Ligand-free palladium catalysed Heck reaction of methyl 2-acetamido acrylate and aryl bromides as key step in the synthesis of enantiopure substituted phenylalanines

Article abstract of DOI:10.1016/j.jorganchem.2003.09.012

A range of substituted aryl bromides were coupled with methyl 2-acetamido acrylate using ligand-free palladium catalysis. Subsequently asymmetric hydrogenation with Rh/MonoPhos yielded substituted phenylalanines in high enantioselectivities (e.e. 92-99%).

Full text of DOI:10.1016/j.jorganchem.2003.09.012

Journal of Organometallic Chemistry 687 (2003) 494Á497
/
www.elsevier.com/locate/jorganchem
Ligand-free palladium catalysed Heck reaction of methyl 2-acetamido
acrylate and aryl bromides as key step in the synthesis of enantiopure
substituted phenylalanines
Charlotte E. Willans, Jan M.C.A. Mulders, Johannes G. de Vries,
Andre´ H.M. de Vries *
DSM Pharma Chemicals, Advanced Synthesis, Catalysis & Development, P.O. Box 18, 6160 MD Geleen, Netherlands
Received 4 July 2003; received in revised form 4 September 2003; accepted 4 September 2003
Dedicated to Jean-Pierre Geneˆt on the occasion of his 60th birthday
Abstract
A range of substituted aryl bromides were coupled with methyl 2-acetamido acrylate using ligand-free palladium catalysis.
Subsequently asymmetric hydrogenation with Rh/MonoPhos yielded substituted phenylalanines in high enantioselectivities (e.e. 92Á
/
99%).
# 2003 Elsevier B.V. All rights reserved.
Keywords: Ligand-free; Palladium; Heck; Substituted phenylalanines; MonoPhos
1. Introduction
A wide range of methods has been reported for the
preparation of aromatic dehydroamino acids [4].
Amongst these the classical Erlenmeyer synthesis with
subsequent hydrolysis of the 5(4H)-oxazolone is most
frequently employed. As the Pd-catalysed Heck reaction
tolerates a wide array of functional groups we were
particularly attracted by the coupling of dehydroalanine
derivatives (1) [5] with aryl halides, first reported by the
groups of Naso [6] and Hegedus [7]. The combination of
this Heck reaction followed by (asymmetric) hydrogena-
tion, disclosing an easy access to unnatural phenylala-
nines, has been demonstrated by several groups (see
Scheme 1) [8].
However, in most cases expensive aryl iodides were
used as starting materials. The rare cases where aryl
bromides were used, large amounts of palladium,
usually in combination with phosphine ligands, were
employed as catalyst. In fine chemical processes the
presence of phosphine ligands is not desirable, since they
often hamper the isolation and purification of the
product. We have recently found that it is possible to
perform the Heck reaction on aryl bromides with ligand-
free palladium, using Pd(OAc)2 only, as long as the
amount of palladium is low (usually between 0.01 and
Current methods of drug development are still largely
based upon mimicking the natural substrate for an
enzyme or a receptor. Since these are mostly peptides,
problems arise because of their hydrolytic instability in
biological systems. Stabilisation of peptide type struc-
tures is often done by the use of non-natural amino acids
[1]. The use of non-natural amino acids in drug
development is in turn dependent upon their ready
availability. As enantiopure substituted phenylalanines
are increasingly used in peptidomimetics [2], we decided
to investigate scaleable methods for their production.
Since we, in close collaboration with the group of
Feringa, have recently developed the use of low-cost
monodentate phosphoramidites as ligands for rhodium-
catalysed asymmetric hydrogenation of olefins [3], we
were interested in synthetic methods towards dehydro-
phenylalanines.
* Corresponding author.
E-mail address: andre.vries-de@dsm.com (A.H.M. de Vries).
0022-328X/03/$ - see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2003.09.012

C.E. Willans et al. / Journal of Organometallic Chemistry 687 (2003) 494Á
/497
495
Scheme 1.
0.1 mol%) [9]. These low palladium concentrations
prevent the precipitation of palladium black during the
ligand-free Heck reaction.
