Highly efficient preparation of both enantiomers of versatile chiral synthon for 1,2-diamines via the Fe(III)-catalyzed oxidation of 2-imidazolone

Article abstract of DOI:10.3987/COM-13-S(S)104

A new method was established for the preparation of both of the enantiomers of trans-4,5-dimethoxy-2-imidazolidinone (DMIm) via the Fe(III)-catalyzed oxidation of 2-imidazolone by H₂O₂-urea, which allowed the subsequent achievement o

Full text of DOI:10.3987/COM-13-S(S)104

HETEROCYCLES, Vol. 88, No. 2, 2014
1337
HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 1337 - 1353. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 31st July, 2013, Accepted, 25th September, 2013, Published online, 27th September, 2013
DOI: 10.3987/COM-13-S(S)104
HIGHLY EFFICIENT PREPARATION OF BOTH ENANTIOMERS OF
VERSATILE CHIRAL SYNTHON FOR 1,2-DIAMINES VIA THE
Fe(III)-CATALYZED OXIDATION OF 2-IMIDAZOLONE
Hirofumi Matsunaga,* Iori Eshita, Shoichi Tsunoda, Naoko Ishimoto, Shin
Ando, and Tadao Ishizuka*
Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku,
Kumamoto 862-0973, Japan; E-mail: mtc@gpo.kumamoto-u.ac.jp (H.M.);
tstone@gpo.kumamoto-u.ac.jp (T.I.)
Abstract – A new method was established for the preparation of both of the
enantiomers of trans-4,5-dimethoxy-2-imidazolidinone (DMIm) via the Fe(III)-
catalyzed oxidation of 2-imidazolone by H O -urea, which allowed the subsequent
2
2
achievement of optical resolution via the introduction of a MAC moiety and a
-mesitylenesulfonyl group at the two nitrogen positions of DMIm, which then
2
were easily removed. The two enantiomers are useful as versatile chiral synthons
for 1,2-diamines.
INTRODUCTION
,2-Diamine is a fundamental component of a substantial number of compounds that are of biological and
1
1
,2
medicinal importance. Also, in asymmetric reaction systems 1,2-diamine and its derivatives,
3
imidazoline and Schiff base, function as chiral ligands.
Until now, there have been a number of methodologies for the synthesis of chiral 1,2-diamines such as
4
5
derivatization from amino acids, substitutional induction of nitrogen nucleophiles to haloalkanes,
6
7
conjugate addition of nitrogen nucleophiles to nitroalkenes and aziridines, diamination of 1,2-dilos, and
8
the coupling reaction of imines, and most of these are primarily for the construction of a specific side
chain structure and/or a stereocenter. Therefore, the need remains for a versatile method for the chiral
syntheses of various types of C -symmetric and unsymmetric1,2-diamines.
2
*
Dedicated to Professor Victor Snieckus, Queen’s University, on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 88, No. 2, 2014
We previously reported that optically active trans-4,5-dimethoxy-2-imidazolidinone (DMIm), the
enantiomers of which were both readily available, functioned as a versatile chiral synthon for the
1
2
1
2
construction of various types of symmetric (R = R ) and unsymmetric (R ! R ) 1,2-diamines, including
the stepwise and stereoselective conversion of two aminal moieties to other substituents followed by
9
ring-opening (Scheme 1). This methodology has an advantage over other methods, in that various types
of symmetric and unsymmetric 1,2-diamines and their enantiomers can be easily prepared. The
construction of a chemical library in the field of medicinal research would be easier with this
methodology.
Scheme 1
Both of the optically pure enantiomers of DMIm were provided from a simple 5-membered heterocycle.
1
,3-Diacetyl-2-imidazolone underwent the smooth electrophilic addition of bromine to give trans-1,3-
diacetyl-4,5-dibromo-2-imidazolidinone and that was methanolyzed to the corresponding (4RS,5RS)-
-acetyl-DMIm followed by N-acylation with (1S,2R)-2-exo-methoxyapocamphanecarbonyl chloride
1
1
0
(
MAC-Cl), which proved to be a versatile auxiliary of choice for optical resolution, and led to the
9
subsequent optical resolution of both diastereomers. However, this synthetic methodology includes some
drawbacks: i) bromine is harmful and difficult to handle, and it was needed for the first step; and, ii) the
direct optical resolution of the diastereomers of 1-MAC-DMIm was impossible, which necessitated a
somewhat lengthy and tedious process that included the replacement of one methoxy moiety with a
benzyloxy moiety in the presence of a large amount of benzyl alcohol (that was difficult to remove from
the reaction mixture), and the subsequent optical resolution of their diastereomers had to be followed by
the re-methoxylation of the benzyloxy moiety. Therefore, the need remains for a more practical and facile
method for the preparation of both enantiomers (diastereomers) of DMIm.
Meanwhile, we recently attempted to oxidize the olefinic moiety of a 2-imidazolone heterocycle to obtain
its epoxide as a DMIm equivalent and unexpectedly found that the FeCl -catalyzed oxidation of
3
2
-imidazolone using aqueous hydrogen peroxide (30%) as an oxidant yielded hydroxy/alkoxy-
1
1
functionalized 2-imidazolidinones in place of its epoxide. This accidental result prompted us to conceive
of this new strategy for DMIm without the use of bromine. Concurrently, during the course of other
research, we also discovered that the racemic DMIm were optically resolved by the introduction of a
MAC moiety and a specific arylsulfonyl group at the N-position of DMIm. Herein, we describe an

HETEROCYCLES, Vol. 88, No. 2, 2014
1339
efficient method for the preparation of both enantiomers of DMIm using the Fe(III)-catalyzed oxidation
of 2-imidazolone followed by the optical resolution of the N-arylsulfonyl derivatives using MAC acid.
RESULTS AND DISCUSSION
1
. Exploration of a simple method for the preparation of racemic DMIm using Fe(III)-catalyzed
oxidation:
Table 1. The Fe(III)-catalyzed oxidation of 1-benzoyl-2-imidazolone by hydrogen peroxide
1
1
According to our preliminary results, we first examined the efficient functionalization of 2-imidazolone
to a DMIm precursor using Fe(III)-catalyzed oxidation (Table 1). Using methanol rather than t-butanol as
the solvent, the reaction did not proceed well and gave the corresponding 4-methoxy-5-hydroxy-2-
imidazolone 2 in a poor yield (entry 1). We speculated that this was the result of the oxidation of
methanol, and chose trimethyl orthoacetate as the next candidate for a methoxy donor. However, the

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HETEROCYCLES, Vol. 88, No. 2, 2014
hydrolysis of trimethyl orthoacetate with aqueous hydrogen peroxide solution resulted in methanol, which
resulted in lower reactivity (entry 2). Compared with previous trials, the use of a hydrogen peroxide-urea
complex, instead of aqueous hydrogen peroxide, induced a higher yield of 4-methoxy derivative 2 (entry
3
).
A similar moderate yield of 2 (entry 5) was obtained when we tried a pre-synthesized Fe(III)-dipicolinate
complex (FeCl(dipic)(H O) ) in order to simplify the reaction procedure and maintain uniformity of the
2
2
catalyst: the combination of FeCl(dipic)(H O) , 0.1 equivalent of diisopropylamine, and a hydrogen
2
2
peroxide-urea complex. Intriguingly, the addition of diisopropylammonium chloride in place of
diisopropylamine also activated the reaction to give a higher yield of 2 (entry 6). This reaction system
was also greatly affected by the amount of trimethyl orthoacetate. The 30% trimethyl orthoacetate solvent
system showed the highest reactivity, and produced an 85% yield of 2 (entry 8).
With 5-hydroxy-4-methoxy-2-imidazolidinone 2 thus obtained, the conversion to (4RS,5RS)-DMIm 4
resulted in a 77% yield that was easily accomplished in two steps: i) diacetylation of 2, and ii) the
regioselective cleavage of a 1-benzoyl group followed by the substitution of the acetoxy group with a
methoxy group (Scheme 2).
HO
OMe
NH
AcO
OMe
MeO
HN
OMe
AcCl (2.5 eq)
i-Pr NEt (2.5 eq)
Pyridine (1 eq)
2
N
N
N
N
Bz
CH Cl
Bz
Ac
MeOH
Ac
2
2
rt, 4 h
50 °C, 21 h
O
O
O
"DMIm"
96%
80%
2
3
4
Scheme 2
2
. Effective optical resolution of racemic DMIm:
As mentioned above, a lengthy and tedious process was required for the production of both enantiomers
of DMIm using MAC acid. The process included the conversion of methoxy to a benzyloxy group in the
presence of a large amount of benzyl alcohol. Therefore, the investigation of a more facile method for the
optical resolution of DMIm is needed.
During the course of our recent research, we found that the introduction of some arylsulfonyl moieties to
the nitrogen position of N-MAC-DMIm changed the separability of diastereomers during silicagel column
chromatography. Thus, several types of 1-arylsulfonyl-3-MAC-DMIm were examined and
1
-benzenesulfonyl and 1-(2-mesitylenesulfonyl) derivatives could be effectively separated to the
1
2
diastereomers 6 and 7 (Table 2, entries 5, 6).

