Syntheses of optically active tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones and hexahydroimidazo[1,2-a]pyridin-2(3H)-ones

Article abstract of DOI:10.1021/jo010842w

The reactions of (2S)-2-amino-2-substituted-N-(4-nitrophenyl)acetamides 16a-c, succindialdehyde (13), and benzotriazole afforded enantiopure (3S,5R,7aR)-5-(1H-1,2,3-benzotriazol-1-yl)-3-substituted-1-(4-nitrophenyl) tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 17a-c, which were converted by sodium borohydride into (3S,7aR)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1, 2-a]imidazol-2-ones 18a-c. Chiral (2S)-2-amino-2-substituted-N-(4-methylphenyl)acetamides 12a-d, easily prepared in two steps from N-Boc-α-amino acids 10a-d, similarly reacted with glutaraldehyde (20) and benzotriazole to generate 5-benzotriazolyl-3-substituted-hexahydroimidazo[1,2-a]pyridin 2(3H)-ones 21a-d, which were converted by sodium borohydride directly into optically active 3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 22a-d.

Full text of DOI:10.1021/jo010842w

Syn th eses of Op tica lly Active
Tetr a h yd r o-1H-p yr r olo[1,2-a ]im id a zol-2-on es a n d
Hexa h yd r oim id a zo[1,2-a ]p yr id in -2(3H)-on es
Alan R. Katritzky,* Hai-Ying He, and J ing Wang
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received August 17, 2001
The reactions of (2S)-2-amino-2-substituted-N-(4-nitrophenyl)acetamides 16a -c, succindialdehyde
(13), and benzotriazole afforded enantiopure (3S,5R,7aR)-5-(1H-1,2,3-benzotriazol-1-yl)-3-substituted-
1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 17a -c, which were converted by
sodium borohydride into (3S,7aR)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imid-
azol-2-ones 18a -c. Chiral (2S)-2-amino-2-substituted-N-(4-methylphenyl)acetamides 12a -d , easily
prepared in two steps from N-Boc-R-amino acids 10a -d , similarly reacted with glutaraldehyde
(20) and benzotriazole to generate 5-benzotriazolyl-3-substituted-hexahydroimidazo[1,2-a]pyridin-
2(3H)-ones 21a -d , which were converted by sodium borohydride directly into optically active
3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 22a -d .
SCHEME 1
In tr od u ction
Tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones are bio-
logically active as central nervous system depressants,
sedatives, and anticonvulsants.1 The known routes to
tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones are (i) the
reaction of dimethylketene-N-phenylimine (1) with cyclic
nitrones 22 and (ii) the oxidative cyclizations of pyrrolidin-
1-ylacetamide and R-(pyrrolidin-1-yl)propionamide 4 with
mercuric acetate, potassium hexacyanoferrate(III), or
potassium permanganate3 (Scheme 1). No synthesis of
an optically active compound was reported by any of the
previous methods.
No published synthesis of hexahydroimidazo[1,2-a]-
pyridin-2(3H)-ones 6 was found, although the corre-
sponding dioxo structures, kifunensines 7, which show
promising immunomodulatory activity in R-mannosidase
inhibition,4 have been studied in detail by Kayakiri,
Hashimoto, et al.,5 and the parent was synthesized by
Rouden and Hudlicky.4a
We recently reported reactions of succindialdehyde or
glutaraldehyde with benzotriazole and N-phenylethyl-
enediamine leading to 1-phenyl-5-(benzotriazol-1-yl)-
hexahydro-1H-pyrrolo[1,2-a]imidazole 8 (R ) Bt1) or
1-phenyl-5-benzotriazolyloctahydroimidazo[1,2-a]pyri-
dine 9 (R ) Bt), respectively.6 The Bt group at the
5-position in these intermediates is readily removed by
nucleophilic substitutions with Grignard reagents, allyl-
silanes, silyl enol ethers, or triethyl phosphite to furnish
novel 1-phenyl-5-substituted-hexahydro-1H-pyrrolo[1,2-
a]imidazoles 8 [R ) alkyl, aryl, allyl, CH2COR′, and
P(O)(OEt)2] or 1-phenyl-5-substituted-octahydroimidazo-
[1,2-a]pyridines 9 (R groups same as those in 8). These
(1) (a) Bell, S. C.; Gochman, C. U.S. Patent 3 631 061, 1971; Chem.
Abstr. 1972, 76, 85818q. (b) Bell, S. C.; Gochman, C. U.S. Patent 3
423 459, 1969; Chem. Abstr. 1969, 70, 77971v.
(2) Tsuge, O.; Watanabe, H.; Masuda, K.; Yousif, M. M. J . Org.
Chem. 1979, 44, 4543.
(3) Vasvari-Debreczy, L.; Beckett, A. H.; Vutthikongsirigool, W.
Tetrahedron 1981, 37, 4337.
(4) (a) Rouden, J .; Hudlicky, T. J . Chem. Soc., Perkin Trans. 1 1993,
1095. (b) Kayakiri, H.; Takase, S.; Shibata, T.; Okamoto, M.; Terano,
H.; Hashimoto, M. J . Org. Chem. 1989, 54, 4015.
(5) (a) Kayakiri, H.; Oku, T.; Hashimoto, M. Chem. Pharm. Bull.
1990, 38, 293. (b) Kayakiri, H.; Kasahara, C.; Oku, T.; Hashimoto, M.
Tetrahedron Lett. 1990, 31, 225. (c) Kayakiri, H.; Takase, S.; Shibata,
T.; Hashimoto, M.; Tada, T.; Koda, S. Chem. Pharm. Bull. 1991, 39,
1378. (d) Kayakiri, H.; Kasahara, C.; Nakamura, K.; Oku, T.; Hash-
imoto, M. Chem. Pharm. Bull. 1991, 39, 1392. (e) Kayakiri, H.; Oku,
T.; Hashimoto, M. Chem. Pharm. Bull. 1991, 39, 1397.
