2-Benzazepine analogues from D-glucose: Synthesis of chiral cis- and trans-fused furo[3,2-c][2]benzazepine derivatives

Article abstract of DOI:10.1055/s-2005-870012

Facile annulation of benzazepines onto furano-sugars has been achieved through Pd-catalyzed intramolecular cyclization. Using diisopropylidene D-glucose as a starting material, the first chiron approach to furobenzazepines in both cis and trans forms sele

Full text of DOI:10.1055/s-2005-870012

PAPER
2307
2-Benzazepine Analogues from D-Glucose: Synthesis of Chiral cis- and
trans-Fused Furo[3,2-c][2]benzazepine Derivatives
B
enzazepine An
i
alogue
r
s
from
D
t
-
Gluco
h
se: FusedFu
a
robenzazepine De
P
r
ivatives ada Majhi, Aniruddha Nandi, Arpita Neogi, Ranjan Mukhopadhyay, Partha Chattopadhyay*
Division of Medicinal Chemistry, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700 032, India
Fax +91(33)24735197; E-mail: partha@iicb.res.in
Received 16 March 2005
OH
Abstract: Facile annulation of benzazepines onto furano-sugars
has been achieved through Pd-catalyzed intramolecular cyclization.
Using diisopropylidene D-glucose as a starting material, the first
O
OMe
O
H
N
chiron approach to furobenzazepines in both cis and trans forms se-
lectively introduced a 7-membered azepine ring linearly fused to a
sugar nucleus. Cleavage of the sugar ring of the tricyclic derivatives
provide a convenient route for entry into chiral functionalized 2-
benzazepines, viz. 15 from 12a, and 16 from 14.
Figure 1 (+)-Montabuphine
study therefore provides a potential alternate route11c to al-
kaloids related to montabuphine (Figure 1).
Key words: furans, azepines, cyclizations, palladium, carbohy-
drates
The key starting material 1,2:5,6-di-O-isopropylidene
glucofuranoside was converted to amino derivatives 1
(X = H) according to the reported procedure
(Scheme 1).12 N-Alkylation of the tosyl amide (1, X = Ts)
derived from 1 (X = H) with the appropriately substituted
2-bromobenzyl bromides afforded (Scheme 1) the respec-
tive 3-N-(2-bromobenzylated) tosyl glucofuranoside 2a
and its methoxy derivative 2b. In a parallel series of ex-
periments, N-alkylation of the carbamate (1, X = CO2Me)
derived from 1 (X = H) with 2-bromobenzyl bromide and
its derivatives furnished the respective 3-N-(2-bromoben-
zylated)methoxycarbonyl glucofuranosides 3a–c in ex-
cellent yield. Selective removal of the 5,6-O-
isopropylidene moiety from the benzylated products 2a,b
and 3a–c was smoothly effected with 80% aqueous acetic
acid at room temperature and the resulting diols on dide-
hydroxylation with I2–Ph3P–imidazole in boiling
toluene13 afforded the desired olefins 4a,b and 5a–c in
good yields (Scheme 1).
2-Benzazepine derivatives are of considerable interest be-
cause of their diverse pharmacological properties.1 They
have been reported2 to be used as non-peptide mimics for
the well-known tripeptide sequence Arg-Gly-Asp (RGD),
which interacts with avb3 integrin, a pivotal protein that
plays a key role in cell–cell signaling, and acts as its an-
tagonist. However, the synthesis of 2-benzazepines by
classical ring closure as well as ring expansion methodol-
ogies requires a relatively lengthy sequence of reac-
tions.3,4 Recent reports based on intramolecular
cyclization processes involving ring closing metathesis,5
radical reaction,6 intramolecular Heck reaction7 and trans-
formation of Baylis–Hillman adducts to 2-benzazepines8
offer attractive routes for their synthesis under milder re-
action conditions. Enantiopure benzazepines have also
been synthesized using intramolecular Heck reaction,9 but
it requires the use of chiral ligands. In continuation of our
interest in carbohydrate-based synthesis of linearly benz-
annulated tricyclic ethers,10 we felt that the use of chiron
approach based on conversion of suitable sugar deriva-
tives via palladium-induced cyclization may offer a better
and more convenient alternative to the synthesis of 2-
benzazepine derivatives in optically pure form. Although
the use of this reaction to constitute a seven-membered
ring is precedented,11c synthesis of an azepine ring linear-
ly fused to an aromatic ring and a furanose nucleus, that
may be elaborated to Amaryllidaceae alkaloids,11a,b ap-
peared as an attractive target. In this paper, we describe a
facile conversion of D-glucose to tricyclic benzazepine
derivatives in chiral form. Cleavage of the sugar ring of
these tricyclic derivatives provides a convenient route for
entry into chiral functionalized 2-benzazepines. This
The olefins 8 and 10 were prepared from 3-deoxy-3-ami-
no-1,2:5,6-di-O-isopropylidene
allofuranoside
6
(X = H)14 in moderate yields through the intermediates 7
and 9 using the same sequence of reactions (Scheme 2).
The stereochemistry of all the bromo-olefins is based
upon the comparison of J values with those reported for
comparable products.10b,11
Intramolecular cyclization of each of the xylo-series bro-
moalkenes 4a,b and 5a–c with Pd(OAc)2 (5 mol%),
TBAB and anhyd K2CO3 in anhyd DMF furnished
(Scheme 3) the respective crystalline cis-fused tricyclic
compounds 11a,b and 12a–c in 70–80% yield (Table 1),
as the only isolable product after chromatographic purifi-
cation. The structures of the cis-fused furo[3,2-c][2]benz-
azepine derivatives resulting from regioselective 7-exo-
trig cyclization were based upon spectroscopic data.15 It
may be mentioned that the overwhelming preference for
the exo-mode has been observed in most of the intramo-
lecular Heck cyclization reactions of similar systems.16
SYNTHESIS 2005, No. 14, pp 2307–2314
x
x.
x
x
.
2
0
0
5
Advanced online publication: 13.07.2005
DOI: 10.1055/s-2005-870012; Art ID: P04005SS
© Georg Thieme Verlag Stuttgart · New York

2308
T. P. Majhi et al.
PAPER
1,2:5,6-di-O-isopropylidene glucofuranoside
O
O
O
H
O
O
H
XHN
O
O
O
O
6
i
H
XHN
O
O
H
iii
O
Br
i
O
1
O
O
H
iii
O
Br
O
O
H
N
H
O
O
Ts
H
O
Br
H
O
O
7 (61%)
N
O
R
O
O
Ts
2
O
Br
H
O
O
H
N
R1
H
a R = H (67%)
b R = OMe (58%)
O
ii
CO2Me
9 (74%)
N
R2
CO2Me
3
ii
a R1= R2 = H (74%)
b R1= H, R2 = OMe (78%)
c R1 + R2 = O-CH2-O (75%)
H
iv
O
O
Br
O
N
H
Ts
H
O
H
H
O
Br
O
O
8 (53%)
O
iv
Br
N
O
N
H
R
CO2Me
Ts
4
10 (50%)
H
R1
a R = H (67%)
b R = OMe (53%)
O
H
Br
Scheme 2 Construction of D-glucose based ribo-hexenofurano-
sides: reagents and conditions: (i) TsCl–Py, then substituted 2-bromo-
benzyl bromides, anhyd K2CO3, acetone, r.t., 6 h, sonication; (ii) aq
AcOH (80%), r.t., 12 h then Ph3P, imidazole, I2, toluene, reflux, 4 h;
(iii) methyl chloroformate, acetone, reflux, 12 h, then substituted 2-
bromobenzyl bromide, NaH, TBAI, r.t., 12 h; (iv) aq AcOH (80%),
r.t., then Ph3P, imidazole, I2, toluene, reflux, 4 h.
