A Pd-catalyzed ring opening coupling reaction of 2,3-allenylic carbonates with cyclopropanols

Article abstract of DOI:10.1039/c9cc00979e

A palladium-catalyzed coupling reaction of 2,3-allenylic carbonates with cyclopropanols was developed, affording valuable 1,3-diene products with different functional groups efficiently under mild reaction conditions. Gram scale synthesis was easily conducted with synthetic transformations demonstrated.

Full text of DOI:10.1039/c9cc00979e

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Journal Name
COMMUNICATION
Pd-catalyzed Ring Opening Coupling Reaction of 2,3-Allenylic
Carbonates with Cyclopropanols
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a,b
Jie Lin, Tonghao Zhu, Minqiang Jia, and Shengming Ma*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Palladium-catalyzed coupling reaction of 2,3-allenylic carbonates ligand such as DPPF and BINAP were used, the unexpected
with cyclopropanols was developed, affording valuable 1,3-diene product 3aa was obtained in 8% and 11% yields, the ring-
products with different functional groups efficiently under mild opening-β-H elimination product 4 was also captured in 12%
reaction conditions. Gram scale synthesis was easily conducted and 19% yields, and the formation of allene product, 1-
with synthetic transformations demonstrated.
phenylocta-6,7-dien-2-one 3aaʹ, was not detected (Table 1,
entries 1 and 2). Other ligands such as PPh , PCy , SPhos,
3
3
Cyclopropanols are important building blocks in organic
synthesis, which may serve as the metal homoenolate
surrogates. Transitional metal catalyzed ring-opening coupling
XPhos, DavePhos, RuPhos, t-BuXPhos, Gorlos-Phos, and LB-
Phos were also screened, generating the product 3aa in 6-58%
yields (Table 1, entries 3-11): XPhos was found to be the
optimal ligand, providing the corresponding conjugated 1,3-
1
reaction of cyclopropanol with organic halide, such as aryl and
benzyl halide,2
b-2d
has been reported (Scheme 1A). With our
2
3
diene product 3aa in 58% yield (Table 1, entry 6). PPh and
longstanding interest in functional allene synthesis, we
recently reported the matched coupling reaction of
cyclopropanols with propargylic carbonates delivering the
RuPhos also provided the product 3aa in 40% and 47% yields,
respectively (Table 1, entries 3 & 8). Different palladium
sources, such as Pd(OAc)
Pd(PPh , and [Pd(allyl)Cl]
was still the optimal (Table 1, entries 12-17). Different bases
such as K PO •3H O or Et N were also investigated, however,
2 2 2 3 3 2
, Pd(TFA) , Pd (dba) •CHCl , PdCl ,
3
multi-substituted allene products in good yields (Scheme 1B).
)
3 4
2
were also screened and Pd(dba)
2
Herein we wish to report the coupling reaction of
cyclopropanols with 2,3-allenylic carbonates providing
3
4
2
3
4
conjugated 1,3-diene products efficiently (Scheme 1C).
the effect was NOT obvious (Table 1, entries 18 and 19).
Finally, methyl carbonate was used instead to afford the final
product 3aa in 64% yield (Table 1, entry 20) and the β-H
A) Pd-catalyzed ring-opening reaction of organic halides with cyclopropanols
R1 OH
R1
R2
cat. Pd/L
elimination product 4 was disappeared.
It should be
2
R X
O
highlighted that 3aa was selectively generated in this reaction,
and 3aaʹ was NOT observed in all the cases during our
B) Our recently reported coupling reaction with propargylic carbonates
R1
4
optimization of the reaction conditions.
O
R1
Pd(dba)2
XPhos
OH
OCO2Me
R2
R4
R3
R2
R3
Toluene
5
0 o
C
R4
C) This work - coupling reaction with 2,3-allenylic carbonates
R1
O
O
R1
R1
OCO2Me
OH
Pd/L
R2
R2
R2
NOT observed
Scheme 1 Different coupling reaction types of cyclopropanols.
