Synthesis of the enantiomers of hexahydrodibenz[d,f]azecines

Article abstract of DOI:10.1021/jo049157q

Suzuki coupling procedures were used to make appropriate 2-(3-aminopropyl)-2′-(2-mesyloxy)-ethyl disubstituted biphenyl derivatives 19 and 20 from which the racemic hexahydrodibenz[d,f]-azecines 3 and 4 were produced following intramolecular mesyloxy disp

Full text of DOI:10.1021/jo049157q

Syn th esis of th e En a n tiom er s of Hexa h yd r od iben z[d ,f]a zecin es
Richard H. Furneaux, Graeme J . Gainsford, and J ennifer M. Mason*
Industrial Research Ltd., PO Box 31-310, Lower Hutt, New Zealand
j.mason@irl.cri.nz
Received May 18, 2004
Suzuki coupling procedures were used to make appropriate 2-(3-aminopropyl)- 2′-(2-mesyloxy)-
ethyl disubstituted biphenyl derivatives 19 and 20 from which the racemic hexahydrodibenz[d,f]-
azecines 3 and 4 were produced following intramolecular mesyloxy displacement in dilute solution.
The enantiomers of the former azecine were prepared by use of an analogue of the biphenyl
aminomesylate 19 having a chiral auxiliary bound to the amino group during the closure of the
10-membered ring. Absolute configurations were assigned by X-ray diffraction analysis of compound
28.
In tr od u ction
transformations have been effected under a variety of
conditions.6,7 The object of the present work was to
develop methods for the preparation of a range of
enantiomerically pure hexahydrodibenzazecines required
for biological testing.
Dysazecine (1) is the first alkaloid having the hexahy-
drodibenz[d,f]azecine structure to have been isolated
from plants.1 Members of this group are closely related
to the widespread homoerythrinan alkaloids, for example,
dyshomoerythrine (2),2 which occurs as the major alka-
loid of Lagarostrobos colensoi (New Zealand silver pine)
and exhibits bioactivity against molluscs and agricultur-
ally important insect pests.3
Most reported syntheses of the hexahydrodibenzaze-
cines are based on biphenyl coupling applied to N-2-
phenylethyl-3-phenyl-propylamine8 or -propanoamide5,9
derivatives. Oxidation8 and photochemical dehydrohalo-
genation5,9 have been used to bring about coupling of the
aromatic rings. Additionally, 1,2,3,4-tetrahydro-1-(2-
phenylethyl)isoquinoline derivatives have been converted
to hexahydrodibenzazecines through an oxidative bi-
phenyl coupling.10 Strategies based on hexahydroazecine
ring formation from suitably 2,2′-substituted biphenyl
derivatives appear not to have found much favor, al-
though cyclization of 2-[(2-trifluoroacetylamino)ethyl]-2′-
(2-formylethyl)biphenyl derivatives to give dibenzaze-
cines has been reported.11
To develop a route to hexahydrodibenzazecines with a
variety of substituents and substitution patterns, a
general synthesis, based on biphenyl coupling by applica-
tion of the Suzuki-Miyaura reaction,12 followed by aza
ring closure, has been developed. The syntheses of
compound 3 and its methoxy derivative 4 are based on
coupling of the bromobenzaldehydes 6 and 7 (Scheme 1)
Biosynthetically the homoerythrina alkaloids have
been deemed to arise from hexahydrodibenzazecines,4
and this transformation can be effected in vitro.5 Con-
versely, the hexahydrodibenzazecines are obtainable from
these alkaloids by acid-catalyzed cleavage of their ben-
zylic C-N bond,6 and in earlier work in this laboratory,
dyshomoerythrine 2 was converted to the monomethoxy
dibenzazecine 4 in 55% yield by application of the
Hofmann elimination reaction (N-methylation followed
by heating with sodium iodide in acetone).3 Related
(7) Langlois, N.; Razafimbelo, J . J . Nat. Prod. 1988, 51, 499. Tsuda,
Y.; Murata, M.; Kiuchi, F. Chem. Pharm. Bull. 1986, 34, 3910.
McDonald, E.; Suksamrarn, A. J . Chem. Soc., Perkin Trans. 1 1978,
434.
(1) Aladesanmi, A. J .; Kelley, C. J .; Leary, J . D. J . Nat. Prod. 1983,
46, 127.
(2) Aladesanmi, A. J .; Kelley, C. J .; Leary J . D.; Onan, K. D. J . Chem.
Res., Synop. 1984, 108.
(3) Hart, J . B.; Mason, J . M.; Gerard, P. J . Tetrahedron 2001, 57,
10033.
(8) Miyake, S.; Sasaki, A.; Ohta, T.; Shudo, K. Tetrahedron Lett.
1985, 26, 5815. McDonald, E.; Wylie, R. D. J . Chem. Soc., Perkin Trans.
1 1980, 1104.
(9) Tanaka, H.; Doi, M.; Shimizu, H.; Etoh, H. Heterocycles 1999,
51, 2415; Tanaka, H.; Takamura, Y.; Ito, K.; Ohira, K.; Shibata, M.
Chem. Pharm. Bull. 1984, 32, 2063.
(4) Battersby, A. R.; McDonald, E.; Milner, J . A.; J ohns, S. R.;
Lamberton, J . A.; Sioumis, A. A. Tetrahedron Lett. 1975, 3419.
(5) Tanaka, H.; Takamura, Y.; Shibata, M.; Ito, K. Chem. Pharm.
Bull. 1986, 34, 24.
(6) J ohns, S. R.; Lamberton, J . A.; Sioumis, A. A.; Suares, H. Aust.
J . Chem. 1969, 22, 2203.
(10) Kupchan, S. M.; Dhingra, O. P.; Kim, C.-K. J . Org. Chem. 1978,
43, 4464. Kupchan, S. M.; Dhingra, O. P.; Kim, C.-K. J . Chem. Soc.,
Chem. Commun. 1977, 847.
(11) Kupchan, S. M.; Dhingra, O. P.; Kim, C.-K.; Kameswaran, V.
J . Org. Chem. 1978, 43, 2521.
(12) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
10.1021/jo049157q CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/28/2004
J . Org. Chem. 2004, 69, 7665-7671
7665

Furneaux et al.
SCHEME 1a
SCHEME 3a
a
Reagents: (a) Br2, FeCl3, AcOH, 84%; (b) MeOCHCl2, SnCl4,
then H2O, 63%.
SCHEME 2a
a
Reagents: (a) C6H11NH2, then n-BuLi, then (MeO)3B, then
H2O2, AcOH, 27%; (b) HCl, H2O, 54%; (c) Me2SO4, K2CO3, 88%.
