively (cyclization-bromination) (Scheme 1) suggests that a Cu(II)
soft electrophilic Cu-alkyne complex intermediate.15 In con- species is not involved in the initial cyclization reaction.
trast, the reactions of 9 (P = Ts R = H, R1 = Ph) with CuX We suggest that, in the reactions of CuX with 1 under an
(X = I, Br, Cl) were unsuccessful and resulted in the return of oxygen atmosphere, the intermediate A (M = Cu(I), m = 0)
unreacted starting material. The reactions of substrates 9 in Scheme 1 is formed initially via cyclization of an electro-
having electron-withdrawing (Table 3, entries 4, 6, and 7) philic Cu(I)-alkyne complex intermediate5 which then
and electron-donating (Table 2, entry 3) substituents work undergoes oxidation by molecular oxygen to the correspond-
equally well as 9 (P = Ts or TFA, R = H, R1 = Ph) with ing Cu(II) or Cu(III) species before reductive elimination to give
CuCN. The methoxy-substituted substrate 9 (P = TFA, R = products 3.
OMe, R1 = Ph), however, required heating at 130 °C to
obtain 100% consumption of 9 in 16 h, resulting in a 78% Experimental Section
isolated yield of indole 10e (Table 3, entry 5). The N-TFA pro- General Details. See the Supporting Information. Safety
tected, 1-alkylalkynyl substrate 9 (P = TFA, R = H, R1 = Note. While we have experienced no problems, care must be
n-Pent) reacted efficiently with CuCN to give the 3-cyanated taken when heating DMF above its flash point (58 °C) under an
indole product 10i in 73% yield (Table 3, entry 8), while its oxygen atmosphere.
N-Ts analogue 9 (P = Ts R = H, R1 = n-Pent) gave a mixture Cyclization-Iodination Reaction of 1 (R = Ph) Using N-
of 10i (55% isolated yield) and 11 (R = Ts R = H, R1 = Iodosuccinimide. (3aR,6aS)-4-Benzyl-3-iodo-2-phenyl-6,6a-di-
hydro-3aH-furo[3,2-b]pyrrol-5(4H)-one (3, R = Ph, X = I) and
n-Pent, 24% isolated yield) (Table 3, entry 9).
(4S,5R)-1-Benzyl-5-((E)-1,2-diiodo-2-phenylvinyl)-4-hydroxypyr-
rolidin-2-one (4, X = I). To a solution of 1 (R = Ph)4 (25 mg,
Conclusions 0.085 mmol) and NIS (57 mg, 0.25 mmol) in CH2Cl2 (3 mL) was
In conclusion, we have developed a direct and convenient added NaHCO3 (21 mg, 0.25 mmol), and stirring was continued
method for the cyclization-halogenation and cyclization-
(16) Arai, S.; Sato, T.; Koike, Y.; Hayashi, M.; Nishida, A. Angew.
Chem., Int. Ed. 2009, 48, 4528–4531.
(15) A reviewer has suggested that the NTs or NTFA aniline substrates (17) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248,
may undergo initial deprotonation prior to cyclization, and hence, they are 2337–2364.
more reactive than their N-unsubstituted aniline counterparts. While this (18) (a) Okitsu, T.; Nakazawa, D.; Taniguchi, R.; Wada, A. Org. Lett.
may be a possibility, the absence of a base in these reactions would suggest 2008, 10, 4967–4970. (b) Hatsuda, M.; Seki, M. Tetrahedron 2005, 61,
that this is less likely. 9908–9917. and references cited therein.

J. Org. Chem. Vol. 75, No. 10, 2010 3415

JOC Article Swamy et al.

at rt for 16 h under a N2 atmosphere. The reaction mixture was properties of 3 (R = Ph, X = I) were the same as those described
diluted with water (8 mL), quenched with saturated sodium above.
thiosulfate solution (1 mL), and extracted with EtOAc (2  (3aR,6aS)-4-Benzyl-3-bromo-2-phenyl-6,6a-dihydro-3aH-furo-
10 mL). The combined organic extracts were dried (MgSO4), [3,2-b]pyrrol-5(4H)-one (3, R = Ph, X = Br). Prepared from 1
and the solvent was removed in vacuo. The crude product was (R = Ph) (50 mg, 0.17 mmol) and CuBr (27 mg, 0.19 mmol) ac-
chromatographed on silica gel (1:2 EtOAc/petroleum ether) to cording to the general procedure A described above. Purification
give 3 (R=Ph, X= I) as a white crystalline solid (26 mg, 71%) via flash chromatography (1:1 EtOAc/petroleum ether) provided
and 4 (X = I) as a white solid (6 mg, 13%). the title compound as a colorless gum (55.3 mg, 87%): Rf = 0.72
3 (R = Ph, X = I): mp 140-142 °C; Rf = 0.71 (1:1 EtOAc/ (1:1 EtOAc/petroleum ether); [R]24D þ2.6 (c 0.87, CHCl3); IR
petroleum ether); [R]24D þ6.1 (c 1.8, CHCl3); IR (neat, νmax/ (neat, νmax/cm-1) 1674, 1438, 1226, 1068, 922 and 753; δH
cm-1) 1672, 1406, 1218, 916, 862, 756; δH 7.82-7.29 (10H, m, 7.86-7.29 (10H, m, ArH), 5.18 (1H, d, J = 15.0 Hz, CHHPh),
H), 5.18 (1H, m, HC-6a), 5.15 (1H, d, J = 15.2 Hz, CHHPh), 5.16 (1H, m, HC-6a), 4.73 (1H, d, J = 7.9 Hz, HC-3a), 4.43 (1H,
4.70 (1H, dd, J = 7.8, 0.7 Hz, HC-3a), 4.54 (1H, d, J = 15.2 Hz, d, J = 15.0 Hz, CHHPh), 2.97-2.87 (2H, m, H2C-6). δC 172.1
CHHPh), 2.96-2.86 (2H, m, H2C-6). δC 172.34 (CO), 159.2 (2- (CO), 154.9 (2-C), 136.1 (C), 130.1 (CH), 128.8 (CH), 128.7 (CH),
C), 136.2 (C), 130.2 (CH), 129.3 (CH), 128.6 (CH), 128.4 (CH), 128.6 (C), 128.4 (CH), 128.2 (CH), 127.7 (CH), 87.9 (3-C), 76.3
128.3 (CH), 128.1 (CH), 127.6 (C), 77.4 (6a-C), 71.1 (3a-C), 52.3 (6a-C), 68.7 (3a-C), 44.8 (CH2Ph), 37.9 (6-C); ESIMS m/z 370
(3-C), 44.8 (CH2Ph), 37.6 (6-C); EIMS m/z 417 [(Mþ) 50]; [(MHþ), 79Br, 100], 372 [(MHþ), 81Br, 100]; HREIMS calcd. for
HREIMS calcd for C19H16NO2I (Mþ) 417.0225, found C19H16NO279Br (Mþ) 369.0365, found 369.0364.
