Synthesis of chiral benzoxa(thia)zepine and pyridoxazepine derivatives using palladium-catalyzed intramolecular aryl amination reaction

Article abstract of DOI:10.1002/ejoc.201101174

A palladium-catalyzed method employing different bulky biaryl phosphanes as ligands has been developed for the intramolecular amination of aryl bromides and iodides. A variety of aryl halide substrates have been aminated through the intramolecular pathway

Full text of DOI:10.1002/ejoc.201101174

FULL PAPER
DOI: 10.1002/ejoc.201101174
Synthesis of Chiral Benzoxa(thia)zepine and Pyridoxazepine Derivatives Using
Palladium-Catalyzed Intramolecular Aryl Amination Reaction
Nirmal Das Adhikary[a] and Partha Chattopadhyay*[a]
Keywords: Heterocycles / Amination / Cyclization / Palladium / Phosphane ligands
A palladium-catalyzed method employing different bulky bi-
aryl phosphanes as ligands has been developed for the intra-
molecular amination of aryl bromides and iodides. A variety
of aryl halide substrates have been aminated through the in-
tramolecular pathway in good yield using different sugar-de-
rived amines to give furo-benzoxa(thia)zepine and pyridox-
azepine derivatives. The method is capable of furnishing chi-
ral, enantiopure benzoxa(thia)zepines and pyridoxazepines
of significant biological importance.
Introduction
tain to achiral substrates, use lengthy reaction sequences,
or furnish low yields of products. A palladium-catalyzed
sequential intra- and intermolecular aryl amination has
been applied to the syntheses of benzazepine and benzo-
xazepine,[14h] however, these suffer from low yields of prod-
uct (51–56%). In addition, because of preparation difficult-
ies, the synthesis of benzothiazepine, generally less reported
than benzoxazepine, is completely ignored. We were en-
couraged to apply the palladium-catalyzed aromatic C–N
bond-forming reaction which involves the cross coupling of
aryl halides (triflates, nonaflates, or mesylates) and amines.
There has recently been an upsurge of interest in this
method as a useful synthetic tool for this task.[15] A number
of studies have reported that an intramolecular version of
this aryl amination chemistry has been utilized for the syn-
thesis of benzofused heterocycles.[16] The chiron approach
to the synthesis of chiral target molecules involves the use
of sugars as starting materials.[17] A key element in this
strategy is the ability to form optically active heterocycles
from carbohydrate molecules.[18] In a continuation of our
research activities related to the synthesis of benzannulated
medium-ring heterocycles through C–N/C–O bond forma-
tion,[16d,16g,19] we felt that an intramolecular cycloamination
strategy leading to the formation of highly functionalized
benzoxa(thia)zepine derivatives starting from carbohydrate
precursors would be an interesting task.
Benzofused cyclic molecules that incorporate the nitro-
gen atom into the ring are capable of binding to multiple
receptors with a high affinity, and hence, are described as
“privileged structures.”[1] Among them, medium-sized het-
erocycles, particularly seven-membered ring heterocycles,
receive a great deal of attention, as these structural units
are widely found in numerous natural products[2] and are
also components of a number of biologically interesting
molecules.[3] The abundance of oxygen-, nitrogen-, and sul-
fur-containing medium rings in pharmaceuticals and agro-
chemicals continues to ensure that they are important syn-
thetic targets for organic chemists. Derivatives of 1,5-benzo-
xazepine exhibit a wide range of bioactivities, for example,
as antidepressants, anxiolytics,[4] and antioxidant and lipid
peroxidation inhibitors,[5] and are used for treating bron-
chial asthma or allergic bronchitis.[6] Several compounds
contain this structural unit such as non-nucleoside HIV-1
reverse transcriptase and human adenosine kinase inhibi-
tors,[7] 5HT2C and nonpeptidic vasopressin V2 receptor ag-
onists, and calcium antagonists.[8] In addition, 1,5-benzothi-
azepines[9] and pyridoxazepines[10] have attracted attention
for many reasons including their biological activities. As
seven-membered rings are generally more difficult to pre-
pare, because of enthalpic and entropic reasons, and direct
cyclization methods are ineffective unless certain conforma-
tional constraints are present in the acyclic precursor,[11]
only a few synthetic procedures are known for benzo-
xa(thia)zepines and pyridoxazepines. These include re-
ductive ring expansion,[12] multicomponent reactions,[13]
microwave-assisted synthesis,[5] or catalytic cycliza-
tion.[7a,7b,9,14] Most of these are either intermolecular, per-
In this paper, we report an intramolecular aryl amination
strategy to furnish chiral tricyclic furo-benzoxa(thia)zepine
and pyridoxazepine derivatives. The cleavage of the sugar
ring in one of these tricyclic derivatives and appropriate fol-
low-up reactions provide the chiral, functionalized benzo-
xazepine.
[a] Chemistry Division, Indian Institute of Chemical Biology,
4, Raja S. C. Mullick Road, Kolkata-700032, India
Fax: +91-33-24735197
Results and Discussion
The starting material 1,2:5,6-di-O-isopropylidene allofu-
ranose (1) was converted into the triflate derivative which
E-mail: partha@iicb.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101174.
7346
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7346–7354

Chiral Benzoxa(thia)zepine and Pyridoxazepine Derivatives
was subsequently treated with the 2-bromo/iodophenol/2- Table 2. Preparation of sugar amines 3a–h.
bromothiophenol derivatives to give 3-O-(2-bromophenyl)
glucofuranosides 2a–c, 3-O-(2-iodophenyl) glucofuranoside
2d, and 3-S-(2-bromophenyl) glucofuranoside 2e (Scheme 1
and Table 1). Selective removal of the 5,6-O-isopropylidene
moiety from 2a–e was smoothly effected with 70% aqueous
HOAc at 25 °C. Oxidation of the resulting diol with NaIO4,
followed by imine formation by treatment with aliphatic
amines, and subsequent NaBH4 reduction in MeOH af-
forded the desired amines 3a–h in good yields (Scheme 1
and Table 2). The structures of 3a–h were supported by
spectroscopic data and by comparison to data of similar
compounds previously prepared by us.[20]
[a] Isolated yield.
as the ligand, a combination of K2CO3 (2.0 equiv.) with
tBuOK (2.0 equiv.) as the base, and toluene (10 mL/mmol
substrate) as the solvent (Table 3, Entry 3). Using a less or
excess amount of catalyst as well as ligand gave a low yield
of product 4a (Table 3, Entries 2 and 4). Other catalytic sys-
tems like Pd(PPh3)4,[16p] Pd2(dba)3-dppf,[15d] or Pd2(dba)3-
Xantphos[15c] were less effective (Table 3, Entries 1, 6, and
[15d]
7). As an alternative palladium source, Pd(OAc)2
also
gave the desired cyclized product, but did it less efficiently
(Table 3, Entry 5). Changing the solvent to DMF (dimeth-
ylformamide)[16o] in place of toluene was also ineffective
(Table 3, Entry 8).
Table 3. Optimization of the intramolecular palladium-catalyzed
cycloamination reaction of 3a.
Scheme 1. Synthesis of o-bromo/iodophenyl/thiophenyl sugar
amines 3a–h. Reagents and conditions: (i) Tf2O, pyridine, dry
DCM (dichloromethane), –10 °C, 1 h, N2; (ii) 2-bromo/iodophenol/
2-bromothiophenol, K2CO3, dry CH3CN, reflux, 6 h; (iii) HOAc
(70%, v/v), room temp., overnight; (iv) aqueous NaIO4, MeOH,
room temp., 45 min; (v) R2NH2, anhydrous CH2Cl2, MS (molecu-
lar sieves, 4 Å), room temp., 12 h, N2; (vi) NaBH4, dry MeOH,
room temp., 3 h.
Entry Reaction conditions[a]
Yield [%]
n.r.[b]
1
2
3
4
5
6
7
8
Pd(PPh3)4, K2CO3 + tBuONa,
toluene, reflux, 24 h
Pd2(dba)3, (Ϯ)-BINAP, K2CO3 + tBuOK,
toluene, reflux, 15 h
Pd2(dba)3, (Ϯ)-BINAP, K2CO3 + tBuOK,
toluene, reflux, 15 h
Pd2(dba)3, (Ϯ)-BINAP, K2CO3 + tBuOK,
toluene, reflux, 18 h
Pd(OAc)2, (Ϯ)-BINAP, Cs2CO3,
toluene, reflux, 16 h
Pd2(dba)3, dppf, tBuONa,
toluene, reflux, 17 h
Pd2(dba)3, Xantphos, tBuOK,
toluene, reflux, 19 h
56[c]
77
74[d]
53
Table 1. Preparation of 2a–e from 1.
Entry R1
X
Y
Z
Product
Yield[a] [%]
62
1
2
3
4
5
H
O
O
O
O
S
CH
CH
N
CH
CH
Br
Br
Br
I
2a
2b
2c
2d
2e
82
72
78
80
71
CN
CH3
H
58
Pd2(dba)3, (Ϯ)-BINAP, K2CO3 + tBuOK,
DMF, 110 °C, 15 h
32
H
Br
[a] Isolated yield.
[a] Catalyst (10 mol-%), ligand (7 mol-%), for base pair (2 equiv.
each) or a single base (4 equiv. each), solvent (10 mL/mmol).
[b] NR = no reaction. [c] Catalyst (5 mol-%), ligand (3 mol-%).
[d] Catalyst (15 mol-%), ligand (10 mol-%).
Our initial goal was to explore the synthesis of benzo-
xazepine-annulated furanose derivatives 4 from 3 through a
palladium-catalyzed intramolecular cycloamination reac-
tion in the presence of bases and ligands. For this, we ap-
We then applied our standardized reagent system (condi-
plied different reported reagent systems for the aryl amin- tions A) to the cycloamination reaction of synthesized
ation reaction of substrate 3a. Evaluation of these showed haloamines 3b–h. Although the yields of cyclized product
that the best conditions for this reaction were using for bromo substrates 3b–d and 3f–h were satisfactory
Pd2(dba)3 (10 mol-%) as the palladium source,[16l] (Ϯ)-BI- (Table 4), that of iodo substrate 3e was significantly lower
NAP (2,2Ј-bis(diphenylphosphino)-1,1Ј-binaphthyl, 7 mol-%) (48%, see Table 4, Entry 5). We then applied different rea-
Eur. J. Org. Chem. 2011, 7346–7354
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7347

N. Das Adhikary, P. Chattopadhyay
FULL PAPER
Table 4. Synthesis of benzoxa(thia)zepine and pyridoxazepine de- (conditions B, see Table 4, Entry 5). The structures of the
rivatives 4a–f.[a]
cyclized products 4a–h were supported by spectroscopic
data and determined by single-crystal X-ray analysis[22] of
4a (Figure 1).
