Carbon-carbon bond formation: Palladium-catalyzed oxidative cross-coupling of N-tosylhydrazones with allylic alcohols

Article abstract of DOI:10.1002/chem.201200949

In the zone: Pd-catalyzed oxidative cross-coupling of N-tosylhydrazones with allylic alcohols leads to C-C bond formation. A palladium-carbene migratory insertion is proposed to play the key role in this transformation. The reaction proceeds with readily available starting materials to afford substituted alkenes in a highly stereoselective manner (see scheme). Copyright

Full text of DOI:10.1002/chem.201200949

COMMUNICATION
DOI: 10.1002/chem.201200949
Carbon–Carbon Bond Formation: Palladium-Catalyzed Oxidative Cross-
Coupling of N-Tosylhydrazones with Allylic Alcohols
Huoji Chen, Li Huang, Wei Fu, Xiaohang Liu, and Huanfeng Jiang*[a]
Table 1. Optimization of reaction conditions.[a]
Over the past few decades, the development of palladi-
um-catalyzed carbon–carbon bond-forming reactions has
dramatically advanced “state-of-the-art” organic synthesis.[1]
The most commonly applied palladium-catalyzed carbon–
carbon bond-forming reactions in synthesis are the Heck,
Entry
Catalyst
Oxidant
Yield [%][b]
Stille, Suzuki, Sonogashira, Tsuji–Trost, and the Negishi re-
actions. In particular, the development of alternative meth-
odologies that could be advantageous in terms of the selec-
tivity and the availability of starting materials prior to the
carbon–carbon bond-forming event is of interest.[2] Recently,
Pd-catalyzed cross-coupling reactions of diazo compounds
have emerged as a new type of cross-coupling reaction for
the construction of carbon–carbon bonds.[3] An alternative
route that makes use of N-tosylhydrazones as nucleophiles,
which are an in situ source of diazo compounds for this
transformation, has attracted much attention. The required
N-tosylhydrazones are easily generated from carbonyl com-
pounds, and the reaction can be seen as a cross-coupling of
carbonyl groups, a process of high synthetic relevance that
involves several steps and other methodologies. Recently,
the groups of Barluenga and Wang have made significant
progress towards palladium-catalyzed coupling reactions by
using N-tosylhydrazones as the coupling partner.[4,5,6] A mi-
gratory insertion involving a palladium–carbene is proposed
to account for these cross-coupling reactions.[7] However,
palladium-catalyzed oxidative cross-coupling reactions using
N-tosylhydrazones as the nucleophile are less developed.[5]
Herein, we report a new palladium-catalyzed oxidative
cross-coupling reaction of N-tosylhydrazones with allylic al-
cohols for the formation of carbon–carbon bonds. The reac-
tion proceeds with readily available starting materials and
1
2
3
4
5
6
7
8
9
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
N
O2 (1 atm)
TBHP
DDQ
8
5
0
11
5
15
88 (84)
0
0
Ag2CO3
PhI
N
Cu(OAc)2
N
BQ
BQ
BQ
Cu
G
–
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), catalyst
(10 mol%), and oxidant (2.0 equiv) in MeCN (3 mL) for 8 h. [b] Yields
determined by GC; number in parentheses is the yield of isolated prod-
uct.
tion conditions for the synthesis of product 3aa. Subse-
quently, we tested a series of oxidants in the reaction; how-
ever, inferior results were obtained when using tert-butyl hy-
droperoxide (TBHP), 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ), Ag2CO3, PhIACTHNUTRGENN(UG OAc)2, or CuACHUTGNTREN(NUGN OAc)2 as an oxi-
dant (Table 1, entries 2–6). To our delight, the use of
benzoquinone (BQ) as the oxidant greatly promoted the Pd-
AHCTUNGRTEG(NNUN OAc)2-catalyzed reaction of 1a with 2a, leading to the cor-
responding product 3aa in 88% GC yield (Table 1, entry 7).
