The Heck-Matsuda arylation of 2-hetero-substituted acrylates

Article abstract of DOI:10.1016/j.tetlet.2010.10.132

The Heck-Matsuda arylation of 2-aza and 2-oxo-substituted acrylates is described. Several reaction conditions were evaluated including the influence of solvents, temperature, catalysts, and stoichiometry. While the oxygenated system was successfully aryla

Full text of DOI:10.1016/j.tetlet.2010.10.132

Tetrahedron Letters 52 (2011) 42–45
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The Heck–Matsuda arylation of 2-hetero-substituted acrylates
⇑
Francisco de Azambuja, Carlos Roque Duarte Correia
Instituto de Química, Universidade Estadual de Campinas, UNICAMP, 13084-971 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:
The Heck–Matsuda arylation of 2-aza and 2-oxo-substituted acrylates is described. Several reaction
conditions were evaluated including the influence of solvents, temperature, catalysts, and stoichiome-
try. While the oxygenated system was successfully arylated in benzonitrile with Pd2(dba)3 as catalyst,
the aza-acrylate furnished methoxylated products. The methoxylated products were subjected to an
elimination/reduction protocol to obtain the corresponding N,O-protected phenylalanine derivatives.
A one-pot procedure for the preparation of phenylalanine derivatives from 2-aza-substituted acrylates
is presented.
Received 13 August 2010
Revised 22 October 2010
Accepted 26 October 2010
Available online 31 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The
a large number of biologically important compounds found in nat-
ure.1
-Amino acids, for example, display valuable characteristics
such as conformational restrictions, which are cleverly exploited
in peptidomimetics research.2 Aromatic amino acids having lumi-
nescent properties3 are important probes in protein structural
a
-amino and
a
-hydroxy acid structural motifs are central to
We began this study with the oxygenated system 1 and p-meth-
oxyphenyldiazonium tetrafluoroborate 2. For our initial studies,
we used equimolar amounts of olefin and diazonium salts and
evaluated the base, the sources of palladium, the temperature,
and the reaction medium (Table 1).
Product 3 was isolated in low to modest yields under the reac-
tion condition tested (Table 1, entries 2–8). Other solvents different
from those presented in Table 1 were also tested (toluene, THF,
methylene chloride, acetone, ethyl acetate, and water) with
Pd2(dba)3 and sodium acetate at room temperature, providing low-
er yields of the desired product. Essentially, a base and heating
were necessary, as demonstrated in Table 1 (entries 1–6). Excess
of the olefin or the diazonium salt was also evaluated but no fur-
ther improvements were observed.
a
studies. On the other hand, a-hydroxy acids are present in several
natural products bearing promising biological activities. Several of
such compounds are used in pharmaceutical and medicinal re-
search, namely pulvinic acids and their derivatives,4 thyroid hor-
mone analogs,5 and other natural products such as leprapinic
acid and calycine.6
Among the several syntheses of amino acids described in the lit-
erature,1
a-amino acids bearing aromatic rings were extensively
prepared through the Heck arylation, a powerful C–C coupling
reaction mediated by Pd(0),7 often followed by asymmetric hydro-
genation.8,9 In spite of the efficiency of the traditional Heck proto-
cols, these reactions usually require phosphine ligands, additives
such as quaternary ammonium salts, inert atmosphere, high tem-
peratures, and long reaction times.
A moderate 59% yield was obtained in benzonitrile (entry 7) and
this result is comparable to that described in the literature for the
Heck reaction employing aryl halides.4a,c The conditions reported
herein avoided phosphine ligands, required shorter reaction times,
and used equal amounts of the olefin and the arylating agent. Even
shorter reaction times were achieved under microwave irradiation
albeit with a slight decrease in yields. Remarkably, only the Z iso-
mer was obtained with its configuration assigned by comparison
with the literature data.4a Other arenediazonium salts such as p-
iodo and m-nitrophenyldiazonium tetrafluoroborates were also
evaluated, but gave poor yields (typically <10%).
