Rearrangement of spiro[2H-1-benzopyran-2,2′-[2H]indoles] to pyrrolo[1,2-a]indole derivatives

Article abstract of DOI:10.1002/jhet.5570390602

Heating of 1′-(N-substituted carbamoyl)methylspiro[2H-1-benzopyran-2,2′-[2H]indoles] with potassium hydroxide in ethanol yields diastereomeric 5a,13-methano-6H-1,3-benzoxazepino[3,2-a]indole-12-carboxamides. Reduction of the latter with sodium borohydride

Full text of DOI:10.1002/jhet.5570390602

Nov-Dec 2002
Rearrangement of Spiro[2H-1-benzopyran-2,2'-[2H]indoles] to
Pyrrolo[1,2-a]indole Derivatives
1123
ˇ
Vytas Martynaitis and Algirdas Sacˇkus*
Department of Organic Chemistry, Kaunas University of Technology, Radvilenu pl. 19,
LT-3028 Kaunas, Lithuania
Ulf Berg
Department of Organic Chemistry 1, Department of Chemistry, Lund University, Lund,
P.O. Box 124, 22100, Sweden
Received March 16, 2001
Heating of 1'-(N-substituted carbamoyl)methylspiro[2H-1-benzopyran-2,2'-[2H]indoles] with potassium
hydroxide in ethanol yields diastereomeric 5a,13-methano-6H-1,3-benzoxazepino[3,2-a]indole-12-carbox-
amides. Reduction of the latter with sodium borohydride affords 1,2,3,9a-tetrahydro-2-hydroxyaryl-9H-
pyrrolo[1,2-a]indole-3-carboxamides.
J. Heterocyclic Chem., 39, 1123(2002).
Indoline spiropyrans have been intensively investigated
tem found in the medicinally important mitomycin antibi-
otics [3]. A number of synthesis of pyrrolo[1,2-a]indole
derivatives have been developed, including a preparation
by 1,3-dipolar cycloaddition of electron deficient dipo-
larophiles to 3H-indolium-N-methylides [4], but no direct
transformation of indoline spiropyrans into pyrrolo[1,2-a]-
indoles has been hitherto described.
Condensation of 1-(N-phenylcarbamoyl)methyl-2,3,3-
trimethyl-3H-indolium perchlorate 1a with salicylalde-
hyde or 2-hydroxy-1-naphthaldehyde followed by workup
of 2-styryl-3H-indolium perchlorates 2a,b under basic
conditions gave 1'-(N-phenylcarbamoyl)methylindoline
spiropyrans 3a,b (Scheme 1). 1'-(N-tert-Butylcarbamoyl)-
methylindoline spiropyrans 3c,d were easily prepared by
over the years because of their significant practical appli-
cation, e.g., information imaging and storage [1]. In recent
years a number of investigators have reported advances
towards synthesis of new indoline spiropyrans and under-
standing of their reversible photoconversion into coloured
merocyanine isomers [2]. However, despite continuous
investigations on preparation of new functionalized indo-
line spiropyrans their chemical properties remain still
poorly disclosed.
In the present paper we wish to report a new synthetic
method for the preparation of pyrrolo[1,2-a]indoles start-
ing from indoline spiropyran derivatives. The pyrrolo[1,2-
a]indole ring system is closely related to the basic ring sys-

ˇ
1124
V. Martynaitis and A. Sacˇkus
Vol. 39
the reaction of chloride 1b with the above aromatic alde-
by Bothner-By [6] gives coupling constants as 7.4 and 2.0
Hz, respectively. Very similar values were found for the
corresponding diastereomers 4a,c,d and 5a,c,d. The quan-
titative discrepancy is probably due to the effect of the sub-
stituents and cyclopentane bond angle deformation, as
these molecules exhibit very rigid ring structures.
Stochastic conformational analysis using MM3 force field
shows that there is only one competitive conformation for
each diastereomer, and cis-isomer is ca. 8 kcal/mol more
stable than the trans-isomer. This relation is the same
when low (1.5) or high (25) dielectric constants are used in
the electrostatic calculations.
hydes in ethanol containing piperidine. The structures of
1
the synthesized 3a-d are supported by their H nmr spec-
tra; for example, vicinal coupling between ethene protons
3-H and 4-H of indoline spiropyran 3a is 10.0 Hz and evi-
dences their cis-allocation [5], while the coupling constant
of corresponding ethene protons of 2-[2-(2-hydrox-
yphenyl)ethenyl]-3H-indolium perchlorate 2a is 16.0 Hz
(trans-allocation). The protons of NCH group of the com-
2
pound 3a are diastereotopic due to the presence of a stere-
2
ogenic center at C and showed an AB-quadruplet ( J =
2
16.0 Hz) at 3.96 ppm.
Heating of compounds 3a-d with potassium hydroxide
in ethanol afforded diastereomeric 5a,13-methano-1,3-
benzoxazepino[3,2-a]indoles 4a-d and 5a-d. The cis/trans
The mechanism of this recyclization reaction can be
explained by the formation of an intermediate azomethine
ylide (Scheme 2). When the spiro[indoline-pyrans] 3a-d
and a base are refluxed in ethanol, heterolytic cleavage of
C-O bond occurs and the zwitter ion A is formed. The pos-
itively charged nitrogen atom of the indolium ring together
with electron-accepting carboxamide group polarizes the
C-H bonds of the methylene group, thus enabling for the
hydroxide ion to deprotonate it to give the azomethine
ylide B. The ylide is a strong nucleophile and may attack
the partially positive carbon atom. Concerted addition of
the oxygen atom to the a -carbon atom of the indole ring
gives the two diastereomeric intermediates C and D, and
derivatives 4a-d and 5a-d are obtained after reprotonation.
