C2-Selective Branched Alkylation of Benzimidazoles by Rhodium(I)-Catalyzed C-H Activation

Article abstract of DOI:10.1021/acs.joc.7b01723

Herein, we report a Rh(I)/bisphosphine/K₃PO₄ catalytic system allowing for the first time the selective branched C-H alkylation of benzimidazoles with Michael acceptors. Branched alkylation with N,N-dimethyl acrylamide was successfully applied to the alkylation of a broad range of benzimidazoles incorporating a variety of N-substituents and with both electron-rich and -poor functionality displayed at different sites of the arene. Moreover, the introduction of a quaternary carbon was achieved by alkylation with ethyl methacrylate. The method was also shown to be applicable to the C2-selective branched alkylation of azabenzimidazoles.

Full text of DOI:10.1021/acs.joc.7b01723

Note
pubs.acs.org/joc
C2-Selective Branched Alkylation of Benzimidazoles by Rhodium(I)-
Catalyzed C−H Activation
Gael Tran,† Danielle Confair,† Kevin D. Hesp,‡ Vincent Mascitti,‡ and Jonathan A. Ellman*,†
̈
†Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, United States
‡Medicinal Sciences, Pfizer, Inc., Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: Herein, we report a Rh(I)/bisphosphine/
K3PO4 catalytic system allowing for the first time the selective
branched C−H alkylation of benzimidazoles with Michael
acceptors. Branched alkylation with N,N-dimethyl acrylamide
was successfully applied to the alkylation of a broad range of
benzimidazoles incorporating a variety of N-substituents and
with both electron-rich and -poor functionality displayed at
different sites of the arene. Moreover, the introduction of a
quaternary carbon was achieved by alkylation with ethyl
methacrylate. The method was also shown to be applicable to
the C2-selective branched alkylation of azabenzimidazoles.
Scheme 1. C2-Selective Alkylations of Benzimidazoles
he benzimidazole framework is among the most
1
Textensively used scaffolds in the pharmaceutical industry,
and the synthesis and functionalization of benzimidazoles have
been the subject of a considerable number of studies.2 Among
them, the regioselective transition metal-catalyzed C−H
functionalization of benzimidazoles has elicited significant
interest because it allows rapid access to elaborated substrates
from simple precursors.3 In particular, the direct C−H
alkylation of C2-unsubstituted benzimidazoles with alkenes
proceeds with complete atom economy.4 Both Rh and Ni
catalyst systems have been reported to promote intermolecular
benzimidazole C−H alkylations with very high linear selectivity,
and depending on the reaction conditions and catalyst used, a
vinyl group can be substituted with alkyl,5 aryl,6 or electron-
withdrawing7 groups (Scheme 1, eq 1). In contrast, branched-
selective intermolecular alkylation of benzimidazoles is limited
to a single report, which employs styrenes with a Ni catalyst
system (Scheme 1, eq 2).8,9 We have recently demonstrated
that a Rh(I) precatalyst combined with the electron-poor ligand
dArFpe and K3PO4 enables the completely branched selective
alkylation of pyridines in high yields.10 Herein, we report that
this catalyst system can be extended to the branched selective
alkylation of a wide range of benzimidazole and azabenzimi-
dazole derivatives with N,N-dimethylacrylamide (eq 3) and to
the first examples of branched-selective C−H alkylation to
introduce a quaternary carbon with ethyl methacrylate (eq 4).
After reevaluation of a broad range of reaction parameters, it
was found that the optimal conditions previously reported for
the branched alkylation of pyridines were also the most
effective for the branched alkylation of N-methylbenzimidazole
1a with N,N-dimethylacrylamide 2. Under these conditions,
product 3a was obtained in 71% yield with exclusive
regioselectivity in favor of the C2-position and with complete
Received: July 10, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b01723
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The Journal of Organic Chemistry
Note
branched selectivity (Table 1, entry 1). K3PO4 was the base of
choice as other inorganic bases either led to complete shut-
at the C2 position without any undesired alkylation on the
azine ring. Electron-withdrawing and -donating substituents
were well tolerated in these cases as well (3r and 3s). In very
preliminary studies, an N-methyl and an N-BOM-substituted
imidazole were evaluated under the standard reaction
conditions, but starting material was primarily recovered (3t
and 3u). It is possible that alkylation might occur under
different reaction conditions or with imidazoles having
alternative substitution patterns.
Table 1. Key Reaction Parameters
Although broad in scope with respect to the benzimidazole
substituents, this method is primarily restricted to N,N-
disubstituted acrylamides as the Michael acceptor. We therefore
demonstrated that the amide products can be easily trans-
formed to the corresponding aldehydes by treatment with
Schwartz reagent (Scheme 3).11 Owing to the instability of the
aldehyde products to long-term storage, they were isolated and
characterized as their O-methyl oximes derivatives 4 after
treatment with NH2−OMe·HCl. Given that aldehydes are
among the most versatile functional handles in organic
chemistry, this method can potentially be used to access a
very broad range of branched benzimidazole derivatives.
The introduction of a quaternary carbon center by Rh(I)-
catalyzed C−H bond additions to methacrylate derivatives was
also investigated (Scheme 4). Although N,N-dimethyl meth-
acrylamide did not provide any desired product, ethyl
methacrylate (5) proved to be a suitable alkene partner, thus
allowing the direct incorporation of a quaternary center
(Scheme 4). However, in contrast to what was observed in
the scope exploration using N,N-dimethylacrylamide, we found
that the branched to linear alkylation selectivity of this reaction
is dependent upon the substitution pattern of nitrogen
heterocycle 1. Indeed, although the use of N-BOM-
benzimidazole (1c) led to both branched and linear products
in 32% (6c) and 34% (6c′) yields, respectively, electron-poor
heterocycles provided the branched products such as 6j and 6q
with high selectively and in excellent yields. We also found that
the reaction was very sensitive to any adventitious water, which
resulted in low yields of product. The greater sensitivity of the
alkylation reaction to water when ethyl methacrylate (5) is used
instead of N,N-dimethylacrylamide (2) potentially arises from
the higher propensity of ethyl methacrylate to oligomerize
under basic conditions.
In summary, we have developed a Rh(I)-catalyzed C2-
selective alkylation of benzimidazole derivatives with N,N-
dimethylacrylamide with complete branched selectivity. This
transformation complements the previously reported branched
alkylation of benzimidazoles by styrenes and the linear
alkylation of benzimidazoles by Michael acceptors. Alkylated
benzimidazoles featuring a broad range of different electronic
properties can be accessed in good to excellent yields, and the
amide products can be easily converted to aldehydes as versatile
synthetic intermediates, thereby making the reported method
useful for drug discovery applications. Moreover, the branched
alkylation of benzimidazole derivatives with ethyl methacrylate
was achieved for the preparation of products incorporating a
quaternary carbon.
a
entry
change from optimal conditions
none
yield
1
2
3
4
5
6
7
8
9
10
71% (68%)
0%
K2HPO4 instead of K3PO4
K2CO3 instead of K3PO4
15%
KOPiv instead of K3PO4
dppe instead of dArFpe
0%
13%
100 °C instead of 120 °C
EWG = CO2tBu instead of CONMe2
EWG = CO2Et instead of CONMe2
Mesitylene instead of PhMe
THF instead of PhMe
14%
12%
b
14%
74%
41%
a
1
Determined from the crude reaction mixture by H NMR analysis
using 1,3,5-trimethoxybenzene as an internal standard. Isolated yields
b
in parentheses. 1H NMR also showed the presence of 17% yield of
the linear product.
down of the reaction or drastically reduced yields (Table 1,
entries 2−4). The electron-deficient bisphosphine dArFpe
((3,5-CF3Ph)pe) was also a critical element of the catalytic
system, and the use of its more electron-rich analogue dppe
only led to a 13% yield (Table 1, entry 5). Reducing the
temperature to 100 °C seemed to promote competitive
polymerization of the alkene partner (Table 1, entry 6), as
did the replacement of acrylamide 2 by tert-butyl acrylate and
ethyl acrylate (Table 1, entries 7 and 8). Mesitylene was
evaluated in place of toluene as solvent because its boiling point
of 165 °C is well above the reaction temperature of 120 °C and
gave a comparable reaction yield (Table 1, entry 9). However,
toluene was employed for evaluating reaction scope because it
can be readily purchased in anhydrous form. Other common
solvents such as THF could be used in the reaction, but the
yield was significantly lower (Table 1, entry 10).
The optimized conditions proved to be very general, and a
broad scope was observed for the benzimidazole coupling
partner (Scheme 2). Substitution at the N1-position with a
methyl, phenyl or benzyloxymethyl (BOM) protecting group
led to excellent yields of the corresponding benzimidazoles 3a−
c, and scale-up of the alkylation of benzimidazole 1a from 0.4 to
7.6 mmol did not lead to a significant change in yield.
Benzimidazoles substituted at the C5, C6, or C7 positions with
a wide range of electron-withdrawing groups such as esters (3d
and 3e), sulfonyl (3f), chloro (3g), nitrile (3h), or
trifluoromethyl (3i−l) provided alkylation products in good
to excellent yields. Only benzimidazole 3l, bearing a
trifluoromethyl substituent at the C4-position, was obtained
in a low yield of 12%. Electron-donating group such as methoxy
or methyl were also very well tolerated when used in
conjunction with a BOM-protecting group (3m−o). Because
we previously reported that azines could be efficiently alkylated
using the present method, it was a surprise for us to see that
azine-fused imidazoles 1p and 1q could be selectively alkylated
EXPERIMENTAL SECTION
■
General Experimental. Unless otherwise indicated, all reactions
were performed under a nitrogen gas atmosphere in oven-dried
glassware cooled under nitrogen gas. Toluene, diethyl ether,
dichloromethane, and THF were degassed by argon sparging and
purified by elution through a column of activated alumina under an
B
DOI: 10.1021/acs.joc.7b01723
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Note
Scheme 2. Scope of the Reaction Using N,N-Dimethylacrylamide
Scheme 3. Transformations of Product Amide
Scheme 4. Direct Incorporation of Quaternary Centers with
Ethyl Methacrylate
argon atmosphere prior to use. Mesitylene was dried and distilled
under nitrogen from CaH2 and then degassed by sparging with N2.
1,2-Bis(bis(3,5-bis(trifluoromethyl)phenyl)phosphino)ethane
(dArFpe) was synthesized according to a modified literature procedure.
