Z-Selective Synthesis of γ,δ-Unsaturated Ketones via Pd-Catalyzed Ring Opening of 2-Alkylenecyclobutanones with Arylboronic Acids

Article abstract of DOI:10.1021/acs.orglett.6b01816

Pd-catalyzed 1,2-addition (instead of 1,4-addition) of arylboronic acids to 2-alkylenecyclobutanones followed by β-carbon elimination from the resulting palladium cyclobutanolates to afford γ,δ-unsaturated ketones was developed. The desired γ,δ-unsaturated ketones were obtained in good to excellent yields with Z/E selectivities of up to >99:1 and a broad spectrum of functional group tolerability.

Full text of DOI:10.1021/acs.orglett.6b01816

Letter
pubs.acs.org/OrgLett
Z‑Selective Synthesis of γ,δ-Unsaturated Ketones via Pd-Catalyzed
Ring Opening of 2‑Alkylenecyclobutanones with Arylboronic Acids
†
†
,†,‡
Yao Zhou, Changqing Rao, and Qiuling Song*
†Institute of Next Generation Matter Transformation, College of Chemical Engineering, College of Materials Science & Engineering
at Huaqiao University, 668 Jimei Boulevard, Xiamen, Fujian 361021, P. R. China
‡
National Laboratory for Molecular Sciences, Institute of Chemistry, Beijing 100190, P. R. China
*
S Supporting Information
ABSTRACT: Pd-catalyzed 1,2-addition (instead of 1,4-addition) of
arylboronic acids to 2-alkylenecyclobutanones followed by β-carbon
elimination from the resulting palladium cyclobutanolates to afford γ,δ-
unsaturated ketones was developed. The desired γ,δ-unsaturated ketones
were obtained in good to excellent yields with Z/E selectivities of up to
>
99:1 and a broad spectrum of functional group tolerability.
5
−9
rganoboron compounds are nontoxic and widely used in
butanones,
rhodium has emerged as a valid and frequently
O
transition-metal-catalyzed carbon−carbon bond forma-
used catalyst, and a limited number of examples of using
1
tion reactions. Among the precedent transformations,
transition-metal-catalyzed addition of arylboronic acids and
their analogues to α,β-unsaturated compounds catches our
attention, since there are two types of functional groups on α,β-
unsaturated compounds, namely, olefin and carbonyl groups,
which might bring forth a selectivity issue in the addition
reaction. To date, 1,4-addition rather than 1,2-addition of
arylboronic acids to α,β-unsaturated compounds has been
palladium for C−C bond activation in cyclobutanones have
6
e,f,9
been reported.
As part of our ongoing interest in transition-
1
0
metal-catalyzed carbon−carbon activation reactions, we
herein report C−C bond cleavage of 2-alkylenecyclobutanones
via an unusual palladium-catalyzed 1,2-addition of arylboronic
acids.
In 1971, Cowan disclosed the synthesis of (Z)-1,5-
diphenylpent-4-en-1-ones through E-to-Z isomerization via
2
,3
dominant on most occasions (Figure 1). To our knowledge,
11
intramolecular triplet energy transfer (Scheme 1a). In 2004,
Warren’s group developed a general two-step method to
synthesize ketones via alkylation and dephosphinoylation of β-
Scheme 1. Syntheses of (Z)-1,5-Diphenylpent-4-en-1-ones
Figure 1. Transition-metal-catalyzed 1,4-addition of arylboronic acids
to α,β-unsaturated compounds.
4
there are very few publications in which efficient 1,2-addition
of arylboronic acids to α,β-unsaturated compounds has been
reported. The inherent strain in cyclobutanone derivatives
bestows them with reactivity that cannot be observed in other
less-strained, larger cyclic analogues. Myriad reports have
described the use of cyclobutanone derivatives as versatile
substrates, leading to a variety of structurally diverse synthetic
5
−9
transformations.
