The first examples of the enantioselective Heck-Matsuda reaction: Arylation of unactivated cyclic olefins using chiral bisoxazolines

Article abstract of DOI:10.1016/j.tetlet.2012.04.079

Successful enantioselective Heck-Matsuda arylations were accomplished for the first time using chiral bisoxazolines as ligands. Enantioselective Heck arylations were performed with several cyclic nonactivated olefins to provide the Heck products in 63-96%

Full text of DOI:10.1016/j.tetlet.2012.04.079

Tetrahedron Letters 53 (2012) 3325–3328
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The first examples of the enantioselective Heck–Matsuda reaction: arylation of
unactivated cyclic olefins using chiral bisoxazolines
⇑
Carlos Roque D. Correia , Caio C. Oliveira, Airton G. Salles Jr., Emerson A.F. Santos
Instituto de Química, Universidade Estadual de Campinas, UNICAMP, 13083-970 Campinas, São Paulo, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Successful enantioselective Heck–Matsuda arylations were accomplished for the first time using chiral
bisoxazolines as ligands. Enantioselective Heck arylations were performed with several cyclic nonactiva-
ted olefins to provide the Heck products in 63–96% isolated yields and in enantiomeric excesses of 54% up
to 84%.
Received 31 March 2012
Revised 16 April 2012
Accepted 17 April 2012
Available online 24 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Enantioselective Heck–Matsuda
Bisoxazolines
Arenediazonium salts
Introduction
bisoxazoline ligands (Fig. 1).6,7 The results presented might open
the door for the next stage of development of the Heck–Matsuda
Enantioselective catalysis has revolutionized the field of organic
synthesis and brought huge benefits for society in general. For
example, the development of enantioselective catalysis provides
more selective and less toxic therapeutical drugs, fragrances and
new materials.1 Additionally, the development of effective and
practical catalytic methods, which carry economical and ‘greener’
aspects, has been a topic of great interest in recent years. In this
context, palladium catalyzed coupling of arenediazonium salts to
olefins (Heck–Matsuda reaction) represents a reliable method to
access structurally complex and bioactive molecules.2 The Heck–
Matsuda arylations can be performed under aerobic conditions
without requiring expensive and toxic phosphine ligands. Besides,
these Heck arylations are much easier to carry out than conven-
tional protocols.3 The first example of arenediazonium salts as ary-
lating agents of olefins catalyzed by palladium was described by
Tsutomu Matsuda in 1977.4 In spite of the many advantages and
the long-term existence of the Heck–Matsuda (HM) reaction, its
enantioselective version constitutes a considerable challenge due
to the incompatibility of the phosphine ligands often used in the
conventional Heck reactions with the arenediazonium salts.5
reaction and its consolidation as a robust, reliable and broad scope
synthetic method. The protocols reported in this work are very
mild, fast and do not use any air-sensitive phosphines as chiral li-
gands or any anhydrous solvents.
We started our investigation using the symmetric and nonacti-
vated olefin 1 and the m-CF3-substituted arenediazonium salt 2a as
a model reaction to optimize conditions for asymmetric induction
(Table 1). The Heck–Matsuda arylation of 1 using our previously
reported procedure (Pd(OAc)2, excess of arenediazonium salt in
methanol at 60 °C) gave the desired product 3a in 93% yield after
5 h.8 Prompted by the excellent result obtained with olefin 1, we
decided to employ the same protocol for our initial studies of the
asymmetric version of the HM arylation using the chiral bisoxazo-
line I (Fig. 1). Under these conditions, the product 3a was obtained
H
H
O
O
O
O
N
N
N
N
N
H
H
Ph
Ph
III
Results and discussion
I
O
O
N
Herein, we describe the first protocol to perform an asymmetric
version of the Heck–Matsuda reaction using chiral, nonracemic,
N
Ph
Ph
II
⇑
Corresponding author.
E-mail address: roque@iqm.unicamp.br (C.R.D. Correia).
Figure 1. The chiral bisoxazolines used in this study.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.079

