Metal-Free Synthesis of Unsymmetrical Ureas and Carbamates from CO2 and Amines via Isocyanate Intermediates

Article abstract of DOI:10.1021/acs.joc.7b02905

A mild and metal-free synthesis of aryl isocyanates from arylamines under an atmosphere of CO₂ was developed. The carbamic acid intermediate, derived from the arylamine starting material and CO₂ in the presence of DBU, is dehydrated by activated sulfonium reagents to generate the corresponding isocyanate. The latter can be detected by in situ IR and trapped by various amines and alcohols to make unsymmetrical ureas and carbamates, respectively. Dicarbamates can also be prepared in good yields via the mild dehydration of the corresponding dicarbamic acids.

Full text of DOI:10.1021/acs.joc.7b02905

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Article
Metal-Free Synthesis of Unsymmetrical Ureas and Carbamates
from CO2 and Amines via Isocyanate Intermediates
Yiming Ren, and Sophie A.L. Rousseaux
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02905 • Publication Date (Web): 11 Dec 2017
Downloaded from http://pubs.acs.org on December 11, 2017
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Metal-Free Synthesis of Unsymmetrical Ureas and Carbamates from
CO2 and Amines via Isocyanate Intermediates
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Yiming Ren and Sophie A. L. Rousseaux*
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Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80
St. George Street, Toronto, Ontario, M5S 3H6, Canada
sroussea@chem.utoronto.ca
H
N
NH2
N
ZR
CO2 (1 atm)
ROH or R2NH
C
C
O
O
DMSO, TFAA, DBU
Z = O, NR
ABSTRACT
A mild and metal-free synthesis of aryl isocyanates from arylamines under an atmosphere
of CO2 has been developed. The carbamic acid intermediate, derived from the arylamine
starting material and CO2 in the presence of DBU, is dehydrated by activated sulfonium
reagents to generate the corresponding isocyanate. The latter can be detected by in situ IR
and trapped by various amines and alcohols to make unsymmetrical ureas and
carbamates, respectively. Dicarbamates can also be prepared in good yields via the mild
dehydration of the corresponding dicarbamic acids.
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INTRODUCTION
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Isocyanates are highly valuable intermediates in organic synthesis. They are readily
converted into the ureas and carbamates found in many biologically active compounds
and polymers such as polyurethanes (Scheme 1). 1 The scale of their worldwide
production, which surpasses millions of tons annually, clearly illustrates their importance
as synthetic intermediates. Notably, (di)isocyanates derived from arylamines are of
particular interest as building blocks in the pharmaceutical industry and in the
manufacturing of polyurethanes (Scheme 1b). The applications of these polymers across
sectors as diverse as the medical, automotive and building/construction industries,
continue to grow.2,3
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Scheme 1. Synthesis of ureas and carbamates from isocyanates and their industrial
relevance.
a) Synthetic utility of aryl isocyanates
H
N
H
N
NHR
N
OR
RNH2
ROH
C
O
R
R
R
O
O
valuable synthetic
intermediate
b) Carbamates and unsymmetrical ureas in the pharmaceuticals and polymers
O
O
O
N
OMe
O
N
H
N
H
O
N
Polyurethanes
F
N
O
O
O
Cl
N
H
N
N
H
O
H
N
Omecamtiv mecarbil
N
H
N
H
CF3
Sorafenib
Despite the importance of isocyanates, ureas and carbamates, and the scale of their
annual production, their industrial synthesis usually relies on the reaction of toxic
phosgene (or phosgene equivalents) with amines (Scheme 2a).2,4,5 Besides the health risks
associated with the use of phosgene, there are also major concerns associated with its
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production and storage.6 Due to these issues, significant research efforts have been
dedicated to the development of new methods for the production of isocyanates, avoiding
the use of phosgene gas.2,7,8,9,10 Carbon dioxide has emerged as an ideal C1-building
block to replace phosgene since it is abundant, non-toxic and renewable.11,12 Significant
progress has been made towards the synthesis of isocyanates, ureas and carbamates using
CO2, however many reports require harsh reaction conditions (high pressures and
temperatures) due to the thermodynamic stability of CO2.13,14 Thus, the development of
mild conditions for the laboratory synthesis of isocyanates, ureas and carbamates from
aromatic amines and CO2 should be of significant interest and value.15 Herein we
describe a metal-free method for the preparation of unsymmetrical ureas and carbamates,
via the corresponding isocyanate intermediates, using CO2 under atmospheric pressure.16
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The synthesis of isocyanates from arylamines and CO2 is often plagued by the formation
of symmetrical urea products resulting from the rapid reaction of unreacted amine with
the newly generated isocyanate. Thus, efficient and complete conversion of the arylamine
starting material is necessary for the clean generation of the isocyanate product. Strong
dehydrating agents (such as POCl3 or SOCl2) have been used to convert the carbamic
acid intermediate derived from the reaction of amines with CO2 to the isocyanate, while
consuming the equivalent of H2O produced in the process. The use of POCl3 and SOCl2
potentially limits the functional group compatibility of these reactions.12a,17 Mitsunobu-
18
type protocols have also been employed.
Treating the carbamic acid with
dialkylazodicarboxylates and trialkylphosphines produces the isocyanate, along with the
stoichiometric waste inherently associated with the Mitsunobu reaction. We wondered if
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a dimethylsulfonium reagent (A) could effect the dehydration of carbamic acid
intermediates to generate isocyanates under mild conditions without the need for high
pressure equipment and hazardous reagents (Scheme 2b, This Work).
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Scheme 2. Synthesis of aryl isocyanates, ureas and carbamates
a) CO2 as a C1-building block (replacing phosgene and related reagents)
O
phosgene
toxic
O
RNH2
Cl
Cl
ArHN
ArHN
NHR
OR
N
ArNH2
Ar
C
X
S
O
X
(1 atm)
CO2
O
ROH
this work
b) Synthesis of isocyanates from aryl amines using CO2
Strong dehydrating reagents
O
POCl3
CO2, base
Ar
Ar
Ar
ArNH2
N
C O
N
H
O
or SOCl2
H•base
Mitsunobu conditions
O
O
PBu3, DBAD
CO2, cat. DBU
ArNH2
ArHN
NHR
N
H
OH
RNH2
(via isocyanate)
This Work
TFA
TFA
O
S
CO2, DBU
O
S
Ar
+
Ar
ArNH2
N
C
O
O
N
H
O
A
H•DBU
O
Ar
N
S
✓ mild dehydrating conditions
✓ no Pummerer rearrangement products
✓ CO2 (balloon)
H
TFA
key intermediate
RESULTS AND DISCUSSION
Our synthesis of isocyanates relies on the rapid formation of carbamic acid derivatives
under an atmosphere of CO2 and the dehydration of this intermediate under Swern-like
conditions.19 The optimal reaction conditions for isocyanate formation, and subsequent
quench with n-butylamine to generate the unsymmetrical urea, are demonstrated in Table
1.20 Either TFAA or oxalyl chloride can be used to generate the activated dimethyl
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sulfonium reagent, providing the urea product in excellent yields (entries 1 and 2). Under
these reaction conditions, no products resulting from the Pummerer rearrangement are
observed. We chose TFAA as the ideal activating reagent since the use of oxalyl chloride
required lower reaction temperatures and slow addition of reagents. Control reactions
revealed that DBU is necessary for the formation of the carbamic acid intermediate. In
the absence of DBU or with substoichiometric quantities of DBU, little to no product was
formed, and significant amounts of trifluoroacetylated aniline were isolated (entries 3 and
7). Replacing DBU with TMEDA did not yield any of the desired product (entry 8).
