Direct, Regioselective N-Alkylation of 1,3-Azoles

Article abstract of DOI:10.1021/acs.orglett.5b02994

Regioselective N-alkylation of 1,3-azoles is a valuable transformation. Organomagnesium reagents were discovered to be competent bases to affect regioselective alkylation of various 1,3-azoles. Counterintuitively, substitution selectively occurred at the more sterically hindered nitrogen atom. Numerous examples are provided, on varying 1,3-azole scaffolds, with yields ranging from 25 to 95%.

Full text of DOI:10.1021/acs.orglett.5b02994

Letter
pubs.acs.org/OrgLett
Direct, Regioselective N‑Alkylation of 1,3-Azoles
Shuai Chen,* Russell F. Graceffa,* and Alessandro A. Boezio
Medicinal Chemsitry Department, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States
S
* Supporting Information
ABSTRACT: Regioselective N-alkylation of 1,3-azoles is a
valuable transformation. Organomagnesium reagents were
discovered to be competent bases to affect regioselective
alkylation of various 1,3-azoles. Counterintuitively, substitution
selectively occurred at the more sterically hindered nitrogen
atom. Numerous examples are provided, on varying 1,3-azole scaffolds, with yields ranging from 25 to 95%.
he concept of protecting-group-free (PGF) synthesis has
gained prominence in the synthetic organic chemistry
large quantities of material.5g In order to facilitate the rapid
synthesis of 2a, conditions to reverse the inherent selectivity for
alkylation of the N9 over the N7 position were investigated. It was
discovered that deprotonation of 6-chloropurine with i-PrMgCl·
LiCl followed by alkylation with methyl iodide furnished the
desired regioisomer with 9:1 selectivity (2a/2a′) in 70% yield.
Using this unoptimized method, 30 g of 2a was prepared in a
single reaction (Scheme 1).8
T
community over the past decade.1 A successful PGF synthesis of
a target molecule is advantageous for a number of reasons; it
eliminates time-consuming and tedious manipulation of
protecting groups and increases efficiency with respect to atom
economy, loss of material, waste production, and synthetic
design.2
Numerous biologically interesting natural products and
medicinally important small molecules contain 1,3-azoles (e.g.,
imidazole, benzimidazole, imidazopyridine, and purine) (Figure
1). One challenge for the synthesis of 1,3-azole-containing
Scheme 1. Chemoselective Methylation of 6-Chloropurine
A thorough literature search revealed that the selective
alkylation of the more hindered position of 1,3-azoles was
uncommon. The only examples of direct N7 alkylation of purine
utilized a cobalt complex as a transient protecting group.9
However, difficult access to the cobalt complexes, long reaction
times, and a narrow substrate scope limit the potential
applications for this method. Due to the lack of literature
precedent for direct regioselective alkylation of the more
hindered position of 1,3-azoles, we decided to investigate this
transformation more rigorously.
Starting from our original conditions (Scheme 1), optimiza-
tion was directed toward maximizing selectivity and conversion.
A range of various bases including organomagnesium, organo-
zinc, and lithium reagents were examined in the methylation of 6-
chloropurine in THF at room temperature.10 i-PrMgCl·LiCl and
s-BuMgCl·LiCl gave similar N7/N9 selectivity (25:1 and 26:1,
respectively) with a slightly higher conversion in the former case
(Table 1, entries 1 and 2). Use of the non-nucleophilic Knochel−
Hauser base TMPMgCl·LiCl (2,2,6,6-tetramethylpiperidinyl-
magnesium lithium chloride complex) resulted in lower
selectivity with fair conversion (entry 3). Interestingly, use of i-
Figure 1. Selected examples of natural and biologically active
compounds that contain 1,3-azoles.
molecules is the ambident nature of the azole toward N-
alkylation chemistry.3 A particularly challenging situation arises
when the more sterically hindered nitrogen of the unsymmetrical
azole is the target for alkylation. Under conventional conditions,
alkylation favors the less sterically encumbered site.4 In many
instances, the desired reverse selectivity could be achieved
through protection of the less hindered position followed by
alkylation of the desired position and then deprotection.5,6
A
PGF alternative to this less efficient process would therefore be
desirable.