In this note we describe the synthesis of a range of
substituted phenylalanines by using consecutively a
ligand-free Heck reaction on aryl bromides followed
by an asymmetric hydrogenation reaction catalysed by
Rh/MonoPhos (3).
All the obtained dehydrophenylalanine derivatives
were hydrogenated at 5 bar H2 using 1 mol% of
[Rh(COD)2]BF4 and 1.1 mol% of enantiomerically
pure MonoPhos (3) in CH2Cl2 [10]. As can be seen
from the table the ligand MonoPhos induces excellent
e.e. values for all the different substrates tested. The
2. Results
observed turnover frequencies (200Á
400 hꢀ1, depending
/
Initial tests on the Heck reaction between 4-fluoro-
bromobenzene and methyl 2-acetamido acrylate (1a) in
which we screened several variables of the reaction (32
reactions performed simultaneously in the ASW 2000 of
Chemspeed) resulted in the following optimised condi-
tions that could be used: 0.3 mol% of Pd(OAc)2 in
combination with C6H5CH2NEt3Br and i-PrNEt3 or
NaOAc as base. All reactions were performed in NMP
at 125 8C. The products were purified by crystallisation
from EtOAc. Table 1 shows that the method works well
for electron-poor and electron-rich aryl bromides. The
Heck reaction gave moderate isolated yields of 2, but
these are comparable with the yields reported by others
using more expensive aryl iodides, and/or higher palla-
on the substrate) are similar as when the substrates are
made by the classical Erlenmeyer-hydrolysis sequence
[3e], indicating low impurity profiles in the substrates
obtained via this Heck coupling. The cyano-substituted
analogue did not give a full conversion after 2 h, most
likely due to competitive coordination of the cyano-
moiety to the rhodium. The asymmetric hydrogenation
of the p-chloro substituted compound was also carried
out with a substrate to catalyst ratio of 1000, yielding
pure product with 94% e.e. (80 min, at 5 bar of H2, room
temperature, CH2Cl2).
In conclusion, we have shown that a variety of
substituted phenylalanines can be produced using a
cost-effective sequence of two homogeneously catalysed
steps. The ligand-free palladium catalysed arylation of
methyl 2-acetamido acrylate using aryl bromides fol-
lowed by Rh/MonoPhos catalysed hydrogenation of the
acetamido-cinnamate ester gave good yields of the
various substituted N-Acetyl phenylalanine esters in
very high enantioselectivities.
dium loadings and/or a phosphine ligand [6Á8]. Possible
/
reasons for the moderate yields are the presence of the
electron donating nitrogen substituent on the olefin,
which retards the reaction. Secondly, it is likely that the
NaBr, which is present in the dipolar aprotic solvent,
reacts with the methyl ester 2 to form MeBr and the
sodium salt of the acetamido-cinnamate. Indeed, we
have found the acid upon closer inspection of the
aqueous phase during work-up. Although reported by
others [6], our attempts to perform the Heck reaction on
2-acetamido acrylic acid were unsuccessful. The reac-
tions led to the formation of gels, presumably caused by
polymerisation of the 2-acetamido acrylic acid.
In our efforts to simplify the reaction mixture we were
delighted to see that the coupling of methyl 2-acetamido
acrylate (1a) with 4-bromoacetophenone also proceeds
smoothly with only 0.05 mol% of Pd(OAc)2 and without
any tetraalkylammonium salt (see entry 13).
3. Experimental
3.1. General procedure for the Heck reaction
A 50 ml Schlenk flask was filled with aryl bromide
(13.0 mmol), methyl 2-acetamido acrylate (2.07 g, 14.5
mmol), base (15.0 mmol), C6H5CH2NEt3Br (163 mg,
0.60 mmol), Pd(OAc)2 (8.8 mg, 0.039 mmol, 0.30 mol%
with respect to aryl bromide), and NMP (27 ml).
Nitrogen atmosphere was applied, a stirring bar was

496
C.E. Willans et al. / Journal of Organometallic Chemistry 687 (2003) 494Á497
/
Table 1
Methyl N-acetyl-phenylalanines by ligand-free Heck reaction on 1a followed by asymmetric hydrogenation using Rh/MonoPhos a
Entry
Base
R
2
Isolated yield of 2 (%)
Completion of hydrogenation (min)
e.e. of 4 b (%)
1.