3326
Carlos Roque D. Correia et al. / Tetrahedron Letters 53 (2012) 3325–3328
Table 1
Evaluating conditions for the enantioselective HM
N2BF4
CO2Me
CO2Me
[Pd]
Ligand
MeO2C
CO2Me
∗
additives
3a
MeOH
60 °C
F3C
2a
1
CF3
Entry
[Pd] (10 mol %)
Ligand (20 mol %)
Additive (equiv)
Time (min)
Yield (%)
eea
1
2
3
4
5
6
7
8
Pd(OAc)2
I
—
300
300
45
20
20
53
74
81
81
56
90
90
75
81
85
77
76
83
Ndf
24
48
54
54
14
44
34
0
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
II
II
II
II
II
II
III
I
II
II
II
II
II
Ag2CO3 (1)
Ag2CO3 (2)
Ag2CO3/ Zn(OTf)2 (0.2)/(0.1)
AgClO4 (2)
Zn(OTf)2 (0.1)
Zn(OTf)2 (1)
Zn(OTf)2 (1)
Zn(OTf)2 (1)
Zn(OTf)2 (1)
—
10
15
180
160
180
100
20
9
0
10b
11
12c
13d
14e
34
38
38
84
46
—
—
20
—
a
b
c
d
e
f
Determined by GC on a chiral HP-5 column.
T = 25 °C.
Using 5 mol % of Pd(CF3CO2)2 and 6 mol % of II.
Using 1 equiv of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) as base.
Using 1 equiv of NaOAc as base.
nd = not determined.
in a moderate 53% yield with a modest enantiomeric excess of 24%
after 5 h (Table 1, entry 1). Changing the solvent to CH3CN, PhCN,
or dimethylcarbonate gave the corresponding Heck adduct only
in trace amounts. PdCl2(MeCN)2 was also found to be a viable cat-
alyst for the HM arylation of olefin 1. However, considering that
different mechanisms (cationic, neutral and neutral pentacoordi-
nate) might be operating and potentially eroding the enantioselec-
tivity of the reaction in this case, we decided to use silver salts as
halide scavengers.9 Therefore, when using PdCl2(MeCN)2 as cata-
lyst we also added 1 equiv of Ag2CO3 to the reaction in order to re-
move chloride ions and establish the cationic pathway. We were
delighted to find out that using bisoxazoline II (Fig. 1) the desired
Heck product was isolated in a good 74% yield with a moderate, but
significant, ee of 48% after 5 h (Table 1, entry 2). We hypothesize
that the increase in ee is probably due to the greater stability of
the expected palladium complex as a five-membered chelate.10
Since only catalytic amounts of silver salt would be theoreti-
cally necessary, the amount of Ag2CO3 was reduced to 10 mol %.
Interestingly, under this condition, we observed a sluggish reaction
and a decrease in the ee’s to the extent of affording a roughly race-
mic product. On the other hand, an increase in the amount of
Ag2CO3 (2 equiv) had a striking effect on the reaction time and a
slight increase in yield. After 45 min, the product was obtained in
81% yield and 54% ee (Table 1, entry 3). In an attempt to under-
stand the role of the silver salts, we carried out the arylation with
catalytic Ag2CO3/Zn(OTf)2. Surprisingly, we observed a further de-
crease in reaction time (20 min) while maintaining the good yield
and moderate ee (Table 1, entry 4). Although the role of the
Zn(OTf)2 is not clear, we speculate that this Lewis acid might be
accelerating the oxidative addition of Pd(0) to the arenediazonium
salt. Curiously, changing the nature of the counter-ion associated
with the silver salts (AgClO4) caused a sharp decrease in the
enantioselectivity and yield (Table 1, entry 5). As chelation of Pd
to the chiral bisoxazoline is of utmost importance for enantioselec-
tivity, we decided to replace the Pd catalyst to Pd(CF3CO2)2. The use
of Pd(CF3CO2)2 and Zn(OTf)2 (10 mol %) as Lewis acid provided the
Heck product in 90% yield in 44% ee after only 10 min (Table 1, en-
try 6). Changing the amount of Zn(OTf)2, the catalyst loading and
the temperature resulted in no significant improvements in the
enantioselectivity, affecting basically yields and reaction times (Ta-
ble 1, entries 7,10 and 12). We then decided to evaluate other com-
mercial bisoxazolines. Thus, bisoxazoline II was replaced by
bisoxazolines I and III in the presence of Zn(OTf)2 (Table 1, entries
7–9). The Heck products were obtained in good yields (75% and
81% respectively). However, in spite of the supposedly greater
coordinating power of these ligands only racemic products were
obtained. We then focused our attention on the role of the base
considering that higher enantioselectivities were obtained in the
presence of CO23À (Table 1, entries 2–4). Gratifyingly, the use of
2,6-di-tert-butyl-4-methylpyridine (DTBMP) as base, furnished
the Heck product in 83% yield in a very good ee of 84% after only
20 min (Table 1, entry 13).7 Surprisingly, NaOAc as base had a det-
rimental effect on the reaction providing a complex and insepara-
ble mixture of products (Table 1, entry 14).2a With optimized
conditions in hand, an investigation of the scope of the enantiose-
lective Heck–Matsuda reaction was initiated. As outlined in Table
2, we have found that a broad range of arenediazonium salts can
be enantioselectively coupled to olefin 1. Both electron deficient
and electron rich diazonium salts can be employed providing the
Heck adducts in good to excellent yields (63% up to 96% yields)
and good enantioselectivities (60% up to 84% ee) in less than an
hour.11 Interestingly, higher levels of enantioselectivity were ob-
tained using electron deficient diazonium salts. In a few cases it
was not possible to chromatographically separate the enantiomers.
Therefore, in these cases we performed the measurement of the
optical rotation of each product as an evidence of the asymmetric
induction in the reaction (3i–j, Table 2).
Increasing the olefin ring size from five to six-membered re-
sulted in a decrease in the enantioselectivity of the arylation reac-
tion (5 in Scheme 1). We rationalized this lower enantioselectivity
as a consequence of the increasing conformational freedom of the
six-membered olefin system when compared to the five-membered

