7010
P. Bovonsombat et al. / Tetrahedron Letters 49 (2008) 7008–7011
L
-tyrosine in a one-pot sequence. The role of TsOH in the halogena-
Table 2
Effects of varying the amounts of TsOH on the regioselective halogenations of 1a
tion enhancement is yet to be determined. However, given the
importance of the sequence of the addition of TsOH in the reaction,
we speculate that TsOH might depress the formation of the pheno-
Entry
NXS
% Product ratiob
10% TsOH
1% TsOH
3-
50% TsOH
3-
late form of the phenol ring of L-tyrosine and thereby diminish
1
3,5-
1
3-
3,5-
1
3,5-
halogenation via the phenolic anion. Studies are underway to fur-
ther probe the versatility of this methodology to phenols and other
related systems and the results will be reported in due course.
1
2
3
NCS
NBS
NIS
5
1
11
95
96
84
—
3
5
5
1
4
95
96
95
—
3
1
9
3
2
91
95
97
—
2
1
a
Reaction conditions: TsOH (0.01–0.5 mmol) was added to the stirring solution
containing 1 (1 mmol). After 5 min, 1 equiv of N-halosuccinimide was added and
the reaction mixture was stirred for 6 h at room temperature.
Acknowledgements
We are grateful to the Director’s Initiative Fund of Mahidol Uni-
versity International College. We are indebted to Dr. Sirirat Choos-
iangkriang and Dr. Supachai Supaluknari of the Department of
Chemistry of Silpakorn University for spectroscopic analyses.
b
Product mixtures were converted into methyl esters and analysed by GC–MS.
optimum conditions appear to be the use of 1 equiv of TsOH
relative to both NIS and the starting substrate 1.
Given that dihalogenation is best achieved in the absence of
References and notes
TsOH, a useful route for the synthesis of N-acetyl-3,5-dihalo-L-
1. Fusetani, N.; Matsunaga, S. Chem. Rev. 1993, 93, 1793–1806.
2. Block, P., Jr. J. Med. Chem. 1976, 19, 1067–1069.
tyrosine (compounds 3a–c) is at hand. The synthesis of 3a was
achieved in 91% yield by reacting 1 with 2.2 equiv of NCS in aceto-
nitrile at room temperature for 18 h.17 For 3b, 2.0 equiv of NBS was
reacted with 1 in acetonitrile at room temperature for 18 h to fur-
nish 3b in 99% yield (95% isolated yield).18 X-ray crystal structures
3. Chlorination with SO2Cl2: (a) Allevi, P.; Cribiu, R.; Anastasia, M. Tetrahedron
Lett. 2004, 45, 5841–5843. Bromination with HCl and KBrO3: (b) Tilley, M.;
Benjamin, R. E.; Srivarin, P.; Tilley, K. A. Anal. Biochem. 2004, 334, 193–195;
Sano, S.; Ikai, K.; Takesako, K.; Nakamura, T.; Obayashi, A.; Ezure, Y. J. Antibiot.
1986, 39, 1685–1696. Iodination: (c) Block, P., Jr. J. Med. Chem. 1967, 10, 950–
953.
of both 3a and 3b showed an S-configuration about the methine a-
carbon of tyrosine.19 In addition, the specific optical rotation values
of 3a and 3b matched those of the literature.4b,6,17,18 With 3c, the
absence of TsOH in the reaction mixture and using 2.2 equiv of
NIS to 1 equiv of 1 in acetonitrile at room temperature gave only
a 74% yield. However, the addition of 1 equiv of TsOH to the same
reaction mixture and under identical conditions enhanced the
yield of 3c to 92% (isolated: 85%).20
4. (a) Drabik, G.; Naskalski, J. W. Acta Biochim. Polonica 2001, 48, 271–275; (b)
Dibbo, A.; Stephenson, L.; Walker, T.; Warburton, W. K. J. Chem. Soc. 1961,
2645–2651.
5. Zeynek, R. Z. Physiol. Chem. 1921, 114, 275; Warburton, W. K. J. Chem. Soc. 1961,
2651–2658.
