Facile one-pot synthesis of unsymmetrical ureas, carbamates, and thiocarbamates from Cbz-protected amines

Article abstract of DOI:10.1039/c6ob01290f

A novel one-pot synthesis of unsymmetrical ureas, carbamates and thiocarbamates from Cbz-protected amines has been developed. In the presence of 2-chloropyridine and trifluoromethanesulfonyl anhydride, isocyanates are generated in situ, which facilitate rapid reaction with amines, alcohols, and thiols to afford the corresponding ureas, carbamates and thiocarbamates in high yields.

Full text of DOI:10.1039/c6ob01290f

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DOI: 10.1039/C6OB01290F
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ARTICLE
Facile One‐pot Synthesis of Unsymmetrical Ureas, Carbamates,
and Thiocarbamates from Cbz‐protected Amines†
Hee‐Kwon Kima,b and Anna Lee*c
Received 00th January 20xx,
Accepted 00th January 20xx
A novel one‐pot synthesis of unsymmetrical ureas, carbamates and thiocarbamates from Cbz‐protected amines has been
developed. In the presence of 2‐chloropyridine and trifluoromethanesulfonyl anhydride, isocyanates are generated in situ,
which facilitate rapid reaction with amines, alcohols, and thiols to afford the corresponding ureas, carbamates and
thiocarbamates in high yields.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
In the presence of base and trifluoromethanesulfonyl
anhydride, the isocyanate intermediate could be generated in
Ureas and their derivatives are frequently encountered in situ under mild reaction conditions. This strategy has also been
natural products and bioactive compounds, such as plant and extended to other reactions. For example, 2‐chloropyridine
insect growth regulators,1 enzyme inhibitors,2 natural receptor and trifluoromethanesulfonyl anhydride have been used to
antagonists,3 CCR8 ligands and HIV protease inhibitors.4 In generate the isocyanate intermediate in Friedel‐Crafts
particular, unsymmetrical ureas are found in numerous acylation19 and cyclodehydration reactions.20 Along these lines,
therapeutically relevant compounds, including approved the Kokotos group reported a one‐pot synthesis of ureas from
pharmaceuticals such as sorafenib and cariprazine.5 In addition, Boc‐protected amines. In this study, amines, known as strong
carbamates and thiocarbamates are an important class of nucleophiles, were employed to afford the desired ureas.21
compounds due to their biological activity.6 For example, they
Carbamate‐type protecting groups are the most common
have been employed in a wide range of agrochemicals, such as protecting groups for amines. The Cbz‐protecting group is
herbicides,7 pesticides,7b bactericides,8 and antiviral agents.9 especially useful because of the high stability of resulting
Therefore, the development of new synthetic methods to protected amines under basic and acidic conditions, and the
fashion unsymmetrical ureas, carbamates, and thiocarbamates subsequent easy removal of the protecting group by catalytic
is desirable.
hydrogenolysis or strong acid.22 In addition, there are certain
The traditional approach for the synthesis of ureas, conditions under which other carbamate‐type protecting
carbamates and thiocarbamates involves the use of toxic groups (e.g. the Boc‐protecting group) are not suitable. In
phosgene or triphosgene.10 To avoid the use of hazardous these cases, the Cbz‐protecting group, which is one of the
reagents, several methods have also been reported. For most widely used amine‐protecting groups, can be employed
example, carbonates,11 N,N
′
‐carbonyldiimidazole,12 1,1
′‐
as a good tolerant alternative. However, the direct synthesis of
carbonylbisbenzotriazole,13 S,S‐dimethylthiocarbonate,14 S‐ ureas using Cbz‐protected amines is rarely reported. Therefore,
methylthiocarbamate,15 and others16 have been employed for the development of such a route would be advantageous for
the synthesis of ureas and carbamates. In addition, carbon the synthetic community. To the best of our knowledge, a
monoxide was employed in reactions with amines and thiols in facile, divergent one‐pot route using in situ‐generated
the presence of transition metal catalysts for the synthesis of isocyanates for the synthesis of ureas, carbamates, and
thiocarbamates.17 Despite the development of numerous thiocarbamates from Cbz‐protected amines does not yet exist.
processes, most involve the use of unstable reagents and/or Herein, we report the first one‐pot synthesis of unsymmetrical
toxic metal catalysts, multi‐step procedures, and harsh ureas, carbamates, and thiocarbamates from Cbz‐protected
reaction conditions. Recently, the isocyanate group has been amines (Scheme 1).
widely used as a precursor for urea and carbamate moieties.18
Results and discussion
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9
2-Cl-pyridine (5.0)
2-Cl-pyridine (3.0)
2-Cl-pyridine (3.0)
2-Cl-pyridine (3.0)
2-Cl-pyridine (3.0)
2-Cl-pyridine (3.0)
2-Cl-pyridine (3.0)
2-Cl-pyridine (3.0)
1.5
1.5
1.0
2.0
3.0
3.0
1.5
1.5
3.0
View Arti7cl5e Online
DOI: 10.1039/C6OB01290F
10
11
12
13
14
15c
16d
5.0
3.0
3.0
3.0
5.0
3.0
3.0
86
75
85
82
83
85
84
Scheme 1. In situ generated Isocyanate intermediate and its
applications.
We postulated that the main difficulty in the synthesis of
ureas using Cbz‐protected amines would be the low reactivity
of the benzoyl group. We envisioned that under more efficient
reaction conditions, the one‐pot synthesis of ureas utilizing
isocyanate intermediates starting from Cbz‐protected amines
would be realizable. We hypothesized that a combined
reaction system of 2‐halopyridine as a mild base and
trifluoromethanesulfonyl anhydride could be employed for the
in situ generation of isocyanates, which are active
intermediates for further reactions to ureas, carbamates, and
thiocarbamates. To test our hypothesis, Cbz‐protected
benzylamine was chosen as the model substrate and aniline
was used as the amine nucleophile (Table 1).
aAll reactions performed on 0.5 mmol scale. bYields are of isolated
product after column chromatography. cReaction conducted at 40 oC.
dReaction conducted at 50 oC in 1,2‐dichloroethane.