(6) Katritzky, A. R.; Qiu, G.; He, H.-Y.; Yang, B. J . Org. Chem. 2000,
65, 3683.
10.1021/jo010842w CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/17/2002
J . Org. Chem. 2002, 67, 4951-4956
4951

Katritzky et al.
SCHEME 2
results suggested the use of chiral R-amino amides
instead of N-phenylethylenediamine to control the new
chiral center at the 7a-position in 5 or 8a-position in 6.
We now document the syntheses of novel optically active
3-substituted-tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-
ones 18a -c and 3-substituted-hexahydroimidazo[1,2-a]-
pyridin-2(3H)-ones 22a -d .
Resu lts a n d Discu ssion
P r ep a r a tion of Ch ir a l r-Am in o Am id es 12a -d
fr om N-Boc-r-a m in o Acid s 10a -d . Although (2S)-2-
amino-2-substituted-N-(4-nitrophenyl)acetamides 16a -c
are commercially available, apparently a convenient
general method for the preparation of chiral R-amino
amides 12 has not been described. Douat et al. recently
prepared N-Boc- and N-(Z)-R-amino acylmorpholines by
coupling the corresponding amino acids with morpholine,
using conventional activation (phosphorium or uronium
salts, chloroformates, DCC/HOBt).7 We now show that
isobutyl chloroformate together with N-methylmorpho-
line converts N-Boc-R-amino acids 10a -d to the mixed
anhydrides, and the subsequent addition of p-methyl-
aniline affords the N-Boc-R-amino amides 11a -d in
excellent yields. The structures of 11a -d are supported
by their 1H and 13C NMR spectra and microanalyses.
Treatment of crude N-Boc-R-amino amides 11a -d with
HCl/EtOAc at room temperature removed the Boc protec-
tion to generate the R-amino amide hydrochloride salts,
which were converted by aqueous NaOH into the free
bases R-amino amides 12a -d in 81-92% yields (Scheme
2). R-Amino amides 12a -d were used for the subsequent
cyclizations without further purification.
P r ep a r a tion of 5-(1H-1,2,3-Ben zotr ia zol-1-yl)-3-
su bstitu ted -tetr a h yd r o-1H-p yr r olo[1,2-a ]im id a zol-
2-on es 17a -c F ollow ed by Red u ction w ith Na BH4.
Reaction of commercially available (2S)-2-amino-2-sub-
stituted-N-(4-nitrophenyl)acetamides 16a -c with succin-
dialdehyde (13; obtained by treatment of 2,5-dimethoxy-
tetrahydrofuran with 0.1 M HCl) and benzotriazole in
CH2Cl2 at room temperature for 24 h readily afforded
5-(1H-1,2,3-benzotriazol-1-yl)-3-substituted-tetrahydro-
1H-pyrrolo[1,2-a]imidazol-2-ones 17a -c, which were re-
crystallized from CHCl3/hexanes to give single diastereo-
isomers in 91%, 84%, and 90% yields, respectively
(Scheme 3). The stereochemistry of 17a -c was deter-
mined by NOE NMR experiments. Using 17a as an
a
Isolated yields based on N-Boc-R-amino amides 11.
SCHEME 3
1
example, the H NMR spectrum shows that H(3), H(7a),
and H(5) appear at 3.89 ppm (q), 5.84 ppm (t), and 6.08
ppm (t), respectively. A significant positive NOE effect
was observed between H(3) and H(5); no NOE effect was
observed between H(7a) and either H(3) or H(5). Fur-
thermore, a positive NOE effect was observed between
H(7a) and the annual methyl group (1.25 ppm, d) in 17a .
Thus, NOE analysis demonstrates that in 17a H(3) and
H(5) are in a cis-orientation while H(3) and H(7a) are in
a trans-orientation. Very similar NOE results observed
for 17b,c prove the same configuration as that of 17a .
We previously reported that the benzotriazolyl group
can be substituted with hydrogen by sodium boro-
hydride.8 Reduction of 17a with 3 equiv of NaBH4 in dry
THF at room temperature for 24 h gave a mixture of 17a ,
the desired product 18a , and a byproduct, 4-nitroaniline
(19), in a 3.3:2.3:1 ratio, determined by the 1H NMR
spectrum. Structure 19 was confirmed by GC-MS [MS
(EI) m/z 138 (M+) for 19] and NMR spectra after separa-
tion on column chromatography. Treatment of this
mixture with an additional 2 equiv of NaBH4 at room
(8) (a) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. V. Chem.
Rev. 1998, 98, 409. (b) Katritzky, A. R.; Fan, W.-Q. J . Org. Chem. 1990,
55, 3205. (c) Katritzky, A. R.; Najzarek, Z.; Dega-Szafran, Z. Synthesis
1989, 66. (d) Katritzky, A. R.; Yannakopoulou, K.; Lue, P.; Rasala, D.;
Urogdi, L. J . Chem. Soc., Perkin Trans. 1 1989, 225.
(7) Douat, C.; Heitz, A.; Martinez, J .; Fehrentz, J .-A. Tetrahedron
Lett. 2000, 41, 37.
