Direct Synthesis of Unprotected 4-Aryl Phenylalanines via the Suzuki Reaction under Microwave Irradiation

Article abstract of DOI:10.1021/ol026587z

(Matrix Presented) 4-Aryl phenylalanines were prepared as free amino acids from the Suzuki coupling of 4-borono phenylalanine with aryl halides in high yields within 5-10 min under microwave irradiation.

Full text of DOI:10.1021/ol026587z

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3803-3805
Direct Synthesis of Unprotected 4-Aryl
Phenylalanines via the Suzuki Reaction
under Microwave Irradiation
Yong Gong* and Wei He
Drug DiscoVery, Johnson & Johnson Pharmaceutical Research & DeVelopment, L.L.C,
Welsh & McKean Roads, Spring House, PennsylVania 19477-0776
ygong@prdus.jnj.com
Received July 23, 2002
ABSTRACT
4-Aryl phenylalanines were prepared as free amino acids from the Suzuki coupling of 4-borono phenylalanine with aryl halides in high yields
within 5−10 min under microwave irradiation.
The derivatives of biaryl amino acid possess certain biologi-
cal activities. N-Benzoyl-4-aryl phenylalanines, for example,
represent a major class of alpha4 integrin antagonists.1 The
inhibition of other N-acyl-4-aryl phenylalanines against
endothelin-converting enzyme has also been reported.2
However, the supply of such biaryl amino acids is very
limited. There is a practical need for a versatile and efficient
synthetic method, preferably from coupling of readily
available and properly functionalized aryl amino acid precur-
sors with suitable coupling partners. The Suzuki reaction has
been applied in the preparation of N-protected 4-aryl phe-
nylalanine esters3 from cross couplings of either N-protected
4-Br (I or OTf) phenylalanine esters with aryl boronic acids4
or N-protected 4-borono phenylalanine esters with aryl
halides (or triflates).5 However, the direct cross coupling
involving free amino acids has not been disclosed. Previ-
ously, we reported the synthesis of aryl benzoic acids from
the direct coupling of carboxybenzene boronic acids with
aryl halides.6 We envisioned that the direct coupling of
unprotected 4-borono phenylalanine with aryl halides under
Suzuki conditions would provide structurally diversified
4-aryl phenylalanines without the necessity of protection and
deprotection procedures. The free biaryl amino acids can then
be selectively protected or derivatized depending on the
subsequent chemistry. In addition, the direct coupling of free
amino acids under basic conditions might protect the chiral
center from racemization, which is often a concern with
reactions involved in protected amino acids at elevated
temperature.
Microwave heating has been widely applied in the organic
synthesis and its advantage over traditional heating has been
demonstrated.7 Moreover, recent advances in the microwave
instrumentation have made this technique more accessible
and the results more reproducible. The microwave instru-
ments can be readily automated and programmed for
screening reaction conditions, as well as for high throughput
(1) Tilley, J. W.; Sidduri, A. Drugs Future 2001, 26, 985.
(2) Firooznia, F.; Gude, C.; Chan, K.; Fink, A. C.; Qiao, Y.; Satoh, Y.;
Marcopoulos, N.; Savage, P.; Beil, M. E.; Bruseo, C. W.; Trapani, A. J.;
Jeng, A. Y. Bioorg. Med. Chem. Lett. 2001, 11, 375.
(3) The Stille reaction has also been applied in the synthesis of N-Boc-
4-aryl phenylalanine methyl esters: Morera, E.; Ortar, G. Synlett 1997, 1403.
(4) (a) Shieh, W. C.; Carlson, J. A. J. Org. Chem. 1992, 57, 379. (b)
Burk, M. J.; Lee, J. R.; Martinez, J. P. J. Am. Chem. Soc. 1994, 116, 10847.
(c) Kotha, S.; Lahiri, K. Bioorg. Med. Chem. Lett. 2001, 11, 2887.
(5) (a) Satoh, Y.; Gude, C.; Chan, K.; Firooznia, F. Tetrahedron Lett.
1997, 38, 7645. (b) Firooznia, F.; Gude, C.; Chan, K.; Satoh, Y. Tetrahedron
Lett. 1998, 39, 3985. (c) Firooznia, F.; Gude, C.; Chan, K.; Marcopulos,
N.; Satoh, Y. Tetrahedron Lett. 1999, 40, 213.
(6) (a) Gong, Y.; Pauls, H. W. Synlett 2000, 829. (b) Gong, Y.; Pauls,
H. W.; Spada, A. P.; Czekaj, M.; Liang, G.; Chu, V.; Colussi, D. J.; Brown,
K. D.; Gao, J. Bioorg. Med. Chem. Lett. 2000, 10, 217.
(7) For recent reviews, see: (a) Perreux, L.; Loupy, A. Tetrahedron 2001,
57, 9199. (b) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225. (c) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A.
R. J. Comb. Chem. 2002, 4, 95. (d) Santagada, V.; Perissutti, E.; Caliendo,
G. Curr. Med. Chem. 2002, 9, 1251.
10.1021/ol026587z CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/10/2002

