Acid-Catalyzed Rearrangement of 5-Bromo-3-[1-allyl-2-(3,5-dimethoxyphenyl)ethyl]-2-cyanopyridine

Full text of DOI:10.1021/jo9803378

J . Org. Chem. 1998, 63, 6039-6042
6039
ration of this class of compounds.3 Thus, alkylation of
3-bromopyridine 5 using LDA and 3,5-dimethoxybenzyl
chloride followed by alkylation of the intermediate prod-
uct with allyl bromide afforded 6. The tert-butylamide
6 was converted to nitrile 2b with phosphorus oxy-
chloride. Triflic acid-mediated electrophilic cyclization
of 2b followed by hydrolysis did not afford6 the desired
tricyclic ketone 3b (Scheme 1).
Acid -Ca ta lyzed Rea r r a n gem en t of
5-Br om o-3-[1-a llyl-2-(3,5-d im eth oxyp h en yl)-
eth yl]-2-cya n op yr id in e
J oseph Kelly, Mohindar S. Puar, Adriano Afonso,* and
Andrew T. McPhail†
Schering-Plough Research Institute,
Department of Chemistry, 2015 Galloping Hill Road,
Kenilworth, New J ersey 07033, and Duke University,
P. M. Gross Chemical Laboratory,
Sch em e 1a
Durham, North Carolina 27706
Received February 23, 1998
In tr od u ction
Tricyclic heterocycles 1 are an important class of
chemical structures that display biological activity in
several therapeutic areas.1-4 A convenient synthesis of
these compounds starts with the electrophilic cyclization
of 2-cyanopyridine 2a followed by hydrolysis of the
intermediate imine to afford the versatile tricyclic ketone
3a .3,5 As part of a synthetic effort to develop more potent
compounds related to our lead farnesyl protein trans-
ferase inhibitor 1b,1,4 we were interested in obtaining the
3,8-dihalo-5-allyl tricyclic ketone 3b. Attempted synthe-
sis of 3b by cyclization of the appropriately substituted
cyanopyridine 2b showed that this substrate undergoes
a complex acid-catalyzed chemical rearrangement. We
report here a novel tetracyclic rearrangement product 4
that is formed in the electrophilic cyclization of 2b
(Figure 1) as well as the identification of the intermediate
products and a possible reaction mechanism for the
formation of the rearrangement products.
a
Key: (a) (i) LDA, THF, -78 °C, then 3,5-dimethoxybenzyl
chloride, (ii) LDA, THF, -78 °C, then allyl bromide; (b) POCl3,
PhCH3, 110 °C; 9c) CF3SO3H, 20 °C; (d) 2 N HCl, 110 °C.
Scheme 2 summarizes the reaction course that this
cyclization/hydrolysis follows. Treatment of 2b with
triflic acid afforded a mixture of three products that were
isolated and characterized as 7 (28%), 8 (35%), and 9
(11%). The isolation of these compounds required flash
chromatography to afford the nonpolar nitrile 9 followed
by preparative TLC to isolate the bicyclo amine 7 and
the imine 8. Hydrolysis of 8 in refluxing 2 N hydrochloric
acid led to the formation of the ketone 4, which contains
a new tetracyclic ring system. The same ketone 4 was
also obtained by refluxing a solution of 7, or a mixture
of 7 and 8, in 2 N hydrochloric acid. Treatment of 2b
with triflic acid followed by refluxing a solution of the
crude product in 2 N hydrochloric acid afforded, after
flash chromatography, the tetracyclic ketone 4 (65%) and
9 (10%). The isolation of the components from this
mixture was uneventful since compound 9 is relatively
(3) (a) Wong, J . K.; Piwinski, J . J .; Green, M. J .; Ganguly, A. K.;
Anthes, J . C.; Billah, M. M. Bioorg. Med. Chem. Lett. 1993, 3, 1073.
(b) Piwinski, J . J .; Wong, J . K.; Chan, T. M.; Green, M. J .; Ganguly, A.
