Synthesis of 2-(α-substituted-amidoalkyl)-imidazoles

Article abstract of DOI:10.1016/j.tetlet.2005.05.026

The addition reaction of imidazolium ylides to electron-deficient imines affords orthogonally protected 2-(α-substituted-amidoalkyl)-imidazoles. This reaction serves as a method to incorporate the imidazole nucleus into amine-containing substrates under m

Full text of DOI:10.1016/j.tetlet.2005.05.026

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4789–4792
Synthesis of 2-(a-substituted-amidoalkyl)-imidazoles
Craig A. Zificsak and Dennis J. Hlasta*
Combinatorial Chemistry Team, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 8 Clarke Drive,
Cranbury, NJ 08512, USA
Received 20 April 2005; accepted 10 May 2005
Available online 31 May 2005
Abstract—The addition reaction of imidazolium ylides to electron-deficient imines affords orthogonally protected 2-(a-substituted-
amidoalkyl)-imidazoles. This reaction serves as a method to incorporate the imidazole nucleus into amine-containing substrates
under mild reaction conditions. Microwave-accelerated synthesis provides rapid and general access to a breadth of derivatives.
Ó 2005 Elsevier Ltd. All rights reserved.
Imidazoles are common heterocyclic components in bio-
logically important small molecules, from histidine con-
taining peptides to pharmaceuticals and investigational
drugs.1 As such, new methods for the preparation of
functionalized imidazoles is of general interest.2 Previ-
ous work from this laboratory introduced the use of
1,3-azolium ylides as nucleophiles in addition reactions
to aldehydes.3,4 This method for the preparation of 2-
substituted 1,3-azoles (e.g., imidazoles, thiazoles) is a
mild and general alternative to the classical metalation
chemistry that is often employed for the synthesis of this
type of substrate. A natural extension of this chemistry
was to investigate additional electrophiles in this addi-
tion reaction.
can be applied to diversity-enrichment libraries for use
in high-throughput screening of novel drug targets.
When N-benzylimidazole is treated with a carbamoyl
chloride or di-tert-butyldicarbonate (Boc2O), a 1,3-imid-
azolium intermediate 1 is generated.3,4 This intermediate
activates the C2 hydrogen for deprotonation by a ter-
tiary amine base such as triethylamine or DIEA, or in
the case of Boc2O, by the tert-butylate anion, which is
generated as a result of the initial N-acylation of the
imidazole. This ylide intermediate 2 was found to readily
add to N-sulfonyl imines with mild heating, furnishing
the N-Boc-N-sulfonyl adduct 4 in 87% yield (Fig. 1).
Further exploration of the reaction lead to the utiliza-
tion of microwave heating as a convenient method for
conducting the addition reaction. Under optimized con-
ditions, combining the three reaction components in dry
DCE and heating under microwave conditions at 100 °C
for 5–15 min allowed for complete consumption of the
limiting imine component. The addition of TFA to the
reaction mixture then allows for the isolation of the de-
sired monoprotected amine (Table 1). Attempts to cata-
lyze the reaction of benzylimidazole using various Lewis
acids did not affect an increase in reactivity.7
Electron-deficient imines have widespread use as syn-
thons for the incorporation of nitrogen functionality in
addition reactions.5 Electron-deficient imines are readily
prepared from aromatic aldehydes and are usually stable
to purification and long-term storage, making them
excellent building blocks for the preparation of chemical
libraries.6 The nitrogen of the addition products also
presents an additional site for functionalization, a key
attribute for the preparation of diversity-enrichment li-
braries. In this letter, we describe a method for the prep-
aration of 2-(a-substituted-amidoalkyl)-imidazoles such
as 4. The use of orthogonal protecting groups permits
differential N-substitution leading to a method that
As shown in Table 1, isolated yields range from modest
to excellent, and are dependent on the nucleophilicity of
the imidazolium intermediate. For benzylimidazole and
other simple alkyl imidazoles, the yield is generally high
(entries 1–4). The incorporation of a single withdrawing
group onto the imidazole ring is tolerated, but accompa-
nied by a decrease in yield (entries 5 and 6). Variation of
the aryl portion of the imine is tolerated (entries 7–9) as
Keyword: Imidazolium ylide.
*
Corresponding author: Tel.: +1 (609) 655 6908; fax: +1 (609) 655
6913; e-mail: dhlasta@prdus.jnj.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.026

