Regiocontrolled cyclization reaction of N-(2-hydroxyethyl)ureas by transfer of activation: One-pot synthesis of 2-imidazolidinones

Full text of DOI:10.1021/jo9820061

J . Org. Chem. 1999, 64, 2941-2943
2941
Sch em e 1
Regiocon tr olled Cycliza tion Rea ction of
N-(2-Hyd r oxyeth yl)u r ea s by Tr a n sfer of
Activa tion : On e-P ot Syn th esis of
2-Im id a zolid in on es
Taek Hyeon Kim* and Gue-J ae Lee
Faculty of Applied Chemistry, Chonnam National
University, Kwangju 500-757, Korea
Received October 7, 1998
Sch em e 2
Cyclic ureas have recently gained much interest as
human immunodeficiency virus (HIV) protease inhibi-
tors1 and 5HT3 receptor antagonists2 and are expected
to have increased conformational rigidity relative to the
corresponding linear ureas, which are incorporated in
many pharmaceuticals.3 5-Membered cyclic ureas, 2-imid-
azolidinones, are also used as useful chiral auxiliaries4
in highly diastereoselective alkylation, aldol, and Diels-
Alder reactions. 2-Imidazolidinones are generally pre-
pared by the cyclization reaction of 1,2-diamine with
phosgene5 or its derivatives,2 and these methods cause
the polymerization as a side reaction.6 The intramolecu-
lar cyclization of N-(2-hydroxyethyl)urea 1 having an
ambident nucleophile using PPh3/CCl4 or dimethylamino-
sulfur trifluoride (DAST) generally leads to O-cyclized
2-oxazoline in preference to N-cyclized 2-imidazolidi-
none,7 and there has been no report regarding N-cyclized
2-imidazolidinone formation with substrates 1. In this
paper, we report the result of a new and general method
that gives N-cyclized products, 2-imidazolidinones 2, as
single isomers using N-(2-hydroxyethyl)urea 1 derived
from 1,2-amino alcohol and phenyl isocyanate shown in
Scheme 1.
Sch em e 3
* To whom correspondence should be addressed. Tel: +82-62-530-
1891. Fax: +82-62-530-1889. E-mail: thkim@chonnam.chonnam.ac.kr
(1) (a) Lam, P. Y. S.; J adhav, P. K.; Eyermann, C. J .; Hodge, C. N.;
Ru, Y.; Bacheler, L. T.; Meek, J . L.; Otto, M. J .; Rayner, M. M.; Wong,
Y. N.; Chang, C.-H.; Weber, P. C.; J ackson, D. A.; Sharpe, T. R.;
Erickson-Viitanen, S. Science 1994, 263, 380. (b) Wilkerson, W. W.;
Dax, S.; Cheatham, W. W. J . Med. Chem. 1997, 40, 4079. (c) Patel,
M.; Bacheler, L. T.; Rayner, M. M.; Cordova, B. C.; Klabe, R. M.;
Erickson-Viitanen, S.; Seitz, S. P. Bioorg. Med. Chem. Lett. 1998, 8,
823.
(2) Heidempergher, F.; Pillan, A.; Pinciroli, V.; Vaghi, F.; Arrigoni,
C.; Bolis, G.; Caccia, C.; Dho, L.; McArthur, R.; Varasi, M. J . Med.
Chem. 1997, 40, 3369.
(3) (a) Forbes, I. T.; Ham, P.; Booth, D.; Martin, R. T.; Thompson,
M.; Baxter, G. S.; Blackburn, T. P.; Glen, A.; Kennett, G. A.; Wood, M.
D. J . Med. Chem. 1995, 38, 2524. (b) Lewis, R. T.; Macleod, A. M.;
Merchant, K. J .; Kelleher, F.; Sanderson, I.; Herbert, R. H.; Cascieri,
M. A.; Sadowski, S.; Ball, R. G.; Hoogsteen, K. J . Med. Chem. 1995,
38, 923.