6. Dewitt, H. D.; Ingersoll, A. W. J. Am. Chem. Soc. 1951, 73, 5782–5783.
7. Nishiyama, S.; Suzuki, Y.; Yamamura, S. Tetrahedron Lett. 1989, 30, 379–382;
Yin, Q.; Jiang, B.; Mao, Z.; Sun, X.; Wang, Y. Huaxue Shijie 2001, 42, 29–32.
8. For examples of mono-brominating reagents, see: Oberhauser, T. J. Org. Chem.
1997, 62, 4504–4506.
9. (a) Konishi, H.; Aritomi, K.; Okano, T.; Kijii, J. Bull. Chem. Soc. Jpn. 1989, 62, 591–
593; (b) Paul, V.; Sudalai, A.; Daniel, T.; Srinivasan, K. V. Tetrahedron Lett. 1994,
35, 7055–7056; (c) Ref. 8.; (d) Ganguly, N. C.; De, P.; Dutta, S. Synthesis 2005,
1103–1105; (e) Das, B.; Venkateswarlu, K.; Krishnaiah, M.; Holla, H.
Tetrahedron Lett. 2006, 47, 8693–8697; (f) Das, B.; Venkateswarlu, K.; Majhi,
A.; Siddaiah, V.; Reddy, K. V. J. Mol. Catal. A: Chem. 2007, 267, 30–33.
10. Das, B.; Krishnaiah, M.; Venkateswarlu, K.; Saidi Reddy, V. Tetrahedron Lett.
2007, 48, 81–83.
X2
1) NX1S, rt, TsOH
2) NX2S, rt
HO
X1
O
OH
CH3
1
N
H
O
X1, X2 = a: Cl, I; b: Br, I; c: Br, Cl
4a-c
11. Bovonsombat, P.; Angara, G. J.; McNelis, E. Synlett 1992, 131–132;
Bovonsombat, P.; McNelis, E. Synthesis 1993, 237–241.
12. Typical preparation of N-acetyl-3-halo-L-tyrosine: To a stirring solution of N-
acetyl- -tyrosine (1 mmol) in 20 mL of solvent, TsOH was added and, after
L
5 min, 1 equiv of N-halosuccinimide was added in one portion. The reaction
was left to stir at room temperature for 6–18 h. For the work up, the organic
solution was diluted with ethyl acetate and washed three times with a 5%
aqueous solution of Na2S2O3, followed by three washes with water and lastly
with brine. After evaporation of the solvents under vacuum, the solid was
subjected to silica gel chromatography or converted to the corresponding
methyl ester for GC–MS analysis.
The high regioselectivity of halogenations of 1, enhanced by the
addition of 0.1–1 equiv of TsOH, permits the systematic synthesis
of mixed 3,5-dihalo analogues of N-acetyl-L-tyrosine. Thus, N-acet-
yl-3-chloro-5-iodo- -tyrosine (4a) was obtained in 99% yield (73%
L
isolated yield) from a one-pot reaction mixture initially containing
0.1 equiv each of TsOH, 1.1 equiv of NCS and 1, which was allowed
to be stirred in acetonitrile at room temperature followed by the
13. Compound 2a: 1H NMR (300 MHz, acetone-d6): d 7.51 (d, J = 8 Hz, 1H), 7.23 (d,
J = 2 Hz, 1H), 7.06 (dd, J = 2 and 8 Hz, 1H), 6.93 (d, J = 8 Hz, 1H), 4.75–4.68 (m,
1H), 3.15–3.09 (m, 1H), 2.97–2.89 (m, 1H), 1.95 (s, 3H); 13C NMR (75 MHz,
acetone-d6): d 173.0, 171.1, 152.7, 131.5, 130.5, 129.8, 120.7, 117.5, 54.5, 37.0,
22.6; IR (KBr): 3349, 1732, 1628, 1613 1424, 1334, 1227 cmꢁ1; GC/MS (methyl
ester), (EI) m/z (rel int.): 273 (0.4, (M+2)+), 271 (1, M+), 214 (34, ((M+2)ꢁH2-
NCOCH3)+), 212 (100, (MꢁH2NCOCH3)+), 183 (10, ((M+2)ꢁH2NCOCH3–OCH3)+),
181 (31, (MꢁH2NCOCH3–OCH3)+), 172 (6), 170 (18), 143 (24), 141 (70), 107 (9),
99 (8), 88 (44), 77 (21), 60 (11), 51 (11), 43 (41), 32 (7).
