Palladium-Catalyzed Ring-Opening of 2-Alkylidenecyclobutanols: Stereoselective Synthesis of γ,δ-Unsaturated Ketones by C?C Bond Cleavage

Article abstract of DOI:10.1002/adsc.201701078

A facile synthesis of γ,δ-unsaturated ketones via palladium-catalyzed ring-opening of 2-alkylidenecyclobutanols with organic halides is described. The key step involves C_sp3 ? C_sp2 bond cleavage via palladium-catalyzed β-carbon elimination. The desired γ,δ-unsaturated ketones are obtained in good to excellent yields and broad functional group tolerability. Aryl, heteroaryl, benzyl, and alkynyl halides all readily participate to forge tri-substituted carbon-carbon double bond in a stereoselective manner. (Figure presented.).

Full text of DOI:10.1002/adsc.201701078

Title: Palladium-Catalyzed Ring-Opening of 2-Alkylidenecyclobutanols:
Stereoselective Synthesis of γ,δ-Unsaturated Ketones by C-C
Bond Cleavage
Authors: Ling Chen, Fengna Sun, Yuli Sun, Zheng Xu, Zhan-Jiang
Zheng, yuming cui, jian cao, and Li-Wen Xu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701078
Link to VoR: http://dx.doi.org/10.1002/adsc.201701078

10.1002/adsc.201701078
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Ring-Opening of 2-
Alkylidenecyclobutanols: Stereoselective Synthesis of γ,δ-
Unsaturated Ketones by C-C Bond Cleavage
Ling Chen,a Feng-Na Sun,a Yu-Li Sun,a Zheng Xu,a Zhan-Jiang Zheng,a Yu-Ming Cui,a
Jian Cao,a,* and Li-Wen Xua,*
a
Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal
University, No 1378, Wenyi West Road, Science Park of HZNU, Hangzhou 311121, People’s Republic of China
Fax: (+86)-571-2886-5135; phone: (+86)-571-2886-5135; e-mail: caojian@hznu.edu.cn or liwenxu@hznu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
alkylidenecyclobutanols would participate Pd-
2- catalyzed cross-coupling with organic halides,
Abstract. A facile synthesis of γ,δ-unsaturated ketones via
palladium-catalyzed ring-opening of
alkylidenecyclobutanols with organic halides is described.
The key step involves Csp3-Csp2 bond cleavage via
palladium-catalyzed β-carbon elimination. The desired γ,δ-
unsaturated ketones are obtained in good to excellent yields
and broad functional group tolerability. Aryl, heteroaryl,
benzyl, and alkynyl halides all readily participate to forge
leading to γ,δ-unsaturated ketones via selective Csp
Csp bond cleavage (Scheme 1, c).
3
-
2
(a) Ring-opening of cyclobutanols
R
O
R
O
R
OH
M cat.
or
tri-substituted carbon-carbon double bond in
stereoselective manner.
a
M
M: Rh, Pd...
M: Ag, Mn...
Keywords: C-C activation; palladium-catalysis; β-carbon
(b) Ring-opening of benzocyclobutenols
elimination; C-C coupling
OH
R
M
OH
O
or
R
R
heating / hv / base
Csp3-Csp3 cleavage
TM-catalysis
Csp3-Csp2 cleavage
Transition metals catalyzed selective C-C bond
cleavage ranks among the most challenging goals in
organometallic chemistry.[1] In this context, small
ring organic molecules such as cyclobutanols exhibit
unique reactivity towards C-C bond cleavage due to
the driving force provided by the release of the
inherent ring strain.[2] Rh- and Pd-catalyzed β-carbon
elimination strategy has been shown to be particularly
effective for C-C bond cleavage of cyclobutanols.[3-4]
Recently, Ag- and Mn-catalyzed radical-mediated
ring-opening of cyclobutanols has also been achieved
(Scheme 1, a).[5] On the other hand,
benzocyclobutenols, a special class of cyclobutanol
(c) This work: Pd-catalyzed ring-opening of 2-alkylenecyclobutanols
R3
R1 OH
R1
Pd cat.
