Fast and convenient synthesis of α-N-protected amino acid hydrazides

Article abstract of DOI:10.1055/s-2004-837300

A fast, simple and convenient synthesis of α-N-protected amino acid hydrazides is reported. The procedure involves the reaction between hydrazine monohydrate and the mixed anhydride obtained from an α-N-protected amino acid and ethyl chloroformate. When m

Full text of DOI:10.1055/s-2004-837300

PAPER
559
Fast and Convenient Synthesis of a-N-Protected Amino Acid Hydrazides
Synthesis of
a
-N-
P
i
rotecte
a
dAminoA
n
cidHydrazid
c
e
s. arlo Verardo,* Paola Geatti, Barbara Lesa
Dipartimento di Scienze e Tecnologie Chimiche, Università degli Studi di Udine, Via del Cotonificio 108, 33100 Udine, Italy
Fax +39(0432)558803; E-mail: giancarlo.verardo@uniud.it.
Received 10 September 2004; revised 13 October 2004
Other synthetic methods utilize hydrazine in connection
with amino protected carboxy activated derivatives, such
as acid chlorides,11 and trimethylsilyl13 or hydroxysuccin-
imide14 esters. These procedures are unsatisfactory to
Abstract: A fast, simple and convenient synthesis of a-N-protected
amino acid hydrazides is reported. The procedure involves the reac-
tion between hydrazine monohydrate and the mixed anhydride ob-
tained from an a-N-protected amino acid and ethyl chloroformate.
When methylhydrazine was used, the reaction showed a good selec- some extent, such as the use of strict reaction conditions
tivity, yielding a mixture of 1-acyl-1-methylhydrazine and 1-acyl-
and/or toxic reagents.
2-methylhydrazine in a ratio 87:13. In contrast, when the reaction
The reaction of a-N-acyl-amino acids with the less reac-
tive phenylhydrazine is carried out in the presence of pa-
pain,2a–c,4a,15 DCC–1-hydroxybenzotriazole4c or starting
from the corresponding acid chloride.16
was carried out with phenylhydrazine, only 1-acyl-2-phenylhydra-
zine was obtained. No significant difference in reactivity was ob-
served with the different amino acids and N-protection introduced.
Key words: amino acids, hydrazides, regioselectivity, anhydrides,
protecting groups
Surprisingly, to the best of our knowledge, the mixed car-
boxylic–carbonic anhydrides, prepared from N-protected
amino acids and alkyl chloroformates, have been used ex-
clusively in combination with alkoxycarbonylhy-
drazides.3d,f,g,i Since these mixed anhydrides can be easily
and rapidly obtained, we decided to utilize them in con-
nection with hydrazine.
Amino acid hydrazides are important derivatives in pep-
tide synthesis in that they may be used not only as car-
boxy-activating groups when transformed into the
corresponding acid azides1 or phenyldiimides,2 but also as
carboxy-protecting groups when they are obtained from
alkoxycarbonylhydrazines3 or phenylhydrazine.4 More-
over, they are involved in the synthesis of azapeptides,5 a
class of backbone-modified peptides that has become im-
portant in pharmaceutical chemistry.
The simple and convenient synthesis of a-N-protected
amino acid hydrazides 3 here reported, involves two steps
(Scheme 1; Table 1): the first step of the reaction was the
preparation of the mixed anhydride 2 which was obtained
by reacting the triethylammonium salt of a-N-protected
amino acid 1 with ethyl chloroformate (ECF) in THF at
–10 °C. After a few minutes, Et3N·HCl was filtered off
and the filtrate, second step, was slowly added to a solu-
tion of NH2NH2·H2O in MeOH at 0 °C. The resulting mix-
ture was stirred at room temperature affording, after
workup, 3 in 80–90% yield.
Among all the reported procedures, the most commonly
cited synthesis of a-amino acid hydrazides involves the
reaction of hydrazine with the methyl,6 ethyl7 (used also
in connection with monoalkylhydrazines)3c,8 or
hydroxychloropropyl9 ester of the a-amino protected ac-
ids or peptides.3d,g,i,10 Esters have also been employed in
the a-amino free form in combination with hydrazine11
and phenylhydrazine.12 All these methods require long re-
action times (from several hours to three days) and the
availability of esters which are more expensive than the
corresponding a-amino acids.
