Propylphosphonic anhydride (T3P)-mediated one-pot rearrangement of carboxylic acids to carbamates

Article abstract of DOI:10.1055/s-0030-1259964

A simple one-pot conversion of carboxylic acids to carbamates is achieved by propylphosphonic anhydride (T3P) in combination with azidotrimethylsilane and an alcohol via the Curtius rearrangement. Besides diverse primary to tertiary alcohols, t

Full text of DOI:10.1055/s-0030-1259964

PAPER
1477
Propylphosphonic Anhydride (T3P®)-Mediated One-Pot Rearrangement of
Carboxylic Acids to Carbamates
One-Pot
R
o
earrangemen
h
t
of Carboxy
n
lic
A
cids toCarba
K
mates allikat Augustine,*a Agnes Bombrun,b Ashis Baran Mandal,a Padma Alagarsamy,a Rajendra Nath Atta,a
Panneer Selvama
a
Syngene International Ltd., Biocon Park, Plot Nos. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore – 560 099, India
Fax +91(80)28083150; E-mail: john.kallikat@syngeneintl.com
Merck Serono SA, 9 Chemin des Mines, 1202 Geneva, Switzerland
b
Received 5 February 2011; revised 23 February 2011
carbamates from carboxylic acids. Here, we report a gen-
Abstract: A simple one-pot conversion of carboxylic acids to car-
eral and one-pot procedure for the conversion of carboxy-
lic acids to carbamates in high yields using T3P®8 and
azidotrimethylsilane in the presence of an alcohol.
bamates is achieved by propylphosphonic anhydride (T3P®) in
combination with azidotrimethylsilane and an alcohol via the
Curtius rearrangement. Besides diverse primary to tertiary alcohols,
the reaction tolerated a wide scope of aromatic, heterocyclic, and
aliphatic carboxylic acids which underwent rearrangement in
excellent yields.
Our initial objective was to develop an efficient one-pot
procedure for the synthesis of carbamates from carboxylic
acids through the Curtius rearrangement by employing
T3P® under the reaction conditions reported for ureido-
peptides.7 Accordingly, the transformation of 4-bromo-
benzoic acid into tert-butyl 4-bromophenylcarbamate (1)
was evaluated (Table 1). A solution of 4-bromobenzoic
acid in tetrahydrofuran was treated with T3P® (1.1 equiv)
in the presence of sodium azide (1.1 equiv), triethylamine
(1.5 equiv), and tert-butyl alcohol (entry 1). The heteroge-
neous reaction mixture became a viscous mass after soni-
cation at 45 °C for one hour. As there was no reaction
(entry 1), the mixture was then refluxed for two hours un-
der conventional heating, however, as it then became too
gelatinous, dilution with tetrahydrofuran was necessary
for smooth stirring; no reaction was observed under these
conditions (entry 2). Interestingly, when a mixture of tet-
rahydrofuran–dimethyl sulfoxide (1:1) was used, carbam-
ate 1 was obtained in 17% yield (entry 3). However, there
was no significant reaction when dimethyl sulfoxide was
used as the sole solvent (entry 4). Further improvement
could be achieved by using a soluble source of azide
namely azidotrimethylsilane9 affording 1 in 82% yield in
tetrahydrofuran at room temperature (entry 5). Finally the
optimization of the temperature led to 1 in 98% yield in
tetrahydrofuran in a shorter period (entry 6). The solvent
proved influential, as low conversions were observed with
solvents other than N,N-dimethylformamide and tetrahy-
drofuran (entries 7–10).
Key words: propylphosphonic anhydride, Curtius rearrangement,
carbamates, peptide coupling agents, azidotrimethylsilane
The Curtius rearrangement,1,2 is a thermal decomposition
of acyl azides into amines via isocyanate intermediates,
which has been widely used for the transformation of car-
boxylic acids into isocyanates, carbamates, and ureas. A
number of methods describing it are multistep in nature
and have focused on a stepwise approach wherein the first
step of the synthesis involves the isolation of acyl azides
from carboxylic acid derivatives such as acyl chlorides,3
mixed anhydrides,4 and hydrazides.5 The isocyanates that
are subsequently formed by molecular rearrangement un-
der thermal conditions can be trapped by a variety of nu-
cleophiles to provide the amino derivatives. The acid
chloride method is incompatible with acid-sensitive func-
tionalities and has disadvantages such as the preparation
and storage of the acid chloride itself. Preparation of acid
azides via mixed anhydrides has been used to advantage,
but this method employs chloroformates which are incon-
venient to handle. One-pot transformations of carboxylic
acids into carbamates have become more accepted as they
avoid the isolation of unstable acyl azides. Several report-
ed protocols involve the use of diphenylphosphoryl azide
(DPPA)6 for the one-pot Curtius reaction. Conversely,
toxicity considerations limit its usage and the high boiling
point of DPPA creates additional difficulties during work-
up and purification.