All other catalyst and ligands were purchased from Strem Chemical
and used without further purification. Potassium phosphate was dried
at 160 °C under high vacuum prior to use. N-Methylbenzimidazole 1a
was recrystallized from Et2O/pentane prior to use. All liquid azoles
and N,N-dimethylacrylamide 2 were dried by elution through a small
column of activated basic alumina and degassed by nitrogen sparging
prior to use. Ethyl methacrylate 4 was dried over CaCl2, distilled under
reduced pressure under nitrogen and then degassed by nitrogen
sparging prior to use. All other reagents were purchased from
commercial sources and used without further purification. All
microwave-heated reactions were performed in a Biotage Initiator+
microwave reactor, which employs an external IR sensor. Flash column
chromatography was performed over grade 60 silica gel (230−400
mesh). Preparative TLC was performed over silica gel-coated glass
plates (20 × 20 cm, 1000 or 2000 μm). Reverse-phase column
chromatography was performed on prepacked cartridges of C18 silica
gel using an automated purification system. NMR chemical shifts (δ)
are reported in ppm relative to CHCl3 (δ = 7.26 ppm), acetone (δ =
2.05 ppm), H2O (δ = 4.79 ppm), or (CH3)2SO (δ = 2.50 ppm) for 1H
NMR, CDCl3 (δ = 77.16 ppm) or (CD3)2CO (δ = 29.8 ppm), for 13
C
NMR, 85% aqueous H3PO4 for 31P NMR (external reference, δ = 0
ppm), and trifluoroacetic acid for 19F-NMR (external reference, δ =
−76.55 ppm). All 13C NMR are proton decoupled. All 19F and 31P
NMR are carbon decoupled. The multiplicity and shape of NMR
signals are designated by the following abbreviations: s, singlet; d,
C
DOI: 10.1021/acs.joc.7b01723
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The Journal of Organic Chemistry
Note
doublet; t, triplet; q, quartet; m, multiplet; app, apparent. Coupling
constants (J values) are reported in hertz (Hz). High-resolution mass
spectra (HRMS) were recorded on a quadrupole time-of-flight mass
spectrometer after electrospray ionization. Melting points (mp) are
reported uncorrected.
over Na2SO4 and concentrated in vacuo. Purification by flash
chromatography over silica gel (100% EtOAc) gave desired product
benzimidazole-5-carboxylic acid ethyl ester as a cream-colored
1
amorphous solid (751 mg, 3.95 mmol, 64% yield). H NMR matched
the reported data.16 1H NMR (500 MHz, DMSO-d6) δ 12.79 (s, 1H),
8.40 (s, 1H), 8.23 (s, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.67 (s, 1H), 4.32
(q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).
1,2-Bis(bis(3,5-bis(trifluoromethyl)phenyl)phosphino)ethane
(dArFpe). A freshly titrated solution of iPrMgBr (1.10 M in THF, 26.3
mL, 28.9 mmol, 6.7 equiv)12 was charged in an oven-dried round-
bottom flask previously flushed with nitrogen. Additional dry diethyl
ether (30 mL) was added, and the resulting solution was cooled to
−10 °C. Neat 1-bromo-3,5-bis(trifluoromethyl)benzene (5.20 mL,
30.2 mmol, 7.0 equiv) was added dropwise over 20 min; the reaction
mixture was stirred at −10 °C for 1 h, and then allowed to warm to
room temperature and stirred for 3 h. The resulting clear brown
solution was cooled to 0 °C, and neat 1,2-bis(dichlorophosphino)-
ethane (0.65 mL, 4.3 mmol, 1.0 equiv) was added dropwise over 5
min. The resulting suspension was allowed to warm to room
temperature and stirred for 16 h. The resulting suspension was cooled
to 0 °C and quenched with an aqueous saturated NH4Cl solution. The
organic solvents were removed in vacuo, and water and ethyl acetate
were added to the resulting slurry until two clear phases were obtained.
The phases were separated, and the aqueous phase was extracted twice
with EtOAc. The combined organic phases were dried over Na2SO4
and concentrated in vacuo to give an orange solid. This solid was then
washed with small amounts of peroxide-free and BHT-free diethyl
ether until a white powder was obtained, which was then dried under
high vacuum to give the desired product (3.96 g, 4.20 mmol, 97%
Ethyl 1-((Benzyloxy)methyl)-1H-benzo[d]imidazole-5-carboxy-
late (1d). Benzimidazole-5-carboxylic acid ethyl ester (0.50 g, 2.6
mmol, 1 equiv) was dissolved in DMF (2.5 mL), and the reaction
solution was cooled to 0 °C. Sodium hydride (60% w/w in oil, 91 mg,
3.9 mmol, 1.5 equiv) was added, and the reaction mixture was stirred
for 15 min followed by the addition of BOM-Cl (90% purity, 0.41 mL,
2.6 mmol, 1.0 equiv). The reaction mixture was then stirred for 45 min
at room temperature, and the reaction was quenched with 0.25 mL of
30% w/w aqueous NH3. The solvents were removed in vacuo, and the
residue was partitioned between water and dichloromethane. The
aqueous phase was extracted with dichloromethane (3 × 5 mL), and
the combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. Purification by flash chromatography over silica
gel (65% EtOAc/hexanes) gave desired product 1d as a white
amorphous solid (220 mg, 0.71 mmol, 27% yield). Mp 82−85 °C; IR
(neat) 3066, 2982, 2937, 1709, 1622, 1461, 1278, 1245, 1193, 1058,
748, 702 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.08 (d, J
= 8.5 Hz, 1H), 8.02 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.38−7.32 (m,
3H), 7.26−7.28 (m, 2H), 5.61 (s, 2H), 4.47 (s, 2H), 4.42 (q, J = 7.1
Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
167.0, 144.7, 143.9, 136.8, 136.0, 128.9, 128.6, 128.2, 125.7, 125.3,
123.0, 110.2, 73.6, 70.5, 61.1, 14.6; HRMS (ESI+, m/z) [M + H]+
13
1
yield). H and 19F NMR matched the reported data. 1H NMR (600
MHz, acetone-d6) δ 8.11 (s, 8H), 8.05 (s, 4H), 2.73 (t, J = 5.3 Hz,
4H); 19F NMR (150 MHz, acetone-d6) δ −63.5; 31P NMR (200 MHz,
acetone-d6) δ −9.4.
+
calcd for C18H19N2O3 311.1390, found 311.1410.
1-Methyl-5-methylsulfonyl-benzimidazole (1f). 1-Fluoro-4-meth-
ylsulfonyl-2-nitrobenzene (1.00 g, 4.57 mmol, 1.0 equiv) was weighed
in a 20 mL Biotage microwave vial (#354833, HxD = 8 × 2.8 cm)
followed by a 2 M solution of MeNH2 in THF (11.4 mL, 22.8 mmol, 5
equiv). The vial was sealed with a Teflon-lined cap, and the mixture
was stirred at room temperature for 30 min. The reaction mixture was
then concentrated in vacuo, and the resulting residue was suspended in
Et2O and filtered to give crude N-methyl-4-(methylsulfonyl)-2-
nitroaniline. This solid was then transferred to a 250 mL Morton
flask, to which was added Pd/C (1.06 g, 10 mol %), and the solids
were suspended in EtOH (100 mL), placed under an atmosphere of
H2, and stirred at room temperature for 2.5 h. The reaction mixture
was then filtered through pad of Celite, rinsed with MeOH, and
concentrated to give crude N-methyl-4-(methylsulfonyl)benzene-1,2-
diamine. The crude reaction product was transferred into a 20 mL
Biotage microwave vial (#354833, HxD = 8 × 2.8 cm), to which was
added formic acid (90% w/w in water, 17.1 mL, 407 mmol, 90 equiv).
The vial was sealed with a Teflon-lined cap and heated at 150 °C in a
Biotage Initiator+ microwave reactor for 1 h. The solution was made
basic with 2 M NaOH followed by concentrated NaOH until pH ∼9
was reached. The mixture was extracted with CH2Cl2 (3 × 50 mL),
and the organic layers were combined, dried over Na2SO4, and
concentrated in vacuo. Purification by flash chromatography over silica
gel (100% EtOAc) gave desired product 1f as a pale orange
amorphous solid (711 mg, 3.40 mmol, 68% yield). Mp 162−164
°C; IR (neat) 3081, 2995, 2904, 1612, 1501, 1329, 1284, 1259, 1136,
1-Phenyl-1H-benzo[d]imidazole (1b). 1H-Benzimidazole (236 mg,
2.00 mmol, 1.0 equiv) and Cs2CO3 (3.26 g, 10.0 mmol, 5.0 equiv)
were weighed in a 20 mL Biotage microwave vial (#354833, HxD = 8
× 2.8 cm), followed by dry DMA (20 mL) and fluorobenzene (0.88
mL, 9.3 mmol, 4.7 equiv). The vial was sealed with a Teflon-lined cap
and heated at 190 °C in a Biotage Initiator+ microwave reactor for 16
h. The reaction mixture was poured on water and Et2O; the phases
were separated, and the aqueous phase was extracted three times with
Et2O. The combined organic phases were dried over Na2SO4 and
concentrated in vacuo to give the crude product. Purification by flash
chromatography over silica gel (60% EtOAc/petroleum ether) gave
desired product 1b as a colorless oil (370 mg, 1.90 mmol, 95% yield).
1H NMR spectra matched the reported data.14 1H NMR (600 MHz,
CDCl3) δ 8.13 (s, 1H), 7.93−7.84 (m, 1H), 7.62−7.50 (m, 5H),
7.50−7.43 (m, 1H), 7.39−7.29 (m, 2H).
1-((Benzyloxy)methyl)-1H-benzo[d]imidazole (1c). Under N2 at 0
°C, to a solution of 1H-benzimidazole (1.00 g, 8.46 mmol, 1.0 equiv)
in dry DMF (20 mL) was added NaH (60% w/w in oil, 340 mg, 8.87
mmol, 1.05 equiv) in one portion. The reaction mixture was stirred at
0 °C for 10 min, then neat BOM-Cl (90% purity, 1.38 mL, 8.90 mmol,
1.05 equiv) was added dropwise. The resulting solution was stirred at
rt for 16 h. The reaction mixture was then poured onto a 10% w/w
LiCl aqueous solution. EtOAc was added; the phases were separated,
and the organic phase was washed three more times with a 10% w/w
LiCl solution. The organic phase was dried over Na2SO4 and
concentrated in vacuo to give a yellow oil. Purification by flash
chromatography over silica gel (60−100% EtOAc/petroleum ether)
gave desired product 1c as a white amorphous solid (1.27 g, 5.33
1
1061, 769, 637 cm−1; H NMR (600 MHz, CDCl3) δ 8.42 (s, 1H),
8.04 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 3.92
(s, 3H), 3.09 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 146.4, 143.5,
138.0, 134.7, 121.9, 121.0, 110.4, 45.3, 31.6; HRMS (ESI+, m/z) [M +
H]+ calcd for C9H11N2O2S+ 211.0536, found 211.0528.
