Carbamoyl azides of α-N-protected amino acids: A fast and simple one-pot synthesis

Article abstract of DOI:10.1055/s-2008-1032029

A fast and simple one-pot synthesis of carbamoyl azides of α-N-protected amino acids is reported. The procedure involves the reaction between sodium azide and the mixed anhydride obtained from an α-N-protected amino acid and isobutyl chloroformate, in the presence of KH₂PO₄. The reaction rate was influenced by the nature of both the α-N-protection and the amino acid side chain. Surprisingly, tert-butyloxycarbonyl (α-N-Boc) and benzyloxycarbonyl (α-N-Cbz) protected proline afforded the corresponding isocyanates instead of the expected carbamoyl azides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032029

438
PAPER
Carbamoyl Azides of a-N-Protected Amino Acids: A Fast and Simple One-Pot
Synthesis
S
ynthesisof Carba
i
moyl
A
a
zides of
a
-
n
N-Protected
c
Amino
A
ci
a
ds rlo Verardo,* Elisa Bombardella, Paola Geatti, Paolo Strazzolini
Department of Chemical Sciences and Technologies, University of Udine, Via del Cotonificio 108, 33100 Udine, Italy
Fax +39(0432)558803; E-mail: giancarlo.verardo@uniud.it
Received 10 October 2007
of the mixed anhydride 2, which was obtained by reacting
Abstract: A fast and simple one-pot synthesis of carbamoyl azides
of a-N-protected amino acids is reported. The procedure involves
the reaction between sodium azide and the mixed anhydride ob-
tained from an a-N-protected amino acid and isobutyl chlorofor-
the N-methylmorpholinium salt of an a-N-protected ami-
no acid 1 with isobutyl chloroformate (IBCF), in tetrahy-
drofuran at –10 °C. After a few minutes (second step),
mate, in the presence of KH2PO4. The reaction rate was influenced solid potassium dihydrogenphosphate (6 equiv) was add-
by the nature of both the a-N-protection and the amino acid side
chain. Surprisingly, tert-butyloxycarbonyl (a-N-Boc) and benzyl-
oxycarbonyl (a-N-Cbz) protected proline afforded the correspond-
ing isocyanates instead of the expected carbamoyl azides.
ed in one portion at 0 °C to the resulting well-stirred mix-
ture, followed by slow addition of an aqueous solution of
sodium azide (3 equiv). The resulting mixture was then
stirred at room temperature for 1.5–3 hours to afford, after
work-up, the carbamoyl azide 3 in a spectroscopically
pure form without any further purification in 80–90%
overall yield.
Key words: a-N-protected amino acids, sodium azide, carbamoyl
azide, mixed anhydride, Curtius rearrangement
From a mechanistic point of view, the reaction of the
mixed anhydride 2 with sodium azide, gives rise to the
azide 4 (Scheme 2) which, in contrast to the isolable
Fmoc-amino acid azides reported by Babu et al.,11 proved
to be unstable and led to the corresponding isocyanate 5
by the Curtius rearrangement. Compound 5, in the pres-
ence of excess sodium azide, yields the corresponding
carbamoyl azide 3.
Carbamoyl azides are an important class of compounds
having a wide range of applications in organic synthesis.1
Some are used as intermediates in the synthesis of hetero-
cyclic,2 pharmaceutical3 and non-crosslinked foam4 com-
pounds. Carbamoyl azides are generally prepared by
reacting the corresponding carbonyl halides with inorgan-
ic azides,2d,5 by nitrosation of semicarbazides,2b,3b,6 and by
the addition of hydrazoic acid3c,4,7 or organometallic
polyazides8 to isocyanates. All these procedures suffer
limitations associated with the availability of precursors
and hazards in handling reagents (triphosgene in the syn-
thesis of carbamoyl halides from amines and hydrazoic
acid). Carbamoyl azides have also been obtained starting
from carboxaldehydes9 and carboxylic acids10 but, to our
knowledge, the use of a-N-protected amino acids as pre-
cursors does not appear to have any precedent in the liter-
ature. In this paper we report an efficient extension of the
mixed anhydride method to the one-pot synthesis of a-N-
protected carbamoyl azides.
It was essential for the success of our synthetic method to
carry out the second step of the reaction in the presence of
KH2PO4, which allowed the pH of the mixture to be kept
constant at around 7. In fact, in preliminary experiments
carried out using 1e as a model substrate, without the ad-
dition of KH2PO4, the pH of the final reaction mixture was
approximately 9 and the ESI-MS analysis evidenced the
presence of the carbamoyl azide 3e accompanied by the
corresponding urea 8e (Scheme 3) in a ratio of 65:35.