Recently, a large quantity of N7-methyl-6-chloropurine (2a)
was required as an intermediate toward the scale-up of a
medicinal chemistry lead for in vivo studies.7 Unfortunately, the
only method known for the production of 2a utilized a strategy
that relied upon a reduction/oxidation as well as a protection/
deprotection process, which was nonideal for the preparation of
Received: October 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
unactivated electrophiles was sluggish even at elevated temper-
atures and with excess alkylating reagent. For example, n-butyl
iodide required refluxing temperatures for 3 days to deliver a 25%
yield of alkylated material (entry 4). The product selectivity was
diminished with more reactive electrophiles. Decreased N7
selectivity was observed for phenacyl bromide at room
temperature; however, the product ratio could be improved
(N7/N9 = 5:1) through slow addition of phenacyl bromide to the
reaction mixture at low temperature (entry 9). The present
conditions were also found to be amenable to the regioselective
alkylation of 2,6-dichloropurine, a common building block used
in medicinal chemistry (entries 10−15).3b A small amount of N9-
substituted products were observed in these cases (<10%
Table 1. Base Screen for the Methylation of 6-Chloropurine
a
b
entry
base
conv (%)
2a:2a′
1
2
3
4
5
6
7
8
i-PrMgCl·LiCl
s-BuMgCl·LiCl
TMPMgCl·LiCl
i-PrMgCl
64
50
50
65
73
<5
<5
65
25:1
26:1
15:1
>99:1
>99:1
21:1
MeMgCl
MeMgBr
1
MeMgI
20:1
detected by H NMR analysis of reaction mixtures) albeit in
good to excellent isolated yields for the N7-regioisomer (72−
90%).
TMPMgCl
72:1
a
b
Conversion determined by LC−MS. Product ratio determined by
1H NMR spectroscopy.
To understand whether the selectivity in this transformation
was a result of electronic or steric effects, purine derivatives with
various substituents at the C6 position were investigated (Table
3). TMPMgCl was utilized for the alkylation of 6-bromopurine
PrMgCl without LiCl complexation improved the N7/N9
selectivity to >99:1, with good conversion at ambient temper-
ature (entry 4). Encouraged by this result, MeMgCl was tested
and provided similar selectivity and improved yield in this
transformation (entry 5). Interestingly, when the counterion of
the Grignard reagent was changed from chloride to bromide or
iodide, the conversion and the selectivity dramatically decreased
(entries 6 and 7). Additionally, TMPMgCl could be employed in
this method, with good selectivity (entry 8).11,12 The non-
nucleophilic nature of this base, relative to MeMgCl, allows for
application of this strategy in the presence of sensitive functional
groups.13,14
After MeMgCl was identified as the optimal base, alkylation of
6-chloropurine with a variety of alkylating reagents was studied
(Table 2, entries 1−9). As anticipated, the N7-substituted
regioisomer was obtained irrespective of the aliphatic alkylating
reagent employed in this transformation. Alkylation using
Table 3. Methylation of Purine Derivatives
a
entry
4
R
MeI (equiv) temp (°C) time (h) yield (%)
b
d
1
2
3
4
5
6
a
b
c
d
e
f
NMe2
10.0
10.0
3.0
25
25
70
70
25
70
16
22
16
30
20
24
25
57
80
77
80
78
b
d
OMe
b
SMe
b
Me
3.0
c
Br
3.0
c
CN
1.5
a
b
Isolated yield of desired regioisomer.15 MeMgCl as the base.
c
d
TMPMgCl as the base. Overmethylation of desired prouduct caused
reduced yield in these reactions.
Table 2. Alkylation of 6-Chloropurine and 2,6-
Dichloropurine
and 6-cyanopurine at room temperature. The use of MeMgCl as
a base for these substates resulted in the formation of
dehalogenated and methyl addition byproducts (entries 5 and
6). While selectivity was not affected by the electronic nature of
the substituent on the purine, the yields were influenced by the
electronic nature of the substituent at the C6 position (entries 1
and 2). These observations suggest that steric effects govern the
selectivity in this transformation with respect to this substitution
pattern.
Gratifyingly, this method could also be effectively applied to
various other bicyclic 1,3-azoles (Scheme 2). The methylation of
4-chloro-2-methyl-1H-benzo[d]imidazole gave the more steri-
cally hindered regioisomeric product 6d in 88% yield. 7-
Substituted 1H-imidazo[4,5-b]pyridines provided the desired
N1-methylated products in good yields (6c and 6g). Similarly, 4-
substituted-3H-imidazo[4,5-c]pyridine afforded the desired N3-
methylation under standard conditions (6e and 6f). However, a
benzimidazole substrate with a chloride (EWG) or methoxide
(EDG) at C6 rather than at the C7 position provided a 1:1 ratio of
regioisomeric products (6a−b). In order to reduce the steric
component, we moved the substituent to a remote position (C6).