K. J . Org. Chem. 1990, 55, 3341.
(4) (a) Bishop, R. W.; Bond, R.; Petrin, J .; Wang, L.; Patton, R.; Doll,
R.; Njoroge, G.; Cattino, J .; Schwartz, J .; Windsor, W.; Syto, R.;
Schwartz, J .; Carr, D.; J ames, L.; Kirshmeier, P. J . Biol. Chem. 1995,
270, 30611.(b) For more recent references see Kelly, J .; Wolin, R.;
Connolly, M.; Afonso, A.; J ames, L.; Kirshmeier, P.; Bishop, W. R.;
McPhail, A. T. Bioorg. Med. Chem. 1998, 6, 673.
(5) (a) Villani, F. J .; Daniels, P. J . L.; Ellis, C. A.; Mann, T. A.; Wang,
K.-C. J . Heterocycl. Chem. 1971, 8, 73. (b) Piwinski, J . J .; Wong, J . K.;
Green, M. J .; Ganguly, A. K.; Billah, M. M.; West, R. E.; Kreutner, W.
J . Med. Chem. 1991, 34, 457.
F igu r e 1.
Resu lts a n d Discu ssion
The precursor allyl cyanopyridine 2b was obtained by
applying previously described methodology for the prepa-
† Duke University.
(1) For example, Loratidine (1a ) is a potent nonsedating anti-
histamine drug in current medicinal use.2 Dual PAF/histamine an-
tagonists have been reported for analogues of 1.3 More recently, 1b
has been reported by our laboratories as a lead Ras farnesyl protein
transferase (FPT) inhibitor;4 such inhibitors are of interest for the
development of antitumor agents.
(2) (a) Villani, F. J .; Magatti, C. V.; Vashi, D. B.; Wong, J .; Popper,
T. L. Arzneim.-Forsch/ Drug Res. 1986, 36(II), 1311. (b) Barnett, A.;
Iorio, L. C.; Kreutner, W.; Tozzi, S.; Ahn, H. S.; Gulbenkian, A. Agents
Actions 1984, 14, 590. (c) Drugs Future 1987,12, 544.
(6) Our initial experiment (Scheme 1) involved the reaction of 2b
with triflic acid followed by hydrolysis of the crude intermediate with
aqueous hydrochloric acid and isolation of the single major product
(65% yield) by chromatography. The NMR spectrum of the product
showed a methyl doublet at δ 1.32, which was not consistent with the
desired structure 3b. Further NMR studies elucidated the structure
of the reaction product as 4. The interesting and complicated nature
of this new tetracyclic ring system arising from a simple precursor
prompted us to study the electrophilic cyclization reaction of 2b in
greater detail.
S0022-3263(98)00337-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/30/1998

6040 J . Org. Chem., Vol. 63, No. 17, 1998
Notes
Sch em e 2a
a
Key: (a) CF3SO3H, 20 °C; (b) 2 N HCl, 110 °C; (c) NaBH4, EtOH, 0 °C.
much less polar than 4. Sodium borohydride reduction
The structures of the imine 8 and the borohydride
of the ketone 4 proceeded stereoselectively to afford
exclusively one diastereoisomer, which was characterized
as the alcohol 10.
reduction product 10 were assigned on the basis of NMR
resonance correlations with those of the corresponding
1
ketone 4 (Table 1). Specifically, the H NMR spectrum
Str u ctu r e Assign m en ts.7 Proton NMR data of 9
indicated the presence of resonances at δ 1.30 (d, CH3),
3.79, 3.83 (s, OCH3), 3.24, 2.88 (m, H4,4), 1.58, 2.38 (m,
H2,2), 2.88 (m, H3), 3.24 (m, H1), and aromatic protons at
δ 8.62 (H6′), 7.92 (H4′), 6.21 (H5), and 6.36 (H7); 2D (1H-
1H) COSY, NOSEY, and HMBC data led to the assign-
ment of structure 9 for this product. The relative
stereochemical assignment at H3 is based on the absence
of an observable NOE between the methyl doublet at δ
1.30 and the methine multiplet at δ 2.88. 1H NMR
spectra of 7 indicated the presence of a vinylic function
at δ 5.52, 5.36, 5.24 and an isolated methine proton at δ
3.13 (J ) 9.0 Hz). The relative stereochemistry of H12
was assigned as cis to H5 since a coupling between these
protons was not measurable. In the 13C NMR spectra,
the resonance at δ 65.2 was assigned to the C11 quater-
nary carbon bearing an amino group. The carbon atoms
were easily assignable using standard NMR techniques.