HETEROCYCLES, Vol. 88, No. 2, 2014
1341
Table 2. Trials for the optical resolution of 1-arylsulfonyl-3-MAC-DMIm
1
) RSO Cl (2 eq)
2
MeO
HN
OMe
MeO
OMe
NH
MeO
OMe
MeO
OMe
i-Pr NEt (3 eq)
MAC-Cl (1.2 eq)
NaH (2.4 eq)
2
CH Cl ; rt, 9-24 h
2
2
N
N
N
N
+ RO
N
N
Ac 2) Cs CO (0.1 eq)
RO S
THF; rt, 2 h
RO
2
S
MAC
2
S
MAC
2
3
2
MeOH; rt, 10 min
O
O
O
O
4
5a-f
Cl
6a-f
7a-f
O
OMe
(
MAC-Cl)
Yield (%)a)
separability
of diastereomers
Entry
R
5
6
7
1
2
3
4
5
6
Tol (a)
p-NO C H (b)
97
94
67
92
99
96
0 (48)
0 (48)
X
X
X
!
2 (37) 10 (41)
2 (47) 20 (51)
2
6 4
o-NO C H (c)
2
6 4
p-ClC H (d)
29 (37) 21 (50)
39 (48) 47 (51)
38 (46) 47 (52)
6
4
Ph (e)
2,4,6-Me C H (f)
O
O
3
6 2
1
a) Isolated yields. The values in parentheses are calculated yields based on H-NMR.
There are two ways to transform these diastereomers into chiral synthons for 1,2-diamines.
Desulfonylation and deacylation are the valid routes for mono-N-substituted DMIm, with a methoxy
group at the “NH” side that can be converted into another substituent. As a result of our examinations, the
selective removal of both groups, arylsulfonyl and MAC, was accomplished. Thus, the diastereomers of
1
-(2-mesitylenesulfonyl)-3-MAC-DMIm, 6f and 7f, were treated with LiBH /MeOH (1:2) and PhCH SLi,
4 2
respectively, to yield a pair of deacylated DMIm enantiomers, 8f and 9f, in excellent yields (90 and 98%,
1
3
respectively; Scheme 3). The same trials using 1-benzenesulfonyl derivatives 6e and 7e gave inferior
results (72% of 8e and 68% of 9e).
Scheme 3

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HETEROCYCLES, Vol. 88, No. 2, 2014
On the other hand, UV-irradiation to 1-(2-mesitylenesulfonyl)-3-MAC-DMIm 7f in the presence of
sodium cyanoborohydride and anisole gave the corresponding desulfonylated DMIm 10 in a 90% yield
(Scheme 4). The compound 6f also gave similar results under the same conditions.
Scheme 4
In conclusion, we established a complementary method for the preparation of both of the enantiomers of
DMIm, using the Fe(III)-catalyzed oxidation of 2-imidazolone via a H O -urea complex with subsequent
2
2
optical resolution via the introduction of a MAC moiety and a 2-mesitylenesulfonyl group at the two
nitrogen positions of DMIm, which were then selectively removed. Compared with the previous method,
this new procedure required neither hazardous bromine, which is difficult to handle, nor the multi-step
conversion of the alkoxy moiety, which requires the use of a large amount of benzyl alcohol that is
difficult to remove from the reaction mixture. This new method features ease of handling and a simple
attach-detach process, and, therefore, is more suitable for the multi-gram scale preparation of both
enantiomers of chiral DMIm.
EXPERIMENTAL
Melting points were determined using a Yanaco micro melting point apparatus and were uncorrected.
1
Optical rotations were measured with a JASCO P-1010 polarimeter. H NMR spectra were recorded in
CDCl with tetramethylsilane as the internal standard using JEOL ALPHA 500 (500 MHz), JEOL
3
1
3
JNM-GX400 (400 MHz) and JEOL JNM-AL300 (300 MHz) spectrometers. C NMR spectra were
recorded in CDCl with tetramethylsilane as the internal standard using JEOL ALPHA 500 (125 MHz),
3
JEOL JNM-GX400 (100 MHz) and JEOL JNM-AL300 (75 MHz) spectrometers with broad-band proton
decoupling. Infrared spectra were measured with a JEOL JIR-6500W and JASCO FT/IR-410 FT-IR
spectrometer. MS and HRMS (EI or FAB) were obtained with a JEOL JMS-700 mass spectrometer. Fuji
silysia silica gel (PSQ60B) was used for flash chromatography. Fe(III)-dipicolinate complex
1
4
(
FeCl(dipic)(H O) ) was prepared following a previously reported procedure.
2 2
Fe(III)-catalyzed oxidation of 1-benzoyl-2-imidazolone (1) by hydrogen peroxide (Table 1):
i) Typical procedure using FeCl •6H O/dipicolinic acid/i-Pr NH and 30% H O aq (entry 2). To a
3
2
2
2
2