In order to explore the scope of carboxylic acids tolerated
by this process, diverse carboxylic acids were subjected to
the Curtius rearrangement under the optimal reaction con-
ditions (Table 1, entry 6). The reaction proceeded well
with all substrates to give access to the corresponding tert-
butyl carbamates 1–13 in excellent yields (Table 2). Elec-
tron-withdrawing or electron-donating functionalities on
the substrate had no influence on the yield, but they did in-
fluence the rate of reaction. While electron-rich systems
took approximately one hour to go to completion, carbox-
ylic acids bearing electron-withdrawing groups required
two to three hours for optimum rearrangement. From
Table 2, we can conclude that besides various aromatic,
Peptide coupling agents are versatile reagents for the acti-
vation of carboxylic acids. Conversion of carboxylic acids
into acyl azides and ureidopeptides has recently been de-
scribed using propylphosphonic anhydride (T3P®) in the
presence of sodium azide under ultrasonication.7 Interest-
ingly, T3P® has not been exploited for the synthesis of
SYNTHESIS 2011, No. 9, pp 1477–1483
x
x
.
x
x
.2
0
1
1
Advanced online publication: 22.03.2011
DOI: 10.1055/s-0030-1259964; Art ID: Z17611SS
© Georg Thieme Verlag Stuttgart · New York

1478
J. K. Augustine et al.
PAPER
Table 1 Screening Optimal Conditions
Table 2 T3P®-Mediated Synthesis of tert-Butyl Carbamates
H
R
O
OH
T3P, TMSN3
t-BuOH, Et3N
N
Ot-Bu
H
N
T3P (1.1 equiv)
R
Ot-Bu
azide
OH
O
O
t-BuOH (1.2 equiv)
Et3N (1.5 equiv)
solvent
O
1–13
Br
Br
1
Entry
1
RCO2H
Product
Yielda (%)
98
Entry Azidea
Solvent
Time Tempb Yield
COOH
COOH
(h)
(°C)
45
70
70
90
25
70
70
90
90
90
(%) of 1
1
c,d
1
2
NaN3
THF
1
–
Br
d
NaN3
THF
2
–
2
3
2
3
95
97
3
NaN3
THF–DMSO (1:1)
DMSO
THF
4
17
28
82
98
68
97
86
65
MeO
4
NaN3
3
5
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
3
COOH
6
THF
0.5
3
7
MeNO2
DMF
F
COOH
4
5
4
5
96
96
8
0.5
3
9
toluene
DMSO
NC
O2N
COOH
10
0.5
a Amount used: 1.1 equiv.
b Heating bath temperature.
MeO
COOH
c Reaction was performed under ultrasonication.
d No reaction.
N
6
7
6
7
93
92
S
heteroaromatic, and aliphatic carboxylic acids, the reac-
tion tolerated a wide scope of functional groups and sub-
stituents, such as halo, methoxy, alkyl, nitro, cyano, and
trifluoromethyl, to provide the corresponding tert-butyl
carbamates in excellent yields. It is noteworthy that under
our new reaction conditions, the Curtius rearrangement of
a chiral enantioenriched a-substituted carboxylic acid
proceeded with retention of configuration to afford car-
bamate 12 in 94% yield with almost no loss of enantio-
meric excess (98% ee) during the process (Table 2, entry
12).10
N
S
N
COOH
Cl
Me
N
MeO
8
9
8
9
93
94
O
COOH
COOH
S
COOH
F
F
10
11
10
11
91
86
Next, we investigated the scope of various alcohols toler-
ated by the Curtius rearrangement mediated by T3P®.
Thus, 4-carboxybenzaldehyde was treated with various
alcohols (Table 3) under the standard reaction conditions.
