Regioselective preferential nucleophilic addition of N-heterocycles onto haloarylalkynes over N-arylation of aryl halides

Article abstract of DOI:10.1021/ol203491p

The study of preferential addition of heterocyclic amines onto halo-substituted arylalkynes over N-arylation under various catalytic conditions is described. The present work supports and confirms the mechanistic pathway of our recent work on the tandem synthesis of indolo- and pyrrolo-[2,1-a] isoquinolines via hydroamination followed by oxidative addition and not vice versa.

Full text of DOI:10.1021/ol203491p

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1106–1109
Regioselective Preferential Nucleophilic
Addition of N-Heterocycles onto Haloaryl-
alkynes over N-Arylation of Aryl Halides
Megha Joshi,† Rakesh Tiwari,‡ and Akhilesh Kumar Verma*,†
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry,
University of Delhi, Delhi 110007, India, and Department of Biomedical &
Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston,
Rhode Island 02881, United States
averma@acbr.du.ac.in
Received January 5, 2012
ABSTRACT
The study of preferential addition of heterocyclic amines onto halo-substituted arylalkynes over N-arylation under various catalytic conditions is
described. The present work supports and confirms the mechanistic pathway of our recent work on the tandem synthesis of indolo- and
pyrrolo-[2,1-a]isoquinolines via hydroamination followed by oxidative addition and not vice versa.
Heterocyclic nitrogen-containing substrates are com-
mon constituents of natural products, agrochemicals, and
pharmaceuticals and are also useful intermediates in a
number of industrial processes.1,2 Several synthetic meth-
ods have been described for the preparation of enamines,
and to our knowledge, hydroamination of alkynes pro-
vides an atom-economical route to them.3ꢀ6 Earlier efforts
to synthesize both simple and highly complex molecules by
N-arylation and hydroamination of unsaturated sub-
strates have proved to be very efficient.2 Synthesis of
substituted indoles and analogous heterocyclic substrates
using arylation/hydroamination chemistry has been well
established in the literature.6ꢀ8
† University of Delhi.
‡ University of Rhode Island.
(1) (a) Lawrence, S. A. In Amines: Synthesis, Properties, and Applica-
tions; Cambridge University Press: New York, 2004. (b) Brossi, A. In The
Alkaloids: Chemistry and Pharmacology Cordell, G. A., Eds.; Academic
Press: San Diego, 1993; Vol. 43, pp 119ꢀ183. (c) Daly, J. W.; Garraffo,
H. M.; Spande, T. F. In The Alkaloids: Chemistry and Pharmacology;
Cordell, G. A., Eds.; Academic Press: San Diego, 1993; Vol. 43,
pp 185ꢀ288.
A remarkable progress has been made in tandem synthe-
sis of substituted indoles from o-haloanilines by Sonogashira
coupling followed by intramolecular hydroamination.6
(2) (a) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.;
Terrell, R. J. Am. Chem. Soc. 1963, 85, 207–222. (b) Stork, G. Med. Res.
Rev. 1999, 19, 370–387. (c) Cossy, J.; Belotti, D.; Bellosta, V.; Boggio, C.
Tetrahedron Lett. 1997, 38, 2677–2683.
€
(3) For recent reviews, see: (a) Muller, T. E.; Beller, M. Chem. Rev.
1998, 98, 675–703. (b) Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36,
1407–1420. (c) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.;
€
(5) Hesp, K. D.; Stradiotto, M. J. Am. Chem. Soc. 2010, 132, 18026–
18029 and references cited therein.
Tada, M. Chem. Rev. 2008, 108, 3795–3892. (d) Hesp, K. D.; Stradiotto,
M. Chem. Cat. Chem. 2010, 2, 1192–1207 and references cited therein.
(e) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. Adv. Synth. Catal.
2002, 344, 795–813.
(4) (a) Zhang, Z.; Leitch, D.; Lu, C. M.; Patrick, B. O.; Schafer, L. L.
