Palladium-catalyzed insertion of N-tosylhydrazones and trapping with carbon nucleophiles

Article abstract of DOI:10.1021/ol402457h

A Pd-catalyzed three-component cross-coupling reaction of vinyl iodide, N-tosylhydrazone, and carbon nucleophiles is reported, and a one-pot procedure is also developed. The cross-coupling is proposed to proceed through a palladium-carbene migratory inser

Full text of DOI:10.1021/ol402457h

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed Insertion
of N‑tosylhydrazones and Trapping
with Carbon Nucleophiles
Ping-Xin Zhou, Yu-Ying Ye, and Yong-Min Liang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, and
State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics,
Chinese Academy of Science, Lanzhou 730000, P. R. China
liangym@lzu.edu.cn
Received August 26, 2013
ABSTRACT
A Pd-catalyzed three-component cross-coupling reaction of vinyl iodide, N-tosylhydrazone, and carbon nucleophiles is reported, and a one-pot
procedure is also developed. The cross-coupling is proposed to proceed through a palladiumÀcarbene migratory insertion, carbopalladation
other than classic palladiumÀcarbene migratory insertion, and β-H elimination. Moreover, the reaction proceeds under mild conditions and with
high stereoselectivity.
Transition-metal-catalyzed cross-coupling reactions have
been recognized as a powerful and efficient method for CÀC
bond construction.1 Despite the wide applicability of these
reactions, most of these cross-coupling transformations
involve the participation of a stoichiometric organometallic
reagent, which are usually expensive, toxic, and moisture-
sensitive.2 Moreover, highly reactive organometallic re-
agents often suffer from a problem of functional group
tolerance. Thus, it is highly desirable to further develop a
novel coupling process.
The utilityofN-tosylhydrazones inorganic synthesishas
a longhistory. Bamfordand Stevensinitially demonstrated
that N-tosylhydrazones can be employed as a source of
diazo compounds.3 The first example of showing their
utility in a palladium-catalyzed cross-coupling reaction was
reported by Barluenga.4 Since then, palladium-catalyzed
insertion of N-tosylhydrazones has been emerging as a new
type of cross-coupling reaction and hasattracted increasing
attention. In 2009, Wang reported a palladium-catalyzed
cross-coupling of benzyl halides with tosylhydrazones to
generate a variety of polysubstituted olefins.5 Recently,
Barluenga reported the first examples of the use of alkenyl
halides in cross-coupling reactions with tosylhydrazones to
give linear dienes (Scheme 1, eq 1).6 However, all of these
catalytic cycles involve Pd carbene migratory insertion
followed by β-hydride elimination, and only one C(sp2)À
C(sp2) bond is formed.7 If we can combine Pd-catalyzed
insertion of N-tosylhydrazones and Pd-catalyzed cascade
reactions, it would provide new possibilities for the develop-
ment of more novel coupling processes. Indeed, a three-
component coupling of aryl halides, N-tosylhydrazones,
(5) Xiao, Q.; Ma, J.; Yang, Y.; Zhang, Y.; Wang, J. Org. Lett. 2009,
11, 4732–4735.
(1) (a) Negishi, E. Handbook of Organopalladium Chemistry for
Organic Synthesis; Wiley: New York, 2002. (b) de Meijere, A.; Diederich,
F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH:
Weinheim, 2004. (c) Krische, M. J. Metal Catalyzed Reductive CÀC Bond
Formation: A Departure from Preformed Organometallic Reagents;
Springer: Berlin, 2007.
(2) (a) Komiya, S. Synthesis of Organometallic Compounds: A Prac-
tical Guide; Wiley-VCH: Chichester, 1997. (b) Terao, J.; Kambe, N. Acc.
Chem. Res. 2008, 41, 1545–1554. (c) Jana, R.; Pathak, T. P.; Sigman,
M. S. Chem. Rev. 2011, 111, 1417–1492.
ꢀ
ꢀ
(6) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Adv.
Synth. Catal. 2010, 352, 3235–3240.
(7) For selected palladium-catalyzed insertion of N-tosylhydrazones
processes based on migratory insertion, followed by β-hydride elimina-
ꢀ
tion, see: (a) Barluenga, J.; Escribano, M.; Moriel, P.; Aznar, F.; Valdes,
C. Chem.;Eur. J. 2009, 15, 13291–13294. (b) Zhou, L.; Ye, F.; Ma, J.;
Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2011, 50, 3510–3514. (c)
Chen, Z.-S.; Duan, X.-H.; Wu, L.-Y.; Ali, S.; Ji, K.-G.; Zhou, P.-X.; Liu,
X.-Y.; Liang, Y.-M. Chem.;Eur. J. 2011, 17, 6918–6921. (d) Zhou, L.;
Ye, F.; Zhang, Y.; Wang, J. Org. Lett. 2012, 14, 922–925. (e) Xiao, Q.;
Wang, B.; Tian, L.; Yang, Y.; Ma, J.; Zhang, Y.; Chen, S.; Wang, J.
Angew. Chem., Int. Ed. 2013, 52, 9305–9308. (f) Zeng, X.; Cheng, G.;
Shen, J.; Cui, X. Org. Lett. 2013, 15, 3022–3025.
(3) Bamford, W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4735–4740.
ꢀ
(4) Barluenga, J.; Moriel, P.; Valdes, C.; Aznar, F. Angew. Chem.,
Int. Ed. 2007, 46, 5587–5590.
r
10.1021/ol402457h
XXXX American Chemical Society

