Direct Access to Bridged Tetrahydroquinolines and Chromanes via an InCl3-Catalyzed Sequential Three-Component Cascade

Article abstract of DOI:10.1021/acs.joc.0c00893

A sequential three-component cascade process was developed for the synthesis of bridged tetrahydroquinolines and chromanes bearing 2,6-methanobenzo[d][1,3]diazocine and 2,6-methanobenzo[g][1,3]oxazocine scaffolds, respectively, in good yields from readily

Full text of DOI:10.1021/acs.joc.0c00893

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Article
Direct Access to Bridged Tetrahydroquinolines and Chromanes
via InCl3-Catalyzed Sequential Three-Component Cascade
B.S. Vachan, Muthu Karuppasamy, Gowsia Jan, Nattamai
Bhuvanesh, C. Uma Maheswari, and Vellaisamy Sridharan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00893 • Publication Date (Web): 26 May 2020
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Page 1 of 15
The Journal of Organic Chemistry
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Direct Access to Bridged Tetrahydroquinolines and Chroma-
nes via InCl3-Catalyzed Sequential Three-Component Cascade
B. S. Vachan,a Muthu Karuppasamy,a Gowsia Jan,b Nattamai Bhuvanesh,c C. Uma Mahe-
swari,*a and Vellaisamy Sridharan*a,b
a Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur-
613401, Tamil Nadu, India
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b Department of Chemistry and Chemical Sciences, Central University of Jammu, Rahya-Suchani (Bagla), Dis-
trict-Samba, Jammu-181143, J&K, India
c Department of Chemistry, Texas A & M University, College Station, Texas 77843, United States
Supporting Information Placeholder
O
R4
R2
O
R4
CO2R3
R2
CO2R3
R2
NH
OH
H
H
PG
R3O2C
InCl3 (10 mol %)
InCl3 (10 mol %)
R4
R4
O
N
N
+
R1
R1
new bonds
MeOH, 65 oC, 1 h
(68-84%)
MeOH, 65 oC, 1 h
(65-87%)
N
O
H
H
H2N
R1
PG
new bonds
(1 C–C and 3 C–N)
(22 examples)
(1 C–C, 1 C–O, 2 C–N)
(18 examples)
One-pot, Sequential Three-component Reaction
High atom economy (–2H2O)
ABSTRACT: A sequential three-component cascade process was developed for the synthesis of bridged tetrahydro-
quinolines and chromanes bearing 2,6-methanobenzo[d][1,3]diazocine and 2,6-methanobenzo[g][1,3]oxazocine scaf-
folds, respectively, in good yields from readily available materials. The InCl3 catalyzed reaction progressed via enamine
formation, Michael addition, intramolecular cyclization, and intramolecular iminium ion cyclization steps. Notably, this
high atom economic approach (–2H2O) allowed the generation of four new bonds (1 C–C & 3 C–N or 1 C–C, 1 C–O & 2
C–N) and two heterocyclic rings in a single operation.