In fact, the hydroxide ion formed by the hydrolysis of so-
dium azide and produced in the course of the reaction
(Scheme 3), reacted with the isocyanate 5e and/or the car-
bamoyl azide 3e yielding the ethyl 1-amino-3-methylbu-
tylcarbamate (7e) via the corresponding carbamic acid 6e.
At this point, compound 7e was capable of reacting with
The simple and convenient synthesis of a-N-protected
carbamoyl azides 3, reported here, was accomplished in a
two-step, one-pot reaction sequence (Scheme 1; Table 1).
The first step of the process consisted of the preparation
O
N3
O
O
O
a) KH2PO4 (solid)
NaN3, H2O, 0 °C
IBCF, THF,
–10 °C
R
H
O
R
H
R
H
N
*
*
*
OH
OR1
O
Oi-Bu
H
OR1
+
N
N
OR1
N
b) r.t., 1.5–3 h
N
O
Me
O
O
1
2
3
Scheme 1
SYNTHESIS 2008, No. 3, pp 0438–0444
x
x
.
x
x
.2
0
0
7
Advanced online publication: 10.01.2007
DOI: 10.1055/s-2008-1032029; Art ID: P11607SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Carbamoyl Azides of a-N-Protected Amino Acids
439
O
N3
O
O
C
R
H
R
H
N
N
R
H
NaN3
*
*
*
– N2
N3
OR1
H
OR1
2
NaN3
+
N
N
OR1
N
O
O
O
4
3
5
Scheme 2
3e and/or 5e, giving the urea 8e. The presence of KH2PO4 ESI-MS analysis of the intact reaction mixture obtained
was therefore critical because, upon neutralizing the hy- after 1.5 hours of stirring at room temperature, revealed
droxide ion, the KH2PO4/K2HPO4 couple was produced, only the presence of the corresponding isocyanates 5p and
which effectively buffered the reaction mixture at about 5q, which were finally isolated after suitable workup, in
pH 7. Following the protocol described above, the ESI- 97% and 94% yields, respectively. Prolonged stirring (24
MS analysis of the intact reaction mixtures obtained 30 h) at room temperature after the addition of aqueous sodi-
minutes after the end of the addition of sodium azide, um azide yielded small amounts (10–15%) of the carbam-
showed the presence of the corresponding isocyanate 5 oyl derivatives 3p and 3q.
along with a variable amount of the carbamoyl azide 3.
Carbamoyl azides 3 were found to be fairly stable crystal-
This appears to be a clear indication that the Curtius rear-
line solids that could be stored at –20 °C for up to two
rangement of the acyl azide 4 into the corresponding iso-
weeks; however, storage at room temperature for more
than 24 hours led to their decomposition. Furthermore, so-
lutions of 3 in aprotic solvents were more stable than in
the solid form.
cyanate 5 (Scheme 2) occurs rapidly, the rate determining
step of the reaction leading to 3 being the addition of the
azide ion to 5. With the aid of ESI-MS analysis, we ob-
served that the rate of this reaction was influenced by the
The results obtained and some properties of 3 are reported
nature of both the a-N-protection and the amino acid side
on Table 2. Data pertinent to the synthesized carbamoyl
chain. In detail, the reaction, probably due to steric hin-
azides 3 are collected in Table 3.
drance, was found to proceed slower with tert-butyloxy-
carbonyl (a-N-Boc) and benzyloxycarbonyl (a-N-Cbz)
derivatives as well as in the case of valine and phenylgly-
cine derivatives when bulky substituents in the a-position
of the starting amino acid were present. All these sub-
strates required longer reaction times (3 h instead of 1.5 h)
for complete conversion into the carbamoyl azide 3.
With the exception of the carbamoyl azides of leucine
(3d–g), phenylglycine (3h and 3i) and N-Boc-valine (3b),
1
the H and 13C NMR spectra of 3 appeared complex
(Table 3), due to the restricted rotation around the car-
bamate C–N bond.12
The EI-MS spectra of the carbamoyl azides 3 (Table 3)
exhibited the following common features (Scheme 4): (i)
absence of the molecular ion, (ii) loss of hydrazoic acid
Surprisingly, when N-Boc-protected (1p) and N-Cbz-pro-
tected (1q) proline were treated according to our protocol,
–
H2O
–OH
HN3
+
+
N3
O
O
O
C
N
– i-BuOH
*
– N2
*
–
N3
2e
N3
+
–
–OH,
– CO2
N
OEt
N
OEt
H
H
O
4e
5e
–OH
–
N3
–
–OH
H2O
O
OH
H
N
O
O
N3
NH2
– CO2
*
*
–OH
N
OEt
N
O
N
OEt
*
H
H
H
N
OEt
O
7e
H
6e
5e
7e
O
O
3e
H
H
EtO
N
*
O
N
*
OEt
N
H
N
H
8e
Scheme 3
Synthesis 2008, No. 3, 438–444 © Thieme Stuttgart · New York