63% yield together with the regioisomer (17%) by formy-
lation of the anisole derivative 815 (Scheme 1). The
relative positions of the methoxy and formyl groups of
compound 7 were confirmed by its reduction with hydro-
gen over Raney nickel to the known (4-methoxybenzo-
[1,3]dioxol-5-yl)-methanol (2-methoxypiperonol).16
In an attempt to find another route to compound 12
the hydroxy derivative 21 was made from aldehyde 11
by boronation of the cyclohexylimino-protected aldehyde
followed by oxidative cleavage of the C-B bond with
hydrogen peroxide and acetic acid (Scheme 3). However,
this process proved to be capricious, with 27% of the
phenol 21 being the best yield obtained. Nevertheless,
selective hydrolysis of this product afforded aldehyde 22
from which aldehyde 12 was synthesized. Overall, this
approach was less satisfactory than that illustrated in
Scheme 2.
Further elaboration of biphenyls 11 and 12 to the
target compounds 3 and 4 is also illustrated in Scheme
2. Chain extension by use of the Horner-Emmons
reagent, diethyl N-methylphosphonoacetamide,17 gave
compounds 13 and 14 in 98 and 79% yields, respectively,
and hydrogenation of these enamides over Raney nickel
afforded the dihydro adducts 15 and 16 quantitatively.
Reaction of these amides with lithium aluminum hydride
in dry THF gave the corresponding amines, which were
treated with di-tert-butyl dicarbonate and triethylamine
to yield the N-protected amines 17 and 18 with modest
efficiency (38% and 48%, respectively). From these, the
mesylates 19 and 20, required for amine ring closure,
were produced by acid hydrolytic removal of the tetrahy-
dropyranyl group and O-mesylation. Cleavage of the tert-
butoxycarbonyl group was effected by use of trifluoro-
acetic acid, and ring closure was carried out by treatment
of the resulting secondary amines with diisopropylethyl-
amine (Hunig’s base) in dilute solution18 in refluxing
acetonitrile to give the racemic target dibenzazecines 3
and 4 in 77% and 57%, respectively, from compounds 19
and 20. The yields from the parent biphenyls 11 and 12
were 22% and 13%, respectively.
a
Reagents: (a) n-BuLi, then (MeO)3B, then H2O; (b) Pd(OAc)2,
Ph3P, NaHCO3, 60-80% from 10; (c) (EtO)2POCH2CONHMe,
NaOH, (C6H13)4NI, 79-98%; (d) H2, Raney Ni, 100%; (e) LiAlH4
then (t-BuOCO)2CO, Et3N, 38-48%; (f) AcOH, H2O then MsCl,
Et3N, 61-80%; (g) CF3CO2H then i-Pr2EtN, MeCN, reflux, 57-
77%.
with the substituted phenylboronic acid 9 to give biphen-
yls 11 and 12, respectively, followed by the elaboration
of the 10-membered rings (Scheme 2). Compounds 1, 3,
and 4 are chiral (atropisomeric) as a result of inhibition
of rotation about the biphenyl axis,13 and all of the
aforementioned synthetic procedures yielded racemates.
A suitable method for obtaining pure enantiomers of
compounds of this series involves the use of biphenyls
having chiral groups attached to the amino functions
employed in the aza ring formation. By this approach a
method for preparing the enantiomers of compound 3 was
developed (Scheme 4).
Resu lts a n d Discu ssion
Bromination of piperonal (5) gives 84% of aldehyde 614
(Scheme 1) which was coupled with boronic acid 9, made
from the tetrahydropyranyl acetal 10 of 2-(2-bromophen-
yl)ethanol. The Suzuki coupled biphenyl 11 was thus
obtained in 59% yield based on the bromo-intermediate
10 (Scheme 2). Similarly, compound 12 was made by use
of the same boronic acid 9 and aldehyde 7, derived in
There are no chiral centers in the compounds il-
lustrated in Scheme 2 and no other elements of asym-
metry until the ring-closing final step, assuming that the
chiral rotamers of the biphenyls lacking the heterocyclic
ring would readily racemize.13 To obtain enantiomerically
(15) Magnus, P.; Sebhat, I. K. Tetrahedron 1998, 54, 15509.
(16) Takaba, K.; Komori, K.; Kunimoto, J .; Ishida, T. Heterocycles
1996, 43, 1777.
(13) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley-Interscience: New York, 1994; p 1142.
(14) Conrad, P. C.; Kwiatkowski P. L.; Fuchs, P. L. J . Org. Chem.
1987, 52, 586.
(17) Landor, P. D.; Landor, S. R.; Odyek, O. J . Chem. Soc., Perkin
Trans. 1 1977, 93.
(18) Winkler, J . D.; Axten, J . M. J . Am. Chem. Soc. 1998, 120, 6425.
Lin, X.; Kavash, R. W.; Mariano, P. S. J . Org. Chem. 1996, 61, 7335.
7666 J . Org. Chem., Vol. 69, No. 22, 2004

Enantiomers of Hexahydrodibenz[d,f]azecines
SCHEME 4a
a
Reagents: (a) (S)-(EtO)2POCH2CONHCH(Me)Ph, 71%; (b) H2, Pd/C, 88%; (c) BH3‚SMe2 then (t-BuOCO)2CO, 65%; (d) MsCl, Et3N,
99%; (e) CF3CO2H then i-Pr2EtN, 84%; (f) H2, Pd/C, 94%; (g) HCHO, Na(AcO)3BH, 79-93%.
F IGURE 1. ORTEP diagram of compound 28. Ellipsoids are drawn at 30% probability, R ) 0.030; Space group orthorhombic,
P212121; cell dimensions a ) 9.345(7) Å, b ) 11.304(8) Å, c ) 14.799(11) Å; cell volume 1563(2) Å3.
pure forms of the hexahydrodibenzazecines by the ap-
proach adopted in the present work it was necessary to
introduce a chiral component into the precursors prior
to ring closure, and for this reason analogues of the
aminomesylates 19 and 20 bearing a chiral substituent
on the nitrogen atom were sought.
