Palladium-catalyzed cross-coupling of internal alkenes with terminal alkenes to functionalized 1,3-butadienes using C-H bond activation: Efficient synthesis of bicyclic pyridones

Article abstract of DOI:10.1002/anie.201002737

chemical equation presented A highly regioselective direct cross-coupling of internal alkenes of a-oxoketene dithioacetals with terminal alkenes has been successfully realized by palladiumcatalyzed C-H bond activation, affording functionalized 1,3-butadie

Full text of DOI:10.1002/anie.201002737

Communications
DOI: 10.1002/anie.201002737
À
C H Bond Activation
Palladium-Catalyzed Cross-Coupling of Internal Alkenes with
Terminal Alkenes to Functionalized 1,3-Butadienes Using
À
C H Bond Activation: Efficient Synthesis of Bicyclic Pyridones**
Haifeng Yu, Weiwei Jin, Chenglin Sun, Jiping Chen, Wangmin Du, Songbo He, and
Zhengkun Yu*
À
Transition-metal-catalyzed cross-coupling through C H bond
activation is emerging as one of the most important tools for
carbon–carbon bond formation.[1] In general, vinylogous
compounds can be synthesized by Wittig,[2] Heck,[3] and
Suzuki[4] reactions, from the condensation of carbonyl com-
[6]
pounds,[5] C H addition to alkynes, or by means of
À
organometallic alkenyl compounds,[7] but direct alkenylation
À
using C H bond activation remains particularly attractive for
constructing carbon–carbon double bonds owing to their
Scheme 1. Direct cross-coupling of two terminal alkenes.[16] Ac=ace-
tate, DMSO=dimethyl sulfoxide.
synthetic simplicity and use of readily available reagents.[8]
Vinylborates,[9] vinyl halides,[10] alkenyl acetates,[11] and cyclic
1,3-dicarbonyls[12] have been known for the direct alkenyla-
alkenes with another alkene as the coupling partner. In order
to realize the direct cross-coupling of an internal alkene with a
À
tion of arene and (hetero)arene C H bonds. In a more simple
À
and synthetically useful alkenylation, terminal alkenes have
been applied as the coupling partners.[13–15] However, little
attention has been paid to the direct alkenylation of alkenyl
terminal alkene, the low reactivity of an internal alkenyl C H
bond should be overcome. We envisioned the introduction of
a structural element that could increase the reactivity of an
[19]
À
À
À
C H bonds with an alkene as the coupling partner using C H
internal alkenyl C H bond. Thus, we hypothesized that a
bond activation.[16]
1,2-dithiane group at the terminal position of an alkene
should satisfy the requirement on activating an internal
alkenyl C H bond, and a-oxoketene dithioacetals
chosen as the internal alkenes. Herein, we report the
palladium(II)-catalyzed direct cross-coupling of a-oxoketene
dithioacetals with terminal alkenes as well as the synthesis of
bicyclic pyridones [Eq. (1)].
1,3-Butadienes, as a class of versatile organic synthetic
reagents,[17] have usually been prepared by indirect meth-
ods.[18] To date, only two reports have been documented for
their direct synthesis, involving coupling two simple terminal
alkenes, owing to the difficulty in activating two alkene
substrates at the same time (Scheme 1).[16] Although two
examples involving the reaction of 3-methyl-1H-indenes with
tert-butyl acrylate were also reported,[16b] no work has been
directed to the direct alkenylation of open-chain internal
[20]
À
were
[*] Dr. H. F. Yu, W. W. Jin, Prof. C. L. Sun, Prof. Dr. J. P. Chen, W. M. Du,
Dr. S. B. He, Prof. Dr. Z. K. Yu
Dalian Institute of Chemical Physics, Chinese Academy of Sciences
(CAS), 457 Zhongshan Road, Dalian 116023 (China)
Fax: (+86)411-8437-9227
E-mail: zkyu@dicp.ac.cn
Homepage: http://www.omcat.dicp.ac.cn
The reaction of a-oxoketene dithioacetal 1a with tert-
butyl acrylate (2a) was explored to screen the reaction
conditions (Table 1). With 10 mol% of Pd(OAc)2 as the
catalyst and in the presence of 2 equivalents of AgOAc, the
reaction proceeded in N,N-dimethylformamide (DMF) at
ambient temperature under an air atmosphere, forming the
desired product, 1,3-buta-diene 3a, in 49% yield within
40 hours (Table 1, entry 1). Increasing the temperature to
508C remarkably accelerated the reaction, while further
elevating the reaction temperature did not obviously improve
the reaction efficiency (Table 1, entries 2 and 3). Extending
the reaction time deteriorated the yield of 3a from 63% to
50%, owing to product decomposition (Table 1, entry 4).
N,N-dimethylformamide seemed to be a suitable reaction
solvent. An oxygen atmosphere did not promote the reaction,
Dr. H. F. Yu
Department of Chemistry, Anshan Normal University
Anshan, Liaoning 114007 (China)
Prof. Dr. Z. K. Yu
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences (CAS)
354 Fenglin Road, Shanghai 200032 (China)
[**] We are grateful to the National Basic Research Program of China
(2009CB825300), the Innovation Program of CAS (DICP
K2009D04), NSFC and China Postdoctoral Science Foundation
(20080431160 to H.F.Y) for support of this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002737.
5792
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 5792 –5797