As evident from Table 3, primary alcohols including ben-
zyl alcohol and allyl alcohol gave excellent yields of the
corresponding carbamates 14, 15, 19, 20, 22. This indi-
cates the versatility of this method in producing benzyl-
oxycarbonyl (Cbz) and Alloc-protected amines from
carboxylic acids. In addition, secondary alcohols, both cy-
clic and acyclic, gave the respective carbamates 16–18 in
high yields. Phenol, on the other hand, under these condi-
tions did not yield the desired product (entry 8), probably
due to its poor nucleophilicity. Symmetrical urea was the
sole product isolated from the reaction besides unreacted
phenol.
F
COOH
O
12
13
12
13
94b
85
COOH
COOH
a Reaction conditions: T3P® (1.1 equiv), TMSN3 (1.1 equiv), t-BuOH
(1.2 equiv), Et3N (1.5 equiv), THF, reflux.
b 98% ee.
by smooth orthogonal catalytic hydrogenation and its sta-
bility to basic and most aqueous acidic conditions. Conse-
quently, the one-pot synthesis of carbamates from
carboxylic acids was further surveyed by reacting various
Among the widely used protecting groups for amines, the
Cbz group is extensively used as it can be easily removed
Synthesis 2011, No. 9, 1477–1483 © Thieme Stuttgart · New York

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One-Pot Rearrangement of Carboxylic Acids to Carbamates
1479
Table 3 Scope of T3P®-Mediated Curtius Rearrangement: Synthe-
Table 4 T3P®-Mediated Synthesis of Benzyl Carbamates
sis of Diverse Carbamates from 4-Carboxybenzaldehyde
H
R
OH
T3P, TMSN3
BnOH, Et3N
N
OBn
H
COOH
R
N
O
T3P, TMSN3
ROH, Et3N
O
R
O
23–30
O
OHC
OHC
Product
14
14–22
Entry RCO2H
Product
Yielda (%)
95
Entry
1
ROH
Yielda (%)
95
COOH
COOH
1
23
24
Br
HO
HO
2
3
15
16
96
94
2
96
94
OH
OH
3
25
O
N
O
COOH
4
17
94
HN
COOH
HO
4
5
6
26
27
28
94
91
90
5
6
18
19
91
94
N
O
Cl
O
HO
SiMe3
S
COOH
Br
OH
COOH
HN
COOMe
7
20
88
O
O
7
8
29
30
84
90
COOH
HO
8
9
21
22
0
COOH
96
O
N
HO
a Reaction conditions: T3P® (1.1 equiv), TMSN3 (1.1 equiv), ROH
(1.2 equiv), Et3N (1.5 equiv), THF, reflux, 2–3 h.
O
a Reaction conditions: T3P® (1.1 equiv), TMSN3 (1.1 equiv), BnOH
(1.2 equiv), Et3N (1.5 equiv), THF, reflux, 1–3 h.
carboxylic acids with benzyl alcohol under the standard
reaction conditions (Table 4). As summarized in Table 4,
the reaction proceeded well with most of the substrates af-
fording subsequent Cbz-protected amines 23–30 in excel-
lent yields.
1H and 13C NMR spectra were recorded on 400 MHz and 100 MHz
Bruker spectrometer, respectively and elemental analysis was per-
formed on a Thermo Finnigan FLASH EA 1112 CHN analyzer.
Melting points were recorded (uncorrected) on Buchi Melting Point
B-545 instrument. IR spectra were recorded on a Thermo Scientific
Nicolet 6700 FT-IR spectrophotometer.
In summary, a practical and new method for the direct
conversion of carboxylic acids to carbamates has been de-
veloped. Besides diverse primary to tertiary alcohols, the
reaction tolerated a wide range of aromatic, heterocyclic
and aliphatic carboxylic acids which underwent rear-
rangement in excellent yields. As T3P® offers several ad-
vantages over traditional reagents in terms of higher
yields, low epimerization tendency, nontoxic nature, ease
of isolation of products due to water soluble byproducts,
and shorter reaction periods, this process should make it a
versatile transformation with potential large-scale appli-
cation.