If the regiochemistry was influenced by electronics, we would
expect to observe some selectivity; however, the electronic
character of the substituent had no effect on the regiochemistry
of the products. This observation provides further evidence that
a
alkylating reagent
(equiv)
time
(h)
yield
(%)
entry
2
R1
temp (°C)
1
2
3
4
5
6
a
H
H
H
H
H
H
MeI (3.0)
EtI (3.0)
50
70
70
70
50
70
5
16
16
72
20
16
95
81
85
25
88
90
b
c
d
e
f
n-PrI (20.0)
n-BuI (20.0)
BnBr (3.0)
CH2CHCH2Br
(20.0)
7
8
g
h
i
H
H
H
CHCCH2Br (3.0)
CF3CH2SO3CF3 (2.0)
C6H5COCH2Br (1.1)
70
16
16
8
72
82
69
90
72
77
74
70
b
9
−78 to rt
10
11
12
13
j
Cl MeI (3.0)
Cl EtI (3.0)
Cl BnBr (3.0)
50
70
70
70
16
16
16
16
k
l
m
Cl CH2CHCH2Br
(3.0)
14
15
n
o
Cl CHCCH2Br (3.0)
70
70
16
16
81
74
Cl CF3CH2SO3CF3 (2.0)
a
b
Isolated yield of the desired regioisomer.15 See text for details.
B
DOI: 10.1021/acs.orglett.5b02994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
formation may also be useful for the simplified preparation of 1,3-
azole-containing biologically active compounds.
Scheme 2. Methylation of 1,3-Azoles
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02994.
Synthetic methods, analytical methods, condition opim-
ization, and full characterization of materials (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: schen@fc-cdci.com.
*E-mail: russellg@amgen.com.
a
Isolated yield of desired regioisomer.15
Notes
the alkylation is dictated by steric effects rather than by
electronics. In addition, the presence and position of a nitrogen
atom in the 6-membered ring does not affect the regioselectivity
of 1,3-azole methylation. However, a C7 substituent adjacent to
the site of alkylation is required to differentiate the steric
environment of the two reactive nitrogen atoms in the 1,3-azole
ring.
Encouraged by the excellent selectivity of various bicyclic 1,3-
azoles, we set out to extend this methodology to the alkylation of
unsymmetrical imidazoles. To our delight, the expected N1
substituted imidazole was the major product under standard
reaction conditions (Table 4). Bromide and cyano groups were
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Paul Krolikowski (Amgen) for 2D NMR (HSQC,
HMBC, ROSEY) structure confirmations.
■
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alkylating
reagent
(equiv)
b
temp time yield
entry
8
R1
base
(°C)
(h)
(%)
1
2
3
4
5
6
a
b
c
d
e
f
Ph
MeI (1.1)
MeMgCl
MeMgCl
MeMgCl
MeMgCl
TMPMgCl
TMPMgCl
MeMgCl
25
25
48
48
20
20
20
20
2
76
87
64
69
69
74
42
t-Bu MeI (1.1)
Me
Cl
MeI (1.5)
MeI (1.5)
MeI (1.5)
70
70
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70
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70
a
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CHCH2Br
(1.5)
120
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̈
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(1.1)
a
b
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́ ̌ ́
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azoles has been demonstrated. High yields and regioselectivity
were achieved using commercially available alkylmagnesium
reagents or easily prepared TMPMgCl. It was observed that
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substituents on the purine; however, the yields were influenced
by the electronic character of the substituents. This trans-
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DOI: 10.1021/acs.orglett.5b02994
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National Meeting & Exposition, Dallas, TX, Mar 16−20, 2014; American
Chemical Society, Washington, DC, 2014; p MEDI-177. (b)
Unpublished results.
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use of 1H, 13C, HSQC, and HMBC spectra. There exists clear evidence
in the long-range 1H−13C HMBC data as to what side of the molecule
the methyl group has added. The carbon chemical shifts of the two
bridge carbons are quite distinct from each other. We were able to use
the long-range 1H−13C HMBC data to correlate the methyl protons to
each of the bridge carbons and determine connectivities. Therefore, the
regiochemistry of methylation could be determined (see the Supporting
Information, for example).
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reagent or elevated temperature led to the formation of undesired
overalkylated imidazolium salts.
D
DOI: 10.1021/acs.orglett.5b02994
Org. Lett. XXXX, XXX, XXX−XXX