Highly substituted pyrroles by a gold(I)-catalyzed tandem reaction of 1-(1-alkynyl)cyclopropyl oxime ethers with nucleophiles

Article abstract of DOI:10.1055/s-0031-1290978

A gold(I)-catalyzed tandem reaction of 1-(1-alkynyl) cyclopropyl oxime ethers with nucleophiles under mild conditions has been developed, which provides a facile access to highly substituted pyrroles in moderate to excellent yields. Georg Thieme Verlag St

Full text of DOI:10.1055/s-0031-1290978

LETTER
▌1389
letter
Highly Substituted Pyrroles by a Gold(I)-Catalyzed Tandem Reaction of
1-(1-Alkynyl)cyclopropyl Oxime Ethers with Nucleophiles
Synthesis of Highly Substituted Pyrroles
Yanqing Zhang,a Junliang Zhang*a,b
a
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, 3663 North,
Zhongshan Road, Shanghai 200062, P. R. of China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Road, Shanghai 200032, P. R. of China
Fax +86(21)62235039; E-mail: jlzhang@chem.ecnu.edu.cn
Received: 13.02.2012; Accepted after revision: 20.03.2012
roles by
heterocyclization.
a
metal-catalyzed tandem addition–
Abstract: A gold(I)-catalyzed tandem reaction of 1-(1-alkynyl) cy-
clopropyl oxime ethers with nucleophiles under mild conditions has
been developed, which provides a facile access to highly substituted
pyrroles in moderate to excellent yields.
Table 1 Optimization Studies on Cycloaddition of 1a and 2aa
Ph
O
Ph
Ph
Key words: pyrroles, gold, nucleophiles, cyclization, cyclopropane
Ph
catalyst (5 mol%)
Ph
+
Ph
OH
solvent
2a
Me
MeO
Me
Pyrroles are one of the most popular core units in various
natural products,1 materials science,2 and medicinal
agents.3 For example, Lipitor, as an (HMG-CoA) reduc-
tase inhibitor used to lower LDL cholesterol levels, is the
best-selling drug in past several years, which contains the
pyrrole as the core structural unit. Meanwhile, N-alkoxy-
pyrroles could be used as insecticides in crop protecting.4
As a consequence, these properties continue to stimulate
interest in the development of new synthetic methods for
pyrroles.5 The Hantzsch procedure,6,7 Paal–Knorr synthe-
sis,6,8 and Knorr synthesis6,9 have been widely used as
classic approaches but with drawbacks such as multistep
synthesis, limited scope, and inaccessible starting materi-
als. Recently, more and more attention has been paid on
metal-catalyzed reactions,10 because of their high effi-
ciency and mild conditions. For example, palladium,11
copper,12 gold,13 silver,14 ruthenium,15 and iron16 were
shown to be active catalysts in the pyrrole ring formation
reactions.
N
N
OMe
3a
(E)-1a
Entry Catalyst
Solvent
Temp Time Yield
(°C)
(h)
(%)b
1
2c
3
4
5
6
7
8
9
PPh3AuCl/AgOTf
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
25
80
25
25
40
80
80
25
40
25
25
25
50
25
25
25
3
20
16
11
14
10.5
29
9
49 (78)
63 (74)
22 (26)
38
PPh3AuCl/AgOMs
PPh3AuCl/AgSbF6
AuCl3/AgOTf
AgOTf
33
Yb(OTf)3
trace
trace
52
Sc(OTf)3
(L1)AuCl/AgOTf
(L2)AuCl/AgOTf
(L3)AuCl/AgOTf
(L4)AuCl/AgOTf
PCy3AuCl/AgOTf
PCy3AuCl/AgOTf
PCy3AuCl/AgOTf
PCy3AuCl/AgOTf
PCy3AuCl/AgOTf
7.5
10.5
27
4.5
14
10
10
10
70
On the other hand, gold-catalyzed transformations of
strained small rings such as cyclopropanes and expoxides
have been nicely summarized by Hashmi17,18 and Shi,19
respectively. Recently, 1-(1-alkynyl)cyclopropyl ketones
have been developed as readily available precursors for
the synthesis of highly substituted furans under the catal-
ysis of transition metals.20 During the course of studying
the chemistry of 1-(1-alkynyl)cyclopropyl ketones, we
envisaged that 1-(1-alkynyl)cyclopropyl oxime ethers,
easily prepared from the corresponding ketones, might re-
act with nucleophiles, furnishing highly substituted pyr-
10
82
11
12
13
14
15
16
50
87
42
CHCl3
DMF
44
n.r.
THF
n.r.
a All reactions were carried out using 1a (0.3 mmol), 2a (0.6 mmol),
and catalyst (5 mol%) in toluene (3 mL).
b Yields in parentheses are determined by 1H NMR spectroscopy,
which based on CH2Br2 as the internal standard.
SYNLETT 2012, 23, 1389–1393
Advanced online publication: 14.05.2012
c The reactions in parentheses were carried out at r.t. for 23 h.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290978; Art ID: ST-2012-W0129-L
© Georg Thieme Verlag Stuttgart · New York