Interestingly, TFAA appears to mediate this reaction in the absence of DMSO, although
diminished yield (35%) of the unsymmetrical urea was observed under these conditions
(entry 5). Overall, while the reaction requires stoichiometric quantities of DBU, DMSO
and TFAA to obtain high yields, it should be noted that the resulting waste can be
removed from the desired product without the need for chromatography (see below for
the synthesis of 4a).
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Table 1. Reaction optimizationa
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i) CO2 (balloon), DBU
ii) DMSO, TFAA, −60 °C
H
N
NH2
NHBu
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O
iii) Et3N, then H2NBu
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entry change from standard conditions
% yieldb
1
2
3
4
5
6c
7
8
none
93 (89)
oxalyl chloride instead of TFAA
no DBU
95
0
no TFAA
0
no DMSO
35
50
31
0
no Et3N
DBU (0.5 equiv)
TMEDA instead of DBU
aReactions were performed using aniline (1.0 mmol, 1.0 equiv), DBU (1.0 equiv), DMSO
(1.0 equiv), TFAA (1.0 equiv), Et3N (1.0 equiv) and n-butylamine (1.0 equiv) in CH2Cl2
b
(0.17 M) and under an atmosphere of CO2. NMR yields using diphenylacetonitrile or
c
1,3,5-trimethoxybenzene as an internal standard (isolated yield in parentheses). The
reaction was quenched with MeOH instead of n-BuNH2.
In situ monitoring by IR spectroscopy clearly demonstrated the formation of an
isocyanate intermediate using both the TFAA and oxalyl chloride mediated protocols.21
Upon transferring the solution of the carbamic acid intermediate to the activated
dimethylsulfonium reagent (A, Scheme 2) at low temperature, a signal at 2265 cm-1
corresponding to phenyl isocyanate appeared. This signal increased in strength upon
addition of Et3N to the reaction mixture, indicating complete conversion to the isocyanate
product. This signal disappeared upon quenching the reaction with n-butylamine since the
isocyanate intermediate was consumed to generate the unsymmetrical urea.
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Under our optimized conditions, a range of aryl and alkyl amines (1) could be converted
to unsymmetrical ureas (2) and carbamates (3) in one pot, via the isocyanate, by
quenching the reactions with amines or alcohols, respectively (Schemes 3 and 4). Simple
arylamines, as well as those bearing electron-donating and electron-withdrawing groups,
yielded the corresponding ureas 2a-d,g,i,k and carbamates 3a,b,e in good to excellent
yields. Substituents such as a ketone (2e), thioether (2h), nitrile (2j) and nitro (3c-d)
functional group were tolerated. 2-Aminothiophene could also be converted to urea 2j
and carbamate 3f in good yields (78% and 67%, respectively). An arylamine bearing
halide substituents was converted to urea 2f in 92% yield, providing useful synthetic
handles for subsequent transformations. Aniline derivatives with ortho substituents
generated the isocyanate intermediates in high yields, as illustrated by the formation of
ureas 2f and 2h in 92% and 82%, respectively. Aliphatic amines, including benzylic
amines and a methyl ester-protected amino acid, could also be converted to ureas 2l-o in
good to excellent yields (Scheme 3). Of note, under our mild reaction conditions,
epimerization of enantioenriched amino acid derivative 2o and benzylic amine 2n was
not observed.
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a,b
Scheme 3. Synthesis of unsymmetrical ureas from amines and CO2
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i) CO2 (balloon), DBU
ii) DMSO, TFAA, −60 °C
H
N
NH2
NR'2
R
R
O
iii) Et3N, then HNR'2
1
2
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O
O
H
H
H
H
H
N
N
N
N
N
N
n-Bu
n-Bu
O
O
O
MeO
Me
2c, 88%c
2a, 88%
2b, 86%
O
Br
H
N
H
N
H
N
H
N
H
N
N
n-Bu
O
O
Et
O
F
2f, 92%c
2d, 87%
2e, 82%
Cl
SMe
O
H
N
H
N
H
N
H
N
N
N
O
N
O
O
S
MeO
2h, 82%c
2i, 80%c
2g, 84%
NC
H
N
H
N
H
N
N
O
S
O
F
2k, 83%
2j, 78%
O
H
N
H
N
H
N
H
N
H
N
Ph
Ph
N
n-Bu
n-Bu
O
O
O
2l, 81%
2m, 87%
2n, 92%
O
H
N
H
N
MeO
Bn
O
2o, 83%d
aReactions were performed using arylamine (or alkylamine) (1.0 mmol, 1.0 equiv), DBU
(1.0 equiv), DMSO (1.0 equiv), TFAA (1.0 equiv), Et3N (1.0 equiv) and amine (1.0
equiv) in CH2Cl2 (0.17 M) and under an atmosphere of CO2. bIsolated yields represent the
c
d
average yield for 2 reactions. Using 2.0 equivalents of DBU. Using 1.4 equivalents of
DBU.
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a,b
Scheme 4. Synthesis of carbamates from arylamines and CO2
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i) CO2 (balloon), DBU
ii) DMSO, TFAA, −60 °C
H
N
NH2
OR
R
R
O
iii) Et3N, then HOR
1
3
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H
H
H
N
OMe
N
O
Ph
N
O
O
O
O
O2N
3c, 87%c
3a, 90%
3b, 87%
NC
H
N
H
N
H
N
OMe
O
O
Ph
O
O
S
O
O2N
F
3d, 98%c
3e, 94%
3f, 67%
O
O
O
O
N
H
OMe
MeO
N
H
MeO
N
H
N
H
OMe
4a, 87%d
4b, 81%d
aReactions were performed using arylamine (1.0 mmol, 1.0 equiv), DBU (1.0 equiv),
DMSO (1.0 equiv), TFAA (1.0 equiv), Et3N (1.0 equiv) and alcohol (1.0 equiv) in
CH2Cl2 (0.17 M) and under an atmosphere of CO2. bIsolated yields represent the average
yield for 2 reactions. cUsing 2.0 equivalents of DBU. dUsing aryl diamine (0.5 mmol, 1.0
equiv), DBU (3.0 equiv), DMSO (2.0 equiv), TFAA (2.0 equiv), Et3N (2.0 equiv) and
alcohol (11.0 equiv).
The isocyanate intermediates can be trapped with a variety of nucleophiles, including
aliphatic and arylamines (Scheme 3). Both primary and secondary amines afforded the
products in good to excellent yields. Heterocycles are also compatible, as illustrated by
the formation of indoline- and 2-aminothiazole-derived ureas 2k and 2i in 83% and 80%,
respectively. Quenching the isocyanate with an alcohol yields the carbamate (Scheme 4).