R3
X
+
R2
R2
O
Csp3-Csp2 cleavage
stereoselective trisubstituted C=C formation
R3: aryl, heteroaryl, benzyl, alkynyl
Scheme 1. Ring-opening of cyclobutanol derivatives via
C-C bond cleavages.
derivatives, undergo Csp
Rh- or Pd-catalysis while Csp
dominates upon heating, photo irradiation, or
treatment with
base (Scheme 1, b).[6]
3
-Csp
2
bond cleavage under
Unsaturated ketones ubiquitously exist in natural
products and pharmaceuticals. Compared with α,β-
and β,γ-unsaturated ketones, the synthetic routes to
access γ,δ-unsaturated ketones are still limited.
Conventional approaches to γ,δ-unsaturated ketones
involve Claisen-type rearrangements and copper-
promoted enone alkenylation.[8] Several novel
methods have been reported recently, such as Ni-
catalyzed reductive coupling of enones and alkynes,[9]
Pd-catalyzed oxidative cross-coupling of N-
tosylhydrazones with allylic alcohols,[10] and Pd-
3
-Csp bond cleavage
3
a
Alkylidenecyclopropane and alkylidenecyclobutane
derivatives are interesting structures that have been
intensively
alkylidenecyclobutanols,
investigated.[7] In
contrast,
combined
2-
with
alkylidenecyclobutanes and cyclobutanols, have
drawn little attention. In particular, transition metals
catalyzed ring-opening of 2-alkylidenecyclobutanols
has not been explored. We hypothesize that 2-
catalyzed
ring-opening
of
2-
1
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10.1002/adsc.201701078
Advanced Synthesis & Catalysis
alkylidenecyclobutanones with arylboronic acids.[11]
Herein, we report our strategy for the stereoselective
synthesis of γ,δ-unsaturated ketones via Pd-catalyzed
ring-opening of 2-alkylidenecyclobutanols. Notable
features of our tactic include: (a) the starting
materials organic halides are commercially available
and 2-alkylidenecyclobutanols can be conveniently
prepared via addition of Grignard reagents to easily
available alkylidenecyclobutanones;[12] (b) tri-
substituted carbon−carbon double bond would be
forged in a stereoselective manner; (c) aryl,
heteroaryl, benzyl, and alkynyl groups could all be
efficiently introduced into the products.
Pd2(dba)3 PPh3
Ag2CO3 toluene
6
5
Pd2(dba)3 BINAP Ag2CO3 toluene 59
6
Pd2(dba)3 TFP
Pd2(dba)3 tBu3P
Ag2CO3 toluene NR
Ag2CO3 toluene NR
7
8
9[b]
10[b]
11
Pd2(dba)3 XPhos Ag2CO3 DCE
Pd2(dba)3 XPhos Ag2CO3 dioxane
0
0
Pd2(dba)3 XPhos Ag2CO3 CH3CN trace
Pd2(dba)3 XPhos Ag2CO3 DMF trace
Pd(PPh3)4 XPhos Ag2CO3 toluene 87
Pd(PPh3)4 XPhos KOH toluene 60
12
13
14
15
16
17
18
19
20
21[c]
22[d]
23[e]
24[f]
At the outset of our investigation, 2-
alkylidenecyclobutanol 1a and bromobenzene were
selected as the model substrates to test our hypothesis.
