A practical synthesis of highly functionalized fused 1,6-dihydroimidazo-[1, 2-a]imidazole-2,5-diones, key intermediates for LFA-1 inhibitors

Article abstract of DOI:10.1055/s-2004-835638

An alternative and chromatography-free approach for synthesis of a new class of LFA-1 inhibitors was developed. A key feature of this process involved a transformation of thioureas 14 to acyclic guanidine derivatives 9 followed by intramolecular cyclizati

Full text of DOI:10.1055/s-2004-835638

2800
LETTER
A Practical Synthesis of Highly Functionalized Fused 1,6-Dihydroimidazo-
[1,2-a]imidazole-2,5-diones, Key Intermediates for LFA-1 Inhibitors
K
ey Intermediate
s
i
for
L
F
a
A-
1
Inhibit
o
ors -jun Wang,* Yibo Xu, Li Zhang, Dhileepkumar Krishnamurthy, Laurence Nummy, Vittorio Farina,
Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877, USA
Fax +1(203)7916168; E-mail: xwang@rdg.boehringer-ingelheim.com
Received 23 August 2004
cis- and trans-imidazolidinones 6 and 7. Upon standing in
Abstract: An alternative and chromatography-free approach for
synthesis of a new class of LFA-1 inhibitors was developed. A key
feature of this process involved a transformation of thioureas 14 to
acyclic guanidine derivatives 9 followed by intramolecular cycliza-
a nonpolar solvent such as pentane, trans-isomer 7 was
obtained as a crystalline solid that was subsequently con-
verted to 3. The crystallinity of 7 was the driving force for
tion to highly functionalized bicyclic guanidines 1, that were sub- the stereospecific formation of a single trans-diastereo-
sequently converted to 1H-imidazo[1,2-a]imidazol-2-one LFA-1
inhibitors.
mer. Due to the nature of this process, the efficiency of
preparation of template 3 was highly substrate-dependent.
Key words: LFA-1 inhibitor, bicyclic guanidine, thiourea, imida-
zolidinone, iodoimidazole
While amino arylamides 4a,b afforded trans-7a,b in mod-
erate to excellent yield, certain analogous amino aryl-
amides such as 4c,d failed to produce a crystalline solid of
trans-7c,d. Therefore, preparation of bicyclic guanidines
Recently we reported a practical synthesis of 1H-imida- 1c,d was not feasible using the newly-disclosed process.1
zo[1,2-a]imidazol-2-ones, a new generation of small With the requirement of an efficient entry to large quanti-
molecule, nonpeptidic LFA-1 inhibitors with improved ties of iodoimidazoles bearing different N-aryl substitu-
pharmacological properties.1 These LFA-1 antagonists ents such as 2c,d, we set up to explore an alternative
have therapeutic potential for the treatment of inflamma- synthesis of 1, as these compounds are key intermediates
tory and immune disorders.2 The process involved a to 1H-imidazo[1,2-a]imidazol-2-one LFA-1 inhibitors.1
copper(I)-promoted intramolecular cyclization of thio- In our retrosynthetic analysis (Scheme 2), the previously
hydantoin to highly functionalized bicyclic guanidine de- disclosed process through path A required a template 3,
rivative 1a, that was subsequently converted to 1H- possessing the N-aryl group needed in 1 and 2, that could
imidazo[1,2-a]imidazol-2-one LFA-1 inhibitors through be prepared by Yee’s synthesis (Scheme 1).3 Since con-
iodoimidazole 2a (Figure 1). The introduction of the struction of the quaternary stereocenter in 1 required
quaternary stereogenic center in molecules like 1a relied enantiomerically pure trans templates 3, the failure of
on a highly diastereoselective alkylation of the pivalal- preparation of certain pure trans templates such as 3c,d
dehyde-derived imidazolidinone 3a.3
with different N-aryl groups prompted us to think of tak-
ing advantage of templates 3a,b for introduction of the
quaternary stereocenter. The required N-aryl moieties in
1c,d can be introduced subsequently to replace the N-aryl
groups in 3a,b. Thus, a process through path B would
make use of 3a or 3b. The bicyclic guanidines 1 can be
derived from acylic guanidines 9 by an intramolecular cy-
clization using the aniline moiety in 3 as a leaving group
(Scheme 2, path B). The exact N-aryl group needed in 1
and 2 (R substitution) can then be introduced from 10.1
With this idea, we have focused on synthesis of acyclic
guanidines 9 and subsequent cyclization to 1 still using
Yee’s templates 3a,b as the chiral precursor.
Br
Br
O
O
O
O
R
N
N
R
R
N
N
N
N
O
I
F3C
N
N
1a: R = 3,5-dichloro
1b: R = 4-chloro
1c: R = 4-F
3a: R = 3,5-dichloro
3b: R = 4-chloro
3c: R = 4-F
2a: R = 3,5-dichloro
2b: R = 4-chloro
2c: R = 4-F
1d: R = H
3d: R = H
2d: R = H
Figure 1
Starting from the commercially available D-N-Boc-ala-
nine, imidazolidinone template 3b was prepared in a mod-
erate 42% overall yield using Yee’s procedure, a less
efficient result compared to 78% yield described for 3a.3
Highly diastereoselective alkylation of 3a,b with 4-bro-
mobenzyl bromide in presence of LiN(TMS)2 at –20 °C
afforded 11a,b, in >90% isolated yield after crystalliza-
tion. After deprotecting of 11a,b using the published pro-
cedure,1,3 the crude amino amides 12a,b were then reacted
with a mixed anhydride derived from Boc-glycine and
An efficient synthesis of imidazolidinone 3a was reported
by Yee based on Seebach’s principle.3,4 As shown in
Scheme 1, amino arylamide 4 was treated with pivalalde-
hyde to give an equilibrium mixture of Schiff base 5, and
SYNLETT 2004, No. 15, pp 2800–2802
Advanced online publication: 08.11.2004
DOI: 10.1055/s-2004-835638; Art ID: S07804ST
© Georg Thieme Verlag Stuttgart · New York
0
7
.1
2
.2
0
0
4