multicomponent reactions, offer high atom and step
economy, operational simplicity, waste minimization, and
several other advantages. These reactions allow the
construction of complex biologically significant molecules
starting from simple precursors by generating more than
one covalent bonds and rings, comprising several se-
quential reactions, in a single synthetic operation.10,11
INTRODUCTION
The general approaches involved in modern drug dis-
covery include target-oriented and diversity-oriented syn-
theses. The major objective of the diversity-oriented syn-
thesis remains the synthesis of structurally complex and
diverse small molecules for the identification of therapeu-
tic targets.1 The multicomponent and domino or cascade
reactions, generally named as multibond-forming reac-
tions, have been recognized as potential tools for the
synthesis of privileged structural scaffolds by generating
structural complexity and diversity.2,3 In multicomponent
reactions, three or more reactants combine to deliver a
product that incorporate significant portions of all the
reactants. Some of the classical multicomponent reac-
tions have been developed in the 19th century that in-
clude Strecker reaction,4 Hantzsch dihydropyridine syn-
thesis,5 and Biginelli dihydropyrimidine synthesis,6 and
other notable conventional multicomponent reactions
remain Mannich,7 Passerini,8 and Ugi reactions.9 After
the discovery of Ugi’s four-component bis-amide synthe-
sis, tremendous effort has been devoted to the devel-
opment of novel multicomponent reactions for the syn-
thesis of diverse biologically significant compounds.3
These multicomponent reactions, including sequential
Among the privileged structural scaffolds that provide
ligands
for
diverse
receptors,12
the
1,2,3,4-
tetrahydroquinole ring system is prevalent in a large
number of natural and synthetic compounds of biological
significance.13
In
particular,
the
bicyclic
2,6-
methanobenzo[d][1,3]diazocine framework is present in
several alkaloids, exemplified by isoschizogaline I,14
isoschizogamine II,15 and (–)-calycanthine III16 (Figure
1). Furthermore, tetrahydroquinolines and their fused
analogs are known to act as chemotherapeutic agents
including antiviral, antimalarial, antibacterial, antitumoral
etc., and pharmacodynamic agents i.e. membrane re-
ceptors, steroid and non-steroid hormone receptors, en-
zyme inhibitors, and antagonists and agonists of various
ion
channels.13
Comparable
to
2,6-
methanobenzo[d][1,3]diazocine framework, the bicyclic
2,6-methanobenzo[g][1,3]oxazocine scaffold is also pre-
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Page 2 of 15
sent in many interesting bioactive natural products and
clization, and final nucleophilic displacement of the hy-
pharmaceuticals, represented by schumagnine IV,17 N-
methylschumagnine V,17 and the antidepressant drug
lortalamine VI.18 and consequently few attractive strate-
gies have been demonstrated in literature to access the
related bicyclic chromane derivatives.19
droxy group by the alcohol. The proposed synthesis of
bicyclic tetrahydroquinolines 4 (X = NR) with a 2,6-
methanobenzo[d][1,3]diazocine fragment could be
achieved by introducing an ortho-amino group in the α,β-
unsaturated aldehydes 3 and exclude the external nu-
cleophile i.e. the alcohol (Scheme 1, eq. 2). The poten-
tial restrictions of the proposed approach include (i) the
geometrical constrains of intermediate A in the final in-
tramolecular nucleophilic cyclization step and (ii) the
competitive intramolecular cyclization of the ortho-amino
group with the adjacent ester functionality to deliver the
corresponding lactam. Further, the methodology could
be extended to the synthesis of bicyclic chromane deriv-
atives i.e. 2,6-methanobenzo[g][1,3]oxazocines 6 (X =
O) starting from ortho-hydroxycinnamaldehydes 5. In
1986, Kim has reported the rearrangement of Hantzsch
1
2
3
4
5
6
7
8
Figure 1. Selected Examples of Natural and Biologically
Relevant 2,6-Methanobenzo[d][1,3]diazocines and 2,6-
Methanobenzo[g][1,3]oxazocines.
Me
9
R
H
N
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N
N
MeO
N
N
O
Me
N
H
I: R = H, Isoschizogaline
II: R = OMe, Isoschizogamine
III: (–)-Calycanthine
Me
O
ester
4-(2-aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-
pyridinedicarboxylic acid diethyl ester into the corre-
sponding diazocine derivative in 28% yield in pyridine