Carlos Roque D. Correia et al. / Tetrahedron Letters 53 (2012) 3325–3328
3327
Table 2
of these HM arylations. Arylation of olefin 6 bearing only one methyl
ester group afforded a diastereoisomeric mixture of the Heck ad-
ducts in a ratio of 1:1.2. Despite the low diastereoselectivity in this
case, we observed very good enantiomeric excesses for both Heck
adduct (60% and 82% ee for compound 8 in Scheme 1).
Recently, our group has demonstrated that the chelating prop-
erties of ester, carbamates and amides groups may have a strong
impact on the reactivity and on the regio- and stereoselectivity
of the HM reaction.13 We hypothesize that the esters group might
be participating in the transition states defining the overall out-
come of the HM arylation. Further research is ongoing to confirm
this assumption.
Enantioselective HM arylation of olefin 1 varying the arenediazonium salt
N2BF4
MeO2C
CO2Me
CO2Me
CO2Me
∗
a
R
3a-k
1
2a-k
R
a: Pd(CF3CO2)2 (10 mol%), ligand II (20 mol%), DTBMP (1 equiv),
MeOH (0.14 M), 60 °C, 1h
3a
3b
CO2Me
CO2Me
CO2Me
CO2Me
∗
∗
Conclusion
I
76%
(74% ee)
83%
(84% ee)
In summary, these initial studies demonstrated for the first time
the feasibility of an enantioselective reaction employing arene-
diazonium salts. This method was successfully applied in the enan-
tioselective Heck–Matsuda reaction using chiral bisoxazolines as
ligands.7 The operational conditions found for these first enantio-
selective HM arylations were remarkably simple, providing good
to excellent yields of the HM adducts (63–96%) in enantiomeric ex-
cesses which varied from 54% up to 84% ee. Further investigations
are ongoing in our laboratory to extend the scope of these novel
HM reactions and to define the absolute stereochemistry of the
Heck products.
CF3
3c
CO2Me
CO2Me
3d
CO2Me
CO2Me
∗
∗
74%
87%
(74% ee)
MeO
(72% ee)
NO 2
3f
Cl
3e
CO2Me
CO2Me
CO2Me
CO2Me
∗
∗
63%
91%
(70% ee)
O2N
Me O
(76%
ee)
Acknowledgments
3g
OMe
3h
CO2Me
CO2Me
CO2Me
CO2Me
∗
The authors thank the Brazilian National Research Council
(CNPq) and the Research Supporting Foundation of the State of
São Paulo (FAPESP) for fellowships and financial support.
∗
83%
76%
(60% ee)
Ph
(60%
ee)
Supplementary data
CO2Me
CO2Me
CO2Me
CO2Me
3i
3j
∗
∗
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.04.079.
NC
F3C
96%
85%
20
[α]D + 190 (c 4.9 in MeOH)#
[α]D 20 + 142 ( 12.8 in MeOH)#
c
References and notes
#
Enantiomers were inseperable by chiral HPLC and capillary chiral GC.
1. (a) Tietze, L. F.; Ila, H.; Bell, H. P. Chem. Rev. 2004, 104, 3453; (b) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 4137; (c)
Walsh, P. J.; Kozlowski, M. Fundamentals of Asymmetric Catalysis; University
Science Books: Sausalito, 2009. pp. 549–576.
2. For reviews, see: (a) Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M. Chem.
Rev. 2006, 106, 4622; (b) Taylor, J. G.; Moro, A. V.; Correia, C. R. D. Eur. J. Org.
Chem. 2011, 1403; (c) Felpin, F.-X.; Nassar-Hardy, L.; Callonnec, F. L.; Fouquet,
E. Tetrahedron 2011, 67, 2815.
Me O2C
CO2Me
Pd(CF3CO2)2 (10 mol%)
ligand II (20 mol%)
DTBMP (1 equiv)
MeO2C
CO2Me
+ 2a
∗
3. (a) Nassar-Hardy, L.; Fabre, S.; Amer, A. M.; Fouquet, E.; Felpin, F.-X.
Tetrahedron Lett. 2012, 53, 338; (b) Schwalm, C. S.; de Castro, I. B. D.; Ferrari,
J.; de Oliveira, F. L.; Aparicio, R.; Correia, C. R. D. Tetrahedron Lett. 2012, 53,
1660; (c) Taylor, J. G.; Correia, C. R. D. J. Org. Chem. 2011, 76, 857; (d) da Penha,
E. T.; Forni, J. A.; Biajoli, A. F. P.; Correia, C. R. D. Tetrahedron Lett. 2011, 52, 6342;
(e) Taylor, J. G.; Ribeiro, R. S.; Correia, C. R. D. Tetrahedron Lett. 2011, 52, 3861;
(f) de Azambuja, F.; Correia, C. R. D. Tetrahedron Lett. 2011, 52, 42; (g) Siqueira,
F. A.; Taylor, J. G.; Correia, C. R. D. Tetrahedron Lett. 2010, 51, 2102; (h) Garcia, A.
L. L.; Carpes, M. J. S.; Montes de Oca, A. C. B.; Santos, M. A. G.; Santana, C. C.;
Correia, C. R. D. J. Org. Chem. 2005, 70, 1050; (i) Garcia, A. L. L.; Correia, C. R. D.
Tetrahedron Lett. 2003, 44, 1553; (j) Severino, E. A.; Costenaro, E. R.; Garcia, A. L.
L.; Correia, C. R. D. Org. Lett. 2003, 5, 305.
4. Kikukawa, K.; Matsuda, T. Chem. Lett. 1977, 159.
5. Most phosphines are incompatible with arenediazonium salts due to single-
electron transfer process. See Ref.2a for details.
6. (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325; (b) Evans, D. A.;
Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480;
(c) Evans, D. A.; Johnston, J. N. Org. Lett. 1999, 1, 865; (d) Evans, D. A.;
Johnson, D. S. Org. Lett. 1999, 1, 5985; For PyBox ligand see: Nishiyama, H.;
Sakaguchi, H.; Nakamura, T.; Horihata, M.; Kondo, M.; Itoh, K. Organometallics
1989, 8, 846.
MeOH
5
60 °C, 1h
69% yield
(54% ee)
4
CF3
CO2Me
Pd(CF3CO2)2 (10 mol%)
ligand II (20 mol%)
DTBMP (1 equiv)
CO 2Me
∗
+ 2a
7
MeOH
60 °C, 1h
91% yield
1:1.2
.
d.r
6
(60% ee/ 82% ee)
CF3
Scheme 1. Enantioselective HM arylation of other nonactivated olefins.
7. For an excellent example of a conventional Heck reaction employing chiral
bisoxazoline as ligand, see: Tietze, L. F.; Sommer, K. M.; Zinngrebe, J.; Stecker, F.
Angew. Chem. 2005, 117, 262. Angew. Chem. Int. Ed. 2005, 44, 257.
ones.12 The increasing distance between the esters groups and the
olefin might also have an influence on the stereochemical outcome