Notably, none of the desired product 3aa was detected
when CuACTHNURTGENNG(U OAc)2 was used as the metal catalyst (Table 1,
entry 8). The reaction did not occur without the palladium
catalyst (Table 1, entry 9); thus, the optimal reaction condi-
tions for the cross-coupling of N-tosylhydrazones with allylic
alcohols involved the treatment of allylic alcohol 1a with
N-tosylhydrazone 2a in acetonitrile at 908C in the presence
of palladium acetate (10 mol%) and lithium tert-butoxide
(3.0 equiv) using BQ (2.0 equiv) as an oxidant.
With the optimized reaction conditions identified, the N-
tosylhydrazone substrate scope was then investigated as
shown in Table 2. The cross-coupling reaction of aromatic
N-tosylhydrazones containing electron-withdrawing or elec-
tron-donating groups afforded the desired products (3aa–
3ah) in moderate to good yields. We also found no signifi-
cant effect on the reactivity when compounds were used
which had substituents at the para-, meta-, and ortho posi-
tions of the aromatic ring (products 3ad–3af). The naphthyl
affords substituted alkenes in
manner.
a highly stereoselective
Initially, we explored the Pd-catalyzed reaction of allylic
alcohol 1a with N-tosylhydrazone 2a (Table 1). We found
that a small amount of product 3aa was obtained when
oxygen was used as an oxidant (Table 1, entry 1). This result
peaked our interest and we then screened for suitable reac-
[a] H. Chen, L. Huang, W. Fu, X. Liu, Prof. Dr. H. Jiang
School of Chemistry and Chemical Engineering
South China University of Technology
Guangzhou 510640 (P.R. China)
Fax : (+86)20-8711-2906
E-mail: jianghf@scut.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200949.
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Table 2. Scope of reaction.[a]
2m) also underwent smooth reactions to afford the corre-
sponding products (3l and 3m) in good yield.
Next, we used N-tosylhydrazones 2p, 2q, and 2u to exam-
ine the cross-coupling reaction with a series of allylic alco-
hols (Table 2, allylic alcohol scope). Electron-rich and elec-
tron-poor benzene derivatives, as well as alkyl-substituted
allyl alcohols, can be used. Notably, halide substituents were
tolerated on the aromatic ring and furnished the products
3hu and 3iu in good yields.
Stereochemistry is a very important issue in the synthesis
of polysubstitued olefins, and various trisubstituted olefins
were obtained in this reaction with high stereoselectivity
(Z/E>10:1) (Table 2, see products 3an, 3ao, and allylic
alcohol scope).
We succeeded in performing the reaction in a one-pot
fashion by simply heating the carbonyl compound 4 with to-
sylhydrazide prior to the addition of the allyl alcohol; the
oxidative coupling products were obtained in similar yields,
but without the need to isolate the intermediate tosylhydra-
zone. Selected examples are shown in Scheme 1. It is worth
noting that the reaction can be carried out on a multigram
scale. For example, the reaction using 10 mmol (1.98 g) of 4-
bromoacetophenone resulted in 1.44 g of the coupling prod-
uct 3au (Scheme 1, 57% yield of isolated product). More-
over, the one-pot process can be considered a direct oxida-
tive coupling of a carbonyl compound, a type of transforma-
tion without precedent and of great synthetic interest.
Scheme 1. One-pot synthesis. Reaction conditions: i) carbonyl compound
(0.3 mmol), tosylhydrazide (0.3 mmol), MeCN (3 mL), 908C, 90 min. ii)
allyl alcohol (0.3 mmol), [PdACTHNURGTNEU(GN OAc)2] (10 mol%), BQ (2.0 equiv), tBuOLi
(3.0 equiv), 908C, 8 h. Yields of isolated products are given. [a] Carried
out on a 10 mmol scale.
The exact mechanism for the product formation is not
clear at the present stage. A plausible mechanism for the ox-
idative cross-coupling reaction is proposed in Scheme 2. The
reaction of allyl alcohol 1 with PdII leads to palladium alkox-
ide A by an intramolecular coordination of the alkene to
the palladium center. Next, palladium alkoxide A undergoes
[a] All reactions were conducted on a 0.3 mmol scale: 1 (0.3 mmol), 2
(0.3 mmol), [PdACHTUNGTRENNUNG(OAc)2] (10 mol%), BQ (2.0 equiv), and tBuOLi
(3.0 equiv) in MeCN (3 mL) at 908C for 8 h; yields of isolated products
1
are given. [b] Z/E>10:1; the Z/E selectivity was determined by H NMR
spectroscopy; for product 3au, the configuration was further confirmed
by NOESY and COSY spectra.