(4) (a) (4R,5S)-1,5-Dimethyl-4-phenyl-2-imidazolidinone: Guillena,
G.; Najera, C. Tetrahedron: Asymmetry 1998, 9, 1125 and references
therein. (b) (4S)-4-(1-Methylethyl or phenymethyl)-1-phenyl-2-imid-
azolidinone: Taguchi, T.; Shibuya, A.; Sasaki, H.; Endo, J .; Morikawa,
T.; Shiro, M. Tetrahedron: Asymmetry 1994, 5, 1423 and references
therein. (c) trans-4,5-Tetramethylene-2-imidazolidinone: Davies, S. G.;
Evans, G. B.; Mortlock, A. A. Tetrahedron: Asymmetry 1994, 5, 585.
(d) Camphor-derived 2-imidazolidinone: Palomo, C.; Oiarbide, M.;
Gonzalez, A.; Garcia, J . M.; Berree, F. Tetrahedron Lett. 1996, 37, 4565.
(e) (4S)-4-Carboxylate-2-imidazolidinone: Kubota, H.; Kubo, A.; Ta-
kahashi, M.; Shimizu, R.; Da-te, T.; Okamura, K.; Nunami, K. J . Org.
Chem. 1995, 60, 6776.
(5) Kim, J .-M.; Wilson T. E.; Norman, T. H.; Schultz, P. G.
Tetrahedron Lett. 1996, 37, 5309.
(6) Davies, S. G.; Mortlock, A. A. Tetrahedron 1993, 49, 4419.
(7) (a) Vorbruggen, H.; Krolikiewicz, K. Tetrahedron 1993, 49, 9353.
(b) Burrell, G.; Evans, J . M.; J ones, G. E.; Stemp, G. Tetrahedron Lett.
1990, 31, 3649.
We chose N-(2-hydroxyethyl)ureas 1a and 1f as sub-
strates to investigate the route shown in Scheme 2 in a
variety of reaction conditions. These were readily pre-
pared from the reaction of the corresponding 1,2-amino
alcohols with phenyl isocyanate, and the regioselectivities
in the cyclization reaction of 1a and 1f were investigated
as follows: These reactions are expected to give three
regioisomers, namely, two N-cyclized 2-imidazolidinone
2 and aziridine (in the case of R1 d H) 3 and an O-cyclized
2-oxazoline 4 depending on the nucleophilicity of the
substrate and reaction conditions. Upon the Mitsunobu
reaction conditions (PPh3, EtOCONdNCOOEt), the cy-
clization of 1a gave the mixtures of N-cyclized product
and O-cyclized product in a ratio of 52:48 due to the low
nucleophilicity of the nitrogen atom of 1a . For activation
of the hydroxyl group followed by the intramolecular
reaction with some bases, we treated 1a and 1f with 1.2
equiv of p-toluenesulfonyl chloride (TsCl) in the presence
of excess of Et3N to provide the tosylate product of 55%
and 62% yields, respectively, and then the intramolecular
reaction of tosylate of 1a with tert-butoxide (t-BuOK) gave
no desired cyclized product while the tosylate of 1f
resulted in the O-cyclized 2-oxazoline 4f of 84% good yield
without the 2-imidazolidinone (Scheme 3). We turned to
a one-pot reaction with TsCl (1.2 equiv) and t-BuOK (2.4
10.1021/jo9820061 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/31/1999

2942 J . Org. Chem., Vol. 64, No. 8, 1999
Notes
Ta ble 1. P r ep a r a tion s of Ur ea s 1 a n d
2-Im id a zolid in on es 2
lar attack of alkoxide to the sulfonamide or iminosul-
fonate via seven-membered ring gives a tosylate 8 having
nitrogen anion. Then the newly formed nitrogen anion
affects an intramolecular regioselective nucleophilic sub-
stitution on the tosylate to provide the N-cyclized 2.
Eissenstat and Weaver used a similar reaction, which
they named “transfer of activation” for preparing ana-
logues of indol natural product pravadoline.12 One-pot
reaction of 1f is very fast to give the corresponding
2-imidazolidinone, while the cyclization of tosylate 5f
with the same base occurs very slowly to give 2-oxazoline.
