Halopalladation cyclization of alkynes with azides: Selective synthesis of 4-haloisoquinolines and 3-haloindoles

Article abstract of DOI:10.1055/s-0030-1259722

A new, selective method for the synthesis of 4-haloisoquinolines and 3-haloindoles is presented by the halopalladation cyclizations of alkynes with azides. In the presence of PdX₂ (X = Br, Cl) and halide sources, a variety of 2-alkynyl benzyl a

Full text of DOI:10.1055/s-0030-1259722

982
LETTER
Halopalladation Cyclization of Alkynes with Azides: Selective Synthesis of
4-Haloisoquinolines and 3-Haloindoles
S
elective Synthesi
o
s
of 4-Halois
n
oquinoline
s
a
g
nd 3-Haloin
-
doles Ping Zhang,a,b Shang-Ci Yu,a Yun Liang,a Peng Peng,a Bo-Xiao Tang,a Jin-Heng Li*a
a
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal University,
Changsha 410081, P. R. of China
Fax +86(731)88872101; E-mail: jhli@hunnu.edu.cn
Department of Biology and Chemical Engineering, Shaoyang University, Shaoyang 422000, P. R. of China
b
Received 8 August 2010
Dedicated to Professor Xiyan Lu and Professor Lixin Dai
Pomeranz–Fritsch reaction,3 and the Pictet–Spengler re-
action;4 however, these methods generally require harsh
conditions (often at elevated temperature under strongly
acidic conditions) and/or multistep reaction procedures.
Abstract: A new, selective method for the synthesis of 4-haloiso-
quinolines and 3-haloindoles is presented by the halopalladation cy-
clizations of alkynes with azides. In the presence of PdX2 (X = Br,
Cl) and halide sources, a variety of 2-alkynyl benzyl azides or
2-alkynyl aryl azides smoothly underwent the halopalladation Recently, transition-metal-catalyzed transformations dis-
played highly promising potential for these purposes.5,6
cyclization reaction to afford the corresponding 3-substituted 4-
haloisoquinolines and 2-substituted 3-haloindoles in moderate to
good yields.
For example, Larock and co-workers have reported some
efficient palladium-catalyzed cyclization method for the
synthesis of 3,4-disubstituted isoquinolines using tert-
Key words: palladium, halopalladation, cyclization, 2-alkynyl
azide, 4-haloisoquinoline, 3-haloindole
butylamine, 2-iodobenzaldehydes, and alkynes (or al-
lenes) as the reaction partners.6 The Liang group5c and the
Yamamoto group5g independently employed 2-alkynyl
benzyl azides as the starting materials for 1,3-disubstitut-
Isoquinolines are a recurring functional motif in many
natural products and biologically active compounds.1–10
Consequently, the development of new synthetic ap-
proaches for their preparation remains an active research
area. The traditional methods for isoquinolines prepara-
tion include the Bischler–Napieralski reaction,2 the
ed isoquinolines by Ag or Au/Ag-catalyzed cyclization.
Interestingly, the recent results showed that 2-alkynyl
benzyl azides were suitable substrates for constructing the
1,3-disubstituted 4-haloisoquinoline skeleton through an
electrophilic iodocyclization process (Scheme 1).7b–d
Thus, the development of a transition-metal-catalyzed
ref. 7b,c:
R3
R3
N3
N
[I], base or HBF4
R2
[I] = I2, NIS, Py2IBF4
R1
R1
R2
I
ref. 7d:
R2
E
N3
N
R2
electrophile (E+)
R1
R1
R3
R3
E+ = I2, Br2, NBS, NIS, ICl, H+ or
electrophilic catalysts (often AuCl3/AgNTf2 catalysts)
this work:
H
PdX2
PdX2
N
N
n
N3
CuX2, additive
CuX2, additive
R2
R2
n = 1
R1
n = 0
R1
R1
X
R2
X
1
2: X = Cl
3: X = Br
4: X = Cl
5: X = Br
Scheme 1 Synthesis of halo-substituted heterocycle compounds from the cyclization of alkynes with azides
SYNLETT 2011, No. 7, pp 0982–0988
x
x.
x
x.
2
0
1
1
Advanced online publication: 10.03.2011
DOI: 10.1055/s-0030-1259722; Art ID: W01310ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Selective Synthesis of 4-Haloisoquinolines and 3-Haloindoles
983
route to halo-substituted heterocycle compounds using closed that arylalkynes 1b and 1c reacted with PdBr2,
azides substrates would be interesting. Here, we report a CuBr2 and LiBr smoothly, furnishing 4-haloquinolines 3b
selective method for synthesizing 4-haloisoquinolines and and 3c in moderate yields (entries 2 and 4). Notably, 4-
3-haloindoles through the intramolecular halopalladation bromo-1,2-dihydroisoquinolines 3f–h were obtained
cyclization of 2-alkynyl benzyl azides (Scheme 1).9–11 among the annulation products of aliphatic alkynes 1f–h
Moreover, the standard conditions were compatible with (entries 8, 10 and 12).
2-alkynyl aryl azides leading to 3-haloindoles.12,13
Table 1 Screening Conditionsa