Using this strategy, Cbz- and alloc-protected arylamines 3b,c,f could be prepared from
simple amines, CO2 and the corresponding alcohol. Unfortunately, tert-butanol was not
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an efficient nucleophile in this transformation even after prolonged reaction times. Boc-
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protected arylamine was not detected in the H NMR of the crude reaction mixture;
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instead only unreacted isocyanate and tert-butanol were observed.
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Finally, we set out to prepare the methyl carbamates of 4,4’-methylene diphenyl
diisocyanate (MDI) and 2,4-toluene diisocyanate (TDI), which are relevant building
blocks for the polyurethane industry, from aryl diamines, CO2 and the dimethyl sulfonium
reagent (A) generated in situ from DMSO and TFAA. We anticipated that this reaction
would be challenging due the difficulty in preparing a dicarbamic acid intermediate under
an atmosphere of CO2 and its likely poor solubility in organic solvents. The quantitative
formation of the dicarbamic acid derivative and its subsequent clean dehydration would
also be essential to avoid polymerization over diisocyanate formation. A brief
reoptimization of the reaction conditions revealed that using a slight excess of DBU (3.0
equivalents, or 1.5 equivalents per amine) enabled the clean formation of the methyl ester
derivatives 4a and 4b in 87% and 81%, respectively.22 For the synthesis of 4a, a simple
aqueous wash of the reaction mixture removed reaction side products and afforded the
desired product in 90% purity.
CONCLUSION
In summary, we have developed a metal-free synthesis of unsymmetrical ureas and
carbamates from amines and CO2 under mild reaction conditions. An activated
dimethylsulfonium reagent, reminiscent of those used in Swern oxidation protocols,
mediates this transformation. A wide range of aryl and aliphatic amines can be converted
to unsymmetrical ureas and carbamates, via the isocyanate intermediate, in high yield and
with little to no symmetrical urea byproduct.
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EXPERIMENTAL SECTION
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General information
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All reactions were performed using anhydrous solvents in oven-dried flasks unless
otherwise specified. Anhydrous CH2Cl2 was purchased from Sigma-Aldrich and was
used as received. TFAA was purchased from Sigma-Aldrich and used as received (stored
under air). Reagent grade DMSO was purchased from Sigma-Aldrich and was stored
over 4 Å molecular sieves before use. All other chemicals were purchased from Sigma-
Aldrich, Fisher Scientific and Combi-Blocks, and were used without further purification.
NMR solvents (CDCl3, DMSO-d6, acetone-d6) were purchased from Cambridge Isotope
Laboratories, Inc. or Sigma-Aldrich. Proton chemical shifts are reported in ppm with
respect to TMS (δ 0.00) for CDCl3 or to the residual proton resonance in DMSO-d6 (δ
2.50) and acetone-d6 (δ 2.05). Carbon chemical shifts were internally referenced to the
solvent resonances in CDCl3 (δ 77.2 ppm), DMSO-d6 (δ 39.5) and acetone-d6 (δ 29.8 and
206.3). Peak multiplicities are designated by the following abbreviations: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad; J, coupling constant in Hz. Complex
multiplicities were reported as a combination of the above abbreviations to provide an
appropriate descriptor for the observed pattern (i.e., dt – doublet of triplets). All
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1
synthesized compounds were characterized by H, 19F and 13C NMR, HRMS, IR and
1
melting point (when applicable). H, 19F and 13C NMR were recorded on Varian
MercuryPlus 400 MHz, Bruker AvanceIII-400 MHz, Agilent DD2-500 MHz equipped
with XSens cold probe, Agilent DD2-500 with oneNMR probe and Agilent DD2-600
MHz spectrometers. Mass spectra were obtained by the University of Toronto Advanced
Instrumentation for Molecular Structure (AIMS) mass spectrometry facility; high
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resolution mass spectra (HRMS) were recorded on a JEOL AccuTOF model JMS-
T1000LC mass spectrometer equipped with an IONICS Direct Analysis in Real Time
(DART) ion source. HPLC was performed with a Shimadzu HPLC equipped with a chiral
column and UV detector (254 nm). Chiral HPLC column (Chiralpak® IG 87325A) was
purchased from Chiral Technologies, Inc. HPLC solvents (Hexanes and iPrOH) were
purchased from Sigma-Aldrich. Flash chromatography on silica gel (60 Å, 230-400 mesh,
from Silicycle) was performed. Solvent ratios for chromatography are reported as v/v
ratios. Analytical thin-layer chromatography (TLC) was performed on Merck silica gel
60 F254 pre-coated plates and visualized with a UV lamp and KMnO4 stain. Infrared
FTIR spectra from in situ reaction monitoring were obtained on a Mettler Toledo
instrument equipped with 6.3 mm AgX DiComp probe. FTIR spectrum were obtained on
a Perkin Elmer spectrometer equipped with an ATR sampling head.
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General procedures for the synthesis of ureas
General procedure A for the synthesis of ureas using TFAA: A solution of DMSO
(0.07 mL, 1.00 mmol, 1.00 eq) in 3.0 mL CH2Cl2 under an atmosphere of CO2 (balloon)
was cooled to the appropriate temperature (-60 °C using a dry ice/chloroform bath or -78
°C using an acetone/dry ice bath). TFAA (0.15 mL, 1.00 mmol, 1.00 eq) was added
dropwise to the cold solution. The resulting mixture was stirred at low temperature for 5
minutes. In a second flask, CO2 was bubbled through a solution of amine (1.00 mmol,
1.00 eq) and DBU (0.15 mL, 1.00 mmol, 1.00 eq) in 3.0 mL CH2Cl2 at room temperature.
This mixture was cannula transferred to the first (cold) solution. The resulting cold
mixture was stirred at low temperature for 10 minutes. Triethylamine (0.14 mL, 1.00
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mmol, 1.00 eq) was added and the mixture was stirred for 10 minutes. The solution was
allowed to slowly warm to room temperature and was left to stir for an additional 10
minutes. The amine (1.00 mmol, 1.00 eq) was added rapidly to the flask followed by 5
minutes of rapid stirring. The mixture was concentrated under reduced pressure to afford
the crude material, which was purified by flash chromatography on silica gel to afford the
desired product.
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General procedure B for the synthesis of ureas using oxalyl chloride: A solution of
oxalyl chloride (0.09 mL, 1.00 mmol, 1.00 eq) in 3.0 mL CH2Cl2 under an atmosphere of
CO2 (balloon) was cooled to the appropriate temperature (-60 °C using a dry
ice/chloroform bath or -78 °C using an acetone/dry ice bath). DMSO (0.07 mL, 1.00
mmol, 1.00 eq) was added dropwise to the cold solution as a solution in 1.0 mL CH2Cl2.
The resulting mixture was stirred at low temperature for 5 minutes. In a second flask,
CO2 was bubbled through a solution of amine (1.00 mmol, 1.00 eq) and DBU (0.15 mL,
1.00 mmol, 1.00 eq) in 3.0 mL CH2Cl2 at room temperature. This mixture was cannula
transferred to the first (cold) solution. The resulting cold mixture was stirred at low
temperature for 10 minutes. Triethylamine (0.14 mL, 1.00 mmol, 1.00 eq) was added and
the mixture was stirred for 10 minutes. The solution was allowed to slowly warm to room
temperature and was left to stir for an additional 10 minutes. The amine (1.00 mmol, 1.00
eq) was added rapidly to the flask followed by 5 minutes of rapid stirring. The mixture
was concentrated under reduced pressure to afford the crude material, which was purified
by flash chromatography on silica gel to afford the desired product.
