Palladium-catalyzed direct olefination of urea derivatives with n-butyl acrylate by C-H bond activation under mild reaction conditions

Article abstract of DOI:10.1021/ol202738j

Pd^II-catalyzed aromatic C-H bond activation using urea as a directing group was achieved in a p-TsOH/AcOH medium under mild reaction conditions. The direct olefination products of various urea derivatives were produced from aryl urea derivative

Full text of DOI:10.1021/ol202738j

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6137–6139
Palladium-Catalyzed Direct Olefination of
Urea Derivatives with n-Butyl Acrylate by
CꢀH Bond Activation under Mild Reaction
Conditions
Li Wang,† Shen Liu,‡ Zhi Li,‡ and Yongping Yu*,‡
School of Science & Engineering, Zhejiang International Studies University,
Hangzhou 310012, P. R. China, and Institute of Materia Medica, College of
Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China
yyu@zju.edu.cn
Received October 12, 2011
ABSTRACT
PdII-catalyzed aromatic CꢀH bond activation using urea as a directing group was achieved in a p-TsOH/AcOH medium under mild reaction
conditions. The direct olefination products of various urea derivatives were produced from aryl urea derivatives and butyl acrylate in moderate to
good yields.
In recent years, CꢀH bond activation reactions, involv-
ing the activation of one of the substrate inert CꢀH bonds
and directly coupling with the other starting material to
form the desired product, have been a popular research
area in organic synthesis.1 The advantages for CꢀH bond
activation include the reliance on cheaper readily available
starting materials and shorter synthetic routes.2 Generally,
most of the reported CꢀH bond activation reactions
involve, first, a metal catalyst reacting with the substrate
directing group to form the precomplex, followed by
coupling with the other substrate to give the desired
product.1a,3 Thus, identification of both a suitable metal
catalyst and directing groups are the two key factors for
these CꢀH bond activation reactions. Among CꢀH bond
activation reactions, those directed by an ortho directing
group are dominant. Typical examples, to name a few,
include cobalt-catalyzed ortho-alkylation of secondary
benzamide with alkyl chloride or alkyl Grignard reagent,4
Rh(III)-catalyzed oxidative olefination by the reaction
of N-methoxybenzamides or aryl carboxamides with
alkenes,5 oxidative palladium(II)-catalyzed cyclization of
R,β-unsaturated amides,6 divergent CꢀH functionaliza-
tions directed by sulfonamide pharmacophores,7 palla-
dium(II)-catalyzed annulation of benzamides with [60]-
fullerene,8 Pd-catalyzed aerobic olefination of unactivated
sp3 CꢀH bonds by the nitrogen heterocycles serving as
(4) (a) Chen, Q.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011, 133,
428–429. (b) Chen, Q.; Ilies, L.; Yoshikai, N.; Nakamura, E. Org. Lett.
2011, 13, 3232–3234.
(5) (a) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am.
Chem. Soc. 2011, 133, 2350–2353. (b) Wang, F.; Song, G.-Y.; Li, X.-W.
Org. Lett. 2010, 12, 5430–5433.
(6) Schiffner, J. A.; Oestreich, M. Eur. J. Org. Chem. 2011, 1148–
1154.
(7) Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.; Yu,
J.-Q. J. Am. Chem. Soc. 2011, 133, 7222–7228.
(8) Chuang, S.-C.; Rajeshkumar, V.; Cheng, C.-A.; Deng, J.-C.;
Wang, G.-W. J. Org. Chem. 2011, 76, 1599–1604.
(9) Stowers, K. J.; Fortner, K. C.; Sanford, M. S. J. Am. Chem. Soc.
2011, 133, 6541–6544.
† School of Science & Engineering, Zhejiang International Studies
University.
‡ Institute of Materia Medica, Zhejiang University.
(1) (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624–655. (b) Giri, R.; Shi, B. F.; Engle, K. M.; Maugel, N.; Yu, J. Q.
Chem. Soc. Rev. 2009, 38, 3242–3272.
(2) (a) Li, W.; Xu, Z.-P.; Sun, P.-P.; Jiang, X.-Q.; Fang, M. Org. Lett.
2011, 13, 1286–1389. (b) Gandeepan, P.; Parthasarathy, K.; Cheng, C.-H.
J. Am. Chem. Soc. 2010, 132, 8569–8571. (c) Wang, C.-Y.; Rakshit, S.;
Glorius, F. J. Am. Chem. Soc. 2010, 132, 14006–14008. (d) Hu, Y.-M.;
Yao, H.; Sun, Y.-J.; Wan, J.; Lin, X.-G.; Zhu, T. Chem.;Eur. J. 2010,
16, 7635–7641.
(3) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169.
r
10.1021/ol202738j
2011 American Chemical Society
Published on Web 11/04/2011