1390
Y. Zhang, J. Zhang
LETTER
This hypothesis was initially tested by reacting (E)-1-[2- the catalysis of AuCl3/AgOTf (Table 1, entry 4). AgOTf,
phenyl-1-(phenylethynyl)cyclopropyl]ethanone O-meth- Yb(OTf)3, and Sc(OTf)3 are not effective even at higher
yl oxime [(E)-1a] with benzyl alcohol (2a) in the presence temperature (Table 1, entries 5–7). Several phosphine-
of PPh3AuCl/AgOTf. The reaction afforded an air-sensi- and phosphite-derived cationic gold complexes were then
tive product 3a in 49% isolated yield, which inspired us to investigated (Table 1, entries 8–12, Figure 1). Gratifying-
explore better conditions to improve the yield. We tested ly, 87% yield was obtained when the reaction was carried
other silver salts such as AgSbF6, and AgOMs. The latter out in toluene in the presence of 5 mmol% of
led to 63% isolated yield but a higher temperature was re- PCy3AuCl/AgOTf at room temperature (Table 1, entry
quired (Table 1, entries 1–3). Only 38% yield of 3a21 12). The attempt to improve the yield was failed by
could be isolated when the reaction was carried out under
Table 2 Reaction Scope of (E)-1 with NuH 2a
Entry 1
2
Time
(h)
3
Isolated
yield (%)
1
2
3
4
5
6
7
1b R2 = 1-naphthyl
1c R2 = 4-MeOC6H4
1d R2 = 4-MeC6H4
BnOH (2a)
2a
2a
10
3b R2 = 1-naphthyl
3c R2 = 4-MeOC6H4
3d R2 = 4-MeC6H4
93
72
74
Ph
OBn
Ph
4.5
9.5
12
11
22.5
13.5
R2
1e R2 = 1-cyclohexenyl 2a
3e R2 = 1-cyclohexenyl 72
Me
MeO
1f R2 = n-Bu
2a
2a
2a
3f R2 = n-Bu
72
63
49
R2
Me
1g R2 = C2H4OAc
1h R2 = c-Pr
3g R2 = C2H4OAc
3h R2 = c-Pr
N
N
OMe
R3
R3
OBn
8
9
1i R3 = 4-MeOC6H4
2a
2a
2a
2a
11
9.5
12
7
3i R3 = 4-MeOC6H4
3j R3 = 4-MeC6H4
3k R3 = n-Bu
56
74
82
78
Ph 1j R3 = 4-MeC6H4
1k R3 = n-Bu
10b
11
Me
MeO
Ph
Me
1l R3 = H
3l R3 = H
N
N
OMe
Bn
O
12b
1m
2a
13
3m
68
N
Ph
MeO
N
Ph
OMe
13
14
15
1a
1a
1a
MeOH (2b)
i-PrOH (2c)
t-BuOH (2d)
12.5
29.5
7
3n Nu = MeO
3o Nu = i-PrO
3p Nu = t-BuO
67
88
71
Ph
Ph
Nu
Nu
1a
1a
3q Nu =
16
17
(E)-but-2-en-1-ol (2e)13.5
furfuryl alcohol (2f) 12.5
76
62
Ph
Ph
Me
Me
N
N
O
OMe
OMe
3r Nu =
O
O
18
19
20
1a
1a
1a
PhOH (2g)
AcOH (2h)
PhNH2 (2i)
7.5
7.5
28
3s Nu = PhO
3t Nu = AcO
3u Nu = PhNH
70
80
99
a All reactions were carried out using 1 (0.3 mmol), 2a (0.6 mmol), and PCy3AuCl/AgOTf (5 mol%) in toluene (3 mL) at r.t. unless otherwise
specified.
b 80 °C.
c 60 °C.
Synlett 2012, 23, 1389–1393
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Highly Substituted Pyrroles
1391
F
Ar
F
Ph
O
t-Bu
Ar
O
PCy3AuOTf
(5 mol%)
F
P
P
P
Ph
+
Ph
OH
3
t-Bu
toluene, 10 h
90%
3
Ph
Me
2a
F
Me
MeO
F
N
L1
L3
L2
L4
N
OMe
ent-3j
97% ee
ent-(E)-1j
Ar = 4-MeC6H4
97% ee
P
OMe
CF3
3
3
Equation 1
Figure 1
The mechanism that accounts for this transformation is
depicted in Scheme 1. Under the optimized conditions, the
gold complex coordinates with the substrates 1, leading to
heterocyclization and thus giving the oxocarbenium inter-
mediate IA.20 This would make the cyclopropane reactive
enough to be attacked by the nucleophiles via an SN2 path-
way and substituted gold–pyrrole species IB would be
formed via route A. Subsequent protonation of IB would
lead to the final product 3 and regenerate the gold(I) spe-
cies. An alternative reaction pathway via the carbocation
intermediate IC (route B) can be excluded by the result of
Equation 1.
screening various solvents such as DCE, chloroform, po-
lar DMF, and THF (Table 1, entries 13–16).
With the optimal conditions in hand, the scope and limita-
