A multicomponent reaction of arynes, isocyanides, and terminal alkynes: Highly chemo- And regioselective Synthesis of polysubsti- tuted pyridines and isoquinolines

Full text of DOI:10.1002/anie.200900212

Communications
DOI: 10.1002/anie.200900212
Synthetic Methods
A Multicomponent Reaction of Arynes, Isocyanides, and Terminal
Alkynes: Highly Chemo- and Regioselective Synthesis of Polysubsti-
tuted Pyridines and Isoquinolines**
Feng Sha and Xian Huang*
Pyridine, a class of important heterocycles, is not only the
fundamental motif found in the core of numerous alkaloids[1]
but is also a pivotal building block for pharmaceutical
compounds[2] and chiral ligands.[3] Although many methods
have been developed for their synthesis, lengthy or compli-
cated procedures as well as harsh reaction conditions are
usually applied.[4–5] Thus, it is still important to develop direct
and efficient routes that afford pyridine derivatives under
mild conditions. Arynes are an important intermediate in
organic synthesis and have received attention over the past
decades.[6] Because of their low-lying LUMO, arynes exhibit
highly electrophilic character; even neutral nucleophiles can
easily add to arynes to produce zwitterions, which act as key
intermediates in the subsequent transformation that can lead
to a variety of benzoannulated compounds.[7] This feature has
been successfully explored by Yoshida et al. in the three-
component reaction of arynes, isocyanides, and aldehydes,
ketones, or imines for the direct synthesis of benzoannulated
iminofurans and 2-iminoisoindolines.[8] However, examples of
multicomponent reactions (MCR) containing both arynes
and isocyanides are still limited owing to the obvious
difficulty in regulating the reactivity of the aryne compo-
nent;[8,9] especially the control of chemo- and regioselectivity
remain challenging. We envisioned that an adduct of benzyne
and isocyanide (generated in situ) may be trapped by a
terminal alkyne to form a reactive imide intermediate A,[10]
which may further undergo a 1,5-hydride shift to produce an
allenyl imine intermediate B (Scheme 1).[11b] Then a consec-
utive cycloaddition reaction of B with another molecule of
benzyne or terminal alkyne may occur to afford useful
heterocyclic compounds.[11] Herein we reported our results on
this novel multicomponent reaction, which provides a direct
Scheme 1. MCR strategy for the synthesis of heterocyclic products.
and mild synthesis of polysubstituted pyridines and isoquino-
lines with high chemo- and regioselectivity. An attractive
feature of this protocol is that four molecules could be directly
assembled into the desired azacyclic compounds in a highly
efficient and atom-economic manner.
We initially examined the reaction of 2-(trimethylsilyl)-
phenyl triflate (1a),[12a] benzyl isocyanide (2a), and phenyl
ethyne (3a) in MeCN at room temperature (Table 1, entry 1).
Interestingly, N-benzyl alkynyl imine 4a was formed in 81%
yield together with isoquinoline 5a and pyridine 6a in 6%
and 2% yields, respectively. Efforts were made to optimize
the reaction conditions to afford predominantly one product.
The reaction with 2.5 equivalents of 1a at 408C afforded 5a in
49% yield (Table 1, entry 3). The reaction in toluene/MeCN
(1:3) afforded 5a in 74% yield (Table 1, entry 5).[13] Likewise,
with 3.0 equivalents of 3a, the yield of 6a was increased to
76% (compare Table 1, entries 6 and 7 with entry 8) after 48 h
at 758C.
Under the optimized reaction conditions, we then
employed a variety of aryne precursors 1,[12] isocyanides 2,
and terminal alkynes 3 to examine the scope of the reaction.
As shown in Table 2, the reaction proceeded smoothly to give
the corresponding polysubstituted pyridines 6 in good yields.