synthesis in a very short period of time. Herein, we report
the microwave-assisted direct coupling of 4-borono phenyl-
alanine with aryl halides as a convenient and quick method
for the synthesis of 4-aryl phenylalanines.
identical conditions as for the microwave reaction, i.e., Pd-
(PPh3)2Cl2, 140 °C, 5 min. As expected, lower conversion
(59%) was observed with the traditional thermal conditions
as compared to microwave irradiation (96%).
A set of commonly used palladium catalysts was selected
to screen the coupling reaction between racemic 4-borono
phenylalanine 1 and 1-fluoro-2-iodobenzene 2a (Scheme 1)
The microwave conditions from entry 4 in Table 1 were
identified as the standard reaction conditions, and were
utilized for the synthesis of a diverse set of 4-aryl pheny-
lalanines (3a-i). HPLC analysis of crude mixtures showed
nearly complete conversion in most cases. High isolated
yields (68-83%) were obtained across the board as sum-
marized in Table 2. For substrate 3-iodoanisole 2b and
Scheme 1
Table 2. Preparation of 4-Aryl Phenylalanines 3
under microwave irradiation. In a typical experiment,8 a
mixture of 1 equiv of 1 and 2a in aqueous acetonitrile (1:1)
was microwave heated for 5 min in the presence of 2 equiv
of sodium carbonate and a 5 mol % palladium catalyst. The
reactions were monitored by HPLC and the results were
summarized in Table 1.
Table 1. Reaction Conditions on the Suzuki Coupling via
Scheme 1
entry
microwave conditions
convn (%)a
1
2
3
4
5
6
7
8
9
Pd(PPh3)2Cl2, 120 °C, 5 min
Pd(PPh3)2Cl2, 130 °C, 5 min
Pd(PPh3)2Cl2, 140 °C, 5 min
Pd(PPh3)2Cl2, 150 °C, 5 min
Pd(PPh3)4, 120 °C, 5 min
Pd(PPh3)4, 150 °C, 5 min
Pd(dppf)2Cl2, 150 °C, 5 min
Pd(PCy3)2Cl2, 150 °C, 5 min
Pd2(dba)3, 150 °C, 5 min
Pd(OAc)2, 150 °C, 5 min
58
90
96
99
35
83
93
23
92
82
10
a Determined by HPLC at 215 nm. Based on aryl halide 2a.
Among the catalysts tested, Pd(PPh3)2Cl2 was the most
effective one. The conversion of 1 to 4-aryl phenylalanine
3a was improved from 58% at 120 °C (entry 1) to 90% at
130 °C (entry 2), and reached 99% at 150 °C (entry 4). This
result reflected the effect of temperature on the coupling
reaction. Several other catalysts were also effective. Pd-
(dppf)2Cl2 (entry 7) and Pd2(dba)3 (entry 9) gave >90%
conversion at 150 °C for 5 min. About 80% conversion was
achieved with Pd(PPh3)4 (entry 6) and Pd(OAc)2 (entry 10)
under the same conditions. Pd(PCy3)2Cl2 (entry 8), however,
only gave 23% conversion.
a Isolated by reverse-phase HPLC as TFA salt.
sterically hindered substrate 2-bromo-1,3-dichlorobenzene
2d,11 satisfactory results were achieved after the reaction time
was prolonged from 5 to 10 min.
Furthermore, the effect of switching positions of boronic
acid and halide in the coupling partners was examined. The
cross coupling of racemic 4-bromophenylalanine 4 with
2-fluorophenyl boronic acid 5 was carried out under the same
conditions as shown in Scheme 2. A high yield (75%) of
coupling product 3a was maintained. This alternative ap-
For comparison, the reaction in Scheme 1 was also
conducted using a preheated oil bath under otherwise
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Org. Lett., Vol. 4, No. 22, 2002

