1-propanephosphonic acid cyclic anhydride (T3P) as an efficient promoter for the Lossen rearrangement: Application to the synthesis of urea and carbamate derivatives

Article abstract of DOI:10.1055/s-0030-1258158

The synthesis of hydroxamic acids starting from carboxylic acids employing 1-propanephosphonic acid cyclic anhydride (T3P) activation is described. Application of ultrasonication accelerates this conversion. Further, the T3P has also been employed to activate the hydroxamates, leading to isocyanates via the Lossen rearrangement. The isocyanates were trapped with suitable nucleophiles to afford the corresponding ureas and carbamates. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258158

2990
PAPER
1-Propanephosphonic Acid Cyclic Anhydride (T3P) as an Efficient Promoter
for the Lossen Rearrangement: Application to the Synthesis of Urea and
Carbamate Derivatives
T
3P as anEfficie
a
nt Promote
s
r
for the
L
a
ossen Rear
v
rangement alingappa Vasantha, Hosahalli P. Hemantha, Vommina V. Sureshbabu*
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi,
Bangalore University, Bangalore 560 001, India
E-mail: hariccb@hotmail.com; E-mail: sureshbabuvommina@rediffmail.com; E-mail: hariccb@gmail.com
Received 30 March 2010; revised 30 April 2010
N¢-(3-dimethylaminopropyl)carbodiimide16 have been
Abstract: The synthesis of hydroxamic acids starting from carbox-
utilized to bring about this transformation. Recently, we
ylic acids employing 1-propanephosphonic acid cyclic anhydride
(T3P) activation is described. Application of ultrasonication accel-
erates this conversion. Further, the T3P has also been employed to
reported a facile LR of Na-urethane-protected amino acid
hydroxamates into isocyanates employing N-ethyl-N¢-(3-
activate the hydroxamates, leading to isocyanates via the Lossen re- dimethylaminopropyl)carbodiimide hydrochloride.17 The
arrangement. The isocyanates were trapped with suitable nucleo-
LR of preactivated hydroxamic acids is also known.18a
A
philes to afford the corresponding ureas and carbamates.
common drawback posed by several methods, however, is
the accumulation of isocyanate before the complete acti-
vation of hydroxamic acid leading to self-condensed
byproduct.18b Such complexities of existing protocols
warrant a facile activation of hydroxamic acids leading to
Key words: T3P, hydroxamic acids, Lossen rearrangement, isocy-
anates
Functional group transformation has acquired a signifi- isocyanates.
cant place in organic chemistry. Among a plethora of in-
1-Propanephosphonic acid cyclic anhydride (T3P) is one
termediates described, isocyanates1 have been one of the
outstanding discoveries due to their vast application in
synthetic as well as biological studies.2,3 Consequently,
there has been significant interest in the development of
new and simpler protocols for the preparation of isocyan-
ates.
of the economic and efficient coupling agents and is also
a water scavenger. Advantages such as high-yielding re-
actions, broad functional group tolerance, low epimeriza-
tion and easy workup procedures make the reagent
meritorious over several contemporaries. The byproducts
are water soluble and eliminate the need for chromato-
Classical Curtius rearrangement of acyl azides is a well- graphic purification. Applications of T3P in the synthesis
known reaction for the synthesis of isocyanates.4 Activat- of peptides,19 Weinreb amides and nitriles are well docu-
ed carboxylic acids in the form of acid chlorides or mixed mented.20–24 We reasoned that T3P, being a carboxy acti-
anhydrides are subjected to azidolysis or the carboxylic vator, can be employed for the preparation of
acids are directly converted into acyl azides employing hydroxamates from the corresponding acids and, being a
azide-transfer reagents and then the acyl azides are rear- dehydrating agent, could be a suitable promoter for the LR
ranged under thermal conditions.5–9 Although decent via O-activation. To the best of our knowledge, except for
yields are obtained, multistep sequences, the cost of some a couple of examples of the LR of benzoic acid hydroxam-
of the reagents and the potentially explosive nature of acid ates to Boc/Z-protected anilines,25 a meticulous study on
azides limit this method mainly to bench-scale prepara- the T3P-mediated LR for the conversion of hydroxamates
tions. Isocyanates can also be accessed via the Hofmann into isocyanates is yet to be reported. We herein describe
rearrangement, which involves oxidant-mediated conver- the T3P-promoted LR of hydroxamates derived from aro-
sion of an amide into isocyanate.10 This protocol requires matic acids, as well as Na-protected amino acids, into iso-
a large excess of base and hence is not compatible with cyanates and conversion of the latter into urea, carbamate
amino acid chemistry considering the epimerization prob- and thiocarbamate derivatives (Scheme 1).
lems.