tion of this transformation were next explored by variation
of the 1-(1-alkynyl)cyclopropyl oxime ether component.
Firstly, the substituent effect of R2 was studied by intro-
duction of different alkynyl groups. For example, when
the R2 substituent was a naphthyl group, the pyrrole 3b
was obtained in 93% yield (Table 2, entry 1), whereas,
only modest yield was obtained when R2 was a cyclopro-
pyl group (Table 1, entry 7). Variously substituted aryl
and functionalized alkyl groups can be well introduced to
the pyrroles (Table 2, entries 2–6). The substituent effect
of R3 was next investigated, and it was found that both ar-
omatic and aliphatic R3 was compatible, affording the de-
sired products in 56–82% yields (Table 2, entries 8–10).
The reaction of 1l with R3 = H also proceeded smoothly to
give the 3l in 78% yield (Table 2, entry 11). Finally, a
fused bicyclic pyrrole 3m could also be easily synthesized
from the corresponding substrate 1m and benzyl alcohol
(2a) at 80 °C in 68% yield (Table 2, entry 12). After study-
ing the scope of oxime ethers (E)-1, we then turned our at-
tention on examination of the reaction scope by variation
of nucleophile component 2. Not only methanol (2b), sec-
ondary isopropanol (2c), but also bulky tert-butyl alcohol
(2d) were applicable to this transformation, yielding pyr-
roles 3n–p in 67–88% yields, but the last reaction required
higher temperature (Table 2, entries 13–15). (E)-But-2-
en-1-ol (2e) and furfuryl alcohol (2f) were also compati-
ble, affording 3q and 3r in 76% and 62% yields, respec-
tively (Table 2, entries 16 and 17). The reaction of 1a with
phenol (2g) also proceeded smoothly to afford the desired
product 3s in 70% yield (Table 2, entry 18). Finally, it is
noteworthy that both acetic acid (2h) and aniline (2i) are
good nucleophiles in this transformation, furnishing the
corresponding ester 3t and amine 3u in high yields (Table
2, entries 19 and 20), indicating there is a general substrate
scope.
3
1
Au(I)
H
R3
R3
R3
NuH
Nu
[Au]
R2
[Au]
R2
[Au]
R1
R1
route B
R2
1
R
N
N
N
OMe
IA
OMe
OMe
IB
IC
route A
H
Scheme 1 Plausible mechanism for the tandem reaction
In summary, we have developed a novel, efficient, and
general method to synthesize highly substituted pyrroles
from readily 1-(1-alkynyl)cyclopropyl oxime ethers with
nucleophiles by a gold-catalyzed tandem regioselective
addition and heterocyclization under mild conditions. We
also found that there was no loss of the chirality informa-
tion during the reaction. A plausible mechanism was also
brought forward. Further studies including the mechanism
and synthetic application of this methodology in our lab-
oratory are under way and will be reported in due course.
After that, the asymmetric version of this gold(I)-cata-
lyzed tandem reaction was carried out. A 97% ee of ent-
(E)-1j reacting with benzyl alcohol (2a) under the opti-
mized reaction conditions afforded the desired cycload-
duct ent-3j in 90% yield with 97% ee. The optical activity
was maintained, and this result indicated that the reaction
underwent via a SN2 reaction pathway (Equation 1).
Acknowledgment
We are grateful to National Natural Science Foundation of China
(20972054), Ministry of Education of China, 973 program
(2009CB825300) for financial support. This research is also sup-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1389–1393