1-Methyl-6-chloro-1H-benzo[d]imidazole (1g). 4-Chloro-2-fluoro-
1-nitro-benzene (1.00 g, 5.70 mmol, 1.0 equiv) was weighed in a 20
mL Biotage microwave vial (#354833, HxD = 8 × 2.8 cm), followed by
a 2 M solution of MeNH2 in THF (14.2 mL, 28.5 mmol, 5 equiv). The
vial was sealed with a Teflon-lined cap, and the reaction mixture was
stirred at room temperature for 1 h. The resulting suspension was
filtered over a sintered glass funnel, and the filtrate was concentrated in
vacuo to give crude 5-chloro-N-methyl-2-nitroaniline as an orange
solid. A slurry of Raney nickel in water was then charged in a 100 mL
15
1
mmol, 63% yield). H NMR spectra matched the reported data. 1H
NMR (600 MHz, CDCl3) δ 7.95 (s, 1H), 7.86−7.82 (m 1H), 7.56−
7.53 (m, 1H), 7.38−7.31 (m, 5H), 7.30−7.26 (m, 2H), 5.60 (s, 2H),
4.47 (s, 2H).
Benzimidazole-5-carboxylic Acid Ethyl Ester. Benzimidazole-5-
carboxylic acid (1.00 g, 6.17 mmol, 1.0 equiv) was dissolved in EtOH
(15.5 mL), treated with concentrated H2SO4 (0.36 mL, 6.9 mmol, 1.1
equiv), and heated to reflux for 24 h. After cooling to room
temperature, the mixture was poured onto ice, and 5 N aqueous
NaOH was added until pH ∼9 was reached. The mixture was extracted
with EtOAc (3 × 30 mL). The combined organic layers were dried
D
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The Journal of Organic Chemistry
Note
round-bottom flask; the water was evaporated in vacuo to give ∼1.8 g
of dry Raney nickel (30.7 mmol, 4.8 equiv). Crude 5-chloro-N-methyl-
2-nitroaniline was then added to the Raney nickel as a solution in
MeOH (50 mL), and the resulting suspension was vigorously stirred
under a hydrogen atmosphere for 2 h. The resulting colorless
suspension was filtered over a bed of Celite (Et2O washings) and then
concentrated in vacuo to give crude 5-chloro-N1-methylbenzene-1,2-
diamine as a black oil. This oil was then transferred into a 20 mL
Biotage microwave vial (#354833, HxD = 8 × 2.8 cm) to which was
added formic acid (90% w/w in water, 20.4 mL, 486 mmol, 85 equiv).
The vial was sealed with a Teflon-lined cap and heated at 150 °C for
2.5 h in a Biotage Initiator+ microwave reactor. The reaction mixture
was concentrated in vacuo to give a bright pink solid. Purification by
reverse-phase flash chromatography over C18 silica gel (20−40%
MeCN + 0.1% TFA/H2O + 0.1% TFA) gave the desired product as its
TFA salt, which was then treated with an aqueous saturated solution of
NaHCO3. Extraction with EtOAc, followed by drying with Na2SO4
and in vacuo concentration led to desired product 1g as a white
formic acid (90% w/w in water, 15.0 mL, 358 mmol, 67 equiv). The
vial was sealed with a Teflon-lined cap and heated at 150 °C for 10
min in a Biotage Initiator+ microwave reactor. The reaction mixture
was concentrated in vacuo to give a red oil. Purification by flash
chromatography over silica gel (80% EtOAc/petroleum ether) gave
desired product 1i as a pale yellow amorphous solid (702 mg, 3.51
mmol, 66% overall yield). 1H NMR spectra matched the reported
data.18 1H NMR (600 MHz, CDCl3) δ 8.01 (d, J = 8.2 Hz, 1H), 7.94
(s, broad, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.35 (tapp, J = 7.9 Hz, 1H),
4.00 (q, J = 1.8 Hz, 3H); 19F NMR (470 MHz, CDCl3) δ −55.02.
1-Methyl-6-(trifluoromethyl)-1H-benzo[d]imidazole (1j). 2-
Chloro-1-nitro-4-(trifluoromethyl) benzene (1.00 g, 4.43 mmol, 1.0
equiv) was weighed in a 20 mL Biotage microwave vial (#354833,
HxD = 8 × 2.8 cm) followed by a 2 M solution of MeNH2 in THF
(11.0 mL, 22.2 mmol, 5 equiv). The vial was sealed with a Teflon-lined
cap and heated at 150 °C for 30 min in a Biotage Initiator+ microwave
reactor. The resulting suspension was filtered over a sintered glass
funnel, and the filtrate was concentrated in vacuo to give crude N-
methyl-2-nitro-5-(trifluoromethyl)aniline as a bright orange solid. This
solid was then transferred to a 250 mL Morton flask to which were
added PtO2 (113 mg, 0.500 mmol, 0.11 equiv) and absolute ethanol
(50 mL). This suspension was vigorously stirred under a hydrogen
atmosphere for 2 h. The resulting colorless suspension was filtered
over a bed of Celite (Et2O washings) and then concentrated in vacuo
to give crude N1-methyl-5-(trifluoromethyl)benzene-1,2-diamine as an
orange oil. This oil was then transferred into a 20 mL Biotage
microwave vial (#354833, HxD = 8 × 2.8 cm) to which was added
formic acid (90% w/w in water, 15.0 mL, 358 mmol, 80 equiv). The
vial was sealed with a Teflon-lined cap and heated at 150 °C for 10
min in a Biotage Initiator+ microwave reactor. The reaction mixture
was concentrated in vacuo to give a red oil. Purification by flash
chromatography over silica gel (50% acetone/petroleum ether) gave
desired product 1j as a white amorphous solid (745 mg, 3.72 mmol,
84% overall yield). Mp 96−98 °C; IR (neat) 3031, 1507, 1338, 1302,
1160, 1093, 1063, 901, 814, 663 cm−1; 1H NMR (600 MHz, CDCl3) δ
7.98 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.53 (dd, J = 8.5,
1.2 Hz, 1H), 3.88 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 146.0,
145.9, 134.1, 125.4 (q, J = 32 Hz), 124.9 (q, J = 272 Hz), 120.9, 119.2
(q, J = 4 Hz), 107.4 (q, J = 5 Hz), 31.4; 19F NMR (470 MHz, CDCl3)
1
amorphous solid (720 mg, 4.32 mmol, 76% overall yield). H NMR
spectra matched the reported data.17 1H NMR (600 MHz, CDCl3) δ
7.84 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.25
(dd, J = 8.7, 2.0 Hz, 1H), 3.81 (s, 3H).
1-Methyl-1H-benzo[d]imidazole-5-carbonitrile (1h). 4-Chloro-3-
nitro-benzonitrile (1.00 g, 5.48 mmol, 1.0 equiv) was weighed in a 20
mL Biotage microwave vial (#354833, HxD = 8 × 2.8 cm) followed by
a 2 M solution of MeNH2 in THF (13.7 mL, 2 M in THF, 5 equiv).
The vial was sealed with a Teflon-lined cap, and the reaction mixture
was stirred at room temperature for 30 min. The reaction mixture was
then concentrated in vacuo. The resulting residue was suspended in
Et2O and filtered to give crude 4-methylamino-3-nitro-benzonitrile,
which was then suspended in EtOH/H2O (10:1, 19 mL) under N2 at
room temperature. Iron powder (1.00 g, 1.79 mmol, 3.3 equiv) and
CaCl2 (0.45 g, 4.1 mmol, 0.7 equiv) were added to the reaction
mixture, and the mixture was heated at reflux for 2 h. The reaction
mixture was cooled to room temperature and filtered through a pad of
Celite. The filtrate was concentrated in vacuo, and the residue was
redissolved in CH2Cl2, washed with water and brine, and dried over
Na2SO4. The solvent was removed in vacuo to give crude 3-amino-4-
methylamino-benzonitrile. To trimethyl orthoformate (15.8 mL) were
added 3-amino-4-methylamino-benzonitrile and p-toluenesulfonic acid
monohydrate (17 mg, 0.089 mmol, 0.016 equiv). The reaction mixture
was stirred at 100 °C for 2.5 h, after which time the mixture was
cooled and water (60 mL) was added. The solution was partitioned
with EtOAc (2 × 90 mL), and the organic layers were combined, dried
with MgSO4 and concentrated. Purification by flash chromatography
over silica gel (100% EtOAc) gave desired product 1h as a light brown
amorphous solid (339 mg, 2.15 mmol, 39% overall yield). Mp 136−
137 °C; IR (neat) 3090, 3030, 2955, 2223, 1614, 1503, 1470, 1332,
+
δ −60.67; HRMS (ESI+, m/z) [M + H]+ calcd for C9H8F3N2
201.0634, found 201.0633.
1-Methyl-5-(trifluoromethyl)-1H-benzo[d]imidazole (1k). 1-
Chloro-2-nitro-4-(trifluoromethyl) benzene (1.00 g, 4.43 mmol, 1.0
equiv) was weighed in a 20 mL Biotage microwave vial (#354833,
HxD = 8 × 2.8 cm) followed by a 2 M solution of MeNH2 in THF
(11.0 mL, 22.2 mmol, 5 equiv). The vial was sealed with a Teflon-lined
cap and heated at 150 °C for 15 min in a Biotage Initiator+ microwave
reactor. The resulting suspension was filtered over a sintered glass
funnel, and the filtrate was concentrated in vacuo to give crude N-
methyl-2-nitro-4-(trifluoromethyl)aniline as a bright orange solid. This
solid was then transferred to a 250 mL Morton flask to which were
added PtO2 (113 mg, 0.500 mmol, 0.11 equiv) and absolute ethanol
(50 mL). This suspension was vigorously stirred under a hydrogen
atmosphere for 2 h. The resulting colorless suspension was filtered
over a bed of Celite (Et2O washings) and then concentrated in vacuo
to give crude N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine as an
orange oil. This oil was then transferred into a 20 mL Biotage
microwave vial (#354833, HxD = 8 × 2.8 cm) to which was added
formic acid (90% w/w in water, 15.0 mL, 358 mmol, 80 equiv). The
vial was sealed with a Teflon-lined cap and heated at 150 °C for 10
min in a Biotage Initiator+ microwave reactor. The reaction mixture
was concentrated in vacuo to give a red oil. Purification by flash
chromatography over silica gel (50% acetone/petroleum ether) gave
desired product 1k as a white amorphous solid (676 mg, 3.38 mmol,
1
1260, 877, 825, 646 cm−1; H NMR (600 MHz, CDCl3) δ 8.14 (s,
1H), 8.00 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H),
3.90 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 146.0, 143.5, 137.3,
126.5, 125.7, 119.9, 110.7, 105.8, 31.5; HRMS (ESI+, m/z) [M + H]+
+
calcd for C9H8N3 158.0713, found 158.0719.