417.0211. (3aR,6aS)-4-Benzyl-3-chloro-2-phenyl-6,6a-dihydro-3aH-furo-
4 (X = I): mp 166-168 °C; Rf = 0.75 (1:1 EtOAc/petroleum [3,2-b]pyrrol-5(4H)-one (3, R = Ph, X = Cl). Prepared from 1
ether); [R]24D -0.9 (c 1.28, CHCl3); IR (neat, νmax/cm-1) 3232, (R = Ph) (50 mg, 0.17 mmol) and CuCl (19 mg, 0.19 mmol) ac-
1675, 1408, 1261, 1045, 744 and 703; δH 7.88-7.31 (10H, m, H), cording to the general procedure A described above. Purification
5.40 (1H, d, J = 15.0 Hz, CHHPh), 4.83 (1H, m, HC-4), 4.61 via flash chromatography (1:1 EtOAc/petroleum ether) provided
(1H, d, J = 8.1 Hz, HC-5), 4.30 (1H, d, J = 15.0 Hz, CHHPh), the title compound as an off white solid (43 mg, 77%). This
3.47 (1H, s, OH), 2.93 (1H, dd, J = 18.0, 9.3 Hz, HC-3), 2.80 compound was approximately 90% pure from NMR analysis:
(1H, dd, J = 18.0, 5.3 Hz, HC-3). δC 173.3 (CO), 139.0 (C), mp 158-160 °C; Rf = 0.74 (1:1 EtOAc/petroleum ether); [R]25D
135.3 (C), 129.9 (CH), 128.9 (CH), 128.8 (CH), 127.9 (CH), þ21.2 (c 0.80, CHCl3); IR (neat, νmax/cm-1): 1692, 1485, 1398,
127.8 (CH), 127.6 (CH), 107.2 (IC=CI), 75.1 (ICdCI and 5-C), 1227, 1028, 937 and 768; δH 7.83-7.81 (2H, m, ArH), 7.41-7.25
72.1 (4-C), 45.0 (CH2Ph), 37.5 (3-C); ESIMS m/z 562 [(M þ (8H, m, ArH), 5.20 (1H, d, J=15.0 Hz, CHHPh), 5.15-5.12 (1H,
NH3)þ 100]; HRESIMS calc. for C19H20N2O2I2 (M þ NH3)þ m, HC-6a), 4.68 (1H, d, J = 7.5 Hz, HC-3a), 4.34 (1H, d, J = 15.0
561.9459, found 561.9503. Hz, CHHPh), 2.95-2.88 (2H, m, H2C-6). δC 172.0 (CO), 152.6
Reaction of 1 (R = Ph) with CuBr2. (4S,5R)-1-Benzyl-5-((E)- (2-C), 136.0 (C), 130.0 (CH), 128.7 (CH), 128.4 (CH), 128.3 (CH),
1,2-dibromo-2-phenylvinyl)-4-hydroxypyrrolidin-2-one (4, X = 128.2 (CH), 127.7 (C), 127.2 (CH), 102.5 (3-C), 75.5 (6a-C), 67.4
Br). A mixture of 1 (R = Ph) (20 mg, 0.068 mmol) and CuBr2 (3a-C), 44.8 (CH2Ph), 37.9 (6-C); ESIMS m/z 326 [(MHþ), 35Cl,
(90 mg, 0.4 mmol) in anhydrous DMF (2 mL, Aldrich) was 100]; HREIMS calcd. for C19H16NO235Cl (Mþ) 325.0872, found
stirred at 70 °C for 12 h under a N2 atmosphere. The reaction 325.0869.
mixture was cooled to rt, diluted with water (10 mL), and (3aR,6aS)-4-Benzyl-3-iodo-2-pentyl-6,6a-dihydro-3aH-furo-
extracted with EtOAc (2  10 mL). The combined organic [3,2-b]pyrrol-5(4H) one (3, R = n-Pent, X = I). Prepared from 1
extracts were dried (MgSO4), and the solvent was removed (R = n-Pent) (50 mg, 0.21 mmol) and CuI (44 mg, 0.23 mmol)
under vacuo. The crude product was chromatographed on silica according to the general procedure A described above. Purifica-
gel (1:2 EtOAc/petroleum ether) to give the title compound as a tion via flash chromatography (1:2 EtOAc/petroleum ether)
white powder (20 mg, 67%): mp 178-180 °C; Rf = 0.75 (1:1 provided the title compound 3 (R = Pent, X = I) as a light
EtOAc/petroleum ether); [R]24D -17.7 (c 1.69, CHCl3); IR yellow gum (52 mg, 72%): Rf = 0.82 (1:2 EtOAc/petroleum
(neat, νmax/cm-1) 3230, 1669, 1428, 1215, 1044, 1017 and 754; ether); [R]25D -25.2 (c 4.0, CHCl3); IR (neat, νmax/cm-1) 2945,
δH 7.80-7.32 (10H, m, H), 5.36 (1H, d, J = 14.9 Hz, CHHPh), 2924, 1681, 1408, 1219, 1040, 958, 860 and 702; δH 7.36-7.26
4.85-4.84 (1H, m, HC-4), 4.80 (1H, d, J = 8.3 Hz, HC-5), 4.15 (5H, m, ArH), 5.12 (1H, d, J = 15.0 Hz, CHHPh), 5.02-4.98
(1H, d, J = 14.9 Hz, CHHPh), 3.70 (1H, s, OH), 2.84 (1H, dd, (1H, td, J = 1.5, 8.0 Hz, HC-6a), 4.52 (1H, d, J = 8.0 Hz, HC-
J = 17.9, 8.6 Hz, HC-3), 2.76 (1H, dd, J = 17.9, 5.2 Hz, HC-3); 3a), 4.40 (1H, d, J = 15.0 Hz, CHHPh), 2.90-2.84 (1H, dd, J =
δC 173.0 (CO), 137.3 (C), 135.3 (C), 129.9 (CH), 128.9 (CH), 7.5, 18.5 Hz, HHC-3), 2.75 (1H, d, J = 18.5 Hz, HHC-3),
128.7 (CH), 128.0 (CH), 127.7 (CH), 127.5 (CH), 107.7, 73.2 2.27(2H, t, J = 7.5 Hz, H2C-pent), 1.53-1.47 (2H, m, H2C-
(BrCdCBr), 72.3, 71.5 (5-C, 4-C), 45.0 (CH2Ph), 37.1 (3-C); pent), 1.35-1.25 (4H, m, -H2C-H2C-pent), 0.90 (3H, t, J=7.0
ESIMS m/z 450 [(MHþ), 79Br, 10%]; HRESIMS calcd for Hz, H3C-pent). δC 172.2 (CO), 164.6 (2-C), 136.1 (C), 128.6
C19H18NO279Br2 (MHþ) 449.9642, found 449.9704. (CH), 128.3 (CH), 127.6 (CH), 77.5 (3-C), 68.8 (6a-C), 53.6 (3a-
General Procedure (A) for the Cyclization-halogenation and C), 44.7 (CH2Ph), 37.8 (6-C), 31.1, 28.0, 25.8, 22.3, and 13.9
Cyclization-cyanation Reactions. The preparation of 3 (R = (pent-C); EIMS m/z 411 [(M)þ, 30]; HRESIMS calcd for
Ph, X = I) is representative. To a solution of 1 (R = Ph) (50 mg, C18H23NO2I (MHþ) 412.0761, found 412.0774.