HETEROCYCLES, Vol. 88, No. 2, 2014
1343
suspension of FeCl •6H O (7.2 mg, 0.1 eq) and dipicolinic acid (4.4 mg, 0.1 eq) in CH Cl (1 mL) was
3
2
2
2
added i-Pr NH (7.5 µL) and the suspension was stirred at 26 °C for 30 min. After the addition of a
2
solution of 1-benzoyl-2-imidazolone (1) (50 mg, 0.2657 mmol)in CH Cl (1.4 mL) to the catalyst mixture
2
2
with stirring for 10 min at 26 °C, trimethyl orthoacetate (2.4 mL) was added along with an aqueous H O2
2
solution (30%) in trimethyl orthoacetate (0.48 mL), which were added to the reaction mixture over 1 h
using a syringe pump at 0 °C followed by stirring for 24 h at 0 °C. The reaction mixture was passed
through SiO pad (EtOAc as eluent) to quench the reaction and the eluent was evaporated in vacuo
2
followed by flash column chromatography on silica gel (hexane/EtOAc; 5/5 to 2/8) to yield a mixture of
(4RS,5RS)-trans-1-benzoyl-5-hydroxy-4-methoxy-2-imidazolidinone (2) (18.8 mg, 0.0795 mmol, 30%)
and the starting material (1) (27.9 mg, 0.1484 mmol, 56%) as a colorless amorphous solid, the ratio of
1
which was determined by H NMR spectrometry.
ii) Typical procedure using FeCl(dipic)(H O) /i-Pr NH•HCl and H O urea (entry 8). A suspension
2
2
2
2
2
of FeCl(dipic)(H O) (7.8 mg, 0.1 eq) and i-Pr NH•HCl (3.7 mg, 0.1 eq) in CH Cl (2.3 mL) was stirred at
2
2
2
2
2
2
6 °C for 30 min. After the addition of a solution of 1-benzoyl-2-imidazolone (1) in CH Cl (1.4 mL) to
2 2
the catalyst mixture with stirring for 10 min at 26 °C, trimethyl orthoacetate (1.59 mL) and H O -urea
2
2
(37.5 mg) were subsequently added at 0 °C and then stirred at 26 °C for 3 h. The reaction mixture was
passed through a SiO pad (EtOAc as eluent) to quench the reaction and the eluent was evaporated in
2
vacuo followed by flash column chromatography on silica gel (hexane/EtOAc; 5/5 to 2/8) to yield
(4RS,5RS)-trans-1-benzoyl-5-hydroxy-4-methoxy-2-imidazolidinone (2) (53.3 mg, 0.2256 mmol, 85%)
as colorless crystals; mp 145-148 °C (CH Cl ); IR (KBr) " 3410, 3207, 3128, 2935, 2916, 2835, 1741,
2
2
-
1
1
1
680, 1448, 1427, 1404 cm ; H NMR (300 MHz), CDCl ) d 3.42 (3H, s), 4.29(1H, d, J = 2.6 Hz), 4.68
3
(1H, d, J = 2.6 Hz), 5.73 (1H, d, J = 1.1 Hz), 6.00 (1H, br s), 7.40-7.45 (2H, m), 7.53-7.58 (1H, m),
1
3
7
1
.66-7.69 (2H, m); C-NMR (75 MHz, CD CN) d 53.1, 81.9, 85.7, 126.6, 127.7, 130.6, 133.6, 152.6,
3
+
69.0. MS (FAB) m/z 237 (MH , 52), 105 (PhCO, 100), 77 (Ph, 23); HRMS (FAB) Calcd for C H N O
11
13
2
4
+
(
(
(
MH ): m/z 237.0875. Found: m/z 237.0875.
4RS,5RS)-trans-5-Acetoxy-3-acetyl-1-benzoyl-4-methoxy-2-imidazolidinone (3). To a solution of
4RS,5RS)-trans-1-benzoyl-5-hydroxy-4-methoxy-2-imidazolidinone (2) (340 mg, 1.439 mmol) in
CH Cl (14 mL) were added i-Pr NEt (0.63 mL, 3.598 mmol, 2.5 eq) and acetyl chloride (0.26 mL, 3.598
2
2
2
mmol, 2.5 eq) at 0 °C with stirring at room temperature for 4 h. The reaction mixture was passed through
a SiO pad (EtOAc as eluent) to quench the reaction and the eluent was evaporated in vacuo followed by
2
flash column chromatography on silica gel (hexane/CH Cl (2/8) - CH Cl - EtOAc/CH Cl (2/8)) to yield
2
2
2
2
2
2
3
(440.4 mg, 1.375 mmol, 96%) as a pale yellow oil; IR (KBr) " 3014, 2943, 2846, 1782, 1753, 1716,
-
1 1
1
699, 1373 cm ; H NMR (300 MHz, CDCl ) ! 2.16 (3H, s), 2.50 (3H, s), 3.65 (3H, s), 5.30 (1H, s), 6.54
3
1
3
(
1H, s), 7.44 (2H, m), 7.57-7.66 (3H, m); C NMR (75 MHz, CDCl ) ! 20.7, 24.3, 58.0, 79.6, 85.7, 128.0,
3

1344
HETEROCYCLES, Vol. 88, No. 2, 2014
+
+
1
28.8, 132.7, 132.8, 150.2, 168.6, 169.3, 170.3. MS (FAB) m/z 321 (MH , 4), 289 (M -OMe, 3), 261
+
+
(
M -OAc, 10), 105 (PhCO, 100), 77 (Ph, 7); HRMS (FAB) Calcd for C H N O (MH ): m/z 321.1087.
15 17 2 6
Found: m/z 321.1066.
(4RS,5RS)-trans-1-Acetyl-4,5-dimethoxy-2-imidazolidinone (4). To a solution of (4RS,5RS)-trans-
5
-acetoxy-3-acetyl-1-benzoyl-4-methoxy-2-imidazolidinone (3) (271 mg, 0.846 mmol) in MeOH (17 mL)
was added pyridine (0.067 mL, 0.846 mmol, 1.0 eq) with stirring at 50 °C for 21 h. The reaction mixture
was concentrated in vacuo and the residue was purified by flash column chromatographed on silica gel
(
(
(
CH Cl /EtOAc (9/1 to 7/3)) to obtain 4 (127 mg, 0.677 mmol, 80%) as colorless crystals; mp 100-102 °C
2 2
-
1 1
hexane); IR (KBr) " 3248, 3145, 3014, 2985, 2941, 2846, 2825, 1732, 1707, 1464, 1406 cm ; H NMR
300 MHz, CDCl ) ! 2.52 (3H, s), 3.36 (3H, s), 3.53 (3H, s), 4.57 (1H, d, J = 1.3 Hz), 5.34 (1H, d, J = 1.3
3
1
3
Hz), 6.77 (1H, br s); C NMR (75 MHz, CDCl ) ! 24.0, 54.2, 57.3, 85.6, 88.2, 155.4, 170.9. MS (FAB)
3
+
+
+
m/z 189 (MH , 100), 157 (M -OMe, 20), 115 (MH -OMe-OAc, 37); HRMS (FAB) Calcd for C H N O
4
7
13
2
+
(
MH ): m/z 189.0875. Found: m/z 189.0868.
Typical procedure for the preparation of (4RS,5RS)-1-arylsulfonyl-4,5-dimethoxy-2-
imidazolidinones 5a-f. (4RS,5RS)-4,5-dimethoxy-1-toluenesulfonyl-2-imidazolidinone (5a). To a
solution of (4RS,5RS)-trans-1-acetyl-4,5-dimethoxy-2-imidazolidinone (4) (200 mg, 1.06 mmol) in
CH Cl (11 mL) were added diisopropylethylamine (0.56 mL, 3.18 mmol, 3 eq), p-toluenesulfonyl
2
2
chloride (0.405 g, 2.12 mmol, 2 eq) and DMAP (0.013 g, 0.106 mmol, 0.1 eq) with stirring at room
temperature for 18 h. The reaction mixture was passed through a SiO pad (EtOAc as eluent) to quench
2
the reaction, and the eluent was evaporated in vacuo followed by flash chromatography on silica gel
(
hexane/EtOAc (19/1 to 8/2)) to yield (4RS,5RS)-3-acetyl-4,5-dimethoxy-1-(p-toluenesulfonyl)-2-
imidazolidinone (355 mg, 1.04 mmol) as a colorless oil, which was subsequently dissolved in MeOH
10.4 mL) and Cs CO (34 mg, 0.104 mmol, 0.1 eq) with stirring for 10 min at room temperature. Citric
(
2
3
acid (20 mg, 0.104 mmol, 0.1 eq) was added to the reaction mixture to quench the reaction and the
mixture was concentrated in vacuo followed by flash column chromatography on silica gel
(hexane/EtOAc (6/4 to 5/5)) to yield (4RS,5RS)-4,5-dimethoxy-1-(p-toluenesulfonyl)-2-imidazolidinone
(309 mg, 1.03 mmol, 97% from 4) as a colorless solid; mp 143.5-144.0 °C; IR (KBr) " 3356, 3228, 2947,
-
1 1
1
3
7
1
763, 1338, 1165, 1107, 933, 667, 601, 544 cm ; H NMR (300 MHz, CDCl ) ! 2.43 (3H, s), 3.31 (3H, s),
3
.53 (3H, s), 4.58 (1H, d, J = 1.5 Hz), 5.31(1H, d, J = 1.5 Hz), 5.74 (1H, br s), 7.32 (2H, d, J = 8.1Hz),
1
3
.93 (2H, d, J = 8.1Hz); C NMR (100 MHz, CDCl ) ! 21.7, 54.1, 56.0, 85.9, 91.6, 128.2, 129.5, 135.9,
3
+
+
+
44.9, 154.1. MS (FAB) m/z 301 (MH , 39), 269 (M -OMe, 100), 91 (CH C H , 22); HRMS (FAB)
3
6
5
+
Calcd for C H N O S (MH ): m/z 301.0858. Found: m/z 301.0873.
1
2
17
2
5
(4RS,5RS)-4,5-Dimethoxy-1-(p-nitrobenzenesulfonyl)-2-imidazolidinone (5b): a colorless solid; mp
-
1
1
1
38-139 °C; IR (KBr) " 3251, 3140, 2939, 1743, 1531, 1377, 1184, 949, 856, 744, 621 cm ; H NMR