1
ratio, determined by H nmr, is ~1/3 for the compounds
4a,b, 5a,b and ~1/5 for 4c,d, 5c,d. The structural assign-
ment of compounds 4a-d and 5a-d was based on their
spectroscopic properties, and the distinction of the two
diastereomers was based upon vicinal coupling constants.
For example, coupling constants between protons 14-H
and 15-H of 7a,15-methanonaphth[1',2':6,7][1,3]oxa-
zepino[3,2-a]indole derivatives 4b and 5b are 4.5 Hz and 0
Hz, respectively. The dihedral angles obtained from MM3
optimized structures are 38° for cis-isomer and 91.5° for
trans-isomer. Using the Karplus equation in the version of

Nov-Dec 2002
Spiro[2H-1-benzopyran-2,2'-[2H]indoles] to Pyrrolo[1,2-a]indole Derivatives
1125
When trans-5b was treated with perchloric acid, the het-
In summary, we have reported a new method for the syn-
thesis of pyrrolo[1,2-a]indole system by rearrangement of
indoline spiropyran derivatives via methylides.
erolytic cleavage of C -O bond took place and
7a
pyrrolo[1,2-a]indolium perchlorate 6a was formed.
Reaction of trans-5d with tetrafluoroboric acid gave tetra-
13
fluoroborate 6b (Scheme 3). In the C nmr spectrum of
EXPERIMENTAL
2
compound 6b the signal of the sp -hybridized a -carbon
atom of the indole ring lies at 203.9 ppm, which is typical
of 3H-indolium salts [7].
All melting points were determined with a Kleinfeld melting
point apparatus and are uncorrected. Infrared spectra were
recorded on a UR 20 spectrometer. 1H nmr spectra were recorded
with Bruker DPX 200 and Bruker DPX 300 spectrometers at 200
and 300 MHz; 13C nmr spectra were registered at 50 and 75
MHz, respectively. Chemical shifts, expressed in ppm, were rela-
tive to tetramethylsilane (TMS). For thin layer chromatographic
(TLC) analyses, Merck precoated TLC plates (silica gel 60 F254)
were used. Compound 1b was prepared according to the reported
procedure [8].
2,3,3-Trimethyl-1-(N-phenylcarbamoyl)methyl-3H-indolium
perchlorate (1a).
To a solution of 2.92 g (10 mmoles) of 2,3-dihydro-3,3-
dimethyl-2-methylene-1-(N-phenylcarbamoyl)methyl-1H-indole
[8] in 8 ml of ethanol 60% perchloric acid was added to pH 2.
The mixture was stored at -5° for 12 hours, crystalline substance
was isolated by filtration and recrystallized from ethanol. Yield
of 1a 2.79 g (71%), mp 207-208°; ir (potassium bromide): 3300
(N-H), 1688 (C=O), 1070-1130, 650 (ClO4 ) cm-1; H nmr (tri-
fluoroacetic acid): d 1.30 (s, 6H, 3,3-CH3), 2.52 (s, 3H, 2-CH3),
5.29 (s, 2H, CH2), 6.77-7.60 (m, 10H, Ar-H and NH).
Anal. Calcd. for C19H21ClN2O5: C, 58.09; H, 5.39; Cl, 9.02.
Found: C, 58.44; H, 5.25; Cl, 8.95.
Reduction of the perchlorate 6a with NaBH in ethanol
gave pyrrolo[1,2-a]indole derivative 7a (Scheme 4).
Identical product was obtained when compound 5b was
4
-
1
reduced with NaBH directly. Pyrrolo[1,2-a]indole deriva-
4
tives 7b,c were obtained by a similar way from 5a,d.
Reaction of cis-4a with NaBH afforded pyrrolo[1,2-a]-
4
indole 8. However, no reduction was observed in the case
of cis-4b.
2-[2-(2-Hydroxyphenyl)ethenyl]-3,3-dimethyl-1-(N-phenylcar-
bamoyl)methyl-3H-indolium perchlorate (2a).
To a solution of 1.96 g (5 mmoles) of perchlorate 1a and 0.67
g (5.5 mmoles) of salicylaldehyde in 5 ml of ethanol two drops of
piperidine were added and the mixture was refluxed for 3 hours.
The reaction mixture was poured into 30 ml of 5% sodium
acetate solution and extracted with ether (2 x 20 ml). The com-
bined organic layer was washed with water (30 ml), dried over
calcium chloride and the solvent was evaporated under reduced
pressure. The residue was dissolved in 5 ml of ethanol and per-
chloric acid (60%) was added to pH 2. The mixture was stored at
0° for 12 hours, crystalline substance was isolated by filtration
and recrystallized from ethanol. Yield of 2a 1.69 g (68%), mp
205-206°; ir (potassium bromide): 3392 (O-H), 3270 (N-H),
1688 (C=O), 1550 (amide II), 1100, 630 (ClO4 ) cm-1; H nmr
(trifluoroacetic acid): d 1.53 (s, 6H, 3,3-CH3), 5.37 (s, 2H, CH2),
6.56-7.61 (m, 15H, Ar-H, NH and CH=CH), 8.41 (d, J= 16.0 Hz,
1H, CH=CH).
