Multilevel selectivity in the mild and high-yielding chlorosilane- induced cleavage of carbamates to isocyanates

Article abstract of DOI:10.1021/jo981816+

The silane-induced cleavage of a series of N-p-tolylcarbamates and N- phenethylcarbamates to isocyanates has been investigated as a function of chlorosilane, carbamate substituent, and reaction conditions. Reaction yields were determined from the isolated ureas, which were formed by trapping the corresponding isocyanates with isobutylamine. Under room-temperature conditions, multilevel selectivity in carbamate activation has been demonstrated. This selectivity together with the generality of the methodology enhances the utility of carbamates as synthetic intermediates and protecting groups. To demonstrate the effectiveness of this selectivity, a series of biscarbamates were selectively monoactivated to isocyanates in excellent yields.

Full text of DOI:10.1021/jo981816+

J . Org. Chem. 1998, 63, 8515-8521
8515
Mu ltilevel Selectivity in th e Mild a n d High -Yield in g
Ch lor osila n e-In d u ced Clea va ge of Ca r ba m a tes to Isocya n a tes
Pek Y. Chong, Slawomir Z. J anicki, and Peter A. Petillo*
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801
Received September 8, 1998
The silane-induced cleavage of a series of N-p-tolylcarbamates and N-phenethylcarbamates to
isocyanates has been investigated as a function of chlorosilane, carbamate substituent, and reaction
conditions. Reaction yields were determined from the isolated ureas, which were formed by trapping
the corresponding isocyanates with isobutylamine. Under room-temperature conditions, multilevel
selectivity in carbamate activation has been demonstrated. This selectivity together with the
generality of the methodology enhances the utility of carbamates as synthetic intermediates and
protecting groups. To demonstrate the effectiveness of this selectivity, a series of biscarbamates
were selectively monoactivated to isocyanates in excellent yields.
Sch em e 1
Carbamates that act as useful synthetic intermediates
and protecting groups find widespread use in organic
synthesis. For example, the tert-butoxycarbonyl (t-Boc)
group is one of the most frequently used amino protecting
groups.1 However, the general manipulation of carbam-
ates is limited in both quantity and scope.2-5 Mild and
high-yielding methods for the cleavage of carbamates,
which are both selective and general in scope, would
represent a set of novel and useful transformations in
organic synthesis.4,6,7 The chlorosilane-induced cleavage
of carbamates to isocyanates has previously been shown
to proceed under relatively mild conditions.8-11 Herein,
we report a systematic study of the reactivity of a series
of substrates with various chlorosilanes under mild
reaction conditions. This study uses the dependence of
the ease of cleavage on the reagents and substrates to
effect selective carbamate cleavage. Thus, we demon-
strate for the first time, multi-level selectivity in the
cleavage of a range of carbamates under the mildest
conditions yet reported.
The substrates investigated were the N-arylcarbam-
ates 1 (R ) p-MePh-) and the N-alkylcarbamates 2 (R
) PhCH2CH2-), which sterically and electronically alter
R′. Cleavage was initiated by adding 1.2 equiv of
triethylamine and one of four chlorosilanes (trichlorosi-
lane, methyltrichlorosilane, dichlorodimethylsilane, or
chlorotrimethylsilane) to a solution of the substrate in
benzene. Three sets of reaction conditions were exam-
ined: 70 °C for 4 h, 70 °C for 24 h, and room temperature
for 24 h. The reaction progress was determined for each
carbamate using a combination of GC-MS,13 1H NMR
spectroscopy,14 and isolation of a urea derivative of the
isocyanate.15 The degree of cleavage was easily followed
due to the absence of any side reactions. Representative
selections of our results for the cleavage of the N-p-
tolylcarbamates 1 and N-phenethylcarbamates 2 are
shown in Table 1.
The methodology involves the treatment of a carbam-
ate with a chlorosilane in the presence of triethylamine
to produce an isocyanate 5 and an alkoxysilane 6 (Scheme
1). The reaction is thought to proceed by formation of
the N-silylated species 3, which was previously isolated.9
Although silane-induced carbamate cleavage is known,
the full scope and utility of the reaction were never
explored in depth.12
* To whom correspondence should be attached. Tel.: (217) 333-0695.
Fax: (217) 244-8559. E-mail: alchmist@alchmist.scs.uiuc.edu.
(1) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons: New York, 1991; pp 315-348.
(2) Kocienski, P. J . Protecting Groups; Georg Thiem Verlag: Stut-
tgart, 1994.
(3) Shapiro, G.; Marzi, M. J . Org. Chem. 1997, 62, 7096.
(4) Ozaki, S. Chem. Rev. 1972, 72, 457.
(5) Valli, V. L. K.; Alper, H. J . Org. Chem. 1995, 60, 257.
(6) Richter, R.; Ulrich, H. In The Chemistry of Cyanates and their
Thio Derivatives; Patai, S., Ed.; Wiley: New York, 1977; Part 2, p 619.
(7) Gittos, M. W.; Davies, R. V.; Iddon, B.; Suschitzky, H. J . Chem.
Soc., Perkin Trans. 1 1976, 141.
(8) (a) Mironov, V. F.; Seludjakov, V. D.; Kozjukov, V. P.; Chatuncev,
G. D. Dokl. Akad. Nauk. SSSR. 1968, 181, 115. (b) Mironov, V. F.;
Kozyukov, V. P.; Orlov, G. I. J . Gen. Chem. USSR (Engl. Transl.) 1981,
51, 1555. (c) Bal’on, Y. G. J . Org. Chem. USSR (Engl. Transl.) 1980,
12, 2233. (d) Casara, P.; Metcalf, B. W. Tet. Lett. 1978, 1581. (e)
Donaldson, R. E.; Saddler, J . C.; Byrn, S.; McKenzie, A. T.; Fuchs, P.
L. J . Org. Chem. 1983, 48, 2167.
(9) In most cases where trimethylchlorosilane was used, considerable
heating was required to generate the isocyanate. (a) Greber, G.;
Kricheldorf, H. R. Angew. Chem., Int. Ed. Engl. 1968, 7, 941. (b)
Kricheldorf, H. R. Angew. Chem. 1972, 84, 107. (c) Kricheldorf, H. R.
Synthesis 1970, 649. (d) Kricheldorf, H. R. Liebigs Ann. Chem. 1973,
772. (e) Kricheldorf, H. R. Chem. Ber. 1971, 104, 3146.
(10) The use of trichlorosilane requires less heating than that of
chlorotrimethylsilane. (a) Pirkle, W. H.; Hauske, J . R. J . Org. Chem.
1977, 42, 2781. (b) Pirkle, W. H.; Hoekstra, M. S. J . Org. Chem. 1974,
39, 3904. (c) Pirkle, W. H.; Rinaldi, P. L. J . Org. Chem. 1978, 43, 3803.
(11) Wolfbeis, O. S.; Marhold, H. Monatsh. Chem. 1983, 114, 599.
10.1021/jo981816+ CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/29/1998

8516 J . Org. Chem., Vol. 63, No. 23, 1998
Chong et al.
Ta ble 1. Yield sa (%) for Sila n e-In d u ced Clea va ge of N-p-Tolylca r ba m a tes 1 a n d N-P h en eth ylca r ba m a tes 2 u n d er
Va r iou s Sila n e a n d Rea ction Con d ition s
HSiCl3
70/24
MeSiCl3
70/24
Me2SiCl2
70/24
Me3SiCl
70/24
entry
R
70/4
rt/24
70/4
rt/24
70/4
rt/24
70/4
rt/24
1a
1e
Me
t-Bu
CH2CCl3
p-OMePh
p-NO2Ph
Et
i-Bu
t-Bu
CH2CCl3
p-NO2Ph
95
(
91
90
88
85
81
86
84
94
87
85
86
(
100
-
71b
0b
(
90
-
6b
-
0b
-
0b
-
-
-
-
7b
98
-
-
-
-
97
20b
72b d
89
-
-
1g
1h c
1jc
2b
2d
2e
85
96
88
99
88
(
(
91
100
99
99
97
-
0b
4b
51b
97
(
(
-
0b
37b
97
-
8b
68b
97
-
85b
99
(
90b
100
-
89b
97
81
(
26b
99
-
78
(
88
(
5b
(
-
-
-
60b
(
-
-
-
-
-
-
-
2g
92
97
-
(
98
-
-
0b
97
-
-
-
2jc
96
100
99
99
100
86b
88b
a
b
Yields reported are isolated yields of the urea derivatives. Otherwise, they are 1H NMR-determined yields. 1H NMR-determined
yields. c The isolated yields reported for this carbamate were obtained only when 1H NMR showed complete conversion to the isocyanate.