440
G. Verardo et al.
PAPER
Table 2 Yields and Selected Properties of Carbamoyl Azides 3
Producta Yield (%)b Mp (°C) [a]D20 (c, solvent)
Table 1 R-Group Assignments for All Compounds
R
R1
3a
3b
3c
3d
3e
3f
97
86
92
85
90
90
91
88
86
90
91
89
89
93
95
127–129 (dec)
132–134 (dec)
147–148; 151 (dec)
79–80; 110 (dec)
99–101; 117 (dec)
109–110; 116 (dec)
130 (dec)
–11.8 (1.1, CHCl3)
+33.2 (1.1, THF)
+49.5 (1.0, THF)
–18.5 (1.1, THF)
+9.8 (1.0, CHCl3)
+19.9 (1.0, THF)
+29.9 (1.0, THF)
+7.8 (1.0, THF)
a
b
c
d
e
f
i-Pr
Et
i-Pr
t-Bu
Bn
Me
Et
i-Pr
i-Bu
i-Bu
i-Bu
t-Bu
Bn
Et
3g
3h
3i
g
h
i
i-Bu
136–137; 140 (dec)
116–118 (dec)
144 (dec)
Ph
–10.7 (1.1, THF)
+10.8 (1.0, EtOAc)
–7.8 (1.0, THF)
Ph
t-Bu
Me
Et
3j
j
Bn
3k
3l
146 (dec)
k
l
Bn
138–139; 141 (dec)
77–79; 83 (dec)
65–67; 89 (dec)
115 (dec)
+10.6 (1.0, EtOAc)
–17.0 (1.0, THF)
–6.7 (1.1, EtOAc)
–8.3 (1.0, EtOAc)
Bn
Bn
Et
3m
3n
3o
m
n
o
MeS(CH2)2
1H-indole-3-CH2
1H-indole-3-CH2
Me
Et
a Satisfactory elemental analyses obtained: C 0.15, H 0.10,
0.14.
b Reported yields refer to pure isolated products.
N
(HN3; m/z = 43), (iii) loss of carbamoyl azide (NH2CON3;
m/z = 86) and/or the corresponding radical (NHCON3;
m/z = 85), and (iv) loss of the amino acid chain radical.
Table 3 Spectroscopic Data of Carbamoyl Azides 3
Product IR (KBr) (cm–1) 1H NMR [d (ppm), J (Hz)]
13C NMR [d (ppm)]
EI-MS: m/z (%)
ESI-MS:a m/z
3a
3b
3c
3d
3312(br),2981, 0.91–1.03 [m, 6 H, (CH3)2CH], 1.25 (t, J = 7.1, 14.4, 17.2 and 17.8, 18.6, 186 (100), 144
252 [M + Na]+ →
2255, 2137,
1698, 1517,
3 H, CH3CH2), 1.78–2.05 [m, 1 H, (CH3)2CH], 31.6 and 33.6, 61.1 and
(18), 143 (98), 98 224, 178
(16), 86 (33), 71
(75), 56 (69), 43
(77)
4.03–4.25 (m, 2 H, OCH2), 4.70–4.93 and
61.5, 65.3 and 68.1,
1230, 1042, 711 5.03–5.20 (2 × m, 1 H, *CH), 5.36 and 5.74 (2 155.9, 156.1 (br)b
× br d, J = 8.5 and 7.1, 1 H, NHCO2Et), 6.08
and 6.31 (2 × br s, 1 H, NHCON3)b
3337(br),1983, 0.82 and 0.84 [2 × d, J = 6.8, 6.6, 6 H,
18.4, 28.2, 31.7, 64.2,
214 (3), 171 (5),
158 (22), 141 (4), 224, 196, 152
114 (8), 71 (8), 59
280 [M + Na]+ →
2254, 2136,
1699, 1545,
(CH3)2CH], 1.37 [s, 9 H, (CH3)3C], 1.79 [hept, 78.0, 154.6, 154.8 (br)c
J = 6.6, 1 H, (CH3)2CH], 4.76 (app q, J = 8.3,
1510, 1234, 684 1 H, *CH), 7.08 (br d, J = 8.1, 1 H,
NHCO2tBu), 8.14 (br d, J = 8.3, 1 H,
NHCON3)c
(15), 57 (100)
3312(br),2964, 0.78–0.96 [m, 6 H, (CH3)2CH], 1.71–1.98 [m, 17.8 and 18.1, 18.3 and
248 (2), 205 (5),
314 [M + Na]+ →
2254, 2136,
1699, 1514,
1 H, (CH3)2CH], 4.78–5.13 (m, 3 H, *CH and 18.4, 31.6 and 32.8, 64.7 162 (8), 107 (20), 286, 178