O
O
N
R2
CO2Me
5
a R1 = R2 = H (70%)
b R1 = H, R2 = OMe (57%)
c R1 + R2 = O-CH2-O (55%)
Scheme 1 Construction of D-glucose based xylo-hexenofurano-
sides: reagents and conditions: (i) TsCl–Py, then substituted 2-bromo-
benzyl bromides, anhyd K2CO3, acetone, r.t., 4 h, sonication; (ii) aq
AcOH (80%), r.t., 12 h, then Ph3P, imidazole, I2, toluene, reflux, 4 h;
(iii) methyl chloroformate, acetone, reflux, 12 h, then substituted 2-
bromobenzyl bromide, NaH, TBAI, r.t., 12 h; (iv) aq HOAc (80%),
r.t., then Ph3P, imidazole, I2, toluene, reflux, 4 h.
H
O
Pd (OAc)2
O
O
4
K2CO3, TBAB,
R
N
H
DMF, Argon,
100 °C
11
Ts
a R = H
b R = OCH3
The rigidity imposed on the precursors by the aromatic
and sugar templates presumably assists the cyclization.17
H
R1
R2
O
H
Pd (OAc)2
With the successful intramolecular Heck cyclization of
the olefins having cis disposition of the ring forming
bonds, we next focused upon the corresponding 3-N-
epimeric bromo-olefins 8 and 10 where the ring forming
bonds are trans oriented. Intramolecular Heck cyclization
of 8 and 10 proved successful too, but required a higher
proportion of Pd(OAc)2 (10 mol%). The conversion was
incomplete when 5 mol% of Pd(OAc)2 was used. Usual
work up and chromatographic purification furnished the
respective trans-fused furo[3,2-c][2]benzazepine deriva-
tives 13 and 14 (Scheme 4) (Table 1). The observed value
of 10 Hz for J3a,10a in the 1H NMR spectrum of the product
13 and 14 was in good agreement with the trans-geometry
of the furoazepine ring arrived at from mechanistic con-
sideration. The relative stereochemistry of H-3a and H-
10a in 12a and 14 was further established by NOESY ex-
O
5
K2CO3, TBAB,
DMF, Argon,
100 °C
O
N
12
CO2CH3
a R1 = R2 = H
b R1 = H, R2 = OCH3
c R1 + R2 = O-CH2-O
Scheme 3 Synthesis of cis-fused furo-2-benzazepines
periments. The appearance of distinct cross peaks be-
tween H-3a and H-10a signals of 12a clearly indicates the
cis relationship of the two protons. No such correlation
was observed between these signals in the spectrum of 14,
commensurate with the trans relationship of H-3a and H-
10a.
Synthesis 2005, No. 14, 2307–2314 © Thieme Stuttgart · New York

PAPER
Benzazepine Analogues from D-Glucose: Fused Furobenzazepine Derivatives
2309
In summary, we have established a facile Pd-catalyzed
strategy by which cis and trans fused furo-2-benzazepine
derivatives can be rapidly assembled in a convergent man-
ner from a carbohydrate in three steps. Cleavage of the
sugar ring of the above tricyclic amines provides a conve-
nient route for entry into chiral functionalized 2-benz-
azepines. Synthesis of (+)-montabuphines or analogues
using cis fused furo-2-benzazepine as a chiral synthon is
in progress.
H
O
H
Pd (OAc)2
O
8
K2CO3, TBAB,
DMF, Argon,
100 °C
O
N
Ts
13
H
O
O
Pd (OAc)2
10
K2CO3, TBAB,
DMF, Argon,
100 °C
O
H
N
CO2CH3
14
1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded in a
Bruker AM 300L spectrometer using CDCl3 as solvent and TMS as
internal standard. MS were obtained using either JEOL AX-500 or
Micromass Q-TofmicroTM spectrometers. Elemental analyses were
carried out with a C, H, N analyzer. Specific rotations were mea-
sured at 589 nm on a JASCO P-1020 polarimeter. TLC was per-
formed on pre-coated plates (0.25 nm, silica gel 60 F254). Column
chromatography and flash chromatography were carried out using
commercial-grade silica gel (60–120 mesh or 230–400 mesh). PE
stands for petroleum ether, with a bp of 60–80 °C, except where in-
dicated.
Scheme 4 Synthesis of trans-fused furo 2-benzazepines
Table 1 Synthesis of cis- and trans-Fused Furo[3,2][2]benzazepine
Derivatives
Entry
Bromo-
olefins
Pd(OAc)2
(mol%)
Time (h)
Product (%)
1
2
3
4
5
6
7
4a
4b
5a
5b
5c
8
5
5
12
12
12
12
12
16
16
11a (80)
11b (75)
12a (77)
12b (78)
12c (72)
13 (70)
3-Deoxy-3-(2-bromobenzylamino) Compounds 2a–b, 7; Gener-
al Procedure
5
To a magnetically stirred solution of 3-deoxy-3-amino-1,2:5,6-di-
O-isopropylidene-a-D-glucofuranoside (1, X = H)12 or a-D-allofura-
noside (6, X = H, 6.2 mmol)14 in pyridine (15 mL) was added TsCl
(7.5 mmol) in pyridine (15 mL), and the stirring was continued at
r.t. for 16 h. The mixture was then poured into crushed ice and ex-
tracted with CH2Cl2 (3 × 50 mL). The organic layer was washed
with H2O and dried. Removal of solvent under reduced pressure
gave a syrupy liquid, which was column chromatographed (silica
gel; PE–EtOAc, 4:1) as eluent to give the tosylated product as a pale
yellow viscous liquid. The residue was used in the next step without
further purification. The syrupy material (3.2 mmol), anhyd K2CO3
(5 g) and appropriately substituted 2-bromobenzyl bromide (3.7
mmol) in acetone (30 mL) was sonicated for 4 h at r.t. until comple-
tion of reaction (indicated by TLC). The reaction mixture was then
filtered, the filtrate was concentrated, diluted with H2O and extract-
ed with CH2Cl2 (3 × 50 mL). The CH2Cl2 extract was washed with
H2O, dried and concentrated to afford a syrup which on column
chromatography (silica gel) yielded the corresponding 3-N-(2-bro-
mobenzyl) derivatives.
5
5
10
10
10
14 (72)
As an application of our methodology, the feasibility of
synthesizing chiral functionalized benzazepines from the
annulated sugar derivatives thus obtained could be dem-
onstrated using 12a and 14. Thus, the compounds were
converted to benzazepines 15 and 16 through a sequence
of reactions involving removal of the 1,2-O-isopropyli-
dine group with aqueous H2SO4 (5%) in MeCN–H2O
(3:1), NaIO4 cleavage of the masked aldehyde, NaBH4 re-
duction and acetylation of the resulting diol with acetic
anhydride and pyridine (Scheme 5).
3-Deoxy-3-(2-bromobenzyl-para-toluenesulfonylamino)-
1,2:5,6-di-O-isopropylidene-a-D-glucofuranoside (2a)
25
H
Yield: 67%; viscous oil; eluent, PE–EtOAc (4:1); [a]D –30.1 (c
OAc
OAc
0.65, CHCl3).
i–iv
12a
1H NMR: d = 1.17 (s, 3 H), 1.26 (s, 3 H), 1.23 (s, 3 H), 1.44 (s, 3 H),
2.43 (s, 3 H), 3.55–3.62 (m, 1 H), 3.78 (d, 2 H, J = 5.7 Hz), 3.97 (dt,
2 H, J = 3, 9.5 Hz), 4.56 (d, 1 H, J = 17.5 Hz, Ha of ArCH2), 4.67
(d, 1 H, J = 17.5 Hz, Hb of ArCH2), 5.02 (d, 1 H, J = 3.4 Hz), 5.93
(d, 1 H, J = 3.4 Hz), 7.11–7.81 (m, 8 H, ArH).