For instance, Murakami reported some
elegant transformations based on C−C bond cleavage reactions
6
of 3-phenylcyclobutanones. Recently, Dong also developed a
number of rhodium-catalyzed C−C activations of benzocyclo-
7
butenones. As a special α,β-unsaturated compound, the
seminal study of 2-alkylenecyclobutanones in a (PhSe)2-
catalyzed Baeyer−Villiger oxidation reaction was reported by
8
Yu and co-workers. Very recently, Wu also found tandem
reactions of 2-(2-bromobenzylidene)cyclobutanone with 2-
alkynylphenol or 2-alkynylbenzenesulfonamides. Among tran-
9
Received: June 22, 2016
sition-metal-catalyzed activation of C−C bonds in cyclo-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01816
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
12
keto diphenylphosphine oxides. The ketones were obtained
it turned out that Pd (dba) was the optimal one (Table S2,
2
3
almost exclusively in the E configuration. In only one example
entries 14−18).
was obtained the Z form, when (Z)-PhCHCHCH Br was
With the optimized reaction conditions in hand, the scope of
this Pd-catalyzed ring opening of 2-alkylenecyclobutanones
with arylboronic acids was assessed (Scheme 2). A number of
2
used as the electrophile (Scheme 1b). To date, there have been
no reports of a direct and effective approach to (Z)-1,5-
diphenylpent-4-en-1-ones in one step. (Z)-Alkenes are highly
valuable and abundant feedstocks for bioactive molecules,
Scheme 2. Substrate Scope
13
flavors, and natural products, and therefore, an efficient and
facile method to obtain these thermodynamically less stable
(
Z)-alkenes would be highly desirable. Herein we describe a
Pd-catalyzed ring opening of 2-alkylenecyclobutanones with
arylboronic acids leading to (Z)-1,5-diphenylpent-4-en-1-ones
in good to excellent yields with high stereoselectivity and wide
substrate scope (Scheme 1c).
We commenced our study by using (E)-2-benzylidenecyclo-
butanone (1a) and phenylboronic acid (2a) as model
substrates for optimization of the reaction. The initial attempt
was performed in the presence of Pd (dba) (5 mol %) and
2
3
tricyclohexylphosphine (10 mol %) in 1,4-dioxane at 100 °C
using KOAc as the base (Table 1, entry 1). A 74% yield of 1,5-
a
Table 1. Screening of Conditions
b
c
entry
catalyst
base
ligand
yield (%)
Z:E
1
2
3
4
5
6
7
Pd (dba)3
KOAc
−
KOAc
PCy3
PCy3
−
PCy3
PCy3
PCy3
PCy3
PCy3
74
2.23:1
1.19:1
−
8.36:1
>30:1
1.29:1
8.2:1
20:1
2
Pd (dba)3
2
63
Pd (dba)3
2
N.D.
28
Pd (dba)3
2
KOH
Pd (dba)3
2
Cs CO
2
32
3
Pd (dba)3
2
Na CO
2
98
3
d
Pd (dba)3
2
K CO
98 (93 )
2
3
e
d
8
Pd (dba)3
2
K CO
>99 (95 )
2
3
a
a
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), Pd catalyst (5
mol %), base (1 equiv), and PCy (10 mol %) under N at 100 °C for
8 h. GC yields. Detected by GC. Isolated yield. 22 h.
Unless otherwise noted, the reactions were run with 1 (0.2 mmol), 2
3
2
(0.3 mmol), Pd (dba) (5 mol %), K CO (0.2 mmol), and PCy (10
2
3
2
3
3
b
c
d
e
1
mol %) under N at 100 °C for 22 h. The values in parentheses are the
2
1
b
Z:E ratios detected by H NMR spectroscopy. The reaction was
c
d
performed with 0.1 mmol of 1. 2 equiv of 2 was used. The reaction
time was 24 h.