OCH2), 7.25–7.43 (m, 5 H, Harom), 7.64 (br d, and 69.0, 65.4 and 65.9, 91 (100), 43 (9)
1232, 1032, 705 J = 7.3, 1 H, NHCO2Bn), 8.28 (br d, J = 8.1,
127.8, 128.0, 128.4, 136.6
and 137.0, 154.9, 155.4
(br)c
1 H, NHCON3)c
3321(br),2960, 0.94 [dd, J = 6.4, 2.3, 6 H, (CH3)2CH], 1.45– 22.1, 24.7, 45.2, 58.7,
186 (1), 172 (14), 252 [M + Na]+ →
2252, 2138,
1704, 1521,
1.87 (m, 3 H, CHCH2), 3.68 (s, 3 H, OCH3),
5.04–5.29 (m, 1 H, *CH), 5.96 (br d, J = 7.2,
61.9, 155.9, 156.2 (br)b
144 (12), 129
(100), 101 (13),
88 (9), 59 (21), 43
(19)
224, 192
1245, 1038, 660 1 H, NHCO2Me), 6.48 (br d, J = 7.8, 1 H,
NHCON3)b
Synthesis 2008, No. 3, 438–444 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbamoyl Azides of a-N-Protected Amino Acids
441
Table 3 Spectroscopic Data of Carbamoyl Azides 3 (continued)
Product IR (KBr) (cm–1) 1H NMR [d (ppm), J (Hz)]
13C NMR [d (ppm)]
EI-MS: m/z (%)
ESI-MS:a m/z
3e
3315(br),2170, 0.94 [dd, J = 6.2, 2.0, 6 H, (CH3)2CH], 1.28 (t, 14.4, 22.1, 24.7, 42.6,
200 (1), 186 (88), 266 [M + Na]+ →
158 (14), 155 (8), 238, 192
143 (73), 115 (9),
86 (14), 71 (25),
43 (100)
2135, 1702,
1556, 1516,
1295, 1228,
1039, 708
J = 7.3, 3 H, CH3CH2), 1.54–1.82 (m, 3 H,
58.6, 61.0, 155.9, 156.0
CHCH2), 4.12 (q, J = 7.3, 2 H, OCH2), 5.04– (br)b
5.32 (m, 1 H, *CH), 6.02 (br d, J = 8.6, 1 H,
NHCO2Et), 6.67 (br d, J = 8.5, 1 H,
NHCON3)b
3f
3346(br),2960, 0.84 [dd, J = 6.1, 1.7, 6 H, (CH3)2CH], 1.37 [s, 22.1, 24.1, 28.1, 42.9,
228 (1), 214 (7),
186 (1), 171 (5),
158 (46), 155 (9),
130 (7), 114 (33),
86 (89), 57 (100)
294 [M + Na]+ →
238, 210, 166
2247, 2136,
1701, 1548,
1502, 1223,
1155, 680
9 H, (CH3)3C], 1.30–1.66 (m, 3 H, CHCH2),
5.09 (app qt, J = 7.6, 1 H, *CH), 7.17 (br d,
J = 7.1, 1 H, NHCO2tBu), 8.19 (br d, J = 8.1,
1 H, NHCON3)c
57.6, 78.0, 154.3, 154.5
(br)c
3g
3h
3317(br),2960, 0.85 [dd, J = 6.0, 1.7, 6 H, (CH3)2CH], 1.38– 22.1, 24.0, 42.7, 57.9,
262 (1), 248 (2),
328 [M + Na]+ →
2250, 2137,
1697, 1152,
1514, 1228,
1040, 697
1.66 (m, 3 H, CHCH2), 5.02 (s, 2 H, OCH2),
65.3, 127.8, 127.9, 128.3, 220 (1), 219 (3),
300, 192
5.08–5.26 (m, 1 H, *CH), 7.26–7.45 (m, 5 H, 136.9, 154.6, 154.9 (br)c
Harom), 7.71 (br d, J = 8.1, 1 H, NHCO2Bn),
158 (2), 155 (3),
107 (26), 91
(100), 43 (16)
8.33 (br d, J = 7.6, 1 H, NHCON3)c
3296(br),2248, 1.16 (t, J = 7.1, 3 H, CH3), 4.02 (q, J = 6.9,
14.6, 60.1, 61.4, 126.4,
128.0, 128.3, 139.0,
220 (1), 178 (27), 286 [M + Na]+ →
177 (5), 133 (85), 258, 212
132 (80), 105
(46), 104 (100),
91 (32), 77 (80),
2143, 1706,
1515, 1227,
1042, 694
2 H, OCH2), 6.23 (app t, J = 8.1, 1 H, *CH),
7.18–7.59 (m, 5 H, Harom), 8.22 (br d, J = 8.1, 155.0, 155.3 (br)c