H
N
CO2CH3
15
H
Anal. Calcd for C26H32BrNO7S: C, 53.61; H, 5.54; N, 2.40. Found:
C, 53.35; H, 5.22; N, 2.28.
OAc
H
i–iv
OAc
14
N
3-Deoxy-3-(2-bromo-5-methoxybenzyl-para-toluenesulfonyl-
amino)-1,2:5,6-di-O-isopropylidene-a-D-glucofuranoside (2b)
CO2CH3
16
25
Yield: 58%; syrup; eluent, PE–EtOAc (4:1); [a]D –34.6 (c 0.85,
Scheme 5 Synthesis of functionalized 2-benzazepine carbamates
15 and 16: reagents and conditions: (i) aq H2SO4 (5%), MeCN–H2O,
24 h, r.t.; (ii) NaIO4, MeOH–H2O, 2 h r.t.; (iii) NaBH4, MeOH, 4 h,
r.t.; (iv) Ac2O, Py, r.t., 12 h, 50% overall yield.
CHCl3).
1H NMR: d = 1.18 (s, 3 H), 1.27 (s, 3 H), 1.33 (s, 3 H), 1.44 (s, 3 H),
2.43 (s, 3 H), 3.60–3.67 (m, 1 H), 3.79 (m, 5 H, OCH2 signal over-
lapped by OCH3 signal), 3.95–4.02 (dt, 2 H, J = 3.0, 9.6 Hz), 4.48–
4.54 (1 H, d, J = 17.5 Hz, Ha of ArCH2), 4.60–4.66 (d, 1 H, J = 17.5
Synthesis 2005, No. 14, 2307–2314 © Thieme Stuttgart · New York

2310
T. P. Majhi et al.
PAPER
Hz, Hb of ArCH2), 5.01 (d, 1 H, J = 3.6 Hz), 5.93 (d, 1 H, J = 3.6
Hz), 6.68 (dd, 1 H, J = 3.0, 8.7 Hz), 7.19–7.39 (m, 4 H, ArH), 7.78
(d, 2 H, J = 8.4 Hz, ArH).
Anal. Calcd for C22H30BrNO8: C, 51.17; H, 5.86; N, 2.71. Found:
C, 51.03; H, 5.77; N, 2.56.
3-Deoxy-3-(2-bromo-4,5-methylenedioxybenzylmethoxycarbo-
nylamino)-1,2:5,6-di-O-isopropylidene-a-D-glucofuranoside
Anal. Calcd for C27H34BrNO8S: C, 52.94; H, 5.59; N, 2.29. Found:
C, 52.78; H, 5.42; N, 2.16.
(3c)
Yield: 75%; syrup; eluent, PE–EtOAc (7:1); [a]D25 +15.49 (c 1.20,
3-Deoxy-3-(2-bromobenzyl-para-toluenesulfonylamino)-
1,2:5,6-di-O-isopropylidene-a-D-allofuranoside (7)
CHCl3).
IR (neat) 1709 cm–1.
25
Yield: 61%; syrup; eluent, PE–EtOAc (4:1); [a]D –29.4 (c 0.62,
CHCl3).
1H NMR: d = 1.27 (s, 3 H), 1.37 (s, 3 H), 1.44 (s, 3 H), 1.47 (s, 3 H),
3.72 (s, 3 H), 4.03–4.24 (br, 5 H) 4.47 (br, 1 H), 4.67 (br, 1 H), 5.03
(br, 1 H), 6.06 (br, 3 H), 6.71 (s, 1 H), 7.01 (s, 1 H).
1H NMR: d = 1.08 (s, 3 H), 1.11 (s, 3 H), 1.23 (s, 3 H), 1.34 (s, 3 H),
2.44 (s, 3 H), 3.75–3.81 (dd, 2 H, J = 6.6, 10.8 Hz), 3.87–3.91 (m,
2 H), 4.08–4.14 (dd, 1 H, J = 4.5, 9 Hz), 4.42 (t, 1 H, J = 3.6 Hz),
4.67–4.73 (d, 1 H, J = 18 Hz, Ha of ArCH2), 4.89–4.95 (d, 1 H,
J = 18 Hz, Hb of ArCH2), 5.61 (d, 1 H, J = 3.6 Hz), 7.09 (t, 1 H,
J = 7.5 Hz, ArH), 7.26–7.33 (m, 4 H), 7.46 (d, 1 H, J = 7.6 Hz,
ArH), 7.77 (m, 2 H).
MS (ESI+): m/z = 552, 554 (M + Na+ for 79Br, 81Br).
Anal. Calcd for C22H28BrNO9: C, 49.82; H, 5.32; N, 2.64. Found: C,
49.92; H, 5.17; N, 2.77.
3-Deoxy-3-(2-bromobenzylmethoxycarbonylamino)-1,2:5,6-di-
O-isopropylidene-a-D-allofuranoside (9)
Yield: 74%; syrup; eluent, PE–EtOAc (10:1); [a]D25 +2.47 (c 4.69,
CHCl3).
Anal. Calcd for C26H32BrNO7S: C, 53.61; H, 5.54; N, 2.40. Found:
C, 53.49; H, 5.39; N, 2.22.
Compounds 3a–c and 9; General Procedure
IR (neat): 1709 cm–1.
To a magnetically stirred solution of 1 or 6 (100 mmol) in acetone
(150 mL) was added potassium carbonate (100 mmol) followed by
methyl chloroformate (400 mmol). After refluxing overnight, the
mixture was filtered and the filtrate was concentrated under vacu-
um. Column chromatography of the residual oil (PE–EtOAc, 4:1)
gave the carbamate as a liquid. To a mixture of the appropriately
substituted 2-bromobenzyl bromide (100 mmol), NaH (200 mmol)
and tetrabutylammonium iodide (4.5 mmol) in anhyd THF (300
mL) at 0 °C was added a solution of the carbamate (85 mmol) in an-
hyd THF (100 mL) dropwise under a nitrogen atmosphere. The re-
sulting mixture was stirred at 0 °C for 1 h, then at r.t. overnight. The
suspended solid was removed by filtration and the filtrate was evap-
orated to a syrupy liquid. This was dissolved in EtOAc (150 mL),
the solution was washed with brine (2 × 50 mL), dried (Na2SO4),
and evaporated under reduced pressure. The residual oil on flash
chromatography (PE–EtOAc) yielded the corresponding 3-N-(2-
bromobenzyl) carbamates.
1H NMR: d = 1.15 (s, 3 H), 1.29 (s, 3 H), 1.37 (s, 3 H), 1.46 (s, 3 H),
3.68 (s, 3 H), 3.76–3.94 (s, 3 H), 4.22 (dd, 1 H, J = 4.2, 9.2 Hz), 4.62
(m, 4 H), 5.73 (br s, 1 H), 7.11 (m, 3 H), 7.51 (d, 1 H, J = 7.8 Hz).
MS (ESI+): m/z = 508, 510 (M + Na+ for 79Br, 81Br).
Anal. Calcd for C21H28BrNO7: C, 51.86; H, 5.80; N, 2.88. Found: C,
51.67; H, 5.72; N, 2.68.