2
,3-Allenylic benzyl carbonate 1a’ and cyclopropanol 2a
were selected as the model substrates. Firstly, different ligands
were screened with Pd(dba)
reaction in toluene at 25 C. When bidentate phosphorous
2
as the palladium source for the
o
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Table 1 Optimization of the reaction conditions a
Under the optimized reaction conditions (TableVi
1
ew, eAr
ntry 20),
ticle Online
DOI: 10.1039/C9CC00979E
different cyclopropanols were investigated to show the
generality of this reaction. Different functional groups such as
methoxy, methyl, chloro, and bromo may all be tolerated on
the benzyl group providing the desired 1,3-diene products
ab-3ae in 56%-65% yields; the reaction of 1a with 2e was also
carried out on 10 mmol scale providing the final product 3ae in
.4573 g (52% yield), demonstrating the practicability of this
reaction. With phenylcylopropanols, different substituents on
the phenyl groups, such as H, 2-methyl, 4-methoxy, 4-chloro,
-bromo, may also be introduced providing the corresponding
products 3af-3aj in moderate yields (41%-50%). Thienyl
substituted product 3ak can also be synthesized successfully in
0% yield. Finally, different alkyl groups, such as phenylethyl,
phenoxymethyl, n-hexyl and i-isopropyl also worked well in
this reaction (3al-3ao, 52%-65% yields).
OCbz
Bn
1a' (0.20 mmol)
[Pd] (5 mol%)
Ligand (10 mol%)
Bn
O
O
O
+
+
Toluene, 25 o
Ar, 16 h
C
Bn
3
Bn
3aa
3aa'
NOT observed
4
OH
2a (0.24 mmol)
1
Entry
Ligand
DPPF
[Pd]
(NMR, 3aa/4/1a’, %) b
1
2
3
4
5
6
7
8
9
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
Pd(dba)
2
2
2
2
2
2
2
2
2
2
2
8/12/7
4
BINAP
11/19/0
40/31/0
28/0/31
36/36/0
58/27/0
24/45/0
47/55/0
6/6/0
PPh
PCy
3
5
3
SPhos
XPhos
R1
Pd(dba)2 (5 mol%)
XPhos (10 mol%)
O
OCO2Me
OH
R1
DavePhos
RuPhos
t-BuXPhos
Gorlos-Phos
LB-Phos
XPhos
Toluene, 25 oC, Ar, 16 h
1a
2a-o
3
aa-ao
OMe
Me
Cl
1
1
0c
1c
10/46/0
12/24/0
29/37/0
19/20/21
50/21/0
0/0/82
O
O
O
O
3aa, 64%
3ab, 58%
3ac, 65%
3ad, 56%
OMe
1
2
3
4
5
6
7
Pd(OAc)
Pd(TFA)
(dba) •CHCl
PdCl
Pd(PPh
[Pd(allyl)Cl]
2
1
XPhos
2
Br
O
1
1
1
1
XPhos
Pd
2
3
3
O
O
Me
O
XPhos
2
XPhos
3
)
4
38/26/0
0/0/93
3af
3ag, 48%
3ah
, 50%
3
ae, 58%
, 42%
Br
b
52% , 1.4573 g
XPhos
2
Cl
1
1
8d
XPhos
Pd(dba)
Pd(dba)
2
2
61/20/0
61/24/0
64 (64)/0/0
S
9e
O
O
O
O
XPhos
2
0f
XPhos
Pd(dba)
2
3ai, 41%
3aj, 49%c
3ak, 50%d
3al, 52%
PCy2
PCy2
PCy2
PCy2
iPrO
O Pr
i
MeO
OMe i-Pr
i-Pr
N
O
O
O
O
i-Pr
XPhos
PCy2
SPhos
PCy2
DavePhos
RuPhos
3an, 54%e
3am, 65%
3ao, 50%
iPrO
O Pr MeO
i
OMe
OCO2Me
a
Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), Pd(dba)
XPhos (10 mol%) in toluene (1.0 mL) at 25 C.
Pd(dba) (5 mol%), and XPhos (10 mol%) in toluene (50 mL) at 25 C for 17 h. 3aj
was obtained as a mixture with ring opening protonolysis product. 25 h. e 1a
1.0 mmol), 2n (1.2 mmol), and toluene (5.0 mL) was used.