Otherwise, NMR-determined yields are reported. Isolated yield was 71%. -: Yield estimated by GC-MS <20%. (: yield estimated by
GC-MS was between 20 and 80%. 70/4: 70 °C for 4 h. 70/24: 70 °C for 24 h. rt/24: room temperature for 24 h.
d
Sch em e 2
The reactivity of the silane was found to decrease with
increasing methyl substitution and decreasing Cl sub-
stitution at the silicon atom. This finding is consistent
with previous observations that trichlorosilane-induced
cleavage occurs at temperatures lower than those ob-
served with chlorotrimethylsilane.9,10 Mironov and co-
workers have proposed that the increasing Cl substitu-
tion introduces competing pfd π interactions, which
leads to a weakening of the N-Si bond, thereby lowering
the thermal stability of intermediate 3.8b
Cleavage of the alkyl carbamates was found to be
strongly affected by the steric properties of the alkyl
substituent, R′. This conclusion is based on the observed
reactivity pattern: Me ≈ Et > i-Bu > CH2CCl3 > t-Bu.
Increasing the steric bulk of R′ presumably destabilizes
the proposed transition state 49d due to increased non-
bonding interactions between R′ and the Si ligands.
Comparison of the reactivities of the aryl carbamates
allowed for the assessment of the effect of the electronic
character of the substituent. The rate of carbamate
cleavage increases with the stability of the aryl oxide
anion; the p-nitrophenyl carbamate is more reactive than
the p-methoxyphenyl carbamate. It is clear that the
electron-withdrawing nature of the substituent on the
phenyl moiety assists in the cleavage, presumably by
stabilizing the partial negative charge that develops at
the neighboring oxygen atom in the transition state 4.
This observation has been reported with the chlorotri-
methylsilane-assisted cleavage,9 and our studies found
it to be general for the chlorosilanes. Of particular note
are the p-nitrophenyl carbamates, which were activated
to the isocyanates under all of our reaction conditions
and represent an easily cleaved isocyanate-masking
group that is stable during chromatographic purification.
Our data show that, under mild conditions, selective
carbamate cleavage can be achieved by choosing the
appropriate silane for the substituents R′. This selectiv-
ity has been demonstrated on biscarbamates 7a -d
(Scheme 4), designed using the results in Table 1. The
biscarbamates 7a and 7b were synthesized by Horner-
Wadsworth-Emmons coupling of carbamate aldehyde
11a with o-nitrobenzylphosphonate 12, simultaneous
hydrogenation of the styrene double bond and the nitro
group to result in 13, and carbamoylation of 14 to 7a and
7b (Scheme 2).
group was used during the Horner-Wadsworth-Em-
mons coupling in the synthesis of 7c and 7d (Scheme 3).
Aldehyde 11b was coupled with the o-nitrobenzylphos-
phonate 12 to yield the o-nitrostyrene 15. The Boc group
in 15 was removed with TFA in methylene chloride, and
the resulting free amine was carbamoylated to yield 16.
The o-nitrostyrene 16 was hydrogenated, and the result-
ing bibenzylamine was carbamoylated to yield 7c and 7d .
The biscarbamates 7a -d were selectively transformed
to the monoisocyanates 8a -d (Scheme 4, Table 2). The
internal selectivities in each case were determined by the
isolation of ureas 9a -d . Due to the tendency of some
aryl carbamates to undergo aminolysis to produce ureas,
the consumption of substrates 7b-d was monitored by
1H NMR during the course of the reaction. The presence
of the isocyanates in the reaction mixture was subse-
quently verified by IR spectroscopy.
Selective carbamate cleavages (Table 2) have been
effected in excellent yields at room temperature. In
biscarbamate 7a , the methyl carbamate was selectively
activated in the presence of the tert-butyl carbamate
(Scheme 5). Correspondingly, the p-nitrophenyl carbam-
ate in 7b was selectively cleaved over the methyl car-
bamate using chlorotrimethylsilane to give 9b in 98%
yield. The selective cleavage of the p-methoxyphenyl
carbamate over the 2,2,2-trichloroethyl carbamate in 7c
was achieved with methyl trichlorosilane and mild heat-
The anion of the o-nitrobenzylphosphonate 12 proved
too nucleophilic for the p-methoxyphenyl carbamate to
survive the reaction conditions and so the Boc protecting

Cleavage of Carbamates to Isocyanates
J . Org. Chem., Vol. 63, No. 23, 1998 8517
Sch em e 3
Sch em e 4
Ta ble 2. Yield s of Ur ea 9 for th e In ter n a l Selective
Clea va ge of Bisca r ba m a tes 7
Sch em e 5
entry
silane
R1
R2
yield of 9 (%)
7a
HSiCl3
Me
t-Bu
Me
CH2CCl3
p-MeOPh
95b
98c
88d
90e
7ba
7c
Me2SiCl2
MeSiCl3
Me3SiCl
p-NO2Ph
p-MeOPh
p-NO2Ph
7d a
These reactions were determined by 1H NMR to reach comple-
tion, and the presence of the isocyanates was verified by IR
a
b
d
spectroscopy. Conditions: rt, 72 h. c Conditions: rt, 1 h. Condi-
tions: 40 °C, 53 h. e Conditions: rt, 10 min.
ing at 40 °C to afford 9c in 88% yield. The ease of
p-nitrophenyl carbamate cleavage in the presence of the
p-methoxyphenyl carbamate was demonstrated by the
short reaction time for the monoactivation of biscarbam-
ate 7d . The reaction of biscarbamates 7b-d , carried out
in chloroform,16 suggests that the solvent has little effect
on the selectivity of carbamate cleavage and that the
results from our survey can probably be extended to
reactions in other solvents.
In addition, these results show two levels of selectivity
for the tert-butyl, methyl, and p-nitrophenyl carbamates
(7a and 7b) as well as for the 2,2,2-trichloroethyl,
p-methoxyphenyl, and p-nitrophenyl carbamates (7c and
7d ). Therefore, in the presence of these sets of three
carbamates, the appropriate chlorosilanes can be used
to selectively cleave one carbamate at a time under mild
conditions.
It is worth noting an important outcome of the selective
cleavage of a sterically less demanding carbamate (e.g.,
R′ ) Me) over a t-Boc-protected amine. This methodol-
ogy, together with well-known methods for cleaving t-Boc-
protected amines in the presence of alkyl carbamates,
makes the two protecting groups orthogonal. Likewise,
the 2,2,2-trichloroethyl carbamate, which is useful for the
protection of amino groups due to its facile removal,17,18
can act as a protecting group orthogonal to other less
sterically demanding alkyl or aryl carbamates.
In conclusion, we have demonstrated selectivity in the
silane-induced cleavage of carbamates under mild condi-
tions. Moreover, we have illustrated the effectiveness of
this selectivity in the monoactivation of biscarbamates
to the isocyanates, thereby demonstrating proof-of-
concept.
(13) Although accurate quantitative information was not obtained,
the GC-MS traces provided us with estimates of the progress of
reaction.
(12) The traditional reaction conditions employ chlorotrimethylsi-
lane and high reaction temperatures (>100 °C). See ref 9.

8518 J . Org. Chem., Vol. 63, No. 23, 1998
Chong et al.
Ben zyl N-p-tolylca r ba m a te (1f): mp 79-81 °C (hexane)
(lit.28 mp 81-83 °C). Anal. Calcd for C15H15NO2: C, 74.67;
H, 6.27; N, 5.80. Found: C, 74.92; H, 6.43; N, 5.85.
Exp er im en ta l Section
Gen er a l Exp er im en ta l Meth od s. All elemental analyses
were performed by the University of Illinois Elemental Analy-
sis Lab. All mass spectrometry data were obtained by the
University of Illinois Mass Spectrometry Lab. CH2Cl2, Et3N,
and pyridine were distilled from CaH2 prior to use as reaction
solvents. Benzene and THF were distilled from sodium
benzophenone ketyl.
Analytical thin-layer chromatography (TLC) was performed
using Merck silica gel 60 F254 precoated plates with a
fluorescent indicator. Visualization was accomplished by UV
illumination and ninhydrin solution. Flash chromatography
was performed using silica gel 60 (230-400 mesh) from Merck.