-
1
Anal. Calcd. for C26H25ClN2O6: C, 62.84; H, 5.07; Cl, 7.13;
N, 5.64. Found: C, 62.53; H, 5.17; Cl, 7.26; N, 5.62.
2-[2-(2-Hydroxy-1-naphthyl)ethenyl]-3,3-dimethyl-1-(N-phenyl-
carbamoyl)methyl-3H-indolium perchlorate (2b).
This compound was obtained similarly to compound 2a from
1.96 g (5 mmoles) of perchlorate 1a and 0.95 g (5.5 mmoles) of
2-hydroxy-1-naphthaldehyde. The yield of 2b 1.78 g (65%), mp
165-167°; ir (potassium bromide): 3480 (O-H), 3320 (N-H),
The relative stereochemistry at C and C for 7a-c and
2
9a
8 was determined by NOESY measurement. Observation
of NOEs between protons 2-H and 9a-H proved that they
are in a cis relationship to each other.
1695 (C=O), 1550 (amide II), 1100, 650 (ClO4 ) cm-1; H nmr
-
1
(trifluoroacetic acid): d 1.63 (s, 3H, 3,3-CH3), 5.22 (s, 2H, CH2),

ˇ
1126
V. Martynaitis and A. Sacˇkus
Vol. 39
6.68-7.66 (m, 17H, Ar-H, NH and CH=CH), 7.81 (d, J= 16.0 Hz,
1H, CH=CH).
(AB-q, J= 17.0 Hz, 2H, CH2), 5.75 (d, J= 10.0 Hz, 1H, CH=CH),
6.41-8.13 (m, 12H, Ar-H, CH=CH and NH).
Anal. Calcd. for C30H27ClN2O6: C, 65.87; H, 4.98; Cl, 6.48;
N, 5.12. Found: C, 65.49; H, 5.03; Cl, 6.77; N, 5.32.
Anal. Calcd. for C28H30N2O2: C, 78.84; H, 7.09; N, 6.57.
Found: C, 79.18; H, 7.15; N, 6.72.
1',3'-Dihydro-3',3'-dimethyl-1'-(N-phenylcarbamoyl)methyl-
spiro[2H-1-benzopyran-2,2'-[2H]indole] (3a).
General Procedure for the Rearrangement of 3 to 4, 5.
To a solution of indoline spiropyrans 3 (1 equiv.) in ethanol
fine powdered potassium hydroxide (3 equiv.) was added and the
mixture was refluxed for 2 hours and then was allowed to reach
room temperature. The precipitated crystals of cis-4 were col-
lected by filtration, washed with water to remove sodium hydrox-
ide and recrystallized from ethanol. The filtrate was poured into
water and extracted with ether. The organic layers were washed
with water and dried over calcium chloride. The solvent was
evaporated under reduced pressure and the residue crystallized
from ethanol to afford trans-5.
A solution of perchlorate 2a (1.49 g, 3 mmoles) in 10 ml of
ethanol was poured into 50 ml of 5% potassium hydroxide and
extracted with ether. The organic layers were washed with water
and dried over calcium chloride. After removing of the solvent
under reduced pressure, the residue was crystallized from ethanol
to afford 1.02 g (86%) of 3a, mp 139-140°; ir (potassium bromide):
-1
3275 (N-H), 1680 (C=O), 1550 (amide II) cm ; 1H nmr (deuteri-
ochloroform): d 1.23 (s, 3H, CH3), 1.36 (s, 3H, CH3), 3.96 (AB-q,
J = 16.0 Hz, 2H, CH2), 5.71 (d, J = 10.0 Hz, 1H, CH=CH), 6.48-
7.56 (m, 14H, Ar-H and CH=CH), 8.51 (br s, 1H, NH).
Anal. Calcd. for C26H24N2O2: C, 78.76; H, 6.01; N, 7.07.
Found: C, 79.0; H, 5.85; N, 7.35.
(5aR*,12S*,13S*)-12,13-Dihydro-5a,13-methano-6,6-dimethyl-
6H-1,3-benzoxazepino[3,2-a]indole-12-(N-phenylcarboxamide)
(cis-4a) and its (5aR*,12R*,13S*)-isomer (trans-5a).
1,3-Dihydro-3,3-dimethyl-1-(N-phenylcarbamoyl)methylspiro-
[2H-indole-2,3'-[3H]naphth[2,1-b]pyran] (3b).
Following the general procedure, the spiropyran 3a (1.98 g, 5
mmoles), potassium hydroxide (0.84 g, 15 mmoles) in ethanol (15
ml) gave cis-4a (0.50 g, 25%) and trans-5a (0.83 g, 42%). Isomer
cis-4a: mp 183-184°; ir (potassium bromide): 3295 (N-H), 1680
(C=O), 1535 (amide II) cm-1; 1H nmr (deuteriochloroform): d 1.55
(s, 3H, CH3), 1.59 (s, 3H, CH3), 2.22 (dd, J= 3.7 and 11.3 Hz, 1H
of CH2), 2.28 (d, J = 11.3 Hz, 1H of CH2), 3.78-3.81 (m, 1H, 13-
H), 4.06 (d, J= 4.3 Hz, 1H, 12-H), 6.61-7.23 (m, 13H, Ar-H), 8.64
(br s, 1H, NH); 13C nmr (deuteriochloroform): d 18.37, 21.56,
23.10, 26.43, 33.05, 42.59, 44.98, 78.44, 109.74, 110.57, 115.63,
120.72, 120.89, 122.19, 122.58, 124.35, 124.66, 128.28, 128.36,
128.62, 128.98, 136.49, 138.74, 148.88, 152.43, 168.84.