À
a C H bond cleavage to form intermediate B, with the
double bond still coordinated to the palladium center. This
À
is followed by insertion of the olefin into the Pd H bond to
N-tosylhydrazone (2i) was also a suitable substrate for this
reaction (product 3ai). The reaction of heterocyclic N-tosyl-
hydrazones, such as furan and benzofuran, with allylic alco-
hol 1a under similar conditions also proceeded well (prod-
ucts 3aj and 3ak). Notably, cyclic N-tosylhydrazones (2l and
give the palladium complex C.[8] Then, reaction of the diazo
compound D (generated by the base-mediated decomposi-
tion of the tosylhydrazone 2) with palladium complex C pro-
duces the Pd–carbene complex E.[3–7] Subsequently, a migra-
tory insertion occurs to give cyclic intermediate F (similar to
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Pd-Catalyzed Oxidative Cross-Coupling
COMMUNICATION
desired product 3. To investigate this possible pathway, vinyl
ketone 4 and N-tosylhydrazone 2a were treated with lithium
tert-butoxide at 908C [Eq. (1)]. Only a trace amount of
1
product 3ea was detected in the H NMR spectrum of the
crude product. Moreover, 1e was reacted under the opti-
mized reaction conditions but only the ketone product 5 was
observed, and no vinyl ketone 4 was detected [Eq. (2)].
Consequently, this pathway can be excluded.[10]
In conclusion, we have reported a new type of Pd-cata-
lyzed carbon–carbon bond-forming coupling reaction of N-
tosylhydrazones with allylic alcohols. The main features of
this new methodology are: 1) common and readily available
starting materials; (2 the formation of products with high
stereoselectivity. Additionally, the reaction can be carried
out on a multigram scale and in one pot. For these reasons,
this reaction is highly applicable for target-oriented organic
synthesis.
Scheme 2. Plausible mechanism for the oxidative cross-coupling.
cyclohexane), which is promoted by coordination of the car-
bonyl group to the alkylpalladium intermediate. Finally, the
olefin 3 is produced with exclusive regioselectivity by syn-b-
Hb elimination of F, and Pd0 is oxidized by benzoquinone to
regenerate the PdII species.
In this reaction pathway, the high stereoselectivity for the
formation of (E)-olefins can be explained by the transition
state of the syn-b-H elimination from intermediate F: the
group R3 prefers to eclipse with the less-bulky linear alkyl
moiety, and this arrangement leads to (E)-olefins 3 as the
main products (Scheme 2).
Another plausible mechanism starts with the initial forma-
tion of a palladium–carbene complex I (Scheme 3). After
deprotonation by a base, the palladium–carbene complex I
is transformed into to the alkenylpalladium intermediate II.
Finally, the product 3 is produced by the traditional Heck
route.[9]
Experimental Section
General procedure: [PdACHTNUGTRNEUNG(OAc)2] (0.03 mol, 6.7 mg), BQ (0.6 mmol,
64.8 mg), tBuOLi (0.9 mmol, 72.1 mg), and N-tosylhydrazone 2 were
mixed with acetonitrile (3.0 mL) in a glass vial or round-bottom flask
equipped with a magnetic stirring bar. Then, allyl alcohol 1 was added
and the mixture was stirred at 908C for 8 h. After cooling to room tem-
perature, ethyl acetate and brine were added and the layers were separat-
ed. The aqueous phase was extracted twice with ethyl acetate. The com-
bined organic layers were washed with two portions of brine and then
dried over MgSO4 and filtered. The residue was purified by flash chroma-
tography on silica gel to obtain the desired products 3 using light petrole-
um ether/ethyl acetate (50:1 or 25:1, v/v) as eluent.
Acknowledgements
We thank the National Natural Science Foundation of China (20932002
and 21172076), the National Basic Research Program of China (the 973
Program, 2011CB808600), the Guangdong Natural Science Foundation
(10351064101000000) and the Fundamental Research Funds for the Cen-
tral Universities (2010ZP0003) for financial support.