To the best of our knowledge, the Heck–Matsuda protocol,10
which replaces aryl halides with the more reactive arenediazonium
salts, has not been evaluated for the synthesis of aromatic amino
acids. The Heck–Matsuda reaction offers several advantages over
the traditional Heck reaction, such as shorter reaction times, phos-
phine-free conditions, easy handling of the process, and quite of-
ten, lower reaction temperatures. In the last few years, we11 and
others12 have demonstrated the synthetic potential of the arene-
diazonium salts in several cases, and herein we wish to disclose
our results for the Heck–Matsuda arylation of methyl 2-hetero-
substituted acrylates as presented in Scheme 1.
CO2Me
CO2Me
N2BF4
Pd(0)
+
X
R
O
X
R
O
G
X = O, NH
Scheme 1. Heck–Matsuda arylation of 2-hetero-substituted acrylates.
⇑
Corresponding author.
E-mail address: roque@iqm.unicamp.br (C.R.D. Correia).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.132

F. de Azambuja, C. R. D. Correia / Tetrahedron Letters 52 (2011) 42–45
43
Table 1
Table 2
Representative results for the arylation of methyl 2-acetoxyacrylate 1a
Scope of 2-aza-acrylates arylation with diazonium saltsa
N2BF4
CO2Me
OMe
CO2Me
CO2Me
Pd(OAc)2, DTBMP
MeOH, 65 ºC, 1-2 h
CO2Me
+
NHX
Pd2(dba)3
Ar
N2BF4
+
O
O
NHX
8-16
MeO
5 mol%
R
O
O
4,6 or 7
OMe
1
2
3
Entry
X
Ar
Product
Yield (%)
1
2
3
7
9
6
7
8
9
C(O)CH3 [4]
C(O)CH3 [4]
C(O)CH3 [4]
C(O)CF3 [6]
C(O)CF3 [6]
C(O)CF3 [6]
C(O)CF3 [6]
C(O)CF3 [6]
C(O)CF3 [6]
Ts [7]
p-OMeC6H5
p-FC6H5
p-IC6H5
p-OMeC6H5
p-IC6H5
p-FC6H5
2-Naphthyl
m-NO2C6H5
C6H5
8
9
73
68
46
75
86
81
77
65
67
—
Entry
Solvent
Base (equiv)
T (°C)e
t (h)
Yield (%)
1
2
3
MeCN
MeCN
MeOH
MeCN
MeCN
PhCN
PhCN
PhCN
PhCN
None
25
25
Reflux
Reflux
Reflux
80
110
110
110
2
2
2
27
3
6
3
0.5
3
0
14
16
18
36
46
59
53
6
10
11
12
13
14
15
16
NaOAc (3)
NaOAc (3)
NaOAc (3)
DTBMP (3)
DTBMP (1)
DTBMP (1)
DTBMP (1)
DTBMP (1)
4
5b
6
7
8c
9d
10
p-OMeC6H5
a
Reaction conditions: 0.42 mmol of acrylate, 0.42 mmol of diazonium salt,
0.42 mmol of DTBMP, Pd(OAc)2 10 mol %, 1.6 mL of methanol, 65 °C, 1–2 h.
a
Reaction conditions: 0.42 mmol of acrylate, 0.42 mmol of diazonium salt, 1–
3 equiv of base, Pd2(dba)3 5 mol %, 1.6 mL of solvent.
b
DTBMP: 2,6-di-t-butyl-4-methylpyridine.
Microwave heating.
Catalyst: Pd(OAc)2.
Oil bath temperature.
c
d
Trifluoroacetyl group proved to be the best protecting group
(acrylate 6), providing better yields for all diazonium salts tested.
Examples shown in Table 2 are representative of the type of sub-
stituents evaluated.13 Surprisingly, the tosyl protecting group
(acrylate 7, entry 10) was not effective.
A rationale for the formation of the 2-methoxylated Heck prod-
ucts follows our previous proposal for the Heck–Matsuda mecha-
nism ( Fig. 1).14 Formation of 2-methoxylated Heck products is
proposed to proceed through the iminium ion 17, which could be
formed in situ by the protonation of the enamine portion of the pri-
mary Heck adduct or by a b-elimination with the amide hydrogen
leading to imine 18. These routes involving an iminium ion look
plausible due to the fact that the acid originating from the Heck
catalytic cycle remains complexed with the pyridine base. The 2-
methoxylated product is probably formed by the addition of meth-
anol to the iminium ion 17.
e
As the oxygenated system 1 presented itself rather resistant to
the Heck–Matsuda arylation, we turned our attention to the nitro-
genated acrylate 4. To our surprise, reaction conditions previously
employed for the oxygenated acrylate 1 resulted in low yields or in
no Heck product (Scheme 2).