2-(tert-Butyloxycarbonyl)aminobenzyl alcohol (10b) was pre-
pared according to Liu and Hood’s procedure.19 PCC/Al2O3 was
prepared according to the procedure in Vogel’s Textbook of
Practical Organic Chemistry.20
Gen er a l P r oced u r e for th e P r ep a r a tion of Ca r ba m -
a tes 1a -j a n d 2a -j. Carbamates were synthesized by
reaction of either p-toluidine or phenethylamine with the
chloroformate by the following representative procedure,
except for the tert-butyl carbamates, 1e and 2e, which were
synthesized by the reaction of the amine with 1.1 equiv of (t-
Boc)2O in CH2Cl2. All carbamates were characterized by 1H
NMR, 13C NMR, mass spectrometry, and elemental analyses
and, when possible, further verified by comparison with
literature-reported values.
Rep r esen ta tive P r oced u r e for th e Syn th esis of N-p-
Tolylca r ba m a tes.21 To a stirring solution of p-toluidine (2.1
g, 19.62 mmol) and pyridine (1.7 mL, 21.02 mmol, 1.1 equiv)
in CH2Cl2 (100 mL) was added phenyl chloroformate (2.6 mL,
20.72 mmol, 1.1 equiv) dropwise. The resulting solution was
stirred at room temperature for 3 h, washed with water, 5%
aqueous HCl and 5% aqueous NaOH, dried (MgSO4), and
evaporated under reduced pressure. The residue was crystal-
lized from EtOAc/hexane to afford phenyl N-p-tolylcarbamate
(4.2 g, 94%) as white crystalline needles.
2,2,2-Tr ich lor oeth yl-N-p-tolylcar bam ate (1g): yield 79%;
mp 77-78 °C (hexane); 13C NMR (CDCl3, 126 MHz) δ 151.79,
1
134.63, 134.04, 129.91, 119.22, 95.53, 74.67, 21.00; H NMR
(CDCl3, 500 MHz) δ 7.30 (br d, 2H, J ) 7.8 Hz), 7.14 (br d,
2H, J ) 7.9 Hz), 6.83 (br s, 1H), 4.82 (s, 2H), 2.32 (s, 3H);
HRMS calcd for C10H10Cl3NO2 (M+) 280.9777, found 280.9785.
Anal. Calcd for C10H10Cl3NO2: C, 42.51; H, 3.57; N, 4.96.
Found: C, 42.68; H, 3.69; N, 4.85.
p-Meth oxyp h en yl N-p-tolylca r ba m a te (1h ): yield 90%;
mp 158-160 °C (benzene); 13C NMR (CDCl3, 101 MHz) δ
157.29, 144.29, 135.02, 133.52, 129.76, 122.70, 118.94, 114.56,
55.76, 20.95; 1H NMR (CDCl3, 500 MHz) δ 7.32 (br d, 2H, J )
8.0 Hz), 7.10 (AA′BB′, 2H, J AA′ ) J BB′ ) 3.0 Hz, J AB ) J A′B′
)
9.0 Hz, νA ) νA′ ) 3547.9 Hz, νB ) νB′ ) 3547.9 Hz), 6.90
(AA′BB′, 2H, as above), 6.86 (br s, 1H), 3.80 (s, 3H), 2.32 (s,
3H); HRMS calcd for C15H15NO3 (M+) 257.1052, found 257.1059.
Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44.
Found: C, 70.03; H, 5.82; N, 5.48.
P h en yl N-p-tolylca r ba m a te (1i): mp 114-115 °C (EtOAc/
hexane) (lit.29 mp 113-114 °C, lit.30 mp 115 °C). Anal. Calcd
for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.94;
H, 5.72; N, 6.18.
p-Nitr op h en yl N-p-tolylca r ba m a te (1j): yield 76%; mp
139-140 °C (benzene) (lit.31 mp 135-136 °C); 13C NMR (CDCl3,
126 MHz) δ 155.68, 150.47, 145.18, 134.46, 134.24, 129.97,
125.38, 122.31, 119.34, 20.97; 1H NMR (CDCl3, 500 MHz) δ
8.44 (AA′BB′, 2H, J AA′ ) J BB′ ) 3.0 Hz, J AB ) J A′B′ ) 9.1 Hz, νA
) νA′ ) 4125.7 Hz, νB ) νB′ ) 3681.0 Hz), 7.37 (AA′BB′, 2H, as
above), 7.32 (br d, 2H, J ) 7.9 Hz), 7.15 (br d, 2H, J ) 8.4
Hz), 7.06 (br s, 1H), 2.33 (s, 3H); HRMS calcd for C14H12N2O4
(M+) 272.0797, found 272.0799. Anal. Calcd for C14H12N2O4:
C, 61.76; H, 4.44; N, 10.29. Found: C, 61.60; H, 4.30; N, 10.24.
Meth yl N-p h en eth ylca r ba m a te (2a ): purified by distil-
lation bp 90-92 °C/0.11 mmHg (lit.32 bp 94-95 °C/0.3 mmHg).
Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82.
Found: C, 66.63; H, 7.27; N, 7.84.
Eth yl N-p h en eth ylca r ba m a te (2b): purified by distilla-
tion bp 100-103 °C/0.16 mmHg (lit.32 bp 100-102 °C/0.15
mmHg); mp 32-34 °C (lit.32 mp 31-34 °C, lit.33 mp 33.5 °C,
lit.34 mp 34-35 °C). Anal. Calcd for C11H15NO2: C, 68.37; H,
7.82; N, 7.25. Found: C, 68.22; H, 7.79; N, 7.24.
Isop r op yl N-p h en eth ylca r ba m a te (2c): purified by dis-
tillation bp 98-101 °C/0.16 mmHg (lit.35 bp 115-116 °C/0.6
mmHg). Anal. Calcd for C12H17NO2: C, 69.54; H, 8.27; N,
6.76. Found: C, 69.36; H, 8.27; N, 6.80.
Isobu tyl N-p h en eth ylca r ba m a te (2d ): purified by distil-
lation bp 117-120 °C/0.17 mmHg (lit.36 bp 119-120 °C/0.8
mmHg). Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N,
6.33. Found: C, 70.30; H, 8.62; N, 6.40.
Meth yl N-p-tolylca r ba m a te (1a ): mp 94-95 °C (EtOAc/
cyclohexane) (lit.22 mp 96-98 °C). Anal. Calcd for C9H11
-
NO2: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.24; H, 6.76; N,
8.43.
Eth yl N-p-tolylca r ba m a te (1b): purified by distillation
bp 95-98 °C/0.15 mmHg; 49-50 °C; (lit.19 mp 49-51 °C).
Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82.
Found: C, 67.02; H, 7.31; N, 7.84.
Isop r op yl N-p-tolylca r ba m a te (1c): purified by distilla-
tion bp 97-98 °C/0.11 mmHg; 50-51 °C (lit.24 mp 51-52 °C).
Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25.
Found: C, 68.46; H, 7.86; N, 7.27.
Isobu tyl N-p-tolylca r ba m a te (1d ): mp 49-51 °C; (lit.25
52.5-53 °C). Anal. Calcd for C12H17NO2: C, 69.54; H, 8.27;
N, 6.76. Found: C, 69.66; H, 8.28; N, 6.79.
ter t-Bu tyl N-p-tolylca r ba m a te (1e): mp 89-90 °C (cy-
clohexane) (lit.26 mp 88-88.5 °C, lit.27 mp 91-93 °C). Anal.
Calcd for C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C,
69.54; H, 8.31; N, 6.77.
ter t-Bu tyl N-p h en eth ylca r ba m a te (2e): mp 54-55 °C
(hexane) (lit.37 mp 54-55 °C, lit.38 mp 55-56 °C). Anal. Calcd
(23) (a) Fujisaki, S.; Tomiyasu, K.; Nishida, A.; Kajigaeshi, S. Bull.
Chem. Soc. J pn. 1988, 61, 1401. (b) Stumpe, J .; Schwetlick, K.; Kuzmin,
M. G. J . Prakt. Chem. 1982, 324, 400.
(24) (a) Baskakow;; Melnikow, H. Zh. Obshch. Khim. 1954, 24, 376.
(b) Shulman, S.; Griepentrog, J . A. Microchem. J . 1962, 6, 179.
(25) Lovering, E. G.; Laidler, K. J . Can. J . Chem. 1962, 40, 26.
(26) Tarbell, D. S.; Insalaco, M. A. Proc. Natl. Acad. Sci. U.S.A. 1967,
57, 233.
(27) Stanley, R. L.; Tarbell, D. S. J . Org. Chem. 1977, 42, 3686.
