Silver(I)-catalyzed ring-contractive rearrangement: A new entry to 5-alkylidene-2-cyclopentenones

Article abstract of DOI:10.1021/ol503176y

A novel silver(I)-catalyzed ring-contractive rearrangement of 5-substituted 6-diazo-2-cyclohexenones has been developed, providing a new and efficient access to 5-alkylidene-2-cyclopentenones. The AgOTf-catalyzed reaction proceeds through metal-carbenoid formation followed by endocyclic allyl [1,2] migration with excellent stereoselectivity and broad substrate scope.

Full text of DOI:10.1021/ol503176y

Letter
pubs.acs.org/OrgLett
Silver(I)-Catalyzed Ring-Contractive Rearrangement: A New Entry
to 5‑Alkylidene-2-cyclopentenones
Liang Zhao,†,§ Jinlian Wang,†,§ Hongyan Zheng,† Yun Li,† Ke Yang,† Bin Cheng,† Xiaojie Jin,†
Xiaojun Yao,† and Hongbin Zhai*,†,‡
†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A novel silver(I)-catalyzed ring-contractive
rearrangement of 5-substituted 6-diazo-2-cyclohexenones
has been developed, providing a new and efficient access to
5-alkylidene-2-cyclopentenones. The AgOTf-catalyzed reaction
proceeds through metal−carbenoid formation followed by
endocyclic allyl [1,2] migration with excellent stereoselectivity and broad substrate scope.
ing contraction reactions have been extensively used to build
cyclopentyl-containing molecules,1 such as pinacol rearrange-
pharmaceuticals. Although there are known synthetic strategies
for alkylidene-2-cyclopentenone units including Nazarov cycliza-
tion,9 sulfoxide elimination followed by retro-Diels−Alder
reaction,10 condensation/dehydration elimination,11 and so
on,2c,12 all these methods involve multistep operations and have
limitations in terms of atom economy. Thus, there is an urgent
demand in developing efficient, versatile, and practical protocols
for the synthesis of 5-alkylidene-2-cyclopentenones. Herein,
we wish to report an unprecedented Ag(I)-catalyzed13 ring-
contractive rearrangement, constituting a concise approach to
such useful structures starting from readily available 5-substituted
6-diazo-2-cyclohexenones.
R
ment,1b−d Favorskii rearrangement,1e oxidative rearrangement,1f,g
photochemical rearrangement,1h and Wolff rearrangement.2
Diazo-cycloketones 1 give the corresponding ring contraction
products through intermediary ketene B (eq 1, Scheme 1)3 under
Scheme 1. Rearrangement of α-Diazoketones and the New
Approach to 5-Alkylidene-2-cyclopentenones
The investigations were commenced with irradiation of 5a14 in
MeOH under an argon atmosphere with a high-pressure mercury
lamp (500 W; λ ≥ 300 nm) at room temperature (Scheme 2).
Scheme 2. Wolff Rearrangement and Silver(I)-Catalyzed
Ring-Contractive Rearrangement of 5a
The classic Wolff rearrangement turned out to be the pre-
dominant reaction pathway, and the methyl ester 7a was obtained
as the major product (47%) along with the minor products such
as 6a (2%) and (Z)-6a (5%). In contrast, treatment of 5a with
AgOTf in MeOH induced a reaction pathway different from
Wolff rearrangement,15 through which alkylidene-2-cyclopente-
none 6a was exclusively produced (81%).
The reaction conditions were optimized for the rearrangement
with 5a as the substrate. Solvents for the reaction were first
examined (entries 1−4, Table 1). The reaction in MeCN,
thermal, photolytical, or transition metal-catalyzed conditions.
The migratory aptitude of a certain bond depends on its
environment,4 as demonstrated in an iridium-containing
compound (3, eq 2).5 However, transition metal-catalyzed/
promoted ring contraction reactions of unsaturated diazocycloe-
nones have not been reported.6 For instance, migration of the
C4−C5 bond in silver-carbenoid E [generated from 5 in the
presence of Ag(I)] would afford 5-alkylidene-2-cyclopentenone 6
(eq 3). Furthermore, molecules witha cyclopentenone (especially
alkylidene-2-cyclopentenone) motif, such as Δ7-PGA1, punaglandin
4,7 and leucodin,8 are important in natural products and
Received: October 31, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503176y | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. Optimization for the Reaction Conditions
Table 2. 6-Diazo-2-cyclohexenones of Different Substitution
Patterns and Their Reaction Behavior
a
b
entry
catalyst
solvent
temp (°C)
time
12 h
yield (%)
1
2
3
4
5
6
7
8
AgOTf
AgOTf
AgOTf
AgOTf
Ag2O
MeCN
Et2O
rt
0
85
73
69
86
85
82
78
84
89
92
14
trace
40 min
1 h
PhH
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
10 min
12 h
rt
Ag2CO3
PhCO2Ag
AgBF4
rt
24 h
rt
10 h
0
10 min
10 min
30 min
30 min
30 min
12 h
c
9
AgOTf
AgOTf
In(OTf)3
TMSOTf
TsOH
0
c
c
c
c
,d
10
11
12
13
−10
−10
−10
−10
e
NR
a
Reaction conditions: 5a (0.5 mmol), catalyst (10 mol %), solvent
b
c
d
(10 mL). Isolated yield. Catalyst (5 mol %). Less than 2% of
(Z)-6a was isolated. NR = no reaction.
e
a
Reaction conditions: 5 (0.5 mmol), AgOTf (5 mol %), solvent
b
(10 mL), −10 °C, 3 h. Isolated yield.
an aprotic solvent, gave the rearrangement product in a yield
comparable to that observed in CH2Cl2. A moderate yield was
obtained when the reaction was performed in diethyl ether or
benzene. With AgOTf as the catalyst and CH2Cl2 as the solvent,