4952 J . Org. Chem., Vol. 67, No. 14, 2002

Pyrroloimidazolone and imidazopyridinone Syntheses
TABLE 1. Isola ted Yield s a n d Op tica l Activities for 22
(tr a n s) a n d 22′ (cis)
SCHEME 4
22 (trans)
yielda (%) [R]25
22′ (cis)
yielda (%) [R]25
22, 22′
R
D
D
a
b
c
d
Me
i-Pr
i-Bu
PhCH2
48 (57b)
58
-12.5
-44.3
-26.5
-18.1
11
c
7
+103.3
+79.1
42 (47b)
49
c
a
b
Isolated yields based on R-amino amides 12a -d . Yield
obtained with 1% Et3N eluent, and only a trace amount of the
corresponding cis-isomer was isolated. No detectable amount of
c
the product was isolated.
actions of R-amino amides 12a -d , glutaraldehyde (20;
50% aqueous solution), and benzotriazole in CH2Cl2 at
room temperature for 24 h afforded solid 5-benzotriazolyl-
3-substituted-hexahydroimidazo[1,2-a ]pyridin-2(3H)-
ones 21a -d (Scheme 4). Attempts to obtain pure 21 by
column chromatography (silica gel) failed due to signifi-
cant decomposition of these Bt intermediates. Com-
pounds 21a -d were therefore used directly for the
subsequent reactions. The complex 1H NMR spectra, due
to mixtures of Bt1 and Bt2 isomers and some byproducts,
made it difficult to establish the relative stereochemistry
at the 5- or 8a-position in Bt intermediates 21; thus, we
report only the crude 1H NMR spectral data for the major
diastereoisomers. It is interesting to point out that one
methyl group (in i-Bu) in 21c appears at -0.10 ppm as
a doublet obviously due to its significant shielding by the
benzotriazolyl ring system. We also reacted 12c with
glutaraldehyde in the absence of benzotriazole and did
not obtain any fused ring compounds.
Syn th eses of Optically Active Hexah ydr oim idazo-
[1,2-a ]p yr id in -2(3H)-on es 22 or 22′ via Red u ction of
21a -d w it h Na BH 4. Treatment of crude 5-benzo-
triazolyl-3-substituted-hexahydroimidazo[1,2-a]pyridin-
2(3H)-ones 21a -d with sodium borohydride (2 equiv
based on R-amino amides 12a -d ) in dry THF at room
temperature overnight removed the benzotriazolyl group
to give crude optically active hexahydroimidazo[1,2-a]-
pyridin-2(3H)-ones 22a -d (Scheme 4). The isolated yields
of 22 (trans) or 22′ (cis) depend on the nature of the R
groups in 12 and the conditions of column chromatogra-
phy (cf. Table 1).
temperature for 24 h resulted in a ratio of 17a , 18a , and
19 of 0.5:1:1. When the reaction was carried out with 8
equiv of NaBH4 in 48 h, the ratio became 0.05:0.37:1. The
higher temperature (70 °C in 28 h with 3 equiv of NaBH4)
caused ring opening of 17a and gave a low proportion of
18a . We later found that this reaction was almost
completed by using 4 equiv of NaBH4 in THF at 40 °C
for 36 h (a ratio of 17a , 18a , and 19 of 0.5:3.3:1).
Compounds 18a -c and 19 are difficult to separate by
silica gel column chromatography due to their very close
Rf values. However, 18a -c and 19 were separated by
neutral alumina column chromatography, and 18a -c
were isolated in 48%, 42%, and 51% yields, respectively.
For 18a , partial racemization occurred (de 69%), and a
positive NOE effect between H(7a) and the annual
methyl group confirms the major diastereoisomer as a
trans-isomer.
Reactions of R-amino amides 12c,d with succindialde-
hyde (13) and benzotriazole in CH2Cl2 did not give the
desired fused ring system 14; instead N-substituted
pyrroles 15a ,b were obtained in 57% and 48% yields,
respectively. We later found that 15a ,b were also ob-
tained from 12c,d in 59% and 55% yields, respectively,
in the absence of benzotriazole (Scheme 2). Reactions of
2,5-dimethoxytetrahydrofuran with primary amines un-
der acidic conditions have been developed as a general
method to produce N-substituted pyrroles.9 After acid
hydrolysis of 2,5-dimethoxytetrahydrofuran with 0.1 M
HCl, we neutralized the mixture with 0.5 M NaOH to
pH ca. 8 and then added 12c and BtH, but still failed to
obtain the desired 14. In the absence of exhaustive
mechanistic studies, the weaker acidity of the amide
hydrogen (-CONHC6H4Me-p) in 12c,d than that of
-CONHC6H4NO2-p in 16a -c may reflect the electron-
releasing p-methyl group in 12c,d and the strong electron-
withdrawing p-nitro group in 16a -c.
The structures for 22 or 22′ are clearly supported by
their 1H and 13C NMR spectra, NOE experiments, and
1
microanalyses or HRMS results. In the H NMR spectra,
H(8a) in 22 or 22′, always at the lowest field in the
aliphatic region, can be easily confirmed by its strong
positive NOE effect with the aromatic hydrogens in the
p-methylphenyl group. For 22a -d , when H(8a) was
irradiated, no distinct NOE effect was observed for H(3)
in any compound; conversely, irradiation of H(3) gave no
positive NOE for H(8a). This result suggests that H(8a)
and H(3) in 22a -d are located in a trans-orientation. The
trans-configurations for 22a ,b,d were confirmed by posi-
tive NOE effects observed between H(8a) and the annular
methyl group (for 22a ), the two methyl groups (for 22b),
or PhCH2 (for 22d ). For cis-isomers 22′a ,c, a significant
positive NOE effect was observed between H(8a) and H(3)
in each compound, thus demonstrating their cis-orienta-
tion. It is noteworthy that the chemical shifts for H(8a)
and H(3) in trans-isomers 22a ,c appear at a lower field
as compared to those in cis-isomers 22′a ,c.
Syn th eses of 5-Ben zotr iazolyl-3-su bstitu ted -h exa-
h yd r oim id a zo[1,2-a ]p yr id in -2(3H)-on es 21a -d . Re-
(9) (a) D’Silva, C.; Walker, D. A. J . Org. Chem. 1998, 63, 6715. (b)
Peet, N. P.; Sunder, S. Heterocycles 1986, 24, 3213. (c) Nonoyama, M.