Nitrilic solvents did not provide the desired Heck adduct 5 in
spite of changes in solvent composition (including mixtures with
water) and temperature (from room temperature to 110 °C). How-
ever, the Heck product 5 could be obtained in 37% yield in t-buta-
nol (Pd(OAc)2 as catalyst). Other solvents such as THF, water, and
mixtures of THF/water proved less efficient than t-butanol (lower
yield and longer reaction time).
A completely new scenario was observed when methanol was
applied as solvent (Table 2). Instead of the expected acrylate type
Heck adduct 5, the 2-methoxy-phenylalanines 8–10 were obtained
in good to excellent yields. We also tested isopropanol as solvent,
sodium acetate or silver carbonate as base, Pd2(dba)3 or Pd/C as
catalyst, as well as microwave heating. None of these changes led
to any improvement over the conditions described in Table 2
employing methanol, palladium acetate, and 2,6-di-tert-butyl-4-
methylpyridine (DTBMP) as base. In the absence of a base, a sharp
decrease in yield was observed (12% yield) with lower conversion
(91%).
The scope of the methodology was evaluated with acrylate 4. In
general, the efficiency of the arylation dropped as the electron
withdrawing capacity of the substituent groups on the diazonium
aromatic ring increased (entries 1–3, Table 2). Different nitrogen
protecting groups were also evaluated.
The Heck adducts obtained are highly functionalized small mol-
ecules, and to demonstrate their synthetic usefulness, we envi-
sioned the synthesis of some phenylalanine derivatives from
them. These phenylalanine analogs were obtained from the corre-
sponding 2-methoxylated Heck adducts by an elimination/reduc-
tion protocol using Lewis acids and alkyl/arylsilane.15,16
Methoxylated Heck adducts 8 and 9 gave good yields of the re-
duced products 19 and 20 when reacted with boron trifluoride
diethyl etherate as a Lewis acid and triethylsilane as the reduc-
tant (entries 1 and 2, Table 3). On the other hand, the trifluoro-
methyl adducts 11 and 12 gave lower yields of the reduced
products. Attempts to increase the yields by changing tempera-
ture, solvent, Lewis acid, or reductant proved to be fruitless
(Table 3).
Another possible explanation for the lower yields with trifluoro-
methyl adducts might be the instability of the iminium ion inter-
mediate. Therefore, silane attack must be a fast process or the
system undergoes disproportion to the Heck primary adduct 23.
Other reductants (Et3SiH, Ph3SiH, PhSiH3, H2/AcOH, H2/Et3SiH)
gave low yields of the desired phenylalanine products. The best
protocol was achieved with TMSOTf and Et3SiH in 1,2-dichloroeth-
ane at 83 °C (36% yield). Alternatively, the demethoxylated phenyl-
alanine 22 was obtained after catalytic hydrogenation of the
mixture obtained from the elimination/reduction protocol in good
overall yield (71%, Scheme 3).17
N2BF4
CO2Me
CO2Me
O
A, B or C
+
HN
HN
MeO
O
OMe
4
2
5
A: Pd2(dba)3, NaOAc, MeCN, 25 ºC (no product detected)
B: Pd2(dba)3, DTBMP, PhCN, 110 ºC (no product detected)
C: -BuOH, Pd(OAc)2, DTBMP, 65 ºC, 2 h, 37 %
Finally, since silanes are compatible with the presence of
arenediazonium salts,18 we imagined a one-pot strategy for the
preparation of phenylalanine derivatives (Table 4). Thus, a bal-
ance between diazonium salt, silicon reductant, and methanol
t
Scheme 2. Initial studies for the Heck–Matsuda arylation of 4.

44
F. de Azambuja, C. R. D. Correia / Tetrahedron Letters 52 (2011) 42–45
Pd(II)
Base.HX
+
ArN2
Base
N2
Pd(0)
CO2Me
L2Pd
H
CO2Me
ArPdL2
Ar
HN
X
NHC(O)X
O
L
H
L
Ar
X = CH3, CF3
Pd
Pd
CO2Me
L
L
CO2Me
H+
Pd
CO2Me
Ar
NHC(O)X
Ar
NHC(O)X
Ar
NHC(O)X
CO2Me
H+
CO2Me
Ar
HPd
NHC(O)X
NC(O)X
18
17
MeOH
OMe
CO2Me
Ar
NHC(O)X
Figure 1. Rationale for the formation of 2-methoxy-adducts.