Carbamates 1–30; General Procedure
The appropriate alcohol (0.012 mol) was added to a stirred soln of
carboxylic acid (0.01 mol), T3P® (0.011 mol), TMSN3 (0.011 mol),
and Et3N (0.015 mol) in THF (10 mL) at r.t. The resulting mixture
was stirred at reflux for 1–3 h under N2. When the reaction was
completed (TLC), the volatiles were removed under reduced pres-
sure and the residue was diluted with H2O (25 mL). The product
was extracted with EtOAc (2 × 20 mL) and the combined organic
phases were washed with sat. NaHCO3 soln (10 mL) and brine. The
organic phase was dried (Na2SO4) and evaporated under reduced
pressure. The resulting material was passed through a small plug of
silica (5% EtOAc–hexanes) to afford the desired carbamate in ex-
cellent yield.
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J. K. Augustine et al.
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tert-Butyl 4-Bromophenylcarbamate (1)11
White solid; yield: 98%; mp 101 °C.
tert-Butyl 2-(Pyridin-4-yl)thiazol-4-ylcarbamate (6)12
Off-white solid; yield: 93%; mp 192 °C.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.17 min; m/z = 174.0 [M + 2 –Boc]+.
tR = 3.65 min; m/z = 278.2 [M + H]+.
tert-Butyl 3,5-Dimethyl-4-methoxyphenylcarbamate (2)
White solid; yield: 95%; mp 142 °C.
tert-Butyl 5-Chloro-2-(methylsulfanyl)pyrimidin-4-ylcarbam-
ate (7)
White solid; yield: 92%; mp 77 °C.
IR (KBr): 3222, 1706, 1567, 1547, 1471, 1138 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.45 (s, 9 H), 2.48 (s, 3 H),
8.55 (s, 1 H), 9.80 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 13.9, 27.7, 80.8, 116.0, 150.3,
154.6, 156.8, 168.9.
IR (KBr): 3295, 1722, 1609, 1547, 1147, 995 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.44 (s, 9 H), 2.49 (s, 6 H),
3.56 (s, 3 H), 7.07 (s, 2 H), 9.08 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 15.9, 28.1, 59.3, 118.4, 130.0,
134.8, 151.4, 152.8.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.0 min; m/z = 196.2 [M – 55]+.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 3.86 min; m/z = 276.0 [M + H]+.
Anal. Calcd for C14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found: C,
66.97; H, 8.46; N, 5.52.
Anal. Calcd for C10H14ClN3O2S: C, 43.56; H, 5.12; N, 15.24.
Found: C, 43.62; H, 5.17; N, 15.20.
tert-Butyl 4-Methylnaphthalen-1-ylcarbamate (3)
White solid; yield: 97%; mp 84 °C.
tert-Butyl 5-Methoxybenzofuran-2-ylcarbamate (8)
White solid; yield: 93%; mp 117 °C.
IR (KBr): 3340, 1732, 1612, 1521, 1456, 775 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.47 (s, 9 H), 3.73 (s, 3 H),
6.30 (s, 1 H), 6.68–6.65 (dd, J = 8.8, 2.6 Hz, 1 H), 6.97 (d, J = 2.6
Hz, 1 H), 7.27 (d, J = 8.8 Hz, 1 H), 10.54 (br s, 1 H).
IR (KBr): 3269, 1686, 1531, 1504, 1238, 750 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.47 (s, 9 H), 2.60 (s, 3 H),
7.30 (d, J = 7.5 Hz, 1 H), 7.39 (d, J = 7.5 Hz, 1 H), 7.56–7.50 (m, 2
H), 8.03–7.97 (m, 2 H), 9.10 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.7, 28.1, 78.6, 121.3, 123.3,
124.2, 125.2, 125.7, 126.0, 128.4, 130.6, 132.3, 132.4, 154.1.
13C NMR (100 MHz, DMSO-d6): d = 27.9, 55.4, 80.3, 87.7, 102.9,
109.5, 110.3, 130.0, 144.0, 150.7, 151.3, 155.7.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.16 min; m/z = 202.2 [M – 55]+.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.08 min; m/z = 164.2 [M – 100]+.
Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C,
74.72; H, 7.47; N, 5.39.
Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C,
63.92; H, 6.54; N, 5.29.
tert-Butyl 4-Cyano-2-fluorophenylcarbamate (4)
White solid; yield: 96%; mp 110 °C.
tert-Butyl 5-Methylthiophen-2-ylcarbamate (9)13
White solid; yield: 94%; mp 103 °C.