Detailed NMR studies were performed for the structure
elucidation of 4. 1H NMR data of 4 indicated the
presence of resonances due to a methyl group, a meth-
ylene function, three methine moieties, and two methoxyl
groups. In addition, there were four aromatic proton
resonances. 2D (1H-1H) COSY and NOESY spectra led
to the chemical shift assignments shown in Table 1.
HMBC and SINEPT studies confirmed all of the 13C
assignments. The relative stereochemistry of H5a and
H11a was assigned as cis (J ) 8.0 Hz) and that of H5a and
H6 as trans (J ) 1.6 Hz). Some of the relevant NOESY
and HMBC connectivities for compound 4 are shown in
Figure 2.
of 10 indicated the presence of a methine proton at δ 5.13
(doublet J ) 8.0 Hz) and a 13C NMR resonance at δ 75.2
ppm. The relative stereochemistry of H5 was assigned
as cis to H5a
.
Most importantly, the structure and relative stereo-
chemistry of 10 were confirmed by X-ray crystallogra-
phy;8 this determination also confirms the structure and
stereochemical assignments for compounds 4 and 8.
Mech a n ism . The formation of the minor product 9
is not unexpected since the substrate 2b can undergo an
electrophilic cyclization between the olefinic substituent
and the phenyl ring to afford this product.
The formation of 4, on the other hand, is a more
complex process. The isolation of the amine 7 in the acid-
catalyzed rearrangement of 2b to 4 enables us to postu-
late a reaction mechanism to rationalize the formation
of these products (Scheme 3). The postulated pathway
involves three sequential electrophilic cyclizations start-
ing with the initial formation of 11, the expected imine
intermediate formed in cyclizations of 2-cyanopyridines
2.5 This is followed by a prototropic rearrangement of
the allyl group at C5 of 11 to a 5-trans-propenyl group
affording 12, a key intermediate in this mechanism.
Intermediate 12 undergoes a second electrophilic cycliza-
tion between the propenyl group and the protonated
imine leading to the formation of the vinyl bicyclo
intermediate 7, which was isolated and characterized as
the cis diastereoisomer. The exclusive diastereoselectiv-
ity observed for the formation of 7 may suggest that the
conversion of 12 to 7 is a reversible process, thereby
allowing for the equilibration of the possible trans-
diastereoisomer (vinyl group oriented toward the pyridine
ring) to 7; the electron-rich phenyl ring would have a
stabilizing effect on the cationic species of the propenyl,
thereby favoring the observed orientation for the result-
ing vinyl group in 7. The final step in the rearrangement
of 7 to 8 requires the 1,3-bond migration of 10a-11 f
10a-13, which may be facilitated by the amino group.
Alternatively, the vinyl group of 7 could undergo a third
electrophilic cyclization facilitated by the aromatic meth-
oxyl group, resulting in the highly strained transient
(7) Atom numbering used for listing NMR data and for the nomen-
clature of these compounds is shown in Scheme 2.
(8) An ORTEP diagram and X-ray crystallography data are included
in the Supporting Information.
F igu r e 2. Selected NOESY/HMBC correlations in 4.

Notes
J . Org. Chem., Vol. 63, No. 17, 1998 6041
Ta ble 1. NMR Da ta in CDCl3
compd 8
compd 4
compd 10
R1R2 ) NH
R1R2 ) O
R1 ) H, R2 ) OH
atom no.