1-Methyl-7-(trifluoromethyl)-1H-benzo[d]imidazole (1i). 2-
Chloro-1-nitro-3-(trifluoromethyl)benzene (1.20 g, 5.32 mmol, 1.0
equiv) was weighed in a 20 mL Biotage microwave vial (#354833,
HxD = 8 × 2.8 cm) followed by a 2 M solution of MeNH2 in THF (12
mL, 24 mmol, 4.5 equiv). The vial was sealed with a Teflon-lined cap
and heated at 150 °C for 15 min in a Biotage Initiator+ microwave
reactor. The resulting suspension was filtered over a sintered glass
funnel, and the filtrate was concentrated in vacuo to give crude N-
methyl-2-nitro-6-(trifluoromethyl)aniline as a yellow solid. This solid
was then transferred to a 250 mL Morton flask to which were added
PtO2 (134 mg, 0.591 mmol, 0.11 equiv) and absolute ethanol (50
mL). This suspension was vigorously stirred under a hydrogen
atmosphere for 2 h. The resulting colorless suspension was filtered
over a bed of Celite (Et2O washings) and then concentrated in vacuo
to give crude N1-methyl-6-(trifluoromethyl)benzene-1,2-diamine as an
orange oil. This oil was then transferred into a 20 mL Biotage
microwave vial (#354833, HxD = 8 × 2.8 cm) to which was added
19
1
76% overall yield). H NMR spectra matched the reported data. 1H
NMR (600 MHz, CDCl3) δ 8.08 (s, 1H), 7.96 (s, 1H), 7.56 (dd, J =
8.5, 1.2 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H); 19F NMR
(470 MHz, CDCl3) δ −60.60.
1-Methyl-4-(trifluoromethyl)-1H-benzo[d]imidazole (1l). 1-
Chloro-2-nitro-4-(trifluoromethyl) benzene (1.15 g, 5.10 mmol, 1.0
E
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The Journal of Organic Chemistry
Note
equiv) was weighed in a 20 mL Biotage microwave vial (#354833,
HxD = 8 × 2.8 cm) followed by powdered silicon carbide (1.15 g) and
a 2 M solution of MeNH2 in THF (12.0 mL, 24.0 mmol, 4.7 equiv).
The vial was sealed with a Teflon-lined cap and heated at 190 °C for
30 min in a Biotage Initiator+ microwave reactor. The resulting
suspension was filtered over a sintered glass funnel, and the filtrate was
concentrated in vacuo to give a bright orange solid. This solid was then
purified by flash chromatography over silica gel (10% diethyl ether/
petroleum ether) to give pure 2-chloro-N-methyl-6-trifluoromethyl-
aniline as a bright orange solid (450 mg, 2.15 mmol, 42% yield). This
solid was then transferred to a 50 mL Morton flask to which were
added PtO2 (46 mg, 0.20 mmol, 0.1 equiv) and absolute ethanol (16
mL). This suspension was vigorously stirred under a hydrogen
atmosphere for 2 h. The resulting colorless suspension was filtered
over a bed of Celite (Et2O washings) and then concentrated in vacuo
to give crude N1-methyl-3-(trifluoromethyl)benzene-1,2-diamine as an
orange oil. This oil was then transferred into a 20 mL Biotage
microwave vial (#354833, HxD = 8 × 2.8 cm) to which was added
formic acid (90% w/w in water, 5.50 mL, 131 mmol, 60 equiv). The
vial was sealed with a Teflon-lined cap and heated at 150 °C for 10
min in a Biotage Initiator+ microwave reactor. The reaction mixture
was concentrated in vacuo to give a red oil. Purification by flash
chromatography over silica gel (80% EtOAc/petroleum ether) gave
desired product 1l as a pale yellow amorphous solid (208 mg, 1.04
Purification by flash chromatography over silica gel (90% EtOAc/
hexanes) gave desired product 1o as a pale yellow amorphous solid
(778 mg, 2.92 mmol, 85% yield). Mp 98−99 °C; IR (neat) 3089,
2970, 2883, 1704, 1495, 1356, 1215, 1093, 1001, 844, 742, 697 cm−1;
1H NMR (600 MHz, CDCl3) δ 7.83 (s, 1H), 7.59 (s, 1H), 7.38−7.26
(m, 6H), 5.52 (s, 2H), 4.43 (s, 2H), 2.40 (s, 6H); 13C NMR (151
MHz, CDCl3) δ 142.8, 142.5, 136.3, 132.9, 132.2, 131.8, 128.7, 128.4,
128.1, 120.5, 110.6, 73.3, 70.0, 20.7, 20.4; HRMS (ESI+, m/z) [M +
H]+ calcd for C17H19N2O+ 267.1492, found 267.1512.
1-Methyl-1H-imidazo[4,5-b]pyridine (1p). 3-Fluoro-2-nitro-pyri-
dine (1.00 g, 7.04 mmol, 1.0 equiv) was weighed in a 20 mL Biotage
microwave vial (#354833, HxD = 8 × 2.8 cm) followed by a 2 M
solution of MeNH2 in THF (17.6 mL, 35.2 mmol, 5 equiv). The vial
was sealed with a Teflon-lined cap and stirred at rt for 30 min. The
resulting suspension was filtered over a sintered glass funnel, and the
filtrate was concentrated in vacuo to give crude N-methyl-2-
nitropyridin-3-amine as a bright yellow solid. This solid was then
transferred to a 250 mL Morton flask to which were added 5% w/w
Pd/C (749 mg, 0.352 mmol, 0.05 equiv) and absolute ethanol (50
mL). This suspension was vigorously stirred under a hydrogen
atmosphere for 2 h. The resulting colorless suspension was filtered
over a bed of Celite (Et2O washings) and then concentrated in vacuo
to give crude N3-methylpyridine-2,3-diamine as a beige solid. This oil
was then transferred into a 20 mL Biotage microwave vial (#354833,
HxD = 8 × 2.8 cm) to which was added formic acid (90% w/w in
water, 23.6 mL, 564 mmol, 80 equiv). The vial was sealed with a
Teflon-lined cap and heated at 150 °C for 20 min in a Biotage
microwave Initiator+ reactor. The reaction mixture was concentrated
in vacuo to give a red oil. Purification by flash chromatography over
silica gel (100% acetone) gave desired product 1p as beige crystals
(560 mg, 4.21 mmol, 60% overall yield). 1H NMR spectra matched the
reported data.20 1H NMR (600 MHz, D2O) δ 8.24 (d, J = 4.9 Hz, 1H),
8.10 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.26−7.07 (m, 1H), 3.72 (s,
3H).
1
mmol, 20% overall yield). H NMR spectra matched the reported
data.18 1H NMR (600 MHz, CDCl3) δ 7.99 (s, 1H), 7.58 (ddapp, J =
7.7, 2.3 Hz, 2H), 7.38 (tapp, J = 7.7 Hz, 1H), 3.90 (s, 3H); 19F NMR
(470 MHz, CDCl3) δ −60.96.
1-((Benzyloxy)methyl)-6-methoxy-1H-benzo[d]imidazole (1m)
and 1-((Benzyloxy)methyl)-5-methoxy-1H-benzo[d]imidazole (1n).
Under N2 at 0 °C, to a solution of 5-methoxy-1H-benzo[d]imidazole
(1.00 g, 6.76 mmol, 1.0 equiv) in dry DMF (15 mL) was added NaH
(60% w/w in oil, 405 mg, 10.1 mmol, 1.50 equiv) in one portion. The
reaction mixture was stirred at 0 °C for 1 h, and then neat BOM-Cl
(90% pure, 1.25 mL, 8.10 mmol, 1.2 equiv) was added dropwise. The
resulting solution was stirred at rt for 16 h. The reaction mixture was
then poured onto a 10% w/w LiCl aqueous solution. EtOAc was
added; the phases were separated, and the organic phase was washed
three more times with a 10% w/w LiCl solution. The organic phase
was dried over Na2SO4 and concentrated in vacuo to give a yellow oil.
Purification by flash chromatography over silica gel (60−100%
EtOAc/CH2Cl2) gave, by order of elution, desired products 1m
(325 mg, 1.21 mmol, 18% yield) as a pale yellow amorphous solid and
1n (175 mg, 0.652 mmol, 10% yield) as a pale yellow oil. (1m): mp
67−70 °C; IR (neat) 3099, 2836, 1627, 1587, 1505, 1453, 1361, 1279,
1092, 1022, 955, 817, 733 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.83
(s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.38−7.30 (m, 3H), 7.30−7.24 (m,
2H), 6.99−6.90 (m, 2H), 5.53 (s, 2H), 4.45 (s, 2H), 3.86 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 157.3, 142.3, 138.6, 136.3, 134.4, 128.8,
128.5, 128.2, 121.1, 112.5, 93.8, 73.4, 70.0, 56.0; HRMS (ESI+, m/z)
[M + H]+ calcd for C16H17N2O2+ 269.1285, found 269.1285. (1n): IR
(neat) 2939, 1623, 1593, 1487, 1442, 1349, 1218, 1142, 1071, 941,
829, 697 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.88 (s, 1H), 7.40 (d, J
= 8.8 Hz, 1H), 7.37−7.28 (m, 4 H), 7.27−7.24 (m, 2H), 6.98 (dd, J =
8.8, 1.7 Hz, 1H), 5.53 (s, 2H), 4.43 (s, 2H), 3.87 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 156.7, 145.1, 143.4, 136.2, 128.8, 128.4, 128.2,
128.1, 113.8, 110.9, 102.6, 73.6, 70.1, 55.9; HRMS (ESI+, m/z) [M +
3-Methyl-3H-imidazo[4,5-b]pyridine (1q). Under N2 at 0 °C, to a
solution of 1H-imidazo[4,5-b]pyridine (500 mg, 4.20 mmol, 1.0 equiv)
in dry DMF (2 mL) was added NaH (60% w/w in oil, 252 mg, 6.30
mmol, 1.50 equiv) in one portion. The reaction mixture was stirred at
0 °C for 10 min, and then neat MeI (0.40 mL, 6.30 mmol, 1.5 equiv)
was added dropwise. The resulting solution was stirred at rt for 16 h.
The reaction mixture was then poured onto water. EtOAc was added;
the phases were separated, and the organic phase was washed twice
more with water. The organic phase was dried over Na2SO4 and
concentrated in vacuo to give a red oil. Purification by flash
chromatography over silica gel (80% acetone/petroleum ether) gave
desired product 1q as a pale yellow amorphous solid (275 mg, 2.07
20
1
mmol, 49% yield). H NMR matched the reported data. 1H NMR
(600 MHz, D2O) δ 8.13 (d, J = 5.0 Hz, 1H), 8.09 (s, 1H), 7.87 (d, J =
8.1 Hz, 1H), 7.19 (dd, J = 7.6, 5.0 Hz, 1H), 3.70 (s, 3H).
6-(Benzyloxy)-3-methyl-3H-imidazo[4,5-b]pyridine (1r). 3-Meth-
yl-3H-imidazo[4,5-b]pyridin-6-ol (250 mg, 1.68 mmol, 1.0 equiv) and
K2CO3 (394 mg, 2.85 mmol, 1.7 equiv) were weighed in a 20 mL
Biotage microwave vial (#354833, HxD = 8 × 2.8 cm), followed by
MeCN (12 mL). Benzyl bromide (0.30 mL, 2.5 mmol, 1.5 equiv) was
added. the vial was sealed with a Teflon-lined cap and heated at 80 °C
in a Biotage Initiator+ microwave reactor for 5 h. The reaction mixture
was filtered over cotton-wool, and the filtrate was concentrated in
vacuo. Purification by flash chromatography over silica gel (60%
acetone/petroleum ether) gave desired product 1r as a white
amorphous solid (170 mg, 0.710 mmol, 42% yield). Mp 119−120
°C; IR (neat) 3079, 2922, 1595, 1512, 1453, 1321, 1221, 1116, 1009,
+
H]+ calcd for C16H17N2O2 269.1285, found 269.1281.