and terminal alkynes for the synthesis of propargylarenes
was developed by Wang, in which two separate CÀC bonds
(one sp2Àsp3 bond, one spÀsp3 bond) were formed via
a sequential palladium carbene migratory insertion and
transmetalation process.8 We also reported palladium-
catalyzed cross-coupling reactions of N-(2-iodobenzyl)-
anilines with R,β-unsaturated tosylhydrazones to afford
isoindolines.9 In this reaction, a CÀC bond and a CÀN
bond were formed via carbene migratory insertion and
CÀN bond formation. Recently, we demonstrated that
stabilized carbon nucleophiles can also be used as partners
in cross-coupling with R,β-unsaturated N-tosylhydrazones
(Scheme 1, eq 2).10 In connection with the common
η3-allylpalladium intermediates in Barluenga’s and our
work, we wish to report a palladium-catalyzed cross-
coupling of alkenyl halides, tosylhydrazones and carbon
nucleophiles involving a carbopalladation other than
β-hydride elimination (Scheme 1, eq 3).
3a was afforded in comparable yield (data not shown in
Table 1).11 When 2.0 equiv of BTAC was used as an additive
to enhance the solubility of the sodium dimethyl malonate, it
was found to be ineffective (data not shown in Table 1).
Next, we inspected the stoichiometry of solvent, PPh3,
carbon nucleophiles, and the effect of temperature. Decreas-
ing the amount of solvent led to a slight improvement in yield
(Table 1, entry 2). The yield could be further improved when
the reaction was carried out at a lower temperature (Table 1,
entry 3). Notably, when the PPh3 loading was added, a better
yield was obtained (Table 1, entry 4). In a similar study, Van
Vranken and co-workers showed that using excess inexpen-
sive sodium malonate could significantly improve the yield.12
Indeed, by increasing the amount of malonate, the product
yield was increased to 79% (Table 1, entry 5). Then, we went
on to screen other reaction parameters, such as different
solvents, catalysts, and ligands. Other solvents including
DMF, MeCN, dioxane, and toluene were examined
(Table 1, entries 6À9). However, they were found to be
unfavorable. Further inspection of the reaction conditions
revealed that ligand was essential for this reaction (Table 1,
entries 10À13). No reaction occurred when Phen or
[HPtBu3]BF4 was used, and a lower yield was observed when
Scheme 1. Combine Pd-Catalyzed Insertion of N-Tosylhydra-
zone and Pd-Catalyzed Cascade Reactions
Table 1. Conditions for the Palladium-Catalyzed Reaction of 1a
and 2aa
entry
catalyst
ligand
solvent
yieldb (%)
c
1
Pd2(dba)3 CHCl3 PPh3
THFd
THF
37e,f
42e,f
46f
52f
79
3
c
2
Pd2(dba)3 CHCl3 PPh3
3
3
3
3
3
3
3
3
c
3
Pd2(dba)3 CHCl3 PPh3
THF
4
Pd2(dba)3 CHCl3 PPh3
THF
5
Pd2(dba)3 CHCl3 PPh3
THF
6
Pd2(dba)3 CHCl3 PPh3
toluene
dioxane
MeCN
DMF
THF
NR
22
The three-component reaction was started by employing
vinyl iodide 1a, N-tosylhydrazone 2a, and carbon nucleo-
philes as substrates in the presence of Pd2(dba)3 CHCl3
7
Pd2(dba)3 CHCl3 PPh3
8
Pd2(dba)3 CHCl3 PPh3
66
3
9
Pd2(dba)3 CHCl3 PPh3
NR
NR
61
(2.5 mol %), PPh3 (15 mol %), and K2CO3 (3.0 equiv) in
THF (6 mL) at 70 °C for 2 h. To our delight, the cross-
coupling product 3a was delivered in 37% yield (Table 1,
entry 1). Encouraged by this preliminary result, we pro-
ceeded to optimize the reaction. First, we investigated the
effect of the additive. In order to prevent the undesired
β-hydride elimination, 2.0 equiv of LiCl was added; however,
10
11
12
13
14
15
16
17
18
Pd2(dba)3 CHCl3 Phen
3
Pd2(dba)3 CHCl3 dppb
THF
3
3
Pd2(dba)3 CHCl3 [HPtBu3]BF4 THF
NR
16
Pd2(dba)3 CHCl3
THF
THF
THF
THF
THF
THF
3
Pd2(dba)3
PPh3
PPh3
PPh3
PPh3
PPh3
70
g
Pd(PPh3)4
74
g
Pd(OAc)2
74
g
Pd(PPh3)2Cl2
71
NR
(8) Zhou, L.; Ye, F.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2010,
132, 13590–13591.
(9) Zhou, P.-X.; Luo, J.-Y; Zhao, L.-B.; Ye, Y.-Y.; Liang, Y.-M.
Chem. Commun. 2013, 49, 3254–3256.
(10) Ye, Y.-Y.; Zhou, P.-X.; Luo, J.-Y.; Zhong, M.-J.; Liang, Y.-M.
a 1a (0.3 mmol, 1.0 equiv), 2a (0.675 mmol, 2.25 equiv), carbon
nucleophiles (3.6 mmol, 12.0 equiv), Pd2(dba)3 CHCl3 (2.5 mol %),
ligand (10 mol %), K2CO3 (0.9 mmol, 3.0 equiv), solvent (2 mL), 46 °C,
2 h. b Yield of isolated product. c 15 mol % PPh3 was employed. d 6 mL
of THF was employed. e The reaction was carried at 70 °C. f Carbon
nucleophiles (1.8 mmol, 6.0 equiv). g Pd (5 mol %).
3
Chem. Commun. 201310.1039/C3CC45583A.
(11) The halide ion inhibiting the β-H elimination of palladium(II)
species, see: (a) Wang, Z.; Zhang, Z.; Lu, X. Organometallics 2000, 19,
775–780. (b) Zhang, Z.; Lu, X.; Xu, Z.; Zhang, Q.; Han, X. Organome-
tallics 2001, 20, 3724–3728. (c) Liu, G.; Lu, X. Org. Lett. 2001, 3, 3879–
ꢀ
3882. (d) Aurrecoechea, J. M.; Durana, A.; Perez, E. J. Org. Chem. 2008,
(12) Devine, S. K. J.; Van Vranken, D. L. Org. Lett. 2008, 10, 1909–
73, 3650–3653.
1911.
B
Org. Lett., Vol. XX, No. XX, XXXX

