Palladium-catalyzed oxidative heck-type allylation of β,β- disubstituted enones with allyl carbonates

Article abstract of DOI:10.1002/adsc.201400076

The palladium-catalyzed oxidative Heck-type allylation of β,β-disubstituted enones, i.e., α-oxoketene dithioacetals, was efficiently realized with allyl carbonates, providing a concise route to highly functionalized dienes. The present synthetic methodology utilizes the substrate activation strategy to activate the C-H bond of β,β-disubstituted enones by introduction of a 1,2-dithiolane functionality to make the enone substrate highly polarized and thus increase its reactivity, demonstrating rare examples for transition metal-catalyzed allylic substitution of ss,ss-disubstituted enones through a Heck-type allylation process.

Full text of DOI:10.1002/adsc.201400076

UPDATES
DOI: 10.1002/adsc.201400076
Palladium-Catalyzed Oxidative Heck-Type Allylation of
b,b-Disubstituted Enones with Allyl Carbonates
Weiwei Jin,a Qin Yang,a Ping Wu,a Jiping Chen,a and Zhengkun Yua,b,*
a
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, Liaoning 116023,
Peopleꢀs Republic of China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, 354 Fenglin Road,
Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-411-8437-9227; e-mail: zkyu@dicp.ac.cn
Received: January 21, 2014; Revised: March 3, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400076.
Abstract: The palladium-catalyzed oxidative Heck-
type allylation of b,b-disubstituted enones, i.e., a-
oxoketene dithioacetals, was efficiently realized
with allyl carbonates, providing a concise route to
highly functionalized dienes. The present synthetic
methodology utilizes the substrate activation strat-
in transition metal-catalyzed Heck reactions at the b-
position to deliver linear olefin products,[2,6] the cata-
lytic cross-coupling of enones which act as the inter-
nal alkenes to afford highly branched olefins has at-
tracted less attention. Hirama et al. reported the pal-
ladium-catalyzed intramolecular Heck arylation of
b,b-disubstituted enones to synthesize the congested
benzylic quaternary center.[7] Notably, a pioneer work
of intramolecular allylic substitution at the a-position
of enones via the merging of palladium catalysis and
phosphine organocatalysis was realized by Krische
and co-workers.[8] In 2010, our group realized the
direct oxidative cross-coupling between internal and
terminal olefins, successfully synthesizing multifunc-
tionalized conjugated dienes through Pd(II)-catalyzed
À
egy to activate the C H bond of b,b-disubstituted
enones by introduction of a 1,2-dithiolane function-
ality to make the enone substrate highly polarized
and thus increase its reactivity, demonstrating rare
examples for transition metal-catalyzed allylic sub-
stitution of ß,ß-disubstituted enones through
a Heck-type allylation process.
À
Keywords: allyl carbonates; allylation; C H activa-
À
oxidative C H bond olefination of the internal olefin
tion; enones; ketene dithioacetals; palladium
units of a-oxoketene dithioacetals with terminal ole-
fins such as acrylates and styrenes.[9] We reasonably
attached both the electron-donating cyclic dithioalk-
yl[10] and an electron-withdrawing carbonyl to the two
Functionalized olefins are important building blocks ends of the C=C bond of an internal alkene to tune it
in many natural products, pharmaceuticals, and organ- into a highly polarized state and thus increase the re-
ic functionalized materials.[1] Over the past few de- activity of its C H bond [Eq. (1)]. During our con-
À
cades, the transition metal-catalyzed Heck reaction tinuing investigation of a-oxoketene dithioacetals, we
has emerged as one of the most powerful and envisioned that a-oxoketene dithioacetals, the nature
À
straightforward tools for the construction of new C C of which is a variant of b,b-disubstituted enones,
bonds in the synthesis of functionalized olefins.[2] In might be applied for the synthesis of highly function-
recent years, nickel-[3] and iridium-catalyzed[4] Heck- alized olefins by employing such a substrate activation
type allylic substitution reactions by means of simple strategy in allyl-Heck-type reactions.[11,12] Herein, we
alkenes as nucleophiles and allylating reagents as report a Pd(II)-catalyzed intermolecular oxidative al-
electrophiles to prepare functionalized olefins have lylation of a-oxoketene dithioacetals with allyl
been well developed. An asymmetric version of the carbon
iridium-catalyzed allyl-Heck-type substitution reac-
tion which employed racemic allylic alcohols and
simple alkenes as coupling partners was also docu-
mented for the enantioselective generation of allyl-
functionalized olefin products.[5]
ACHTUNGTNERaNUNG tes.