The chiral Horner-Emmons reagent diethyl (S)-N-(1-
phenylethyl)phosphonoacetamide was made from (S)-1-
phenylethylamine19 and used to synthesize enamide 23
from aldehyde 11 (Scheme 4) in a manner analogous to
that used to prepare enamides 13 and 14 from aldehydes
11 and 12. (Scheme 2). On hydrogenation to saturate the
double bond compound 23 surprisingly also underwent
cleavage of the tetrahydropyranyl group, and the isolated
product was the amido alcohol 24. Reduction of the amide
moiety with borane-methyl sulfide gave an amino
alcohol that was N-protected to give carbamate 25. The
derived N-tert-butoxycarbonyl O-mesylate 26 was sub-
jected to the previously described cyclization to give a
mixture of levo- and dextrorotatory diastereomers 27 and
28 in equal proportions and in 84% yield. Chromato-
graphic separation gave these products in 97% and 98%
purity, respectively (NMR evidence). The latter was
recrystallized to >99% purity, and X-ray diffraction
analysis (Figure 1) revealed it to be the Sa,Sc isomer, the
biphenyl having the Sa configuration and the auxiliary
being Sc. Compound 28 and the Ra,Sc diastereomer 27
were separately hydrogenolyzed, and the products, (+)-
29 and (-)-29, were N-methylated20 to give the dextro-
and levorotatory Sa and Ra enantiomers of compound 3,
respectively (Scheme 4). The crystal structure of (-)-3 is
shown in Figure 2. The configuration shown is derived
from the method of synthesis as the crystallographic
methods used were not enantio-discriminating.
Exp er im en ta l Section
2-(2-Br om op h en yl)et h yl Tet r a h yd r o-2-H -p yr a n -2-yl
Eth er (10). A solution of 2-(2-bromophenyl)ethanol 21 (19.6 g,
92.5 mmol), 3,4-dihydro-2H-pyran (13 mL, 142 mmol) and
(20) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
A.; Shah, R. D. J . Org. Chem. 1996, 61, 3849.
(19) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of
Organic Compounds; Wiley-Interscience: New York, 1994; p 331.
(21) Bos, M. E.; Wulff, W. D.; Miller, R. A.; Chamberlin, S.;
Brandvold, T. A. J . Am. Chem. Soc. 1991, 113, 9293.
J . Org. Chem, Vol. 69, No. 22, 2004 7667

Furneaux et al.
12.6 mmol) and cyclohexylamine (1.73 mL, 15.1 mmol) in
toluene (35 mL) was heated at reflux temperature for 2 h
under a Dean-Stark distillation head to remove the water
produced. The mixture was cooled and concentrated under
reduced pressure to give the imine as a clear oil that was taken
up in dry THF (60 mL), and the solution was cooled under an
argon atmosphere in a CO2-acetone bath. n-Butyllithium (1.7
M in hexanes, 12 mL, 20.4 mmol) was added slowly, and the
mixture was stirred for 15 min. Trimethyl borate (3.4 mL, 30
mmol) was added, and the solution stirred for a further 15
min and transferred to an ice-water bath for 1 h. Acetic acid
(2 mL) and hydrogen peroxide (30%, 5 mL, 45 mmol) were
added, and stirring was continued at 20 °C for 16 h. The
reaction mixture was then diluted with diethyl ether and
washed with aqueous NH4Cl (saturated), aqueous NaHSO3
(5%), and brine, dried, and concentrated under reduced pres-
sure. The residue was chromatographed using hexanes-ethyl
acetate (6:1 and 3:1) as eluant to give the biphenylimine (21)
as a light-brown-colored oil (1.70 g, 27%): 1H NMR δ 9.35 (s,
1H), 7.66 (s, 1H), 7.37 (m, 2H), 7.28 (m, 1H), 7.14 (m, 1H),
6.19 (s, 1H), 6.03 (s, 2H), 4.47 (br s, 1H), 3.74 (m, 1H), 3.68
(m, 1H), 3.43 (m, 2H), 3.09 (br s, 1H), 2.74 (m, 2H), 1.79-1.25
(m, 16H); 13C NMR δ 161.5, 155.9, 151.7, 140.2, 139.1, 138.0,
134.9, 130.9, 130.2, 128.3, 126.3, 113.1, 102.0, 102.0, 101.8,
67.9, 63.2, 62.5, 34.1, 34.0, 33.7, 30.9, 25.8, 25.5, 24.4, 19.9;
HRMS (EI) m/z calcd for C27H33NO5 (M+) 451.2359, found
451.2353.
F IGURE 2. ORTEP diagram of (-)-3. Ellipsoids are drawn
at 30% probability, R ) 0.037; space group tetragonal, P43212;
cell dimensions a ) 11.0639(12) Å, c ) 33.688(7) Å; cell volume
4123.7(11) Å3.
Biphenylimine 21 (1.3 g, 2.8 mmol) was dissolved in THF
(10 mL), HCl (3 mL, 1 M) was added, and the mixture was
heated under reflux for 15 min. After being cooled, it was
diluted with ether, washed with water and brine, dried, and
concentrated under reduced pressure. The residue was column
chromatographed using hexanes-ethyl acetate (4:1) as eluant
to give the hydroxybiphenyl aldehyde (22) as a light brown
oil (0.54 g, 54%): 1H NMR δ 11.85 (s, 1H), 9.35 (s, 1H), 7.37
(m, 2H), 7.24 (m, 1H), 7.16 (m, 1H), 6.41 (s, 1H), 6.12 (s, 2H),
4.47 (br s, 1H), 3.83 (m, 1H), 3.66 (m, 1H), 3.52-3.38 (m, 2H),
2.75 (m, 2H), 1.79-1.47 (m, 6H); 13C NMR δ 196.3, 154.5,
146.8, 143.8, 138.1, 137.3, 133.6, 131.0, 130.0, 128.9, 126.3,
116.3, 104.4, 103.1, 99.2, 67.9, 62.6, 33.7, 30.9, 25.7, 19.9;
HRMS (EI) m/z calcd for C21H22O6 (M+) 370.1416, found
370.1431.
Dimethyl sulfate (0.47 mL, 5.7 mmol) and K2CO3 (0.90 g,
6.5 mmol) were added to a stirred solution of phenol 22 (1.2 g,
3.2 mmol) in dry THF (50 mL). The mixture was heated under
reflux for 3 h, cooled, diluted with ether, washed with water
and brine, dried, and concentrated under reduced pressure.
The residue was column chromatographed using hexanes-
ethyl acetate (3:1) as eluant to give the title compound 12 as
a light brown oil (1.10 g, 88%): 1H NMR δ 9.79 (1H, s), 7.34-
7.18 (m, 3H), 7.06 (m, 1H), 6.44 (s, 1H), 6.06 (s, 2H), 4.48 (br
s, 1H), 4.13 (s, 3H), 3.80 (m, 1H), 3.70 (m, 1H), 3.48 (m, 2H),
2.72 (m, 2H), 1.75-1.50 (m, 6H); 13C NMR δ 189.9, 153.1,
145.1, 142.5, 139.4, 137.3, 136.5, 130.1, 129.8, 128.3, 126.3,
121.9, 106.4, 102.3, 99.1, 67.9, 62.6, 60.8, 33.7, 31.0, 25.8, 19.9;
HRMS (EI) m/z calcd for C22H24O6 (M+) 384.1573, found
384.1568.