So, TsCl in the one-pot reaction affects the fast formation
of a tosylate having a nitrogen anion.
yield (%)
of 1
yield (%)
of 2
entry R1
R2
R3
mp of 1
mp of 2
a
b
c
d
e
f
H
H
Me H
H
H
H
H
H
Me
H
98
92
100
90
88
91
123-4
105-7
104-5
115-7
137-8
129-30
124
71
88
89
65
70
78
61
57
162-3a
108-10b
81-2c
104
Et
H
H
H
H
H
H
Me
Et
Me
(S)-i-Pr
129
128-30
g
h
88
85
80-5
(S)-PhCH2
H
155-6
115-7
a
b
Lit.8 mp 161-3 °C. Lit.9 mp 110-11 °C. c Lit.9 mp 83 °C.
Sch em e 4
In conclusion, we have succeeded in the development
of a new and general synthetic method for 2-imidazoli-
dinones from 1,2-amino alcohol through the regiocontrol
of N-(2-hydroxyethyl)ureas without using phosgene gas.
Furthermore, the present reaction would be applicable
as a new synthetic method for 1,2-diamine from 1,2-
amino alcohol by acid hydrolysis of 2-imidazolidinones.13
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR and 13C NMR spectra were
recorded using 300 and 75 MHz NMR spectrometers; chemical
shifts are reported in ppm using CDCl3 as solvent and TMS as
internal standard. Melting points were determined on a capillary
apparatus and are uncorrected. All chemicals were products of
Aldrich. Analytical TLC was performed on 0.25 mm precoated
silica gel plates. Flash chromatography was carried out with
230-400 mesh silica gel.
In tr a m olecu la r Cycliza tion of 5f. To a stirred solution of
5f (1.3 g, 3.6 mmol) in THF (10 mL) under nitrogen in an ice
bath was added potassium tert-butoxide (1.2 g, 10.8 mmol). The
reaction mixture was stirred in an ice bath for 2 h, and then at
room temperature overnight, monitored by TLC. For disappear-
ance of 5f the stirring was continued in reflux for 2 h, quenched
with water, and extracted with ether. The crude product was
purified by flash column chromatography to give 4f.
4,4-Dim eth yl-4,5-dih ydr o-N-ph en yl-2-oxazolam in e(4f): mp
127-8 °C; 1H NMR (300 MHz, CDCl3) 7.36-7.25 (m, 4H), 7.05-
6.95 (m, 1H), 4.03 (s, 2H), 1.32 (s, 6H); 13C NMR (CDCl3) 155.4,
128.8, 122.2, 120.1, 78.6, 28.1; IR (CDCl3) 1688 (s) cm-1; HRMS
calcd for C11H14N2O 190.1106, found 190.1109.
In tr a m olecu la r Cycliza tion of N-(2-Hyd r oxyeth yl)u r ea .
Gen er a l P r oced u r e. To a stirred suspension of potassium tert-
butoxide (0.4 g, 3.6 mmol) and urea (1.5 mmol) in THF (20 mL)
under nitrogen in an ice bath was added a solution of p-
toluenesulfonyl chloride (0.34 g, 1.8 mmol) in THF (5 mL)
dropwise with a syringe. The reaction mixture was stirred in
an ice bath for 10 min, quenched with water (20 mL), and
extracted with ether (25 mL ×2). The crude product was purified
by flash column chromatography.
equiv) which would avoid the inconvenience of separation
of the tosylates (Scheme 1). One-pot reactions of 1a and
1f afforded N-cyclized product in 71% and 78% yields,
respectively. Thus, in the case of 1f, a remarkable
difference on the regioselectivity of the ambident nucleo-
phile was observed. The N-selectivity with one-pot TsCl
and t-BuOK is noteworthy. We expected to apply this
reaction condition to a general synthesis of 2-imidazoli-
dinones.
