A synthetic approach to N -aryl carbamates via copper-catalyzed Chan-Lam coupling at room temperature

Article abstract of DOI:10.1021/jo502828r

A mild and efficient synthesis of N-arylcarbamates was achieved by reacting azidoformates with boronic acids in the presence of 10 mol % of copper chloride catalyst. The reaction proceeds readily in an open flask at room temperature without additional base, ligand, or additive. Rapid access to urea analogues via a two-step one-pot procedure is enabled by reacting N-arylcarbamates with aluminum-amine complexes. In addition, among several boronic acid derivatives prepared, dimethylphenyl boronate was found to react rapidly in its reaction with benzyl azidoformate, invoking in situ generation of this species in the catalytic cycle.

Full text of DOI:10.1021/jo502828r

Article
pubs.acs.org/joc
A Synthetic Approach to N‑Aryl Carbamates via Copper-Catalyzed
Chan−Lam Coupling at Room Temperature
Soo-Yeon Moon,† U. Bin Kim,† Dan-Bi Sung, and Won-Suk Kim*
Department of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, South Korea
S
* Supporting Information
ABSTRACT: A mild and efficient synthesis of N-arylcarbamates was achieved by reacting azidoformates with boronic acids in
the presence of 10 mol % of copper chloride catalyst. The reaction proceeds readily in an open flask at room temperature without
additional base, ligand, or additive. Rapid access to urea analogues via a two-step one-pot procedure is enabled by reacting N-
arylcarbamates with aluminum−amine complexes. In addition, among several boronic acid derivatives prepared, dimethylphenyl
boronate was found to react rapidly in its reaction with benzyl azidoformate, invoking in situ generation of this species in the
catalytic cycle.
Curtius,6 Lossen,7 and Schmidt8 rearrangement reactions, or
INTRODUCTION
■
the reductive carbonylation of nitroaromatics (Scheme 1, eq
Carbamates are an important class of compounds found in
2).9 Even though these approaches are generally employed, the
pharmaceuticals1 and agrochemicals,2 such as pesticides,
in situ generation of aryl isocyanates via the copper- or
herbicides, insecticides, and fungicides. They serve as chemical
palladium-catalyzed cross-coupling of aryl boronic acids or aryl
intermediates in organic synthesis, protecting groups for amino
halides with potassium and sodium cyanates under elevated
functionalities, and linkers in combinatorial chemistry.3 Thus,
temperatures has been investigated in order to avoid the use of
considerable synthetic attention has been paid to the formation
toxic reagents and the generation of byproducts (Scheme 1, eq
3).10
of the carbamate linkage, which traditionally involved either the
amination of phosgene and phosgene derivatives such as acid
anhydrides and chloroformates (Scheme 1, eq 1),4 the use of
alcohols with isocyanates generated in situ via Hofmann,5
Recently, we have successfully demonstrated a Cu-catalyzed
Chan−Lam coupling reaction between sulfonyl azides and
boronic acids in our efforts to improve methods for N-
arylsulfonamide synthesis (Scheme 2).11
Scheme 1. Synthesis of N-Arylcarbamates
Scheme 2. Previously Reported Chan−Lam Coupling
between Sulfonyl Azides and Boronic Acids
Seeking to expand upon this work, we envisioned an
alternative approach to contribute to the existing methods of
carbamate synthesis. We were hopeful that our reaction, unlike
previously reported methods, would proceed under neutral and
mild conditions at room temperature without the need for any
acid, base, or ligand additive and would not require an exotic or
expensive catalyst (Scheme 1, eq 4). The N-arylcarbamates
produced by our method can be further functionalized with
Received: December 15, 2014
© XXXX American Chemical Society
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a
Table 1. Optimization of the N-Arylation Reaction of Benzyl Azidoformate 1 with Phenylboronic Acid 2
b
b
entry
Cu cat.
CuCI
equiv of 2
oxidant
solvent
time (h)
yield 3a (%)
yield 3 (%)
c
1
2
1.0
air
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
4
4
70
84
88
91
94
78
85
87
79
20
84
0
4
4
4
4
4
4
3
3
4
3
5
0
4
4
3
4
0
0
0
0
0
CuCI
CuCI
CuCI
CuCI
1.2
1.5
1.8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
air
3
air
4
4
air
2
5
air
1
d
6
CuCl
air
2
7
CuBr·S(Me)2
CuBr
air
1
8
air
3
9
Cu(OAc)2
CuS04
CuCI2
CuBr2
CuCI
air
2
10
11
12
13
14
15
16
17
18
19
20
21
air
24
12
24
24
24
1
air
air
Ag2CO3
K2S2O8
O2
20
83
90
92
0
CuCI
CuCI
CuCI
2
none
air
air
air
O2
air
24
24
24
24
24
CuCI
13
0
CuCI
iPrOH
CH2CI2
BnOH
CuCI
0
CuCI
>5
a
b
c
Reaction conditions: 1.0 mmol of benzyl azidoformate, MeOH (0.5 M), rt. Isolated yield. 1.0 mmol of phenylboronic acid, 1.2 mmol of benzyl
d
azidoformate. 5 mol % of CuCl.
aluminum−amine complexes to urea analogues in a single flask.
Furthermore, to the best of our knowledge, the Cu-catalyzed
Chan−Lam coupling reaction of azidoformates or acyclic
carbamates with boronic acids at room temperature has not yet
been reported, and while organic azides are widely used as an
amine source in general organic synthesis, special precautions
are still required.12 With these considerations in mind, we
herein report a mild and efficient synthesis of N-arylcarbamates
using boronic acids and azidoformates.
employed, lower yields were obtained (Table 1, entries 13−15).
Additionally, under an argon atmosphere, the reaction afforded
the desired product in a slightly lower 92% yield in 2 h (Table
1, entry 16), and in the absence of a copper catalyst, the
reaction failed to take place at all (Table 1, entry 17). In
addition, running the reaction in ethanol afforded the desired
product 3a in poor 13% yield in 24 h (Table 1, entry 18), and
the use of isopropanol, dichloromethane, and benzyl alcohol as
solvent afforded product either in trace amounts or not at all
(Table 1, entries 19−21).
With optimized conditions in hand, we began to examine the
scope of the Cu-catalyzed Chan−Lam coupling with respect to
various boronic acids (Table 2). Most of the reactions utilizing
the optimized conditions furnished good to excellent yields in
an open flask at room temperature. In general, arylboronic acids
with electron-neutral and electron-donating alkyl, alkoxy, and
alkenyl groups afforded the desired products 3a−3f in high
yields ranging from 87 to 95%. Naphthalene and methylene-
dioxy substituted arylboronic acids also displayed good
reactivity, affording good yields, with the latter requiring a
slightly longer reaction time to afford 3i and 3j. On the other
hand, the ortho-substituted methoxy and methyl arylboronic
acids furnished the desired products 3g and 3h in 23% and 42%
yield with 41% and 58% conversion, respectively. It is
hypothesized here that the low yield is due to either the
chelation of the metal catalyst to the methoxy group or the
moderate steric crowding provided by the ortho-methyl group
slowing down the rate of the desired coupling. Consequently,
undesired and competing homocoupling of the boronic acid
can take place with complete consumption of the boronic
acid.13 When arylboronic acids containing electron-withdrawing
groups were used as coupling partners, they showed less
RESULTS AND DISCUSSION
■
Optimization of the Cu-catalyzed Chan−Lam coupling was
initiated at room temperature employing benzyl azidoformate 1
and phenylboronic acid 2 (Table 1). When phenylboronic acid
2 was utilized as a limiting reagent in the presence of 10 mol %
of CuCl, desired N-arylcarbamate 3a was isolated in moderate
yield, along with trace amounts of methyl N-arylcarbamate 3
derived from the transesterification of 3a with MeOH (Table 1,
entry 1). However, when an excess of boronic acid was used,
the coupled product 3a was obtained in 84, 88, and 91% yield
(Table 1, entries 2−4). Finally, the use of 2.0 equiv of boronic
acid furnished 3 in 94% yield in 1 h (Table 1, entry 5). In
addition, a lower catalyst loading of 5 mol % CuCl afforded the
desired carbamate in a lower 78% yield (Table 1, entry 6).
