Double isocyanide cyclization: A synthetic strategy for two-carbon-tethered pyrrole/oxazole pairs

Article abstract of DOI:10.1021/ja110864t

A new strategy for the construction of the compounds with two different heterocycles, linked by a C₂-tether via a domino process involving [5 + 1] annulation, ring-opening, and subsequent double isocyanide cyclization, from the reaction of ethy

Full text of DOI:10.1021/ja110864t

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Double Isocyanide Cyclization: A Synthetic Strategy for
Two-Carbon-Tethered Pyrrole/Oxazole Pairs
Yifei Li, Xianxiu Xu,* Jing Tan, Chunyu Xia, Dawei Zhang, and Qun Liu*
Department of Chemistry, Northeast Normal University, Changchun 130024, China
S Supporting Information
b
ABSTRACT: A new strategy for the construction of the
compounds with two different heterocycles, linked by a C2-
tether via a domino process involving [5 þ 1] annulation,
ring-opening, and subsequent double isocyanide cyclization,
from the reaction of ethyl isocyanoacetate with divinyl
ketones (DVKs) has been developed. The chemoselective
fragmentation of the cyclohexanone intermediate is the key
for the formation of not only the C2-tether but also the two
different heterocycles.
Figure 1. Examples of biologically active and natural products contain-
ing C2-tethered heterocyclic pairs.
n recent years several biologically active and natural products
were found in the series of C2-tethered heterocyclic pairs
I
(Figure 1), for example, cyclooroidin (isolated from the Medi-
terranean sponge Agelas oroides),1a siphonazoles (isolated from
the genus Herpetosiphon)1b and (Z)-2-(1H-indol-3-yl)-3-(pyridin-
3-yl)acrylonitrile (which was prepared by condensation of 2-
(1H-indol-3-yl)acetonitrile with nicotinaldehyde and named
paprotrain).1c The synthesis of siphonazoles was achieved by
the use of 4-carbethoxy-5-methyl-2-(phenylsulfonyl)methyloxa-
zole as a conjunctive reagent2a or through the construction of two
suitable oxazole units followed by their coupling.2b The synthesis
of cyclooroidin starting from histidine or (()-longamide B was
also reported.3 In this communication, a new synthetic strategy
for the construction of two different heterocycles (pyrrole and oxazole)
connected through a C2 bridge in a single step starting from the easily
available divinyl ketone derivatives is described (Scheme 1).
Divinyl ketones (DVKs) are typically associated with the
Nazarov and related reactions.4,5 The present study arose from
our interest in developing the synthetic potential of R-alkenoyl
ketene dithioacetals 1, the DVKs with terminal gem-dialkylthio
substituents (Scheme 1).5a,6-8 Our previous studies revealed
that the reactions of ethyl isocyanoacetate with DVKs 1 under
basic conditions can lead to very different products, depending
on the nature of the functional group at the 2-position of 1.7 For
instance, pyrrolizidines and fused oxazolines were synthesized in
a single step from DVKs 1 bearing 2-cyano and 2-acyl groups,
respectively, through different domino reactions (Scheme 1).7
In organic synthesis, the one-pot tandem strategy is used to
improve the efficiency of a chemical reaction whereby multiple
bonds are formed in a single reaction without the need to isolate
intermediates.5-7,9 Although several methods have been devel-
oped for the construction of C2-tethered heterocyclic pairs,1c,2,3
to our knowledge, no report has appeared on the synthesis of C2-
tethered heterocyclic pairs from simple acyclic precursors in a
single step. The present experiments focused on DVKs 1 (bearing
a N-(alkyl or aryl)-carbonyl group at the 2-position)8 showed
Scheme 1. Domino Reactions of DVKs 1 with Nitroalkanes
or Ethyl Isocyanoacetate
that the C2-tethered pyrrole/oxazole pair 2a could be obtained in
37% isolated yield from the reaction of DVK 1a (1.0 mmol) with
ethyl isocyanoacetate (2.0 mmol) in acetonitrile (5 mL) in the
presence of DBU (0.5 mmol; DBU = 1,8-diazabicyclo-
[5.4.0]undec-7-ene) at room temperature for 24 h (Table 1,
entry 2). The yield of 2a was raised to 84% with shorter reaction
time (5 h) by increasing the temperature to 80 °C (Table 1, entry
1).10 In comparison, t-BuOK and NaOH were less effective
catalysts than DBU (Table 1, entries 5 and 6). Other solvents,
Received: December 3, 2010
Published: January 18, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja110864t J. Am. Chem. Soc. 2011, 133, 1775–1777
|

