Pd-catalyzed oxidative cross-coupling of N-tosylhydrazones with arylboronic acids

Article abstract of DOI:10.1039/b925590g

The Pd-catalyzed reaction of N-tosylhydrazones and arylboronic acids provides olefin derivatives. This oxidative cross-coupling is suggested to proceed through a migratory insertion process of a Pd carbene intermediate.

Full text of DOI:10.1039/b925590g

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Pd-catalyzed oxidative cross-coupling of N-tosylhydrazones
with arylboronic acidsw
Xia Zhao,a Jing Jing,a Kui Lu,a Yan Zhanga and Jianbo Wang*ab
Received (in College Park, MD, USA) 7th December 2009, Accepted 20th January 2010
First published as an Advance Article on the web 3rd February 2010
DOI: 10.1039/b925590g
The Pd-catalyzed reaction of N-tosylhydrazones and arylboronic
acids provides olefin derivatives. This oxidative cross-coupling is
suggested to proceed through a migratory insertion process of a
Pd carbene intermediate.
of the reaction was focused on the search for a suitable
t
oxidant. A number of oxidants such as Ag2CO3, BuOOtBu,
KBrO3, CuCl2 and Cu(OAc)2 were screened and none of them
was efficient for the reaction (entries 2–6). To our delight, we
observed that the combination of CuCl and oxygen under
balloon pressure was effective and promoted the reaction in
moderate to high yield (entry 7).
Pd-catalyzed cross-coupling reactions of diazo compounds
have recently emerged as a new type of cross-coupling
reaction.1–4 We have reported a Pd-catalyzed cross-coupling
reaction of a-diazocarbonyl compounds with boronic acids,
which affords a,b-unsaturated carbonyl compounds in high
yields.1e The reaction presumably proceeds through a migratory
insertion process of the Pd carbene intermediate.5 To further
extend the scope of this cross-coupling reaction, we conceived
to employ diazo compounds that do not bear electron with-
drawing substituents as the substrates in this reaction. Diazo
compounds without electron withdrawing groups are usually
unstable and thus difficult to handle. The recently developed
methods of in situ generation of diazo compounds have largely
circumvented this problem. Treatment of N-tosylhydrazones
with base is the most widely practised method for this
purpose.6 The reaction conditions are compatible with the
Pd-catalyzed cross-coupling reaction, as demonstrated by
Barluenga and co-workers’ reports on a Pd-catalyzed reaction
of N-tosylhydrazones with aryl bromides in the presence of
lithium tert-butoxide,1b,c and by our own recent report on
the Pd-catalyzed reaction of N-tosylhydrazones with benzyl
halides.2c As a continuation, we report in this communication
the Pd-catalyzed oxidative cross-coupling of N-tosylhydrazone
with aromatic boronic acids.
Next, we observed that solvent significantly affected this
coupling reaction. Toluene, MeCN and DMSO were tested,
but they were all less effective as compared with dioxane
(entries 8–10). To further optimize the reaction, some copper
salts were examined.w We found that both Cu(II) and Cu(I)
could work for the reaction (entries 13–16). For CuCl, the
molar percentage could be reduced to 10%, affording the
highest yield (entry 12). Since the base used in the reaction
also plays an important role, several bases such as KOtBu,
NaOtBu, Cs2CO3, were also examined. However, they are all
less efficient compared with LiOtBu. Finally, we studied
different palladium catalysts.w Although either Pd(0) or Pd(II)
catalysts could catalyze the cross-coupling reaction, none of
them exceeded the simple Pd(PPh3)4. Thus, the optimized
reaction conditions were as follows: 1a (0.25 mmol), 2a
(0.75 mmol), Pd(PPh3)4 (5 mol%), CuCl (10 mol%), LiOtBu
(1.25 mmol), in dioxane at 70 1C.