In addition to symmetric arynes (Table 2, entries 1–5),
various unsymmetrical arynes could also undergo the reaction
smoothly. For example, when o-methyl aryne (Table 2,
entry 6) was employed, the reaction occurred with high
regioselectivity, probably as a result of an electronic effect
from the methyl substituent, which generated the thermody-
namically stable intermediate and introduced the imino
moiety ortho to the methyl group.[6b,8b,c] A similar result was
also observed using 1d as the aryne precursor (Table 2,
[*] F. Sha, Prof. X. Huang
Department of Chemistry
Zhejiang University (Xixi Campus)
Hangzhou 310028 (China)
Fax: (+86)571-8880-7077
E-mail: huangx@mail.hz.zj.cn
Prof. X. Huang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (China)
[**] We are grateful to the National Natural Science Foundation of China
(Project Nos. 20672095, 20872127, and 20732005) and the National
Basic Research Program of China (973 Program, 2009CB825300) for
financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200900212.
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Chemie
Table 1: Optimization of the reaction conditions for the multicomponent
entry 7). The reaction of p-fluorobenzyne precursor 1e
reactions.[a]
produced regioisomer 6i exclusively. This outcome could be
rationalized by the strong electron-withdrawing effect of the
fluoro substituent, which causes the negative charge at the
meta position to be greater than at the para position (in the
transition state for the addition of an isocyanide to p-
fluorobenzyne), thus facilitating the introduction of the
imino moiety at the para position (Table 2, entry 8).[8a,14]
Our results demonstrated that aromatic alkynes, including
p-C2H5- and p-Cl-substituted phenyl ethynes, could be
successfully applied to the reactions (Table 2, entries 1, 3–5).
However, when alkyl alkynes were employed the reaction
gave the corresponding products in lower yields (Table 2,
entries 9 and 10). In addition, the reaction of the electron-
deficient alkyne 3 f afforded the corresponding product 6l in
modest yield (Table 2, entry 11). It should be noted that the
reactions showed excellent regioselectivity with respect to the
alkyne to give 3-aryl-substituted pyridines 6, whose structures
were confirmed by NOESY experiments (Scheme 2).
Entry 1a/2a/3a Toluene/MeCN t [h] T [8C]
Yield [%][b]
4a 5a 6a
[mmol]
[v/v]
1
2
3
4
5
6
7
8
9
1.3:1.0:1.0
2.5:1.0:1.0
2.5:1.0:1.0
2.5:1.0:1.0
2.5:1.0:1.0
1.3:1.0:2.0
1.3:1.0:2.5
1.3:1.0:3.0
1.3:1.0:3.0
0:1
0:1
0:1
1:5
1:3
1:1
4:1
4:1
5:1
37
37
10
13
18
22
48
48
40
RT
RT
40
40
40
75
75
75
85
81
6
2
72 13
26 49
12 68
3
3
1
2
0
0
0
0
74
16
6
0.4 76
0.3 70
0.6
57
69
[a] The reactions were conducted using 1a, 2a, 3a, and CsF (2.0 equiv,
based on 1a) in 5 mL of solvent (toluene/MeCN). [b] Yield of isolated
product was based on the isocyanide 2a. Tf=trifluoromethanesulfonyl,
TMS=trimethylsilyl.
Scheme 2. NOE interactions were used to confirm the configuration of
pyridines 6.
Further experiments under the optimized reaction con-
ditions (Table 1, entry 5) demonstrated that the multicompo-
nent reaction could be extended to generate substituted
isoquinolines in good yields (Table 3). The phenyl ethyne
derivatives that are substituted with either an electron-
withdrawing or -donating group could be smoothly trans-
formed into the corresponding products (Table 3, entries 1–
5). In addition to benzyl and p-methyl benzyl isocyanides,
naphthalen-1-yl methyl and p-fluoro benzyl isocyanides
participated in the reaction to afford the desired products in
72% and 76%, respectively (Table 3, entries 4 and 5).
Furthermore, the reaction of unsymmetrical aryne precursor
1c afforded two regioisomers 5ia and 5ib with good
selectivity (Table 3, entry 8). The structure of the product
5g was confirmed by X-ray diffraction studies (Figure 1).[15]
Interestingly, when an alkyl isocyanide substrate was used
the reaction stopped at the alkynyl imine 4b (Scheme 3), thus
indicating the importance of the phenyl group (R1) in the
isomerization from A to B (Scheme 1). In fact, mechanistic
experiments demonstrated that the treatment of alkynyl
imine 4a with 2-(trimethylsilyl)phenyl triflate (1a) or alkyne
3a in the presence of CsF could furnish isoquinoline 5a and
pyridine 6a in 75% and 77% yields, respectively (Scheme 3).
