A Practical and Efficient Large-Scale Preparation of (4R,58)-N-Propenoyl-1,5-dimethyl-4-phenylimidazolidin-2-one. A Simple Procedure for the Preparation of N-Acylimidazolidin-2-ones and N-Acylbornane 2,10-Sultams

Full text of DOI:10.1021/jo980717t

6732
J . Org. Chem. 1998, 63, 6732-6734
Sch em e 1
A P r a ctica l a n d Efficien t La r ge-Sca le
P r ep a r a tion of (4R,5S)-N-P r op en oyl-1,5-
d im eth yl-4-p h en ylim id a zolid in -2-on e. A
Sim p le P r oced u r e for th e P r ep a r a tion of
N-Acylim id a zolid in -2-on es a n d
N-Acylbor n a n e 2,10-Su lta m s
William M. Clark* and Corey Bender
Synthetic Chemistry Department, SmithKline Beecham
Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539,
King of Prussia, Pennsylvania 19406
Received April 17, 1998
The (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one
1 is a powerful auxiliary for numerous asymmetric
transformations and is readily prepared from the fusion
reaction of (1R,2S)-ephedrine hydrochloride and urea (eq
1).1,2 Excellent stereoselectivities have been observed
toward the development of an improved procedure for the
large scale synthesis of 3a will be described in this note.8
Due to increasing emphasis for the swift development
of promising new chemotherapeutics, our primary goal
was to develop methodology for the preparation of 3a
which was not only inexpensive but also amenable to
synthesis on a manufacturing scale. With this in mind,
we wanted to avoid the use of chemistry which required
special reactors, such as low-temperature chemistry (-78
°C), or costly reagents, such as alkyllithium or Grignard
reagents, thus ruling out traditional metalation pro-
cedures.2,7d-f,9 Our investigations therefore focused on
simple acylation conditions of imidazolidinone 1. Ini-
tially, reaction conditions using a tertiary amine (Et3N,
iPr2NEt) and acryloyl chloride in an aprotic solvent (CH2-
Cl2, THF) at -15 °C showed promise on a small scale.
However, the exothermic reaction proved difficult to
control upon scale-up (>50 g), which typically delivered
3a in moderate yield (65-70%). In addition, chromato-
graphic separation was required to remove polymeric
material formed during the reaction.10 We then inves-
tigated anhydride procedures developed for the Evans
and Oppolzer auxiliaries, such as that reported by Ho
and Mathre using LiCl/Et3N/THF/acrylic anhydride,11 as
well as similar methodology using DABCO/Et3N.12 How-
ever, in both cases, low yields of 3a were obtained due to
the sluggish acylation of 1.
We then turned to the work of Kocienski,13 who
reported that N-TMS-oxazolidinones and bornane 2,10-
sultams undergo efficient acylation with an excess of acid
chloride in the presence of catalytic copper at elevated
temperatures. We reasoned that imidazolidinone 1
should exhibit similar reactivity with acid chlorides and
therefore heated a solution of 1 with acryloyl chloride (1.5
equiv) in CH3CN at 80 °C for 2 h. The reaction afforded
a 1:5:1 mixture of 2, 3a , and the Michael adduct 4 (vide
supra). Dehydrohalogenation of 2 was then achieved
with K2CO3 (1.5 equiv) in CH3CN heated to 80 °C for 4
h, which afforded 3a and 4 in 75% and 12% yields,
respectively (not shown).
with 1 and its antipode in the asymmetric aldol2 and
homoaldol reactions,3 the Diels-Alder reaction,4 the
Michael addition reaction of organometallics5 and
phthalimide,6 and asymmetric alkylation reactions.7 Re-
cently as part of our endothelin receptor antagonist
program, we required multikilo quantities of the N-
propenoylimidazolidinone 3a . Our successful efforts
(1) Close, W. J . J . Org. Chem. 1950, 15, 1131.
(2) Drewes, S. E.; Malissar, D. G. S.; Roos, G. H. P. Chem. Ber. 1993,
126, 2663.
(3) Roder, H.; Helmchen, G.; Peters, E.-M.; Peters, K.; von Schner-
ing, H. G. Angew. Chem., Int. Ed. Engl. 1984, 23, 898.
(4) J ensen, K. N.; Roos, G. H. P. Tetrahedron: Asymmetry 1992, 3,
1553.