Figure 1. ORTEP diagram of 4a.
After successful tests with secondary amines, we focused
on extending our methodology to the aryl amination of pri-
mary amines, realizing that the resulting secondary amine
would be amenable to functionalization and give varying
substituted products. For this purpose, we synthesized com-
pound 5 from 2a in 42% yield through a sequence of reac-
tions beginning with the selective removal of the 5,6-O-iso-
propylidine moiety with 70% aqueous HOAc. Oxidation of
the resulting diol with NaIO4 and NaBH4 reduction to the
alcohol was followed by mesylation and azidation with
NaN3. Reduction with LAH (lithium aluminum hydride)
afforded 5 which was heated to reflux under the standard
conditions A described for the bromo derivatives to afford
the desired cyclized product 6 in 78% yield (Scheme 2). The
spectroscopic data of 6 were in agreement with the assigned
structure.
Scheme 2. Synthesis of a 1,5-benzoxazepine from the primary
amine. Reagents and conditions: (i) HOAc (70%, v/v), room temp.,
overnight; (ii) aqueous NaIO4, MeOH, room temp., 45 min;
(iii) NaBH4, dry MeOH, room temp., 2 h; (iv) MsCl, Et3N, dry
DCM, room temp., 1 h, N2; (v) NaN3, dry DMF, 80 °C, 5 h, N2;
(vi) LAH, dry Et2O, room temp., 3 h, N2. (vii) Pd2(dba)3 (10 mol-
[a] Reagents and conditions: (A) Pd2(dba)3 (10 mol-%), (Ϯ)-BI-
%), (Ϯ)-BINAP (7 mol-%), K2CO3 and tBuOK (2 equiv. each), tol-
NAP (7 mol-%), K2CO3 (2.0 equiv.), tBuOK (2.0 equiv.), toluene
uene, reflux, 14 h, N2.
(10 mL/mmol), reflux. (B) Pd2(dba)3 (10 mol-%), Xantphos
(7 mol-%), tBuOK (4.0 equiv.), toluene (10 mL/mmol), reflux.
[b] Isolated yield. [c] 48% for conditions A.
As an application of our methodology, we investigated
the feasibility of synthesizing chiral functionalized benzo-
gent systems for the cyclization of 3e and finally observed xazepines from the obtained annulated sugar derivatives.
that our previously standardized reaction conditions re- Thus, subjecting 4a to a sequence of reactions involving re-
quired modification entailing the use of Xantphos[21] moval of the 1,2-O-isopropylidine group with H2SO4 in
(7 mol-%) as the ligand and tBuOK (4.0 equiv.) as the base MeCN/H2O, cleavage of the diol with NaIO4, reduction of
7348
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7346–7354

Chiral Benzoxa(thia)zepine and Pyridoxazepine Derivatives
concentrated. Column chromatography over silica gel yielded the
corresponding 3-O-bromophenyl derivatives.
the generated carbonyl group with NaBH4, and then acety-
lation with acetic anhydride and pyridine furnished benzo-
xazepine derivative 7 (Scheme 3).
(3aR,5R,6S,6aR)-6-(2-Bromophenoxy)-5-(2,2-dimethyl-1,3-di-
oxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (2a): Oil
(1.36 g, 3.28 mmol, 82%); Rf = 0.7 (PS/EA, 2:1), column eluent
(PS/EA, 11:1). [α]2D5 = –24.6 (c = 0.3, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 1.31 (s, 3 H), 1.33 (s, 3 H), 1.44 (s, 3 H), 1.55 (s, 3 H),
4.13 (dd, J = 8.7, 5.4 Hz, 1 H), 4.22 (dd, J = 8.7, 6.3 Hz, 1 H), 4.33
(dd, J = 7.5, 3.0 Hz, 1 H), 4.57–4.63 (m, 2 H), 4.75 (d, J = 3.0 Hz,
1 H), 5.99 (d, J = 3.0 Hz, 1 H), 6.87–7.56 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 25.2 (CH3), 26.2 (CH3), 26.7 (CH3), 26.8
(CH3), 67.3 (CH2), 72.3 (CH), 80.6 (CH), 81.4 (CH), 82.1 (CH),
105.4 (CH), 109.1 (C), 112.1 (C), 113.2 (C), 114.6 (CH), 122.9
Scheme 3. Conversion of 4a to benzoxazepine derivative. Reagents
and conditions: (i) CH3CN/H2O/H2SO4 (18:5:2), room temp., 24 h;
(ii) aqueous NaIO4, MeOH, room temp., 45 min; (iii) NaBH4,
MeOH, room temp., 3 h; (iv) Ac2O, pyridine, room temp., 12 h,
overall yield 63%.
(CH), 128.5 (CH), 133.7 (CH), 153.5 (C) ppm. IR (neat): ν
=
˜
max
2986, 2934, 2229, 1594, 1487 cm–1. C18H23BrO6 (415.28): calcd. C
52.06, H 5.58; found C 51.88, H 5.45. MS (ESI): m/z = 437 [M +
Na]+ for 79Br.
Conclusions
(3aR,5R,6S,6aR)-6-(2-Bromo-4-cyanophenoxy)-5-(2,2-dimethyl-
1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole
In conclusion, we have developed a straightforward, ef-
ficient synthetic strategy for the palladium-catalyzed intra- (2b): Foamy solid (1.268 g, 2.88 mmol, 72%). Rf = 0.7 (PS/EA, 2:1),
column eluent (PS/EA, 11:1). [α]2D5 = –31.5 (c = 0.65, CHCl3). H
1
molecular C–N bond formation and demonstrated its appli-
cability in the syntheses of benzoxa(thia)zepines and pyri-
doxazepines fused to a sugar template. The reaction was
NMR (300 MHz, CDCl3): δ = 1.31 (s, 3 H), 1.32 (s, 3 H), 1.42 (s,
3 H), 1.56 (s, 3 H), 4.09 (dd, J = 8.4, 5.1 Hz, 1 H), 4.20 (apparent
dd, 1 H), 4.28 (dd, J = 8.1, 2.7 Hz, 1 H), 4.50–4.56 (m, 2 H), 4.80
successful with a variety of d-glucose-derived secondary
(d, J = 2.4 Hz, 1 H), 5.99 (d, J = 3.6 Hz, 1 H), 7.12 (d, J = 8.4 Hz,
amines, and the products were smoothly converted to chiral
benzoxazepines. These findings reveal the possibility of ob-
taining functionalized benzoxa(thia)zepines and pyridox-
azepines in the chiral form.
1 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.85 (s, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 25.0 (CH3), 26.1 (CH3), 26.5 (CH3), 26.7
(CH3), 67.3 (CH2), 71.9 (CH), 80.4 (CH), 81.6 (CH), 82.0 (CH),
105.2 (CH), 106.2 (C), 109.3 (C), 112.4 (C), 113.4 (C), 113.9 (CH),
117.3 (C), 132.9 (CH), 137.0 (CH), 157.0 (C) ppm. IR (KBr): ν
˜
max
= 2986, 2934, 2229, 1594, 1487 cm–1. C19H22BrNO6 (440.29): calcd.
C 51.83, H 5.04, N 3.18; found C 51.70, H 4.95, N 3.07. MS (ESI):
m/z = 462 [M + Na]+ for 79Br.
Experimental Section
General Remarks: 1H and 13C NMR spectroscopic data were re-
corded with a Bruker AM 300L or Avance 600 MHz spectrometer
using CDCl3 as the solvent and TMS as the internal standard.
Mass spectra were obtained with either a JEOL AX-500 or Micro-
mass Q-Tof micro mass spectrometer. X-ray diffraction data were
collected with a Bruker Kappa Apex II diffractometer. IR spectra
were obtained employing a JASCO FTIR Model 410. Elemental
analyses were carried out with a CHN analyzer. Specific rotations
were measured at 589 nm with a JASCO P-1020 polarimeter. TLC
was performed on precoated plates (0.25 mm, silica gel 60F254).
Column chromatography and flash chromatography were carried
out using commercial-grade silica gel (100–200 mesh or 230–
400 mesh). PS and EA are abbreviations for petroleum ether (boil-
ing range 60–80 °C) and ethyl acetate, respectively.
(3aR,5R,6S,6aR)-6-(3-Bromo-5-methylpyridine-2-yloxy)-5-(2,2-
dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]-
dioxole (2c): Foamy solid (1.34 g, 3.12 mmol, 78%). Rf = 0.65 (PS/
EA, 2:1), column eluent (PS/EA, 10:1). [α]2D5 = –21.4 (c = 0.22,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.32 (s, 6 H), 1.42 (s, 3
H), 1.56 (s, 3 H), 2.25 (s, 3 H), 4.11–4.21 (m, 2 H), 4.39 (dd, J =
6.9, 3.3 Hz, 1 H), 4.54 (dd, J = 12.6, 6.0 Hz, 1 H), 4.63 (d, J =
3.6 Hz, 1 H), 5.44 (d, J = 3.0 Hz, 1 H), 5.95 (d, J = 3.6 Hz, 1 H),
7.66 (d, J = 1.5 Hz, 1 H), 7.94 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 16.9 (CH3), 25.1 (CH3), 26.2 (CH3), 26.67 (CH3), 26.69
(CH3), 66.9 (CH2), 72.6 (CH), 78.5 (CH), 79.9 (CH), 82.9 (CH),
105.0 (CH), 106.6 (C), 108.8 (C), 111.9 (C), 128.1 (C), 142.6 (CH),
145.0 (CH), 156.5 (C) ppm. IR (KBr): ν
= 2986, 2936, 2896,
˜
max
1596, 1454 cm–1. C18H24BrNO6 (430.29): calcd. C 50.24, H 5.62, N
3.26; found C 50.08, H 5.48, N 3.18. MS (ESI): m/z = 452 [M +
Na]+ for 79Br.