2.
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
NaOAc
4-F
3-F
a
b
c
d
e
f
67
62
31
71
23
62
55
53
63
44
56
52
55
25
30
15
96
95
95
99
94
94
99
92
95
95
93
94
99
3.
2-F
4.
4-COMe
4-OMe
4-Cl
15
c
5.
6.
20
30
7.
3,4-di-Cl
4-CN
4-Ph
g
h
i
d
8.
9.
25
c
10.
11.
12.
13. e
NaOAc
NaOAc
4-NO2
2-F,4-Ph
4-COPh
4-COMe
j
k
l
25
30
15
NaOAc
NaOAc
d
a
General method of Heck coupling: aryl bromide (13.0 mmol), 1a (14.5 mmol), base (15.0 mmol), C6H5CH2NEt3Br (0.60 mmol), Pd(OAc)2 (0.039
mmol, 0.30 mol% with respect to aryl bromide), NMP (27 ml), at 125 8C during 3 h. General method of asymmetric hydrogenation:
Dehydrophenylalanine 2 (1.0 mmol), [Rh(COD)2]BF4 (0.010 mmol), MonoPhos (0.011 mmol), CH2Cl2 (5 ml), H2 (5 bar), room temperature, full
conversions were obtained in all cases unless stated otherwise.
b
E.e. values were determined by chiral HPLC.
Not determined.
c
d
Conversion is only 70% (2 h reaction time).
Conditions of Heck reaction: 4-bromoacetophenone (26.4 mmol), 1a (31.7 mmol), NaOAc (31.3 mmol), Pd(OAc)2 (0.013 mmol, 0.049 mol%
e
with respect to aryl bromide), NMP (34 ml) at 130 8C during 3 h.
added and the vessel was closed with a septum. The
mixture was stirred and heated to 125 8C. After 3 h
reaction time, the mixture was cooled and poured into
water (50 ml) and extracted with EtOAc (four times 50
ml). The collected organic layers were washed with
water (three times 50 ml), brine (50 ml), dried with
Na2SO4, filtered and the filtrate was concentrated. The
crude product was recrystallised with EtOAc. Yields are
given in Table 1. Most products were characterised by
1H- and 13C-NMR, m.p. and exact mass determination.
2d: 1H-NMR (CDCl3) d 7.95 (d, Jꢁ
8.4 Hz, 2H), 7.42 (s, 1H), 7.16 (s, 1H), 3.89 (s,
/
8.4 Hz, 2H), 7.52
(d, Jꢁ
/
3H), 2.61 (s, 3H), 2.15 (s, 3H); 13C-NMR (CDCl3) d
197.75, 196.77, 165.75, 138.37, 136.96, 128.82 (C),
130.18, 129.36, 128.69 (CH), 52.65, 27.12, 22.80 (CH3);
M.p. 168.9Á/170.0; Calculated mass: 261.1001; Observed
mass: 261.0984.
1
2e: H-NMR (CDCl3) d 9.56 (s, 1H), 7.63 (d, Jꢁ
Hz, 2H), 7.21 (s, 1H), 7.00 (d, Jꢁ8.8 Hz, 2H), 3.34 (s,
3H), 2.51 (s, 3H), 2.10 (s, 3H).
/
8.8
/
1
1
2a: H-NMR (CDCl3) d 7.37 (m, 3H), 6.97 (m, 3H),
3.79 (s, 3H), 2.09 (s, 3H); 13C-NMR (CDCl3) d 169.22,
166.12, 130.37, 123.95 (C), 132.03, 131.78, 116.19,
2f: H-NMR (CDCl3) d 7.37 (m, 5H), 7.05 (s, 1H),
3.87 (s, 3H), 2.15 (s, 3H) 13C-NMR (CDCl3) d 169.12,
166.00, 135.56, 132.72, 124.64 (C), 131.26, 129.14 (CH),
115.90 (CH), 53.12, 23.81 (CH3); M.p. 140.6Á
/142.3;
53.17, 23.80 (CH3); M.p. 168.9Á/170.2; Calculated mass:
Calculated mass: 237.0801; Observed mass: 237.0788.