(28) (a) Ruggli, P.; Dahn, H. Helv. Chim. Acta 1944, 27, 1116. (b)
Blaha, K.; Rudinger, J . Collect. Czech. Chem. Commun. 1965, 30, 585.
(c) Mukaiyama, T.; Akiba, T. Bull. Chem. Soc. J pn. 1960, 33, 1707.
(29) Hegarty, A. F.; Frost, L. N. J . Chem. Soc., Perkin Trans. 2 1973,
82, 1721.
(14) For the cleavage of some of the aryl carbamates, the reaction
progress was studied by 1H NMR since the substrates react with
isobutylamine.
(15) Isocyanates were derivatized by reaction with isobutylamine.
(16) Reactions of biscarbamates 7b-d were carried out in chloroform
due to their poor solubilities in benzene.
(17) The trichloroethoxycarbonyl group is easily removed by reduc-
tion with zinc metal in acetic acid or hot ethanol. See refs 1 and 3.
(18) Semmelhack, M. F.; Heinsohn, G. E. J . Am. Chem. Soc. 1972,
94, 5139.
(19) Liu, J .; Hood, R. H. J . Heterocyc. Chem. 1995, 32, 523.
(20) Vogel, A. I. Vogel’s Textbook of Practical Organic Chemistry,
5th ed.; Longman Scientific and Technical: Essex, England, 1989; p
426.
(30) Eckenroth, R. Chem. Ber. 1890, 23, 698.
(21) All carbamates were synthesized by reaction of either p-
toluidine or phenethylamine with the chloroformate by this represen-
tative procedure, except for the tert-butyl carbamates, which were
synthesized by reaction of the amine with 1.1 equiv of (t-Boc)2O.
(22) (a) ICI Ltd. Patent, DE 2254611; Chem. Abstr. 1973, 79, 65996.
(b) Baldwin, J . E.; Smith, R. A. J . Org. Chem. 1967, 32, 3511.
(31) Shawali, A. S.; Harhash, A.; Sidky, M. M.; Hassaneen, H. M.;
Elkaabi, S. S. J . Org. Chem. 1986, 51, 3498.
(32) Bal’on, Y. G.; Moskaleva, R. N.; Nazarenko, T. G. Sov. Prog.
Chem. 1977, 43, 100.
(33) Curtius, T.; J ordan, H. J . Prakt. Chem. 1901, 64, 297.
(34) Shriner, R. L.; Child, R. G. J . Am. Chem. Soc. 1952, 74, 549.

Cleavage of Carbamates to Isocyanates
J . Org. Chem., Vol. 63, No. 23, 1998 8519
for C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.28;
H, 8.60; N, 6.30.
Calcd for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C,
59.44; H, 6.15; N, 7.57.
2-(Meth yloxyca r bon yl)a m in oben za ld eh yd e (11a ). To
a solution of methyl carbamate 10a (5.49 g, 30.3 mmol) in 230
mL of CHCl3 was added PCC/Al2O3 (45 g). The reaction
mixture was stirred at room temperature for 30 min and then
filtered through a bed of silica. The filtrate was concentrated
under reduced pressure and chromatographed (300:4 CHCl3:
EtOH) to give 11a (3.96 g, 73%) as a white solid: mp 90-92.5
°C; 13C NMR (CDCl3, 101 MHz) δ 195.22, 154.19, 141.31,
136.14, 122.06, 121.38, 118.30, 52.54; 1H NMR (CDCl3, 400
MHz) δ 10.60 (br s, 1H), 9.88 (s, 1H), 8.44 (d, 1H, J ) 8.7 Hz),
7.60 (m, 2H), 7.15 (td, 1H, J ) 7.6, 0.9 Hz), 3.79 (s, 3H); HRMS
calcd for C9H9NO3 (M+) 179.0582, found 179.0584. Anal.
Calcd for C9H9NO3: C, 60.33; H, 5.06; N, 7.82. Found: C,
60.41; H, 5.05; N, 7.77.40
Ben zyl N-ph en eth ylcar bam ate (2f): mp 60-62 °C (EtOAc/
cyclohexane); (lit.37a mp 56-58 °C). Anal. Calcd for C16H17
-
NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.34; H, 6.71; N,
5.50.
2,2,2-Tr ich lor oeth yl N-p h en eth ylca r ba m a te (2 g): mp
58-59 °C (EtOAc/cyclohexane); 13C NMR (CDCl3, 101 MHz) δ
154.58, 138.49, 128.85, 128.70, 126.64, 74.40, 42.50, 35.92; 1H
NMR (CDCl3, 500 MHz) δ 7.35-7.29 (m, 2H), 7.25-7.18 (m,
3H), 4.98 (br s, 1H), 4.72 (s, 2H), 3.50(q, 2H, J ) 6.7 Hz), 2.85
(t, 2H, J ) 7.0 Hz); HRMS calcd for C10H10Cl3NO2 (M+)
294.9934, found 294.9937. Anal. Calcd for C11H12Cl3NO2: C,
44.55; H, 4.08; N, 4.72. Found: C, 44.50; H, 4.04; N, 4.59.
p-Meth oxyp h en yl N-p h en eth ylca r ba m a te (2h ): yield
94%; mp 87-88 °C (hexane); 13C NMR (CDCl3, 126 MHz) δ
157.15, 155.19, 144.75, 138.80, 129.03, 128.93, 126.83, 122.66,
114.54, 55.79, 42.55, 36.13; 1H NMR (CDCl3, 500 MHz) δ 7.36-
2-(ter t-Bu tyloxyca r bon yl)a m in oben za ld eh yd e (11b).
To a solution of 2-(tert-butyloxycarbonyl)aminobenzyl alcohol
(10b) (6.72 g, 30.1 mmol) in 350 mL of CHCl3 was added PCC/
Al2O3 (33 g). The reaction mixture was stirred at room
temperature for 30 min, after which time TLC indicated that
the reaction was incomplete. More PCC/Al2O3 (18 g) was
added, and the reaction mixture was stirred for another 30
min and then filtered through a bed of silica. The filtrate was
concentrated under reduced pressure and chromatographed
(300:4 CHCl3/EtOH) to give a yellow oil that was crystallized
from hexane to afford 11b (3.73 g, 56%) as an off-white solid:
mp 54.5-56.5 °C; 13C NMR (CDCl3, 126 MHz) δ 195.26,
153.08, 141.99, 136.28, 136.15, 121.68, 121.39, 118.41, 81.13,
7.21 (m, 5H), 7.01 (AA′BB′, 2H, J AA′ ) J BB′ ) 3.0 Hz, J AB
)
J A′B′ ) 8.9 Hz, νA ) νA′ ) 3505.2 Hz, νB ) νB′ ) 3428.4 Hz),
6.86 (AA′BB′, 2H, as above), 4.98 (br s, 1H), 3.79 (s, 3H), 3.53
(q, 2H, J ) 6.6 Hz), 2.89 (t, 2H, J ) 6.8 Hz); HRMS calcd for
C
C
16H17NO3 (M+) 271.1208, found 271.1202). Anal. Calcd for
16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C, 70.77; H,
6.08; N, 5.14.
P h en yl N-p h en et h ylca r b a m a t e (2i): mp 90-91 °C
(EtOAc/cyclohexane) (lit.39 mp 89-90 °C). Anal. Calcd for
C
15H15NO2: C, 74.67; H, 6.27; N, 5.80. Found: C, 74.56; H,
6.18; N, 5.80.
1
28.44; H NMR (CDCl3, 500 MHz) δ 10.39 (br s, 1H), 9.89 (s,
p-Nitr op h en yl N-p h en eth ylca r ba m a te (2j): yield 90%;
mp 106-107 °C (benzene); 13C NMR (CDCl3, 126 MHz) δ
156.11, 153.25, 144.91, 138.38, 128.99, 128.98, 127.00, 125.30,
122.14, 42.59, 35.95. 1H NMR (CDCl3, 500 MHz) δ 8.23
1H), 8.45 (d, 1H, J ) 8.4 Hz), 7.61 (dd, 1H, J ) 7.6, 1.5 Hz),
7.56 (m, 1H), 7.12 (m, 1H), 1.53 (s, 9H); HRMS calcd for C12H15
-
-
NO3 (M+) 221.1052, found 221.1058. Anal. Calcd for C12H15
NO3: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.16; H, 6.95; N,
6.18.