(5) (a) Pourcelot, G.; Aubouet, J .; Caspar, A.; Cresson, P. J . Orga-
nomet. Chem. 1987, 328, C43. (b) Bongini, A.; Cardillo, G.; Mingardi,
A.; Tomasini, C. Tetrahedron: Asymmetry 1996, 7, 1457. (c) van
Heerden, P. S.; Bezuidenhoudt, B. C. B.; Ferreira, D. Tetrahedron Lett.
1997, 38, 1821.
(6) Cardillo, G.; De Simone, A.; Gentiluci, L.; Sabatino, P.; Tomasini,
C. Tetrahedron Lett. 1994, 35, 5051.
(7) For C- and N-alkyations, see: (a) Cardillo, G.; D′Amico, A.;
Orena, M.; Sandri, S. J . Org. Chem. 1988, 53, 2354. (b) Orena, M.;
Porzi, G.; Sandri, S. Tetrahedron Lett. 1992, 33, 3797. (c) Trost, B. M.;
Ceschi, M. A.; Ko¨nig, B. Angew. Chem., Int. Ed. Engl. 1997, 36, 1486.
(d) Cardillo, G.; Gentilucci, L.; Tomasini, C.; Castejon-Bordas, M. P.
V. Tetrahedron: Asymmetry 1996, 7, 755. (e) Amoroso, R.; Cardillo,
G.; Sabatino, P.; Tomasini, C.; Trere, A. J . Org. Chem. 1993, 58, 5615.
(f) Bongini, A.; Cardillo, G.; Gentiluci, L.; Tomasini, C. J . Org. Chem.
1997, 62, 9148.
(8) We have prepared in excess of 1000 kg of 3a using this procedure.
(9) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am. Chem. Soc.
1988, 110, 1238. (b) Corey, E. J .; Pikul, S. Org. Synth. 1993, 71, 30.
(10) Methodology has been reported recently using DABCO/CuCl
(1.0 equiv)/Cu (1.0 equiv) and acryloyl chloride to prepare 3a in
excellent yield; however, the use of copper to inhibit polymerization
made this method unattractive for our purposes. Kriel, K. N.; Emslie,
N. D.; Roos, G. H. P. Tetrahedron Lett. 1997, 38, 109. See also ref 7f.
(11) Ho, G.-J ., Mathre, D. J . J . Org. Chem. 1995, 60, 2271.
(12) Ager, D. J .; Allen, D. R.; Schaad, D. R. Synthesis 1996, 1283.
The mixed anhydride procedure described in this communication
(pivaloyl chloride/acrylic acid) was equally ineffective.
(13) Thom, C.; Kocienski, P. Synthesis 1992, 582.
Further improvements to the reaction were made by
heating a solution of 1 and 3-chloropropionyl chloride (1.3
equiv) in CH3CN at 80 °C for 4-6 h to give 2 in >95%
yield (Scheme 1). Without isolation, 2 was then treated
S0022-3263(98)00717-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/28/1998

Notes
J . Org. Chem., Vol. 63, No. 19, 1998 6733
Ta ble 1. Acyla tion of 1 w ith Acid Ch lor id es
of the N-acylimidazolidinones 3b-h shown in Table 1.
In the R,â-unsaturated acid chloride examples, a K2CO3
charge was required to dehydrohalogenate the â-chloro-
N-acylimidazolidinone formed during the acylation,
whereas the reaction with saturated acid chlorides did
not require base treatment. In all cases, complete
acylation was obtained after 4-6 h of heating at 80 °C
in CH3CN with 1.25-1.50 equiv of the acid chloride. The
crude product was then easily purified by recrystalliza-
tion from EtOH/H2O or flash column chromatography to
deliver the N-acylimidazolidinone in excellent yield and
purity.
The remarkably simple procedure is also effective with
Oppolzer’s bornane 2,10-sultam auxiliary 5 (eq 2). With
the acid chlorides attempted, i.e., 3-chloropropionyl chlo-
ride, trans-crotonyl chloride, and cinnamoyl chloride,
efficient acylation was observed after 8-10 h of heating
at reflux in CH3CN. After base treatment, the R,â-
unsaturated N-acylbornane sultams were delivered in
excellent yields and purities comparable to earlier re-
ported procedures.11,13
In contrast to 1 and 5, the Evans 2-oxazolidinone
auxiliary 7 did not succumb to simple acylation with acid
chlorides. For example, heating a solution of 7 with
cinnamoyl chloride or propionyl chloride in CH3CN at
reflux for 24 h gave only recovered starting material.