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Table 1. Optimization of Reaction Conditions
Scheme 2
entry
base (equiv)
solvent
T (°C)
t (h)
yield (%)
1
2
3
4
5
6
7
8
DBU (0.5)
DBU (0.5)
DBU (1.0)
DBU (0.3)
t-BuOK (0.5)
NaOH (0.5)
DBU (0.5)
DBU (0.5)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
80
5
24
6
84
37a
79
25
25
80
5
53b
80
5
57
80
5
17c
63
reflux
5
CH2Cl2
reflux
5
64
a 1a was recovered in 52% yield. b 1a was recovered in 29% yield. c 1a was
recovered in 20% yield.
the desired pyrrole/oxazole pairs 2j-l were synthesized in good
yields from substrates 1j-l bearing an alkyl R1 group (entries
9-12).11
Table 2. Synthesis of C2-Tethered Pyrrole/Oxazole Pairs 2
It was found that the reaction of 1m bearing a bulky tert-butyl
R group with ethyl isocyanoacetate under optimal conditions for
7 h gave bicyclic aminal 3 in 61% yield with high diastereoselec-
tivity (Scheme 2, A).10 In addition, the reaction of 1n bearing a
cyclohexanyl R group with ethyl isocyanoacetate gave a compli-
cated mixture. In a separate experiment, highly substituted
cyclohexanone 4c was obtained in 31% yield by quenching the
reaction of 1c at room temperature for 1 h with saturated
aqueous NH4Cl solution (Scheme 2, B).10,12 It was proven that
the reaction of 4c with ethyl isocyanoacetate (1.2 equiv) in the
presence of DBU (50 mol %) in acetonitrile at room temperature
for 16 h led to 2c in 92% yield. These results indicate that
cyclohexanone 4 is a key intermediate in the synthesis of C2-
tethered pyrrole/oxazole pairs 2.
entry
1
R
R1
time (h)
2
yield (%)
1
a
b
c
d
e
f
4-ClPh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
3-MePh
Ph
5.0
5.0
a
b
c
d
e
f
84
78
89 a
74
65
72
76
67
72
67 b
60
50
2
Ph
3
4-MeOPh
3,4-O2CH2Ph
2-Furyl
4-BrPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
Ph
24.0
10.0
9.0
4
Taken together, the previous6,7,12-14 and present results
(Tables 1, 2 and Scheme 2), a plausible mechanism for the
formation of pyrrole/oxazole pairs 2 is proposed in Scheme 3.
The overall process may involve: (1) the diastereoselective double
Michael addition ([5 þ 1] annulation) of ethyl isocyanoacetate
to 1,5-dielectrophile 1 under basic conditions to provide cyclo-
hexanone intermediate 4 (Scheme 2, B);6,12 (2) intramolecular
elimination of a thiol group (4fI)6 followed by elimination of a
thiirane molecule from I leading to the thione intermediate II;13
(3) the preferential cleavage of the C-C bond of II upon
nucleophilic attack by ethyl isocyanoacetate anion (IIfIII)14
followed by double isocyanide cyclization, generating a pyrrole
(IIIfIV) and a oxazole ring (IVfV) respectively, to afford C2-
tethered pyrrole/oxazole pairs 2. The mechanism indicates that
insertion of an additional functional group in the molecule of
divinyl ketone opens broad possibility for heterocyclization using
isocyanoacetates and analogues.7,15
5
6
6.0
7
g
h
i
6.0
g
h
I
8
5.0
9
4-ClPh
Me
6.0
10
11
12
j
5.0
j
k
Bn
5.0
k
l
l
4- NO2Ph
Bn
2.0
a 1.0 equiv DBU was used. b rt.
such as THF and dichloromethane, gave relatively lower yields of
2a (Table 1, entries 7 and 8).
Under optimal conditions as in Table 1, entry 1, a series of
experiments were performed, and the results are summarized in
Table 2. It was proven that the reactions of ethyl isocyanoacetate
with DVKs 1 having phenyl (entry 2), electron-rich (entries 3
and 4), electron-deficient (entries 1 and 7-9), aromatic and
hetero aromatic R groups (entry 5) can afford the corresponding
C2-tethered pyrrole/oxazole pairs 2a-i in good to high yields
with high diastereoselectivity where R1 = 4-MePh (entries 1-6),
3-MePh (entry 7), Ph (entry 8) or 4-ClPh (entry 9). Similarly,
In conclusion, we have developed a new strategy for the syn-
thesis of C2-tethered pyrrole/oxazole pairs in good to high yields
under mild reaction conditions from the easily available acyclic
substrates. This domino process comprises two [3 þ 2] cycload-
ditions and allows the construction of two different heterocycles
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dx.doi.org/10.1021/ja110864t |J. Am. Chem. Soc. 2011, 133, 1775–1777

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Scheme 3. Proposed Mechanism for the Formation of 2
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(11) In the reaction of 1l, a byproduct, formed via intramolecular
aza-anti Michael addition was obtained in 24% yield (see ref 8).
in a single step. This new strategy involves the formation of four
C-C and one C-O bonds in a regio- and diastereoselective
manner with the chemoselective fragmentation of the cyclohex-
anone intermediate as the key. Further studies are in progress.
’ ASSOCIATED CONTENT
(12) (a) Zhang, D.; Xu, X.; Tan, J.; Liu, Q. Synlett 2010, 917.
(b) Silvanus, A. C.; Groombridge, B. J.; Andrews, B. I.; Kociok-Kohn, G.;
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S
Supporting Information. Experimental details and spec-
b
tral data for 2a-l and3 and a cif file of crystallographic data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
(15) For a review on the synthetic utility of isocyanoacetate deriva-
tives, see: Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A; Nenajdenko,
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’ AUTHOR INFORMATION
Corresponding Author
xuxx677@nenu.edu.cn; liuqun@nenu.edu.cn
’ ACKNOWLEDGMENT
Financial supports of this research provided by the NNSFC
(21072027), the Young Scientific Research Foundation of Jilin
Province (20090149), and the Fundamental Research Funds for
the Central Universities (09 QNJJ017) are greatly acknowledged.
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