Novel and expeditious microwave-assisted three-component reactions for the synthesis of spiroimidazolin-4-ones

Article abstract of DOI:10.1021/jo060228q

Highly efficient methods for the syntheses of spiroimidazolinones via microwave-assisted three-component one-pot sequential reactions or one-pot domino reactions are described. The efficiency and utility of the methods have been demonstrated by quickly accessing the antihypertensive drug irbesartan (2).

Full text of DOI:10.1021/jo060228q

Novel and Expeditious Microwave-Assisted Three-Component
Reactions for the Synthesis of Spiroimidazolin-4-ones†
Ping Ye, Katie Sargent, Ethan Stewart, Ji-Feng Liu,* Daniel Yohannes, and Libing Yu
ArQule, Incorporated, DiVision of Chemical Technologies, 19 Presidential Way,
Woburn, Massachusetts 01801
jifeng.liu@yahoo.com; jliu@arqule.com
ReceiVed February 3, 2006
Highly efficient methods for the syntheses of spiroimidazolinones via microwave-assisted three-component
one-pot sequential reactions or one-pot domino reactions are described. The efficiency and utility of the
methods have been demonstrated by quickly accessing the antihypertensive drug irbesartan (2).
Introduction
of quinazolinone compounds including both natural products3j-l
and natural product-templated libraries.10 As an extension of
this highly efficient methodology and in conjunction with our
interests in the synthesis of other drug-like heterocycles, we
started the investigation of a spiroimidazolinone heterocyclic
system. We envisioned that the development of efficient and
concise methods for the synthesis of this heterocyclic system,
Microwave-assisted organic synthesis has impacted synthetic
chemistry significantly since the introduction of precision-
controlled microwave reactors.1 Numerous reactions including
heterocycle-forming, metal catalyzed cross-coupling, condensa-
tion, and cycloaddition reactions have been explored under
microwave conditions.2 In addition, microwave-heating technol-
ogy has been applied in the total syntheses of natural products.3
Imidazolin-4-ones (1) constitute an important class of phar-
macologically active compounds (Figure 1). The spiroimid-
azolinone irbesartan (2), in particular, has been a marketed drug
for the treatment of hypertension.4 Moreover, the compounds
containing core 1 also show the potential for the treatment of
cancer5 and obesity-related disorders.6 Arsenal herbicide also
embodies this core scaffold.7 For these reasons, much attention
has been paid to the synthesis and biological evaluation of this
class of compounds.8
(3) For recent applications of microwave technology in syntheses of
natural products, see: (a) Baxendale, I. R.; Ley, S. V.; Piutti, C. Angew.
Chem., Int. Ed. 2002, 41, 2194. (b) Kang, Y.; Mei, Y.; Du, Y.; Jin, Z. Org.
Lett. 2003, 5, 4481. (c) Grainger, R. S.; Patel, A. Chem. Commun. 2003,
1072. (d) Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem.
Soc. 2004, 126, 706. (e) Baran, P. S.; O’Malley, D. P.; Zografos, A. L.
Angew. Chem., Int. Ed. 2004, 43, 2674. (f) Hughes, R. A.; Thompson, S.
P.; Alcaraz, L.; Moody, C. J. Chem. Commun. 2004, 946. (g) Wolkenberg,
S. E.; Wisnoski, D. D.; Leister, W. H.; Wang, Y.; Zhao, Z.; Lindsley, C.
W. Org. Lett. 2004, 6, 1453. (h) Le´pine, R.; Zhu, J. Org. Lett. 2005, 7,
2981. (i) Geske, G. D.; Wezeman, R. J.; Siegel, A. P.; Blackwell, H. E. J.
Am. Chem. Soc. 2005, 127, 12762. (j) Liu, J.-F.; Ye, P.; Zhang, B.-L.; Bi,
G.; Sargent, K.; Yu, L.; Yohannes, D.; Baldino, C. M. J. Org. Chem. 2005,
70, 6339. (k) Liu, J.-F.; Ye, P.; Sprague, K.; Sargent, K.; Yohannes, D.;
Baldino, C. M.; Wilson, C. J.; Ng, S.-C. Org. Lett. 2005, 7, 3363. (l) Liu,
J.-F.; Kaselj, M.; Isome, Y.; Chapnick, J.; Zhang, B.; Bi, G.; Yohannes,
D.; Yu, L.; Baldino, C. M. J. Org. Chem. 2005, 70, 10488.
