Novel syntheses of enantiopure hexahydroimidazo[1,5-b]isoquinolines and tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-ones via iminium cation cyclizations

Article abstract of DOI:10.1021/jo0203241

Condensations of chiral diamines 11a-c with benzotriazole and formaldehyde gave benzotriazolyl intermediates 12a-c; similar condensations of α-amino-amides 10a-c with benzotriazole and paraformaldehyde gave 14a-c. Subsequent treatment of 12a-c and 14a-c with AlCl₃ led to enantiopure tricyclic 1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinolines 1a-c and 2,3,10,10a-tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-ones 15a-c, respectively, via Lewis acid promoted iminium cation cyclizations.

Full text of DOI:10.1021/jo0203241

Novel Syn th eses of En a n tiop u r e
Hexa h yd r oim id a zo[1,5-b]isoqu in olin es a n d
Tetr a h yd r oim id a zo[1,5-b]isoqu in olin -1(5H)-on es via Im in iu m
Ca tion Cycliza tion s
Alan R. Katritzky,* Kazuyuki Suzuki, and Hai-Ying He
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received May 8, 2002
Condensations of chiral diamines 11a -c with benzotriazole and formaldehyde gave benzotriazolyl
intermediates 12a -c; similar condensations of R-amino-amides 10a -c with benzotriazole and
paraformaldehyde gave 14a -c. Subsequent treatment of 12a -c and 14a -c with AlCl3 led to
enantiopure tricyclic 1,2,3,5,10,10a-hexahydroimidazo[1,5-b]isoquinolines 1a -c and 2,3,10,10a-
tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-ones 15a -c, respectively, via Lewis acid promoted
iminium cation cyclizations.
In tr od u ction
Optically active imidazolidines 6 were synthesized by
Mannich condensations of chiral diamines 4 with ben-
zotriazole and formaldehyde, followed by the nucleophilic
substitutions of the benzotriazolyl group in 5.1 Previous
syntheses of 1,4-dihydro-3(2H)-isoquinolinones,6a tetrahy-
dro[1,3]oxazolo[3,4-b]isoquinolin-3-ones,6b and tetrahy-
droisoquinolines6c by intramolecular cyclizations utilizing
Lewis acid-activated benzotriazole as a leaving group
suggested a route to 1 by iminium cation Lewis acid-
promoted cyclizations of intermediates 5 (Scheme 1).
Success of the methodology led to its extension to prepare
2,3,10,10a-tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-
ones 2.
Following our recent syntheses of optically active
imidazolidines 6 from N-Boc-R-amino acids,1 we have now
developed routes to novel tricyclic 1,2,3,5,10,10a-hexahy-
droimidazo[1,5-b]isoquinolines 1 and 2,3,10,10a-tetrahy-
droimidazo[1,5-b]isoquinolin-1(5H)-ones 2. The nearest
known analogues of 1 and 2 are 10,10a-dihydroimidazo-
[1,5-b]isoquinoline-1,3(2H,5H)-diones 3, which are of
interest as inhibitors of inflammation,2a,b apoprotein
B-100 biosynthesis,2c and matrix-degrading metallopro-
teinase.2d
Parent compound 3 (R1 ) R2 ) R3 ) H) was obtained
by cyclization of 1,2,3,4-tetrahydro-3-isoquinolinecar-
boxylic acid with KOCN.2a,b Significant synthetic activity
to prepare derivatives of 3 has involved (i) N-alkylation
of 3 (R1 ) R2 ) R3 ) H) with N-(2-chloroethyl)-
piperidine;2a,b (ii) Mannich condensation of 3 (R1 ) R2 )
R3 ) H) with formaldehyde and secondary amines;3 and
(iii) modification of 3 (R1 ) H, alkyl, or Ph, R2 ) R3 ) H)
via bromination and nucleophilic substitutions.2c,4 Ad-
ditional analogues of 3 have been made by (iv) solid phase
supported intramolecular cyclization of N-CBZ-R-amino-
amides.5 No previous reports have been found for the
preparation of compounds of type 1 and 2.
Resu lts a n d Discu ssion
P r ep a r a tion of Ch ir a l Dia m in es 11a -c fr om N-
Boc-P h e-OH (7). N-Boc-R-amino-amides 9a -c were
readily obtained from optically active N-Boc-Phe-OH (7)
and primary amines 8a -c (R ) p-CH3C6H4, c-C6H11, or
PhCH2) by using the mixed anhydride method.7 We
previously used excess HCl/EtOAc to remove the N-Boc
protection group (usually needs 12-24 h until the disap-
pearance of 9).1,7a We now find that 8 equiv of CF3COOH
in dry CH2Cl2 efficiently removes N-Boc in 2-5 h giving
the R-amino-amides 10a -c in g88% yields. Treatment
of 10a -c with 6 equiv of LiAlH4 in refluxing THF for 2
days afforded chiral diamines 11a -c in g90% yields.
Intermediates 9a -c, 10a -c, and 11a -c were all used
as crude products for the subsequent reactions.
* Author to whom correspondence should be addressed.
(1) Katritzky, A. R.; Suzuki, K.; He, H.-Y. J . Org. Chem. 2002, 67,
3109.
(2) (a) Schwan, T. J . U.S. Patent 4,001,245, 1977; Chem. Abstr. 1977,
86, 155653q. (b) Schwan, T. J .; Goldenberg, M. M.; IIse, A. C. J . Pharm.
Sci. 1978, 67, 718. (c) Sierra, M. L.; Pianetti, P. M. C. PCT Int. Appl.
WO 98 56,790, 1998; Chem. Abstr. 1999, 130, 52421k. (d) Kukkola, P.
J .; Robinson, L. A.; Sakaki, J .; Nakajima, M. PCT Int. Appl. WO 99
42,443, 1999; Chem. Abstr. 1999, 131, 184961s.
(3) Niopas, I.; Smail, G. A. Collect. Czech. Chem. Commun. 1990,
55, 540.
(4) (a) Niopas, I.; Smail, G. A. J . Chem. Soc., Perkin Trans. 1 1991,
113. (b) Niopas, I.; Smail, G. A. J . Chem. Soc., Perkin Trans. 1 1991,
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(5) Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron Lett.
1996, 37, 937.
Syn t h eses of 1,2,3,5,10,10a -Hexa h yd r oim id a zo-
[1,5-b]isoq u in olin es 1a -c. Mannich condensation of
(6) (a) Katritzky, A. R.; Lan, X.; Zhang, Z. J . Heterocycl. Chem. 1993,
30, 381. (b) Katritzky, A. R.; Cobo-Domingo, J .; Yang, B.; Steel, P. J .
Tetrahedron: Asymmetry 1999, 10, 255. (c) Katritzky, A. R.; He, H.-
Y.; J iang, R.; Long, Q. Tetrahedron: Asymmetry 2001, 12, 2427.