under reflux conditions along with two other products.21
Encouraged by this result, we began our optimization
studies for the one-pot synthesis of bicyclic tetrahydro-
quinolines using n-butylamine 1a, methyl acetoacetate
O
Cl
Me
N
O
N
R
HN
O
HO
O
IV: R = H, Schumagnine
VI: Lortalamine
V: R = Me, N-Methylschumagnine
(antidepressant drug)
2a,
and
(E)-4-methyl-N-(2-(3-oxoprop-1-en-1-
yl)phenyl)benzenesulfonamide 3a as model substrates
in the presence of 10 mol% of previously studied CAN22
as the catalyst in ethanol at room temperature. To our
delight, as shown in Table 1, entry 1, the expected bicy-
RESULTS AND DISCUSSION
Owing to the biological significance of tetrahydroquino-
lines and chromanes, we envisioned to develop a simple
one-pot, three-component approach for the synthesis of
bicyclic tetrahydroquinoline derivatives bearing a 2,6-
methanobenzo[d][1,3]diazocine fragment, and their
chromane analogs. A decade ago, a four-component
strategy was developed for the synthesis of 6-alkoxy-
1,4,5,6-tetrahydropyridines involving cerium(IV) ammo-
nium nitrate (CAN) catalyzed reaction between primary
amines, 1,3-dicarbonyl compounds, α,β-unsaturated
aldehydes and alcohols (Scheme 1, eq. 1).20 The mech-
anism of this approach involves initial formation of β-
enaminones from primary amines and 1,3-dicarbonyl
compounds followed by Michael addition with α,β-
unsaturated aldehydes, subsequent intramolecular cy-
clic
tetrahydroquinoline
4a
bearing
a
2,6-
methanobenzo[d][1,3]diazocine moiety was obtained in
24% yield without traces of the competitive lactam. The
reaction rate was increased at elevated temperature (65
oC) and the yield was improved significantly (Table 1,
entry 1, 63%). With an aim to further improve the product
yield, a set of Lewis acids including InCl3, BiCl3,
Yb(OTf)3, Sc(OTf)3 and AgOTf, and copper salts CuCl
o
and CuCl2 were screened at 65 C (entries 2-8). Among
the tested catalysts, InCl3 and Yb(OTf)3 were superior,
yielding 74% and 76% of the desired product 4a, respec-
tively (entries 2 and 4). Encouraged by these preliminary
results, screening of solvents was performed by fixing
Scheme 1. Multicomponent Synthesis of Tetrahydropyridines and Envisioned Synthesis of Bridged Heterocycles
Previous work: Four-component synthesis of 6-alkoxy-1,4,5,6-tetrahydropyridines
(Sridharan, Maiti and Menéndez, 2009)
R4
R4
O
O
R5
O
R5
R6O
R3
Me
CAN (5 mol%)
MeCN, rt
R3
Me
(1)
+
N
R1
O
NH2
R1
OH
R6
This work: Three-component synthesis of bridged tetrahydroquinolines and chromanes (2,6-methanobenzo[d][1,3]
diazocines and 2H-2,6-methanobenzo[g][1,3]oxazocines)
CO2R3
R4
CO2R3
R2
R2
H
R2
R3O2C
InCl3
HX
HO
(2)
O
(10 mol %)
R4
O
2
R4
N
R1
+
MeOH, 65 oC
XH
3/5
X = NR, O
X
H
H2N
R1
4/6
N
R1
1
A
Sequential formation of 6-hydroxy-1,4,5,6-tetrahydropyridine-intramolecualr iminium ion cyclization
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The Journal of Organic Chemistry
With the optimized condition in hand, the scope and
Table 1. Optimization of Reaction Conditionsa
1
generality of the three-component cascade process was
demonstrated involving a variety of primary amines 1, β-
ketoesters 2 and ortho-amino α,β-unsaturated aldehydes
3 for the synthesis of bicyclic tetrahydroquinolines 4
(Scheme 2). At the outset, the effect of primary amines 1
including alkyl and arylamines was investigated. The
combination of methyl acetoacetate, unsubstituted (E)-4-
CO2Me
Me
Me
H
2
3
4
5
MeO2C
+
O
Catalyst
Solvent
O
2a
N
n-Bu
NH
Ts
N
H2N
H
n-Bu
1a
Ts
3a
4a
6
7
entry
catalyst
solvent
time (h)
4a (%)b
methyl-N-(2-(3-oxoprop-1-en-1-yl)phenyl)
benzenesul-
8
(10 mol %)
CAN
fonamides, and alkyl amines such as n-butylamine, n-
hexylamine, benzylamine and phenethylamine furnished
the corresponding 2,6-methanobenzo[d][1,3]diazocines
4a-d in good yields (72-83%). Likewise, aniline (4e,
81%) and arylamines bearing electron-releasing (p-Me,
4f, 82%; p-OMe, 4g, 65%), and -withdrawing (p-Cl, 4h,
70%) substituents delivered the N-aryl substituted prod-
ucts in moderate to good yields. Interestingly, when ethyl
and t-butyl acetoacetates were employed as substrates
in combination with benzylamine and phenethylamine,
the reaction proceeded smoothly to furnish the corre-
sponding products 4i-l in good yields (75-82%). Here,
the yields of t-butyl acetoacetate reactions were slightly
inferior (75-76%) to that of their ethyl counterparts (80-
82%).