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1-Butyl-3-phenylurea (2a): This compound was synthesized from aniline (1.55 mmol
scale) using general procedure A (TFAA method) at -60 °C. Purification by flash column
chromatography on silica gel (35% EtOAc/Hexanes) afforded 265 mg (1.38 mmol, 89%)
of the desired product as a white solid. Second trial of reaction yielded 255 mg (1.33
mmol, 86%) of the desired product. Average yield: 88%. Exhibited spectral data identical
to a previous report.23
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1H NMR (400 MHz, CDCl3, 298K): δ 7.26-7.18 (m, 4H), 7.01-6.96 (m, 1H), 6.81 (br s,
1H), 5.09 (br s, 1H), 3.14 (td, J = 7.2, 5.7 Hz, 2H), 1.61-1.44 (m, 2H), 1.30-1.17 (m, 2H),
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0.83 (t, J = 7.2 Hz, 3H). C NMR (100 MHz, CDCl3, 298K): δ 156.2, 138.8, 129.2,
123.6, 121.0, 40.1, 32.2, 20.1, 13.8.
1-Butyl-3-(p-tolyl)urea (2b): This compound was synthesized from p-toluidine (1.08
mmol scale) using general procedure A (TFAA method) at -60 °C. Purification by flash
column chromatography on silica gel (30% EtOAc/hexanes) afforded 198 mg (0.94
mmol, 87%) of the desired product as a white solid. Second trial of reaction yielded 192
mg (0.92 mmol, 85%) of the desired product. Average yield: 86%. Exhibited spectral
data identical to a previous report.24
1H NMR (500 MHz, CDCl3, 298 K): δ 7.91 (br s, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.00 (d,
J = 8.6 Hz, 2H), 6.03 (br t, J = 5.8 Hz, 1H), 3.12 (td, J = 7.2, 5.7 Hz, 2H), 2.26 (s, 3H),
1.41-1.33 (m, 2H), 1.30-1.22 (m, 2H), 0.86 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz,
CDCl3, 298 K): δ 157.3, 136.7, 132.2, 129.4, 120.4, 40.0, 32.4, 20.8, 20.2, 13.9.
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N-(4-methoxyphenyl)morpholine-4-carboxamide (2c): This compound was
synthesized from p-anisidine (1.00 mmol scale) using general procedure A (TFAA
method) with 2 equivalents of DBU at -78 °C. Purification by flash column
chromatography on silica gel (25% EtOAc/Hexanes) afforded 205 mg (0.87 mmol, 87%)
of the desired product as a white solid. Second trial of reaction yielded 207 mg (0.88
mmol, 88%) of the desired product. Average yield: 88%. Exhibited spectral data identical
to a previous report.25
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1H NMR (600 MHz, CDCl3, 298 K): δ 7.20 (s, 1H), 7.13-7.11 (m, 2H), 6.73-6.70 (m,
2H), 3.69 (s, 3H), 3.50 (t, J = 5.9 Hz, 4H), 3.27 (t, J = 4.6 Hz, 4H). 13C NMR (150 MHz,
CDCl3, 298 K): δ 156.2, 155.9, 132.0, 123.3, 113.8, 66.4, 55.4, 44.1.
1-Butyl-3-(4-fluorophenyl)urea (2d): This compound was synthesized from p-
fluoroaniline (1.53 mmol scale) using general procedure A (TFAA method) at -60 °C.
Purification by flash column chromatography on silica gel (30% EtOAc/hexanes)
afforded 279 mg (1.33 mmol, 87%) of the desired product as a white solid. Second trial
of reaction yielded 275 mg (1.32 mmol, 86%) of the desired product. Average yield:
87%.
1H NMR (400 MHz, DMSO-d6, 298 K): δ 8.39 (s, 1H), 7.39-7.35 (m, 2H), 7.06-7.00 (m,
2H), 6.07 (t, J = 5.9 Hz, 1H), 3.07 (q, J = 5.9 Hz, 2H), 1.44-1.25 (m, 4H), 0.89 (t, J = 7.1
Hz, 3H) 1H {19F } NMR (400 MHz, DMSO-d6, 298 K): δ 8.38 (s, 1H), 7.37 (d, J = 9.1
Hz, 2H), 7.04 (d, J = 9.1 Hz, 2H), 6.06 (t, J = 5.8 Hz, 1H), 3.06 (td, J = 6.8, 5.6 Hz, 2H),
1.44-1.25 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H). 19F {1H } NMR (377 MHz, DMSO-d6, 298
K): δ -118.1. 13C NMR (100 MHz, DMSO-d6, 298 K): δ 156.8 (d, J = 236.9 Hz), 155.2,
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136.9 (d, J = 2.4 Hz), 119.1 (d, J = 7.6 Hz), 115.0 (d, J = 22.0 Hz), 38.7, 31.85, 19.5,
13.7. HRMS (DART-TOF+) m/z: [M+H]+ calcd for C11H16FN2O 211.1247; found
211.1249. IR (neat): 3360, 1562, 1504, 1211, 833 cm-1. Melting point: 128.1-131.1 °C.
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1-(3-Acetylphenyl)-3-(sec-butyl)urea (2e): This compound was synthesized from
3-aminoacetophenone (1.00 mmol scale) using general procedure A (TFAA method) at -
78 °C. Purification by flash column chromatography on silica gel (35% EtOAc/Hexanes)
afforded 190 mg (0.81 mmol, 81%) of the desired product as a white solid. Second trial
of reaction yielded 194 mg (0.83 mmol, 83%) of the desired product. Average yield:
82%.
1H NMR (400 MHz, CDCl3, 298 K, mixture of rotamers in a 1.5:1 ratio): δ 8.29 (s,
1H), 7.89 (dd, J = 1.9, 1.0 Hz, 1H), 7.61 (ddd, J =8.1, 2.3, 1.0 Hz, 1H), 7.48 (ddd, J = 7.7,
1.7, 1.0 Hz, 1H), 7.24 (dd, J = 7.7, 7.7 Hz, 1H), 5.93 (d, J = 8.3 Hz, 1H, major rotamer),
4.99 (d, J = 8.2 Hz, 1H, minor rotamer), 3.82-3.72 (m, 1H, major rotamer), 3.69-3.61 (m,
1H, minor rotamer), 2.49 (s, 3H), 1.47-1.35 (m, 2H), 1.10 (d, J = 6.6 Hz, 3H, major
rotamer), 1.06 (dd, J = 6.6, 1.1 Hz, 3H, minor rotamer), 0.87 (t, J = 7.4 Hz, 3H, major
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rotamer), 0.84 (td, J = 7.5, 1.4 Hz, 3H, minor rotamer). C NMR (100 MHz, CDCl3,
298 K, mixture of rotamers): δ 198.8, 158.3, 156.0, 140.3, 137.5, 129.1, 123.8, 122.0,
118.5, 47.4, 47.2, 30.2, 30.0, 26.67, 21.0, 20.9, 10.4. HRMS (DART-TOF+) m/z:
[M+H]+ calcd for C13H19N2O2 235.1447; found 235.1447. IR (neat): 2880, 1660, 1539,
1240, 686 cm-1. Melting point: 111.8-116.8 °C.