(7) (a) Katritzky, A. R.; Xu, Y.-J .; He, H.-Y.; Steel, P. J . J . Chem.
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10.1021/jo0203241 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/10/2002
8224
J . Org. Chem. 2002, 67, 8224-8229

Novel Syntheses of Isoquinolines and Isoquinolinones
SCHEME 1
SCHEME 3
SCHEME 4a
SCHEME 2a
a
For trans-16a , the cis-16′a was isolated in 31% yield. bThis
a
route resulted in a mixture of trans-18a -c and cis-18′a -c in a
ratio range from 4:1 to 5:1.
Conditions: (i) ClCOOBu-i, N-methylmorpholine; (ii) CF3COOH;
(iii) aq NaOH; (iv) LiAlH4; (v) BtH, 2 HCHO (aq); (vi) AlCl3.
Attempts to purify 14a -c by column chromatography
failed due to their significant decomposition on silica gel.
Therefore, compounds 14a -c were used directly for the
subsequent cyclizations.
chiral diamines 11a -c with 1 equiv of benzotriazole and
2 equiv of formaldehyde (37% aqueous solution) in an
aqueous solution at 25 °C gave benzotriazolyl intermedi-
ates 12a -c in 93%, 96%, and 90% yields, respectively.
Compounds 12a ,c were obtained solely as benzotriazol-
1-yl isomers; 12b was obtained as a mixture of Bt1 and
Bt2 isomers in ca. 26:1 ratio.
Treatment of crude 12a -c with 3 equiv of AlCl3 in
refluxing CH2Cl2 afforded 2-substituted-1,2,3,5,10,10a-
hexahydroimidazo[1,5-b]isoquinolines 1a -c (Scheme 2).
The structures of 1a -c are clearly supported by their
1H, 13C NMR spectra and microanalyses. Lewis acid AlCl3
facilitates loss of the benzotriazolyl anion to form an
iminium cation, which then undergoes intramolecular
cyclization to afford 1a -c.
Syn th eses of 2,3,10,10a -Tetr a h yd r oim id a zo[1,5-b]-
isoqu in olin -1(5H)-on es 15a -c (cf. Sch em e 3). The
reaction of R-amino-amide 10a with benzotriazole and
formaldehyde in aqueous solution at 25 °C did not
produce the desired cyclized compound 14a ; instead
acyclic 13 was obtained in 92% yield, due to the lower
nucleophilic activity of amide nitrogen. Therefore, strong-
er conditions using azeotropic distillation with paraform-
aldehyde were applied and Bt intermediates 14a -c were
prepared in 92%, 91%, and 94% yields, respectively.
The subsequent treatment of 14a -c with 3 equiv of
AlCl3 in refluxing CH2Cl2 furnished 2,3,10,10a-tetrahy-
droimidazo[1,5-b]isoquinolin-1(5H)-ones 15a -c in 82%,
83%, and 78% yields, respectively. The structures of
15a -c are clearly supported by their 1H, 13C NMR
spectra and microanalyses. The two methylene protons
at the 5-position in 15a -c appear at 3.7-4.0 ppm as a
typical AB system with ca. 14 Hz coupling constant.
We attempted direct treatment of R-amino-amide 10a
with excess paraformaldehyde in the presence of AlCl3,
but could not isolate any desired tricyclic 15a . This result
proves the necessity of using benzotriazole.
Syn th eses of Ch ir a l 3-Su bstitu ted -2,3,10,10a -tet-
r a h yd r oim id a zo[1,5-b]isoqu in olin -1(5H)-on es 18a -c
(cf. Sch em e 4). We further investigated the modification
of 2,3,10,10a-tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-
ones 15 at the 3-position. In agreement with the previous
reactions of R-amino-amides and aldehydes,8 we obtained
(8) (a) Polonski, T. Tetrahedron 1985, 41, 611. (b) Sunjic, V.; Kajfez,
F.; Blazevic, N.; Oklobdzija, M.; Mildner, P. J . Heterocycl. Chem. 1975,
12, 995.
J . Org. Chem, Vol. 67, No. 23, 2002 8225

Katritzky et al.
SCHEME 5a
16b,c as the sole trans-isomers; however, trans-16a was
isolated in 38% yield together with the corresponding cis-
16′a in 31% isolated yield. The absolute configurations
of trans-16a -c and cis-16′a were determined by NOE
experiments. For example, strong positive NOE effect
between H(2) (5.81 ppm, s) and H(5) (4.00 ppm, t) in 16′a
confirms its cis-configuration. For trans-16a -c, no posi-
tive NOE effect was observed between H(2) and H(5);
however, small but distinct NOE effects between H(2)
and PhCH2 at the 5-position prove their trans-configura-
tions.
Reaction of 16a -c with benzotriazole and aqueous
formaldehyde readily gave Bt intermediates 17a -c,
which were directly treated with AlCl3 to furnish enan-
tiopure trans-3-substituted-2,3,10,10a-tetrahydroimidazo-
[1,5-b]isoquinolin-1(5H)-ones 18a -c. The same route
1
from cis-16′a led to enantiopure cis-18′a . The H NMR
spectra show that NCHN (5.68 ppm, d) in trans-18a
appears at a lower field than NCHN (5.32 ppm, d) in cis-
18′a . The positive NOE effect of H(3) and H(10a) in 18′a
also confirms its cis-configuration.
a
Ar ) p-MeC6H4; reflux of only trans-16a resulted in a mixture
of trans-16a and cis-16′a in ca. 4:1 ratio.
We attempted reactions of 16a -c with paraformalde-
hyde and AlCl3 in the absence of benzotriazole. The crude
NMR spectra of the products show a mixture of trans-
18a -c and cis-18′a -c in a ratio ranging from 4:1 to 5:1.
It is impossible to separate trans-18a -c and cis-18′a -c
by column chromatography due to their very close reten-
tion factors on alumina or silica gel TLC plate. This result
indicates the possible Lewis acid-promoted ring opening
and closing of the five-membered ring in 16a -c. We
further treated trans-16a with AlCl3 only, and did
observe the formation of cis-16′a in 1:4 ratio. Therefore,
we believe that the nitrogen at the 1-position may
coordinate with AlCl3 to form intermediate A, which
undergoes ring opening to generate an iminium cation
intermediate B. The lone electron pair of the nitrogen in
B attacks the iminium cation from above (I) or below (II)
the plane, leading to trans-16a and cis-16′a , respectively.
Attem p ts to Syn th esize 1,2a ,3,4a ,5,9b-Hexa h y-
dr oben zo[g]im idazo[2,1,5-cd]in dolizin -4(2H)-on e (23).