When various copper(I) catalysts, such as CuBr·S(Me)2 and
CuBr, and copper(II) catalysts, such as Cu(OAc)2, CuSO4,
CuCl2, and CuBr2, were investigated in MeOH, all proved
inferior to CuCl in terms of yield and reaction time (Table 1,
entries 7−12). Although performing the reaction in an open
flask proved suitable for this transformation, different oxidants
were nevertheless screened under Schlenk conditions. Thus,
when Ag2CO3, K2S2O8, and pure oxygen in the place of air were
B
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the preparation of various carbamate protecting groups such as
the Fmoc, Troc, and Boc group. As shown in Table 3, most of
Table 2. Cu-Catalyzed N-Arylation of Benzyl Azidoformate 1
with Boronic Acids 4
a b c d e f
, , , , ,
Table 3. Cu-Catalyzed N-Arylation of Phenylboronic Acid 2
a b c
, ,
with Various Azidoformates 5
a
Reaction conditions: 1.0 mmol of benzyl azidoformate, 2.0 mmol of
phenylboronic acid, 10 mol % of CuCl, MeOH (0.5 M), air, rt.
MeOH:CH2Cl2 = 1:1. Trace amounts of methyl N-arylcarbamate
b
c
a
Reaction conditions: 1.0 mmol of benzyl azidoformate, 2.0 mmol
b
was observed unless otherwise noted.
boronic acid, 10 mol % of CuCl, MeOH (0.5 M), air, rt. 2.5 mmol of
boronic acid. 20 mol % of CuCl. Trace amounts of methyl N-
c
d
e
arylcarbamate was observed unless otherwise noted. Conversion.
the reactions readily proceeded at room temperature to yield
the desired carbamate product in moderate to excellent yields
within 1 h except for Fmoc azidoformate, which required a
considerably longer reaction time to reach completion due to
its poor solubility in MeOH. However, addition of CH2Cl2 to
the reaction solvent afforded the corresponding Fmoc
carbamate 5d in 63% yield in 24 h. Interestingly, when phenyl
azidoformate was used as a coupling partner, a considerable
amount of methyl N-arylcarbamate 3 was isolated in 23% yield
alongside 5e (70%), presumably due to the good leaving group
ability of the phenol moiety. Use of tert-butyl azidoformate
under the optimized reaction conditions afforded Boc
carbamate 5h in a moderate yield of 54%.
Encouraged by the viability of the Cu-catalyzed Chan−Lam
reaction for the synthesis of N-arylcarbamates, we next turned
our attention to the preparation of the N,N′-unsymmetrical
substituted ureas14 present in many biologically active
compounds in a two-step one-pot process (Scheme 3). This
would allow synthesis of N,N′-unsymmetrical ureas directly
from boronic acids. We, therefore, decided to modify the
established method, demonstrated by Clapham, Janda, and co-
workers, for the preparation of ureas from N-arylcarbamates.15
Pleasingly, addition of an aluminum−amine complex,
prepared from amines and trimethylaluminum, to the
aforementioned N-arylcarbamates obtained via the Cu-
catalyzed Cham−Lam coupling furnished multicomponent
f
Reaction time based on complete consumption of boronic acid as
determined by TLC analysis.
reactivity and provided lower yields of 3k, 3l, and 3m.
Particularly, when arylboronic acids bearing a chloro or bromo
group were used, the reaction did not go to completion due to
competitive homocoupling of the arylboronic acid. The use of
2.5 equiv of the arylboronic acid with CuCl (20 mol %),
however, furnished full conversion and gave the desired
carbamates 3l and 3m, along with a significant amount of
methyl N-arylcarbamate 3l′ and 3m′, respectively. The
tolerance of halo groups under the optimized conditions is
especially meaningful due to their potential for use in sequential
catalytic cross-coupling reactions. Non-aryl boronic acids such
as (E)-styrylboronic acid tolerated the reaction conditions,
furnishing the desired product 3o in 87% yield after 2 h.
Cyclohexylboronic acid, however, was unsuitable; the desired
product 3p was not formed even after 24 h. In the reaction
between benzyl azidoformate 1 and 3-thienylboronic acid, a
good yield of 77% was obtained in 12 h with 85% conversion
using 20 mol % of CuCl to furnish 3q. Use of furan-3-ylboronic
acid and 2-methoxy-5-pyridineboronic acid afforded less than
5% of the desired carbamates 3r and 3s.
Next, we turned our attention to the N-arylation of
phenylboronic acid 2 with a variety of azidoformates 5 for
Scheme 3. Synthesis of N-Aryl N′-Ureas from Boronic Acids and Azidoformates
C
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adducts 6a−6h in yields ranging from 70 to 94% (Table 4).16
In most instances, when heated at 70 °C, the benzyl carbamate
(Cbz) intermediate directly proceeded into the corresponding
urea in the presence of primary and secondary amines within
1−5 h. Even milder reaction conditions proved optimal in the
reaction between the crude benzyl carbamate (Cbz)
intermediate and piperidine, affording the desired urea 6e in
86% yield in 1 h at room temperature. However, in the case of
diisopropylamine, the reaction went to completion, affording
6d only when heated at 110 °C for 17 h, presumably due to the
low nucleophilicity. In addition, a chiral primary amine could
form the corresponding urea 6h with some epimerization (11%
loss of ee down to 87% ee).
Table 4. Two-Step One-Pot Synthesis of Urea Derivatives
a b
,
from Boronic Acids
To further investigate the scope of this Cu-catalyzed Chan−
Lam coupling utilizing azidoformate, various phenylboronic
acid derivatives were used as a coupling partner under the
optimized conditions (Scheme 4). When either pinacol
phenylboronate 7 or potassium phenyltrifluoroborate 8 was
used, reaction times were longer and the desired N-
arylcarbamate 3a and 3 were obtained in 6% and 11% yield,
respectively; benzyl carbamate 9 derived from reduction of the
azide was also formed (Scheme 4, eqs 1 and 2). Addition of a
catalytic amount of silica gel to the reaction with trifluoroborate
8 accelerated the reaction significantly, affording carbamate 3a
and 3 in 45% and 13% yield along with the significant amount
of benzyl carbamate 9 in 4 h (Scheme 4, eq 3). Finally, when
dimethyl phenylboronate 10 was reacted with benzyl
azidoformate 1, the desired carbamate 3a was furnished in
95% yield in 0.5 h (Scheme 4, eq 4).
From the outset of this work, it was recognized that the use
of azides as an amine source for a Chan−Lam type reaction
with boronic acids could be anticipated. With this in mind, a
control experiment where benzyl carbamate 9 and phenyl-
boronic acid 2 were reacted under traditional Chan−Lam
coupling conditions17 was designed, to highlight the unique
necessity of the azidoformate functionality in preparation of N-
a
Reaction conditions: 1.0 mmol of benzyl azidoformate, 2.0 mmol of
phenylboronic acid, 10 mol % of CuCl, MeOH (0.5 M), air, rt.
Reaction conditions: 3.0 mmol of amine, 2.5 mmol of AlMe3 in
b
toluene (2.0 M), toluene (0.5 M), argon.
a b c
, ,
Scheme 4. Cu-Catalyzed N-Arylation of Benzyl Azidoformate 1 with Boronic Acid Derivatives
a
b
Reaction conditions: 1.0 mmol of benzyl azidoformate, 2.0 mmol of boronic acid derivative, 10 mol % of CuCl, MeOH (0.5 M), air, rt. 20 mol %
c
of SiO2 was used as an additive. Conversion.