(AA′BB′, 2H, J AA′ ) J BB′ ) 3.0 Hz, J AB ) J A′B′ ) 9.2 Hz, νA
)
νA′ ) 4112.2 Hz, νB ) νB′ ) 3638.7 Hz), 7.37-7.21 (m, 5H),
7.28 (AA′BB′, 2H, as above), 5.18 (br s, 1H), 5.57 (q, 2H, J )
6.7 Hz), 2.91 (t, 2H, J ) 6.9 Hz); HRMS calcd for C15H14N2O4
(M+) 286.0954, found 286.0952. Anal. Calcd for C15H14N2O4:
C, 62.93; H, 4.93; N, 9.79. Found: C, 62.53; H, 4.77; N, 9.68.
(2-Nitr oben zyl)p h osp h on ic Acid Dieth yl Ester (12). A
mixture of 1-(bromomethyl)-2-nitrobenzene (5.35 g, 24.8 mmol)
and triethyl phosphite (4.7 mL, 27.4 mmol) was heated in a
simple distillation apparatus to 110 °C. Ethyl bromide was
collected for 40 min and the reaction mixture was maintained
at 110 °C for another 1 h. After being cooled to room
temperature, the reaction mixture was purified by Kugehlrohr
distillation (150 °C/0.25 mmHg) to give 12 (6.55 g, 97%) as a
Gen er a l P r oced u r e for th e Sila n e-In d u ced Clea va ge
of Ca r ba m a tes. To a solution of the carbamate (approxi-
mately 0.5 mmol) in 2 mL of benzene was added 1.2 equiv of
Et3N and 1.2 equiv of the chlorosilane. The reaction was
shaken in a sealed vial and subjected to the appropriate
reaction conditions. The isocyanate was trapped by addition
of 0.2 mL of isobutylamine and the urea purified by flash
yellow liquid: 13C NMR (CDCl3, 126 MHz) δ 149.48 (Cq, J CP
)
7.0 Hz), 133.31 (CH, J CP ) 4.9 Hz), 133.10 (CH, J CP ) 2.6 Hz),
128.14 (CH, J CP ) 4.0 Hz), 127.39 (Cq, J CP ) 9.0 Hz), 125.32
(CH, J CP ) 3.5 Hz), 62.46 (CH2), 30.57 (CH2, J CP ) 137.9 Hz),
1
1
column chromatography. All ureas were characterized by H
16.32 (CH3, J CP ) 6.2 Hz); H NMR (CDCl3, 500 MHz) δ 7.90
and 13C NMR. Purity and composition were verified by
elemental analyses and mass spectral analyses.
(br d, 1H, J ) 8.2 Hz), 7.51 (br t, 1H, J ) 7.6 Hz), 7.42 (m, 1H,
J ) 7.8 Hz), 7.37 (m, 1H, J ) 7.8 Hz), 3.98 (m, 4H), 3.66 (d,
2H, J ) 22.6 Hz), 1.18 (t, 6H, J ) 7.0 Hz).43
2-(Meth yloxyca r bon yl)a m in oben zyl Alcoh ol (10a ). To
a stirring solution of 2-aminobenzyl alcohol (4.01 g, 32.5 mmol)
in 20 mL of dioxane, 20 mL of saturated NaHCO3 solution,
and 8 mL of water at 0 °C was added methyl chloroformate
(2.5 mL, 32.4 mmol) dropwise. The resulting mixture was
stirred at room temperature for 15 h, and then more methyl
chloroformate (0.5 mL, 6.5 mmol) was added dropwise while
the reaction mixture was cooled to 0 °C. After being warmed
to room temperature, the reaction was diluted with brine and
extracted with CHCl3 (4×). The organic layers were pooled,
dried (MgSO4), and evaporated under reduced pressure. The
residue was chromatographed (1:25 EtOAc/CHCl3) to afford
10a (5.49 g, 93%) as a light yellow syrup: 13C NMR (CDCl3,
101 MHz) δ 154.82, 137.78, 129.37, 129.02, 123.65, 121.14,
64.39, 52.54; 1H NMR (CDCl3, 400 MHz) δ 7.96 (br s, 1H), 7.89
(br d, 1H, J ) 7.1 Hz), 7.31 (td, 1H, J ) 7.8, 1.6 Hz), 7.14 (dd,
1H, J ) 7.6, 1.5 Hz), 7.03 (td, 1H, J ) 7.4, 1.1 Hz), 4.66 (d,
2H, J ) 5.7 Hz), 3.75 (s, 3H), 2.54 (t, 1H, J ) 5.7 Hz); HRMS
calcd for C9H11NO3 (M+) 181.0739, found 181.0737. Anal.
N-[(2′-n itr ostilben -2-yl)p h en yl]m eth ylca r ba m a te (13).
To a solution of 12 (2.01 g, 7.4 mmol) in 10 mL of THF at 0 °C
was added 7.8 mL of a 1 M solution of NaHMDS in THF
dropwise. The reaction mixture was stirred at 0 °C for 10 min,
11a (1.32 g, 7.4 mmol) was then added in one portion, and
stirring was continued for another 20 min. The mixture was
diluted with 100 mL of Et2O, washed with brine (2×), dried
(MgSO4), and concentrated under reduced pressure. The
residue was chromatographed (100:3 CHCl3/EtOH) to yield 13
(1.87 g, 85%) as a yellow solid; 13C NMR (CDCl3, 101 MHz) δ
147.95, 135.14, 133.41, 132.94, 129.28, 128.67, 128.61, 128.48,
127.22, 127.03, 125.29, 124.88, 52.69; 1H NMR (CDCl3, 500
MHz) δ 7.99 (dd, 1H, J ) 8.2, 1.1 Hz), 7.73 (dd, 2H, J ) 7.9,
0.7 Hz), 7.62 (t, 1H, J ) 7.6 Hz), 7.55 (br d, 1H, J ) 7.7 Hz),
7.48 (d, 1H, J ) 16.2 Hz), 7.44 (td, 1H, J ) 7.7, 1.4 Hz), 7.33
(td, 1H, J ) 7.7, 1.4 Hz), 7.19 (br t, 1H, J ) 7.8 Hz), 7.13 (d,
1H, J ) 15.9 Hz), 6.65 (br s, 1H), 3.79 (s, 3H); HRMS calcd for
C
C
16H14N2O4 (M+) 298.0954, found 298.0957. Anal. Calcd for
16H14N2O4: C, 64.42; H, 4.73; N, 9.39. Found: C, 64.35; H,
4.73; N, 9.29.
(35) Merck, E. Patent, DE 817461, 1948.
(36) Bernasconi, S.; Comini, A.; Corbella, A.; Gariboldi, P.; Sisti, M.
Synthesis 1980, 5, 385.
(37) Tanaka, K.; Yoshifuji, S.; Nitta, Y. Chem. Pharm. Bull. 1988,
36, 3125.
N-(2′-a m in obiben zyl-2-yl)m eth ylca r ba m a te (14). A so-
lution of 13 in 30 mL of THF was stirred vigorously under
hydrogen (65 psi) with 5% Pd/C for 4 h. The catalyst was
filtered off, and the filtrate was concentrated under reduced

8520 J . Org. Chem., Vol. 63, No. 23, 1998
Chong et al.
pressure to give 14 (1.66 g, 98%) as an off-white residue: mp
85-87 °C; 13C NMR (CDCl3, 101 MHz) δ 144.10, 135.68,
129.89, 129.71, 127.58, 127.14, 126.10, 125.01, 119.50, 116.51,
to give the corresponding amine as a yellow solid (2.05 g, 5.7
mmol) that was used without further purification.
To a suspension of the above amine in 15 mL of dioxane
was added 30 mL of saturated NaHCO3 slowly, and the rapidly
stirred reaction mixture was cooled to 0 °C. p-Methoxyphenyl
chloroformate (0.89 mL, 5.9 mmol) was introduced by dropwise
addition to the reaction mixture. After CO2 evolution ceased,
stirring was continued at 0 °C for another 30 min. The
solution was diluted with water to a final volume of 100 mL.