4790
C. A. Zificsak, D. J. Hlasta / Tetrahedron Letters 46 (2005) 4789–4792
t-Boc2O
PhCH=NTs
COO-t-Bu
COO-t-Bu
N
N
N
t-BuO-
N
Bn
N
Bn
N
Bn
DCE
60 oC, 2 h
- CO2
1
2
COO-t-Bu
Ts
N
N
N
PhCH=NTs
NTs
COO-t-Bu
N
Bn
N
Bn
Ph
Ph
4
3
Figure 1. Proposed mechanism for the addition of N-benzylimidazole to an N-tosyl-imine.
Table 1. Addition of imidazolium ylides to imines and subsequent deprotectiona
R3
R2
R3
R2
1) R5CH=NR4
Boc2O, DCE
N
N
H
N
R4
N
N
2) TFA
R5
R1
R1
5
Entry
R1
R2
R3
R4
R5
Yieldb
1
Bn
H
H
H
H
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ph
Ph
85
75
2
Me
Allyl
Me
Me
Me
Bn
H
3
H
Ph
Ph
93
95
4
CH@CH
Cl
CO2Me
CH@CH
5
H
H
H
H
H
H
H
H
H
Ph
Ph
53
45
6
7
H
H
H
H
H
H
H
4-MeOPh
3-Pyr
75
69
8
Bn
Bn
9
CH@CHPh
80
10
11
12
13
Bn
Bn
PO(OPh)2
Boc
Cbz
Mtre
Ph
Ph
Ph
Ph
95c
84c,d
47
Bn
Bn
89c
a Conditions: (i) 1.0 equiv imine, 1.1 equiv imidazole derivative, 1.6 equiv Boc2O, 0.5 M in DCE, 5–15 min, 100 °C (CEM Explorer microwave); (ii)
then add 25% v/v TFA, 60 °C, 15 min (oil bath).
b Isolated yield, characterized by HRMS, 1H NMR, and 13C NMR.
c These reactions were run at 65 °C in an oil bath for 2 h.
d Isolated as the bis-Boc adduct without TFA treatment.
e Mtr = 4-methoxy-2,3,6-trimethylphenylsulfonyl.
is the use of alternative activating groups (entries 10–
13).6 For entry 11, the TFA deprotection step was not
conducted, leading to the bis-Boc adduct. The modest
yield of the Cbz-derivative is attributable to the sensitiv-
ity of the imine starting material, which suffered from
hydrolysis in handling and resulted in the O-Boc adduct
of benzaldehyde as a major side product. The use of less
electron-rich imidazoles (i.e., 4,5-dichloro- or 4,5-di-
cyano-1-methylimidazole, or caffeine) does not lead to
addition products. Two azoles that were productive in
the addition to aldehydes, thiazole, and 1-methyl-1,2,4-
triazole, afforded less than 5% conversion to the
addition product as measured by LCMS.4 No addition
products were observed for oxazole or 5-phenyloxazole,
consistent with the aldehyde series. Electron-rich imines
(e.g., N-benzylidene diphenylmethylamine or N-benzyl-
idene-o-anisidine) did not afford any addition products.
The incorporation of an additional point of diversity
was accomplished by N-alkylation of 68 (Table 1, entry
1). Benzyl halides in the presence of either cesium or
potassium carbonate gave good yields of N-benzyl ad-
ducts. Additionally, the Mitsunobu reaction was equally
effective in the generation of disubstituted sulfonamides
(Scheme 1).
We next investigated the use of the Mtr-protecting
group as a readily cleaved sulfonamide protecting group
that would permit the installation of a third point of
diversity. Originally developed as a protecting group
for the guanidine side chain of arginine and lysine, the
Mtr group has seen limited use as an amine protecting
group.9,10 The addition of benzylimidazole to the Mtr-
benzaldehyde imine was straightforward to afford the
Mtr amide 911 (Table 1, entry 13) after TFA removal