Hydroxamic acids are valuable compounds for their phar-
The Lossen rearrangement (LR), which describes the macokinetic merits as well as their synthetic utility.26,27
transformation of activated hydroxamic acids into isocy- Reaction of hydroxylamine with activated carboxylic acid
anates, is a valid alternative for an easy access to isocyan- derivatives (such as acid chlorides, mixed anhydrides, ox-
ates.4 Reagents such as p-toluenesulfonyl chloride,11 azolidinones, esters)28,29 is employed for their preparation.
cyanuric chloride,12 1,1¢-carbonyldiimidazole,13 acylating They have also been obtained starting from aldehydes by
agents,14 N,N¢-dicyclohexylcarbodiimide15 and N-benzyl- employing the Angeli–Riminis reaction on a solid sup-
port.30a Hypervalent iodine(III) mediated oxidation of al-
doximes has also been demonstrated.30b T3P is a superior,
traceless and environmentally benign promoter for N-acy-
lation. Appendino’s group reported a 12-hour reaction
SYNTHESIS 2010, No. 17, pp 2990–2996
Advanced online publication: 07.07.2010
DOI: 10.1055/s-0030-1258158; Art ID: P05010SS
x
x.
x
x
.
2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

PAPER
T3P as an Efficient Promoter for the Lossen Rearrangement
2991
O
O
H
T3P, NMM
T3P, NMM
N
X
R1
R2
R1
OH
NH2OH
MeCN
R1
NHOH
R2XH, reflux
X = NH, O, S
O
1
2
3
R1 =
S
O
O2N
Br
Scheme 1 Synthesis of hydroxamates and urea/carbamate derivatives
Table 1 Hydroxamates 2 and Urea/Carbamate Derivatives 3
Entry R1CONHOH 2,
HRMS [M + Na]+ Mp
R1NHCOXR2 3,
HRMS [M + Na]+ Mp
Yield (%)
obsd (calcd)
(°C)
Yield (%)
obsd (calcd)
(°C)
O
N
H
N
H
Cl
283.0619
(283.0614)
272.1091
NHOH
gum38a
gum
3a, 85
174.0535
(174.0531)
1
waxy solid30a
O
(272.1085)
O
2a, 88
N
H
S
3b, 75
O2N
O
N
H
N
O2N
H
294.0849
(294.0855)
233.07a
187–188
(188)38a
92–93
205.01a
(205.02)
3c, 86
NHOH
2
135–137
(233.05)
(93)38a
O2N
O
O
2b, 86
N
H
O
3d, 75
O
NHOH
NHOH
165.9944
(165.9939)
122–123
318.9511
(318.9517)
244
3
4
(122–123)30a
(245)38a
S
N
N
S
H
H
O
O
Br
2c, 85
3e, 89
O
128.0341b
(128.0348)
219.0751
(219.0746)
N
H
N
120–121
176
188
O
O
O
2d, 89
3f, 91
O
160.0368
(160.0374)
125–127
250.09a
(250.08)
NHOH
5
6
N
H
O
(126–127)30a
O
2e, 85
3g, 84
Br
Br
O
237.9486
(237.9480)
184–185
327.9941
(327.9949)
NHOH
167
(184–185)30b
N
O
H
O
2f, 83
3h, 79
a ESI-MS.
b [M + H]+.