J . Organomet. Chem. 1984, 262, 407. (d) Kashima, C.; Hibi, S.;
Maruyama, T.; Harada, K.; Omote, Y. J . Heterocycl. Chem. 1987, 24,
913. (e) Okawara, T.; Okamoto, Y.; Ehara, S.; Yamasaki, T.; Furukawa,
M. Heterocycles 1996, 43, 2487.
J . Org. Chem, Vol. 67, No. 14, 2002 4953

Katritzky et al.
at the 8a-position prefer to locate at equatorial positions.
According to our previous discussion6 and other related
reports,10 the major conformation for 22 or 22′ is ring-
trans due to its significantly lower energy than that of
the ring-cis conformation.
In summary, we have developed a novel route to
synthesize optically active 3-substituted-tetrahydro-1H-
pyrrolo[1,2-a]imidazol-2-ones 18a -c and 3-substituted-
hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 22a -d via
the reduction of 5-benzotriazolyl-3-substituted-tetra-
hydro-1H-pyrrolo[1,2-a]imidazol-2-ones 17a-c and 5-ben-
zotriazolyl-3-substituted-hexahydroimidazo[1,2-a]pyridin-
2(3H)-ones 21a -d with sodium borohydride. Bt inter-
mediates 17a -c were obtained by the reaction of
succindialdehyde (13) with benzotriazole and (2S)-2-
amino-2-substituted-N-(4-nitrophenyl)acetamides 16a -
c. Similarly, Bt intermediates 21a -d were prepared by
the reaction of glutaraldehyde (20), benzotriazole, and
(2S)-2-amino-2-substituted-N-(4-methylphenyl)acet-
amides 12a -d , readily available in two steps from N-Boc-
R-amino acids 10a -d .
F IGURE 1.
After we confirmed the structures of the trans-isomers
22 and cis-isomers 22′, careful comparison of the 1H NMR
spectra showed that crude 22a -d (before column chro-
matography) were obtained as only trans-isomers. After
column chromatography on silica gel, 22b and 22d were
obtained as single diastereoisomers in 58% and 49%
yields, respectively. However, purification of trans-
isomers 22a ,c by column chromatography (silica gel,
eluent hexanes/EtOAc) resulted in the formation of cis-
isomers 22′a ,c, probably because of the weak acidity of
silica gel. Furthermore, when we subjected pure trans-
isomer 22a (100 mg) to column chromatography (15 g of
silica gel using 5:1 hexanes/EtOAc as an eluent), we
recovered most of 22a (88 mg) and isolated cis-isomer
22′a (8 mg). Stirring of trans-isomer 22a (80 mg) in
hexanes/EtOAc (1:1, 15 mL) with silica gel (2 g) overnight
formed a mixture with the cis-isomer 22′a in a ratio of
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of Ch ir a l
N-Boc-r-Am in o Am id es 11a -d . To a cold solution (-15 °C)
of N-Boc-R-amino acids 10a -d (10 mmol) and 4-methylmor-
pholine (1.01 g, 10 mmol) in dry THF (30 mL) was added
dropwise isobutyl chloroformate (1.36 g, 10 mmol) in dry THF
(5 mL) over 15 min. After the mixture was stirred for another
15 min, 4-methylaniline (1.07 g, 10 mmol) was added. Then
the mixture was allowed to slowly warm to room temperature
and stirred overnight. After evaporation of the solvent in
vacuo, the residue was diluted with EtOAc and the organic
phase was washed with 10% aq Na2CO3, 0.1 M HCl, and brine
and dried over anhydrous Na2SO4. Evaporation of the solvents
gave crude N-Boc-R-amino amides 11a -d , which were used
for the subsequent acid hydrolysis without further purification.
For microanalysis purposes, 11a -d were recrystallized from
the appropriate solvents.
Da t a for ter t-Bu t yl N-[(1S)-1-Met h yl-2-oxo-2-(4-t olu -
id in o)eth yl]ca r ba m a te (11a ): colorless plates (from CHCl3/
1
22′a :22a ) 1:4.8, as determined by the H NMR spectra.
hexanes); yield 88%; mp 121-122 °C; [R]25 ) -45.1 (c 1.63,
D
Treatment of pure trans-22a with neutral Al2O3 instead
of silica gel gave a mixture of trans-22a and cis-22′a in
a 9:1 ratio. Using silica gel, washed with a mixture of
hexanes/EtOAc/Et3N (10:1:0.1) to ca. pH 8 for the flash
column chromatography of pure 22a , gave only traces of
22′a , and most of the 22a was unchanged. Repetition of
the preparation of 22a ,c using flash column chromatog-
raphy with 1% Et3N eluent improved the yields of 22a ,c
from 48% and 42% to 57% and 47%, respectively. We also
assessed the stability of the final products. Using 22a
and 22′a as examples, no changes in the 1H NMR spectra
were observed for each compound in chloroform-d for 3
days at room temperature, and no obvious change for
each compound in chloroform-d overnight at ca. 50 °C.
On the basis of the above experimental results, we
believe that the C(8a)-N(1) bonds in trans-isomers 22a ,c
can be broken on weak acidic silica gel to form the
iminium cation and an R-hydroxyimine transient inter-
mediate, X, via protonation of the amide carbonyl. Due
to the equilibrium between X and Y by ring inversion,
the lone electron pair of N(1) in X or Y subsequently
attacks the iminium cation from the equatorial direction
to form trans-isomers 22a ,c or cis-isomers 22′a ,c (Figure
1). The coupling constants for H(8a) (from 7.2 to 10.2 Hz)