1 H, NHCO2Et), 8.84 (br d, J = 7.8, 1 H,
NHCON3)c
51 (41), 43 (55)
3i
3j
3333(br),2981, 1.40 [s, 9 H, (CH3)3C], 6.21 (app t, J = 8.1,
28.1, 61.1, 78.6, 126.4,
248 (1), 206 (13), 314 [M + Na]+ →
2249, 2139,
1699, 1543,
1508, 1232,
1172, 695
1 H, *CH), 7.24–7.50 (m, 5 H, Harom), 7.92 (br 127.9, 128.3, 139.3,
d, J = 7.6, 1 H, NHCO2tBu), 8.77 (br d,
J = 8.1, 1 H, NHCON3)c
192 (5), 175 (6),
150 (7), 132 (19),
104 (15), 77 (17),
57 (100)
258, 230, 186
154.3, 154.8 (br)c
3309(br),2254, 2.83–3.08 (m, 2 H, PhCH2), 3.49 and 3.56 (2 × 39.9 and 40.2, 51.3 and
220 (1), 178 (5),
286 [M + Na]+ →
258, 226
2143, 1704,
1551, 1507,
s, 3 H, OCH3), 5.11–5.43 (m, 1 H, *CH), 7.16– 51.7, 61.0 and 64.6, 126.4 177 (30), 172
7.38 (m, 5 H, Harom), 7.66 and 7.74 (2 × br d,
and 126.9, 128.2 and
128.3, 129.2 and 129.4,
(24), 129 (100),
91 (36), 59 (18),
43 (36)
1226, 1053, 704 J = 7.2 and 7.7, 1 H, NHCO2Me), 8.26 and
8.49 (2 × br d, J = 7.8 and 7.7, 1 H, NHCON3)c 136.3 and 137.1, 154.7,
155.5 (br)c
3k
3l
3304(br),2253, 1.13 (app q, J = 7.3, 3 H, CH3), 2.82–3.12 (m, 14.5, 39.7 and 40.1, 59.8 234 (1), 192 (7),
300 [M + Na]+ →
2140, 1699,
1552, 1511,
1229, 1055,
1037, 702
2 H, PhCH2), 3.85–4.08 (m, 2 H, OCH2),
5.10–5.38 (m, 1 H, *CH), 7.12–7.37 (m, 5 H, 126.5 and 126.8, 128.2
and 60.2, 60.9 and 64.6,
191 (54), 143
(42), 119 (45),
118 (100), 117
(41), 91 (81), 43
(21)
272, 226
Harom), 7.71 and 7.78 (2 × br d, J = 7.1 and 7.8, and 128.4, 129.2 and
1 H, NHCO2Et), 8.25 and 8.48 (2 × br d,
129.4, 136.3 and 137.1,
J = 7.8 and 7.8, 1 H, NHCON3)c
154.6, 155.1 (br)c
3315(br),2264, 2.83–3.18 (m, 2 H, PhCH2), 5.00 and 5.06 (2 × 39.8 and 40.4, 61.0 and
254 (1), 253 (6),
362 [M + Na]+ →
334, 226
2135, 1699,
1549, 1510,
1227, 1023
s, 2 H, OCH2), 5.21–5.43 (m, 1 H, *CH), 7.22– 64.6, 65.3 and 65.8, 126.5 248 (1), 209 (5),
7.39 (m, 10 H, Harom), 7.95 and 7.99 (2 × br d, and 126.9, 127.7, 127.8
205 (3), 118 (4),
117 (3), 91 (100),
65 (10), 43 (12)
J = 8.1 and 8.3, 1 H, NHCO2Bn), 8.42 and
and 127.9, 128.2, 128.3,
8.56 (2 × br d, J = 7.5 and 7.6, 1 H, NHCON3)c 129.3 and 129.4, 136.0,
136.3 and 136.9, 154.7,
155.4 (br)c
3m
3303(br),2983, 1.18 (app q, J = 7.1, 3 H, CH3CH2), 1.76–1.98 14.4 and 14.6, 28.8 and
218 (1), 186 (8),
284 [M + Na]+ →
2250, 2138,
1700, 1518,
1243, 1227,
1055, 709
(m, 2 H, *CHCH2), 2.03 and 2.04 (2 × s, 3 H, 29.0, 33.3 and 34.5, 58.5 176 (6), 175 (20), 256, 210
SCH3), 2.35–2.58 (m, 2 H, SCH2), 3.90–4.15 and 62.7, 59.8 and 60.5,
172 (11), 128
(57), 61 (100), 56
(79), 43 (41)
(m, 2 H, OCH2), 5.07–5.34 (m, 1 H, *CH),
7.58 and 7.73 (2 × br d, J = 7.0 and 7.1, 1 H,