A simple catalyst system involving Pd2(dba)3 and
Pd(PPh3)4 XPhos Na2CO3 toluene NR
Pd(PPh3)4 XPhos tBuOLi toluene 13
Pd(PPh3)4 XPhos tBuOK
Pd(PPh3)4 XPhos K2CO3
Pd(PPh3)4 XPhos KF
Pd(PPh3)4 XPhos DBU
toluene 69
toluene 60
toluene 12
toluene trace
o
XPhos, with Ag2CO3 as the base in toluene at 65 C
provided the expected product γ,δ-unsaturated ketone
2a in good yield (Table 1, entry 1). Screening of the
palladium source and ligands demonstrated that Pd(II)
catalysts were ineffective (entries 2-3) and XPhos
was superior to other common ligands such as
BINAP and tBu3P (entries 4-8). Solvents proved to be
important as well: toluene was the best choice and
other common solvents were not applicable (entries
9-12). Although the combination of Pd2(dba)3 and
XPhos was effective, the removal of dba
(dibenzylideneacetone) from the product 2a was non-
trivial. To circumvent this obstacle, Pd(PPh3)4 was
chosen as the palladium source instead of Pd2(dba)3
without reducing the yield (entry 13). Ag2CO3 was
found to be the best base although other common
Pd(PPh3)4 XPhos Ag2CO3 toluene
7
Pd(PPh3)4 XPhos Ag2CO3 toluene 93
Pd(PPh3)4 XPhos Ag2CO3 toluene 73
Pd(PPh3)4 XPhos Ag2CO3 toluene 71
Pd(PPh3)4 XPhos Ag2CO3 toluene 17
25[g]
[a]
Unless otherwise specified, the reaction was carried out
using 1a (0.3 mmol), PhBr (0.36 mmol), [Pd] 5 mol%,
Ligand 10 mol%, and base (0.33 mmol) in solvent (3 mL)
at 65 C under N2 for 24 h. [b] Mizoroki-Heck product was
o
[c]
[d]
o
[e]
found in 15~16% yield. Room temperature. 80 C.
t
base such as KOH and BuOK were also competent
100 oC. [f] 80 oC, X = I. [g] 80 oC, X = Cl. NR: no reaction.
(entries 14-20). Further optimization of the reaction
o
temperature showed that 80 C was the best choice
for this transformation and 2a was obtained in
excellent yield (entries 21-23). Use of iodobenzene or
chlorobenzene in lieu of bromobenzene resulted in
diminished yield (entries 24-25). The configuration of
2a was assigned as (E) by comparison with the
reported data[9-10] and the (Z)-isomer was not
Under the optimal conditions (Table 1, entry 22),
the scope and limitations of this ring-opening reaction
was then examined using an array of 2-
alkylidenecyclobutanols 1. As depicted in Table 2,
aryl, heteroaryl, alkyl and alkenyl groups can all be
tolerated at the R1 and R2 positions (2a-2i).[13]
Notably, although the starting materials 1 and the
products 2 contained internal and even terminal
carbon-carbon double bonds, the competitive
Mizoroki-Heck reaction was never observed,
showing the excellent chemoselectivity of our
approach. On the other hand, the scope of organic
halides was also screened and a wide variety of
organic halides proved to be amenable to this
transformation. Aryl bromides bearing both electron
withdrawing and donating groups regardless of their
positions participated in the ring-opening efficiently
to afford the desired products 2j-2n. Functional
groups including chloride, methoxyl and acetyl were
well tolerated, thus providing ample room for further
1
observed within the detection limit of H NMR,
indicating the configurational retention in this ring-
opening process.
Table 1. Optimization of the reaction conditions.[a]
Pd cat.
ligand
base
O
Ph
OH
+
PhX
solvent
temp.
Ph
Ph
1a
X = Br, I, Cl
2a
Entry [Pd]
Ligand Base
Solvent Yield
(%)
functionalization.
Heteroaromatics
such
as
Pd2(dba)3 XPhos Ag2CO3 toluene 85
Pd(OAc)2 XPhos Ag2CO3 toluene NR
1
2
3
4
unprotected indole and thiophene were compatible
(2o-2p). To our surprise, benzyl chlorides and
alkynyl bromides[4b] were also competent substrates
under the identical conditions, leading to γ-benzyl
and γ-alkynyl γ,δ-unsaturated ketones 2q-2t.
PdCl2
XPhos Ag2CO3 toluene NR
Ag2CO3 toluene
Pd(PPh3)4
/
7
2
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10.1002/adsc.201701078
Advanced Synthesis & Catalysis
Table 2. Synthesis of γ,δ-unsaturated ketones 2.[a]
reductive elimination produces the product γ,δ-
unsaturated ketone 2 and regenerates Pd(0) catalyst.