We recently reported reaction of succindialdehyde (19)
with benzotriazole and N-phenylethylenediamine leading
to 1-phenyl-5-(benzotriazol-1-yl)hexahydro-1H-pyrrolo-
[1,2-a]imidazole 20. The benzotriazolyl group at the
5-position in 20 is readily removed by nucleophilic
substitutions with Grignard reagents, allylsilanes, silyl
enol ethers, or triethyl phosphite to furnish novel 1-phen-
yl-5-substituted-hexahydro-1H-pyrrolo[1,2-a]imidazoles
21 [Nu ) alkyl, aryl, allyl, and P(O)(OEt)2] (Scheme 6).9
Since chiral diamines 11a -c were readily obtained in
high yields, our initial idea intended to use chiral diamine
11a instead of N-phenylethylenediamine, to control the
two new chiral centers at the 5- and 7a-positions.
Subsequent treatment of Bt intermediates 22 was sup-
posed to undergo intramolecular cyclizations at the
tethered phenyl group to give 23.
SCHEME 6
The stereochemistry of 22 was determined by NOE NMR
experiments. 1H NMR spectra of 22 show that H(3),
H(7a), and H(5) appear at 3.7 (multiplet), 5.1 (doublet-
doublet), and 6.0 ppm (triplet), respectively. A significant
positive NOE effect was observed between H(3) and H(5),
and no NOE effect was observed between H(7a) with
either H(3) or H(5). Thus, NOE analysis demonstrates
that H(3) and H(5) in 22 are in cis-orientation, while H(3)
and H(7a) are in trans-orientation.
Treatment of 22 with 2 equiv of AlCl3 or ZnBr2 did not
afford the desired 23, but gave a decomposed mixture
possibly due to the labile NCHN moiety in the presence
of a Lewis acid.
In summary, starting from easily available N-Boc-R-
amino acids, we have developed an efficient method for
the preparation of novel enantiopure 1,2,3,5,10,10a-
hexahydroimidazo[1,5-b]isoquinolines 1a -c, 2,3,10,10a-
tetrahydroimidazo[1,5-b]isoquinolin-1(5H)-ones 15a -c,
and 18a -c via Lewis acid-promoted iminium cation
intramolecular cyclizations.
Reaction of chiral diamines 11a with succindialdehyde
(19, obtained by treatment of 2,5-dimethoxytetrahydro-
furan with 0.1 M HCl) and benzotriazole in CH2Cl2 at
room temperature for 24 h readily afforded Bt intermedi-
ates 22 as single enantiomers in 81% yield (Scheme 6).
Exp er im en ta l Section
1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded
in CDCl3 (with TMS for 1H and chloroform-d for 13C as the
internal reference). Column chromatography was performed
(9) Katritzky, A. R.; Qiu, G.; He, H.-Y.; Yang, B. J . Org. Chem. 2000,
65, 3683.
8226 J . Org. Chem., Vol. 67, No. 23, 2002

Novel Syntheses of Isoquinolines and Isoquinolinones
on silica gel (200-425 mesh). All of the reactions were carried
out under nitrogen.
1H), 6.45 (d, J ) 8.5 Hz, 2H), 7.05-7.19 (m, 6H); 13C NMR
20.3, 33.2, 52.8, 53.0, 59.2, 71.1, 111.3, 125.3, 126.0, 126.5,
126.8, 129.1, 129.7, 133.5, 134.0, 144.3. Anal. Calcd for
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Ch ir a l
r-Am in o-a m id es 10a-c a n d Dia m in es 11a -c fr om N-Boc-
P h e-OH (7). R-Amino-amides 10a -c and diamines 11a -c
were prepared from N-Boc-Phe-OH (7) and primary amines
8a -c according to our recent paper.1,7a,10
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zotr i-
a zolyl in ter m ed ia tes 12a -c. A mixture of a diamine 11a -c
(3.0 mmol), BtH (0.36 g, 3.0 mmol), and formaldehyde (37%
aqueous solution, 0.49 g, 6 mmol) in CH3OH/H2O (10 mL/5
mL) was stirred at 25 °C for 4 h. The precipitate formed was
filtered and washed with cool Et2O to give 12a -c, which was
used directly for the subsequent reactions. For microanalyses
and optical activity, crude 12a -c was recrystallized from
appropriate solvents.
Da ta for 1-{[(5S)-5-ben zyl-3-(4-m eth ylp h en yl)tetr a h y-
dr o-1H-im idazol-1-yl]m eth yl}-1H-1,2,3-ben zotr iazole (12a):
white microcrystals (from EtOH); yield 93%; mp 94-95 °C;
[R]25D +1.8 (c 1.70, CHCl3); 1H NMR δ 2.21 (s, 3H), 2.74 (dd, J
) 13.2, 8.3 Hz, 1H), 3.08 (t, J ) 7.6 Hz, 1H), 3.22-3.31 (m,
2H), 3.58-3.63 (m, 1H), 4.24, 4.39 (AB, J ) 5.0 Hz, 2H), 5.56,
5.67 (AB, J ) 13.7 Hz, 2H), 6.35 (d, J ) 8.4 Hz, 2H), 6.98 (d,
J ) 8.1 Hz, 2H), 7.22-7.40 (m, 6H), 7.48 (d, J ) 3.6 Hz, 2H),
8.05 (d, J ) 8.2 Hz, 1H); 13C NMR δ 20.3, 39.2, 52.2, 61.2,
63.7, 68.2, 109.7, 112.3, 120.0, 124.0, 126.4, 126.6, 127.7, 128.6,
129.0, 129.7, 133.5, 138.1, 144.0, 146.0. Anal. Calcd for
C
18H20N2: C, 81.78; H, 7.63; N, 10.60. Found: C, 81.31; H,
8.18; N, 10.71.
Da t a for (10a S)-2-cycloh exyl-1,2,3,5,10,10a -h exa h y-
d r oim id a zo[1,5-b]isoqu in olin e (1b): colorless prism (from
hexanes/CHCl3); yield 77%; mp 101-102 °C; [R]25 -35.5 (c
D
1
1.66, CHCl3); H NMR δ 1.24 (br s, 5H), 1.56-1.62 (m, 1H),
1.74 (br s, 2H), 1.88 (br s, 2H), 2.31 (br s, 1H), 2.63 (t, J ) 8.4
Hz, 1H), 2.76-2.93 (m, 3H), 3.17 (dd, J ) 8.4, 5.5 Hz, 1H),
3.43 (d, J ) 4.6 Hz, 1H), 3.56, 4.02 (AB, J ) 14.3 Hz, 2H),
4.03 (d, J ) 4.6 Hz, 1H), 7.04-7.26 (m, 4H); 13C NMR δ 24.7,
24.8, 26.0, 31.6, 32.2, 33.5, 52.9, 56.0, 58.8, 62.2, 74.1, 125.7,
126.2, 126.7, 129.0, 134.4, 134.8. Anal. Calcd for C17H24N2: C,
79.64; H, 9.44; N, 10.93. Found: C, 79.94; H, 9.69; N, 10.87.