Synthesis 2010, No. 17, 2990–2996 © Thieme Stuttgart · New York

2992
B. Vasantha et al.
PAPER
protocol for the T3P-mediated synthesis of hydroxamic rides;36 however, due to the instability of the acid chlo-
acids at room temperature.31 With our previous experi- rides, the protocol could not be extended to N-Boc or Z-
ence and published work on ultrasound-accelerated reac- protected amino acids. To develop a common and mild
tions,32 we reasoned that ultrasonic waves may hasten this protocol for the synthesis of hydroxamates compatible
process and render the formation of hydroxamic acids with all three of the common urethane-protected amino
from the corresponding carboxylic acids in a shorter dura- acids (Fmoc, Boc, Z), we began our study with a Na-Boc-
tion of time. Practically, this was the case and we could re- protected amino acid. Thus, a solution of Na-Boc-Phe-OH
duce the reaction time from 12 hours to 60 minutes under in acetonitrile in the presence of NMM was treated with
ultrasonication. Initially, a solution of p-nitrobenzoic acid T3P at 0 °C for 15 minutes. After the addition of hydrox-
and an equimolar quantity of T3P in acetonitrile in the ylamine, the mixture was subjected to ultrasonication.
presence of N-methylmorpholine (NMM) was stirred at Satisfactorily, the reaction proceeded smoothly and was
0 °C to facilitate activation. After 15 minutes, hydroxyl- complete in about 90 minutes, to yield Na-Boc-Phe-
amine was added and the reaction was run under ultra- NHOH (4h) in 89% yield. Similarly, Fmoc- and Z-pro-
sonication for another 30 minutes to allow for the tected a-amino acids were also converted into their corre-
completion of the reaction (Scheme 1). A simple workup sponding hydroxamates 4 (Table 2).
led to the isolation of N-hydroxy-4-nitrobenzamide (2b)
in good yield (86%); a single recrystallization from tet-
rahydrofuran–hexane gave analytically pure sample as a
crystalline solid (Table 1, entry 2). Five more hydroxamic
In the next stage, the LR of the hydroxamates, mediated
by T3P, was carried out. A chilled solution of hydroxam-
ate 2b and T3P in tetrahydrofuran in the presence of
NMM was stirred for about 30 minutes. After the comple-
acids, 2a, 2c–f, were also made in a similar way, starting
tion of O-activation of the hydroxamate (TLC analysis),
from phenylacetic acid, 2-thiophenic acid, 2-furoic acid,
the mixture was refluxed for 1.5 hours. The IR spectrum
benzoic acid and p-bromobenzoic acid (Table 1, entries 1,
of the reaction mixture showed a strong peak at 2240 cm–1,
corresponding to the isocyanate. The O-activation of hy-
3–6).
Further, the protocol was extended to the preparation of a droxamic acids takes a longer time than that required for
series of Na-protected amino acid hydroxamates 4 carboxy activation during the preparation of hydroxam-
(Table 2). Several procedures have been reported33 for ates, and an excess of T3P is required to drive the reaction
such compounds, including a one-pot preparation em- towards completion. After confirming the formation of
ploying cyanuric chloride in the presence of 4-(dimethyl- isocyanates, our next objective was to trap them with nu-
amino)pyridine.34 Mordini and co-workers demonstrated cleophiles such as amines, alcohols and thiols. Towards
the microwave-assisted transformation of N-protected this end, typically, after stirring a solution of hydroxamate
amino acid esters into the corresponding hydroxamic 2b along with T3P and NMM in tetrahydrofuran at 0 °C
acids.35 Previously, we have reported the magnesium ox- for 30 minutes, the reaction mixture was refluxed in the
ide mediated synthesis of Na-Fmoc-protected amino acid presence of a nucleophile such as p-methylaniline. After
hydroxamates employing the corresponding acid chlo- completion of the reaction (3 h), a simple workup led to
Table 2 N-Urethane-Protected Amino Acid Hydroxamates 4
Hydroxamate 4
PG-Xaa-NHOH
PG
Reaction time (min)
Yield (%)
Mp (°C)
Xaa
Ala
4a
4b
4c
4d
4e
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
90
80
97
93
95
93
84
128
(128)36
Phe
151–152
(150–152)34
Glu(Ot-Bu)
Ser(OBn)
Phg
85
132–133
(131–133)17
110
80
163–164
(164)36
132–133
(132)36
4f
Z
Z
Ala
Phg
90
90
91
92
oil
4g
160
(159–161)17
4h
4i
Boc
Boc
Phe
90
89
79
oil
Glu(OBn)
110
81–82
(82–83)34
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PAPER
T3P as an Efficient Promoter for the Lossen Rearrangement
2993
the isolation of urea 3c in 86% yield (Table 1, entry 2).