the reaction was performed in the absence of PPh3. Employ-
ing dppb as a ligand could not further improve the yield.
Various palladium catalysts including Pd(II) and Pd(0)
were investigated and showed they are less efficient than
The reaction also worked with ethyl cyanoacetate
(Scheme 3, eq 3). Dimethyl 2-allylmalonate and dimethyl
2-phenylmalonate were also investigated. To our disap-
pointment, none of desired products was obtained, which
is consistent with the previous report.12
Pd2(dba)3 CHCl3 (Table 1, entries 14À17). Finally, the
3
reaction could not proceed without palladium catalysis
(Table 1, entry 18).
With the optimized conditions, the scope of this reac-
tion was then explored. For meta- or para-substituted
N-tosylhydrazones, both electron-donating and electron-
withdrawing groups were tolerated and reacted smoothly
with 1a to afford the desired products in moderate to good
yields (Scheme 2). For ortho-substituted N-tosylhydrazones,
the yield was found to decrease with increasing size of the
substituent. When R1 is a small methyl group, 3j is given in
comparable yield with 3f. With a sterically bulky Cl group,
the product 3l was obtained in lower yield. Additionally,
using naphthyl N-tosylhydrazone as substrate, the reaction
worked efficiently to afford 3m in 56% yield. Notably, the
halogen group was tolerated under the Pd-catalyzed condi-
tions, which allowed a transition-metal-catalyzed coupling
reaction. However, no reaction occurred when alkyl tosyl-
hydrazones were utilized as coupling partners.
Scheme 3. Scope of the Palladium-Catalyzed Reactions with 2a
We further studied the different malonates and found:
Diethyl malonate gave good yield, and diisopropyl malo-
nate was less efficient. No reaction occurred when ditert-
butyl malonate was used (Scheme 4). Those phenomenon
may be may be due to the steric hindrance.
Scheme 2. Palladium-Catalyzed Reactions of 1a with 2a
Scheme 4. Reactions of Different Malonates with 2a
As is known, N-tosylhydrazone 2a is readily formed
by the condensation of aldehyde with tosylhydrazide
(Scheme 5). Thus, we decided to conduct this reaction in
a one-pot fashion. Treatment of the benzaldehyde with
tosylhydrazide generated 2a in situ, then catalyst, ligand,
base, and another cross-coupling partner were added.
Indeed, product 3a could be isolated in 76% yield.
a Reaction conditions: vinyl iodide 1a (0.3 mmol, 1.0 equiv),
N-tosylhydrazone 2 (0.675 mmol, 2.25 equiv), sodium malonate (3.6 mmol,
12.0 equiv), Pd2(dba)3 CHCl3 (2.5 mol %), PPh3 (10 mol %), K2CO3
(0.9 mmol, 3.0 equiv), THF (2 mL), 46 °C, 2 h. Yields are calculated on
isolated products.
A plausible mechanism is proposed as shown in Scheme 6.
The cross-coupling starts with oxidative addition of Pd(0)
3
Scheme 5. One-Pot Cross-Coupling Starting from Aldehyde
Moreover, the reaction of vinyl iodide 1b with
N-tosylhydrazone 2a was also investigated, and 3n was
obtained in lower yield, with an all-carbon quaternary
center. A better result was observed when the reaction was
carried outat55°C (Scheme 3, eq1). Addition, vinyliodide
1c worked well with 2a. However, no reaction occurred
when (Z)-2-iodo-3-phenylacrylaldehyde was employed.
Org. Lett., Vol. XX, No. XX, XXXX
C