Presumably, the lower reactivity of 7 with acid chlorides
is due to a greater delocalization of the urethane nitrogen
lone pair relative to the imidazolidinone and bornane
2,10-sultam auxiliaries.
a
b
Xc ) (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one. Iso-
lated yield. c c ) 1, CHCl3. lit. [R]25 -100.6° (c ) 1, CHCl3), mp
d
D
135-140 °C (ref 7f). e lit. [R]25 -100° (c ) 1, CHCl3), mp 184 °C
D
(ref 7e). f lit. [R]25 -105.4° (c ) 1, CH2Cl2), mp 158 °C (ref 7a).
D
In conclusion, we have developed a simple and effective
procedure for the synthesis of N-acylimidazolidinones and
N-acylbornane 2,10-sultams amenable for large-scale
synthesis. The method utilizes the modest nucleophilic-
ity of the respective auxiliaries which undergo acylation
with acid chlorides in high yield at elevated temperatures
in polar solvents.
lit. [R]25 -21° (c ) 1, CHCl3), mp 184 °C (ref 7d). lit. [R]25
g
h
D
D
-54.7° (c ) 1, CH2Cl2), mp 90 °C (ref 7a).
with base to deliver 3a in 85% yield after purification. A
small amount of 4 (2-3%) was observed with these
conditions; however, the byproduct was easily removed
via a slurry of crude 3a in cold (-10 °C) CH3CN. With
this procedure, 3a was typically isolated as a white
crystalline solid with >99.9% ee14 and could be stored at
room temperature for an extended period of time (>6
months) without significant decomposition.
Exp er im en ta l Section
All commercially available reagents were purchased from
Aldrich Chemical Co. and were used without further purification
except trans-crotonyl chloride, which was distilled prior to use.
All solvents were high-performance liquid chromatography
(HPLC) grade and used without further purification. Unless
otherwise indicated, all reactions were magnetically stirred and
monitored by reverse-phase HPLC using a Supelcosil ABZ+
column. Yields refer to chromatographically and spectroscopi-
cally pure compounds. Melting points are uncorrected. 1H and
The method has also proven to be a general procedure
for the acylation of 1, affording excellent yields (>80%)
(14) Enantiomeric purity of 3a was determined by chiral HPLC
using Daicel Chiralpak AD column (9:1 hexane/2-propanol, 1 mL/min,
210 nm) with retention times of 8.73 min (en t-3a ) and 14.08 min (3a ).

6734 J . Org. Chem., Vol. 63, No. 19, 1998
Notes
13C NMR spectra were recorded at 300 and 75 MHz, respectively.
Infrared spectra were recorded on an FT-IR spectrometer using
KBr plates with film or in solution.
Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C,
74.36; H, 6.87; N, 8.64.
(4R,5S)-N-(P r op ion yl)-1,5-d im eth yl-4-p h en ylim id a zoli-
d in -2-on e (3f).7a White solid (6.2 g, 96%) after recrystallization.
Anal. Calcd for C14H18N2O2: C, 68.27; H, 7.37; N, 11.37.
Found: C, 68.44; H, 7.27; N, 11.43.
(-)-(4R,5S)-N-(P r op en oyl)-1,5-d im eth yl-4-p h en ylim id a -
zolid in -2-on e (3a ).7f To a 12-L three-necked flask equipped
with an air-driven mechanical stirrer, thermometer, and reflux
condenser was charged (4R,5S)-1,5-dimethyl-4-phenylimidazo-
lidin-2-one (1) (710 g, 3.74 mol), CH3CN (7 L), and 3-chloropro-
pionyl chloride (500 mL, 5.24 mol) under nitrogen. The sus-
pension was heated to 80 °C for 6 h and then cooled to room
temperature, and K2CO3 (1032 g, 7.48 mol) added portionwise
over 10 min. The mixture was stirred for 0.5 h at ambient
temperature and heated to 80 °C for 5-6 h, followed by filtration
of the inorganics at room temperature. The filter cake was
washed with CH3CN (7 L), the filtrate was transferred to a 12-L
three-necked flask, and 1500 mL of solvent was removed via
distillation under reduced pressure (20 mmHg). The slurry was
cooled to -15 °C for 3 h and filtered, and the filter cake was
washed with cold (0 °C) nPrOH/heptane (1:9, 500 mL) and dried
under vacuum (20 mmHg) at 25 °C to afford 3a as a white
crystalline solid (769 g, 85%). Anal. Calcd for C14H16N2O2: C,
68.83; H 6.60; N 11.47. Found: C, 69.10; H, 6.66; N 11.50.