Da ta for (10a S)-2-ben zyl-1,2,3,5,10,10a -h exa h yd r oim i-
d a zo[1,5-b]isoqu in olin e (1c): white needles (from hexanes/
EtOH); yield 85%; mp 73-74 °C; [R]25 -30.3 (c 1.77, CHCl3);
D
1H NMR δ 2.64 (t, J ) 8.7 Hz, 1H), 2.77-2.95 (m, 3H), 3.21
(dd, J ) 8.7, 5.7 Hz, 1H), 3.43, 3.93 (AB, J ) 5.4 Hz, 2H), 3.55,
3.99 (AB, J ) 14.2 Hz, 2H), 3.84 (s, 2H), 7.04-7.16 (m, 4H),
7.23-7.39 (m, 5H); 13C NMR δ 33.5, 52.6, 59.0, 59.1, 60.6, 76.5,
125.9, 126.4, 126.7, 127.0, 128.3, 128.5, 128.9, 134.4, 134.7,
139.4. Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N, 10.60.
Found: C, 81.52; H, 7.37; N, 10.65.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zotr ia -
zolyl In ter m ed ia tes 13 a n d 14a -c. Using the same proce-
dure as for the preparation of 12a -c, reaction of 10a with
benzotriazole and aqueous formaldehyde (1 or 2 equiv) led to
13.
C
24H25N5: C, 75.17; H, 6.57; N, 18.26. Found: C, 74.95; H,
6.77; N, 18.29.
Da ta for 1-{[(5S)-5-ben zyl-3-cycloh exyltetr a h yd r o-1H-
im id a zol-1-yl]m eth yl}ben zotr ia zole (12b): obtained as a
mixture of Bt1 and Bt2 isomers in 26:1 ratio, and NMR data
are reported for the major Bt1 isomer; white needles (from
Da t a for (2S)-2-[(1H -1,2,3-b en zot r ia zol-1-ylm et h yl)-
a m in o]-N-(4-m eth ylp h en yl)-3-p h en ylp r op a n a m id e (13):
EtOH); yield 96%; mp 94-95 °C; [R]25 +30.5 (c 1.64, CHCl3);
D
white microcrystals (from CH3OH); yield 92%; mp 136-137
1H NMR δ 1.02-1.14 (m, 5H), 1.53-1.67 (m, 5H), 1.90 (br s,
1H), 2.41 (dd, J ) 8.8, 6.8 Hz, 1H), 2.65-2.77 (m, 2H), 2.99
(dd, J ) 13.4, 6.1 Hz, 1H), 3.43-3.48 (m, 1H), 3.70 (s, 2H),
5.31, 5.49 (AB, J ) 13.5 Hz, 2H), 7.20-7.48 (m, 8H), 8.04 (d,
J ) 8.2 Hz, 1H); 13C NMR δ 24.4, 24.6, 25.8, 31.6, 31.7, 41.1,
56.3, 61.4, 61.5, 65.1, 72.3, 109.8, 119.8, 123.8, 126.3, 127.3,
128.4, 129.1, 133.4, 138.8, 145.8. Anal. Calcd for C23H29N5: C,
73.57; H, 7.78; N, 18.65. Found: C, 73.94; H, 8.17; N, 18.77.
Da ta for 1-{[(5S)-3,5-d iben zyltetr a h yd r o-1H-im id a zol-
1-yl]m et h yl}-1H -1,2,3-b en zot r ia zole (12c): white micro-
1
°C; [R]25 -74.5 (c 1.76, CHCl3); H NMR δ 2.32 (s, 3H), 2.70
D
(br s, 1H), 2.79 (dd, J ) 13.8, 8.7 Hz, 1H), 3.01 (dd, J ) 14.1,
4.8 Hz, 1H), 3.61 (dd, J ) 8.4, 4.5 Hz, 1H), 5.41-5.53 (m, 2H),
6.87-6.89 (m, 2H), 7.08-7.14 (m, 5H), 7.33-7.40 (m, 4H), 7.44
(d, J ) 7.8 Hz, 1H), 8.04 (d, J ) 8.7 Hz, 1H), 8.67 (s, 1H);
13CNMR δ 20.8, 39.0, 60.9, 61.3, 108.8, 119.7, 120.1, 124.1,
127.0, 127.8, 128.6, 128.7, 129.4, 132.5, 134.1, 134.6, 135.9,
146.0, 170.2. Anal. Calcd for C23H23N5O: C, 71.67; H, 6.01; N,
18.17. Found: C, 71.60; H, 6.25; N, 18.29.
A mixture of 10a -c (2.0 mmol), BtH (0.48 g, 4.0 mmol), and
paraformaldehyde (0.18 g, 6.0 mmol) with p-TsOH‚H2O (0.08
g, 0.4 mmol) was refluxed in benzene (25 mL) with a Dean-
Stark apparatus for 2 h. After cooling, benzene was evaporated
and toluene (25 mL) was added, and then the mixture was
refluxed for another 1 h. The mixture was washed with 2 M
NaOH. The aqueous phase was extracted with EtOAc and the
combined organic phase was washed with water and brine and
dried over anhydrous K2CO3. Removal of solvent in vacuo gave
the crude 14a -c, which were directly used for the subsequent
reactions. Attempts to purify 14a -c failed due to their
significant decomposition on silica gel.
crystals (from EtOH); yield 90%; mp 81-82 °C; [R]25 +40.8
D
(c 1.87, CHCl3); 1H NMR δ 2.34 (dd, J ) 9.4, 6.5 Hz, 1H), 2.67-
2.81 (m, 2H), 2.92 (dd, J ) 13.2, 6.6 Hz, 1H), 3.42, 3.52 (AB,
J ) 13.2 Hz, 2H), 3.52-3.60 (m, 1H), 3.62, 3.70 (AB, J ) 6.3
Hz, 2H), 5.38, 5.43 (AB, J ) 13.6 Hz, 2H), 7.12-7.45 (m, 13H),
8.05 (d, J ) 8.1 Hz, 1H); 13C NMR δ 41.3, 57.8, 58.6, 61.8,
65.5, 73.9, 109.8, 119.8, 123.8, 126.3, 127.0, 127.3, 128.2, 128.3,
128.4, 129.2, 133.4, 138.3, 138.8, 145.9. Anal. Calcd for
C
24H25N5: C, 75.17; H, 6.57; N, 18.26. Found: C, 75.03; H,
6.32; N, 18.30.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,2,3,5,10,-
10a -Hexa h yd r oim id a zo[1,5-b]isoqu in olin es 1a -c. A mix-
ture of 12a -c (1.0 mmol) and anhydrous AlCl3 (0.40 g, 3.0
mmol) was refluxed in dry CH2Cl2 (20 mL) for 12 h. After
cooling, the reaction mixture was added to CH2Cl2 (30 mL),
washed with 2 M NaOH and brine, and dried over anhydrous
K2CO3. After removal of the solvent in vacuo, the crude product
was purified by column chromatography with hexanes/EtOAc
(3:1 to 1:1) as an eluent to give 1a -c.