This compound was obtained similarly to compound 3a from
1.64 g (3 mmoles) of perchlorate 2b. The yield of oily 3b was
1.14 g (85%); 1H nmr (deuteriochloroform): d 1.06 (s, 3H, CH3),
1.22 (s, 3H, CH3), 3.73 (AB-q, J= 16.0 Hz, 2H, CH2), 5.63 (d, J =
10.0 Hz, 1H, CH=CH), 6.39-7.90 (m, 16H, Ar-H and CH=CH),
8.37 (br s, 1H, NH).
Anal. Calcd. for C30H26N2O2: C, 80.69; H, 5.87; N, 6.27.
Found: C, 80.93; H, 6.01; N, 6.11.
1'-(N-tert-Butylcarbamoyl)methyl-1',3'-dihydro-3',3'-dimethyl-
spiro[2H-1-benzopyran-2,2'-[2H]indole] (3c).
Anal. Calcd. for C26H24N2O2: C, 78.76; H, 6.01; N, 7.06.
Found: C, 78.69; H, 5.78; N, 7.32.
To a solution of 3.09 g (10 mmoles) of chloride 1b and 1.34 g
(11 mmoles) salicylaldehyde in 10 ml of ethanol, three drops of
piperidine were added and the mixture was refluxed for 5 hours.
The reaction mixture was poured into 50 ml of 5% sodium
acetate and extracted with ether. The organic layers were
washed with water, dried over calcium chloride and the solvent
was evaporated under reduced pressure. The residue was crys-
tallized from ethanol to afford 2.22 g (59%) of 3c, mp 144-
145°; ir (potassium bromide): 3380 (N-H), 1680 (C=O), 1520
(amide II) cm-1; 1H nmr (deuteriochloroform): d 1.20 (s, 3H,
CH3), 1.29 (s, 9H, C(CH3)3), 1.34 (s, 3H, CH3), 3.71 (AB-q, J =
17.4 Hz, 2H, CH2), 5.62 (d, J = 10.2 Hz, 1H, CH=CH), 6.48-
7.19 (m, 8H, Ar-H), 6.54 (br s, 1H, NH), 6.87 (d, J = 10.2 Hz,
1H, CH=CH); 13C nmr (deuteriochloroform): d 20.11, 25.85,
28.43 (3C), 48.78, 50.63, 51.91, 104.06, 107.36, 114.93,
118.07, 118.27, 120.44, 120.75, 121.86, 127.04, 127.76,
130.09, 130.46, 136.44, 146.06, 153.46, 169.03.
Isomer trans-5a: mp 174-175°; ir (potassium bromide): 3315
-1
(N-H), 1680 (C=O), 1530 (amide II) cm ; 1H nmr (deuteriochlo-
roform): d 1.37 (s, 3H, CH3), 1.67 (s, 3H, CH3), 2.15 (d, J = 11.2
Hz, 1H of CH2), 2.51 (dd, J = 2.3 and 11.2 Hz, 1H of CH2), 3.85
(d, J = 2.3 Hz, 1H, 13-H), 4.53 (s, 1H, 12-H), 6.40-7.62 (m, 14H,
Ar-H and NH); 13C nmr (deuteriochloroform): d 20.57, 28.19,
28.69, 44.79, 46.97, 68.30, 77.21, 106.90, 107.22, 116.77,
119.72, 119.79, 120.12, 122.91, 124.82, 126.82, 127.64, 127.99,
128.71, 129.07 (2C), 136.93, 140.99, 141.92, 153.19, 168.25.
Anal. Calcd. for C26H24N2O2: C, 78.76; H, 6.01; N, 7.06.
Found: C, 78.53; H, 6.07; N, 7.31.
(7aR*,14S*,15S*)-14,15-Dihydro-7a,15-methano-8,8-dimethyl-
8H-naphth[1',2':6,7][1,3]oxazepino[3,2-a]indole-14-(N-phenylcar-
boxamide) (cis-4b) and its (7aR*,14R*,15S*)-isomer (trans-5b).
Following the general procedure, the spiropyran 3b (2.23 g,
5 mmoles), potassium hydroxide (0.84 g, 15 mmoles) and 15
ml of ethanol gave cis-4b (0.36 g, 16%) and trans-5b (1.0 g,
45%). Isomer cis-4b: mp 206-207°; ir (potassium bromide):
3300 (N-H); 1660 (C=O); 1530 (amide II) cm-1; 1H nmr (deu-
teriochloroform): d 1.56 (s, 3H, CH3), 1.62 (s, 3H, CH3), 2.29
(dd, J = 1.1 and 11.0 Hz, 1H of CH2), 2.34 (dd, J = 3.8 and
11.0 Hz, 1H of CH2), 4.20 (d, J = 4.5 Hz, 1H, 14-H), 4.58-4.60
(m, 1H, 15H), 6.65-8.08 (m, 15H, Ar-H), 8.50 (br s, 1H, NH).