IR (KBr): 3295, 1727, 1523, 1239, 1154, 684 cm–1.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
1H NMR (400 MHz, DMSO-d6): d = 1.46 (s, 9 H), 7.61 (d, J = 8.5
Hz, 1 H), 7.82–7.79 (dd, J = 10.9, 1.8 Hz, 1 H), 7.98 (t, J = 8.2 Hz,
1 H), 9.55 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.8, 80.4, 105.1 (d,
JCF = 10.0 Hz), 117.9 (d, JCF = 21.5 Hz), 119.3 (d, JCF = 21.5 Hz),
122.4 (d, JCF = 2.8 Hz), 129.2 (d, JCF = 2.8 Hz), 132.0 (d, JCF = 10.2
Hz), 151.5 (d, JCF = 231 Hz), 152.4.
tR = 3.75 min; m/z = 114.2 [M – 100]+.
tert-Butyl {2-[4-(Trifluoromethyl)phenyl]ethenyl}carbamate
(10)
White solid; yield: 91%; mp 127 °C.
IR (KBr): 3334, 1697, 1651, 1524, 1498, 1326, 1100, 944 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.44 (s, 9 H), 6.02 (d, J = 14.6
Hz, 1 H), 7.33–7.27 (dd, J = 14.2, 10.6 Hz, 1 H), 7.46 (d, J = 8.3 Hz,
2 H), 7.55 (d, J = 8.3 Hz, 2 H), 9.72 (d, J = 9.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.9, 79.7, 107.2, 123.1,
125.4 (m), 125.6, 125.8, 128.2 (d), 141.4, 152.8.
19F NMR (376.5 MHz, DMSO-d6): d = –122.8 (s, 1 F).
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 3.81 min; m/z = 237.2 [M + H]+.
Anal. Calcd for C12H13FN2O2: C, 61.01; H, 5.55; N, 11.86. Found:
C, 61.07; H, 5.58; N, 11.81.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.38 min; m/z = 188.2 [M – 100]+.
tert-Butyl 4-Methoxy-3-nitrophenylcarbamate (5)
White solid; yield: 96%; mp 159 °C.
IR (KBr): 3348, 1719, 1586, 1540, 1231, 1148 cm–1.
Anal. Calcd for C14H16F3NO2: C, 58.53; H, 5.61; N, 4.88. Found: C,
58.57; H, 5.65; N, 4.83.
1H NMR (400 MHz, DMSO-d6): d = 1.48 (s, 9 H), 3.86 (s, 3 H),
7.11–7.08 (dd, J = 9.0, 2.0 Hz, 1 H), 7.52 (d, J = 2.0 Hz, 1 H), 7.89
(d, J = 9.0 Hz, 1 H), 10.04 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 27.9, 56.1, 80.2, 101.8, 109.1,
127.0, 132.4, 146.1, 152.3, 154.2.
tert-Butyl Tetrahydro-2H-pyran-4-ylcarbamate (11)
White solid; yield: 86%; mp 93 °C.
IR (KBr): 3357, 1679, 1515, 1232, 1143 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.39–1.32 (m, 11 H), 1.65–
1.62 (m, 2 H), 3.30–3.24 (m, 2 H), 3.41–3.40 (m, 1 H), 3.80–3.76
(m, 2 H), 6.81 (d, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 28.2, 32.7, 46.3, 65.9, 77.4,
154.7.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 3.89 min; m/z = 269.2 [M + H]+.
Anal. Calcd for C12H16N2O5: C, 53.73; H, 6.01; N, 10.44. Found: C,
53.80; H, 6.06; N, 10.41.
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One-Pot Rearrangement of Carboxylic Acids to Carbamates
1481
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 3.76 min; product not ionized.
13C NMR (100 MHz, DMSO-d6): d = 28.0, 30.5, 70.4, 78.6, 117.6,
130.6, 130.8, 144.9, 152.5, 153.8, 191.3.
Anal. Calcd for C10H19NO3: C, 59.68; H, 9.52; N, 6.96. Found: C,
59.73; H, 9.57; N, 6.91.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.01 min; m/z = 347.2 [M – H]+.
Anal. Calcd for C18H24N2O5: C, 62.05; H, 6.94; N, 8.04. Found: C,
62.10; H, 6.99; N, 8.00.
tert-Butyl (1R)-1-Phenylethylcarbamate (12)14
White solid; yield: 94%; mp 72 °C.