In order to optimize the reaction conditions, we examined
the following parameters using 1ea as a model substrate:
amount of NH2NH2·H2O, order of addition of ECF,
amount of ECF and Et3N, and reaction time required to ac-
complish the two steps. On the basis of this study, the syn-
thesis of the mixed anhydride 2ea was carried out by
Scheme 1
SYNTHESIS 2005, No. 4, pp 0559–0564
x
x
.
x
x
.2
0
0
5
Advanced online publication: 23.12.2004
DOI: 10.1055/s-2004-837300; Art ID: P11004SS
© Georg Thieme Verlag Stuttgart · New York

560
G. Verardo et al.
PAPER
Table 1 Identity of Compounds 1–3
Compounds 1–3
R
R¢
Et
Bn
Et
Et
Bn
Et
Compounds 1–3
R
R¢
aa
ab
ba
ca
cb
da
Me2CH
ea
eb
fa
PhCH2
Et
Me2CH
PhCH2
Bn
Et
Me2CHCH2
NH2COCH2CH2
NH2COCH2CH2
CH3SCH2CH2
Ph
ga
gc
1H-indole-3-CH2
1H-indole-3-CH2
Et
t-Bu
adding a solution of 1ea and Et3N (1.05 equivalents) in Table 2 Yields and Some Properties of Hydrazides 3 Prepared
THF to a solution of ECF (1.05 equivalents) in THF at
Producta
Yield (%)b
Mp (°C) (Lit.)
[a]D20 (c, MeOH)
–15.5 (1.0)
–12.6 (1.0)
+17.8 (1.1)
–13.7 (1.1)
–22.7 (1.1)
–11.8 (1.0)
+15.0 (1.0)
+10.3 (1.0)
–75.0 (1.0)
+19.0 (1.0)
+14.7 (1.0)
+20.0 (1.0)
–10 °C. The reaction mixture was stirred ten additional
minutes at –10 °C, Et3N·HCl was filtered off and the fil-
trate was slowly added to a solution of NH2NH2·H2O (2.0
equivalents) in MeOH at 0 °C. The reaction mixture was
allowed to warm up to r.t. and stirred for one hour furnish-
ing, after work-up, the hydrazide 3ea in a spectroscopical-
ly pure form without any further purification in a 91%
overall yield.
3aa
87
93
86
80
81
92
91
90
89
90
89
90
160
3ab
3ba
3ca
178 (178)6b
74 (56–59)6i
118
3cb
180 (173)6f
Following this procedure we prepared all the hydrazides 3
depicted in the Table 1.
3da
3ea
77
124
The protection of the a-amino function of tyrosine via
ECF produced N,O-dicarbethoxytyrosine (1ha)17 but,
when 1ha was used to prepare the corresponding hy-
drazide 3ha, 1H NMR analysis of the crude reaction mix-
ture showed the presence of two compounds: 3ha, and the
corresponding O-deprotected hydrazide 3ha¢ promoted by
the action of excess NH2NH2. Thus, to improve the con-
version of 3ha into 3ha¢, two additional equivalents of
NH2NH2·H2O were added at the end of the second step of
the reaction and the stirring was continued for two hours
at room temperature.
3eb
165 (164–166)9
3fa
132
155
150
142
3ga
3gc
3ha¢
a Satisfactory microanalyses obtained: C 0.16, H 0.10, N 0.14.
b Yields refer to pure isolated products.
The results obtained and some properties of 3 are reported
in Table 2.
anti isomerism characteristic of amides, at d = 3.10 and
3.05, and 1-(N-ethoxycarbonyl-L-phenylalanyl)-2-meth-
ylhydrazine (6), a singlet at d = 2.41. The integration of
these peaks evidenced a good selectivity towards the for-
mation of 5 in a ratio 87:13.
Since several authors reported18 that the acylation of
methylhydrazine (4) with acid anhydrides produces chief-
ly 1-acyl-1-methylhydrazines, while acylation with esters
gives chiefly 1-acyl-2-methylhydrazines, we tested our
methodology by reacting 1ea with 4. The 1H NMR analy-
sis of the reaction mixture after work up allowed us to dis-
tinguish the two isomers by means of their N-methyl
signals: 1-(N-ethoxycarbonyl-L-phenylalanyl)-1-methyl-
hydrazine (5) showed two singlets, indicative of the syn–
When our procedure was carried out with the less reactive
phenylhydrazine (7), only the 1-acyl-2-phenylhydrazines
8 were obtained in good yields (Scheme 2, Tables 3
and 4) using 1.5 mol equivalents of 7.