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N-(2-Bromo-5-chlorophenyl)morpholine-4-carboxamide (2f): This compound was
synthesized from 2-bromo-5-chloroaniline (1.00 mmol scale) using general procedure A
(TFAA method) with 2 equivalent of DBU at -78 °C . Purification by flash column
chromatography on silica gel (25% EtOAc/Hexanes) afforded 293 mg (0.92 mmol, 92%)
of the desired product as a yellow oil. Second trial of reaction yielded 289 mg (0.91
mmol, 91%) of the desired product. Average yield: 92%.
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1H NMR (400 MHz, CDCl3, 298 K): δ 8.24 (d, J = 2.5 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H),
6.99 (br s, 1H), 6.84 (dd, J = 8.5, 2.5 Hz, 1H), 3.78-3.67 (m, 4H), 3.52-3.44 (m, 4H). 13C
NMR (100 MHz, CDCl3, 298 K): δ 153.8, 137.6, 134.2, 132.5, 123.7, 120.9, 110.8,
66.4, 44.2. HRMS (DART-TOF+) m/z: [M+H]+ calcd for C11H13BrClN2O2 318.9849;
found 318.9850. IR (neat): 2860, 1643, 1504, 1115, 860 cm-1.
N-(p-Tolyl)pyrrolidine-1-carboxamide (2g): This compound was synthesized from p-
toluidine (1.00 mmol scale) using general procedure B (oxalyl chloride method) at -78
°C. Purification by flash column chromatography on silica gel (30% EtOAc/Hexanes)
afforded 170 mg (0.83 mmol, 83%) of the desired product as a white solid. Exhibited
spectral data identical to a previous report.26 Second trial of reaction yielded 172 mg
(0.84 mmol, 84%) of the desired product. Average yield: 84%.
1H NMR (500 MHz, CDCl3, 298 K): δ 7.30-7.27 (m, 2H), 7.07-7.05 (m, 2H), 6.17 (s,
1H), 3.44-3.41 (m, 4H), 2.28 (s, 3H), 1.94-1.92 (m, 4H). 13C NMR (125 MHz, CDCl3,
298 K): δ 154.2, 136.6, 132.2, 129.3, 119.8, 45.7, 25.6, 20.7
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N-(2-(methylthio)phenyl)morpholine-4-carboxamide (2h): This compound was
synthesized from 2-(methylthio)aniline (1.00 mmol scale) using general procedure A
(TFAA method) with 2 equivalents of DBU at -78 °C. Purification by flash column
chromatography on silica gel (40% EtOAc/Hexanes) afforded 207 mg (0.82 mmol, 82%)
of the desired product as a white solid. Second trial of reaction yielded 205 mg (0.81
mmol, 81%) of the desired product. Average yield: 82%.
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1H NMR (600 MHz, CDCl3, 298 K): δ 8.13 (dd, J = 8.3, 1.4 Hz, 1H), 7.81 (br, 1H), 7.43
(dd, J = 7.7, 1.6 Hz, 1H), 7.28-7.21 (m, 1H), 6.96 (ddd, J = 7.5, 7.5, 1.4 Hz, 1H), 3.73-
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3.71 (m, 4H), 3.51-3.49 (m, 4H), 2.33 (s, 3H). C NMR (150 MHz, CDCl3, 298 K): δ
154.6, 139.5, 133.1, 129.1, 124.4, 123.0, 119.7, 66.5, 44.1, 19.0. HRMS (DART-TOF+)
m/z: [M+H]+ calcd for C12H17N2O2S 253.1011; found 253.1010. IR (neat): 3226, 1623,
1507, 1394, 1246, 737 cm-1. Melting point: 96.9-100.1 °C.
1-(4-Methoxyphenyl)-3-(thiazol-2-yl)urea (2i): This compound was synthesized from
p-anisidine (1.00 mmol scale) using general procedure A (TFAA method) with 2
equivalents of DBU at -78 °C. Purification by flash column chromatography on silica gel
(65% EtOAc/Hexanes) afforded 202 mg (0.80 mmol, 80%) of the desired product as a
white solid. Second trial of reaction yielded 201 mg (0.80 mmol, 80%) of the desired
product. Average yield: 80%. Exhibited spectral data identical to a previous report.27
1H NMR (500 MHz, DMSO-d6, 298 K): δ 10.54 (br s, 1H), 8.77 (s, 1H), 7.39-7.35 (m,
3H), 7.08 (d, J = 3.6 Hz, 1H), 6.91-6.87 (m, 2H), 3.72 (s, 3H). 13C NMR (125 MHz,
DMSO-d6, 298 K): δ 160.1, 155.5, 152.2, 137.6, 132.0, 120.9, 114.5, 112.7, 55.6.
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1-(3-Cyanothiophen-2-yl)-3-cyclopropylurea (2j): This compound was synthesized
from 2-aminothiophene-3-carbonitrile (1.00 mmol scale) using general procedure A
(TFAA method) at -78 °C. Purification by flash column chromatography on silica gel
(20% EtOAc/Hexanes) afforded 162 mg (0.78 mmol, 78%) of the desired product as a
white solid. Second trial of reaction yielded 161 mg (0.78 mmol, 78%) of the desired
product. Average yield: 78%.
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1H NMR (500 MHz, CDCl3, 298 K): δ 9.01 (br, 1H), 6.85 (d, J = 6.0 Hz, 1H), 6.68 (d,
J = 5.7 Hz, 1H), 6.32 (s, 1H), 2.70-2.66 (m, 1H), 0.79 (br d, J = 4.5 Hz, 2H), 0.60 (br s,
2H). 13C NMR (125 MHz, CDCl3, 298 K): δ 155.2, 153.2 (br), 123.5, 116.7, 115.6, 89.5
(br), 22.7, 7.0. HRMS (DART-TOF+) m/z: [M+H]+ calcd for C9H10N3OS 208.0545;
found 208.0542. IR (neat): 3336, 2216, 1644, 1552, 1255 cm-1. Melting point: 149.2-
159.1 °C.
N-(4-Fluorophenyl)indoline-1-carboxamide (2k): This compound was synthesized
from p-fluoroaniline (1.00 mmol scale) using general procedure A (TFAA method) at -78
°C. Purification by flash column chromatography on silica gel (20% EtOAc/Hexanes)
afforded 215 mg (0.84 mmol, 84%) of the desired product as a white solid. Second trial
of reaction yielded 210 mg (0.82 mmol, 82%) of the desired product. Average yield:
83%.
