Iridium-catalyzed regioselective decarboxylative allylation of β-ketoacids: Efficient construction of γ,δ-unsaturated ketones

Article abstract of DOI:10.1039/c5cc03591k

A highly regioselective protocol for the direct synthesis of γ,δ-unsaturated ketones from β-ketoacids and allylic alcohols was proposed and accomplished relying on the combination of [Ir(cod)Cl]₂ and 10-camphorsulfonic acid via decarboxylative allylation.

Full text of DOI:10.1039/c5cc03591k

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DOI: 10.1039/C5CC03591K
COMMUNICATION
Iridium‐catalyzed regioselective decarboxylative
allylation of β‐ketoacids: efficient construction of γ,
δ‐unsaturated ketones
Cite this: DOI: 10.1039/x0xx00000x
Shu‐Jie Chen, Guo‐Ping Lu and Chun Cai*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly regioselective protocol for the direct synthesis of
γ,
O
R2
O
O
O
O
Decarboxylative Allylation
δ
-unsaturated ketones from -ketoacids and allylic alcohols
β
R1
R2
-CO2
+
R1
OH
OH
OH
was proposed and accomplished relying on the combination
of [Ir(cod)Cl]2 and 10-camphorsulfonic acid via
decarboxylative allylation.
Acid
[Ir]
Acid
[Ir]
-H2O
Ir
O
O
H
R1
OH
Transition‐metal‐catalyzed allylic alkylation is one of the most
R1
R2
R2
efficient tools for constructing
C−C bonds in natural products
synthesis and medicinal chemistry.1 Although high regioselective and
enantioselective allylic alkylation has been realized with a wide range
Scheme 1. Proposed iridium‐catalyzed decarboxylative allylation of β‐ketoacids
with allylic alcohols.
of soft
C‐nucleophiles including both stabilized (malonates, β‐
unsaturated ketones.12 The reaction is thought to occur through the
ketoesters etc.) and unstabilized ketone enolates (simple ketone
enolates), the allylation of methyl ketone enolates with allylic
substrates remains challenging because the allylation product must
resist a second allylation with another allylic substrate.2 So far, only a
handful of protocols have been developed to meet these challenges.
For example, Hartwig and coworkers realized an iridium‐catalyzed
highly regio‐ and enantioselective allylation of silyl enol ethers and
enamines with allylic carbonates through combination of
stoichiometric amount of CsF and ZnF2.3 Thus, the development of
more readily accessible approach for the pre‐activation of such less
reactive methyl ketones is still in high demand.
intermediacy of
nucleophilic attack by
work, we have demonstrated the direct allylation of indoles with
allylic alcohol via ‐allyl iridium intermediate in the presence of
π
‐allyl rhodium intermediate which undergoes
β
‐ketoacid via its enol form. In our previous
a
π
Bronsted acids, which exhibited excellent regioselectivity for
branched products.13 Thus, we envisaged that highly regioselective
allylation of methyl ketone might be achieved through
decarboxylative allylation of
β‐ketoacids with allylic alcohols via
catalytic cleavage of C‐O and C‐C bonds in the presence of [Ir(cod)Cl]2
and appropriate acid (Scheme 1, for more details see SI).
To test our hypothesis, the reaction of β‐ketoacid 1a and allylic
As the precursors of methyl ketones,
β‐ketoacids could act as
alcohol 2a in 1,2‐dichloroethane was carried out at room temperature
with [Ir(cod)Cl]2 and acid (Table 1). In the presence of 10 mol% of FeCl3,
the reaction gave a 29% yield of the branched product 3a with a 46:54
ratio of 3a to the linear product 4a (entry 1). The investigation of
several metal triflate salts gave the desired product 3a in moderate
yield but still with unsatisfactory regioselectivity (<80:20) (entries 2‐4).