9
1
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
i-PrOH
THF
3
63 (24)c
74
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58
59
60
2
InCl3
2.5
3
3
BiCl3
56
4
Yb(OTf)3
Sc(OTf)3
AgOTf
3
76
5
3
68
6
4
55
7
CuCl2
3
66
8
CuCl
3
62
9
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
InCl3
2
78
10
11
12
13
14
15
16
17
18
19
20
2
71
2
55
MeCN
DCM
2
66
Next, we examined the effect of substituent on ortho-
amino α,β-unsaturated aldehyde 3, and it revealed that
the presence of electron-withdrawing substituent (Br)
afforded the products in slightly better yields compared
to the unsubstituted analogue. The reactions between
bromo substituted ortho-amino α,β-unsaturated alde-
hyde, methyl acetoacetate, and primary amines including
n-butylamine, benzylamine, phenethylamine, aniline and
p-chloroaniline delivered the products 4m-q in high
yields (77-87%). The reactivity of ethyl and t-butyl aceto-
acetates was comparable to the unsubstituted deriva-
tives (4r-u, 76-86%). Finally, the N-Boc protected ortho-
amino α,β-unsaturated aldehyde was also tested under
the optimized reaction conditions to access the corre-
sponding product 4v in 66% yield. In general, the reactiv-
ity of alkyl amines were superior to that of arylamines
that could be attributed to the high nucleophilicity of alkyl
amines to deliver the initial β-enaminone intermediates
effectively. One of the limitations of this strategy is that
the reaction failed to deliver the corresponding products
when we replaced β-ketoesters by β-diketones. The re-
action between acetyl acetone, benzylamine, and alde-
hyde 3a delivered a complex mixture under the standard
conditions. When the reaction was monitored carefully,
the β-enaminone intermediate was formed initially, and
after addition of aldehyde 3a, slow decomposition took
place. This was the case when ethyl 3-oxo-3-
phenylpropanoate (R2 = Ph, R3 = Et) was used as the
substrate (4w and 4x). The structure and stereochemis-
try of the bicyclic tetrahydroquinolines 4 were estab-
lished from spectral studies and single crystal analysis of
2
59
DCE
2
74
DMSO
DMF
3
59
3
58
Toluene
MeOH
DCE
4
65
83d
1
InCl3
3
75
e
No catalyst
MeOH
10
-
aUnless otherwise noted, all reactions were carried out with
1a (1.2 mmol), 2a (1.0 mmol) and 3a (1.0 mmol) with cata-
lyst (10 mol %) in 6 mL solvent at 65 oC. bIsolated yield.
cReaction was carried out at rt for 6 h, and incomplete con-
d
e
version was observed. Optimized reaction condition. Small
quantity of intermediate enamine was observed in the crude
1H-NMR spectrum.
Yb(OTf)3 as the catalyst, and the study revealed that
MeOH (entry 9, 78%) was the high yielding solvent com-
pared to other tested solvents such as i-PrOH, THF,
MeCN, DCM, DCE, DMSO, DMF and toluene (entries
10-17). Gratifyingly, switching the catalyst to InCl3 (10
mol%) in MeOH showcased further significant improve-
ment in yield and reaction rate. The reaction was com-
pleted in just one hour delivering the product 4a in 83%
yield (entry 18). Another high yielding solvent DCE (entry
14) was also tested in the presence of InCl3, however,
the results were inferior to MeOH (entry 19). Finally,
when the reaction was performed in the absence of any
catalyst in MeOH, only a small quantity of the intermedi-
ate β-enaminone obtained from n-butylamine 1a and
methyl acetoacetate 2a was detected in the crude 1H-
NMR spectrum of the reaction mixture (entry 20). Con-
sequently, we selected entry 18 (10 mol% of InCl3,
MeOH, 65 oC) as the optimized reaction condition for the
subsequent studies.
a
representative compound 4n (CCDC number:
1993226).
Next, we conceptualized a similar strategy to access
bicyclic
chromanes
6
bearing
a
2,6-
methanobenzo[g][1,3]oxazocine scaffold by replacing
ortho-amino α,β-unsaturated aldehydes 3 by the ortho-
hydroxy analog 5 (Scheme 3). The Biginelli reaction
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Scheme 2. Scope and Limitations of the Three-Component Synthesis Bridged Tetrahydroquinolinesa,b
1
2
3
4
5
6
CO2R3
H
R2
R2
R1
R3O2C
+
InCl3 (10 mol %)
O
R4
R4
O
2
N
MeOH, 65 oC, 1 h
(65-87%)
NH
PG
N
H
H2N
R1
PG
4a-v
3
1
7
8
CO2t-Bu
CO2Me
CO2Me
Me
CO2Et
Me
H
H
H
H
Me
Me
9
N
N
N
N
R1
R1
R1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
N
H
H
H
H
Ts
Ts
Ts
R
Ts
4a: R1 = n-Bu, 83%
4b: R1 = n-Hex, 72%
4c: R1 = Bn, 81%
4d: R1 = (CH2)2Ph, 80%
CO2Me
Me
4k: R1 = Bn, 76%
4l: R1 = (CH2)2Ph, 75%
4i: R1 = Bn, 80% (83%)c
4j: R1 = (CH2)2Ph, 82%
4e: R = H, 81%
4f: R = Me, 82%
4g: R = OMe, 65%
4h: R = Cl, 70%
CO2t-Bu
CO2Et
H
H
H
Me
Me
Br
Br
Br
N
N
N
R1
R1
R1
N
N
N
H
H
H
Ts
Ts
Ts
4t: R1 = Bn, 76%
4u: R1 = (CH2)2Ph, 77%
4r: R1 = Bn, 85%
4s: R1 = (CH2)2Ph, 86%
4m: R1 = n-Bu, 87%
4n: R1 = Bn, 85%
4o: R1 = (CH2)2Ph, 85%
4p: R1 = Ph, 80%
4q: R1 = p-ClC6H4, 77%
COR
CO2Me
H
R2
H
Me
Br
N
H
N
n-Bu
Bn
N
N
H
Ts
Boc
4w: R = R2 = Me, 0%
4x: R = OEt, R2 = Ph, 0%
4v (66%)
aReaction conditions: 1 (1.2 mmol), 2 (1.0 mmol), 3 (1.0 mmol), InCl3 (10 mol %), MeOH (6 mL), 65 oC.
bIsolated yields. cReaction was performed with isolated β-enaminone intermediate and 3a.
between salicylaldehydes, active methylene compounds
workers reported the synthesis of few related com-
pounds in poor yields with limited substrate scope.24
and urea/thiourea was also identified as a direct ap-
proach for the synthesis of related chromane-fused bicy-
clic compounds.23
We have proposed a mechanism involving enamine
formation, Michael addition, intramolecular cyclization
and intramolecular iminium ion cyclization steps for the
three-component reaction between primary amines 1, β-
ketoesters 2 and ortho-amino/hydroxy α,β-unsaturated
aldehydes 3/5 for the synthesis of the bicyclic tetrahy-
droquinolines and chromanes (Scheme 4). Initial InCl3
catalyzed reaction between primary amine 1 and β-
ketoester 2 generates the β-enaminone intermediate
A,25 which undergoes Michael addition with compound
3/5 to deliver intermediate B. Successive InCl3 catalyzed
intramolecular cyclization provides 6-hydroxy-1,4,5,6-
tetrahydropyridine intermediate C.20,26 Final iminium ion
(D) generation and intramolecular cyclization steps fur-
nished the desired products. The observed cis stereo-
chemistry in 2,4-positions could be explained via the
cyclization of intermediate D2, where the geometry of
this intermediate was visualized based on the single
crystal structure of the product. In a separate experi-
ment, isolated β-enaminone A, derived from benzyla-
mine and ethyl acetoacetate, was treated with α,β-
unsaturated aldehyde 3a under the optimized reaction
conditions, wherein the corresponding bridged tetrahy-
droquinoline 4i was isolated in 83% yield. This experi-
The three-component cascade reaction between pri-
mary amines 1, β-ketoesters 2, and ortho-hydroxy α,β-