Chem.;Eur. J. 2007, 13, 2012–2022. (b) Heutling, A.; Pohlki, F.; Doye,
S. Chem.;Eur. J. 2004, 10, 3059–3071. (c) Ackermann, L. Organome-
tallics 2003, 22, 4367–4368. (d) Tillack, A.; Castro, I. G.; C. Hartung, G.;
Beller, M. Angew. Chem., Int. Ed. 2002, 41, 2541–2543. (e) Walsh, P. J.;
Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 1708–
1719. (f) Leitch, D. C.; Payne, P. R.; Dunbar, C. R.; Schafer, L. L. J. Am.
Chem. Soc. 2009, 131, 18246–18247.
(6) (a) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999,
40, 6193–6195. (b) Rodriguez, A.; Koradin, C.; Dohle, W.; Knochel, P.
Angew. Chem., Int. Ed. 2000, 39, 2488–2490. (c) Koradin, C.; Dohle, W.;
Rodriguez, A.; Schmid, B.; Knochel, P. Tetrahedron. 2003, 59, 1571–
1587. (d) Imahori, T.; Hori, C.; Kondo, Y. Adv. Synth. Catal. 2004, 346,
1090–1092. (e) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Yamanaka, H.
Chem. Pharm. Bull. 1987, 5, 1823–1828. (f) Sakamoto, T.; Kondo, Y.;
Iwashita, S.; Nagano, T.; Yamanaka, H. Chem. Pharm. Bull. 1988, 4,
1305–1308. (g) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles
1986, 24, 31–32. (h) Iritani, K.; Matsubara, S.; Utimoto, K. Tetrahedron
Lett. 1988, 29, 1799–1802.
r
10.1021/ol203491p
Published on Web 02/07/2012
2012 American Chemical Society

A notable work has been reported by Knochel in 2000
(eq 1).6b Recently, Ackermann7 and Alsabeh8 (eq 2)
showed the synthesis of indoles from o-haloarylalkynes
and anilines via arylation followed by intramolecular
hydroamination.7,8 Since, the discovery of coupling of
aryl/heteroaryl halides with N-heterocycles and aryla-
mines using metal and ligands is well documented in the
literature and these procedures are known for the toler-
ance of variety of functional groups,9 study of the nu-
cleophilic addition or arylation of N-heterocycles and
halo-substituted arylalkynes remains elusive. In this con-
text, preferential addition of heterocyclic amines to ha-
loalkynes over arylation reactions would be of great
interest to synthetic chemists.
This study supports and confirms the previously proposed
mechanism via hydroamination followed by oxidative
addition (route 2).
Scheme 1. Possible Pathways for the Tandem Synthesis of
Indolo[2,1-a]isoquinolines via Intermediate R
Our initial studies focused on the use of benzotriazole
(L1) as ligand for the N-arylation of heterocycles.10c Thus,
reaction of 3-methylindole 1a and ((4-bromophenyl)-
ethynyl)trimethylsilane 2a using 2.0 equiv of KþOtBu,
10 mol % of CuI, and 20 mol % of L1 at 120 °C for 1 h
was examined (Table 1, entry 1). Under basic reaction condi-
tions, hydrolysis of the trimethylsilyl group occurred, and a
mixture of E- and Z-addition products 4a was obtained in
72% yield in 80:20 stereoisomeric ratios along with 5%
homocoupling product of alkyne (Table 1, entry 1). Inter-
estingly, the reaction did not show the formation of any
N-arylated product 5a. Increase in the reaction time from
1 to 5 h provided the thermodynamically stable trans-
isomer in 95:5 ratios in 68% yield (Table 1, entry 2).
Screening of other bases in the presence of metal and
catalyst did not show any formation of aminated products
and only mixtures of hydroaminated products were ob-
tained (Table 1, entries 3ꢀ6). Weak bases like K2CO3 and
Cs2CO3 provided the Z- as the major stereoisomer
(Table 1, entries 3 and 4), and strong bases K3PO4 and
KOH yielded the addition product with E- as the major
isomer (Table 1, entries 5 and 6). In the absence of copper
and L1, KOH yielded the Z-isomer in 89% yield in 30:70
stereoisomeric ratio (Table 1, entry 7). The reaction also
proceeded well in the catalytic amount of the base with the
formation of Z- isomer as a major product within 20ꢀ25
min (Table 1, entry 8). With the recent report on the
transition-metal free N-arylation of heterocycles using
KOH and DMSO by Cano et al.12 and iron-catalyzed
amidation of alkynyl bromides by Yao et al.,13 when a
similar catalytic system was used, only hydroaminated
product 4a was obtained in 82 and 55% yields, respec-
tively (Table 1, entries 9 and 10).
