Synthesis of furans and pyrroles via migratory and double migratory cycloisomerization reactions of homopropargylic aldehydes and imines

Article abstract of DOI:10.1016/j.tetlet.2015.01.006

A novel gold-catalyzed divergent synthesis of furans and pyrroles employing readily available homopropargylic aldehydes and imines has been developed. The regiochemical outcome of this reaction is dependent on the substituent on the terminal alkyne of sub

Full text of DOI:10.1016/j.tetlet.2015.01.006

Accepted Manuscript
Synthesis of furans and pyrroles via migratory and double migratory cycloiso-
merization reactions of homopropargylic aldehydes and imines
Roohollah Kazem Shiroodi, Claudia I. Rivera Vera, Alexander S. Dudnik,
Vladimir Gevorgyan
PII:
S0040-4039(15)00009-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.01.006
TETL 45675
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 November 2014
18 December 2014
2 January 2015
Please cite this article as: Shiroodi, R.K., Rivera Vera, C.I., Dudnik, A.S., Gevorgyan, V., Synthesis of furans and
pyrroles via migratory and double migratory cycloisomerization reactions of homopropargylic aldehydes and
imines, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.01.006
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Synthesis of furans and pyrroles via
double
Leave this area blank for abstract info.
migratory and
cycloisomerization
migratory
of
reactions
homopropargylic aldehydes and imines
Roohollah Kazem Shiroodi, Claudia I. Rivera Vera, Alexander S. Dudnik, Vladimir Gevorgyan

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of furans and pyrroles via migratory and double migratory
cycloisomerization reactions of homopropargylic aldehydes and imines
Roohollah Kazem Shiroodi, Claudia I. Rivera Vera, Alexander S. Dudnik, Vladimir Gevorgyan∗
Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor Street, Chicago, IL 60607-7061, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
A novel gold-catalyzed divergent sysnthesis of furans and pyrroles employing readily available
homopropargylic aldehydes and imines have been developed. The regiochemical outcome of this
reaction is dependent on the substituent on the terminal alkyne of substrate. Thus, substrates
possessing alkyl and aryl substituent at the alkyne moiety produce 2,3,5-substituted furans and
pyrroles via a migratory cycloisomerizaton reaction. Whereas, their silicon analogues are
capable to undergo a double migratory process leading to 2,3,4-substituted heterocycles.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Cycloisomerization
Heterocycles
Double migration
Silicon migration
Gold catalyst
Furans and pyrroles are highly important motifs exist in a
broad range of biologically active natural products1 and
drugs.2 They also have broad applications as synthetic
intermediates3 and are widely used in material science.4
Accordingly, a vast number of efficient methodologies toward
these important scaffolds have been developed.1a,5 Among
these methods, the transition metal-catalyzed migratory
cycloisomerization reaction is one of the powerful
approaches, which offers mild and selective assembly of
furans and pyrroles with a diverse substitution pattern.6
Scheme 1. Cycloisomerization of homopropargylic systems
involving a 1,2-migration
Readily available homopropargylic ketones and imines have
5a,6a
been employed in migratory cascade reactions
giving
access to a variety of heterocycles (Scheme 1). For instance,
Kirsch reported7 a platinum-catalyzed cascade reaction of 1
toward 3(2H)-furanones and 3-pyrrolones 2 proceeding via a
pinacol-type 1,2-alkyl migration8 (eq. 1). Moreover, Tang and
Shi reported synthesis of densely-substituted pyrroles 4 from
the rhodium-catalyzed reaction of propargylic imines 3, where
one of the substituents of the heterocyclic core is formed via a
1,2-alkyl migration from the adjacent carbon (eq. 2).9
Recently, Zhang disclosed a divergent reactivity of ketones 5
in the presence of gold catalysts, where a selective 1,2-alkyl
migration to the neighboring carbon affords dihydrofurans 6
or furans 7 (eq. 3).10 Herein, we report a mild and
regiodivergent reaction of homopropargylic aldehydes and
imines
heterocycles 9 and 10. Thus, a gold-catalyzed migratory
cycloisomerization of
(R1= Alk/Ar) produces 2,3,5-
substituted heterocycles 9. Whereas, employment of silylated
8 (R1=SiR3) affords 2,3,4-substituted furans and pyrroles 10
8 in the presence of gold catalysts towards
8
proceeding via
reaction (eq. 4).
a double migratory cycloisomerization
———
∗ Corresponding author. Tel.: +1-312-355-3579; e-mail: vlad@uic.edu (V. Gevorgyan)