1H NMR (600 MHz, acetone-d6, 298 K): δ 8.01 (ddd, J = 8.1, 1.1, 0.6 Hz, 1H), 7.91 (br
s, 1H), 7.64-7.61 (m, 2H), 7.17-7.16 (m, 1H), 7.14-7.11 (m, 1H), 7.07-7.03 (m, 2H), 6.89
(ddd, J = 6.9, 6.9, 1.2 Hz, 1H), 4.17 (dd, J = 9.2, 8.3 Hz, 2H), 3.21 (dd, J = 9.1, 8.2 Hz,
2H). 13C NMR (125 MHz, acetone-d6, 298 K): δ 158.4 (d, J = 236.2 Hz), 152.6, 144.0,
136.1 (d, J = 2.6 Hz), 130.8, 126.9, 124.4, 121.9 (d, J = 7.7 Hz), 121.7, 115.2, 114.7 (d, J
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= 22.3 Hz), 47.1, 27.5. F NMR (564 MHz, acetone-d6, 298 K): δ -122.43. HRMS
(DART-TOF+) m/z: [M+H]+ calcd for C15H14FN2O 257.1090; found 257.1090. IR (neat):
3367, 1649, 1510, 1476, 785 cm-1. Melting point: 155.6-161.4 °C.
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1-Benzyl-3-butylurea (2l): This compound was synthesized from benzylamine (1.61
mmol scale) using general procedure A (TFAA method) at -60 °C. Purification by flash
column chromatography on silica gel (50% EtOAc/Hexanes) afforded 285 mg (1.38
mmol, 86%) of the desired product as a white solid. Second trial of reaction yielded 290
mg (1.40 mmol, 88%) of the desired product. Average yield: 87%. Exhibited spectral
data identical to a previous report.28
1H NMR (400 MHz, CDCl3, 298K): δ 7.24-7.13 (m, 5H), 6.12 (br t, J = 6.0 Hz, 1H),
5.76 (br t, J = 5.6 Hz, 1H), 4.16 (d, J = 5.6 Hz, 2H), 2.98 (td, J = 7.0, 5.5 Hz, 2H), 1.35-
1.17 (m, 4H), 0.84 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3, 298K): δ 159.4,
139.8, 128.4, 127.0, 126.8, 43.8, 39.9, 32.4, 20.0, 13.8.
N-benzylmorpholine-4-carboxamide (2m): This compound was synthesized from
benzylamine (1.00 mmol scale) using general procedure A (TFAA method) at -78 °C.
Purification by flash column chromatography on silica gel (100% EtOAc) afforded 174
mg (0.79 mmol, 79%) of the desired product as a white solid. Second trial of reaction
yielded 180 mg (0.82 mmol, 82%) of the desired product. Average yield: 81%. Exhibited
spectral data identical to a previous report.29
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1H NMR (600 MHz, acetone-d6, 298 K): δ 7.32-7.27 (m, 4H), 7.22-7.19 (m, 1H), 6.38
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(br s, 1H), 4.37 (d, J = 5.9 Hz, 2H), 3.59-3.58 (m, 4H), 3.37-3.35 (m, 4H). C NMR
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(150 MHz, acetone-d6, 298 K): δ 157.8, 141.0, 128.1, 127.3, 126.5, 66.3, 44.2, 43.9.
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(S)-1-Butyl-3-(1-phenylethyl)urea (2n): This compound was synthesized from
(S)-α-methylbenzylamine (1.62 mmol scale) using general procedure A (TFAA method)
at -60 °C. Purification by flash column chromatography on silica gel (50%
EtOAc/Hexanes) afforded 308 mg (1.40 mmol, 91%) of (S)-1-butyl-3-(1-
phenylethyl)urea as a colorless oil. Second trial of reaction yielded 310 mg (1.41 mmol,
92%) of the desired product. Average yield: 92%. Enantiomeric excess (>99%) was
determined by HPLC [Chiralpak IG, hexanes/i-PrOH 80:20, 0.98 mL/min., (minor) tr =
5.55 min, (major) tr = 6.42 min]. [α]D 23: -22.2° (c 1.00, CHCl3).
1H NMR (500 MHz, CDCl3, 298 K): δ 7.28-7.16 (m, 5H), 5.96 (br d, J = 7.8 Hz, 1H),
5.59 (br s, 1H), 4.83 (p, J = 7.0 Hz, 1H), 3.08-2.97 (m, 2H), 1.35 (d, J = 7.0 Hz, 3H),
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1.34-1.17 (m, 4H), 0.85 (t, J = 7.1 Hz, 3H). C NMR (125 MHz, CDCl3, 298 K): δ
158.6, 145.0, 128.5, 126.8, 125.8, 49.5, 39.9, 32.5, 23.4, 20.1, 13.9. HRMS (DART-
TOF+) m/z: [M+H]+ calcd for C13H21N2O 221.1654; found 221.1654. IR (neat): 3333,
2930,1624, 1563, 1243, 697 cm-1.
Methyl (allylcarbamoyl)-L-phenylalaninate (2o): This compound was synthesized
from L-alanine methyl ester (1.00 mmol scale) using general procedure A (TFAA
method) with 1.40 eq of DBU at -60 °C. Purification by flash column chromatography on
silica gel (40% EtOAc/Hexanes) afforded 218 mg (0.83 mmol, 83%) of the desired
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product as a white solid. Enantiomeric excess (>99%) was determined by HPLC
[Chiralpak IG, hexanes/i-PrOH 74:26, 0.98 mL/min., (minor) tr = 6.95 min, (major) tr =
10.16 min]. [α]D 23: +51.2° (c 1.00, CHCl3).
1H NMR (500 MHz, CDCl3, 298 K): δ 7.29-7.19 (m, 3H), 7.12-7.07 (m, 2H), 5.79 (ddt,
J = 17.2, 10.3, 5.4 Hz, 1H), 5.20 (br d, J = 8.1 Hz, 1H), 5.13 (dq, J = 17.1, 1.7 Hz, 1H),
5.08-5.05 (m, 2H), 4.77 (dt, J = 8.1, 5.9 Hz, 1H), 3.74-3.71 (m, 2H), 3.69 (s, 3H), 3.07
(dd, J = 13.8, 5.9 Hz, 1H), 3.01 (dd, J = 13.8, 6.1 Hz, 1H). 13C NMR (125 MHz, CDCl3,
298 K): δ 173.4, 157.3, 136.3, 135.1, 129.3, 128.4, 126.9, 115.7, 51.0, 52.2, 42.9, 38.5.
HRMS (DART-TOF+) m/z: [M+H]+ calcd for C14H19N2O3 263.1396; found 263.1392.
IR (neat): 3369, 1732, 1619, 1566, 1223, 697 cm-1. Melting point: 96.2-101.7 °C.
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General procedures for the synthesis of carbamates
General procedure C for the synthesis of carbamates using TFAA: A solution of
DMSO (0.07 mL, 1.00 mmol, 1.00 eq) in 3.0 mL CH2Cl2 under an atmosphere of CO2
(balloon) was cooled to the appropriate temperature (-60 °C using a dry ice/chloroform
bath or -78 °C using an acetone/dry ice bath). TFAA (0.15 mL, 1.00 mmol, 1.00 eq) was
added dropwise to the cold solution. The resulting mixture was stirred at low temperature
for 5 minutes. In a second flask, CO2 was bubbled through a solution of amine (1.00
mmol, 1.00 eq) and DBU (0.15 mL, 1.00 mmol, 1.00 eq) in 3.0 mL CH2Cl2 at room
temperature. This mixture was cannula transferred to the first (cold) solution. The
resulting cold mixture was stirred at low temperature for 10 minutes. Triethylamine (0.14
mL, 1.00 mmol, 1.00 eq) was added and the mixture was stirred for 10 minutes. The
solution was allowed to slowly warm to room temperature and was left to stir for an
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additional 10 minutes. The alcohol was added rapidly to the flask followed by 15 minutes
of rapid stirring. The mixture was concentrated under reduced pressure to afford the
crude material which was purified by flash chromatography on silica gel to afford the
desired product.