First, triethylamine and 4‐dimethylaminopyridine (DMAP)
were employed as bases, however, we did not observe any
desired product in either case (entries 1‐2). When we
employed pyridine, the product was obtained, albeit in low
yield (entry 3). Significant improvement in yield was realized
when we used 2‐halopyridine as the base (entries 5‐16). The
best result was obtained in the presence of 2‐Cl‐pyridine, with
which the desired product was afforded in 87% yield (entry 5).
When 2‐Br‐pyridine was employed, the product was obtained
in high yield, but slightly lower reactivity was observed (67%
yield, entry 6). Dramatically reduced yield was observed when
2‐Me‐pyridine was used (entry 4). Next, we tested the amount
of base, trifluoromethanesulfonyl anhydride, and amine
nucleophile (entries 7‐14). Increasing the amount of
trifluoromethanesulfonyl anhydride did not affect the reaction
yield (entries 12 and 13). However, a decrease in the amount
resulted in low yield (entry 11). Similar results were obtained
with the amine nucleophiles (entries 7‐10). In addition, the
optimal amount of base was confirmed by changing the
amount of 2‐Cl‐pyridine (entries 5, 8 and 9). Raising the
reaction temperature did not make any difference in terms of
reactivity under the reaction conditions (entries 15 and 16).
With the optimized reaction conditions in hand, the scope of
this one‐pot procedure for unsymmetrical ureas was explored
(Table 2). The reaction turned out to be tolerant of various
amines. The desired ureas were obtained in high yields (70‐
94%). Gratifyingly, various Cbz‐protected amines, including
benzyl, phenyl, and aliphatic amines, were all suitable
substrates under the reaction conditions (entries 1‐10).
Table 1. Conditions and results of the one‐pot approach for the synthesis
of unsymmetrical ureasa
Entry
Base
(equiv)
Tf2O
(equiv)
Amine
(equiv)
Yield
(%)b
1
2
3
4
Et3N (3.0)
1.5
1.5
1.5
1.5
3.0
3.0
3.0
3.0
0
0
DMAP (3.0)
Pyridine (3.0)
2-Me-pyridine (3.0)
27
37
5
6
7
8
2-Cl-pyridine (3.0)
2-Br-pyridine (3.0)
2-Cl-pyridine (3.0)
2-Cl-pyridine (1.5)
1.5
1.5
1.5
1.5
3.0
3.0
2.0
3.0
87
67
76
60
Table 2. Synthesis of Unsymmetrical Ureasa
2 | J. Name., 2012, 00, 1‐3
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We also utilized various alcohols with Cbz‐protected amines
View Article Online
for the synthesis of carbamates (Table 3,DeOnI:tr1i0e.1s0139‐9/C).6AOlBip01h2a9t0icF
and aromatic alcohols were employed in the reaction
successfully.
Table 3. Synthesis of Carbamates from Cbz‐protected aminesa
aAll reactions performed on 0.5 mmol scale. bYields are of isolated
product after column chromatography.
aAll reactions performed on 0.5 mmol scale. bYields are of isolated product
after column chromatography.
In addition, aromatic and aliphatic amine nucleophiles,
including primary, secondary, and tertiary amines, provided
the desired products in good to high yields. The desired
products were obtained in high yields when morpholine was
used (entries 3 and 4). Interestingly, sterically hindered tert‐
butylamine also provided the desired urea even though the
reaction yield was slightly decreased (65%, entry 10).
However, we could not obtain any desired product when 4‐
chloroaniline was used as the amine nucleophile (not shown).
Presumably, amine nucleophiles containing an electron
withdrawing group would not be suitable substrates due to
their weak nucleophilicity under the reaction conditions.
The desired carbamates were obtained in high yields (73‐93%).
Alkynyl alcohol 4a was also employed in the reaction as the
alcohol nucleophile (entry 1). The desired product 5a was
obtained in high yield (90%). Benzyl‐protected alcohol 4h
afforded the desired carbamate in high yield (80%, entry 8). In
addition, Cbz‐protected tetrahydroisoquinolines, which would
be interesting bioactive compound scaffolds, provided the
products in high yields (entries 5 and 6). It is noteworthy that
relatively weak nucleophilic alcohols were successfully
employed in the reactions.
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This one‐pot method could be easily extended to the
synthesis of thiocarbamates starting from Cbz‐protected
amines (Table 4, entries 1‐8). The reaction was tolerant of both
electron deficient (entries 3 and 6) and electron rich thiols
View Article Online
DOI: 10.1039/C6OB01290F
(entries 2 and 7); the desired thiocarbamates (7b‐c, 7f‐g) were
obtained in high yields (70‐85%). In addition, 1‐butanethiol
was also suitable substrate under our reaction conditions. The
desired thiocarbamate 7h was obtained in high yield (85%).
Scheme 2. Synthesis of enantioenriched urea 9 and carbamate 10.
Table 4. Synthesis of Thiocarbamates from Cbz‐protected aminesa
Conclusions
In conclusion, we have developed a highly efficient one‐pot
procedure starting from Cbz‐protected amines that features a
divergent transformation from in situ‐generated isocyanates23
into unsymmetrical ureas, carbamates, and thiocarbamates.
This novel method has enabled us to broaden the scope of the
reaction; the enantioenriched urea and carbamate were
synthesized successfully without loss of enantioselectivity. The
mild reaction conditions and facile approach for the synthesis
of useful compounds make this method attractive in organic
synthesis.