Da ta for (5S)-1-(ben zotr ia zolylm eth yl)-5-ben zyl-3-(4-
m eth ylp h en yl)tetr a h yd r o-4H-im id a zol-4-on e (14a ): ob-
tained as a mixture of Bt1 and Bt2 isomers in 3:1 ratio, and
NMR data are reported for the major Bt1 isomer; yellowish
1
oil; yield 92%; H NMR δ 2.29 (s, 3H), 3.09 (dd, J ) 14.2, 7.4
Hz, 1H), 3.35 (dd, J ) 14.2, 3.9 Hz, 1H), 3.91 (dd, J ) 7.3, 3.8
Hz, 1H), 4.63, 4.85 (AB, J ) 5.6 Hz, 2H), 5.41 (s, 2H), 7.06-
7.46 (m, 12H), 8.04 (d, J ) 8.2 Hz, 1H).
Da ta for (10aS)-2-(4-m eth ylp h en yl)-1,2,3,5,10,10a -h exa -
h yd r oim id a zo[1,5-b]isoqu in olin e (1a ): colorless microcrys-
Da ta for (5S)-1-(ben zotr ia zolylm eth yl)-5-ben zyl-3-cy-
cloh exyltetr a h yd r o-4H-im id a zol-4-on e (14b): obtained as
a mixture of Bt1 and Bt2 isomers in 4:1 ratio, and NMR data
are reported for the major Bt1 isomer; yellowish oil; yield 91%;
1H NMR δ 0.90-1.40 (m, 6H), 1.50-1.80 (m, 4H), 2.95 (dd, J
) 13.9, 7.4 Hz, 1H), 3.24 (dd, J ) 13.8, 3.4 Hz, 1H), 3.70-3.81
(m, 2H), 4.21, 4.43 (AB, J ) 5.6 Hz, 2H), 5.31 (d, J ) 4.8 Hz,
2H), 7.11 (d, J ) 8.1 Hz, 1H), 7.27-7.45 (m, 7H), 8.04 (d, J )
8.1 Hz, 1H).
tals (from hexanes/CHCl3); yield 76%; mp 189-190 °C; [R]25
D
1
-50.3 (c 1.68, CHCl3); H NMR δ 2.26 (s, 3H), 2.91-3.06 (m,
3H), 3.24 (t, J ) 8.2 Hz, 1H), 3.62-3.70 (m, 2H), 3.84 (d, J )
3.6 Hz, 1H), 4.18 (d, J ) 14.4 Hz, 1H), 4.60 (d, J ) 3.6 Hz,
(10) Katritzky, A. R.; He, H.-Y.; Verma, A. K. Tetrahedron: Asym-
metry 2002, 13, 933.
J . Org. Chem, Vol. 67, No. 23, 2002 8227

Katritzky et al.
Da ta for (5S)-1-(ben zotr ia zolylm eth yl)-3,5-d iben zyltet-
r a h yd r o-4H-im id a zol-4-on e (14c): obtained as a mixture
of Bt1 and Bt2 isomers in 5:1 ratio, and NMR data are reported
crystals; yield 31%; mp 97-98 °C; [R]25D -29.8 (c 1.58, CHCl3);
1H NMR δ 1.88 (br s, 1H), 2.20 (s, 3H), 3.17 (dd, J ) 14.1, 4.8
Hz, 1H), 3.40 (dd, J ) 14.1, 5.4 Hz, 1H), 4.00 (t, J ) 4.6 Hz,
1H), 5.81 (s, 1H), 6.81 (d, J ) 7.0 Hz, 2H), 6.98-7.33 (m, 12H);
13C NMR δ 20.9, 36.6, 60.9, 77.2, 122.8, 127.0, 127.1, 128.8,
128.9, 129.1, 129.3, 129.9, 134.0, 135.3, 136.4, 138.5, 174.0.
Anal. Calcd for C23H22N2O: C, 80.67; H, 6.48; N, 8.18. Found:
C, 80.40; H, 6.30; N, 8.28.
Da t a for (2R,5S)-5-b en zyl-3-cycloh exyl-2-p h en ylt et -
r a h yd r o-4H-im id a zol-4-on e (16b): colorless microcrystals;
yield 69%; mp 92-93 °C; [R]25D -32.2 (c 1.81, CHCl3); 1H NMR
δ 0.87-0.99 (m, 2H), 1.07-1.28 (m, 2H), 1.43-1.61 (m, 5H),
1.65-1.70 (m, 1H), 1.99 (br s, 1H), 2.90 (dd, J ) 13.5, 7.5 Hz,
1H), 3.13 (dd, J ) 13.6, 3.9 Hz, 1H), 3.53-3.64 (m, 1H), 4.07-
4.11 (m, 1H), 5.16 (s, 1H), 7.20-7.34 (m, 10H); 13C NMR δ
25.1, 25.6, 25.7, 29.9, 30.9, 38.7, 52.8, 59.7, 75.0, 126.4, 126.5,
128.3, 128.8, 129.0, 129.7, 137.8, 141.9, 173.6. Anal. Calcd for
1
for the major Bt1 isomer; pale brown oil; yield 94%; H NMR
δ 3.04 (dd, J ) 14.0, 6.8 Hz, 1H), 3.29 (dd, J ) 14.0, 3.7 Hz,
1H), 3.87-3.90 (m, 1H), 4.09, 4.57 (AB, J ) 10.7 Hz, 2H), 4.11-
4.13 (m, 1H), 4.32 (d, J ) 5.2 Hz, 1H), 5.35 (s, 2H), 6.91-6.93
(m, 2H), 7.11-7.45 (m, 11H), 8.05 (d, J ) 8.1 Hz, 1H); 13C NMR
δ 37.4, 44.9, 62.9, 63.3, 65.1, 109.1, 120.0, 124.2, 126.8, 127.5,
127.7, 127.9, 128.5, 128.7, 130.0, 133.4, 134.9, 137.3, 145.7,
170.6.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2,3,10,10a -
Tetr a h yd r oim id a zo[1,5-b]isoqu in olin -1(5H)-on es 15a -c.
Treatment of crude 14a -c with 3 equiv of AlCl3 afforded
15a -c with use of the same procedure as for the preparation
of 1a -c. The isolated yields of 15a -c were based on R-amino-
amides 10a -c.