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Methyl phenylcarbamate (3a): This compound was synthesized from aniline (1.00
mmol scale) using general procedure C (TFAA method) at -78 °C. The reaction mixture
was quenched with MeOH (0.08 ml, 2 mmol, 2 eq). Purification by flash column
chromatography on silica gel (10-15% EtOAc/Hexanes) afforded 133 mg (0.88 mmol,
88%) of the desired product as a white solid. Second trial of reaction yielded 138 mg
(0.91 mmol, 91%) of the desired product. Average yield: 90%. Exhibited spectral data
identical to a previous report.30
1H NMR (400 MHz, CDCl3, 298 K): δ 7.43 (br d, J = 7.4 Hz, 2H), 7.32-7.27 (m, 2H),
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7.15 (br s, 1H), 7.09-7.05 (m, 1H), 3.77 (s, 3H). C NMR (100 MHz, CDCl3, 298 K): δ
154.4, 138.0, 129.0, 123.5, 118.9, 52.3.
Benzyl p-tolylcarbamate (3b): This compound was synthesized from p-toludine (1.00
mmol scale) using general procedure C (TFAA method) at -78 °C. The reaction mixture
was quenched with BnOH (0.10 ml, 1 mmol, 1 eq). Purification by flash column
chromatography on silica gel (15% EtOAc/Hexanes) afforded 211 mg (0.87 mmol, 87%)
of the desired product as a white solid. Second trial of reaction yielded 208 mg (0.86
mmol, 86%) of the desired product. Average yield: 87%. Exhibited spectral data identical
to a previous report.30
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1H NMR (500 MHz, CDCl3, 298 K): δ 7.46-7.31 (m, 7H), 7.14 (d, J = 8.1 Hz, 2H), 7.00
(br s, 1H), 5.23 (s, 2H), 2.35 (s, 3H). 13C NMR (125 MHz, CDCl3, 298 K): δ 153.7,
136.3, 135.4, 133.0, 129.6, 128.6, 128.3, 119.0, 66.9, 20.8.
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Allyl (4-nitrophenyl)carbamate (3c): This compound was synthesized from
p-nitroaniline (1.00 mmol scale) using general procedure C (TFAA method) with 2
equivalents of DBU at -78 °C. The reaction mixture was quenched with allyl alcohol (0.4
ml, excess). Purification by flash column chromatography on silica gel (15%
EtOAc/Hexanes) afforded 187 mg (0.84 mmol, 84%) of the desired product as a white
solid. Second trial of reaction yielded 199 mg (0.90mmol, 90%) of the desired product.
Average yield: 87%. Exhibited spectral data identical to a previous report.31
1H NMR (400 MHz, CDCl3, 298 K): δ 8.23 (d, J = 9.6 Hz, 2H), 7.59 (d, J = 8.9 Hz, 2H),
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7.11 (br s, 1H), 6.05-5.93 (m, 1H), 5.45-5.28 (m, 2H), 4.76-4.67 (m, 2H). C NMR (100
MHz, CDCl3, 298 K): δ 152.5, 143.8, 143.1, 131.8, 125.3, 119.0, 117.8, 66.5.
Methyl (4-nitrophenyl)carbamate (3d): This compound was synthesized from p-
nitroaniline (1.00 mmol scale) using general procedure C (TFAA method) with 2
equivalents of DBU at -78 °C. The reaction mixture was quenched with MeOH (0.4 ml,
excess). Purification by flash column chromatography on silica gel (30%
EtOAc/Hexanes) afforded 187 mg (0.95 mmol, 95%) of the desired product as a pale
yellow solid. Second trial of reaction yielded 198 mg (1.00 mmol, 100%) of the desired
product. Average yield: 98%. Exhibited spectral data identical to a previous report.32
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1H NMR (400 MHz, DMSO-d6, 298 K): δ 10.38 (br s, 1H), 8.20 (d, J = 9.3 Hz, 2H)
7.69 (d, J = 9.3 Hz, 2H), 3.73 (s, 3H). 13C NMR (100 MHz, DMSO-d6, 298 K): δ 153.7,
145.6, 141.6, 125.0, 117.5, 52.1.
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Isopropyl (4-fluorophenyl)carbamate (3e): This compound was synthesized from
p-fluoroaniline (1.00 mmol scale) using general procedure C (TFAA method) at -78 °C.
The reaction mixture was quenched with iPrOH (0.8 ml, excess). Purification by flash
column chromatography on silica gel (10% EtOAc/Hexanes) afforded 181 mg (0.91
mmol, 91%) of the desired product as a white solid. Second trial of reaction yielded 193
mg (0.97 mmol, 97%) of the desired product. Average yield: 94%. Exhibited spectral
data identical to a previous report.33
1H NMR (400 MHz, CDCl3, 298 K): δ 7.38-7.29 (m, 2H), 6.99-6.92 (m, 2H), 6.88 (br s,
1H), 5.04-4.95 (m, 1H), 1.27 (d, J = 6.2 Hz, 6H). 13C NMR (100 MHz, CDCl3, 298 K):
δ 158.8 (d, J = 242 Hz), 153.6, 134.1 (d, J = 2.6 Hz), 120.7, 115.5 (d, J = 23.1 Hz), 68.8,
22.0.
Benzyl (3-cyanothiophen-2-yl)carbamate (3f): This compound was synthesized from
2-aminothiophene-3-carbonitrile (1.00 mmol scale) using general procedure C (TFAA
method) at -78 °C. The reaction mixture was quenched with BnOH (0.2 ml, 2 eq).
Purification by flash column chromatography on silica gel (20% EtOAc/Hexanes)
afforded 181 mg (0.70 mmol, 70%) of the desired product as a white solid. Second trial
of reaction yielded 166 mg (0.64 mmol, 64%) of the desired product. Average yield:
67%.
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1H NMR (500 MHz, DMSO-d6, 298 K): δ 11.46 (s br, 1H), 7.45-7.29 (m, 5H), 7.15 (d,
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J = 6.0 Hz, 1H), 7.09 (d, J = 5.8 Hz, 1H), 5.22 (s, 2H). C NMR (125 MHz, DMSO-d6,
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298 K): δ 154.0, 151.4, 136.3, 128.9, 128.7, 128.5, 125.9, 119.3, 114.9, 93.9 (br) 67.6.
HRMS (DART-TOF+) m/z: [M+H]+ calcd for C13H11N2O2S 259.0541; found 259.0549.
IR (neat): 2225, 1723, 1567, 1248, 704 cm-1. Melting point: 158.8-161.9 °C.