To our delight, when the Lewis acid was replaced with Brønsted acid,
the regioselectivity was dramatically improved. The acidity and subtle
structural effects on reaction yield and regioselectivity were observed.
stabilized ketone enolates and react with suitable electrophilic
substrates. In fact, a series of electrophiles, such as imines,4
aldehydes,5 ketones,6 alcohol,7 sulfonamide,8 allylic acetates,9
isatins,10 and activated alkenes11 has been proved to be good reaction
partners under certain conditions. Very recently, the Breit’s group
reported a rhodium‐catalyzed regioselective decarboxylative addition
between β‐ketoacids and terminal allenes to generate a series of γ,δ‐
This journal is © The Royal Society of Chemistry 2012
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Table 2 Decarboxylative allylation of β-ketoacid 1a with allylic alcoholsa,b
Weak acids resulted in low yields (entries 5‐8), while stronger acid
gave better results (entries 9‐11). Camphorsulfonic acid (CSA) (pKa 1.2)
was found to be the best acid in terms of both yield and
regioselectivity (entry 9). Stronger acids CF3COOH (pKa 0.3) and
TsOH∙H2O (pKa ‐2.8) led to a drop in yield and regioselectivity (entries
10 and 11). Increasing the loading of CSA showed that 0.5 equiv was
enough to achieve a satisfactory result (entries 12‐13). Lowering the
catalyst loading to 0.5 mol% led to diminished yield and
regioselectivity (entry 14). In the absence of [Ir(cod)Cl]2, only 24% of
3a was obtained with a low regioselcetivity (entry 15). Surprisingly,
O
O
OH 1.5 mol% [IrCl(cod)]2
O
O
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+
+
DOI: 10.1039/C5CC03591K
0.5 equiv CSA
DCE, 25 oC, 0.2 M
Ph
OH
R
Ph
R
Ph
R
1a
2
3
4
O
O
O
Br
Cl
O
Cl
Cl
3b:
3c:
3d:
85% (>30:1)
78% (>30:1)
O
84% (>30:1)
O
O
the acidity of β‐ketoacid 1a itself could activate the allylic alcohol 2a
O
slowly, delivering 3a in 27% yield with excellent regioselcetivity (entry
16).
3e: 68% (>30:1)
3f: 74% (>30:1)
3g: 82% (>30:1)
O
Table 1 Optimization of reaction conditionsa
O
O
O
CF3
NO2
O
3h:
3i:
3j:
63% (10:1)
80% (>30:1)
O
77% (>30:1)
O
O
S
O
Entry
1
2
3
4
5
6
7
8
Acid
FeCl3
x
Yield 3a (%)b
3a:4ac
46:54
69:31
72:28
74:26
95:5
91:9
97:3
90:10
95:5
94:6
80:20
98:2
99:1
90:10
43:57
99:1
CN
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.5
1
29
43
55
46
5
11
4
9
80
Cu(OTf)2
Zn(OTf)2
Sc(OTf)3
HCOOH
PhCOOH
H3PO4
3k: 73% (>30:1)
3l: 54% (10:1)
3m: 45% (10:1)c
O
O
3n: 71% (75:25)d
(E/Z>99:1)d
3o: 0%; 40% (>30:1)e
a
Reaction conditions: β-ketoacid 1a (0.39 mmol), allylic alcohol 2 (0.30
(PhSO2)2NH
mmol), [Ir(cod)Cl]2 (1.5 mol%), CSA (0.15 mmol), 1,2-dichloroethane (1.5
9
CSAd
mL), N2, 25 oC, 10 h; regioselectivity (reported in brackets) was determined
10
11
12
13
14f
15g
16h
CF3COOH
TsOH·H2O
CSA
50
68
by 1H NMR analysis of the crude reaction mixtures. Isolated yields.
b
c
d
Under CSA-free condition, β-ketoacid 1a (0.6 mmol), 24 h.
92 (84)e
93
1
Regioselectivity and stereoselectivity was determined by H NMR analysis
CSA
CSA
CSA
-
of the isolated product. e TsOH·H2O (0.15 mmol) was used instead of CSA.
0.5
0.5
-
78
24
27
also suitable substrates for the present condition (3i‐3k). Furthermore,
a Reaction conditions: β-ketoacid 1a (0.39 mmol), allylic alcohol 2a (0.30
mmol), [Ir(cod)Cl]2 (1.5 mol%), acid, 1,2-dichloroethane (1.5 mL), N2, 25 oC,
10 h. b GC yield. c The ratio of branched and linear isomers (3a:4a) was
determined by 1H NMR analysis of the crude reaction mixtures. d CSA = (±)-
10-Camphorsulfonic Acid. e Isolated yield. f 0.5 mol% [Ir(cod)Cl]2 was used.
g Without [Ir(cod)Cl]2. h 24 h.