Olefins 4a,b, 5a–c, 8, 10; General Procedure
3-N-(2-Bromobenzyl)-1,2:5,6-di-O-isopropylidene-a-D-glucofura-
noside (2a,b, 3a–c) or a-D-allofuranoside (7, 9a,b) (5 mmol) was
stirred overnight with aq HOAc (80%) at r.t. (monitored by TLC un-
til the disappearance of starting material). Removal of HOAc on a
rotary evaporator (40 °C) using anhyd toluene (3 × 50 mL) afforded
the intermediate diol as a highly viscous syrup. A solution of the
crude diol, imidazole (15 mmol) and Ph3P (15 mmol) in anhyd tol-
uene (100 mL) was heated under reflux, while I2 (13 mmol) was
added to the boiling mixture in small portions over a period of 1 h,
refluxing was continued for an additional 3 h, until the reaction was
complete. The organic layer was decanted off and the residue was
extracted with toluene (4 × 20 mL). The combined organic layer
was washed with sat. aq Na2S2O3, then H2O, dried (Na2SO4), and
evaporated under reduced pressure to afford an oily material. The
crude product thus obtained yielded the olefins on column chroma-
tography (PE–EtOAc).
3-Deoxy-3-(2-bromobenzylmethoxycarbonylamino)-1,2:5,6-di-
O-isopropylidene-a-D-glucofuranoside (3a)
Yield: 74%; syrup; eluent PE–EtOAc (1:7); [a]D + 2.47 (c 4.69,
25
CHCl3).
IR (neat): 1711 cm–1.
1H NMR: d = 1.27 (s, 3 H), 1.38 (s, 3 H), 1.44 (s, 3 H), 1.46 (s, 3 H),
3.70 (s, 3 H), 4.02–4.24 (br, 5 H), 4.55 (d, 1 H, J = 16.8 Hz), 4.84
(d, 1 H, J = 15.3 Hz), 5.29 (br s, 1 H), 6.10 (br, 1 H), 7.19 (m, 2 H),
7.34 (d, 1 H, J = 7.3 Hz), 7.56 (d, 1 H, J = 7.4 Hz).
3,5,6-Trideoxy-3-(2-bromobenzyl-para-toluenesulfonylamino)-
1,2-O-isopropylidene-a-D-xylo-hexenofuranoside (4a)
Yield: 67%; syrup; eluent, PE–EtOAc (19:1); [a]D25 +32.4 (c 0.68,
CHCl3).
1H NMR: d = 1.14 (s, 3 H), 1.43 (s, 3 H), 2.46 (s, 3 H), 4.38 (d, 1 H,
J = 4.5 Hz), 4.53 (d, 1 H, J = 18.5 Hz), 4.56 (d, 1 H, J = 4.4 Hz),
4.65–4.71 (m, 2 H), 4.94 (d, 1 H, J = 10.7 Hz), 5.05–5.16 (m, 1 H),
5.33 (d, 1 H, J = 3.4 Hz), 5.34 (d, 1 H, J = 17.1 Hz), 7.14 (t, 1 H,
J = 7.5 Hz), 7.32–7.37 (m, 3 H), 7.52 (d, 1 H, J = 7.8 Hz), 7.69 (d,
1 H, J = 7.7 Hz), 7.72–7.77 (m, 2 H).
13C NMR: d = 22.0 (CH3), 26.2 (CH3), 26.9 (CH3), 51.0 (CH2), 66.0
(CH), 84.5 (CH), 104.2 (CH), 111.7 (C), 118.9 (CH2), 122.8 (C),
127.8 (C), 128.0 (3 × CH), 128.1 (CH), 129.3 (CH), 129.8 (CH),
130.2 (CH), 130.9 (CH), 133.1 (CH), 136.9 (C), 137.6 (C), 144.4
(C).
MS (ESI+): m/z = 508, 510 (M + Na+ for 79Br, 81Br).
Anal. Calcd for C21H28BrNO7: C, 51.86; H, 5.80; N, 2.88. Found: C,
51.62; H, 5.97; N, 2.76.
3-Deoxy-3-(2-bromo-5-methoxybenzylmethoxycarbonylami-
no)-1,2:5,6-di-O-isopropylidene-a-D-glucofuranoside (3b)
25
Yield: 78%; syrup; eluent, PE–EtOAc (7:1); [a]D +5.95 (c 3.46,
CHCl3).
IR (neat): 1711 cm–1.
1H NMR: d = 1.28 (s, 3 H), 1.38 (s, 3 H), 1.44 (s, 3 H), 1.46 (s, 3 H),
3.71 (s, 3 H), 3.80 (s, 3 H), 3.95–4.25 (br, 5 H), 4.50 (d, 1 H,
J = 16.5 Hz), 4.82 (d, 1 H, J = 16.3 Hz), 5.1 (br s, 1 H), 6.1 (br s, 1
H), 6.71 (dd, 1 H, J = 8.6, 2.4 Hz), 6.78 (d, 1 H, J = 2.4 Hz), 7.44
(d, 1 H, J = 8.6 Hz).
MS (ESI+): m/z = 530, 532 (M + Na+ 79Br, 81Br).
MS (ESI+): m/z = 538, 540 (M + Na+ for 79Br, 81Br).
Synthesis 2005, No. 14, 2307–2314 © Thieme Stuttgart · New York

PAPER
Benzazepine Analogues from D-Glucose: Fused Furobenzazepine Derivatives
2311
Anal. Calcd for C23H26BrNO5S: C, 54.33; H, 5.15; N, 2.75. Found:
C, 54.12; H, 4.97; N, 2.86.
3,5,6-Trideoxy-3-(2-bromo-4,5-methylenedioxybenzylmethoxy-
carbonylamino)-1,2-O-isopropylidene-a-D-xylo-hexenofurano-
side (5c)
3,5,6-Trideoxy-3-(2-bromo-5-methoxybenzyl-para-toluene-
sulfonylamino)-1,2-O-isopropylidene-a-D-xylo-hexenofurano-
side (4b)
Yield: 53%; syrup; eluent, PE–EtOAc (5:1); [a]D +19.4 (c 0.56,
CHCl3).
1H NMR: d = 1.17 (s, 3 H), 1.48 (s, 3 H), 2.45 (s, 3 H), 3.79 (s, 3 H),
4.39 (d, 1 H, J = 4.6 Hz), 4.47 (d, 1 H, J = 17.8 Hz), 4.59–4.65 (m,
3 H), 4.97 (d, 1 H, J = 10.6 Hz), 5.11–5.22 (m, 1 H), 5.35 (d, 1 H,
J = 17.2 Hz), 5.43 (d, 1 H, J = 3.6 Hz), 6.70 (dd, 1 H, J = 3, 6.3 Hz),
7.22 (d, 1 H, J = 2.9 Hz), 7.31–7.39 (m, 3 H), 7.75 (d, 2 H, J = 8.1
Hz).
13C NMR: d = 21.9 (CH3), 26.3 (CH3), 26.9 (CH3), 51.1 (CH2), 55.9
(CH3), 66.3 (CH), 80.1 (CH), 84.5 (CH), 104.3 (CH), 111.7 (C),
113.0 (CH2), 115.3 (CH), 115.6 (CH), 118.9 (CH2), 128.0 (2 CH),
130.1 (2 CH), 131.1 (CH), 133.6 (CH), 137.6 (C), 138.0 (C), 144.3
(C), 159.4 (C).
Yield: 55%; foam; eluent, PE–EtOAc (19:1); [a]D25 +22.11 (c 2.17,
CHCl3).
IR (neat): 1708 cm–1.
1H NMR: d = 1.24 (s, 3 H), 1.49 (s, 3 H), 3.71 (s, 3 H), 4.33–4.70
(br, 4 H), 4.87 (t, 1 H, J = 4.8 Hz), 5.32 (d, 1 H, J = 10.6 Hz), 5.51
(d, 1 H, J = 17.2 Hz), 5.78–6.00 (br, 4 H), 6.71 (s, 1 H), 6.99 (s, 1
H).
