The reaction of carbonyldiimidazole with alcohols to form carbamates and N-alkylimidazoles

Article abstract of DOI:10.1055/s-2004-831215

The reactions of non-benzylic primary and secondary aliphatic alcohols with carbonyldiimidazole (CDI) afford the corresponding carbamates but not N-alkylimidazoles. For benzylic primary alcohols, formation of N-alkylimidazoles proceeds reasonably at 170 °C in several different solvents and occurs by way of the initially formed carbamate. However, under these rather forcing conditions, or even at lower reaction temperatures, elimination is a significant side reaction for benzylic secondary alcohols with β-hydrogen atoms. With one exception, reactions of six N,N-disubstituted β-aminoalcohols with CDI to form N-alkylimidazoles proceed under relatively mild conditions and may occur by way of an aziridinium intermediate.

Full text of DOI:10.1055/s-2004-831215

2540
PAPER
The Reaction of Carbonyldiimidazole with Alcohols to Form Carbamates and
N-Alkylimidazoles
Formationof
Carb
u
a
mates and
N
a
-
A
lkylimid
n
a
zoles from
q
Carbonyldii
i
midazo
n
le g Tang, Yuxiang Dong, Jonathan L. Vennerstrom*
College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, USA
Fax +1(402)5599543; E-mail: jvenners@unmc.edu
Received 15 January 2004; revised 9 July 2004
a facile reaction with carbonyldiimidazole (CDI) or car-
Abstract: The reactions of non-benzylic primary and secondary al-
bonylditriazole at room temperature or in refluxing aceto-
nitrile (MeCN), ethyl acetate, and dichloromethane.
When we repeated this reaction for three of these alcohols,
iphatic alcohols with carbonyldiimidazole (CDI) afford the corre-
sponding carbamates but not N-alkylimidazoles. For benzylic
primary alcohols, formation of N-alkylimidazoles proceeds reason-
ably at 170 °C in several different solvents and occurs by way of the we obtained only carbamates for 3,4-dimethylbenzyl al-
initially formed carbamate. However, under these rather forcing
conditions, or even at lower reaction temperatures, elimination is a
significant side reaction for benzylic secondary alcohols with b-hy-
Njar’s method,4 Fischer5 isolated only the corresponding
drogen atoms. With one exception, reactions of six N,N-disubstitut-
ed b-aminoalcohols with CDI to form N-alkylimidazoles proceed
under relatively mild conditions and may occur by way of an aziri-
dinium intermediate.
cohol and benzhydrol, and a mixture of the carbamate and
N-alkylimidazole for 1-indanol. In a similar exploration of
carbamates from 2,6-dimethylphenol and 1-indanol. We
also note that Njar4 reports nearly identical melting point
and 1H NMR data for the N-alkylimidazole and carbamate
reaction products of the secondary alcohol testosterone;
Keywords: alcohols, alkylations, carbonyldiimidazole (CDI), car-
the NMR data is consistent with an imidazole carbamate,
not an N-alkylimidazole (vide infra). In order to further
clarify the scope of the reaction of alcohols (Figure 1)
with CDI to form N-alkylimidazoles, we investigated this
reaction further and our results are reported herein.