HETEROCYCLES, Vol. 88, No. 2, 2014
1345
(
300 MHz, CDCl ) ! 3.33 (3H, s), 3.54 (3H, s), 4.60 (1H, d, J = 1.3 Hz), 5.28 (1H, d, J = 1.3 Hz), 6.61
3
1
3
(
1H, br s), 8.23 (2H, d, J = 9.1 Hz), 8.35 (2H, d, J = 9.1 Hz); C NMR (100 MHz, CDCl ) ! 54.5, 56.4,
3
+
+
8
5.9, 91.8, 124.1, 129.7, 144.2, 150.7, 153.6. MS (FAB) m/z 332 (MH , 3), 300 (M -OMe, 4), 154 (100);
+
+
HRMS (FAB) Calcd for C H N O SNa (MNa ): m/z 354.0372. Found (MNa ): m/z 354.0382.
11
13
3
7
(4RS,5RS)-4,5-Dimethoxy-1-(o-nitrobenzenesulfonyl)-2-imidazolidinone (5c): a colorless solid; mp
-
1 1
1
61-162 °C; IR (KBr) " 3313, 3124, 2951, 1751, 1543, 1369, 1180, 1088, 602 cm ; H NMR (300 MHz,
CDCl ) ! 3.41 (3H, s), 3.61 (3H, s), 4.64 (1H, s), 5.40 (1H, s), 5.95 (1H, br s), 7.67-7.84 (3H, m),
3
1
3
8
1
.42-8.44 (1H, m); C NMR (100 MHz, CDCl ) ! 54.7, 56.9, 87.4, 91.6, 124.6, 131.6, 132.1, 134.4,
3
+
+
35.0, 148.1, 153.1. MS (FAB) m/z 332 (MH , 3), 300 (M -OMe, 29), 154 (100); HRMS (FAB) Calcd for
+
C H N O S (MH ): m/z 332.0552. Found: m/z 332.0564.
11
14
3
7
(4RS,5RS)-1-(p-Chlorobenzenesulfonyl)-4,5-dimethoxy-2-imidazolidinone (5d): a colorless solid; mp
-
1
1
19.5-120.5 °C; IR (KBr) " 3356, 3105, 2943, 2839, 1755, 1577, 1365, 1176, 1095, 945, 764, 633 cm ;
1
H NMR (300 MHz, CDCl ) ! 3.30 (3H, s), 3.52 (3H, s), 4.58 (1H, s), 5.27 (1H, s), 6.50 (1H, br s),
3
1
3
7
!
1
3
.47-7.50 (2H, d, J = 8.6 Hz), 7.96-7.99 (2H, d, J = 8.6 Hz); C NMR (125 MHz, CDCl3)
+
+
54.1, 56.2, 85.9, 91.6, 129.2, 129.8, 137.3, 140.5, 153.5. MS (FAB) m/z 321 (MH , 43), 323 ((M+2)H ,
+
+
+
8), 289 (M -OMe, 100), 291 ((M+2) -OMe, 39); HRMS (FAB) Calcd for C H ClN O S (MH ): m/z
11
14
2
5
21.0312. Found: m/z 321.0307.
(4RS,5RS)-1-Benzenesulfonyl-4,5-dimethoxy-2-imidazolidinone (5e):
a
colorless solid; mp
-
1 1
1
61-162 °C; IR (KBr) " 3602, 3305, 2951, 1763, 1724, 1430, 1365, 1173, 1099, 945, 605 cm ; H NMR
(
300 MHz, CDCl ) ! 3.28 (3H, s), 3.51 (3H, s), 4.58 (1H, d, J = 1.1 Hz), 5.30 (1H, d, J = 1.1 Hz), 6.48
3
1
3
(
1H, br s), 7.49-7.54 (2H, m), 7.59-7.65 (1H, m), 8.02-8.06 (2H, m); C NMR (125 MHz, CDCl )
3
+
+
!
1
54.0, 56.1, 85.9, 91.5, 128.2, 128.8, 133.8, 138.9, 153.7. MS (FAB) m/z 287 (MH , 43), 255 (M -OMe,
+
+
00), 77 (C H , 21); HRMS (FAB) Calcd for C H N O S (MH ): m/z 287.0702. Found: m/z 287.0707.
6
5
11 15
2
5
(4RS,5RS)-4,5-Dimethoxy-1-(2-mesitylenesulfonyl)-2-imidazolidinone (5f): a colorless solid; mp
1
5
5
9
79-182 °C; IR (KBr) " 3317, 2951, 1755, 1601, 1450, 1400, 1353, 1288, 1168, 1072, 941, 852, 660, 598,
-
1 1
36 cm ; H NMR (300 MHz, CDCl ) ! 2.29 (3H, s), 2.65 (6H, s), 3.28 (3H, s), 3.61 (3H, s), 4.56 (1H, s),
3
1
3
.33 (1H, s), 6.28 (1H, br s), 6.95 (2H, s); C NMR (125 MHz, CDCl ) ! 21.0, 22.6, 54.5, 56.2, 86.8,
3
+
+
1.5, 132.0, 132.3, 141.3, 143.7, 154.1. MS (FAB) m/z 329 (MH , 28), 297 (M -OMe, 81), 183
+
(
Me C H SO , 72), 119 (Me C H , 100); HRMS (FAB) Calcd for C H N O S (MH ): m/z 329.1171.
3
6
2
2
3
6
2
14 21
2
5
Found: m/z 329.1176.
Typical procedure for the conjunction of (4RS,5RS)-1-arylsulfonyl-4,5-dimethoxy-2-
imidazolidinones 5a-f with MAC-Cl. Optical resolution of 6a and 7a. To a solution of
(4RS,5RS)-4,5-dimethoxy-1-toluenesulfonyl-2-imidazolidinone (5a) (251 mg, 0.837 mmol) in THF (4.2
mL) was added NaH (60% in oli, 81 mg, 2.4 eq) at 0 °C with stirring for 15 min at room temperature