1
253.0506; Observed mass: 253.0510.
1
2b: H-NMR (CDCl3) d 7.33 (m, 2H), 7.20 (m, 2H),
2g: H-NMR (CDCl3) d 7.53 (s, 1H), 7.43 (d, Jꢁ8.1
/
7.04 (m, 2H), 3.87 (s, 3H), 2.16 (s, 3H); 13C-NMR
(CDCl3) d169.04, 165.92, 164.04, 152.98 (C), 130.96,
130.41, 116.83, 116.56, 116.12 (CH), 53.22, 23.84 (CH3);
Hz, 1H), 7.31 (s, 1H), 7.27 (m, 1H), 7.18 (s, 1H), 3.88 (s,
1H), 2.16 (s, 3H); 13C-NMR (CDCl3) d 169.71, 165.59,
134.60, 128.12 (C), 131.62, 131.05, 129.97, 128.59 (CH),
M.p. 104.2Á
/
104.8; Calculated mass: 237.0801; Observed
52.67, 22.78 (CH3); M.p. 167.6Á
287.0116; Observed mass: 287.0108.
2h: 1H-NMR (CDCl3) d 7.64 (d, Jꢁ
7.6 Hz, 2H), 7.50
/
168.3; Calculated mass:
mass: 237.0775.
1
2c: H-NMR (CDCl3) d 7.45 (s, 2H), 7.34 (m, 1H),
/
7.12 (s, 3H), 3.88 (s, 3H), 2.12 (s, 3H); 13C-NMR
(CDCl3) d 174.18, 168.34, 164.56, 163.20, 159.94 (C),
134.82, 129.77, 129.01, 124.70, 115.06 (CH), 51.71, 22.15
(d, Jꢁ7.6 Hz, 2H), 7.37 (s, 1H), 3.90 (s, 3H), 2.15 (s,
/
3H); 13C-NMR (CDCl3) d 169.79, 166.40, 165.61,
138.65, 118.99, 111.15, (C), 132.72, 130.60, 128.28
(CH3); M.p. 149.7Á/150.0; Calculated mass: 237.0801;
(CH), 52.72, 22.81 (CH3); M.p. 208.0Á/209.2; Calculated
Observed mass: 237.0798.
mass: 244.0848; Observed mass: 244.0866.

C.E. Willans et al. / Journal of Organometallic Chemistry 687 (2003) 494Á
/497
497
2i: 1H-NMR (CDCl3) d 7.52 (m, 5H), 7.85 (d, Jꢁ
/
6.9
(c) A.E. Pojitkov, E.N. Efremenko, S.D. Varfolomeev, J. Mol.
Cat. B: Enz. 10 (2000) 47Á55.
[2] See for example: W. Wang, M. Cai, C. Xiong, J. Zhang, D.
Trivedi, V.J. Hruby, Tetrahedron 58 (2002) 7365 (and references
therein).
/
Hz, 2H), 7.38 (s, 1H), 7.31 (d, Jꢁ
/
6.9 Hz, 2H), 3.80 (s,
3H), 2.11 (s, 3H); 13C-NMR (CDCl3) d 169.41, 166.21,
145.07, 142.49, 140.52 (C), 133.03, 132.56, 132.24,
130.68, 129.28, 128.18, 127.55, 127.42, 124.45 (CH),
[3] (a) M. van den Berg, A.J. Minnaard, E.P. Schudde, J. van Esch,
A.H.M. de Vries, J.G. de Vries, B.L. Feringa, J. Am. Chem. Soc.
122 (2000) 11539;
53.09, 23.78 (CH3); M.p. 159.0Á
/
159.3; Calculated mass:
295.1208; Observed mass: 295.1200.
1
(b) M. van den Berg, A.J. Minnaard, B.L. Feringa, J.G. de Vries,
Catalyst for asymmetric (transfer) hydrogenation, WO 02 04466,
17-01-2002;
2j: H-NMR (CDCl3) d 9.88 (s, 1H), 8.26 (d, Jꢁ8.8
/
Hz, 2H), 7.86 (d, Jꢁ8.8 Hz, 2H), 7.20 (s, 1H), 3.75 (s,
/
1H), 2.03 (s, 1H); 13C-NMR (CDCl3) d 169.79, 165.58,
147.27, 140.73, 130.03 (C), 131.00, 127.52, 123.96 (CH),
(c) M. van den Berg, R.M. Haak, A.J. Minnaard, A.H.M. de
Vries, J.G. de Vries, B.L. Feringa, Adv. Synth. Catal. 344 (2002)
1003;
52.78, 22.86 (CH3); M.p. 166.9Á167.6.