2
(5 mol%), and
OMe
o
b
1a (10 mmol), 2e (12 mmol),
o
c
Gorlos-Phos
LB-Phos
1a
2
d
(
a
Reaction conditions: 1a’ (0.20 mmol), 2a (0.24 mmol), [Pd] (5 mol%), and Ligand
b
c
(
10 mol%) in toluene (1.0 mL). NMR yield with CH
CO (10 mol%) was added by using Gorlos-Phos•HBF
Phos•HBF
1.0 equiv) was added. f 1a (0.20 mmol) was used; NMR yield with mesitylene as
the internal standard; Isolated yield is in the parentheses.
Br
2 2
as the internal standard.
(10 mol%) or LB-
O (1.0 equiv) was added. e Et
Scheme 2. Substrate scope referred to cyclopropanols.a
K
2
3
4
d
4
(10 mol%) as the ligand.
K PO
3
4
•3H
2
3
N
However, the reaction of sterically crowded substrate 2p
failed (eq 1).
(
2
| J. Name., 2012, 00, 1-3
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The final diene product 3ae may undergo different
View Article Online
DOI: 10.1039/C9CC00979E
transformations to show the utility of this reaction (scheme 5).
Pd(dba)2 (5 mol%)
XPhos (10 mol%)
No reaction
Intermolecular Diels-Alder reaction of 3ae with dimethyl but-2-
ynedioate 5 provided the cyclohexadiene product 6 in 88%
yield. The intermolecular Diels-Alder reaction with 5 followed
by oxidation with DDQ delivered the aromatization product 7
The intermolecular Diels-Alder reaction with
another acceptor N-Methylmaleimide 8 gave the cyclohexene
OCO2Me
Bn
(1)
Toluene, 25 oC, Ar, 16 h
1a 68% NMR recovery
OH
4
g
1
a (0.2 mmol)
2p (1.2 equiv)
The scope of 2,3-allenyl methyl carbonates was also
investigated with cyclopropanol 2a (Scheme 3). R could be
either phenyl or n-butyl group providing the corresponding
,3-disubstituted dienes 3ba and 3ca in 68% and 76% yield. R
could also be either phenyl or n-pentyl group providing the
corresponding 1,3-disubstituted dienes E-3da and 3ea in 63%
and 68% yield. In the generated E-3da, a E/Z ratio of 7.2/1 was
4
g,5
(83% yield).
2
4
g
product 9 in as high as 93% yield. Finally, the Suzuki coupling
reaction of 3ae with (3-nitrophenyl) boronic acid 10 generated
3
2
6
the coupling product 11 efficiently in 71% yield.
Br
Br
1
observed by H NMR analysis using mesitylene as the internal
standard ， however, Z-isomer was converted to E-isomer
O
O
exclusively after purification by column chromatography on
silica gel. R could also be phenyl or n-hexyl group providing
CO Me
CO Me
2
2
5
MeO C
2
CO2Me
CO2Me
5
6
7
the corresponding 3,4-disubstituted dienes Z-3fa and Z-3ga
5
CO2Me
O
Br
b
4
5
a
highly stereoselectively in 73% and 78% yield. When R and R
were both methyl groups, the desired product 3ha was
obtained in 33% yield.
O
O
NO2
NO2
N
3ae
(HO)2B
Br
Bn
O
10
8
R3
Pd(dba)2 (5 mol%)
XPhos (10 mol%)
c
R4
R5
OH
Bn
R4
R5
d
OCO2Me
R3
O
Toluene, 25 oC, Ar, 16 h
O
H
H
R2
R2
O
N
1b-h
2a
3ba-ha
11
9
O
O
O
O
O
O
a
ae (0.5 mmol), 5 (2.5 equiv), DCM, dark, reflux, 77 h, 88%; b 3ae (0.5 mmol), 5
3
Bn
Bn
Bn
Bn
Bn
c
(3.0 equiv), DCM, dark, reflux, 77 h; then DDQ (1.1 equiv), toluene, rt, 41 h, 83%;
d
3
ae (0.5 mmol), 8 (1.5 equiv), DCM, reflux, 24 h, 93%; 3ae (0.2 mmol), 10 (3.0
o
equiv), Pd(PPh
)
3 4
(5 mol%), K PO
3 4
(2.0 equiv), DMF, 50 C, 65 h, 71%.
Ph
Ph
n-Bu
Ph
E-3da, 63%b
n-C5H11
Scheme 5 Synthetic applications.