13C NMR: d = 25.9 (CH3), 26.5 (CH3), 50.6 (CH2), 53.0 (CH), 65.7
(CH3), 81.1 (CH), 83.6 (CH), 101.7 (CH2), 104.9 (CH), 107.5 (CH),
110.8 (C), 112.1 (C), 112.6 (CH), 118.5 (CH2), 129.9 (C), 131.5
(CH), 147.3 (C), 147.6 (C), 156.8 (C).
25
MS (ESI+): m/z = 478, 480 (M + Na+ for 79Br, 81Br).
Anal. Calcd for C19H22BrNO7: C, 50.01; H, 4.86; N, 3.07. Found: C,
49.84; H, 4.95; N, 3.12.
MS (ESI+): m/z = 560, 562 (M + Na+ for 79Br, 81Br).
3,5,6-Trideoxy-3-(2-bromobenzyl-para-toluenesulfonylamino)-
1,2-O-isopropylidene-a-D-ribo-hexenofuranoside (8)
Yield: 53%; viscous oil; eluent, PE–EtOAc (19:1); [a]D25 –16.2 (c
1.28, CHCl3).
Anal. Calcd for C24H28BrNO6S: C, 53.53; H, 5.24; N, 2.60. Found:
C, 53.36; H, 5.11; N, 2.45.
IR (neat): 1604, 1707 cm–1.
3,5,6-Trideoxy-3-(2-bromobenzylmethoxycarbonylamino)-1,2-
O-isopropylidene-a-D-xylo-hexenofuranoside (5a)
Yield: 70%; foam; eluent, PE–EtOAc (19:1); [a]D25 +25.68 (c 1.16,
CHCl3).
1H NMR: d = 1.10 (s, 3 H), 1.42 (s, 3 H), 2.46 (s, 3 H), 3.92 (dd, 1
H, J = 4.2, 9.8 Hz), 4.28–4.34 (m, 2 H), 4.70 (d, 1 H, J = 17.8 Hz),
4.93 (d, 1 H, J = 17.3 Hz), 5.00 (d, 1 H, J = 10.2 Hz), 5.11 (d, 1 H,
J = 17.9 Hz), 5.37–5.49 (m, 1 H), 5.63 (d, 1 H, J = 3.6 Hz), 7.09 (d,
1 H, J = 9 Hz), 7.25–7.30 (m, 1 H), 7.34 (d, 2 H, J = 8.1 Hz), 7.48
(d, 1 H, J = 9 Hz), 7.68 (d, 1 H, J = 7.7 Hz), 7.80 (d, 2 H, J = 8.4
Hz).
13C NMR: d = 21.9 (CH3), 26.1 (CH3), 26.8 (CH3), 50.6 (CH2), 63.7
(CH), 76.8 (CH), 79.3 (CH), 103.8 (CH), 113.0 (C), 121.0 (CH2),
122.1 (C), 127.5 (CH), 128.0 (2 CH), 129.0 (CH), 130.1 (CH),
131.1 (CH), 132.4 (CH), 133.7 (2 CH), 137.4 (C), 137.6 (C), 144.4
(C).
IR (neat): 1597, 1709 cm–1.
1H NMR: d = 1.21 (s, 3 H), 1.48 (s, 3 H), 3.69 (s, 3 H), 4.41–4.72
(br, 4 H), 4.87 (t, 1 H, J = 5.1 Hz), 5.34 (d, 1 H, J = 10.6 Hz), 5.53
(d, 1 H, J = 17.2 Hz), 5.88 (br, 2 H), 7.14 (t, 1 H, J = 7.4 Hz), 7.20
(d, 1 H, J = 7.4 Hz), 7.33 (t, 1 H, J = 7.4 Hz), 7.55 (d, 1 H, J = 7.9
Hz).
13C NMR: d = 26.4 (CH3), 27.1 (CH3), 51.3 (CH2), 53.5 (CH), 66.3
(CH3), 81.6 (CH), 84.1 (CH), 105.4 (CH), 111.4 (C), 119.1 (CH2),
122.5 (C), 127.7 (CH), 128.0 (CH), 129.0 (CH), 132.0 (CH), 133.2
(CH), 137.1 (C), 157.4 (C).
MS (ESI+): m/z = 530, 532 (M + Na+ for 79Br, 81Br).
MS (ESI+): m/z = 434, 436 (M + Na+ for 79Br, 81Br).
Anal. Calcd for C23H26BrNO5S: C, 54.33; H, 5.15; N, 2.75. Found:
C, 54.25; H, 5.03; N, 2.58.
Anal. Calcd for C18H22BrNO5: C, 52.44; H, 5.38; N, 3.40. Found: C,
52.39; H, 5.25; N, 3.27.
3,5,6-Trideoxy-3-(2-bromobenzylmethoxycarbonylamino)-1,2-
O-isopropylidene-a-D-ribo-hexenofuranoside (10)
Yield: 50%; foam; eluent, PE–EtOAc (19:1); [a]D25 +44.58 (c 1.40,
CHCl3).
3,5,6-Trideoxy-3-(2-bromo-5-methoxybenzylmethoxycarbo-
nylamino)-1,2-O-isopropylidene-a-D-xylo-hexenofuranoside
(5b)
IR (neat): 1613, 1702 cm–1.
Yield: 57%; foam; eluent, PE–EtOAc (9:1); [a]D25 +29.01 (c 1.18,
1H NMR: d = 1.27 (s, 3 H), 1.58 (s, 3 H), 3.72 (s, 3 H), 4.43–4.85
(br, 5 H), 4.93 (d, 1 H, J = 16.8 Hz), 5.03 (d, 1 H, J = 10.0 Hz), 5.55
(br, 1 H), 5.79 (d, 1 H, J = 3.5 Hz), 7.15 (m, 3 H), 7.50 (d, 1 H,
J = 7.7 Hz).
13C NMR: d = 26.4 (CH3), 26.9 (CH3), 49.6 (CH2), 53.6 (CH), 62.8
(CH3), 77.8 (CH), 79.7 (CH), 104.0 (CH), 112.9 (C), 120.5 (CH2),
122.3 (C), 127.3 (CH), 128.6 (CH), 128.7 (CH), 132.6 (CH), 134.5
(CH), 138.0 (C), 155.0 (C).
CHCl3).
IR (neat): 1601, 1706 cm–1.
1H NMR: d = 1.22 (s, 3 H), 1.49 (s, 3 H), 3.70 (s, 3 H), 3.79 (s, 3 H),
4.37–4.73 (br, 4 H), 4.87 (t, 1 H, J = 5.1 Hz), 5.33 (d, 1 H, J = 10.6
Hz), 5.52 (d, 1 H, J = 17.2 Hz), 5.84–5.91 (br, 2 H), 6.70 (dd, 1 H,
J = 8.6, 2.8 Hz), 6.75 (s, 1 H), 7.43 (d, 1 H, J = 8.6 Hz).
13C NMR: d = 26.0 (CH3), 26.7 (CH3), 51.0 (CH2), 53.2 (CH), 55.4
(CH3), 66.0 (CH3), 81.1 (CH), 83.8 (CH), 105.0 (CH), 111.0 (C),
112.3 (C), 113.6 (CH), 118.8 (CH2), 131.6 (2 CH), 133.4 (CH),
137.9 (C), 157.0 (C), 159.2 (C).
MS (ESI+): m/z = 434, 436 (M + Na+ for 79Br, 81Br).
Anal. Calcd for C18H22BrNO5: C, 52.44; H, 5.38; N, 3.40. Found: C,
52.31; H, 5.26; N, 3.44.
MS (ESI+): m/z = 464, 466 (M + Na+ for 79Br, 81Br).
Anal. Calcd for C19H24BrNO6: C, 51.59; H, 5.47; N, 3.17. Found: C,
51.42; H, 5.31; N, 3.04.