diphenylpent-4-en-1-one (3a) was obtained as a mixture of (E)-
a and (Z)-3a. Although the product 3a was obtained in 63%
3
yield when the reaction was performed in the absence of base,
both the conversion of the starting material and the Z/E
selectivity decreased (Table 1, entry 2). When the model
reaction was performed in the absence of ligand, no product 3a
was detected (Table 1, entry 3). In view of the importance of
the ligand, we attempted to change the ligand to enhance the
reactivity and selectivity. Disappointingly, only marginal
inprovements were gained when other ligands, such as dba,
P(t-Bu) , PPh , DPPE, Xantphos, Ruphos, X-phos, and BINAP,
functionalized 2-alkylenecyclobutanone derivatives were in-
spected initially. Interestingly, ortho-, meta-, and para-
substituted groups on the aromatic rings of the 2-
alkylenecyclobutanones had no influence on the selectivity
and gave the desired products 3ba−da in excellent yields.
Moreover, electronic effects of the substituents on the aromatic
rings of the 2-alkylenecyclobutanones had no significant
influence on the selectivity, and the corresponding products
were obtained in good yields (3ea−ha). Heteroaromatic
cyclobutanones such as 1i−k were also good candidates in
this transformation, rendering the products 3ia−ka in 97%,
96% and 94% yield, respectively. Compared to 2-(furan-2-
ylmethylene)cyclobutanone (1k), lower Z/E selectivities of the
products (3ia and 3ja) were observed when a thiophene group
was installed in the 2-alkylenecyclobutanone. When sterically
demanding (E)-2-(naphthalen-2-ylmethylene)cyclobutanone
(1l) was employed under the standard conditions, the ring-
opening product 3la was obtained in 79% yield with a Z/E
selectivity of 94:6.
3
3
were used in place of PCy3 (see Table S1 for details).
Subsequently, the model reaction was submitted to various
bases to examine the effect of the bases (Table S2, entries 1−
1
3). Strong inorganic bases such as KOH and Cs CO
2 3
improved the Z/E selectivity but gave the product 3a in
much lower yields (Table 1, entries 4 and 5). To our delight,
both the selectivity and the yield were significantly increased
when K CO was employed as the base and the reaction time
2
3
was 22 h (Table 1, entry 8), leading to compound 3a in 95%
yield with a Z/E selectivity of 20:1. The reason for the
preference for the thermodynamically less stable (Z)-alkene still
remained unclear. We also screened the palladium catalysts and
Next we focused on the scope of arylboronic acids. To our
delight, a variety of arylboronic acid derivatives having different
B
DOI: 10.1021/acs.orglett.6b01816
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
electronic properties were well-tolerated, giving the desired
products in good to excellent yields with good Z/E selectivities
(
3ab−ah). Moreover, boronic acid derivatives bearing vinyl
groups, such as 2i and 2j, were very compatible with this
transformation as well, delivering the corresponding products
3
>
ai and 3aj in good yields with high Z/E selectivities of up to
99:1. When the reactions were performed with larger arenes,
with arylpalladium and Pd(0) insertion into the cyclo-
butanone could release the strain of the four-membered
ring (Scheme 4). To determine which pathway is the inceptive
21
such as 2n and 2o, the corresponding products 3an and 3ao
were obtained with a slightly lower selectivity for the Z
configuration in good yields as a result of steric hindrance. (1H-
indol-4-yl)boronic acid (2p) was also amenable to this
transformation, generating an 85% yield of 3ap with a Z/E
selectivity of 94:6. Notably, the Z/E selectivity of the product
Scheme 4. Two Possible Pathways To Release the Strain in
1a
(3aa) was preserved after several weeks of storage at room
temperature. Moreover, when current protocol was scaled up 5
times, the γ,δ-unsaturated ketone 3ba was reduced without
affecting either the yield or the selectivity.
