Phosphine-Catalyzed Activation of Vinylcyclopropanes: Rearrangement of Vinylcyclopropylketones to Cycloheptenones

Article abstract of DOI:10.1002/anie.201800555

We report a phosphine-catalyzed activation of electron-deficient vinylcyclopropanes (VCPs) to generate an ambident C₅ synthon that is poised to undergo consecutive reactions. The utility of the activation is demonstrated in a phosphine-catalyzed rearrangement of vinylcyclopropylketones to cycloheptenones in good yields with a broad substrate scope. Mechanistic investigations support a stepwise process comprising homoconjugate addition, water-assisted proton transfer, and 7-endo-trig S_N2′ ring closure.

Full text of DOI:10.1002/anie.201800555

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Accepted Article
Title: Phosphine-Catalyzed Activation of Vinylcyclopropanes:
Rearrangement of Vinylcyclopropylketones to Cycloheptenones
Authors: Jun Wu, Yuhai Tang, Wen Wei, Yong Wu, Yang Li, Junjie
Zhang, Yuansuo Zheng, and Silong Xu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800555
Angew. Chem. 10.1002/ange.201800555
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Phosphine-Catalyzed Activation of Vinylcyclopropanes:
Rearrangement of Vinylcyclopropylketones to Cycloheptenones
Jun Wu, Yuhai Tang, Wen Wei, Yong Wu, Yang Li, Junjie Zhang, Yuansuo Zheng, and Silong Xu*
Abstract: We report a phosphine-catalyzed activation of electron-
deficient vinylcyclopropanes (VCPs) to generate an ambident C5
synthon that is poised to undergo consecutive reactions. The utility
C5 surrogate under phosphine catalysis.
VCPs[10] have drawn tremendous interests in contemporary
organic synthesis due to their unique and versatile reactivity.
Transition-metal coordination has played a prominent role on the
catalytic activation of VCPs,[10c] and complexes of rhodium,
palladium, nickel, etc. have facilitated a diverse range of [3 +
n][11] and [5 + n][12] cycloadditions. A thiyl radical-catalyzed
activation of VCPs has also been demonstrated to effect [3 + 2]
annulations.[13] To our knowledge, the organocatalytic Lewis
base-triggered activation of VCPs remains thus far unexplored.
Stemming from our interest in Lewis base catalysis,[14] we herein
report a phosphine-catalyzed activation of electron-deficient
VCPs and its utility in an efficient rearrangement of
vinylcyclopropylketones to cycloheptenones in good yields with
a broad scope (vide infra).
of the activation is demonstrated in
a phosphine-catalyzed
rearrangement of vinylcyclopropylketones to cycloheptenones in
good yields with a broad substrate scope. Mechanistic investigations
support a stepwise process comprising homoconjugate addition,
water-involved hydrogen transfer, and 7-endo-trig SN2’ ring closure.
Phosphine catalysis[1] has emerged as a reliable and powerful
platform for the construction of structurally diverse carbo- and
heterocycles. Lu’s [3 + 2],[2] Kwon’s [4 + 2][3] and Tong’s [4 + 1][4]
annulations represent seminal paradigms in the area, which
have inspired a myriad of cyclization reactions[5] including
asymmetric
variants.[6]
To
date,
phosphine-catalyzed
annulations typically rely on electron-deficient alkenes, alkynes,
allenes, and their derivatives (Scheme 1).[1e] These precursors
serve as effective C1 to C4 synthons for generating various cyclic
structures, especially five- and six-membered ring systems.
However, phosphine-catalyzed formation of seven- or eight-
membered rings[7] are comparatively underdeveloped, despite
their great potential in natural product synthesis.[8]
Scheme 2. Initial investigation.
We began by examining the reactivity of vinylcyclopropane
1a[15] with 1.0 equiv of PPh3 by NMR tracking (Scheme 2).
Significantly, the reaction in CDCl3 at 40 °C cleanly generated a
zwitterion 2a in 40% yield after 24 h. It is likely that 2a is derived
from the putative intermediate A via a double bond migration
(see Supporting Information (SI)). We reasoned that the vinyl of
A would lend itself easily to eventual annulation reactions.