Heck Cyclization; General Procedure
A mixture of the olefin 4a,b, 5a–c, 8 or 10 (0.2 mmol), K2CO3 (1.2
mmol), Bu4NBr (0.2 mmol), and Pd(OAc)2 in DMF (20 mL) was
heated at 100 °C under an argon atmosphere for 12 h. After comple-
tion of the reaction, as indicated by TLC, the mixture was diluted
with H2O (50 mL) and extracted with CH2Cl2. The combined organ-
Synthesis 2005, No. 14, 2307–2314 © Thieme Stuttgart · New York

2312
T. P. Majhi et al.
PAPER
ic extract was washed successively with brine and H2O, dried
(Na2SO4) and concentrated. The residual DMF was removed under
reduced pressure to give a syrupy liquid, which, after chromato-
graphic separation (silica gel; PS–EtOAc), afforded a residue. This
was crystallized from Et2O–PE (40–60 °C) to give the desired cy-
clized product in some cases.
(128.6) (CH), 130.3 (130.5) (C) 135.9 (136.1) (CH), 135.9 (136.1)
(C), 144.2 (144.5) (C), 156.4 (156.9) (C).
MS (ESI+): m/z = 354 (M + Na+).
Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 3.23; Found: C,
65.16; H, 6.46; N, 3.11.
(2R,3R,3aS,10aR)-7-Methoxy-10-methylene-2,3-isopropy-
lidenedioxy-3,3a,5,10a-tetrahydro-2H-furo[3,2-c][2]benz-
azepine-4-carboxylic Acid Methyl Ester (12b)18
(2R,3R,3aS,10aR)-10-Methylene-2,3-isopropylidenedioxy-4-
(toluene-4-sulfonyl)-3,3a,5,10a-tetrahydro-2H-furo[3,2-
c][2]benzazepine (11a)
White crystalline solid; mp 177–178 °C; [a]D +31.1 (c 1.15,
CHCl3).
White crystalline solid; mp 172 °C; [a]D29 +138 (c 0.9, CHCl3).
25
IR (KBr): 1609, 1705 cm–1.
1H NMR: d = 1.30 (s, 3 H, CH3), 1.54 (s, 3 H, CH3), 2.34 (s, 3 H,
CH3), 4.07 (1 H, d, J = 17.6 Hz, Ha of ArCH2), 4.51 (1 H, d,
J3a,10a = 5.4 Hz, H-3a), 4.62 (d, 1 H, J2,3 = 3.8 Hz, H-3), 4.83 (s, 1 H,
Ha of =CH2), 5.02 (s, 1 H, Hb of =CH2), 5.05 (d, 1 H, J = 17.6 Hz,
Hb of ArCH2), 5.07 (d, 1 H, J3a,10a = 5.4 Hz, H-10a), 5.91 (d, 1 H,
1H NMR (500 MHz, CDCl3): d = 1.32 (1.33) (s, 3 H, CH3), 1.56 (s,
3 H, CH3), 3.61 (3.67) (s, 3 H, CO2CH3), 3.78 (3.80) (s, 3 H, OCH3),
3.89 (3.95) (d, 1 H, J = 17 Hz, Ha of ArCH2), 4.69 (4.70) (d, 1 H,
J2,3 = 4 Hz, H-3), 4.77 (4.97) (d, 1 H, J = 17 Hz, Hb of ArCH2), 4.81
(4.99) (d, 1 H, J3a, 10a = 5 Hz, H-3a), 5.17 (5.20) (d, 1 H, J3a,10a = 5
Hz, H-10a), 5.25 (s, 1 H, Ha of =CH2), 5.29 (s, 1 H, Hb of =CH2),
5.99 (br s, 1 H, H-2), 6.61 (6.68) (s, 1 H), 6.77 (m, 1 H), 7.32 (m, 1
H).
13C NMR: d = 26.3 (CH3), 27.0 (CH3), 49.7 (CH2), 53.6 (CO2CH3),
55.7 (OCH3), 65.5 (65.8) (CH), 84.8 (85.0) (CH), 85.4 (CH), 105.8
(CH), 111.6 (C), 112.9 (113.6) (2 CH), 116.6 (117.1) (=CH2), 128.2
(128.7) (C), 131.6 (131.8) (CH), 137.4 (137.7) (C), 143.6 (143.8)
(C), 156.4 (156.8) (C), 159.7 (159.9) (C).
J2,3 = 3.8 Hz, H-2), 7.04 (d, 2 H, J = 8.1 Hz), 7.09 (br d, 1 H), 7.23
(m, 3 H), 7.42 (d, 2 H, J = 8.1 Hz, H of Ts).
13C NMR: d = 21.8 (CH3), 26.2 (CH3), 26.8 (CH3), 50.1 (CH2), 67.1
(CH), 84.2 (CH), 85.4 (CH), 105.5 (CH), 111.8 (C), 118.4 (=CH2),
127.4 (CH), 127.7 (2 CH), 128.1 (CH), 128.5 (CH), 129.5 (2 CH),
130.0 (CH), 134.9 (C), 135.8 (C), 137.6 (C), 143.4 (C), 143.5 (C).
MS (ESI+): m/z = 450 (M + Na+).
Anal. Calcd for C23H25NO5S: C, 64.62; H, 5.89; N, 3.28. Found: C,
64.47; H, 5.68; N, 3.15.
MS (ESI+): m/z = 384 (M + Na+).
Anal. Calcd for C19H23NO6: C, 63.15; H, 6.41; N, 3.88. Found: C,
63.06; H, 6.27; N, 3.63.
(2R,3R,3aS,10aR)-7-Methoxy-10-methylene-2,3-isopropy-
lidenedioxy-4-(toluene-4-sulfonyl)-3,3a,5,10a-tetrahydro-2H-
furo[3,2-c][2]benzazepine (11b)
(2R,3R,3aS,10aR)-10-Methylene-7,8-methylenedioxy-2,3-isopro-
pylidenedioxy-3,3a,5,10a-tetrahydro-2H-furo[3,2-c][2]benz-
azepine-4-carboxylic Acid Methyl Ester (12c)18
White crystalline solid; mp 72 °C; [a]D25 +85.3 (c 1.08, CHCl3).
1H NMR: d = 1.30 (s, 3 H, CH3), 1.54 (s, 3 H, CH3), 2.34 (s, 3 H,
CH3), 3.81 (s, 3 H, OCH3), 4.06 (d, 1 H, J = 17.6 Hz, Ha of ArCH2),
4.48 (d with fine splitting, 1 H, J3a,10a = 5.3 Hz, H-3a), 4.63 (d, 1 H,
White crystalline solid; mp 177 °C; [a]D29 +92 (c 1.18, CHCl3).
IR (KBr): 1625, 1704 cm–1.
J
2,3 = 3.8 Hz, H-3), 4.73 (s, 1 H, Ha of =CH2), 4.92 (s, 1 H, Hb
1H NMR: d = 1.33 (s, 3 H, CH3), 1.57 (s, 3 H, CH3), 3.62 (3.66) (s,
3 H, CO2CH3), 3.83 (3.89) (d, 1 H, J = 17 Hz, Ha of ArCH2), 4.69
(d, 1 H, J2, 3 = 3.6 Hz, H-3), 4.73–4.79 (4.92–4.97) (m, 2 H, over-
lapped signals by H-3a and Hb of ArCH2), 5.18 (m, 1 H, H-10a),
5.30 (br s, 2 H, =CH2), 5.92 (s, 2 H, OCH2O), 6.00 (br s, 1 H, H-2),
6.55 (6.63) (s, 1 H), 6.86 (s, 1 H).