C
22H26N2O: C, 79.00; H, 7.84; N, 8.38. Found: C, 78.55; H,
Da ta for (10a S)-2-(4-m eth ylp h en yl)-2,3,10,10a -tetr a h y-
d r oim id a zo[1,5-b]isoqu in olin -1(5H)-on e (15a ): colorless
7.99; N, 8.29.
needles; yield 82%; mp 185-186 °C; [R]25 -62.7 (c 1.66,
Da ta for (2R,5S)-3,5-d iben zyl-2-p h en yltetr a h yd r o-4H-
im id a zol-4-on e (16c): colorless needles (from hexanes/
D
CHCl3); 1H NMR δ 2.32 (s, 3H), 3.04-3.21 (m, 2H), 3.38-3.43
(m, 1H), 3.83, 4.05 (AB, J ) 14.0 Hz, 2H), 4.48 (dd, J ) 4.8,
1.6 Hz, 1H), 4.76 (d, J ) 5.0 Hz, 1H), 7.10-7.21 (m, 6H), 7.44
(d, J ) 8.5 Hz, 2H); 13C NMR δ 20.8, 29.9, 52.3, 61.4, 69.6,
119.2, 126.2, 126.6, 126.9, 129.4, 129.5, 133.3, 133.7, 134.5,
135.0, 170.9. Anal. Calcd for C18H18N2O: C, 77.67; H, 6.52; N,
10.06. Found: C, 77.28; H, 6.54; N, 10.10.
EtOAc); yield 74%; mp 128-129 °C; [R]25 -19.7 (c 1.73,
D
1
CHCl3); H NMR δ 2.15 (br s, 1H), 3.04 (AB dd, J ) 13.8, 6.9
Hz, 1H), 3.16 (AB dd, J ) 13.8, 4.2 Hz, 1H), 3.46, 5.02 (AB, J
) 14.9 Hz, 2H), 4.17 (br s, 1H), 4.96 (s, 1H), 6.85-6.87 (m,
2H), 7.14-7.36 (m, 13H); 13C NMR δ 38.1, 43.9, 59.8, 74.8,
126.7, 126.8, 127.5, 128.0, 128.5, 128.6, 129.1, 129.2, 129.8,
135.5, 137.2, 139.3, 173.6. Anal. Calcd for C23H22N2O: C, 80.67;
H, 6.48; N, 8.18. Found: C, 80.31; H, 6.63; N, 8.13.
Da ta for (10a S)-2-cycloh exyl-2,3,10,10a -tetr a h yd r oim i-
d a zo[1,5-b]isoq u in olin -1(5H )-on e (15b ): colorless micro-
crystals; yield 83%; mp 72-73 °C; [R]25D -89.8 (c 1.75, CHCl3);
1H NMR δ 1.03-1.16 (m, 1H), 1.23-1.42 (m, 4H), 1.66-1.82
(m, 5H), 2.98 (AB dd, J ) 15.6, 9.6 Hz, 1H), 3.10 (AB dd, J )
15.6, 4.8 Hz, 1H), 3.28 (dd, J ) 9.2, 4.8 Hz, 1H), 3.78, 3.96
(AB, J ) 14.1 Hz, 2H), 3.90-3.95 (m, 1H), 4.04 (dd, J ) 4.8,
2.1 Hz, 1H), 4.36 (d, J ) 4.8 Hz, 1H), 7.08-7.10 (m, 1H), 7.17-
7.20 (m, 3H); 13C NMR δ 25.2, 25.2, 25.4, 29.8, 30.2, 30.6, 49.9,
52.3, 60.9, 65.1, 126.1, 126.5, 126.8, 129.3, 133.6, 133.9, 171.3;
HRMS m/z calcd for C17H22N2O 270.1732 (M), found 270.1738.
Anal. Calcd for C17H22N2O: C, 75.52; N, 10.36. Found: C,
75.18; N, 10.32.
Gen er a l P r oced u r e for th e P r ep a r a tion of Bt In ter -
m ed ia tes 17a -c a n d 17′a . A mixture of 16a -c or 16′a (1.0
mmol), benzotriazole (0.14 g, 1.2 mmol), and formaldehyde
(37% aqueous solution, 0.12 g, 1.5 mmol) was stirred in CH3-
OH (15 mL) at 25 °C overnight. After evaporation of CH3OH,
EtOAc was added to the mixture. The organic phase was
washed with 1 M NaOH aqueous solution, brine, and water
and dried over anhydrous K2CO3. Removal of solvent in vacuo
gave essentially pure 17a and 17′a , which were purified by
recrystallization for analytical purposes. Attempt to purify
17b,c (both obtained as sticky oil) by column chromatography
(silica gel) failed, thus they were used directly for the subse-
quent reaction as crude products.
Data for (10aS)-2-ben zyl-2,3,10,10a-tetr ah ydr oim idazo-
[1,5-b]isoqu in olin -1(5H)-on e (15c): colorless prism; yield
1
78%; mp 50-51 °C; [R]25 -64.8 (c 1.66, CHCl3); H NMR δ
Da ta for (2R,5S)-1-(1H-1,2,3-ben zotr ia zol-1-ylm eth yl)-
5-ben zyl-3-(4-m eth ylp h en yl)-2-p h en yltetr a h yd r o-4H-im i-
D
3.10 (d, J ) 6.6 Hz, 2H), 3.49 (t, J ) 6.9 Hz, 1H), 3.77, 3.84
(AB, J ) 14.5 Hz, 2H), 4.05 (dd, J ) 5.2, 1.8 Hz, 1H), 4.12 (d,
J ) 5.0 Hz, 1H), 4.29, 4.65 (AB, J ) 15.3 Hz, 2H), 7.02-7.15
(m, 3H), 7.16-7.27 (m, 6H); 13C NMR δ 30.0, 44.8, 52.4, 60.4,
68.4, 126.3, 126.6, 127.0, 127.5, 127.6, 128.7, 129.2, 133.8,
134.4, 135.6, 172.3. Anal. Calcd for C18H18N2O: C, 77.67; H,
6.52; N, 10.06. Found: C, 77.50; H, 6.83; N, 10.09.
d a zol-4-on e (17a ): white needles (from EtOH); yield 89%; mp
1
153-154 °C; [R]25 -20.4 (c 1.80, CHCl3); H NMR δ 2.19 (s,
D
3H), 3.30-3.43 (m, 2H), 4.46 (br s, 1H), 5.34, 5.65 (AB, J )
13.8 Hz, 2H), 5.45 (d, J ) 2.1 Hz, 1H, NCHN), 6.84-6.97 (m,
5H), 7.08-7.32 (m, 12H), 7.98-8.01 (m, 1H); 13C NMR δ 20.8,
36.3, 60.2, 63.2, 80.1, 109.7, 119.7, 123.6, 123.9, 126.8, 127.2,
128.0, 128.5, 128.8, 129.4, 129.6, 129.8, 132.3, 132.9, 135.9,
136.0, 136.7, 145.9, 170.6. Anal. Calcd for C30H27N5O: C, 76.09;
H, 5.75; N, 14.79. Found: C, 75.74; H, 6.01; N, 14.69.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 2,3,5-
Tr isu bstitu ted -tetr a h yd r o-4H-im id a zol-4-on es 16a -c. A
mixture of R-amino-amide 10a -c (2.0 mmol), benzaldehyde
(0.27 g, 2 mmol), and p-TsOH (0.4 mmol) was refluxed in CH3-
OH (15 mL) with anhydrous Na2SO4 (3.0 g) for 12 h. After
evaporation of CH3OH in vacuo, the reaction mixture was
diluted with EtOAc. The organic phase was washed with 2 M
NaOH, water, and brine and dried over anhydrous K2CO3.