/
1
(d) D. Pena, A.J. Minnaard, J.G. de Vries, B.L. Feringa, J. Am.
˜
Chem. Soc. 124 (2002) 14552;
2k: H-NMR (CDCl3) d 7.57 (m, 2H), 7.44 (m, 6H),
7.31 (s, 1H), 7.11 (s, 1H), 3.87 (s, 3H), 2.20 (s, 3H); 13C-
NMR (CDCl3) d 165.98, 131.04, 130.81, 124.87 (C),
129.35, 129.30, 128.91, 128.45, 126.43 (CH), 53.26, 23.98
(e) M. van den Berg, A.J. Minnaard, R.M. Haak, M. Leeman,
E.P. Schudde, A. Meetsma, B.L. Feringa, A.H.M. de Vries,
C.E.P. Maljaars, C.E. Willans, D.J. Hyett, J.A.F. Boogers,
H.J.W. Henderickx, J.G. de Vries, Adv. Synth. Catal. 345
(2003) 308;
(CH3); M.p. 157.5Á158.2.
/
1
2l: H-NMR (CDCl3) d 9.84 (s, 1H), 7.74 (m, 7H),
7.59 (m, 2H), 7.22 (s, 1H), 3.74 (s, 3H), 2.04 (s, 3H); 13C-
NMR (CDCl3) d 195.66, 170.02, 165.94, 138.10, 137.46,
137.38, 129.10 (C), 133.32, 130.34, 130.27, 130.09,
(f) D. Pen˜a, A.J. Minnaard, A.H.M. de Vries, J.G. de Vries, B.L.
Feringa, Org. Lett. 5 (2003) 475;
(g) D. Pena, A.J. Minnaard, J.A.F. Boogers, A.H.M. de Vries,
˜
J.G. de Vries, B.L. Feringa, Org. Biomol. Chem. 1 (2003) 1087.
[4] (a) U. Schmidt, A. Lieberknecht, J. Wild, Synthesis (1988) 159;
129.43, 129.16 (CH), 52.83, 22.99 (CH3); M.p. 172.7Á
174.0; Calculated mass: 323.1158; Observed mass:
323.1121.
/
¨
(b) U. Schmidt, E. .Ohler, J. Hausler, H. Poisel, Progress in the
¨
Chemistry of Organic Natural Products, vol. 37, Springer Verlag,
Wien, 1979, pp. 251Á327.
/
[5] For the synthesis of dehydroalanines, see Ref. [4].
[6] M. Cutolo, V. Fiandanese, F. Naso, O. Sciacovelli, Tetrahedron
Lett. 24 (1983) 4603.
3.2. Asymmetric hydrogenation
[7] (a) P. Harrington, L.S. Hegedus, J. Org. Chem. 49 (1984) 2657;
(b) P. Harrington, L.S. Hegedus, K.F. McDaniel, J. Am. Chem.
Soc. 109 (1987) 4335.
Glass tubes, suitable for a parallel reactor were
individually filled with 1 mmol of substrate, 0.01
mmol (1 mol%) of Rh(COD)2BF4 and 0.011 mmol of
ligand 3. The glass tubes were placed in the reactor and 5
ml of CH2Cl2 was added. The reactors were then purged
for with N2 (10 cycles) before applying a hydrogen
atmosphere of 5 bars. The pressure was kept constant
during the reaction and the hydrogen uptake was
monitored. After completion of the reaction, the reac-
tors were opened and samples were taken which were
filtered over a short silica column and subjected to e.e.
determination by chiral HPLC. Conversions were de-
termined by means of 1H-NMR. Results are depicted in
Table 1.
[8] (a) A.-S. Carlstrom, T. Frejd, Synthesis (1989) 414;
¨
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/