À
Keywords: allylic compounds
coupling · N-tosylhydrazones · palladium
·
C C coupling
·
cross-
Scheme 3. Another plausible mechanism for the oxidative cross-coupling.
However, it is possible that the allylic alcohol could be
oxidized by PdII to afford vinyl ketone, and then the base-
mediated 1,4-addition of hydrazones could occur to give the
[1] For monographs on palladium catalysis, see: a) Handbook of Orga-
nopalladium Chemistry for Organic Synthesis (Ed.: E. Negishi),
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
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ÞÞ
These are not the final page numbers!

H. Jiang et al.
Wiley, Hoboken, 2002; b) J.-L. Malleron, J.-C. Fiaud, J.-Y. Legros,
Handbook of Palladium-Catalyzed Organic Reactions, Academic
Press, London, 1997; c) J. Tsuji, Palladium Reagents and Catalysts,
Wiley, Chichester, 1995.
b) L. Zhou, Fe. Ye, J. Ma, Y. Zhang, J. Wang, Angew. Chem. 2011,
123, 3572; Angew. Chem. Int. Ed. 2011, 50, 3510.
[6] For recent reviews, see: a) Z. Shao, H. Zhang, Chem. Soc. Rev. 2012,
41, 560; b) J. Barluenga, C. Valdꢁs, Angew. Chem. 2011, 123, 7626;
Angew. Chem. Int. Ed. 2011, 50, 7486.
[2] K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005, 117,
4516; Angew. Chem. Int. Ed. 2005, 44, 4442.
[7] For reports on the migratory insertion of stable palladium–carbene
species, see: a) A. C. Albꢁniz, P. Espinet, R. Manrique, A. Pꢁrez-
Mateo, Angew. Chem. 2002, 114, 2469; Angew. Chem. Int. Ed. 2002,
41, 2363; b) M. Brçring, C. D. Brandt, S. Stellwag, Chem. Commun.
2003, 2344; c) D. Solꢁ, L. Vallverdffl, X. Solans, M. Font-Bardia, J.
Bonjoch, Organometallics 2004, 23, 1438; d) A. C. Albꢁniz, P. Espi-
net, R. Manrique, A. Pꢁrez-Mateo, Chem. Eur. J. 2005, 11, 1565;
e) A. C. Albꢁniz, P. Espinet, A. Pꢁrez-Mateo, A. Nova, G. Ujaque,
Organometallics 2006, 25, 1293.
[8] a) J. A. Keith, P. M. Henry, Angew. Chem. 2009, 121, 9200; Angew.
Chem. Int. Ed. 2009, 48, 9038; b) K. M. Gligorich, M. S. Sigman,
Angew. Chem. 2006, 118, 6764; Angew. Chem. Int. Ed. 2006, 45,
6612; c) K. B. Urkalan, M. S. Sigman, J. Am. Chem. Soc. 2009, 131,
18042; d) K. B. Urkalan, M. S. Sigman, J. Am. Chem. Soc. 2011, 133,
11454.
[3] a) K. J. Greenman, D. L. Van Vranken, Tetrahedron 2005, 61, 6438;
b) C. Peng, J. Cheng, J. Wang, J. Am. Chem. Soc. 2007, 129, 8708;
c) S. Chen, J. Wang, Chem. Commun. 2008, 4198; d) C. Peng, Y.
Wang, J. Wang, J. Am. Chem. Soc. 2008, 130, 1566; e) W. Y. Yu,
Y. T. Tsoi, Z. Zhou, A. S. C. Chan, Org. Lett. 2009, 11, 469; f) R. Ku-
dirka, S. K. J. Devine, C. S. Adams, D. L. Van Vranken, Angew.
Chem. 2009, 121, 3731; Angew. Chem. Int. Ed. 2009, 48, 3677; g) Z.-
S. Chen, X.-H. Duan, P.-X. Zhou, S. Ali, J.-Y. Luo, Y.-M. Liang,
Angew. Chem. 2012, 124, 1399; Angew. Chem. Int. Ed. 2012, 51,
1370.
[4] For examples, see: a) J. Barluenga, P. Moriel, C. Valdꢁs, F. Aznar,
Angew. Chem. 2007, 119, 5683; Angew. Chem. Int. Ed. 2007, 46,
5587; b) J. Barluenga, M. Tomꢂs-Gamasa, P. Moriel, F. Aznar, C.