Table 3
Preparation of the phenylalanine derivativesa
OMe
CO2Me
CO2Me
CO2Me
NHX
Lewis acid, Silane
+
NHX
solvent, 0 °C - T
NHX
R
R
R
19 X = C(O)CH3, R = OMe
20 X = C(O)CH3, R = F
21 X = C(O)CF3, R = I
8,9, 11 or 12
23 X = C(O)CF3, R = OMe
22 X = C(O)CF3, R = OMe
Entry
S.M.
R
X
Solventb
Lewis acid
Silane
T (°C)
Time (h)
Yield (%)d
1
2
3
4
5
8
9
OMe
F
I
I
I
I
I
OMe
OMe
OMe
OMe
C(O)CH3
C(O)CH3
C(O)CF3
C(O)CF3
C(O)CF3
C(O)CF3
C(O)CF3
C(O)CF3
C(O)CF3
C(O)CF3
C(O)CF3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH2Cl2
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
TMSOTf
BF3ÁOEt2
BF3ÁOEt2
TMSOTf
TMSOTf
TMSOTf
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
PhSiH3
Ph3SiH
25
25
25
40
65
25
83
83
83
83
83
18
20
18
18
27
36
28
120
17
17
20
78 [19]
75 [20]
—
43 [21]
—
12
12
12
12
12
11
11
11
11
6
—
7c
8c
9
28 [21]
32 [22]
36 [22], 35 [23]
31 [22], 54 [23]
22 [22], 5 [23]
10
11
a
b
c
Reaction conditions: starting material (1 equiv), Lewis acid (4 equiv), silane (10 equiv), concentration (0.06 mol LÀ1).
1,2-DCE: 1,2-dichloroethane.
8 equiv of Lewis acid and 20 equiv of silane were used.
Product numbers are in brackets.
d
amounts was screened to find the best condition to provide the
phenylalanine derivative 19. As shown in Table 4, the best yield
was 54%, using a mixture of THF:MeOH = 3:2 as the solvent and
a lower temperature compared to the original Heck process
(Table 2). Although not fully optimized, the overall yield is com-
parable to that observed for the two-step process (Scheme 4).
In summary, the Heck–Matsuda arylation of 2-aza and 2-oxo-
substituted acrylates was investigated. Several reaction condi-
tions were evaluated including solvents, temperature, catalysts,
substituted acrylates 4 and 6 were arylated in methanol in lower
temperature furnishing the corresponding methoxylated adducts
8–16.
As a demonstration of the synthetic potential of this Heck–Mat-
suda protocol, the functionalized products were submitted to an
elimination/reduction protocol to obtain the phenylalanine deriva-
tives. A one-pot procedure for the preparation of phenylalanine
derivatives starting from 2-aza-substituted acrylates was also
demonstrated. Further developments of the Heck–Matsuda aryla-
tion of 2-hetero-substituted acrylates are under investigation in
our laboratories.
and stoichiometry.
A more vigorous protocol was needed
for the arylation of the oxygenated system 1, while the 2-aza-

F. de Azambuja, C. R. D. Correia / Tetrahedron Letters 52 (2011) 42–45
45
CO2Me
References and notes
OMe
CO2Me
Et3SiH
TMSOTf
HN
CF3
1. Nájera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584. and references cited.
2. (a) Voyer, N.; Lamothe, J. Tetrahedron 1995, 51, 9241; (b) Humphrey, J. M.;
Chamberlin, A. R. Chem. Rev. 1997, 97, 2243.
MeO
MeO
HN
CF3
1,2-DCE
0 - 83 ºC
O
MeO
22, 36 %
O
3. (a) Wang, Q.; Parrish, A. R.; Wang, L. Chem. Biol. 2009, 16, 323; (b) Tanaka, Y.;
Bond, M. R.; Kohler, J. J. Mol. BioSyst. 2008, 4, 473; (c) Agris, P. F. Nucleic Acids
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Bergman, R. G.; Ellman, J. A. J. Nat. Prod. 2006, 69, 1231; (c) Han, X.; Jiang, X.-J.;
Civiello, R. L.; Degnan, A. P.; Chaturvedula, P. V.; Macor, J. E.; Dubowchik, G. M.