bamates, N-alkylimidazoles
A number of medicinally important molecules contain an
N-alkylimidazole moiety,1 most notably the large family
of azole antifungal drugs. This heterocycle is either as-
sembled as one step of a synthetic sequence, or is added
preformed, usually by imidazole anion nucleophilic dis-
placement of an alkyl halide2 or sulfonate.3 In our plans to
incorporate N-alkylimidazoles into target molecules, we
were attracted by a recent paper in this journal4 that de-
scribed high-yield conversions of a large variety of prima-
ry and secondary alcohols and phenols into their
corresponding N-alkylimidazoles and N-alkyltriazoles by
Primary and Secondary Alcohols. Following the proce-
dure of Njar,4 reaction of primary alcohol 1a with 1.3
equivalents of CDI in MeCN at room temperature formed
carbamate 3a in quantitative yield (Table 1, entry 1) in-
stead of the expected N-alkylimidazole 2a. The 1H NMR
spectrum (Table 2) of 3a showed one peak at d 8.14 ppm,
typical for the imidazole H-2 in imidazole carbamates, in-
stead of the imidazole H-2 in N-alkylimidazoles which is
in the range of d 7.4–7.7 ppm. In addition, the signal at d
OH
O
O
O
OH
OH
H3CO
OH
1d
1b
1f
1c
1a
1e
H
N
S
OH
OH
OH
O2N
OH
OH
1g
1h
OH
OH
1j
1k
1i
Figure 1 Structures of alcohols 1
SYNTHESIS 2004, No. 15, pp 2540–2544
x
x.
x
x
.
2
0
0
4
Advanced online publication: 16.09.2004
DOI: 10.1055/s-2004-831215; Art ID: M00504SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Formation of Carbamates and N-Alkylimidazoles from Carbonyldiimidazole
2541
Table 1 Reactions of CDI with Alcohols
Table 2 Characteristic 1H NMR (CDCl3, 500 MHz, d, ppm) Data of
Imidazole Carbamates (3 or 7) and N-Alkylimidazoles (2, 8 or 10)
O
R
3 or 7
1H (d, ppm)
2, 8 or 10
1H (d, ppm)
CDI
N
RO
N
ROH
N
+
N
3a
8.14, 7.43, 7.07
2a
7.43, 7.05, 6.88
(Im), 3.80 (a)
(Im)a, 4.27 (a)
2
1
Entry
1
3
3e
3h
3i
8.14, 7.42, 7.05
(Im), 5.35 (a)
2e
2h
2i
7.52, 7.06, 6.88
(Im), 5.03 (a)
Alcohol Conditions
Products, yield [%]a
3a, 100
1a
1a
1c
1d
1e
1f
MeCN, r.t., 2 h
8.13, 7.42, 7.05
(Im), 5.57 (a)
7.54, 7.05, 6.95
(Im), 5.26 (a)
2
NMP, 170 °C, 5 h
NMP, 170 °C, 24 h
NMP, 170 °C, 1 h
NMP, 170 °C, 1 h
NMP, 170 °C, 1 h
3a, 92
8.10, 7.40, 7.04
(Im), 6.41 (a)
7.41, 7.05, 6.81
(Im), 5.65 (a)
3
3c, 90
4
2d, 80
3k
7a
7b
7c
7d
7e
7f
8.22, 7.50, 7.09
(Im), 7.05 (a)
2k
8a
8b
8c
7.39, 7.08, 6.84
(Im), 6.51 (a)
5
2e, 70
6
2f, 82
8.14, 7.43, 7.07
(Im), 4.46 (a)
7.59, 7.03, 6.96
(Im), 3.97 (a)
7
1f
diglyme, 170 °C, 1 h
2f, 92; 3f, 8
8.34, 7.42, 7.06
(Im), 5.19 (a)
7.51, 7.01, 6.92
(Im), 4.15 (a)
8
1f
diglyme, 170 °C, 18 h 2f, 94
9
1f
xylene, 170 °C, 1 h
xylene, 170 °C, 18 h
decane, 170 °C, 18 h
THF, reflux, 5 h
2f, 65; 3f, 35
8.18, 7.46, 7.07
(Im), 6.15 (a)
7.66, 7.04, 6.96
(Im), 5.22 (a)
10
11
12
13
14
15
16
17
1f
2f, 74
8.15, 7.44, 7.08
(Im), 4.45 (a)
8d
8e
7.59, 7.03, 6.93
(Im), 3.88 (a)
1f
2f, 10
1g
1g
1h
1h
1h
1i
2g, 60
8.15, 7.44, 7.06
(Im), 5.08 (a)
Not formed
MeCN, r.t., 4 h
2g, 50
8.13, 7.43, 7.05
(Im), 4.96 (a)
8f
7.46, 7.01, 6.90
(Im), 3.86 (a)
EtOAc, r.t., 7 h
3h, 99
EtOAc, reflux, 7 h
MeCN, reflux, 24 h
MeCN, reflux, 5 h
2h, 25; 3h, 70
2h, 70
10b
10c
7.49, 7.02, 6.94
(Im), 3.94, 3.72 (a)
7.64, 6.94, 6.77
(Im), 4.40, 4.13 (a)
2i, 30; 3i, 10;
indene, 30
a Im = imidazole.