0.17 mmol) in anhydrous DMF (2 mL, Aldrich) under an O2 (3aS,6aS)-4-Benzyl-5-oxo-2-phenyl-4,5,6,6a-tetrahydro-3aH-
atmosphere (balloon) was added CuI (36 mg, 0.19 mmol), and furo[3,2-b]pyrrole-3-carbonitrile (3, R = Ph, X = CN). Prepared
the reaction flask was inserted into a preheated oil bath at 100 °C from 1 (R = Ph) (25 mg, 0.085 mmol) and CuCN (17 mg, 0.19
(see the safety note above). Stirring was continued for 16 h at the mmol) and anhydrous DMF (1.5 mL), according to the general
same temperature, until the reaction was complete as deter- procedure A described above. The crude product (93: 07 ratio of
mined by TLC. The reaction mixture was cooled to rt, diluted 3 (R = Ph, X = CN):2 (R = Ph) was chromatographed on silica
with water (15 mL), and extracted with ethyl acetate (2  gel (1:1 EtOAc/petroleum ether) to give the title compound as a
30 mL). The combined organic extracts were dried (MgSO4), colorless gum (20.4 mg, 76%) and 2 (R = Ph)4 (1.6 mg, 6%).
and the solvent was removed in vacuo. The crude product Data for 3 (R = Ph, X = CN): Rf = 0.65 (1:2 EtOAc/petroleum
was chromatographed on silica gel (1:2 EtOAc/petroleum ether); [R]24D þ26.1 (c 0.42, CHCl3); IR (neat, νmax/cm-1) 2194,
ether) to give compound 3 (R = Ph, X = I) as a white crystalline 1692, 1618, 1233, 1019 and 750; δH 7.96-7.32 (10H, m, ArH),
solid (61 mg, 85%). The spectroscopic data and physical 5.30-5.29 (1H, m, HC-6a), 5.23 (1H, d, J = 15.0 Hz, CHHPh),

3416 J. Org. Chem. Vol. 75, No. 10, 2010

Swamy et al.
JOC Article
4.87 (1H, d, J = 7.5 Hz, HC-3a), 4.18 (1H, d, J = 15.0 Hz, according to the general procedure B described above. The
CHHPh), 3.01-2.92 (2H, m, H2C-6). δC 171.0 (CO), 170.5 crude product (ratio of 7d:8d was 93:7) was chromatographed
(2-C), 135.2 (C), 132.6 (CH), 128.9 (CH), 128.85 (CH), 128.7 on silica gel (1:8, EtOAc/petroleum ether) to give 7d as a white
(CH), 128.0 (CH), 127.6 (CH), 126.8 (C), 80.9 (CN), 79.3 (6a-C), solid (31.3 mg, 67%) and 2-(4-methoxyphenyl)benzofuran (8d)
64,5 (3a-C), 44.3 (CH2Ph), 37.1 (6-C); ESIMS m/z 317 [(MHþ) as a white solid (1 mg, 3%).
100]; HREIMS calcd for C20H16N2O2, (Mþ) 316.1220, found 7d: mp 138-140 °C; Rf = 0.65 (1:4 EtOAc/petroleum ether);
316.1211. IR (neat, νmax/cm-1) 2225, 1608, 1506, 1266, 1024, 831 and 738;
(3aR,6aS)-4-Benzyl-5-oxo-2-pentyl-4,5,6,6a-tetrahydro-3aH- δH 8.14 (2H, d, J = 9.0 Hz), 7.66 (1H, dd, J = 2.5, 6.5 Hz), 7.52
furo[3,2-b]pyrrole-3-carbonitrile (3, R = n-Pent, X = CN). Pre- (1H, dd, J = 2.5, 6.5 Hz), 7.37 - 7.34 (2H, m), 7.03 (2H, d, J =
pared from 1 (R = Pent) (60 mg, 0.21 mmol) and CuCN (41 mg, 9.0 Hz), 3.88 (3H, s, OMe); δC 162.0 (2-C), 161.8 (C), 153.0 (C),
0.46 mmol) according to the general procedure A described 128.3 (CH), 127.4 (C), 125.8 (CH), 124.5 (CH), 120.4 (C), 119.6
above. Purification via flash chromatography (1:2 EtOAc/ (CH), 114.7 (C), 114.5 (CH), 111.5 (CH), 86.2 (CN), 55.4 (OMe);
petroleum ether) provided the title compound as a light yellow EIMS m/z 249 [(Mþ) 100]; HREIMS calcd for C16H11NO2 (Mþ)
gum (52 mg, 79%): Rf = 0.63 (1:2 EtOAc/petroleum ether); 249.0784, found 249.0789.