Although enone compounds usually serve as the
terminal alkenes, and have been widely demonstrated
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Table 1. Examination of allylating reagents for the allylation
of 1a.[a]
Table 2. Screening of conditions for the reaction of 1a and
2a.[a]
Entry Catalyst
Oxidant
AgOAc
Solvent Time Yield
[h]
[%][b]
Entry LG in 2
Yield
[%][b]
Entry LG in 2 Yield
[%][b]
1
2
3
4
Pd
PdCl
Pd(TFA)2
[PdCl
N
DMF
DMF
DMF
DMF
DMF
DMF
12
12
12
12
12
12
12
12
12
12
12
12
12
56
59
43
18
72
9
41
35
32
13
40
65
35
17
95
(70)[d]
54
1
2
3
4
Br
2
0
0
73
5
6
7
8
OCO2Me 72
OCO2Et 81
OCO2Ph 51
Bpin
P(O)
OAc
N
(OEt)2
5
6
7
8
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
ACHTUNGTRENNUNG
A
OBoc
64
Ag2CO3
[a]
E
E
Cu
N
Reaction conditions: 1a (0.3 mmol),
2
(0.6 mmol),
BQ
PhI
DMF
ACHTUNGRTEN(NUNG OAc)2 DMF
PdACHTUNGTRENNUNG(OAc)2 (20 mol%), AgOAc (0.6 mmol), DMF (2 mL),
9
R
air atmosphere, 508C, 24 h. The reactions were carried
out in a sealed 15-mL Pyrex glass screw-cap tube.
Determined by GC analysis using mesitylene as the inter-
nal standard; pin=pinacolato, Boc=t-BuOCO.
10
11
12
13
14
15[c]
E
TBHP
DMF
DMF
DMA
THF
[b]
N
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
N
TEMPO
AgOAc
AgOAc
AgOAc
AgOAc
DMSO 24
N
DMF/
DMSO
DMF/
DMSO
DMF/
DMSO
DMF/
DMSO
24
24
24
24
Initially, we tested the reactions of a-oxoketene di-
thioacetal (1a) with the allylating reagents bearing
various leaving groups under the typical conditions
used for the direct olefination of 1a with terminal ole-
fins.[9] It was found that the leaving groups had a re-
markable effect on the reactivity of the allylating re-
agents. Allyl bromide, allylboronic acid pinacol ester,
and diethyl allylphosphonate exhibited very poor re-
activity (Table 1, entries 1–3), while allyl acetate and
carbonates showed good reactivity to yield the de-
sired product. This is presumably attributed to the rel-
atively strong basicity of acetate and carbonate anions
[e]
16[c]
17[c]
18[c]
Pd
–
N
AgOAc
AgOAc
–
0
Pd
23
[a]
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), cata-
lyst (20 mol%), oxidant (0.6 mmol), solvent (2 mL), air
atmosphere.
Determined by GC analysis using mesitylene as the inter-
nal standard.
DMF/DMSO=20:1 (v/v).
Isolated yield given in parentheses.
PdACTHNUTRGEN(UGN OAc)2 (10 mol%); TFA=trifluoroacetic acetate,
[b]
[c]
[d]
[e]
À
which serve as the bases to facilitate the C H bond
cleavage and the catalyst dissociation process.[13] Allyl
ethyl carbonate behaved as the most effective allylat-
ing reagent to form 3a in 81% yield (Table 1, en-
tries 4–8). It has been well known that allyl carbo-
nates can be utilized as decarboxylative allylation re-
agents.[14]
BQ=benzoquinone, TBHP=tert-butyl hydroperoxide,
TEMPO=2,2,6,6-tetramethylpiperidine 1-oxyl, DMA=
N,N-dimethylacetamide.
Next, the cross-coupling reaction of 1a with allyl DMSO (v/v, 20/1), reaching 95% yield (70% isolated
ethyl carbonate (2a) was employed as the model reac- yield) for 3a over a period of 24 h (Table 2, entry 15).