General Procedure for the Synthesis of Compounds 2a–e: To a mag-
netically stirred solution of 1,2:5,6-di-O-isopropylidine-α-d-allofu-
ranose (1, 1.04 g, 4 mmol) in dry CH2Cl2 (10 mL) at –10 °C was
added pyridine (1 mL) followed by trifluoromethanesulfonic anhy-
dride (1.7 g, 1 mL, 6 mmol). The solution was stirred for 1 h under
a N2 atmosphere, and then it was poured onto crushed ice. The
(3aR,5R,6S,6aR)-6-(2-Iodophenoxy)-5-(2,2-dimethyl-1,3-dioxolan-
4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (2d): Thick oil
(1.48 g, 3.2 mmol, 80%). Rf = 0.7 (PS/EA, 2:1), column eluent (PS/
resulting mixture was extracted with CH2Cl2 (3ϫ30 mL), and the EA, 11:1). [α]2D5 = –28.8 (c = 0.2, CHCl3). 1H NMR (300 MHz,
combined CH2Cl2 extracts were washed with H2O, dried, and con-
centrated to afford a gummy material that was dissolved in dry
CH3CN (25 mL). Anhydrous K2CO3 (1.4 g, 10 mmol) and an ap-
propriately substituted 2-bromophenol/thiophenol (4.8 mmol) were
added to the mixture which was then heated to reflux for 6 h until
completion of reaction (indicated by TLC). The mixture was then
filtered, and the filtrate was concentrated. The residue was diluted
with H2O, and the mixture was extracted with CH2Cl2 (3ϫ30 mL).
The combined CH2Cl2 extracts were washed with H2O, dried, and
CDCl3): δ = 1.31 (s, 3 H), 1.34 (s, 3 H), 1.44 (s, 3 H), 1.55 (s, 3 H),
4.10–4.15 (m, 1 H), 4.23 (dd, J = 7.8, 6.3 Hz, 1 H), 4.29 (dd, J =
8.1, 3.0 Hz, 1 H), 4.58 (d, J = 3.9 Hz, 1 H), 4.63–4.69 (m, 1 H),
4.77 (d, J = 3.0 Hz, 1 H), 6.00 (d, J = 3.9 Hz, 1 H), 6.74–7.80 (m,
4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.2 (CH3), 26.2
(CH3), 26.7 (CH3), 26.8 (CH3), 67.5 (CH2), 72.3 (CH), 80.7 (CH),
81.3 (CH), 82.0 (CH), 87.3 (C), 105.3 (CH), 109.2 (C), 112.1 (C),
113.4 (CH), 123.5 (CH), 129.5 (CH), 139.8 (CH), 155.5 (C) ppm.
IR (neat): ν
= 3397, 2985, 2936, 1577, 1468, 1376, 1240 cm–1.
˜
max
Eur. J. Org. Chem. 2011, 7346–7354
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7349

N. Das Adhikary, P. Chattopadhyay
FULL PAPER
C18H23IO6 (462.28): calcd. C 46.77, H 5.01; found C 46.60, H 4.88.
H), 3.05 (dd, J = 12.3, 5.4 Hz, 1 H), 3.17 (dd, J = 12.3, 7.2 Hz, 1
H), 3.74 (s, 2 H), 4.49–4.55 (m, 1 H), 4.59 (d, J = 3.9 Hz, 1 H),
4.64 (d, J = 3.3 Hz, 1 H), 5.92 (s, 2 H), 5.99 (d, J = 3.9 Hz, 1 H),
6.70–6.77 (m, 2 H), 6.81 (s, 1 H), 6.89 (t, J = 7.5 Hz, 1 H), 7.01 (d,
J = 8.1 Hz, 1 H), 7.26–7.56 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 26.2 (CH3), 26.6 (CH3), 47.1 (CH2), 53.9 (CH2), 79.4
(CH), 81.7 (CH), 82.2 (CH), 100.7 (CH2), 104.9 (CH), 107.9 (CH),
108.6 (CH), 111.7 (C), 112.8 (C), 113.8 (CH), 121.2 (CH), 122.7
(CH), 128.4 (CH), 133.6 (CH), 133.9 (C), 146.3 (C), 147.5 (C),
MS (ESI): m/z = 485 [M + Na]+.
(3aR,5R,6S,6aR)-6-(2-Bromophenylsulfanyl)-5-(2,2-dimethyl-1,3-di-
oxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (2e):
Thick oil (1.224 g, 2.84 mmol, 71%). Rf = 0.7 (PS/EA, 2:1), column
eluent (PS/EA, 11:1). [α]2D5 = –36.2 (c = 0.25, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.29 (s, 3 H), 1.35 (s, 3 H), 1.44 (s, 3 H),
1.54 (s, 3 H), 3.93 (d, J = 3.0 Hz, 1 H), 4.03–4.07 (m, 1 H), 4.15–
4.19 (m, 1 H), 4.36–4.45 (m, 2 H), 4.59 (d, J = 3.3 Hz, 1 H), 5.94
(d, J = 3.3 Hz, 1 H), 7.07–7.59 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 25.1 (CH3), 26.2 (CH3), 26.5 (CH3), 26.8 (CH3), 52.5
(CH), 67.6 (CH2), 73.6 (CH), 79.9 (CH), 84.9 (CH), 105.0 (CH),
109.6 (C), 112.0 (C), 124.5 (C), 127.3 (CH), 127.9 (CH), 129.0
153.3 (C) ppm. IR (KBr): ν
= 3341, 2984, 2931, 1581,
˜
max
1482 cm–1. C22H24BrNO6 (478.33): calcd. C 55.24, H 5.06, N 2.93;
found C 55.02, H 4.93, N 2.78. MS (ESI): m/z = 478 [M + Na]+
for 79Br.
(CH), 133.2 (CH), 135.4 (C) ppm. IR (neat): ν
= 2985, 2935,
˜
max
(3aR,5R,6S,6aR)-N-Benzyl-[6-(2-bromo-4-cyanophenoxy)-2,2-di-
methyltetrahydrofuro[2,3-d][1,3]dioxol-5-ylmethyl]amine (3c):
Gummy material (0.57 g, 1.24 mmol, 62%). Rf = 0.3 (PS/EA, 2:1),
column eluent (PS/EA, 4:1). [α]2D5 = –51.2 (c = 1.12, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 1.32 (s, 3 H), 1.53 (s, 3 H), 1.61 (s,
1 H), 3.03 (dd, J = 12.3, 6.0 Hz, 1 H), 3.19 (dd, J = 12.3, 7.2 Hz,
1 H), 3.82 (s, 2 H), 4.51–4.56 (m, 2 H), 4.69 (d, J = 3.3 Hz, 1 H),
5.99 (d, J = 3.9 Hz, 1 H), 7.08 (d, J = 8.7 Hz, 1 H), 7.21–7.32 (m,
5 H), 7.61 (dd, J = 8.4, 1.8 Hz, 1 H) 7.84 (d, J = 2.1 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 26.2 (CH3), 26.5 (CH3), 47.0
(CH2), 54.1 (CH2), 79.2 (CH), 82.1 (CH), 82.2 (CH), 104.8 (CH),
106.1 (C), 112.1 (C), 113.3 (C), 113.5 (CH), 117.3 (C), 127.0 (CH),
128.0 (2 CH), 128.3 (2 CH), 133.0 (CH), 137.0 (CH), 139.8 (C),
2885, 1580, 1449, 1376 cm–1. C18H23BrO5S (431.34): calcd. C 50.12,
H 5.37; found C 49.94, H 5.24. MS (ESI): m/z = 453 [M + Na]+
for 79Br.
General Procedure for the Synthesis of Compounds 3a–h: Each com-
pound 2a–e (2 mmol) was dissolved in aqueous HOAc (70%, v/v,
60 mL), and the solution was stirred overnight at room temperature
(monitored by TLC until the starting material disappeared). Re-
moval of the HOAc with a rotary evaporator (40 °C) using anhy-
drous toluene (3 ϫ 50 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 slowly treated with a solution of NaIO4
(513 mg, 2.4 mmol) dissolved in water (5 mL). The reaction mix-
ture was stirred for 45 min and then was filtered (using a sintered
funnel). The filtrate was evaporated under reduced pressure, and
the residue was extracted with CHCl3 (4ϫ30 mL). The combined
organic layers were washed with water, dried, and evaporated to
afford the crude aldehyde. This aldehyde was dissolved in dry
CH2Cl2 (35 mL), and the resulting solution was treated with acti-
vated molecular sieves (4 Å) and the appropriate amine (2.4 mmol)
at 0 °C. The mixture was then stirred at room temperature for 12 h
under a N2 atmosphere. Dry MeOH (15 mL) was added followed
by the addition in small portions of NaBH4 (151 mg, 4 mmol) over
a period of 1 h at 0 °C. Stirring was continued for another 2 h at
room temperature. The solvent was evaporated under reduced pres-
sure, and the residue was extracted with CH2Cl2 (4ϫ30 mL). The
combined organic layers were washed with water, dried, and evapo-
rated. Chromatography over silica gel afforded amine 3a–h.
157.0 (C) ppm. IR (KBr): ν
= 3340, 2985, 2931, 2228, 1594,
˜
max
1487, 1378 cm–1. C22H23BrN2O4 (459.33): calcd. C 57.53, H 5.05,
N 6.10; found C 57.31, H 4.95, N 5.98. MS (ESI): m/z = 459 [M
+ H]+ for 79Br.
(3aR,5R,6S,6aR)-N-Benzyl-[6-(3-bromo-5-methylpyridine-2-yl-
oxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-ylmethyl]amine
(3d): Gummy material (0.62 g, 1.38 mmol, 69%). Rf = 0.25 (PS/
EA, 2:1), column eluent (PS/EA, 3:1). [α]2D5 = –38.7 (c = 0.36,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.32 (s, 3 H), 1.54 (s, 3
H), 2.24 (s, 3 H), 2.95 (dd, J = 12.3, 5.4 Hz, 1 H), 3.10 (dd, J =
12.3, 7.5 Hz, 1 H), 3.79 (dd, J = 18.0, 13.2 Hz, 2 H), 4.54–4.59 (m,
1 H), 4.67 (d, J = 3.6 Hz, 1 H), 5.39 (d, J = 3.0 Hz, 1 H), 5.98 (d,
J = 3.9 Hz, 1 H), 7.18–7.31 (m, 5 H), 7.65 (d, J = 1.5 Hz, 1 H)
7.89 (d, J = 1.2 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3,0): δ =
16.9 (CH3), 26.3 (CH3), 26.7 (CH3), 47.5 (CH2), 54.1 (CH2), 79.0
(2 CH), 83.5 (CH), 104.7 (CH), 106.8 (C), 111.7 (C), 126.8 (CH),
128.10 (2 CH), 128.19 (C), 128.2 (2 CH), 140.1 (C), 142.7 (CH),
(3aR,5R,6S,6aR)-N-Benzyl-[6-(2-bromophenoxy)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-ylmethyl]amine (3a): Thick oil
(0.616 g, 1.42 mmol, 71%). Rf = 0.3 (PS/EA, 2:1), column eluent
145.0 (CH), 156.7 (C) ppm. IR (KBr): ν
= 3343, 2983, 2930,
˜
max
1596, 1454, 1380, 1290 cm–1. C21H25BrN2O4 (449.34): calcd. C
56.13, H 5.61, N 6.23; found C 55.92, H 5.46, N 6.07. MS (ESI):
m/z = 449 [M + H]+ for 79Br.