18
19
1j
1j
EtOAc, reflux, 18 h
NMP, 170 °C, 1 h
3j, 94
2j, 55; 3j, 5;
styrene, 20
3a (Table 1, entry 2). Similarly, 2-hydroxyacetophenone
(1b) and S–(–)-menthol (1c) formed only the correspond-
ing carbamates (Table 1, entry 3) regardless of the solvent
(MeCN, NMP) or reaction temperature.
20
21
22
1j
NMP, 170 °C, 5 h
MeCN, r.t., 2 h
2j, 55; styrene, 5
3k, 80
1k
1k
NMP, 170 °C, 1 h
2k, 80
Benzylic Primary Alcohols. The reaction of benzylic pri-
mary alcohols with CDI was dependent both on alcohol
structure and reaction conditions. In refluxing MeCN or
ethyl acetate, benzyl alcohols 1d–1f afforded only the cor-
responding carbamates (data not shown). In contrast, in
NMP at 170 °C, the three benzyl alcohols gave good
yields of N-alkylimidazoles 2d,6 2e,6 and 2f6 (Table 1, en-
tries 4–6). At the same temperature, the conversion of 1f
to 2f also proceeded readily in less polar solvents such as
diglyme and xylene (Table 1, entries 7–10), but in decane,
the yield dropped to 10% even with an 18 h reaction time
(Table 1, entry 11). Consistent with the results of Le
Borgne,7 indole carbinol 1g readily formed N-alkylimida-
zole 2g in either refluxing THF or in MeCN at room tem-
perature (Table 1, entries 12 and 13). In ethyl acetate at
room temperature (Table 1, entry 14) thiophene carbinol
a Isolated yields except for entries 7, 9, 15, 17, 19 and 20. For those
entries, estimated yields are based on integration of 1H NMR spectra.
In each case, all signals could be assigned.
4.27 (J = 6.3 Hz, 2 H) indicated a –CH2O– rather than
–CH2N–. More important, a signal at d 148.7 ppm in the
13C NMR spectrum of 3a unambiguously pointed to the
carbamate carbonyl group. In order to confirm this, 2a
was independently prepared in a reaction between imida-
zole sodium salt (NaH in DMF) and the mesylate of 1a.
The 1H NMR spectrum of 2a showed signals at d 3.80 (d,
J = 6.8 Hz, 2 H) and 6.88 (s, 1 H), 7.05 (s, 1 H), 7.43 (s, 1
H) consistent with –CH2N– and imidazole substructures.
The reaction of 1a and CDI in hot NMP also yielded only
Synthesis 2004, No. 15, 2540–2544 © Thieme Stuttgart · New York

2542
Y. Tang et al.
PAPER
1h formed only carbamate 3h, whereas in refluxing ethyl ed b-aminoalcohols with CDI forms oxazolidine-2-ones,
acetate or MeCN, N-alkylimidazole 2h8 was obtained in and in some cases, aziridines,13 we investigated the reac-
25% and 70% yields, respectively (Table 1, entries 15 and tion of N,N-disubstituted b-aminoalcohols 6 with CDI in
16). These data suggest that formation of N-alkylimida- refluxing ethyl acetate (Figure 2, Table 3). Primary alco-
zoles occurs more easily for electron-rich benzylic sys- hols 6a and 6d formed, along with carbamate 7d and car-
tems.