the directing group,9 Pd(II)-catalyzed CꢀH alkenyla-
tion of phenols directed by silanol,10 the ortho-silylation of
aryl ketone, benzaldehyde, and benzyl alcohol derivatives
directed by a hydroxyl group,11 and rhodium-catalyzed
ortho-olefination of benzoates and benzaldehydes directed
by ester and carboxaldehyde units.12 Based on the cata-
lyzed CꢀH bond activation reactions directed by amide
units,4ꢀ6 we postulated that aryl urea derivatives should
be an ideal substrate for CꢀH bond activation; however
there are few reports of aryl urea derivatives catalyzed by
CꢀH bond activation. Recently, Glorius and co-workers
reported the rhodium-catalyzed oxidative CꢀH Olefina-
tion of N-methoxy-N0-aryl ureas13 and Lipshutz and his
research group developed the palladium-catalyzed CꢀH
cross-coupling of N,N-dimethyl-N0-aryl ureas with aryl
boronic acid or aryl iodides.14 Booker-Milburn et al.14c
and other groups14dꢀe reported a palladium(II)-catalyzed
CꢀH bond olefination reaction on the use of aryl urea
derivatives as a directing group. Herein, we report palla-
dium-catalyzed direct olefination of various aryl urea deri-
vatives with n-butyl acrylate by CꢀH bond activation under
mild catalyzed conditions. In our experiments, we found that
the urea moiety serves as an efficient directing group in the
Pd(II)-catalyzed olefination of various aryl urea derivatives.
Ethyl-3-(p-tolyl)urea was chosen as a test substrate for
the reaction with n-butylacrylate and Pd(OAc)2 catalyst
under various conditions (Table 1). We were pleased to
observe that the Pd(OAc)2 (5 mol %) exhibited notable
catalytic activity affording the desired product in high yield
in the presence of p-TsOH (30 mol %) and 1.0 equiv of p-
benzoquinone (B.Q.) (entry 3). The generateddouble bond
was almost exclusively in the E-form, and acetic acid was
the solvent of choice; other solvents provided limited
olefination (entries 1ꢀ2, 4ꢀ5). Among the selective addi-
tives, p-TsOH was the best additive (entry 3). By the
transition-metal-catalyzed mechanism,15 Pd(0) should be
oxidized by an oxidant and B.Q. had the best catalytic
effectiveness. In our tests, addition of more than 1 equiv of
B.Q. did not increase the yield significantly. Other oxidants
had lower yields than B.Q.
Table 1. Optimization of the Reaction Conditionsa
yield
(%)b
entry
catalyst
solvent
additive
oxidant
B.Q.
1
Pd(AcO)2
Pd(AcO)2
Pd(AcO)2
Pd(AcO)2
Pd(AcO)2
Pd(AcO)2
Pd(AcO)2
Pd(AcO)2
Pd(AcO)2
Pd(AcO)2
Pd(AcO)2
Pd(AcO)2
Pd(AcO)2
Ni(AcO)2
Cu(AcO)2
Co(AcO)2
Toluene
t-BuOH
AcOH
DMF
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
HBF4
trace
37
2
B.Q.
B.Q.
B.Q.
B.Q.
B.Q.
B.Q.
B.Q.
B.Q.
O2
3
72
4
trace
trace
63
5
DMSO
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
6
7
B(OCH3)3
KAcO
68
8
trace
trace
45
9
KOBu-t
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
10
11
12
13
14
15
16
Air
34
PhI(AcO)2
K2S2O8
B.Q.
B.Q.
B.Q.
52
63
trace
trace
trace
a Ethyl-3-(p-tolyl)urea (0.5 mmol), n-butyl acrylate (0.6 mmol),
catalyst (0.05 mmol), oxidant (0.5 mmol), and 1.5 mL of solvent. For
the detailed reaction procedure, see the Supporting Information.
b Yields are isolated.
regioselectivity of mono-olefination was observed in all
of the aryl urea derivative reactions. For the ethyl aryl urea
substrate, it was shown that there was high functional
group tolerance as demostrated in the yields aquired from
reactions 3aꢀ3h. Substituents on the aromatic moiety of
the urea substrate influenced the efficiency of the olefina-
tion coupling reaction significantly (see Scheme 1). Due to
the steric effect, the yield of the ortho methyl substitution
(3c) was lower than that of para position substitution (3a).
The aromatic rings bearing chloro and bromo groups
(3dꢀ3e) had modest yields compared to the corresponding
methyl (3a) version. The ethyl R-naphthalene urea under-
went the olefination smoothly and provided the desired
product (3g) with a good yield.
We studied various types of aryl urea derivatives in
the reaction with n-butylacrylate (see Scheme 1). High
(10) Huang, C.-H; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem.
Soc. 2011, 133, 12406–12409.
(11) Simmons, E. M.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132,
17092–17095.
(12) Park, S. H.; Kim, J. Y.; Chang, S. Org. Lett. 2011, 13, 2372–2375.
(13) Willwacher, J.; Rakshit, S.; Glorius, F. Org. Biomol. Chem. 2011,
9, 4736–4740.
In order to investigate the regioselectivity of the urea
directing group, benzyl urea derivatives were chosen for
the study. A range of benzyl urea derivatives were next
examined. Only the methyl substituent on the aromatic
moiety of the aryl benzyl urea substrate underwent mono-
olefination with acceptable yields (3jꢀ3k). For other
benzyl urea derivatives, debenzyl group reactions may have
occurred. Experiments indicated that the benzene ring in
the benzyl group did not undergo the olefination and
mono-olefination was only located on the ortho position
of the aryl ring ortho from the urea directing group
(3jꢀ3k). N-Butyl benzyl urea did not effectively undergo
olefination (3l), providing further evidence that this CꢀH
bond activation of the urea derivative catalyzed by Pd(II)
was to the sp2 carbon atom in the aryl ring.
(14) (a) Nishikata, T.; Abela, A. R.; Lipshutz, B. H. Angew. Chem.,
Int. Ed. 2010, 49, 781–784. (b) Nishikata, T.; Abela, A. R.; Huang, S.;
Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 4978–4979. (c) Houlden,
ꢀ
C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.;
Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066–10067. (d)
Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler, S. N. G.;
ꢀ
Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew.
Chem., Int. Ed. 2009, 48, 1830–1833. (e) Rauf, W.; Thompson, A. L.;
Brown, J. M. Chem. Commun. 2009, 3874–3876.
(15) (a) Xiao, Q.; Wang, W.-H.; Liu, G.; Meng, F.-K.; Chen, J.-H.;
Yang, Z.; Shi, Z.-J.. Chem.;Eur. J. 2009, 15, 7292–7296. (b) Shi, Z.;
Zhang, B.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2010, 49, 4036–4041.
(c) Yin, G.-Y.; Wu, Y.-C.; Liu, G.-S. J. Am. Chem. Soc. 2010, 132,
11978–11987.
6138
Org. Lett., Vol. 13, No. 23, 2011