We began our investigation using 2-phenylethynyl benzyl
N3
azide (1a) as the model substrate to explore the optimal
conditions (Table 1). Initially, the effect of solvents on the
reaction of azide 1a was examined. The results demon-
strated that CH2ClCH2Cl (DCE) was the most effective
solvent (entries 1–3). While the reaction of 1a with PdCl2
and CuCl2 in DCE provided the target product 2a in 57%
yield (entry 1), low yields of 2a were observed in either
MeCN or toluene (entries 2 and 3). In light of these re-
sults, the amount of CuCl2 was subsequently examined:
three equivalents of CuCl2 were the most suitable (entries
1, 4 and 5). To improve the reaction, a number of halide
sources were tested (entries 6–12). While low yields were
isolated using LiCl or Cy2NH2Cl alone (entries 6 and 7), a
mixture of halide sources could promote the desired reac-
tion (entries 8–12): three equivalents of CuCl2 combined
with 0.2 equivalent of Cy2NH2Cl provided the best results
(entry 11). It is noteworthy that product 2a can still be
achieved in a low yield without Pd catalysts (entry 13).
We found that the reaction temperatures also affected the
reaction to some extent, and the best results were obtained
at 80 °C (entries 11, 14 and 15). To our surprise, the
PdBr2–CuBr2–Cy2NH2Br–CH2ClCH2Cl system was un-
successful for the bromopalladation annulation of 1a (en-
try 16). After a series of trials, we were pleased to discover
that the PdBr2–CuBr2–LiBr–MeCN system was suitable
for the bromopalladation reaction (entries 17 and 18);
treatment of substrate 1a with PdBr2, CuBr2 and LiBr af-
forded 65% yield of the target product 3a in MeCN (entry
18).
N
PdX2, CuX2
Ph
Ph
X
1a
2a: X = Cl
3a: X = Br
Entry [Pd]
Halide source
(equiv)
Solvent Time Yield
(h) (%)b
1
2
3
4
5
6
7
8
9
PdCl2 CuCl2 (3)
DCE
26 57 (2a)
PdCl2 CuCl2 (3)
MeCN 22 29 (2a)
toluene 32 12 (2a)
PdCl2 CuCl2 (3)
PdCl2 CuCl2 (5)
DCE
DCE
DCE
DCE
DCE
DCE
26 56 (2a)
26 34 (2a)
26 8 (2a)
PdCl2 CuCl2 (2)
PdCl2 LiCl (3)
PdCl2 Cy2NH2Cl (3)
PdCl2 CuCl2 (3)–LiCl (2)
PdCl2 CuCl2 (3)–LiCl (4)
26 7 (2a)
22 72 (2a)
22 50 (2a)
22 58 (2a)
22 84 (2a)
22 59 (2a)
22 17 (2a)
22 23 (2a)
22 71 (2a)
26 trace (3a)
26 31 (3a)
10 PdCl2 CuCl2 (3)–Cy2NH2Cl (1) DCE
11 PdCl2 CuCl2 (3)–Cy2NH2Cl (0.2) DCE
12 PdCl2 CuCl2 (3)–Bu4NCl (0.2)
DCE
13 CuCl2 (3)–Cy2NH2Cl (0.2) DCE
0
14c PdCl2 CuCl2 (3)–Cy2NH2Cl (0.2) DCE
15d PdCl2 CuCl2 (3)–Cy2NH2Cl (0.2) DCE
16 PdBr2 CuBr2 (3)–Cy2NH2Cl (0.2) DCE
With the optimized reaction conditions in hand, the 2-
alkynyl azides scope was investigated (Tables 2 and 3).14
As shown in Table 2, a variety of 2-alkynyl benzyl azides
1b–h were treated with PdCl2, CuCl2 and Cy2NCl in DCE
(conditions A) smoothly to afford the corresponding 4-
chloroquinolines in moderate to good yields (entries 1, 3,
5–7, 9 and 11). We found that substrates 1b and 1c, bear-
ing an electron-donating aryl group at the terminal alkyne,
were tolerated well, but substrate 1d with an electron-
withdrawing NO2 group was deactivated (entries 1, 3 and
5). It is noteworthy that thiophen-2-yl-containing sub-
strate 1e successfully underwent the chloropalladation re-
action to afford the unexpected dichloro addition product
2e in 77% yield (entry 6). Gratifyingly, the standard con-
ditions were also compatible with both aliphatic and vinyl
alkynes 1f–g (entries 7, 9 and 11). Substrate 1h with a cy-
clohexenyl group, for instance, gave the desired product
2h in 70% yield (entry 11). Subsequently, the bromopal-
ladation annulation of azides 1b, 1c and 1f–g was carried
out under the standard conditions B (PdBr2, CuBr2 and
LiBr in MeCN; entries 2, 4, 8, 10 and 12). The results dis-
17 PdBr2 CuBr2 (3)–LiBr (2)
18 PdBr2 CuBr2 (3)–LiBr (2)
DCE
MeCN 26 65 (3a)
a Reaction conditions: 1a (0.3 mmol), PdCl2 (5 mol%), halide source,
and solvent (5 mL) at 80 °C. DCE: ClCH2CH2Cl.
b Isolated yield.
c The reaction was carried out at r.t.
d The reaction was carried out at 100 °C.
Encouraged by these results, a number of 2-alkynyl aryl
azides were employed for the halopalladation reaction
(Table 3). In the presence of PdCl2, CuCl2 and Cy2NCl,
alkynes 1i–l, having electron-donating or electron-defi-
cient aryl groups, underwent the chloropalladation reac-
tion in moderate yields (entries 1 and 3–5). Thiophen-2-yl
alkyne 1m was also a suitable substrate leading to 3-chlo-
ro-2-(thiophen-2-yl)-1H-indole (4m) in 66% yield (entry
6). We were delighted to find that substituents, NO2 or
Synlett 2011, No. 7, 982–988 © Thieme Stuttgart · New York