D
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aryl carbamates. Under these reaction conditions and despite
the prolonged reaction time of 48 h, the desired carbamate was
found only in trace amounts (Scheme 5, eq 1). On the other
Scheme 6. Direct Synthesis of Urea and Phosphoramide
from Organic Azides
a b
,
a b c
, ,
Scheme 5. Control Experiments
a
Reaction conditions: 1.0 mmol of azide, 2.0 mmol of phenylboronic
b
acid, 10 mol % of CuCl, MeOH (0.5 M), air, rt. Conversion.
Scheme 7. Plausible Mechanism
a
Reaction conditions: 1.0 mmol of benzyl carbamate, 2.0 mmol of
phenylboronic acid, 1.0 mmol of Cu(OAc)2, 2.0 mmol of Et3N,
b
MeOH (0.5 M), air or Ar, rt. Reaction conditions: 1.0 mmol of
benzyl azidoformate, 2.0 mmol of phenylboronic acid, 10 mol % of
c
CuCl, MeOH or MeOD (0.5 M), air, rt. Deuterium incorporation
was determined by Mass-Spec analysis. For details, see the Supporting
Information.
hand, under the optimized conditions employing benzyl
azidoformate 1 and phenylboronic acid 2, the desired
carbamate 3a was afforded in 94% in only 1 h (Scheme 5, eq
2). Next, to investigate the proton source required for the azide
reduction, we repeated the reaction using methanol-d4 as a
solvent and oxygen gas as the reaction atmosphere. (Scheme 5,
eq 3). To our surprise, although the desired product 3a was
isolated in 92% yield after a reaction time of 1 h, we found only
14.5% deuterium incorporation in the final product. In
consideration of this result, it can be hypothesized that both
the solvent and the boronic acid can act as a proton source.
Encouraged by the feasibility of Cu-catalyzed Chan−Lam
reactions using azidoformates as coupling partners for boronic
acids, we investigated the use of organic azides for the direct
preparation of ureas. Thus, in the reaction of diphenyl-
carbamoyl azide 11 with phenylboronic acid 2, urea 12 was
furnished in 11% yield after 24 h, with 26% conversion
(Scheme 6, eq 1). Despite this poor result, we next investigated
the feasibility of direct phosphoramide synthesis from its azide.
In the reaction between phenylboronic acid 2 and dimethyl
phosphorazidate 13, no phosphoramide 14 was formed,
suggesting that the reaction conditions optimized in this report
may be limited to reactions with azidoformates.
We propose the following mechanism for the coupling
reaction between azidoformates and boronic acids (Scheme
7).18 Reaction of Cu(I) salt A and an azidoformate yields
Cu(II) complex B via copper nitrene formation.19 The aryl
boronic acid, meanwhile, is in equilibrium with the methyl
boronate ester,20 which can undergo transmetalation with B to
afford Cu(II) complex C. Oxidation of C can in turn afford
Cu(III) complex D, and final reductive elimination would
furnish the coupled product carbamate E regenerating Cu(I)
catalyst A in the process.
CONCLUSION
■
In conclusion, we have described a new synthetic method for
the preparation of N-arylcarbamates via Cu-catalyzed Chan−
Lam C−N cross-coupling reactions under neutral conditions.
The reaction requires 10 mol % of CuCl catalyst in an open
flask at room temperature, without the need for any additional
additives. The scope of this method has been explored
employing different azidoformates and boronic acids. Fur-
thermore, it was found that N-arylcarbamates prepared in this
manner from boronic acids can be converted into N-aryl N′-
ureas via a two-step one-pot reaction by treatment with
aluminum−amine complexes. The rapid reaction of dimethyl-
phenyl boronate with azidoformate under the optimized
conditions has been demonstrated, presumably indicating the
reactive species for the transmetalation step in the catalytic
cycle. Direct synthesis of N-aryl N′-ureas and phosphoramides
from their corresponding azides remains a challenge, and
research into this matter is ongoing in our laboratory.
EXPERIMENTAL SECTION
■
General Considerations. Unless otherwise indicated, all chemical
reagents were purchased from commercial suppliers and were used
without further purification. All reactions were carried out in oven-
dried glassware equipped with a magnetic stir bar. Reactions were
monitored by thin-layer chromatography (TLC) with 0.25 mm
precoated silica gel plates (Kieselgel 60F254). Products were detected
E
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by viewing under a UV light, by staining with an anisaldehyde solution
composed of acetic acid, sulfuric acid, and MeOH, or by staining with
a KMnO4 solution composed of potassium carbonate, sodium
hydroxide, and water. Flash column chromatography was performed
on silica gel (70−230 mesh). Yields refer to chromatographically and
118.8, 66.9, 20.7; Data are consistent with those reported in the
literature.28
Benzyl (3,5-Dimethylphenyl)carbamate (3c). General procedure I
was used employing (3,5-dimethylphenyl)boronic acid (0.303 g, 2.02
mmol) and benzyl azidoformate (0.179 g, 1.01 mmol), and the
reaction was complete in 2 h. Flash chromatography on silica gel using
hexane/dichloromethane (2:1−1:1) provided pure 3c (0.245 g, 0.96
mmol, 95%) as a pale yellow solid. Rf 0.54 (hexane/diethyl ether =
spectroscopically pure compounds unless otherwise noted. 1H and 13
C
spectra were recorded on a 300 or 500 MHz NMR spectrometer.
Chemical shifts are reported as δ values relative to internal SiMe4 or
chloroform (δ 0.00 for 1H and δ 77.0 for 13C) or DMSO-d6 (δ 2.50 for
1H and δ 39.5 for 13C). IR spectra were measured as neat oils and
solids on an FT-IR spectrometer. HRMS data were obtained by
electron ionization with a double-focusing high-resolution magnetic
sector mass analyzer and electrospray ionization with a time-of-flight
mass analyzer.
Preparation of Azidoformate Precursors. Benzyl azidofor-
mate,21 methyl azidoformate,22 2-methoxyethyl azidoformate,23 (9H-
fluoren-9-yl)methyl azidoformate,24 phenyl azidoformate,25 2,2,2-
trichloroethyl azidoformate,26 1,1,1-trichloro-2-methylpropan-2-yl
azidoformate,26 and tert-butyl azidoformate27 were prepared as
according to cited literature procedures. Synthesis of iso-butyl
azidoformate and butyl azidoformate is as follows:
1
2:1); H NMR (300 MHz, CDCl3) δ 7.42−7.31 (m, 5H), 7.01 (s,
2H), 6.71 (d, J = 0.6 Hz, 1H), 6.57 (br, 1H), 5.19 (s, 2H), 2.28 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 153.3, 138.6, 137.5, 136.1, 128.5,
128.2, 128.19, 125.17, 116.4, 66.8, 21.3; Data are consistent with those
reported in the literature.29
Benzyl (4-Vinylphenyl)carbamate (3d). General procedure I was
used employing 4-vinylphenylboronic acid (0.311 g, 2.10 mmol) and
benzyl azidoformate (0.186 g, 1.05 mmol), and the reaction was
complete in 3 h. Flash chromatography on silica gel using hexane/
dichloromethane (2:1−1:1) provided pure 3d (0.231 g, 0.91 mmol,
87%) as a white solid. Rf 0.55 (hexane/diethyl ether = 2:1); 1H NMR
(300 MHz, CDCl3) δ 7.37−7.31 (m, 9H), 6.85 (br, 1H), 6.64 (dd, J =
17.7 and 11.1 Hz, 1H), 5.64 (d, J = 17.4 Hz, 1H), 5.19−5.13 (m, 3H);
13C NMR (75 MHz, CDCl3) δ 153.3, 137.3, 136.0, 135.9, 132.9, 128.5,
128.3, 128.2, 126.8, 118.6, 112.6, 67.0; Data are consistent with those
reported in the literature.30
Benzyl (4-Methoxyphenyl)carbamate (3e). General procedure I
was used employing 4-methoxyphenylboronic acid (0.304 g, 2.00
mmol) and benzyl azidoformate (0.177 g, 1.00 mmol), and the
reaction was complete in 2 h. Flash chromatography on silica gel using
hexane/dichloromethane (2:1−1:1) provided pure 3e (0.229 g, 0.89
mmol, 89%) as a pale yellow solid. Rf 0.20 (hexane/ethyl acetate =
5:1); 1H NMR (300 MHz, CDCl3) δ 7.41−7.27 (m, 7H), 6.84 (d, J =
9.0 Hz, 2H), 6.58 (br, 1H), 5.18 (s, 2H), 3.78 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 156.0, 153.9, 136.2, 130.9, 128.6, 128.5, 128.3, 120.8,
114.3, 66.9, 55.5; Data are consistent with those reported in the
literature.28
iso-Butyl Azidoformate. To a solution of iso-butyl chloroformate
(1.37 g, 10.0 mmol) in acetone was added sodium azide (0.759 g, 11.7
mmol), and the reaction mixture was stirred at room temperature for
12 h. The reaction mixture was then filtered and washed with acetone,
and solvent was removed in vacuo to afford iso-butyl azidoformate
(1.40 g, 9.8 mmol, 98%) as a colorless oil. Rf 0.67 (hexane/ethyl
acetate = 4:1); IR (neat) 2967, 2878, 2415, 2139, 1732, 1470, 1380,
1247, 995, 754, 562 cm−1; 1H NMR (300 MHz, CDCl3) δ 4.00 (d, J =
6.69 Hz, 2H), 2.09−1.92 (m, 1H), 0.95 (d, J = 6.77 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 157.6, 74.5, 27.7, 18.8; HRMS-EI: m/z
+
143.0689 [M+; calcd for C5H9O2N3 : 143.0695].