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Dimethyl (methylenebis(4,1-phenylene))dicarbamate (4a): This compound was
synthesized from 4,4′-diaminodiphenylmethane (0.50 mmol scale) using general
procedure C (TFAA method) with 3 equivalents of DBU at -78 °C. The reaction mixture
was quenched with MeOH (0.5 ml, excess). Purification by flash column chromatography
on silica gel (30% EtOAc/Hexanes) afforded 133 mg (0.42 mmol, 85%) of the desired
product as a white solid. Second trial of reaction yielded 138 mg (0.44 mmol, 88%) of the
desired product. Average yield: 87%. Exhibited spectral data identical to a previous
report.34
Compound 4a could also be isolated in 90% purity after simple aqueous wash (instead of
flash column chromatography on silica gel). Upon completion of the reaction, the
reaction mixture was diluted with dichloromethane and washed with a saturated solution
of NH4Cl followed by brine (×3). The organic layer was dried over MgSO4 and
concentrated under vacuum to afford 4a in 73% yield and 90% purity.
1H NMR (400 MHz, DMSO-d6, 298 K): δ 9.54 (s, 2H), 7.36 (d, J = 8.4 Hz, 4H), 7.11
(d, J = 8.5 Hz, 4H), 3.80 (s, 2H), 3.65 (s, 6H). 13C NMR (100 MHz, DMSO-d6, 298 K):
δ 154.5, 137.5, 136.0, 129.3, 118.8, 52.0, 40.3.
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Dimethyl (4-methyl-1,3-phenylene)dicarbamate (4b): This compound was synthesized
from 2,4-diaminotoluene (0.50 mmol scale) using general procedure C (TFAA method)
with 3 equivalents of DBU at -78 °C. The reaction mixture was quenched with MeOH
(0.5 ml, excess). Purification by flash column chromatography on silica gel (25%
EtOAc/Hexanes) afforded 96 mg (0.40 mmol, 81%) of the desired product as a white
solid. Second trial of reaction yielded 95 mg (0.39 mmol, 80%) of the desired product.
Average yield: 81%. Exhibited spectral data identical to a previous report.34
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1H NMR (400 MHz, DMSO-d6, 298 K): δ 9.54 (s, 1H), 8.80 (s, 1H), 7.50 (br, 1H),
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7.19-7.16 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 3.66-3.63 (m, 6H), 2.12 (s, 3H). C NMR
(100 MHz, DMSO-d6, 298 K): δ 154.7, 153.9, 137.2, 136.4, 130.2, 125.6, 115.0, 114.8,
51.6, 51.5, 17.0.
React IR data for the formation of isocyanate
Experimental set-up using DMSO/oxalyl chloride reaction conditions: Aniline (1.0
mmol) and DBU (1.0 mmol) were dissolved in CH2Cl2 (2.0 mL) under CO2 (1 atm). This
mixture was then transferred via cannula to a three-necked flask equipped with the React
IR probe and containing a solution of DMSO (1.0 mmol) and oxalyl chloride (1.0 mmol)
in CH2Cl2 at -60 °C under an atmosphere of CO2 (1 atm). After 10 minutes, Et3N (1.0
mmol) was added to the flask and the reaction was allowed to gradually warm to room
temperature.
SUPPORTING INFORMATION
The Supporting Information is available free of charge on the ACS Publications website.
In situ IR data, HPLC traces for compounds 2n and 2o and NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*sroussea@chem.utoronto.ca
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank NSERC (Discovery Grants and Canada Research Chairs programs), the Canada
Foundation for Innovation (project number 35261), the Ontario Research Fund and the
University of Toronto for generous financial support of this work. Y. R. thanks the
Government of Ontario for an Ontario Trillium Scholarship. The Canada Foundation for
Innovation (project number 19119) and the Ontario Research Fund are also
acknowledged for funding of the Centre for Spectroscopic Investigation of Complex
Organic Molecules and Polymers (CSICOMP). Graham E. Garrett is thanked for
assistance in acquiring in situ IR spectra and Nicholas Michel is thanked for checking the
experimental procedure.
REFERENCES
(1) Ghosh, A. K.; Brindisi, M. J. Med. Chem. 2015, 58, 2895–2940.
(2) Engels, H.-W.; Pirkl, H.-G.; Albers, R.; Albach, R. W.; Krause, J.; Hoffmann, A.;
Casselmann, H.; Dormish, J. Angew. Chem. Int. Ed. 2013, 52, 9422-9441.
(3) For selected reviews on the phosgene-free synthesis of polyurethanes and their
precursors, see: (a) Kreye, O.; Mutlu, H.; Meier, M. A. R. Green Chem. 2013, 15, 1431-
1455; (b) Maisonneuve, L.; Lamarzelle, O.; Rix, E.; Grau, E.; Cramail, H. Chem. Rev.
2015, 115, 12407-12439.
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(4) Six, C.; Richter, F. Isocyanates, Organic. In Ullmann’s Encyclopedia of Industrial
Chemistry; Wiley-VCH: Weinheim, 2003.
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(5) For the use of phosgene in the multi kilogram-scale preparation of a medicinally
important compound, see: Storace, L.; Anzalone, L.; Confalone, P. N.; Davis, W. P.;
Fortunak, J. M.; Giangiordano, M.; Haley, J. J. Jr.; Kamholz, K. ; Li, H.-Y.; Ma, P.;
Nugent, W. A.; Parsons, R. L. Jr.; Sheeran, P. J.; Silverman, C. E.; Waltermire, R. E.;
Wood, C. C. Org. Process Res. Dev. 2002, 6, 54-63.
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(6) Phosgene was used as a chemical weapon during WWI and is currently listed on
Schedule 3 of the Chemical Weapons Convention. Schedule 3, Organisation for the
Prohibition of Chemical Weapons, https://www.opcw.org/chemical-weapons-
convention/annexes/annex-on-chemicals/schedule-3/ (accessed on 19/01/2017)
(7) For selected developments in the phosgene-free synthesis of isocyanates, see: (a) Jay,
L. P.; Barker, T. J. Eur. J. Org. Chem. 2016, 1829-1831; (b) Grange, R. L.; Evans, P. A.
J. Am. Chem. Soc. 2014, 136, 11870-11873; (c) Spyropoulos, C.; Kokotos, C. G. J. Org.
Chem. 2014, 136, 11870-11873; (d) Vinogradova, E. V.; Fors, B. P.; Buchwald, S. L. J.
Am. Chem. Soc. 2012, 134, 11132-11135; (e) Yoshimura, A.; Luedtke, M. W.; Zhdankin,
V. V. J. Org. Chem. 2012, 77, 2087-2091; (f) Le, H. V.; Ganem, B. Org. Lett. 2011, 13,
2584-2585; (g) Knölker, H.-J.; Braxmeier, T.; Schlechtingen, G. Angew. Chem. Int. Ed.
Engl. 1995, 34, 2497-2500.
(8) For selected developments in the phosgene-free synthesis of ureas, see: (a) Kulkarni,
A. R.; Garai, S.; Thakur, G. A. J. Org. Chem. 2017, 82, 992-999; (b) Zhao, J.; Li, Z.;
Yan, S.; Xu, S.; Wang, M.-A.; Fu, B.; Zhang, Z. Org. Lett. 2016, 18, 1736-1739; (c) Wei,
Y.; Liu, J.; Lin, S.; Ding, H.; Liang, F.; Zhao, B. Org. Lett. 2010, 12, 4220-4223; (d)
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