LETTER
Key Intermediates for LFA-1 Inhibitors
2801
O
Br
t-BuCHO
7
3
H2N HN
Ar
O
4
O
X
N
N
F3C
a
b
t-BuCHO
cryst.
X
N
N
O
F3C
O
O
O
O
HN
+
N
N
HN
HN
N
+
Ar
Ar
Ar
3a: X=3,5-dichloro
3b: X=4-chloro
11a: X=3,5-dichloro
11b: X=4-chloro
Br
Br
5
6
7
Ar = a: 3,5-dichlorophenyl; b: 4-chlorophenyl;
c: 4-fluorophenyl; d: phenyl
O
O
Scheme 1
c
d
O
X
X
H2N HN
NH HN
NHBoc
Br
O
Br
O
12a: X=3,5-dichloro
12b: X=4-chloro
13a: X=3,5-dichloro
13b: X=4-chloro
X
Br
B
B
N
H
R
N
O
N
N
O
HN
A
R
N
N
O
9
1
O
X
NH HN
A
Br
O
Br
NH2.TsOH
10a: X=3,5-dichloro
10b: X=4-chloro
R
X
O
Scheme 3 (a) 4-BrC6H4CH2Br, LiHMDS, dioxane, –20 °C (90–
93%); (b) 1. 40% BnMe3NOH, 50% NaOH, THF, 45 °C, 2. 6 N HCl,
50 °C (>95%); (c) BocNHCH2CO2H, t-BuCOCl, THF, 0–10 °C (83–
85%); (d) TsOH·H2O, MeOH, 50 °C (>85%).
O
N
H
O
N
H
N
NH
S
N
NH2
H
8
10
Scheme 2
Br
Br
pivaloyl chloride in THF to give 13a,b in 83–85% isolated
yield after crystallization. Deprotection of 13a,b was per-
formed with p-TsOH·H2O in methanol, and the resulting
amino amides 10a,b were isolated in 85% yield from ace-
tonitrile as their p-toluenesulfonic acid salts (Scheme 3).
O
O
X
a
b
O
N
H
O
NH
S
X
NH HN
NH2
N
H
R
N
H
Since synthesis of guanidines from thioureas has been
well documented,5 attention was turned to the examina-
tion of the synthesis of acyclic guanidine derivatives 9 via
thioureas derived from amino amides 10 (Scheme 4). Al-
though a variety of aryl thioisocyanates are commercially
available, we preferred the coupling of 10 with aryl in situ
prepared isothiocyanates.6 Thus, addition of 1 equivalent
of arylamines to a solution of thiocarbonyl diimidazole in
THF followed by addition of 10 produced thioureas 14 in
>81% isolated yield by crystallization from a mixture of
heptane and ethyl acetate (Table 1). Upon treatment of the
resulting thioureas 14 with 1.2 equivalents of EDC in me-
thylene chloride or THF in presence of i-Pr2NEt–DMAP,
guanidines 9 were obtained in essentially quantitative
yield, presumably via a transient carbodiimide that
cyclized spontaneously.7 We found that conversion of
10
14
Br
O
Br
X
c
d
O
2
N
H
R
N
N
N
O
O
HN
N
N
R
9
1
Scheme 4 (a) ArNH2, CSIm2, THF, 22 °C (81–93%); (b) EDC,
CH2Cl2, 22 °C; (c) PPTS, CH2Cl2, 22 °C (85–96%); (d) ref.1
Synlett 2004, No. 15, 2800–2802 © Thieme Stuttgart · New York