(ii) By Su zu k i Cou p lin g of Com p ou n d 7 (Der ived fr om
Com p ou n d 8) a n d Bor on ic Acid 9. A stirred solution of
6-bromo-4-methoxybenzodioxole 815 (4.6 g, 20 mmol) in CH2-
Cl2 (80 mL) was cooled under argon in a CO2-acetone bath.
Dichloromethyl methyl ether (1.9 mL, 20.1 mmol) and SnCl4
(4.2 mL, 35 mmol) were added, and the mixture was brought
to room temperature over 6 h. The mixture was washed with
water, HCl (2 M), and aqueous NaHCO3 (saturated), dried,
and concentrated under reduced pressure. The residue was
eluted through a plug of silica gel with hexanes-ethyl acetate
(4:1) to give a two-component mixture of aldehyde 7 and its
regioisomer in the ratio 3.7:1. The mixture was column
chromatographed using hexanes-ethyl acetate (6:1) as eluant
to give 6-bromo-4-methoxybenzo[1,3]dioxole-5-carbaldehyde (7)
(2.70 g, 52%), mp 120-122 °C (dec) (from EtOH): 1H NMR δ
camphorsulfonic acid monohydrate (5 mg) in dry CH2Cl2 (100
mL) was stirred overnight at 20 °C. The reaction mixture was
concentrated under reduced pressure, and the residue was
column chromatographed with hexanes-ethyl acetate (19:1
and 9:1) as eluant to give the title compound as a light brown
oil (19.0 g, 72%): 1H NMR δ 7.52 (m, 1H), 7.20 (m, 2H), 7.06
(m, 1H), 4.61 (m, 1H), 3.94 (m, 1H), 3.76 (m, 1H), 3.65 (m,
1H), 3.48 (m, 1H), 3.16 (m, 2H), 1.86-1.47 (m, 6H); 13C NMR
δ 138.5, 132.7, 131.3, 128.0, 127.3, 124.8, 98.7, 66.5, 62.2, 36.6,
30.7, 25.5 19.5; HRMS (EI) m/z calcd for C13H17BrO2 (M)+
284.0412, found 284.0413.
Bip h en yla ld eh yd e 11. A solution of the bromoacetal 10
(21.4 g, 75.1 mmol) in dry THF (160 mL) was cooled under
argon to -78 °C. n-Butyllithium (1.1 M in hexanes, 82 mL,
90.0 mmol) was added with stirring over 15 min with the
temperature kept below -50 °C, and trimethyl borate (16.6
mL, 160 mmol) was added over 15 min at this temperature.
After a further 15 min with stirring the solution was trans-
ferred to an ice-water bath for 1 h and then quenched with
aqueous NH4Cl (saturated). The mixture, containing boronic
acid 9, was extracted twice with diethyl ether, and the extracts
were washed with brine, dried, and concentrated under
reduced pressure. The residue was taken up in dioxane (150
mL) containing 6-bromopiperonal (6, 13 g, 58 mmol), made
according to the literature method14 except that FeCl3 was used
instead of FeBr3. Palladium acetate (0.235 g, 1.05 mmol) and
Ph3P (1.1 g, 4.2 mmol) were dissolved with heating in aqueous
NaHCO3 (50 mL, saturated), and the two solutions were mixed.
The resulting pale yellow solution was heated at reflux under
argon for 12 h. After it had been cooled, the mixture was
extracted twice with diethyl ether, and the combined extracts
were washed with aqueous NaOH (10%), HCl (2 M) and brine,
dried, and concentrated under reduced pressure. The residue
was column chromatographed with hexanes-ethyl acetate (6:1
and 4:1) as eluant to give 11 as a light brown oil (15.8 g, 77%
based on compound 6): 1H NMR δ 9.43 (s, 1H), 7.37 (s, 1H),
7.29 (m, 2H) 7.18 (m, 1H), 7.08 (m, 1H), 6.67 (s, 1H), 6.01 (s,
2H), 4.37 (br s, 1H) 3.73 (m, 1H), 3.57 (m, 1H), 3.41-3.30 (m,
2H), 2.68 (m, 2H), 1.68-1.35 (m, 6H); 13C NMR δ 190.1, 151.8,
147.6, 142.4, 137.4, 137.1, 130.5, 129.5, 129.0, 128.6, 125.7,
110.4, 105.6, 101.8, 98.5, 67.2, 61.9, 33.1, 30.2, 25.1,19.2;
HRMS (EI) m/z calcd for C21H22O5 (M+) 354.1467, found
354.1469.
Bip h en yla ld eh yd e 12. (i) By Meth oxyla tion of Ald e-
h yd e 11 via 21 a n d 22. A solution of aldehyde 11 (4.46 g,
7668 J . Org. Chem., Vol. 69, No. 22, 2004

Enantiomers of Hexahydrodibenz[d,f]azecines
10.23 (s, 1H), 6.86 (s, 1H), 6.04 (s, 2H), 4.08 (s, 3H); 13C NMR
δ 189.5, 154.8, 146.2, 137.1, 121.1, 118.9, 109.5, 102.8, 61.0;
HRMS (EI) m/z calcd for C9H7BrO4 (M+) 259.9507, found
259.9505. Anal. Calcd for C9H7BrO4: C 41.73, H 2.72. Found:
C 42.02, H 2.56. Eluted second was 5-bromo-7-methoxybenzo-
[1,3]dioxole-4-carbaldehyde as a colorless oil (0.73 g, 14%): 1H
NMR δ 10.17 (s, 1H), 6.81 (s, 1H), 6.15 (s, 2H), 3.98 (s, 3H);
13C NMR δ 189.6, 150.8, 148.0, 136.2, 118.3, 113.3, 113.1,
103.9, 57.5; HRMS (EI) m/z found 259.9496.
compound 16 as a tan-colored oil (0.92 g, 99%): 1H NMR δ
7.28-7.12 (m, 3H), 7.00 (m, 1H), 6.27 (s, 1H), 5.87 (s, 2H), 5.16
(br s, 1H), 4.42 (br s, 1H), 3.98 (s, 3H), 3.74-3.60 (m, 2H),
3.43-3.34 (m, 2H), 2.60 (m, 6H), 2.35 (m, 1H), 2.08 (m, 2H),
1.71-1.27 (m, 6H); 13C NMR δ 173.0, 147.6, 142.0, 141.2, 137.3,
135.9, 135.1, 130.4, 130.0, 127.9, 126.3, 124.5, 104.8, 101.2,
99.1, 67.8, 62.6, 60.1, 37.3, 33.6, 31.0, 26.5, 25.8, 24.3, 19.9;
HRMS (EI) m/z calcd for C25H31NO6 (M+) 441.2151, found
441.2152.