3328
Carlos Roque D. Correia et al. / Tetrahedron Letters 53 (2012) 3325–3328
8. (a) Pastre, J. C.; Correia, C. R. D. Adv. Synth. Catal. 2009, 351, 1217; For previous
attempts of an enantioselective HM reaction using chiral ionic liquids, see: (b)
Pastre, J. C.; Genisson, Y.; Saffon, N.; Dandurand, J.; Correia, C. R. D. J. Braz. Chem.
Soc. 2010, 21, 821.
9. (a) Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57, 4571; (b) Amatore, C.;
Jutand, A.; Suarez, A. J. Am. Chem. Soc. 1993, 115, 9531; (c) Cabri, W.; Candiani,
I.; Bedeschi, A.; Santi, R. J. Org. Chem. 1993, 58, 7421.
S.; Sodeoka, M.; Shibasaki, M. Tetrahedron 1994, 50, 371; (d) Shibasaki, M.;
Sodeoka, M. J. Synth. Org. Chem. Jpn. 1994, 52, 955.
11. For application of similar carbocycles in the synthesis of bioactive molecules
see: (a) Grunewald, G. L.; Ye, Q. J. Org. Chem. 1988, 53, 4021; (b) Moriaty, R. M.;
Enache, L. A.; Zhao, L.; Gilardi, R.; Mattson, M. V.; Prakash, O. J. Med. Chem.
1998, 41, 468.
12. For an interesting review: Hancock, R. D. J. Chem. Edu. 1992, 69, 615.
13. (a) Moro, A. V.; Cardoso, F. S. P.; Correia, C. R. D. Org. Lett. 2009, 11, 3642; (b)
Prediger, P.;Barbosa, L. F.;Genisson,Y.;Correia, C. R. D. J. Org. Chem. 2011, 76, 7737.
10. (a) Sato, Y.; Sodeoka, M.; Shibasaki, M. Chem. Lett. 1990, 1953; (b) Sato, Y.;
Watanabe, S.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 2589; (c) Sato, Y.; Nukui,