2802
X.-j. Wang et al.
LETTER
Table 1 Preparation of 14 and 1
References
(1) (a) Wang, X.-J.; Zhang, L.; Xu, Y.; Krishnamurthy, D.;
Varsolona, R.; Nummy, L.; Frutos, R. P.; Byrne, D.; Chung,
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Entry
X
R
Yield of 14 Yield of 1
(%)a
89
92
84
94
92
95
87
92
(%)b
93
96
87
93
85
87
88
88
92
1
2
3
4
5
6
7
8
9
3,5-Dichloro
3,5-Dichloro
3,5-Dichloro
3,5-Dichloro
3,5-Dichloro
4-Chloro
4-Chloro
3-Chloro
4-Fluoro
4-Cyano
H
4-Fluoro
3-Bromo
H
4-Chloro
(3) (a) Yee, N. K. Org. Lett. 2000, 2, 2781. (b) Frutos, R. P.;
Stehle, S.; Nummy, L.; Yee, N. K. Tetrahedron: Asymmetry
2001, 12, 101.
4-Chloro
4-Chloro
3,5-Dichloro 95
(4) (a) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2708. (b) Haef, R.; Aehi, J. D.;
Weber, T. Helv. Chim. Acta 1985, 68, 144.
a Isolated yield.
b Weight% assay by HPLC.
(5) For examples, see: (a) Linton, B. R.; Carr, A. J.; Orner, B.
P.; Hamilton, A. D. J. Org. Chem. 2000, 65, 1566.
(b) Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org.
Chem. 1997, 62, 1540. (c) Roue, N.; Bergman, J.
Tetrahedron 1999, 55, 14729. (d) Schneider, S. E.; Bishop,
P. A.; Salazar, M. A.; Bishop, O. A.; Anslyn, E. V.
Tetrahedron 1998, 54, 15063.
(6) Perkins, J. J.; Zartman, A. E.; Meissner, R. S. Tetrahedron
Lett. 1999, 40, 1103.
(7) Seth, P. P.; Robison, D. E.; Jefferson, E. A.; Swayze, E. E.
Tetrahedron Lett. 2002, 43, 7303.
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thioureas 14 to 9 followed by cyclization to 1 can be per-
formed in a one-pot operation. Once complete transforma-
tion of 14 to 9 was achieved, 0.1 equivalents of PPTS was
added to the reaction mixture and PPTS-promoted cy-
clization of 9 took place smoothly to afford 1 in >85%
yield over two steps.8 It was unnecessary to isolate bicy-
clic guanidines 1 since the crude products had a purity of
>95%. Bicyclic guanidines 1 were successfully converted
to iodoimidazoles 2 using the published procedure with-
out any difficulty for further elaboration to LFA-1 inhibi-
tors.1 3,5-Dichloro and 4-chloroaniline as by-products in
this step were recovered.
In conclusion, a practical synthesis of highly functional-
ized fused 1,6-dihydroimidazo[1,2-a]imidazole-2,5-di-
ones, key intermediates for the synthesis of LFA-1
inhibitors, has been developed. Contrary to the ones pre-
vious described, this route represents the first practical
approach to a series of bicyclic guanidine derivatives 1
that are flexible enough to accommodate many different
aryl substituents at the lactam moiety.
Synlett 2004, No. 15, 2800–2802 © Thieme Stuttgart · New York