Development of a regioselective N-methylation of (benz)imidazoles providing the more sterically hindered isomer

Article abstract of DOI:10.1021/jo401978b

An efficient and highly regioselective N-methylation of (NH)-(benz)imidazoles furnishing the sterically more hindered, less stable, and usually minor regioisomer has been developed. The methodology involves very mild reaction conditions and tolerates a wide range of functional groups.

Full text of DOI:10.1021/jo401978b

Note
pubs.acs.org/joc
Development of a Regioselective N‑Methylation of (Benz)imidazoles
Providing the More Sterically Hindered Isomer
Emilie Van Den Berge and Raphael Robiette*
̈
Institute of Condensed Matter and Nanosciences, Universite
Louvain-la-Neuve, Belgium
́
Catholique de Louvain, Place Louis Pasteur 1 bte L4.01.02, B-1348
S
* Supporting Information
ABSTRACT: An efficient and highly regioselective N-
methylation of (NH)-(benz)imidazoles furnishing the steri-
cally more hindered, less stable, and usually minor regioisomer
has been developed. The methodology involves very mild
reaction conditions and tolerates a wide range of functional
groups.
midazoles are the central structure of numerous medicinally
N-PG should allow displacing the tautomeric equilibrium
1
Iimportant compounds. They are also versatile precursors in toward the sterically less hindered isomer (Scheme 2). An
the preparation of synthetically useful compounds such as
catalysts,2 ligands,3 or ionic solvents.4 As a result, a number of
Scheme 2. Designed Strategy for the Regioselective N-
strategies have been explored for the synthesis of this
heterocyclic motif.5 One common challenge in the synthesis
of N-alkyl imidazoles is the control of the regioselectivity.
Indeed, N-alkylation gives usually a mixture of isomers in which
the major product is the sterically less hindered isomer, the 1,4-
isomer (Scheme 1).6,7 This observed poor regioselectivity is
due to a rapid tautomeric equilibrium of (NH)-derivatives and
the (slightly) faster alkylation of the less hindered nitrogen.
Methylation of the More Hindered Nitrogen of (NH)-
(Benz)imidazoles
a
Scheme 1. Classical N-Alkylation Reaction of Imidazoles
a
S = small group; L = large group.
We recently reported the divergent synthesis of 1,2,4- and
1,2,5-trisubstituted imidazoles from a common N-protected
intermediate.7 In the course of this study, we showed that
under our alkylation reaction conditions a rapid equilibrium
between the two N-protected regioisomers was taking place,
and a selective N-alkylation of the more stable 1,2,4-isomer (K
> 24) was observed. We thus reasoned that this observation
could be exploited to develop a general method for the N-
methylation of (NH)-(benz)imidazoles providing selectively
the sterically more hindered isomer. Indeed, replacing N−H by
alkylation/deprotection process (instead of classical depro-
tection/alkylation) should then lead selectively to the more
hindered N-methylated derivatives.8,9 Protection of the less
hindered nitrogen should indeed prevent alkylation in this
position and will therefore direct it on the other nitrogen, the
most hindered one.10
Received: September 6, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo401978b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
First, we have investigated each step of our designed strategy
separately on a model compound, 4-methyl-1H-imidazole, in
order to find the most appropriate protecting group (PG) and
the best reaction conditions. We then have developed a one-pot
procedure of our methodology before exploring its scope.
The ideal protecting group must allow high conversion in N-
protected imidazole with a high regioselectivity. We thus
investigated the reaction of our model compound with a series
of protecting group, observing the evolution of the
regioselectivity over time (Table 1).
obtained in low yield, whereas in the case of phenylsulfonyl
group (1d), the alkylation−deprotection process allowed
obtaining 4 in excellent yield and regioselectivity. The
phenylsulfonyl protecting group was thus considered for
further developments of our methodology.
Relying on observations made during the optimization of
each step, we searched for suitable reaction conditions allowing
setting up a one-pot procedure of our methodology. In the
event, we found that the three steps could be performed
sequentially by dissolution of 4-methyl-1H-imidazole in
acetonitrile and successive addition of triethylamine, phenyl-
sulfonyl chloride, methyltriflate, and then N-methylbutyl-
amine12 (Table 3). This procedure allows obtaining 1,5-
dimethyl-1H-imidazole (4) in good yield (80%) with an
excellent regioselectivity (>98/2) in one synthetic step.
a
Table 1. Investigation of the Protection Step
b
conversion (%) (1/2)
Table 3. Regioselective N-Methylation of (NH)-
(Benz)imidazoles
a
PG-X
after 1 h
after 15 h
TBSCl (a)
53 (55/45)
81 (65/35)
40 (67/33)
97 (93/7)
70 (71/29)
88 (77/23)
<5 (n.d.)