984
H.-P. Zhang et al.
LETTER
chloro groups, on the aromatic ring of the 1-azidobenzene CuBr2–LiBr catalytic system in MeCN, providing the cor-
moiety were perfectly tolerated (entries 8 and 9). The re- responding 3-bromoindoles 5i and 5o in 90% and 54%
sults showed that bromopalladation cyclization of sub- yields, respectively (entries 2 and 10).
strates 1i and 1o was also successful using the PdBr2–
Table 2 Halopalladation of 2-Alkynyl Benzyl Azides 1a
PdX2, CuX2
N3
N
R
R
X
1
2: X = Cl
3: X = Br
Entry
1
Azide 1
Conditions
A
Time (h)
20
Yield (%)b
N
N
N3
Cl
1b
1b
2b (56)
N3
2
3
B
A
20
18
Br
3b (42)
N3
N
N
N
Cl
OMe
OMe
OMe
NO2
2c (60)
1c
1c
N3
4
5
B
A
20
30
Br
OMe
3c (55)
N3
Cl
NO2
2d (38)
1d
1e
1f
N
N3
S
6
7
8
A
A
B
22
22
22
S
Cl
Cl
N
2e (77)
2f (76)
3f (62)
N3
n-C5H11
n-C5H11
Cl
Br
N3
NH
n-C5H11
n-C5H11
1f
Synlett 2011, No. 7, 982–988 © Thieme Stuttgart · New York

LETTER
Selective Synthesis of 4-Haloisoquinolines and 3-Haloindoles
985
Table 2 Halopalladation of 2-Alkynyl Benzyl Azides 1a (continued)
PdX2, CuX2
N3
N
R
R
X
1
2: X = Cl
3: X = Br
Entry
9
Azide 1
Conditions
A
Time (h)
22
Yield (%)b
N3
N
n-C8H17
n-C8H17
Cl
1g
1g
2g (66)
N3
NH
10
11
B
A
22
24
n-C8H17
n-C8H17
Br
3g (68)
N
N3
Cl
1h
2h (70)
NH
N3
12
B
24
Br
1h
3h (60)
a Reaction conditions: 1 (0.3 mmol) at 80 °C for 24–48 h. Conditions A: PdCl2 (5 mol%), CuCl2 (3 equiv) and Cy2NH2Cl (0.2 equiv) in DCE
(5 mL); Conditions B: PdBr2 (5 mol%), CuBr2 (3 equiv) and LiBr (2 equiv) in MeCN (5 mL).
b Isolated yield.
Table 3 Halopalladation of 2-Alkynyl Aryl Azides 1a
N3
H
N
PdX2, CuX2
R2
R1
R1
R2
X
1
4: X = Cl
5: X = Br
Entry
1
Azide 1
Conditions
A
Product, Yield (%)b
H
N
N3
Ph
Cl
1i
1i
4i (46)
H
N
N3
Ph
2
3
B
A
Br
5i (90)
Cl
N
H
N3
4j (52)
1j
Synlett 2011, No. 7, 982–988 © Thieme Stuttgart · New York