bonates 9a and 9d, N-alkylimidazoles 8a14 and 8d
(Table 3, entries 23 and 26), whereas secondary alcohols
6b and 6c formed N-alkylimidazoles 8b and 8c along with
the regioisomeric N-alkylimidazoles 10b and 10c, respec-
tively (Table 3, entries 24 and 25, Figure 3). Interestingly,
carbamate 7b was quite unstable, and when treated with
H2O–EtOAc, it was partially converted to carbonate 9b
along with alcohol 6b (data not shown). Formation of 10b
and 10c suggest that the imidazole alkylations occurred
via aziridinium intermediates.15,16 The failure of 6e to
form N-alkylimidazole 8e (Table 3, entry 27), and the low
conversion of 6d and 6f to their corresponding N-alkylim-
idazoles 8d and 8f (Table 3, entries 26 and 28), may re-
flect the diminished tendency to form their more strained
and sterically hindered bicyclic aziridium intermediates.
Indeed, treatment of the N,N-dimethyl analog of 6f with
2.1 equivalents of CDI in refluxing THF (3.5 h) formed
only the corresponding carbamate.17
Benzylic Secondary Alcohols. In refluxing MeCN, in-
danol (1i) gave a modest yield of N-alkylimidazole 2i
along with carbamate 3i4,5 and indene, the dehydration
product (Table 1, entry 17). In refluxing ethyl acetate, 1-
phenylethanol (1j) formed carbamate 3j9 in high yield
(Table 1, entry 18), whereas in hot NMP, N-alkylimida-
zole 2j10 was formed in moderate yield along with car-
bamate 3j and styrene, the dehydration product (Table 1,
Entry 19). With prolonged reaction times (Table 1, entry
20), the yield of 2j remained the same, and the yield of
styrene decreased, most likely due to polymerization. In
MeCN at room temperature, benzhydrol (1k) afforded
only carbamate 3k11 (Table 1, entry 21), whereas in hot
NMP, N-alkylimidazole 2k11 was obtained (Table 1, entry
22).
Mechanistic Considerations. The following experiment
provided some clues to the mechanism of the reaction of
alcohols with CDI to form N-alkylimidazoles (Scheme 1).
Preformed carbamate 3e4 in hot NMP afforded a mixture
of alcohol 1e, N-alkylimidazole 2e, and carbonate 4e. Us-
ing the same reaction conditions, the reaction of 3e in the
presence of 1, 2, and 5 equivalents of 2-methylimidazole
afforded N-alkylimidazole 2e in progressively decreasing
yields and N-alkyl-2-methylimidazole 5e in progressively
increasing yields. This outcome is inconsistent with the
SNi pathway postulated by Njar.4 Instead, the reaction ap-
pears to proceed by entropy-driven decarboxylation of the
initially formed imidazole carbamate.
OH
OH
OH
N
N
OH
N
N
R
CH3
CH3
6d
6e
6f
6a R = H
6b R = Me
6c R = Ph
Figure 2 Structures of N,N-disubstituted b-aminoalcohols 6
In summary, the reaction to form N-alkylimidazoles from
alcohols appears to proceed by entropy-driven decarbox-
ylation of the initially formed imidazole carbamate. For
benzylic primary alcohols with both electron-donating
(1d) and electron-withdrawing (1f) substituents, forma-
N,N-Disubstituted b-Aminoalcohols. Intrigued by re-
ports that treatment of a N,N-dimethyl-b-aminoalcohol
with CDI and excess imidazole afforded the correspond-
ing N-alkylimidazole,12 and that treatment of N-substitut-
O
O
NMP
O
N
OH
N
O
O
N
N
+
+
170 °C, 18 h
2e, 40%
4e, 30%
1e, 30%
3e
NMP
N
HN
N
3e
+
1e
+
2e
+
+
4e
170 °C, 18 h
N
5e
1 equiv
25%
26%
10%
39%
2 equiv
5 equiv
21%
10%
24%
12%
0%
0%
55%
78%
Scheme 1
Synthesis 2004, No. 15, 2540–2544 © Thieme Stuttgart · New York

PAPER
Formation of Carbamates and N-Alkylimidazoles from Carbonyldiimidazole
2543
1
ternal TMS for H and CDCl3 (77.0 ppm) for 13C NMR. FAB-
Table 3 Reactions of CDI with N,N-Disubstituted b-Aminoalco-
hols
HRMS spectra were obtained using a Kratos MS-50 spectrometer.