Scheme 2
Synthesis 2005, No. 4, 559–564 © Thieme Stuttgart · New York

PAPER
Synthesis of a-N-Protected Amino Acid Hydrazides
561
Table 4 Yields and Some Properties of Phenylhydrazides 8 Pre-
pared
Table 3 Identity of Compounds 1, 2, and 8
Com-
pounds
1, 2, 8
R
R¢
Com-
pounds
1, 2, 8
R
R¢
Producta
8aa
Yield (%)b
Mp (°C)
190
[a]D20 (c, MeOH)
–20.0 (1.0)
80
84
89
82
aa
Me2CH
Et
ca
ea
NH2COCH2CH2
PhCH2
Et
Et
8bb
138
–18.3 (1.0)
bb
Me2CHCH2 Bn
8ca
220
–20.8 (1.0)
8ea
187
–13.5 (1.0)
We did not observe any significant difference in reactivity
among the different N-protecting groups introduced into
the a-amino function. The HPLC analysis of the hy-
drazides 3 and 8 using a chiral column showed that no ra-
cemization occurred during the reaction. When the
hydrazides 3 were analysed by GC-MS using a chiral col-
umn, we observed, in addition to the L-enantiomer of 3, a
peak whose spectrum was consistent with the product of
thermal cyclization of the hydrazide, namely 5-substitut-
ed-1,2,4-triazinane-3,6-dione, generated in the injector of
the gas chromatograph. The amount of this compound in-
creased with the rising temperature of the injector.
a Satisfactory microanalyses obtained: C 0.11, H 0.13, N 0.14.
b Yields refer to pure isolated products.
Data pertinent to the synthesized hydrazides 3 and 8 are
collected on Table 5.
To summarize, we have presented here a fast, simple, and
versatile method for the preparation of a-N-protected ami-
no acid hydrazides, an important class of organic com-
pounds.
Table 5 Spectroscopic Data of Hydrazides 3 and 8
Product IR (KBr) (cm–1)
1H NMR d, J (Hz)
13C NMR d
MS m/z (%)
3aa
3ab
3307, 2976, 2964, 0.95 [d, 6 H, J = 6.7, CH(CH3)2], 1.25 (t, 3 H, J = 7.0,
14.5, 19.2, 30.8,
203 (M+, 1), 172 (18),
144 (100), 129 (21), 116
(13), 98 (20), 72 (63), 70
(10), 55 (26)
1674, 1649, 1542, CH2CH3), 2.08 [app sext, 1 H, J = 6.7, CH(CH3)2], 3.80 59.2, 61.3, 156.7,
1443, 1296, 1246, (br s, 2 H, NH2), 3.90–4.02 (m, 1 H, *CH), 4.12 (q, 2 H, 172.3a
1047, 931, 776,
676, 580
J = 7.0, CH2), 5.60 (br d, 1 H, J = 9.1, *CHNH), 8.18 (br
s, 1 H, NHNH2)a
3316, 3251, 2937, 0.93 and 0.94 [2 d, 6 H, J = 6.8, 6.8, CH(CH3)2], 2.09
1685, 1658, 1635, [app sext, 1 H, J = 6.8, CH(CH3)2], 3.69 (br s, 2 H, NH2), 59.0, 65.2, 127.4,