Angewandte
Chemie
Table 1: Screening of reaction conditions for the direct cross-coupling of
a-oxoketene dithioacetal 1a with terminal alkene 2a.[a]
and Cu(OAc)2, para-benzoquinone (BQ), and PhI(OAc)2
were much less efficient oxidants than AgOAc. The use of
PdCl2, [Pd(PPh3)2Cl2], or [Pd(PPh3)4] as the catalyst led to
poor formation of the product (Table 1, entries 15–17).
Increasing the catalyst loading from 10 to 20 mol% signifi-
cantly increased the product yield from 63% to 94% (Table 1,
entries 2, 18, and 19). It is noteworthy that 2 equivalents of
AgOAc were necessary for a satisfactory conversion of 1a
(Table 1, entries 20–22).
Entry Catalyst
(mol%)
Oxidant
AgOAc
Solvent T [8C] t [h] Yield
[%][b]
1
Pd(OAc)2 (10)
DMF
RT 40
49
(39)[c]
63
64
50
32
15
n.r.
52
40
3
64
11
20
n.r.
15
6
5
75
Using these optimized conditions, the scope of the
procedure was then examined (Table 2). The reactions of 1a
with electron-deficient terminal alkenes, i.e., alkyl acrylates
and N,N-dimethylacrylamide 2a–d, afforded 1,3-butadienes
3a–d in 83–89% yield (Table 2, entries 1–4). With acrolein 2e,
product 3e was obtained in only 45% yield (Table 2, entry 5).
Treatment of 1a with styrene (2 f) generated the desired
product 3 f (69%) and its isomer 3 f’ (11%; Table 2, entry 6).
In a similar fashion, the reaction of 1a with 4-chlorostyrene
(2g) also resulted in the separable isomers 3g (73%) and 3g’
(10%; Table 2, entry 7). However, the reaction of 1a and 4-
methoxystyrene (2h) or 2-methylstyrene (2i) led to insepa-
rable mixtures of isomers 3 and 3’ (Table 2, entries 8 and 9).
Unexpectedly, the reaction of 1a and allyl benzoate (2j)
formed the allylation product 3j in 56% yield. Vinyl acetate
(2k) only exhibited a moderate reactivity. Allyl alcohol (2l)
underwent the cross-coupling reaction with 1a to afford 1,3-
butadiene 3e (37%), thus suggesting oxidation of the
alcoholic hydroxyl during the reaction. The reactions of
1ba–c with 2c and 2d produced the desired products 3l–o in
54-67% yields (Table 2, entries 13–16), respectively, while the
reactions of heteroaryl a-oxoketene dithioacetals 1bd and
1be with 2c formed the desired major products 3p (62%) and
3q (60%) as well as the by-products 3p’ (7%) and 3q’ (7%)
[Table 2, entries 17 and 18; Eq. (2)]. However, a-oxoketene
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
PdCl2 (10)
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
DMF
DMF
DMF
DMSO
toluene
TFA
50
70
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
12
12
22
12
12
12
12
12
12
12
12
12
12
12
12
12
8
DMA
THF
[d]
O2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
[d]
AgOAc/O2
Cu(OAc)2
BQ
PhI(OAc)2
AgOAc
[Pd(PPh3)2Cl2] (10) AgOAc
[Pd(PPh3)4] (10)
Pd(OAc)2 (15)
Pd(OAc)2 (20)
AgOAc
AgOAc
AgOAc
8
94
(86)[c]
74
20
21
22
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
AgOAc[e]
AgOAc[f]
AgOAc[g]
DMF
DMF
DMF
50
50
50
8
8
8
81
90
[a] Conditions: 1a (0.5 mmol), 2a (1.0 mmol), oxidant (1.0 mmol),
solvent (2 mL), in air. [b] Determined by GC analysis. [c] Yield of isolated
product given in parentheses. [d] Atmospheric O2. [e] 1.0 equivalent.
[f] 1.5 equivalents. [g] 3 equivalents. n.r.=no reaction, TFA=trifluoro-
acetic acid.
Table 2: Direct alkenylation of a-oxoketene dithioacetals 1a–d with terminal alkenes 2.[a]
Entry
1
1
2
Product 3
Yield
[%][b]
Entry
1
2
Product 3
Yield
[%][b]
86
10[c]
1a
56
2
3
4
1a
1a
1a
83
85
89
11[c]
12[c]
13
1a
1a
35
37
56
3e
2c
2c
5[c]
1a
45
14
64
Angew. Chem. Int. Ed. 2010, 49, 5792 –5797
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5793