1346
HETEROCYCLES, Vol. 88, No. 2, 2014
followed by the addition of MAC-Cl, prepared from MAC acid (200 mg, 1 mmol, 1.2 eq) and thoinyl
chloride (0.293 mL, 4 mmol, 4.8 eq) under reflux for 1 h with the subsequent removal of the remaining
thoinyl chloride, HCl and SO by toluene-azeotrope, and further stirring for 2 h. The reaction was
2
quenched by the addition of satd. NH Cl aq., and the product was extracted (EtOAc, 40 mL x 3), washed
4
(
brine, 30 mL x 3) and dried (anhyd. Na SO ). After the concentration of the organic layer in vacuo, the
2 4
residue was purified by flash column chromatography on silica gel (hexane/EtOAc (6/4 to 5/5)) to afford
a colorless amorphous solid of a 1:1 mixture of 6a and 7a (386 mg, 0.804 mmol, 96%), the elements of
which were scarcely separable on SiO . Absolute configurations of both products were estimated based on
2
1
15
comparisons of the H NMR spectroscopies of 6f and 7f.
4S,5S)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-toluenesulfonyl)-2-
imidazolidinone (7a, higher polarity): IR (neat) " 3664, 3521, 3020, 2877, 1766, 1697, 1597, 1454,
(
-
1 1
1
1
373, 1180, 1092, 945, 814, 733, 667 cm ; H NMR (300 MHz, CDCl ) ! 1.05-1.11 (1H, m), 1.11 (3H, s),
3
.19 (3H, s), 1.54-1.65 (2H, m), 1.76-1.80 (3H, m), 2.27-2.33 (1H, m), 2.42 (3H, s), 2.78 (3H, s), 3.45
(3H, s), 3.48 (3H, s), 4.11 (1H, dd, J = 3.7, 7.7 Hz), 5.21 (1H, s), 5.30 (1H, s), 7.33 (2H, d, J = 8.4 Hz),
1
3
7
5
4
5
.95 (2H, d, J = 8.4 Hz); C NMR (100 MHz, CDCl ) ! 21.1, 21.7, 21.8, 27.0, 28.5, 37.2, 45.4, 50.7,
3
+
5.5, 55.7, 56.8, 62.1, 83.0, 87.1, 88.9, 128.8, 129.5, 135.3, 145.2, 148.7, 173.2. MS (FAB) m/z 481 (MH ,
+
+
), 449 (M -OMe, 14), 181 (MAC moiety, 100); HRMS (FAB) Calcd for C H N O SNa (MNa ): m/z
2
3
32
2
7
+
03.1828. Found (MNa ): m/z 503.1793.
(
4R,5R)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-toluenesulfonyl)-2-
imidazolidinone (6a, lower polarity): IR (neat) " 3687, 2943, 1766, 1697, 1597, 1454, 1373, 1184, 1107,
-
1
1
9
41, 818, 744, 667 cm ; H NMR (300 MHz, CDCl ) ! 1.04 (3H, s), 1.04-1.08 (1H, m), 1.25 (3H, s),
3
1
.59-1.69 (5H, m), 2.04-2.09 (1H, m), 2.42 (3H, s), 2.92 (3H, s), 3.40 (3H, s), 3.54 (3H, s), 4.37 (1H, dd,
1
3
J = 3.7, 7.9 Hz), 5.18 (1H, s), 5.41 (1H, s), 7.32 (2H, d, J = 7.9 Hz), 7.92 (2H, d, J = 7.9 Hz) ; C NMR
(
100 MHz, CDCl ) ! 21.3, 21.5, 21.7, 26.65, 26.67, 37.9, 45.4, 50.7, 56.1, 56.3, 56.8, 62.0, 84.4, 86.7,
3
+
+
8
9.2, 128.7, 129.5, 135.3, 145.2, 148.6, 173.1. MS (FAB) m/z 481 (MH , 4), 449 (M -OMe, 8), 181
+
+
(
MAC moiety, 100); HRMS (FAB) Calcd for C H N O SNa (MNa ): m/z 503.1828. Found (MNa ): m/z
23 32 2 7
5
03.1865.
trans-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-nitrobenzenesulfonyl)-
-imidazolidinone (6b, 7b): From 277 mg (0.837 mmol) of 5b, a colorless amorphous solid of a mixture
2
of 6b and 7b (331 mg, 0.65 mmol, 78%), both of which were slightly separable on SiO , was obtained.
2
1
Absolute configurations of both products were estimated based on comparisons of the H NMR
1
5
spectroscopies of 6f and 7f.
4S,5S)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-nitrobenzenesulfonyl)-
-imidazolidinone (7b, higher polarity): IR (neat) " 3656, 3109, 3001, 2881, 1770, 1701, 1608, 1535,
(
2

HETEROCYCLES, Vol. 88, No. 2, 2014
1347
-
1
1
1
1
3
458, 1377, 1188, 1088, 945, 856, 741, 621, 567 cm ; H NMR (300 MHz, CDCl ) ! 1.10 (3H, s),
3
.04-1.14 (1H, m), 1.19 (3H, s), 1.53-1.64 (3H, m), 1.71-1.84 (2H, m), 2.16-2.28 (1H, m), 2.79 (3H, s),
.47 (3H, s), 3.53 (3H, s), 4.07 (1H, dd, J = 7.7, 3.7 Hz), 5.20 (1H, s), 5.34 (1H, s), 8.27 (2H, d, J = 9.1
1
3
Hz), 8.38 (2H, d, J = 9.1 Hz); C NMR (100 MHz, CDCl ) ! 21.0, 21.5, 26.8, 28.4, 37.0, 45.2, 50.7,
3
5
5.4, 56.0, 57.2, 62.1, 83.0, 87.1, 89.2, 124.0, 130.2, 143.6, 148.4, 150.8, 173.0. MS (FAB; +NaI) m/z 534
+
+
(
MNa , 45), 181 (MAC moiety, 100); HRMS (FAB) Calcd for C H N O SNa (MNa ): m/z 534.1522.
22 29 3 9
+
Found (MNa ): m/z 534.1537.
4R,5R)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-nitrobenzenesulfon-
yl)-2-imidazolidinone (6b, lower polarity): IR (neat) " 3599, 3109, 2943, 1770, 1701, 1608, 1535, 1458,
(
-
1
1
1
373, 1188, 1092, 945, 856, 741, 621, 567 cm ; H NMR (300 MHz, CDCl ) ! 1.04 (3H, s), 1.02-1.16
3
(1H, m), 1.25 (3H, s), 1.55-1.75 (3H, m), 1.78-1.88 (1H, m), 1.95-2.03 (1H, m), 2.99 (3H, s), 3.43 (3H, s),
3
.56 (3H, s), 4.34 (1H, dd, J = 7.9, 3.7 Hz), 5.19 (1H, s), 5.46 (1H, s), 8.26 (2H, d, J = 9.2 Hz), 8.38 (2H,
1
3
d, J = 9.2 Hz); C NMR (100 MHz, CDCl ) ! 21.2, 21.4, 26.6, 26.7, 37.7, 45.3, 50.7, 56.0, 56.4, 57.0,
3
+
6
2.0, 84.2, 86.3, 89.3, 124.0, 130.1, 143.7, 148.3, 150.8, 173.0. MS (FAB; +NaI) m/z 534 (MNa , 100),
+
+
1
81 (MAC moiety, 97); HRMS (FAB) Calcd for C H N O SNa (MNa ): m/z 534.1522. Found (MNa ):
22 29 3 9
m/z 534.1534.
trans-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(o-nitrobenzenesulfonyl)-
-imidazolidinone (6c, 7c): From 277 mg (0.837 mmol) of 5c, a colorless amorphous solid of a mixture
2
of 6c and 7c (418 mg, 0.82 mmol, 98%), both of which were slightly separable on SiO , was obtained.
2
1
Absolute configurations of both products were estimated based on comparisons of the H NMR
1
5
spectroscopies of 6f and 7f.
4S,5S)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(o-nitrobenzenesulfon-
yl)-2-imidazolidinone (7c, lower polarity): IR (neat) " 3575, 3101, 2943, 1766, 1701, 1547, 1454, 1377,
(
-
1
1
1
188, 1092, 945, 737 cm ; H NMR (300 MHz, CDCl ) ! 1.12 (3H, s), 1.05-1.16 (1H, m), 1.24 (3H, s),
3
1
.60-1.87 (5H, m), 2.15-2.24 (1H, m), 3.18 (3H, s), 3.55 (3H, s), 3.57 (3H, s), 4.20 (1H, dd, J = 7.6, 3.8
1
3
Hz), 5.28 (1H, s), 5.30 (1H, s), 7.77-7.80 (3H, m), 8.44-8.47 (1H, m); C NMR (100 MHz, CDCl )
3
!
21.1, 21.7, 27.1, 28.6, 37.3, 45.4, 50.9, 56.2, 56.3, 57.1, 62.1, 83.0, 88.7, 89.0, 124.9, 131.3, 132.1,
+
1
34.4, 135.3, 148.3, 148.5, 172.9. MS (FAB; +NaI) m/z 534 (MNa , 86), 181 (MAC moiety, 100); HRMS
+
+
(
FAB) Calcd for C H N O SNa (MNa ): m/z 534.1522. Found (MNa ): m/z 534.1530.
22 29 3 9
(
4R,5R)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(o-nitrobenzenesulfon-
yl)-2-imidazolidinone (6c, higher polarity): IR (neat) " 3683, 3105, 2943, 1766, 1701, 1547, 1454,
-
1 1
1
377, 1188, 1095, 945, 737 cm ; H NMR (300 MHz, CDCl ) ! 1.07 (3H, s), 1.07-1.12 (1H, m), 1.26 (3H,
3
s), 1.56-1.87 (5H, m), 2.05-2.15 (1H, m), 2.86 (3H, s), 3.48 (3H, s), 3.59 (3H, s), 4.31 (1H, dd, J = 7.7,
1
3
3
.8 Hz), 5.26 (1H, s), 5.38 (1H, s), 7.76-7.80 (3H, m), 8.49-8.43 (1H, m); C NMR (100 MHz, CDCl )
3