1) 2-Cl-pyridine (3.0 equiv)
O
R1
Cbz
Tf2O (1.5 equiv), DCM, RT, 1 h
R1
R4
N
H
N
S
H
2) R3SH (6, 3.0 equiv), 1 h , RT
7
1
Productb
O
Entry
1
Substrate
Thiol (6)
Cbz
PhSH
Ph
Ph
N
H
1a
Ph
N
H
S
6a
7a, 74%
Me
Cl
O
Cbz
Cbz
2
3
Me
Cl
SH
SH
Ph
Ph
N
H
Ph
N
S
H
1a
6b
6c
7b, 85%
O
Experimental
General methods
N
H
Ph
N
S
H
1a
7c, 80%
Reactions were performed in a well‐dried flask under argon
atmosphere unless noted otherwise. Solvents used as reaction
media were dried over pre‐dried molecular sieves (4 Å) in a
microwave oven. Solvents for extraction and chromatography
were reagent grade and used as received. Column
chromatography was performed with silica gel 60 (70−230
mesh) using a mixture of EtOAc/hexane as eluent. 1H and 13C
NMR spectra were, respectively, recorded on a 400 or 600
MHz (1H NMR), 100 or 150 MHz (13C NMR) spectrometer in
deuterated chloroform (CDCl3) with tetramethylsilane (TMS) as
an internal reference. Data are reported as (ap = apparent, s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broad; coupling constant(s) in Hz, integration). High‐resolution
mass spectroscopy was performed using a magnetic sector
analyzer. All of the new compounds were identified by 1H and
13C NMR, IR, and high resolution mass spectroscopy. The
identity of the known compounds was established by the
O
Ph
Cbz
PhSH
Ph
Ph
4
5
N
H
N
S
H
6a
1b
7d, 72%
O
Ph
Cbz
Cbz
PhSH
N
S
N
H
H
1e
6a
7e, 72%
Cl
O
6
7
8
Cl
SH
SH
N
N
S
H
H
1e
6c
7f, 70%
Me
O
Cbz
Cbz
Me
N
N
S
H
H
1e
6b
6d
7g, 72%
O
Me
SH
N
N
S
Me
H
H
1e
7h, 85%
1
comparison of their H and 13C NMR peaks with the authentic
aAll reactions performed on 0.5 mmol scale. bYields are of isolated product
after column chromatography.
values.
General procedure for synthesis of unsymmetrical ureas,
carbamates, and thiocarbamates from Cbz‐protected amines. Cbz‐
Next, we carried out asymmetric syntheses of urea and
carbamate to examine whether racemization would occur
protected amine
1 (0.5 mmol. 1.0 equiv) and 2‐Cl‐pyridine (1.5
mmol, 3.0 equiv) were dissolved in dry dichloromethane (2 mL,
0.25 M). Tf2O (0.75 mmol, 1.5 equiv) was added dropwise over
5 min. After stirring for 1 hour at room temperature, three
equivalents of amine or alcohol (or thiol) were added to the
resulting mixture. In the case of carbamate synthesis, three
equivalents of triethylamine were added additionally. After the
completion of the reaction, the mixture was diluted with
during
phenylethyl)carbamate
substrate and the resulting urea
this
one‐pot
procedure.
was used as the starting amine
and carbamate 10 were
(S)‐benzyl
(1‐
8
9
obtained without loss of enantioselectivity (Scheme 2).
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dichloromethane and water, the mixture was extracted with
dichloromethane and the combined organic layer was washed
with brine and water, dried over MgSO4, filtered and
concentrated under reduced pressure. The resulting residue
was purified by flash column chromatography with
EtOAc/hexanes (1:9 to 2:8, v/v).
mixture was purified by flash chromatography using 30%
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EtOAc/hexane to afford 83 mg (86% yDieOldI:)10o.1f03p9r/oCd6uOcBt01a2s90aF
white solid. mp152−153°C; IR; 3386, 3257, 2965, 2922, 2869,
1642, 1551, 1441, 1310, 1238 cm‐1; 1H NMR (600 MHz, CDCl3):
δ 7.27 – 7.23 (m, 4H), 7.03 (s, 1H), 7.01 (t, J = 7.2 Hz, 1H), 5.41
(s, 1H), 3.01 (t, J = 6.0 Hz, 2H), 1.70 (m, 1H), 0.87 (d, J = 8.4 Hz,
6H); 13C NMR (150 MHz, CDCl3): δ 156.5, 138.9, 129.2 (2C),
123.5, 120.8, 47.7, 28.9, 20.1 (2C); HRMS (ESI) m/z (M+H)+
calcd for C11H17N2O = 193.1341, found 193.1342.
1‐Benzyl‐3‐phenylurea (3a). Prepared according to the
general procedure using Cbz‐protected benzylamine (benzyl
benzylcarbamate, 1a) and aniline. The reaction mixture was
purified by flash chromatography using 20% EtOAc/hexane to
N
‐Phenyl‐3,4‐dihydroisoquinoline‐2(1H)‐carboxamide (3f).
afford 98 mg (87% yield) of product as a yellowish solid. 1
H
Prepared according to the general procedure using Cbz‐
protected phenylamine (benzyl phenylcarbamate, 1b) and
1,2,3,4‐tetrahydroisoquinoline. The reaction mixture was
purified by flash chromatography using 20% EtOAc/hexane to
afford 90 mg (71% yield) of product as a white solid. mp
145−147°C; IR 3252, 2913, 1631 cm‐1; 1H NMR (600 MHz,
CDCl3): δ 7.39 (m, 2H), 7.29 (m, 2H), 7.11 (m, 4H), 7.03 (t, J =
6.6 Hz, 1H), 6.38 (s, 1H), 4.66 (s, 2H), 3.72 (t, J = 6.0 Hz, 2H),
2.94 (t, J = 5.4 Hz, 2H); 13C NMR (150 MHz, CDCl3): δ 154.9,
139.2, 135.1, 133.3, 128.9, 128.5, 126.9, 126.6, 126.4, 123.2,
120.1, 45.8, 41.7, 29.1; HRMS (ESI) m/z (M+H)+ calcd for
C16H17N2O = 253.1341, found 253.1346. The analytical data
were identical in all respects to those previously reported.24b
NMR (400 MHz, CDCl3): δ 7.33‐7.20 (m, 10H), 7.10 (t, J = 7.2 Hz,
1H), 6.51 (s, 1H), 4.41 (s, 2H) ppm; 13C NMR (100 MHz, CDCl3):
δ 156.0, 139.0, 138.2, 129.0, 128.5, 127.1, 127.0, 123.8, 121.0,
44.0. HRMS (ESI) m/z (M+H)+ calcd for C14H15N2O = 227.1179,
found 227.1175. The analytical data were identical in all
respects to those previously reported.24
1‐Benzyl‐3‐(4‐methoxyphenyl)urea
according to the general procedure using Cbz‐protected
benzylamine (benzyl benzylcarbamate, 1a and 4‐
(3b).