Communications
Table 2: (Continued)
Entry
1
2
Product 3
Yield
[%][b]
Entry
15
1
2
Product 3
Yield
[%][b]
6[c]
1a
69
11
1bb
2d
67
54
16
2c
7[c,d]
1a
73
10
17[g]
2c
2c
62
60
18[g]
71
8[c,e]
1a
19
20
2a
2a
38
(3h/3h’=4:1)[f]
<5
67
9[c]
1a
(3i/3i’=1:4)[f]
[a] Conditions: 1 (0.5 mmol), 2 (1.0 mmol), Pd(OAc)2 (20 mol%), AgOAc (1.0 mmol), DMF (2 mL), 508C, in air. Entries 1–4, 8 h; entries 5–8 and 10–
12, 12 h; entries 9 and 13–18, 24 h. [b] Yield of isolated products. [c] 2 (2.5 mmol). [d] R’=4-ClC6H4. [e] R’=4-MeOC6H4. [f] Determined by 1H NMR
spectroscopy. [g] See Equation (2).
dithioacetals 1c and 1d only exhibited poor reactivity
(Table 2, entries 19 and 20), thus revealing an obvious
substituent effect of the alkylthio groups. The molecular
structures of 3 were confirmed by the X-ray crystallographic
structural determination of 3n, in which the newly coupled
carbon–carbon double bond exists in an E configuration (see
the Supporting Information).
The cross-coupling reactions of a-cinnamoyl ketene
dithioacetals 1ea with alkenes 2a–d gave ployene products
4a–d in 71–82% yields (Table 3, entries 1–4). Using styrene
2 f, the desired product 4e was obtained in 62% yield.
Treatment of 1eb and 1ec with 2a also efficiently afforded the
desired products in 79% and 78% yields, respectively
(Table 3, entries 6 and 7). Heteroaryl dithioacetals 1ed and
1ee were coupled with 2a to afford 4h and 4i (60% and 62%,
respectively) as well as the separable double alkenylation
products 4h’ and 4i’ (8% and 10%, respectively; Table 3,
entries 8 and 9). Triene 1ef underwent the same reaction,
5794
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 5792 –5797

Angewandte
Chemie
Table 3: Direct alkenylation of a-cinnamoyl ketene dithioacetals 1e with terminal alkenes 2.[a]
Entry
1
2
Product 4
Yield
[%][b]
Entry
1
2
Product 4
Yield
[%][b]
1
2a
82
7
2a
78
2
1ea
1ea
1ea
1ea
2b
2c
2d
2 f
75
73
71
62
8
2a
60
10
62
8
3
4
9
2a
5[c]
6
2a
79
10
2a
59
[a] Conditions: 1e (0.5 mmol), 2 (1.0 mmol), Pd(OAc)2 (20 mol%), AgOAc (1.0 mmol), DMF (2 mL), 508C, in air, 8 h. [b] Yield of isolated product.
[c] 2 f (2.5 mmol).
forming tetraene 4j (59%; Table 3, entry 10). Trienes of type
A were not detected from the reactions, thus suggesting that
so that double alkenylation occurred at C(5’) instead of C(4)
in 1e.
À
À
the C(4) H bond is much less reactive than the C(2) H bond
in 1e. This observation is rationalized by the electronic nature
of the carbon–carbon double bonds of 1e, wherein polar-
ization flows from the two electron-donating sulfur atoms to
the electron-withdrawing carbonyl group[20] and makes C(2)
The reaction of 1 and 2 is presumably initiated by
formation of the organometallic ketene species B from the
electrophilic attack of the catalyst precursor Pd(OAc)2 at
À
C(2) H bond of a-oxoketene dithioacetal 1 (Scheme 2).
Coordination of terminal alkene 2 to the metal center,
À
more nucleophilic than C(4). Therefore, the C(2) H bond in
1e can be more easily activated to couple with terminal
followed by insertion of the coordinated carbon–carbon
À
double bond to the Pd C bond forms species C which
À
alkenes 2. In addition, the C(5’) H bond in 2’-furyl or 2’-
thienyl substrates is also more reactive than the C(4) H bond,
controls the stereochemical configuration of the products. b-
À
Hydrogen elimination occurs to afford the desired 1,3-
Angew. Chem. Int. Ed. 2010, 49, 5792 –5797
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5795