O
Reaction of Alcohols with CDI to Form Carbamates 3; Typical
Procedure
1,4-Dioxaspiro[4,5]dec-8-ylmethyl 1H-Imidazole-1-carboxyl-
ate (3a, Table 1, Entry 1)
A mixture of 1a (172 mg, 1 mmol), CDI (210 mg, 1.3 mmol) and
MeCN (15 mL) was stirred at r.t. for 2 h before quenching with cold
H2O (50 mL). The reaction mixture was extracted with CHCl3 and
the organic extract was washed with H2O and brine, dried over
MgSO4, filtered and dried in vacuo to afford 3a as a colorless solid
(266 mg, 100%).
O
R
CDI
N
RO
N
ROH
+
N
+
RO
OR
N
6
7
8
9
Entry
23
Alcohol
6a
Products, yield [%]a
8a, 90; 9a, 10
24
6b
8b, 25; 10b,b 75
8c, 82; 10c,b 8
Mp 48–50 °C.
25
6c
1H NMR (CDCl3): d = 1.38–1.45 (m, 2 H), 1.52–1.61 (m, 2 H),
1.78–1.90 (m, 5 H), 3.94–4.00 (m, 4 H), 4.27 (d, J = 6.3 Hz, 2 H),
7.07 (s, 1 H), 7.43 (s, 1 H), 8.14 (s, 1 H).
13C NMR (CDCl3): d = 26.6, 33.9, 35.9, 64.30, 64.33, 72.3, 108.4,
117.1, 130.7, 137.1, 148.7.
26
6d
7d, 37; 8d, 6; 9d, 57
7e, 65; 9e, 35
27
6e
28
6f
7f, 62; 8f, 21
HRMS–FAB: m/z [M + H]+ calcd for C13H19N2O4: 267.1345;
found: 267.1354.
a Estimated yields are based on integration of 1H NMR spectra. In
each case, all signals could be assigned.
b Rearranged N-alkylimidazole products (see Figure 3).
2-Oxo-2-phenylethyl 1H-Imidazole-1-carboxylate (3b)
Brown solid (207 mg, 90%); mp 62–65 °C.
1H NMR (CDCl3): d = 5.63 (s, 2 H), 7.09 (s, 1 H), 7.49 (s, 1 H), 7.50
(t, J = 7.8 Hz, 2 H), 7.64 (t, J = 7.3 Hz, 1 H), 7.92 (d, J = 7.4 Hz, 2
H), 8.21 (s, 1 H).
13C NMR (CDCl3): d = 68.3, 117.1, 127.5, 128.8, 130.5, 133.3,
134.2, 137.1, 148.2, 190.2.
R
N
N
N
HRMS–FAB: m/z [M + H]+ calcd for C12H11N2O3: 231.0770;
found: 231.0772.
10b R = Me
10c R = Ph
Figure 3 Structures of N-alkylimidazoles 10b and 10c
Menthyl 1H-Imidazole-1-carboxylate (3c, Table 1, Entry 3)
Colorless oil (yield 90%).
1H NMR (CDCl3): d = 0.82 (d, J = 7.3 Hz, 3 H), 0.93 (d, J = 7.3 Hz,
3 H), 0.95 (d, J = 7.0 Hz, 3 H), 1.14–1.20 (m, 2 H), 1.50–1.60 (m, 2
H), 1.71–1.79 (m, 2 H), 1.84–1.88 (m, 1 H), 2.14–2.20 (m, 1 H),
4.86–4.92 (m, 1 H), 7.07 (s, 1 H), 7.42 (s, 1 H), 8.13 (s, 1 H).