1348
HETEROCYCLES, Vol. 88, No. 2, 2014
!
21.2, 21.4, 26.6, 26.9, 37.8, 45.3, 50.7, 55.9, 56.9, 57.0, 62.0, 84.5, 87.9, 89.3, 124.7, 131.2,131.9, 133.8,
+
1
35.0, 148.1, 148.3, 172.7. MS (FAB; +NaI) m/z 534 (MNa , 100), 181 (MAC moiety, 92); HRMS (FAB)
+
+
Calcd for C H N O SNa (MNa ): m/z 534.1522. Found (MNa ): m/z 534.1531.
2
2
29
3
9
trans-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-chlorobenzenesulfonyl)-
-imidazolidinone (6d, 7d): From 162 mg (0.505 mmol) of 5d, a mixture of 6d and 7d (218 mg, 0.44
mmol, 87%), both of which were partly separable on SiO , was obtained. Absolute configurations of both
2
2
1
15
products were estimated based on comparisons of the H NMR spectroscopies of 6f and 7f.
4S,5S)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-chlorobenzenesulfon-
yl)-2-imidazolidinone (7d, higher polarity): colorless crystals; mp 102-103 °C (from hexane-CH Cl );
(
2
2
3
0
[
"]D -9.5 (c 1.01, CHCl ); IR (KBr) " 3390, 2966, 1770, 1693, 1581, 1466, 1377, 1188, 1092, 945, 764,
3
-
1 1
6
29, 567 cm ; H NMR (300 MHz, CDCl ) ! 1.04-1.13 (1H, m), 1.11 (3H, s), 1.20 (3H, s), 1.55-1.65 (2H,
3
m), 1.71-1.85 (3H, m), 2.20-2.30 (1H, m), 2.79 (3H,s), 3.46 (3H, s), 3.49 (3H, s), 4.09 (1H, dd, J = 7.9,
1
3
3
.8 Hz), 5.18 (1H, s), 5.32 (1H, s), 7.51 (2H, d, J = 8.7 Hz), 8.01 (2H, d, J = 8.7 Hz); C NMR (125 MHz,
CDCl ) ! 21.0, 21.6, 26.9, 28.4, 37.2, 45.3, 50.7, 55.4, 55.8, 56.9, 62.1, 83.0, 87.0, 89.0, 129.1, 130.2,
3
+
+
1
36.7, 140.8, 148.6, 173.1. MS (FAB) m/z 501 (MH , 4), 469 (M -OMe, 7), 181 (MAC moiety, 100);
+
+
HRMS (FAB) Calcd for C H ClN O SNa (MNa ): m/z 523.1282. Found (MNa ): m/z 523.1291.
2
2
29
2
7
(4R,5R)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(p-chlorobenzenesulfon-
yl)-2-imidazolidinone (6d, lower polarity): colorless crystals; mp 118-118.5 °C (from hexane-CH Cl );
2
2
3
0
[
"]D -35.1 (c 1.00, CHCl ); IR (KBr) " 3429, 2947, 1766, 1701, 1581, 1466, 1377, 1184, 1095, 945, 760,
3
-
1 1
6
29, 575 cm ; H NMR (300 MHz, CDCl ) ! 1.04 (3H, s), 1.04-1.11 (1H, m), 1.25 (3H, s), 1.59-1.75 (4H,
3
m), 1.78-1.86 (1H, m), 2.00-2.07 (1H, m), 2.96 (3H, s), 3.41 (3H, s), 3.54 (3H, s), 4.36 (1H, dd, J = 7.7,
1
3
3
.7 Hz), 5.17 (1H, s), 5.43 (1H, s), 7.51 (2H, d, J = 8.7 Hz), 7.99 (2H, d, J = 8.7 Hz); C NMR (125 MHz,
CDCl ) ! 21.2, 21.4, 26.61, 26.64, 37.8, 45.3, 50.7, 56.0, 56.3, 56.8, 62.0, 84.3, 86.6, 89.3, 129.1, 130.1,
3
+
+
1
36.6, 140.8, 148.5, 173.0. MS (FAB) m/z 501 (MH , 5), 469 (M -OMe, 6), 181 (MAC moiety, 100);
+
+
HRMS (FAB) Calcd for C H ClN O SNa (MNa ): m/z 523.1282. Found (MNa ): m/z 523.1267.
2
2
29
2
7
trans-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-benzenesulfonyl-2-
imidazolidinone (6e, 7e): From 140 mg (0.489 mmol) of 5e, a mixture of 6e and 7e (218 mg, 0.44 mmol,
8
7%), both of which were almost separable on SiO , was obtained. Absolute configurations of both
2
1
15
products were estimated based on comparisons of the H NMR spectroscopies of 6f and 7f.
(
4S,5S)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-benzenesulfonyl-2-
3
0
imidazolidinone (7e, higher polarity): colorless crystals; mp 163-164 °C (from hexane-CH Cl ); ["]
D
2
2
-
3.8 (c 1.01, CHCl ); IR (KBr) " 3440, 2943, 1774, 1697, 1454, 1381, 1180, 1107, 945, 764, 725, 606,
3
-
1 1
5
71 cm ; H NMR (300 MHz, CDCl ) ! 1.04-1.11 (1H, m), 1.11 (3H, s), 1.19 (3H, s), 1.53-1.62 (2H, m),
3
1
.69-1.84 (3H, m), 2.26-2.33 (1H, m), 2.72 (3H, s), 3.45 (3H, s), 3.48 (3H, s), 4.09 (1H, dd, J = 7.7, 3.7