83 (60/40)
91 (63/37)
45 (68/32)
100 (>98/2)
98 (85/15)
100 (75/25)
<5 (n.d.)
SEMCl (b)
BnBr (c)
PhSO2Cl (d)
Me2NSO2Cl (e)
(Boc2)O (f)
O(COCF3)2 (g)
a
Reaction conditions: 1.1 equiv of PG-X, 1.2 equiv of Et3N, CH2Cl2,
b
rt. Conversion was determined by 1H NMR using an internal
standard.
Only two protecting groups led to both a high conversion
and a good regioselectivity: N,N-dimethylsulfamoyl and
phenylsulfone. It is interesting to note that it is the two cases
in which an increase in regioselectivity was observed over time,
suggesting the presence of an equilibrium between the two
regioisomers under the reaction conditions. We selected these
two protecting groups to carry on the next step.
The methylation was performed with methyltriflate11 in
dichloromethane-d2 in order to study the reaction directly by
1H NMR. Observed conversion in salt 3 was high for the two
considered protecting groups (Table 2). No change in
regioisomeric ratio was observed, salts 3d,e being obtained in
a similar regioisomeric distribution to starting 1d,e.
The sequence alkylation-deprotection was then investigated.
N-Protected 4-methyl-1H-imidazoles 1d,e were reacted with
methyltriflate at room temperature for one day and then in situ
deprotected by addition of a nucleophile (N-butylmethyl-
amine). Starting from 1e, 1,5-dimethyl-1H-imidazole (4) was
a
Table 2. Alkylation and Deprotection Steps
3
4
b
PG
conv
regio
conv
regio
SO2Ph (d)
>95%
>95%
>98/2
83/17
>95%
40%
>98/2
n.d.
SO2NMe2 (e)
a
Regioselectivity and yield were determined by 1H NMR on the crude
a
Conversion and regioselectivity were determined by 1H NMR.
mixture (using an internal standard). Isolated yields are reported in
parentheses. See Supporting Information for determination of
regiochemistry. Heating during the methylation step.
Solvent for methylation is CD2Cl2 and for methylation-deprotection is
CH3CN. Conversion over two steps (from 1).
b
b
B
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The Journal of Organic Chemistry
Note
Characterization of N,N-4-Trimethyl-1H-imidazole-1-sulfona-
mide (1e).21 1H NMR (300 MHz, CDCl3) δ 7.85 (s, 1H), 6.95 (s,
1H), 2.85 (s, 6H), 2.25 (s, 3H).
With the optimized one-pot reaction conditions in hand, the
substrate scope of the regioselective N-methylation was
explored. As shown in Table 3, a variety of 5-substituted N-
methyl-1H-imidazoles could be obtained in moderate to
quantitative yield with excellent regioselectivities.13 No 1,4-
General Procedure for N-Methylation. (Benz)imidazole (1
equiv, 100 mg) was dissolved in acetonitrile under argon atmosphere.
Et3N (1.2 equiv) and PhSO2Cl (1.1 equiv) were successively added
dropwise, and the mixture was stirred for 8 h. Methyltriflate (1.5
equiv) was then added. After 24 h, N,N-butylmethylamine (2.1 equiv)
was added, and the solution was heated at 80 °C overnight. DCM (10
mL) was added, and the solution was washed twice with NaOHaq 1 M
(10 mL). The aqueous phases were extracted with DCM (10 mL).
The organic phases were dried (MgSO4) and concentrated under
reduced pressure.
1
isomer could be detected by H NMR in the crude mixture
(except in the case of 7 where 10% of the undesired isomer was
observed). Interestingly, the mild reaction conditions of our
methodology tolerate a wide range of functional groups: esters,
Boc groups, aldehydes, and α,β-unsaturated carbonyls.14
2,4(5)-Disubstituted imidazoles can also be N-methylated
with good regioselectivity (>98/2). Even 4,5-disubstituted
derivatives such as 4-methyl-5-phenyl-1H-imidazole led to
corresponding N-methylimidazole compound (15) with a
high regioselectivity (82/18) showing a good discrimination
between phenyl and methyl substituents.15
Our methodology can also be applied to 4-substituted (NH)-
benzimidazole derivatives with the more hindered isomer, the
7-substituted N-methyl-1H-benzimidazole, being obtained with
a total regiocontrol.