with the notion that the presence of carboxylate anion and a
free amino group in R-amino acid shields R-C-H from
deprotonation and thus limits racemization.14 Similarly,
coupling of (L)-1 with 2-chloro-1-methyl-1H-benzoimidazole
2j and 2-chloro-1-methyl-1H-indole-3-carbonitrile 2k af-
forded the corresponding coupling products (L)-3j and (L)-
3k in good yields (Scheme 4) within 5 and 10 min,
respectively.
Scheme 2
Scheme 4
proach can serve as a complement to the methodology
involving 4-borono phenylalanine and aryl halides.
The application in asymmetric synthesis was also inves-
tigated. The coupling reaction of 4-borono-L-phenylalanine12
(L)-1 with 1-fluoro-2-iodobenzene 2a (Scheme 3) was
Scheme 3
In conclusion, we have described a straightforward ap-
proach to the synthesis of unprotected 4-aryl phenylalanines.
Microwave irradiation facilitates the coupling reaction to
5-10 min. The amino group and carboxylic group are well
tolerated. This method offers an easy access to a variety of
free biaryl amino acids.
Acknowledgment. The authors thank Dr. Steven Coats
for his initial assistance in the operation of SmithSynthesizer.
conducted under the standard conditions. In addition to the
excellent conversion as expected, no significant racemization
was observed with coupling product (L)-3a, according to the
analysis of (+)-Mosher’s amide of (L)-3a and racemic 3a
OL026587Z
(9) The reaction can be performed at higher concentration to (but not
limited to) 2-mmol scale in the same vial, which broadens its preparative
usefulness.
1
by HPLC and H NMR.13 This observation is in agreement
(8) General procedure: A 10-mL SmithPrcess vial containing a magnetic
stir bar was charged with 4-borono phenylalanine (0.11 g, 0.50 mmol),9
aryl halide (0.50 mmol), palladium catalyst (0.025 mmol), 1.0 M Na2CO3
(1.0 mL), and acetonitrile (1.0 mL). After vacuum degassing, the vial was
sealed and the suspension was heated in the SmithSynthesizer10 under
selected microwave conditions. The conversion was monitored and analyzed
by HPLC. The crude reaction mixture was concentrated to dryness, acidified
with trifluoroacetic acid (TFA) in MeOH, and purified by reverse phase
HPLC, eluted with 0.1% TFA H2O/MeCN gradient. All products were
characterized by NMR and MS. Selected compound 3a was obtained as a
white solid: 1H NMR (CD3OD, 300 MHz) δ 7.56 (d, J ) 6.7 Hz, 2H),
7.54-7.14 (m, 6H), 4.22 (dd, J ) 5.2, 7.9 Hz, 1H), 3.38 (dd, J ) 5.2, 14.5
Hz, 1H), 3.18 (dd, J ) 7.9, 14.5 Hz, 1H); 13C NMR (CD3OD, 300 MHz)
δ 172.05, 163.14, 137.10, 135.84, 132.18, 131.03, 130.20, 126.15, 117.57,
117.27, 55.89, 37.61; MS m/z 260 (MH+).
(10) For the commentary of SmithSynthesizer, see: Watkins, K. J. Chem.
Eng. News, 2002, 80 (6), 17.
(11) 1,3-Dichloro-2-iodobenzene gave similar results to dichloro phenyl
product 3d.
(12) The coupling reaction can also be applied to 4-borono-D-phenyla-
lanine. Both enantiomers are commercially available. For the preparation,
see: (a) Malan, C.; Morin, C. J. Org. Chem. 1998, 63, 8019. (b) Nakamura,
H.; Fujiwara, M.; Yamamoto, Y. Bull. Chem. Soc. Jpn. 2000, 73, 231.
(13) For the Mosher’s amide of (L)-3a one set of characteristic 1H NMR
(CDCl3, 300 MHz) signals was observed with chemical shifts δ 4.95 (m,
1H) and 3.20 (s, 3H). Two sets of the corresponding signals were obtained
at δ 5.05 (m, 1H), 4.95 (m, 1H), 3.40 (S, 3H), and 3.20 (s, 3H) for the
Mosher’s amides of racemic 3a.
(14) (a) Bergmeier, S. C.; Ismail, K. A. Synthesis 2000, 1369. (b) Rios,
A.; Richard, J. P.; Amyes, T. L. J. Am. Chem. Soc. 2002, 124, 8251.
Org. Lett., Vol. 4, No. 22, 2002
3805