indicate their axial positions, as the larger substituents
1
EtOH); H NMR δ 8.57 (br s, 1H), 7.37 (d, J ) 8.3 Hz, 2H),
7.05 (d, J ) 8.1 Hz, 2H), 5.37-5.28 (m, 1H), 4.37 (br s, 1H),
2.28 (s, 3H), 1.45 (s, 9H), 1.43 (d, J ) 8.7 Hz, 3H); 13C NMR δ
171.2, 156.0, 135.3, 133.6, 129.2, 119.9, 80.3, 50.7, 28.3, 20.8,
18.0. Anal. Calcd for C15H22N2O3: C, 64.73; H, 7.97; N, 10.06.
Found: C, 64.84; H, 8.13; N, 10.02.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ch ir a l
r-Am in o Am id es 12a -d fr om N-Boc-r-a m in o Am id es
11a -d . To a stirred solution of N-Boc-R-amino amides 11a -d
(3 mmol) in EtOAc (15 mL) was added HCl in EtOAc (ca. 1 M,
15 mL). The mixture was stirred at room temperature until
TLC showed the disappearance of the starting material
(usually 10-20 h). Then the mixture was treated with 1 M aq
NaOH and extracted with EtOAc. The organic phase was
washed with brine and dried over anhydrous K2CO3. Evapora-
tion of the solvent in vacuo gave the crude products 12a -d ,
which were used for the subsequent reactions without further
purification. For microanalysis purposes, 12a -d were recrys-
tallized from appropriate solvents.
Da t a for (2S)-2-Am in o-N-(4-m et h ylp h en yl)p r op a n -
a m id e (12a ): colorless plates (from EtOAc); yield 81%; mp
1
60-61 °C; [R]25 ) +13.8 (c 1.37, EtOH); H NMR δ 9.39 (s,
D
(10) (a) J ones, R. C. F.; Turner, I.; Howard, K. J . Tetrahedron Lett.
1993, 34, 6329. (b) Takahashi, K.; Tachiki, A.; Ogura, K.; Iida, H.
Heterocycles 1986, 24, 2835. (c) Poupon, E.; Luong, B.-X.; Chiaroni,
A.; Kunesch, N.; Husson, H.-P. J . Org. Chem. 2000, 65, 7208. (d) Crabb,
T. A.; Newton, R. F. Tetrahedron 1968, 24, 6327.
4954 J . Org. Chem., Vol. 67, No. 14, 2002

Pyrroloimidazolone and imidazopyridinone Syntheses
1H), 7.48 (d, J ) 8.3 Hz, 2H), 7.11 (d, J ) 8.1 Hz, 2H), 3.62 (q,
J ) 7.0 Hz, 1H), 2.30 (s, 3H), 1.93 (s, 2H), 1.42 (d, J ) 7.0 Hz,
3H); 13C NMR δ 173.4, 135.2, 133.5, 129.4, 119.4, 51.1, 21.5,
20.8. Anal. Calcd for C10H14N2O: C, 67.39; H, 7.92; N, 15.72.
Found: C, 67.24; H, 7.80; N, 15.67.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Su bsti-
t u t ed P yr r oles 15a ,b . A mixture of 2,5-dimethoxytetra-
hydrofuran (0.26 g, 2 mmol) and HCl aqueous solution (0.1
M, 8 mL) was heated to 100 °C for 0.5 h and then cooled to
room temperature. A solution of 12c,d (2 mmol) in CH2Cl2 (20
mL) was added and stirred at room temperature for 16 h. The
reaction mixture was washed with 2 M aq NaOH, and the
aqueous phase was extracted with CH2Cl2. The combined
organic phase was washed with brine and dried over anhy-
drous Na2SO4. After removal of the solvent in vacuo, the
residue was purified by column chromatography with hexanes/
EtOAc (2:1) as an eluent to give 15a ,b.
mixture of diastereoisomers, and NMR data are reported for
its major isomer (3S,7aR); yellow microcrystals; Rf ) 0.51
(hexanes:EtOAc ) 2:1; alumina TLC plate); yield 48%; de 69%;