The utility of this method is illustrated by its application to
decoration of natural products. Estrone boronic acid 2q was
applicable to the transformation and gave estrone derivative
step, deuterium experiments were performed. When the
reaction was performed in 3 equiv of D O without phenyl-
2
3
boronic acid (2a), 60% deuteration was detected at the sp
carbon adjacent to the carbonyl group of 1a (eq 2). However,
3aq in moderate yield (Scheme 3a). Moreover, 2-alkylenecy-
Scheme 3. Synthetic Applications and Transformations
when 1a and 2a were reacted in 3 equiv of D O under the
2
standard conditions, deuterium was incorporated at both the α-
and γ-positions of the produced (Z)-1,5-diphenylpent-4-en-1-
one (eq 3). Furthermore, we were able to detect the
homocoupling product of the excess arylboronic acid by
GC−MS, implying the existence of arylpalladium in this
transformation. The homocoupling product along with the
deuterium experiments verified that path B in Scheme 4 was a
possible pathway.
On the basis of all of the experimental results mentioned
above, a plausible mechanism is described in Scheme 5. The
Scheme 5. Plausible Reaction Mechanism
clobutanone 1m, prepared from geranialdehyde and cyclo-
butanone, delivered the product 3ma in 82% yield (Scheme
3
b). Some other conversions of the (Z)-1,5-diphenylpent-4-en-
1-ones were also performed (Scheme 3c). 2,3-Bis-substituted
unprotected indole 4 was obtained via Fischer indole synthesis
of 3ba with phenylhydrazine. Asymmetric cyclopropane
(
1R,2R,1′R)-5, which appears in a range of natural products
and medicinally active molecules, could be obtained from 3ba
on the basis of previous work. Cyclic ethers such as
14
tetrahydropyrans and tetrahydrofurans are prevalent scaffolds
1
5
in a great variety of natural products and bioactive
1
6
compounds, and they are also widely used in cosmetic
17
18
19
formulations and flavors. Cyclic ethers 7 and 8 were
readily obtained via intramolecular hydroalkoxylation of olefins
from unsaturated alcohol 6, the reduction product of
compound 3ba. Cyclic nitrones 10 could also be synthesized
via a two-step transformation initiating from 3ba. When the
reaction was extended to 11 and 12, no corresponding desired
products were obtained (eq 1), suggesting that the strain of the
four-membered ring is requisite for this ring-opening reaction.
Subsequently, we turned our attention to the reaction
mechanism. Both 1,2-addition to the 2-alkylenecyclobutanone
catalytic cycle involves (1) 1,2-addition of arylpalladium species
I to 2-alkylenecyclobutanone 1, leading to Pd(II) cyclo-
butanolate intermediate II; (2) β-carbon elimination from
20
22
3
2
intermediate II via C −C bond cleavage, generating
sp
sp
vinylpalladium species III; and (3) protonolysis and trans-
metalation with ArB(OH) , producing the corresponding ring-
2
opening product 3 and arylpalladium species I. Enol−keto
tautomerism of 2-alkylenecyclobutanone 1 could occur under
C
DOI: 10.1021/acs.orglett.6b01816
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
basic conditions, which could explain the results of deuterium
experiments in eqs 2 and 3. In addition, probably because of the
exocyclic CC bond and inherent ring strain of the carbonyl
group, 1,2-addition of arylpalladium species I to 2-alkylenecy-
clobutanone 1 is more preferable than the 1,4-addition. The
desired γ,δ-unsaturated ketone products are obtained with
favorable Z selectivity, possibly on account of the E
configuration of the 2-alkylenecyclobutanones.
Shigeno, M.; Murakami, M. Org. Lett. 2008, 10, 5219. (f) Ishida, N.;
Ikemoto, W.; Murakami, M. J. Am. Chem. Soc. 2014, 136, 5912.
(7) (a) Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2012, 51, 7567.
(b) Xu, T.; Ko, H. M.; Savage, N. A.; Dong, G. J. Am. Chem. Soc. 2012,
134, 20005. (c) Chen, P.; Xu, T.; Dong, G. Angew. Chem., Int. Ed.
2014, 53, 1674. (d) Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2014, 53,
10733. (e) Chen, P.-H.; Sieber, J.; Senanayake, C. H.; Dong, G. Chem.
Sci. 2015, 6, 5440.