NHCO2Et), 8.22 and 8.34 (2 × br d, J = 7.8 and
7.8, 1 H, NHCON3)c
154.7, 155.2 (br)c
Synthesis 2008, No. 3, 438–444 © Thieme Stuttgart · New York

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G. Verardo et al.
PAPER
Table 3 Spectroscopic Data of Carbamoyl Azides 3 (continued)
Product IR (KBr) (cm–1) 1H NMR [d (ppm), J (Hz)]
13C NMR [d (ppm)]
EI-MS: m/z (%)
ESI-MS:a m/z
3n
3405 (br), 3331 3.05–3.22 (m, 2 H, *CHCH2), 3.56 and 3.62 (2 29.9, 52.3 and 52.4, 60.5 259 (1), 216
325 [M + Na]+ →
297, 265
(br), 2250,
2139, 1717,
1515, 1233,
1045, 744
× s, 3 H, OCH3), 5.40–5.68 (m, 1 H, *CH),
and 63.2, 108.3 and 109.3, (100), 184 (43),
5.80 and 6.26 (2 × br d, J = 8.0 and 8.2, 1 H,
111.5, 118.3, 119.7 and
119.9, 122.2 and 122.3,
123.4, 129.3, 136.3,
155.8, 156.2 (br)b
157 (33), 156
(32), 130 (86),
103 (19), 77 (18),
43 (64)
NHCO2Me), 6.84–7.62 (m, 6 H, Harom and
b
NHCON3), 8.53 (br s, 1 H, NHarom
)
3o
3404 (br), 3321 1.05–1.30 (m, 3 H, CH3), 2.98–3.34 (m, 2 H,
14.3, 29.9, 60.0 and 63.1, 273 (1), 231 (9),
339 [M + Na]+ →
311, 265
(br), 2979,
2174, 2138,
1695, 1519,
*CHCH2), 3.90–4.21 (m, 2 H, OCH2), 5.28–
5.61 (m, 1 H, *CH), 5.82 and 6.25 (2 × br d,
J = 8.1 and 8.3, 1 H, NHCO2Et), 6.81–7.75
61.2, 108.1 and 109.3,
111.4, 118.3, 119.5 and
119.6, 122.0 and 122.1,
230 (57), 202
(14), 184 (16),
158 (25), 157
(62), 156 (31),
130 (100), 103
(9), 77 (8), 43
(55)
1239, 1054, 741 (m, 6 H, Harom and NHCON3), 8.56 (br s, 1 H, 123.3, 127.1, 136.2,
b
NHarom
)
155.7, 156.0 (br)b
a Positively ionized molecule [M + Na]+ and fragments obtained with MS2 experiments are reported.
b Solvent: CDCl3.
c Solvent: DMSO-d6.
The ESI-MS spectra of carbamoyl azides 3 (Table 3) evi- sponding to the loss of isobutene, N2 and CO2 as indicated
denced only the sodium-cationized molecule [M + Na]+ in in Scheme 6.
the positive ion mode. With the exception of N-Boc deriv-
In summary, we have developed a simple, one-pot synthe-
atives 3b, 3f and 3i, the MS2 spectra of [M + Na]+ for 3
sis of carbamoyl azides starting from a-N-protected ami-
were characterized by the presence of an intense ion (base
no acids. These intermediates are suitable building blocks
peak), due to the loss of N2, and a less intense, abundant
for the synthesis of carbamates, asymmetric ureas and
peak (10–80% relative intensity) derived from the elimi-
peptidyl ureas because their reactivity may be compared
nation of N2 and the alcohol fragment present in the car-
to those of the corresponding isocyanates. Moreover, the
final reaction mixture obtained with our procedure can be
bamate moiety (Scheme 5).