13C NMR (CDCl3): d = 16.4, 20.6, 21.9, 23.5, 26.5, 31.4, 33.9, 40.5,
47.0, 79.3, 117.1, 130.5, 137.0, 148.3.
tion of N-alkylimidazoles works reasonably well at ele-
vated reaction temperatures. However, under these rather
forcing conditions, or even at lower reaction tempera-
tures, elimination is a significant side reaction for benzyl-
ic secondary alcohols with b-hydrogen atoms such as 1i
and 1j. Only for indole and thiophene carbinols 1g and 1h,
did we obtain the corresponding N-alkylimidazoles under
relatively mild conditions, a result consistent with previ-
ous data.7 Several reports2b,17,18 disclose that in refluxing
dichloromethane or THF, several substituted benzhydrols
form the corresponding N-alkylimidazoles in low to ex-
cellent yields, but we observed that benzhydrol formed
HRMS–FAB: m/z [M + H]+ calcd for C14H23N2O2: 251.1760;
found: 251.1762.
1-(1,4-Dioxaspiro[4,5]dec-8-ylmethyl-1H-imidazole (2a)
A solution of methanesulfonyl chloride (1.38 g, 12 mmol) in
CH2Cl2 (5 mL) was added dropwise to a mixture of 1a (1.38 g, 8
mmol), Et3N (1.52 g, 15 mmol) and CH2Cl2 (20 mL). Upon comple-
the corresponding N-alkylimidazole only at elevated reac- tion of the addition, the reaction mixture was stirred for 1 h at r.t.,
and washed successively with 0.5 M HCl, H2O and brine, dried over
MgSO4, filtered and dried in vacuo to afford the mesylate as a col-
orless oil (2.0 g, 100%).
tion temperatures. It is apparent from this data that reac-
tion of alcohols with CDI to form N-alkylimidazoles is not
a generally applicable synthetic method, although the cor-
1H NMR (CDCl3): d = 1.30–1.40 (m, 2 H), 1.50–1.60 (m, 2 H),
responding reaction of N,N-disubstituted b-aminoalco-
1.76–1.86 (m, 5 H), 3.00 (s, 3 H), 3.90–4.00 (m, 4 H), 4.06 (d,
hols proceeded under relatively mild conditions and may
J = 6.3 Hz, 2 H).
have occurred by way of aziridinium intermediates. Final-
ly, 1H NMR and 13C NMR spectra unambiguously differ-
To a suspension of 60% NaH (0.08 g, 2 mmol) in DMF (4 mL) un-
der nitrogen at 0 °C was added a solution of imidazole (0.14 g, 2
entiate N-alkylimidazoles and the corresponding
carbamates.
mmol) in DMF (4 mL). The mixture was stirred for 30 min before
a solution of the above mesylate (0.25 g, 1 mmol) in DMF (4 mL)
was added dropwise. The mixture was heated at 60 °C for 2 h before
The melting points are uncorrected. 1H and 13C NMR spectra were
recorded on a Varian 500 MHz spectrometer using CDCl3 as sol-
vent. All chemical shifts are reported in ppm and are relative to in-
being quenched with H2O (40 mL) and then extracted with EtOAc
(3 × 30 mL). The combined organic extracts were washed with
brine (3 × 30 mL), dried over MgSO4, filtered, and concentrated to
afford 2a (0.20 g, 90%) as a colorless oil.
Synthesis 2004, No. 15, 2540–2544 © Thieme Stuttgart · New York

2544
Y. Tang et al.
PAPER
1H NMR (CDCl3): d = 1.22–1.36 (m, 2 H), 1.48–1.56 (m, 2 H), 1.62
(d, J = 5.6 Hz, 2 H), 1.70–1.80 (m, 3 H), 3.80 (d, J = 6.8 Hz, 2 H),
3.90–3.97 (m, 4 H), 6.88 (s, 1 H), 7.05 (s, 1 H), 7.43 (s, 1 H).