1392
Y. Zhang, J. Zhang
LETTER
ported by the Program for Professor of Special Appointment
(Eastern Scholar) at Shanghai Institutions of Higher Learning. This
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(21) General Procedure for the Gold(I)-Catalyzed Tandem
Reaction of 1-(1-Alkynyl)cyclopropyl Oxime Ethers with
Nucleophiles
Synlett 2012, 23, 1389–1393
© Georg Thieme Verlag Stuttgart · New York

LETTER
A solution of PCy3AuOTf (generated from 1:1 mol ratio of
Synthesis of Highly Substituted Pyrroles
1393
(s, 1 H), 4.42–4.34 (m, 2 H), 4.20 (d, J = 12.4 Hz, 1 H), 3.51
(s, 3 H), 2.92–2.86 (m, 1 H), 2.66–2.60 (m, 1 H), 1.80 (s, 3
H). 13C NMR (100 MHz, CDCl3): δ = 142.22, 138.69,
131.57, 128.44, 128.20, 128.13, 127.54, 127.40, 127.28,
126.88, 125.77, 125.68, 125.60, 124.06, 112.25, 104.78,
82.63, 70.43, 65.07, 35.59, 8.08 ppm. IR (neat): ν = 1602,
1517, 1493, 1452, 1351, 1263, 1238, 1218, 1068, 1026, 971,
910 cm–1. MS (EI): m/z (%): 397 (15.33) [M]+, 91 (100).
HRMS: m/z calcd for C27H27NO2: 397.2042; found:
397.2045.
PCy3AuCl/AgOTf, 3 mL, 0.005 M in toluene, 5 mol%) was
added to a dry Schlenk tube under Ar. Oxime ether 1a (0.20
mmol, 57.8 mg) and nucleophile 2a (0.4 mmol, 43.3 mg)
were added to the mixture. The resulting mixture was stirred
at r.t. unless otherwise specified until the reactions were
complete, as determined by TLC analysis. The residue was
purified by flash column chromatography on silica gel
(hexanes–EtOAc = 30:1) to afford the pure product 3a (0.17
mmol, 68.8 mg) in 87% yield; oil. 1H NMR (400 MHz,
CDCl3): δ = 7.60–7.48 (m, 2 H), 7.30–7.04 (m, 13 H), 5.96
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1389–1393

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