2
Tetrahedron
In continuation of our interest in development of
triphenylphosphine gold with hexafluoroantimonate counter
ion, was the best choice. Thus, we explored the scope of this
migratory cycloisomerization. Hence, aldehydes 8a-c
possessing phenyl, electron poor aryl, as well as alkyl
substituents at the terminal alkyne position underwent a five-
cycloisomerization reactions toward synthesis of densely
substituted heterocycles,11 we aimed at employing aldehyde 8
possessing a cyclopentyl group (Scheme 1, X=O, R1=Ph,
R2=R3= (CH2)4) in the transition metal-catalyzed migratory
cascade reaction. It was hypothesized that cyclization of the
to-six-membered
ring
expansion
during
the
latter in the presence of
a
metal catalyst would be
cycloisomerization process to afford furans 9a-c in good to
excellent yields (entry 1-3). Importantly, this reaction is not
limited to cyclic substrates only. Thus, by employing 2,2-
accompanied with a five-to-six-membered ring expansion12
and therefore producing the bicyclic fused furan 9 (Scheme 1,
X=O, R1=Ph, R2=R3= (CH2)4). Our optimization study
indicated that the use of the cationic gold catalyst,13 such as
diphenyl homopropargyl aldehyde 8d, a phenyl group
migration occurs smoothly to afford the triarylated furan 9d
Table 1. Scope of the migratory cycloisomerization reaction
Entry
1
Substrate
Product
Yield %a,b
8a
8b
9a
9b
90
2
3
80
71
8c
9c
4
5
6
8d
8e
8f
9d
9e
9f
90
56
58
7
8g
8h
9g
9h
74
72
8
9
8i
8j
9i
9j
70
71
10
a Isolated Yield.
b Reactions were performed in 0.5 mmol scale

3
in an excellent yield (entry 4). Expectedly,12 a phenyl migration
took place over the methyl- and benzyl group migration in
cycloisomerization of 8e and 8f to furnish 9e and 9f in moderate
yields (entries 5 and 6). Moreover, tetrasubstituted pyrrols can
also be synthesized using 2,2-substituted homopropargylic
imines under these reaction conditions. Therefore, the five-to-six-
membered ring expansion of imines 8g and 8h proceeded
smoothly during cyclization to provide pyrroles 9g and 9h in
good yields (entry 7 and 8). Expectedly, a phenyl group
migration occurred preferably over the methyl- and benzyl group
migrations to produce pyrroles 9i and 9j selectively in good
yields (entry 9 and 10).
furan 10n in a reasonable yield (entry 4). Notably, employment
of t-Bu- and Ph-protected imines 8o and 8p in this double
migratory process afforded silylated fused pyrroles 10o and 10p.
We propose the following plausible mechanism for these
cascade reactions (Scheme 2). First, the π-philic gold catalyst
activates substrate 8, which upon the following nucleophilic
attack of carbonyl at the activated alkyne moiety of A in a 5-
endo-dig fashion produces cyclic oxonium intermediate B. A 1,2-
R2 migration in the latter takes place to generate an allylic cation
C, which upon proton loss furnishes the key furyl gold
intermediate D. In the case of G=Alk or Ar, a protiodematallation
(α-protonation) of D takes place to produce 2,3,5-trisubstituted
furan 9. Whereas, the β-protonation of the furyl gold species D
occurs14 when G=SiR3 to furnish E, in which the positive charge
at the carbene carbon is stabilized by the silicon atom.18 A 1,2-
silicon- over hydrogen 1,2-migration in the latter takes place14 to
form F, which upon aromatization affords 2,3,4-trisusbstituted
furan 10.
Next, we hypothesized that employing homopropargylic
aldehyde 8 possessing a silicon terminus (Scheme 1, X=O,
R1=SiMe3, R2=R3= (CH2)4) would enable a 1,2-migration of
silicon group during the cyclization process.14 This 1,2-alkyl-/Si-
double migratory cascade15 would allow synthesis of 2,3,4-
trisubstituted fused furan 10. Indeed, it was found that cationic
(C6F5)3PAuSbF6 catalyst16 efficiently catalyzes this reaction
(Table 2).17 Thus, homopropargylic aldehyde 8k-m underwent a
Scheme 2. Proposed Mechanism for the migratory and double
migratory cascade reactions
facile
ring
expansion/trimethyl-,
triethyl-,
and
t-
butyldimethylsilyl migration-cycloisomerization cascade to
efficiently produce furans 10k-m, respectively. Aldehyde 8n
possessing a strained four-membered ring produced bicyclic
R1 R2
R1
R2
R3Si
H
8
G
O
O
10
[Au]+
Table 2. Scope of double migratory reaction
[Au]
R1
R2
R1 R2
[Au]+
G
R3Si
+
H
O
O
5-endo-dig
[Au]
F
A
Entry
1
Substrate
Product
Yield %a
1,2-Si migration
R1
R2
[Au]+
R3Si
[Au]
R1
R2
R1
R2
G
+
O
+
R3Si
86
B
O
O
H
H
E
1,2-R2 migration
R1
[Au]
G
+
+ H+
R2
G=SiR3
-protonation
2
3
91
89
β
O
H
C
R1
[Au]
α
-protonation
α
+ H+
R1
G= Alk/Ar
H+
R2
β
G
O
H
D
Alk/Ar
R2
O
9
In
summary,
two
complementary
gold-catalyzed
4
5
6
61
52b
74b
cycloisomerization reaction protocols of homopropargylic
aldehydes and imines toward differently substituted furans and
pyrrols have been developed. The regiochemical outcome
depends on the substituent at the terminal alkyne moiety of the
substrates. Thus, employment of homopropargylic aldehydes and
imines possessing alkyl and aryl substituent at the alkyne moiety
produces 2,3,5-substituted heterocycles via
a
migratory
cycloisomerizaton reaction. Whereas, substrates possessing a
silicon atom at the terminal position of alkyne undergo a double
migratory cascade to afford 2,3,4-substituted furans and pyrrols.19
Acknowledgments
We thank National Institutes of Health (GM-64444) for
financial support of this work.
a Isolated yield.
b NMR yield.