tion to optimize the reaction conditions [Eq. (3), DMSO may function as a ligand to stabilize the cata-
Table 2]. Examination of the palladium sources re- lytically active species in the catalytic cycle,[15] enhanc-
vealed that PdACHTUNGTRENNUNG(OAc)2 was the most effective catalyst ing the reaction efficiency. Both lowering and elevat-
for the reaction in DMF at 508C, leading to the de- ing the reaction temperature deteriorated the reaction
sired product 3a in 72% yield within 12 h (Table 2, en- efficiency (see the Supporting Information for de-
tries 1–5). AgOAc acted as the most efficient oxidant tails). Reducing the catalyst loading to 10 mol% re-
among the screened oxidizing reagents, i.e., AgOAc, sulted in 3a in a lower yield (54%), and the reaction
Ag2CO3, CuACHTUNGTRENNUNG(OAc)2, benzoquinone (BQ), PhIACHTUNREGTGNUN(N OAc)2, did not occur without PdACHTUNGTREN(NUGN OAc)2 catalyst (Table 2, en-
tert-butyl hydroperoxide (TBHP), and TEMPO tries 16 and 17). It should be noted that direct oxida-
(Table 2, entries 5–11). The desired product was also tive coupling of internal olefins is very difficult, and
formed in a moderate yield (65%) in DMA (Table 2, in general a relatively high catalyst loading should be
entry 12). To our delight, the reaction proceeded applied.[9] Without an added oxidant, the reaction
more efficiently in a mixed solvent of DMF and proceeded only slowly in air (Table 2, entry 18). The
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Palladium-Catalyzed Oxidative Heck-Type Allylation of b,b-Disubstituted Enones
Table 3. Oxidative allylation of b,b-disubstituted enones
1 with allyl carbonate 2a.[a,b]
dithioacetal substrates with electron-deficient olefins,
double olefination products could be obtained.[9] Un-
expectedly, a-aroylketene dithioacetals only exhibited
very low reactivity under the same conditions, which
may be attributed to the steric hindrance from the
bulky aryl groups attached to the a-oxo moiety. These
results have demonstrated that the direct allylation of
1 is much more difficult than their olefination under
similar conditions.[8] As expected, decreasing the
steric hindrance of the a-oxoketene dithioacetals by
altering a-aroyl groups to a-cinnamoyls made the al-
lylation reactions proceed smoothly to form products
3f–3j in 62–69% yields. The electronic effect of the
substituents on the cinnamoyl aryls had little influ-
ence on the reaction efficiency. Methoxy, chloro,
bromo and trifluoromethyl groups were tolerated,
suggesting potential applications of the present syn-
thetic protocol due to the easy transformations of
these functionalities in organic synthesis. Surprisingly,
tetraene product 3l was also obtained in 55% yield.
The substrates of type 1 exhibited an obvious sub-
stituent effect of the alkylthio groups. Under the
same conditions, only trace amounts of the desired
product could be detected when an a-oxoketene 1,3-
dithioacetal was used as the starting material.
Under the same conditions as shown in Table 3, 2-
substituted allyl ethyl carbonates were employed to
explore the generality of the direct oxidative allyla-
tion methodology (Table 4). A notable steric effect
was observed from the substituted allyl carbonate
substrates. As the steric hindrance of the aryl moieties
in the substituted substrates 2 gradually decreased
from 2-Me, 3-Me, to 4-Me, the yields of products 4b–
4d were increased from 35%, 62%, to 71%, and 4a
was also obtained in a good yield (Table 4, entries 1–
4). Electron-donating and electron-withdrawing sub-
stituents were tolerated on the aryl groups of 2
(Table 4, entries 2–7). It is noteworthy that 2-alkyl-
substituted allyl ethyl carbonates 2i and 2j underwent
the allylation reactions to furnish the desired products
4i and 4j in moderate yields (Table 4, entries 8 and 9).
[a]
Reaction conditions:
1
(0.5 mmol), 2a (1.0 mmol),
Pd(OAc)2 (20 mol%), AgOAc (1.0 mmol), DMF/DMSO
ACHTUNGTRENNUNG
(2 mL, v/v=20/1), air atmosphere, 508C, 24 h.
Isolated yields.
[b]
reaction conditions were thus optimized as those for However, 2-naphthyl-substituted allyl ethyl carbonate
entry 15 in Table 2. showed very poor reactivity due to the high steric hin-
With the optimized reaction conditions in hand, the drance from the naphthyl substituent. a-Heteroaroyl-
substrate scope of a-oxoketene dithioacetals 1 was and cinnamoyl-ketene dithioacetals reacted well with
then investigated (Table 3). a-Cyanoketene dithioace- 2-aryl-substituted allyl ethyl carbonates to afford the
tal (1b) and a-ester ketene dithioacetal (1c) reacted the desired products in 55–68% yields (Table 4, en-
with 2a to afford the desired olefin products 3b and tries 10–13).