1
mp 87-88 °C; H NMR δ 8.26 (d, J ) 9.3 Hz, 2H), 7.74 (d, J
) 9.3 Hz, 2H), 5.47 (dd, J ) 6.5, 3.8 Hz, NCHN, 1H), 3.57 (q,
J ) 7.1 Hz, NCHCO, 1H), 3.28 (dt, J ) 9.8, 5.2 Hz, 1H), 2.79
(dt, J ) 9.8, 7.5 Hz, 1H), 2.46-2.36 (m, 1H), 1.98-1.89 (m,
2H), 1.87-1.79 (m, 1H), 1.40 (d, J ) 7.1 Hz, 3H); 13C NMR δ
174.9 (CdO), 143.6, 142.9, 124.7, 119.6, 78.9, 63.1, 54.6, 31.2,
24.0, 17.8. Anal. Calcd for C13H15N3O3: C, 59.75; H, 5.80; N,
16.08. Found: C, 59.66; H, 5.92; N, 16.03.
Da ta for (3S,7a R)-3-Isobu tyl-1-(4-n itr op h en yl)tetr a h y-
d r o-1H-p yr r olo[1,2-a ]im id a zol-2(3H)-on e (18b): colorless
flakes; Rf ) 0.64 (hexanes:EtOAc ) 2:1; alumina TLC plate);
yield 42%; de 95%; mp 131-132 °C; [R]25 ) -52.1 (c 1.83,
D
1
CHCl3); H NMR δ 8.25 (d, J ) 9.3 Hz, 2H), 7.73 (d, J ) 9.3
Hz, 2H), 5.45 (dd, J ) 6.0, 3.9 Hz, NCHN, 1H), 3.51 (dd, J )
9.6, 5.4 Hz, NCHCO, 1H), 3.28 (dt, J ) 9.3, 4.8 Hz, 1H), 2.77
(dt, J ) 9.0, 7.9 Hz, 1H), 2.47-2.36 (m, 1H), 2.00-1.88 (m,
3H), 1.84-1.73 (m, 1H), 1.58-1.52 (m, 2H), 0.99 (d, J ) 6.7
Hz, 3H), 0.98 (d, J ) 6.7 Hz, 3H); 13C NMR δ 175.1 (CdO),
143.5, 143.1, 124.6, 119.6, 79.1, 66.2, 55.5, 40.9, 31.3, 25.0, 24.2,
23.2, 21.4. GC-MS (EI) m/z 303 (M+). Anal. Calcd for
Da ta for (2S)-4-Meth yl-N-(4-m eth ylp h en yl)-2-(1H-p yr -
r ol-1-yl)p en ta n a m id e (15a ): colorless prisms (from the
column); yield 59%; mp 107-108 °C; [R]25 ) -22.0 (c 1.67,
D
1
CHCl3); H NMR δ 7.21 (d, J ) 8.4 Hz, 2H), 7.05 (d, J ) 8.3
Hz, 2H), 6.90 (br s, 1H, NH), 6.78 (dd, J ) 2.0, 2.0 Hz, 2H),
6.31 (dd, J ) 2.0, 2.0 Hz, 2H), 4.70 (dd, J ) 11.3, 4.5 Hz, 1H),
2.27 (s, 3H), 2.24-2.00 (m, 2H), 1.60-1.42 (m, 1H), 0.94 (d, J
) 6.5 Hz, 3H), 0.93 (d, J ) 6.7 Hz, 3H); 13C NMR δ 169.6,
134.5, 134.3, 129.4, 120.1, 119.9, 110.1, 62.3, 40.0, 24.7, 23.1,
21.1, 20.8. Anal. Calcd for C17H22N2O: C, 75.52; H, 8.20; N,
10.36. Found: C, 75.22; H, 8.36; N, 10.17.
C
16H21N3O3: C, 63.35; H, 6.98; N, 13.85. Found: C, 63.38; H,
7.34; N, 13.87.
Da ta for (3S,7a R)-3-Ben zyl-1-(4-n itr op h en yl)tetr a h y-
d r o-1H-p yr r olo[1,2-a ]im id a zol-2(3H)-on e (18c): colorless
microcrystals; Rf ) 0.52 (hexanes:EtOAc ) 2:1; alumina TLC
plate); yield 51%; de > 99%; mp 128-129 °C; [R]25 ) -138 (c
P r oced u r e for th e Syn th esis of (3S,5R,7a R)-5-(1H-1,2,3-
Ben zotr iazol-1-yl)-3-su bstitu ted-1-(4-n itr oph en yl)tetr ah y-
d r o-1H-p yr r olo[1,2-a ]im id a zol-2-on es 17a -c. A mixture of
2,5-dimethoxytetrahydrofuran (0.40 g, 3 mmol) and 0.1 M HCl
aqueous solution (12 mL) was heated to 100 °C for 0.5 h and
then cooled to room temperature. A solution of benzotriazole
(0.36 g, 3 mmol) and (2S)-2-amino-2-substituted-N-(4-nitro-
phenyl)acetamides 16a -c (2.5 mmol) in CH2Cl2 (40 mL) was
added and stirred at 25 °C for 24 h. The reaction mixture was
washed with 1 M aq NaOH solution, and the aqueous phase
was extracted with CH2Cl2. The combined organic layers were
washed with brine and dried over anhydrous Na2SO4. Removal
of the solvent in vacuo gave a solid, which was recrystallized
from CHCl3/hexanes to afford essentially a single diastereo-
isomer, 17a -c.
D
1.79, CHCl3); 1H NMR δ 8.23 (d, J ) 9.2 Hz, 2H), 7.55 (d, J )
9.2 Hz, 2H), 7.26-7.21 (m, 5H), 4.83 (dd, J ) 6.2, 4.0 Hz,
NCHN, 1H), 3.76 (dd, J ) 6.6, 4.4, NCHCO, 1H), 3.18-2.96
(m, 3H), 2.64-2.59 (m, 1H), 2.28-2.17 (m, 1H), 1.87-1.78 (m,
2H), 1.69-1.59 (m, 1H); 13C NMR δ 173.9 (CdO), 143.8, 142.8,
137.6, 129.6, 128.2, 126.7, 124.6, 119.9, 79.6, 69.7, 55.7, 38.7,
31.4, 24.0. Anal. Calcd for C19H19N3O3: C, 67.64; H, 5.68; N,
12.45. Found: C, 67.51; H, 5.78; N, 12.48.
Gen er a l P r oced u r e for th e P r ep a r a tion of 5-Ben zo-
tr ia zolyl-3-su bstitu ted -h exa h yd r oim id a zo[1,2-a ]p yr id in -
2(3H)-on es 21a -d . A mixture of glutaraldehyde (0.60 g, 3
mmol, 50% aqueous solution), benzotriazole (0.39 g, 3.3 mmol),
and 12a -d (3 mmol) in CH2Cl2 (40 mL) was stirred at room
temperature for 24 h. The reaction mixture was washed with
2 M aq NaOH solution, and the aqueous phase was extracted
with CH2Cl2. The combined organic layers were washed with
brine and dried over anhydrous Na2SO4. Removal of the
solvent in vacuo afforded 21a -d as a solid. Attempts to purify
21 by column chromatography (silica gel) failed due to their
decomposition on silica gel. Therefore, Bt intermediates 21a -d
were used for the following reactions as crude products.
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Su bsti-
tu ted -h exa h yd r oim id a zo[1,2-a ]p yr id in -2(3H)-on es 21 or
21′ via Red u ction of 21a -d w ith Na BH4. To a solution of
crude 5-benzotriazolyl-3-substituted-hexahydroimidazo[1,2-a]-
pyridin-2(3H)-ones 21a -d (prepared from 3.0 mmol of 12a -
d ) in dry THF (40 mL) was added NaBH4 (0.23 g, 6.0 mmol).
The mixture was stirred overnight at room temperature. After
evaporation of the solvent in vacuo, the residue was diluted
with EtOAc. The organic phase was washed with 1 M aq
NaOH and brine and dried over anhydrous Na2SO4. After
removal of the solvent in vacuo, the residue was purified by
column chromatography with hexanes/EtOAc (10-6:1) as an
eluent to afford 22 or 22′.