In conclusion, we have developed a highly regioselective N-
methylation of (NH)-(benz)imidazoles. The interest of our
methodology does not only reside in the excellent observed
regioselectivity but also in the nature of the regioisomer
formed: the sterically more hindered, less stable, and usually
minor regioisomer. Finally, our methodology involves very mild
reaction conditions and tolerates a wide range of functional
groups which should make it very practical in the context of
total synthesis.
Characterization of 1,5-Dimethyl-1H-imidazole (4).22 Purification
by semipreparative HPLC CH3CN/H2O 10/90. Isolated yield: 44.6
1
mg, 49%; H NMR (300 MHz, CDCl3) δ 7.42 (s, 1H), 6.77 (s, 1H),
3.54 (s, 3H), 2.19 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 137.2,
127.8, 126.1, 31.3, 9.1.
Characterization of 5-Iodo-1-methyl-1H-imidazole (5).23 Purifi-
cation by semipreparative HPLC CH3CN/H2O 10/90. Isolated yield:
1
55.2 mg, 55%; H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.16 (s,
1H), 3.64 (s, 3H).
Characterization of 1-Methyl-1H-imidazole-5-carbaldehyde
(6).24 Purification by semipreparative HPLC CH3CN/H2O 10/90.
1
Isolated yield: 41.2 mg, 37%; H NMR (300 MHz, CDCl3) δ 9.77 (s,
1H), 7.61 (s, 1H), 3.95 (s, 3H).
Characterization of (E)-Methyl 3-(1-methyl-1H-imidazol-5-yl)-
acrylate (7).25 Purification by flash chromatography DCM/MeOH
1
92/8 + 3% Et3N. Isolated yield: 116 mg, 51%; H NMR (300 MHz,
CDCl3) δ 7.55−7.47 (m, 3H), 6.27 (d, 2H, J = 16.2 Hz), 3.80 (s, 3H),
3.73 (s, 3H).
Characterization of (S)-Methyl 2-(tert-butoxycarbonylamino)-3-
(1-methyl-1H-imidazol-5-yl)propanoate (8).26 Purification by flash
chromatography DCM/MeOH 92:08 + 3% Et3N. Isolated yield: 56
EXPERIMENTAL SECTION
1
mg, 53%; H NMR (300 MHz, CDCl3) δ 7.36 (s, 1H), 6.77 (s, 1H),
■
1
5.15 (m, 1H), 4.52 (m, 1H), 3.72 (s, 3H), 3.55 (s, 3H), 3.07−3.08 (m,
NMR spectra were recorded at 300 or 500 MHz for H NMR, and at
75 or 125 MHz for 13C NMR. Chemical shifts (δ) are given in parts
2H), 1.40 (s, 9H).
Characterization of 1-Methyl-5-phenyl-1H-imidazole (9).27 Puri-
fication by flash chromatography DCM/MeOH 97/3 + 3% Et3N.
per million downfield from TMS. For H−15N HMBC experiments,
1
CH3NO2 was used as internal standard (381.70 ppm). Mass spectra
(MS) were recorded on an Orbitrap instrument; masses are given in
Daltons. Regiochemistry was determined by 1H−15N HMBC for
compounds 4, 15, and 16 (see the Supporting Information for full
details). For compounds 5−14 and 17, data were compared to the
literature (see below for references). Flash chromatography was
performed on silica gel (230−400 mesh). For compounds 4−6, the
purification was done on a C18 solid phase extraction.
1
Isolated yield: 77 mg, 70%; H NMR (300 MHz, CDCl3) δ7.61 (s,
1H), 7.45−7.38 (m, 5H), 7.12 (s, 1H), 3.69 (s, 3H).
Characterization of 5-(4-Methoxyphenyl)-1-methyl-1H-imidazole
(10).27 Purification by flash chromatography CH2Cl2 + 3% Et3N.
Isolated yield: 75 mg, 70%; Et3N 1H NMR (300 MHz, CDCl3) δ7.54
(s, 1H), 7.31 (d, 2H, J = 8.73 Hz), 7.04 (s, 1H), 6.97 (d, 2H, J = 8.73
Hz), 3.85 (s, 3H), 3.64 (s, 3H).