1H δ (mult, J (Hz))
13C δ
1H δ (mult, J (Hz))
13C δ
1H δ (mult, J (Hz))
1
2
3
4a
5
7.70 (dd 2.0, 1.0)
136.7
126.2
152.5
152.5
206.0
28.7
8.12 (dd 2.0, 0.9)
135.7
123.0
148.7
162.3
75.2
7.68 (d 2.0)
8.40 (dd 2.0, 0.5)
8.69 (dd 2.0, 0.7)
8.38 (d 2.0)
5.13 (d 8)
2.95 (dt 8, 8. 1.7)
3.79 (dq 7.5,1.7)
5a
6
2.68 (m)
3.63 (dq 7.5, 0.5)
2.96 (dd 8, 1.6)
4.14 (dq 7.5, 1.6)
23.3
48.2
52.4
6a
6b
7
7a
8
121.0
20.1
157.2
55.7
120.4
22.3
157.3
55.5
1.31 (d 7.5)
1.32 (d 7.5)
3.86 (s)
6.10 (d 2.0)
3.73 (s)
6.20 (d 2.2)
3.75 (s)
6.24 (d 2.5)
96.9
96.9
9
158.9
55.2
105.2
134.6
32.9
158.4
55.2
105.2
136.0
32.6
9a
10
10a
11
3.70 (s)
6.23 (d 2.0)
3.66 (s)
6.04 (d 2.2)
3.73 (s)
6.16 (d 2.5)
2.70 (m)
2.88 (dd 15.4, 1.2)
2.87 (dd 16, 3)
3.26 (dd 16, 7)
3.30 (dd 16.0, 4.5)
3.47 (ddd 15.4, 7.7, 0.9)
11b
11a
154.1
35.6
141.8
38.9
3.40 (m)
4.01 (dt 7.8, 7.7, 1.0)
3.73 (m)
Sch em e 3
intermediacy of a cyclobutane 13 which then undergoes
cleavage of the 10a-11 bond and rearomatization to
afford 8 which is the final stable product in the sequence.
The exclusive diasteroselectivity observed for 8, is derived
from the vinyl-phenyl π-overlap in 7 required for the
10a-13 bond formation of 13. Hydrolysis of the imine 8
then leads to the formation of the tetracyclic ketone 4.
In summary, we report here the acid-catalyzed re-
arrangement of the allyl cyanopyridine 2b, which affords
the novel tetracyclic structures 7, 8, and 4; the re-
arrangement proceeds with a high degree of stereo-
selectivity, resulting in the formation of these products
as single diastereoisomers. Dibenzo ring system ana-
logues of 7 have been reported previously;9 however, the
tetracyclic product 7 is the first example of a compound
containing a 6,11-dihydro-5,11-methano-5H-benzo[5.6]-
cyclohepta[1,2-b]pyridine ring system. The 5,6,11,11a-
tetrahydro-5H-benzo[5.6]indeno[2,1-b]pyridine ring sys-
tem of the products 8, 4, and 10 is new and has not been
reported previously.10
Exp er im en ta l Section
Melting points are uncorrected. Column chromatography was
performed on silica gel (Selecto, 32-63 mesh), and reactions were
monitored by TLC on silica gel plates (Analtech).
3-[1-Allyl-2-(3,5-d im eth oxyp h en yl)eth yl]-N-(1,1-d im eth -
yleth yl)-2-p yr id in eca r boxa m id e (6). n-Butyllithium in hex-
anes (2.5 M, 18.33 mL, 45.83 mmol) was added to a solution of
diisopropylamine (6.85 mL, 50.33 mmol) in THF (40 mL) at -78
°C, and the mixture stirred at that temperature for 15 min and
at 0 °C for 15 min. The reaction mixture was cooled to -78 °C,
(9) For references on compounds containing the corresponding 10,11-
dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptene ring system, see:
(a) Hagishita, S.; Kuriyama, K. Bull. Chem. Soc. J pn. 1981, 54, 2790.
(b) Cristol, S. J .; Aeling, E. O.; Heng, R. J . Am. Chem. Soc. 1987, 109,
830.
(10) The ring system of these compounds is not listed in the Ring
Systems Handbook (Chemical Abstracts Service) published by the
American Chemical Society, 1997; Suppl. 8. Conventional nomencla-
ture guidelines were followed in naming compounds 4, 8, and 10.

