Base-mediated regio- and stereoselective intermolecular addition of alkynes to N-heterocycles

Article abstract of DOI:10.1021/ol200048z

The regio- and stereoselective addition of N-heterocycles to alkynes using KOH is reported. Formation of (Z)-isomers and their conversion to (E)-products were found to be dependent upon time as well as the choice of base. Selective attack of N-heterocycles on a more electrophilic alkynyl carbon was supported by DFT calculations, and the stereochemistry of the products was established by X-ray crystallographic studies and intramolecular cyclization of ortho-haloalkynes in indolo-[2,1-a]isoquinolines.

Full text of DOI:10.1021/ol200048z

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1630–1633
Base-Mediated Regio- and Stereoselective
Intermolecular Addition of Alkynes to N-
Heterocycles
Akhilesh Kumar Verma,*,† Megha Joshi,† and Ved Prakash Singh‡
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry,
University of Delhi, Delhi 110007, India, and Department of Chemistry, Banaras Hindu
University, Varanasi-221005, India
averma@acbr.du.ac.in
Received January 7, 2011
ABSTRACT
The regio- and stereoselective addition of N-heterocycles to alkynes using KOH is reported. Formation of (Z)-isomers and their conversion to (E)-
products were found to be dependent upon time as well as the choice of base. Selective attack of N-heterocycles on a more electrophilic alkynyl
carbon was supported by DFT calculations, and the stereochemistry of the products was established by X-ray crystallographic studies and
intramolecular cyclization of ortho-haloalkynes in indolo-[2,1-a]isoquinolines.
Hydroamination of alkenes, alkynes, and related unsa-
turated substrates represents an attractive strategy for the
preparation of nitrogen heterocycles, enamines and
imines.1 Enamines occupy a prominent place in organic
synthesis,2 and a variety of methods have been reported in
the literature for their synthesis.1,3 The intermolecular
addition of alkynes to primary4 and secondary amines5
have been well studied; however, the addition of N-hetero-
cycles onto internal alkynes remains elusive.
A notable work was reported by Knochel in 1999 for the
addition of heterocyclic amines to phenylacetylene using
CsOH H2O in NMP.6 Later Kondo reported the addition
3
of O- and N-nucleophiles to alkynes using phosphazene
base t-Bu-P4.7 Moreover, only one example of the addition
of pyrrole on diphenylacetylene was reported using t-Bu-
P4 with poor stereoselectivity.7 In this regard, the stereo- and
(3) (a) Dash, C.; Shaikh, M.; Butcher, R. J.; Ghosh, P. Inorg. Chem.
2010, 49, 4972. (b) Cui, D.; Zheng, J.; Yang, L.; Zhang, C. Synlett 2010,
809. (c) Widenhoefer, R. A. Chem.;Eur. J. 2008, 14, 5382. (d) Hultzsch,
K. C. Adv. Synth. Catal. 2005, 347, 367. (e) Beller, M.; Seayad, J.;
Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368. (f) Duncan,
A. P.; Bergman, R. G. Chem. Rec. 2002, 2, 431. (g) Ackermann, L. Org.
Lett. 2005, 7, 439. (h) Sandmann, R.; Kaspar, L.; Ackermann, L. Org.
Lett. 2009, 7, 2031 and references cited therein. (i) Klein, D. P.; Ellern,
A.; Angelici, R. J. Organometallics 2004, 23, 5662. (j) Brunet, J. J.; Chu,
N. C.; Diallo, O.; Vincendeau, S. J. Mol. Catal. A: Chem. 2005, 240, 245.
(k) Castro, I. G.; Tillack, A.; Hartung, C. G.; Beller, M. Tetrahedron
Lett. 2003, 44, 3217. (l) Shanbhag, G. V.; Kumbar, S. M.; Joseph, T.;
Halligudi, S. B. Tetrahedron Lett. 2006, 47, 141. (m) Tillack, A.; Jiao,
H. J.; Castro, I. G.; Hartung, C. G.; Beller, M. Chem.;Eur. J. 2004, 10,
2409. (n) Yi, C. S.; Yun, S. Y. J. Am. Chem. Soc. 2005, 127, 17000. (o)
Zhang, Y. H.; Donahue, J. P.; Li, C. J. Org. Lett. 2007, 9, 627.
† University of Delhi.
‡ Banaras Hindu University.
€
(1) For recent reviews: (a) Muller, T. E.; Beller, M. Chem. Rev. 1998,
98, 675. (b) Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36, 1407. (c)
€
Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104. (d) Muller, T. E.;
Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev., 2008, 108,
3795 and references cited therein.
(2) (a) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.;
Terrell, R. J. Am. Chem. Soc. 1963, 85, 207. (b) Stork, G. Med. Res. Rev.
1999, 19, 370. (d) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaugh-
nessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575. (e)
Trofimov, B. A.; Mikhaleva, A. I.; Morozova, L. V. Russ. Chem. Rev.
1985, 54, 1034. (f) Cossy, J.; Belotti, D.; Bellosta, V.; Boggio, C.
Tetrahedron Lett. 1997, 38, 2677.
r
10.1021/ol200048z
Published on Web 03/03/2011
2011 American Chemical Society