In contrast, the MS2 spectra of [M + Na]+ for N-Boc deriv- used in further transformations without additional purifi-
atives 3b, 3f and 3i evidenced three fragment ions corre- cation.
+•
+•
O
N
N3
O
C
R
H
R
H
N
R
H
N
O
•
– HN3
H
OR1
– NHCON3
m/z = 85
N+
OR1
m/z = 43
N
OR1
O
O
– NH2CON3
m/z = 86
3
– R •
+•
O
N
N3
O
N3
R
+
+
OR1
N
O
N
O
N
H
OR1
or
H
OR1
N
O
H
H
Scheme 4
Na+
Na+
Na+
O
O
N3
C
O
N
N
C
R
H
N
R
N
– N2, – R1OH
M2
– N2
M2
R
H
OR1
H
O
N
N
OR1
N
H
C
O
O
3
Scheme 5
Synthesis 2008, No. 3, 438–444 © Thieme Stuttgart · New York

PAPER
Synthesis of Carbamoyl Azides of a-N-Protected Amino Acids
443
Na+
Na+
Na+
O
O
N
N3
O
N
N3
C
H
N
N
– Me2CCH2,
– N2, – CO2
R
H
N
O
R
H
N
O
– Me2CCH2
M2
R
H
O
H
M2
OH
NH2
3
M2
– Me2CCH2, – N2
Na+
O
C
N
R
N
H
N
OH
H
O
Scheme 6
Isocyanates of N-Boc-proline (5p) and N-Cbz-proline (5q);
General Procedure
Caution! Carbamoyl azides are sensitive to thermal and mechanical
shock in the solid state and should be handled with due care.
NMM (0.30 mL, 2.73 mmol) was slowly added into a stirred solu-
tion of a-N-protected proline 1p or 1q (2.50 mmol) in THF (15 mL).
After 5 min, the reaction mixture was cooled down to –10 °C and
isobutyl chloroformate (0.36 mL, 2.72 mmol) was added. Stirring
was continued for 20 min at –10 °C then the mixture was warmed
to 0 °C and KH2PO4 (1.03 g, 7.50 mmol) was added, followed by
the slow addition of a solution of NaN3 (0.25 g, 3.75 mmol) in H2O
(2 mL). The mixture was allowed to warm to r.t. and additionally
stirred for 1.5 h. The organic phase was separated and THF was re-
moved under reduced pressure; the residue was dissolved in EtOAc
(30 mL) and the solution was washed with H2O (10 mL), a potassi-
um phosphate buffer solution (pH ~7; KH2PO4/K2HPO4, 20 mL),
10% HCl (10 mL), sat. brine (15 mL), and finally dried over
Na2SO4. After filtration and evaporation of the solvent in vacuo, the
residue consisted of the isocyanate 5 in analytically pure form.
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 60 °C and 120 °C were
found suitable to vaporize all the compounds into the ion source.
The reactions were monitored by ESI-MS in the positive ion mode
with a Finnigan LXQ (linear trap). The intact reaction mixture was
diluted with MeCN and the obtained solution was directly infused
into the ion source with the aid of a syringe pump. IR spectra were
obtained with a Nicolet FT-IR Magna 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 room
temperature or DMSO-d6 at 40 °C as solvents. NMR peak locations
are reported as d values (ppm) 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 (Model
1106) elemental analyzer. Melting points were determined with an
automatic Mettler (Model FP61) melting point apparatus and are
not corrected. All N-protected amino acids 1 were prepared by re-
ported procedures.13 All solvents and reagents were purchased from
Aldrich Chemical Company and used without further purification.
1-tert-Butylcarbonyl-2-isocyanatopyrrolidine (5p)
Yield: 97%; oil; [a]D20 –62.3 (c 1.0, CHCl3).
IR (KBr): 2978, 2934, 2883, 2246, 2139, 1699, 1384, 1215, 1170,
757 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.45 [app d, J = 7.5 Hz, 9 H,
(CH3)3C], 1.80–2.37 (m, 4 H, CH2CH2), 3.31–3.61 (m, 2 H, N-
CH2), 4.08–4.32 (m, 1 H, *CH).