Butyl Azidoformate. To a solution of butyl chloroformate (1.37 g,
10.0 mmol) in acetone was added sodium azide (0.759 g, 11.7 mmol),
and the reaction mixture was stirred at room temperature for 12 h.
The reaction mixture was then filtered and washed with acetone, and
solvent was removed in vacuo to afford butyl azidoformate (1.42 g, 9.9
mmol, 99%) as a colorless oil. Rf 0.68 (hexane/ethyl acetate = 4:1); IR
Benzyl (3-Methoxyphenyl)carbamate (3f). General procedure I
was used employing 3-methoxyphenylboronic acid (0.322 g, 2.12
mmol) and benzyl azidoformate (0.188 g, 1.06 mmol), and the
reaction was complete in 1 h. Flash chromatography on silica gel using
hexane/dichloromethane (2:1−1:1) provided pure 3f (0.257 g, 1.00
mmol, 94%) as a yellow oil. Rf 0.36 (hexane/diethyl ether = 2:1); IR
(neat) 3326, 3953, 1611, 1538, 1456, 1221, 1045, 913, 768, 735, 696
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.41−7.33 (m, 5H), 7.19 (t, J =
8.1 Hz, 1H), 7.12 (s, 1H), 6.86 (dd, J = 8.0 and 1.4 Hz, 1H), 6.68 (br,
1H), 6.62 (ddd, J = 8.2, 2.5 and 0.8, 1H), 5.19 (s, 2H), 3.79 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 160.2, 153.2, 139.0, 135.9, 129.7, 128.6,
128.3, 128.2, 110.8, 109.2, 104.3, 66.9, 55.2; HRMS-ESI-TOF: m/z
1
(neat) 2965, 2186, 2137, 1730, 1249, 1060, 1021, 948, 753 cm−1; H
NMR (300 MHz, CDCl3) δ 4.22 (t, J = 6.66 Hz, 2H), 1.71−1.59 (m,
2H), 1.45−1.31 (m, 2H), 0.94 (t, J = 7.34 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 175.6, 68.5, 30.4, 18.8, 13.6; HRMS-EI: m/z 143.0689
+
[M+; calcd for C5H9O2N3 : 143.0695].
General Procedure I for Synthesis of N-Arylcarbamates. A 10
mL round-bottom flask was charged with arylboronic acid (2.0 mmol),
CuCl (10 mol %) and the corresponding azidoformate (1.0 mmol).
MeOH (2 mL) was then added to the flask. The reaction mixture was
stirred at room temperature in an open flask. After completion of the
reaction as monitored by TLC analysis, the solvent was removed in
vacuo and the residue was purified by flash column chromatography on
silica gel to obtain the desired product.
+
280.0945 [(M + Na)+; calcd for C15H15NNaO3 : 280.0944].
Benzyl (2-Methoxyphenyl)carbamate (3g). General procedure I
was used employing 2-methoxyphenylboronic acid (0.403 g, 2.65
mmol) and benzyl azidoformate (0.187 g, 1.06 mmol), and the
reaction was complete in 5 h. Flash chromatography on silica gel using
hexane/diethyl ether (20:1) provided pure 3g (0.062 g, 0.24 mmol,
23%) as a yellow oil. Rf 0.39 (hexane/dichloromethane = 1:1); IR
(neat) 3424, 2925, 1728, 1601, 1459, 1332, 1212, 1037, 847, 744, 581
cm−1; 1H NMR (300 MHz, CDCl3) δ 8.20−8.09 (m, 1H), 7.50−7.33
(m, 6H), 7.08−6.95 (m, 2H), 6.91−6.84 (m, 1H), 5.24 (s, 2H), 3.87
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 153.2, 147.5, 136.2, 128.6,
128.3, 127.5, 122.8, 121.1, 118.1, 112.5, 109.9, 66.9, 55.6; HRMS-ESI-
Benzyl Phenylcarbamate (3a). General procedure I was used
employing phenylboronic acid (0.245 g, 2.02 mmol) and benzyl
azidoformate (0.179 g, 1.01 mmol), and the reaction was complete in
1 h. Flash chromatography on silica gel using hexane/dichloromethane
(2:1−1:1) provided pure 3a (0.216 g, 0.95 mmol, 94%) as a pale
1
yellow solid. Rf 0.55 (hexane/diethyl ether = 2:1); H NMR (300
MHz, CDCl3) δ 7.45−7.28 (m, 9H), 7.07 (t, J = 7.2 Hz, 1H), 6.68 (br,
1H), 5.21 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 153.4, 137.7, 135.9,
128.9, 128.5, 128.2, 128.17, 123.4, 118.7, 66.9; Data are consistent with
those reported in the literature.28
+
TOF: m/z 280.0945 [(M + Na)+; calcd for C15H15NNaO3 :
280.0944].
Benzyl p-Tolylcarbamate (3b). General procedure I was used
employing p-tolylboronic acid (0.283 g, 2.08 mmol) and benzyl
azidoformate (0.184 g, 1.04 mmol), and the reaction was complete in
2 h. Flash chromatography on silica gel using hexane/dichloromethane
(2:1−1:1) provided pure 3b (0.229 g, 0.95 mmol, 91%) as a white
solid. Rf 0.49 (hexane/diethyl ether = 2:1); 1H NMR (300 MHz,
CDCl3) δ 7.43−7.33 (m, 5H), 7.26 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4
Hz, 2H), 6.61 (br, 1H), 5.19 (s, 2H), 2.30 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 153.4, 136.1, 135.1, 133.1, 129.5, 128.6, 128.3, 128.28,
Benzyl o-Tolylcarbamate (3h). General procedure I was used
employing o-tolylboronic acid (0.343 g, 2.52 mmol) and benzyl
azidoformate (0.179 g, 1.01 mmol), and the reaction was complete in
12 h. Flash chromatography on silica gel using hexane/ethyl acetate
(10:1) provided pure 3h (0.102 g, 0.42 mmol, 42%) as a white solid. Rf
0.63 (hexane/ethyl acetate = 3:1); 1H NMR (300 MHz, DMSO-d6) δ
9.00 (br, 1H), 7.48−7.32 (m, 6H), 7.23−7.13 (m, 2H), 7.11−7.02 (m,
1H), 5.15 (s, 2H), 2.21 (s, 3H); 13C NMR (125 MHz, DMSO-d6, 350
K) δ 153.9, 136.6, 136.1, 131.4, 129.9, 128.0, 127.4, 127.38, 125.6,
F
DOI: 10.1021/jo502828r
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
124.5, 124.3, 65.4, 17.2; Data are consistent with those reported in the
literature.28
tert-Butyl 4-(((Benzyloxy)carbonyl)amino)benzoate (3n). General
procedure I was used employing 4-(tert-butoxycarbonyl) phenyl-
boronic acid (0.443 g, 1.90 mmol) and benzyl azidoformate (0.168 g,
0.95 mmol), and the reaction was complete in 4 h. Flash
chromatography on silica gel using hexane/dichloromethane (2:1−
1:1) provided pure 3n (0.170 g, 0.52 mmol, 55%) a pale yellow solid.