HETEROCYCLES, Vol. 88, No. 2, 2014
1349
1
3
Hz), 5.22 (1H, s), 5.32 (1H, s), 7.52-7.57 (2H, m), 7.60-7.66 (1H, m), 8.07-8.10 (2H, m); C NMR (125
MHz, CDCl ) ! 21.0, 21.6, 26.9, 28.4, 37.1, 45.3, 50.6, 55.4, 55.6, 56.8, 62.0, 83.0, 87.0, 88.8, 128.7,
3
+
+
1
1
4
28.8, 134.0, 138.3, 148.6, 173.1. MS (FAB) m/z 467 (MH , 8), 435 (M -OMe, 16), 181 (MAC moiety,
+
+
+
00), 77 (C H , 13); HRMS (FAB) Calcd for C H N O SNa (MNa ): m/z 489.1671. Found (MNa ): m/z
6
5
22 30
2
7
89.1682.
(
4R,5R)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-benzenesulfonyl-2-
3
0
imidazolidinone (6e, lower polarity): colorless crystals; mp 108-109 °C (from hexane-CH Cl ); ["]
2
2
D
-
1
-
35.3 (c 1.00, CHCl ); IR (KBr) " 3444, 2947, 1774, 1701, 1454, 1373, 1180, 1103, 949, 756, 602 cm ;
3
1
H NMR (300 MHz, CDCl ) ! 1.02-1.09 (1H, m), 1.04 (3H, s) 1.24 (3H, s), 1.57-1.72 (4H, m), 1.76-1.84
3
(1H, m), 2.02-2.09 (1H, m), 2.89 (3H, s), 3.40 (3H, s), 3.56 (3H, s), 4.35 (1H, dd, J = 7.7, 3.7 Hz), 5.20
1
3
(
1H, s), 5.42 (1H, s), 7.51-7.56 (2H, m), 7.60-7.66 (1H, m), 8.04-8.07 (2H, m); C NMR (125 MHz,
CDCl3) ! 21.2, 21.4, 26.6, 37.9, 45.4, 50.6, 56.0, 56.3, 56.7, 62.0, 84.3, 86.8, 89.3, 128.6, 128.8, 134.0,
+
+
+
1
38.3, 148.5, 173.1. MS (FAB) m/z 467 (MH , 4), 435 (M -OMe, 8), 181 (MAC moiety, 100), 77 (C H ,
6 5
+
+
1
2); HRMS (FAB) Calcd for C H N O SNa (MNa ): m/z 489.1671. Found (MNa ): m/z 489.1677.
2
2
30
2
7
trans-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(2-mesitylenesulfonyl)-2-
imidazolidinone (6f, 7f): From 135 mg (0.411 mmol) of 5f, the mixture of 6f and 7f (205 mg, 0.40 mmol,
9
8%), both of which were almost separable on SiO , was obtained. The absolute configuration of 7f was
2
1
assigned based on the fact that the optical rotation and H NMR data of desulfonylated compound 10
9
identified it as the same compound that was previously reported.
(4S,5S)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(2-mesitylenesulfonyl)-2-
3
0
imidazolidinone (7f, higher polarity): colorless crystals; mp 152-153 °C (from hexane-CH Cl ); ["]
D
2
2
-
27.4 (c 1.00, CHCl ); IR (KBr) " 3440, 2947, 1763, 1697, 1604, 1458, 1362, 1196, 1176, 1088, 941, 733,
3
-
1 1
6
63, 586, 528 cm ; H NMR (300 MHz, CDCl ) ! 1.04-1.12 (1H, m), 1.12 (3H, s), 1.21 (3H, s), 1.58-1.85
3
(5H, m), 2.12-2.19 (1H, m), 2.31 (3H, s), 2.69 (6H, s), 3.13 (3H, s), 3.48 (3H, s), 3.58 (3H, s), 4.13 (1H,
1
3
dd, J = 7.7, 3.7 Hz), 5.23 (1H, s), 5.30 (1H, s), 6.98 (2H, s); C NMR (100 MHz, CDCl ) ! 21.0, 21.1,
3
2
1
1.8, 22.7, 27.0, 28.7, 37.2, 45.3, 50.7, 55.8, 56.1, 57.1, 61.9, 82.9, 88.1, 88.8, 131.8, 132.0, 141.6, 143.9,
+
+
48.9, 173.4. MS (FAB) m/z 509 (MH , 4), 477 (M -OMe, 6), 181 (MAC moiety, 100); HRMS (FAB)
+
+
Calcd for C H N O SNa (MNa ): m/z 531.2141. Found (MNa ): m/z 531.2176.
2
5
36
2
7
(
4R,5R)-4,5-Dimethoxy-3-[(1S,2R)-2-exo-methoxyapocamphanecarbonyl]-1-(2-mesitylenesulfonyl)-
-imidazolidinone (6f, lower polarity): colorless crystals; mp 135-135.5 °C (from hexane-CH Cl );
2
2
2
3
0
[
"]D -19.4 (c 1.00, CHCl ); IR (KBr) " 3001, 1763, 1697, 1601, 1458, 1365, 1192, 1173, 1111, 1080,
3
-
1 1
9
37, 741, 663, 586, 528 cm ; H NMR (300 MHz, CDCl ) ! 1.03-1.11 (1H, m), 1.08 (3H, s), 1.21 (3H, s),
3
1
.54-1.64 (2H, m), 1.68-1.77 (3H, m), 2.10-2.16 (1H, m), 2.28 (3H, s), 2.67 (3H, s), 2.69 (6H, s), 3.44
1
3
(
3H, s), 3.61 (3H, s), 4.15 (1H, dd, J = 7.7, 3.7 Hz), 5.21 (1H, s), 5.42 (1H, s), 6.95 (2H, s); C NMR

1350
HETEROCYCLES, Vol. 88, No. 2, 2014
(
100 MHz, CDCl ) ! 21.0, 21.6, 22.7, 26.7, 27.1, 37.8, 45.3, 50.6, 55.8, 56.4, 57.3, 61.8, 84.1, 87.4, 88.8,
3
+
+
1
31.6, 131.8, 141.7, 143.8, 148.4, 173.2. MS (FAB) m/z 509 (MH , 4), 477 (M -OMe, 5), 181 (MAC
+
+
moiety, 100); HRMS (FAB) Calcd for C H N O SNa (MNa ): m/z 531.2141. Found (MNa ): m/z
2
5
36
2
7
5
31.2162.
Removal of the MAC moiety from 6f. (4R,5R)-4,5-dimethoxy-1-(2-mesitylenesulfonyl)-2-
imidazolidinone (8f). To a solution of 6f (170 mg, 0.334 mmol) in THF (3.4 mL) under an argon
atmosphere were subsequently added LiBH (1.0 M in THF; 0.67 mL, 1.336 mmol, 4 eq) and MeOH
4
(0.11 mL, 2.67 mmol, 8 eq; dissolved in THF (1 mL)) at 0 °C with stirring for 6 h at 0 °C. The reaction
was quenched by the addition of satd. NH Cl aq., and the product was extracted (EtOAc, 40 mL x 3),
4
washed (brine, 30 mL x 3) and dried (anhyd. Na SO ). After concentration of the organic layer in vacuo,
2
4
the residue was purified by flash column chromatography on silica gel (hexane/EtOAc (8/2 to 5/5)) to
afford 6f (5 mg, 3%) and 8f (99 mg, 0.301 mmol, 90%) as a colorless solid along with an oily amount (50
mg, 80%) of 2-exo-methoxy-l-apocamphanemethanol. 8f: a colorless crystals; mp 158.5-159 °C (from
2
9
hexane/CH Cl ); ["] -67.9 (c 0.72, CHCl ); IR (KBr) " 3320, 2950, 2839, 1755, 1605, 1450, 1354,
2
2
D
3
-
1
1
1
288, 1169, 1074, 941, 852, 775, 660, 590, 525 cm ; H NMR (300 MHz, CDCl ) ! 2.29 (3H, s), 2.65
3
1
3
(
6H, s), 3.28 (3H, s), 3.61 (3H, s), 4.56 (1H, s), 5.33 (1H, s), 6.26 (1H, br s), 6.95 (2H, s); C NMR (125
+
MHz, CDCl ) ! 21.0, 22.6, 54.5, 56.2, 86.8, 91.5, 132.0, 141.3, 143.7, 154.1. MS (FAB) m/z 329 (MH ,
3
+
4
8), 297 (M -OMe, 88), 183 (Me C H SO , 62), 119 (Me C H , 72); HRMS (FAB) Calcd for
3
6
2
2
3
6
2
+
C H N O SNa (MNa ): m/z 351.0991. Found: m/z 351.0992.
1
4
20
2
5
Removal of the MAC moiety from 7f. (4S,5S)-4,5-dimethoxy-1-(2-mesitylenesulfonyl)-2-
imidazolidinone (9f). To a solution of PhCH SH (42 µL, 0.358 mmol, 2 eq) in THF (1.8 mL) was added
2
n-BuLi (2.66 M in n-hexane; 0.10 mL, 0.268 mmol, 1.5 eq) at 0 °C under an argon atmosphere with
stirring for 10 min to form PhCH SLi, to which was added 7f (91 mg, 0.18 mmol) in THF (1.8 mL) at
2
0
°C with stirring for 1 h at 0 °C. The reaction was quenched by the addition of satd. NH Cl aq. and the
4
product was extracted (EtOAc, 20 mL x 3), washed (brine, 10 mL x 3) and dried (anhyd. Na SO ). After
2
4
concentration of the organic layer in vacuo, the residue was purified by flash column chromatography on
silica gel (hexane/EtOAc (19/1 to 5/5)) to afford, in addition to the oily thiobenzyl ester of MAC acid (54
mg, 98%), 9f (58 mg, 0.178 mmol, 98%) as colorless crystals; mp 159-160 ꢀ (from hexane/CH Cl );
2
2
3
0
[
"]D 68.8 (c 0.90, CHCl ); IR (KBr) " 3316, 2950, 1755, 1600, 1340, 1282, 1160, 1085, 941, 852, 775,
3
-
1
1
5
97, 536 cm ; H NMR (400 MHz, CDCl ) ! 2.28 (3H, s), 2.64 (6H, s), 3.21 (3H, s), 3.60 (3H, s), 4.56
3
1
3
(
1H, s), 5.31 (1H, s), 6.83 (1H, br s), 6.93 (2H, s); C NMR (125 MHz, CDCl ) ! 21.0, 22.6, 54.5, 56.2,
3
+
+
8
6.8, 91.5, 132.0, 141.3, 143.7, 154.1. MS (FAB) m/z 329 (MH , 41), 297 (M -OMe, 92), 183
+
(
Me C H SO , 74), 119 (Me C H , 98); HRMS (FAB) Calcd for C H N O SNa (MNa ): m/z 351.0991.
3
6
2
2
3
6
2
14 20
2
5
Found: m/z 351.0997.