(4) (a) Bernhart, C. A.; Breliere, J.-C.; Clement, J.; Nisato, D.; Perreaut,
P. M. EP 454511, 1991; FR 2659967, 1990; US 5270317, 1993; WO
9114679, 1991. (b) Bernhart, C. A.; Perreaut, P. M.; Ferrari, B. P.; Muneaux,
Y. A.; Assens, J.-L. A.; Clement, J.; Haudricourt, F.; Muneaux, C. F.;
Taillades, J. E.; Vignal, M.-A.; Gougat, J.; Guiraudou, P. R.; Lacour, C.
A.; Roccon, A.; Cazaubon, C. F.; Breliere, J.-C.; Le Fur, G.; Nisato, D. J.
Med. Chem. 1993, 36, 3371.
As part of our ongoing efforts to develop efficient method-
ologies and processes for the high-throughput synthesis of
pharmacologically interesting libraries for drug discovery, we
recently developed highly efficient protocols using microwave
technology.9 This new methodology was used for the synthesis
† This paper is dedicated to Professor Akira Mori for his retirement from
Kyushu University, Japan, in March 2006.
(1) For a recent review of microwave-assisted organic synthesis, see:
(a) Kappe, C. O.; Dallinger, D. Nat. ReV. Drug DiscoVery 2006, 5, 55. (b)
Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250. (c) Lidstro¨m, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225. (d)
Perreux, L.; Loupy, A. Tetrahedron, 2001, 57, 9199 and references therein.
(2) (a) Shipe, W. D.; Wolkenberg, S. E.; Lindsley, C. W. Drug DiscoVery
Today 2005, 2, 155. (b) Leadbeater, N. E. Chem. Commun. 2005, 2881
and references therein.
(5) (a) Qian, X.; Bergnes, G.; Morgans, D. WO 2004103282, 2004. (b)
Lyssikatos, J. P. WO 9749700, 1997. (c) Yang, B. V.; Lyssikatos, J. P. US
6194438, 2001.
(6) Chen, Y.; O′Connor, S. J.; Guan, D.; Newcom, J.; Chen, J.; Yi, L.;
Zhang, H.; Hunyadi, L. M.; Natero, R. WO 2004058727, 2004.
(7) Los, M. EP 41623, 1981; GB 2174395, 1986.
10.1021/jo060228q CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/18/2006
J. Org. Chem. 2006, 71, 3137-3140
3137

Ye et al.
FIGURE 1. The structures of the imidazolin-4-one (1) and irbesartan
(2).
which overcomes the drawbacks of the existing methods in terms
of simplicity and versatility, would provide a practical way for
both target-oriented and diversity-oriented syntheses of this class
of compounds.11 Herein, we report our methodologies for the
synthesis of spiroimidazolinones and demonstrate their utilities
by the highly efficient synthesis of irbesartan (2) in two steps
from the readily available starting materials.
FIGURE 2. Retrosynthetic strategy of 3 (three-component one-pot
sequential process, method A).
TABLE 1. Optimization of Microwave-Assisted Three-Component
One-Pot (Method A) Imidazolinone Formationa
A number of methods have been reported for the synthesis
of spiroimidazolinones. One way was the dehydration-cycliza-
tion of a diamide to generate (3H)-imidazolinones, followed
by the installation of R2 via a nucleophilic substitution.4 An
alternative way was to construct the spiroimidazolinone scaffold
by a condensation of an amino acid ester with a pre-made
imidate ester or an imidoyl chloride.8c However, the existing
methods are not practical for the high-throughput synthesis
because of low yield, instability of the intermediates, and the
use of hazardous reagents.
Results and Discussion
temp
(°C)
reaction time
(min)
6ab
(%)
9ab
(%)
3ab
(%)
Our retrosynthetic design of 3 envisions the reactions taking
place as a three-component one-pot sequential process from
commercially available starting materials as illustrated in Figure
2. Spiroimidazolinone 3 could be formed via a cyclization
reaction of 4, which could be generated in situ by the amidation
of the ester 6 with an amine 5. Intermediate 6, in turn, could be
formed in situ via a coupling reaction of an amino acid ester 8
with a carboxylic acid 7. All of these transformations would be
carried out under microwave conditions.
200
220
240
250
10
10
10
10
30
28
2
30
30
62
98
100 (75)c
a Reactions were conducted on a 0.2-mmol scale. b The reactions were
monitored by HPLC (ELSD) from LC-MS results of the reaction mixture.
c Isolated yield.