The generality of this reaction was confirmed by the syn-
thesis of ureas 3a, 3e, 3f, carbamates 3d, 3g, 3h, and thio-
carbamate 3b (see Scheme 1 and Table 1).
Table 3 Ureidopeptides 5 and Active Carbamates 6
Urea 5/Carbamate 6
Yield (%)
Mp (°C)
O
180
Finally, the utility of this protocol for the preparation of
peptidomimetics was studied. To a chilled solution of Na-
Boc-Phe-NHOH (4h) in tetrahydrofuran, T3P and NMM
were added, and the mixture was stirred for 30 minutes.
Then, after adding H2N-Val-OMe (obtained by deproto-
nation of the corresponding hydrochloride salt using Zn
dust37), the mixture was refluxed for two hours to obtain
the ureidopeptide, albeit in low yield. The not-so-encour-
aging result obtained using the thermal method led us to
test the feasibility of this transformation under ultrasoni-
cation. To our delight, when the reaction mixture, after the
O-activation step, was subjected to ultrasonication, the ac-
tivated hydroxamic acid underwent the LR and the isocy-
anate formed in situ reacted with the amine to afford urea
5c in a shorter duration (an hour) in good yield (85%)
(Scheme 2 and Table 3). A few Boc- and Z-protected a-
amino acid hydroxamates were subjected to the LR and
the corresponding ureas 5c–e were isolated as analytically
pure products (Table 3). Fmoc-Protected ureidopeptides
precipitated as solids from the reaction mixture and a sin-
gle recrystallization step led to crystalline products (5a
and 5b). The protocol was further extended to the prepa-
ration of a few active carbamates 6a–c derived from Na-
protected amino acids by trapping the intermediate isocy-
anates with substituted phenols (Scheme 2 and Table 3).
All products were isolated and characterized by NMR and
mass spectroscopy.
96
(181)38a
FmocNH
N
H
N
COOMe
H
5a
t-BuOOC
Ph
O
2
140–141
(140)5a
84
85
FmocNH
N
N
COOMe
H
H
5b
Ph
O
138–139
BocHN
N
N
H
COOMe
H
5c
BnOOC
O
79
89
139
2
BocHN
N
N
COOMe
H
H
5d
O
142–143
(142–144)38a
ZHN
N
N
COOMe
H
H
5e
Cl
Cl
Ph
O
91
142
FmocHN
N
O
H
R1
Cl
F
NHOH
PgNH
6a
O
4
F
F
F
BnOOC
BocHN
R1
O
R2
a) T3P, NMM
O
117–118
(117)38c
2
85
89
0 °C
b)
N
O
PgNH
PgNH
N
N
COOMe
H
H
H
F
5
R1
6b
R1
O
NO2
PgNH
N
C
O
X
O
N
O
170–171
(171)38b
H
FmocHN
N
O
6
H
6c
Scheme 2 Synthesis of ureidopeptides 5 and carbamates 6 by the
LR of hydroxamates 4
suggests that Na-Fmoc-Phg-NHOH (4e) is epimerically
pure, and thus also the urea derivatives prepared from it
via the LR to the extent detectable by NMR analysis.
The protocol was revisited to check whether the method-
ology demonstrated here is free from racemization. A set
of epimeric ureidopeptides, Na-Fmoc-PhgU-L-Ala-OMe
(5f) and Na-Fmoc-PhgU-D-Ala-OMe (5g), were prepared
starting from racemization-prone Na-Fmoc-Phg-OH and
In summary, a facile conversion of aromatic acids, as well
as N-protected amino acids, into hydroxamates under ul-
trasonication using T3P as carboxy activator is described.
Further, the T3P was employed to mediate the Lossen re-
arrangement of these hydroxamates. The generated isocy-
anates were utilized to synthesize urea, carbamate and
thiocarbamate derivatives.
1
their H NMR spectra were examined for the methyl
group resonance of the alanyl residue. Distinct doublets
were observed at d = 1.28 and 1.30 ppm for 5f and at d =
1.29 and 1.32 ppm for 5g. This clearly indicates the pres-
ence of a single diastereomer in each sample. This, in turn,
Synthesis 2010, No. 17, 2990–2996 © Thieme Stuttgart · New York

2994
B. Vasantha et al.
PAPER
All solvents were distilled prior to use and reagents were used as re-
ceived from Sigma-Aldrich. Melting points were determined on a
Buchi model 150 melting point apparatus in open capillaries and are
uncorrected. IR spectra were recorded on a Nicolet Impact model
400D FT-IR spectrometer (KBr pellets, 3 cm–1 resolution). 1H and
13C NMR spectra were recorded on a Bruker AMX 300-MHz spec-
trometer. High-resolution mass spectra were recorded on a Micro-
mass Q-TOF mass spectrometer.