1-((Benzyloxy)methyl)-5,6-dimethyl-1H-benzo[d]imidazole (1o).
5,6-Dimethylbenzimidazole (0.500 g, 3.42 mmol, 1.0 equiv) was
dissolved in DMF (2.5 mL), and the reaction solution was cooled to 0
°C. Sodium hydride (60% w/w oil oil, 118 mg, 5.13 mmol, 1.5 equiv)
was added, and the reaction mixture was stirred for 15 min before the
addition of BOM-Cl (90% purity, 0.53 mL, 3.42 mmol, 1.0 equiv). The
reaction mixture was stirred for 45 min at room temperature, and the
reaction was quenched with 0.25 mL of a 30% w/w aqueous NH3. The
solvents were removed in vacuo, and the residue was partitioned
between water and dichloromethane. The aqueous phase was extracted
with dichloromethane (3 × 5 mL), and the combined organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo.
1
898, 743, 701 cm−1; H NMR (600 MHz, CDCl3) δ 8.26 (d, J = 2.5
Hz, 1H), 7.96 (s, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.46 (d, J = 7.4 Hz,
2H), 7.39 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 5.15 (s, 2H),
3.89 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 152.4, 145.0, 142.5,
136.5, 136.0, 135.6, 128.8, 128.3, 127.8, 112.4, 71.5, 30.0; HRMS (ESI
+, m/z) [M + H]+ calcd for C14H14N3O+ 240.1131, found 240.1132.
Ethyl 3-Methyl-3H-imidazo[4,5-b]pyridine-6-carboxylate (1s). 3-
Methylimidazo[4,5-b]pyridine-6-carboxylic acid (0.126 g, 0.710 mmol,
1.0 equiv) was heated in SOCl2 (15 mL) at 80 °C for 2 h. The excess
F
DOI: 10.1021/acs.joc.7b01723
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The Journal of Organic Chemistry
Note
SOCl2 was removed in vacuo. The remaining residue was dissolved in
EtOH (10 mL) and heated at reflux for 1 h. EtOH was then removed
in vacuo. Purification by flash chromatography over silica gel (100%
EtOAc) gave desired product 1s as a white amorphous solid (79 mg,
0.38 mmol, 54% yield). Mp 89−90 °C; IR (neat) 3058, 2993, 2928,
1H), 7.39−7.31 (m, 4H), 7.30−7.26 (m, 4H), 5.67 (d, J = 11.0 Hz,
1H), 5.56 (d, J = 11.0 Hz, 1H), 4.51 (s, 2H), 4.44 (q, J = 7.1 Hz, 1H),
2.96 (s, 3H), 2.93 (s, 3H), 1.69 (d, J = 7.1 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 170.7, 153.9, 142.4, 136.8, 135.9, 128.7, 128.3, 127.9,
123.3, 122.7, 120.0, 109.8, 72.5, 70.6, 38.6, 37.4, 36.3, 16.7; HRMS
1
1700, 1603, 1403, 1297, 1240, 1180, 1026, 784, 637 cm−1; H NMR
+
(ESI+, m/z) [M + H]+ calcd for C20H24N3O2 338.1863, found
(600 MHz, CDCl3) δ 9.10 (s, 1H), 8.69 (s, 1H), 8.13 (s, 1H), 4.44 (q,
J = 7.1 Hz, 2H), 3.95 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H); 13C NMR (151
MHz, CDCl3) δ 166.1, 150.1, 146.7, 146.5, 134.8, 129.7, 121.6, 61.4,
338.1869.
Ethyl 1-((Benzyloxy)methyl)-2-(1-(dimethylamino)-1-oxopropan-
2-yl)-1H-benzo[d]imidazole-5-carboxylate (3d). Prepared according
to the general procedure from 1d (124 mg, 0.400 mmol, 1.0 equiv)
and N,N-dimethylacrylamide 2 (0.17 mL, 1.6 mmol, 4.0 equiv).
Purification by flash chromatography over silica gel (30% acetone/
CH2Cl2) gave desired product 3d as a cream-colored amorphous solid
(134 mg, 0.330 mmol, 82% yield). Mp 93−94 °C; IR (neat) 3064,
2976, 2939, 1700, 1643, 1618, 1420, 1277, 1216, 1112, 1013, 774, 700
+
30.1, 14.5; HRMS (ESI+, m/z) [M + H]+ calcd for C10H12N3O2
206.0924, found 206.0930.
General Procedure for Branched Alkylation. In a N2-filled
glovebox, an oven-dried Biotage microwave vial (#352016, HxD = 8 ×
1.5 cm) was charged with [Rh(cod)Cl]2 (0.05 equiv), 1,2-bis(bis(3,5-
bis(trifluoromethyl)phenyl)phosphino)ethane (dArFpe) (0.125
equiv), potassium phosphate (0.25 equiv), and the azole (1.0 equiv).
Toluene was then added (c = 0.6 M), and the reaction mixture was
stirred for 5 min to give a yellow-red suspension. The alkene was then
added (4.0 equiv). The vial was sealed with a Teflon-lined septum,
taken out of the glovebox, and heated for 24 h at 120 °C in a pre-
equilibrated oil bath. The reaction mixture was then filtered over a
short pad of silica gel (∼2 cm) in a pasteur pipet followed by washing
with acetone until the filtrate came out clear. The filtrate was then
concentrated in vacuo, and the products were purified by the indicated
chromatography techniques.
1
cm−1; H NMR (500 MHz, CDCl3) δ 8.49 (s, 1H), 8.00 (d, J = 9.5
Hz, 1H), 7.39−7.30 (m, 4H), 7.27−7.21 (m, 2H), 5.67 (d, J = 11.0
Hz, 1H), 5.55 (d, J = 11.0 Hz, 1H), 4.49 (s, 2H), 4.44 (q, J = 7.2 Hz,
1H), 4.39 (q, J = 7.1 Hz, 2H), 2.98 (s, 3H), 2.93 (s, 3H), 1.71 (d, J =
7.2 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ
170.6, 167.1, 155.5, 142.0, 139.1, 136.4, 128.8, 128.5, 128.0, 125.3,
124.8, 122.3, 109.5, 72.6, 70.6, 61.0, 38.6, 37.4, 36.3, 16.4, 14.5; HRMS
+
(ESI+, m/z) [M + H]+ calcd for C23H28N3O4 410.2074, found
410.2074.
2-(1-(Dimethylamino)-1-oxopropan-2-yl)-1-methyl-1H-benzo[d]-
imidazol-5-yl propionate (3e). Prepared according to the general
procedure from ethyl 1-methyl-1H-benzo[d]imidazole-5-carboxylate
1e (82.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2
(0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over
silica gel (5−20% acetone/CH2Cl2) gave desired product 3e as an
orange amorphous solid (87 mg, 0.287 mmol, 72% yield). Mp 108−
110 °C; IR (neat) 2982, 1705, 1636, 1618, 1453, 1392, 1296, 1247,
1205, 1102, 1083, 907, 773 cm−1; 1H NMR (600 MHz, CDCl3) δ 8.46
(s, 1H), 8.01 (dd, J = 8.6, 1.2 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 4.44
(q, J = 7.2 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.03 (s,
3H), 2.99 (s, 3H), 1.70 (d, J = 7.2 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 170.3, 167.3, 155.0, 141.8, 139.7,
N,N-Dimethyl-2-(1-methyl-1H-benzo[d]imidazol-2-yl)-
propanamide (3a). Scale of 0.4 mmol: Prepared according to the
general procedure from 1-methyl-1H-benzo[d]imidazole 1a (53 mg,
0.40 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2 (0.17 mL, 1.6
mmol, 4.0 equiv). Purification by flash chromatography over silica gel
(50% acetone/CH2Cl2) followed by further purification by preparative
TLC (5% MeOH/CH2Cl2) gave desired product 3a as an off-white
solid (63 mg, 0.27 mmol, 68% yield). Scale of 7.6 mmol: Prepared
according to the general procedure from 1-methyl-1H-benzo[d]-
imidazole 1a (1.00 g, 7.57 mmol, 1.0 equiv) and N,N-dimethylacry-
lamide 2 (0.17 mL, 1.6 mmol, 4.0 equiv) using a 10−20 mL Biotage
vial (#354833, HxD = 8 × 2.8 cm). Purification by flash
chromatography over silica gel (20% acetone/CH2Cl2 + 1% aqueous
NH4OH) followed by trituration with 10% Et2O/pentane gave desired
product 3a as an off-white amorphous solid (1.32 g, 5.71 mmol, 75%
yield). Mp 104−105 °C; IR (neat) 2941, 1631, 1495, 1458, 1432,
124.8, 124.3, 122.0, 108.9, 61.0, 39.3, 37.5, 36.4, 30.7, 15.9, 14.5;
HRMS (ESI+, m/z) [M + H]+ calcd for C16H22N3O3 304.1656,
+
found 304.1673.
N,N-Dimethyl-2-(1-methyl-5-methylsulfonyl-benzimidazol-2-yl)-
propanamide (3f). Prepared according to the general procedure from
1f (84.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2
(0.17 mL, 1.6 mmol, 4.0 equiv). Purification by flash chromatography
over silica gel (0−5% methanol/EtOAc) followed by trituration with
10% Et2O/pentane gave desired product 3f as a cream-colored solid
(105 mg, 0.34 mmol, 85% yield). Mp 176−178 °C; IR (neat) 3012,
1
1390, 1369, 1305, 1283, 1261, 1132, 1072, 769 cm−1; H NMR (600
MHz, CDCl3) δ 7.73 (m, 1H), 7.37−7.22 (m, 3H), 4.44 (q, J = 7.2 Hz,
1H), 3.80 (s, 3H), 3.01 (s, 3H), 2.98 (s, 3H), 1.68 (d, J = 7.2 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 170.5, 153.2, 142.2, 136.6, 122.7,
122.2, 119.7, 109.3, 39.4, 37.4, 36.4, 30.5, 16.1; HRMS (ESI+, m/z)
[M + H]+ calcd for C13H18N3O+ 232.1444, found 232.1449.