986
H.-P. Zhang et al.
LETTER
Table 3 Halopalladation of 2-Alkynyl Aryl Azides 1a (continued)
N3
H
N
PdX2, CuX2
R2
R1
R1
R2
X
1
4: X = Cl
5: X = Br
Entry
Azide 1
Conditions
Product, Yield (%)b
H
N
4
5
A
Cl
N3
4k (50)
1k
NO2
Cl
A
N
H
NO2
N3
4l (42)
1l
H
N3
N
S
S
S
S
6
7
A
B
Cl
1m
4m (66)
5m (78)
H
N3
N
Br
1m
N3
H
N
Ph
Ph
8
9
A
A
O2N
Cl
O2N
1n
5n (70)
Cl
Cl
N3
H
N
Ph
Ph
Ph
Cl
Cl
Cl
1o
4o (90)
Cl
Cl
N3
H
N
10
B
Ph
Cl
Cl
Br
1o
5o (54)
a Reaction conditions: 1 (0.3 mmol) at 80 °C for 24–48 h. Conditions A: PdCl2 (5 mol%), CuCl2 (3 equiv) and Cy2NH2Cl (0.2 equiv) in DCE
(5 mL); Conditions B: PdBr2 (5 mol%), CuBr2 (3 equiv) and LiBr (2 equiv) in MeCN (5 mL).
b Isolated yield.
Working mechanisms as outlined in Scheme 2 are pro- action of the N–N double bond with Pd within the
posed on the basis of the present results and the reported intermediate B gives the intermediate C. Reductive elim-
mechanisms.5c,g,7,10–12 Coordination of PdX2 with an ination–deprotonation of intermediate C takes place to
alkyne produces the intermediate A, followed by halopal- yield the desired product, N2 and Pd(0) species. The active
ladation of alkyne, which affords the intermediate B. Re- Pd(II)X2 species are regenerated by the oxidation of Pd(0)
Synlett 2011, No. 7, 982–988 © Thieme Stuttgart · New York