Prepared
)
methoxyaniline. The reaction mixture was purified by flash
chromatography using 20% EtOAc/hexane to afford 108 mg
(84% yield) of product as a yellowish solid. 1H NMR (400 MHz,
CDCl3): δ 7.36 – 7.11 (m, 7H), 6.84 (d, J = 8.8 Hz, 2H), 6.29 (s,
1H), 5.04 (s, 1H), 4.40 (d, J = 5.6 Hz, 2H), 3.77 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 157.1, 138.9, 130.6, 128.6, 127.3, 125.1,
114.6, 55.5, 44.2; HRMS (ESI) m/z (M+H)+ calcd for C15H17N2O2
= 257.1280, found 257.1278. The analytical data were identical
in all respects to those previously reported.25
N
‐Methyl‐
N
‐phenylpiperidine‐1‐carboxamide
(3g).
Prepared according to the general procedure using Cbz‐
protected N‐methylaniline (benzyl (methyl)phenylcarbamate,
1c) and piperidine. The reaction mixture was purified by flash
chromatography using 25% EtOAc/hexane to afford 76 mg (70%
yield) of product as a colorless oil. 1H NMR (600 MHz, CDCl3):
δ
7.27 – 7.24 (m, 2H), 7.03 – 7.01 (m, 3H), 3.15 (s, 3H), 3.11 –
3.07 (m, 4H), 1.41 – 1.39 (m, 2H), 1.30 – 1.27 (m, 4H); 13C NMR
(150 MHz, CDCl3): δ 161.3, 147.3, 129.3, 129.1, 124.1, 123.5,
48.2, 46.7, 41.9, 39.5, 25.8, 25.4, 24.5; HRMS (ESI) m/z (M+H)+
calcd for C13H19N2O = 219.1490, found 219.1494. The analytical
data were identical in all respects to those previously
reported.27
N
‐Benzylmorpholine‐4‐carboxamide
(3c).
Prepared
according to the general procedure using Cbz‐protected
benzylamine (benzyl benzylcarbamate, 1a) and morpholine.
The reaction mixture was purified by flash chromatography
using 50% EtOAc/hexane to afford 93 mg (84% yield) of
product as a white solid. mp 138−140°C; 1H NMR (600 MHz,
CDCl3): δ 7.34–7.25 (m, 5H), 4.71 (s, 1H), 4.42 (d, J = 5.4 Hz, 2H),
3.67 (t, J = 4.8 Hz, 4H), 3.35 (t, J = 4.8 Hz, 4H); 13C NMR (150
MHz, CDCl3): δ 157.7, 139.2, 128.8, 127.9, 127.5, 66.6, 45.1,
44.1; HRMS (ESI) m/z (M+H)+ calcd for C12H17N2O2 = 221.1290,
found 221.1287. The analytical data were identical in all
respects to those previously reported.24b
N
‐Cyclohexyl‐3,4‐dihydroisoquinoline‐2(1H)‐carboxamide
(3h). Prepared according to the general procedure using Cbz‐
protected
dihydroisoquinoline‐2(1H)‐carboxylate,
1,2,3,4‐tetrahydroisoquinoline
(benzyl
1d
3,4‐
and
)
cyclohexylamine. The reaction mixture was purified by flash
chromatography using 92% EtOAc/hexane to afford 119 mg
(70% yield) of product as a white solid. mp 122−123°C; IR 3282,
2925, 2851, 1616, 1531, 1415, 1250 cm‐1; 1H NMR (600 MHz,
CDCl3): δ 7.18 – 7.11 (m, 4H), 4.51 (s, 2H), 4.28 (d, J = 5.4 Hz,
1H), 3.69 (m, 1H), 3.59 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 2H),
1.96 (dd, J = 3.6, 6.6 Hz, 2H), 1.69 (m, 3H), 1.37 (m, 2H), 1.12
(m, 3H); 13C NMR (150 MHz, CDCl3): δ 156.9, 135.3, 133.6,
128.4 (2C), 126.7, 126.4, 120.4, 49.5 (2C), 45.5, 41.1, 34.2 (2C),
29.2, 25.8, 25.2; HRMS (ESI) m/z (M+H)+ calcd for C16H23N2O =
259.1810, found 259.1813.
N
‐Phenylmorpholine‐4‐carboxamide
(3d).
Prepared
according to the general procedure using Cbz‐protected
phenylamine (benzyl phenylcarbamate, 1b) and morpholine.
The reaction mixture was purified by flash chromatography
using 20% EtOAc/hexane to afford 72 mg (70% yield) of
product as a yellowish solid. 1H NMR (400 MHz, CDCl3): δ 7.39
– 7.20 (m, 4H), 7.03 (t, J = 7.3 Hz, 1H), 6.75 (s, 1H), 3.71 – 3.59
(m, 4H), 3.48 – 3.34 (m, 4H); 13C NMR (100 MHz, CDCl3):
δ
155.3, 138.8, 128.8, 123.3, 120.4, 66.5, 44.2; HRMS (ESI) m/z
(M+H)+ calcd for C11H15N2O2 = 207.1128, found 207.1121. The
analytical data were identical in all respects to those previously
reported.26
1‐Isobutyl‐3‐phenylurea (3e). Prepared according to the
general procedure using Cbz‐protected phenylamine (benzyl
phenylcarbamate, 1b) and 2‐methyl‐1‐propanol. The reaction
N
‐Isobutyl‐3,4‐dihydroisoquinoline‐2(1H)‐carboxamide (3i).