This result further proved that 4 is an intermediate for this
type of transformation.
Table 2: Multicomponent reactions for the synthesis of pyridines 6.[a]
Entry
Aryne 1
Isocyanide 2 Ethyne 3
Yield Prod.
6
R1 R2 R3
R4
R5
[%][b]
1
2
3
4
5
6
7
1a
1a
1a
H
H
H
2a Ph
2b p-Tol
2b
3b p-EtC6H4
3a Ph
3c p-ClC6H4
3c
65
73
81
70
77
69
78
82
31
43
6b
6c
6d
6e
6 f
6g
6h
6i
1b Me Me
1b
1c
1d Br
1e
1a
H
2b
2c p-FC6H4 3c
H
H
H
H
Me 2a
Me 2a
H
3a
3a
3a
8
F
2a
2a
2a
2a
9[c]
3d n-C6H13
3e c-C3H5
3 f p-FC6H4CO 53
6j
6k
6l
10[d] 1a
11[e] 1a
[a] Unless otherwise specified, the reactions were conducted using 1
(0.65 mmol), 2 (0.5 mmol), 3 (1.5 mmol), and CsF (1.3 mmol) in MeCN
(0.5 mL) and toluene (2 mL) at 758C for 48 hours. [b] Yield of isolated
product was based on the isocyanide 2. [c] The reaction was conducted
in MeCN (0.25 mL) and toluene (2.25 mL) for 91 h. [d] The reaction was
carried out in a sealed tube with a screw cap. [e] The reaction was
conducted in MeCN (2.5 mL) at room temperature overnight. Tol=tolyl.
In conclusion, we have developed a new multicomponent
reaction of arynes, isocyanides, and terminal alkynes with
good selectivity. The different reaction pathways could be
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Communications
Table 3: Multicomponent reactions for the synthesis of isoquinolines 5.[a]
Entry Aryne 1 Isocyanide 2
Ethyne 3
Yield
[%][c]
Prod. 5
R4
R5
1
2
3
4
1a
1a
1a
1a
1b
1a
1b
1c
2a
2a
2b
3c
3b
3a
75
67
79
72
76
71
64
55
5b
5c
5d
5e
5 f
2d 1-naphthyl 3c
5
2c
2a
2b
2a
3c
6[b]
7[b]
8[b]
3g CO2Et
3g
3g
5g
5h
5ia/5ib
Scheme 3. MCR using alkyl isocyanide and experiments that confirm 4
as the intermediate for the MCR.
(7:1)[d]
[a] Unless otherwise specified, the reactions were conducted using 1
(1.25 mmol), 2 (0.5 mmol), 3 (0.5 mmol), and CsF (2.5 mmol) in MeCN
(1.88 mL) and toluene (0.63 mL) at 408C overnight. [b] The reactions
were conducted using 1 (1.25 mmol), 2 (0.5 mmol), 3g (0.5 mmol),
[18]crown-6 (3.0 mmol), and KF (2.5 mmol) in THF (2.5 mL) at 08C
overnight. [c] Yield of isolated product was based on the isocyanide 2.
[d] Determined by isolation of the products. The configuration of 5ia was
confirmed by NOESY experiments.
Experimental Section
Synthesis of 6a–i: CsF (1.3 mmol, 198 mg) was added to a stirred
solution of 2-(trimethylsilyl)aryl triflate 1 (0.65 mmol), isocyanide 2
(0.5 mmol), and aryl ethyne 3 (1.5 mmol) in dry MeCN (0.5 mL) and
dry toluene (2 mL) under nitrogen. The reaction mixture was stirred
at 758C for 48 hours. When the reaction was judged to be complete
(as evident by TLC), the mixture was filtered through a layer of silica
gel and eluted with Et2O. The filtrate was concentrated under reduced
pressure, and the residue was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate, 35:1) to afford 6.
Received: January 13, 2009
Revised: February 26, 2009
Published online: April 6, 2009
Keywords: arynes · isoquinolines · multicomponent reactions ·
.
pyridines · regioselectivity
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