N,N-Dimethyl-2-(1-phenyl-1H-benzo[d]imidazol-2-yl)-
propanamide (3b). Prepared according to the general procedure from
1b (78.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2
(0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over
silica gel (30% acetone/CH2Cl2) gave desired product 3b as a pale
yellow amorphous solid (108 mg, 0.368 mmol, 92% yield). Mp 135−
137 °C. IR (neat) 3059, 2937, 1642, 1595, 1501, 1454, 1395, 1267,
1148, 1089, 752, 699 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.84 (d, J
= 7.9 Hz, 1H), 7.63−7.50 (m, 3H), 7.39−7.31 (m, 2H), 7.31−7.22 (m,
1H), 7.19 (td, J = 7.7, 1.1 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 4.10 (q, J
= 7.0 Hz, 1H), 2.80 (s, 3H), 2.66 (s, 3H), 1.66 (d, J = 7.0 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 171.0, 153.8, 142.5, 137.2, 135.8, 130.0,
129.5, 128.1, 123.1, 122.4, 120.0, 110.0, 37.1, 37.0, 36.0, 16.4; HRMS
(ESI+, m/z) [M + H]+ calcd for C18H20N3O+ 294.1601, found
294.1609.
2997, 2933, 1635, 1421, 1292, 1246, 1143, 974, 774, 620 cm−1; H
1
NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H),
7.45 (d, J = 8.5 Hz, 1H), 4.47 (q, J = 7.2 Hz, 1H), 3.85 (s, 3H), 3.07
(s, 3H), 3.07 (s, 3H), 3.00 (s, 3H), 1.72 (d, J = 7.2 Hz, 3H); 13C NMR
(151 MHz, CDCl3) δ 170.1, 156.5, 142.0, 139.9, 134.4, 121.5, 120.1,
110.1, 45.3, 39.1, 37.5, 36.4, 30.9, 15.8; HRMS (ESI+, m/z) [M + H]+
calcd for C14H20N3O3S+ 310.1220, found 310.1217.
2-(6-Chloro-1-methyl-1H-benzo[d]imidazol-2-yl)-N,N-dimethyl-
propanamide (3g). Prepared according to the general procedure from
1g (82.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2
(0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over
silica gel (5−20% acetone/CH2Cl2) gave desired product 3g as a pale
yellow amorphous solid (94 mg, 0.354 mmol, 88% yield. Mp 139−140
°C; IR (neat) 3065, 2950, 1644, 1502, 1474, 1392, 1270, 1133, 1052,
922, 821, 671 cm−1; H NMR (600 MHz, CDCl3) δ 7.62 (d, J = 8.6
1
Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 8.6, 1.9 Hz, 1H), 4.40
(q, J = 7.2 Hz, 1H), 3.75 (s, 3H), 3.02 (s, 3H), 2.99 (s, 3H), 1.68 (d, J
= 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 170.3, 154.1, 140.9,
137.2, 128.5, 122.8, 120.5, 109.5, 39.3, 37.4, 36.4, 30.6, 16.0; HRMS
(ESI+, m/z) [M + H]+ calcd for C13H17ClN3O+ 266.1055, found
266.1055.
2-(1-((Benzyloxy)methyl)-1H-benzo[d]imidazol-2-yl)-N,N-dime-
thylpropanamide (3c). Prepared according to the general procedure
from 1c (95.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacryla-
mide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash
chromatography over silica gel (30% acetone/CH2Cl2) gave desired
product 1c as a yellow amorphous solid (129 mg, 0.382 mmol, 96%
yield). Mp 55−56 °C; IR (neat) 2934, 1648, 1507, 1454, 1394, 1358,
1298, 1137, 1052, 768 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.77 (m,
2-(5-Cyano-1-methyl-1H-benzo[d]imidazol-2-yl)-N,N-dimethyl-
propanamide (3h). Prepared according to the general procedure from
G
DOI: 10.1021/acs.joc.7b01723
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1h (63 mg, 0.40 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2
(0.17 mL, 1.6 mmol, 4.0 equiv). Purification by reverse-phase flash
chromatography over C18 silica gel (10−20% MeCN + 0.1% TFA/
H2O + 0.1% TFA) gave the desired product as its TFA salt, which was
treated with an aqueous saturated solution of NaHCO3. Extraction
with EtOAc followed by drying with Na2SO4 and in vacuo
concentration led to desired product 3h as a white amorphous solid
(51 mg, 0.20 mmol, 50% yield). Mp 150 °C (decomp); IR (neat)
3083, 2994, 2945, 2216, 1634, 1615, 1483, 1388, 1297, 1075, 915, 823,
636 cm−1; 1H NMR (600 MHz, CDCl3) δ 8.04 (s, 1H), 7.53 (dd, J =
8.4, 1.5 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 4.44 (q, J = 7.2 Hz, 1H),
3.82 (s, 3H), 3.06 (s, 3H), 3.00 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H); 13C
NMR (151 MHz, CDCl3) δ 170.0, 156.1, 141.9, 139.3, 126.2, 124.7,
120.1, 110.4, 105.5, 39.9, 37.5, 36.4, 30.8, 15.8; HRMS (ESI+, m/z)
[M + H]+ calcd for C14H17N4O+ 257.1397, found 257.1405.
1H), 3.87 (s, 3H), 3.08 (s, 3H), 2.97 (s, 3H), 1.68 (d, J = 7.2 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 170.2, 154.7, 139.0 (q, J = 1 Hz),
137.8, 124.1 (q, J = 273 Hz), 121.8, 120.7 (q, J = 32 Hz), 119.6 (q, J =
5 Hz), 113.2, 39.8, 37.6, 36.5, 31.0, 16.0; 19F NMR (470 MHz, CDCl3)
δ −60.77; HRMS (ESI+, m/z) [M + H]+ calcd for C14H17F3N3O+
300.1318, found 300.1324.
2-(1-((Benzyloxy)methyl)-6-methoxy-1H-benzo[d]imidazol-2-yl)-
N,N-dimethylpropanamide (3m). Prepared according to the general
procedure from 1m (107 mg, 0.400 mmol, 1.0 equiv) and N,N-
dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash
chromatography over silica gel (20−40% acetone/CH2Cl2) gave
desired product 3m as a pale yellow oil (124 mg, 0.337 mmol, 84%
yield). IR (neat) 2936, 1644, 1486, 1454, 1393, 1207, 1139, 1074,
1056, 816, 733 cm−1; 1H NMR (600 MHz, CDCl3) δ 7.63 (d, J = 8.7
Hz, 1H), 7.38−7.27 (m, 5H), 6.89 (dd, J = 8.7, 2.3 Hz, 1H), 6.79 (d, J
= 2.3 Hz, 1H), 5.61 (d, J = 11.0 Hz, 1H), 5.50 (d, J = 11.0 Hz, 1H),
4.50 (s, 2H), 4.40 (q, J = 7.2 Hz, 1H), 3.81 (s, 3H), 2.96 (s, 3H), 2.93
(s, 3H), 1.67 (d, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
170.8, 157.0, 152.8, 136.8 (2C), 136.5, 128.7, 128.3, 128.0, 120.4,
111.7, 93.8, 72.4, 70.3, 56.0, 38.7, 37.3, 36.3, 16.6; HRMS (ESI+, m/z)
N,N-Dimethyl-2-(1-methyl-7-(trifluoromethyl)-1H-benzo[d]-
imidazol-2-yl)propanamide (3i). Prepared according to the general
procedure from 1i (80.0 mg, 0.400 mmol, 1.0 equiv) and N,N-
dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash
chromatography over silica gel (35% acetone/CH2Cl2) gave desired
product 3i as a pale yellow amorphous solid (101 mg, 0.337 mmol,
85% yield). Mp 112−114 °C; IR (neat) 2993, 1641, 1528, 1461, 1388,
+
[M + H]+ calcd for C21H26N3O3 368.1969, found 368.1970.
2-(1-((Benzyloxy)methyl)-5-methoxy-1H-benzo[d]imidazol-2-yl)-
N,N-dimethylpropanamide (3n). Prepared according to the general
procedure from 1n (107 mg, 0.400 mmol, 1.0 equiv) and N,N-
dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash
chromatography over silica gel (20−40% acetone/CH2Cl2) gave
desired product 3n as a pale yellow oil (139 mg, 0.378 mmol, 95%
yield). IR (neat) 2938, 1643, 1487, 1441, 1394, 1276, 1197, 1151,
1
1284, 1215, 1169, 1108, 1089, 957, 805, 750 cm−1; H NMR (600
MHz, CDCl3) δ 7.94 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H),
7.29 (tapp, J = 7.9 Hz, 1H), 4.40 (q, J = 7.2 Hz, 1H), 3.88 (q, J = 1.7
Hz, 3H), 3.023 (s, 3H), 3.02 (s, 3H), 1.72 (d, J = 7.2 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 170.4, 155.6, 144.4, 132.2, 124.3, 124.0 (q,
J = 271 Hz), 121.22 (q, J = 6 Hz), 121.18, 113.7 (q, J = 33 Hz), 39.1,
37.4, 36.5, 32.5 (q, J = 6 Hz), 16.0; 19F NMR (470 MHz, CDCl3) δ
−53.94; HRMS (ESI+, m/z) [M + H]+ calcd for C14H17F3N3O+
300.1318, found 300.1324
N,N-Dimethyl-2-(1-methyl-6-(trifluoromethyl)-1H-benzo[d]-
imidazol-2-yl)propanamide (3j). Prepared according to the general
procedure from 1j (80.0 mg, 0.400 mmol, 1.0 equiv) and N,N-
dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash
chromatography over silica gel (35% acetone/CH2Cl2) gave desired
product 3j as a pale yellow oil (111 mg, 0.371 mmol, 93% yield). Mp
128−130 °C; IR (neat) 2945, 1647, 1471, 1391, 1341, 1307, 1278,
1154, 1107, 1048, 923, 832, 666 cm−1; 1H NMR (600 MHz, CDCl3) δ
7.80 (d, J = 8.3 Hz, 1H), 7.60 (s, 1H), 7.51 (d, J = 8.3 Hz, 1H), 4.45
(q, J = 7.1 Hz, 1H), 3.84 (s, 3H), 3.03 (s, 3H), 3.00 (s, 3H), 1.71 (d, J
= 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 170.1, 155.9, 144.5,
136.0, 125.0 (q, J = 32 Hz), 124.9 (q, J = 272 Hz), 120.0, 119.2 (q, J =
4 Hz), 107.1 (q, J = 4 Hz), 39.3, 37.5, 36.4, 30.7, 15.9; 19F NMR (470
MHz, CDCl3) δ −60.66; HRMS (ESI+, m/z) [M + H]+ calcd for
C14H17F3N3O+ 300.1318, found 300.1313.
N,N-Dimethyl-2-(1-methyl-5-(trifluoromethyl)-1H-benzo[d]-
imidazol-2-yl)propanamide (3k). Prepared according to the general
procedure from 1k (80.0 mg, 0.400 mmol, 1.0 equiv) and N,N-
dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash
chromatography over silica gel (35% acetone/CH2Cl2) gave desired
product 3k as a pale yellow oil (105 mg, 0.351 mmol, 88% yield). Mp
148−149 °C; IR (neat) 2944, 1646, 1629, 1495, 1391, 1326, 1256,
1228, 1098, 1049, 925, 816, 707 cm−1; 1H NMR (600 MHz, CDCl3) δ
8.01 (s, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 4.46
(q, J = 7.1 Hz, 1H), 3.83 (s, 3H), 3.04 (s, 3H), 2.99 (s, 3H), 1.70 (d, J
= 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 170.2, 155.3, 141.7,
138.5, 125.0 (q, J = 272 Hz), 124.8 (q, J = 32 Hz), 119.7 (q, J = 4 Hz),
117.4 (q, J = 4 Hz), 109.7, 39.3, 37.5, 36.4, 30.8, 15.9; 19F NMR (470
MHz, CDCl3) δ −60.66; HRMS (ESI+, m/z) [M + H]+ calcd for
C14H17F3N3O+ 300.1318, found 300.1331.