Communications
Table 4: Synthesis of bicyclic pyridones 6.[a,b]
6a, 79%
6 f, 87%
6b, 58%
6g, 74%
6c, 85%
6h, 71%
6d, 84%
6i, 63%[c]
6e, 88%
[a] Conditions: 3 or 4 (0.25 mmol), diamine 5 (0.3 mmol), EtOH (2 mL), reflux, 14 h. [b] Yield of isolated product. [c] 1008C.
À
size functionalized 1,3-butadienes using C H bond activation.
Condensation of the resultant 1,3-butadienes with diamines
efficiently afforded potentially bioactive bicyclic pyridones.
Experimental Section
Synthesis of 3a: A mixture of 1a (80 mg, 0.5 mmol), 2a (128 mg,
1.0 mmol), Pd(OAc)2 (23 mg, 0.1 mmol), and AgOAc (167 mg,
1.0 mmol) in DMF (2 mL) was stirred at 508C for 8 h. Water
(30 mL) was then added, the solution was filtered, and extracted with
CH2Cl2 (3 ꢀ 10 mL). The combined organic phases were dried over
anhydrous MgSO4, filtered, and the volatile compounds were
evaporated under reduced pressure. The resultant residue was
purified by column chromatography on silica gel (petroleum ether
(60–908C)/diethyl ether 9:1, v/v) to afford 3a as a yellow solid
(123 mg, 86%).
Received: May 6, 2010
Published online: July 13, 2010
Scheme 2. A proposed mechanism.
À
Keywords: alkenes · alkenylation · C H activation · heterocycles ·
palladium
.
butadiene product 3 or 4 as well as a HPdOAc species which
can be further reduced to palladium(0). Oxidation of the
palladium(0) species regenerates Pd(OAc)2 and finishes the
catalytic cycle. Production of 3i’ and 3j is presumably
attributed to the formation of palladium(II) intermediate C’.
Pharmacologically active bicyclic pyridones[21] are usually
synthesized by cyclocondensation of ketenaminals,[22] addi-
tion of diamines to thiomethyl pyridones,[23] intramolecular
Mitsunobu reactions of 2,6-difluoropyridines,[24] and the
functionalization of simple bicyclic pyridones.[25] Intrigued
by the structural features, we reacted 3 and 4 with different
diamines in ethanol at reflux, efficiently affording bicyclic
pyridones 6 in 58–88% yields (Table 4). The molecular
structures of 6 were further confirmed by X-ray crystallog-
raphy of 6b in which multiple hydrogen bonds are present
(see the Supporting Information).
[1] For selected recent reviews, see: a) L. M. Xu, B. J. Li, Z. Yang,
Z. J. Shi, Chem. Soc. Rev. 2010, 39, 712; b) L. Ackermann, R.
Vicente, A. R. Kapdi, Angew. Chem. 2009, 121, 9976; Angew.
Chem. Int. Ed. 2009, 48, 9792; c) X. Chen, K. M. Engle, D.-H.
Wang, J.-Q. Yu, Angew. Chem. 2009, 121, 5196; Angew. Chem.
Int. Ed. 2009, 48, 5094.
[2] D. J. Dong, H. H. Li, S. K. Tian, J. Am. Chem. Soc. 2010, 132,
5018.
[3] C. Torborg, M. Beller, Adv. Synth. Catal. 2009, 351, 3027.
[4] G. A. Molander, B. Canturk, Angew. Chem. 2009, 121, 9404;
Angew. Chem. Int. Ed. 2009, 48, 9240.
[5] G. Fridkin, N. Boutard, W. D. Lubell, J. Org. Chem. 2009, 74,
5603.
[6] R. Tanaka, K. Noguchi, K. Tanaka, J. Am. Chem. Soc. 2010, 132,
1238.
[7] J. Sakurada, T. Satoh, Tetrahedron 2007, 63, 3806.
[8] E.-I. Negishi, Z. H. Huang, G. W. Wang, S. Mohan, C. Wang, H.
Hattori, Acc. Chem. Res. 2008, 41, 1474.
[9] R. E. Shade, A. M. Hyde, J.-C. Olsen, C. A. Merlic, J. Am. Chem.
Soc. 2010, 132, 1202.
In summary, a novel palladium-catalyzed direct alkenyla-
tion of internal alkenes a-oxoketene dithioacetals with
terminal alkenes has been successfully developed to synthe-
5796
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 5792 –5797