[a]D +34.4 (c 0.1, MeOH).
2-(Trimethylsilyl)ethyl 4-Formylphenylcarbamate (19)
White solid; yield: 94%; mp 82 °C.
IR (KBr): 3311, 1730, 1662, 1579, 1528, 1208 cm–1.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 3.85 min; m/z = 122.2 [M – 100]+.
1H NMR (400 MHz, DMSO-d6): d = 0.04 (s, 9 H), 1.04–0.99 (m, 2
H), 4.22–4.18 (m, 2 H), 7.66 (d, J = 8.6 Hz, 2 H), 7.81 (d, J = 8.6
Hz, 2 H), 9.80 (s, 1 H), 10.08 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = –1.4, 17.2, 62.7, 117.6, 130.5,
130.9, 145.1, 153.4, 191.4.
tert-Butyl Pent-4-ynylcarbamate (13)15
Colorless liquid; yield: 85%.
IR (liquid film): 1695, 1509, 1247, 1166, 755 cm–1.
Benzyl (4-Formylphenyl)carbamate (14)16
White solid; yield: 95%; mp 187 °C.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.24 min; m/z = 264.2 [M – H]+.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 3.78 min; m/z = 256.2 [M + H]+.
Anal. Calcd for C13H19NO3Si: C, 58.84; H, 7.22; N, 5.28. Found: C,
58.87; H, 7.27; N, 5.23.
Prop-2-enyl 4-Formylphenylcarbamate (15)17
White solid; yield: 96%; mp 119 °C.
Methyl 2-[(tert-Butoxycarbonyl)amino]-3-{[(4-formylphe-
nyl)carbamoyl]oxy}propanoate (20)
White solid; yield: 88%; mp 114 °C.
IR (KBr): 3345, 1707, 1588, 1518, 1159 cm–1.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 3.27 min; m/z = 206.2 [M + H]+.
1H NMR (400 MHz, DMSO-d6): d = 1.37 (s, 9 H), 3.66 (s, 3 H),
4.26–4.21 (m, 1 H), 4.46–4.38 (m, 2 H), 7.40 (d, J = 7.7 Hz, 1 H),
7.67 (d, J = 8.2 Hz, 2 H), 7.83 (d, J = 8.4 Hz, 2 H), 9.84 (s, 1 H),
10.22 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 28.0, 52.1, 52.8, 63.3, 78.6,
117.8, 130.7, 130.8, 144.7, 152.8, 155.3, 170.2, 191.4.
Isopropyl 4-Formylphenylcarbamate (16)
White solid; yield: 94%; mp 110 °C.
IR (KBr): 3328, 1724, 1673, 1579, 1523, 1210 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.26–1.25 (d, 6 H), 4.94–4.88
(m, 1 H), 7.66 (d, J = 8.6 Hz, 2 H), 7.81 (d, J = 8.6 Hz, 2 H), 9.83
(s, 1 H), 10.09 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 21.8, 68.0, 117.6, 130.5,
130.8, 145.1, 152.8, 191.3.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 3.60 min; m/z = 267.2 [M – 100]+.
Anal. Calcd for C17H22N2O7: C, 55.73; H, 6.05; N, 7.65. Found: C,
55.80; H, 6.09; N, 7.62.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 3.40 min; m/z = 208.2 [M + H]+.
Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C,
63.82; H, 6.37; N, 6.71.
Prop-2-ynyl 4-Formylphenylcarbamate (22)
White solid; yield: 96%; mp 167 °C.
IR (KBr): 1728, 1670, 1597, 1533, 1215, 1057 cm–1.
Cyclohexyl 4-Formylphenylcarbamate (17)
1H NMR (400 MHz, DMSO-d6): d = 3.59 (s, 1 H), 4.80 (s, 2 H),
7.66 (d, J = 8.6 Hz, 2 H), 7.84 (d, J = 8.6 Hz, 2 H), 9.85 (s, 1 H),
10.37 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 52.3, 77.8, 78.5, 117.8, 130.9,
144.5, 152.4, 191.4.
White solid; yield: 94%; mp 123 °C.