3
ba, 68%
3ca, 76%
3ea, 68%
Z
-3fa,
73%
E/Z=1/1.36
O
O
Several control experiments were carried out in order to
unveil the reaction mechanism (Scheme 6). Firstly, when
cyclopropanol 2a reacted under the standard conditions, 98%
yield of the starting material 2a was recovered, and 2% of the
ring opening-protonolysis product 12 was observed (eq 1).
Bn
Bn
n-C6H13
Z-3ga, 78%
3ha, 33%c
2 2
When Pd(OAc) was used instead of Pd(dba) , the yield of ring
a
2
Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), Pd(dba) (5 mol%), and
o
b
XPhos (10 mol%) in toluene (1.0 mL) at 25 C. 1 (0.26 mmol) and 2a (0.2 mmol)
opening-protonolysis product 12 was improved to 11%, and
the ring opening/β-H elimination product 4 was also observed
in 4% NMR yield (eq 2). Additionally, when MeONa was added,
the ring opening-protonolysis product 12 was formed in 74%
were used. c 1 (0.4 mmol) and 2a (0.2 mmol) were used.
Scheme 3 Substrate scope of 2,3-allenylic carbonates.a
To our great delight, the steroid containing 2,3-disubstituted with no 2a recovered (eq 3). The reaction in the presence of
diene 3cq could also be synthesized successfully in 76% yield, Pd(OAc) (5 mol%) and NaOMe (10 mol%) afforded the diene
2
further proving the wide scope of this reaction(Scheme 4).
product 3aa in only 49% NMR yield together with 9% NMR
yield of protonolysis product 12 and 17% of ring opening/β-H
elimination enone product 4 being yield (eq. 4). These
experiments revealed that Pd(II) and MeONa were facilitating
the ring opening protonolysis of cyclopropanol 2a.
TBSO
OCO2Me
1c
(0.2 mmol)
n-Bu
H
H
OH
Pd(dba)2 (5 mol%)
XPhos (10 mol%)
H
+
H
Toluene, 25 oC, Ar, 24 h
H
H
H
O
H
H
n-Bu
TBSO
H
2
q
(
0.24 mmol)
3cq, 76%
Scheme 4 Synthesis of conjugated diene containing a steroidal skeleton.
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Financial support from the National Basic Research Program
(2015CB856600) and the National Natural Science Foundation
of China (21502020) is greatly appreciated. We also thank
Yang Tang in this group for reproducing the results of 3af, 3ca,
and 3aj.
Pd(dba)2 (5 mol%)
XPhos (10 mol%)
OH Toluene, 25 oC, Ar, 16 h
View Article Online
DOI: 10.1039/C9CC00979E
Bn
Bn
Bn
1
)
12 2% NMR yield
2a 98% NMR recovery
O
2
a (1 mmol)
12
Pd(OAc)2 (5 mol%)
XPhos (10 mol%)
Bn
2
)
Bn
OH Toluene, 25 oC, Ar, 16 h
+
12 11% NMR yield
O
O
4
4% NMR yield
2
a 66% NMR recovery
2
a (0.5 mmol)
12
4
Pd(OAc)2 (5 mol%)
XPhos (10 mol%)
MeONa ( 1 equiv)
Bn
Conflicts of interest
Bn
3)
1
2 74% NMR yield
69% isolated yield
OH
Toluene, 25 oC, Ar, 16 h
O
There are no conflicts to declare.
2a (0.5 mmol)
12
OCO2Me
4)
Pd(OAc)2 (5 mol%)
Xphos (10 mol%)
MeONa (0.1 equiv)
Notes and references
1
a (0.20 mmol)
Bn
O
1
For reaction of cyclopropanols, see reviews: (a) N. Nithiy, D.
Rosa and A. Orellana, Synthesis, 2013, 45, 3199; (b) D. Rosa,
A. Nikolaev, N. Nithiy and A. Orellana, Synlett, 2015, 26, 441;
Bn
Bn
Toluene, 25 oC, Ar, 16 h
+
+
Bn
O
O
OH
3aa
9% NMR yield
4
12
(
c) A. Nikolaev and A. Orellana, Synthesis, 2016, 48, 1741.
4
17% NMR yield 9% NMR yield
2a (0.24 mmol)
2
Selected recent examples, see: (a) P. P. Das, K. Belmore and J.
K. Cha, Angew. Chem. Int. Ed., 2012, 51, 9517; (b) K. Cheng
and P. J. Walsh, Org. Lett., 2013, 15, 2298; (c) D. Rosa and A.