heteroaromatic systems could also be employed successfully, albeit
with lower regioselectivity (3l and 3m). It should be noted that 3m was
obtained under the CSA‐free conditions, since the furyl‐substituted
allylic alcohol was unstable under strong acid condition. In the case of
1,3‐disubstituted allylic alcohols
，
the regioselectivity was
‐selectivity was observed
dramatically decreased while an excellent
E
With the optimized conditions in hand (Table 1, entry 12), the
substrate scope of the reaction with regard to the allylic alcohol
for both two isomers (3n). Aliphatic allylic alcohol was proved to be
sluggish substrate due to the poor leaving ability of the hydroxyl
group, and the use of a stronger promoter was required to give a
moderate yield (3o).
component was explored (Table 2). A number of halo‐ (3b
‐3d), alkyl‐
(
3e), and alkoxy‐substituted aromatic alcohols (3f and 3g) all affored
corresponding products in good yields and regioselectivities. The
tolerance of this reaction toward more sterically hindered substrate
To gain further insight into the regioselectivity of this reaction,
more challenging and special allylic alcohols were investigated, as
was also demonstrated in the successful conversion of the
substituted aryl allylic alcohol 3h), although decrease in
regioselectivity was observed. More electron‐deficient molecules,
such as ‐CF3‐, ‐NO2, and ‐CN‐substituted aryl allylic alcohols were
o‐MeO‐
showcased with the example of 2p and 2q. The α‐alkyl allylic alcohol
(
a
2p was also proved to be suitable substrate, and the regioselectivity
was similar to that of 3n [Eq. (1)]. Replacement of the methyl group
m
m
p
with a vinyl also resulted in a mixture consisting of isomers 3q and 3q’
while linear product 3q’’ was not observed. Likewise, both the product
3q and 3q’ have an excellent ‐selectivity (up to 20:1) [Eq. (2)].
,
E
2 | J. Name., 2012, 00, 1‐3
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COMMUNICATION
γ,δ‐unsaturated ketones. Branched isomers were obtained as the
major product under mild conditions with commercially available
[Ir(cod)Cl]2 and CSA. This decarboxylative allylation VrieewprAertsicelnetOsnlainne
DOI: 10.1039/C5CC03591K
atom economical method that directly using allylic alcohols as
substrates without prior activation. Further investigations on the
asymmetric version of this reaction is ongoing and will be reported as
the results become available.
This work is supported by Chinese National Natural Science
Foundation (21402093, 21476116) and the Fundamental Research
Funds for the Central Universities (30915011315).
Notes and references
School of Chemical Engineering, Nanjing University of Science and
Technology, Nanjing 210094, Nanjing 210094, P. R. China
Fax: (+86)-25-8431-5030; phone: (+86)-25-8431-5514; e-mail:
c.cai@mail.njust.edu.cn.
Electronic Supplementary Information (ESI) available: Experimental
procedures and analytical data for products. See DOI: 10.1039/c000000x/
Table 3 Decarboxylative allylation of β-ketoacid with allylic alcohol 2aa,b
1
(a) Z. Lu and S.-M Ma, Angew. Chem., Int. Ed. 2008, 47, 258; (2) B.
M. Trost and M. L. Crawley, Chem. Rev., 2003, 103, 2921; (c) B. M.
Trost and D. L. Van Vranken, Chem. Rev., 1996, 96, 395.
2
3
B. M. Trost and E. Keinan, Tetrahedron Lett., 1980, 21, 2591.
(a) T. Graening and J. F. Hartwig, J. Am. Chem. Soc., 2005, 127
,
O
O
O
17192; (b) D. J. Weix and J. F. Hartwig, J. Am. Chem. Soc., 2007,
129, 7720.
O
4 (a) A. Ricci, D. Pettersen, L. Bernardi, F. Fini, M. Fochi, R. P. Herrera
and V. Sgarzani, Adv. Synth. Catal,. 2007, 349, 1037; (b) J. Baudoux,
P. Lefebvre, R. Legay, M.-C. Lasne and J. Rouden, Green Chem.,
2010, 12, 252; (c) Y.-H. Pan, C. W. Kee, Z.-Y. Jiang, T. Ma, Y.-J.
Zhao, Y.-Y. Yang, H.-S. Xue and C.-H. Tan, Chem.-Eur. J., 2011, 17
5a: 81% (>30:1)
5b: 83% (>30:1)
5c: 87% (>30:1)
O
O
O
Br
I
,
5d: 78% (>30:1)
5e: 84% (>30:1)
5f: 90% (>30:1)
8363; (d) C.-F. Yang, C. Shen, J.-Y. Wang and S.-K. Tian, Org. Lett.