On the basis of the above reaction conditions, the
cyclization of a variety of substrates 1a -h was examined
that led to the 2-imidazolidinones in good yields as
expected (Table 1). Any O-cyclized products were not
observed in the NMR data of the crude products; that is,
all reactions proceeded in good yields through regiocon-
trol (N-cyclization > O-cyclization) to give 2-imidazoli-
dinone. Chiral 2g and 2h followed by acylation are
expected to be used as the chiral auxiliaries for alkyla-
tion, aldol, and Diels-Alder reactions.10 All ureas 1a -h
were prepared from the reaction of primary 1,2-amino
alcohol with phenyl isocyanate in tetrahydrofuran (THF)
solution at room temperature in good yields (Table 1).
The reaction mechanism for the formation of 2-imid-
azolidinone could be proposed as shown in Scheme 4. The
sulfonamide 6 or iminosulfonate 711 having alkoxide
anion in an excess base is first formed, and intramolecu-
1-P h en yl-2-im id a zolid in on e (2a ): 1H NMR (300 MHz,
CDCl3) 7.56-7.52 (m, 2H), 7.37-7.26 (m, 2H), 7.08-7.06 (m,
1H), 3.97-3.92 (m, 2H), 3.62-3.55 (m, 2H); 13C NMR (CDCl3)
159.9, 140.0, 128.8, 122.3, 117.9, 45.3, 37.5; IR (CDCl3) 1684 (s)
cm-1; HRMS calcd for C9H11N2O 162.0793, found 162.0726.
1-Meth yl-3-p h en yl-2-im id a zolid in on e (2b): 1H NMR (300
MHz, CDCl3) 7.57-7.53 (m, 2H), 7.35-7.26 (m, 2H), 7.04-6.99
(8) Heine, H. W.; Kenyon, W. G.; J ohnson, E. M. J . Am. Chem. Soc.
1961, 83, 2570.
(9) Helmut, T. Ger. Patent 1,126,392, 1962; Chem. Abstr. 1962, 57,
9859i.
(10) Recently, Prasad reported that chiral N-acylated 2g and 2f were
prepared from the ring opening of oxazolines with aniline followed by
cyclization with phosgene and used for highly diastereoselective
benzylations and methylations; see: Konigsberger, K.; Prasad, K.;
Repic, O.; Blacklock, T. J . Tetrahedron: Asymmetry 1997, 8, 2347. We
found these compounds were readily prepared from a convenient short
course via acylation of 2g and 2f, and its results will be published in
another paper.
(m, 1H), 3.81-3.76 (m, 2H), 3.47-3.42 (m, 2H), 2.89 (s, 3H); 13
C
NMR (CDCl3) 158.2, 140.6, 128.7, 122.2, 117.2, 44.1, 42.3, 31.2;
IR (CDCl3) 1696 (s) cm-1
.
1-Eth yl-3-p h en yl-2-im id a zolid in on e (2c): 1H NMR (300
MHz, CDCl3) 7.57-7.54 (m, 2H), 7.35-7.26 (m, 2H), 7.04-6.99
(m, 1H), 3.82-3.78 (m, 2H), 3.49-3.44 (m, 2H), 3.31 (q, 2H, J )
7.2 Hz), 1.17 (t, 3H, J ) 7.2 Hz); 13C NMR (CDCl3) 157.6, 140.2,
(11) (a) Charette, A. B.; Chua, P. J . Org. Chem. 1998, 63, 908. (b)
Sisti, N. J .; Foeler, F. W.; Grierson, D. S. Synlett 1991, 816. (c) Sisti,
N. J .; Zeller, E.; Grierson, D. S.; Fowler, F. W. J . Org. Chem. 1997,
62, 2093. (d) Thomas, E. W. Synthesis 1993, 767.
(12) For a general discussion of the transfer of activation, see: (a)
Sobolov, S. B.; Sun, J .; Cooper, B. A. Tetrahedron Lett. 1998, 39, 5685.
(b) Eissenstat, M. A.; Weaver, J . D. Tetrahedron Lett. 1995, 36, 2029.
(13) Akester, J .; Cui, J .; Fraenkel, G. J . Org. Chem. 1997, 62, 431.