13C NMR (50 MHz, CDCl3): d = 23.5 and 24.2, 28.1 and 28.3, 29.8
and 30.8, 46.3 and 46.6, 60.5 and 60.8, 80.1 and 80.3, 153.4 and
154.2, 180.3 and 180.6.
Carbamoyl Azides 3; General Procedure
EI-MS: m/z (%) = 212 (1) [M+], 170 (19), 139 (23), 114 (65), 70
(89), 57 (100).
NMM (0.30 mL, 2.73 mmol) was slowly added into a stirred solu-
tion of a-N-protected amino acid 1 (2.50 mmol) in THF (15 mL).
After 5 min, the reaction mixture was cooled down to –10 °C and
isobutyl chloroformate (0.36 mL, 2.72 mmol) was added dropwise.
Stirring was continued for 20 min at –10 °C then the mixture was
warmed to 0 °C and KH2PO4 (2.05 g, 15.00 mmol) was added, fol-
lowed by the slow addition of a solution of NaN3 (0.49 g, 7.50
mmol) in H2O (3 mL). The mixture was allowed to warm to r.t. and
additionally stirred for 1.5 h (3 h in the case of a-N-Boc and a-N-
Cbz derivatives, as well as for valine 1a and phenylglycine 1h). The
organic phase was separated and THF was removed under reduced
pressure; the residue was dissolved in EtOAc (35 mL) and the solu-
tion was washed with H2O (15 mL), a potassium phosphate buffer
solution (pH ~7; KH2PO4/K2HPO4, 20 mL), 10% HCl (10 mL), sat.
brine (15 mL), and finally dried over Na2SO4. After filtration and
evaporation of the solvent in vacuo, the residue consisted of the car-
bamoyl azide 3 in analytically pure form (Table 2 and Table 3).
Anal. Calcd for C10H16N2O3: C, 56.59; H, 7.60; N, 13.20. Found: C,
56.51; H, 7.68; N, 13.12.
1-Benzyloxycarbonyl-2-isocyanatopyrrolidine (5q)
Yield: 94%; oil; [a]D20 –77.9 (c 1.0, CHCl3).
IR (KBr): 2979, 2958, 2884, 2246, 2142, 1709, 1414, 1354, 1173,
1122, 770, 699 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.81–2.36 (m, 4 H, CH2CH2),
3.40–3.73 (m, 2 H, N-CH2), 4.25–4.43 (m, 1 H, *CH), 5.01–5.28
(m, 2 H, OCH2), 7.23–7.50 (m, 5 H, Harom).
13C NMR (50 MHz, CDCl3): d = 23.4 and 24.2, 29.8 and 30.9, 46.5
and 46.9, 60.5 and 60.9, 67.1, 127.8, 128.3, 136.4, 153.2 and 154.1,
179.9 and 180.2.
Synthesis 2008, No. 3, 438–444 © Thieme Stuttgart · New York

444
G. Verardo et al.
PAPER
EI-MS: m/z (%) = 246 (1) [M+], 204 (6), 203 (10), 160 (8), 146 (8),
91 (100).
V. K.; Deshmukh, A. R. A. S. Tetrahedron Lett. 2004, 45,
6571.
(6) (a) Larson, H. O.; Ooi, T.-C.; Luke, W. K. H.; Ebisu, K. J.
Org. Chem. 1969, 34, 525. (b) Lenoir, D.; Glaser, R.;
Mison, P.; Rague Scheleyer, P. J. Org. Chem. 1971, 36,
1821.
Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C,
63.50; H, 5.66; N, 11.27.
(7) (a) Oliveri-Mandala, E.; Noto, F. Gazz. Chim. Ital. 1913, 43,
514. (b) Oliveri-Mandala, E. Gazz. Chim. Ital. 1914, 44,
662. (c) Brugman, F. W.; Arens, J. F. Recl. Trav. Chim.
Pays-Bas 1955, 74, 209. (d) Maffei, S.; Bettinetti, G. F.
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(k) Quast, H.; Bieber, L. Chem. Ber. 1981, 114, 216.
(l) Eisenbrand, G. AU Patent 531375, 1983; Chem. Abstr.
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Acknowledgment
Financial support was obtained from MIUR (FURD 2006-2007 to
GV). The authors are grateful to Dr. S. Turco for recording 1H and
13C NMR spectra, Dr. A. Callea for MS measurements and Mr P.
Padovani for expert instrumental maintenance.
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Synthesis 2008, No. 3, 438–444 © Thieme Stuttgart · New York