mp: 123−124 °C; Rf 0.75 (hexane/ethyl acetate = 2:1); IR (neat)
3323, 2980, 1716, 1599, 1301, 1221, 1168, 1048, 857, 773, 694 cm−1;
1H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 8.4 Hz, 2H), 7.45 (d, J =
8.7 Hz, 2H), 7.33 (m, 6H), 5.17 (s, 2H), 1.57 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 165.4, 153.0, 141.8, 135.7, 130.6, 128.5, 128.3, 128.2,
126.5, 117.4, 80.7, 67.1, 28.1; HRMS-ESI-TOF: m/z 350.1362 [(M +
Benzyl Naphthalen-2-ylcarbamate (3i). General procedure I was
used employing naphthalene-2-ylboronic acid (0.355 g, 2.06 mmol)
and benzyl azidoformate (0.183 g, 1.03 mmol), and the reaction was
complete in 1 h. Flash chromatography on silica gel using hexane/
dichloromethane (2:1−1:1) provided pure 3i (0.261 g, 0.94 mmol,
1
91%) as a pale yellow solid. Rf 0.50 (hexane/diethyl ether = 2:1); H
NMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.76 (d, J = 8.6 Hz, 3H),
7.47−7.34 (m, 8H), 6.86 (br, 1H), 5.23 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 153.4, 135.9, 135.2, 133.8, 130.1, 128.8, 128.6, 128.3,
128.26, 127.5, 127.3, 126.4, 124.6, 119.1, 114.9, 67.0; Data are
consistent with those reported in the literature.29
+
Na)+; calcd for C19H21NNaO4 : 350.1363].
Benzyl Benzo[d][1,3]dioxol-5-ylcarbamate (3j). General procedure
I was used employing 3,4-(methylenedioxy)phenylboronic acid (0.332
g, 2.00 mmol) and benzyl azidoformate (0.177 g, 1.00 mmol), and the
reaction was complete in 3 h. Flash chromatography on silica gel using
hexane/dichloromethane (2:1−1:1) provided pure 3j (0.255 g, 0.94
mmol, 94%) as a white solid. mp: 97−99 °C; Rf 0.33 (hexane/diethyl
ether = 2:1); IR (neat) 3407, 3328, 1699, 1545, 1255, 1055, 837, 776,
(E)-Benzyl Styrylcarbamate (3o). General procedure I was used
employing (E)-styrylboronic acid (0.296 g, 2.00 mmol) and benzyl
azidoformate (0.177 g, 1.00 mmol), and the reaction was complete in
2 h. Flash chromatography on silica gel using hexane/ethyl acetate
(10:1) provided pure 3o (0.220 g, 0.87 mmol, 87%) as a white solid. Rf
1
0.57 (hexane/ethyl acetate = 3:1); H NMR (300 MHz, CDCl3) δ
9.00 (br, 1H), 7.44−7.12 (m, 11H), 6.61 (d, J = 10.5 Hz, 1H), 5.96 (d,
J = 14.5 Hz, 1H), 5.19 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 153.5,
136.1, 135.7, 128.6, 128.55, 128.4, 128.2, 126.3, 125.2, 123.9, 110.9,
67.3; Data are consistent with those reported in the literature.34
Benzyl Thiophen-3-ylcarbamate (3q). General procedure I was
used employing 3-thiopheneboronic acid (0.354 g, 2.77 mmol) and
benzyl azidoformate (0.196 g, 1.10 mmol), and the reaction was
complete in 12 h. Flash chromatography on silica gel using hexane/
dichloromethane (2:1−1:1) provided pure 3q (0.198 g, 0.85 mmol,
77%) as a pale brown solid. mp: 60−61 °C; Rf 0.53 (hexane/ethyl
acetate = 5:1); IR (neat) 3404, 3336, 2957, 2332, 1700, 1250, 1219,
1
735, 696, 620 cm−1; H NMR (300 MHz, CDCl3) δ 7.42−7.34 (m,
5H), 7.09 (s, 1H), 6.74−6.65 (m, 2H), 6.52 (br, 1H), 5.94 (s, 2H),
5.19 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 153.6, 147.9, 143.8,
136.0, 132.0, 128.6, 128.3, 128.27, 111.9, 108.0, 101.8, 101.2, 67.0;
HRMS-ESI-TOF: m/z 294.0735 [(M
C15H13NNaO4 : 294.0737].
+
Na)+; calcd for
+
Benzyl (4-Fluorophenyl)carbamate (3k). General procedure I was
used employing 4-fluorophenylboronic acid (0.283 g, 2.02 mmol) and
benzyl azidoformate (0.179 g, 1.01 mmol), and the reaction was
complete in 4 h. Flash chromatography on silica gel using hexane/
dichloromethane (2:1−1:1) provided pure 3k (0.186 g, 0.76 mmol,
75%) as a pale yellow solid. mp: 69−70 °C; Rf 0.38 (hexane/diethyl
ether = 2:1); IR (neat) 3323, 3072, 1884, 1697, 1522, 1219, 1068, 832,
1
1052, 839, 695, 621 cm−1; H NMR (300 MHz, CDCl3) δ 7.42−7.30
(m, 5H), 7.28−7.14 (m, 2H), 6.99−6.83 (m, 2H), 5.19 (s, 2H); 13C
NMR (75 MHz, CDCl3) δ 153.5, 135.9, 135.5, 128.5, 128.2, 128.1,
124.7, 120.7, 108.0, 67.0; HRMS-ESI-TOF: m/z 256.0402 [(M +
Na)+; calcd for C12H11NNaO2S+: 256.0403].
1
737, 693, 519 cm−1; H NMR (300 MHz, CDCl3) δ 7.41−7.31 (m,
7H), 7.01 (t, J = 8.4 Hz, 2H), 6.61 (br, 1H), 5.20 (s, 2H); 13C NMR
(75 MHz, CDCl3) δ 158.9 (d, J = 240.9 Hz), 153.6, 135.9, 133.7,
128.5, 128.3, 128.2, 120.5, 115.5 (d, J = 22.4 Hz), 67.0; HRMS-ESI-
Methyl Phenylcarbamate (3). General procedure I was used
employing phenylboronic acid (0.245 g, 2.02 mmol) and methyl
azidoformate (0.102 g, 1.01 mmol), and the reaction was complete in
1 h. Flash chromatography on silica gel using hexane/dichloromethane
(2:1−1:1) provided pure 3 (0.141 g, 0.93 mmol, 92%) as a white solid.
+
TOF: m/z 268.0745 [(M + Na)+; calcd for C14H12FNNaO2 :
268.0744].
Benzyl (4-Chlorophenyl)carbamate (3l) and Methyl (4-Chloro-
phenyl)carbamate (3l′). General procedure I was used employing 4-
chlorophenylboronic acid (0.391 g, 2.50 mmol) and benzyl azido-
formate (0.177 g, 1.00 mmol), and the reaction was complete in 7 h.