In continuation of our interest in the coupling reac-
tions10 and synthesis of fused heterocycles,11 we recently
reported the copper-catalyzed tandem synthesis of indolo-
and pyrrolo[2,1-a]isoquinolines. In the proposed mecha-
nism, wehaveshowntwo possibleroutesforthe generation
of the key intermediate R (Scheme 1).11a Herein, we report
that nucleophilic addition of heterocyclic amines onto
halo-substituted arylalkynes is preferred over N-arylation.
(7) (a) Ackermann, L.; Song, W.; Sandmann, R. J. Organomet.
Chem. 2011, 696, 195–201. (b) Ackermann, L. Org. Lett. 2005, 7, 439–
442. (c) Kaspar, L. T.; Ackermann, L. Tetrahedron 2005, 61, 11311–
11316. (d) Ackermann, L.; Sandmann, R.; Kondrashov, M. V. Synlett
2009, 8, 1219–1222. (e) Ackermann, L.; Barfußer, S.; Potukuchi, H. K.
Adv. Synth. Catal. 2009, 346, 1064–1072.
(8) Alsabeh, P. G.; Lundgren, R. J.; Longobardi, L. E.; Stradiotto,
M. Chem. Commun. 2011, 47, 6936–6938.
(9) (a) Jiang, L.; Buchwald, S. L. In Palladium-Catalyzed Aromatic
CarbonꢀNitrogen Bond Formation in Metal-Catalyzed Cross-Coupling
Reactions; De Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004; pp 699ꢀ760. (b) Corbet, J. P.; Mignani, G. Chem. Rev. 2006, 106,
2651–2710. (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003,
42, 5400–5499 and references cited therein.
(10) (a) Verma, A. K.; Singh, J.; Sankar, V. K.; Chaudhary, R.;
Chandra, R. Tetrahedron Lett. 2007, 48, 4207–4210. (b) Verma, A. K.;
Singh, J.; Chaudhary, R. Tetrahedron Lett. 2007, 48, 7199–7202. (c)
Verma, A. K.; Singh, J.; Larock., R. C. Tetrahedron. 2009, 65, 8434–
8439.
(11) (a) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.;
Larock, R. C. Angew. Chem., Int. Ed. 2009, 48, 1138–1143. (b) Verma,
A. K.; Joshi, M.; Singh, V. P. Org. Lett. 2011, 13, 1630–1633. (c) Verma,
A. K.; Aggarwal, T.; Rustagi, V.; Larock, R. C. Chem. Commun. 2010,
46, 4064–4066. (d) Verma, A. K.; Shukla, S. P.; Singh, J.; Rustagi, V.
J. Org. Chem. 2011, 76, 5670–5684. (e) Rustagi, V.; Aggarwal, T.;
Verma, A. K. Green Chem. 2011, 13, 1640–1643. (f) Aggarwal, T.; Imam,
M.; Kaushik, N. K.; Chauhan, V. S.; Verma., A. K. ACS Comb. Sci.
2011, 13, 530–536. (g) Katritzky, A. R.; Verma, A. K.; He, H.; Chandra,
R. J. Org. Chem. 2003, 68, 4938–4940. (h) Tiwari, R. K.; Singh, D; Singh,
J.; Yadav, V.; Phatak, A. K.; Dabur, R.; Chhillar, A.; Singh, R.; Sharma,
G. L.; Chandra, R.; Verma, A. K. Bioorg. Med. Chem. Lett. 2006, 413–
416. (i) Tiwari, R. K.; Singh, D; Singh; Chhillar, A.; Chandra, R.;
Verma, A. K. Eur. J. Med. Chem. 2006, 41, 40–49. (j) Tiwari, R. K.;
Singh, J.; Singh, D.; Verma, A. K.; Chandra, R. Tetrahedron 2005, 61,
9513–9518.