Pd(PPh3)4
XPhos
R3
R1
OH
1, Ag2CO3
Ag2CO3
R1
R3X
+
R3X
R3-Pd-X
toluene
80 oC
AgX
R2
O
R2
A
1
X = Br, Cl
2
R3
R1
O
Pd
Alkylidenecyclobutenol scope
b
a
R1
O
Pd(0)
Ph
Ph
Ph
R2
R1
R3
B
R3
Pd
O
Ph
O
R2
Pd
R2
O
path b
R1
2a 93% R1 = Me
2b 73% R1 = iPr
2c 90% R1 = Ph
2d 66% R2 = 4-MeC6H4
2e 59% R2 = 4-ClC6H4
2f 91% R2 = Cy
not observed
2
path a
O
2g 57%
O
R2
C
Ph
Ph
Scheme 2. Proposed reaction mechanism.
O
The practicality of our strategy was illustrated by
the gram-scale preparation of 2c, which was readily
obtained in 90% yield under the standard conditions
(Scheme 3A). The ketone group could be easily
converted to various motifs. For instance, Fischer
indole synthesis using phenylhydrazine in the
presence of p-toluenesulfonic acid produced 3-allyl-
indole 3.[11] Two-step protocols involving N-
tosylhydrazone[15] intermediate 4 lead to multi-
substituted alkene 5 and 1,4-diene 6 via metal-free
reductive coupling with boronic acid[16] and Pd-
catalyzed cross-coupling with aryl bromide
respectviely.[17]
O
Cy
Ph
2h 83%
2i 63%
Halides scope
R3X = ArBr
R
NH
S
O
Ph
Ph
2j 70% R = 3,5-Me2
2k 78% R = 4-MeO
2l 84% R = 3-MeO
2m 60% R = 4-Cl
2n 63% R = 4-Ac
O
Ph
O
Ph
2p 68%
2o 63%
F
R3X = ArCH2Cl
A. Gram-scale preparation
Ph
Ph
standard
Ph
OH
conditions
Ph
+
PhBr
90%
Ph
O
Ph
O
Ph
O
Ph
O
Ph
2c
1c
2q 70%[b]
71%[c]
2r 51%
2s 76%
(1.70 g)
(1.42 g)
TIPS
B. Synthetic applications
R3X = TIPS
Br
Ph
Ph
Ph
PhNHNH2
Ph
TsOH
Ph
toluene, 80 oC
O
2t 82%
Ph
O
Ph
Ph
N
2c
H
[a]
Unless otherwise specified, the reaction was carried out
3 67%
using 1 (0.3 mmol), R3X (0.36 mmol), Pd(PPh3)4 (5 mol%),
XPhos (10 mol%), and Ag2CO3 (0.33 mmol) in toluene (3
mL) under N2 for 24 h. Pd2(dba)3 (2.5 mol%) was used.
Pd2(dba)3 (2.5 mol%) and benzyl bromide were used.
TsNHNH2
CH3OH, rt
Ph
Ph
PhB(OH)2
K2CO3
dioxane, 110 oC
b
c
Ph
Ph
Ph
5 84%
Ph
Ph
Ph
PhBr
NNHTs
4 82%
Ph
A plausible mechanism was proposed for the
coupling-reaction as described in Scheme 2. Initially,
an aryl/benzyl/alkynyl palladium species A would be
formed by oxidative addition of R3X and Pd(0)
phosphine complex. Subsequent ligand exchange
with 2-alkylidenecyclobutanol 1 affords a palladium
alcoholate B in the presence of Ag2CO3. Selective β-
Pd2(dba)3/XPhos
LiOtBu
dioxane, 110 oC
Ph
Ph
6 85%
Scheme 3. Gram-scale preparation and synthetic
applications.
carbon elimination exclusively occurs at Csp
3
-Csp
2
bond (path a), leading to the intermediate C.[14] Final
In summary, we have described a novel synthesis
of γ,δ-unsaturated ketones via palladium-catalyzed
3
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10.1002/adsc.201701078
Advanced Synthesis & Catalysis
ring-opening of 2-alkylidenecyclobutanols with
organic halides. This strategy features mild reaction
conditions and broad functional group tolerability,
providing an efficient entrance to aryl, heteroaryl,
benzyl, and alkynyl substituted γ,δ-unsaturated
ketones with excellent stereoselectivity. A plausible
1455; g) T. Nishimura, S. Matsumura, Y. Maeda, S.
Uemura, Chem. Commun. 2002, 50.