13C NMR: d = 25.8 (CH3), 26.5 (CH3), 48.9 (CH2), 53.1 (CO2CH3),
65.0 (65.2) (CH), 84.2 (84.4) (CH), 84.8 (CH), 101.2 (CH2), 105.3
(CH), 106.9 (107.4) (CH), 109.8 (110.0) (CH), 111.2 (C), 116.8
(117.3) (=CH2), 128.7 (129.1) (C), 129.6 (129.7) (C), 143.4 (143.6)
(C), 146.9 (C), 147.4 (C), 155.9 (156.3) (C).
of =CH2), 5.00 (d, 1 H, J = 17.6 Hz, Hb of ArCH2), 5.01 (d, 1 H,
J3a,10a = 5.3 Hz, H-10a), 5.92 (d, 1 H, J2,3 = 3.8 Hz, H-2), 6.62 (d, 1
H, J = 2.7 Hz), 6.74 (dd, 1 H, J = 2.5, 8.5 Hz), 7.05 (d, 2 H, J = 8
Hz, H of Ts), 7.15 (d, 1 H, J = 8.5 Hz), 7.43 (d, 2 H, J = 8 Hz, H of
Ts).
13C NMR: d = 21.8 (CH3), 26.2 (CH3), 26.8 (CH3), 50.1 (CH2), 55.7
(OCH3), 67.0 (CH), 84.2 (CH), 85.5 (CH), 105.4 (CH), 111.7 (C),
112.6 (CH), 113.7 (CH), 116.9 (=CH2), 127.7 (2 CH), 128.4 (C),
129.4 (2 CH), 131.4 (CH), 136.3 (C), 137.5 (C), 142.8 (C), 143.6
(C), 159.8 (C).
MS (EI): m/z = 457 (M+, 90%).
MS (ESI+): m/z = 398 (M + Na+).
Anal. Calcd for C24H27NO6S: C, 63.00; H, 5.95; N, 3.06. Found: C,
62.85; H, 5.78; N, 2.92.
Anal. Calcd for C19H21NO7: C, 60.79; H, 5.64; N, 3.73. Found: C,
60.51; H, 5.51; N, 3.55.
(2R,3R,3aS,10aR)-10-Methylene-2,3-isopropylidenedioxy-
3,3a,5,10a-tetrahydro-2H-furo[3,2-c][2]benzazepine-4-carbox-
ylic Acid Methyl Ester (12a)18
(2R,3R,3aR,10aR)-10-Methylene-2,3-isopropylidenedioxy-4-
(toluene-4-sulfonyl)-3,3a,5,10a-tetrahydro-2H-furo[3,2-
c][2]benzazepine (13)
White crystalline solid; mp 169–170 °C; [a]D –66.5 (c 1.31,
CHCl3).
Viscous liquid; [a]D29 +124.6 (c 0.5, CHCl3).
25
IR (neat): 1630, 1707 cm–1.
1H NMR: d = 1.33 (s, 3 H, CH3), 1.57 (s, 3 H, CH3), 3.60 (3.67) (s,
3 H, CO2CH3), 3.91 (3.97) (d, 1 H, J = 17 Hz, Ha of ArCH2), 4.71
(d, 1 H, J2,3 = 4 Hz, H-3), 4.81–4.86 (5.00–5.06) (m, 2 H, over-
lapped signals H-3a and Hb of ArCH2), 5.21 (5.24) (d, 1 H,
1H NMR: d = 1.38 (s, 3 H, CH3), 1.55 (s, 3 H, CH3), 2.26 (s, 3 H,
CH3), 3.44 (dd, 1 H, J3,3a = 3.6 Hz, J3a,10a = 10 Hz, H-3a), 4.84–4.94
(unresolved, 3 H, H-3 and Ha, Hb of ArCH2), 4.95 (d, 1 H,
J3a,10a = 10 Hz, H-10a), 5.15 (s, 1 H, Ha of =CH2), 5.33 (s, 1 H, Hb
of =CH2), 5.94 (d, 1 H, J2,3 = 3.6 Hz, H-2), 6.88 (d, 2 H, J = 8 Hz,
H of Ts), 7.10–7.38 (m, 6 H, overlapping aromatic protons).
J
3a,10a = 5 Hz, H-10a), 5.34 (s, 1 H, Ha of =CH2), 5.38 (s, 1 H, Hb
of =CH2), 5.99 (d, 1 H, J2,3 = 4 Hz, H-2), 7.07–7.38 (m, 4 H).
13C NMR: d = 26.3 (CH3), 27.0 (CH3), 49.6 (CH2), 53.6 (CO2CH3),
65.6 (65.8) (CH), 84.7 (84.9) (CH), 85.4 (CH), 105.8 (CH), 111.7
(C), 118.0 (118.5) (=CH2), 127.2 (127.7) (CH), 127.9 (CH), 128.3
13C NMR: d = 21.7 (CH3), 26.5 (CH3), 26.7 (CH3), 52.5 (CH2), 67.0
(CH), 75.8 (CH), 80.9 (CH), 105.1 (CH), 110.4 (=CH2), 113.2 (C),
Synthesis 2005, No. 14, 2307–2314 © Thieme Stuttgart · New York

PAPER
Benzazepine Analogues from D-Glucose: Fused Furobenzazepine Derivatives
2313
127.4 (CH), 127.9 (2 CH), 128.3 (CH), 128.4 (CH), 129.1 (2 CH),
130.6 (CH), 134.4 (C), 135.5 (C), 135.8 (C), 143.4 (C), 143.7 (C).
MS (ESI+): m/z = 450 (M + Na+).
IR (neat): 1630, 1705, 1744 cm–1.
1H NMR: d = 1.98 (2.02) (s, 3 H, OCOCH3), 2.08 (2.09) (s, 3 H,
OCOCH3), 3.64 (3.66) (s, 3 H, CO2CH3), 4.25–4.45 (m, 3 H), 4.61–
4.85 (m, 2 H), 5.38 (s, 1 H, Ha of =CH2), 5.41 (5.43) (s, 1 H, Hb
of =CH2), 5.48 (5.53) (d, 1 H, J = 7.0 Hz), 7.21–7.32 (br s, 4 H).
Anal. Calcd for C23H25NO5S: C, 64.62; H, 5.89; N, 3.28. Found: C,
64.75; H, 5.77; N, 3.14.
13C NMR: d = 20.7 (20.8) (CH3), 20.8 (20.9) (CH3), 46.7 (46.8)
(CH2), 52.9 (53.0) (CH3), 57.3 (57.4) (CH), 61.7 (61.9) (CH2), 72.5
(73.0) (CH), 115.7 (116.2) (CH2), 126.7 (CH), 127.7 (127.9) (CH),
128.0 (128.2) (CH), 128.8 (128.9) (CH), 135.0 (135.3) (C), 135.6
(C), 137.6 (137.7) (C), 145.5 (145.6) (C), 169.5 (169.6) (C), 170.7
(C).
(2R,3R,3aR,10aR)-10-Methylene-2,3-isopropylidenedioxy-
3,3a,5,10a-tetrahydro-2H-furo[3,2-c][2]benzazepine-4-carbox-
ylic Acid Methyl Ester (14)18
Viscous oil; eluent, PE–EtOAc (9:1); [a]D29 +43 (c 0.9, CHCl3).
IR (neat): 1602, 1701 cm–1.
MS (ESI+): m/z = 370 (M + Na+).
1H NMR: d = 1.37 (1.43) (s, 3 H, CH3), 1.57 (s, 3 H, CH3), 3.71
(3.73) (s, 3 H, CO2CH3), 4.55 (4.61) (d, 1 H, J = 16 Hz, Ha of
ArCH2), 4.86–5.03 (m, 3 H, overlapped signals of H-3, H-3a, Hb of
ArCH2), 5.18 (d, 1 H, J3a, 10 = 10 Hz, H-10a), 5.60 (s, 1 H, Ha
of =CH2), 5.68 (s, 1 H, Hb of =CH2), 5.98 (d, 1 H, J2, 3 = 4 Hz, H-2),
7.18–7.36 (m, 3 H), 7.72 (d, 1 H, J = 7 Hz).