(12) Cano, R.; Ramon, D. J.; Yus., M. J. Org. Chem. 2011, 76, 654–
660.
(13) Yao, B.; Liang, Z.; Niu, T.; Zhang, Y. J. Org. Chem. 2009, 74,
4630–4633.
Org. Lett., Vol. 14, No. 4, 2012
1107

Table 1. Optimization of the Reaction Conditionsa
Table 2. Hydroamination of Alkynyl Bromidesa
yield (%)b
4 (E:Z)
entry
base
catalyst
CuI
ligand
BtH
5/6
1
KþOtBu
KþOtBu
K2CO3
Cs2CO3
K3PO4
KOH
72 (80:20)
68 (95:05)
60 (30:70)
52 (40:60)
70 (80:20)
80 (60:40)
89 (30:70)
85 (05:95)
82 (90:10)
55 (60:40)
45 (70:30)
70 (80:20)
65 (75:25)
56 (80:20)
2c
3
CuI
CuI
CuI
CuI
CuI
ꢀ
BtH
BtH
BtH
BtH
BtH
ꢀ
4
5
6
7
KOH
8d
9e
10
11
12
13
14
15
16
17f
18f,g
KOH
ꢀ
ꢀ
KOH
ꢀ
ꢀ
K2CO3
K2CO3
KþOtBu
Cs2CO3
Cs2CO3
Cs2CO3
FeCl3.H2O DMEDA
CuI
L-proline
BtCH2OH
dppf
CuI
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Xantphos
(()-BINAP 62 (70:30)
(()-BINAP 58 (90:10)
NaþOtBu Pd2(dba)3
K3PO4
K3PO4
CuI
CuI
BtH
52 (90:10)
10
92
BtH
a Reactions were carried out using 1a (2.0 equiv), 2 (1.0 equiv),
catalyst (10 mol %), ligand (20 mol %),and base (2.0 equiv) in DMSO
(1.5 mL) at 120 °C for 1 h. b Isolated yield of mixture of E/Z isomers.
c Time (5 h). d Base (0.2 equiv) and time (20ꢀ25 min). e Time (72 h) and
base (2.5 equiv). f 3a (1.0 equiv), time (24 h). g Without 2a.
Other well established copper- and palladium-catalyzed
systems reported in the literature for the arylation of hetero-
cyclic amines14,15 were also tried, but all of them provided
the stereoisomeric mixture of hydroaminated products 4a
along with 5ꢀ10% of homocoupling product (Table 1,
entries 11ꢀ16). Further, addition of 4-iodoanisole (3a) to
the reaction of 1a and 2a in the presence of K3PO4 and BtH
provided the products 4 in 52% yield along with 6a in 10%
Scheme 2. Selective Hydroamination
(14) For recent reviews, see: (a) Kunz, K.; Scholz, U.; Ganzer, D.
Synlett. 2003, 2428–2439. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem.
Rev. 2004, 248, 2337–2364. (c) Antilla, J. C.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 11684–11688.
(15) (a) Harris, M. C.; Geis, O.; Buchwald, S. L. J. Org. Chem. 1999,
64, 6019–6022. (b) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2,
27–50. (c) Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.;
Buchwald, S. L. Chem. Sci. 2011, 2, 57–68. (d) Magano, J.; Dunetz, J. R.
Chem. Rev. 2011, 111, 2177–2250.
a Reactions were carried out using 1a (2.0 equiv) and 2 (1.0 equiv) in
DMSO (1.5 mL) at 120 °C for 20ꢀ30 min. b Isolated yield. c CuI (10 mol %),
BtCH2OH (20 mol %), andKOH (2.0 equiv).d KOH = 0.2 equiv. e Time =
10ꢀ12 h.
1108
Org. Lett., Vol. 14, No. 4, 2012

yield (Table 1, entry 17).10c However, in the absence of 2a
only N-arylated product 6a was obtained in 92% yield
(Table 1, entry 18).