1
(PS/EA, 4:1). [α]2D5 = –48.2 (c = 1.0, CHCl3). H NMR (300 MHz,
CDCl3): δ = 1.31 (s, 3 H), 1.53 (s, 3 H), 1.64 (s, 1 H), 3.08 (dd, J
= 12.3, 5.4 Hz, 1 H), 3.21 (dd, J = 12.3, 7.2 Hz, 1 H), 3.84 (s, 2
H), 4.51–4.57 (m, 1 H), 4.60 (d, J = 3.9 Hz, 1 H), 4.65 (d, J =
3.3 Hz, 1 H), 6.00 (d, J = 3.3 Hz, 1 H), 6.86–6.91 (m, 1 H), 7.01
(d, J = 8.1 Hz, 1 H), 7.22–7.56 (m, 7 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 26.3 (CH3), 26.6 (CH3), 47.4 (CH2), 54.2 (CH2), 79.5
(CH), 81.8 (CH), 82.3 (CH), 105.0 (CH), 111.8 (C), 112.9 (C), 113.9
(CH), 122.7 (CH), 126.9 (CH), 128.17 (2 CH), 128.19 (2 CH), 128.3
(3aR,5R,6S,6aR)-N-[6-(2-Iodophenoxy)-2,2-dimethyltetrahydro-
furo[2,3-d][1,3]dioxol-5-ylmethyl]isopropylamine (3e): Gummy mate-
rial (0.606 g, 1.4 mmol, 70%). Rf = 0.3 (PS/EA, 2:1), column eluent
(PS/EA, 4:1). [α]2D5 = –31.2 (c = 0.45, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 1.05–1.10 (m, 6 H), 1.31 (s, 3 H), 1.54 (s, 3 H), 1.62
(s, 1 H), 2.85–2.89 (m, 1 H), 3.09–3.23 (m, 2 H), 4.53–4.67 (m, 3
H), 6.00 (s, 1 H), 6.77 (s, 1 H), 6.95 (d, J = 7.8 Hz, 1 H), 7.32 (d, J
= 6.6 Hz, 1 H), 7.79 (d, J = 7.5 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 22.6 (CH3), 22.9 (CH3), 26.3 (CH3), 26.6 (CH3), 45.9
(CH2), 49.0 (CH), 79.6 (CH), 81.8 (CH), 82.2 (CH), 86.9 (C), 104.9
(CH), 133.7 (CH), 140.0 (C), 153.4 (C) ppm. IR (neat): ν
=
˜
max
3328, 3062, 2984, 2929, 2854, 1663, 1581 cm–1. C21H24BrNO4
(434.32): calcd. C 58.07, H 5.57, N 3.22; found C 57.88, H 5.43, N
3.08. MS (ESI): m/z = 456 [M + Na]+ for 79Br.
(3aR,5R,6S,6aR)-N-(1,3-Benzodioxol-5-ylmethyl)-[6-(2-bromo- (CH), 111.8 (C), 112.7 (CH), 123.3 (CH), 129.5 (CH), 139.8 (CH),
phenoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-ylmethyl]-
amine (3b): Gummy material (0.65 g, 1.36 mmol, 68%). Rf = 0.3
155.4 (C) ppm. IR (KBr): ν
= 3403, 2963, 1577, 1467, 1375,
˜
max
1240, 1164 cm–1. C17H24INO4 (433.28): calcd. C 47.12, H 5.58, N
(PS/EA, 2:1), column eluent (PS/EA, 4:1). [α]2D5 = –39.3 (c = 1.2,
3.23; found C 46.93, H 5.41, N 3.03. MS (ESI): m/z = 434 [M +
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.31 (s, 3 H), 1.53 (s, 3 H]+.
7350
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7346–7354

Chiral Benzoxa(thia)zepine and Pyridoxazepine Derivatives
(3aR,5R,6S,6aR)-N-Benzyl-[6-(2-bromophenylsulfanyl)-2,2-di-
methyltetrahydrofuro[2,3-d][1,3]dioxol-5-ylmethyl]amine (3f): Thick
oil (0.585 g, 1.3 mmol, 65%). Rf = 0.3 (PS/EA, 2:1), column eluent
(0.6 mL) was added dropwise. After 1 h, the mixture was poured
onto crushed ice, and the resulting solution was extracted with
CH2Cl2 (3 ϫ25 mL). The combined organic layers were washed
with water and dried with Na2SO4. Evaporation of the solvent af-
forded the mesylate as a brown, gummy material which was dis-
solved in dry DMF (20 mL). NaN3 (1.95 g, 30 mmol) was added,
(PS/EA, 4:1). [α]2D5 = –43.7 (c = 0.6, CHCl3). H NMR (300 MHz,
1
CDCl3): δ = 1.28 (s, 3 H), 1.52 (s, 3 H), 1.65 (s, 1 H), 2.99 (dd, J
= 12.3, 5.4 Hz, 1 H), 3.09 (dd, J = 10.8, 7.5 Hz, 1 H), 3.80 (d, J =
3.9 Hz, 1 H), 3.86 (d, J = 3.6 Hz, 2 H), 4.57 (d, J = 3.6 Hz, 1 H), and the mixture was heated to 80 °C for 5 h under a N2 atmosphere
4.66–4.71 (m, 1 H), 5.97 (d, J = 3.6 Hz, 1 H), 7.08–7.35 (m, 6 H), and then filtered. The filtrate was extracted with ethyl acetate
7.41 (dd, J = 7.8, 1.5 Hz, 2 H), 7.58–7.61 (m, 1 H) ppm. 13C NMR (3ϫ25 mL), and the combined organic layers were washed with
(75 MHz, CDCl3): δ = 26.2 (CH3), 26.4 (CH3), 49.2 (CH2), 54.0 water and dried with Na2SO4. Evaporation of the solvent afforded
(CH2), 78.2 (CH), 85.0 (CH), 104.7 (CH), 111.7 (C), 125.2 (C),
126.8 (CH), 127.7 (CH), 128.0 (3 CH), 128.2 (2 CH), 129.7 (CH),
the azide as a syrupy liquid which was dissolved in dry Et2O
(20 mL). This solution was added dropwise to a stirred suspension
of LAH (275 mg, 7 mmol) in dry Et2O (20 mL) at 0 °C under a N2
atmosphere. After 3 h of stirring, a saturated solution of Na2SO4
(2 mL) was added dropwise. The mixture was filtered, washed, and
evaporated. Column chromatography over neutral alumina af-
forded the desired amine as a colorless, thick oil (0.435 g,
1.26 mmol, 42%). Rf = 0.4 (PS/EA, 1:1), column eluent (PS/EA,
133.3 (CH), 135.1 (C), 139.7 (C), 160.2 (C) ppm. IR (neat): ν
˜
max
= 3330, 2985, 2934, 2834, 1950, 1662, 1577 cm–1. C21H24BrNO3S
(450.39): calcd. C 56.00, H 5.37, N 3.11; found C 55.76, H 5.23, N
2.95. MS (ESI): m/z = 450 [M + H]+ for 79Br.
(3aR,5R,6S,6aR)-N-(1,3-Benzodioxol-5-ylmethyl)-[6-(2-bromo-
phenylsulfanyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl-
methyl]amine (3g): Oil (0.65 g, 1.32 mmol, 66%). Rf = 0.3 (PS/EA,
2:1), column eluent (PS/EA, 4:1). [α]2D5 = –36.8 (c = 0.7, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 1.44 (s, 3 H), 1.47 (s, 3 H), 1.59
(s, 1 H), 2.95 (dd, J = 12.3, 5.4 Hz, 1 H), 3.05 (dd, J = 12.3, 7.2 Hz,
1 H), 3.69 (d, J = 5.4 Hz, 2 H), 4.63–4.69 (m, 1 H), 5.11 (apparent
d, 1 H), 5.29 (d, J = 3.3 Hz, 1 H), 5.93 (s, 2 H), 5.96 (d, J = 3.6 Hz,
1 H), 6.75 (s, 1 H), 6.79–6.85 (m, 2 H), 7.08–7.61 (m, 4 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 27.7 (CH3), 28.1 (CH3), 45.6
(CH2), 52.8 (CH2), 78.3 (CH), 83.6 (CH), 85.1 (CH), 100.8 (CH2),
104.8 (CH), 106.0 (CH), 108.0 (CH), 111.9 (C), 121.2 (CH), 125.4
(C), 127.8 (CH), 128.1 (CH), 130.0 (CH), 133.4 (CH), 133.9 (C),
2:1). [α]2D5 = –53.7 (c = 1.4, CHCl3). H NMR (300 MHz, CDCl3):
1
δ = 1.32 (s, 3 H), 1.47 (s, 2 H), 1.55 (s, 3 H), 3.16 (dd, J = 13.2,
6.0 Hz, 1 H), 3.26 (dd, J = 13.2, 6.6 Hz, 1 H), 4.39–4.44 (m, 1 H),
4.60 (d, J = 3.9 Hz, 1 H), 4.69 (d, J = 3.3 Hz, 1 H), 6.02 (d, J =
4.2 Hz, 1 H), 6.87–7.57 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 26.2 (CH3), 26.6 (CH3), 40.5 (CH2), 81.2 (CH), 81.8
(CH), 82.3 (CH), 104.9 (CH), 111.8 (C), 112.8 (C), 113.8 (CH),
122.8 (CH), 128.5 (CH), 133.7 (CH), 153.3 (C) ppm. IR (neat): ν
˜
max
= 3382, 2983, 2935, 2102, 1590, 1477 cm–1. C14H18BrNO4 (344.20):
calcd. C 48.85, H 5.27, N 4.07; found C 48.61, H 5.11, N 3.85. MS
(ESI): m/z = 344 [M + H]+ for 79Br.