,
O
O
O
2012, 14, 3092; (e) H.-X. Zhang, J. Nie, H. Cai and J.-A. Ma, Org.
Lett., 2014, 16, 2542.
S
O
5i: 77% (>30:1)c
5
(a) G. Lalic, A. D. Aloise and M. D. Shair, J. Am. Chem. Soc., 2003,
5g: 82% (>30:1)
5h: 67% (>30:1)
125, 2852; (b) D. Magdziak, G. Lalic, H. M. Lee, K. C. Fortner, A. D.
Aloise and M. D. Shair, J. Am. Chem. Soc., 2005, 127, 7284; (c) K.
Rohr and R. Mahrwald, Org. Lett., 2011, 13, 1878;
O
O
O
5j: 85% (>30:1)c
5k: 79% (>30:1)c
5l: 72% (10:1)c
6
7
(a) N. Blaquiere, D. G. Shore, S. Rousseaux and K. Fagnou, J. Org.
Chem., 2009, 74, 6190; (b) Y. Zheng, H.-Y. Xiong, J. Nie, M.-Q.
Hua and J.-A. Ma, Chem. Commun., 2012, 48, 4308.
a Reaction conditions: β-ketoacid 1a (0.39 mmol), allylic alcohol 2 (0.30
mmol), [Ir(cod)Cl]2 (1.5 mol%), CSA (0.15 mmol), 1,2-dichloroethane (1.5
mL), N2, 25 oC, 10 h; regioselectivity (reported in brackets) was determined
by 1H NMR analysis of the crude reaction mixtures. b Isolated yields. c 0.6
mmol β-ketoacid was used.
C.-F. Yang, C. Shen, H.-H. Li and S.-K. Tian, Chinese Sci. Bull., 2012,
57, 2377.
8
9
C.-F. Yang, J.-Y. Wang, S.-K. Tian, Chem. Commun., 2011, 47, 8343.
Additionally, a variety of
1a Table 3 ‐Ketoacids substituted with electron‐rich (5a
halogenated (5d and 5e) arenes underwent the decarboxylative
allylation smoothly, delivering corresponding ‐unsaturated ketones
β
‐ketoacids were tested with allylic alcohol
T. Tsuda, M. Okada, S. Nishi and T. Saegusa, J. Org. Chem., 1986, 51
,
（
）
.
β
‐
5c) and
421;
10 (a) F.-R. Zhong, W.-J. Yao, X.-W. Dou and Y.-X. Lu, Org. Lett.
,
γ,δ
2012, 14, 4018; (b) J. Zuo, Y.-H. Liao, X.-M. Zhang and W.-C. Yuan,
J. Org. Chem., 2012, 77, 11325.
in good yields with excellent regioselectivities. Naphthyl (5f) and
heterocycles such as thiophene (5g) and furan (5h) were also
11 (a) J. Lubkoll and H. Wennemers, Angew. Chem., Int. Ed., 2007, 46
,
compatible with the reaction condition. Furthermore, aliphatic
ketoacids possessing alkyl groups, including methyl (5i), isopropyl (5j),
tert‐butyl (5k and ‐propyl (5l), furnished products in comparable
yields although a modest decrease in regioselectivity was observed
for 5l
β‐
6841; (b) D. A. Evans, S. Mito and D. Seidel, J. Am. Chem. Soc.,
2007, 129, 11583; (c) M. Furutachi, S. Mouri, S. Matsunaga and M.
)
，
n
Shibasaki, Chem.-Asian J., 2010, 5, 2351.
，
12 C.-K. Li and B. Breit, J. Am. Chem. Soc., 2014, 136, 862.
.
13 (a) S.-J. Chen, G.-P. Lu, C. Cai, Synthesis 2014, 46, 1717. Allylation
using allylic alcohols as substrates, see: (b) J. Y. Hamilton, D. Sarlah,
E. M. Carreira, J. Am. Chem. Soc., 2014, 136, 3006; (c) S. Krautwald,
D. Sarlah, M. A. Schafroth, E. M. Carreira, Science, 2013, 340, 1065.
In summary, we have developed an iridium‐catalyzed
decarboxylative allylic substitution which employs allylic alcohols and
readily accessible β‐ketoacids as nucleophiles to afford bifunctional
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