Anal. Calcd for C18H21NO6: C, 62.24; H, 6.09; N, 4.03. Found: C,
62.08; H, 5.91; N, 4.11.
Acknowledgment
13C NMR: d = 26.1 (CH3), 26.3 (CH3), 49.6 (50.2) (CH2), 52.9
(53.0) (CO2CH3), 61.3 (65.5) (CH), 75.5 (CH), 79.2 (79.7) (CH),
103.6 (104.6) (C), 110.5 (=CH2), 112.1 (112.4) (C), 127.1 (127.2)
(CH), 128.0 (128.2) (CH), 128.8 (130.1) (CH), 130.1 (131.3) (CH),
134.4 (135.3) (C), 143.9 (C), 156.1 (C), 157.3 (C).
We are grateful to Prof. U. R. Ghatak and Dr. B. Achari of our De-
partment for suggestions and valuable advice regarding NMR ana-
lyses, and to CSIR for the award of Research Fellowships (T. M.
and A. N.)
MS (ESI+): m/z = 354 (M + Na+).
References
Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 3.23. Found: C,
65.01; H, 6.52; N, 3.10.
(1) (a) Fuller, R. W.; Molloy, B. B.; Henrick, S. K. Biochem.
Pharmacol. 1979, 28, 528. (b) Trybulski, E. J.; Benjamine,
L.; Vitone, S.; Walser, A.; Fryer, R. I. J. Med. Chem. 1983,
26, 367. (c) Trybulski, E. J.; Reeder, E.; Fryer, R. I.; Walser,
A.; Blount, J. J. Med. Chem. 1983, 26, 1596.
2-Benzazepines 15 and 16
Compound 12a or 14 (1 mmol) was dissolved in MeCN–H2O (1:1)
containing aq H2SO4 (5%) and kept at r.t. for 24 h. The acidic solu-
tion was neutralized with solid NaHCO3, filtered, and the filtrate
was evaporated under vacuum. The residue was dissolved in MeOH
(20 mL) and treated dropwise at 0 °C with aq NaIO4 (25 mL, 1.2
mmol) with stirring for 1 h. Usual work up followed by NaBH4 re-
duction in MeOH afforded the diol. This was acetylated with Ac2O
(0.5 mL) and pyridine (2 mL) at r.t. for 12 h to furnish a crude prod-
uct, purified by flash chromatography (silica gel; EtOAc–PE, 1:9)
to afford 15 or 16.
(d) Grunewald, G. L.; Dahanukar, V. H.; Ching, P.;
Criscione, K. R. J. Med. Chem. 1996, 39, 3539.
(e) Varlamov, A.; Kouznetsov, V.; Zuvkov, F.; Chernyshev,
A.; Alexandrov, G.; Palma, A.; Vargas, L.; Salas, S.
Synthesis 2001, 849.
(2) Miller, W. H.; Alberts, D. P.; Bhatnagar, P. K.; Bondinell,
W. E.; Callahan, J. F.; Calvo, R. R.; Cousins, R. D.; Erhard,
K. F.; Herding, D. A.; Keenan, R. M.; Kwon, C.; Manley, P.
J.; Newlander, K. A.; Ross, S. T.; Samanen, J. M.; Uzinskas,
I. N.; Venslavsky, J. W.; Yuan, C. C.-K.; Haltiwanger, R. C.;
Gowen, M.; Hwang, S.-M.; James, I. E.; Lark, M. W.;
Rieman, D. J.; Stroup, G. B.; Azzarano, L. M.; Salyers, K.
L.; Smith, B. R.; Ward, K. W.; Johanson, K. O.; Huffman,
W. F. J. Med. Chem. 2000, 43, 22.
(3R,4S)-4-Acetoxy-3-acetoxymethyl-5-methylene-1,3,4,5-tet-
rahydro-2-benzazepine-2-carboxylic Acid Methyl Ester (15)18
Yield: 50%; viscous oil; [a]D24.5 +32 (c 2.67, CHCl3).
IR (neat): 1630, 1706, 1744 cm–1.
1H NMR: d = 1.85 (1.87) (s, 3 H, OCOCH3), 2.07 (s, 3 H,
OCOCH3), 3.60 (3.65) (s, 3 H, CO2CH3), 4.26 (m, 1 H), 4.39 (m, 1
H), 4.50 (d, 1 H, J = 16.2 Hz), 4.70 (d, 1 H, J = 17 Hz, Ha of
ArCH2), 4.87 (d, 1 H, J = 17 Hz, Hb of ArCH2), 5.37 (s, 1 H, Ha
of =CH2), 5.38 (s, 1 H, Hb of =CH2), 5.78 (5.83) (d, 1 H, J = 5.1 Hz),
7.13–7.35 (br s, 4 H).
13C NMR: d = 20.7 (2 CH3), 47.1 (CH2), 53.0 (53.1) (CH3), 57.2
(57.4) (CH), 59.7 (59.8) (CH2), 75.8 (76.0) (CH), 115.9 (116.3)
(CH2), 127.1 (127.4) (CH), 127.6 (127.9) (CH), 128.2 (CH), 129.5
(129.7) (CH), 136.4 (136.7) (C), 144.8 (145.1) (C), 156.7 (2 C),
169.2 (169.3) (C), 170.8 (C).
(3) (a) Kasparek, S. Advances in Heterocyclic Chemistry, Vol.
17; Katritzky, A. R.; Boulton, A. J., Eds.; Academic Press:
New York, 1974, 49. (b) Grunewald, G. L.; Dahanukar, V.
H. J. Heterocycl. Chem. 1994, 31, 1609. (c) Miller, W. H.;
Newlander, K. A.; Eggleston, D. S.; Haltiwanger, R. C.
Tetrahedron Lett. 1995, 36, 373. (d) For known routes to 2-
benzazepine synthesis, see: Katritzky, A. R.; Maimait, R.;
Xu, Y.-J.; Akhmedova, R. G. Synthesis 2002, 601; and
references cited therein.
(4) For recent reviews on the synthesis of 2-benzazepine
derivatives, see: (a) Kouznetsov, V.; Palma, A.; Ewert, C.
Curr. Org. Chem. 2001, 5, 519. (b) Katritzky, A. R.;
Akhmedov, N. G.; Ghiviriga, I.; Maimait, R. J. Chem. Soc.,
Perkin. Trans. 2 2002, 1986; and references cited therein.
(c) Ek, F.; Wistrand, L.-G.; Frejd, T. J. Org. Chem. 2003, 68,
1911.
MS (ESI+): m/z = 370 (M + Na+).
Anal. Calcd for C18H21NO6: C, 62.24; H, 6.09; N, 4.03. Found: C,
62.13; H, 5.21; N, 4.16.
(5) Van Otterlo, W. A. L.; Pathak, R.; de Koning, C. B. Synlett
2003, 1859.
(6) Kamimura, A.; Taguchi, Y.; Omato, Y.; Hagihara, M. J.
Org. Chem. 2003, 68, 4996.
(3S,4S)-4-Acetoxy-3-acetoxymethyl-5-methylene-1,3,4,5-tet-
rahydro-2-benzazepine-2-carboxylic Acid Methyl Ester (16)18
Yield: 50%; viscous oil; eluent, PE–EtOAc (9:1); [a]D24.5 +5.96 (c
1.05, CHCl3).
Synthesis 2005, No. 14, 2307–2314 © Thieme Stuttgart · New York

2314
T. P. Majhi et al.
PAPER
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Synthesis 2005, No. 14, 2307–2314 © Thieme Stuttgart · New York