Notes
J . Org. Chem., Vol. 64, No. 8, 1999 2943
128.6, 122.0, 117.1, 42.3, 41.0, 38.5, 12.5; IR (CDCl3) 1701 (s)
cm-1; HRMS calcd for C11H14N2O 190.1106, found 190.1098.
4-Meth yl-1-p h en yl-2-im id a zolid in on e (2d ): 1H NMR (300
MHz, CDCl3) 7.54-7.51 (m, 2H), 7.36-7.26 (m, 2H), 7.07-7.02
(m, 1H), 4.04-3.87 (m, 1H+1H), 3.51-3.43 (m, 1H), 1.34 (d, 3H,
J ) 6.0 Hz); 13C NMR (CDCl3) 159.1, 140.1, 128.7, 122.5, 117.8,
0.92 (d, 3H, J ) 6.7 Hz); 13C NMR (CDCl3) 159.3, 140.2, 128.7,
122.3, 117.6, 54.8, 49.0, 33.1, 18.0, 17.0; IR (CDCl3) 1716 (s) cm-1
.
(4S)-1-P h en yl-4-p h en ylm et h yl-2-im id a zolid in on e (2h ):
1H NMR (300 MHz, CDCl3) 7.53-7.20 (m, 10H), 4.95 (bs, 1H),
4.04-3.95 (m, 2H), 3.65-3.61 (m, 1H), 2.92-2.84 (m, 2H); 13C
NMR (CDCl3) 158.7, 139.9, 136.6, 129.3, 129.1, 128.9, 128.8,
128.5, 127.0, 122.7, 117.8, 50.4, 50.4, 42.2; IR (CDCl3) 1705 (s)
cm-1; HRMS calcd for C16H16N2O 252.1263, found 252.1266.
52.5, 44.8, 21.7; IR (CDCl3) 1700 (s) cm-1
.
4-Eth yl-1-p h en yl-2-im id a zolid in on e (2e): 1H NMR (300
MHz, CDCl3) 7.56-7.52 (m, 2H), 7.36-7.26 (m, 2H), 7.07-7.02-
(m, 1H), 4.02-3.96 (m, 1H), 3.77-3.68 (m, 1H), 3.55-3.50 (m,
1H), 1.70-1.60 (m, 2H), 0.99 (t, 3H, J ) 7.4 Hz); 13C NMR
(CDCl3) 159. 1, 140. 1, 128.7, 122.4, 117.7, 50.6, 50.4, 28.9, 9.4;
Ack n ow led gm en t. Financial support for this work
(1995) from Chonnam National University Research
Foundation is gratefully acknowledged. Appreciation is
expressed to OPC Laboratory in Korea Advanced Insti-
tute of Science and Technology for providing high-
resolution mass spectra.
IR (CDCl3) 1698 (s) cm-1
.
4,4-Dim eth yl-1-p h en yl-2-im id a zolid in on e (2f): 1H NMR
(300 MHz, CDCl3) 1H NMR (300 MHz, CDCl3) 7.55-7.52 (m,
2H), 7.36-7.26 (m, 2H), 7.07-7.02 (m, 1H), 5.95 (bs, 1H), 3.65
(s, 2H), 1.36 (s, 6H); 13C NMR (CDCl3) 158.1, 140.2, 128.8, 122.5,
117.7, 58.2, 51.3, 28.6; IR (CDCl3) 1700 (s) cm-1; HRMS calcd
for C11H14N2O 190.1106, found 190.1110.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(4S )-4-(1-Me t h y le t h y l)-1-p h e n y l-2-im id a zo lid in o n e
(2g): 1H NMR (300 MHz, CDCl3) 7.56-7.53 (m, 2H), 7.35-7.12
(m, 2H), 7.05-7.02(m, 1H), 6.32 (bs, 1H), 3.95-3.88 (m, 1H),
3.57-3.47 (m, 2H), 1.79-1.69 (m, 1H), 0.98 (d, 3H, J ) 6.7 Hz),
J O9820061