13C NMR (CDCl3): d = 27.6, 33.9, 38.0, 52.5, 64.2, 64.3, 108.4,
119.2, 129.4, 137.4.
J = 7.2 Hz, 2 H), 3.05 (m, 1 H), 3.72 (dd, J = 4.3, 13.7 Hz, 1 H), 3.94
(dd, J = 7.6, 13.7 Hz, 1 H), 6.94 (s, 1 H), 7.02 (s, 1 H), 7.49 (s, 1 H).
13C NMR (CDCl3): d = 12.2, 14.1, 43.2, 50.7, 56.2, 119.3, 128.9,
137.6.
HRMS–FAB: m/z [M + H]+ calcd for C10H20N3: 182.1657; found:
182.1655.
HRMS–FAB: m/z [M + H]+ calcd for C12H19N2O2: 223.1446;
found: 223.1434.
Acknowledgement
Reaction of Benzylic Alcohols with CDI to Form N-Alkylimida-
zoles 2; Typical Procedure
1-Benzhydryl-1H-imidazole (2k)
A mixture of 1k (184 mg, 1 mmol), CDI (210 mg, 1.3 mmol) and
NMP (10 mL) was heated at 170 °C for 1 h. After cooling to r.t., the
reaction mixture was diluted with EtOAc (30 mL) and washed with
H2O (2 × 20 mL), brine (20 mL) and dried over MgSO4. Filtration
and removal of solvents in vacuo afford 2k11 as a colorless solid
(178 mg, 80%).
We thank the Medicines for Malaria Venture (MMV) for generous
support of this research and the Nebraska Center for Mass Spectro-
metry for the HRMS data.
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Miyazaki, M.; Tsuruta, H.; Nambu, F.; Ohuchida, S.;
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Chem., Int. Ed. Engl. 1989, 28, 462; Angew. Chem.; 1989,
101, 507. (d) Kato, A.; Ikeda, Y.; Sugita, N.; Nitta, T.; Enari,
H.; Kashima, A.; Konno, M.; Niimura, K. Chem. Pharm.
Bull. 1995, 43, 2152.
Reaction of 3,4-Dimethylbenzyl 1H-Imidazole-1-carboxylate
with 2-Methylimidazole
1-(3,4-Dimethylbenzyl)-2-methyl-1H-imidazole (5e)
A mixture of 3,4-dimethylbenzyl 1H-imidazole-1-carboxylate (3e)
(230 mg, 1 mmol), 2-methylimidazole (420 mg, 5 mmol) and NMP
(10 mL) was heated at 170 °C for 16 h. After cooling to r.t., the re-
action mixture was diluted with EtOAc (30 mL) and washed with
H2O (2 × 20 mL), brine (20 mL) and dried over MgSO4. Filtration
and removal of solvents in vacuo afford a mixture of 2e6 and 5e
(1:4).
For 5e
1H NMR (CDCl3): d = 2.22 (s, 3 H), 2.23 (s, 3 H), 2.33 (s, 3 H), 4.95
(s, 2 H), 6.78 (d, J = 7.8 Hz, 1 H), 6.81 (s, 1 H), 6.83 (s, 1 H), 6.92
(s, 1 H), 7.08 (d, J = 7.8 Hz, 1 H).
13C NMR (CDCl3): d = 12.9, 19.2, 19.6, 49.3, 119.7, 124.0, 126.9,
133.5, 136.1, 144.6.
HRMS–FAB: m/z [M + H]+ calcd for C13H17N2: 201.1392; found:
201.1390.
(4) Njar, V. C. O. Synthesis 2000, 2019.
(5) Fischer, W. Synthesis 2002, 29.
(6) Kamijo, T.; Yamamoto, R.; Harada, H.; Iizuka, K. Chem.