135.2 (C), 146.5 (C), 147.6 (C) ppm. IR (neat): ν
= 3327, 2965,
General Procedure for the Cycloamination Reaction of 3a–h, and 5:
˜
max
2618, 1663, 1451, 1376, 1322 cm–1. C22H24BrNO5S (494.39): calcd. To a solution of each amine 3a–d, f–h, and 5 (1 mmol) in dry tolu-
C 53.45, H 4.89, N 2.83; found C 53.23, H 4.63, N 2.71. MS (ESI):
ene (10 mL/mmol substrate) were added tBuOK (224 mg, 2 equiv.),
K2CO3 (276 mg, 2 equiv.), Pd2(dba)3 (10 mol-%), and (Ϯ)-BINAP
(7 mol-%). To a solution of amine 3e (1 mmol) in dry toluene
(10 mL/mmol substrate) were added tBuOK (448 mg, 4 equiv.),
Pd2(dba)3 (10 mol-%), and Xantphos (7 mol-%). The reaction mix-
tures were heated at reflux for 15 h under an argon atmosphere.
After completion of each reaction (monitored by TLC), the crude
mixtures were passed through a bed of silica gel. The solvents were
evaporated, and the residues were extracted with CH2Cl2
(4ϫ25 mL). The organic layers were washed with water and then
dried. The solvents were evaporated under reduced pressure to give
the crude products which were purified by column chromatography
over silica gel to furnish each pure cyclized product 4a–h, and 6.
m/z = 494 [M + H]+ for 79Br.
(3aR,5R,6S,6aR)-N-[6-(2-Bromophenylsulfanyl)-2,2-dimethyltetra-
hydrofuro[2,3-d][1,3]dioxol-5-ylmethyl]butylamine (3h): Oil (0.575 g,
1.38 mmol, 69%). Rf = 0.3 (PS/EA, 2:1), column eluent (PS/EA,
4:1). [α]2D5 = –38.5 (c = 0.55, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 0.91 (t, J = 7.2 Hz, 3 H), 1.32–1.39 (m, 2 H), 1.44 (s, 3 H), 1.46
(s, 3 H), 1.49–1.51 (m, 2 H), 1.53 (s, 1 H), 2.58–2.69 (m, 2 H), 2.96
(dd, J = 12.3, 5.1 Hz, 1 H), 3.05 (dd, J = 12.3, 7.8 Hz, 1 H), 4.65–
4.71 (m, 1 H), 5.09 (apparent d, 1 H), 5.28 (d, J = 3.3 Hz, 1 H), 6.05
(d, J = 5.4 Hz, 1 H), 7.10–7.62 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 13.8 (CH3), 20.2 (CH2), 27.7 (CH3), 28.0 (CH3), 32.0
(CH2), 46.6 (CH2), 49.0 (CH2), 78.2 (CH), 83.6 (CH), 98.4 (CH),
106.0 (CH), 111.8 (C), 125.4 (C), 127.7 (CH), 128.0 (CH), 129.9
(2R,3R,3aS,10aR)-9-Benzyl-2,3-isopropylidenedioxy-2,3,3a,9,
(CH), 133.4 (CH), 135.1 (C) ppm. IR (neat): ν
= 3404, 2931, 10,10a-hexahydro-2H-furo[3,2-c][1,5]benzoxazepine (4a): Crystalline
˜
max
2864, 1661, 1455, 1376, 1321 cm–1. C18H26BrNO3S (416.37): calcd. solid (0.27 g, 0.77 mmol, 77%); m.p. 162 °C. Rf = 0.7 (PS/EA, 2:1),
C 51.92, H 6.29, N 3.36; found C 51.78, H 6.11, N 3.18. MS (ESI):
column eluent (PS/EA, 11:1). [α]2D5 = +36.9 (c = 0.7, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 1.33 (s, 3 H), 1.48 (s, 3 H), 3.39 (dd,
J = 13.8, 6.3 Hz, 1 H), 3.78 (dd, J = 13.8, 9.9 Hz, 1 H), 4.36 (d, J
= 15.6 Hz, 1 H), 4.50–4.57 (m, 2 H), 4.62 (d, J = 3.0 Hz, 1 H), 4.76
(d, J = 3.6 Hz, 1 H), 6.02 (d, J = 3.6 Hz, 1 H), 6.65–7.36 (m, 9
H) ppm. 13C NMR (150 MHz, CDCl3): δ = 26.4 (CH3), 27.0 (CH3),
51.8 (CH2), 56.4 (CH2), 77.9 (CH), 84.5 (CH), 85.3 (CH), 105.9
(CH), 111.8 (C), 116.3 (CH), 119.4 (CH), 121.0 (CH), 123.8 (CH),
127.2 (3 CH), 128.6 (2 CH), 138.1 (C), 141.2 (C), 147.0 (C) ppm.
m/z = 416 [M + H]+ for 79Br.
(3aR,5R,6S,6aR)-[6-(2-Bromophenoxy)-2,2-dimethyltetrahydro-
furo[2,3-d][1,3]dioxol-5-yl]methylamine (5): To an ice-cold, stirred
solution of the aldehyde derived from compound 2a (3 mmol), pre-
pared by the above procedure, dissolved in dry MeOH (30 mL) was
added NaBH4 (220 mg, 6 mmol) in small portions over 1 h. The
stirring was continued for another 1 h at room temperature to com-
plete the reaction. The solvent was evaporated under reduced pres-
sure, and the residue was extracted with CH2Cl2 (4ϫ25 mL). The
combined organic layers were washed with water and dried with
Na2SO4. Evaporation of the solvent afforded the alcohol as a crude
oil. To an ice-cold, stirred solution of this alcohol in CH2Cl2
(25 mL) was added Et3N (5 mL). The reaction mixture was stirred
for 15 min under a N2 atmosphere. Methanesulfonyl chloride
IR (KBr): ν
= 2990, 2938, 1598, 1498, 1449 cm–1. C21H23NO4
˜
max
(353.41): calcd. C 71.37, H 6.56, N 3.96; found C 71.13, H 6.40, N
3.82. MS (ESI): m/z = 376 [M + Na]+.
(2R,3R,3aS,10aR)-9-(1,3-Benzodioxol-5-yl-methyl)-2,3-isopropyl-
idenedioxy-2,3,3a,9,10,10a-hexahydro-2H-furo[3,2-c][1,5]-
benzoxazepine (4b): Foamy solid (0.315 g, 0.79 mmol, 79%). Rf =
Eur. J. Org. Chem. 2011, 7346–7354
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7351

N. Das Adhikary, P. Chattopadhyay
FULL PAPER
0.7 (PS/EA, 2:1), column eluent (PS/EA, 9:1). [α]2D5 = +49.3 (c =
(2R,3R,3aS,10aR)-9-Benzyl-2,3-isopropylidenedioxy-2,3,3a,9,
1.15, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.34 (s, 3 H), 1.49 10,10a-hexahydro-2H-furo[3,2-c][1,5]benzothiazepine (4f): Foamy
(s, 3 H), 3.37 (dd, J = 13.8, 6.0 Hz, 1 H), 3.72 (dd, J = 13.8, 9.9 Hz,
1 H), 4.24 (d, J = 15.3 Hz, 1 H), 4.43 (d, J = 15.3 Hz, 1 H), 4.49–
4.55 (m, 1 H), 4.60 (d, J = 3.0 Hz, 1 H), 4.76 (d, J = 3.6 Hz, 1 H),
5.94 (s, 2 H), 6.02 (d, J = 3.9 Hz, 1 H), 6.67–7.33 (m, 7 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 26.2 (CH3), 26.8 (CH3), 51.3
solid (0.275 g, 0.75 mmol, 75%). Rf = 0.7 (PS/EA, 2:1), column
eluent (PS/EA, 9:1). [α]2D5 = +29.6 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 1.31 (s, 3 H), 1.48 (s, 3 H), 3.40 (dd, J =
14.4, 4.8 Hz, 1 H), 4.21 (d, J = 3.9 Hz, 1 H), 4.36 (dd, J = 14.4,
9.6 Hz, 1 H), 4.41 (d, J = 6.9 Hz, 1 H), 4.51–4.56 (m, 3 H), 5.91
(CH2), 56.0 (CH2), 77.9 (CH), 84.4 (CH), 85.1 (CH), 100.8 (CH2), (d, J = 3.6 Hz, 1 H), 6.62–7.52 (m, 9 H) ppm. 13C NMR (75 MHz,
105.8 (CH), 107.6 (CH), 108.1 (CH), 111.6 (C), 116.3 (CH), 119.3 CDCl3): δ = 26.4 (CH3), 26.8 (CH3), 51.5 (CH2), 53.5 (CH), 56.6
(CH), 120.3 (CH), 120.9 (CH), 123.6 (CH), 131.8 (C), 141.1 (C), (CH2), 76.8 (CH), 84.5 (CH), 105.7 (CH), 111.8 (C), 116.5 (CH),
146.6 (C), 146.9 (C), 147.8 (C) ppm. IR (KBr): ν
= 2979, 2934, 119.2 (CH), 119.5 (C), 127.2 (3 CH), 127.5 (CH), 128.6 (2 CH),
˜
max
1600, 1495, 1444 cm–1. C22H23NO6 (397.42): calcd. C 66.49, H 5.83,
N 3.52; found C 66.27, H 5.61, N 3.38. MS (ESI): m/z = 420 [M
+ Na]+.
131.4 (CH), 137.8 (C), 149.2 (C) ppm. IR (KBr): νmax = 2986 cm–1.
˜
HRMS: calcd. for C21H23NO3SNa+ [M + Na]+ 392.1296; found
392.1302.