[R]25D-42.8 (c 4.5, CHCl3); IR (neat, νmax/cm-1) 2960, 2924, 8d: colorless solid; mp 142-144 °C (lit.19 mp 143 °C); δH 7.81
2207, 1692, 1632, 1239, 994, 772, and 731. δH 7.35-7.26 (5H, m, (2H, d, J = 8.5 Hz), 7.56 (1H, d, J = 7.0 Hz), 7.50 (1H, d, J =
ArH), 5.20 (1H, d, J = 15.0 Hz, CHHPh), 5.15 (1H, t, J = 7.5 8.0 Hz), 7.26-7.20 (3H, m), 6.99 (2H, d, J = 8.9 Hz), 6.89
Hz, HC-6a), 4.68 (1H, d, J = 7.5 Hz, HC-3a), 4.05 (1H, d, J = (1H, s), 3.87 (3H, s, OMe); EIMS m/z 224 [(Mþ) 80]. The
15.0 Hz, CHHPh), 2.94-2.88 (1H, dd, J = 7.5, 18.5 Hz, HHC- analytical and spectroscopic data matched with those reported
3), 2.81 (1H, d, J = 18.5 Hz, HHC-3), 2.43-2.40 (2H, m, H2C- in the literature.19
pent), 1.61-1.56 (2H, m, H2C-pent), 1.35-1.30 (4H, m, 2-(4-Fluorophenyl)benzofuran-3-carbonitrile (7e). Prepared
-H2C-H2C-pent), 0.90 (3H, t, J = 6.5 Hz, H3C-pent). δC from 6 (R = H, R1 = p-FPh) (50 mg, 0.19 mmol) and CuCN
179.3 (CO), 170.4 (2-C), 135.2 (C), 128.9 (CH), 128.7 (CH), (39 mg, 0.43 mmol) according to the general procedure (B)
128.1 (CH), 115.9 (3-C), 83.8 (CN), 80.1 (6a-C), 63.3 (3a-C), 44.3 described above. The crude product was chromatographed on
(CH2Ph), 37.1 (6-C), 31.0, 28.0, 25.7, 22.1, and 13.8 (pent-C). silica gel (9:1, petrol/EtOAc) to give 7e as a colorless solid (34.5
EIMS m/z 310 [(Mþ) 40]; HREIMS calcd for C19H22N2O2 (Mþ) mg, 74%): mp 124-126 °C; Rf = 0.68 (1:4 EtOAc/petroleum
310.1687, found 310.1681. ether); IR (neat, νmax/cm-1) 2226, 1606, 1503, 1236, 1040, 835 and
General Procedure (B) for the Synthesis of Substituted 3-Halo- 748; δH 8.19-8.16 (2H, dd, J = 5.5, 9.0 Hz), 7.69 (1H, d, J = 7.5
and 3-Cyanobenzo[b]furans. The preparation of 3-iodo-2- Hz), 7.55 (1H, d, J = 8.5 Hz), 7.42-7.35 (2H, m), 7.21 (2H, t, J =
phenylbenzofuran is representative. To a mixture of 6 (R = H, 8.5 Hz); δC 164.2 (C, d, J = 251.7 Hz), 160.7 (C), 153.2 (C), 128.7
R1 = Ph) (50 mg, 0.21 mmol) in anhydrous DMF (2 mL) under (CH, d, J = 9.2 Hz), 127.0 (C), 126.4 (CH), 124.7 (CH), 124.1 (C,
an O2 atmosphere (balloon) was added CuI (88 mg, 0.46 mmol), d, J = 3.7 Hz), 120.0 (CH), 116.4 (CH, d, J = 22.2 Hz), 114.2 (C),
and the reaction flask was inserted in to a preheated oil bath at 111.6 (CH), 87.8 (CN); EIMS m/z 237 [(Mþ) 100%]; HREIMS
135-140 °C (see the safety note above). Stirring was continued calcd. for C15H8FNO (Mþ) 237.0589, found 237.0589.
for 16 h at the same temperature until complete consumption of 2-Phenylbenzofuran-3,5-dicarbonitrile (7g). To a solution of 6
starting material as determined by TLC. The reaction mixture (R = CN, R1 = Ph) (50 mg, 0.19 mmol) in anhydrous DMF
was cooled to rt, diluted with water (8 mL), and extracted with (2 mL) under an O2 atmosphere (balloon) was added CuCN
EtOAc (2  10 mL). The combined organic extracts were dried (39 mg, 0.42 mmol), and the reaction flask was inserted into a
(MgSO4), and the solvent was removed in vacuo. The crude preheated oil bath at 100 °C. Stirring was continued for 16 h at
product was chromatographed on silica gel (petroleum ether) the same temperature, until complete consumption of starting
to give the product 7a as a yellow oil (47 mg, 70%): Rf = 0.82 material as determined by TLC. Workup was according to the
(1:4 EtOAc/petroleum ether); δH 8.19 (2H, d, J = 8.0 Hz), general procedure B described above. The crude product was
7.28 -7.51 (7H, m); EIMS m/z 320 [(Mþ) 100]. The analytical chromatographed on silica gel (5:1 petrol/EtOAc) to give 7g
and spectroscopic data matched with those reported in the as a colorless solid (37.3 mg, 80%): mp 168-170 °C; Rf = 0.51
literature.10a (1:4 EtOAc/petroleum ether); IR (neat, νmax/cm-1) 2230, 1562,
3-Bromo-2-phenylbenzofuran (7b). Prepared from 6 (R = H, 1465, 1448, 1169, 897, 817 and 770; δH 8.18 (2H, dd, J = 1.5, 5.5
R1 = Ph) (50 mg, 0.21 mmol) and CuBr (66 mg, 0.46 mmol) ac- Hz), 8.02 (1H, s), 7.69 (2H, s), 7.58-7.57 (3H, m); δC 163.8
cording to the general procedure B described above. The crude (2-C), 154.6 (C), 132.2 (CH), 129.9 (CH), 129.3 (CH), 128.0 (C),
product was chromatographed on silica gel (petroleum ether) to 126.8 (CH), 126.7 (C), 124.6 (CH), 118.2 (C), 113.0 (CH), 112.9
give the title compound 7b as a colorless solid (35 mg, 62%): mp (C), 109.0 (CN), 87.8 (CN); EIMS m/z 244 [(Mþ) 100]; HREIMS
62-64 °C (lit.7 mp 62-63 °C); Rf = 0.83 (1:4 EtOAc/petroleum calcd. for C16H8N2O (Mþ) 244.0640, found 244.0636.