After removal of solvent in vacuo, the residue was purified by
column chromatography with hexanes/EtOAc (6:4) as an eluent
to give trans-16a , cis-16′a , and trans-16b,c.
Da ta for (2S,5S)-1-(ben zotr ia zolylm eth yl)-5-ben zyl-3-
(4-m e t h ylp h e n yl)-2-p h e n ylt e t r a h yd r o-4H -im id a zol-4-
on e (17′a ): obtained as a mixture of Bt1 and Bt2 isomers in
17:1 ratio, and NMR data are reported for the major Bt1
isomer; white prism (from EtOH); yield 85%; mp 197-198 °C;
1
[R]25 -185 (c 1.56, CHCl3); H NMR δ 2.16 (s, 3H), 3.38 (AB
D
dd, J ) 14.0, 4.4 Hz, 1H), 3.47 (AB dd, J ) 14.0, 4.4 Hz, 1H),
4.08 (br s, 1H), 5.34, 5.46 (AB, J ) 14.8 Hz, 2H), 5.82 (s, 1H,
NCHN), 6.84 (d, J ) 8.2 Hz, 2H), 6.88-6.96 (m, 4H), 7.13-
Da ta for (2R,5S)-5-ben zyl-3-(4-m eth ylp h en yl)-2-p h en -
ylt et r a h yd r o-4H -im id a zol-4-on e (16a ): yellowish micro-
7.36 (m, 4H), 7.40-7.50 (m, 7H), 8.11 (d, J ) 8.1 Hz, 1H); 13
C
crystals; yield 38%; mp 106-107 °C; [R]25 -52.5 (c 1.86,
NMR δ 20.9, 36.9, 58.9, 61.6, 77.8, 108.8, 120.2, 124.2, 124.5,
126.8, 128.0, 128.4, 128.5, 128.9, 129.3, 129.4, 130.5, 132.5,
134.0, 136.3, 136.7, 137.1, 145.6, 169.5. Anal. Calcd for
D
CHCl3); 1H NMR δ 1.70 (br s, 1H), 2.24 (s, 3H), 3.09-3.21(m,
2H), 4.13 (t, J ) 5.5 Hz, 1H), 5.55 (s, 1H), 7.03, 7.11 (AB, J )
8.5 Hz, 4H), 7.22-7.32 (m, 10H); 13C NMR δ 20.8, 38.0, 60.2,
77.1, 122.0, 126.4, 126.8, 128.5, 128.8, 128.9, 129.4, 129.8,
134.2, 135.1, 137.3, 139.4, 173.7. Anal. Calcd for C23H22N2O:
C, 80.67; H, 6.48; N, 8.18. Found: C, 80.39; H, 6.51; N, 7.94.
Da ta for (2S,5S)-5-ben zyl-3-(4-m eth ylp h en yl)-2-p h en -
ylt et r a h yd r o-4H -im id a zol-4-on e (16′a ): yellowish micro-
C
30H27N5O: C, 76.09; H, 5.75; N, 14.79. Found: C, 75.84; H,
5.96; N, 14.54.
(2R,5S)-1-(Ben zotr iazolylm eth yl)-5-ben zyl-3-cycloh exyl-
2-p h en yltetr a h yd r o-4H-im id a zol-4-on e (17b): obtained as
a mixture of Bt1 and Bt2 isomers in 10:1 ratio, and NMR data
are reported for the major Bt1 isomer; yellowish oil; yield 94%;
8228 J . Org. Chem., Vol. 67, No. 23, 2002

Novel Syntheses of Isoquinolines and Isoquinolinones
1H NMR δ 0.85-1.07 (m, 2H), 1.12-1.26 (m, 2H), 1.40-1.72
(m, 6H), 3.20-3.30 (m, 2H), 3.40-3.60 (m, 1H), 4.40 (s, 1H),
5.15 (s, 1H), 5.24, 5.41 (AB, J ) 13.6 Hz, 2H), 7.09-7.45 (m,
12H), 7.55 (d, J ) 8.1 Hz, 1H), 8.03 (d, J ) 8.1 Hz, 1H).
Da ta for (2R,5S)-1-(ben zotr ia zolylm eth yl)-5-ben zyl-3-
ben zyl-2-p h en yltetr a h yd r o-4H-im id a zol-4-on e (17c): ob-
tained as a mixture of Bt1 and Bt2 isomers in 7:1 ratio, and
NMR data are reported for the major Bt1 isomer; yellowish
58.1, 79.4, 126.1, 126.5, 126.9, 127.4, 128.7, 129.0, 131.7, 134.1,
134.7, 138.8, 172.7; HRMS m/z calcd for C23H26N2O 346.2045
(M), found 346.2042. Anal. Calcd for C23H26N2O: N, 8.09.
Found: N, 8.05.
Da t a for (3R,10a S)-2-b en zyl-3-p h en yl-2,3,10,10a -t et -
r a h yd r oim id a zo[1,5-b]isoqu in olin -1(5H)-on e (18c): white
needles; yield 78%; mp 108-109 °C; [R]25 +65.1 (c 1.23,
D
CHCl3); 1H NMR δ 3.05 (dd, J ) 15.2, 6.7 Hz, 1H), 3.22 (dd, J
) 15.2, 4.8 Hz, 1H), 3.29, 4.99 (AB, J ) 15.2 Hz, 2H), 3.58,
3.81 (AB, J ) 15.2 Hz, 2H), 4.24 (br t, J ) 4.7 Hz, 1H), 4.66
(d, J ) 2.3 Hz, 1H, NCHN), 6.53 (d, J ) 7.0 Hz, 2H), 7.02-
7.39 (m, 12H); 13C NMR δ 29.9, 43.4, 50.1, 59.2, 80.5, 126.5,
127.1, 127.2, 127.3, 127.5, 128.4, 128.5, 128.6, 128.8, 129.2,
134.6, 134.9, 135.6, 138.1, 172.9. Anal. Calcd for C24H22N2O:
C, 81.32; H, 6.26; N, 7.90. Found: C, 80.76; H, 6.38; N, 7.87.
1
oil; yield 95%; H NMR δ 3.21-3.35 (m, 2H), 4.60 (d, J ) 3.3
Hz, 1H), 5.01-5.07 (m, 2H), 5.05 (d, J ) 2.1 Hz, 1H), 5.30,
5.55 (AB, J ) 14.2 Hz, 2H), 6.58 (d, J ) 7.0 Hz, 2H), 6.90-
7.38 (m, 16H), 7.95 (d, J ) 8.1 Hz, 1H).