Flash chromatography on silica gel using hexane/dichloromethane
(2:1−1:1) provided pure 3l (0.175 g, 0.67 mmol, 67%) as a pale
1
Rf 0.40 (hexane/diethyl ether = 2:1); H NMR (300 MHz, CDCl3) δ
7.42−7.33 (m, 2H), 7.25−7.33 (m, 2H), 7.05 (t, J = 7.3 Hz, 1H), 6.86
(br, 1H), 3.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.1, 137.8,
128.9, 123.4, 118.7, 52.2; Data are consistent with those reported in
the literature.35
1
yellow solid. Rf 0.45 (hexane/diethyl ether = 2:1); H NMR (300
iso-Butyl Phenylcarbamate (5a). General procedure I was used
employing phenylboronic acid (0.244 g, 2.00 mmol) and iso-butyl
azidoformate (0.143 g, 1.00 mmol), and the reaction was complete in
1 h. Flash chromatography on silica gel using hexane/ethyl acetate
(20:1) provided pure 5a (0.168 g, 0.87 mmol, 87%) as a white solid. Rf
MHz, CDCl3) δ 7.41−7.32 (m, 7H), 7.28−7.24 (m, 2H), 6.67 (br,
1H), 5.20 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 153.3, 136.3, 135.7,
128.9, 128.7, 128.5, 128.3, 128.2, 120.0, 67.1; Data are consistent with
those reported in the literature;28 and 3l′ (0.026 g, 0.14 mmol, 14%)
1
1
as a pale yellow solid. Rf 0.39 (hexane/diethyl ether = 2:1); H NMR
0.60 (hexane/ethyl acetate = 4:1); H NMR (300 MHz, CDCl3) δ
(300 MHz, CDCl3) δ 7.43−7.23 (m, 4H), 6.64 (br, 1H), 3.77 (s, 3H);
7.45−7.34 (m, 2H), 7.34−7.26 (m, 2H), 7.10−7.01 (m, 1H), 6.68 (br,
1H), 3.95 (d, J = 6.67 Hz, 2H), 2.07−1.87 (m, 1H), 0.97 (d, J = 6.76
Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 153.9, 138.1, 129.2, 123.5,
118.8, 71.5, 28.1, 19.2; Data are consistent with those reported in the
literature.36
13C NMR (75 MHz, CDCl3) δ 153.8, 136.4, 129.0, 128.5, 119.9, 52.5;
Data are consistent with those reported in the literature.31
Benzyl (4-Bromophenyl)carbamate (3m) and Methyl (4-Bromo-
phenyl)carbamate (3m′). General procedure I was used employing 4-
bromophenylboronic acid (0.418 g, 2.08 mmol) and benzyl azido-
formate (0.185 g, 1.04 mmol), and the reaction was complete in 3 h.
Flash chromatography on silica gel using hexane/dichloromethane
(2:1−1:1) provided pure 3m (0.196 g, 0.64 mmol, 62%) as a pale
Butyl Phenylcarbamate (5b). General procedure I was used
employing phenylboronic acid (0.244 g, 2.00 mmol) and butyl
azidoformate (0.143 g, 1.00 mmol), and the reaction was complete in
1 h. Flash chromatography on silica gel using hexane/ethyl acetate
(20:1) provided pure 5b (0.156 g, 0.81 mmol, 81%) as a white solid. Rf
1
yellow solid. Rf 0.67 (hexane/ethyl acetate = 2:1); H NMR (300
1
MHz, CDCl3) δ 7.38−7.32 (m, 7H), 7.24 (d, J = 8.8 Hz, 2H), 6.87
(br, 1H), 5.16 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 153.2, 136.8,
135.7, 131.9, 128.6, 128.4, 128.2, 120.2, 115.9, 67.1; Data are
consistent with those reported in the literature;32 and 3m′ (0.032 g,
0.14 mmol, 13%) as a pale yellow solid. Rf 0.50 (hexane/ethyl acetate
= 2:1); 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J = 8.8 Hz, 2H), 7.28
(d, J = 8.8 Hz, 2H), 6.78 (br, 1H), 3.77 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 153.9, 136.9, 131.9, 120.2, 115.9, 52.4; Data are consistent
with those reported in the literature.33
0.58 (hexane/ethyl acetate = 4:1); H NMR (300 MHz, CDCl3) δ
7.44−7.23 (m, 4H), 7.00−7.11 (m, 1H), 6.16 (br, 1H), 4.17 (t, J =
6.72 Hz, 2H), 1.72−1.57 (m, 2H), 1.50−1.34 (m, 2H), 0.95 (t, J =
7.36 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 153.9, 138.1, 129.2,
123.5, 118.8, 65.3, 31.1, 19.2, 13.9; Data are consistent with those
reported in the literature.37
2-Methoxyethyl Phenylcarbamate (5c). General procedure I was
used employing phenylboronic acid (0.244 g, 2.00 mmol) and 2-
methoxyethyl azidoformate (0.145 g, 1.00 mmol), and the reaction was
G
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The Journal of Organic Chemistry
Article
complete in 1 h. Flash chromatography on silica gel using hexane/
ethyl acetate (10:1−4:1) provided pure 5c (0.130 g, 0.67 mmol, 67%)
as a colorless oil. Rf 0.30 (hexane/ethyl acetate = 4:1); 1H NMR (300
MHz, CDCl3) δ 7.41−7.33 (m, 2H), 7.36−7.24 (m, 2H), 7.09−7.01
(m, 1H), 6.99 (br, 1H), 4.32 (t, J = 4.54 Hz, 2H), 3.63 (t, J = 4.54 Hz,
2H), 3.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 153.5, 137.9, 129.1,
123.5, 118.8, 70.8, 64.1, 59.0; Data are consistent with those reported
in the literature.38
(9H-Fluoren-9-yl)methyl Phenylcarbamate (5d). General proce-
dure I was used employing phenylboronic acid (0.257 g, 2.10 mmol)
and (9H-fluoren-9-yl)methyl azidoformate (0.280 g, 1.10 mmol) in
MeOH/dichloromethane (1:1), and the reaction was complete in 24
h. Flash chromatography on silica gel using hexane/ethyl acetate
(20:1−2:1) provided pure 5d (0.212 g, 0.69 mmol, 63%) as an off-
white solid. Rf 0.64 (hexane/ethyl acetate = 4:1); 1H NMR (300 MHz,
CDCl3) δ 7.86−7.75 (m, 2H), 7.71−7.58 (m, 2H), 7.50−7.22 (m,
8H), 7.16−7.03 (m, 1H), 6.65 (br, 1H), 4.57 (d, J = 6.52 Hz, 2H),
4.31 (t, J = 6.52 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 153.4, 143.8,
141.4, 137.7, 129.1, 127.8, 127.1, 124.9, 123.6, 120.1, 118.8, 66.8, 47.1;
Data are consistent with those reported in the literature.39
the flask containing crude carbamate solution, and the reaction mixture
was stirred at a specified temperature. Upon completion of the
reaction, water was added, followed by excess potassium sodium
tartrate (Rochelle’s salt) and EtOAc. The reaction mixture was
extracted with EtOAc (×3), and the organic layer was washed once
with brine. The combined organic extracts were dried over MgSO4 and
filtered, and the solvent was removed in vacuo. The crude product was
purified via flash column chromatography to afford the desired urea.