The resultant yellow solid was filtered, washed with water,
air-dried, and recrystallized (EtOAc/petroleum ether) to yield
16 as yellow needles (1.69 g, 75%): mp 168-170 °C; 13C NMR
(CDCl3, 101 MHz) δ 157.38, 148.12, 144.28, 134.85, 133.58,
132.98, 129.55, 128.86, 128.74, 128.52, 128.06, 127.67, 125.06,
1
52.47, 32.52, 30.83; H NMR (CDCl3, 500 MHz) δ 7.66 (br s,
1H), 7.23 (m, 2H), 7.13 (dd, 1H, J ) 7.4, 1.1 Hz), 7.08 (td, 1H,
J ) 7.6, 1.5 Hz), 6.98 (dd, 1H, J ) 7.6, 1.4 Hz), 6.76 (td, 2H,
J ) 7.5, 1.1 Hz), 6.70 (d, 1H, J ) 7.9, 1.1 Hz), 3.74 (s, 3H),
2.89 (AA′BB′, 2H, νA ) νA′ ) 1156.9 Hz, νB ) νB′ ) 1117.3 Hz,
J AA′ ) J BB′ ) 14.0 Hz, J AB ) J A′B′ ) 6.0 Hz, J AB′ ) J A′B ) 9.5
Hz), 3.59 (br s, 2H), 2.79 (AA′BB′, 2H, as above); HRMS calcd
for C16H18N2O2 (M+) 270.1368, found 270.1365. Anal. Calcd
for C16H18N2O2: C, 71.09; H, 6.71; N, 10.36. Found: C, 70.83;
H, 6.77; N, 10.38.
N-(2′-(Met h ylca r b a m a t e)b ib en zyl-2-yl)-ter t-b u t ylca r -
ba m a te (7a ). To a stirring solution of 14 (0.64 g, 2.3 mmol)
in 6 mL of CH2Cl2 at room temperature was added (t-Boc)2O
(0.54 g, 2.5 mmol) in one portion. The resulting mixture was
stirred at room temperature overnight and then filtered,
evaporated under reduced pressure, and recrystallized (EtOAc/
petroleum ether) to yield 7a (0.71 g, 82%) as a white solid:
13C NMR (CDCl3, 101 MHz) δ 155.13, 153.82, 135.80, 135.46,
132.65, 129.80, 129.71, 127.39, 127.29, 125.41, 125.02, 123.66,
1
122.61, 114.60, 55.79; H NMR (CDCl3, 400 MHz) δ 8.01 (dd,
1H, J ) 8.3, 1.2 Hz), 7.87 (br s, 1H), 7.77 (dd, 1H, J ) 8.0, 1.0
Hz), 7.64 (td, 1H, J ) 7.6, 1.0 Hz), 7.57 (br d, 1H, J ) 7.3 Hz),
7.52 (d, 1H, J ) 16.0 Hz), 7.46 (td, 1H, J ) 7.8, 1.3 Hz), 7.36
(td, 1H, J ) 6.7, 1.4 Hz), 7.21 (m, 1H), 7.19 (d, 1H, J ) 16.4
Hz), 7.12 (AA′BB′, 2H, νA ) νA′ ) 2848.4 Hz, νB ) νB′ ) 2754.7
Hz, J AA′ ) J BB′ ) 3.0 Hz, J AB ) J A′B′ ) 8.7 Hz, J AB′ ) J A′B ) 0
Hz), 7.00 (br s, 1H), 6.89 (AA′BB′, 2H, as above), 3.80(s, 3H);
HRFABMS calcd for C22H19N2O5 (M + H)+ 391.1294, found
391.1294. Anal. Calcd for C22H18N2O5: C, 67.69; H, 4.65; N,
7.18. Found: C, 67.68; H, 4.66; N, 7.18.
1
80.47, 52.52, 32.19, 31.96, 28.43; H NMR (CDCl3, 500 MHz)
δ 7.61 (br d, 2H, J ) 7.9 Hz), 7.26-7.17 (m, 3H), 7.16-7.10
(m, 2H), 7.08 (td, 1H, J ) 7.4, 1.3 Hz), 6.29 (br s, 1H), 6.08 (br
s, 1H), 3.72 (s, 3H), 2.87 (AA′BB′, 2H, νA ) νA′ ) 1436.0 Hz, νB
) νB′ ) 1428.7 Hz, J AA′ ) J BB′ ) 15.0 Hz, J AB ) J A′B′ ) 6.5 Hz,
J AB′ ) J A′B ) 9.0 Hz), 2.86 (AA′BB′, 2H, as above), 1.48 (s, 9H);
HRMS calcd for C21H26N2O4 (M+) 370.1893, found 370.1887.
Anal. Calcd for C21H26N2O4: C, 68.09; H, 7.07; N, 7.56.
Found: C, 67.94; H, 7.10; N, 7.32.
N-(2′-(Meth ylca r ba m a te)biben zyl-2-yl)-p-n itr op h en yl-
ca r ba m a te (7b). A mixture of 14 (0.64 g, 2.4 mmol), p-
nitrochloroformate (0.48 g, 2.4 mmol), and 0.20 mL of pyridine
in 6.5 mL of CH2Cl2 was stirred at room temperature over-
night. The reaction mixture was diluted with 100 mL of
CHCl3, washed with 1% KHSO4 (pH ∼4), dried (MgSO4), and
evaporated under reduced pressure. The yellow residue was
recrystallized (EtOAc/petroleum ether) to yield 7b (0.77 g,
74%) as a white solid: mp 157-161 °C; 1H NMR (CDCl3, 500
MHz) δ 8.26 (d, 2H, J ) 9.0 Hz), 7.68 (br d, 1H, J ) 6.0 Hz),
7.51 (br d, 1H, J ) 7.0 Hz), 7.35 (d, 2H, J ) 8.5 Hz), 7.30-
7.17 (m, 4H), 7.14 (d, 2H, J ) 4.4 Hz), 6.91 (br s, 1H), 6.21 (br
s, 1H), 3.71 (s, 3H), 3.03 (AA′BB′, 2H, νA ) νA′ ) 1514.5 Hz, νB
) νB′ ) 1479.3 Hz, J AA′ ) J BB′ ) 16.0 Hz, J AB ) J A′B′ ) 6.5 Hz,
J AB′ ) J A′B ) 7.5 Hz), 2.96 (AA′BB′, 2H, as above); HRFABMS
calcd for C23H22N3O6 (M + H)+ 436.1509, found 436.1509.
Anal. Calcd for C23H21N3O6: C, 63.44; H, 4.86; N, 9.65.
Found: C, 63.25; H, 4.88; N, 9.52.44
N-[(2′-Nit r ost ilb en -2-yl)p h en yl]-ter t-b u t ylca r b a m a t e
(15). To a solution of 12 (2.00 g, 7.3 mmol) in 10 mL of THF
at 0 °C was added 7.7 mL of a 1 M solution of NaHMDS in
THF dropwise. The reaction was stirred at 0 °C for 10 min,
11b (1.63 g, 7.4 mmol) was added in one portion, and the
reaction mixture was allowed to warm to room temperature
overnight. The reaction mixture was diluted with 100 mL of
CHCl3, washed with brine (2×), dried (MgSO4), and evaporated
under reduced pressure. The yellow residue was recrystallized
(EtOAc/petroleum ether) to yield 15 (2.00 g, 80%) as yellow
crystals: mp 130-132 °C; 13C NMR (CDCl3, 126 MHz) δ
135.78, 133.47, 133.22, 129.41, 129.16, 128.83, 128.56, 127.55,
127.15, 125.04, 124.86, 28.50; 1H NMR (CDCl3, 500 MHz) δ
8.00 (dd, 1H, J ) 8.2, 1.2 Hz), 7.76 (d, 2H, J ) 7.7 Hz), 7.63 (t,
1H, J ) 7.7 Hz), 7.54 (br d, 1H, J ) 7.6 Hz), 7.48 (d, 1H, J )
16.1 Hz), 7.45 (td, 1H, J ) 7.7, 1.4 Hz), 7.32 (td, 1H, J ) 7.8,
1.5 Hz), 7.16 (br t, 1H, J ) 7.6 Hz), 7.14 (d, 1H, J ) 16.0 Hz),
6.47 (br s, 1H), 1.53 (s, 9H); HRMS calcd for C19H20N2O4 (M+)
340.1423, found 340.1417. Anal. Calcd for C19H20N2O4: C,
67.05; H, 5.92; N, 8.23. Found: C, 67.12; H, 5.73; N, 8.01.
N-(2′-(2,2,2-Tr ich lor oeth ylca r ba m a te)biben zyl-2-yl)-p-
m eth oxyp h en ylca r ba m a te (7c). A solution of 16 (0.53 g,
1.4 mmol) in 20 mL of THF was stirred vigorously under
hydrogen (60 psi) with 5% Pd/C for 1 h. To the solution at
atmospheric pressure were added pyridine (0.12 mL, 1.5 mmol)
and 2,2,2-trichloroethyl chloroformate (0.20 mL, 1.4 mmol).