IR (KBr): 3321, 1721, 1589, 1532, 1212 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.37–1.36 (m, 1 H), 1.45–1.39
(m, 4 H), 1.53–1.50 (m, 1 H), 1.72–1.69 (m, 2 H), 1.91–1.88 (m, 2
H), 4.68–4.62 (m, 1 H), 7.66 (d, J = 8.6 Hz, 2 H), 7.81 (d, J = 8.6
Hz, 2 H), 9.83 (s, 1 H), 10.10 (br s, 1 H).
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 2.96 min; m/z = 204.2 [M + H]+.
13C NMR (100 MHz, DMSO-d6): d = 23.4, 24.9, 31.5, 72.9, 117.6,
130.5, 130.9, 145.2, 152.8, 191.4.
Anal. Calcd for C11H9NO3: C, 65.02; H, 4.46; N, 6.89. Found: C,
65.07; H, 4.51; N, 6.82.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.03 min; m/z = 248.2 [M + H]+.
Benzyl 4-Bromophenylcarbamate (23)18
White solid; yield: 95%; mp 113 °C.
Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C,
68.06; H, 6.98; N, 5.61.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.23 min; product not ionized.
tert-Butyl 4-{[(4-Formylphenyl)carbamoyl]oxy}piperidine-1-
carboxylate (18)
White solid; yield: 91%; mp 162 °C.
IR (KBr): 1721, 1667, 1601, 1524, 1213, 1054 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.38 (s, 9 H), 1.54–1.48 (m, 2
H), 1.91–1.87 (m, 2 H), 3.71–3.67 (m, 2 H), 4.87–4.81 (m, 2 H),
5.73 (m, 1 H), 7.67 (d, J = 8.6 Hz, 2 H), 7.81 (d, J = 8.6 Hz, 2 H),
9.83 (s, 1 H), 10.16 (br s, 1 H).
Benzyl 4-Methylnaphthalen-1-ylcarbamate (24)
Semi-solid; yield: 96%.
IR (KBr): 1691, 1533, 1090, 750 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 2.61 (s, 3 H), 5.17 (s, 2 H),
7.58–7.32 (m, 9 H), 8.06–7.99 (m, 2 H), 9.56 (br s, 1 H).
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J. K. Augustine et al.
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13C NMR (100 MHz, DMSO-d6): d = 18.8, 65.7, 121.4, 123.2,
124.3, 125.5, 125.9, 126.1, 127.8, 128.4, 131.1, 131.9, 132.4, 136.8,
154.9.
13C NMR (100 MHz, DMSO-d6): d = 18.0, 34.5, 34.5, 65.1, 124.6,
125.5, 127.7, 128.0, 128.3, 137.1, 143.7, 156.0.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
LC-MS (0.1% TFA in H2O, 0.1% TFA–MeCN, 2.0 mL/min,
tR = 3.91 min; m/z = 268.2 [M + H]+.
Xbridge C8): tR = 5.13 min; m/z = 292.2 [M + H]+.
Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C,
76.43; H, 6.46; N, 5.20.
Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found: C,
78.39; H, 5.93; N, 4.78.
tert-Butyl 4-{[(Benzyloxy)carbonyl]amino}piperidine-1-car-
boxylate (30)20
White solid; yield: 90%; mp 88 °C.
Benzyl 4-{[(tert-Butoxycarbonyl)amino]methyl}phenylcarbam-
ate (25)19
White solid; yield: 94%; mp 107 °C.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.02 min; m/z = 235.2 [M – 100]+.
tR = 4.00 min; product not ionized.
Benzyl 4-Chloropyridin-2-ylcarbamate (26)
White solid; yield: 94%; mp 187 °C.
IR (KBr): 1718, 1572, 1529, 1409, 1210 cm–1.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
1H NMR (400 MHz, DMSO-d6): d = 5.18 (s, 2 H), 7.19–7.17 (dd,
J = 5.4, 1.7 Hz, 1 H), 7.43–7.31 (m, 5 H), 7.91 (d, J = 1.7 Hz, 1 H),
8.23 (d, J = 5.4 Hz, 1 H), 10.60 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 66.1, 111.6, 118.6, 127.9,
128.0, 128.4, 136.2, 143.9, 149.4, 153.3, 153.4.
References
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LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.18 min; m/z = 264.2 [M + H]+.
Anal. Calcd for C13H11ClN2O2: C, 59.44; H, 4.22; N, 10.66. Found:
C, 59.49; H, 4.26; N, 10.61.