Valdꢁs, Chem. Eur. J. 2008, 14, 4792; c) J. Barluenga, M. Escribano,
P. Moriel, F. Aznar, C. Valdꢁs, Chem. Eur. J. 2009, 15, 13291; d) Q.
Xiao, J. Ma, Y. Yang, Y. Zhang, J. Wang, Org. Lett. 2009, 11, 4732;
e) B. Trꢁguier, A. Hamze, O. Provot, D. J. Brion, M. Alami, Tetrahe-
dron Lett. 2009, 50, 6549; f) Z. Zhang, Y. Liu, M. Gong, X. Zhao, Y.
Zhang, J. Wang, Angew. Chem. 2010, 122, 1157; Angew. Chem. Int.
Ed. 2010, 49, 1139; g) E. Brachet, A. Hamze, J. F. Peyrat, J. D.
Brion, M. Alami, Org. Lett. 2010, 12, 4042; h) Q. Xiao, Y. Xia, H.
Li, Y. Zhang, J. Wang, Angew. Chem. 2011, 123, 1146; Angew.
Chem. Int. Ed. 2011, 50, 1114; i) L. Zhou, Fe. Ye, Y. Zhang, J. Wang,
J. Am. Chem. Soc. 2010, 132, 13590; j) J. Barluenga, L. Florentino, F.
Aznar, C. Valdꢁs, Org. Lett. 2011, 13, 510; k) J. Barluenga, M.
Tomꢂs-Gamasa, F. Aznar, C. Valdꢁs, Angew. Chem. 2010, 122, 7008;
Angew. Chem. Int. Ed. 2010, 49, 6856; l) J. Barluenga, N. QuiÇones,
M.-J. Cabal, F. Aznar, C. Valdꢁs, Angew. Chem. 2011, 123, 2398;
Angew. Chem. Int. Ed. 2011, 50, 2350; m) Z.-S. Chen, X.-H. Duan,
L.-Y. Wu, S. Ali, K.-G. Ji, P.-X. Zhou, X.-Y. Liu, Y.-M. Liang, Chem.
Eur. J. 2011, 17, 6918; n) F. Zhou, K. Ding, Q. Cai, Chem. Eur. J.
2011, 17, 12268; o) J. Zhang, Y. Liu, L. Ling, Y. Li, Y. Dong, M.
Gong, X. Zhao, Y. Zhang, J. Wang, J. Am. Chem. Soc. 2011, 133,
4330; p) L. Zhou, F. Ye, Y. Zhang, J. Wang, Org. Lett. 2012, 14, 922.
[5] For examples of palladium-catalyzed oxidative cross-coupling reac-
tions using N-tosylhydrazones as nucleophiles, see: a) X. Zhao, J.
Jing, K. Lu, Y. Zhang, J. Wang, Chem. Commun. 2010, 46, 1724;
[9] J. B. Melpolder, R. F. Heck, J. Org. Chem. 1976, 41, 265.
[10] Additionally, vinyl ketone 4b and N-tosylhydrazone 2a were treated
under similar conditions. Both the cyclization product and the chain
product were detected in the 1H NMR spectrum of the crude prod-
uct. These results suggest that the allylic alcohol is not oxidized by
PdII to the vinyl ketone.
Received: March 20, 2012
Published online: && &&, 0000
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Pd-Catalyzed Oxidative Cross-Coupling
COMMUNICATION
Cross-Coupling
H. Chen, L. Huang, W. Fu, X. Liu,
H. Jiang* ...................... &&&& — &&&&
Carbon–Carbon Bond Formation:
Palladium-Catalyzed Oxidative Cross-
Coupling of N-Tosylhydrazones with
Allylic Alcohols
In the zone: Pd-catalyzed oxidative
cross-coupling of N-tosylhydrazones
the key role in this transformation.
The reaction proceeds with readily
available starting materials to afford
substituted alkenes in a highly stereo-
selective manner (see scheme).
À
with allylic alcohols leads to C C bond
formation. A palladium–carbene
migratory insertion is proposed to play
Chem. Eur. J. 2012, 00, 0 – 0
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