3c in 64% and 65% yields (Table 3), respectively. The
The mechanism is unclear at the present stage.
cyano (latent carbonyl) and ester groups exist as two Based upon our previous work[8] and observations,
important convertible functionalities for the potential a plausible mechanism is proposed (Scheme 1). The
utilitization of the products in organic synthesis. initial reaction of a-oxoketene dithioacetal 1 with
Treatment of heteroaryl a-oxoketene dithioacetals PdACHTNUTRGNEUNG(OAc)2 leads to the palladated ketene species A
with 2a exclusively afforded product 3d (63%) and 3e and acetic acid by electrophilic attack of the catalyst
À
(60%), respectively, and no double allylation occurred precursor at the C H bond of olefins. Species A
at the 5-positions of the furyl and thienyl rings. How- reacts with allyl carbonate 2 to form p-allyl-Pd(II) in-
ever, during the olefination of the same a-oxoketene termediate B. A following reductive elimination from
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Table 4. Oxidative allylation of b,b-disubstituted enones 1 with substituted allyl ethyl carbonates 2.[a]
Entry
1
1
2
Product 4
Yield [%][b]
1a
1a
2b
2c
4a
4b
69
2
3
35
62
1a
1a
2d
2e
4c
4
5
6
4d
71
65
70
1a
1a
2f
2g
4e
4f
7
8
1a
1a
2h
2i
4g
4h
75
58
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Palladium-Catalyzed Oxidative Heck-Type Allylation of b,b-Disubstituted Enones
Table 4. (Continued)
Entry
1
2
Product 4
Yield [%][b]
40
9
1a
1d
2j
2i
4i
4j
10
55
65
11
1f
2h
4k
12
1h
2h
4l
68
13
1j
2g
4m
65
[a]
[b]
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), PdACTHNUTRGENNG(U OAc)2 (20 mol%), AgOAc (1.0 mmol), DMF/DMSO (2 mL, v/v=
20/1), 508C, air atmosphere, 24 h.
Isolated yields.
B produces the desired product 3 or 4 as well as the a concise route to highly functionalized olefins. The
Pd(0) species. Oxidation of the Pd(0) species by present synthetic methodology has demonstrated rare
AgOAc regenerates the PdACHTNUGTRENUNG(OAc)2 catalyst, and an air examples for catalytic intermolecular allylic substitu-
atmosphere (oxygen) facilitates the catalyst regenera- tion of b,b-disubstituted enones.
tion. Alternatively, the Heck-type pathway involving
oxidative addition of Pd(0) to allyl carbonate 2 and
with subsequent carbopalladation and reductive elimi-
nation,[2] and the Tsuji–Trost-type process facilitating
formation of a p-allyl intermediate for nucleophilic
attack cannot be ruled out.[7]
Experimental Section
Typical Procedure for the Synthesis of 3 and 4:
Synthesis of 3a
In summary, palladium-catalyzed oxidative Heck-
type allylation of a-oxoketene dithioacetals with allyl
carbonates has been efficiently realized, providing PdACTHNUGRTNE(NUG OAc)2 (23 mg, 0.1 mmol) and AgOAc (167 mg,
A mixture of 1a (80 mg, 0.5 mmol), 2a (130 mg, 1.0 mmol),
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Rev. 2000, 100, 3009; d) G. T. Crisp, Chem. Soc. Rev.
1998, 27, 427; e) W. Cabri, I. Candiani, Acc. Chem. Res.
1995, 28, 2; f) R. F. Heck, Acc. Chem. Res. 1979, 12,
146.
[3] R. Matsubara, T. F. Jamison, J. Am. Chem. Soc. 2010,
132, 6880.
[4] H. He, W.-B. Liu, L.-X. Dai, S.-L. You, J. Am. Chem.
Soc. 2009, 131, 8346.
[5] J. Y. Hamilton, D. Sarlah, E. M. Carreira, J. Am. Chem.
Soc. 2014, 136, 3006.
[6] a) X. Zhang, M. Wang, M.-X. Zhang, Y.-H. Xu, T.-P.
Loh, Org. Lett. 2013, 15, 5531; b) A. Bianco, C. Cavari-
schia, M. Guiso, Eur. J. Org. Chem. 2004, 2894.
[7] a) G. Hirai, Y. Koizumi, S. M. Moharram, H. Oguri, M.
Hirama, Org. Lett. 2002, 4, 1627; b) G. Hirai, H. Oguri,
S. M. Moharram, K. Koyama, M. Hirama, Tetrahedron
Lett. 2001, 42, 5783.
[8] B. G. Jellerichs, J.-R. Kong, M. J. Krische, J. Am. Chem.
Scheme 1. A proposed mechanism.
Soc. 2003, 125, 7758.