Da ta for (3S,5R,7a R)-5-(1H-1,2,3-Ben zotr ia zol-1-yl)-3-
m et h yl-1-(4-n it r op h en yl)t et r a h yd r o-1H -p yr r olo[1,2-a ]-
im id a zol-2-on e (17a ): colorless needles; yield 91%; de > 99%;
mp 174-175 °C; [R]25 ) +62.7 (c 1.38, CHCl3); 1H NMR δ
D
8.32 (d, J ) 9.2 Hz, 2H), 8.12 (d, J ) 8.2 Hz, 1H), 7.81 (d, J )
8.2 Hz, 1H), 7.78 (d, J ) 9.0 Hz, 2H), 7.54 (dd, J ) 7.5, 7.5 Hz,
1H), 7.43 (dd, J ) 7.4, 7.4 Hz, 1H), 6.08 (t, J ) 6.8 Hz, Bt1CHN,
1H), 5.84 (t, J ) 4.9 Hz, NCHN, 1H), 3.89 (q, J ) 7.1 Hz,
NCHCO, 1H), 2.93-2.81 (m, 1H), 2.81-2.69 (m, 1H), 2.62-
2.52 (m, 1H), 2.23-2.11 (m, 1H), 1.25 (d, J ) 7.2 Hz, 3H); 13
C
NMR δ 173.5 (CdO), 146.9, 144.1, 142.1, 131.5, 127.5, 124.9,
124.3, 120.4, 119.9, 110.7, 81.5, 77.7, 62.0, 30.0, 29.9, 18.0.
Anal. Calcd for C19H18N6O3: C, 60.31; H, 4.79; N, 22.21.
Found: C, 59.98; H, 4.94; N, 21.91.
Gen er a l P r oced u r e for th e Syn th esis of (3S,7a R)-3-
su bstitu ted -1-(4-n itr op h en yl)tetr a h yd r o-1H-p yr r olo[1,2-
a ]im id a zol-2(3H)-on es 18a -c. To a solution of 17a -c (1.2
mmol) in dry THF (15 mL) was added NaBH4 (0.18 g, 4.8
mmol), and the mixture was stirred at 40 °C for 36 h. After
evaporation of the solvent in vacuo, the residue was diluted
with EtOAc. The organic phase was washed with 1 M aq
NaOH and brine and dried over anhydrous Na2SO4. After
removal of the solvent in vacuo, the residue was purified by
neutral Al2O3 (60-325 mesh) column chromatography with
hexanes/EtOAc (4:1) as an eluent to afford 18a -c. The Rf value
for the byproduct 4-nitroaniline (19) is 0.33 (hexanes:EtOAc
) 2:1; alumina TLC plate).
Da t a for (3S,8a R)-3-Met h yl-1-(4-m et h ylp h en yl)h exa -
h yd r oim id a zo[1,2-a ]p yr id in -2(3H )-on e (22a ): colorless
flakes (from the column); mp 75-76 °C; [R]25D ) -12.5 (c 1.47,
1
CHCl3); Rf ) 0.23 (hexanes:EtOAc ) 1:1); H NMR δ 7.30 (d,
J ) 8.2 Hz, 2H), 7.17 (d, J ) 8.1 Hz, 2H), 4.76 [dd, J ) 9.3,
3.0 Hz, 1H, H(8a)], 3.68 [q, J ) 6.6 Hz, 1H, H(3)], 3.11-3.00
(m, 1H), 2.86 (ddd, J ) 13.7, 10.8, 3.2 Hz, 1H), 2.33 (s, 3H),
1.96-1.88 (m, 1H), 1.88-1.73 (m, 1H), 1.63-1.35 (m, 4H), 1.30
(d, J ) 6.6 Hz, 3H); 13C NMR δ 173.2 (CdO), 135.4, 133.7,
Da t a for 3-Met h yl-1-(4-n it r op h en yl)t et r a h yd r o-1H -
p yr r olo[1,2-a ]im id a zol-2(3H)-on e (18a ): obtained as a
J . Org. Chem, Vol. 67, No. 14, 2002 4955

Katritzky et al.
129.6, 123.0, 74.4, 57.1, 45.6, 27.7, 21.9, 21.4, 20.9, 13.0. Anal.
Calcd for C15H20N2O: C, 73.74; H, 8.25; N, 11.46. Found: C,
73.36; H, 8.32; N, 11.65.
129.6, 123.4, 74.0, 61.8, 47.1, 36.8, 26.9, 25.1, 22.8, 22.7, 22.2,
21.0, 21.0. Anal. Calcd for C18H26N2O: C, 75.48; H, 9.15; N,
9.78. Found: C, 75.58; H, 9.33; N, 10.18.
Da t a for (3S,8a S)-3-Met h yl-1-(4-m et h ylp h en yl)h exa -
h yd r oim id a zo[1,2-a ]p yr id in -2(3H )-on e (22′a ): colorless
flakes (from the column); mp 75-76 °C; [R]25D ) +103.3 (c 2.87,
Da ta for (3S,8a S)-3-Isobu tyl-1-(4-m eth ylp h en yl)h exa -
h yd r oim id a zo[1,2-a ]p yr id in -2(3H)-on e (22′c): colorless oil;
[R]25 ) +79.1 (c 2.33, CHCl3); Rf ) 0.50 (hexanes:EtOAc )
D
1
1
CHCl3); Rf ) 0.42 (hexanes:EtOAc ) 1:1); H NMR δ 7.18 (d,
3:1); H NMR δ 7.17 (d, J ) 8.7 Hz, 2H), 7.09 (d, J ) 8.4 Hz,
J ) 8.1 Hz, 2H), 7.10 (d, J ) 8.1 Hz, 2H), 3.97 [d, J ) 9.9 Hz,
1H, H(8a)], 3.11 (d, J ) 10.5 Hz, 1H), 2.93 [q, J ) 6.6 Hz, 1 H,
H(3)], 2.33 (s, 3H), 2.76 (dd, J ) 11.0, 4.9 Hz, 1H), 2.03-1.83
(m, 2H), 1.78-1.55 (m, 2H), 1.20-1.54 (m, 5H); 13C NMR δ
173.3 (CdO), 135.9, 133.0, 129.4, 124.5, 78.0, 60.1, 47.9, 28.6,
25.0, 22.8, 21.0, 14.0. Anal. Calcd for C15H20N2O: C, 73.74; H,
8.25; N, 11.46. Found: C, 73.43; H, 8.61; N, 11.64.