Table 1. Optimization of the Reaction Conditionsa
yield (%)b
entry alkyne
base
solvent time (h)/ t °C
(3:4)c
1d
2e
3f
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2aa
2ba
2ba
2ba
2ba
2ba
2ba
2ba
2ba
KOtBu
KOtBu
KOtBu
KOtBu
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
24/110
24/110
24/120
24/120
24/120
24/120
24/120
24/120
24/30
68 (40:60)
45 (20:80)
55 (30:70)
62 (20:80)
76 (5:95)
-
4g
5
6
Cs2CO3 DMSO
7
TEA
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
-
8
K2CO3
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
-
Figure 1. X-ray crystallographic ORTEP drawing of compound
4aa drawn at the 50% probability level and NOESY studies of
compounds 4aa, 4ae, and 4af. See Supporting Information.9
9
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24h
24/80
-
05/120
12/120
48/120
24/120
24/110
24/120
24/120
24/120
24/120
24/30
10 (0:100)
50 (2:98)
60 (50:50)
35 (10:90)
-
Herein, we report the base-mediated regio- and stereose-
lective addition of N-heterocycles onto internal and
terminal alkynes and confirmation of the products by
X-ray crystallography, NOESY, and intramolecular
cyclization of ortho-haloalkynes to form indolo[2,1-
a]isoquinolines.
Toluene
DMA
-
DMSO
85 (50:50)
80 (0:100)
77 (90:10)
-
Cs2CO3 DMSO
KOtBu
KOH
KOH
KOH
KOH
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
We followed reaction conditions used for the synthesis
of indolo-and pyrrolo[2,1-a]isoquinolines.8 Thus when
indole 1a and alkyne 1,2-di-p-tolylethyne 2aa were treated
with CuI (5.0 mol %), ligand BtCH2OH (10 mol %), and
KOtBu (1.4 equiv) in DMSO at 110 °C for 24 h, a mixture
ofE/Z isomers of (E)-1-(1,2-di-p-tolylvinyl)-1H-indole3aa
and (Z)-1-(1,2-di-p-tolylvinyl)-1H-indole 4aa was ob-
tained in 68% yield with 40:60 stereoselectivity (Table 1,
entry 1). When the reaction occurred without CuI and the
ligand, 3aa and 4aa were obtained in 45% yield and 20:80
stereoselectivity (entry 2). An increase in the amount of 1a
from 1.0 to 2.0 equiv and base from 1.4 to 2.5 equiv
afforded the hydroaminated product in 55 and 62% yields
respectively (entries 3 and 4). When different bases were
testedin thisreaction, KOH proved tobe the mosteffective
and provided the hydroaminated product 4aa in 76% yield
in high stereoselectivity and the structure of the product
formed was confirmed by X-ray (Figure 1;9 Table 1, entry
5), other bases like Cs2CO3, Et3N, and K2CO3 were found
to be ineffective (entries 6-8). With a selective base in
hand, other parameters such as temperature and solvent
were investigated. At lower temperatures, 30 and 80 °C,
hydroaminated product 3aa/4aa was not observed (entries
9 and 10). The reaction was found to proceed smoothly
at elevated temperature, and it is worth noting that
longer reaction times led to the conversion of the Z-isomer
12/80
60 (20:80)
90 (0:100)
92 (10:90)
90 (20:80)
0.5/120
2/120
04/120
a Reactions were carried out using 1a (2.0 equiv), 2aa/2ba (1.0 equiv),
and base (2.5 equiv) in solvent (2.0 mL). b Total yield of two isomers.
c Stereoisomeric ratio. d 1 (1.0 equiv), 2 (1.0 equiv), CuI (5 mol %),
BtCH2OH (10 mol %), and base (1.4 equiv) were added. e 1a (1.0 equiv),
2 (1.0 equiv). f 1a (2.0 equiv), 2 (1.0 equiv). g Base (2.5 equiv). h Base (0.20
equiv) was taken.
regioselective addition of N-heterocycles on internal alkynes
is important and challenging.
Recently, we reported the copper-catalyzed tandem
synthesisof indolo- and pyrrolo[2,1-a]isoquinolines, which
was believed to occur via a hydroamination reaction.8
(4) (a) Zhang, Z.; Leitch, D. C.; Lu, M.; Patrick, B. O.; Schafer, L. L.
Chem.;Eur. J. 2007, 13, 2012. (b) Heutling, A.; Pohlki, F.; Doye, S.
Chem.;Eur. J. 2004, 10, 3059. (c) Ackermann, L. Organometallics 2003,
22, 4367. (d) Tillack, A.; Garcia Castro, I.; Hartung, C. G.; Beller, M.
Angew. Chem., Int. Ed. 2002, 41, 2541. (e) Walsh, P. J.; Baranger, A. M.;
Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 1708. (f) Leitch, D. C.;
Payne, P. R.; Dunbar, C. R.; Schafer, L. L. J. Am. Chem. Soc. 2009, 131,
18246.
(5) Hesp, K. D.; Stradiotto, M. J. Am. Chem. Soc. 2010, 132, 18026
and references cited therein.
(6) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999, 40,
6193. (b) Rodriguez, A.; Koradin, C.; Dohle, W.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 2488. (c) Koradin, C.; Dohle, W.; Rodriguez,
A.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571.
(7) Imahori, T.; Hori, C.; Kondo, Y. Adv. Synth. Catal. 2004, 346,
1090.
(9) CCDC 802285 (4aa) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
request/cif.
(8) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock,
R. C. Angew. Chem., Int. Ed. 2009, 48, 1138.
Org. Lett., Vol. 13, No. 7, 2011
1631