Characterization of 4-(1-Methyl-1H-imidazol-5-yl)phenyl propi-
onate (11). Purification by flash chromatography DCM + 3% Et3N.
Isolated yield: 42 mg, 40%, yellow oil; 1H NMR (300 MHz, CDCl3) δ
8.11 (d, 2H, J = 8.4 Hz), 7.62 (s, 1H,), 7.47 (d, 2H, J = 8.4 Hz), 7.20
(S, 1H), 4.40 (q, 2H, J = 7.1 Hz), 3.72 (s, 3H), 1.41 (t, 3H, J = 7.1
Hz); 13C NMR (75 Hz, CDCl3) δ 166.2, 140.0, 134.2, 132.6, 130.0,
129.6, 129.2, 127.8, 61.2, 32.9, 14.4; IR (cm−1) ν 1709, 1610, 1489,
1275, 1180, 1103, 1013, 922, 825, 773, 706; ESI-MS m/z M + 1 231;
HRMS (ESI) calcd for C13H15N2O2 231.1134, found 231.1126.
Characterization of 5-(2-Fluorophenyl)-1-methyl-1H-imidazole
(12). Purification by flash chromatography DCM + 3% Et3N. Isolated
yield: 34 mg, 32%; yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.56 (s,
1H), 7.43−7.13 (m, 4H), 7.10 (s, 1H), 3.59 (s, 3H); 19F NMR (282
MHz, CDF3) δ −113.1; 13C NMR (75 Hz, CDCl3) δ 160.0 (J = 246.4
Hz), 139.2, 131.9, 130.5 (J = 8.1 Hz), 129.5, 127.7, 124.5, 117.7 (J =
15.4 Hz), 116.0 (J = 21.9 Hz), 32.2; IR (cm−1) ν 1556, 1477, 1229,
1203, 1111, 916, 760; APCI-MS m/z M + 1 177; HRMS (APCI) calcd
for C10H9N2F 176.07443, found 176.07414.
(NH)-(Benz)imidazoles used in the regioselective methylation were
either commercially available or prepared according to a reported
procedure: (E)-methyl 3-(1H-imidazol-5-yl)acrylate,16 (S)-methyl 2-
((tert-butoxycarbonyl)amino)-3-(1H-imidazol-4-yl)propanoate,17 4,5-
methyl-phenylimidazole, 4-(p-substituted-aryl)imidazoles,18 5-(2-fluo-
rophenyl)-1H-imidazole,19 and benzimidazoles.20
General Procedure for Protection of 4-Methyl-1H-imidazole.
4-Methyl-1H-imidazole (1.83 mmol, 1 equiv, 150 mg) was dissolved in
DCM (4.5 mL) under argon atmosphere. Successively, Et3N (2.20
mmol, 1.2 equiv, 0.31 mL) and PG-Cl (2.01 mmol, 1.1 equiv) were
added dropwise. The mixture was stirred overnight. DCM/MeOH (30
mL) were added and washed twice with an aqueous solution of 10% of
K2CO3 (15 mL). The combined aqueous phases were extracted twice
with DCM/MeOH (15 mL). The organic phases were collected and
washed with brine, dried (MgSO4), and concentrated under reduced
pressure.
Characterization of 4-Methyl-1-(phenylsulfonyl)-1H-imidazole
(1d). Purification by flash chromatography DCM/MeOH 98/2.
1
Yield: 102 mg, 75%; white solid; H NMR (300 MHz, CDCl3) δ
Characterization of 5-Iodo-1-methyl-2-(phenylthio)-1H-imida-
zole (13).7a Purification by flash chromatography DCM/MeOH 95/
5 + 3% Et3N. Isolated yield: 55 mg, 53%; 1H NMR (300 MHz,
CDCl3) δ 7.31−7.19 (m, 6H), 3.64 (s, 3H).
7.97−7.92 (m, 3H), 7.71−7.55 (m, 3H), 7.00 (s, 1H), 2.20 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 141.4, 138.3, 136.3, 134.8, 129.9 (2C),
127.3 (2C), 113.5, 13.7; IR (cm−1) ν 3107, 1448, 1375, 1174, 1091,
1080, 997, 729, 685; mp 70−71 °C; ESI-MS m/z M + 1 223; HRMS
(ESI) calcd for C10H11N2O2S 223.0541, found 223.0551.