Further, when reaction of aniline 7 was done with 2a, in
the presence of 1a using CuI, KþOtBu, and BtH, interest-
ingly, no hydroamination product of aniline 8 was observed
and only 4a was isolated (Scheme 2). This observation
suggested that hydroamination of heterocyclic aromatic
amines is preferred over aryl amines.
4m in 68% yield (Table 2, entry 13). Further, the X-ray
crystallographic data of 4i also confirmed the stereo-
chemistry and selective formation of hydroaminated
product (Figure 1).16
To check the scope and limitations of the reaction,
further various N-heterocycles 1aꢀg were examined with
different bromo-substituted alkynes 2aꢀe under arylation
(Table 2, entries 1ꢀ3) and hydroamination conditions
(Table 2, entries 4ꢀ11). It was observed that the presence
of an electron-donating group at the third position of the
indole ring in 1a enhances the conversion of kinetically
stable cis- to trans-isomer, and the reaction was completed
within 10ꢀ15 min and afforded the hydroaminated prod-
uct 4a in 75% yield in 89:11 stereoisomeric ratios (Table 2,
entry 1). Electron-deficient heterocycle imidazole 1b pro-
vided the addition product 4b in 58% yield with the
Z-isomer as the major product (Table 2, entry 2). It was
interesting to see that electron-rich pyrrole 1c when reacted
with ((2- bromophenyl)ethynyl)trimethylsilane 2b under
the catalytic conditions provided the mixture of E:Z
addition products instead of the expected pyrrolo[2,1-a]-
isoquinoline (Table 2, entry 3). The stereochemistry and
isomeric ratio of these products were confirmed and
calculated by NMR spectroscopy. Reaction of electron-
rich and electron-deficient N-heterocycles 1aꢀg with ortho-,
meta-, and para-substituted bromoarylalkynes using
20 mol % of KOH at 120 °C afforded the correspond-
ing hydroaminated products 4dꢀj stereoselectively in 62ꢀ
90% yields, respectively, within 15ꢀ20 min (Table 2,
entries 4ꢀ10). Reaction with longer times (10ꢀ12 h) using
a catalytic amount of KOH afforded the E-isomer in 82%
yield (Table 2, entry 11).
Figure 1. X-ray crystallographic ORTEP drawings of com-
pound 4i drawn at the 50% probability level.
In summary, for the first time, a reaction of various
N-heterocycles and halo-substituted arylalkynes was per-
formed, and it was observed that hydroamination is pre-
ferred over amination of aryl halide. The results of the
present study, preferential addition of N-heterocycles onto
halo-substituted arylalkynes suggests that the mechanism
of the copper-catalyzed tandem synthesis of indolo- and
pyrrolo[2,1-a]isoquinolines proceeds via generation of in-
termediate Q through hydroamination followed by oxida-
tive addition to the key intermediate R and not vice versa
(Scheme 2, route 2). Further theoretical investigations in
this area are currently underway and will be reported in
due course.
Acknowledgment. We gratefully acknowledge the Coun-
cil of Scientific and Industrial Research [01(2466)/11/
EMR-II] for financial support and USIC for providing
instrumentation facilties. We thank Sushil Kumar, Uni-
versity of Delhi, for his kind help in solving X-ray crystal-
lographic data. M.J. thanks UGC for a fellowship.
Internal alkyne 1-bromo-4-(p-tolylethynyl)benzene 2d also
provided the mixture of hydroaminated products in 63%
yield (Table 2, entry 12). o-Bromoarylalkyne 2e afforded the
cyclized product 12-methyl-6-p-tolylindolo[2,1-a]isoquinoline
Supporting Information Available. Detailed experimen-
tal procedures and copies of HRMS, 1H NMR, and 13
C
NMR spectra for all new compounds. CIF for compound
4i. This material is available free of charge via the Internet
at http://pubs.acs.org.
(16) Crystallographic data have been deposited at the Cambridge
Crystallographic data Centre as a CIF deposit with file number 855111.
Copies of these data can be obtained free of charge on application to
CCDC, email deposit@ccdc.cam.ac.uk. The CIF is also included in the
Supporting Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
1109