Table 2. Hydroamination of Symmetrical Internal Alkynesa
Table 3. Hydroamination of Terminal Alkynesa
a The reactions were performed using N-heterocycle 1 (2.0 equiv), 1.0
equiv of the alkyne 2, and 0.2 equiv of KOH in 1.5 mL of DMSO at
120 °C for 0.5-1 h unless otherwise noted. b Yield of isolated product.
c Time = 2 h . d Time = 15 min.
The addition of 1a onto 1-ethynyl-4-methylbenzene
(2ba) using optimized conditions afforded a mixture of
E/Z isomers (E)-1-(4-methylstyryl)-1H-indole 3ba and
(Z)-1-(4-methylstyryl)-1H-indole 4ba in 85% yield and
50:50 stereoselectivity (entry 17). The effective addition
of heterocyclic amines followed the anti-Markovnikov
rule, and the stereoselectivity of product was found to be
dependent on the nature of the base, reaction time, and
temperature.1 Cs2CO3 afforded only the Z-isomer (4ba)
in 80% yield (entry 18); however KOtBu provided the
a The reactions were performed using N-heterocycle 1 (2.0 equiv), 1.0
equiv of the alkyne 2, and 2.5 equiv of KOH in 1.5 mL of DMSO at 120 °C
for 24 h unless otherwise noted. b Yield of isolated product. c Time = 18 h .
to an E-isomer (entries 11-13). Among different solvents
such as DMSO, DMF, toluene, and dimethylacetamide,
DMSO was found to be most effective (entries 14-16).
1632
Org. Lett., Vol. 13, No. 7, 2011