addition of 1.5 equiv of NIS.21 For N-acetyl-3-bromo-5-iodo-
L-tyro-
sine (4b), the synthesis was conducted in the same manner with
bromination (1 equiv of NBS and 15 mol % TsOH) implemented
first for 18 h at room temperature followed by iodination
(1.5 equiv of NIS).22 This one-pot bromination–iodination combi-
nation reaction furnished 4b in 92% yield (82% isolated yield).
Using the same solvent and room temperature conditions as previ-
14. Compound 2b: 1H NMR (300 MHz, acetone-d6): d 7.32 (d, J = 7 Hz, 1H), 7.25 (d,
J = 2 Hz, 1H), 6.96 (dd, J = 2 and 8 Hz, 1H), 6.78 (d, J = 8 Hz, 1H), 4.58–4.51 (m,
1H), 3.00–2.94 (m, 1H), 2.81–2.74 (m, 1H), 1.79 (s, 3H); 13C NMR (75 MHz,
acetone-d6): d 173.1, 170.8, 153.7, 134.5, 130.9, 130.5, 117.1, 110.0, 54.5, 36.9,
22.6; IR (KBr): 3349, 1726, 1632, 1612, 1422, 1341, 1221 cmꢁ1; GC/MS (methyl
ester), (EI) m/z (rel int.): 317 (2, (M+2)+), 315 (2, M+), 258 (98,
((M+2)ꢁH2NCOCH3)+), 256 (100, (MꢁH2NCOCH3)+), 227 (22, ((M+2)ꢁH2-
NCOCH3–OCH3)+), 225 (22, (MꢁH2NCOCH3–OCH3)+), 216 (12), 214 (14), 187
(55), 185 (56), 146 (4), 135 (12), 118 (5), 107 (10), 99 (9), 88 (45), 77 (21), 60
(11), 51 (11), 43 (39), 33 (3).
ously applied to 4a and 4b, N-acetyl-3-bromo-5-chloro-L-tyrosine
(4c) was obtained from the one-pot reaction in 98% yield (95% iso-
lated yield) with the combination sequence of chlorination
(0.1 equiv of TsOH and 1.1 equiv of NCS) and bromination
(1.1 equiv of NBS).23
The finding that the addition of TsOH prior to the addition of N-
halosuccinimide enhances the selectivity for monohalogenation of
15. Compound 2c: 1H NMR (300 MHz, acetone-d6): d 7.47 (d, J = 2 Hz, 1H), 7.44 (s,
1H, N–H), 6.98 (dd, J = 2 and 8 Hz, 1H), 6.73 (d, J = 8 Hz, 1H), 4.57–4.50 (m, 1H),
2.99–2.92 (m, 1H), 2.79–2.72 (m, 1H), 1.81 (s, 3H); 13C NMR (75 MHz, acetone-
d6): d 173.2, 171.4, 156.4, 140.7, 131.3, 131.5, 115.6, 84.3, 54.5, 36.7, 22.7; IR
(KBr): 3356, 1709, 1630, 1604, 1416, 1344, 1221 cmꢁ1; GC/MS (methyl ester),
(EI) m/z (rel int.): 363 (2, M+), 304 (100, (MꢁH2NCOCH3)+), 273 (14,
the phenol ring of
L-tyrosine has led to the development of a simple
methodology for monohalogenation of the ring of N-acetyl-
L-tyro-
sine. The versatility of this methodology has permitted the synthe-
ses of either 3,5-dihalo or mixed 3,5-dihalo analogues of N-acetyl-