C. A. Zificsak, D. J. Hlasta / Tetrahedron Letters 46 (2005) 4789–4792
4791
OCH3
Ts
N
Base, DMF
rt, 24 h
N
N
Bn
MeO
Cl
7
Cs2CO3: 52%
K2CO3: 67%
N
N
H
N
Ts
N
Base, DMF
60 °C, 24 h
N
Ts
N
Bn
N
Bn
N
Cl
8
6
Cs2CO3: 67%
K2CO3: 71 %
or
PPh3, DBAD
THF, rt, 4 h
8
N
75%
OH
Scheme 1. Functionalization of sulfonamide adducts.
TFA:PhSMe:Me2S
N
N
0.2M MeSO3H
NH2
Ph
N
N
N
N
Bn
10 52%
1) PhCH=NTs
Boc2O, DCE
NHTs
Ph
N
N
N
OCH3
N
2) TFA
1) PMBCl, K2CO3
DMF, 61%
R'
13
H
N
N
R
H
N
N
Mtr
R = R' = H
59%
N
Bn
2) TFA:PhSMe:Me2S
0.2M MeSO3H
R = H, R' = CH3- 58% (2:1 d.r.)
N
Bn
Ph
R-R' = -CH2CH2 70% (2:1 d.r. )
Ph
9
11 65%
Scheme 3. 2-Alkylimidazoles as azolium ylide precursors.
1) CyCOCl, DIEA
DCM, 66%
H
N
N
ation of diastereomeric mixtures for the latter two exam-
ples was independent of the reaction temperature (rt,
60 °C, or 100 °C/microwave) and the relative configura-
tion was not determined.
N
Bn
2) TFA:Me2S (9:1)
0.2M MeSO3H
O
Ph
12 78%
Scheme 2. Functionalization of sulfonamide adducts. Mtr = 4-meth-
oxy-2,3,6-trimethylphenylsulfonyl.
Acknowledgements
We thank the Johnson & Johnson Corporate Office of
Science and Technology for postdoctoral fellowship
funding for C.A.Z. through the Excellence in Science
Award Program. We also thank Julie Innocent for assis-
tance with sample purification.
of the N-Boc, as was functionalization of the sulfon-
amide (Scheme 2). The use of Fujinoꢀs deprotection pro-
tocol (TFA:PhSMe:Me2S 0.2 M MeSO3H)9 cleanly
provided the deprotected amines, even in the presence
of the acid-labile PMB protecting group.
Lastly, the use of 1,2-dimethylimidazole in addition to
benzaldehyde was previously accomplished via the azo-
lium ylide reaction,4 and extension of this reaction to sul-
fonylimines was also successful. As shown in Scheme 3,
1,2-dimethylimidazole, 2-ethyl-1-methylimidazole, and
the tetrahydroimidazo[1,2-a]pyridine12 afforded the
homologated 2-alkylimidazole adducts when treated
with benzaldehyde sulfonylimine and Boc2O. The gener-
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(m, 2H), 6.71 (d, 1H, J = 1.3 Hz), 6.49 (d, 1H,
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1H, J = 1.2 Hz), 6.81 (br d, 1H, J = 7.5 Hz), 6.72 (d, 1H,
J = 1.2 Hz), 6.69 (br s, 1H), 5.49 (br s, 1H), 4.82 (d, 1H,
J = 15.5 Hz), 4.70 (d, 1H, J = 15.5 Hz), 2.33 (s, 3H); 13C
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126.9, 120.8, 54.0, 49.4, 21.4; HRMS (TOF) m/z 418.1587
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