18.2, 18.9, 30.1,
265 (M+, 1), 234 (3), 162
(2), 129 (7), 122 (11), 108
1539, 1295, 1244, 3.93 (dd, 1 H, J = 8.5, 7.0, *CH), 5.05 and 5.13 (AB sys- 127.5, 128.1, 155.8, (16), 107 (13), 91 (100),
1037, 705, 656,
594
tem, 2 × d, 2 H, J = 12.6, CH2), 5.51 (br d, 1 H, J = 8.5, 170.2a
*CHNH), 7.32 (app s, 5 H, Harom), 7.69 (br s, 1H,
NHNH2)a
79 (9), 77 (5), 72 (8)
3ba
3ca
3cb
3da
3307, 2959, 1689, 0.92 and 0.94 [2 d, 6 H, J = 5.9, 5.9, CH(CH3)2], 1.23 (t, 14.4, 21.6, 22.7,
217 (M+, 1), 186 (22),
172 (4), 158 (100), 102
(27), 86 (24), 74 (11), 72
(22), 58 (26), 44 (72), 43
(52), 41 (31)
1653, 1606, 1539, 3 H, J = 7.0, CH2CH3), 1.46–1.78 [m, 3 H,
24.5, 41.4, 51.8,
1286, 1250, 1045, CH2CH(CH3)2], 4.00–4.41 (m, 5 H, OCH2, NH2, *CH),
61.0, 156.4, 173.2a
677
5.95 (br d, 1 H, J = 8.9, *CHNH), 8.70 (br s, NHNH2)a
3422, 3301, 1692, 1.13 (t, 3 H, J = 7.0, CH3), 1.62–1.90 (m, 2 H, *CHCH2), 14.5, 27.9, 31.4,
232 (M+, 1), 216 (6), 215
(5), 187 (2), 173 (4), 170
(5), 128 (22), 99 (60), 98
(43), 84 (100)
1653, 1616, 1531, 1.98–2.18 (m, 2 H, CH2CO), 3.83–4.03 (m, 3 H, *CH,
1408, 1253, 1060, OCH2), 4.40 (br s, 2 H, NHNH2), 6.67 (br s, 1 H,
53.2, 59.8, 155.9,
170.9, 173.9b
779, 667
*CHNH), 7.05 (br s, 1 H, NHNH2), 7.29 (br s, 2 H,
NH2CO)b
3552, 3432, 3314, 1.60–1.98 (m, 2 H, *CHCH2), 2.03–2.21 (m, 2 H,
1678, 1665, 1635, CH2CO), 3.87–4.04 (m, 1 H, *CH), 4.10 (br s, 2 H,
1539, 1277, 1251, NHNH2), 5.01 (app s, 2 H, PhCH2), 6.69 (br s, 1 H,
27.9, 31.4, 53.2,
65.4, 127.6, 127.7,
294 (M+, 1), 277 (2), 261
(1), 191 (2), 174 (5), 169
128.3, 136.9, 155.7, (17), 108 (19), 107 (13),
1052, 749, 680
*CHNH), 7.22 (br s, 2 H, CONH2), 7.23–7.51 (m, 5 H,
170.8, 173.7b
91 (100), 84 (10), 79 (15),
44 (10)
Harom), 9.06 (br s, 1 H, NHNH2)b
3299, 2980, 2918, 1.24 (t, 3 H, J = 7.0, CH2CH3), 1.81–2.15 (m, 2 H,
14.3, 15.1, 29.9,
235 (M+, 17), 204 (30),
176 (89), 161 (100), 128
(15), 61 (16)
1691, 1653, 1644, *CHCH2), 2.09 (s, 3 H, CH3S), 2.55 (app t, 2 H, J = 7.0, 31.6, 52.2, 61.1,
1539, 1285, 1251, CH2S), 3.91–4.55 (m, 5 H, *CH, OCH2, NH2), 6.33 (br d, 156.4, 172.1a
1056, 680
1 H, J = 8.8, *CHNH), 8.30 (br s, 1 H, NHNH2)a
Synthesis 2005, No. 4, 559–564 © Thieme Stuttgart · New York

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G. Verardo et al.