E. This intermediate is then trapped with sodium mal-
onate to generate product 3.14
Scheme 6. Plausible Catalytic Cycle
In conclusion, we have developed a new palladium-
catalyzed three-component coupling of vinyl iodide,
N-tosylhydrazone, and carbon nucleophiles, in which two
separate CÀC bonds were formed. This reaction proceeds
via Pd carbene migratory insertion, followed by carbopal-
ladation instead of classic β-H elimination. This reaction
further demonstrates the concept of combination Pd-
catalyzed insertion of diazo compounds and Pd-catalyzed
cascade reactions, which opens a new avenue for the
development of more novel Pd-catalyzed transformations.
Acknowledgment. We thank the National Science
Foundation (NSF 21072080 and 21272101) and National
Basic Research Program of China (973 Program)
2010CB833203 and “111” program of MOE and PCSIRT:
IRT1138 for financial support.
Supporting Information Available. Detailed experimen-
1
tal procedure and copies of H NMR and 13C NMR
spectra of all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
to the vinyl iodide to afford intermediate A, followed by
decomposition of the diazo compound B (generated in situ
from N-tosylhydrazone) to give a palladium carbene com-
plex C.13 Subsequently, migratory insertion of a vinyl
group to the carbonic carbon led to the η1-allylpalladium
complex D, which can isomerize to the η3-allylpalladium
(14) The intermolecular substitution could occur on either end of the
η3-allylpalladium and it can generate two regioisomeric products. Three
were isolated in complete regioselectivities due to the steric hindrance.
For a similar example, see: (a) Deardorff, D. R.; Savin, K. A.; Justman,
C. J.; Karanjawala, Z. E.; Sheppeck, J. E., II; Hager, D. C.; Aydin, N. J.
Org. Chem. 1996, 61, 3616–3622. (b) Yamada, Y. M. A.; Watanabe, T.;
(13) For early studies on
a palladium-catalyzed reaction of
ꢀ
N-tosylhydrazones, see: (a) Barluenga, J.; Valdes, C. Angew. Chem.,
Int. Ed. 2011, 50, 7486–7500. (b) Franssen, N. M. G.; Walters, A. J. C.;
Reek, J. N. H.; de Bruin, B. Catal. Sci. Technol. 2011, 1, 153–165. (c)
Shao, Z.; Zhang, H. Chem. Soc. Rev 2012, 41, 560–572. (d) Xiao, Q.;
Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46, 236–247.
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Torii, K.; Uozumi, Y. Chem. Commun. 2009, 5594–5596. (c) Sebesta, R.;
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Skvorcova, A.; Horvath, B. Tetrahedron: Asymmetry 2010, 21, 1910–1915.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX