Palladium-catalyzed intramolecular aryl amination reaction: An expeditious approach to the synthesis of chiral benzodiazocine derivatives

Article abstract of DOI:10.1002/ejoc.200901472

A palladium-catalyzed method for intramolecular amination of aryl bromides and iodides has been developed employing different bulky biaryl phosphanes as ligands and toluene as solvent. A variety of electron-rich aryl halide substrates have been aminated b

Full text of DOI:10.1002/ejoc.200901472

FULL PAPER
DOI: 10.1002/ejoc.200901472
Palladium-Catalyzed Intramolecular Aryl Amination Reaction: An Expeditious
Approach to the Synthesis of Chiral Benzodiazocine Derivatives
Nirmal Das Adhikary[a] and Partha Chattopadhyay*[a]
Keywords: Palladium / Catalysts / Ligands / Amination / Diazocine
A palladium-catalyzed method for intramolecular amination
of aryl bromides and iodides has been developed employing
different bulky biaryl phosphanes as ligands and toluene as
solvent. A variety of electron-rich aryl halide substrates have
been aminated by the intramolecular pathway in good yield
using different sugar-derived amines as well as benzylamine.
The method is capable of furnishing benzodiazocines in chi-
ral form besides dibenzodiazocine derivatives of potential
biological interest.
benzofused five, six and seven membered heterocycles,[11]
though only a few approaches have been made to synthesize
benzofused eight membered heterocycles.[12] In continua-
tion of our research activities related to the synthesis of
benzannulated medium-ring heterocycles by C–N/C–O
bond formation[12b,13] we therefore felt that an intramolecu-
lar cycloamination strategy leading to the formation of
highly functionalized benzodiazocine derivatives offers a
solution to this problem. Applied to chiral furanose deriva-
tives, the strategy could furnish chiral products, while exten-
sion to synthesize dibenzodiazocine derivatives was attract-
ive as these serve as precursors of different Tröger’s
bases.[14]
In this paper, we report an intramolecular aryl amination
strategy which, when applied to -glucose-derived sugar
amines, furnished chiral tricyclic furo-benzodiazocine deriv-
atives. Cleavage of the sugar ring of one of these tricyclic
derivatives provided an optically active, functionalized
benzodiazocine. The strategy has also been extended to syn-
thesize a dibenzodiazocine derivative.
Introduction
Heterocyclic compounds attract attention for many
reasons including their biological activities. Benzo-fused cy-
clic molecules incorporating nitrogen atom in the structure
are often referred to as “privileged structures” owing to
their capability of binding to multiple receptors with high
affinity.[1] Benzodiazocines, containing two nitrogen atoms,
exhibit important pharmacological properties.[2] For exam-
ple, 9-decyl benzolactam-V8 is known to be a potent PKC
activator similar to the teleocidines[3] and buflavine has
been shown to possess interesting adrenolytic and anti-sero-
tonin activities.[4] Moreover, 1,5-benzodiazocines have at-
tracted much interest as homologues of 1,4-benzodiazepine
drugs.[5] As eight-membered rings are generally more diffi-
cult to prepare due to enthalpic and entropic reasons, and
direct cyclization methods are ineffective unless certain con-
formational constraints are present in the acyclic precur-
sor,[6] only a few synthetic procedures are known for benzo-
diazocines. Most of these are either intermolecular or deal
with achiral substrates.[7] We were encouraged to apply the
palladium catalyzed aromatic carbon–nitrogen bond form-
ing reaction involving the cross coupling of aryl halides (or
triflates, nonaflates, mesitylates) and amines which has re-
cently seen an upsurge in interest as a useful synthetic
tool.[8] Amination of aryl bromides under tin free condi-
tions, initially achieved both by Buchwald[9a] and Hart-
wig[9b] groups, mainly focused on the intermolecular amin-
ation of aryl bromides or iodides to give substituted ani-
lines.[10] However, recently a number of studies have been
reported where an intramolecular version of this aryl
amination chemistry has been utilized for the synthesis of
Results and Discussion
The starting material 1,2:5,6-di-O-isopropylidene gluco-
furanose was converted to amino derivatives 1a and 1b ac-
cording to the reported procedure (Scheme 1).[15] N-Alk-
ylation of the corresponding tosyl amides 2a, 2c and Boc
amide (2b, derived from 1a) with appropriately substituted
2-bromo/iodobenzyl bromides afforded the respective 3-N-
(2-bromobenzyl)tosyl-glucofuranoses 3a–d and 3-N-(2-
bromo/iodobenzyl)-N-tert-butoxycarbonyl-glucofuranoses
3e–f in good yields (Scheme 1; Table 1). Selective removal
of the 5,6-O-isopropylidene moiety from 3a–f was smoothly
effected with 80% aqueous HOAc at 25 °C, and the re-
sulting diol on NaIO4 oxidation, imine formation with ali-
phatic amines, and subsequent NaBH4 reduction in MeOH
[a] Chemistry Division, Indian Institute of Chemical Biology,
4, Raja S. C. Mullick Road, Kolkata 700032, India
Fax: +91-33-24735197
E-mail: partha@iicb.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901472.
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Pd-Catalyzed Intramolecular Aryl Amination Reaction
afforded the desired amines 4a–h in good yields (Scheme 1; Table 1. Preparation of 3a–f.
Table 2). The structures of 4a–h were derived from the spec-
troscopic data and comparison with data for similar com-
pounds prepared by us.[16]
Entry
Substrate R2
R3
X
Product Yield[a] (%)
1
2
3
4
5
6
2a
2a
2a
2c
2b
2b
H
OMe
H
H
Br
Br
Br
Br
Br
I
3a
3b
3c
3d
3e
3f
74
78
68
61
77
74
–O–CH2–O–
H
H
H
H
H
H
[a] Isolated yield.
Table 2. Preparation of sugar amines 4a–h.
Entry
Substrate
R4
C-6 con-
fig.
Product
Yield[a]
(%)
1
2
3
4
5
6
3a
3b
3c
3a
3d
3d
PhCH2–
PhCH2–
PhCH2–
(CH3)2CH–
PhCH2–
S
S
S
S
R
R
4a
4b
4c
4d
4e
4f
70
73
78
72
75
83
7
8
3e
3f
PhCH2–
PhCH2–
S
S
4g
4h
68
78
[a] Isolated yield.
Our initial goal was to explore the synthesis of benzodi-
azocine-annulated furanose derivatives 5 from 4 through
Pd-catalyzed intramolecular cycloamination reactions in
the presence of bases and ligands. For this, we tested the
reagent system [Pd2(dba)3/ϮBINAP/tBuOK + K2CO3] re-
ported by Rogers et al.[11d] on substrate 4a. However, as no
reaction took place (TLC) even after 20 h of heating at
90 °C, the reaction mixture was allowed to reflux gently. To
our satisfaction, the reactant was fully consumed after 17 h
Scheme 1. Synthesis of o-bromo/iodo benzylated sugar amines 4a–
h. Reaction conditions: (i) TsCl, Py, room temp., 16 h (when R1 =
Ts, crude yield 88% for 2a, 85% for 2c) or Boc2O, dry DCM, room
temp., 1 h (when R1 = Boc, crude yield 92% for 2b); (ii) 2-bromo/
iodobenzyl bromide derivative, K2CO3, acetone, room temp., 6 h;
(iii) 80% AcOH (v/v), room temp., overnight; (iv) aq. NaIO4,
MeOH, room temp., 45 min; (v) RNH2, anhydrous CH2Cl2, MS
(4 Å), room temp., 12 h, N2; (vi) NaBH4, dry MeOH, room temp.,
3 h.
Table 3. Optimization of the intramolecular palladium catalyzed cycloamination reactions.
Entry
Substrate
Base
Catalyst
Ligand
Solvent
Product
Yield[a] (%)
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
K2CO3 + tBuOK
tBuONa
Cs2CO3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
ϮBINAP
DPPF
toluene
toluene
toluene
toluene
DMF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
5a
5a
5a
5a
5a
5a
5b
5c
5d
5e
5f
72[b]
62[c]
55[d]
58[e]
32[f]
51[g]
66[b]
68[b]
79[b]
68[b]
71[b]
75[b]
66[e]
ϮBINAP
xantphos
ϮBINAP
ϮBINAP
ϮBINAP
ϮBINAP
ϮBINAP
ϮBINAP
ϮBINAP
ϮBINAP
xantphos
tBuOK
K2CO3 + tBuOK
K2CO3 + tBuOK
K2CO3 + tBuOK
K2CO3 + tBuOK
K2CO3 + tBuOK
K2CO3 + tBuOK
K2CO3 + tBuOK
K2CO3 + tBuOK
tBuOK
9
10
11
12
13
4g
4h
5g
5g
[a] Isolated yield. [b] Reaction conditions: 10 mol-% Pd2(dba)3, 7 mol-% ϮBINAP, 2.0 equiv. K2CO3, 2.0 equiv. tBuOK, toluene (10 L/
mol), reflux (17 h). [c] Reaction conditions: 10 mol-% Pd2(dba)3, 7 mol-% DPPF, 4.0 equiv. tBuONa, toluene (10 L/mol), reflux (17 h).
[d] Reaction conditions: 10 mol-% Pd(OAc)2, 7 mol-% ϮBINAP, 5.0 equiv. Cs2CO3, toluene (10 L/mol), reflux (16 h). [e] Reaction condi-
tions: 10 mol-% Pd2(dba)3, 7 mol-% xantphos, 4.0 equiv. tBuOK, toluene (10 L/mol), reflux (19 h). [f] Reaction conditions: 10 mol-%
Pd2(dba)3, 7 mol-% ϮBINAP, 2.0 equiv. K2CO3, 2.0 equiv. tBuOK, DMF (10 L/mol), 110 °C (15 h). [g] Reaction conditions: 15 mol-%
Pd2(dba)3, 10 mol-% ϮBINAP, 2.0 equiv. K2CO3, 2.0 equiv. tBuOK, toluene (10 L/mol), reflux (18 h).
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N. D. Adhikary, P. Chattopadhyay
FULL PAPER
of reflux. Usual work-up followed by chromatographic pu- of the generated carbonyl group, and acetylation of the re-
rification gave the desired cyclized product 5a in 72% yield sulting diol with acetic anhydride and pyridine furnished
(entry 1, Table 3). The spectroscopic data of 5a was in excel- the benzodiazocine derivative 6 (Scheme 3).
lent agreement with the assigned structure.
We then applied other reported reagent systems[17] in an
effort to improve the yield. Evaluation of these systems
showed that use of DPPF/tBuONa or xantphos/tBuOK was
less effective (entry 2, 4, Table 3). As an alternative palla-
dium source, Pd(OAc)2 also gave the desired cyclized prod-
uct but less efficiently (entry 3, Table 3). The best conditions
for the reaction were Pd2(dba)3 (10 mol-%) as the palladium
source, ϮBINAP (7 mol-%) as the ligand, a combination of
K2CO3 (2.0 equiv.) with tBuOK (2.0 equiv.) as the base, and
Scheme 3. Conversion of 5g to benzodiazocine derivative 6. Reac-
tion conditions: (i) CH3CN/H2O/H2SO4 (18:5:2), room temp., 36 h;
toluene (10 L/mol substrate) as the solvent when the bromo
substrates were used (reactants 4a–g, products 5a–g,
Scheme 2). For the iodo substrate (reactant 4h, product 5g,
Scheme 2) the applied condition was that recommended by
Guari et al.,[17b] i.e, Pd2(dba)3 (10 mol-%) as the palladium
source, xantphos (7 mol-%) as the ligand, tBuOK
(4.0 equiv.) as the base and toluene (10 L/mol substrate) as
the solvent (entry 13, Table 3). The structures of 5a–g were
determined by spectroscopic data and supported by single-
crystal X-ray analysis[18] of 5e (Figure 1).
(ii) aq. NaIO4, MeOH, room temp., 45 min; (iii) NaBH4, MeOH,
room temp., 3 h; (iv) Ac2O, pyridine, room temp., 12 h, overall
yield, 62%.
We next focused our attention on extending our method-
ology to the synthesis of dibenzodiazocine derivatives. For
this, we synthesized compound 7 through a sequence of re-
actions involving thioacetalization of o-nitrobenzaldehyde
using propanedithiol,[19] reduction of the nitro group with
Pd/C and hydrazine hydrate, tosylation of the resulting
amino group and benzylation of the tosyl amide with 2-
bromobenzyl bromide. Compound 7 was converted into the
cyclization substrate 8 by dethioketalization in the presence
of MeI/aq. MeCN,[20] imine formation with benzyl amine
in EtOH, and subsequent NaBH4 reduction. Refluxing of
8 under the standard conditions for bromo derivatives af-
forded the desired cyclized product 9 in 72% yield
(Scheme 4). The spectroscopic data and single-crystal X-ray
analysis[21] (Figure 2) of 9 are in excellent agreement with
the assigned structure. A probable mechanism of intramo-
lecular aryl amination[8a,10d] for the synthesis of benzodi-
azocines and dibenzodiazocines has been outlined
(Scheme 5).
Scheme 2. Synthesis of fused furo-benzodiazocines.
Figure 1. ORTEP diagram of 5e.
As an application of our methodology, the feasibility of
synthesizing chiral functionalized benzodiazocines from the
annulated sugar derivatives thus obtained could be demon-
strated using 5g. Thus, subjecting 5g to a sequence of reac-
tions involving removal of the 1,2-O-isopropylidine group
as well as tert-butoxycarbonyl group with H2SO4 in MeCN/
Scheme 4. Synthesis of dibenzodiazocine derivative. Reaction con-
ditions: (i) 1,3-propanedithiol, I2, dry DCM, 0 °C; (ii) hydrazine
hydrate, Pd/C (10%), EtOH, reflux; (iii) TsCl, Py, room temp., 16 h;
(iv) 2-bromobenzyl bromide, K2CO3, acetone, room temp., 6 h; (v)
CH3I, CH3CN/H2O (90:1), room temp., 24 h; (vi) benzylamine,
EtOH, room temp., 12 h, then NaBH4, 0 °C, 3 h; (vii) Pd2(dba)3
(10 mol-%), ϮBINAP (7 mol-%), K2CO3 + tBuOK (2 equiv. each),
H2O (2:18:5), NaIO4 cleavage of the diol, NaBH4 reduction toluene, reflux.
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Eur. J. Org. Chem. 2010, 1754–1762

Pd-Catalyzed Intramolecular Aryl Amination Reaction
and TMS as internal standard. Mass spectra were obtained using
either JEOL AX-500 or Micromass Q-TofmicroTM spectrometers.
X-ray diffraction data were collected in Bruker Kappa Apex II dif-
fractometer. IR spectra were obtained employing JASCO FT/IR
Model 410. Elemental analyses were carried out with a C,H,N ana-
lyzer. Specific rotations were measured at 589 nm on a JASCO P-
1020 polarimeter. TLC was performed on pre-coated plates
(0.25 mm, silica gel 60F254). Column chromatography and flash
chromatography were carried out using commercial-grade silica gel
(60–120 mesh or 230–400 mesh). PS and EA are abbreviated for
petroleum ether (boiling range 60–80 °C) and ethyl acetate, respec-
tively.
General Procedure for the Synthesis of Compounds 3a–b,[16c] 3c and
3d:[16c] To a magnetically stirred solution of 3-amino-3-deoxy-
1,2:5,6-di-O-isopropylidene-α--glucofuranoside (1a) or α--allof-
uranoside (1b) (4 mmol) in pyridine (12 mL) was added TsCl
(4.8 mmol) in pyridine (12 mL), and the stirring was continued at
room temp. for 16 h. The mixture was then poured into crushed
ice and extracted with CH2Cl2 (3ϫ30 mL). The organic layer was
washed with H2O and dried. Removal of solvent under reduced
pressure gave a syrupy liquid, which was dissolved in 25 mL of dry
acetone. Anhydrous K2CO3 (4 g) and appropriately substituted 2-
bromobenzyl bromide (4.4 mmol) were added to it. The mixture
was sonicated for 15 min and stirred for 6 h at room temp. until
completion of reaction (indicated by TLC). The reaction mixture
was then filtered; the filtrate was concentrated, diluted with H2O
and extracted with CH2Cl2 (3ϫ30 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-bromobenzyl)tosyl derivatives.
Figure 2. ORTEP diagram of 9.
3-{[(6-Bromo-1,3-benzodioxol-5-yl)methyl](p-tolylsulfonyl)amino}-3-
deoxy-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (3c): Foamy
solid; yield 1.704 g (2.72 mmol, 68%). Rf = 0.55 (PS/EA, 2:1), elu-
ent PS/EA (5:1). [α]2D5 = –36.2 (c = 0.92, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.17 (s, 3 H), 1.28 (s, 3 H), 1.32 (s, 3 H),
1.45 (s, 3 H), 2.44 (s, 3 H), 3.52–3.54 (m, 1 H), 3.78 (d, J = 4.8 Hz,
2 H), 3.93–3.97 (m, 2 H), 4.43 (d, J = 16.8 Hz, 1 H), 4.56 (d, J =
17.1 Hz, 1 H), 4.97 (br. s, 1 H), 5.97 (s, 2 H), 5.97–5.99 (d-like, 1
H), 6.96 (s, 1 H), 7.21 (s, 1 H), 7.32 (d, J = 7.8 Hz, 2 H), 7.78–7.80
(d-like, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 21.5 (CH3),
25.0 (CH3), 25.8 (CH3), 26.4 (CH3), 26.5 (CH3), 52.6 (CH2), 67.0
(CH), 68.1 (CH2), 71.7 (CH), 80.8 (CH), 84.3 (CH), 101.8 (CH2),
105.3 (CH), 108.9 (CH), 109.5 (C), 111.0 (C), 112.5 (CH), 112.9
(C), 128.0 (2 CH), 128.8 (C), 129.5 (2 CH), 136.9 (C), 143.9 (C),
Scheme 5. Proposed mechanism of intramolecular aryl amination
for the synthesis of benzodiazocines and dibenzodiazocines.
Conclusions
147.74 (C), 147.76 (C) ppm. IR (neat): ν = (ν
= 3535), 2986,
˜
˜
max
In summary, we have developed a straightforward, ef-
ficient synthetic route to benzannulated eight-membered di-
azacycles by using the Buchwald–Hartwig aryl amination
for appropriate furanose derivatives. The reaction worked
on a variety of -glucose-derived substrates and the prod-
ucts could be smoothly converted to chiral, optically active
benzodiazocines. The strategy could be extended to synthe-
size dibenzannulated eight-membered diazacycles also. The
findings open up the possibility of obtaining functionalized
benzodiazocines in chiral form and also dibenzodiazocine
derivatives.
2936, 1703, 1595 cm–1. C27H32BrNO9S (626.51): calcd. C 51.76, H
5.15, N, 2.24; found C 51.57, H 5.08, N 2.16. MS (ESI): m/z = 648
(M+ + Na for Br79).
General Procedure for the Synthesis of Compounds 3e–f: To a mag-
netically stirred solution of 1a (4 mmol) in 30 mL of CH2Cl2,
Boc2O (4 mmol) was added drop wise and the solution was stirred
for 1 h. Then it was treated with 20 mL of saturated NaHCO3 solu-
tion and extracted with CH2Cl2 (3ϫ30 mL). The organic layer was
washed with H2O and dried. Removal of solvent under reduced
pressure gave a syrupy liquid, which was dissolved in 25 mL of dry
acetone. Anhydrous K2CO3 (4 g) and appropriately substituted 2-
bromobenzyl bromide (4.4 mmol) were added to it. The mixture
was sonicated for 15 min and stirred for 6 h at room temp. until
completion of reaction (indicated by TLC). The reaction mixture
was then filtered; the filtrate was concentrated, diluted with H2O
and extracted with CH2Cl2 (3ϫ30 mL). The CH2Cl2 extract was
washed with H2O, dried and concentrated to afford a syrup which
Experimental Section
1
General: H and 13C NMR spectra were recorded in a Bruker AM
300L or AVANCE 600 MHz spectrometer using CDCl3 as solvent
Eur. J. Org. Chem. 2010, 1754–1762
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1757

N. D. Adhikary, P. Chattopadhyay
FULL PAPER
on column chromatography (silica gel) yielded the corresponding
3-N-(2-bromo/iodobenzyl) Boc derivatives.
J = 17.7 Hz, 1 H), 5.58 (d, J = 3.4 Hz, 1 H), 7.12 (t, J = 7.2 Hz, 1
H), 7.21–7.42 (m, 8 H), 7.48–7.51 (m, 1 H), 7.62 (d, J = 7.5 Hz, 1
H), 7.73–7.76 (d-like, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
21.4 (CH3), 25.7 (CH3), 26.2 (CH3), 47.4 (CH2), 50.9 (CH2), 53.7
(CH2), 65.3 (CH), 78.9 (CH), 83.3 (CH), 104 (CH), 111 (C), 122.1
(C), 126.9 (CH), 127.5 (2 CH), 127.8 (2 CH), 128.3 (2 CH), 128.5
(CH), 128.8 (CH), 129.1 (CH), 129.8 (2 CH), 132.5 (CH), 135.9
3-Deoxy-3-[(2-bromobenzyl)(tert-butoxycarbonyl)amino]-1,2:5,6-di-
O-isopropylidene-α-D-glucofuranose (3e): Syrup; yield 1.625 g
(3.08 mmol, 77%) (eluent PS/EA, 5:1). [α]2D5 = –31.4 (c = 0.76,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.27 (s, 3 H), 1.38–1.52
(m, 15 H), 1.56 (s, 3 H), 4.03–4.18 (m, 4 H), 4.23 (br. s, 1 H), 4.48
(br. s, 1 H), 4.63 (br. s, 1 H), 5.02 (br. s, 1 H), 6.08 (br. s, 1 H),
7.11–7.37 (m, 3 H), 7.55 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR
(CDCl3, 150 MHz): δ = 25.4 (CH3), 26.1 (CH3), 26.8 (CH3), 26.9
(CH3), 28.2 (3 CH3), 64.0 (CH2), 66.5 (CH), 67.9 (CH2), 73.5 (CH),
80.6 (CH), 81.8 (CH), 85.1 (C), 106.3 (CH), 109.4 (C), 110.7 (C),
127.5 (CH), 128.3 (C), 128.4 (CH), 132.8 (2 CH), 138.5 (C), 155.3
(C), 136.4 (C), 139.6 (C), 144 (C) ppm. IR (neat): ν = (νmax = 2985),
˜
˜
2931, 1665, 1597, 1449 cm–1. C29H33BrN2O5S (601.55): calcd. C
57.90, H 5.53, N 4.66; found C 57.78, H 5.47, N 4.58. MS (ESI):
m/z = 601 (M+ + H for Br79).
(3aR,5R,6S,6aR)-5-(Benzylaminomethyl)-6-[(2-bromo-5-methoxy-
benzyl)(p-tolylsulfonyl)amino]-2,2-dimethyl-tetrahydrofuro-
[2,3-d][1,3]dioxole (4b): Gummy material; yield 0.92 g (1.46 mmol,
73%) (eluent PS/EA, 4:1). [α]2D5 = –27.6 (c = 1.2, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.15 (s, 3 H), 1.44 (s, 3 H), 1.60 (br. s, 1 H),
2.30–2.35 (dd-like, 1 H), 2.42 (s, 3 H), 2.57 (dd, J = 12.3, 7.5 Hz, 1
H), 3.58 (d, J = 13.5 Hz, 1 H), 3.65 (d, J = 13.5 Hz, 1 H), 3.76 (s,
3 H), 3.81 (br. s, 1 H), 4.32–4.34 (d-like, 1 H), 4.35 (d, J = 18 Hz,
1 H), 4.48–4.50 (d-like, 1 H), 4.53 (d, J = 18 Hz, 1 H), 5.63 (d, J
= 3 Hz, 1 H), 6.69 (dd, J = 6.9, 2.7 Hz, 1 H), 7.17–7.39 (m, 9 H),
7.73–7.75 (d-like, 2 H) ppm. 13C NMR (CDCl3, 150 MHz): δ =
21.5 (CH3), 25.8 (CH3), 26.4 (CH3), 47.7 (CH2), 53.1 (CH2), 53.8
(CH2), 55.4 (CH3), 65.5 (CH), 79.1 (CH), 83.4 (CH), 104.1 (CH),
111.1 (C), 112.4 (C), 114.8 (CH), 114.9 (CH), 126.9 (CH), 127.6
(CH), 127.9 (2 CH), 128.1 (CH), 128.3 (3 CH), 129.8 (CH), 133.1
(CH), 136.5 (C), 136.9 (C), 139.7 (C), 144.0 (C), 158.9 (C) ppm.
(C) ppm. IR (neat): ν = (νmax = 2984), 2936, 2887, 1701, 1568 cm–1.
˜
˜
C24H34BrNO7 (528.43): calcd. C 54.55, H 6.49, N 2.65; found C
54.32, H 6.26, N 2.45. MS (ESI): m/z = 550 (M+ + Na for Br79).
3-Deoxy-3-[(2-iodobenzyl)(tert-butoxycarbonyl)amino]-1,2:5,6-di-O-
isopropylidene-α-D-glucofuranose (3f): Syrup; yield 1.705 g (2.96
mmol, 74%) (eluent PS/EA, 5:1). [α]2D5 = –34.8 (c = 0.82, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 1.27 (s, 3 H), 1.39–1.52 (m, 15
H), 1.57 (s, 3 H), 4.03–4.23 (m, 5 H), 4.38 (br. s, 1 H), 4.57 (br. s,
1 H), 5.04 (br. s, 1 H), 6.09 (br. s, 1 H), 6.97 (t, J = 7.2 Hz 1 H),
7.20 (br. s, 1 H), 7.38 (t, J = 7.2 Hz 1 H), 7.30 (d, J = 7.5 Hz 1 H)
ppm. 13C NMR (CDCl3, 150 MHz): δ = 25.5 (CH3), 26.1 (CH3),
27.0 (CH3), 27.4 (CH3), 28.2 (3 CH3), 63.9 (CH2), 66.9 (CH), 67.9
(CH2), 73.5 (CH), 80.5 (CH), 81.9 (CH), 85.1 (C), 106.5 (CH),
109.4 (C), 110.7 (C), 128.0 (CH), 128.4 (C), 128.6 (CH), 139.4
IR (neat): ν
= 3330, 2986, 2934, 2837, 1671, 1596 cm–1
.