1H NMR (300 MHz, DMSO-d6): d = 1.28–1.46 (m, 6 H), 1.52–1.68
(m, 4 H), 4.36 (d, J = 6.2 Hz, 2 H), 5.98 (br, 1 H), 7.12–7.22 (m, 5
H).
13C NMR (75 MHz, DMSO-d6): d = 22.5, 31.1, 34.6, 46.7, 47.9,
125.6, 126.7, 127.5, 139.9, 166.7.
HRMS: m/z [M + Na]+ calcd for C14H19NOS: 272.1085; found:
272.1091.
Anal. Calcd for C14H19NOS: C, 67.43; H, 7.68; N, 5.62. Found: C,
67.48; H, 7.71; N, 5.68.
Hydroxamic Acids 2; General Procedure
To a chilled (0 °C) soln of an aromatic acid or a N-protected amino
acid (1 mmol) and NMM (0.12 mL, 1.1 mmol) in MeCN (10 mL)
was added 50% T3P in EtOAc (0.71 mL, 1.2 mmol). The reaction
mixture was stirred at the same temperature for 15 min and then
subjected to ultrasonication after the addition of NH2OH (83 mg,
1.2 mmol; obtained by neutralization of the corresponding hydro-
chloride salt with NMM) until the reaction was completed. The
mixture was diluted with EtOAc (15 mL), and washed with H2O and
brine. The organic phase was dried (anhyd Na2SO4), the solvent was
evaporated under reduced pressure, and the residue was recrystal-
lized (THF–hexane).
N-(Furan-2-yl)morpholine-4-carboxamide (3f)
Yield: 178 mg (91%); white solid; mp 176 °C; Rf = 0.45 (n-hexane–
EtOAc, 7:3).
IR (KBr): 1655 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 3.52 (t, J = 7.2 Hz, 4 H), 3.72
(t, J = 7.6 Hz, 4 H), 6.85 (m, 1 H), 7.21 (d, J = 6.9 Hz, 1 H), 7.43 (d,
J = 7.0 Hz, 1 H), 8.61 (br, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 45.2, 66.7, 112.3, 116.8, 143.1,
145.9, 155.8.
HRMS: m/z [M + Na]+ calcd for C9H12N2O3: 219.0746; found:
219.0751.
N-Hydroxy-4-nitrobenzamide (2b)
Yield: 157 mg (86%); white solid; mp 135–137 °C; Rf = 0.35
(CHCl3–MeOH, 9:1).
IR (KBr): 1642 cm–1.
Anal. Calcd for C9H12N2O3: C, 55.09; H, 6.16; N, 14.28. Found: C,
55.12; H, 6.13; N, 14.35.
1H NMR (300 MHz, DMSO-d6): d = 7.72 (d, J = 5.4 Hz, 2 H), 7.91
(d, J = 5.4 Hz, 2 H), 8.57 (s, 1 H), 10.58 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 122.8, 128.1, 139.8, 146.8,
166.8.
Benzyl Phenylcarbamate (3g)
Yield: 191 mg (84%); white solid; mp 188 °C; Rf = 0.50 (n-hexane–
EtOAc, 7:3).
IR (KBr): 1738 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 5.11 (s, 2 H), 6.91 (br, 1 H),
7.21–7.65 (m, 10 H).
13C NMR (75 MHz, DMSO-d6): d = 66.4, 126.8, 127.1, 127.5,
129.1, 132.6, 133.4, 138.2, 143.1, 155.1.
ESI-MS: m/z [M + Na]+ calcd for C7H6N2O4: 205.02; found: 205.01.
Anal. Calcd for C7H6N2O4: C, 46.16; H, 3.32; N, 15.38. Found: C,
46.20; H, 3.28; N, 15.47.
N-Hydroxyfuran-2-carboxamide (2d)
ESI-MS: m/z [M + Na]+ calcd for C14H13NO2: 250.08; found:
250.09.