Pharm. Bull. 1983, 31, 1213.
(7) Le Borgne, M.; Marchand, P.; Duflos, M.; Delevoye-Seiller,
B.; Piessard-Robert, S.; Le Baut, G.; Hartmann, R. W.;
Palzer, M. Arch. Pharm. Pharm. Med. Chem. 1997, 330,
141.
(8) Whitten, J. P.; McCarthy, J. R.; Matthews, D. P. Synthesis
1988, 470.
(9) Bertolini, G.; Pavich, G.; Vergani, B. J. Org. Chem. 1998,
63, 6031.
(10) Botta, M.; Summa, V.; Trapassi, G.; Monteagudo, E.;
Corelli, F. Tetrahedron: Asymmetry 1994, 5, 181.
(11) Ogata, M.; Matsumoto, H.; Kida, S.; Shimizu, S. Chem. Ind.
(London) 1980, 85.
Reaction of N,N-Disubstituted b-Aminoalcohols with CDI; Typ-
ical Procedure
N,N-Diethyl-2-(1H-imidazol-1-yl)propan-1-amine (8b) and
N,N-Diethyl-1-(1H-imidazol-1-yl)propan-2-amine (10b)
A mixture of 6b (400 mg, 3 mmol), CDI (582 mg, 3.6 mmol) and
EtOAc (20 mL) was refluxed overnight. After cooling to r.t., the re-
action mixture was washed with H2O (2 × 20 mL), brine (20 mL)
and dried over MgSO4. Filtration and removal of solvents in vacuo
afford a 1:3 mixture of 8b and 10b.
For 8b
1H NMR (CDCl3): d = 0.92 (t, J = 6.8 Hz, 3 H), 0.94 (t, J = 6.8 Hz,
3 H), 1.47 (d, J = 6.8 Hz, 3 H), 2.39 (q, J = 6.8 Hz, 2 H), 2.43–2.47
(m, 1 H), 2.53 (q, J = 6.8 Hz, 2 H), 2.55–2.59 (m, 1 H), 4.13–4.17
(m, 1 H), 6.95 (s, 1 H), 7.04 (s, 1 H), 7.54 (s, 1 H).
(12) Aelterman, W.; Lang, Y.; Willemsens, B.; Vervest, I.; Leurs,
S.; De Knaep, F. Org. Process Res. Dev. 2001, 5, 467.
(13) Cutugno, S.; Martelli, G.; Negro, L.; Savoia, D. Eur. J. Org.
Chem. 2001, 517.
13C NMR (CDCl3): d = 12.0, 19.2, 47.8, 53.0, 60.5, 116.6, 128.9,
(14) Adolphi, H.; Steimmig, A.; Spaenig, H. Fr. Patent FR
1486817 19670630, 1967; Chem. Abstr. 1968, 77228.
(15) O’Brien, P.; Towers, T. D. J. Org. Chem. 2002, 67, 304.
(16) Mulvihill, M. J.; Cesario, C.; Smith, V.; Beck, P.; Nigro, A.
J. Org. Chem. 2004, 69, 5124.
136.1.
HRMS–FAB: m/z [M + H]+ calcd for C10H20N3: 182.1657; found:
182.1655.
(17) Totleben, M. J.; Freeman, J. P.; Szmuszkovicz, J. J. Org.
Chem. 1997, 62, 7319.
(18) Freyne, E.; Raeymaekers, A.; Venet, M.; Sanz, G.; Wouters,
W.; De Coster, R.; Van Wauwe, J. Bioorg. Med. Chem. Lett.
1998, 8, 267.
For 10b
1H NMR (CDCl3): d = 0.96 (t, J = 7.2 Hz, 3 H), 0.97 (t, J = 7.2 Hz,
3 H), 0.98 (d, J = 6.8 Hz, 3 H), 2.41 (q, J = 7.2 Hz, 2 H) 2.56 (q,
Synthesis 2004, No. 15, 2540–2544 © Thieme Stuttgart · New York