Prepared according to the general procedure using Cbz‐
protected 1,2,3,4‐tetrahydroisoquinoline ((benzyl 3,4‐
dihydroisoquinoline‐2(1H)‐carboxylate, 1d) and 2‐methyl‐1‐
propanol. The reaction mixture was purified by flash
chromatography using 30% EtOAc/hexane to afford 109 mg
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(94% yield) of product as a white solid. mp 77−79°C; IR 3325, protected N‐methylaniline (benzyl (methyl)phenVyielcwaArrbticalemOantliene,
2923, 1623, 1551, 1265, 1237 cm‐1; 1H NMR (600 MHz, CDCl3): 1c) and 3‐methyl‐2‐buten‐1‐ol. The reaction mixture was
DOI: 10.1039/C6OB01290F
δ 7.17 – 7.10 (m, 4H), 4.52 (m, 3H), 3.60 (t, J = 6.0 Hz, 2H), 3.08 purified by flash chromatography using 20% EtOAc/hexane to
(t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 2H), 1.77 (m, 1H), 0.91 (d, J afford 91 mg (83% yield) of product as a colorless oil. 1H NMR
= 7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3): δ 157.7, 135.3, 133.6, (600 MHz, CDCl3): δ 7.26 – 7.24 (m, 2H), 6.77 – 6.72 (m, 3H),
128.5, 126.7, 126.4(2C), 120.4, 48.4, 45.6, 41.2, 29.1, 28.9, 5.24 (t, J = 1.2 Hz, 1H), 3.91 (d, J = 6.0 Hz, 2H), 2.91 (s, 3H), 1.75
20.2(2); HRMS (ESI) m/z (M+H)+ calcd for C14H21N2O = (s, 6H); 13C NMR (150 MHz, CDCl3): δ 149.9, 134.6, 129.2,
233.1654, found 233.1656.
121.0 (2C), 116.5, 113.0 (2C), 50.6, 38.0, 25.8, 18.0; HRMS (ESI)
1‐Benzyl‐3‐tert‐butylurea (3j). Prepared according to the m/z (M+H)+ calcd for C13H18NO2 = 220.1338, found 220.1334.
general procedure using Cbz‐protected benzylamine (benzyl The analytical data were identical in all respects to those
benzylcarbamate, 1a) and tert‐butylamine. The reaction previously reported.30
mixture was purified by flash chromatography using 20%
EtOAc/hexane to afford 67 mg (65% yield) of product as a Prepared according to the general procedure using Cbz‐
white solid. mp 109−111°C; 1H NMR (600 MHz, CDCl3): δ 7.29– protected
1,2,3,4‐tetrahydroisoquinoline (benzyl 3,4‐
Butyl
3,4‐dihydroisoquinoline‐2(1H)‐carboxylate
(5e):
7.26 (m, 2H), 7.24–7.22 (m, 3H), 4.78 (s, 1H), 4.49 (s, 1H), dihydroisoquinoline‐2(1H)‐carboxylate, 1c) and butanol. The
4.25(s, 2H), 1.28 (s, 9H); 13C NMR (150 MHz, CDCl3): δ 157.6, reaction mixture was purified by flash chromatography using
138.6, 128.6, 127.5, 127.2, 50.5, 44.4, 29.6 ; LRMS (EI); Mass 20% EtOAc/hexane to afford 108 mg (93% yield) of product as
calcd for C12H19N2O [M+H]+: 207.1; found 207.1. The analytical a colorless oil. IR 2959, 1700, 1429, 1295, 1228, 1121 cm‐1; 1
H
data were identical in all respects to those previously NMR (600 MHz, CDCl3): δ 7.25 – 7.11 (m, 4H), 4.62 (s, 2H), 4.14
reported.24b
(t, J = 5.4 Hz, 2H), 3.69 (s, 2H), 2.85 (s, 2H), 1.65 (m, 2H), 1.43
Prop‐2‐ynyl benzylcarbamate (5a). Prepared according to (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3):
δ
the general procedure using Cbz‐protected benzylamine 155.9, 134.7, 133.6, 128.9, 128.3, 126.5, 126.3, 63.4, 45.7, 41.5,
(benzyl benzylcarbamate, 1a) and propargyl alcohol. The 31.2, 29.0, 19.2, 13.8; HRMS (ESI) m/z (M+H)+ calcd for
reaction mixture was purified by flash chromatography using C14H20NO2 = 234.1494, found 234.1492.
20% EtOAc/hexane to afford 85 mg (90% yield) of product as a
Isopropyl 3,4‐dihydroisoquinoline‐2(1H)‐carboxylate (5f).
colorless oil. 1H NMR (600 MHz, CDCl3): δ 7.34 – 7.25 (m, 5H), Prepared according to the general procedure using Cbz‐
5.12 (s, 1H), 4.70 (d, J = 3.0 Hz, 2H), 4.37 (d, J = 5.4 Hz, 2H), protected
1,2,3,4‐tetrahydroisoquinoline
(benzyl
3,4‐
2.46 (t, J = 3.6 Hz, 1 H); 13C NMR (150 MHz, CDCl3): δ 155.5, dihydroisoquinoline‐2(1H)‐carboxylate, 1a) and 2‐propanol.