1
1057, 949, 736 cm−1; H NMR (600 MHz, CDCl3) δ 7.38−7.29 (m,
3H), 7.28−7.26 (m, 3H), 7.22 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 8.8,
2.3 Hz, 1H), 5.62 (d, J = 11.0 Hz, 1H), 5.52 (d, J = 11.0 Hz, 1H), 4.49
(s, 2H), 4.39 (q, J = 7.2 Hz, 1H), 3.85 (s, 3H), 2.95 (s, 3H), 2.93 (s,
3H), 1.68 (d, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 170.6,
156.3, 154.0, 143.0, 136.5, 130.1, 128.5, 128.1, 127.8, 112.8, 110.0,
102.2, 72.3, 70.3, 55.7, 38.2, 37.1, 36.1, 16.5; HRMS (ESI+, m/z) [M +
+
H]+ calcd for C21H26N3O3 368.1969, found 368.1959.
2-(1-((Benzyloxy)methyl)-5,6-dimethyl-1H-benzo[d]imidazol-2-
yl)-N,N-dimethylpropanamide (3o). Prepared according to the
general procedure from 1o (107 mg, 0.400 mmol, 1.0 equiv) and
N,N-dimethylacrylamide 2 (0.17 mL, 1.6 mmol, 4.0 equiv).
Purification by flash chromatography over silica gel (30% acetone/
CH2Cl2) gave desired product 3o as a cream-colored amorphous solid
(85 mg, 0.23 mmol, 58% yield). Mp 121−123 °C; IR (neat) 2982,
1
2948, 2844, 1651, 1466, 1382, 1069, 1026, 852, 743, 697 cm−1; H
NMR (600 MHz, CDCl3) δ 7.51 (s, 1H), 7.38−7.27 (m, 5H), 7.08 (s,
1H), 5.62 (d, J = 11.0 Hz, 1H), 5.51 (d, J = 11.0 Hz, 1H), 4.50 (s, 2H),
4.39 (q, J = 7.2 Hz, 1H), 2.93 (s, 3H), 2.92 (s, 3H), 2.36 (s, 6H), 1.66
(d, J = 7.2 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 170.8, 153.0,
141.0, 136.9, 134.4, 132.3, 131.5, 128.7, 128.3, 128.0, 120.1, 110.1,
72.4, 70.4, 38.8, 37.3, 36.4, 20.7, 20.4, 16.8; HRMS (ESI+, m/z) [M +
+
H]+ calcd for C22H28N3O2 366.2176, found 366.2186.
N,N-Dimethyl-2-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-
propanamide (3p). Prepared according to the general procedure from
1p (100 mg, 0.751 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2
(0.31, 3.0 mmol, 4.0 equiv). Purification by flash chromatography over
silica gel (5−10% MeOH/CH2Cl2) gave desired product 3p as a beige
amorphous solid (148 mg, 0.637 mmol, 85% yield). Mp 141−143 °C;
IR (neat) 2940, 1637, 1612, 1506, 1445, 1408, 1389, 1274, 1142, 1081,
781, 755, 581 cm−1; 1H NMR (600 MHz, CDCl3) δ 8.52 (dd, J = 4.8,
1.2 Hz, 1H), 7.61 (dd, J = 7.9, 1.2 Hz, 1H), 7.19 (dd, J = 7.9, 4.8 Hz,
1H), 4.55 (q, J = 7.2 Hz, 1H), 3.83 (s, 3H), 3.07 (s, 3H), 2.97 (s, 3H),
1.71 (d, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 170.2, 155.6,
155.2, 144.9, 128.9, 117.8, 117.2, 39.7, 37.6, 36.4, 30.8, 15.8; HRMS
(ESI+, m/z) [M + H]+ calcd for C12H17N4O+ 233.1397, found
233.1397.
N,N-Dimethyl-2-(1-methyl-4-(trifluoromethyl)-1H-benzo[d]-
imidazol-2-yl)propanamide (3l). Prepared according to the general
procedure from 1l (80.0 mg, 0.400 mmol, 1.0 equiv) and N,N-
dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash
chromatography over silica gel (5−20% acetone/CH2Cl2) gave desired
product 3l as a pale yellow oil (15 mg, 0.050 mmol, 12% yield). IR
(neat) 2926, 1642, 1464, 1428, 1393, 1318, 1212, 1119, 1101, 936, 754
N,N-Dimethyl-2-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-
propanamide (3q). Prepared according to the general procedure from
1q (53.0 mg, 0.400 mmol, 1.0 equiv) and N,N-dimethylacrylamide 2
(0.17, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over
silica gel (60% acetone/CH2Cl2) gave desired product 3q as a pale
1
cm−1; H NMR (600 MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 1H), 7.50
(d, J = 8.1 Hz, 1H), 7.33 (tapp, J = 7.8 Hz, 1H), 4.65 (q, J = 7.2 Hz,
H
DOI: 10.1021/acs.joc.7b01723
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
yellow amorphous solid (90 mg, 0.387 mmol, 97% yield). Mp 105−
106 °C; IR (neat) 3029, 2977, 1636, 1601, 1509, 1475, 1448, 1399,
1281, 1132, 1076, 806, 782, 702 cm−1; 1H NMR (600 MHz, CDCl3) δ
8.35 (dd, J = 4.8, 1.4 Hz, 1H), 7.99 (dd, J = 8.0, 1.4 Hz, 1H), 7.21 (dd,
J = 8.0, 4.8 Hz, 1H), 4.39 (q, J = 7.2 Hz, 1H), 3.86 (s, 3H), 3.02 (s,
3H), 3.00 (s, 3H), 1.71 (d, J = 7.2 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 170.1, 154.7, 148.9, 143.7, 134.5, 127.1, 118.3, 39.3, 37.4,
36.4, 29.0, 15.7; HRMS (ESI+, m/z) [M + H]+ calcd for C12H17N4O+
233.1397, found 233.1406.
16.7; HRMS (ESI+, m/z) [M + H]+ calcd for C12H16N3O+ 218.1288,
found 218.1289.
2-(1-Methyl-1H-imidazo[4,5-b]pyridin-2-yl)propanal O-Methyl
Oxime (4p). In a N2-filled glovebox, a flame-dried Biotage microwave
vial (#351521, HxD = 8 × 1.5 cm) was charged with bis-
(cyclopentadienyl)zirconium(IV) chloride hydride (62 mg, 0.24
mmol, 1.2 equiv) followed by THF (3 mL). To this suspension was
added 3p (47 mg, 0.2 mmol, 1.0 equiv) suspended in THF (3.1 mL),
and the vial was sealed with a Teflon-lined septum. The mixture was
stirred at room temperature for 2.5 h, after which time NH2−OMe·
HCl (50 mg, 0.6 mmol, 3 equiv) was added, and the reaction mixture
was stirred for an additional 2.5 h. The reaction mixture was
concentrated in vacuo. An aqueous saturated solution of NaHCO3 was
added until pH ∼8 was reached, and the resulting mixture was
extracted with EtOAc (3 × 25 mL). The organic phase was dried over
Na2SO4 and concentrated in vacuo. Purification by flash chromatog-
raphy over silica gel (80% EtOAc/hexanes + 1% Et3N) gave a mixture
of E- and Z-isomers as a pale yellow oil (29 mg, 0.131 mmol, 66%
yield, 3:1 dr). IR (neat) 2987, 2939, 2819, 1612, 1503, 1454, 1408,
1279, 1050, 888, 778, 731 cm−1; 1H NMR (600 MHz, CDCl3) δ 8.51
(d, J = 4.7 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz,
0.75H), 7.19 (t, J = 8.0, 4.8 Hz, 1H), 6.96 (d, J = 7.3 Hz, 0.25H), 4.68
(p, J = 7.0 Hz, 0.25H), 4.03 (p, J = 7.1 Hz, 0.75H), 3.93 (s, 0.75H),
3.83 (s, 2.25H), 3.80 (s, 2.25H), 3.77 (s, 0.75H), 1.69 (d, J = 7.0 Hz,
2.25H), 1.62 (d, J = 7.0 Hz, 0.75H); 13C NMR (151 MHz, CDCl3) δ
156.9, 156.4, 155.4, 155.3, 150.2, 149.9, 144.6, 144.6, 128.1, 127.9,
117.7, 117.6, 116.99, 116.97, 62.0, 61.7, 33.7, 29.9, 29.7, 28.8, 17.1,
16.6; HRMS (ESI+, m/z) [M + H]+ calcd for C11H15N4O+ 219.1240,
found 219.1247.
2-(6-(Benzyloxy)-3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-N,N-di-
methylpropanamide (3r). Prepared according to the general
procedure from 1r (96.0 mg, 0.400 mmol, 1.0 equiv) and N,N-
dimethylacrylamide 2 (0.17, 1.6 mmol, 4.0 equiv). Purification by flash
chromatography over silica gel (40% acetone/CH2Cl2) gave desired
product 3r as an off-white amorphous solid (125 mg, 0.369 mmol,
92% yield). Mp 128−129 °C; IR (neat) 2941, 1636, 1498, 1453, 1393,
1258, 1174, 1028, 869, 731, 692 cm−1; 1H NMR (600 MHz, CDCl3) δ
8.19 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 7.2 Hz,
2H), 7.38 (tapp, J = 7.3 Hz, 2H), 7.32 (m, 1H), 5.13 (s, 2H), 4.33 (q, J
= 7.2 Hz, 1H), 3.81 (s, 3H), 3.00 (s, 6H), 1.67 (d, J = 7.2 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 170.1, 155.0, 152.4, 143.8, 136.6, 134.9,
134.6, 128.8, 128.3, 127.7, 112.0, 71.6, 39.3, 37.4, 36.4, 29.0, 15.7;
+
HRMS (ESI+, m/z) [M + H]+ calcd for C19H23N4O2 339.1816,
found 339.1821.
Ethyl 2-(1-(Dimethylamino)-1-oxopropan-2-yl)-3-methyl-3H-
imidazo[4,5-b]pyridine-6-carboxylate (3s). Prepared according to
the general procedure from 1s (82 mg, 0.40 mmol, 1.0 equiv) and
N,N-dimethylacrylamide 2 (0.17 mL, 1.6 mmol, 4.0 equiv).