ether); δH 8.17 (2H, d, J = 7.5 Hz), 7.58-7.31 (7H, m); EIMS m/ 3-Iodo-2-pentylbenzofuran (7h). Prepared from 6 (R = H, R1 =
z 272 [(Mþ), 79Br, 100], 274 [(Mþ), 81Br, 98]. The analytical and n-Pent) (50 mg, 0.21 mmol) and CuI (90 mg, 0.47 mmol) accord-
spectroscopic data matched with those reported in the ing to the general procedure B described above. The crude product
literature.13a was chromatographed on silica gel (petroleum ether) to give 7h as
2-Phenylbenzofuran-3-carbonitrile (7c). Prepared from 6 a pale yellow gum (51 mg, 76%): Rf = 0.75 (1:4 EtOAc/petroleum
(R = H, R1 = Ph) (50 mg, 0.21 mmol) and CuCN (41 mg, ether); IR (neat, νmax/cm-1) 2955, 2919, 1582, 1449, 1014 and 742;
0.46 mmol) according to the general procedure B described δH 7.38-7.24 (4H, m), 2.84 (2H, t, J = 7.5 Hz), 1.75-1.72 (2H,
above. The crude product was chromatographed on silica gel m), 1.36-1.33 (4H, m), 0.90 (3H, t, J = 7.5 Hz); δC 159.1 (2-C),
(9:1, petroleum ether/EtOAc) to give 7c as a colorless solid 154.2 (C), 131.0 (C), 124.4 (CH), 123.0 (CH), 120.7 (CH), 110.9
(36 mg, 78%): mp 58-60 °C (lit.8 mp 57.5-59.4 °C); Rf = 0.69 (CH), 62.5 (3-C), 31.1, 28.0, 27.5, 22.3, and 13.9 (pent-C); EIMS
(1:4 EtOAc/petroleum ether); δH 8.19 (2H, d, J = 7.5 Hz), m/z 314 [(Mþ) 40]; HREIMS calcd for C13H15OI (Mþ) 314.0166,
7.70 (1H, d, J = 7.5 Hz), 7.57-7.36 (6H, m); EIMS m/z 219 found 314.0167.
[(Mþ) 100]. The analytical and spectroscopic data matched 2-Pentylbenzofuran-3-carbonitrile (7i) and 2-Pentylbenzofuran
with those reported in the literature.10b (8i). Prepared from 6 (R = H, R1 = n-Pent) (50 mg, 0.21 mmol)
2-(4-Methoxyphenyl)benzofuran-3-carbonitrile (7d) and 2-(4-
Methoxyphenyl)benzofuran (8d). Prepared from 6 (R = H, R1 = (19) Razler, T. M.; Hsiao, Y.; Qian, F.; Fu, R.; Khan, R. K.; Doubleday,
p-MeOPh) (50 mg, 0.18 mmol) and CuCN (37 mg, 0.41 mmol) W. J. Org. Chem. 2009, 74, 1381–1384.

J. Org. Chem. Vol. 75, No. 10, 2010 3417

JOC Article Swamy et al.

and CuCN (43 mg, 0.47 mmol) according to the general proce- purified by column chromatography (silica gel, 1:3 EtOAc/
dure B described above. The crude product (ratio of 7i:8i was petroleum ether) to give the title compound (0.059 g, 80%)
92:8) was chromatographed on silica gel (1:8, EtOAc/petroleum as a white solid: Rf = 0.22 (1:3 EtOAc/petroleum ether); mp
ether) to give 7i as a pale yellow gum (51 mg, 76%) and 224-226 °C; IR (neat, νmax/cm-1) 3221, 2361, 2335, 2217, 1654,
2-pentylbenzofuran (8i) as a colorless oil (2 mg, 5%). 1490, 1451, 1424, 1250, 732; δH (acetone-d6) 11.5 (1H, br s, NH),
7i: Rf = 0.69 (1:4 EtOAc/petroleum ether); IR (neat, νmax/ 8.05-8.02 (2H, m, ArH), 7.71-7.68 (1H, m, ArH), 7.61-7.56
cm-1) 2960, 2924, 2233, 1593, 1454, 1178 and 747; δH 7.62-7.33 (4H, m, ArH), 7.35-7.26 (2H, m, ArH); δC (acetone-d6) 145.5
(4H, m), 2.96 (2H, t, J = 7.5 Hz), 1.83 (2H, t, J = 7.5 Hz), 1.39- (C), 136.6 (C), 130.7 (C), 130.6 (CH), 130.1 (CH), 129.7 (C), 127.8
1.37 (4H, m), 0.91 (3H, t, J = 7.5 Hz); δC 168.7 (2-C), 153.6 (C), (CH), 124.8 (CH), 122.9 (CH), 119.4 (CH), 117.1 (C), 113.2 (CH),
126.0 (C), 125.4 (CH), 124.2 (CH), 119.5 (CH), 113.4 (3-C), 83.7 (CN), ESIMS m/z 218 [(MH)þ, 100]; HRESIMS calcd for
111.5 (CH), 90.6 (CN), 31.1, 28.1, 27.1, 22.3, and 13.8 (pent-C); C15H10N2 (MH)þ 218.0846, found 218.0843.