13C nmr (deuteriochloroform): d 23.28, 26.43, 33.04, 37.52,
44.89, 78.97, 109.52, 110.66, 116.99, 117.37, 120.89 (2C),
122.24, 122.62, 122.77, 123.52, 124.43, 126.64, 128.00 (2C),
Anal. Calcd. for C24H28N2O2: C, 76.56; H, 7.50; N, 7.44.
Found: C, 76.60; H, 7.62; N, 7.25.
1-(N-tert-Butylcarbamoyl)methyl-1,3-dihydro-3,3-dimethyl-
spiro[2H-indole-2,3'-[3H]naphth[2,1-b]pyran] (3d).
This compound was obtained similarly to compound 3c from
0.92 g (3 mmoles) of chloride 1b and 0.52 g (3 mmoles) of 2-
hydroxy-1-naphthaldehyde. The yield was 0.64 g (50%), mp 202-
203° (ethanol); ir (potassium bromide): 3210 (N-H), 1680 (C=O),
1
1530 (amide II) cm-1; H nmr (deuteriochloroform): d 1.24 (s,
3H, 3-CH3), 1.29 (s, 9H, 3 x CH3), 1.36 (s, 3H, 3-CH3), 3.79

Nov-Dec 2002
Spiro[2H-1-benzopyran-2,2'-[2H]indoles] to Pyrrolo[1,2-a]indole Derivatives
1127
128.36, 128.44, 128.98, 129.46, 131.31, 136.30, 138.83,
148.92, 150.07, 168.75.
Anal. Calcd. for C30H26N2O2: C, 80.69; H, 5.87; N, 6.27.
Found: C, 80.35; H, 5.74; N, 6.46.
Isomer trans-5b: mp 201-203°; ir (potassium bromide): 3320
(N-H), 1660 (C=O), 1530 (amide II) cm-1; 1H nmr (deuteriochlo-
roform): d 1.44 (s, 3H, CH3), 1.74 (s, 3H, CH3), 2.24 (d, J = 11.2
Hz, 1H of CH2), 2.60 (dd, J = 3.8 and 11.2 Hz, 1H of CH2), 4.56
(d, J = 3.8 Hz, 1H, 15-H), 4.57 (s, 1H, 14-H), 6.34-8.13 (m, 16H,
Ar-H and NH); 13C nmr (deuteriochloroform): d 20.57, 28.18,
28.42, 42.01, 44.70, 68.08, 107.14 (2C), 118.71, 119.35, 119.70,
119.71 (2C), 121.19, 122.97, 123.34, 124.85, 126.93, 128.06,
128.82 (2C), 128.90, 129.11 (2C), 130.57, 137.04, 141.03,
141.97, 150.82, 168.37.
Hz, 1H, 15-H), 5.74 (br s, 1H, NH), 6.33-8.18 (m, 10H, Ar-H);
13C nmr (deuteriochloroform): d 20.54, 27.97, 28.21, 28.63 (3C),
41.49, 44.42, 51.31, 68.20, 106.80, 107.12, 118.55, 119.32,
119.52, 121.28, 122.72, 123.16, 126.70, 127.64, 128.43, 128.49,
128.75, 130.60, 141.15, 141.74, 150.65, 169.03.
Anal. Calcd. for C28H30N2O2: C, 78.84; H, 7.09; N, 6.57.
Found: C, 78.48; H, 7.22; N, 6.76.
(2R*,3S*)-1,2-Dihydro-2-(2-hydroxy-1-naphthyl)-9,9-dimethyl-
3-(N-phenylcarbamoyl)-3H,9H-pyrrolo[1,2-a]indolium perchlo-
rate (6a).
To a solution of trans-5b (1.12 g, 2.5 mmoles) in 6 ml of
ethanol, perchloric acid was added to pH 1 and the solution was
stored at 5° for 14 hours. The precipitated crystals were isolated
by filtration and recrystallized from ethanol to yield 0.99 g (72%)
of perchlorate 6a with m.p. 250-251°; ir (potassium bromide):
Anal. Calcd. for C30H26N2O2: C, 80.69; H, 5.87; N, 6.27.
Found: C, 80.94; H, 6.03; N, 6.01.
-
3300 (O-H), 3250 (N-H), 1700 (C=O), 1065-1130, 750 (ClO4 )
(5aR*,12R*,13S*)-12,13-Dihydro-5a,13-methano-6,6-dimethyl-
6H-1,3-benzoxazepino[3,2-a]indole-12-(N-tert-butylcarboxam-
ide) (trans-5c).
cm-1; 1H nmr (deuteriodimethyl sulfoxide): d 1.42 (s, 3H, CH3),
1.60 (s, 3H, CH3), 1.74 (d, J= 11.1 Hz, 1H of CH2), 3.09 (dd, J =
3.7 and 11.1 Hz, 1H of CH2), 4.44 (d, J = 3.2 Hz, 1H, 2-H), 5.36
(s, 1H, 3-H), 6.21-8.13 (m, 15H, Ar-H), 10.43 (s, 1H, OH), 10.51
(br s, 1H, NH ).
Following the general procedure, heating of spiropyran 3c
(0.94 g, 2.5 mmoles) with potassium hydroxide (0.42 g, 7.5
mmoles) in 15 ml of ethanol gave a mixture of two diastere-
omers, from which only trans-5c was separated with the yield
0.58 g (62%) by crystallization of the mixture from ethanol.