Table 1 Conditions of Pd-catalyzed reaction of 1a and 2aa
Initially, the cross-coupling reaction between acetophenone
N-tosylhydrazone 1a and phenyl boronic acid 2a was carried
out under various conditions. From the mechanistic rational
(vide infra), the cross-coupling reaction starts from the trans-
metallation of boronic acid to the Pd(II) catalyst.7 At the end
of the reaction, a Pd(0) species is released, which needs to be
oxidized in order to regenerate the Pd(II) catalyst. Initially,
Ag2CO3 was employed as the oxidant. Thus, with Pd(PPh3)4
as catalyst and LiOtBu as base, the reaction of N-tosylhydrazone
1a and boronic acid 2a in dioxane at 70 1C affords 1,1-diphenyl-
ethylene 3a in 16% yield (Table 1, entry 1). Further optimization
Entry
Oxidant (% mol)
Base (equiv.)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ag2CO3 (200)
tBuOOtBu (200)
tBuOOtBu (300)
Cu(OAc)2 (200)
CuCl2 (200)
LiOtBu (3)
LiOtBu (3)
LiOtBu (3)
LiOtBu (4)
LiOtBu (4)
LiOtBu (5)
LiOtBu (4)
LiOtBu (4)
LiOtBu (4)
LiOtBu (5)
LiOtBu (5)
LiOtBu (5)
LiOtBu (5)
LiOtBu (5)
LiOtBu (5)
LiOtBu (5)
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
MeCN
16
10
13
Trace
Trace
8
KBrO3 (150)
O2, CuCl (20)
O2, CuCl (20)
O2, CuCl (20)
O2, CuCl (10)
O2, CuCl (20)
O2, CuCl (10)
O2, CuBr (20)
O2, CuCl2 (20)
O2, CuI (20)
47
34
22
7
68
71
DMSO
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
a Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry, Peking University,
Beijing 100871, China. E-mail: wangjb@pku.edu.cn
60
64c
13
O2, CuOTf (10)
26
b The State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
a
Reaction conditions: 1a (0.25 mmol), 2a (0.75 mmol), Pd(PPh3)4
b
c
(5 mol%), solvent (2 mL). Isolated yield. In an atmosphere of
O2 : N2 = 1 : 4.
w Electronic supplementary information (ESI) available: Experimental
details and characterization data. See DOI: 10.1039/b925590g
ꢀc
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A series of substituted acetophenone N-tosylhydrazones
1a–i and arylboronic acids 2a–e were examined under the
optimal reaction conditions. As shown in Table 2, the reaction
gave moderate to good yields in most cases. The results do not
show a significant electronic effect in this reaction. Since the
homocoupling of arylboronic acids is inevitable as a side
reaction,8 in all cases 3 equiv. of arylboronic acids were needed
in order to completely transform the N-tosylhydrazones to the
products.
The reaction could be extended to hydrazone substrates
bearing substituents other than a methyl group. Thus, the
Pd-catalyzed reaction of 4a–g and 2a,b under identical reaction
conditions afforded 5a–h in good yields in most cases (Scheme 1).
A plausible mechanism for this Pd-catalyzed oxidative
coupling is proposed in Scheme 2. The reaction is initiated
by the oxidation of the CuCl to Cu(II) species by oxygen,
which then oxidize Pd(0) to Pd(II) species. Transmetallation
of the Pd(II) species with the arylboronic acid affords aryl-
palladium species A, which reacts with the in situ generated
diazo substrate to give Pd carbene complex B. Migratory
insertion of the aryl group to the carbenic carbon of the Pd
carbene species affords the intermediate C.1–5 Finally, b-hydride
elimination of C affords the product and regenerates the Pd(0)
species in the presence of base.
Scheme 1 Pd-catalyzed reaction of 4a–g with 2a,b.
of the Pd carbene intermediate and subsequent Heck–Mizoroki-
type reaction.9,10 To confirm this possible pathway, styrene 6
and phenyl boronic acid 2a were reacted under the identical
conditions (eqn (1)). Only a trace amount of 1,2-diphenyl-
ethylene 7 was observed and no 1,1-diphenylethylene could be
detected in the 1H NMR spectrum of the crude product.
Consequently, this pathway can be excluded.
However, the possibility exists that the Pd carbene is
generated directly from Pd(II) and the diazo substrate. The
formation of the olefin product may be due to the 1,2-H shift
Table 2 Pd(PPh3)4-catalyzed reactions of 1a–i and 2a–ea
ð1Þ
To gain further insight into the reaction mechanism, we
examined the kinetic isotope effect (KIE) of the reaction
(Scheme 3). At first, intermolecular competition was carried
out with d3-deuterated N-tosylhydrazone 8 and 1a. The com-
petition reaction gave 3b and 9 in equal amount (kH/kD = 1.0).