HETEROCYCLES, Vol. 88, No. 2, 2014
1351
Removal of the mesitylenesulfonyl moiety from 7f. (4S,5S)-4,5-dimethoxy-1-[(1S,2R)-2-exo-
methoxyapocamphanecarbonyl]-2-imidazolidinone (10). A mixture of 7f (87 mg, 0.17 mmol),
NaBH CN (107 mg, 1.7 mmol, 10 eq) and anisole (56 µL, 0.51 mmol, 3 eq) in EtOAc (17 mL) and
3
t-BuOH (1 mL) was placed into a 30 mL quartz flask under an argon atmosphere and was irradiated with
a 100 W high-pressure Hg lamp (Ushio Inc.) at 0 °C for 30 min under vigorous stirring. The reaction
mixture was passed through SiO pad (EtOAc as eluent), and the eluent was evaporated in vacuo followed
2
by flash chromatography on silica gel (hexane/EtOAc (8/2 to 6/4)) to yield 10 (50 mg, 0.154 mmol, 90 %)
2
8
as colorless crystals; mp 84.5-85.0 # (from hexane); ["]D -64.8 (c 1.00, CHCl ); IR (KBr) " 3460,
3
-
1
1
3
178, 3012, 2831, 1755, 1685, 1454, 1396, 1323, 1238, 1095, 945, 818, 729 cm ; H NMR (300 MHz,
CDCl ) ! 1.09-1.17 (1H, m), 1.13 (3H, s), 1.29 (3H, s), 1.61-1.67 (2H, m), 1.75-1.92 (3H, m), 2.39-2.47
3
(1H, m), 3.15 (3H, s), 3.32 (3H, s), 3.49 (3H, s), 4.40 (1H, dd, J = 3.8, 7.7 Hz), 4.59 (1H, d, J = 1.7 Hz),
1
3
5
.45 (1H, d, J = 1.7 Hz), 6.08 (1H, br s); C NMR (100 MHz, CDCl ) ! 21.3, 21.6, 26.8, 28.2, 37.4, 45.5,
3
5
0.4, 53.1, 55.9, 56.7, 61.9, 83.6, 85.2, 89.4, 154.3, 173.4. Anal. Calcd for C H N O : C, 58.88; H, 8.03;
1
6
26
2
5
N, 8.58. Found: C, 58.65; H, 8.27; N, 8.50.
ACKNOWLEDGEMENTS
This research was financially supported in part by JSPS KAKENHI (NO. 23590011 to H.M.) and by the
Hoansha Foundation (to T.I.).
REFERENCES AND NOTES
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1
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3
D. Lucet, T. Le Gall, and C. Mioskowski, Angew. Chem. Int. Ed., 1998, 37, 2580 and references
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5
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W. Shiow-Jyi, K. J. O’Connor, and C. J. Burrow, Tetrahedron Lett., 1993, 34, 1905.
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HETEROCYCLES, Vol. 88, No. 2, 2014
and F. Aznar, Synthesis, 1974, 504; (c) J. Barluenga, F. Aznar, M. C. S. De Mattos, W. B. Kover, S.
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7
.
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.
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A. Iuliano, C. Rosini, and P. Salvadori, Synthesis, 1990, 1023.
8
(a) M. Shimizu, T. Iida, and T. Fujisawa, Chem. Lett., 1995, 609; (b) N. Taniguchi and M. Uemura,
Synlett, 1997, 51.
9
1
R. Seo, T. Ishizuka, A. A.-M. Abdel-Aziz, and T. Kunieda, Tetrahedron Lett., 2001, 42, 6353.
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1
6
1
1. Unpublished data. Following Beller’s procedure, the treatment of N-benzoyl-2-imidazolone with
aqueous hydrogen peroxide solution (30%) in the presence of catalytic amount of FeCl •6H O,
3
2
dipicolinic acid and diisopropylamine in t-BuOH/CH Cl (1:1) mixture as solvent yielded
2
2
4
-tert-butoxy-5-hydroxy- and 4,5-dihydroxy-2-imidazolidinone (11, 12) (Sheme 5).
Scheme 5
1
1
1
1
1
2. Absolute configulation of 7f was assigned from the fact that the optical rotation and H NMR data of
9
desulfonylated compound 10 was identical as the same compound which was previously reported.
3. Selective removal of MAC group of 6f using PhCH SLi had also tried and only 13% yield of 8f was
2
obtained, accompanying 59% recovered yield of the starting material 6f.
4. (a) P. Laine, A. Gourdon, and J. -P. Launay, Inorg. Chem., 1995, 34, 5129; (b) Idem, ibid., 1995, 34,
5
156.
5. The chemical shifts of 2-endo protons at MAC moieties (1H, dd) of 6 and 7 were mainly compared.
4R,5R)-6f showed 4.15 ppm (lower field) and (4S,5S)-7f showed 4.13 ppm (higher field).
Alternatively, two methyl signals (3H, s) of MAC group appeared at 1.08 and 1.21 ppm in
4R,5R)-6f (differential of each ! values (!!): 0.13 ppm, larger value than 7f) and also appeared at
.12 and 1.21 ppm in (4S,5S)-7f (!!: 0.09 ppm, smaller value than 6f). Other diastereomers showed
similar larger/smaller ! and !! values.
(
(
1

HETEROCYCLES, Vol. 88, No. 2, 2014
1353
1
6. (a) B. Bitterlich, G. Anilkumar, F. G. Gelalcha, B. Spilker, A. Grotevendt, R. Jackstell, M. K. Tse,
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Spannenberg, M. K. Tse, K. Junge, and M Beller, Chem. Eur. J., 2009, 15, 5471; (c) F. G. Gelalcha,
B. Bitterlich, G. Anilkumar, M. K. Tse, and M. Beller, Angew. Chem. Int. Ed., 2007, 46, 7293.