EIMS m/z 213 [(Mþ) 40]; HREIMS calcd for C14H15NO (Mþ) 2-(4-Methoxyphenyl)-1H-indole-3-carbonitrile (10c). Using
213.1154, found 213.1153. the general indole preparation procedure C above, a mixture
8i: δH 7.47(1H, d, J = 7.0 Hz), 7.40 (d, J = 8.0 Hz, 1H), 7.20- of 9 (R=H, R1=4-MeOC6H4-, P=TFA) (0.100 g, 0.32 mmol),
7.16 (2H, m), 6.36 (s, 1H), 2.75 (2H, t, J = 7.0 Hz), 1.76-1.73 DMF (4 mL), and CuCN (0.086 g, 0.95 mmol) was stirred at
(2H, m), 1.39-1.36 (4H, m), 0.90 (3H, t, J = 7.0 Hz); EIMS m/z 100 °C for 16 h. Workup procedure B was applied. The crude
188 [(Mþ) 90]. The analytical and spectroscopic data matched product was purified by column chromatography (silica gel,
with those reported in the literature.20 EtOAc) to give the title compound (0.061 g, 77%) as a white
General Procedure (C) for the Synthesis of 3-Cyanoindoles. To solid: Rf = 0.15 (3:1 EtOAc/petroleum ether); mp 99-101 °C;
a solution of the 2-ethynylaniline derivative (0.30 mmol) in IR (neat, νmax/cm-1) 3257, 2212, 1613, 1499, 1446, 1255, 1245,
anhydrous DMF (4 mL) under an oxygen atmosphere (balloon) 1173, 1040, 836; δH (acetone-d6) 11.4 (1H, br s, NH), 7.99 (2H, d,
was added CuCN (0.90 mmol), and the reaction vessel was J =8.5 Hz, ArH), 7.67 (1H, d, J = 7.5 Hz, ArH), 7.53 (1H, d,
inserted into a preheated oil bath at 100 °C (see the safety note J =7.5 Hz, ArH), 7.30-7.24 (2H, m, ArH), 7.15 (2H, d, J = 8.5
above). The reaction mixture was stirred at this temperature for Hz, ArH), 3.89 (3H, s, CH3O); δC (acetone-d6) 161.3 (C), 145.1
16 h. Two different workup procedures were followed. Workup (C), 135.8 (C), 129.1 (C), 128.7 (CH) 123.8 (CH), 122.4 (C),
procedure A: Water (5 mL) was added and the aqueous layer was 122.1 (CH), 118.6 (CH), 116.8 (C), 114.9 (CH), 112.3 (CH), 81.9
extracted with EtOAc (3  5 mL), dried (MgSO4), filtered, and (CN), 55.2 (CH3O); EIMS m/z 248 [(M)þ, 80]; HREIMS calcd
concentrated in vacuo. The crude product was purified by column for C16H12N2O (M)þ 248.0943, found 248.0949.
chromatography. Workup procedure B: The solvent was removed 2-(4-Fluorophenyl)-1H-indole-3-carbonitrile (10d). Using the
in vacuo at 60 °C. The crude residue was purified by column general indole preparation procedure C above, a mixture of 9
chromatography. (R = H, R1 = 4-FC6H4-, P = TFA) (0.080 g, 0.26 mmol), DMF
2-Phenyl-1-(4-methylbenzenesulfonyl)-1H-indole-3-carbonitrile (3 mL), and CuCN (0.072 g, 0.79 mmol) was stirred at 100 °C for
(10a) and 2-Phenyl-1-(4-methylbenzenesulfonyl)-1H-indole (11; R = 16 h. Workup procedure B was applied. The crude product was
H, R1 = Ph, R2 = Ts). Using the general indole preparation pro- purified by column chromatography (silica gel, 1:3 EtOAc/
cedure C above, a mixture of 9 (R = H, R1 = Ph, P = Ts) petroleum ether) to give the title compound (0.041 g, 65%)
(0.100 g, 0.288 mmol), DMF (4 mL), and CuCN (0.080 g,0.86 as a white solid: Rf = 0.26 (1:3 EtOAc/petroleum ether); mp
mmol) was stirred at 100 °C for 16 h. Workup procedure A was 239-241 °C; (neat, νmax/cm-1) 3257, 2213, 1675, 1613, 1498,
applied. The crude product was purified by column chromato- 1448, 1241, 1173, 830; δH (acetone-d6) 11.5 (1H, br s, NH),
graphy (silica gel, 1:5 EtOAc/petroleum ether) to give the 8.08-8.06 (2H, m, ArH), 7.69 (1H, d, J = 7.5 Hz, ArH), 7.56
compound 10a (0.080 g, 74%) as a white solid and compound 11 (1H, d, J = 7.5 Hz, ArH), 7.39-7.34 (2H, m. ArH), 7.32-7.27
(R = H, R1 = Ph, R2 = Ts) (0.003 g, 3%) as a colorless solid. (2H, m, ArH); δC (acetone-d6) 164.2 (C, d, J = 247.6 Hz), 144.5
10a: Rf = 0.35 (1:5 EtOAc/petroleum ether); mp 148-150 °C; (C), 136.6 (C), 130.2 (CH, d, J = 8.5 Hz), 129.5 (C), 127.3 (C),
IR (neat, νmax/cm-1) 2361, 1342, 2230, 1451, 1375, 1197, 1178; 124.9 (CH), 122.9 (CH), 119.4 (CH), 116.9 (CH, d, J = 7.1 Hz),
δH 8.36 (1H, d, J = 8.5 Hz, ArH), 7.65 (1H, d, J = 7.5 Hz, ArH), 116.5 (C, d, J = 3.1 Hz), 113.1 (CH), 83.7 (CN); EIMS m/z 236
7.55-754 (1H, m, ArH), 7.51-7.46 (5H, m, ArH), 7.42 (1H, t, [(M)þ, 100]; HREIMS calcd for C15H9N2F (M)þ 236.0760,
J=7.5 Hz, ArH), 7.28 (2H, d, J = 8.0 Hz, ArH), 7.10 (2H, d, found 236.0749.