Aldehyde 7 (50 mg, 0.19 mmol), boronic acid 9 (52 mg, 0.21
mmol), and Ph3P (11 mg, 0.04 mmol) were dissolved in 1,4-
dioxane (1.5 mL), and Pd(OAc)2 (2 mg, 0.01 mmol) in hot
aqueous NaHCO3 (0.5 mL, saturated) was added. The mixture
and the product formed were treated as described for com-
pound 11 to give biphenylaldehyde 12 (60 mg, 80%), which
gave 1H and 13C NMR spectra identical to those obtained from
a sample made by route i.
(4-Meth oxyben zo[1,3]d ioxol-5-yl) Meth a n ol. A solution
of aldehyde 7 (10 mg) in methanol (1 mL) was stirred over
Raney nickel (10 mg added in a MeOH suspension, 100 mL)
under hydrogen for 18 h. The catalyst was removed by
filtration through Celite, and concentration of the filtrate
under reduced pressure gave the known title compound (5 mg):
16 1H NMR identical to the published data;16 13C NMR δ 149.7,
142.1, 136.4, 126.5, 122.4, 102.6, 101.4, 62.2, 60.1.
En a m id e 13. Diethyl-N-methylphosphonoacetamide was
made according to literature procedures17 and was used
without purification: 1H NMR δ 6.76 (br s, 1H), 4.14 (m, 4H),
2.83 (m, 5H), 1.34 (t, J ) Hz, 6H); 13C NMR δ 164.9, 63.1,
35.2 (d, J C,P ) 125 Hz), 27.0, 16.7. A solution of aldehyde 11
(0.67 g, 1.9 mmol), the phosphonate (1.0 g, 4.8 mmol), and
tetrahexylammonium iodide (5 mg) in CH2Cl2 (8 mL) was
added to aqueous sodium hydroxide (50%, 3 mL) with rapid
stirring, which was continued overnight. Dichloromethane was
added; the solution was washed with water, aqueous NH4Cl
(saturated), and brine and dried; and the volatiles were
removed under reduced pressure. The residue was column
chromatographed using ethyl acetate as eluant to give 13 (0.77
g, 98%) as a light brown oil: 1H NMR δ 7.35-7.04 (m, 6H),
6.69 (s, 1H), 6.07 (m, 1H), 6.02 (s, 2H), 5.79 (br s, 1H), 4.43
(m, 1H), 3.74 (m, 2H), 3.43 (m, 2H), 2.78 (m, 3H), 2.68 (m,
2H), 1.74-1.40 (6H, m); 13C NMR δ 167.1, 148.8, 147.8, 140.0,
138.5, 137.5, 130.8, 130.3, 128.3, 127.8, 126.6, 120.5, 111.0,
105.6, 101.9, 99.1, 67.9, 62.5, 33.8, 31.0, 26.7, 25.8, 19.9. HRMS
(EI) m/z calcd for C24H27NO5 (M+) 409.1889, found 409.1887.
En a m id e 14. A solution of aldehyde 12 (1.0 g, 2.6 mmol)
and diethyl-N-methylphosphonoacetamide (1.5 g, 7.2 mmol)
was treated by the method described for the preparation of
13. The yield of light brown oil was 0.90 g (79%): 1H NMR δ
7.34-7.18 (m, 4H), 7.06 (m, 1H), 6.44 (s, 1H), 6.16 (dd, 1H, J
) 15.9, 3.3 Hz), 6.00 (s, 2H), 5.42 (br s, 1H), 4.45 (m, 1H), 4.04
(s, 3H), 3.74 (m, 2H), 3.43 (m, 2H), 2.78 (m, 3H), 2.68 (m, 2H),
1.74-1.40 (m, 6H); 13C NMR δ 167.8, 149.4, 143.3, 140.9, 138.3,
137.2, 136.7, 135.2, 130.5, 130.2, 128.1, 126.6, 123.6, 120.3,
106.0, 101.7, 99.1, 67.7, 62.6, 60.1, 33.6, 31.0, 26.6, 25.8, 19.9;
HRMS (EI) m/z calcd for C25H29NO6 (M+) 439.1995, found
439.2004.
Ca r ba m a te 17. Lithium aluminum hydride (0.17 g, 4.5
mmol) was added to a solution of amide 15 (0.75 g, 1.87 mmol)
in dry THF (17 mL), and the suspension was heated under
reflux for 2 h. Water (0.5 mL) and MgSO4 (excess) were added
in rapid succession to the cooled mixture, which was filtered
through Celite. The filter cake was stirred for 10 min with
CH2Cl2 (5 × 17 mL), and the extracts were dried and taken to
dryness under reduced pressure. The resulting amine was
taken up in CH2Cl2 and treated with di-tert-butyl dicarbonate
(4.1 g, 2.3 mmol) and triethylamine (0.2 mL). After 1 h the
reaction mixture was washed with HCl (2 M), aqueous K2CO3
(10%), and brine, dried, and concentrated under reduced
pressure. The residue was column chromatographed with
hexanes-ethyl acetate (5:1) as eluant to give carbamate 17
as a light brown oil (0.34 g, 37%): 1H NMR δ 7.34-7.18 (br
m, 3H), 7.07 (m, 1H), 6.75 (s, 1H), 6.60 (s, 1H), 5.95 (s, 2H),
4.47 (m, 1H), 3.74 (m, 2H), 3.44 (m, 2H), 3.03 (m, 2H), 2.67
(m, 5H), 2.21 (m, 2H), 1.74-1.40 (m, 8H), 1.38 (s, 9H); 13C NMR
δ 156.0, 147.3, 145.7, 141.4, 137.4, 134.0, 133.4, 130.6, 129.9,
127.7, 126.3, 110.5, 109.1, 101.3, 99.0, 79.4, 67.9, 62.5, 48.9,
34.1, 33.7, 31.0, 30.6, 29.6, 28.8, 25.8, 19.9; HRMS (FAB) m/z
calcd for C29H39NO6 (M+) 497.2777, found 497.2772.
Ca r ba m a te 18. Amide 16 (0.87 g, 1.97 mmol) was treated
as described for compound 15 to give carbamate 18 as a light-
brown-colored oil (0.50 g, 48%): 1H NMR δ 7.47-7.09 (m, 3H),
7.00 (m, 1H), 6.27 (s, 1H), 5.87 (s, 2H), 4.42 (br s, 1H), 3.96 (s,
3H), 3.74-3.60 (m, 2H), 3.39-3.32 (m, 2H), 2.91 (br s, 2H),
2.60 (m, 5H), 2.33 (m, 1H), 1.94 (m, 1H), 1.72-1.32 (m, 17H);
13C NMR δ 156.1, 147.2, 142.0, 141.5, 137.2, 136.0, 134.9,
130.4, 129.9, 127.7, 126.2, 125.8, 104.8, 101.1, 99.0, 79.2, 68.0,
62.5, 59.9, 49.1, 33.9, 33.8, 31.0, 28.8, 28.8, 25.8, 25.2, 19.9;
HRMS (EI) m/z calcd for C30H41NO7 (M+) 527.2885, found
527.2885.