LETTER
Selective Synthesis of 4-Haloisoquinolines and 3-Haloindoles
987
N3
CuX2
N2
N
R
PdX2
Pd(0)
N
R
X2Pd
A
R
X = Br, Cl
X
+ HX + N2
N2X
N2
R
NH
N2
N
N
N
Pd
R
PdX
X
X
R
X
R
X
R = alkyl
C
B
B'
N2
– N2
N
R
R
X
X
D
Scheme 2 Possible mechanisms
with CuX2 to start a new catalytic cycle. We can not rule References and Notes
out that the desired product is obtained via another mech-
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can be selectively accessed by judicious choice of 2-alky-
nyl azides and the reaction conditions. In the presence of
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The authors thank the Scientific Research Fund of Hunan Provincial
Education Department (Nos. 08C582 and 08A037) and the National
Natural Science Foundation of China (No. 20872112) for financial
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Li, J.-H. Chin. J. Org. Chem. 2007, 27, 819.
(10) For pioneering papers on the halopalladation reactions, see:
(a) Kanada, K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.;
Teranish, S. J. Org. Chem. 1979, 44, 55. (b) Ma, S.; Lu, X.
J. Chem. Soc., Chem. Commun. 1990, 733. (c) Ma, S.; Lu,
X. J. Org. Chem. 1991, 56, 5120. (d) Ma, S.; Lu, X. J. Org.
Chem. 1993, 58, 3692. (e) Zhu, G.; Lu, X. Organometallics
1995, 14, 4899.
(13) For selected recent reviews, see: (a) Cacchi, S.; Fabrizi, G.
Chem. Rev. 2005, 105, 2873. (b) Krüger, K.; Tillack, A.;
Beller, M. Adv. Synth. Catal. 2008, 350, 2153.
(c) Thansandote, P.; Lautens, M. Chem. Eur. J. 2009, 15,
5874.
(14) General Procedure for the Chloropalladation Reaction:
To a flame-dried Schlenk tube equipped with a magnetic
stirring bar were added azide 1 (0.3 mmol), PdCl2 (5 mol%),
CuCl2 (3 equiv), Cy2NH2Cl (0.2 equiv) and CH2ClCH2Cl (5
mL). The reaction mixture was stirred at 80 °C for 24 h until
complete consumption of starting material as monitored by
TLC and GC–MS analysis. After the reaction was finished,
the mixture was poured into EtOAc, washed with brine (3 ×
10 mL), and extracted with EtOAc. The combined organic
layers were dried over anhyd Na2SO4 and evaporated under
vacuum. The residue was purified by flash column
chromatography on silica gel (hexane–EtOAc) to afford the
desired product.
4-Chloro-3-phenylisoquinoline (2a):6g,15 colorless oil. 1H
NMR (500 MHz, CDCl3): d = 9.24 (s, 1 H), 8.35 (d, J = 8.5
Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.85 (t, J = 8.5 Hz, 1 H),
7.81 (d, J = 11.5 Hz, 2 H), 7.69 (t, J = 7.5 Hz, 1 H), 7.51 (t,
J = 7.5 Hz, 2 H), 7.45 (t, J = 8.5 Hz, 1 H). 13C NMR (125
MHz, CDCl3): d = 150.5, 150.1, 139.1, 134.7, 131.6, 130.0,
128.5, 128.4, 128.0, 127.9, 127.7, 124.1, 109.4. LRMS (EI,
70 eV): m/z (%) = 241 (21) [M+ + 2], 239 (67) [M+], 204
(100) [M+ – Cl].
General Procedure for the Bromopalladation Reaction:
To a flame-dried Schlenk tube equipped with a magnetic
stirring bar were added azide 1 (0.3 mmol), PdBr2 (5 mol%),
CuBr2 (3 equiv), LiBr (2 equiv) and MeCN (5 mL). The
reaction mixture was stirred at 80 °C for 24 h until complete
consumption of starting material as monitored by TLC and
GC–MS analysis. After the reaction was finished, the
mixture was poured into EtOAc, washed with brine (3 × 10
mL), and extracted with EtOAc. The combined organic
layers were dried over anhyd Na2SO4 and evaporated under
vacuum. The residue was purified by flash column
chromatography on silica gel (hexane–EtOAc) to afford the
desired product.
(11) For other papers on the halopalladation reactions using
PdX2/CuX2 as the catalytic system, see: (a) Bäckvall, J. E.;
Nordberg, R. E. J. Am. Chem. Soc. 1980, 102, 393. (b) Ji,
J.; Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 1160. (c) Ma,
S.; Lu, X. J. Org. Chem. 1993, 58, 1245. (d) Li, J.-H.;
Jiang, H.-F.; Feng, A.-Q.; Jia, L.-Q. J. Org. Chem. 1999, 64,
5984. (e) Li, J.-H.; Jiang, H.-F.; Chen, M.-C. J. Org. Chem.
2001, 66, 3627. (f) Li, J.-H.; Liang, Y.; Xie, Y.-X. J. Org.
Chem. 2004, 69, 8125. (g) Li, J.-H.; Tang, S.; Xie, Y.-X.
J. Org. Chem. 2005, 70, 477. (h) Ma, S.; Wu, B.; Zhao, S.
Org. Lett. 2003, 5, 4429. (i) Ma, S.; Wu, B.; Jiang, X.; Zhao,
S. J. Org. Chem. 2005, 70, 2568. (j) Huang, J.; Zhou, L.;
Jiang, H. Angew. Chem. Int. Ed. 2006, 45, 1945. (k) Liang,
4-Bromo-3-phenylisoquinoline (3a):15 Colorless oil.
1H NMR (500 MHz, CDCl3): d = 9.23 (s, 1 H), 8.33 (d, J =
8.5 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.84 (t, J = 8.0 Hz, 1
H), 7.73 (d, J = 8.5 Hz, 2 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.50
(t, J = 7.8 Hz, 2 H), 7.45 (t, J = 8.0 Hz, 1 H). 13C NMR (125
MHz, CDCl3): d = 152.3, 151.1, 140.7, 136.0, 131.9, 129.9,
128.6, 128.3, 128.0, 127.9, 127.7, 127.0, 118.3. LRMS (EI,
70 eV): m/z (%) = 285 (23) [M+ + 2], 283 (25) [M+], 204
(100) [M+ – Br].
(15) Yu, X.; Wu, J. J. Comb. Chem. 2009, 11, 895.
Synlett 2011, No. 7, 982–988 © Thieme Stuttgart · New York

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