Gen er a l P r oced u r e for r,â-Un sa tu r a ted N-Acylim id a -
zolid in -2-on es (3b-3d ). To a CH3CN (50 mL) suspension of
1 (5.0 g, 26.3 mmol) was added the acid chloride (39.7 mmol) in
one portion at 25 °C. The mixture was heated to 80 °C for 4-6
h under nitrogen and cooled to room temperature, and K2CO3
(3.6 g, 26.3 mmol) was added portionwise over 10 min. The
mixture was heated to 80 °C for 2-4 h and cooled to room
temperature, and the inorganics were removed via filtration. The
filtrate was then concentrated under reduced pressure; the
residue was partitioned between CH2Cl2 and H2O; and the
organic phase was washed with saturated Na2CO3 and saturated
NaCl, dried (MgSO4), filtered, and concentrated. The crude
product was purified via recrystallization from EtOH/H2O (9:1,
5 mL/g substrate) at 0 °C or flash column chromatography [SiO2,
EtOAc/hexane (1:1)] unless otherwise indicated.
(4R,5S)-N-(tr a n s-Cr oton yl)-1,5-d im eth yl-4-p h en ylim id a -
zolid in -2-on e (3b).7e White solid (6.1 g, 91%) after flash
chromatography. Anal. Calcd for C15H18N2O2: C, 69.74; H, 7.02;
N, 10.84. Found: C, 69.68; H, 7.01; N, 10.67.
(4R,5S)-N-(3,3-Dim et h yla cr yloyl)-1,5-d im et h yl-4-p h en -
ylim id a zolid in -2-on e (3c).7a White crystalline solid (6.2 g,
87%) after recrystallization. Anal. Calcd for C16H20N2O2: C,
70.56; H, 7.4; N, 10.29. Found: C, 70.60; H, 7.32; N, 10.24.
(4R,5S)-N-(tr a n s-Cin n a m oyl)-1,5-d im eth yl-4-p h en ylim i-
d a zolid in -2-on e (3d ).7d Recrystallization from EtOAc (5 mL/g
substrate) at -10 °C afforded 3d as white flakes (7.3 g, 87%).
Anal. Calcd for C20H20N2O2: C, 74.98; H, 6.29; N, 8.74.
Found: C, 75.20; H, 6.32; N, 8.68.
Gen er a l P r oced u r e for Sa tu r a ted N-Acylim id a zolid in -
2-on es (3e-3h ). To a CH3CN (50 mL) suspension of 1 (5.0 g,
26.3 mmol) was added the acid chloride (32.9 mmol) in one
portion at 25 °C. The mixture was heated to 80 °C for 4-6 h
under nitrogen and cooled to room temperature, and the solution
was concentrated under reduced pressure. The residue was then
partitioned between CH2Cl2 and H2O, and the organic phase was
washed with saturated Na2CO3 and brine, dried (MgSO4),
filtered, and concentrated. The crude product was purified via
recrystallization from EtOH/H2O (9:1, 5 mL/g substrate) at 0
°C or flash column chromatography [SiO2, EtOAc/hexane (1:1)].
(4R,5S)-N-(3-P h en ylp r op ion yl)-1,5-d im eth yl-4-ph en ylim -
id a zolid in -2-on e (3e). White solid (6.9 g, 81%) after recrys-
tallization. 3e: IR (Nujol) 1760, 1740 cm-1; 1H NMR (CDCl3) δ
0.8 (d, 3H, J ) 6.6 Hz), 2.8 (s, 3H), 2.9 (m, 2H), 3.3 (m, 2H), 3.9
(dq, 1H, J ) 6.6, 8.5 Hz), 5.3 (d, 1H, J ) 8.5 Hz), 7.10-7.40 (m,
10H); 13C NMR (CDCl3) δ 14.9, 28.1, 30.6, 37.3, 53.9, 59.3, 125.9,
126.9, 128.0, 128.3, 128.5 (2C), 136.8, 140.1, 156.0, 172.0. Anal.
(4R,5S)-N-(3-Cyclopen tylpr opion yl)-1,5-dim eth yl-4-ph en -
ylim id a zolid in -2-on e (3g). White solid (7.5 g, 91%) after
recrystallization. 3g: IR (Nujol) 1760, 1740 cm-1 1H NMR
;
(CDCl3): δ 0.8 (d, 3H, J ) 6.6 Hz), 1.1 (m, 2H), 1.4-1.8 (m, 9H),
2.8 (s, 3H), 3.0 (m, 2H), 3.9 (dq, 1H, J ) 6.6, 8.5 Hz), 5.3 (d, 1H,
J ) 8.5 Hz), 7.15 (m, 2H), 7.20-7.35 (m, 3H); 13C NMR (CDCl3)
δ 14.9, 25.1, 28.1, 30.8, 32.4 (2C), 35.0, 53.9, 59.3, 126.9, 127.9,
128.4, 136.8, 155.9, 172.9. Anal. Calcd for C19H26N2O2: C,
72.58; H, 8.33; N, 8.91. Found: C, 72.79; H, 8.28; N, 8.87.