J. Org. Chem. 2009, 74, 3993.
+
11
CO2Me
CF3
HN
O
23, 35 %
CO2Me
CF3
5. Koh, J. T.; Hassan, A. Q. Angew. Chem., Int. Ed. 2008, 47, 7280.
6. (a) Fracchiolla, G.; Laghezza, A.; Piemontese, L.; Tortorella, P.; Mazza, F.;
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Pd/C, H2
HN
MeO
THF, r.t., 20 h
quant.
O
22, 71 % overall yield
Scheme 3. Route to the phenylalanine derivatives.
8. (a) Chan, C.; Zheng, S.; Zhou, B.; Guo, J.; Heid, R. M.; Wright, B. J. D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2006, 45, 1749; (b) Yamada, K.;
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J. Organomet. Chem. 2003, 687, 494.
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K. Eur. J. Med. Chem. 2009, 44, 1001; (b) Zheng, H.; Comeforo, K.; Gao, J. J. Am.
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Table 4
One-pot approach to the phenylalanine derivatives
N2BF4
Pd(OAc)2
DTBMP
CO2Me
NHAc
CO2Me
+
NHAc
Et3SiH
T (ºC), solvent
MeO
OMe
2
4
19
Entry
Equiv 4:2:silane
T (°C)
Solvent
Yield (%)
1
2
3
4
1:1:2
65
65
65
65
0
MeOH
MeOH
THF:MeOH (3:2)
THF:MeOH (6:1)
THF:MeOH (3:2)
THF:MeOH (3:2)
21
35
42
34
54
43
1:1:10
1:1:10
1:1:10
1:2:5
6
7a
1:2:2
0
a
Silane: Ph3SiH.
N2BF4
Pd(OAc)2
CO2Me
NHAc
CO2Me
+
DTBMP (1 equiv.)
NHAc
THF:MeOH (3:2)
Et3SiH
0 ºC, 40 min
MeO
OMe
4
2
19
13. Application of the reaction conditions reported by Felpin (Ref. 12a). to the
reaction of acrylate 4 with diazonium salt 2 (methanol, room temperature,
2 mol % of Pd(OAc)2) furnished the methoxylated product 8 in only 4% yield
after four days (10% conversion of the starting material). However, reaction of
acrylate 6 with diazonium salt 2 under the same conditions furnished the
methoxylated product 8 in 92% yield after 18 h. On the other hand, reaction of
one-pot: 54 %
two-step process: 57 %
OMe
Pd(OAc)2
DTBMP
BF3.OEt2
Et3SiH
CO2Me
acrylate 6 with m-nitrodiazonium tetrafluoroborate salt furnished the
methoxylated product 15 in <10% yield, after 18 h.
NHAc
14. (a) Sabino, A. A.; Machado, A. H. L.; Correia, C. R. D.; Eberlin, M. N. Angew. Chem.,
Int. Ed. 2004, 43, 2514; (b) Sabino, A. A.; Machado, A. H. L.; Correia, C. R. D.;
Eberlin, M. N. Angew. Chem., Int. Ed. 2004, 43, 4389.
MeOH
65 ºC, 2 h
MeO
r.t., 18 h
8
15. Roos, E. C.; López, M. C.; Brook, M. A.; Hiemstra, H.; Speckamp, W. N.; Kaptein,
K.; Kamphuis, J.; Schoemaker, H. E. J. Org. Chem. 1993, 58, 3259.
16. For earlier examples of amino acid synthesis using iminium chemistry: (a) Ben-
Ishai, D.; Moshenberg, R.; Altman, J. Tetrahedron 1977, 33, 1533. and references
cited; (b) Ben-Ishai, D.; Altman, J.; Peled, N. Tetrahedron 1977, 33, 2715.
17. See Ref. 15 for the synthesis of this particular phenylalanine.
18. (a) Kikukawa, K.; Totoki, T.; Wada, F.; Matsuda, T. J. Organomet. Chem. 1984,
270, 283.
Scheme 4. Comparison between one- and two-step processes.
Acknowledgments
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.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.132.