Mesyla te 19. A solution of tetrahydropyranyl ether 17 (0.32
g, 0.64 mmol) in acetic acid-THF-water (4:2:1, 10 mL) was
heated at 50 °C for 5 h. The solvents were removed under
reduced pressure, and the residue was chromatographed on a
column of silica gel using hexanes-ethyl acetate (2:1) as
eluant. The product, after evaporation of the solvent, was
taken up in CH2Cl2 (10 mL) and treated with methanesulfonyl
chloride (0.10 mL, 0.7 mmol) and triethylamine (0.25 mL, 1.5
mmol). After being stirred for 2 h the reaction mixture was
extracted with HCl (2 M) and brine, dried, and concentrated
under reduced pressure. The residue was column chromato-
graphed using CH2Cl2-ethyl acetate (9:1 and 6:1) as eluant
to give the title mesylate 19 as a light brown oil (0.25 g, 80%):
1H NMR δ 7.23 (br m, 3H), 7.05 (m, 1H), 6.71 (s, 1H), 6.51 (s,
1H), 5.90 (m, 2H), 4.13 (m, 2H), 2.98 (m, 2H), 2.77 (m, 5H),
2.57 (m, 3H), 2.11 (m, 2H), 1.50 (m, 2H), 1.32 (s, 9H); 13C NMR
δ 156.0, 147.6, 146.0, 141.6, 134.6, 133.4, 133.2, 130.9, 130.6,
128.1, 127.4, 110.2, 109.2, 101.4, 79.5, 69.7, 48.8, 37.7, 34.1,
33.2, 30.6, 29.6, 28.8; HRMS (EI) m/z calcd for C25H33NO7S
(M+) 491.1978, found 491.1976.
Am id e 15. Compound 13 (0.77 g, 1.88 mmol) was dissolved
in methanol (30 mL) and stirred with Raney nickel (0.7 g)
under hydrogen at atmospheric pressure. After 24 h the
mixture was filtered through Celite, and the filtrate was
concentrated under reduced pressure to give amide 15 as a
tan-colored oil (0.75 g, 97%): 1H NMR δ 7.36-7.19 (br m, 3H),
7.09 (m, 1H), 6.79 (s, 1H), 6.60 (s, 1H), 5.95 (s, 2H), 5.47 (br s,
1H), 4.48 (m, 1H), 3.80 (m, 1H), 3.67 (m, 1H), 3.45 (m, 2H),
2.67 (m, 7H), 2.17 (m, 2H), 1.74-1.40 (m, 6H); 13C NMR δ
173.0, 147.3, 146.0, 141.2, 137.4, 134.5, 132.1, 130.6, 129.9,
127.9, 126.4, 110.6, 109.4, 101.4, 99.2, 67.7, 62.7, 37.9, 33.6,
Mesyla te 20. By application of the method used to prepare
mesylate 19, tetrahydropyranyl ether 18 (0.45 g, 0.85 mmol)
was converted to the mesylate 20 as a light-colored oil (0.27
g, 61%): 1H NMR δ 7.61-7.23 (m, 3H), 7.12 (m, 1H), 6.32 (s,
1H), 5.95 (m, 2H), 4.20 (t, J ) 7.2 Hz, 3H), 4.04 (s, 3H), 3.01
(br s, 2H), 2.84 (m, 5H), 2.61 (br s, 3H), 2.42 (m, 1H), 1.94 (m,
1H), 1.53 (m, 1H), 1.38 (m, 9H); 13C NMR δ 156.1, 147.5, 142.2,
141.7, 136.2, 134.5, 134.1, 130.8, 130.0, 128.1, 127.2, 125.8,
104.4, 101.2, 79.2, 69.8, 60.0, 49.1, 37.7, 33.9, 33.3, 28.8, 28.8,
31.0, 29.5, 26.7, 25.8, 19.9; HRMS (EI) m/z calcd for C24H29
-
NO5 (M+) 411.2046, found 411.2038.
Am id e 16. Unsaturated amide 14 (0.93 g, 2.1 mmol) was
hydrogenated as described for compound 13 to give the dihydro
J . Org. Chem, Vol. 69, No. 22, 2004 7669

Furneaux et al.
25.2; HRMS (EI) m/z calcd for C26H35NO8S (M+) 521.2090,
found 521.2090.
methyl sulfide (0.34 mL, 3.6 mmol) was added by syringe, and
the mixture was heated slowly to reflux temperature by which
time the amide had reacted (TLC observation). The solution
was cooled to room temperature, HCl (0.75 mL, 6M, 4.5 mmol)
was added slowly, and the mixture was briefly heated under
reflux. After cooling, neutralization was effected with aqueous
K2CO3 (10%), and the mixture was extracted with CH2Cl2 (20
mL × 3), the combined extracts were washed with water (×
3) and dried, and the solvents were removed under reduced
pressure. The residue was taken up in CH2Cl2 and treated with
di-tert-butyl dicarbonate (0.70 g, 3.2 mmol). This solution was
stirred overnight, concentrated under reduced pressure, and
column chromatographed using hexanes-ethyl acetate (2:1)
as eluant to give the protected amine 25 as a pale brown oil
(0.79 g, 65%), [R]D -47.0 (c 1, CH2Cl2): 1H NMR δ 7.3 (m, 8H),
6.96 (m, 1H), 6.61 (s, 1H), 6.54 (s, 1H), 5.91 (m, 2H), 5.25 (m,
1H), 3.60 (m, 2H), 2.83 (br s, 1H), 2.61 (m, 3H), 2.17 (m, 2H),
1.83 (br s, 1H), 1.51 (m, 2H), 1.40 (m, 12H); 13C NMR δ 156.1,
147.3, 145.7, 142.3, 141.6, 137.0, 133.8, 133.4, 130.8, 129.9,
128.7, 127.8, 127.4, 126.5, 110.6, 109.6, 101.3, 79.9, 63.2, 53.8,
43.8, 36.8, 31.6, 30.8, 28.9, 17.8; HRMS (FAB) m/z calcd for
Hexa h yd r od iben za zecin e (()-3. A solution of compound
19 (0.15 g, 0.31 mmol) in trifluoroacetic acid (1 mL) was stirred
at room temperature for 1 h. The acid was removed under
reduced pressure, the residue was taken up in acetonitrile (175
mL) containing diisopropylethylamine (0.6 mL, 3.4 mmol), and
the solution was heated under reflux for 16 h. After being
cooled, it was taken to dryness under reduced pressure, and
the residue was dissolved in CH2Cl2, washed with water, dried,
and concentrated under reduced pressure. The new residue
was column chromatographed using CH2Cl2-ethyl acetate
(19:1 and 9:1) as eluant and then on a short column of neutral
alumina using CHCl3 as eluant to give the racemic title
compound 3 as a light yellow oil that solidified on standing
(0.070 g, 77%). Recrystallization from hexanes-ethyl acetate
gave white prisms, mp 138-142 °C: 1H NMR δ 7.18 (m, 2H),
7.05 (m, 1H), 6.92 (m, 1H), 6.66 (s, 1H), 6.42 (s, 1H), 5.84 (m,
2H), 2.54 (m, 3H), 2.27 (m, 2H), 2.18 (m, 2H), 1.97 (s, 3H),
1.62 (m, 2H), 1.37 (m, 1H); 13C NMR δ 147.4, 145.3, 143.1,
141.1, 136.3, 134.6, 130.1, 128.3, 127.7, 125.3, 110.0, 108.4,
101.2, 59.7, 50.0, 44.8, 31.0, 29.0, 28.6; HRMS (EI) m/z calcd
for C19H21NO2 (M+) 295.1572, found 295.1573. Anal. Calcd for
C
31H38NO5 (MH+) 504.2750, found 504.2739.