˜
max
(CH), 139.5 (CH), 140.1 (C), 155.3 (C) ppm. IR (neat): ν = (ν
˜
˜
max
C30H35BrN2O6S (631.58): calcd. C 57.05, H 5.59, N 4.44; found C
= 2983), 2935, 1700, 1582, 1564 cm–1. C24H34INO7 (575.43): calcd.
C 50.09, H 5.96, N 2.43; found C 50.21, H 5.76, N 2.35. MS (ESI):
m/z 576, (M+ + H).
57.18, H 5.42, N 4.36. MS (ESI): m/z = 631 (M+ + H for Br79).
(3aR,5R,6S,6aR)-5-(Benzylaminomethyl)-6-{[(6-bromo-1,3-benzodi-
oxol-5-yl)methyl](p-tolylsulfonyl)amino}-2,2-dimethyl-tetrahydro-
furo[2,3-d][1,3]dioxole (4c): Gummy material; yield 1.006 g
(1.56 mmol, 78%) (eluent PS/EA, 4:1). [α]2D5 = –29.7 (c = 0.94,
General Procedure for the Synthesis of Compounds 4a–h: Each of
the compounds 3a–f (2 mmol) was dissolved in 80% aq. HOAc
(v/v, 60 mL) and the solution was stirred overnight at room tem-
perature (monitored by TLC until the disappearance of starting
material). Removal of HOAc on a rotary evaporator (40 °C) using
anhydrous toluene (3ϫ50 mL) afforded the intermediate diol as a
highly viscous syrup. A solution of the diol in methanol (10 mL)
was cooled to 0 °C and treated with aq. NaIO4 (513 mg, 2.4 mmol,
dissolved in 5 mL of water) slowly with stirring (45 min). The reac-
tion mixture was filtered (using sintered funnel), evaporated under
reduced pressure and extracted with CHCl3 (4ϫ30 mL). The com-
bined organic layer was washed with water, dried and evaporated
to afford the crude aldehyde. This aldehyde was dissolved in dry
CH2Cl2 (35 mL) and treated with activated molecular sieves (4 Å)
and appropriate amine (2.4 mmol) at 0 °C. Then the mixture was
stirred at room temperature for 12 h under N2 atmosphere. Dry
MeOH (15 mL) was added to the reaction mixture and NaBH4
(151 mg, 4 mmol) was added to it (in small portions) over a period
of 1 h at 0 °C. The stirring was continued for another 2 h at room
temperature. The solvent was evaporated under reduced pressure
and the residue was extracted with CH2Cl2 (4ϫ30 mL). The com-
bined organic layer was washed with water, dried, evaporated, and
chromatographed on silica gel to afford the amine 4a–h.
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.17 (s, 3 H), 1.44 (s, 3
H), 1.57 (br. s, 1 H), 2.24–2.29 (dd-like, 1 H), 2.43 (s, 3 H), 2.49–
2.55 (dd-like, 1 H), 3.56 (d, J = 13.2 Hz, 1 H), 3.64 (d, J = 13.2 Hz,
1 H), 4.26 (m, 3 H), 4.45 (m, 2 H), 5.66 (br. s, 1 H), 5.98 (s, 2 H),
6.94 (s, 1 H), 7.15 (s, 1 H), 7.21–7.32 (m, 7 H), 7.72–7.75 (d-like, 2
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 21.4 (CH3), 25.8 (CH3),
26.3 (CH3), 47.4 (CH2), 50.8 (CH2), 53.7 (CH2), 65.3 (CH), 78.9
(CH), 83.4 (CH), 101.7 (CH2), 104 (CH), 109.1 (CH), 111.0 (C),
112.3 (CH), 112.4 (C), 126.8 (CH), 127.5 (2 CH), 127.8 (2 CH),
128.2 (2 CH), 129.0 (C), 129.7 (2 CH), 136.4 (C), 139.5 (C), 144.0
(C), 147.5 (2 C) ppm. IR (neat): ν = (ν
= 2924), 1593, 1479,
˜
˜
max
1378, 1345 cm–1. C30H33BrN2O7S (645.56): calcd. C 55.82, H 5.15,
N 4.34; found C 55.68, H 5.06, N 4.25. MS (ESI): m/z = 645 (M+
+ H for Br79).
(3aR,5R,6S,6aR)-5-(Isopropylaminomethyl)-6-[(2-bromobenzyl)(p-
tolylsulfonyl)amino]-2,2-dimethyl-tetrahydrofuro[2,3-d][1,3]dioxole
(4d): Syrup; yield 0.795 g (1.44 mmol, 72%) (eluent PS/EA, 4:1).
1
[α]2D5 = –32.4 (c = 1.36, CHCl3). H NMR (300 MHz, CDCl3): δ =
1.03 (d, J = 6 Hz, 3 H), 1.39–1.18 (m, 6 H), 1.42 (s, 3 H), 1.49 (br.
s, 1 H), 2.46 (s, 3 H), 2.64–2.65 (d-like, 2 H), 3.01 (br. s, 1 H), 4.19–
4.35 (m, 2 H), 4.42–4.46 (m, 1 H), 5.58 (dd, J = 17.7, 8.3 Hz, 2 H),
(3aR,5R,6S,6aR)-5-(Benzylaminomethyl)-6-[(2-bromobenzyl)(p-tol-
ylsulfonyl)amino]-2,2-dimethyl-tetrahydrofuro[2,3-d][1,3]dioxole 5.72 (br. s, 1 H), 7.12–7.19 (m, 1 H), 7.33–7.39 (m, 3 H), 7.50–7.55
(4a): Syrup; yield 0.84 g (1.4 mmol, 70%). Rf = 0.36 (PS/EA, 2:1), (m, 1 H), 7.63–7.65 (d-like, 1 H), 7.76–7.82 (m, 2 H) ppm. 13C
eluent PS/EA (4:1). [α]2D5 = –28.2 (c = 1.42, CHCl3). 1H NMR
NMR (CDCl3, 75 MHz): δ = 21.9 (CH3), 22.6 (CH3), 23.1 (CH3),
(300 MHz, CDCl3): δ = 1.13 (s, 3 H), 1.43 (s, 3 H), 1.98 (br. s, 1 26.2 (CH3), 26.7 (CH3), 46.3 (CH2), 49.2 (CH2), 51.5 (CH2), 65.8
H), 2.26 (dd, J = 12.3, 4.2 Hz, 1 H), 2.43 (s, 3 H), 2.54 (dd, J = (CH), 79.6 (CH), 83.8 (CH), 104.5 (CH), 111.6 (C), 122.6 (C), 127.8
16.8, 7.5 Hz, 1 H), 3.57 (d, J = 13.2 Hz, 1 H), 3.64 (d, J = 13.2 Hz, (CH), 128.0 (2 CH), 129.2 (CH), 129.7 (CH), 130.3 (2 CH), 133.0
1 H), 4.33 (dd, J = 13.5, 4.8 Hz, 2 H), 4.40–4.43 (m, 2 H), 4.55 (d, (CH), 136.5 (C), 137.1 (C), 144.5 (C) ppm. IR (neat): ν = (ν
=
˜
˜
max
1758
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1754–1762

Pd-Catalyzed Intramolecular Aryl Amination Reaction
2964), 1595, 1442, 1378, 1345 cm–1. C25H33BrN2O5S (553.51):
calcd. C 54.25, H 6.01, N 5.06; found C 54.12, H 5.88, N 4.92. MS
(ESI): m/z = 553 (M+ + H for Br79).
4:1). [α]2D5 = –29.4 (c = 1.16, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 1.19 (s, 3 H), 1.25–1.42 (m, 9 H), 1.47 (s, 3 H), 1.61 (br. s, 1
H), 2.86 (br. s, 2 H), 3.83 (d, J = 8.7 Hz, 3 H), 4.48–4.58 (m, 4 H),
5.84 (br. s, 1 H), 6.94–6.99 (m, 1 H), 7.15 (br. s, 1 H), 7.26–7.38
(m, 6 H), 7.81 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR (CDCl3,
150 MHz): δ = 26.0 (CH3), 26.6 (CH3), 28.0 (3 CH3), 48.2 (CH2),
53.1 (CH2), 54.2 (CH2), 63.8 (CH), 80.2 (CH), 83.5 (CH), 96.7 (C),
104.8 (CH), 111.0 (C), 126.7 (CH), 126.9 (CH), 127.8 (C), 128.1 (2
CH), 128.3 (3 CH), 128.6 (CH), 137.5 (C), 139.4 (CH), 139.9 (C)
(3aR,5R,6R,6aR)-5-(Benzylaminomethyl)-6-[(2-bromobenzyl)(p-tol-
ylsulfonyl)amino]-2,2-dimethyl-tetrahydrofuro[2,3-d][1,3]dioxole (4e):
Gummy material; yield 0.9 g (1.5 mmol, 75%) (eluent PS/EA, 4:1).
[α]2D5 = +66.3 (c = 0.26, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
1.09 (s, 3 H), 1.45 (s, 3 H), 1.54 (br. s, 1 H), 2.32 (dd, J = 13.1,
5.2 Hz, 1 H), 2.44 (s, 3 H), 2.56–2.61 (dd-like, 1 H), 3.51 (d, J =
13.4 Hz, 1 H), 3.66 (d, J = 13.4 Hz, 1 H), 4.01–4.03 (m, 1 H), 4.19
(t, J = 3.9 Hz, 1 H), 4.27 (dd, J = 9.7, 4.2 Hz, 1 H), 4.73 (d, J =
18 Hz, 1 H), 5.13 (d, J = 18 Hz, 1 H), 5.58 (d, J = 3.6 Hz, 1 H);
7.04–7.12 (m, 3 H), 7.24–7.32 (m, 6 H), 7.44–7.47 (dd-like, 1 H),
7.56 (d, J = 7.5 Hz, 1 H), 7.81–7.84 (d-like, 2 H) ppm. 13C NMR
155.4 (C) ppm. IR (neat): ν = (νmax = 2978), 2930, 1696, 1452 cm–1.
˜
˜
C27H35IN2O5 (594.48): calcd. C 54.55, H 5.93, N 4.71; found C
59.12, H 6.34, N 5.04. MS (ESI): m/z = 595 (M+ + H).
General Procedure for the Cycloamination Reactions: To a solution
of each of the amines 4a–g (1 mmol) in dry toluene (10 mL/mmol
(CDCl3, 150 MHz): δ = 21.6 (CH3), 26.0 (CH3), 26.6 (CH3), 49.5 substrate) were added tBuOK (224 mg, 2 equiv.) and K2CO3
(CH2), 50.1 (CH2), 54.1 (CH2), 59.6 (CH), 74.3 (CH), 80.6 (CH), (276 mg, 2 equiv.) [only tBuOK (448 mg, 4 equiv.) for 4h], Pd2(dba)
103.7 (CH), 112.7 (C), 126.3 (CH), 126.9 (CH), 128.0 (4ϫ CH),
(10 mol-%) and ϮBINAP (7 mol-%) (for 4a–g) or xantphos
3
128.3 (2 CH), 128.7 (CH), 129.1 (CH), 129.2 (CH), 130.0 (CH),
(7 mol-%) (for 4h), and the reaction mixture was heated at reflux
130.3 (CH), 134.0 (C), 134.4 (C), 139.5 (C), 139.9 (C), 143.8 (C) for 17 h under argon atmosphere. After completion of the reaction
ppm. IR (neat): ν = (ν
= 3024), 2985, 2930, 1674, 1599 cm–1.
(monitored by TLC), the crude mixture was passed through a bed
of silica gel. The solvent was evaporated and the residue was ex-
tracted with CH2Cl2 (4ϫ25 mL). The organic layer was washed
with water and dried. The solvent was evaporated under reduced
pressure to give the crude product which was purified by column
chromatography over silica gel to furnish the pure cyclized product.
˜
˜
max
C29H33BrN2O5S (601.55): calcd. C 57.90, H 5.53, N 4.66; found C
57.74, H 5.48, N, 4.52. MS (ESI): m/z = 601 (M+ + H for Br79).
(3aR,5R,6R,6aR)-5-{[(6-Bromo-1,3-benzodioxol-5-yl)methyl]-
aminomethyl}-6-[(2-bromobenzyl)(p-tolylsulfonyl)amino]-2,2-dimeth-
yltetrahydrofuro[2,3-d][1,3]dioxole (4f): Gummy material; yield
1.07 g (1.66 mmol, 83%) (eluent PS/EA, 4:1). [α]2D5 = +64.8 (c =
(2R,3R,3aS,11aR)-10-Benzyl-2,3-(isopropylidenedioxy)-4-(p-tolyl-
0.24, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.08 (s, 3 H), 1.45 sulfonyl)-3a,4,5,10,11,11a-hexahydrofuro[3,2-b][1,5]benzodiazocine
(s, 3 H), 1.51 (br. s, 1 H), 2.30 (dd, J = 12.9, 4.8 Hz, 1 H), 2.44 (s,
3 H), 2.54–2.59 (dd-like, 1 H), 3.42 (d, J = 13.2 Hz, 1 H), 3.54 (d,
J = 13.2 Hz, 1 H), 3.99 (d, J = 7.8 Hz 1 H), 4.18–4.25 (m, 2 H),
4.73 (d, J = 18 Hz, 1 H), 5.14 (d, J = 18 Hz, 1 H), 5.57 (d, J =
2.7 Hz, 1 H), 5.95 (s, 2 H), 6.67 (d, J = 7.8 Hz, 1 H), 6.76 (d, J =
8.1 Hz, 2 H), 7.07 (t, J = 7.5 Hz, 1 H), 7.19 (t, J = 7.5 Hz, 1 H),
(5a): Gummy material; yield 0.375 g (0.72 mmol, 72%). Rf = 0.64
(PS/EA, 2:1), eluent PS/EA (6:1). [α]2D5 = +69.4 (c = 1.56, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 1.29 (s, 6 H), 2.31 (s, 3 H), 3.10
(dd, J = 15.6, 8.5 Hz, 1 H), 3.49 (dd, J = 15.3, 7.3 Hz, 1 H), 3.71–
3.87 (m, 4 H), 4.67 (d, J = 16.8 Hz, 1 H), 4.74 (d, J = 17.1 Hz, 1
H), 4.94 (br. s, 1 H), 5.90 (br. s, 1 H), 6.69 (d, J = 7.8 Hz, 1 H),
7.32 (d, J = 7.8 Hz, 2 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.60 (d, J = 6.86–6.96 (m, 3 H), 7.06–7.45 (m, 9 H) ppm. 13C NMR (CDCl3,
7.5 Hz, 1 H), 7.81–7.83 (d-like, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 21.3 (CH3), 26.3 (CH3), 26.4 (CH3), 47.2 (CH2), 51.8
75 MHz): δ = 21.5 (CH3), 25.6 (CH3), 26.5 (CH3), 48.8 (CH2), 50.2 (CH2), 56.1 (CH2), 65.8 (CH), 76.7 (CH), 86.8 (CH), 104.5 (CH),
(CH2), 53.2 (CH2), 59.0 (CH), 75.8 (CH), 79.0 (CH), 100.8 (CH2), 111.4 (C), 116.0 (CH), 120.5 (CH), 127.0 (C), 127.5 (CH), 127.8 (2
103.5 (CH), 107.9 (CH), 108.5 (CH), 112.5 (C), 120.9 (CH), 121.7
(C), 127.2 (CH), 127.5 (2 CH), 128.5 (CH), 129.6 (2 CH), 129.7
CH), 128.5 (3 CH), 128.8 (2 CH), 129.1 (2 CH), 132.8 (CH), 136.1
(C), 137.6 (C), 142.8 (C), 151.8 (C) ppm. IR (neat): ν = (ν
=
˜
˜
max
(CH), 132.2 (CH), 134.1 (C), 137.1 (C), 137.4 (C), 143.9 (C), 146.3 2924), 1651, 1597, 1496 cm–1. C29H32N2O5S (520.63): calcd. C
(C), 147.5 (C) ppm. IR (neat): ν = (νmax = 3395), 2924, 1645, 1597, 66.90, H 6.20, N 5.38; found C 66.78, H 6.08, N 5.25. MS (ESI):
˜
˜
1488 cm–1. C30H33BrN2O7S (645.56): calcd. C 55.82, H 5.15, N
m/z = 543 (M+ + Na).
4.34; found C 55.67, H 5.03, N 4.21. MS (ESI): m/z = 645 (M+
+
(2R,3R,3aS,11aR)-10-Benzyl-2,3-(isopropylidenedioxy)-7-methoxy-
4-(p-tolylsulfonyl)-3a,4,5,10,11,11a-hexahydrofuro[3,2-b][1,5]benzo-
H for Br79).
(3aR,5R,6S,6aR)-5-(Benzylaminomethyl)-6-[(2-bromobenzyl)(tert-but- diazocine (5b): Gummy material; yield 0.365 g (0.66 mmol, 66%)
oxycarbonyl)amino]-2,2-dimethyl-tetrahydrofuro[2,3-d][1,3]di- (eluent PS/EA, 6:1). [α]2D5 = +63.7 (c = 1.48, CHCl3). 1H NMR
oxole (4g): Syrup; yield 0.745 g (1.36 mmol, 68%) (eluent PS/EA,
4:1). [α]2D5 = –30.8 (c = 1.36, CHCl3). 1H NMR (300 MHz, CDCl3):
(300 MHz, CDCl3): δ = 1.28 (s, 3 H), 1.30 (s, 3 H), 2.33 (s, 3 H),
3.01 (dd, J = 11.4, 8.2 Hz, 1 H), 3.35 (d, J = 9.3 Hz, 1 H), 3.74–
δ = 1.19 (s, 3 H), 1.25–1.42 (m, 9 H), 1.47 (s, 3 H), 1.68 (br. s, 1 3.95 (m, 4 H) overlapped with 3.80 (s, 3 H), 4.58 (br. s, 2 H), 4.96
H), 2.85 (br. s, 2 H), 3.82 (d, J = 5.1 Hz, 2 H), 4.13–4.18 (d-like, 1
H), 4.46–4.75 (m, 4 H), 5.84 (br. s, 1 H), 7.10–7.33 (m, 8 H), 7.53
(br. s, 1 H), 5.93 (d, J = 3.3 Hz, 1 H), 6.73–6.80 (m, 2 H), 6.86 (s,
1 H), 6.94 (d, J = 4.5 Hz, 2 H), 7.10 (d, J = 7.8 Hz, 2 H), 7.16–
(d, J = 7.8 Hz, 1 H) ppm. 13C NMR (CDCl3, 150 MHz): δ = 26.0 7.32 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 21.4 (CH3),
(CH3), 26.6 (CH3), 28.0 (3 CH3), 48.2 (CH2), 53.0 (CH2), 54.2 26.3 (CH3), 26.5 (CH3), 47.2 (CH2), 55.1 (CH), 55.6 (CH3), 57.2
(CH2), 63.5 (CH), 80.2 (CH), 83.4 (CH), 97.9 (C), 104.4 (CH),
110.9 (C), 126.9 (CH), 127.5 (C), 128.1 (4ϫ CH), 128.3 (3 CH),
(CH2), 61.3 (CH2), 77.2 (CH), 86.1 (CH), 104.8 (CH), 111.4 (C),
113.6 (CH), 117.8 (CH), 120.1 (C), 127.4 (CH), 127.8 (3 CH), 128.4
128.8 (C), 132.7 (CH), 137.9 (C), 140.1 (C), 155.2 (C) ppm. IR (3 CH), 128.9 (3 CH), 129.7 (CH), 136.5 (C), 138.2 (C), 143.0 (C),
(neat): ν = (ν 145.8 (C) 153.9 (C) ppm. IR (neat): ν = (νmax = 3431), 2916, 1691,
= 3327), 3062, 2978, 2934, 1697, 1599 cm–1
.
˜
˜
˜
˜
max
C27H35BrN2O5 (547.48): calcd. C 59.23, H 6.44, N 5.12; found C 1596 cm–1. C30H34N2O6S (550.67): calcd. C 65.43, H 6.22, N 5.09;
59.12, H 6.34, N 5.04. MS (ESI): m/z = 547 (M+ + H for Br79). found C 65.04, H 6.11, N 4.95. MS (ESI): m/z = 573 (M+ + Na).
(3aR,5R,6S,6aR)-5-(Benzylaminomethyl)-6-[(2-iodobenzyl)(tert-but- (2R,3R,3aS,11aR)-10-Benzyl-2,3-(isopropylidenedioxy)-7,8-(methyl-
oxycarbonyl)amino]-2,2-dimethyl-tetrahydrofuro[2,3-d][1,3]di- enedioxy)-4-(p-tolylsulfonyl)-3a,4,5,10,11,11a-hexahydrofuro[3,2-b]-
oxole (4h): Syrup; yield 0.925 g (1.56 mmol, 78%) (eluent PS/EA,
[1,5]benzodiazocine (5c): Gummy material; yield 0.384 g
Eur. J. Org. Chem. 2010, 1754–1762
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1759

N. D. Adhikary, P. Chattopadhyay
FULL PAPER
(0.68 mmol, 68%) (eluent PS/EA, 6:1). [α]2D5 = +74.3 (c = 1.63,
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.28 (s, 3 H), 1.34 (s, 3 (C), 132.7 (CH), 135.7 (C), 142.8 (C), 146.6 (C), 147.8 (C), 151.1
(CH), 121.8 (CH), 127.8 (2 CH), 128.2 (C), 128.9 (3 CH), 131.9
1
H), 2.36 (s, 3 H), 3.10 (br. s, 1 H), 3.28 (br. s, 1 H), 3.97 (br. s, 4
H), 4.44 (br. s, 2 H), 4.90 (br. s, 1 H), 5.88 (br. s, 1 H), 5.93 (s, 2
(C) ppm. IR (KBr): ν = (νmax = 3429), 2984, 2928, 1599, 1494 cm–1.
˜ ˜
C30H32N2O7S (564.65): calcd. C 63.81, H 5.71, N 4.96; found C
H), 6.45 (s, 1 H), 6.80 (s, 1 H), 6.99 (br. s, 2 H), 7.16–7.32 (m, 5 63.65, H 5.59, N 4.83. MS (ESI): m/z = 587 (M+ + Na).
H), 7.38 (br. s, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 21.4
(2R,3R,3aS,11aR)-10-Benzyl-4-(tert-butoxycarbonyl)-2,3-(isopro-
(CH3), 26.3 (CH3), 26.6 (CH3), 45.2 (CH2), 54.1 (CH2), 57.5 (CH2),
pylidenedioxy)-3a,4,5,10,11,11a-hexahydrofuro[3,2-b][1,5]benzodi-
67.9 (CH), 77.9 (CH), 85.5 (CH), 101.0 (CH2), 104.9 (CH), 111.4
azocine (5g): Syrup; yield 0.35 g (0.75 mmol, 75%) (eluent PS/EA,
(C), 112.0 (CH), 121.5 (C), 127.3 (CH), 127.7 (3 CH), 128.4 (3
6:1). [α]2D5 = +61.3 (c = 1.12, CHCl3). 1H NMR (300 MHz, CDCl3):
CH), 128.7 (CH), 129.1 (2 CH), 136.5 (C), 138.1 (C), 141.7 (C),
δ = 1.09–1.33 (m, 15 H), 2.79 (d, J = 11.5 Hz, 1 H), 3.34–3.38 (m,
143.2 (C), 147.1 (C), 147.6 (C) ppm. IR (neat): ν = (ν
= 3429),
˜
˜
max
1 H), 4.02–4.23 (m, 4 H), 4.46 (d, J = 13.5 Hz, 1 H), 5.56 (d, J =
14.7 Hz, 1 H), 5.11 (br. s, 1 H), 6.04 (br. s, 1 H), 6.93–7.33 (m, 9
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 26.3 (CH3), 26.8 (CH3),
28.3 (3 CH3), 52.9 (CH2), 56.0 (CH2), 58.7 (CH2), 71.6 (CH), 79.0
(CH), 80.2 (C), 84.5 (CH), 106.7 (CH), 110.3 (C), 127.0 (CH), 127.3
(CH), 128.2 (CH), 128.4 (4ϫ CH), 128.6 (C), 132.6 (CH), 139.2
3059, 3021, 2921, 2805, 1751 cm–1. C30H32N2O7S (564.65): calcd.
C 63.81, H 5.71, N 4.96; found C 63.67, H 5.59, N 4.88. MS (ESI):
m/z = 587 (M+ + Na).
(2R,3R,3aS,11aR)-10-Isopropyl-2,3-(isopropylidenedioxy)-4-(p-tolyl-
sulfonyl)-3a,4,5,10,11,11a-hexahydrofuro[3,2-b][1,5]benzodiazocine
(5d): Gummy material; yield 0.375 g (0.79 mmol, 79%) (eluent PS/
EA, 6:1). [α]2D5 = +69.4 (c = 1.56, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.80 (d, J = 6.0 Hz, 3 H), 1.08 (d, J = 6 Hz, 3 H), 1.36
(s, 3 H), 1.53 (s, 3 H), 2.32 (s, 3 H), 2.90 (br. s, 1 H), 3.69 (dd, J =
15.0, 8.2 Hz, 1 H), 3.93–4.00 (m, 1 H), 4.59–4.83 (m, 4 H), 5.00
(C), 139.7 (C), 155.0 (C) ppm. IR (neat): ν = (v
= 2925), 2855,
˜
max
1697, 1599 cm–1. C27H34N2O5 (466.57): calcd. C 69.50, H 7.35, N
6.00; found C 69.32, H 7.22, N 5.43. MS (ESI): m/z = 489 (M+
+
Na).
Synthesis of Benzodiazocine Derivative 6: Compound 5g (0.5 mmol)
was dissolved in 25 mL of CH3CN/H2O (1:1) containing 5 %
H2SO4 and the solution was kept at room temperature for 36 h.
Then the acidic solution was neutralized with solid NaHCO3, fil-
tered, and the filtrate was evaporated in vacuo. The residue was
dissolved in minimum volume of MeOH and treated dropwise at
0 °C with an aqueous solution of NaIO4 (128 mg, 0.6 mmol) with
stirring for 1 h. Usual work up followed by NaBH4 reduction in
MeOH afforded the diol. This was acetylated with Ac2O (0.3 mL)
and pyridine (2 mL) at room temperature for 12 h to furnish a
crude product, which was purified by silica gel flash chromatog-
raphy to afford 6.
(br. s, 1 H), 6.00 (d, J = 2.4 Hz, 1 H), 6.71–7.34 (m, 8 H) ppm. 13
C
NMR (CDCl3, 75 MHz): δ = 16.6 (CH3), 20.9 (CH3), 22.7 (CH3),
25.7 (CH3), 26.2 (CH3), 45.0 (CH), 48.0 (CH2), 50.2 (CH2), 64.0
(CH), 77.6 (CH), 87.7 (CH), 104.1 (CH), 111.3 (C), 116.7 (CH),
127.4 (2 CH), 127.7 (CH), 128.1 (2 CH), 131.9 (CH), 132.8 (CH),
132.8 (CH), 135.4 (C), 141.8 (C), 150.6 (C), 154.4 (C) ppm. IR
(neat): ν = (ν
= 3420), 2975, 2935, 1692 cm–1. C25H32N2O5S
˜
˜
max
(472.60): calcd. C 63.54, H 6.82, N 5.93; found C 63.39, H 6.66, N
5.75. MS (ESI): m/z = 495 (M+ + Na).
(2R,3R,3aR,11aR)-10-Benzyl-2,3-(isopropylidenedioxy)-4-(p-tolyl-
sulfonyl)-3a,4,5,10,11,11a-hexahydrofuro[3,2-b][1,5]benzodiazocine
(5e): Pale yellow solid, m.p. 158 °C; yield 0.355 g (0.68 mmol, 68%)
(eluent PS/EA, 6:1). [α]2D5 = +34.1 (c = 0.2, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.24 (s, 3 H), 1.45 (s, 3 H), 2.36 (s, 3 H),
3.23–3.28 (d-like, 1 H), 3.37–3.46 (m, 2 H), 3.97 (d, J = 14.8 Hz, 1
H), 4.21 (d, J = 15.0 Hz, 1 H), 4.53 (t, J = 4.6 Hz, 1 H), 4.65 (d, J
= 16.3 Hz, 1 H), 4.85 (d, J = 16.3 Hz, 1 H), 4.92 (t, J = 3.4 Hz, 1
H), 5.56 (d, J = 3.6 Hz, 1 H), 6.76–7.48 (m, 13 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 21.4 (CH3), 26.1 (CH3), 26.3 (CH3), 51.4
(CH2), 54.4 (CH2), 58.1 (CH2), 63.0 (CH), 77.8 (CH), 80.0 (CH),
103.0 (CH), 112.0 (C), 118.6 (CH), 121.5 (CH), 127.0 (CH), 127.7
(2 CH), 127.8 (2 CH), 128.4 (2 CH), 128.9 (2 CH), 129.0 (CH),
133.0 (CH), 135.4 (C), 137.9 (C), 141.7 (C), 142.8 (C), 151.1 (C)
(3R,4R)-3-Acetoxy-4-(acetoxymethyl)-5-acetyl-1-benzyl-1,2,3,4,5,6-
hexahydro-benzo[b][1,5]diazocine (6): Syrup; yield 0.132 g
(0.31 mmol, 62 %). Rf = 0.65 (PS/EA, 2:1), eluent PS/EA (6:1).
[α]2D5 = +73.5 (c = 0.98, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
1.98 (s, 3 H), 2.04 (s, 3 H), 2.09 (s, 3 H), 2.81 (dd, J = 8.1, 5.1 Hz,
1 H), 3.00–3.07 (dd-like, 1 H), 4.00–4.10 (m, 2 H), 4.16–4.27 (dd-
like, 1 H), 4.37 (d, J = 15.9 Hz, 1 H), 4.46–4.56 (dd-like, 1 H), 4.68–
4.97 (m, 2 H), 5.18 (d, J = 13.2 Hz, 1 H),7.00–7.68 (m, 9 H) ppm.
13C NMR (CDCl3, 150 MHz): δ = 20.7 (CH3), 20.9 (2 CH3), 56.6
(CH2), 59.0 (CH2), 59.8 (CH), 61.0 (CH2), 72.6 (CH), 126.3 (CH),
127.6 (3 CH), 128.4 (CH), 128.6 (3 CH), 130.1 (C), 131.7 (CH),
136.7 (C), 137.7 (C), 169.5 (C), 170.5 (C), 171.1 (C) ppm. IR (neat):
= 3431), 2987, 2935, 1599, 1494 cm–1.
max
ν = (ν
= 3408), 2926, 2855, 1739, 1644 cm–1. C24H28N2O5
ppm. IR (KBr): ν = (ν
˜
˜
˜
˜
max
C29H32N2O5S (520.63): calcd. C 66.90, H 6.20, N 5.38; found C
(424.49): calcd. C 67.91, H 6.65, N 6.60; found C 67.79, H 6.53, N
66.75, H 6.09, N 5.22. MS (ESI): m/z = 543 (M+ + Na).
6.46. MS (ESI): m/z = 447 (M+ + Na).
(2R,3R,3aR,11aR)-10-[(1,3-Benzodioxol-5-yl)methyl]-2,3-(isopro-
pylidenedioxy)-4-(p-tolylsulfonyl)-3a,4,5,10,11,11a-hexahydrofuro-
[3,2-b][1,5]benzodiazocine (5f): Pale yellow solid, m.p. 165 °C; yield
Procedure for the Synthesis of the Dibenzodiazocine Derivative: To
a stirring solution of o-nitrobenzaldehyde (4 mmol) and 1,3-pro-
panedithiol (4.4 mmol) in dry CH2Cl2 (30 mL), 0.4 mmol of I2 was
added at 0 °C. After 15 min, the mixture was brought to room
0.4 g (0.71 mmol, 71%) (eluent PS/EA, 6:1), [α]2D5 = +32.6 (c = 0.26,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.21 (s, 3 H), 1.43 (s, 3 temp. and stirred for another half an hour. After complete conver-
H), 2.37 (s, 3 H), 3.16 (d, J = 10.2 Hz, 1 H), 3.33–3.43 (m, 2 H),
3.92 (d, J = 14.4 Hz, 1 H), 4.10 (d, J = 14.4 Hz, 1 H), 4.48 (t, J =
4.5 Hz, 1 H), 4.64 (d, J = 16.2 Hz, 1 H), 4.85 (d, J = 16.8 Hz, 1 H)
overlapped with 4.89 (d, J = 3.6 Hz, 1 H), 5.56 (d, J = 3.3 Hz, 1
sion (indicated by TLC), the reaction mixture was washed with
saturated Na2S2O3 solution (2ϫ30 mL), dried (Na2SO4) and con-
centrated under reduced pressure to afford a solid material. It was
dissolved in 95% ethanol (50 mL), Pd/C (0.1 g) was added and the
H), 5.93 (d, J = 4.2 Hz, 2 H), 6.64 (d, J = 7.5 Hz, 2 H), 6.70–6.73 mixture was heated to reflux under N2. Hydrazine hydrate
(m, 2 H), 6.83 (d, J = 7.5 Hz, 1 H), 6.97 (t, J = 7.2 Hz, 1 H), 7.12– (6 mmol) was then added dropwise. The refluxing was continued
7.21 (m, 3 H), 7.42–7.44 (d-like, 3 H) ppm. 13C NMR (CDCl3,
for another 4 h. After completion of reaction (indicated by TLC)
75 MHz): δ = 21.3 (CH3), 26.0 (CH3), 26.2 (CH3), 51.0 (CH2), 54.9 the reaction mixture was cooled to r. t., filtered through celite to
(CH2), 58.1 (CH2), 63.1 (CH), 77.6 (CH), 80.1 (CH), 100.8 (CH2), remove the insoluble part, and evaporated in vacuum. The amine
102.9 (CH), 108.0 (CH), 108.2 (CH), 111.9 (C), 118.9 (CH), 121.0
was tosylated and the tosylamine was arylated as earlier to afford
1760
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1754–1762

Pd-Catalyzed Intramolecular Aryl Amination Reaction
7. Compound 7 (2 mmol) was dissolved in 40 mL of CH3CN/H2O
(90:1), methyl iodide (12 mmol) was added, and the mixture was
stirred at room temperature for 24 h. After completion of reaction
(indicated by TLC) the solvent was removed under reduced pres-
sure and the mixture was extracted with CH2Cl2 (3ϫ30 mL). The
extract was washed with saturated Na2S2O3 solution (2ϫ30 mL),
dried (Na2SO4), and concentrated under reduced pressure to afford
the intermediate benzaldehyde. This was dissolved in 20 mL of de-
hydrated ethanol, treated with benzylamine (2.4 mmol), and stirred
for 12 h. Then it was cooled to 0 °C, NaBH4 (4 mmol) was added,
and the mixture was stirred for 6 h. The solvent was evaporated
under reduced pressure and the residue was extracted with CH2Cl2
(4ϫ 30 mL). The combined organic layer was washed with water,
dried, and the solvents evaporated. The product was chromato-
graphed on silica gel to afford the amine 8. It was then subjected
to cycloamination reaction as in the earlier procedure.
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR spectra for compounds 4a,b, 4f,
5a,b, 5f, 6, 8, 9.
Acknowledgments
Financial assistance from Department of Science and Technology
(Government of India) is highly acknowledged. N. D. A. thanks the
Council of Scientific and Industrial Research for providing a re-
search fellowship. We acknowledge Dr. B. Achari, emeritus scien-
tist, Indian Institute of Chemical Biology, for his interest in this
work. We are also grateful to Dr. R. Mukherjee of chemistry divi-
sion for NMR studies.
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N-(2-Bromobenzyl)-N-[2-(1,3-dithian-2-yl)phenyl]-4-methylbenzene-
sulfonamide (7): Gummy material. Overall yield 1.37 g (2.56 mmol,
64 %). Rf = 0.68 (PS/EA, 2:1), eluent PS/EA (7:1). 1H NMR
(300 MHz, CDCl3): δ = 1.82–1.91 (m, 1 H), 2.08–2.17 (m, 1 H),
2.46 (s, 3 H), 2.69 (d, J = 12.6 Hz, 1 H), 2.88–3.04 (m, 3 H), 4.55
(d, J = 13.5 Hz, 1 H), 5.19 (d, J = 13.8 Hz, 1 H), 5.37 (s, 1 H),
6.77 (d, J = 8.1 Hz, 1 H), 7.03 (t, J = 7.2 Hz, 1 H), 7.13 (br. s, 2
H), 7.20–7.37 (m, 4 H), 7.42 (d, J = 7.2 Hz, 1 H), 7.53–7.61 (m, 1
H), 7.69–7.71 (d-like, 2 H) ppm. 13C NMR (CDCl3, 150 MHz): δ
= 21.6 (CH3), 25.1 (CH2), 32.4 (CH2), 32.5 (CH2), 46.7 (CH), 55.5
(CH2), 124.8 (C), 128.3 (CH), 128.4 (3 CH), 129.0 (CH), 129.2
(CH), 129.4 (CH), 129.6 (2 CH), 130.0 (CH), 131.9 (CH), 133.0
(CH), 134.6 (C), 135.2 (C), 136.1 (C), 1140.4 (C), 143.8 (C) ppm.
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I R ( n eat) : ν = (ν
= 2923), 2855, 1659, 1444 cm–1
.
˜
˜
m a x
C24H24BrNO2S3 (534.55): calcd. C 53.92, H 4.53, N 2.62; found C
53.77, H 4.38, N 2.51. MS (ESI): m/z = 556 (M+ + Na for Br79).
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7 (Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Perga-
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9131–9166.
N-[2-(Benzylaminomethyl)phenyl]-N-(2-bromobenzyl)-4-methylbenz-
enesulfonamide (8): Syrup; yield 0.835 g (1.56 mmol, 78%). Rf =
0.40 (PS/EA, 2:1), eluent PS/EA (4:1). 1H NMR (300 MHz,
CDCl3): δ = 1.54 (br. s, 1 H), 2.45 (s, 3 H), 3.48 (br. s, 1 H), 3.59
(s, 2 H), 3.66 (br. s, 1 H), 4.46 (d, J = 12.9 Hz, 1 H), 5.18 (d, J =
12.9 Hz, 1 H), 6.67 (d, J = 7.8 Hz, 1 H), 6.96–7.00 (m, 1 H), 7.09
(dd, J = 18, 7.8 Hz, 2 H), 7.22–7.36 (m, 10 H), 7.48 (d, J = 7.5 Hz,
1 H), 7.59–7.61 (d-like, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 21.6 (CH3), 48.4 (CH2), 53.7 (CH2), 55.2 (CH2), 124.5 (C), 126.7
(CH), 127.0 (CH), 127.3 (CH), 128.1 (2 CH), 128.2 (5ϫ CH), 128.6
(CH), 129.5 (3 CH), 130.2 (CH), 132.1 (CH), 132.8 (CH), 134.7
(C), 135.2 (C), 136.9 (C), 140.5 (C), 142.1 (C), 143.8 (C) ppm. IR
(neat): ν = (νmax = 3338), 3061, 3027, 2921, 2856, 1924, 1811, 1596
˜
˜
cm–1. C28H27BrN2O2S (535.5): calcd. C 62.80, H 5.08, N 5.23;
found C 62.64, H 4.92, N 5.08. MS (ESI): m/z = 557 (M+ + Na
for Br79).
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5-Benzyl-11-(p-tolylsulfonyl)-5,6,11,12-tetrahydrodibenzo[b,f][1,5]di-
azocine (9): Colorless solid, m.p. 132 °C; yield 0.53 g (1.17 mmol,
75%). Rf = 0.62 (PS/EA, 2:1), eluent PS/EA (6:1). 1H NMR
(300 MHz, CDCl3): δ = 2.30 (s, 3 H), 3.41 (br. s, 2 H), 4.07 (s, 2
H), 4.83 (br. s, 2 H), 6.60 (br. s, 1 H), 6.82 (br. s, 1 H), 6.92–7.03
(m, 4 H), 7.08–7.14 (m, 5 H), 7.19–7.23 (m, 4 H), 7.40 (br. s, 4 H),
7.61 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
21.4 (CH3), 55.0 (CH2), 57.4 (2 CH2), 119.1 (CH), 121.4 (C), 126.9
(3 CH), 127.0 (CH), 127.3 (CH), 128.1 (2 CH), 128.3 (3 CH), 128.9
(CH), 129.1 (3 CH), 130.4 (CH), 133.0 (CH), 136.4 (2 C), 138.4 (2
C), 142.8 (2 C) ppm. IR (neat): ν = (ν
= 3064), 3027, 2929,
˜
˜
max
1710, 1598 cm–1. C28H26N2O2S (454.58): calcd. C 73.98, H 5.76, N
6.16; found C 73.82, H 5.61, N 6.05. MS (ESI): m/z = 477 (M+
+
Na).
Eur. J. Org. Chem. 2010, 1754–1762
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1761

N. D. Adhikary, P. Chattopadhyay
FULL PAPER
[8]
[17] a) J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 2000, 65, 1144–
1157; b) Y. Guari, V. E. Es, N. H. Reek, J. Kamer,
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I. A. J. F. Guzei, J. Am. Chem. Soc. 1998, 120, 9205–9219.
[18] Crystal data of compound 5e: C29H32N2O5S, FW = 520.63,
monoclinic, space group P21, a = 11.8542 (10) Å, b = 8.0618
(6) Å, c = 14.7356 (13) Å, α = 90.00°, β = 112.119 (6)°, γ =
a) J. F. Hartwig, Nature 2008, 455, 314–322; b) D. S. Surry,
S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 6338–6361; c)
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Int. Ed. Engl. 1995, 34, 1348–1350; b) J. Louie, J. F. Hartwig,
Tetrahedron Lett. 1995, 36, 3609–3612.
[9]
90.00°, V = 1304.58 (19) Å3, Z = 2, T = 296(2) K, dcalcd.
=
1.325 gcm–3, F (000) = 336. Diffraction data were measured
with Mo-Kα (λ = 0.71073 Å) radiation at 296 K using a Bruker
Kappa Apex 2 CCD system. A total of 1989 unique reflections
were measured (θmax = 24.49°). Data analyses were carried out
with the Fast Fourier Transform program. The structures were
solved by direct methods using the SHELXS-97 program.[22]
Refinements were carried out with a full-matrix least-squares
method against F2 using SHELXL-97.[23] Non-hydrogen atoms
were refined with anisotropic thermal parameters. The final R
value was R1 = 0.0291 and wR2 = 0.0966 with I Ͼ 2σ(I).
CCDC-755652 contains the supplementary crystallographic
data for 5e. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif..
[10]
a) M. D. Charles, P. Schultz, S. L. Buchwald, Org. Lett. 2005,
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Shaughnessy, L. M. Alcazar-Roman, J. Org. Chem. 1999, 64,
5575–5580; d) G. Mann, J. F. Hartwig, J. Am. Chem. Soc. 1996,
118, 13109–13110; e) J. P. Wolfe, S. Wagaw, S. L. Buchwald, J.
Am. Chem. Soc. 1996, 118, 7215–7216; f) M. S. Driver, J. F.
Hartwig, J. Am. Chem. Soc. 1996, 118, 7217–7218.
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=
1.292 gcm–3, F (000) = 336. Diffraction data were measured
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value was R1 = 0.0436 and wR2 = 0.1234 with I Ͼ 2σ (I).
CCDC-756007 contains the supplementary crystallographic
data for 9. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
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[22] G. M. Sheldrick, SHELXS-97, Program for solution of crystal
structures, University of Göttingen, Germany, 1997; G. M.
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[23] G. M. Sheldrick, SHELXL-97, Program for refinement of crys-
tal structures, University of Göttingen, Germany, 1997.
Received: December 17, 2009
Published Online: February 12, 2010
1762
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Eur. J. Org. Chem. 2010, 1754–1762