Yield: 113 mg (89%); white solid; mp 120–121 °C (Lit.28c 119–
122 °C); Rf = 0.40 (CHCl3–MeOH, 9:1).
IR (KBr): 1641 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 6.80 (m, 1 H), 7.21 (d, J = 6.0
Hz, 1 H), 7.23 (d, J = 6.0 Hz, 1 H), 8.89 (s, 1 H), 10.89 (br, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 118.0, 121.5, 146.3, 148.8,
172.9.
Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C,
73.93; H, 5.81; N, 6.20.
Benzyl 4-Bromophenylcarbamate (3h)
Yield: 242 mg (79%); pale yellow solid; mp 167 °C; Rf = 0.45 (n-
hexane–EtOAc, 7:3).
IR (KBr): 1742 cm–1.
HRMS: m/z [M + H]+ calcd for C5H5NO3: 128.0348; found:
128.0341.
1H NMR (300 MHz, DMSO-d6): d = 5.12 (s, 2 H), 6.31 (br, 1 H),
7.23–7.37 (m, 5 H), 7.53 (d, J = 8.2 Hz, 2 H), 7.78 (d, J = 8.4 Hz, 2
Anal. Calcd for C5H5NO3: C, 47.25; H, 3.97; N, 11.02. Found: C,
47.32; H, 3.97; N, 11.09.
H).
13C NMR (75 MHz, DMSO-d6): d = 65.6, 121.3, 122.9, 127.2,
127.8, 128.9, 132.4, 134.9, 141.5, 155.9.
Organic Ureas/Carbamates 3; General Procedure
To a soln of a hydroxamic acid 2 (1.0 mmol) in THF (10 mL) at
0 °C, NMM (0.16 mL, 1.5 mmol) and T3P (0.89 mL, 1.5 mmol)
were added and the mixture was stirred for 30 min. Then, the nu-
cleophile (amine or alcohol, 1.5 mmol) was added and the mixture
was refluxed for 3 h. The solvent was removed under reduced pres-
sure, the residue was diluted with EtOAc (15 mL), and the organic
layer was washed with 10% HCl (10 mL), H2O (10 mL) and brine,
then dried (anhyd Na2SO4). The solvent was evaporated under re-
duced pressure to afford the product.
HRMS: m/z [M + Na]+ calcd for C14H12BrNO2: 327.9949; found:
327.9941.
Anal. Calcd for C14H12BrNO2: C, 54.92; H, 3.95; N, 4.58. Found: C,
54.96; H, 3.88; N, 4.58.
Ureidopeptides 5/Active Carbamates 6; General Procedure
To a soln of a N-protected amino acid hydroxamate 4 (1.0 mmol) in
THF (10 mL) at 0 °C, NMM (0.16 mL, 1.5 mmol) and T3P (0.89
mL, 1.5 mmol) were added and the reaction mixture was stirred at
0 °C for 30 min. Then, H2N-Xaa-OMe or a substituted phenol (1.2
mmol) was added and the reaction mixture was subjected to ultra-
sonication until completion (90 min, TLC analysis). Urea products
which precipitated out from the reaction mixture were collected by
filtration and recrystallized (DMSO–H2O). Otherwise, the urea or
S-Cyclohexyl Benzylthiocarbamate (3b)
Yield: 187 mg (75%); gum; Rf = 0.50 (n-hexane–EtOAc, 7:3).
IR (KBr): 1655 cm–1.
Synthesis 2010, No. 17, 2990–2996 © Thieme Stuttgart · New York

PAPER
T3P as an Efficient Promoter for the Lossen Rearrangement
2995
carbamate products were isolated via the same simple workup as
and Inorganic and Physical Chemistry, and NMR Center at the IISc,
described in the general procedure for ureas/carbamates 3.
Bangalore for NMR and mass data.
Methyl (S)-2-{[(S)-1-(tert-Butoxycarbonylamino)-2-phenyleth-
yl]ureido}-3-methylbutanoate (Boc-Phe-y[NHCO]-Val-OMe,
5c)
Yield: 334 mg (85%); white solid; mp 138–139 °C; Rf = 0.50
(CHCl3–MeOH, 9:1).