the rearrangement of 5a went to completion in 10 min at 0 °C
to furnish 6a as the single product in 86% yield (entry 4).
After switching the catalyst from AgOTf to Ag2O, Ag2CO3 or
PhCO2Ag (entries 5−7), the reaction proceeded smoothly at
room temperature and afforded 6a in 78−85% yield, although
longer reaction time was required (10−24 h). AgBF4 (entry 8)
performed with similar catalytic efficiency to AgOTf. On the
basis of the above findings, AgOTf seemed to be the optimal
catalyst for this ring-contractive rearrangement. Moreover,
decreasing the catalyst loading to 5 mol % (entries 9, 10) or
lowering the reaction temperature to −10 °C (entry 10) resulted
in a slightly improved yield of 6a. With Lewis acids and Brønsted
acid as the catalysts (entries 11−13), however, less or even none
of 6a was isolated.
rearrangement proceeded as anticipated to form 6o−u in
76−97% yields. The fully substituted substrates 5v and 5w
exhibited excellent reactivity to produce cyclopentenoes with
multiple substituents. Note that the (E)-configuration was
observed for the exocyclic carbon−carbon double bond in the
major product in every case.16
Since the stereochemistry of C5 was removed during the ring-
contractive rearrangement, the enantiomerically pure (4S,5R)-5x
containing two adjacent stereochemical centers was synthesized
and then treated with AgOTf under the standard reaction
conditions (Scheme 3). The product 6x was isolated in 75% yield
Scheme 3. Ag(I)-Catalyzed Rearrangement of (4S,5R)-5x
Subsequently, we examined the rearrangement with some
other substrates. It was found that the presence of a substituent
at C5 was critical for the above rearrangement, as evidenced by
the fact that treatment of 6-diazo-2-cyclohexenones 5b−e of
different substitution patterns with AgOTf in CH2Cl2 afforded
phenols 6b−e as the major products (Table 2). The generation
of phenol products in the latter case was assumed to result
from the migration of a hydrogen atom at C5 rather than the
endocyclic allylic moiety to the adjacent C6 atom.
To explore the scope of the current ring-contractive
rearrangement, a series of substrates were scrutinized with the
optimized reaction conditions (Table 3). Ketodiazo compounds
5f−n, each bearing only one alkyl (methyl, cyclohexyl, allyl,
or benzyl), vinyl, or aryl (phenyl or naphthyl) group (at C5),
underwent the rearrangement to give the corresponding
5-alkylidene-2-cyclopentenones 6f−n in 67−82% yields. For
the phenyl-containing substrates 5k−m, the order of the yields
[6m (p-MeO-C6H4−) > 6k (C6H5−) > 6l (p-Cl-C6H4−)] was
consistent with the proposed carbocation mechanism. As for the
2,5-disubstituted and 2,3,5- and 3,5,5-trisubstituted ketodiazo
compounds 5o−u (featuring various types of substituents), the
with 99% ee, demonstrating that the rearrangement presumably
occurred with retention of the stereochemistry at the migratory
center, i.e., no racemization took place at C4.17 Therefore,
the current protocol provides an efficient access to chiral
5-alkylidene-2-cyclopentenoes.
A plausible mechanism for the ring-contractive rearrangement
is proposed in Scheme 4. The reaction is presumably initiated
by loss of nitrogen gas from 5 in the presence of Ag(I) forming
silver−carbenoid E.18 When R2 ≠ H (path a), intermediate E
undergoes endocyclic allyl migration to produce carbocation F,
which delivers 5-alkylidene-2-cyclopentenone 6 with con-
comitant regeneration of the active Ag(I) catalyst. On the
other hand, when R2 = H (path b), one of the hydrogen atoms at
C5 migrates to afford carbocation G, and extrusion of Ag(I)
provides phenol 8 via the dienone H intermediate.
In conclusion, we have developed a novel method for the one-
step synthesis of 5-alkylidene-2-cyclopentenones, an important
B
dx.doi.org/10.1021/ol503176y | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Ag(I)-Catalyzed Rearrangement of Substrates 5
Scheme 4. Proposed Mechanism
generality, and practicality, this protocol might find broad
applications in organic synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
Procedural, spectral, and crystallographic data and computa-
tional details. This material is available free of charge via the
Internet at http://pubs.acs.org.
DEDICATION
■
Dedicated to the memory of Professor Puzhu Cong. Professor
Puzhu Cong, who passed away on Nov. 19, 2014.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhaih@lzu.edu.cn.
Author Contributions
§L.Z. and J.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China (973
Program: 2010CB833200), NSFC (21172100; 21272105;
21290183), Program for Changjiang Scholars and Innovative
Research Team in University (PCSIRT: IRT1138), FRFCU
(lzujbky-2013-ct02), and “111” Program of MOE for financial
support. We are grateful to Professor Fayang Qiu of Guangzhou
Institute of Biomedicine and Health (Chinese Academy of
Sciences), Wei Liao and Professor Zhixiang Yu of Peking
University, and Jixing Peng of Ocean University of China for
enlightening discussions.
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D
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