J = 8.0 Hz, ArH), 2.33 (3H, s, CH3); δC 148.6 (C),145.8 (C), 5-Methoxy-2-phenyl-1H-indole-3-carbonitrile (10e). Using the
136.4 (C), 134.6 (C), 130.9 (CH), 130.5 (CH), 129.7 (CH), 128.3 general indole preparation procedure C above, a mixture of 9
(C), 127.9 (CH), 127.8 (C), 126.9 (CH), 126.6 (CH), 125.3 (CH), (R = OMe, R1 = Ph, P = TFA) (0.100 g, 0.32 mmol), DMF
119.6 (CH), 116.3 (CH), 113.9 (C), 96.7 (CN), 21.6 (CH3); EIMS (4 mL), and CuCN (0.086 g, 0.95 mmol) was stirred at 100 °C for
m/z 372 [(M)þ, 65]; HREIMS calcd for C22H16N2O2S (M)þ 16 h at 130 °C. Workup procedure B was applied. The crude
372.0935, found 372.0932. product was purified by column chromatography (silica gel, 1:3
11 (R = H, R1 = Ph, R2 = Ts): Rf = 0.52 (1:3 EtOAc/petro- EtOAc/petroleum ether) to give the title compound (0.062 g,
leum ether); mp 144-146 °C (lit.11 mp 146-148 °C); IR (neat, 78%) as a white solid: Rf = 0.35 (1:3 EtOAc/petroleum ether);
νmax/cm-1) 1598, 1449, 1367, 1306, 1167, 1060, 978, 809; δH 8.31 mp 120-122 °C; IR (neat, νmax/cm-1) 3216, 2965, 2909, 2358,
(1H, d, J = 8.5 Hz, ArH), 7.50-7.48 (2H, m, ArH), 7.43 (4H, m, 2341, 2217, 1685, 1652, 1558, 1540, 1456, 1055, 752; δH (acetone-
ArH), 7.35 (1H, t, J = 7.5 Hz, ArH), 7.27-7.24 (3H, m, ArH), d6) 11.4 (1H, br s, NH), 8.01 (2H, d, J = 7.0 Hz, ArH), 5.95 (2H, t,
7.03 (2H, d, J = 8.5 Hz, ArH), 6.54 (1H, s, ArH), 2.28 (3H, s, J = 7.0 Hz, ArH), 7.53 (1H, d, J = 7.0 Hz, ArH), 7.46 (1H, d, J =
CH3); EIMS m/z 348 [(M)þ, 100]; HREIMS calcd. for C21H18- 8.5 Hz, ArH), 7.16 (1H, s, ArH), 6.94 (1H, d, J = 8.5 Hz, ArH),
NO2S (M)þ 348.1042, found 348.1058. 3.90 (3H, s, CH3O); δC (acetone-d6) 156.7 (C), 145.1 (C), 131.2
2-Phenyl-1H-indole-3-carbonitrile (10b). Using the general (C), 130.5 (C), 130.3 (CH), 130.2 (CH), 129.8 (CH), 127.3 (CH),
indole preparation procedure C above, a mixture of 9 (R = H, 117.1 (C), 115.1 (CH), 113.8 (C), 100.4 (CH), 83.2 (CN), 55.6
(CH3O); EIMS m/z 248 [(M)þ, 100]; HREIMS calcd for
1
R = Ph, P = TFA) (0.100 g, 0.34 mmol), DMF (4 mL), and
CuCN (0.093 g, 1.02 mmol) was stirred at 100 °C for 16 h. C16H12N2O (M)þ 248.0938, found 248.0949.
Workup procedure A was applied. The crude product was 2-Phenyl-1-(4-methylbenzenesulfonyl)-1H-indole-3,5-dicarbo-
nitrile (10f) and 2-Phenyl-1-(4-methylbenzenesulfonyl)-1H-in-
(20) Furstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024– dole-5-carbonitrile (11; R = CN, R1 =Ph, R2 = Ts). Using the
15025. general indole preparation procedure above, a mixture of 9

3418 J. Org. Chem. Vol. 75, No. 10, 2010

Swamy et al.
JOC Article
(R = CN, R1 = Ph, P = Ts) (0.100 g, 0.26 mmol), DMF (4 mL), 1557, 1490, 1452, 1332, 1239, 742; δH 8.70 (1H, br s, NH), 7.65
and CuCN (0.072 g, 0.78 mmol) was stirred at 100 °C for 16 h. (1H, d, J = 8.5 Hz, ArH), 7.38 (1H, d, J = 8.5 Hz, ArH), 7.25-
Workup procedure A was applied. The crude product was 7.22 (2H, m, ArH), 2.94 (2H, t, J = 7.0 Hz, CH2), 1.80-1.78
purified by column chromatography (silica gel, 1:4 EtOAc/ (2H, m, CH2), 1.38-1.35 (4H, m, 2  CH2), 0.90 (3H, t, J = 7.0
petroleum ether) to give the compound 11 (R = CN, R1 = Hz, CH3); δC 149.3 (C), 134.5 (C), 127.6 (C), 123.3 (CH), 121.9
Ph, R2 = Ts) (0.037 g, 38%) and compound 10f (0.023 g, 22%) (CH), 118.9 (CH), 116.4 (C), 111.3 (CH), 84.7 (CN), 31.1 (CH2),
both as a white solid. 28.7 (CH2), 27.5 (CH2), 22.2 (CH2), 13.8 (CH3); ESIMS m/z 213
10f: Rf = 0.32 (1:4 EtOAc/petroleum ether); mp 131-133 °C; [(MH)þ, 100]; HREIMS calcd for C14H17N2 (MH)þ 213.1360,
IR (neat, νmax/cm-1) 2228, 1598, 1465, 1378, 1260, 1378, 1260, found 213.1392.
1175, 1091, 819; δH 8.50 (1H, d, J=8.5 Hz, ArH), 7.99 (1H, s, 2-Pentyl-1-(4-methylbenzenesulfonyl)-1H-indole-3-carbonitrile
ArH), 7.59 (1H, t, J =7.0 Hz, ArH), 7.74 (1H, d, J =8.5 Hz, (10i) and 2-Pentyl-1-(4-methylbenzenesulfonyl)-1H-indole (11;
ArH), 7.49 (2H, t, J =7.0 Hz, ArH), 7.42 (2H, d, J = 7.0 Hz, R = H, R1 = n-Pent, R2 = Ts). Using the general indole pre-
ArH), 7.25 (2H, d, J = 8.0 Hz, ArH), 7.14 (2H, d, J = 8.0 Hz, paration procedure C above, a mixture of 9 (R = H, R1 =
ArH), 2.36 (3H, s, CH3); δC 150.6 (C), 146.6 (C), 138.0 (C), 134.1 n-Pentyl, R2 = Ts) (0.0.080 g, 0.23 mmol), DMF (3 mL), and
(C), 131.3 (CH), 130.2 (CH), 129.6 (CH), 128.3 (CH), 127.7 (C), CuCN (0.063 g, 0.69 mmol) was stirred at 100 °C for 16 h.