(8) Yu, L.; Wu, Y.; Cao, H.; Zhang, X.; Shi, X.; Luan, J.; Chen, T.;
In conclusion, we have disclosed a new method for the Z-
selective synthesis of γ,δ-unsaturated ketones via Pd-catalyzed
ring opening of 2-alkylenecyclobutanones with arylboronic
acids. The γ,δ-unsaturated ketones were obtained in good to
high yields with high Z stereoselectivity and a broad spectrum
of functional group tolerance. Further mechanistic studies and
synthetic applications of this novel protocol are in progress in
our laboratory.
Pan, Y.; Xu, Q. Green Chem. 2014, 16, 287.
(9) (a) Pan, X.; Luo, Y.; Xia, H.-G.; Wu, J. Chem. Commun. 2015, 51,
16483. (b) Gong, X.; Xia, H.; Wu, J. Org. Chem. Front. 2016, 3, 697.
(10) (a) Song, Q.; Feng, Q.; Zhou, M. Org. Lett. 2013, 15, 5990.
(b) Feng, Q.; Song, Q. J. Org. Chem. 2014, 79, 1867. (c) Song, Q.;
Feng, Q.; Yang, K. Org. Lett. 2014, 16, 624. (d) Xu, X.; Ding, W.; Lin,
Y.; Song, Q. Org. Lett. 2015, 17, 516. (e) Zhou, Y.; Zhou, M.; Chen,
M.; Su, J.; Du, J.; Song, Q. RSC Adv. 2015, 5, 103977. (f) Ding, W.;
Song, Q. Org. Chem. Front. 2015, 2, 765. (g) Zhou, Y.; Rao, C.; Mai,
S.; Song, Q. J. Org. Chem. 2016, 81, 2027.
ASSOCIATED CONTENT
Supporting Information
■
(11) Cowan, D. O.; Baum, A. A. J. Am. Chem. Soc. 1971, 93, 1153.
(12) (a) Fox, D. J.; Pedersen, D. S.; Warren, S. Chem. Commun. 2004,
*
S
2
2
598. (b) Fox, D. J.; Pedersen, D. S.; Warren, S. Org. Biomol. Chem.
006, 4, 3102.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01816.
(13) (a) Furstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem.
Soc. 1999, 121, 11108. (b) Fouche, M.; Rooney, L.; Barrett, A. G. M. J.
Org. Chem. 2012, 77, 3060. (c) Odinokov, V. N. Chem. Nat. Compd.
2000, 36, 11. (d) Winssinger, N.; Barluenga, S. Chem. Commun. 2007,
General experimental procedures and spectroscopic data
for the corresponding products (PDF)
2
(
2.
14) Boesen, T.; Fox, D. J.; Galloway, W.; Pedersen, D. S.; Tyzack, C.
R.; Warren, S. Org. Biomol. Chem. 2005, 3, 630.
15) (a) Donohoe, T. J.; Harris, R. M.; Williams, O.; Hargaden, G.
C.; Burrows, J.; Parker, J. J. Am. Chem. Soc. 2009, 131, 12854.
b) Nicolaou, K. C.; Li, A.; Edmonds, D. J.; Tria, G. S.; Ellery, S. P. J.
AUTHOR INFORMATION
Corresponding Author
■
(
*E-mail: qsong@hqu.edu.cn.
(
Notes
Am. Chem. Soc. 2009, 131, 16905.
The authors declare no competing financial interest.
(16) (a) Singh, P.; Mittal, A.; Kaur, S.; Kumar, S. Eur. J. Med. Chem.
2
008, 43, 2792. (b) Germay, O.; Kumar, N.; Moore, C. G.; Thomas, E.
ACKNOWLEDGMENTS
J. Org. Biomol. Chem. 2012, 10, 9709.
■
(
(
17) Narula, A. P. S. Perfum. Flavor. 2003, 28, 62.
Financial support from the National Natural Science
Foundation of China (21202049), the Recruitment Program
of Global Experts (1000 Talents Plan), the Natural Science
Foundation of Fujian Province (2016J01064), the Fujian
Hundred Talents Plan, the Program of Innovative Research
Team of Huaqiao University (Z14X0047), and the Graduate
Innovation Fund of Huaqiao University (to Y.Z.) is gratefully
acknowledged. We also thank the Instrumental Analysis Center
of Huaqiao University for analysis support.