Mesyla te 26. Methanesulfonyl chloride (0.23 mL, 2.9 mmol)
C
19H21NO2: C 77.26, H 7.17, N 4.74. Found: C 77.14, H 7.16,
N 4.70.
Hexa h yd r od iben za zecin e (()-4. Mesylate 20 (0.18 g, 0.35
and triethylamine (0.46 mL, excess) were added to an ice-cold
solution of hydroxyamine 25 (0.74 g, 1.47 mmol) in CH2Cl2 (5
mL). The mixture was brought to room temperature and
stirred for 3 h. Extractive isolation and chromatography as
for compound 19 gave the mesylate 26 as a pale brown oil (0.85
g, 99%), [R]D -41.8 (c 1.1, CH2Cl2): 1H NMR δ 7.3 (m, 8H),
6.99 (m, 1H), 6.62 (s, 1H), 6.53 (s, 1H), 5.96 (m, 2H), 5.35 (br
s, 1H), 4.16 (m, 2H), 2.81 (s, 3H), 2.75 (m, 3H), 2.68 (m, 1H),
2.15 (m, 2H), 1.51 (m, 2H), 1.40 (m, 12H); 13C NMR δ 156.0,
147.6, 145.9, 142.3, 141.6, 134.6, 133.4, 133.1, 130.9, 130.0,
128.6, 128.0, 127.4, 127.3, 110.0, 109.1, 101.4, 79.8, 69.8, 53.4,
43.8, 37.6, 33.2, 31.8, 30.8, 28.9, 17.8; HRMS (FAB) m/z calcd
for C32H40NO7S (MH+) 582.2526, found 582.2471.
mmol) was treated as described for compound 19 to give the
title product as a light yellow oil that solidified on standing
(0.064 g, 57%). A sample was recrystallized from ethyl
acetate-hexanes to give colorless needles, mp 146-149 °C:
1H and 13C NMR spectral data identical to those already
reported;3 HRMS (EI) m/z calcd for C20H23NO3 (M+) 325.1682,
found 325.1682. Anal. Calcd for C20H23NO3: C 73.82, H 7.12,
N 4.30. Found: C 74.10, H 7.04, N 4.59.
En a m id e 23. Diethyl (S)-N-(1-phenylethyl)phosphonoacet-
amide was made by use of literature procedures17 with (S)-1-
phenylethylamine and was used without purification: 1H NMR
δ 7.33 (m, 5H), 7.11 (br s, 1H), 5.12 (m, 1H), 4.63 (m, 2H),
4.61 (m, 2H), 2.84 (dd, J ) 5.1, 20.4 Hz, 2H), 1.49 (d, J ) 6.9
Dia ster eom er ic Hexa h yd r od iben za zecin es 27 a n d 28.
Compound 26 (1.8 g, 3.1 mmol) was stirred with trifluoroacetic
acid (10 mL) at 20 °C for 1.5 h. The acid was evaporated under
reduced pressure, the residue was taken up in acetonitrile (420
mL) containing diisopropylethylamine (7.2 mL, 75.4 mmol),
and the solution was heated under reflux for 48 h. After cooling
of the solution, the volatiles were removed under reduced
pressure, and the residue was column chromatographed using
hexanes-ethyl acetate (9:1) as eluant to give a 1:1 mixture of
the cyclized diastereomers 27 and 28 (1.0 g, 84%) as a white
solid. Further column chromatography with hexanes-ethyl
acetate-CH2Cl2, (190:5:5) as eluant afforded the separated
diastereomers in quantitative yields, containing 3% and 2%,
respectively, of the other isomers (NMR evidence). Compound
28 was further purified by crystallization from ethanol.
Hz, 3H), 1.34 (t, J ) 7.1 Hz, 3H), 1.24 (t, J ) 7.1 Hz, 3H); 13
C
NMR δ 163.3, 143.5, 129.0, 127.7, 126.5, 63.1, 63.0, 49.7, 35.5
(d, J CP ) 130 Hz), 22.4, 16.7, 16.6. Aldehyde 11 (10 g, 28.2
mmol) was treated with the phosphonate (10 g, 33.4 mmol)
by the method described for making compound 13. The crude
reaction product was column chromatographed using hex-
anes-ethyl acetate (4:1-1:1) as eluant to give enamide 23
(10.0 g, 71%) as a light yellow oil: [R]D -15.8 (c 1.1, CH2Cl2);
1H NMR δ 7.28 (m, 9H), 7.08 (m, 2H), 6.68 (s, 1H), 6.15 (d, J
) 15.5 Hz, 1H), 6.00 (s, 2H), 5.83 (br s, 1H), 5.12 (m, 1H), 4.44
(m, 1H), 3.70 (m, 2H), 3.40 (m, 2H), 2.67 (m, 2H), 1.47 (br m,
9H); 13C NMR δ 165.4, 148.9, 147.8, 143.7, 139.9, 139.3, 137.8,
137.6, 130.8, 130.3, 130.2, 129.0, 128.3, 127.7, 126.6, 120.0,
111.0, 105.4, 101.9, 99.0, 67.8, 62.5, 49.2, 33.7, 31.0, 25.8, 19.9,
14.6; HRMS (FAB) m/z calcd for C31H34NO5 (MH+) 500.2437,
found 500.2424.