(4R,5S)-N-(Ch lor oa cetyl)-1,5-d im eth yl-4-p h en ylim id a zo-
lid in -2-on e (3h ). White flakes (6.5 g, 93%) after recrystalliza-
1
tion. 3h : IR (Nujol): 1725, 1700 cm-1; H NMR (CDCl3) δ 0.8
(d, 3H, J ) 6.6 Hz), 2.8 (s, 3H), 3.9 (dq, 1H, J ) 6.6, 8.5 Hz),
4.75 (AB q, 2H, J ) 19.5, 15.2 Hz), 5.3 (d, 1H, J ) 8.5 Hz), 7.15
(m, 2H), 7.20-7.35 (m, 3H). 13C NMR (CDCl3) δ 14.8, 28.1, 43.8,
54.4, 59.5, 126.9, 128.2, 128.5, 135.8, 155.2, 165.2. Anal. Calcd
for C13H15N2O2Cl: C, 58.54; H, 5.67; N, 10.50. Found: C, 58.79;
H, 5.61; N, 10.44.
(+)-N-P r op en oylbor n a n e 2,10-Su lta m (6a ).13 To a solution
of (1R)-(+)-2,10-bornane sultam 5 (500 mg, 2.32 mmol) in CH3-
CN (10 mL) under nitrogen was added 3-chloropropionyl chloride
(0.28 mL, 2.90 mmol) and the solution was heated to reflux for
10 h. The solution was cooled to room temperature and charged
with K2CO3 (640 mg, 4.64 mmol), and heating was continued
for 4 h. After cooling to ambient temperature, the mixture was
partitioned with CH2Cl2 and H2O, and the organic phase was
washed with saturated NaCl, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
chromatographed [SiO2, EtOAc/hexane (1:1)] to afford 6a as a
white solid (510 mg, 82%): mp 200 °C dec (lit. mp 180 °C dec);
[R]25 +100.9° (c 1.1, CHCl3), [lit. [R]25 +102° (c 1.7, CHCl3)].
D
D
Anal. Calcd for
C
13H19NSO3: C, 57.97; H, 7.11; N, 5.20.
Found: C, 58.09; H, 7.18; N, 5.21.
(+)-N-(2-Bu ten oyl)bor n a n e 2,10-Su lta m (6b).13 The sul-
tam 5 (500 mg, 2.32 mmol) was acylated with trans-crotonyl
chloride (0.33 mL, 3.48 mmol) using the procedure described
above to give 6b as a white solid (610 mg, 92%): mp 180-182
°C (lit. mp 181-183 °C); [R]25D +100.2° (c 1.04, CHCl3), [lit. [R]25
D
+102° (c 1.6, CHCl3)]. Anal. Calcd for C14H21NSO3: C, 59.34;
H, 7.47; N, 4.94. Found: C, 59.52; H, 7.35; N, 4.79.
(+)-N-(3-P h en ylp r op en oyl)bor n a n e 2,10-Su lta m (6c).13
To a solution of (1R)-(+)-2,10-bornane sultam 5 (500 mg, 2.32
mmol) in CH3CN (10 mL) under nitrogen was added cinnamoyl
chloride (502 mg, 3.02 mmol), and the solution was heated to
reflux for 10 h. After the solution cooled to ambient tempera-
ture, the CH3CN was removed in vacuo. The residue was diluted
with EtOAc, and the organic phase was washed with saturated
Na2CO3 and saturated NaCl, dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was
chromatographed [SiO2, EtOAc/hexane (1:1)] to afford 6c as a
white solid (700 mg, 87%): mp 188-189.5 °C (lit. mp 187-189);
[R]25D +97.2° (c 1.1, CHCl3), [lit. [R]25D +98° (c 1.7, CHCl3)]. Anal.
Calcd for C19H23NSO3: C, 66.06; H, 6.71; N, 4.05. Found: C,
66.14; H, 6.71; N, 4.01.
Ack n ow led gm en t. The authors would like to thank
the Analytical and Physical & Structural Chemistry
Departments for the supporting analytical data and
SmithKline Beecham for the financial support of C.B.
J O980717T