On the other hand, the intramolecular competition experiment
with d1-deuterated N-tosylhydrazone 10 gave a KIE of 2.54.
The significant KIE in the b-hydride elimination step and lack
of KIE for the overall reaction (intermolecular competition)
clearly suggest that b-hydride elimination is not in the rate
determining step. It is noted that the KIE value observed
in the intramolecular competition is comparable to those
Entry 1, Ar1
2, Ar2
t/h
Yield (3, %)b
1
2
3
1a, C6H5
1a, C6H5
1a, C6H5
2a, C6H5
7
7
7
3a, 71c
3b, 70
3c, 47
2b, p-MeOC6H4
2c, m-ClC6H4
2a, C6H5
2b, p-MeOC6H4 10
2d, p-MeC6H4
2a, C6H5
2b, p-MeOC6H4
2a, C6H5
2d, p-MeC6H4
2a, C6H5
2b, p-MeOC6H4
2c, m-ClC6H4
2d, p-MeC6H4
2e, m-MeC6H4
2a, C6H5
4
5
6
7
1b, p-MeC6H4
1b, p-MeC6H4
1b, p-MeC6H4
1c, p-ClC6H4
6.5 3d, 70c
3e, 71
3f, 67d
3g, 52
3h, 67
10
9
8
8
1c, p-ClC6H4
9
1d, m-MeOC6H4
1d, m-MeOC6H4
1e, p-MeOC6H4
1e, p-MeOC6H4
1e, p-MeOC6H4
1e, p-MeOC6H4
1e, p-MeOC6H4
1f, 3,4-Me2C6H3
1g, 3,5-Me2C6H3 2a, C6H5
1g, 3,5-Me2C6H3 2b, p-MeOC6H4
1h, p-CF3C6H4
1i, p-NCC6H4
8.5 3i, 57
10
11
12
13
14
15
16
17
18
19
20
7
7
7
7
7
7
9
7
9
6
5
3j, 68
3b, 67
3k, 76
3l, 40
3e, 82
3m, 71
3n, 57c
3o, 63c
3p, 30
3q, 64
3r, 51
2b, p-MeOC6H4
2a, C6H5
a
Reaction conditions: 1a–i (0.25 mmol), 2a–e (0.75 mmol), Pd(PPh3)4
(5 mol%), CuCl (10 mol%), LiOtBu (1.25 mmol), dioxane (2 mL),
b
c
70 1C. Yield of isolated product after chromatography. The
product and by-product biphenyl were inseparable on a column.
The yield was determined by 1H NMR. The product and by-product
d
4,40-dimethylbiphenyl were inseparable on a column. The yield was
1
determined by H NMR.
Scheme 2 Possible reaction pathways.
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and D. L. Van Vranken, J. Org. Chem., 2008, 73, 3585;
(e) C. Peng, Y. Wang and J. Wang, J. Am. Chem. Soc., 2008,
130, 1566.
2 (a) K. L. Greenman and D. L. Van Vranken, Tetrahedron, 2005,
61, 6438; (b) W.-Y. Yu, Y.-T. Tsoi, Z. Zhou and A. S. C. Chan,
Org. Lett., 2009, 11, 469; (c) Q. Xiao, J. Ma, Y. Yang, Y. Zhang
and J. Wang, Org. Lett., 2009, 11, 4732.
3 (a) S. K. J. Devine and D. L. Van Vranken, Org. Lett., 2007, 9,
2047; (b) S. K. J. Devine and D. L. Van Vranken, Org. Lett., 2008,
10, 1909; (c) R. Kudirka, S. K. J. Devine, C. S. Adams and
D. L. Van Vranken, Angew. Chem., Int. Ed., 2009, 48, 3677.
4 S. Chen and J. Wang, Chem. Commun., 2008, 4198.
5 For reports on the migratory insertion process of stable Pd carbene
species, see: (a) A. C. Albe
A. Perez-Mateo, Angew. Chem., Int. Ed., 2002, 41, 2363;
(b) M. Broring, C. D. Brandt and S. Stellwag, Chem. Commun.,
´
niz, P. Espinet, R. Manrique and
´
¨
2003, 2344; (c) D. Sole
and J. Bonjoch, Organometallics, 2004, 23, 1438; (d) A. C. Albe
P. Espinet, R. Manrique and A. Perez-Mateo, Chem.–Eur. J., 2005,
11, 1565; (e) A. C. Albeniz, P. Espinet, A. Perez-Mateo, A. Nova
´
, L. Vallverdu
´
, X. Solans, M. Font-Bardia
´
niz,
´
´
´
and G. Ujaque, Organometallics, 2006, 25, 1293.