Gen er a l P r oced u r e for th e Lew is Acid -P r om oted Cy-
cliza tion of 17a -c a n d 17′a . Using the same procedure as
for the preparation of 1a -c, treatment of 17a -c and 17′a with
3 equiv of AlCl3 afforded 18a -c and 18′a . After workup, all of
the products were obtained as essentially NMR pure solids
which were recrystallized from EtOH for analytical purposes.
Da t a for (3R,10a S)-2-(4-m et h ylp h en yl)-3-p h en yl-2,3,-
10,10a -t et r a h yd r oim id a zo[1,5-b]isoq u in olin -1(5H )-on e
P r oced u r e for th e P r ep a r a tion of Bt In ter m ed ia te 22.
A mixture of 2,5-dimethoxytetrahydrofuran (0.66 g, 5.1 mmol)
and HCl aqueous solution (0.1 M, 20 mL) was heated to 100
°C for 45 min, then cooled to room temperature. CH2Cl2 (40
mL), benzotriazole (0.61 g, 5.1 mmol), and diamine 11a (1.20
g, 5 mmol) were successively added and stirred at room
temperature for 24 h. The reaction mixture was washed with
1 M NaOH and the aqueous phase was extracted with CH2-
Cl2. The combined organic phase was washed with brine and
dried over anhydrous Na2SO4. After removal of the solvent in
vacuo, the residue was purified by column chromatography
with hexanes/EtOAc (3:1) as an eluent to give 22. However,
subsequent treatment of 22 with 2 equiv of AlCl3 or ZnBr2 did
not afford the desired tetracyclic compound 23.
(18a ): colorless needles (from EtOH); yield 91%; mp 189-190
1
°C; [R]25 -79.2 (c 1.83, CHCl3); H NMR δ 2.22 (s, 3H), 3.14
D
(d, J ) 6.9 Hz, 2H), 3.62, 3.81 (AB, J ) 14.7 Hz, 2H), 4.02 (td,
J ) 7.0, 1.4 Hz, 1H), 5.68 (d, J ) 1.4 Hz, 1H, NCHN), 7.00-
7.08 (m, 3H), 7.15-7.28 (m, 5H), 7.32-7.39 (m, 5H); 13C NMR
δ 20.8, 30.0, 49.6, 58.3, 81.9, 122.4, 124.2, 126.3, 126.6, 127.0,
127.3, 128.8, 129.1, 129.4, 133.9, 134.0, 134.5, 135.3, 136.7,
172.3. Anal. Calcd for C24H22N2O: C, 81.32; H, 6.26; N, 7.90.
Found: C, 81.07; H, 6.53; N, 7.97.
Da ta for (3S,10a S)-2-(4-m eth ylp h en yl)-3-p h en yl-2,3,-
10,10a -t et r a h yd r oim id a zo[1,5-b]isoq u in olin -1(5H )-on e
Da t a for (3S,5R,7a S)-5-b en zot r ia zolyl-3-b en zyl-1-(4-
m et h ylp h en yl)h exa h yd r o-1H -p yr r olo[1,2-a ]im id a zole
(22): obtained as a mixture of Bt1 and Bt2 isomers in 4.5:1
ratio, and NMR data are reported for the major Bt1 isomer;
(18′a ): colorless needles (from EtOH); yield 91%; mp 212.5-
1
213 °C; [R]25 -83.9 (c 1.59, CHCl3); H NMR δ 2.22 (s, 3H),
D
3.22-3.35 (m, 2H), 3.44 (ddd, J ) 10.8, 4.2, 2.2 Hz, 1H), 3.79
(s, 2H), 5.32 (d, J ) 2.1 Hz, 1H, NCHN), 6.97-7.11 (m, 5H),
7.11-7.33 (m, 6H), 7.40-7.43 (m, 2H); 13C NMR δ 20.9, 30.8,
50.6, 60.8, 82.7, 124.2, 126.1, 126.6, 126.8, 128.4, 128.9, 129.3,
129.4, 129.8, 133.3, 133.4, 133.7, 135.6, 136.1, 171.4. Anal.
Calcd for C24H22N2O: C, 81.32; H, 6.26; N, 7.90. Found: C,
81.07; H, 6.61; N, 8.04.
colorless needles (from CHCl3/Et2O); mp 145-146 °C; [R]25
D
1
-4.2 (c 1.37, CHCl3); H NMR δ 2.06-2.17 (m, 1H), 2.29 (s,
3H), 2.45-2.64 (m, 5H), 3.18 (dd, J ) 9.2, 4.0 Hz, 1H), 3.70-
3.80 [m, 1H, H(3)], 3.85 (dd, J ) 9.2, 6.5 Hz, 1H), 5.10 (dd, J
) 5.3, 4.0 Hz, 1H, NCHN), 6.02 (t, J ) 7.0 Hz, 1H, BtCHN),
6.58 (d, J ) 8.3 Hz, 2H), 6.79-6.82 (m, 2H), 6.92-6.98 (m,
3H), 7.10 (d, J ) 8.1 Hz, 2H), 7.32-7.36 (m, 2H), 7.61-7.64
(m, 1H), 8.00-8.03 (m, 1H); 13C NMR δ 20.2, 30.6, 30.9, 41.0,
52.8, 63.7, 79.2, 81.6, 111.5, 113.5, 119.6, 123.6, 125.9, 126.7,
126.8, 127.8, 128.4, 129.7, 131.2, 137.8, 143.9, 146.6. Anal.
Calcd for C26H27N5: C, 76.25; H, 6.65; N, 17.10. Found: C,
76.05; H, 6.88; N, 17.03.
Da ta for (3R,10a S)-2-cycloh exyl-3-p h en yl-2,3,10,10a -
t et r a h yd r oim id a zo[1,5-b]isoq u in olin -1(5H )-on e (18b ):
white microcrystals (from EtOH); yield 78%; mp 150-151 °C;
[R]25 -66.6 (c 1.79, CHCl3); 1H NMR δ 0.84-1.00 (m, 2H),
D
1.11-1.26 (m, 2H), 1.40-1.72 (m, 6H), 2.80-3.12 (m, 2H), 3.47,
3.64 (AB, J ) 14.5 Hz, 2H), 3.60-3.70 (m, 1H), 3.86-3.91 (m,
1H), 5.19 (s, 1H, NCHN), 7.02 (d, J ) 6.4 Hz, 1H), 7.12-7.41
(m, 8H); 13C NMR δ 25.1, 25.6, 25.7. 30.1, 30.3. 31.1, 49.6, 52.4,
J O0203241
J . Org. Chem, Vol. 67, No. 23, 2002 8229