The reaction mixture was stirred at room temperature for 30
min, and the catalyst was filtered off and washed with 100
mL CHCl3. The filtrate was diluted with 100 mL of CHCl3,
washed with 5% aqueous KHSO4 and saturated aqueous
NaHCO3, dried (MgSO4), and evaporated under reduced pres-
sure. The white residue was recrystallized (EtOAc/hexane)
to yield 7c (0.62 g, 85%) as a white solid: mp 159.5-164.5 °C;
13C NMR (CDCl3, 101 MHz) δ 157.27, 153.01, 144.34, 135.23,
134.60, 130.25, 130.09, 127.75, 127.66, 126.65, 122.64, 114.53,
1
74.70, 55.80, 32.50; H NMR (CDCl3, 500 MHz) δ 7.72 (br s,
1H), 7.50 (br d, 1H, J ) 7.1 Hz), 7.29-7.18 (m, 5H), 7.14 (br
t, 1H, J ) 7.4 Hz), 7.06 (AA′BB′, 2H, νA ) νA′ ) 3529.0 Hz, νB
) νB′ ) 3437.9 Hz, J AA′ ) J BB′ ) 2.5 Hz, J AB ) J A′B′ ) 9.0 Hz,
J AB′ ) J A′B ) 0 Hz), 6.87 (AA′BB′, 2H, as above), 6.67 (br s,
1H), 6.37 (br s, 1H), 4.75 (s, 2H), 3.79 (s, 3H), 2.98 (AA′BB′,
2H, νA ) νA′ ) 1488.4 Hz, νB ) νB′ ) 1469.1 Hz, J AA′ ) J BB′
)
14.0 Hz, J AB ) J A′B′ ) 7.0 Hz, J AB′ ) J A′B ) 7.5 Hz), 2.94
(AA′BB′, 2H, as above); HRFABMS calcd for C25H24Cl3N2O5
(M + H)+ 537.0751, found 537.0749. Anal. Calcd for C25H23
-
Cl3N2O5‚?H2O: C, 54.91; H, 4.42; N, 5.12. Found: C, 55.22;
H, 4.27; N, 4.94.
N-(2′-(p-Nitr op h en ylca r ba m a te)biben zyl-2-yl)-p-m eth -
oxyp h en ylca r ba m a te (7d ). A solution of 16 (0.51 g, 1.3
mmol) in 20 mL of THF was stirred vigorously under hydrogen
(60 psi) with 5% Pd/C for 1 h. To this solution at atmospheric
pressure were added pyridine (0.12 mL, 1.5 mmol) and
p-nitrophenyl chloroformate (0.28 g, 1.4 mmol). The reaction
mixture was stirred at room temperature for 30 min, and the
catalyst was filtered off and washed with 100 mL of CHCl3.
The filtrate was diluted with 400 mL of CHCl3, washed with
3% aqueous KHSO4 (100 mL) and saturated aqueous NaHCO3
(100 mL), dried (MgSO4), and evaporated under reduced
pressure. The white residue was recrystallized (EtOAc/
hexane) to yield 7d (0.61 g, 88%) as a white solid: mp 193-
1
195 °C; H NMR (CDCl3, 400 MHz) δ 8.84 (br d, 1H, J ) 5.4
Hz), 8.18 (d, 1H, J ) 9.0 Hz), 7.63 (br m, 2H), 7.38-7.28 (m,
3H), 7.24-7.14 (m, 4H), 7.01 (AA′BB′, 2H, νA ) νA′ ) 2802.1
N-[(2′-Nitr ostilben -2-yl)p h en yl]-p-m eth oxyp h en ylca r -
ba m a te (16). A solution of 15 (1.93 g, 5.7 mmol) in 10 mL of
CH2Cl2 and 5 mL of TFA was stirred at room temperature.
Stirring was continued for 20 min after CO2 evolution ceased.
The reaction mixture was evaporated under reduced pressure
Hz, νB ) νB′ ) 2729.0 Hz, J AA′ ) J BB′ ) 2.5 Hz, J AB ) J A′B′
)
8.7 Hz, J AB′ ) J A′B ) 0 Hz), 6.82 (AA′BB′, 2H, as above), 6.82
(br s, 1H), 6.55 (br s, 1H), 3.76 (s, 3H), 3.00 (br s, 4H);
HRFABMS calcd for C29H26N3O7 (M + H)+ 528.1771, found

Cleavage of Carbamates to Isocyanates
J . Org. Chem., Vol. 63, No. 23, 1998 8521
yield 9c (39.2 mg, 88%) as a white solid: mp 206-208 °C; 13
528.1772. Anal. Calcd for C29H25N3O7‚?H2O: C, 64.92; H,
4.88; N, 7.83. Found: C, 64.99; H, 4.75; N, 7.90.41
C
NMR (DMSO-d6, 101 MHz) δ 155.65, 153.38, 137.60, 136.78,
135.18, 131.01, 129.53, 128.63, 126.50, 126.15, 126.07, 122.35,
122.20, 121.68, 96.19, 73.45, 46.63, 30.75, 30.50, 28.55, 20.08;
1H NMR (DMSO-d6, 400 MHz) δ 9.56 (br s, 1H), 7.76 (d, 1H,
J ) 8.1 Hz), 7.62 (s, 1H), 7.29 (td, 2H, J ) 8.1, 1.6 Hz), 7.23
(td, 1H, J ) 7.5, 1.7 Hz), 7.18 (td, 1H, J ) 7.3, 1.6 Hz), 7.10
(m, 2H), 6.91 (td, 1H, J ) 7.5, 1.3 Hz), 6.55 (t, 1H, J ) 5.9
Hz), 4.92 (s, 2H), 2.92 (t, 2H, J ) 6.3 Hz), 2.84 (AA′BB′, 2H,
νA ) νA′ ) 1137.0 Hz, νB ) νB′ ) 1095.3 Hz, J AA′ ) J BB′ ) 14.0
Hz, J AB ) J A′B′ ) 5.0 Hz, J AB′ ) J A′B ) 9.5 Hz), 2.74 (AA′BB′,
2H, as above), 1.86 (non, 1H, J ) 6.7 Hz), 0.87 (d, 6H, J ) 6.7
Hz); HRFABMS calcd for C22H27Cl3N3O3 (M + H)+ 486.1118,
found 486.1119. Anal. Calcd for C22H26Cl3N3O3: C, 54.28; H,
5.38; N, 8.63. Found: C, 54.43; H, 5.70; N, 8.38.
Selective Mon oa ctiva tion of Bisca r ba m a tes. N-(2′-
(ter t-Bu tylca r ba m a te)biben zyl-2-yl)isobu tylu r ea (9a ). To
a solution of 7a (50 mg, 0.13 mmol) in 2 mL of benzene were
added Et3N (23 µL, 1.2 equiv) and HSiCl3 (16 µL, 1.2 equiv).