(3) For selected examples, see: (a) Van Reijendam, J. W.;
Baardman, F. Synthesis 1973, 413. (b) Erhardt, P. W.
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E. Synthesis 1983, 38. (d) Govindan, C. K. Org. Process
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F.; Petty, C. B.; Jessup, P. J. J. Org. Chem. 1978, 43, 2164.
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2001, 1917. (b) Jean, L.; Baglin, I.; Rouden, J.; Maddaluno,
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(c) Koza, G.; Ozcan, S.; Sahin, E.; Balci, M. Tetrahedron
2009, 65, 5973.
Benzyl 5-Bromothiophen-2-ylcarbamate (27)
White solid; yield: 91%; mp 53 °C.
IR (KBr): 1688, 1564, 1495, 1240, 1056 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 5.16 (s, 2 H), 6.32 (d, J = 4.0
Hz, 1 H), 6.91 (d, J = 4.0 Hz, 1 H), 7.40–7.34 (m, 5 H), 11.0 (br s,
1 H).
13C NMR (100 MHz, DMSO-d6): d = 66.7, 101.2, 110.0, 127.5,
128.1, 128.2, 128.4, 136.0, 141.6, 153.2.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.15 min; m/z = 314.2 [M + 2]+.
Anal. Calcd for C12H10BrNO2S: C, 46.17; H, 3.23; N, 4.49. Found:
C, 46.24; H, 3.27; N, 4.43.
Benzyl [2-(4-tert-Butylphenyl)ethenyl]carbamate (28)
White solid; yield: 90%; mp 119 °C.
IR (KBr): 1691, 1657, 1501, 1221, 1055, 689 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.24 (s, 9 H), 5.12 (s, 2 H),
5.99 (d, J = 14.4 Hz, 1 H), 7.12–7.06 (dd, J = 14.4, 10.2 Hz, 1 H),
7.19 (d, J = 8.4 Hz, 2 H), 7.26 (d, J = 8.4 Hz, 2 H), 7.39–7.32 (m, 5
H), 9.83 (d, J = 10.2 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 31.0, 34.0, 66.0, 109.7, 124.4,
124.5, 125.3, 128.0, 128.4, 133.7, 136.4, 148.2, 153.7.
(6) For selected examples, see: (a) Shioiri, T.; Ninomiya, K.;
Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203.
(b) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974,
30, 2151. (c) Capson, T. L.; Poulter, C. D. Tetrahedron Lett.
1984, 25, 3515. (d) Ma, D.; Sun, H. J. Org. Chem. 2000, 65,
6009. (e) Migawa, M. T.; Swayze, E. E. Org. Lett. 2000, 2,
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(7) Narendra, B. N.; Lamani, R. S.; Sureshbabu, V. V.
Tetrahedron Lett. 2010, 51, 3002.
LC-MS (MeOH–0.1% HCO2H, 1.0 mL/min, Atlantis dC18):
tR = 4.63 min; m/z = 310.2 [M + H]+.
Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C,
77.71; H, 7.53; N, 4.49.
(8) For other applications of T3P®, see: (a) Wissmann, H.;
Kleiner, H.-J. Angew. Chem., Int. Ed. Engl. 1980, 19, 133.
(b) Escher, R.; Bünning, P. Angew. Chem., Int. Ed. Engl.
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Montforts, F.-P. Eur. J. Org. Chem. 2001, 1681.
Benzyl (1-Phenylcyclopropyl)carbamate (29)
White solid; yield: 84%; mp 103 °C.
IR (KBr): 1701, 1399, 1337, 1087, 693 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.14 (br s, 4 H), 4.99 (s, 2 H),
7.30–12 (m, 5 H), 7.36–7.32 (m, 4 H), 8.14 (br s, 1 H).
(f) Hermann, S. DE10063493, 2002; Chem. Abstr. 2002,
137, 47003. (g) Meudt, A.; Scherer, S.; Nerdinger, S.
Synthesis 2011, No. 9, 1477–1483 © Thieme Stuttgart · New York

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One-Pot Rearrangement of Carboxylic Acids to Carbamates
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(10) The enantiomeric excess was determined by SFC
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Synthesis 2011, No. 9, 1477–1483 © Thieme Stuttgart · New York