Scheme 1. Substrates of Phosphine-Catalyzed Annulations
In principle, the direct cyclization of intermediate A via 5-
endo-trig SN2’ pathway would result in a vinylcyclopropane–
cyclpentene (VCP–CP) rearrangement,[16] which, however, was
not observed presumably disfavored by Baldwin’s rules[17]
(Scheme 2). Instead, when 1,1-diacetyl-2-vinylcyclopropane 1b
was employed, we were pleased to observe an unprecedented
phosphine-catalyzed rearrangement of vinylcyclopropylketones
to cycloheptenones (Table 1). Heating 1b with 20 mol % of PPh3
in toluene at 110 °C for 24 h resulted in the formation of 2-
acetyl-4-cycloheptenone 2b in 10% yield existing in keto–enol
tautomers (keto/enol = 1 : 2) (entry 1). Replacing PPh3 with
electron-rich triarylphosphines or trialkylphosphines enhanced
the efficiency (entries 2–6), among which PnBu3 stood out giving
85% yield of the product. The reaction is reminiscent of
divinylcyclopropane–cycloheptene rearrangement under thermal
conditions.[18] However, the lack of reactivity in the absence of
phosphines suggests the crucial role of the catalyst (entries 7
and 8). Of note DABCO as the catalyst produced a small
amount of 2b (14%) together with a dihydrofuran product 2b’ in
37% yield (entry 9).[14a] Solvent screening indicated that toluene
remained the best, while acetonitrile, DMSO, acetone,
In an effort to expand phosphine catalysis, we hypothesized
that electron-deficient vinylcyclopropanes (VCPs) 1 might serve
as a complementary C5 synthon capable of producing value-
added
medium-sized
ring
structures
(Scheme
1).
Mechanistically, regioselective homoconjugate addition[9] of a
phosphine to VCPs 1 may generate an allylic phosphonium
intermediate A. By virtue of the leaving group ability of the
phosphonium, the alkene of A can be rendered electrophilic for
a potential SN2’ reaction, thus making it possible to be used as a
[*] J. Wu, Y. Tang, W. Wei, Y. Wu, Y. Li, J. Zhang, Y. Zheng, and S. Xu*
Department of Chemistry, School of Science, and Xi’an Key
Laboratory of Sustainable Energy Materials Chemistry, Xi’an Jiaotong
University, Xi’an 710049, P. R. China
E-mail: silongxu@mail.xjtu.edu.cn.
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
http://www.angewandte.org or from the author.
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10.1002/anie.201800555
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dichloromethane, and THF all provided diminished yields or
trace amounts of the product (entries 10–14). A lowered
temperature at 60 °C was insufficient to promote the reaction
(entry 15). It was found the rearrangement could tolerate 1.0
equiv of H2O giving a comparable 82% yield, whereas strictly
anhydrous conditions led to a decreased 69% yield, suggesting
that water may play a role in the reaction (vide infra) (entries 16
and 17). Lowering the catalyst loading to 2.5 mol % could still
furnish 72% yield; however, increasing that to 50 mol % or 1.0
equiv decreased the yield to 71% or 22%, respectively, and
oligomerization of 1b was observed (entries 18–20).
albeit as mixtures of diastereomers favoring trans configuration
which is confirmed by 2D NOESY.
Table 2. Investigation on Substrate Scope.[a]
Table 1. Investigation on Conditions.[a]
Entry Catalyst
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
acetonitrile
DMSO
Temp (°C)
110
Time (h) Yield (%)[b]
1
PPh3
24
24
24
24
24
24
48
48
24
24
24
24
24
24
24
24
24
24
24
36
10
2
P(PMP)3
P(p-tolyl)3
PtBu3
110
39
3
110
62
4
110
61
5
PCp3
110
69
6
PnBu3
110
85
7
none
110
trace
trace
14
8
K2CO3
DABCO
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
PnBu3
110
9[c]
10
11
12
13
14
15
16[d]
17[e]
18[f]
19[g]
20[h]
110
reflux
110
77
30
acetone
CH2Cl2
THF
reflux
reflux
reflux
60
51
trace
trace
trace
82
toluene
toluene
toluene
toluene
toluene
toluene
110
110
69
110
72
[a] Conditions: under N2 and at 110 °C, the reaction was carried out with PnBu3
(20 mol %) in toluene for 24–36 h, except that for 2h and 2i, DABCO (50
mol %) was used as the catalyst, and for 2j–t, PtBu3 (50 mol %) was employed
as the catalyst and PhCl or DMSO as the solvent.
110
71
110
22
[a] Under N2 and indicated temperature, to a solution of 1b (0.5 mmol) in the
solvent (5.0 mL) was added the catalyst (20 mol %). [b] Isolated yield. [c]
Dihydrofuran 2b’ was obtained in 37% yield. [d] 1.0 equiv of H2O was added.
[e] Under strictly anhydrous conditions. [f] 2.5 mol % of catalyst was used. [g]
50 mol % catalyst loading. [h] 1.0 equiv of PnBu3 was adopted.
The scope of the phosphine-catalyzed rearrangement was
then probed (Table 2). Substitution at either internal or external
positions (R1 and R2) of the vinyl group could be tolerated,
affording the corresponding cycloheptenones 2c–g in 47–88%
yields with enol isomers as the major. Introduction of a phenyl
on the acetyl fragment (R3 = Ph), in combination with a benzoyl
EWG group, led to the formation of 2h and 2i in 90% and 62%
yields, respectively. Of note DABCO was a superior catalyst in
these two cases. Substrates with an amide group (EWG =
CONHAr) also worked well under similar conditions (PtBu3, PhCl
or DMSO, 110°C), and the corresponding products 2j–t,
including those bearing varied R3 substituents, were generated
in 60–71% yields. The structure of 2j was unequivocally
established by single-crystal X-ray diffraction analysis (CCDC
1816803). Finally, it was found that ketoester substrates were
Scheme 3. Diversification of Products.