Isomer trans-5c: mp 151-152°; ir (potassium bromide): 3380 (N-
Anal. Calcd. for C30H27ClN2O6: C, 65.87; H, 4.98; Cl, 6.48;
N, 5.12. Found: C, 65.73; H, 5.12; Cl, 6.78; N, 5.39.
(2R*,3S*)-3-(N-tert-Butylcarbamoyl)-1,2-dihydro-2-(2-
hydroxy-1-naphthyl)-9,9-dimethyl-3H,9H-pyrrolo[1,2-a]-
indolium tetrafluoroborate (6b).
1
H), 1680 (C=O), 1550 (amide II) cm-1; H nmr (deuteriochloro-
form): d 1.26 (s, 9H, C(CH3)3), 1.31 (s, 3H, CH3), 1.64 (s, 3H,
CH3), 2.08 (d, J= 11.0 Hz, 1H of CH2), 2.38 (dd, J= 4.0 and 11.0
Hz, 1H of CH2), 3.72 (d, J = 4.0 Hz, 1H, 13-H), 4.27 (s, 1H, 12-
H), 5.60 (br s, 1H, NH), 6.32-7.20 (m, 8H, Ar-H); 13C nmr (deu-
teriochloroform): d 20.73, 28.04, 28.66 (4C), 44.67, 46.59, 51.41,
68.67, 106.79, 107.30, 116.66, 119.38, 120.03, 122.75, 126.80,
127.70, 128.06, 128.49, 141.30, 141.81, 153.30, 168.93.
Anal. Calcd. for C24H28N2O2: C, 76.56; H, 7.50; N, 7.44.
Found: C, 76.70; H, 7.61; N, 7.41.
To a solution of trans-5d (1.07 g, 2.5 mmoles) in 6 ml of ethanol,
tetrafluoroboric acid was added to pH 1 and the solution was stored
at 5° for 18 hours. The precipitated crystals were isolated by filtra-
tion and recrystallized from ethanol to yield 0.85 g (66%) of tetraflu-
oroborate 6b with mp 238-239°; ir (potassium bromide): 3350-3200
(O-H and N-H), 1685 (C=O), 1545 (amide II), 1100 (BF4 ) cm ; H
nmr (a mixture of trifluoroacetic acid and deuteriobenzene): d 1.31
(s, 9H, C(CH3)3), 1.66 (s, 3H, 9-CH3), 1.72 (s, 3H, 9-CH3), 3.64 (m,
1H of CH2), 3.78 (m, 1H, of CH2), 5.18 (m, 1H, 2-H), 5.76 (m, 1H,
3-H), 7.18-7.92 (m, 11H, Ar-H and NH); 13C-nmr (a mixture of tri-
fluoroacetic acid and deuteriobenzene): d 20.54, 21.73, 26.74 (3C),
34.51, 41.98, 50.23, 54.11, 71.37, 114.47, 115.22, 117.27, 120.10,
123.53, 123.96, 127.87, 129.11, 129.33, 129.51, 130.59, 131.35,
132.00, 136.39, 145.34, 152.52, 167.19, 203.92.
-
-1 1
(7aR*,14S*,15S*)-14,15-Dihydro-8,8-dimethyl-8H-7a,15-
methanonaphth[1',2':6,7][1,3]oxazepino[3,2-a]indole-14-(N-tert-
butylcarboxamide) (cis-4d) and its (7aR*,14R*,15S*)-isomer
(trans-5d).
Following the general procedure, the spiropyran 3d (2.14 g, 5
mmoles), potassium hydroxide (0.17 g, 15 mmoles) and 15 ml of
ethanol gave cis-4a (0.21 g, 10%) and trans-5a (1.11 g, 52%).
Isomer cis-4d: mp 134-135°; ir (potassium bromide): 3350 (N-
Anal. Calcd. for C28H31BF4N2O2: C, 65.38; H, 6.07; N, 5.45.
Found: C, 65.55; H, 5.77; N, 5.28.
General Procedure for the Reduction of cis-4a and trans-5a,b,d.
1
H), 1675 (C=O), 1520 (amide II) cm-1; H nmr (deuteriochloro-
To a solution of 5a,13-methano-6H-1,3-benzoxazepino[3,2-
a]indole (5 mmoles) in 20 ml of ethanol was added sodium boro-
hydride (0.57 g, 15.0 mmoles) and the mixture was heated at 70°
for 1 hour. The reaction mixture was poured into 100 ml of water
and was extracted with ether. The organic layers were washed
with water and dried over calcium chloride. The solvent was
removed by distillation and the residue crystallized from ethanol.
form): d 0.66 (s, 9H, C(CH3)3), 1.54 (s, 3H, CH3), 1.59 (s, 3H,
CH3), 2.24 (dd, J = 4.1 and 11.6 Hz, 1H of CH2), 2.26 (d, J =
11.6 Hz, 1H of CH2), 3.95 (d, J = 4.8 Hz, 1H, 14-H), 4.48-4.50
(m, 1H, 15-H), 6.54-8.06 (m, 10H, Ar-H), 6.59 (br s, 1H, NH);
13C nmr (deuteriochloroform): d 23.86, 26.77, 28.23 (3C), 33.28,
37.79, 45.24, 50.40, 79.29, 109.71, 110.88, 117.75, 117.88,
122.20, 122.89, 123.61, 123.87, 126.90, 128.24, 128.64, 129.42,
129.46, 132.15, 139.27, 149.56, 150.58, 169.64.