N-Phenylmorpholine-4-carboxamide (6a). General procedure II
was used employing phenylboronic acid (0.292 g, 2.40 mmol), benzyl
azidoformate (0.188 g, 1.06 mmol), morpholine (0.21 mL, 3.50
mmol), and 2.0 M AlMe3 in toluene (1.45 mL, 2.90 mmol), and the
reaction was complete in 4 h at 70 °C. Flash chromatography on silica
gel using hexane/ethyl acetate (3:1) provided pure 6a (0.179 g, 0.87
mmol, 82%) as a white solid. mp: 150−152 °C; Rf 0.13 (hexane/ethyl
acetate = 1:1); IR (neat) 3275, 2858, 1594, 1445, 1250, 1116, 748, 694
cm−1; 1H NMR (300 MHz, CDCl3) δ 7.38−7.21 (m, 4H), 7.09−6.99
(m, 1H), 6.63 (br, 1H), 3.73−3.62 (m, 4H), 3.49−3.38 (m, 4H); 13C
NMR (75 MHz, CDCl3) δ 155.4, 138.9, 129.0, 123.5, 120.4, 66.6,
44.3; HRMS-ESI-TOF: m/z 229.0947 [(M + Na)+; calcd for
+
Phenyl Phenylcarbamate (5e). General procedure I was used
employing phenylboronic acid (0.284 g, 2.33 mmol) and phenyl
azidoformate (0.190 g, 1.16 mmol), and the reaction was complete in
1 h. Flash chromatography on silica gel using hexane/ethyl acetate
(10:1) provided pure 5e (0.172 g, 0.81 mmol, 70%) as an off-white
solid. Rf 0.45 (hexane/ethyl acetate = 4:1); 1H NMR (300 MHz,
C11H14N2NaO2 : 229.0947].
1-(3,5-Dimethylphenyl)-3-phenylurea (6b). General procedure II
was used employing (3,5-dimethylphenyl)boronic acid (0.325 g, 2.20
mmol), benzyl azidoformate (0.195 g, 1.10 mmol), aniline (0.32 mL,
3.50 mmol), and 2.0 M AlMe3 in toluene (1.45 mL, 2.90 mmol), and
the reaction was complete in 2 h at 70 °C. Flash chromatography on
silica gel using hexane/ethyl acetate (3:1) provided pure 6b (0.271 g,
0.92 mmol, 84%) as a white solid. Rf 0.24 (hexane/ethyl acetate =
CDCl3) δ 7.50−7.15 (m, 9H), 7.15−7.06 (m, 1H), 6.94 (br, 1H); 13
C
NMR (75 MHz, CDCl3) δ 150.6, 137.4, 129.4, 129.2, 125.7, 123.9,
121.7, 120.9, 118.7; Data are consistent with those reported in the
literature.40
1
4:1); H NMR (300 MHz, CDCl3) δ 7.37−7.27 (m, 4H), 7.15−7.03
(m, 1H), 6.94 (s, 2H), 6.76 (s, 2H), 6.62 (s, 1H), 2.27 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 153.6, 139.3, 138.2, 137.7, 129.4, 126.5,
124.3, 121.1, 119.5, 21.5; Data are consistent with those reported in
the literature.43
2,2,2-Trichloroethyl Phenylcarbamate (5f). General procedure I
was used employing phenylboronic acid (0.244 g, 2.00 mmol) and
2,2,2-trichloroethyl azidoformate (0.218 g, 1.00 mmol), and the
reaction was complete in 1 h. Flash chromatography on silica gel using
hexane/ethyl acetate (20:1−2:1) provided pure 5f (0.213 g, 0.74
mmol, 74%) as a white solid. Rf 0.63 (hexane/ethyl acetate = 4:1); 1H
NMR (300 MHz, CDCl3) δ 7.48−7.36 (m, 2H), 7.36−7.25 (m, 2H),
7.15−6.98 (m, 2H), 4.81 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
151.7, 137.1, 129.3, 124.3, 119.1, 95.4, 74.6; Data are consistent with
those reported in the literature.41
N-(3,5-Dimethylphenyl)piperidine-1-carboxamide (6c). General
procedure II was used employing (3,5-dimethylphenyl)boronic acid
(0.318 g, 2.12 mmol), benzyl azidoformate (0.188 g, 1.06 mmol),
piperidine (0.20 mL, 3.04 mmol), and 2.0 M AlMe3 in toluene (1.25
mL, 2.50 mmol), and the reaction was complete in 5 h at 70 °C. Flash
chromatography on silica gel using hexane/ethyl acetate (3:1)
provided pure 6c (0.260 g, 1.01 mmol, 95%) as a white solid. mp:
236−240 °C; Rf 0.12 (hexane/ethyl acetate = 4:1); IR (neat) 3322,
1,1,1-Trichloro-2-methylpropan-2-yl phenylcarbamate (5g).
General procedure I was used employing phenylboronic acid (0.244
g, 2.00 mmol) and 1,1,1-trichloro-2-methylpropan-2-yl azidoformate
(0.247 g, 1.00 mmol), and the reaction was complete in 1 h. Flash
chromatography on silica gel using hexane/ethyl acetate (40:1−10:1)
provided pure 5g (0.194 g, 0.65 mmol, 65%) as a white solid. mp:
112−114 °C; Rf 0.72 (hexane/ethyl acetate = 4:1); IR (neat) 3318, 31
1
2935, 2855, 1616, 1554, 1271, 1233, 1028, 838 cm−1; H NMR (300
MHz, CDCl3) δ 7.00 (s, 2H), 6.66 (s, 1H), 6.28 (br, 1H), 3.61−3.35
(m, 4H), 2.27 (s, 6H), 1.70−1.52 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 155.2, 139.2, 138.6, 124.7, 117.7, 45.4, 25.8, 24.5, 21.5;
HRMS-ESI-TOF: m/z 255.1467 [(M + Na)+; calcd for C14H20-
N2NaO+: 255.1468].
1
32, 2359, 1701, 1598, 1540, 1445, 1371, 1243, 1049, 800 cm−1; H
1,1-Diisopropyl-3-phenylurea (6d). General procedure II was used
employing phenylboronic acid (0.283 g, 2.32 mmol), benzyl
azidoformate (0.206 g, 1.16 mmol), diisopropylamine (0.50 mL,
3.50 mmol), and 2.0 M AlMe3 in toluene (1.45 mL, 2.90 mmol), and
the reaction was complete in 17 h at 110 °C. Flash chromatography on
silica gel using hexane/ethyl acetate (5:1) provided pure 6d (0.179 g,
0.81 mmol, 70%) as a white solid. Rf 0.30 (hexane/ethyl acetate =
NMR (300 MHz, CDCl3) δ 7.26−7.46 (m, 4H), 7.15−7.02 (m,1H),
6.72 (br, 1H), 1.99 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 151.1,
137.6, 129.2, 123.9, 118.9, 106.4, 89.0, 21.8; HRMS-ESI-TOF: m/z
+
317.9825 [(M + Na)+; calcd for C11H12Cl3NNaO2 : 317.9826].