Onthebasis of the above data and precedent literature,16
a plausible pathway is proposed in Scheme 2.
Scheme 1. Highly Regioselective Monoalkenylation of Various
Urea Derivatives with n-Butyl Acrylatea
Scheme 2. Plausible Catalyic Mechanism for CꢀH Bond Acti-
vation
It is postulated that Pd(OAc)2 was coordinated with the
urea substrate; subsequent CꢀH bond activation at the
ortho-position wasassumed totake placeleadingtoanaryl
Pd metastable complex. Then, olefin insertion takes place
followed by β-hydride elimination of the intermediate,
producing the E-olefinated products. The reduced Pd(0)
was oxidized to the Pd(II) oxidation state by B.Q. The role
of additives may be related to coordination with the Pd(II)
ion, which decreased the stability of the urea substrate
metal ion complex and promoted the intermediate to
decompose into olefins.
a Aryl urea (1.5 mmol), n-butyl acrylate (1.8 mmol), Pd(OAc)2
catalyst (0.15 mmol), oxidant (1.5 mmol), and 3.0 mL of HOAc. The
reaction was run in a sealed tube at 60 °C. For the detailed reaction
procedure, see the Supporting Information. Yields are isolated.
In summary, a selective and mild oxidative coupling
reaction between three types of aryl urea derivatives and
n-butylacrylate was reported. The reaction occurs through
ortho CꢀH bond activation under Pd(OAc)2 catalyzed
reaction conditions. This aspect is noteworthy since various
aryl urea derivatives are not only readily available but also
easily converted to important aryl amine compounds.15c
In addition, to further explore the scope of urea deriva-
tive reaction activity, we chose the monoaryl urea deriva-
tives to test the olefination reaction. The experimental
results showed that, under the reaction conditions, the
reactivity of thistype of urea derivativewas lower thanthat
of the former types. To improve the yield, trimethyl
boroate was added and a moderate yield was obtained
(3hꢀ3i). Among many substrates of this class that were
tested, only the two products (3hꢀ3i) were obtained. These
are the first reports of a CꢀH bond activation olefination
reaction utilizing this type of urea derivative. The reason
forthe low reactivitymaybedue inparttothe aminogroup
in the urea unit chealating with Pd(II), forming a relatively
stable intermediate that is difficult to decompose into the
desired product.
Acknowledgment. This research was supported by the
National Natural Science Foundation of China (81072516)
and Natural Science Foundation of Zhejiang Province
(No. Z2110655).
Supporting Information Available. Experimental details,
1
and H and 13C NMR spectra of new compounds. This
material is available free of charge via the Internetat http://
pubs.acs.org.
(16) (a) Engelin, C. J.; Fristrup, P. Molecules 2011, 16, 951–969. (b)
Li, L.; Brennessel, W.; Jones, W. D. J. Am. Chem. Soc. 2008, 130, 12414–
12419. (c) Boutadla, Y.; Al-Duaij, O.; Davies, D. L.; Griffith, G. A.;
Singh, K. Organometallics 2009, 28, 433–440.
Note Added after ASAP Publication. References 14cꢀe
and text citations were added and the revised paper
reposted on November 28, 2011.
Org. Lett., Vol. 13, No. 23, 2011
6139