corresponding Z-products 4ba-4bh in good to excellent
yields (Table 3, entries 1-8). It is interesting to note that
electron-deficient heterocycle 1f and 1g reacted well with
terminal alkynes 2bf and 2ba and afforded the hydroami-
nated products 4bi and 4bj in 86 and 89% yields respec-
tively (entries 9 and 10). No reaction was observed with
1-hexyne (2bf) (entry 11). Table 4 summarizes the scope of
the addition of N-heterocycles 1b-1c and 1e on unsymme-
trical alkynes 2ad-2ah. The electronic bias of the groups
on both carbons of the triple bond plays an important role
in the selective attack of the nucleophile. The major isomer
in the mixture of the two possible Z-regioisomers was
assumed to form by preferential attack on a more electro-
philic carbon as per the DFT-B3LYP/6-31þG* calcula-
tions using Gausian 03 software10 (Table 4, entry 1 and 2;
Figure 2) and was supported by the formation of indolo-
[2,1-a] isoquinolines4ak and 4al (entries 3 and 4).8,11 TMS-
substituted alkyne 2ah afforded the product 4am in 90%
yield with the removal of the TMS group, presumably due
to the basic conditions employed (entry 5).
Table 4. Hydroamination of Unsymmetrical Internal Alkynesa
a The reactions were performed using N-heterocycle 1 (2.0 equiv), 1.0
equiv of the alkyne 2, and 2.5 equiv of KOH in 1.5 mL of DMSO at 120
°C for 24 h unless otherwise noted. b Total yield of two isomers. c CuI (5
mol %) and ligand/BtCH2OH (10 mol %) were added. d Time = 1 h.
Figure 2. Natural population analysis (B3LYP/6-31þG*).
In summary, an efficient base-mediated regio- and
stereoselective hydroamination of alkynes has been devel-
oped to synthesize a wide array of (Z)-styryl and vinyl-
enamines that are useful in organic synthesis. Stereoselec-
tivity was largely affected by the nature of the base and
reaction time. The developed protocol avoids the use of
expensive catalysts and ligands. Based upon this stereo-
selective hydroamination, we should be able to develop
new synthetic methods to a variety of fused heterocycles.
These studies are currently under investigation and will be
reported in due course.
E-isomer 3ba as a major product (entry 19). No addition
product was obtained at 30 °C and was found to be
initiated at 80 °C (entries 20 and 21). The reaction of 1a
with 3ba at 120 °C afforded the hydraminated product 4ba
in 90% yield within 30 min (entry 22). We have noticed
that an increase in reaction time leads to the conversion of
the Z-isomer to an E-isomer (entry 23). In terminal alkynes,
use of a catalytic amount of KOH (20 mol %) also afforded
4ba in good yield (entry 24) in contrast to internal alkynes.
Under optimized conditions (Table 1, entries 5 and 22),
the scope and limitations of this process were examined
next with various substituted N-heterocycles 1a-1g and
alkynes 2aa-ac.
Heterocyclic amines with an electron-donating group
such as 3-methyl indole (1b) and 5-methoxy indole (1c)
afforded the addition products with Z-stereoselectivity (X-
ray and NOESY, Figure 1) in good yield in comparison to
1a (Table 2, entries 1-6). 5-Bromoindole (1d) afforded the
hydroaminated product 4ag in 68% yield (entry 7). Pyrrole
(1e) being more nucleophilic afforded the hydroaminated
product 4ah in lesser reaction time in 75% yield (entry 8).
No reaction was observed with electron-deficient N-het-
erocycles such as imidazole 1f and 1g with alkyne 2aa
(entries 9 and 10). The addition of N-heterocycles 1a-1c
and 1e onto terminal alkynes 2ba-2be provided the
Acknowledgment. We gratefully acknowledge the Uni-
versity of Delhi and Department of Science and Technology
for financial support and USIC for providing instrumenta-
tion facilities. Our sincere thanks is given to Sushil Kumar,
University of Delhi for his kind help in solving X-ray
crystallographic data. M.J. thanks UGC for a fellowship.
Supporting Information Available. General experimen-
tal procedures and characterization data for all starting
materials and products are available free of charge via the
Internet at http://pubs.acs.org.
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