138.1, 128.9, 128.8, 127.7, 127.6, 127.3, 78.3, 74.7, 52.6, 45.2; The reaction mixture was purified by flash chromatography
HRMS (ESI) m/z (M+H)+ calcd for C11H12NO2 = 190.0868, found using 20% EtOAc/hexane to afford 94 mg (86% yield) of
190.0865. The analytical data were identical in all respects to product as a colorless oil. 1H NMR (600 MHz, CDCl3): δ 7.17 –
those previously reported.28
7.09 (m, 4H), 4.96 (m, 1H), 4.59 (s, 2H), 3.67 (s, 2H), 2.83 (s,
Cyclohexyl benzylcarbamate (5b). Prepared according to 2H), 1.26 (d, J = 6.6 Hz, 6H); 13C NMR (150 MHz, CDCl3):
δ
the general procedure using Cbz‐protected benzylamine 155.4, 134.8, 133.9, 128.9, 128.5, 126.5, 126.3, 68.7, 45.7, 41.5,
(benzyl benzylcarbamate, 1a) and cyclohexanol. The reaction 29.0, 22.4 (2C); HRMS (ESI) m/z (M+H)+ calcd for C13H18NO2 =
mixture was purified by flash chromatography using 20% 220.1338, found 220.1340. The analytical data were identical
EtOAc/hexane to afford 101 mg (87% yield) of product as a in all respects to those previously reported.24b
white solid. mp 80−82°C; 1H NMR (600 MHz, CDCl3): δ 7.33 –
Phenyl cyclohexylcarbamate (5g). Prepared according to
7.26 (m, 5H), 4.91 (s, 1H), 4.66 (s, 1H) 4.35 (d, J = 6.0 Hz, 2H), the general procedure using Cbz‐protected cyclohexylamine
1.87 (s, 2H), 1.70 (s, 2H), 1.51 (s, 1H), 1.41 – 1.21 (m, 4H), 1.22 (benzyl cyclohexylcarbamate, 1e) and phenol. The reaction
(s, 1H);13C NMR (150 MHz, CDCl3): δ 156.3, 138.8, 128.7 (2C), mixture was purified by flash chromatography using 20%
127.6, 127.5 (2C), 73.3, 45.0, 32.1 (2C), 25.5, 23.9 (2C); HRMS EtOAc/hexane to afford 90 mg (82% yield) of product as a
(ESI) m/z (M+H)+ calcd for C14H20NO2 = 234.1494, found white solid. mp: 134‐136 °C. 1H NMR (600 MHz, CDCl3): δ 7.35
234.1495. The analytical data were identical in all respects to – 7.32 (m, 2H), 7.18 – 7.01 (m, 3H), 4.87 (s, 1H), 3.55 (m, 1H),
those previously reported.29
2.00 (m, 2H), 1.73 (m, 2H), 1.62 (m, 1H), 1.37 (m, 2H), 1.20 (m,
Isobutyl benzylcarbamate (5c). Prepared according to the 3H); 13C NMR (150 MHz, CDCl3): δ 155.7, 151.2, 129.3 (2C),
general procedure using Cbz‐protected benzylamine (benzyl 125.1, 121.7 (2C), 50.1, 33.3 (2C), 25.5, 24.8 (2C); HRMS (ESI)
benzylcarbamate, 1a) and isobutanol. The reaction mixture m/z (M+H)+ calcd for C13H18NO2 = 220.1338, found 220.1334.
was purified by flash chromatography using 20% The analytical data were identical in all respects to those
EtOAc/hexane. White solid, 94 mg, 91% yield. mp 37−39°C; 1
NMR (600 MHz, CDCl3): δ 7.33 – 7.24 (m, 5H), 4.95 (s, 1H), 4.35
H
previously reported.31
3‐(Benzyloxy)propyl benzylcarbamate (5h). Prepared
(d, J = 6.6 Hz, 2H), 3.86 (d, J = 6.6 Hz, 2H), 1.90 (m, 1H), 0.91 (d, according to the general procedure using Cbz‐protected
J = 7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3): δ 156.9, 138.7, benzylamine (benzyl benzylcarbamate, 1a
and 3‐
128.7, 127.6, 127.5, 71.2, 45.1, 28.1, 19.2, 19.1; HRMS (ESI) (benzyloxy)propan‐1‐ol. The reaction mixture was purified by
)
m/z (M+H)+ calcd for C12H18NO2 = 208.1338, found 208.1335.
3‐Methylbut‐2‐enyl methyl(phenyl)carbamate
flash chromatography using 20% EtOAc/hexane to afford 120
(5d). mg (80% yield) of product as a white solid. 1H NMR (400 MHz,
Prepared according to the general procedure using Cbz‐ CDCl3): δ 7.31 ‐ 7.24 (m, 10H), 7.14 (s, 1H), 4.43 – 4.24 (m, 4H),
6 | J. Name., 2012, 00, 1‐3
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4.43 (s, 2H), 3.46 (t, J = 6.3 Hz, 2H), 1.96 – 1.93 (m, 2H); 13C yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.66 – 7.02 (m, 10H),
View Article Online
13
DOI: 10.1039/C6OB01290F
NMR (100 MHz, CDCl3): δ156.8, 128.6, 128.3, 127.5, 77.3, 76.9, 5.29 (d, J = 2.2 Hz, 1H); C NMR (100 MHz, CDCl3): δ 164.4,
76.7, 66.7, 62.9, 29.6; LRMS (EI); Mass calcd for C18H22NO3 137.5, 135.4, 129.9, 129.5, 129.2, 128.7, 128.4, 127.9, 119.6;
[M+H]+: 300.1; found 300.1.