6042 J . Org. Chem., Vol. 63, No. 17, 1998
Notes
and a solution of the tert-butylamide 5 (5.0 g, 18.45 mmol)3 in
THF (20 mL) was added dropwise. The resulting purple solution
was stirred at this temperature for 1 h, and then 3,5-dimethoxy-
benzyl chloride (4.6 g, 24.65 mmol) in THF (20 mL) was added
at -78 °C. The dry ice-acetone bath was replaced with an ice-
water bath, and the light brown solution was stirred at 0 °C for
3 h. The reaction was quenched by addition of water (150 mL)
and then extracted with EtOAc (2 × 200 mL). The organic
extracts were combined, dried over MgSO4, and filtered, and the
solvent evaporated, yielding a red oil that was chromatographed
on silica gel. Elution with 20% v/v EtOAc/hexanes yielded
3-[2-(3,5-d im et h oxyp h en yl)et h yl]-N-(1,1-d im et h ylet h yl)-
2-p yr id in eca r boxa m id e (5a ) as a colorless oil: 5.5 g (84%);
1H NMR (CDCl3, 300 MHz) δ 1.43 (s,9H), 2.90 (t, 2H), 3.50 (t,
2H), 3.75 (s, 6H), 6.30 (s, 1H), 6.35 (s, 2H), 7.55 (s, 1H), 7.75
(bs, 1H), 8.40 (s, 1H); MS (FAB) m/ z 421 (MH+).
compound 7 as a colorless foam (40 mg, 28% yield) and the
slower eluting compound 8 as an amorphous powder (50 mg,
35% yield).
7: 1H NMR (CDCl3, 400 MHz) δ 2.75 (dd 17, 1.5, H6), 3.47
(dd 17, 5.0, H6), 3.13 (d 9.0, H12), 3.26 (dd 5.0, 1.5, H5), 3.70 (s,
C8-OCH3), 3.88 (s, C10-OCH3), 5.36 (dd 17, 2, H14), 5.24 (dd
10, 2, H14), 5.52 (ddd 17, 10, 9 H13), 6.16 (d 2.0, H7), 6.29 (d 2.0,
H9), 7.65 (d 2.0, H4), 8.32 (d 2.0, H2); 13C NMR (CDCl3, 100.6
MHz) δ 36.0 (C6), 41.9 (C12), 55.3 (C8-OCH3), 56.3 (C10-OCH3),
61.7 (C5), 65.2 (C11), 98.1 (C9), 106.4 (C7), 120.5 (C14), 135.1 (C4),
135.4 (C13), 135.7 (C6a), 138.9 (C4a), 148.0 (C11a), 148.9 (C2), 158.1
(C10), 159.9 (C8); HRMS (FAB) calcd for C19H20N2O2Br 387.0708,
found 387.0702 (MH+).
8: NMR data are included in Table 1; HRMS (FAB) calcd for
C19H20N2O2Br 387.0708, found 387.0714 (MH+).
n-Butyllithium in hexanes (2.5 M, 12 mL, 30 mmol) was added
to a solution of diisopropylamine (4.20 mL, 32.5 mmol) in THF
(30 mL) at -78 °C, and the mixture was stirred at that
temperature for 30 min and at 0 °C for 15 min. The reaction
was cooled to -78 °C, and a solution of 5a (5.0 g, 11.85 mmol)
in THF (20 mL) was added dropwise. The resulting purple
solution was stirred at -78 °C for 1 h, and then allyl bromide
(2.5 mL, 28.8 mmol) was added dropwise. The dry ice-acetone
bath was replaced with an ice-water bath, and the light brown
solution was stirred at 0 °C for 2 h. The reaction was quenched
by addition of water (150 mL) and then extracted with EtOAc
(2 × 200 mL). The organic extracts were combined, dried over
MgSO4, and filtered, and the solvent was evaporated, yielding
an oil that was chromatographed on silica gel. Elution with 20%
EtOAc/hexanes yielded the title product 6 as a colorless oil: 4.9
2-Br om o-5a (RS),6,11,11a (SR)-tetr a h yd r o-7,9-d im eth oxy-
6(RS)-m eth yl-5H-ben zo[5.6]in d en o[2,1-b]p yr id in -5-on e (4).