(2R*,3S*,9aS*)-1,2,3,9a-Tetrahydro-2-(2-hydroxy-1-naphthyl)-9,9-
dimethyl-9H-pyrrolo[1,2-a]indole-3-(N-phenylcarboxamide) (7a).
Anal. Calcd. for C28H30N2O2: C, 78.84; H, 7.09; N, 6.57.
Found: C, 78.53; H, 7.43; N, 6.51.
Method A.
Isomer trans-5d: mp 189-190°; ir (potassium bromide): 3400
(N-H), 1660 (C=O), 1520 (amide II) cm-1; 1H nmr (deuteri-
ochloroform): d 1.28 (s, 9H, C(CH3)3), 1.37 (s, 3H, CH3), 1.70
(s, 3H, CH3), 2.20 (d, J = 10.5 Hz, 1H of CH2), 2.52 (dd, J = 4.5
and 10.5 Hz, 1H of CH2), 4.41 (s, 1H, 14-H), 4.52 (d, J = 4.5
To a solution of perchlorate 6a (1.37 g, 2.5 mmoles) in 15 ml of
ethanol was added sodium borohydride (0.28 g, 7.5 mmoles) and
the mixture was heated at 70° for 1 hour. The reaction mixture was
poured into 100 ml of water and extracted with ether. The organic

ˇ
1128
V. Martynaitis and A. Sacˇkus
Vol. 39
layers were washed with water and dried over calcium chloride.
The solvent was removed by distillation and the residue was crys-
tallized from ethanol to afford 0.85 g (76%) of 7a with mp 228-
229°; ir (potassium bromide): 3400-3180 (N-H and O-H), 1665
(2R*,3R*,9aS*)-1,2,3,9a-Tetrahydro-2-(2-hydroxyphenyl)-9,9-
dimethyl-9H-pyrrolo[1,2-a]indole-3-(N-phenylcarboxamide) (8).
Following the general procedure, the compound cis-4a (0.79 g, 2
mmoles), sodium borohydride (0.23 g, 6 mmoles) and 10 ml of
ethanol gave 0.61 g (77%) of 8 with mp 186-187° (ethanol); ir
(potassium bromide): 3410-3200 (N-H and O-H), 1670 (C=O),
1520 (amide II) cm-1; 1H nmr (deuteriochloroform): d 1.41 (s, 3H,
CH3), 1.46 (s, 3H, CH3), 1.96-2.18 (m, 2H, CH2), 3.71 (dd, J= 13.2
and 6.0 Hz, 1H, 9a-H), 3.99 (ddd, J = 7.0, 8.3 and 11.2 Hz, 1H, 2-
H), 4.11 (d, J = 8.3 Hz, 1H, 3-H), 6.57-7.38 (m, 13H, Ar-H), 9.21
(br s, 1H, NH), 9.40 (br s, 1H, OH); 13C nmr (deuteriochloroform):
d 21.13, 30.19, 33.76, 42.07, 42.72, 73.55, 77.10, 109.78, 118.41,
119.51 (2C), 120.12, 121.11, 122.60, 124.62, 125.01, 127.55 (2C),
128.12, 128.60 (2C), 136.07, 137.31, 149.87, 154.80, 173.31.
Anal. Calcd. for C26H26N2O2: C, 78.36; H, 6.58; N, 7.03.
Found: C, 78.42; H, 6.79; N, 7.37.
1
(C=O), 1520 (amide II) cm-1; H nmr (deuteriochloroform): d
1.39 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.96 (ddd, J = 6.0, 7.1 and
11.5 Hz, 1H of CH2), 2.58 (ddd, J= 11.4, 11.5 and 12.0 Hz, 1H of
CH2), 3.90 (dd, J = 7.9 and 11.4 Hz, 9a-H), 4.57 (ddd, J= 7.1, 7.7
and 12.0 Hz, 2-H), 4.80 (d, J = 7.7 Hz, 3-H), 6.73-7.70 (m, 10H,
Ar-H), 8.04 (br s, 1H, NH), 9.37 (s, 1H, OH).
Anal. Calcd. for C30H28N2O2: C, 80.33; H, 6.29; N, 6.25.
Found: C, 80.08; H, 6.21; N, 6.52.
Method B.
Following the general procedure, reduction of trans-5b (2.23
g, 5 mmoles) with sodium borohydride (0.58 g, 15.0 mmoles) in
ethanol gave 1.82 g (81%) of 7a.
(2R*,3S*,9aS*)-1,2,3,9a-Tetrahydro-2-(2-hydroxyphenyl)-9,9-
dimethyl-9H-pyrrolo[1,2-a]indole-3-(N-phenylcarboxamide) (7b).
REFERENCES AND NOTES
Following the general procedure, reduction of trans-5a (1.98
g, 5 mmoles) with sodium borohydride (0.57 g, 15.0 mmoles) in
ethanol gave 1.81 g (91%) of 7b with mp 184-185° (ethanol); ir
(potassium bromide): 3415-3210 (N-H and O-H), 1670 (C=O),
[1] R. C. Bertelson, in Photochromism, Techniques of
Chemistry, Vol. 3, G. H. Brown, ed, Wiley Interscience, New York,
1971, pp. 45; R. Guglielmetti, in Photochromism - Molecules and
Systems, Studies in Organic Chemistry, Vol. 40, H. Dürr and H. Bouas-
Laurent, ed, Elsevier, Amsterdam, 1990, pp. 314; H. Dürr, Angew.