LRMS (EI); Mass calcd for C13H12NOS [M+H]+: 230.1; found
Ethyl 4‐(cyclohexylcarbamoyloxy)benzoate (5i). Prepared 230.0. The analytical data were identical in all respects to
according to the general procedure using Cbz‐protected those previously reported.24b
cyclohexylamine (benzyl cyclohexylcarbamate, 1e) and ethyl 4‐
S
‐Phenyl
cyclohexylcarbamothioate
(7e): Prepared
hydroxybenzoate. The reaction mixture was purified by flash according to the general procedure using benzyl
chromatography using 20% EtOAc/hexane to afford 106 mg cyclohexylcarbamate 1e and benzenethiol. The reaction
(73% yield) of product as a white solid. White solid; mp mixture was purified by flash chromatography using 20%
108−110°C; 1H NMR (600 MHz, CDCl3): δ 8.02 (d, J = 8.4 Hz, EtOAc/hexane to afford 85 mg (72% yield) of product as a
2H), 7.06 (d, J = 9.0 Hz, 2H), 4.98 (s, 1H), 4.33 (m, 2H), 3.54 (m, yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.78 – 7.32 (m, 5H),
1H), 1.98 (m, 2H), 1.72 (m, 2H), 1.61 (m, 1H), 1.35 (m, 5H), 1.17 5.24 (s, 1H), 3.73 (s, 1H), 1.89 (d, J = 9.2 Hz, 2H), 1.62 (d, J = 9.2
(m, 3H); 13C NMR (150 MHz, CDCl3): δ 166.1, 154.8, 152.9, Hz, 2H), 1.17 (ddd, J = 105.7, 59.1, 47.3 Hz, 6H). 13C NMR (100
131.0, 127.2, 121.3, 61.1, 50.3, 33.3, 25.5, 24.8, 14.4; LRMS (EI); MHz, CDCl3): δ 164.9, 135.4, 129.4, 50.5, 25.3, 24.5; LRMS (EI);
Mass calcd for C16H22NO4 [M+H]+: 292.1; found 292.1.
‐Phenyl benzylcarbamothioate (7a). Prepared according to analytical data were identical in all respects to those previously
the general procedure using Cbz‐protected benzylamine reported.33
(benzyl benzylcarbamate, 1a) and benzenethiol. The reaction ‐(4‐Chlorophenyl) (7f).
Mass calcd for C13H18NOS [M+H]+: 236.1; found 236.1. The
S
S
cyclohexylcarbamothioate
mixture was purified by flash chromatography using 20% Prepared according to the general procedure using benzyl
EtOAc/hexane to afford 90 mg (74% yield) of product as a cyclohexylcarbamate 1e and 4‐chlorobenzenethiol. The
yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.56‐7.54 (m, 2H), reaction mixture was purified by flash chromatography using
7.40‐7.21 (m, 8H), 5.76 (s, 1H), 4.42 (d, J = 5.7 Hz, 2H); 13C NMR 20% EtOAc/hexane to afford 94 mg (70% yield) of product as a
(100 MHz, CDCl3): δ 166.2, 149.8, 138.7, 137.5, 135.5, 129.7, yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.57 – 7.13 (m, 4H),
129.4, 128.7, 127.6, 124.5, 122.3, 45.3, 29.7; LRMS (EI); Mass 5.34 (s, 1H), 3.72 (d, J = 6.6 Hz, 1H), 1.91 (d, J = 9.6 Hz, 2H),
calcd for C13H14NOS [M+H]+: 244.1, found 244.0. The analytical 1.81 – 1.48 (m, 3H), 1.48 – 1.01 (m, 5H); 13C NMR (100 MHz,
data were identical in all respects to those previously CDCl3): δ 164.2, 136.5, 135.7, 133.9, 130.1, 129.7, 129.3, 50.8,
reported.32
‐Tolyl benzylcarbamothioate (7b). Prepared according to 270.1; found 270.0. The analytical data were identical in all
the general procedure using Cbz‐protected benzylamine respects to those previously reported.24b
(benzyl benzylcarbamate, 1a) and 4‐methylbenzenethiol. The ‐Tolyl cyclohexylcarbamothioate Prepared
29.7, 25.3, 24.6; LRMS (EI); Mass calcd for C13H17ClNOS [M+H]+:
S‐p
S
‐p
(7g).
reaction mixture was purified by flash chromatography using according to the general procedure using benzyl
20% EtOAc/hexane to afford 109 mg (74% yield) of product as cyclohexylcarbamate 1e and 4‐methylbenzenethiol. The
a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 8.0 Hz, reaction mixture was purified by flash chromatography using
2H), 7.26 (ddd, J = 27.6, 13.9, 7.6 Hz, 7H), 5.64 (s, 1H), 4.44 (d, J 20% EtOAc/hexane to afford 90 mg (72% yield) of product as a
= 5.7 Hz, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 166.6, yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 8.0 Hz,
140.2, 135.5, 130.5, 130.1, 128.9, 128.6, 127.8, 127.4, 45.5, 2H), 7.21 (d, J = 8.0 Hz, 2H), 5.24 (s, 1H), 3.72 (d, J = 3.4 Hz, 1H),
44.9, 21.4, 21.2; LRMS (EI); Mass calcd for C15H16NOS [M+H]+: 2.37 (s, 3H), 1.87 (d, J = 9.4 Hz, 2H), 1.78 – 1.47 (m, 3H), 1.29
258.1; found 258.0. The analytical data were identical in all (dd, J = 20.7, 8.7 Hz, 2H), 1.11 (dd, J = 19.7, 7.6 Hz, 3H); 13C
respects to those previously reported.24b
‐(4‐Chlorophenyl) benzylcarbamothioate (7c). Prepared 50.4, 32.8, 25.3, 24.6, 21.3; LRMS (EI); Mass calcd for
according to the general procedure using Cbz‐protected C14H20NOS [M+H]+: 250.1; found 250.1. The analytical data
benzylamine (benzyl benzylcarbamate, 1a
and 4‐ were identical in all respects to those previously reported.24b
chlorobenzenethiol. The reaction mixture was purified by flash ‐Butyl cyclohexylcarbamothioate (7h). Prepared according