(Ra,Sc) Isomer 27 was obtained as a white amorphous solid,
mp 45-55 °C; [R]D -60.7 (c 1, CH2Cl2): 1H NMR δ 7.4-7.0
(m, 9H), 6.76 (s, 1H), 6.49 (s, 1H), 5.94 (m, 2H), 3.53 (m, 1H),
2.96 (m, 1H), 2.71 (m, 1H), 2.57 (m, 1H), 2.4-2.2 (br m, 5H),
1.86 (m, 1H), 1.43 (m, 1H), 1.03 (m, 3H); 13C NMR δ 147.4,
145.3, 143.3, 142.8, 140.8, 136.2, 134.5, 129.8, 128.8, 128.3,
127.4, 126.9, 125.1, 110.0, 108.3, 101.2, 59.0, 51.0, 45.3, 31.0,
29.2, 28.2, 20.2; HRMS (FAB) m/z calcd for C26H28NO2 (MH+)
386.2120, found 386.2113. Anal. Calcd for C26H27NO2: C 81.00,
H 7.06, N 3.64. Found: C 81.08, H 7.34, N 3.43.
Am id e 24. Acrylamide 23 (10.0 g, 20.0 mmol) was dissolved
in methanol (100 mL) and stirred with palladium on carbon
(10%, 0.5 g) under hydrogen (1 atm) overnight. The mixture
was filtered through Celite, and the filtrate was concentrated
under reduced pressure. Column chromatography of the
residue eluted with hexanes-ethyl acetate (1:1) and ethyl
acetate gave the title compound (7.4 g, 88%) as a light yellow
oil, [R]D -24.5 (c 1.0, CH2Cl2): 1H NMR δ 7.3-7.1 (m, 9H),
6.78 (s, 1H), 6.57 (s, 1H), 5.94 (m, 2H), 5.79 (br s, 1H), 4.98
(m, 1H), 4.46 (m, 1H), 3.66 (m, 2H), 2.67 (m, 2H), 2.56 (m,
2H), 2.17 (m, 2H), 1.34 (m, 3H); 13C NMR δ 171.5, 147.4, 146.1,
143.6, 141.4, 137.0, 134.1, 132.2, 130.8, 129.6, 128.9, 128.1,
127.6, 126.5, 120.0, 110.6, 109.6, 101.4, 62.7, 48.8, 37.8, 36.4,
29.5, 22.0; HRMS (FAB) m/z calcd for C26H28NO4 (MH+)
418.2018, found 418.1996.
(Sa,Sc) Isomer 28 was crystallized from ethanol as white
needles, mp 170-172 °C; [R]D + 206 (c 1, CH2Cl2): 1H NMR δ
7.2-6.7 (m, 9H), 6.54 (m, 1H), 6.41 (s, 1H), 5.87 (m, 2H), 3.66
(m, 1H), 2.81 (m, 1H), 2.6-2.2 (br m, 5H), 2.13 (br m, 2H),
1.76 (m, 1H), 1.45 (m, 1H), 1.17 (m, 3H); 13C NMR δ 147.4,
145.3, 144.5, 142.8, 140.2, 136.5, 134.5, 129.7, 129.0, 128.2,
127.7, 126.2, 124.9, 110.0, 108.3, 101.2, 55.9, 48.3, 44.5, 30.7,
29.1, 28.6, 9.4. HRMS (FAB) m/z calcd for C26H28NO2 (MH+)
386.2120, found 386.2120. Anal. Calcd for C26H27NO2: C 81.00,
H 7.06, N 3.64. Found: C 81.03, H 6.87, N 3.64.
Ca r ba m a te 25. Amide 24 (1.0 g, 2.4 mmol) was dissolved
in dry THF (20 mL) and cooled in an ice-water bath. Borane-
7670 J . Org. Chem., Vol. 69, No. 22, 2004

Enantiomers of Hexahydrodibenz[d,f]azecines
En a n tiom er s of Hexa h yd r od iben za zecin e 3. Separate
solutions of diastereomers 28 and 27 (0.215 g, 0.54 mmol) in
ethanol (300 mL) were stirred over palladium-on-charcoal (0.1
g, 10%) under an atmosphere of hydrogen (30 psi) for 20 h.
The solutions were filtered through Celite, and the filtrates
were taken to dryness under reduced pressure to give the (+)-
and (-)-enantiomers of secondary amine 29 (each 0.15 g,
94%): 1H NMR δ 7.32 (m, 2H), 7.21 (m, 1H), 7.06 (m, 1H),
6.73 (s, 1H), 6.50 (s, 1H), 5.92 (m, 2H), 2.87 (m, 3H), 2.47 (m,
4H), 2.08 (m, 1H), 1.74 (m, 1H), 1.64 (m, 2H); 13C NMR δ 147.6,
145.6, 143.5, 139.2, 135.7, 132.9, 130.6, 129.4, 128.3, 126.1,
110.1, 108.5, 101.3, 49.4, 42.0, 30.0, 29.9, 28.0.
The crude amines (each 0.14 g, 0.47 mmol) were separately
taken up in CH2ClCH2Cl (10 mL) and stirred with formalin
(0.075 mL, 1 mmol) and sodium triacetoxyborohydride (0.16
g, 0.8 mmol) for 0.5 h at room temperature.20 The solutions
were washed with aqueous K2CO3 (10%) and brine, dried, and
concentrated under reduced pressure, and the residues were
column chromatographed with CH2Cl2-MeOH (19:1 and 9:1)
as eluant to give the title N-methyl derivatives (+)-3 (0.13 g,
93%) and (-)-3 (0.11 g, 79%) as colorless needles.
(+)-Enantiomer, mp 120-124 °C (from hexanes-ethyl
acetate); [R]D +73 (c 0.47, CH2Cl2): 1H and 13C NMR data
identical to data for the (-)-enantiomer and the racemate.
Anal. Calcd for C19H21NO2: C 77.26, H 7.17, N 4.74. Found:
C 77.18, H 7.04, N 4.79.
(-)-Enantiomer, mp 122-124 °C (from ethanol); [R]D -68
(c 0.48, CH2Cl2): 1H and 13C NMR data identical to data for
the (+)-enantiomer and the racemate. Anal. Found: C 77.12,
H 7.05, N 4.79.
Ack n ow led gm en t. Dr. Herbert Wong is thanked for
recording the NMR data. Dr. Andrew Falshaw is
thanked for suggesting the use of the resolving auxiliary
and for helpful discussions. Prof. Robin Ferrier assisted
with the preparation of the manuscript.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
compounds 10-26 and 29. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O049157Q
J . Org. Chem, Vol. 69, No. 22, 2004 7671