(2R,3R,3aS,10aR)-9-Benzyl-2,3-isopropylidenedioxy-7-cyano- (2R,3R,3aS,10aR)-9-(1,3-Benzodioxol-5-yl-methyl)-2,3-isopropyl-
2,3,3a,9,10,10a-hexahydro-2H-furo[3,2-c][1,5]benzoxazepine (4c):
Gummy material (0.235 g, 0.62 mmol, 62%). Rf = 0.7 (PS/EA, 2:1),
column eluent (PS/EA, 9:1). [α]2D5 = +58.4 (c = 1.2, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 1.34 (s, 3 H), 1.48 (s, 3 H), 3.43 (dd,
J = 13.8, 6.3 Hz, 1 H), 3.74 (dd, J = 13.8, 10.2 Hz, 1 H), 4.32 (d,
idenedioxy-2,3,3a,9,10,10a-hexahydro-2H-furo[3,2-c][1,5]benzo-
thiazepine (4g): Gummy material (0.315 g, 0.76 mmol, 76%). Rf =
0.7 (PS/EA, 2:1), column eluent (PS/EA, 9:1). [α]2D5 = +32.2 (c =
0.68, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.31 (s, 3 H), 1.49
(s, 3 H), 3.37 (dd, J = 14.7, 4.8 Hz, 1 H), 4.17 (d, J = 3.9 Hz, 1 H),
J = 15.8 Hz, 1 H), 4.48–4.57 (m, 2 H), 4.66 (d, J = 3.0 Hz, 1 H), 4.29 (d, J = 15.6 Hz, 1 H), overlapped with 4.29–4.34 (m, 1 H),
4.76 (d, J = 3.6 Hz, 1 H), 6.02 (d, J = 3.6 Hz, 1 H), 6.88–7.39 (m, 4.43 (d, J = 15.6 Hz, 1 H), 4.51–4.55 (m, 2 H), 5.91 (d, J = 3.9 Hz,
8 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.3 (CH3), 26.8
1 H), 5.94 (d, J = 2.1 Hz, 2 H), 6.64–6.78 (m, 4 H), 6.98 (d, J =
(CH3), 51.7 (CH2), 56.3 (CH2), 77.1 (CH), 84.2 (CH), 85.6 (CH), 6.9 Hz, 1 H), 7.18 (dd, J = 7.8, 1.2 Hz, 2 H) ppm. 13C NMR
106.0 (CH), 107.2 (C), 112.1 (C), 119.1 (C), 119.4 (CH), 121.9 (C), (75 MHz, CDCl3): δ = 26.3 (CH3), 26.7 (CH3), 51.3 (CH2), 53.4
123.6 (CH), 127.1 (2 CH), 127.7 (CH), 128.9 (2 CH), 136.6 (CH),
141.9 (C), 150.3 (C) ppm. IR (KBr): νmax = 2985, 2936, 2225, 1595,
(CH), 56.4 (CH2), 76.7 (CH), 84.4 (CH), 100.9 (CH2), 105.6 (CH),
107.7 (CH), 108.3 (CH), 111.7 (C), 116.5 (CH), 119.3 (CH), 119.8
˜
1501, 1428 cm–1. C22H22N2O4 (378.42): calcd. C 69.83, H 5.86, N (C), 120.3 (CH), 127.5 (CH), 131.4 (CH), 131.6 (C), 147.7 (C),
7.40; found C 69.67, H 5.68, N 7.26. MS (ESI): m/z = 401 [M +
147.9 (C), 149.2 (C) ppm. IR (KBr): νmax = 3058, 2925, 2857, 2361,
˜
Na]+.
1726, 1671 cm–1. C22H23NO5S (413.48): calcd. C 63.90, H 5.61, N
3.39; found C 63.68, H 5.49, N 3.27. MS (ESI): m/z = 436 [M +
Na]+.
(2R,3R,3aS,10aR)-9-Benzyl-2,3-isopropylidenedioxy-7-methyl-
2,3,3a,9,10,10a-hexahydro-5-aza-2H-furo[3,2-c][1,5]benzoxazepine
(4d): Gummy material (0.27 g, 0.73 mmol, 73%). Rf = 0.65 (PS/
(2R,3R,3aS,10aR)-9-Butyl-2,3-isopropylidenedioxy-2,3,3a,9,
10,10a-hexahydro-2H-furo[3,2-c][1,5]benzothiazepine (4h): Oil
EA, 2:1), column eluent (PS/EA, 9:1). [α]2D5 = +21.9 (c = 0.85,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.33 (s, 3 H), 1.48 (s, 3 (0.245 g, 0.73 mmol, 73%). Rf = 0.7 (PS/EA, 2:1), column eluent
H), 2.15 (s, 3 H), 3.40 (dd, J = 13.8, 6.6 Hz, 1 H), 3.71 (dd, J = (PS/EA, 9:1). [α]2D5 = +23.7 (c = 0.4, CHCl3). 1H NMR (300 MHz,
13.8, 10.2 Hz, 1 H), 4.28 (d, J = 15.6 Hz, 1 H), 4.51–4.56 (m, 2 H), CDCl3): δ = 0.95 (t, J = 7.5 Hz, 3 H), 1.25–1.42 (m, 2 H), over-
4.73 (d, J = 2.7 Hz, 1 H), 4.87 (d, J = 3.3 Hz, 1 H), 6.03 (d, J = lapped with 1.34 (s, 3 H), 1.55 (s, 3 H), 1.59–1.64 (m, 2 H), 3.07–
3.6 Hz, 1 H), 6.77 (s, 1 H), 7.22–7.38 (m, 5 H), 7.49 (s, 1 H) ppm.
3.16 (s, 1 H), 3.23 (dd, J = 8.7, 6.0 Hz, 1 H), 3.31 (dd, J = 14.4,
4.8 Hz, 1 H), 4.11 (d, J = 3.9 Hz, 1 H), 4.24 (dd, J = 14.4, 9.3 Hz,
13C NMR (75 MHz, CDCl3): δ = 17.6 (CH3), 26.2 (CH3), 26.9
(CH3), 51.6 (CH2), 55.8 (CH2), 77.5 (CH), 84.0 (CH), 84.2 (CH), 1 H), 4.51 (d, J = 3.6 Hz, 1 H), 4.68 (dd, J = 10.8, 4.8 Hz, 1 H), 5.94
106 (CH), 111.9 (C), 124.5 (CH), 127.2 (2 CH), 127.4 (CH), 128.7 (d, J = 3.6 Hz, 1 H), 6.63–7.18 (m, 4 H) ppm. 13C NMR (75 MHz,
(2 CH), 129.6 (C), 135.8 (C), 136.9 (CH), 137.2 (C), 150.9 (C) ppm.
IR (KBr): ν
= 2986, 2934, 1590, 1454, 1377, 1246 cm–1
CDCl3): δ = 13.8 (CH3), 20.2 (CH2), 26.2 (CH3), 26.8 (CH3), 29.3
(CH2), 51.7 (CH2), 52.6 (CH2), 53.1 (CH), 77.1 (CH), 84.4 (CH),
105.6 (CH), 111.7 (C), 115.9 (CH), 118.7 (CH), 119.8 (C), 127.4
.
˜
max
C21H24N2O4 (368.43): calcd. C 68.46, H 6.57, N 7.60; found C
68.24, H 6.39, N 7.44. MS (ESI): m/z = 391 [M + Na]+.
(CH), 131.7 (CH), 149.4 (C) ppm. IR (neat): ν
= 2955, 2929,
˜
max
2868, 1727, 1584, 1481, 1375 cm–1. C18H25NO3S (335.46): calcd. C
64.45, H 7.51, N 4.18; found C 64.19, H 7.29, N 3.04. MS (ESI):
m/z = 358 [M + Na]+.
(2R,3R,3aS,10aR)-9-Isopropyl-2,3-isopropylidenedioxy-2,3,3a,9,
10,10a-hexahydro-2H-furo[3,2-c][1,5]benzoxazepine (4e): Foamy so-
lid (0.21 g, 0.69 mmol, 69%). Rf = 0.7 (PS/EA, 2:1), column eluent
(PS/EA, 9:1). [α]2D5 = +47.4 (c = 1.11, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 1.12 (d, J = 6.6 Hz, 3 H), 1.24 (d, J = 6.9 Hz, 3 H),
1.34 (s, 3 H), 1.52 (s, 3 H), 3.36 (dd, J = 14.1, 9.9 Hz, 1 H), 3.47
(dd, J = 14.1, 6.3 Hz, 1 H), 3.86 (t, J = 6.6 Hz, 1 H), 4.48–4.54 (m,
1 H), 4.58 (d, J = 3.0 Hz, 1 H), 4.73 (d, J = 3.9 Hz, 1 H), 6.05 (d,
(2R,3R,3aS,10aR)-2,3-Isopropylidenedioxy-2,3,3a,9,10,10a-hexa-
hydro-2H-furo[3,2-c][1,5]benzoxazepine (6): Foamy solid (0.205 g,
0.78 mmol, 78%). Rf = 0.5 (PS/EA, 2:1), column eluent (PS/EA,
5:1). [α]2D5 = +54.2 (c = 1.25, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 1.34 (s, 3 H), 1.51 (s, 3 H), 3.49–3.53 (m, 1 H), 3.60–3.67 (m,
2 H), 4.59–4.65 (m, 2 H), 4.76 (d, J = 3.9 Hz, 1 H), 6.05 (d, J =
J = 3.6 Hz, 1 H), 6.63–6.73 (m, 2 H), 6.86–6.94 (m, 2 H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 17.3 (CH3), 21.6 (CH3), 26.2 (CH3), 3.6 Hz, 1 H), 6.56–6.88 (m, 4 H) ppm. 13C NMR (75 MHz,
26.9 (CH3), 44.6 (CH2), 47.8 (CH), 79.6 (CH), 84.4 (CH), 84.5 CDCl3): δ = 26.3 (CH3), 26.9 (CH3), 46.2 (CH2), 78.9 (CH), 84.6
(CH), 106.1 (CH), 111.8 (C), 115.1 (CH), 118.4 (CH), 121.1 (CH), (CH), 85.6 (CH), 105.7 (CH), 111.7 (C), 117.7 (CH), 119.6 (CH),
123.6 (CH), 141.5 (C), 146.6 (C) ppm. IR (KBr): νmax = 2980, 2941, 121.2 (CH), 123.7 (CH), 140.0 (C), 146.0 (C) ppm. IR (KBr): ν
˜
2889, 1597, 1496, 1381 cm–1. C17H23NO4 (305.37): calcd. C 66.86,
H 7.59, N 4.59; found C 66.58, H 7.41, N 4.39. MS (ESI): m/z =
328 [M + Na]+.
˜
max
= 3396, 2990, 2954, 1601, 1496, 1378 cm–1. C14H17NO4 (263.29):
calcd. C 63.87, H 6.51, N 5.32; found C 63.69, H 6.37, N 5.18. MS
(ESI): m/z = 286 [M + Na]+.
7352
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7346–7354

Chiral Benzoxa(thia)zepine and Pyridoxazepine Derivatives
Weintraub, J. S. Sabol, J. M. Kane, D. R. Borcherding, Tetrahe-
dron 2003, 59, 2953–2989; c) F. E. Dutton, B. H. Lee, S. S.
Johnson, E. M. Coscarell, P. H. Lee, J. Med. Chem. 2003, 46,
2057–2073; d) H. Yoshida, E. Shirakawa, Y. Honda, T. Hi-
yama, Angew. Chem. 2002, 114, 3381; Angew. Chem. Int. Ed.
2002, 41, 3247–3249; e) Z.-Y. Zhan, P. B. Dervan, Bioorg. Med.
Chem. 2000, 8, 2467–2474; f) M. Bujard, V. Gouverneur, C.
Mioskowski, J. Org. Chem. 1999, 64, 2119–2123; g) J.-L.
Montchamp, J. W. Frost, J. Org. Chem. 1994, 59, 7596–7601;
h) C. N. Hodge, J. Pierce, Bioorg. Med. Chem. Lett. 1993, 3,
1605–1608; i) R. A. Gibbs, S. Taylor, S. J. Benkovic, Science
1992, 258, 803–805; j) C. S. Cooper, P. L. Klock, D. T. W. Chu,
P. B. Fernandes, J. Med. Chem. 1990, 33, 1246–1252; k) K. P.
Boegesoe, J. Arnt, V. Boeck, A. V. Christensen, J. Hyttel, K. G.
Jensen, J. Med. Chem. 1988, 31, 2247–2256.
(2R,3R)-3-Acetoxy-2-acetoxymethyl-5-benzyl-2,3,4,5-tetrahydro-
benzo[b][1,5]oxazepine (7): Compound 4a (0.5 mmol) was dissolved
in 5% H2SO4 (25 mL) in CH3CN/H2O (3:1), and the solution was
kept at room temperature for 24 h. Then the acidic solution was
neutralized with solid NaHCO3, and the resulting solution was fil-
tered. The filtrate was evaporated in vacuo. The residue was dis-
solved in a minimum volume of MeOH, and the solution was
treated dropwise with an aqueous solution of NaIO4 (128 mg,
0.6 mmol) at 0 °C and then stirred for 45 min. Usual workup fol-
lowed by a 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 the crude product. Purification by
silica gel flash chromatography to afforded 7 as a gummy material
(0.115 g, 0.315 mmol, 63%). Rf = 0.65 (PS/EA, 2:1), column eluent
[4]
[5]
W. J. Van der Burg, DE2347727, 1974 [Chem. Abstr. 1974,
3986, DE2347727].
C. G. Neochoritis, C. A. Tsoleridis, J. S. Stephanatou, C. A.
Kontogiorgis, D. J. Hadjipavlou-Litina, J. Med. Chem. 2010,
53, 8409–8420.
1
(PS/EA, 9:1). [α]2D5 = –6.2 (c = 1.6, CHCl3). H NMR (300 MHz,
CDCl3): δ = 2.03 (s, 3 H), 2.07 (s, 3 H), 3.40 (dd, J = 13.8, 6.0 Hz,
1 H), 3.68 (dd, J = 13.8, 9.0 Hz, 1 H), 4.20 (dd, J = 11.7, 4.8 Hz,
1 H), 4.33–4.53 (m, 3 H), 4.62–4.65 (m, 1 H), 5.11–5.15 (m, 1 H),
6.74–7.37 (m, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.6 (2
CH3), 52.0 (CH2), 56.4 (CH2), 62.7 (CH2), 69.9 (CH), 78.8 (CH),
116.8 (CH), 120.1 (CH), 120.6 (CH), 123.6 (CH), 127.1 (CH), 127.2
(2 CH), 128.5 (2 CH), 137.9 (C), 141.3 (C), 148.7 (C), 170.0 (C),
[6]
[7]
G. Walther, C. S. Schneider, K. H. Weber, A. Fuegner,
DE3008944, 1981 [Chem. Abstr. 1982, 6777, DE3008944].
a) S. Butini, S. Gemma, M. Brindisi, G. Borrelli, A. Lossani,
A. M. Ponte, M. Torti, G. Maga, L. Marinelli, V. L. Pietra, I.
Fiorini, S. Lamponi, G. Campiani, D. M. Zisterer, S. M.
Nathwani, S. Sartini, C. L. Motta, F. D. Settimo, E. Novellino,
F. Focher, J. Med. Chem. 2011, 54, 1401–1420; b) G. Campiani,
V. Nacci, I. Fiorini, M. P. D. Filippis, A. Garofalo, G. Greco,
E. Novellino, S. Altamura, L. D. Renzo, J. Med. Chem. 1996,
39, 2672–2680; c) J. M. Klunder, K. D. Hargrave, M. West, E.
Cullen, K. Pal, M. L. Behnke, S. R. Kapadia, D. W. McNeil,
J. C. Wu, G. C. Chow, J. Adams, J. Med. Chem. 1992, 35, 1887–
1897; d) V. J. Merluzzi, K. D. Hargrave, M. Labadia, K. Groz-
inger, M. Skoog, J. C. Wu, C.-K. Shih, K. Eckner, S. Hattox,
J. Adams, A. S. Rosenthal, R. Faanes, R. J. Eckner, R. A.
Koup, J. L. Sullivan, Science 1990, 250, 1411–1413.
a) R. A. Smits, H. D. Lim, B. Stegink, R. A. Bakker, I. J. P.
de Esch, R. Leurs, J. Med. Chem. 2006, 49, 4512–4516; b) G.
Campiani, V. Nacci, I. Fiorini, M. P. D. Filippis, A. Garofalo,
G. Greco, E. Novellino, S. Altamura, D. Renzo, J. Med. Chem.
1996, 39, 2672–2680; c) R. Li, P. S. Farmer, J. Wang, R. J. Boyd,
T. S. Cameron, M. A. Quilliam, J. A. Walter, S. E. Howlett,
Drug Des. Discovery 1995, 12, 337–358.
170.5 (C) ppm. IR (KBr): ν
= 3450, 3029, 2968, 2910, 2856,
˜
max
1732, 1599 cm–1. C21H23NO5 (369.41): calcd. C 68.28, H 6.28, N
3.79; found C 68.04, H 6.12, N 3.65. MS (ESI): m/z = 392 [M +
Na]+.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra for 2a–e, 3a–f, 4a–h, 5, 6, and 7.
Acknowledgments
Financial assistance from the Department of Science and Technol-
ogy (DST), New Delhi is highly acknowledged. N. D. A. thanks the
Council of Scientific and Industrial Research (CSIR) for providing
a research fellowship. We acknowledge Dr. B. Achari, emeritus sci-
entist at the Indian Institute of Chemical Biology, for his interest
in this work.
[8]
[9]
J. B. Bariwal, K. D. Upadhyay, A. T. Manvar, J. C. Trivedi, J. S.
Singh, K. S. Jain, A. K. Shah, Eur. J. Med. Chem. 2008, 43,
2279–2290.
J. F. F. Liegeois, F. A. Rogister, J. Bruhwyler, J. Damas, T. P.
Nguyen, M. O. E. Inarejos, M. G. Chleide, M. G. A. Mercier,
J. E. Delarge, J. Med. Chem. 1994, 37, 519–525.
[1] a) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev.
2003, 103, 893–930; b) K. C. Nicolaou, J. A. Pfefferkorn, A. J.
Roecker, G. Q. Cao, S. Berluenga, H. J. Mitchell, J. Am. Chem.
Soc. 2000, 122, 9939–9953; c) B. E. Evans, K. E. Rittle, M. G.
Bock, R. M. DiPardo, R. M. Freidinger, W. L. Whitter, G. F.
Lundell, D. F. Veber, P. S. Anderson, S. L. R. Chang, V. J.
Lotti, D. J. Chen, T. B. Carino, P. J. Kling, K. A. Kunkel, J. P.
Springes, J. Hirshfield, J. Med. Chem. 1988, 31, 2235–2246.
[2] For selected examples, see: a) E. G. Occhiato, C. Prandi, A.
Ferrali, A. Guarna, P. Venturello, J. Org. Chem. 2003, 68,
9728–9741; b) D. Renneberg, P. B. Dervan, J. Am. Chem. Soc.
2003, 125, 5707–5716; c) A. Cutignano, A. Tramice, S.
De Caro, G. Villani, G. Cimino, A. Fontana, Angew. Chem.
2003, 115, 2737; Angew. Chem. Int. Ed. 2003, 42, 2633–2636;
d) A. S. Kende, J. I. M. Hernando, J. B. J. Milbank, Org. Lett.
2001, 3, 2505–2508; e) J. D. Hepworth, B. M. Heron, Prog. Het-
erocycl. Chem. 2001, 13, 317–339; f) J. A. Joule, K. Mills, in:
Heterocyclic Chemistry, 4th ed., Blackwell, Oxford, 2000; g) J.
Deng, S. Zhao, Z. Miao, Nat. Prod. Lett. 1993, 2, 283–286; h)
R. Zimmer, Synthesis 1993, 165–178; i) P. A. Evans, A. B.
Holmes, Tetrahedron 1991, 47, 9131–9166; j) A. P. Kozikowski,
P. Pa rk , J. Org. Chem. 1990, 55, 4668–4682.
[10]
[11]
For overviews, see: a) M. Harmata, W. Ying, C. L. Barnes, Tet-
rahedron Lett. 2009, 50, 2326–2328; b) S. M. Lu, H. Alper, J.
Am. Chem. Soc. 2008, 130, 6451–6455; c) E. M. Beccalli, G.
Broggini, M. Martinelli, G. Paladino, E. Rossi, Synthesis 2006,
2404–2412; d) C. Ferrer, A. M. Echavarren, Angew. Chem.
2006, 118, 1123; Angew. Chem. Int. Ed. 2006, 45, 1105–1109;
e) H. Bieraügel, T. P. Jansen, H. E. Schoemaker, H. Hiemstra,
J. H. Maarseveen, Org. Lett. 2002, 4, 2673–2676; f) U. M.
Lindström, P. Somfai, Chem. Eur. J. 2001, 7, 94–98; g) U. Nub-
bemeyer, Top. Curr. Chem. 2001, 216, 125–196; h) S. Derrer,
J. E. Davies, A. B. Holmes, J. Chem. Soc. Perkin Trans. 1 2000,
2957–2967; i) M. E. Maier, Angew. Chem. Int. Ed. 2000, 39,
2073–2077; j) P. A. Evans, B. Holmes, Tetrahedron 1991, 47,
9131–9166.
a) H. Cho, Y. Iwama, K. Sugimoto, S. Mori, H. Tokuyama, J.
Org. Chem. 2010, 75, 627–636; b) H. Cho, Y. Iwama, K. Sugim-
oto, E. Kwon, H. Tokuyama, Heterocycles 2009, 78, 1183–
1190; c) C. M. Yea, C. E. Allan, D. M. Ashworth, J. Barnett,
A. J. Baxter, J. D. Broadbridge, R. J. Franklin, S. L. Hampton,
P. Hudson, J. A. Horton, P. D. Jenkins, A. M. Penson, G. R. W.
Pitt, P. Riviere, P. A. Robson, D. P. Rooker, G. Semple, A.