2H), 3.96 [d, J ) 9.6 Hz, 1H, H(8a)], 3.10 (d, J ) 10.8 Hz, 1H),
2.98-2.90 [m, 1H, H(3)], 2.35-2.24 (m, 4H), 2.10-1.22 (m, 9H),
0.99 (d, J ) 7.2 Hz, 3H), 0.96 (d, J ) 7.2 Hz, 3H); 13C NMR δ
173.3 (CdO), 135.6, 133.1, 129.3, 124.3, 77.7, 62.6, 48.0, 37.4,
28.7, 25.0, 24.9, 23.2, 22.7, 22.6, 20.9. Anal. Calcd for
C
18H26N2O: C, 75.48; H, 9.15; N, 9.78. Found: C, 75.62; H,
9.52; N, 10.14.
Da ta for (3S,8a R)-3-Isop r op yl-1-(4-m eth ylp h en yl)h exa -
h yd r oim id a zo[1,2-a ]p yr id in -2(3H)-on e (22b): colorless oil;
Da t a for (3S,8a R)-3-Ben zyl-1-(4-m et h ylp h en yl)h exa -
h yd r oim id a zo[1,2-a ]p yr id in -2(3H)-on e (22d ): colorless oil;
[R]25 ) -44.3 (c 1.80, CHCl3); Rf ) 0.48 (hexanes:EtOAc )
D
1
[R]25 ) -18.1 (c 1.80, CHCl3); Rf ) 0.43 (hexanes:EtOAc )
D
1
3:1); H NMR δ 7.27 (d, J ) 8.1 Hz, 2H), 7.16 (d, J ) 8.4 Hz,
3:1); H NMR δ 7.33-7.24 (m, 4H), 7.24-7.18 (m, 1H), 7.16
2H), 4.92 [dd, J ) 7.2, 3.6 Hz, 1H, H(8a)], 3.38 [dd, J ) 4.1,
1.1 Hz, 1H, H(3)], 3.04-2.97 (m, 1H), 2.92-2.83 (m, 1H), 2.40-
2.26 (m, 1H), 2.32 (s, 3H), 2.18-2.08 (m, 1H), 1.84-1.79 (m,
1H), 1.65-1.38 (m, 4H), 1.12 (d, J ) 6.9 Hz, 3H), 1.04 (d, J )
6.9 Hz, 3H); 13C NMR δ 172.6 (CdO), 135.4, 133.9, 129.5, 123.3,
74.7, 68.0, 46.9, 29.1, 27.5, 21.8, 20.8, 20.8, 18.9, 18.4; HRMS
m/z calcd for C17H25N2O 273.1967 (M + 1), found 273.1968.
Anal. Calcd for C17H24N2O: H, 8.88; N, 10.28. Found: H, 8.68;
N, 10.35.
(d, J ) 8.1 Hz, 2H), 7.04 (d, J ) 8.4 Hz, 2H), 3.94 [d, J ) 10.2
Hz, 1H, H(8a)], 3.34 (dd, J ) 15.5, 4.0 Hz, 1H), 3.34-3.26 [m,
1H, H(3)], 2.98 (dt, J ) 7.5, 7.5 Hz, 1H), 2.92-2.82 (m, 1H),
2.32 (s, 3H), 2.26-2.14 (m, 1H), 1.94-1.74 (m, 2H), 1.62-1.50
(m, 2H), 1.42-1.12 (m, 2H); 13C NMR δ 172.1 (CdO), 138.7,
136.0, 132.9, 129.5, 129.4, 128.0, 126.1, 124.6, 77.9, 65.3, 48.5,
36.1, 28.8, 25.0, 22.7, 21.0; HRMS m/z calcd for C21H25N2O
321.1967 (M
+ 1), found 321.1970. Anal. Calcd for
C
21H24N2O: H, 7.55; N, 8.74. Found: H, 7.61; N, 8.66.
Da ta for (3S,8a R)-3-Isobu tyl-1-(4-m eth ylp h en yl)h exa -
h yd r oim id a zo[1,2-a ]p yr id in -2(3H)-on e (22c): colorless oil;
[R]25 ) -26.5 (c 2.60, CHCl3); Rf ) 0.33 (hexanes:EtOAc )
D
1
Su p p or tin g In for m a tion Ava ila ble: Characterization
3:1); H NMR δ 7.25 (d, J ) 8.7 Hz, 2H), 7.17 (d, J ) 8.4 Hz,
data for compounds 11b-d , 12b-d , 15b, 17b,c, and 21a -d
and 1H and 13C spectra for 17a ,c and 18a ,c. This material is
available free of charge via the Internet at http://pubs.acs.org.
2H), 4.87 [dd, J ) 7.2, 3.6 Hz, 1H, H(8a)], 3.51 [t, J ) 6.5 Hz,
1H, H(3)], 3.01-2.90 (m, 1H), 2.90-2.80 (m, 1H), 2.26 (s, 3H),
2.04-1.90 (m, 1H), 1.90-1.78 (m, 1H), 1.66-1.40 (m, 7H), 0.96
(d, J ) 6.9 Hz, 6H); 13C NMR δ 174.2 (CdO), 135.5, 133.8,
J O010842W
4956 J . Org. Chem., Vol. 67, No. 14, 2002