References
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IR (KBr): 1644, 1690, 1726 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.93 (d, J = 5.8 Hz, 6 H), 1.35
(s, 9 H), 1.8 (m, 1 H), 2.85 (d, J = 7.2 Hz, 2 H), 3.63 (s, 3 H), 3.83–
3.93 (m, 2 H), 5.2 (br, 1 H), 6.35 (br, 1 H), 6.45 (d, J = 7.0 Hz, 1 H),
7.15–7.30 (m, 5 H).
13C NMR (75 MHz, DMSO-d6): d = 18.7, 19.5, 29.5, 37.1, 54.7,
57.5, 63.1, 78.2, 126.9, 127.6, 129.1, 137.9, 155.3, 156.9, 174.5.
HRMS: m/z [M + Na]+ calcd for C20H31N3O5: 416.2161; found:
461.2169.
Anal. Calcd for C20H31N3O5: C, 61.05; H, 7.94; N, 10.68. Found: C,
61.09; H, 7.98; N, 10.75.
Methyl (S)-2-{[(S)-4-Benzyloxy-1-(tert-butoxycarbonylamino)-
4-oxobutyl]ureido}-4-methylpentanoate {Boc-Glu(OBn)-
y[NHCO]-Leu-OMe, 5d}
Yield: 379 mg (79%); white solid; mp 139 °C; Rf = 0.4 (CHCl3–
MeOH, 9:1).
IR (KBr): 1656, 1702, 1742 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 0.91 (d, J = 4.8 Hz, 6 H), 1.32
(s, 9 H), 1.42 (m, 2 H), 1.65 (m, 1 H), 2.55 (m, 2 H), 2.92 (m, 2 H),
3.65 (s, 3 H), 3.81–3.92 (m, 2 H), 5.15 (s, 2 H), 5.33 (d, J = 4.7 Hz,
1 H), 6.35 (d, J = 6.4 Hz, 1 H), 6.54 (d, J = 5.8 Hz, 1 H), 7.3–7.4
(m, 5 H).
13C NMR (75 MHz, DMSO-d6): d = 22.1, 23.1, 24.7, 28.6, 37.9,
39.7, 41.9, 50.9, 61.9, 63.1, 78.7, 126.7, 127.6, 128.9, 137.7, 155.3,
156.8, 157.5, 178.1.
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HRMS: m/z [M + Na]+ calcd for C24H37N3O7: 502.2529; found:
502.2531.
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Anal. Calcd for C24H37N3O7: C, 60.11; H, 7.78; N, 8.76. Found: C,
60.18; H, 7.73; N, 8.74.
2,4,5-Trichlorophenyl 1-[(9H-Fluoren-9-ylmethoxy)carbonyl-
amino]-2-phenylethylcarbamate (Fmoc-Phe-y[NHCO]-OTcp,
6a)
Yield: 529 mg (91%); white solid; mp 142 °C; Rf = 0.35 (n-hexane–
EtOAc, 7:3).
IR (KBr): 1695, 1742 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.85 (d, J = 6.2 Hz, 2 H), 3.81
(m, 1 H), 4.11 (t, J = 4.6 Hz, 1 H), 4.25 (d, J = 7.0 Hz, 2 H), 6.58
(br, 2 H), 7.23–8.15 (m, 15 H).
13C NMR (75 MHz, DMSO-d6): d = 38.9, 47.6, 52.5, 66.7, 120.0,
122.5, 124.6, 125.0, 127.1, 127.2, 127.8, 128.7, 129.1, 129.8, 132.0,
136.9, 141.2, 143.4, 151.4, 155.8, 156.6.
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HRMS: m/z [M + Na]+ calcd for C30H23Cl3N2O4: 603.0621; found:
603.0626.
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Anal. Calcd for C30H23Cl3N2O4: C, 61.92; H, 3.98; N, 4.81. Found:
C, 61.96; H, 3.95; N, 4.86.
Acknowledgment
We gratefully acknowledge the financial support from the Council
of Scientific and Industrial Research (CSIR), New Delhi [Grant No.
01(2323)/09/EMR-II]. Also, the Departments of Organic Chemistry
(20) Zumpe, F. L.; Flüß, M.; Schmitz, K.; Lender, A.
Tetrahedron Lett. 2007, 48, 1421.
Synthesis 2010, No. 17, 2990–2996 © Thieme Stuttgart · New York

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