NMR (100 MHz, CDCl3): δ 165.4, 139.9, 135.4, 130.2, 125.4,
S
)
S
chromatography using 20% EtOAc/hexane to afford 111 mg to the general procedure using benzyl cyclohexylcarbamate 1e
(80% yield) of product as a white solid. 1H NMR (400 MHz, and 1‐butanethiol. The reaction mixture was purified by flash
CDCl3): δ 7.48 (d, J = 8.5 Hz, 2H), 7.43 – 7.19 (m, 7H), 5.67 (s, chromatography using 20% EtOAc/hexane to afford 92 mg (85%
1H), 4.46 (d, J = 5.7 Hz, 2H); 13C NMR (100 MHz, CDCl3):
δ
yield) of product as a pale yellow oil. 1H NMR (400 MHz, CDCl3):
165.4, 136.6, 129.5, 128.8, 127.8 (d, J = 8.7 Hz), 45.5; LRMS (EI); δ 5.24, (s, 1H), 3.72 (s, 1H), 2.86 (t, J = 7.3 Hz, 2H), 1.92 – 1.89
Mass calcd for C14H13ClNOS [M+H]+: 278.0; found 278.0. The (m, 2H), 1.70 – 1.65 (m, 2H), 1.60‐1.08 (m, 10H), 0.89 (t, J = 7.3
analytical data were identical in all respects to those previously Hz, 3H); 13C NMR (100 MHz, CDCl3): δ166.2, 50.4, 33.2, 32.5,
reported.24b
S
29.6, 25.4, 24.7, 21.9, 13.6; LRMS (EI); Mass calcd for
‐(4‐Chlorophenyl) benzylcarbamothioate (7d). Prepared C11H22NOS [M+H]+: 215.1; found 215.1. The analytical data
according to the general procedure using benzyl were identical in all respects to those previously reported.34
phenylcarbamate 1b and benzenethiol. The reaction mixture )‐1‐Phenyl‐3‐(1‐phenylethyl)urea (9). Prepared according
(
S
was purified by flash chromatography using 20% to the general procedure using Cbz‐protected (S)‐(‐)‐α‐
EtOAc/hexane to afford 83 mg (72% yield) of product as a methylbenzylamine ((S)‐(‐)‐α‐benzyl 1‐phenylethylcarbamate,
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) and aniline. The reaction mixture was purified by flash
Journal Name
Rummel; S. Thiele; M. M. Rosenkilde; A. Ritzen; T. Ulven Chem. Eur.
8
View Article Online
J. 2013, 19, 9343‐9350.
DOI: 10.1039/C6OB01290F
chromatography using 20% EtOAc/hexane to afford 202.4 mg
(82% yield, 1.0 mmol scale) of product as a yellowish solid. mp:
148−150 °C; [α]D20 −8.03 (c 1.00, CHCl3); 1H NMR (600 MHz,
CDCl3): δ 7.17−7.34 (m, 10H), 6.97−6.99 (m, 1H), 5.82 (d, J =
6.6 Hz, 1H), 4.88 (m, 1H), 1.32 (d, J = 6.6 Hz, 3H); 13C NMR (150
MHz, CDCl3): δ 155.7, 144.2, 138.9, 129.1, 128.7, 127.2, 125.9,
123.2, 120.2, 49.9, 23.0; HRMS (ESI) m/z (M+H)+ calcd for
C15H17N2O = 241.1341, found 241.1345. Enantiomeric ratio was
measured by chiral phase HPLC (Chiralpak AD‐H, 30%, i‐
PrOH/Hexanes, 0.8 mL/min, 360 nm), Rt1 (major) = 7.6 min, Rt2
(minor) = 4.7 min; e.r. > 99.5:0.5. The analytical data were
identical in all respects to those previously reported.35
5 (a) T. J. Barker; K. K. Duncan; K. Otrubova; D. L. Boger ACS Med.
Chem. Lett. 2013, 4, 985‐988. (b) J. D. Sidda; L. Song; V. Poon; M. Al‐
Bassam; O. Lazos; M. J. Buttner; G. L. Challis; C. Corre Chem. Sci.
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Beattie; P. C. Healy; R. A. Davis Org. Biomol. Chem. 2015, 13, 1558‐
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(
S
)‐Methyl
1‐phenylethylcarbamate
(10). Prepared
according to the general procedure using Cbz‐protected (S)‐(‐)‐
α‐methylbenzylamine
((S)‐(‐)‐α‐benzyl
1‐
phenylethylcarbamate,
8) and methanol. The reaction mixture
was purified by flash chromatography using 20%
EtOAc/hexane to afford 145 mg (81% yield, 1.0 mmol scale) of
product as a yellowish solid. mp 55−57°C; 1H NMR (600 MHz,
CDCl3): δ 7.34–7.23 (m, 5H), 4.99 (s, 1H), 4.84 (s, 1H), 3.64 (s,
3H), 1.47 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3):
δ
156.3, 143.6, 128.7, 127.3, 126.0, 52.1, 50.7, 22.5; LRMS (EI);
Mass calcd for C10H14NO2 [M+H]+: 180.1; found 180.1.
Enantiomeric ratio was measured by chiral phase HPLC
(Chiralcel OD‐H, 5%, i‐PrOH/Hexanes, 1.0 mL/min, 210 nm), Rt1
(major) = 13.3 min, Rt2 (minor) = 16.4 min; e.r. > 99.5:0.5. The
analytical data were identical in all respects to those previously
reported.36
13 A. R. Katritzky; D. P. M. Pleynet; B. Yang J. Org. Chem. 1997, 62,
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14 M.‐K. Leung; J.‐L. Lai; K.‐H. Lau; H.‐H. Yu; H.‐J. Hsiao J. Org. Chem.
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Acknowledgements
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This work was supported by 2016 Research Fund of Myongji
University. We thank Prof. Jeung Gon Kim (Chonbuk National
University) and Prof. Hyunwoo Kim (KAIST) for assistance with
HPLC experiments.
17 T. Mizuno; I. Nishiguchi; N. Sonoda Tetrahedron 1994, 50, 5669‐
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Notes and references
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