The reaction mixture was shaken and allowed to react in a
sealed vial at room temperature for 72 h. The isocyanate was
then trapped by the addition of 0.3 mL of isobutylamine. The
resultant urea was purified by chromatography (1:7 EtOAc/
CHCl3) to yield 9a (52.7 mg, 95%) as a white solid; mp >320
°C; 13C NMR (DMSO-d6, 101 MHz) δ 155.66, 154.16, 137.64,
136.15, 135.93, 131.15, 129.28, 128.70, 126.23, 126.12, 125.02,
122.19, 121.66, 78.65, 46.62, 30.68, 28.56, 28.17, 20.06; 1H
NMR (CDCl3, 500 MHz) δ 7.84 (br d, 1H, J ) 8.2 Hz), 7.31
(dd, 1H, J ) 7.9, 1.0 Hz), 7.21-7.13 (m, 3H), 7.01 (td, 1H, J )
7.5, 1.3 Hz), 7.00 (td, 1H, J ) 7.6, 1.1 Hz), 6.63 (br s, 1H),
6.32 (s, 1H), 6.19 (s, 1H), 5.36 (br s, 1H), 2.90 (m, 2H), 2.88
(AA′BB′, 2H, νA ) νA′ ) 1150.2 Hz, νB ) νB′ ) 1122.5 Hz, J AA′
) J BB′ ) 16.0 Hz, J AB ) J A′B′ ) 5.5 Hz, J AB′ ) J A′B ) 7.5 Hz),
2.81 (AA′BB′, 2H, as above), 1.68 (non, 1H, J ) 6.7 Hz), 1.53
(s, 9H), 0.86 (d, 6H, J ) 6.7 Hz); HRFABMS calcd for
N-(2′-(p-Meth oxyph en ylcar bam ate)biben zyl-2-yl)isobu -
tylu r ea (9d ). To a solution of 7d (22.8 mg, 0.043 mmol) in 1
mL of CHCl3 were added Et3N (8 µL, 1.3 equiv) and Me3SiCl
(6 µL, 1.1 equiv). The reaction was shaken and kept at room
temperature. After 10 min, 0.2 mL of isobutylamine was
added. The reaction was determined by NMR to reach full
conversion within this time, and although the isocyanate was
not isolated, its presence was confirmed by IR spectroscopy
(Ar NCO asymmetric strech 2272.5 cm-1 (lit.42 PhNCO asym-
metric stretch ∼2275 cm-1)). After the isobutylamine was
allowed to react with the isocyanate for 1 min,46 the reaction
mixture was poured into a 1:2 mixture of 10% HCl/10% (NH4)2-
SO4. The organic layer was dried (MgSO4) and concentrated
under reduced pressure, and the resulting white solid was
dissolved in CHCl3 and evaporated in the presence of silica
gel. The silica with adsorbed residue was loaded onto a
column, and the residue was chromatographed (1:5 EtOAc/
CHCl3). The product fractions were combined, washed with
10% NaOH (2×) and water, dried (MgSO4), and concentrated
under reduced pressure to yield 9d (17.9 mg, 90%) as a white
solid: mp >320 °C; 13C NMR (DMSO-d6, 101 MHz) δ 156.54,
155.72, 153.55, 144.22, 137.65, 135.50, 131.20, 129.55, 128.74,
126.52, 126.21, 125.62, 122.76, 122.34, 121.83, 114.30, 55.41,
46.65, 30.92, 30.55, 28.58, 20.08; 1H NMR (DMSO-d6, 400
MHz) δ 9.50 (br s, 1H), 7.76 (dd, 1H, J ) 8.2, 1.1 Hz), 7.67 (s,
1H), 7.44 (dd, 1H, J ) 7.9, 1.0 Hz), 7.30 (dd, 1H, J ) 7.5, 1.5
Hz), 7.23 (td, 1H, J ) 7.7, 1.6 Hz), 7.20-7.06 (m, 5H), 6.97-
6.91 (m, 3H), 6.53 (t, 1H, J ) 5.8 Hz), 3.75 (s, 3H), 2.90 (t, 2H,
J ) 6.1 Hz), 2.90 (AA′BB′, 2H, νA ) νA′ ) 1161.6 Hz, νB ) νB′
) 1114.8 Hz, J AA′ ) J BB′ ) 14.0 Hz, J AB ) J A′B′ ) 5.5 Hz, J AB′
) J A′B ) 11.0 Hz), 2.79 (AA′BB′, 2H, as above), 1.66 (non, 1H,
J ) 6.7 Hz), 0.86 (d, 6H, J ) 6.7 Hz); HRFABMS calcd for
C
24H34N3O3 (M + H)+ 412.2600, found 412.2598. Anal. Calcd
for C24H33N3O3: C, 70.04; H, 8.08; N, 10.21. Found: C, 69.67;
H, 8.11; N, 10.04.
N-(2′-(Meth ylcar bam ate)biben zyl-2-yl)isobu tylu r ea (9b).
To a solution of 7b (48.7 Mg, 0.11 mmol) in 2 mL of CHCl3
were added Et3N (31 µL, 2 equiv) and Me2SiCl2 (27 µL, 2
equiv). The reaction mixture was shaken and allowed to react
at room temperature in a sealed vial for 1 h. The reaction
was determined by NMR to reach full conversion within this
time, and although the isocyanate was not isolated, its
presence was confirmed by IR spectroscopy (Ar NCO asym-
metric stretch 2275.6 cm-1 (lit.45 PhNCO asymmetric stretch
∼2275 cm-1)). The isocyanate was trapped by addition of 0.3
mL of isobutylamine to form the urea 9b, which was chro-
matographed (1:4 EtOAc/CHCl3), washed with 10% NaOH (2×)
and water, dried (MgSO4), and rechromatographed (1:5 EtOAc/
CHCl3) to yield 9b (40.3 mg, 98%) as a white solid: 13C NMR
(DMSO-d6, 101 MHz) δ 155.69, 155.31, 137.61, 135.91, 135.62,
131.20, 129.39, 128.70, 126.38, 126.15, 125.16, 122.30, 121.80,
1
51.74, 46.65, 30.80, 30.43, 28.58, 20.08; H NMR (CDCl3, 500
MHz) δ 7.69 (br d, 1H, J ) 7.9 Hz), 7.36 (br d, 1H, J ) 7.9
Hz), 7.24-7.16 (m, 3H), 7.10-7.03 (m, 2H), 6.85 (br s, 1H),
6.51 (s, 1H), 6.12 (s, 1H), 5.21 (br s, 1H), 3.79 (s, 3H), 2.96 (t,
2H, J ) 6.1 Hz), 2.86 (AA′BB′, 2H, νA ) νA′ ) 1454.3 Hz, νB
)
νB′ ) 1439.3 Hz, J AA′ ) J BB′ ) 14.0 Hz, J AB ) J A′B′ ) 7.0 Hz,
J AB′ ) J A′B ) 7.5 Hz), 2.83 (AA′BB′, 2H, as above), 1.70 (non,
1H, J ) 6.7 Hz), 0.88 (d, 6H, J ) 6.5 Hz); HRFABMS calcd for
C
27H32N3O4 (M+H)+ 462.2393, found 462.2394. Anal. Calcd
for C27H31N3O4‚1/3H2O : C, 69.36; H, 6.83; N, 8.99. Found: C,
C
21H28N3O3 (M + H)+ 370.2131, found 370.2131. Anal. Calcd
69.35; H, 6.78; N, 9.02.
for C21H27N3O3: C, 68.27; H, 7.37; N, 11.37. Found: C, 67.99;
H, 7.46; N, 11.06.
N-(2′-(2,2,2-Tr ich lor oet h ylca r b a m a t e)b ib en zyl-2-yl)-
isobu tylu r ea (9c). To a solution of 7c (49.0 mg, 0.091 mmol)
in 2 mL of CHCl3 were added Et3N (15 µL, 1.2 equiv) and
MeSiCl3 (13 µL, 1.2 equiv). The reaction mixture was heated
at 40 °C in a sealed vial for 49 h, after which time the reaction
was allowed to cool to room temperature and 0.3 mL of
isobutylamine was added. The reaction was determined by
NMR to reach full conversion within this time. After the
isobutylamine was allowed to react with the isocyanate for 1
min, the reaction mixture was poured into a 1:2 solution of
10% HCl/10% (NH4)2SO4. The organic layer was washed with
10% NaOH (2×), dried (MgSO4), and evaporated under re-
duced pressure in the presence of silica gel. The silica with
adsorbed residue was loaded onto a column, and the residue
was chromatographed (1:5 EtOAc/CHCl3). The product frac-
tions were combined, washed with 10% NaOH (2×) and water,
dried (MgSO4), and concentrated under reduced pressure to
Ack n ow led gm en t. We gratefully acknowledge NIH,
PRF, American Heart Association, UIUC Research
Board, and Critical Research Initiatives Program for
financial support. We would like to thank Mr. Micheal
Williams for assistance with melting point deter-
minations.
J O981816+
(42) LeCorre, M.; Hercouet, A.; LeStanc, Y.; LeBaron, H. Tetrahe-
dron 1985, 41, 5313.
(43) The spectroscopic data were in agreement with the references:
(a) Le Corre, M.; Hercouet, A.; Le Stanc, Y.; Le Baron, H. Tetrahedron
1985, 41, 5313. (b) Aboujaoude, E. E.; Collignon, N.; Savignac, P.
Tetrahedron 1985, 41, 427.
(44) No 13C NMR is reported because the compound was not
sufficiently soluble in CHCl3 and was not fully stable with more polar
solvents.
(45) Pretsch, E.; Seibl, J .; Clerc, T.; Simon, W. Tables of Spectral
Data for Structure Determination of Organic Compounds, 2nd ed.;
Springer-Verlag: Berlin Heidelberg, 1989; p 275.
(46) The short reaction time was necessary to prevent isobutylamine
from reacting with the p-methoxyphenyl carbamate, which would have
resulted in formation of the bis-urea.
(38) Baumgarten, H. E. J . Org. Chem. 1975, 40, 3554.
(39) Kita, Y.; Haruta, J .; Tagawa, H.; Tamura, Y. J . Org. Chem.
1980, 45, 4519.
(40) Witek et. al J . Prakt. Chem. 1979, 321, 804.
(41) Rai, R.; Katzenellenbogen, J . A. J . Med. Chem. 1992, 35, 4150.