[5] Examples of Ag or Mn-catalyzed ring-opening of
cyclobutanols: a) R. Ren, H. Zhao, L. Huan, C. Zhu,
Angew. Chem. 2015, 127, 12883; Angew. Chem. Int. Ed.
2015, 54, 12692; b) H. Zhao, X. Fan, J. Yu, C. Zhu, J.
Am. Chem. Soc. 2015, 137, 3490; c) R. Ren, Z. Wu, Y.
Xu, C. Zhu, Angew. Chem. 2016, 128, 2916; Angew.
Chem. Int. Ed. 2016, 55, 2866; d) R. Ren, Z. Wu, C.
Zhu, Chem. Commun. 2016, 52, 8160; e) X. Fan, H.
Zhao, J. Yu, X. Bao, C. Zhu, Org. Chem. Front. 2016,
3, 227.
mechanism involving exclusive Csp
3
-Csp
2
bond
cleavage via palladium-catalyzed
β-carbon
elimination was proposed and various synthetic
applications were conducted to provide structurally
diverse products.
[6] Examples of ring-opening of benzocyclobutenols: a) A.
Chtchemelinine, D. Rosa, A. Orellana, J. Org. Chem.
2011, 76, 9157; b) N. Ishida, S. Sawano, M. Murakami,
Nat. Commun. 2014, 5, 3111; c) J. Yu, H. Yan, C. Zhu,
Angew. Chem. 2016, 128, 1155; Angew. Chem. Int. Ed.
2016, 55, 1143.
Experimental Section
Representative Procedure for the Synthesis of γ,δ-
unsaturated ketones 2a
A vial was charged with 2-alkylidenecyclobutanol 1a (52.2
mg, 0.3 mmol), Pd(PPh3)4 (17.3 mg, 5 mol%), XPhos (14.3
mg, 10 mol%) and Ag2CO3 (90.9 mg, 0.33 mmol) and
evacuated under high vacuum and backfilled with N2.
Toluene (3 mL) and PhBr (56.2 mg, 0.36 mmol) were next
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Yu, X. Li, Chem. Soc. Rev. 2016, 45, 6462; c) D.-H.
Zhang, X.-Y. Tang, M. Shi, Acc. Chem. Res, 2014, 47,
913.
o
added and the solution was stirred at 80 C. Upon reaction
completion (24 h, TLC, eluent: hexane-EtOAc, 15:1), the
mixture was filtered over a plug of silica gel (washed with
50 mL EtOAc), and the filtrate was concentrated. The
mobile phase for flash chromatography: hexane/ethyl
acetate = 15:1. Yellow oil (70.0 mg, 93%).
[8] a) B. H. Lipshutz, E. L. Ellsworth, J. Am. Chem. Soc.
1990, 112, 7440; b) B. H. Lipshutz, M. R. Wood, J. Am.
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Acknowledgements
[9] A. Herath, B. B. Thompson, J. Montgomery, J. Am.
Chem. Soc. 2007, 129, 8712.
We are grateful for financial support by the Natural Science
Foundation of China (No. 21173064, and 21472031) and
Zhejiang Provincial Natural Science Foundation of China (No.
LY18B020013 and LR14B030001).
[10] H. Chen, L. Huang, W. Fu, X. Liu, H. Jiang, Chem.
Eur. J. 2012, 18, 10497.
[11] Y. Zhou, C. Rao, Q. Song, Org. Lett. 2016, 18, 4000.
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4
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10.1002/adsc.201701078
Advanced Synthesis & Catalysis
COMMUNICATION
Palladium-Catalyzed Ring-Opening of 2-
Alkylidenecyclobutanols: Stereoselective Synthesis
of γ,δ-Unsaturated Ketones by C-C Bond Cleavage
Pd(PPh3)4
XPhos
Ag2CO3
R3
R1 OH
R1
R3
X
+
toluene
80 oC
R2
R2
O
Adv. Synth. Catal. Year, Volume, Page – Page
Csp3-Csp2 cleavage
stereoselective trisubstituted C=C formation
R3: aryl, heteroaryl, benzyl, alkynyl
Ling Chen, Feng-Na Sun, Yu-Li Sun, Zheng Xu,
Zhan-Jiang Zheng, Yu-Ming Cui, Jian Cao,* and
Li-Wen Xu*
5
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