An empirical validation of our design (method A) started from
the synthesis of 3a by employing our standard microwave
conditions.9 Initial efforts focused on optimizing microwave
conditions (Table 1). The reaction of methyl-1-amino-1-cyclo-
pentanecarboxylate hydrochloride (8a, 1.0 equiv) with valeric
acid (7a, 1.0 equiv) in the presence of P(OPh)3 (1.2 equiv) in
pyridine under microwave irradiation at 150 °C for 10 min
generated intermediate 6a as the only product detected by LC-
MS. Without isolating 6a, benzylamine (5a, 1.0 equiv) was
added to the reaction mixture. The conditions for forming the
final product 3a via a dehydration-cyclization reaction were
examined (Table 1). While the reactions at lower temperatures
(200-240 °C) for 10 min only gave a mixture of intermediates
(6a and 9a) and product 3a, microwave irradiation of the
reaction mixture at 250 °C for 10 min triggered the effective
dehydration-cyclization reaction, which resulted in a one-pot
assembling of the desired product 3a in 75% isolated yield.
The successful synthesis of 3a via a three-component one-
pot sequential process (method A) encouraged us to further
simplify this sequential process to a domino process (method
B), which carries out a series of transformations as a single
operation in one pot.12,13 The modified retrosynthetic strategy
is depicted in Figure 3. We postulated that by heating the
reaction mixture of the three reactants 7, 8, and 10, the reaction
(8) (a) Murugesan, N.; Gu, Z.; Fadnis, L.; Tellew, J. E.; Baska, R. A.
F.; Yang, Y.; Beyer, S. M.; Monshizadegan, H.; Dickinson, K. E.; Valentine,
M. T.; Humphreys, W. G.; Lan, S.-J.; Ewing, W. R.; Carlson, K. E.; Kowala,
M. C.; Zahler, R.; Macor, J. E. J. Med. Chem. 2005, 48, 171. (b) Kumar,
Y.; Prasad, M.; Nath, A.; Arora, S. K. WO 2005 051943, 2005. (c)
Nisnevich, G.; Rukhman, I.; Pertsikov, B.; Kaftanov, J.; Dolitzky, B.-Z.
WO 2004 072064, 2004. (d) Nisnevich, G.; Rukhman, I.; Pertsikov, B.;
Kaftanov, J. WO 2004 065383, 2004.
(9) Liu, J.-F.; Lee, J.; Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C. M.;
McElory, E.; Brown, M. Tetrahedron Lett. 2005, 46, 1241.
(10) (a) Liu, J.-F.; Kaselj, M.; Isome, Y.; Ye, P.; Sargent, K.; Sprague,
K.; Cherrak, D.; Wilson, C. J.; Si, Y.; Yohannes, D.; Ng, S.-C. J. Comb.
Chem. 2006, 8, 7. (b) Liu, J.-F.; Wilson, C. J.; Ye, P.; Sprague, K.; Sargent,
K.; Si, Y.; Beletsky, G.; Yohannes, D.; Ng, S.-C. Bioorg. Med. Chem. Lett.
2006, 16, 686.
(11) For examples of diversity-oriented syntheses, see: (a) Schreiber,
S. L. Science 2000, 287, 1964. (b) Tan, D. S. Comb. Chem. High Throughput
Screening 2004, 7, 631 and references therein.
(12) For multicomponent reactions, see: (a) Multicomponent Reactions;
Zhu, J., Bienayme´, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005. (b)
Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (c) Hulme,
C.; Gore, V. Curr. Med. Chem. 2003, 10, 51. (d) Orru, R. V. A.; De Greef,
M. Synthesis 2003, 1471. (e) Murakami, M. Angew. Chem., Int. Ed. 2003,
42, 718. (f) Zhu, J. Eur. J. Org. Chem. 2003, 1133.
(13) For domino reactions, see: (a) Tietze, L. F. Chem. ReV. 1996, 96,
115. (b) Tietze, L. F.; Haunert, F. In Stimulating Concepts in Chemistry;
Shibasaki, M., Stoddart, J. F., Vo¨gtle, F., Eds.; Wiley-VCH: Weinheim,
Germany, 2000.
3138 J. Org. Chem., Vol. 71, No. 8, 2006

Synthesis of Spiroimidazolin-4-ones
TABLE 2. Representative Imidazolinones 3 with Different Amino
Acid Esters 8
FIGURE 3. Retrosynthetic strategy of 3 (one-pot domino process,
method B).