6 J. R. Fulton, V. K. Aggarwal and J. de Vicente, Eur. J. Org. Chem.,
2005, 1479.
7 For selected reviews on Pd-catalyzed coupling reactions with
arylboronic compounds, see: (a) A. Suzuki, Acc. Chem. Res.,
1982, 15, 178; (b) N. Miyaura and A. Suzuki, Chem. Rev., 1995,
95, 2457; (c) N. Miyaura, J. Organomet. Chem., 2002, 653, 54;
(d) N. Miyaura, in Advances in Metal Organic Chemistry, ed.
Scheme 3 Kinetic isotopic effect experiment.
reported for b-hydride elimination in Pd-catalyzed reactions.11
Thus, the KIE results are in accordance with the proposed
reaction mechanism shown in Scheme 2.
L. S. Liebeskind,
J AI, London, 1998, vol. 6, p. 187;
(e) A. Suzuki, in Metal-Catalyzed Cross-Coupling Reactions, ed.
F. Diederich and P. J. Stang, Wiley-VCH, New York, 1998, ch. 2;
(f) N. Miyaura, Top. Curr. Chem., 2002, 219, 11.
8 For examples of Pd-catalyzed homocoupling of arylboronic
compounds under oxidative conditions, see: (a) H. Yoshida,
Y. Yamaryo, J. Ohshita and A. Kunai, Tetrahedron Lett., 2003,
44, 1541; (b) S. Punna, D. D. Diaz and M. G. Finn, Synlett, 2004,
2351; (c) C. Zhou and R. C. Larock, J. Org. Chem., 2006, 71, 3184;
(d) A. Christian, C. Chama and J. Anny, Eur. J. Org. Chem., 2008,
4567.
In conclusion, we have reported the first oxidative cross-
coupling reaction between N-tosylhydrazone and arylboronic
acids. This study shows that the coupling of N-tosylhydrazone
and arylboronic acids under oxidative conditions can compete
with the oxidative homocoupling of arylboronic acids, which
indicates that the interaction of arylpalladium species with
diazo substrates and the subsequent processes are both highly
efficient. This study further demonstrates the generality of the
transformations based on Pd carbene processes.
9 For a recent report on the 1,2-H shift of Rh(II) carbenes, see:
F. Xiao and J. Wang, J. Org. Chem., 2006, 71, 5789.
10 For examples, see: (a) X. Du, M. Suguro, K. Hirabayashi and
A. Mori, Org. Lett., 2001, 3, 3313; (b) P.-A. Enquist, J. Lindh,
P. Nilsson and M. Larhed, Green Chem., 2006, 8, 338;
(c) K. S. Yoo, C. H. Yoon and K. W. Jung, J. Am. Chem. Soc.,
2006, 128, 16384.
11 (a) E. Keinan, S. Kumar, V. Dangur and J. Vaya, J. Am. Chem.
Soc., 1994, 116, 11151; (b) M. R. Netherton and G. C. Fu, Angew.
Chem., Int. Ed., 2002, 41, 3910; (c) D. R. Chrisope, P. Beak and
W. H. Saunders, Jr., J. Am. Chem. Soc., 1988, 110, 230;
(d) J. M. Takacs, E. C. Lawson and F. Clement, J. Am. Chem.
Soc., 1997, 119, 5956.
The project was supported by the NSFC (Grant No. 20832002,
20772003, 20821062) and 973 Program (No. 2009CB825300).
Notes and references
1 (a) K. L. Greenman, D. S. Carter and D. L. Van Vranken,
Tetrahedron, 2001, 57, 5219; (b) J. Barluenga, P. Moriel,
C. Valde
(c) J. Barluenga, M. Toma
and C. Valdes, Chem.–Eur. J., 2008, 14, 4792; (d) R. Kudirka
´
s and F. Aznar, Angew. Chem., Int. Ed., 2007, 46, 5587;
´
s-Gamasa, P. Moriel, F. Aznar
´
ꢀc
This journal is The Royal Society of Chemistry 2010
1726 | Chem. Commun., 2010, 46, 1724–1726