̌
́
18) Perez-Mayoral, E.; Matos, I.; Fonseca, I.; Cejka, J. Chem. - Eur. J.
2
(
(
(
010, 16, 12079.
19) (a) Coulombel, L.; Dun
b) Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C. Org. Lett. 2005, 7, 4553.
c) Francesco, I. N.; Cacciuttolo, B.; Pucheault, M.; Antoniotti, S.
̃
ach, E. Green Chem. 2004, 6, 499.
Green Chem. 2015, 17, 837.
(20) Peng, X.; Tong, B.; Hirao, H.; Chiba, S. Angew. Chem., Int. Ed.
2014, 53, 1959.
(21) For examples of Pd(0) insertion into four-membered rings, see:
(a) Shintani, R.; Moriya, K.; Hayashi, T. J. Am. Chem. Soc. 2011, 133,
1
2
(
6440. (b) Yada, A.; Okajima, S.; Murakami, M. J. Am. Chem. Soc.
015, 137, 8708.
22) For examples of β-carbon elimination from Pd(II) cyclo-
REFERENCES
■
(
1) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
b) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288.
2) For a review of Pd-catalyzed 1,4-additions of arylboronic acids to
α,β-unsaturated compounds, see: Shockley, S. E.; Holder, J. C.; Stoltz,
(
butanolate intermediates, see: (a) Nishimura, T.; Ohe, K.; Uemura, S.
J. Am. Chem. Soc. 1999, 121, 2645. (b) Nishimura, T.; Uemura, S. J.
Am. Chem. Soc. 1999, 121, 11010. (c) Nishimura, T.; Ohe, K.;
Uemura, S. J. Org. Chem. 2001, 66, 1455. (d) Matsumura, S.; Maeda,
Y.; Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2003, 125, 8862.
(
B. M. Org. Process Res. Dev. 2015, 19, 974.
(
3) For a review of Rh-catalyzed 1,4-additions of arylboronic acids to
α,β-unsaturated compounds, see: Hayashi, T.; Yamasaki, K. Chem. Rev.
003, 103, 2829.
4) (a) Duan, H.-F.; Xie, J.-H.; Qiao, X.-C.; Wang, L.-X.; Zhou, Q.-L.
(e) Chtchemelinine, A.; Rosa, D.; Orellana, A. J. Org. Chem. 2011, 76,
2
(
9
157. (f) Ziadi, A.; Martin, R. Org. Lett. 2012, 14, 1266.
Angew. Chem., Int. Ed. 2008, 47, 4351. (b) Duan, H.-F.; Xie, J.-H.; Shi,
W.-J.; Zhang, Q.; Zhou, Q.-L. Org. Lett. 2006, 8, 1479.
(
5) (a) Murakami, M.; Makino, M.; Ashida, S.; Matsuda, T. Bull.
Chem. Soc. Jpn. 2006, 79, 1315. (b) Seiser, T.; Saget, T.; Tran, D. N.;
Cramer, N. Angew. Chem., Int. Ed. 2011, 50, 7740. (c) Leemans, E.;
D’hooghe, M.; De Kimpe, N. Chem. Rev. 2011, 111, 3268.
(
6) (a) Matsuda, T.; Makino, M.; Murakami, M. Org. Lett. 2004, 6,
1257. (b) Matsuda, T.; Makino, M.; Murakami, M. Angew. Chem., Int.
Ed. 2005, 44, 4608. (c) Matsuda, T.; Shigeno, M.; Makino, M.;
Murakami, M. Org. Lett. 2006, 8, 3379. (d) Matsuda, T.; Shigeno, M.;
Murakami, M. J. Am. Chem. Soc. 2007, 129, 12086. (e) Matsuda, T.;
D
DOI: 10.1021/acs.orglett.6b01816
Org. Lett. XXXX, XXX, XXX−XXX