SCHEME 1
a The yields are determined by HPLC (ELSD) from LC-MS results of
the reaction mixture. In parentheses are the isolated yields by preparative
TLC. b This reaction needs 250 °C for 15 min.
sequence would be (I) to form 6, (II) to generate amine 5, (III)
to form 4, and (IV) to yield products 3. To realize this designed
domino sequence, the key would be the in situ de-Boc of the
masked amines 10 to amine 5 at the right step in the process of
a series of transformations under the reaction conditions. This
new design allows access to the products 3 in one operation
step (despite using masked amines 10), which would be an
attractive complementary method of a three-component one-
pot sequential process. For a faster exploration of the structure-
activity relationships (SAR) in drug discovery, this one-pot
domino process would be, in particular, simple and efficient in
the synthesis of a focused library that crosses only a few
numbers of masked amines, 10, but large numbers of amino
acid esters, 8, and carboxylic acids, 7.
TABLE 3. Representative Spiroimidazolinones 3 with Different
Carboxylic Acids 7
Toward this end, we first evaluated the following modified
reaction process (Scheme 1). Gratifyingly, simply by mixing
8a (1.0 equiv), 7a (1.0 equiv), N-Boc-benzylamine (10a, 1.0
equiv), and P(OPh)3 (1.2 equiv) in pyridine and heating in
microwave at 250 °C for 10 min, the desired product 3a was
obtained with a yield of 72%, which was essentially as good as
method A.
The preliminary success with two sets of reactions on both
method A and method B prompted us to commence with the
evaluation of the reaction scope by applying an array of
carboxylic acids 7, amino acid esters 8, and amines 5 (or N-Boc
amines 10), aiming at achieving the ultimate goal of applying
these two methods for both the target-oriented and the diversity-
oriented synthesis.
Different amino acid esters 8 were evaluated with method
A, as shown in Table 2. In general, all the reactions gave
excellent conversion (82-100%) with good isolated yields (65-
75%).14 The HCl or TFA salt forms of 8 (entries 1 and 3-5)
worked, essentially, equally as well as the free base form (entry
2). In addition, tert-butyl ester (entry 4) also worked as
a Microwave irradiation at 250 °C for 10 min. The yields were determined
by HPLC (ELSD) from LC-MS results of the reaction mixture. In
parentheses are the isolated yields by preparative TLC.
effectively as methyl ester. These features allow for the easy
selection of the amino acid esters from whichever readily
available forms. To further expand the diversity, nonspiro
imidazolinones 3 were synthesized in good yields from the
corresponding 8 (entries 4 and 5).
In addition, these microwave reaction conditions also proved
to be general for carboxylic acids 7, as shown in Table 3
(evaluated with method A). Aliphatic (entry 1), aromatic (entry
2), and benzyl carboxylic acids (entries 3 and 4) all worked
smoothly, providing overall yields ranging from 59 to 74% with
conversion >90%, except pyridin-3-yl-acetic acid (entry 4,
77%).14
(14) We isolated ∼10% of the products of the oxidized benzylic position
of the benzyl group, which were not observed in the reaction mixture. This
may contribute to the discrepancy between the conversion yield and the
isolated yield. For example, the product of entry 1 in Table 2 was oxidized
after sitting in a NMR tube for days.
Next, the amines 5 and masked amine 10 were examined
with both methods (Table 4). Aliphatic amines (entries 1 and
J. Org. Chem, Vol. 71, No. 8, 2006 3139

Ye et al.
TABLE 4. Representative Spiroimidazolinones 3 with Different
Amines, 5 or 10
via a three-component sequential process and domino process
from readily available starting materials. These new approaches
also feature applying only one reagent and one solvent in the
entire synthesis. All of these would greatly facilitate both the
target-oriented and diversity-oriented syntheses of spiroimid-
azolinones. The efficiency and utility of the methods have been
demonstrated by quickly accessing the antihypertensive drug
irbesartan. The further application of this microwave methodol-
ogy to the synthesis of other heterocycles will be described in
due course.
Experimental Section
4′-(2-Butyl-4-oxo-1,3-diaza-spiro[4.4]non-1-en-3-ylmethyl)-
biphenyl-2-carbonitrile (3n). Compound 3n was prepared via
a sequential process (method A) and a domino process (method
B).
Method A. To a conical-bottomed Smith Process vial were added
0.4 mL of a 0.5 M solution of methyl 1-amino-1-cyclopentane-
carboxylate (0.2 mmol, 8a) in anhydrous pyridine, 0.4 mL of a 0.5
M solution of valeric acid (0.2 mmol, 7a) in anhydrous pyridine,
and 63 µL (0.24 mmol) of triphenyl phosphate (neat). The reaction
vessel was sealed and placed in a monomode microwave reactor.