Characterization of 2-Bromo-1,5-dimethyl-1H-imidazole (14).28
Purification by flash chromatography DCM + 3% Et3N. Isolated yield:
C
dx.doi.org/10.1021/jo401978b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
42 mg, 38%; H NMR (300 MHz, CDCl3) δ 6.74 (s, 1H), 3.47 (s,
3287. (b) Qian, W.; Liu, F.; Burke, T. R., Jr. J. Org. Chem. 2011, 76,
8885−8890. (c) Reiter, L. A. J. Org. Chem. 1987, 52, 2714−2726.
(10) For steric and electronic (availability of the lone pair) reasons,
only the nonsubstituted nitrogen reacts with alkylating reagents. See,
for instance: (a) Lee, H. K.; Bang, M.; Pak, C. S. Tetrahedron Lett.
2005, 46, 7139−7142. (b) Beaudouin, S.; Kinsey, K. E.; Burns, J. F. J.
Org. Chem. 2003, 68, 115−119. (c) Horvath, A. Synthesis 1995, 1183−
1189.
(11) We have also attempted to alkylate 1d with other alkylating
reagents such as ethyl bromoacetate, ethyltriflate, or benzyl bromide,
but no alkylation product could be observed.
(12) In some cases, a simple workup with NaOHaq was found to be
sufficient for deprotecting N(1).
(13) The significant difference between isolated and NMR yields for
some compounds is due to chromatographic tailing during the
purification (probably because of a protonation/deprotonation
process) and the subsequent difficulty of separating the imidazole
compound from the side product (Me2NSO2N(Me)Bu).
(14) The absence of variation in regioselectivity with electronic
properties of substituents suggest that electronic effects have no
significant role in determining regioselectivity, this latter being
governed by steric factors.
3H), 2.20 (s, 3H); APCI-MS m/z M + 1 175 (79Br), 177 (81Br).
Characterization of 1,4-Dimethyl-5-phenyl-1H-imidazole (15).29
Purification by flash chromatography DCM/MeOH 93/7 + 3% Et3N.
Isolated yield: 26 mg, 47%; 1H NMR (300 MHz, CDCl3) δ 7.48−7.28
(m, 6H), 3.55 (s, 3H), 2.23 (s, 3H).
Characterization of 1,7-Dimethyl-1H-benzo[d]imidazole (16).30
Purification by flash chromatography DCM/MeOH 98/2. Isolated
yield: 89 mg, 90%; 1H NMR (300 MHz, CDCl3) δ 7.88 (s, 1H), 7.63
(d, 1H, J = 8.1 Hz), 7.15 (t, 1H, J = 7.7 Hz), 7.03 (d, 1H, J = 7.2 Hz),
4.08 (s, 3H), 2.74 (s, 3H).
Characterization of 1-Methyl-7-nitro-1H-benzo[d]imidazole
(17).31 Purification by flash chromatography DCM/MeOH 95/5.
1
Isolated yield: 57 mg, 52%; H NMR (300 MHz, CDCl3) δ 8.28 (s,
1H), 8.16−8.07 (m, 2H), 7.41 (t, 1H, J = 8.1 Hz), 4.11 (s, 3H).
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of H, 13C, and H−15N HMBC NMR spectra and
details on determination of regiochemistry. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
1
(15) The regioselectivity could be increased without heating during
the methylation step, but the yield was then lower (reactant found).
(16) Pirrung, M. C.; Pei, T. J. Org. Chem. 2000, 65, 2229−2230.
(17) Lopez-Larrubio, P.; Garcia-Amo, M.; Mayoral, E.; Gillies, R. J.;
Cerdan, S.; Ballesteros, P. ARKIVOC 2004, iv, 26−31.
(18) Bellina, F.; Cauteruccio, S.; Rossi, R. J. Org. Chem. 2007, 72,
8543−8546.
AUTHOR INFORMATION
Corresponding Author
*E-mail: raphael.robiette@uclouvain.be.
Notes
■
The authors declare no competing financial interest.
(19) Kumar, S.; Jaller, D.; Patel, B.; Lalonde, J. M.; DuHadaway, J. B.;
Malachowski, W. P.; Prendergast, G. C.; Muller, A. J. J. Med. Chem.
2008, 51, 4968−4977.
ACKNOWLEDGMENTS
■
We thank Cec
technical assistance in NMR spectroscopy and HPLC
́
ile Le Duff and Laurent Collard for their
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