A. F r om 7. A solution of 7 (1.0 g, 2.59 mmol) was refluxed
overnight in 2 N HCl (10 mL) and then cooled to 0 °C and
basified with 2 N NaOH. The mixture was extracted with
CH2Cl2 (100 mL), dried over MgSO4, and filtered, and the extract
was evaporated, yielding a residue that was chromatographed
on silica gel. Elution with 5% EtOAc/CH2Cl2 yielded the title
compound 4 as a white crystalline solid: 800 mg (80%); mp 225-
227 °C; NMR data are included in Table 1; IR (CH2Cl2) 1727,
1607 cm-1; HRMS (FAB) calcd for C19H19NO3Br 388.0548, found
388.0551 (MH+). Anal. Calcd for C19H18NO3Br‚0.25H2O: C,
58.10; H, 4.75; N, 3.57. Found: C, 58.19; H, 4.59; N, 3.95.
B. F r om 8. From procedure A, substituting compound 8 (100
mg) for 7, the title compound 4 was obtained: 85 mg (85%), data
(mp, TLC, NMR) identical with 4 prepared above from 7.
1
g (90.7% yield); H NMR (CDCl3, 300 MHz) δ 1.43 (s,9H), 2.40
(m, 2H), 2.84 (m, 2H), 3.75 (s, 6H), 4.75 (m, 1H), 4.92 (dd, 2H),
5.70 (m, 1H), 6.25 (s, 3H), 7.28 (b, 1H), 7.77 (s, 1H), 8.35 (s,1H);
HRMS (FAB) calcd for C23H30N2O3Br 461.1440, found 461.1434.
C. F r om
a Mixtu r e of 7 a n d 8. From procedure A,
substituting the mixture of 7 and 8 (1.7 g) for compound 7, the
title compound 4 was obtained: 1.36 g (80%), data (mp, TLC,
NMR) identical with 4 prepared above from 7.
3-[1-Allyl-2-(3,5-d im eth oxyp h en yl)eth yl]-N-(1,1-d im eth -
yleth yl)-2-p yr id in eca r bon itr ile (2b). A solution of 6 (5 g,
10.8 mmol) and phosphorus oxychloride (15 mL) in toluene (15
mL) was stirred at 110 °C for 5 h. The reaction was cooled to
room temperature and evaporated under reduced pressure.
Water (200 mL) was added, and the mixture was basified by
addition of 10% NaOH and then extracted with CH2Cl2 (2 × 200
mL). The organic extracts were combined, dried over MgSO4,
filtered, and evaporated, yielding an oil that was chromato-
graphed on silica gel. Elution with 20% EtOAc/hexanes yielded
2b as a pale yellow solid: 4.0 g (95% yield); 1H NMR (CDCl3,
300 MHz) δ 2.25 (m, 1H), 2.55 (m, 1H), 2.80 (m, 1H), 3.0 (m,
1H), 3.55 (m, 1H), 3.77 (s, 6H), 5.0 (dd, 2H), 5.65 (q, 1H), 6.22
(s, 2H), 6.28 (s, 1H), 7.80 (s,1H), 8.55 (s,1H); HRMS (FAB) calcd
for C19H20N2O2Br 387.0708, found 387.0700.
D. F r om 2b. The crude product obtained from the reaction
of 2b (3.0 g) in triflic acid (30 mL) was hydrolyzed in 2 N HCl
using procedure A to afford 9 (0.3 g, 10% yield) and 4 (1.96 g,
65% yield).