Orellana, Chem. Commun., 2013, 49, 5420; (d) N. Nithiy and
A. Orellana, Org. Lett., 2014, 16, 5854; (e) Y. Li, Z. Ye, T. M.
Bellman, T. Chi and M. Dai, Org. Lett., 2015, 17, 2186; (f) Z.
Ye and M. Dai, Org. Lett., 2015, 17, 2190; (g) S. Wang, L. Guo,
H. Wang and X.-H. Duan, Org. Lett., 2015, 17, 4798; (h) Z. Ye,
K. E. Gettys, X. Shen and M. Dai, Org. Lett., 2015, 17, 6074; (i)
H. Zhao, X. Fan, J. Yu and C. Zhu, J. Am. Chem. Soc., 2015, 137,
3490; (j) X. Zhou, S. Yu, L. Kong and X. Li, ACS Catal., 2016, 6,
Scheme 6 Mechanistic studies.
Based on these results, a possible mechanism was proposed
Scheme 7). Firstly, oxidative addition of 1a with Pd(0) would
form the methylene (π-allyl) palladium methoxide η -I by
releasing one molecule of CO
cyclopropanol 2 with intermediate η -I with the help of MeO
gave the intermediate η -II. Subsequent β-C elimination
generated the branched intermediate η -III highly selectively.
Finally reductive elimination would form the desired product 3
(
3
2
3
.
Ligand exchange of
-
3
1
4
6
47; (k) K. Jia, F. Zhang, H. Huang and Y. Chen, J. Am. Chem.
Soc., 2016, 138, 1514; (l) H. Zhang, G. Wu, H. Yi, T. Sun, B.
Wang, Y. Zhang, G. Dong and J. Wang, Angew. Chem. Int. Ed.,
and regenerate Pd(0).
2
017, 56, 3945; (m) A. Nikolaev, C. Y. Legault, M. Zhang and
R1
OCOOMe
A. Orellana, Org. Lett., 2018, 20, 796.
O
1a
3
4
P. Wu, M. Jia, W. Lin and S. Ma, Org. Lett., 2018, 20, 554.
For selective generation of 1,3-diene products, see: (a) D.
Djahanbini, B. Cazes and J. Gore, Tetrahedron Lett., 1984, 25,
203; (b) D. Djahanbini, B. Cazes and J. Gore, Tetrahedron,
3
Pd(0)L
S 2'
N
CO2
1
984, 40, 3645; (c) D. Djahanbini, B. Cazes, J. Gore and F.
Gobert, Tetrahedron, 1985, 41, 867; (d) J. Nokami, A.
Maiham and J. Tsuji, Tetrahedron Lett., 1990, 31, 5629; (e) T.
Moriya, T. Furuuchi, N. Miyaura and A. Suzuki, Tetrahedron,
1994, 50, 7961; (f) J. S. Schneekloth Jr., M. Pucheault and C.
M. Crews, Eur. J. Org. Chem., 2007, 40-43; (g) H. Wang, B.
Beiring, D. Yu, K. D. Collins and F. Glorius, Angew. Chem. Int.
Ed. 2013, 52, 12430.
R1
OMe
PdL
3
-I
O
PdL
1
-III
R1
OH
5
6
G. Hilt and M. Danz, Synthesis, 2008, 14, 2257.

-C elimination
T. Watanabe, N. Miyaura and A. Suzuki, Synlett, 1992, 207.
2
R1
MeOH
O
PdL
3
-II
Scheme 7 A proposed mechanism.
In conclusion, the palladium catalyzed coupling reaction of
,3-allenylic carbonates with cyclopropanols was developed
2
providing the synthetically useful 1,3-diene products
efficiently. The reaction worked under very mild reaction
conditions (at rt) with various different functional groups being
tolerated. Several useful transformations, such as Diels-Alder
reaction and Suzuki coupling reaction of the final diene
products were also demonstrated.
4
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DOI: 10.1039/C9CC00979E
O
R1
R1
Pd/XPhos
OH
OCO2Me
Toluene, 25 o
C
R2
R2
23 examples, up to 78% yield




Room temperature reaction
Without base
Wide substrate scope
Gram scale reaction and steroid
skeleton tolerated
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