Chem., Int. Ed. Engl., 28, 413 (1989).
[2] H. Dürr, Y. Ma and G. Cortellaro, Synthesis, 294 (1995); R.
Blonder, S. Levi, G. Tao, I. Ben-Dov and I. Willner, J. Am. Chem. Soc.,
119, 10467 (1997); H. Görner, Chemical Physics, 222, 315 (1997); A.
K. Chibisov and H. Görner, Chemical Physics, 237, 425 (1998); Y. J.
Cho, K. Y. Rho, S. R. Keum, S. H. Kim and C. M. Yoon, Synth.
Commun., 29, 2061 (1999); X. Li, Y. Wang, T. Matsuura and J. Meng,
Heterocycles, 51, 2639 (1999); G. Berkovic, V. Krongauz and V.
Weiss, Chem. Rev., 100, 1741 (2000).
1
1520 (amide II) cm-1; H nmr (deuteriochloroform): d 1.44 (s,
3H, CH3), 1.53 (s, 3H, CH3), 1.93 (ddd, J = 6.2, 6.9 and 13.0 Hz,
1H of CH2), 2.38-2.56 (m, 1H of CH2), 4.02 (dd, J= 5.0 and 10.7
Hz, 1H, 9a-H), 4.16-4.24 (m, 1H, 2-H), 4.62 (d, J = 9.0 Hz, 1H,
3-H), 6.35-7.21 (m, 13H, Ar-H), 7.51 (s, 1H, OH), 7.71 (br s, 1H,
NH); 13C nmr (deuteriochloroform): d 26.15, 28.09, 29.65,
42.39, 47.02, 63.59, 75.96, 108.84, 116.02, 119.14, 120.62,
122.35 (2C), 123.08, 125.26, 125.50, 127.86 (2C), 128.62,
129.02 (2C), 136.63, 142.91, 147.42, 154.70, 170.35.
Anal. Calcd. for C26H26N2O2: C, 78.36; H, 6.58; N, 7.03.
Found: C, 78.52; H, 6.85; N, 7.09.
[3] K. Takahashi and T. Kametani, Heterocycles, 13, 411
(1979); K. Jones and J. M. D. Storey, Tetrahedron, 49, 4901 (1993); S.
Lee, H.-J. Lim, K. L. Cha and G. A. Sulikowski, Tetrahedron, 53,
16521 (1997); A. P. Dobbs, K. Jones and K. T. Veal, Tetrahedron, 54,
2149 (1998); C. J. Moody and C. L. Norton, J. Chem. Soc., Perkin
Trans. 1, 2639 (1997); B. G. Jones, M. Guzel and J. E. Mathews,
Tetrahedron Lett., 41, 1123 (2000).
[4] C. W. G. Fishwick, A. D. Jones, M. B. Mitchell and C.
Szantay, Tetrahedron Lett., 29, 5325 (1988); C. W. G. Fishwick, A. D.
Jones and M. B. Mitchell, Tetrahedron Lett., 30, 4447 (1989); C. W. G.
Fishwick, A. D. Jones, M. B. Mitchell, D. S. Eggleston and P. W.
Baures, Synlett, 359 (1990).
(2R*,3S*,9aS*)-1,2,3,9a-Tetrahydro-2-(2-hydroxy-1-naphthyl)-
9,9-dimethyl-9H-pyrrolo[1,2-a]indole-3-(N-tert-butylcarboxam-
ide) (7c).
Following the general procedure, reduction of trans-5d (2.13 g,
5 mmoles) with sodium borohydride (0.57 g, 15.0 mmoles) in
ethanol gave 1.54 g (72%) of 7c with mp 192-193° (ethanol); ir
(potassium bromide): 3350 (N-H), 3250 (O-H), 1660 (C=O), 1520
1
(amide II) cm-1; H nmr (deuteriochloroform): d 1.38 (s, 3H, 9-
CH3), 1.41 (s, 12H, 9-CH3, C(CH3)3), 1.92 (ddd, J = 6.0, 6.4 and
12.4 Hz, 1H of CH2), 2.58 (ddd, J= 11.3, 11.4 and 12.4 Hz, 1H, of
CH2), 3.76 (dd, J= 6.4 and 11.3 Hz, 1H, 9a-H), 4.44 (ddd, J= 6.0,
8.0 and 11.4 Hz, 1H, 2-H), 4.50 (d, J= 8.0 Hz, 1H, 3-H), 6.68-7.70
(m, 10H, Ar-H), 7.42 (br s, 1H, NH), 9.17 (s, 1H, OH).
Anal. Calcd. for C28H32N2O2: C, 78.47; H, 7.53; N, 6.54.
Found: C, 78.37; H, 7.22; N, 6.68.
[5] S.-R. Keum, K.-B. Lee, P. M. Kazmaier, R. A. Manderville
and E. Buncel, Magn. Reson. Chem., 30, 1128 (1992).
[6] A. A. Bothner-By, Adv. Magn. Res., 1, 195 (1965).
[7] E. Kleinpeter and R. Borsdorf, J. Prakt. Chem., 315, 765
(1973);W.Grahn, Tetrahedron, 32, 1931 (1976).
[8] A. A. Sackus and J. A. Degutis, Khim. Geterotsikl. Soedin.,
11, 1485 (1986).