PAPER
Table 5 Spectroscopic Data of Hydrazides 3 and 8 (continued)
Product IR (KBr) (cm–1) 1H NMR d, J (Hz)
13C NMR d
MS m/z (%)
3ea
3295, 2979, 1693, 1.18 (t, 3 H, J = 7.2, CH3), 2.99 and 3.07 (AB of ABX, 2 14.4, 38.5, 54.8,
1657, 1538, 1290, H, J = 14.1, 7.3, 7.0, PhCH2), 3.66 (br s, 2 H, NH2), 4.05 61.3, 126.9, 128.6,
251 (M+, 1), 220 (19),
192 (92), 177 (8), 160
1265, 1246, 1051, (q, 2 H, J = 7.1, OCH2), 4.42 (app q, 1 H, J = 7.0, *CH), 129.1, 136.3, 156.2, (20), 148 (18), 131 (21),
751, 703, 675
5.77 (d, 1 H, J = 8.8, *CHNH), 7.12–7.36 (m, 5 H, Harom), 171.8a
8.09 (br s, 1 H, NHNH2)a
120 (100), 103 (19), 91
(51)
3eb
3316, 1688, 1654, 3.03 (d, 2 H, J = 7.1, *CHCH2), 3.83 (br s, 2 H, NH2),
38.4, 55.0, 67.1,
313 (M+, 1), 282 (2), 205
1609, 1535, 1264, 4.39 (app q, 1 H, J = 7.3, *CH), 4.99 and 5.07 (AB sys- 127.1, 127.9, 128.2, (1), 178 (2), 177 (3), 131
1250, 1041, 745,
697
tem, 2 × d, 2 H, J = 12.2, OCH2), 5.60 (d, 1 H, J = 8.5,
*CHNH), 7.09–7.38 (m, 10 H, Harom), 7.64 (br s, 1 H,
NHNH2)a
128.5, 128.7, 129.1, (5), 122 (18), 120 (21),
135.9, 136.1, 155.9, 108 (15), 107 (10), 91
171.6a
(100)
3fa
3307, 2983, 1685, 1.22 (t, 3 H, J = 7.1, CH3), 3.89 (br s, 2 H, NH2), 4.10 (q, 14.4, 57.3, 61.4,
237 (M+, 1), 206 (10),
1653, 1540, 1256, 2 H, J = 7.1, CH2), 5.31 (d, 1 H, J = 7.4, *CH), 6.22 (br d, 127.0, 128.4, 128.9, 178 (100), 147 (16), 134
1052, 696
1 H, J = 7.4, *CHNH), 7.26–7.48 (m, 5 H, Harom), 8.07 (br 137.5, 156.1, 171.0a (16), 118 (15), 106 (76),
s, 1 H, NHNH2)a
3348, 3278, 1700, 1.10 (t, 3 H, J = 6.8, CH3), 2.90 and 3.05 (AB of ABX, 2 14.4, 27.9, 53.9,
104 (28), 79 (32), 77 (21)
3ga
290 (M+, 1), 244 (2), 201
(3), 170 (7), 158 (1), 143
1653, 1646, 1558, H, J = 14.4, 8.8, 5.0, *CHCH2), 3.33 (br s, 2 H, NH2),
1539, 1534, 1522, 3.90 (q, 2 H, J = 6.8, OCH2), 4.13–4.33 (m, 1 H, *CH),
1258, 750, 651
59.6, 110.0, 111.1,
118.1, 118.3, 120.7, (1), 130 (100)
123.6, 127.2, 135.9,
6.92–7.17 (m, 4 H, Harom, *CHNH), 7.29–7.38 (m, 1 H,
Harom), 7.56–7.66 (m, 1 H, Harom), 9.14 (s, 1 H, NHNH2), 171.0b
b
10.75 (s, 1 H, NHarom
)
3gc
3345, 3319, 3221, 1.31 [s, 9 H, C(CH3)3], 2.90 and 3.04 (AB of ABX, 2 H, 28.0, 39.9, 53.7,
2982, 1685, 1675, J = 14.4, 5.3, 5.3, *CHCH2), 4.11–4.30 (m, 3 H, *CH, 77.8, 110.0, 111.1,
318 (M+, 1), 262 (1), 201
(4), 170 (6), 159 (3), 130
1654, 1526, 1367, NH2), 6.64 (br d, 1 H, J = 7.3, *CHNH), 6.91–7.17 (m, 3 118.0, 118.3, 120.7, (100), 117 (2), 57 (1), 41
1249, 1170, 1025, H, Harom), 7.28–7.37 (m, 1 H, Harom), 7.54–7.66 (m, 1 H, 123.5, 127.3, 135.9, (1)
b
731, 643
Harom), 9.07 (s, 1 H, NHNH2), 10.74 (br s, 1 H, NHarom
)
154.9, 171.1b
3ha¢
3305, 3279, 1688, 1.09 (t, 3 H, J = 7.0, CH3), 2.63 and 2.78 (AB of ABX, 2 14.5, 37.0, 59.7,