tert-Butyl Phenylcarbamate (5h). General procedure I was used
employing phenylboronic acid (0.283 g, 2.32 mmol) and tert-butyl
azidoformate (0.167 g, 1.17 mmol), and the reaction was complete in
1 h. Flash chromatography on silica gel using hexane/ethyl acetate
(20:1) provided pure 5h (0.122 g, 0.63 mmol, 54%) as a white solid. Rf
1
4:1); H NMR (300 MHz, CDCl3) δ 7.40−7.33 (m, 2H), 7.32−7.23
(m, 2H), 7.05−6.95 (m, 1H), 6.18 (br, 1H), 4.07−3.90 (m, 2H), 1.33
(d, J = 6.85 Hz, 12H); 13C NMR (75 MHz, CDCl3) δ 154.7, 139.5,
128.9, 122.7, 119.8, 45.6, 21.6; Data are consistent with those reported
in the literature.44
1
0.63 (hexane/ethyl acetate = 20:1); H NMR (300 MHz, CDCl3) δ
7.20−7.43 (m, 4H), 6.96−7.10 (m, 1H), 6.48 (br, 1H), 1.52 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 152.7, 138.3, 128.9, 123.0, 118.5, 80.5,
28.3; Data are consistent with those reported in the literature.42
General Procedure II for Synthesis of N-Aryl N′-Ureas. To a
solution of amine (3.0 mmol) in toluene (5 mL) at 0 °C was added
dropwise a solution of AlMe3 (2.0 M in toluene, 2.5 mmol), and the
solution was stirred at 0 °C for 10 min. The reaction mixture was then
warmed to r.t. and stirred for 1 h. In another flask, general procedure I
for the synthesis of the carbamate was followed, and the MeOH was
removed in vacuo to afford the crude carbamate. Without purification,
toluene (3 mL) was added under argon and the solution cooled to 0
°C. The prepared aluminum amide solution was then cannulated into
N-Phenylpiperidine-1-carboxamide (6e). General procedure II was
used employing phenylboronic acid (0.259 g, 2.12 mmol), benzyl
azidoformate (0.188 g, 1.06 mmol), piperidine (0.30 mL, 3.03 mmol),
and 2.0 M AlMe3 in toluene (1.25 mL, 2.50 mmol), and the reaction
was complete in 1 h at rt. Flash chromatography on silica gel using
hexane/ethyl acetate (10:1) provided pure 6e (0.185 g, 0.91 mmol,
86%) as a white solid. Rf 0.12 (hexane/ethyl acetate = 4:1); 1H NMR
(300 MHz, CDCl3) δ 7.40−7.31 (m, 2H), 7.31−7.23 (m, 2H), 7.07−
6.96 (m, 1H), 6.34 (br, 1H), 3.54−3.33 (m, 4H), 1.74−1.50 (m 6H);
13C NMR (75 MHz, CDCl3) δ 155.1, 139.4, 129.0, 123.0, 119.9, 45.4,
25.8, 24.5; Data are consistent with those reported in the literature.45
H
DOI: 10.1021/jo502828r
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
N-(Benzo[d][1,3]dioxol-5-yl)morpholine-4-carboxamide (6f).
General procedure II was used employing 3,4-(methylenedioxy)-
phenylboronic acid (0.330 g, 1.99 mmol), benzyl azidoformate (0.176
g, 0.99 mmol), morpholine (0.26 mL, 3.00 mmol), and 2.0 M AlMe3 in
toluene (1.25 mL, 2.50 mmol), and the reaction was complete in 2 h at
70 °C. Flash chromatography on silica gel using dichloromethane/
ethyl acetate (1:0−3:1) provided pure 6f (0.220 g, 0.88 mmol, 89%) as
a white solid. Rf 0.11 (dichloromethane/ethyl acetate = 10:1); 1H
NMR (300 MHz, CDCl3) δ 7.02 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.3
and 0.3 Hz, 1H), 6.62 (dd, J = 8.4 and 2.1 Hz, 1H), 6.30 (br, 1H), 5.93
(s, 2H), 3.72 (t, J = 5.0 Hz, 4H), 3.45 (t, J = 5.0 Hz, 4H); 13C NMR
(75 MHz, CDCl3) δ 155.7, 147.6, 143.8, 132.8, 114.0, 107.8, 104.0,
101.1, 66.4, 44.1; Data are consistent with those reported in the
literature.46
126.7, 123.3, 119.3; Data are consistent with those reported in the
literature.15
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H, 13C spectra and HRMS data for all novel
compounds prepared and chiral HPLC trace for 6h. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wonsukk@ewha.ac.kr (W.-S.K.).
■
N-(3-Methoxyphenyl)morpholine-4-carboxamide (6g). General
procedure II was used employing 3-methoxyphenylboronic acid
(0.348 g, 2.29 mmol), benzyl azidoformate (0.203 g, 1.14 mmol),
piperidine (0.30 mL, 3.42 mmol), and 2.0 M AlMe3 in toluene (1.43
mL, 2.85 mmol), and the reaction was complete in 2 h at 70 °C. Flash
chromatography on silica gel using dichloromethane/ethyl acetate
(1:0−3:1) provided pure 6g (0.253 g, 1.07 mmol, 94%) as a pale
orange solid. mp: 106−107 °C; Rf 0.11 (dichloromethane/ethyl
acetate = 10:1); IR (neat) 3302, 2850, 2363, 1635, 1463, 1251, 1038,
Author Contributions
†S.-Y. Moon and U. B. Kim contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) (NRF-2012R1A1A1006123) and the New & Renew-
able Energy of the Korea Institute of Energy Technology
Evaluation and Planning (KETEP) grant (No.
20133030000210).
1
783, 576 cm−1; H NMR (300 MHz, CDCl3) δ7.18 (t, J = 8.1 Hz,
1H), 7.12 (t, J = 2.2 Hz, 1H), 6.83 (ddd, J = 8.0, 2.0, and 0.8 Hz, 1H),
6.61 (ddd, J = 8.3, 2.5, and 0.8 Hz, 1H), 6.38 (br, 1H), 3.79 (s, 3H),
3.74 (t, J = 4.7 Hz, 4H), 3.47 (t, J = 4.7 Hz, 4H); 13C NMR (75 MHz,
CDCl3) δ 160.1, 155.1, 140.0, 129.5, 112.2, 109.1, 105.8, 66.4, 55.2,
44.2; HRMS-ESI-TOF: m/z 259.1053 [(M + Na)+; calcd for
+
C12H16N2NaO3 : 259.1053].
REFERENCES
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pale yellow solid. mp: 148−150 °C; [α]D20 −8.03 (c 1.00, CHCl3); Rf
0.50 (hexane/ethyl acetate = 2:1); IR (neat) 3316, 2986, 2971, 2363,
■
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2337, 1635, 1558, 1231, 1038, 668, 501 cm−1; H NMR (300 MHz,
CDCl3) δ 7.32−7.18 (m, 10H), 7.00−6.94 (m, 1H), 5.80 (d, J = 7.4
Hz, 1H), 4.88 (m, 1H), 1.32 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 155.6, 144.1, 138.8, 129.0, 128.6, 127.1, 125.8, 123.1, 120.1,
49.8, 22.9; HRMS-ESI-TOF: m/z 263.1156 [(M + Na)+; calcd for
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Preparation of Azide Precursors (Scheme 6). Diphenylcarba-
moyl azide (12) was prepared as according to the cited literature
procedure.47 Synthesis of dimethyl phosphorazidate is as follows:
Dimethyl Phosphorazidate (13). To a solution of dimethylchloro
phosphate (2.68 g, 18.5 mmol) in acetone (50 mL) was added sodium
azide (2.59 g, 37.0 mmol), and the reaction mixture was stirred at
room temperature for 12 h. The reaction mixture was then filtered,
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using hexane/ethyl acetate (10:1) provided pure 13 (1.79 g, 11.9
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IR (neat) 3423, 3011, 2962, 2859, 2170, 1453, 1273, 1188, 1047, 802,
1
602, 445 cm−1; H NMR (300 MHz, CDCl3) δ 3.85 (d, J = 12.0 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 54.9; 31P NMR (120 MHz,
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151.0141].
Direct Synthesis of Urea (Scheme 5). 1,1,3-Triphenylurea (12).
To a solution of diphenylcarbamoyl azide (0.55 g, 2.30 mmol) in
MeOH (4.6 mL) was added phenylboronic acid (0.56 g, 4.59 mmol)
and copper(I) chloride (22.7 mg, 0.23 mmol), and reaction mixture
was stirred at rt for 24 h. Solvent was then removed in vacuo. Flash
chromatography on silica gel using hexane/ethyl acetate (6:1)
́
P.; Fine
́
1
provided pure 12 (0.76 g, 0.26 mmol, 11%). H NMR (300 MHz,
CDCl3) 7.19−7.45 (m, 14H), 6.98−7.07 (m, 1H), 6.45 (br, 1H); 13C
NMR (75 MHz, CDCl3) δ 153.5, 142.4, 138.5, 129.6, 128.9, 127.5,
I
DOI: 10.1021/jo502828r
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