Angewandte
Chemie
[10] J. J. Mousseau, J. A. Bull, A. B. Charette, Angew. Chem. 2010,
122, 1133; Angew. Chem. Int. Ed. 2010, 49, 1115.
[11] Y. Matsuura, M. Tamura, T. Kochi, M. Sato, N. Chatani, F.
Kakiuchi, J. Am. Chem. Soc. 2007, 129, 9858.
[12] A. Arcadi, M. Alfonsi, F. Marinelli, J. Organomet. Chem. 2007,
692, 5322.
[13] Selected recent reports, see: a) D.-H. Wang, K. M. Engle, B.-F.
Shi, J.-Q. Yu, Science 2010, 327, 315; b) M. Wasa, K. M. Engle, J.-
Q. Yu, J. Am. Chem. Soc. 2010, 132, 3680; c) B.-F. Shi, Y.-H.
Zhang, J. K. Lam, D.- H. Wang, J.-Q. Yu, J. Am. Chem. Soc. 2010,
132, 460; d) J. L. Wu, X. L. Cui, L. M. Chen, G. J. Jiang, Y. J. Wu,
J. Am. Chem. Soc. 2009, 131, 13888; e) A. Garcꢁa-Rubia, R. G.
Arrayꢂs, J. C. Carretero, Angew. Chem. 2009, 121, 6633; Angew.
Chem. Int. Ed. 2009, 48, 6511.
[18] C. Vovard-Le Bray, S. Dꢃrien, P. Dixneuf, Angew. Chem. 2009,
121, 1467; Angew. Chem. Int. Ed. 2009, 48, 1439.
[19] T. Kobatake, S. Yoshida, H. Yorimitsu, K. Oshima, Angew.
Chem. 2010, 122, 2390; Angew. Chem. Int. Ed. 2010, 49, 2340.
[20] For selected recent reports, see: a) H. F. Yu, Z. K. Yu, Angew.
Chem. 2009, 121, 2973; Angew. Chem. Int. Ed. 2009, 48, 2929;
b) J. Tan, X. X. Xu, L. J. Zhang, Y. F. Li, Q. Liu, Angew. Chem.
2009, 121, 2912; Angew. Chem. Int. Ed. 2009, 48, 2868; c) P. P.
Singh, A. K. Yadav, H. Ila, H, Junjappa, J. Org. Chem. 2009, 74,
5496.
[21] a) L. A. Smyth, T. P. Matthews, P. N. Horton, M. B. Hursthouse,
I. Collins, Tetrahedron 2010, 66, 2843; b) L. A. Marcaurelle, C.
Johannes, D. Yohannes, B. P. Tillotson, D. Mann, Bioorg. Med.
Chem. Lett. 2009, 19, 2500.
[14] H. Zhou, Y.-H. Xu, W.-J. Chung, T.-P. Loh, Angew. Chem. 2009,
121, 5459; Angew. Chem. Int. Ed. 2009, 48, 5355.
[22] M. X. Zhao, M. X. Wang, Z. T. Huang, Tetrahedron 2002, 58,
1309.
[15] Y.-H. Zhang, B.-F. Shi, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131,
5072.
[16] a) Y. Hatamoto, S. Sakaguchi, Y. Ishii, Org. Lett. 2004, 6, 4623;
b) Y.-H. Xu, J. Lu, T.-P. Loh, J. Am. Chem. Soc. 2009, 131, 1372.
[17] C. Schotes, A. Mezzetti, J. Am. Chem. Soc. 2010, 132, 3652.
[23] D. G. Hehemann, W. Winnik, J. Heterocycl. Chem. 1994, 31, 393.
[24] D. C. Cheng, L. Croft, M. Abdi, A. Lightfoot, T. Gallagher, Org.
Lett. 2007, 9, 5175.
[25] D. C. Cheng, T. Gallagher, Org. Lett. 2009, 11, 2639.
Angew. Chem. Int. Ed. 2010, 49, 5792 –5797
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5797