267 (M+, 1), 221 (1), 208
114.8, 128.0, 130.0, (12), 178 (37), 177 (16),
1653, 1542, 1516, H, J = 13.8, 9.7, 5.0, *CHCH2), 3.39 (br s, 2 H, NH2),
1291, 1248, 1046, 3.89 (q, 2 H, J = 7.0, OCH2), 4.03–4.14 (m, 1 H, *CH),
155.7, 170.9b
160 (13), 147 (82), 136
(24), 107 (100), 91 (14)
837, 650
4.20 (br s, 1 H, OH), 6.60–6.69 (m, 2 H, Harom), 6.98–7.08
(m, 2 H, Harom), 7.10 (br d, 1 H, J = 8.5, *CHNH), 9.08 (br
s, 1 H, NHNH2)b
8aa
8bb
3296, 3256, 2960, 0.91 and 0.92 [2 d, 6 H, J = 6.7, 6.7, CH(CH3)2], 1.19 (t, 14.5, 18.3, 19.1,
1691, 1657, 1541, 3 H, J = 7.0, CH2CH3), 2.00 [app sext, 1 H, J = 7.0, 29.9, 59.0, 59.7,
279 (M+, 12), 233 (2),
172 (9), 144 (91), 134
1497, 1298, 1251, CH(CH3)2], 3.86 (app t, 1 H, J = 8.2, *CH), 4.03 (q, 2 H, 112.2, 118.3, 128.4, (11), 116 (17), 108 (100),
1045, 772, 660
J = 7.0, CH2), 6.63 (m, 3 H, Harom), 6.98–7.20 (m, 3 H,
Harom, *CHNH), 7.65 (br s, 1 H, NHPh), 9.71 (s, 1 H,
NHNHPh)b
149.2, 156.1, 171.1b 93 (11), 92 (15), 77 (15),
72 (38)
3385, 3306, 3257, 0.91 [app t, 6 H, J = 6.7, CH(CH3)2], 1.36–1.70 [m, 3 H, 21.5, 22.7, 24.1,
2957, 1696, 1659, (CH3)2CHCH2], 4.07–4.22 (m, 1 H, *CH), 5.02 and 5.10 40.5, 51.8, 65.3,
355 (M+, 1), 247 (20),
198 (3), 176 (2), 134 (14),
1541, 1496, 1267, (AB system, 2 × d, 2 H, J = 13.8, OCH2), 6.63–6.78 (m, 112.1, 118.3, 127.5, 108 (66), 107 (100), 86
1251, 1239,1035,
752, 699
3 H, Harom), 7.04–7.18 (m, 2 H, Harom), 7.30–7.49 (m, 6 H, 127.6, 128.2, 128.4, (69), 79 (18), 77 (23)
Harom, *CHNH), 7.64 (br s, 1 H, NHPh), 9.78 (s, 1 H,
136.9, 149.2, 155.8,
NHNHPh)b
172.0b
8ca
8ea
3410, 3315, 3259, 1.18 (t, 3 H, J = 7.0, CH3), 1.62–2.02 (m, 2 H, *CHCH2), 14.5, 27.5, 31.4,
308 (M+, 22), 291 (15),
262 (6), 201 (6), 174 (28),
1684, 1653, 1540, 2.05–2.25 (m, 2 H, CH2CO), 3.91–4.09 (m, 3 H, *CH,
53.2, 59.8, 114.5,
1496, 1270, 1258, OCH2), 6.61–6.83 (m, 4 H, Harom, *CHNH), 6.94–7.23
1062, 888, 768,
693
121.4, 128.8, 149.2, 173 (17), 134 (13), 128
(m, 5 H, Harom, NH2, NHPh), 10.21 (br s, 1 H, NHNHPh)b 155.8, 171.6, 173.6b (35), 108 (100), 93 (40),
84 (88), 77 (10)
3301, 3242, 3034, 1.18 (t, 3 H, J = 7.2, CH3), 3.06 (app d, 2 H, J = 7.3,
2983, 1689, 1657, PhCH2), 4.05 (q, 2 H, J = 7.2, OCH2), 4.57 (app q, 1 H,
14.4, 38.4, 54.8,
61.5, 113.5, 121.1,
327 (M+, 43), 281 (10),
236 (8), 220 (4), 192 (57),
1535, 1496, 1289, J = 7.8, *CH), 5.52 (d, 1 H, J = 8.5, *CHNH), 6.04 (br d, 127.1, 128.8, 129.0, 147 (30), 134 (18), 131
1251, 1047, 752,
699
1 H, J = 3.0, NHPh), 6.42–6.57 (m, 1 H, Harom), 6.78–6.94 129.4, 136.1, 147.4, (13), 120 (100), 108 (78),
(m, 1 H, Harom), 6.93–7.35 (m, 8 H, Harom), 8.37 (br d, 1 H, 156.4, 171.3b
91 (14), 77 (9)
J = 3.0, NHNHPh)b
a Solvent: CDCl3.