Collectively, the above results suggest a broad scope of the
phosphine-catalyzed rearrangement of vinylcyclopropylketones,
which allows controlled synthesis of 2-, 3-, or 4-substituted
cycloheptenones. As cycloheptenones are ubiquitous, though
synthetically challenging, units in natural products and
biologically active molecules,[8] this reaction thus offers a mild
protocol for accessing this kind of medium-sized carbocycles. In
order to underline the usefulness, treatment of diketone 2b with
hydrazines or hydroxylamine led to the formation of pyrazole- or
also
competent,
whose
rearrangement
afforded
cycloheptenones 2u–w in 53–85% yields. Noteworthy amide
and ester functionalized products 2j–w exist only in keto isomers,
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10.1002/anie.201800555
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oxazole-fused cycloheptenes 3 in good yields (Scheme 3a).
Benzyne insertion into ketoester 2v was also achieved to access
a nine-membered carbocycle 4 in 52% yield (Scheme 3b).[19]
A plausible mechanism is illustrated in Figure 1. Initial
regioselective attack of PnBu3 on vinylcyclopropane 1b, via the
well-known
homoconjugate
addition,[9],[14a]
produces
a
zwitterionic intermediate A. Species A then undergoes a proton
transfer to shuttle the anion to the methyl carbon leading to the
formation of intermediate B. Finally, a favored 7-endo-trig SN2’
cyclization[17] furnishes the product 2b and releases the catalyst.
Figure 2. 31P NMR Tracking on the Rearragement of 1j.
In summary, we have expanded phosphine catalysis to
encompass activation of electron-deficient VCPs. This has been
utilized
in
an
unprecedented
phosphine-catalyzed
rearrangement of vinylcyclopropylketones to cycloheptenones in
good yields with a broad scope. Mechanistic investigations
including deuterium labeling and 31P NMR tracking support a
stepwise mechanism comprising homoconjugate addition, water-
involved proton transfer, and 7-endo-trig SN2’ ring closure. This
organocatalytic activation not only enriches the reactivity of
VCPs, but also introduces a new subset of phosphine catalysis
by supplying a distinct C5 synthon. Future efforts will focus on
detailed survey on mechanism and exploring intermolecular
reactivity of the phosphine-catalyzed activation of electron-
deficient VCPs.
Figure 1. A Proposed Catalytic Cycle.
Although the formation of 2a (Scheme 2) could be supportive
to the mechanism, several mechanistic studies were conducted
to gain more insights. To inspect the proton transfer step, a
deuterated substrate 1j-d3 (91% D at CH3) was subjected to the
standard conditions, which produced a deuterated product 2j-d2
in 39% yield with significant loss of deuterium (Scheme 4a).[20]
In addition, it was found that the presence of 1.0 equiv of D2O in
the rearrangement of non-deuterated 1j led to full deuteration at
the α-methylene of the product (Scheme 4b).[21] These results
suggest that the proton transfer is presumably stepwise and
assisted by trace amount of water in the solvent.[22],[23]
Acknowledgements
We are thankful for financial support from the National Natural
Science Foundation of China (Nos. 21402149; 21602167), the
Natural Science Basic Research Plan in Shaanxi Province of
China (No. 2015JQ2050), the China Postdoctoral Science
Foundation (Nos. 2014M550484; 2015T81013; 2015M580830),
and Shaanxi Province Postdoctoral Science Foundation. We
also thank Prof. Justin Mohr (UIC) for helpful discussions.
Keywords: phosphine catalysis • vinylcyclopropanes •
cycloheptenones • organocatalysis • rearrangement
Scheme 4. Deuterium Labeling Investigations.
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identical conditions of Scheme 4b incorporated 18% D on the α-
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possible for it has a activation barrier of 42.5 kcal mol-1.
[24] tBu3P=O was confirmed by comparing 31P NMR with authentic samples,
which may be from oxidizing of PtBu3 by residual molecular oxygen.
[25] Due to overlap and complex splitting of signals, it is difficult to discern
the intermediates via 1H NMR. However, quenching with acetic acid
forms observable zwitterions resembling 2a. For details, see SI.
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10.1002/anie.201800555
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
J. Wu, Y. Tang, W. Wei, Y. Wu, Y. Li, J.
Zhang, Y. Zheng, and S. Xu*
Page No. – Page No.
Phosphine-Catalyzed Activation of
Vinylcyclopropanes: Rearrangement
of Vinylcyclopropylketones to
Cycloheptenones
Phosphine-catalyzed activation of VCPs: A phosphine-catalyzed activation of
electron-deficient vinylcyclopropanes (VCPs) for the generation of an ambident C5
synthon is presented, which effects a phosphine-catalyzed rearrangement of
vinylcyclopropylketones to cycloheptenones in good yields with a broad substrate
scope.
This article is protected by copyright. All rights reserved.