2-Br om o-5a (RS),6,11,11a (SR)-tetr a h yd r o-7,9-d im eth oxy-
6(RS)-m et h yl-5H -b en zo[5.6]in d en o[2,1-b]p yr id in -5(RS)-
ol (10). Sodium borohydride (500 mg, 13.51 mmol) was added
to a suspension of 4 (500 mg, 1.288 mmol) in EtOH (15 mL) at
0 °C and stirred at this temperature for 1 h and at room
temperature for 1 h. The solvent was evaporated, the residue
was extracted with CH2Cl2 (50 mL), washed with H2O (50 mL),
dried over MgSO4, and filtered, and the solvent was evaporated,
yielding a white solid (500 mg, 100%) that was homogeneous
on TLC (silica gel, 40% EtOAC/hexanes). Recrystallization from
hot EtOAc/acetone furnished the title compound 10 as white
crystals: 410 mg (82%); mp 204-205 °C; NMR data are included
in Table 1; IR (CH2Cl2) 3565, 1607 cm-1; HRMS (FAB) calcd for
3 - B r o m o - 1 2 ( R S ) - e t h e n y l - 6 , 1 1 - d i h y d r o - 8 , 1 0 -
d i m e t h o x y -5 ( R S ) ,1 1 -m e t h a n o -5 H -b e n z o [5 .6 ]c y c l o -
h ep ta [1,2-b]p yr id in -11(SR)-a m in e (7), 2-Br om o-5a (RS),6,
11,11a (SR)-t et r a h yd r o-7,9-d im et h oxy-6(RS)-m et h yl-5H -
ben zo[5.6]in d en o[2,1-b]p yr id in -5-im in e (8), a n d 5′-Br om o-
3′-(1,2,3,4-t et r a h yd r o-6,8-d im et h oxy-1(SR)-m et h yl-3(RS)-
n a p h th a len yl)-2′-p yr id in eca r bon itr ile (9). The nitrile 2b
(2.7 g, 6.99 mmol) was added portionwise with stirring during
10 min to triflic acid (25 mL) at 20 °C, and the solution was
stirred overnight at room temperature. The reaction mixture
was then poured into ice (200 g) and basified with 10% NaOH.
The precipitated solid was filtered, washed with water (50 mL),
dried, and chromatographed on silica gel. Elution with 10%
EtOAc/hexanes yielded compound 9 as a low-melting amorphous
C
C
19H21NO3Br 390.0705, found 390.0700 (MH+). Anal. Calcd for
19H20NO3Br: C, 58.47; H, 5.16; N, 3.59. Found: C, 58.33; H,
5.21; N, 3.75.
Ack n ow led gm en t. The authors thank our Analyti-
cal Services Department for physical data, Prof. J .
Meinwald and Dr. S. Chackalamannil for helpful chemi-
cal discussions, and Mr. R. Budich and Ms. E. Shar-
vordskaya for library reasearch on new compounds.
resin: mp 55-57 °C; 0.3 g (11% yield); IR (CH2Cl2) 2235 cm-1
;
1H NMR data are included in the text; 13C NMR (CDCl3, 100.62
MHz) δ 150.1 (C6′),7 125.2 (C5′), 137.2 (C4′), 131.7 (C3′), 37.4 (C3),
37.9 (C4), 136.0 (C4a), 104.3 (C5), 158.5 (C6), 97.3 (C7), 159.3 (C8),
121.3 (C8a), 29.5 (C1), 40.5 (C2), 115.8 (C2′-CN), 147.9 (C2′), 55.3
(C6/8-OCH3), 22.7 (C1-CH3); HRMS (FAB) calcd for C19H20N2O2-
Br 389.0688, found 389.0670 (MH+). Anal. Calcd for C19H19N2O2-
Br: C, 58.92; H, 4.94; N, 7.23. Found: C, 59.06; H, 5.03; N,
7.24. Further elution with 5% methanol/ethyl acetate yielded
a mixture of compounds 7 and 8 (1.89 g, 70% yield). The mixture
7 and 8 (100 mg) was purified by preparative TLC (Analtech
silica gel plates 20 × 20 × 0.1 cm), eluting with EtOAc to yield
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR, correlation spectra for compounds 2b, 4, 6, 7, 9, and
10, and an ORTEP diagram and X-ray crystallographic data
for compound 10 (31 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O9803378