[9] H. F. Yu, W. W. Jin, C. L. Sun, J. P. Chen, W. M. Du,
S. B. He, Z. K. Yu, Angew. Chem. 2010, 122, 5928;
Angew. Chem. Int. Ed. 2010, 49, 5792.
[10] T. Kobatake, S. Yoshida, H. Yorimitsu, K. Oshima,
Angew. Chem. 2010, 122, 2390; Angew. Chem. Int. Ed.
2010, 49, 2340.
[11] a) L. D. Wang, W. He, Z. K. Yu, Chem. Soc. Rev. 2013,
42, 599; b) Z. F. Mao, F. Huang, H. F. Yu, J. P. Chen,
Z. K. Yu, Z. Q. Xu, Chem. Eur. J. 2014, DOI: 10.1002/
chem.201305069; c) W. W. Jin, W. M. Du, Q. Yang,
H. F. Yu, J. P. Chen, Z. K. Yu, Org. Lett. 2011, 13, 4272;
d) H. F. Yu, Z. K. Yu, Angew. Chem. 2009, 121, 2973;
Angew. Chem. Int. Ed. 2009, 48, 2929.
1.0 mmol) in 2 mL DMSO/DMF (1/20, v/v) was stirred at
508C for 24 h. After being cooled to ambient temperature,
the resulting mixture was filtered through a short pad of
celite and rinsed with 10 mL of diethyl ether. Brine (30 mL)
was added and the mixture extracted with diethyl ether (3ꢂ
10 mL). The combined organic phase was dried over anhy-
drous MgSO4, filtered, and all the volatiles were evaporated
under reduced pressure. The resultant residue was purified
by silica gel column chromatography [eluent: petroleum
ether (60–908C)/diethyl ether=30:1, v/v] to afford 3a as
a yellow oil; yield: 100 mg (70%).
[12] L. Pan, X. H. Bi, Q. Liu, Chem. Soc. Rev. 2013, 42,
1251.
Acknowledgements
[13] a) C.-Y. He, Z. Wang, C.-Z. Wu, F.-L. Qing, X. G.
Zhang, Chem. Sci. 2013, 4, 3508; b) L.-Y. Jiao, M. Oes-
treich, Chem. Eur. J. 2013, 19, 10845; c) A. M. Wagner,
A. J. Hickman, M. S. Sanford, J. Am. Chem. Soc. 2013,
135, 15710; d) L. B. Huang, J. Qi, X. Wu, W. Q. Wu,
H. F. Jiang, Chem. Eur. J. 2013, 19, 15462.
We are grateful to the National Natural Science Foundation
of China (21272232) for financial support of this research.
[14] K. Ohmatsu, M. Ito, T. Kunieda, T. Ooi, J. Am. Chem.
References
Soc. 2013, 135, 590.
[15] a) Y. X. Zhang, Z. J. Li, Z.-Q. Liu, Org. Lett. 2012, 14,
226; b) Z. J. Li, Y. X. Zhang, Z.-Q. Liu, Org. Lett. 2012,
14, 74; c) J. T. Wang, Z. L. Cui, Y. X. Zhang, H. J. Li,
L.-M. Wu, Z. Q. Liu, Org. Biomol. Chem. 2011, 9, 663;
d) D. Tanaka, S. P. Romeril, A. G. Myers, J. Am. Chem.
Soc. 2005, 127, 10323; e) M. S. Chen, N. Prabagaran,
N. A. Labenz, M. C. White, J. Am. Chem. Soc. 2005,
127, 6970; f) M. S. Chen, M. C. White, J. Am. Chem.
Soc. 2004, 126, 1346.
[1] a) V. Tran, T. G. Minehan, Org. Lett. 2012, 14, 6100;
b) A. C. Oliveira, E. A. Hillard, P. Pigeon, D. D. Rocha,
F. A. R. Rodrigues, R. C. Montenegro, L. V. Costa-
Lotufo, M. O. F. Goulart, G. Jaouen, Eur. J. Med.
Chem. 2011, 46, 3778; c) T. S. Navale, K. Thakur, R.
Rathore, Org. Lett. 2011, 13, 1634.
[2] a) J. L. Bras, J. Muzart, Chem. Rev. 2011, 111, 1170;
b) A. B. Dounary, L. E. Overman, Chem. Rev. 2003,
103, 2945; c) I. P. Beletskaya, A. V. Cheprakov, Chem.
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Palladium-Catalyzed Oxidative Heck-Type Allylation of
7
b,b-Disubstituted Enones with Allyl Carbonates
Adv. Synth. Catal. 2014, 356, 1 – 7
Weiwei Jin, Qin Yang, Ping Wu, Jiping Chen,
Zhengkun Yu*
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