4
Tetrahedron
References and notes
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19. (a) General Procedure for the migratory cycloisomerization reaction of 8
to furans and pyrroles 9: An oven dried 1 mL V-shape vial equipped with
magnetic stir bar was loaded with commercially available
chloro(triphenylphosphine) gold (5 mol%, 12.5 mg) and silver
hexafluoroantimonate (5 mol%, 8.5 mg) in the glove box. 1,2-
dichloroethane (500 µL) was then added and reaction mixture was stirred
for 5 min at room temperature. Homopropargylic aldehydes or imines 8
(1.0 equiv, 0.5 mmol) as a solution in 1,2-dichloroethane (500 µL) was
added through cannula and the reaction mixture stirred at room
temperature until judged completed by GC/MS. The reaction mixture was
then passed through Celite®, solvents were removed under reduced
pressure, and the residue was purified by flash chromatography using
silica gel (Hex/EtOAc= 40/1) to give furans or pyrroles 9. Representative
example: 9e: 1H NMR (500 MHz, CDCl3) δ ppm 7.75 (d, J = 7.4 Hz, 4
H), 7.47 (t, J = 7.8 Hz, 2 H), 7.42 (t, J = 7.8 Hz, 2 H), 7.35-7.24 (m, 2H),
6.64 (s, 1 H), 2.36 (s, 3 H). 13C NMR (126 MHz, CDCl3) δ ppm 151.7,
148.2, 131.8, 130.8, 128.7, 128.6, 127.2, 126.7, 125.3, 123.7, 118.7,
110.8, 12.2.
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(b) General Procedure for the double migratory cycloisomerization
reaction of 8 to furans and pyrroles 10: An oven dried 20 mL round
buttom flask equipped with magnetic stir bar was loaded with
commercially
available
chloro[tris(2,3,4,5,6-pentafluorophenyl)-
phosphine] gold (5 mol%, , 19.1 mg) and silver hexafluoroantimonate (5
mol%, 8.5 mg) in the glove box. 1,2-dichloroethane (11 mL) was then
added and reaction mixture was stirred for 5 min at room temperature.
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reaction mixture stirred at room temperature until judged completed by
GC/MS. The reaction mixture was then passed through Celite®, solvents
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ppm 7.15 (s, 1 H), 2.64 - 2.55 (m, 2 H), 2.48 (tt, J = 1.8, 6.1 Hz, 2 H),
1.88 - 1.80 (m, 2 H), 1.79 - 1.72 (m, 2 H), 0.23 (s, 9 H). 13C NMR (126
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0.7.
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1) did not work for the double migratory process (Table 2). Thus, it was
found that the highly electrophilic (C6F5)3PAuSbF5 catalyst under more
diluted reaction conditions was the best.