b Solvent: DMSO-d6.
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Synthesis of a-N-Protected Amino Acid Hydrazides
563
The optical purities of hydrazides 3 and 8 were determined by
HPLC analysis with a Waters M-45 apparatus using a Daicel
Chiracel OD column (0.46 cm I.D. × 25 cm; eluent: hexane–
i-PrOH, 50:50; flow rate, 0.5 mL/min; UV detector, 254 nm). Direct
inlet mass spectra (DI-MS) were obtained with a Fisons TRIO 2000
gas chromatograph–mass spectrometer, working in the positive ion
70 eV electron impact mode. Spectra were recorded in the range 35–
450 u. Temperatures between 100 and 200 °C were found suitable
to volatilise all the compounds into the ion source. Chiral GC-MS
analyses were performed on the same instrument using a
Chrompack Chirasil-val-L column (26 m × 0.22 mm I.D., 0.14 mm
film thickness). IR spectra were obtained with a Nicolet FT-IR Ma-
gna 550 spectrophotometer using the KBr technique for solids and
recorded in the range 4000–400 cm–1. 1H and 13C NMR spectra were
recorded on a Bruker AC-F 200 spectrometer at 200 and 50 MHz,
respectively, using CDCl3 at r.t. or DMSO-d6 at 40 °C as solvents.
NMR peak locations are reported as d values from TMS. Some 1H
multiplets are characterized by the term app (apparent): this refers
only to their appearance and may be an oversimplification. Optical
rotations were determined at 20 °C (concentration in g/100 mL of
solvent) using a POLAX-D polarimeter purchased from ATAGO
(Japan). Elemental analyses were performed with a Carlo Erba
Mod. 1106 elemental analyser. Mps were determined with an auto-
matic Mettler (Mod. FP61) mp apparatus and are not corrected. All
N-protected amino acids 1 were prepared by traditional proce-
dures.19 All solvents and reagents were purchased from Aldrich
Chemical Company and used without further purification. ECF is
ethyl chloroformate. The bp of the petroleum ether used was 40–60
ºC.
with THF (2 × 3 mL) and the filtrate was slowly added to a solution
of methylhydrazine (0.24 g, 5.32 mmol) in MeOH (7 mL) at 0 °C.
The mixture was allowed to warm up to r.t. and stirred for 1 h. The
solvents were removed under reduced pressure and the residue was
dissolved in EtOAc (25 mL). The organic mixture was washed suc-
cessively with sat. aq NaHCO3 (3 mL) and sat. brine (3 mL), dried
(Na2SO4), filtered and the solvent was evaporated in vacuo. The 1H
NMR spectrum (CD3OD) of the residue (0.62 g, 88%) evidenced
the presence of a mixture of 1-(N-ethoxycarbonyl-L-phenylalanyl)-
1-methylhydrazine (5) and 1-(N-ethoxycarbonyl-L-phenylalanyl)-
2-methylhydrazine (6) in a ratio 87:13 as measured by the integra-
tion of the N-methyl signals of 5 at d = 3.10 and 3.05 and 6 at d =
2.41.
Acknowledgment
Financial support was obtained from MIUR (FURD 2002-2004 to
GV). The authors are grateful to Dr. P. Martinuzzi for recording 1H
and 13C NMR spectra and Mr P. Padovani for expert instrumental
maintenance.
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Synthesis 2005, No. 4, 559–564 © Thieme Stuttgart · New York