Irradiation was initiated at 300 W to raise the temperature to the
set point, and then power was applied at intervals and levels to
maintain the desired temperature. Reaction times reported included
time for the vial to ramp to the desired temperature. The sealed
vial was first irradiated for 10 min at 150 °C. After cooling, to this
reaction mixture was added 0.2 mL of a 1.0 M solution of
4′-aminomethyl-biphenyl-2-carbonitrile (0.2 mmol, 5b) in anhy-
drous pyridine. The sealed vial was irradiated for 10 min at 250
°C, with the pressure around 10 bar. After cooling, the reaction
mixture was concentrated in vacuo and the product was purified
by prep-TLC (ethyl acetate/hexane ) 1/1), giving the purified
product as a yellow solid (58 mg, 75%).
a Method A. b Method B. c The yields are determined by HPLC (ELSD)
from LC-MS results of the reaction mixture. In parentheses are the isolated
yields by preparative HPLC. d In parentheses are the isolated yields by
preparative TLC.
SCHEME 2
Method B. To a conical-bottomed Smith Process vial were added
0.4 mL of a 0.5 M solution of methyl 1-amino-1-cyclopentane-
carboxylate (0.2 mmol, 8a) in anhydrous pyridine, 0.4 mL of a 0.5
M solution of valeric acid (0.2 mmol, 7a) in anhydrous pyridine,
0.2 mL of a 1.0 M solution of (2′-cyano-biphenyl-4-ylmethyl)-
carbamic acid tert-butyl ester (0.2 mmol, 10b) in anhydrous
pyridine, and 63 µL (0.24 mmol) of triphenyl phosphate (neat).
The sealed vial was irradiated in the microwave for 10 min at 250
°C with the pressure around 15 bar. After cooling, the reaction
mixture was then concentrated in vacuo, and the product was
purified by prep-TLC (ethyl acetate/hexane ) 1/1), giving the
purified product as a yellow solid (55 mg, 71%).
2-Butyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1,3-diaza-
spiro[4.4]non-1-en-4-one (Irbesartan, 2). To a conical-bottomed
Smith Process vial was added tri-n-butyltin chloride (195 mg, 0.6
mmol) along with 0.6 mL of DMF, followed by the addition of
sodium azide (39 mg, 0.6 mmol) and tetrabutylammonium bromide
(6.4 mg, 0.02 mmol). After vortexing the mixture, compound 3n
(77 mg, 0.2 mmol) in 0.4 mL of DMF was added. The sealed vial
was irradiated in the microwave for 1 h at 220 °C with the pressure
around 8 bar. The reaction mixture was concentrated in vacuo, and
the product was purified by prep-TLC (ethyl acetate/hexane/
methanol ) 45/45/10), giving the purified product as a light yellow
solid (62 mg, 73%).
2), anilines (entry 3), benzylamines (entries 4-7), as well as
heterocyclic amines (entries 8 and 9), generally provided
excellent conversion (90-98%). To evaluate the purification
conditions for the library synthesis, products were purified using
standard in-house high-throughput HPLC methods, which
provided moderate to good recoveries (36-78%). In addition,
method B proved to work as well as method A (entries 2, 4, 6,
and 9). It is noteworthy that the benzyl-protecting group stayed
intact under the microwave-reaction conditions (entry 9).
To demonstrate the feasibilities of these two methods, the
synthesis of irbesartan (2) was conducted from its precursor 3n
using a modified method (Scheme 2).8b Under microwave
irradiation at 220 °C, treatment of 3n with Bu3SnCl, NaN3, and
a catalytic amount of tetrabutyl ammonium bromide in DMF
for 1 h afforded 2 in 73% yield. Thus, the synthesis of irbesartan
was achieved in two steps within several hours from com-
mercially available starting materials with a 55% overall yield,
which is nearly ideal in terms of step efficiency and operational
simplicity.
Supporting Information Available: General information,
1
characterization data, and copies of H and 13C NMR spectra for
Summary
compounds 2 and 3a-q. This material is available free of charge
via the Internet at http://pubs.acs.org.
In summary, we have developed novel one-pot reactions using
microwave technology for the synthesis of spiroimidazolinones
JO060228Q
3140 J. Org. Chem., Vol. 71, No. 8, 2006