[12]
[3] For selected examples, see: a) A. A. Geronikaki, J. C. Dearden,
D. Filimonov, I. Galaeva, T. L. Garibova, T. Gloriozova, V.
Krajneva, A. Lagunin, F. Z. Macaev, G. Molodavkin, V. V. Po-
roikov, S. I. Pogrebnoi, F. Shepeli, T. A. Voronina, M. Tsitlaki-
dou, L. Vlad, J. Med. Chem. 2004, 47, 2870–2876; b) P. M.
Eur. J. Org. Chem. 2011, 7346–7354
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7353

N. Das Adhikary, P. Chattopadhyay
FULL PAPER
Sheppard, R. M. Haigh, M. B. Roe, J. Med. Chem. 2008, 51,
8124–8134; d) L. A. Hobson, W. A. Nugent, S. R. Anderson,
S. S. Deshmukh, J. J. Haley, P. Liu, N. A. Magnus, P. Sheeran,
J. P. Sherbine, B. R. P. Stone, J. Zhu, Org. Process Res. Dev.
2007, 11, 985–995; e) M. Ortiz-Marciales, L. D. Rivera, M.
De Jesus, S. Espinosa, J. A. Benjamin, O. E. Casanova, I. G.
Figueroa, S. Rodriguez, W. Correa, J. Org. Chem. 2005, 70,
10132–10134; f) N. Willand, T. Beghyn, G. Nowogrocki, J.-C.
Gesquiere, B. Deprez, Tetrahedron Lett. 2004, 45, 1051–1054;
g) Z. Li, Q. Wang, F. Tao, Synth. Commun. 2004, 34, 1691–
1702.
1754–1762; e) E. L. Cropper, A.-P. Yuen, A. Ford, A. J. P.
White, K. K. Hii, Tetrahedron 2009, 65, 525–530; f) A. Minatti,
K. Muñiz, Chem. Soc. Rev. 2007, 36, 1142–1152; g) A. Neogi,
T. P. Majhi, R. Mukhopadhyay, P. Chattopadhyay, J. Org.
Chem. 2006, 71, 3291–3294; h) Y. Kitamura, A. Hashimoto, S.
Yoshikawa, J. Odaira, T. Furuta, T. Kan, K. Tanaka, Synlett
2006, 115–117; i) E. M. Beccalli, G. Broggini, G. Paladino, C.
Zoni, Tetrahedron 2005, 61, 61–68; j) B. E. Fink, A. V. Gavai,
G. D. Vite, W.-C. Han, R. N. Misra, H.-Y. Xia, D. J. Norris,
J. S. Tokarski, US Patent 0250753, 2005; k) R. Omar-Amrani,
R. Schneider, Y. Fort, Synthesis 2004, 2527–2534; l) B. J. Marg-
olis, J. J. Swidorski, B. N. Rogers, J. Org. Chem. 2003, 68, 644–
647; m) M. Qadir, R. E. Priestley, T. Rising, T. Gelbrich, S. J.
Coles, M. B. Hursthouse, P. W. Sheldrake, N. Whittall, K. K.
Hii, Tetrahedron Lett. 2003, 44, 3675–3678; n) B. H. Yang, S. L.
Buchwald, Org. Lett. 1999, 1, 35–37; o) A. Abouabdellah,
R. H. Dodd, Tetrahedron Lett. 1998, 39, 2119–2122; p) J. P.
Wolfe, R. A. Rennels, S. L. Buchwald, Tetrahedron 1996, 52,
7525–7546; q) A. S. Guram, R. A. Rennels, S. L. Buchwald,
Angew. Chem. 1995, 107, 1456; Angew. Chem. Int. Ed. Engl.
1995, 34, 1348–1350.
[13] a) A. Shaabani, H. Mofakham, A. Maleki, F. Hajishaabanha,
J. Comb. Chem. 2010, 12, 630–632; b) X. Xing, J. Wu, J. Luo,
W.-M. Dai, Synlett 2006, 2099–2103.
[14] a) Y.-L. Zhou, S.-W. Shen, F.-M. Liu, J. Heterocycl. Chem.
2011, 48, 105–112; b) P. Thansandote, E. Chong, K.-O. Feld-
mann, M. Lautens, J. Org. Chem. 2010, 75, 3495–3498; c) Q.
Meng, Q. Liu, J. Li, R.-G. Xing, X.-X. Shen, B. Zhou, Synlett
2009, 3283–3286; d) L. Guo, B. Li, W. Huang, G. Pei, D. Ma,
Synlett 2008, 1833–1836; e) J. C. Lanter, Z. Sui, J. J. Fiordeliso,
US Patent 040917, 2006; f) A. J. Matthew, L. M. Smith, S.
Burdzovic-Wizeman, A. Burns, H. Liu, Y. Mao, W. C. Wong,
A. S. Kiselyov, J. Org. Chem. 2005, 70, 9629–9631; g) M. M.
McGee, S. Gemma, S. Butini, A. Ramunno, D. M. Zisterer, C.
Fattorusso, B. Catalanotti, G. Kukreja, I. Fiorini, C. Pisano,
C. Cucco, E. Novellino, V. Nacci, D. C. Williams, G. Campiani,
J. Med. Chem. 2005, 48, 4367–4377; h) R. Omar-Amrani, R.
Schneider, Y. Fort, Synthesis 2004, 2527–2534; i) R. A. Bunce,
C. L. Smith, J. R. Lewis, J. Heterocycl. Chem. 2004, 41, 963–
970; j) C. Mukherjee, E. Biehl, Heterocycles 2004, 63, 2309–
2318; k) R. Omar-Amrani, A. Thomas, E. Brenner, R. Schnei-
der, Y. Fort, Org. Lett. 2003, 5, 2311–2314; l) B. Chandrasek-
har, G. O. Reddy, M. R. Sarma, A. S. R. Prasad, R. Bera,
T. S. V. P. Reddy, Heterocycl. Commun. 2002, 8, 141–144; m)
L. G. Levkovskaya, N. V. Sazonov, N. A. Grineva, I. E. Mama-
eva, L. A. Serochkina, T. S. Safonova, Chem. Heterocycl.
Compd. 1985, 21, 100–103.
[15] For overviews on aryl amination, see: a) D. S. Surry, S. L.
Buchwald, Angew. Chem. 2008, 120, 6438; Angew. Chem. Int.
Ed. 2008, 47, 6338–6361; b) J. F. Hartwig, Nature 2008, 455,
314–322; c) J. Barluenga, M. A. Fernμndez, F. Aznar, C.
Valdÿs, Chem. Eur. J. 2004, 10, 494–507; d) J. P. Wolfe, S. L.
Buchwald, J. Org. Chem. 2000, 65, 1144–1157; e) B. H. Yang,
S. L. Buchwald, J. Organomet. Chem. 1999, 576, 125–146; f) Y.
Guari, V. E. Es, N. H. Reek, J. Kamer, P. W. N. M. V. Leeuwen,
Tetrahedron Lett. 1999, 40, 3789–3790; g) J. P. Wolfe, S. Wagaw,
J. F. Marcoux, S. L. Buchwald, Acc. Chem. Res. 1998, 31, 805–
818; h) J. F. Hartwig, Angew. Chem. 1998, 110, 2154; Angew.
Chem. Int. Ed. 1998, 37, 2046–2067.
[17]
[18]
S. Hanessian, in: Total Synthesis of Natural Products: The Chi-
ron Approach, Pergamon, Oxford, 1993.
For selected examples, see: a) L. Abrous, P. A. Jokiel, S. R.
Friedrich, J. Hynes, A. B. Smith, R. Hirschmann, J. Org. Chem.
2004, 69, 280–302; b) M. W. Peczuh, N. L. Snyder, Tetrahedron
Lett. 2003, 44, 4057–4061; c) M. A. Leeuwenburgh, R. E. Z. N.
Litjens, J. D. C. Codee, H. S. Overkleeft, G. A. Van der Marel,
J. H. Van Boom, Org. Lett. 2000, 2, 1275–1277; d) T. Oishi, H.
Uehara, Y. Nagumo, M. Shoji, J.-Y. L. Brazidec, M. Kosaka,
M. Hirama, Chem. Commun. 2001, 381–382; e) D. J. Holt,
W. D. Barker, P. R. Jenkins, J. Panda, S. Ghosh, J. Org. Chem.
2000, 65, 482–493; f) J. C. B. Lopez, B. Fraser-Reid, Chem.
Commun. 1997, 2251–2257; g) R. J. Ferrier, S. Middleton,
Chem. Rev. 1993, 93, 2779–2831.
[19]
a) D. Bhattacharya, A. Behera, S. K. Hota, P. Chattopadhyay,
Synthesis 2011, 585–592; b) A. Neogi, T. P. Majhi, B. Achari,
P. Chattopadhyay, Eur. J. Org. Chem. 2008, 330–336.
[20] a) T. P. Majhi, A. Neogi, S. Ghosh, A. K. Mukherjee, P. Chat-
topadhyay, Tetrahedron 2006, 62, 12003–12010; b) T. P. Majhi,
A. Nandi, A. Neogi, R. Mukhopadhyay, P. Chattopadhyay,
Synthesis 2005, 2307–2314; c) A. Neogi, T. P. Majhi, N. Gho-
sal, P. Chattopadhyay, Tetrahedron 2005, 61, 9368–9374; d) P.
Chattopadhyay, M. Mukherjee, S. Ghosh, Chem. Commun.
1997, 2139–2140.
[21] For the superiority of Xantphos used with palladium in the
amination of aryl iodides, see: M. H. Ali, S. L. Buchwald, J.
Org. Chem. 2001, 66, 2560–2565.
[22] CCDC-819083 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[16] For selected examples, see: a) E. M. Beccalli, G. Broggini, A.
Fasana, M. Rigamonti, J. Organomet. Chem. 2011, 696, 277–
295; b) J. L. Bras, J. Muzart, Chem. Rev. 2011, 111, 1170–1214;
c) K. C. Majumdar, B. Chattopadhyay, P. K. Maji, S. K. Chat-
topadhyay, S. Samanta, Heterocycles 2010, 81, 795–866; d)
N. D. Adhikary, P. Chattopadhyay, Eur. J. Org. Chem. 2010,
Received: August 9, 2011
Published Online: November 4, 2011
7354
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7346–7354