Purification by flash chromatography over silica gel (20% acetone/
CH2Cl2) gave desired product 3s as a pale yellow solid (90 mg, 0.30
mmol, 74% yield). Mp 137−138 °C; IR (neat) 3041, 2987, 2942,
1715, 1636, 1602, 1481, 1371, 1293, 1197, 1086, 1009, 789, 621 cm−1;
1H NMR (400 MHz, CDCl3) δ 9.04 (d, J = 1.8 Hz, 1H), 8.61 (d, J =
Ethyl 2-(1-((Benzyloxy)methyl)-1H-benzo[d]imidazol-2-yl)-2-
methylpropanoate (6c) and Ethyl 3-(1-((Benzyloxy)methyl)-1H-
benzo[d]imidazol-2-yl)-2-methylpropanoate (6c′). Prepared accord-
ing to the general procedure from 1c (95 mg, 0.400 mmol, 1.0 equiv)
and ethyl methacrylate 5 (0.190 mL, 1.6 mmol, 4.0 equiv). Purification
by flash chromatography over silica gel (5−10% diethyl ether/
CH2Cl2) gave, by order of elution, desired products 6c as a pale yellow
oil (45 mg, 0.128 mmol, 32% yield) and 6c′ as a pale yellow oil (48
mg, 0.136 mmol, 34% yield). (6c): IR (neat) 2985, 1728, 1457, 1361,
1247, 1147, 1064, 1025, 909, 728 cm−1; 1H NMR (600 MHz, CDCl3)
δ 7.88−7.74 (m, 1H), 7.43−7.19 (m, 8H), 5.46 (s, 2H), 4.56 (s, 2H),
4.10 (q, J = 7.1 Hz, 2H), 1.81 (s, 6H), 1.13 (t, J = 7.1 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 175.1, 156.1, 141.7, 136.6, 136.4, 128.7,
128.3, 127.9, 123.4, 122.6, 120.0, 110.1, 73.0, 70.8, 61.7, 44.7, 26.1,
14.1; HRMS (ESI+, m/z) [M + H]+ calcd for C21H25N2O3+ 353.1860,
found 353.1851. (6c′): IR (neat) 2979, 1725, 1519, 1456, 167, 1281,
1.8 Hz, 1H), 4.46−4.37 (m, 3H), 3.88 (s, 3H), 3.05 (s, 3H), 3.01 (s,
3H), 1.73 (d, J = 7.2 Hz, 3H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (151
MHz, CDCl3) δ 169.9, 166.2, 156.7, 151.5, 146.0, 133.8, 128.6, 121.6,
61.3, 39.3, 37.5, 36.4, 29.3, 15.5, 14.5; HRMS (ESI+, m/z) [M + H]+
+
calcd for C15H21N4O3 305.1608, found 305.1624.
2-(1-Methyl-1H-benzo[d]imidazol-2-yl)propanal O-Methyl Oxime
(4a). In a N2-filled glovebox, a flame-dried Biotage microwave vial
(#351521, HxD = 8 × 1.5 cm) was charged with bis-
(cyclopentadienyl)zirconium(IV) chloride hydride (62 mg, 0.24
mmol, 1.2 equiv) followed by THF (3 mL). To this suspension was
added 3a (46 mg, 0.2 mmol, 1.0 equiv) in THF (2.1 mL), and the vial
was sealed with a Teflon-lined septum. The mixture was stirred at
room temperature for 1.5 h, after which time NH2−OMe·HCl (50 mg,
0.6 mmol, 3 equiv) was added, and the reaction mixture was stirred for
an additional 2 h. The reaction mixture was then concentrated in
vacuo. An aqueous saturated solution of NaHCO3 was added until pH
∼8 was reached, and the resulting mixture was then extracted with
EtOAc (3 × 25 mL). The organic phase was dried over Na2SO4 and
concentrated in vacuo. Purification by flash chromatography over silica
gel (15% EtOAc/hexanes + 1% Et3N) gave a mixture of oxime isomers
as a clear oil (38 mg, 0.176 mmol, 88% yield, 3:1 dr). For
characterization purposes, stereoisomerically pure samples of each of
the isomers were obtained by chromatography over silica gel (1%
acetone/CH2Cl2 + 1% Et3N) followed by a second silica gel column
(10% EtOAc/Hexanes +1% Et3N). (Major isomer of 4a): IR (neat)
2991, 2937, 2824, 1615, 1500, 1473, 1279, 1048, 1031, 840, 748 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 6.8 Hz, 1H), 7.50 (d, J =
1
1178, 1066, 906, 736, 697 cm−1; H NMR (600 MHz, CDCl3) δ
7.87−7.61 (m, 1H), 7.40−7.21 (m, 8H), 5.65 (d, J = 11.3 Hz, 1H),
5.54 (d, J = 11.3 Hz, 1H), 4.49 (s, 2H), 4.17−4.04 (m, 2H), 3.39−3.28
(m, 2H), 2.93 (qapp, J = 9.6 Hz, 1H), 1.33 (d, J = 6.7 Hz, 3H), 1.20 (t, J
= 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 175.7, 153.7, 142.7,
136.7, 135.3, 128.7, 128.3, 127.9, 122.8, 122.5, 119.5, 109.5, 71.9, 70.3,
60.7, 38.3, 30.8, 17.7, 14.2; HRMS (ESI+, m/z) [M + H]+ calcd for
+
C21H25N2O3 353.1860, found 353.1847.
Ethyl 2-Methyl-2-(1-methyl-6-trifluoromethyl-1H-benzo[d]-
imidazol-2-yl)propanoate (6j). Prepared according to the general
procedure from 1j (80.0 mg, 0.400 mmol, 1.0 equiv) and ethyl
methacrylate 5 (0.190 mL, 1.6 mmol, 4.0 equiv). Purification by flash
chromatography over silica gel (10% acetone/CH2Cl2) gave desired
product 6j as a pale yellow oil (108 mg, 0.344 mmol, 86% yield). IR
(neat) 2987, 1732, 1509, 1469, 1335, 1279, 1151, 1010, 1049, 822, 732
1
cm−1; H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 1H), 7.59
7.6 Hz, 1H), 7.36−7.23 (m, 3H), 4.03 (p, J = 7.1 Hz, 1H), 3.84 (s,
3H), 3.78 (s, 3H), 1.68 (d, J = 7.0 Hz, 3H); 13C NMR (151 MHz,
CDCl3) δ 153.9, 150.6, 142.5, 136.0, 122.7, 122.2, 119.7, 109.2, 61.8,
33.7, 30.0, 17.3; HRMS (ESI+, m/z) [M + H]+ calcd for C12H16N3O+
218.1288, found 218.1310. (Minor isomer of 4a): IR (neat) 2976,
(s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.69 (s,
3H), 1.78 (s, 6H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 174.8, 158.7, 144.0, 136.3, 125.0 (q, J = 32 Hz), 124.9 (d, J
= 272 Hz), 120.2, 119.2 (q, J = 3 Hz), 107.0 (q, J = 4 Hz), 62.0, 44.6,
31.1, 25.5, 14.3; 19F NMR (470 MHz, CDCl3) δ −60.63. HRMS (ESI
1
2938, 2833, 1616, 1504, 1468, 1279, 1050, 1031, 872, 743 cm−1; H
+
+, m/z) [M + H]+ calcd for C15H18F3N2O2 315.1315, found
NMR (400 MHz, CDCl3) δ 7.76 (d, J = 6.6 Hz, 1H), 7.34−7.23 (m,
3H), 6.91 (d, J = 7.4 Hz, 1H), 4.67 (p, J = 7.1 Hz, 1H), 3.94 (s, 3H),
3.74 (s, 3H), 1.61 (d, J = 7.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
154.5, 150.5, 142.6, 135.8, 122.6, 122.2, 119.8, 109.3, 62.1, 29.7, 28.8,
315.1310.
Ethyl 2-Methyl-2-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-
propanoate (6q). Prepared according to the general procedure from
I
DOI: 10.1021/acs.joc.7b01723
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1q (53.0 mg, 0.400 mmol, 1.0 equiv) and ethyl methacrylate 5 (0.190
mL, 1.6 mmol, 4.0 equiv). Purification by flash chromatography over
silica gel (10% acetone/CH2Cl2) gave desired product 4q as a pale
yellow oil (95 mg, 0.384 mmol, 96% yield). IR (neat) 2982, 1731,
1602, 1500, 1464, 1407, 1387, 1283, 258, 1229, 1147, 1021, 774 cm−1;
1H NMR (600 MHz, CDCl3) δ 8.36 (dd, J = 4.8, 1.4 Hz, 1H), 8.03
(dd, J = 7.9, 1.4 Hz, 1H), 7.22 (dd, J = 7.9, 4.8 Hz, 1H), 4.22 (q, J =
7.1 Hz, 2H), 3.75 (s, 3H), 1.78 (s, 6H), 1.22 (t, J = 7.1 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 174.7, 157.3, 149.3, 143.8, 134.0, 127.2,
118.3, 61.9, 44.8, 29.5, 25.2, 14.3; HRMS (ESI+, m/z) [M + H]+ calcd
(10) Tran, G.; Hesp, K. D.; Mascitti, V.; Ellman, J. A. Angew. Chem.,
Int. Ed. 2017, 56, 5899.
(11) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J.
Am. Chem. Soc. 2007, 129, 3408.
(12) Titrated twice against menthol according to the Paquette
protocol: Lin, H.-S.; Paquette, L. A. Synth. Commun. 1994, 24, 2503.
(13) Wursche, R.; Debaerdemaeker, T.; Klinga, M.; Rieger, B. Eur. J.
Inorg. Chem. 2000, 2000, 2063.
(14) Diness, F.; Fairlie, D. P. Angew. Chem., Int. Ed. 2012, 51, 8012−
8016.
+
for C13H18N3O2 248.1394, found 248.1400.
(15) Pereira, K. C.; Porter, A. L.; DeBoef, B. Tetrahedron Lett. 2014,
55, 1729−1732.
(16) Yu, B.; Zhang, H.; Zhao, Y.; Chen, S.; Xu, J.; Huang, C.; Liu, Z.
Green Chem. 2013, 15, 95−99.
ASSOCIATED CONTENT
■
S
* Supporting Information
(17) Nakao, Y.; Kanyiva, K. S.; Oda, S.; Hiyama, T. J. Am. Chem. Soc.
2006, 128, 8146−8147.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b01723.
(18) Gao, G.-L.; Yang, C.; Xia, W. Chem. Commun. 2017, 53, 1041−
1044.
1H, 13C, and 19F NMR spectra for all new compounds
and 1H NMR spectra for previously reported compounds
(PDF)
(19) Yin, H.; Cheng, K. WO Patent 2015171951, p 28.
(20) Muller, J.; Polonius, F.-A.; Roitzsch, M. Inorg. Chim. Acta 2005,
̈
358, 1225−1230.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jonathan.ellman@yale.edu.
ORCID
Jonathan A. Ellman: 0000-0001-9320-5512
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this work by the NIH (R35GM122473) and Pfizer
is gratefully acknowledged.
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DOI: 10.1021/acs.joc.7b01723
J. Org. Chem. XXXX, XXX, XXX−XXX