127.3 (CH), 124.4 (CH), 118.2 (C), 117.4 (CH), 112.7 (C), 109.1 Workup procedure A was applied. The crude product was
(CN), 96.0 (CN), 21.6 (CH3); ESIMS m/z 398 [(MH)þ, 100]; purified by column chromatography (silica gel, 1:5 EtOAc/
HRESIMS calcd for C23H16N3O2S (MH)þ 398.0944, found petroleum ether) to give the compound 10i (0.046 g, 55%) as
398.0963. a colorless oil and compound 11 (R = H, R1 = Pent, R2 = Ts)
11 (R = CN, R1 = Ph, R2 = Ts): Rf = 0.34 (1:4 EtOAc/petro- (0.019 g, 24%) as a white solid. 10i: Rf = 0.42 (1:5 EtOAc/
leum ether); mp 78-80 °C; IR (neat, νmax/cm-1) 2970, 2361, 1340, petroleum ether); (neat, νmax/cm-1) 2955, 2924, 2863, 2228, 1598,
2223, 1654, 1375, 1173, 1091, 1081, 756; δH 8.42 (1H, d, J = 8.0 1451, 1384, 1191, 1178, 1155, 1098, 969; δH 8.17 (1H, d, J = 8.5
Hz, ArH), 7.70 (1H, s, ArH), 7.60 (1H, dd, J = 1.5, 8.0 Hz, ArH), Hz, ArH), 7.65 (1H, d, J = 8.5 Hz, ArH), 7.58 (1H, d, J = 8.0 Hz,
7.45-7.42 (5H, m, ArH), 7.24 (2H, d, J = 7.0 Hz, ArH), 7.07 ArH) 7.39-7.33 (2H, m, ArH), 7.25 (3H, d, J = 8.0 Hz, ArH),
(2H, d, J = 7.0 Hz, ArH), 6.56 (1H, s, ArH), 2.31 (3H, s, CH3); δC 3.20 (2H, t, J = 7.5 Hz, CH2), 2.37 (3H, s, CH3), 1.82-1.77 (2H,
145.3 (C), 144.1 (C), 139.8 (C), 134.5 (C), 130.5 (CH), 129.5 (CH), m, CH2), 1.43-1.35 (4H, m, 2  CH2), 0.91 (3H, t, J = 7.5 Hz,
129.2 (CH), 127.7 (CH), 127.5 (CH), 126.9 (CH), 125.3 (CH), CH3); δC 151.4 (C), 145.9 (C), 135.6 (C), 135.3 (C), 130.2 (CH),
123.5 (C), 119.2 (C), 117.0 (CH), 111.9 (CH), 107.6 (CN), 21.6 127.2 (C), 126.4 (CH), 125.7 (CH), 124.8 (CH), 119.1 (CH), 115.1
(CH3); ESIMS m/z 373 [(MH)þ, 100]; HRESIMS calcd for (CH), 114.1 (C), 94.5 (CN), 31.4 (CH2), 30.4 (CH2), 28.5 (CH2),
C22H17N2O2S (MH)þ 373.1018, found 373.1011. 22.2 (CH2), 21.6 (CH3), 13.9 (CH3); ESIMS m/z 367 [(MH)þ,
Phenyl-1H-indole-3,5-dicarbonitrile (10g). Using the general 100]; HRESIMS calcd for C21H23N2O2S (MH)þ 367.1470, found
indole preparation procedure C above, a mixture of 9 (R = CN, 367.1480.
R1 = Ph, P = TFA) (0.070 g, 0.21 mmol), DMF (3 mL), and 11 (R = H, R1 = Pent, R2 = Ts): Rf = 0.55 (1:5 EtOAc/
CuCN (0.059 g, 0.64 mmol) was stirred at 100 °C for 16 h. petroleum ether); mp 57-59 °C; IR (neat, νmax/cm-1) 2955,
Workup procedure B was applied. The crude product was 2924, 2356, 2330, 1444, 1369, 1224, 1170, 1139, 1092, 1060, 804;
purified by column chromatography (silica gel, 2:1 EtOAc/ δH 8.16 (1H, d, J = 8.0 Hz, ArH), 7.61 (2H, d, J = 8.0 Hz, ArH),
petroleum ether) to give the title compound (0.031 g, 60%) as 7.39 (1H, d, J = 8.0 Hz, ArH), 7.25-7.16 (4H, m, ArH), 6.37
a white solid: Rf = 0.64 (EtOAc); mp 265-267 °C; IR (neat, (1H, s, ArH), 2.97 (2H, t, J = 7.5 Hz, CH2), 2.32 (3H, s, CH3),
νmax/cm-1) 3231, 2360, 2335, 2224, 1685, 1654, 1475, 1449, 1367, 1.75-1.72 (2H, m, CH2), 1.39-1.35 (4H, m, 2  CH2), 0.91 (3H,
1255, 1070, 906; δH (acetone-d6) 12.1 (1H, br s, NH), 8.13 (1H, d, t, J = 7.5 Hz, CH3); δC 144.2 (C), 142.5 (C), 137.1 (C), 136.2 (C),
J = 1.5 Hz, ArH), 8.06 (2H, dd, J = 1.5, 7.0 Hz, ArH), 7.76 (1H, 129.7 (CH), 126.6 (CH), 126.2 (C), 123.7 (CH), 123.4 (CH),
d, J = 7.0 Hz, ArH), 7.68-7.59 (4H, m, ArH); δC (acetone-d6) 119.9 (CH), 114.7 (CH), 108.5 (CH), 31.5 (CH2), 28.9 (CH2),
147.8 (C), 138.0 (C), 131.1 (CH), 130.0 (CH), 129.4 (C), 129.0 28.5 (CH2), 22.4 (CH2), 21.5 (CH3), 14.0 (CH3); EIMS m/z 341
(C), 127.8 (CH), 127.4 (CH), 124.3 (CH), 119.7 (C), 115.7 (C), [(M)þ, 50]; HREIMS calcd for C20H23NO2S (M)þ 341.1451,
114.2 (CH), 106.0 (CN), 84.1 (CN); EIMS m/z 243 [(M)þ, 100]; found 341.1449.
HREIMS calcd for C16H9N3 (M)þ 243.0813, found 243.0796.
2-Pentyl-1H-indole-3-carbonitrile (10h). Using the general Acknowledgment. We thank the Australian Research
indole preparation procedure C above, a mixture of 9 (R = Council and the University of Wollongong for financial
H, R1 = n-Pentyl, P = TFA) (0.100 g, 0.32 mmol), DMF support.
(4 mL), and CuCN (0.088 g, 0.96 mmol) was stirred at 100 °C for
16 h. Workup procedure A was applied. The crude product was Supporting Information Available: Full experimental and
purified by column chromatography (silica gel, 1:3 EtOAc/ spectroscopic details for the synthesis of the substrates 1 (R =
petroleum ether) to give the title compound (0.050 g, 73%) n-Pentyl), 5, 6, and 9 and copies of the 1H and 13C NMR spectra
as a white solid: Rf = 0.31 (1:3 EtOAc/petroleum ether); mp of all new compounds. This information is available free of
49-51 °C; IR (neat, νmax/cm-1) 3262, 2955, 2929, 2858, 2208, charge via the Internet at http://pubs.acs.org.

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