unsaturated aldehydes 5 was investigated by employing
the previously established reaction conditions i.e. 10
mol% InCl3 in MeOH at 65 oC to access 2,6-
methanobenzo[g][1,3]oxazocines 6. As summarized in
Scheme 3, the reaction tolerated a wide range of primary
amines including n-butylamine (6a, 74%) and n-
hexylamine (6b, 69%), benzylamine (6c, 6l, 6n, 6q, 6r;
68-84%) and phenethylamine (6d, 6i, 6m, 6o, 6p; 76-
84%) delivering the corresponding products in good
yields. Aryl amines bearing both electron-releasing (p-
OMe) and -withdrawing (p-F, p-Br) groups were also
equally effective (6e-h, 6j, 6k), and furnished the prod-
ucts in 68-77% yields. In order to show the generality of
the protocol, the influence of β-ketoesters such as me-
thyl, ethyl and tert-butyl acetoacetate was assayed, and
comparable yields were observed in all the cases. The
reaction was also tolerated bromo (6n-p; 82-84%) and
nitro (6q, r; 68-70%) substituents on ortho-hydroxy α,β-
unsaturated aldehyde moiety, and the reaction times and
yields were similar to those observed for unsubstituted
system. It should be mentioned here that Světlík and co-
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Scheme 4. Proposed Mechanism
ment supports the involvement of the β-enaminone in-
1
termediate in the three-component reaction.
1 + 2
2
3
4
5
6
7
8
9
Scheme 3. Scope and Limitations of the Three-
InCl3
-H2O
Component Synthesis Bridged Chromanesa,b
R4
CO2R3
R2
R4
CO2R3
HX
O
HX
O
CO2R3
R2
InCl3
(10 mol %)
R3O2C
+
H
Michael addition
R2
O
R4
O
HN
R1
R2
2
R4
N
MeOH
65 oC, 1 h
R1
HN
R1
OH
InIII
H2N
O
InIII
3/5
A
5
R1
H
(68-84%)
B
6a-r
1
CO2Me
CO2Me
Me
Intramolecular
cyclization
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11
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13
14
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16
17
18
19
20
21
22
23
24
25
26
27
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
Me
OH
R2
N
R1
N
N
R1
R4
CO2R3
R2
R4
Iminium
ion
formation
O
O
CO2R3
H
H
HX
HX
HO
R
CO2R3
R2
H
6a: R1 = n-Bu, 74%
6b: R1 = n-Hex, 69%
6c: R1 = Bn, 82%
H
6e: R = H, 77%
6f: R = OMe, 68%
6g: R = F, 72%
6h: R = Br, 76%
HX
R4
N
R1
N
R1
OH
6d: R1 = (CH2)2Ph, 82%
D2
D1
C
CO2Et
CO2Et
Intramolecular
iminium ion cyclization
H
H
Me
Me
-H2O
CO2R3
N
N
R1
N
Ph
R2
H
R2
O
H
O
H
CO2R3
H
R
R4
6i (84%)
6j: R = OMe, 74%
6k: R = F, 74%
N
H
R1
X
X
H
CO2R3
H
4/6
CO2t-Bu
R4
H
Me
X = NR, O
Me
Br
N
N
R1
R1
O
O
H
H
EXPERIMENTAL SECTION
6n: R1 = Bn, R2 = Me, 84%
6o: R1 = (CH2)2Ph, R3 = Me, 82%
6p: R1 = (CH2)2Ph, R3 = Et, 83%
6l: R1 = Bn, 78%
6m: R1 = (CH2)2Ph, 76%
General information. All reagents and solvents were
purchased from commercial suppliers (Avra, Alfa Aesar,
Sigma-Aldrich, CDH, Merck) and used without further
purification. The reactions were monitored by thin layer
chromatography using Merck silica gel 60 F254 and visu-
alized by UV detection or using p-anisaldehyde stain or
molecular iodine. Silica gel (230-400 mesh) was used for
flash column chromatography. Melting points were rec-
orded on a melting point apparatus in capillaries and are
CO2R3
H
Me
O2N
N
R1
O
H
6q: R1 = Bn, R3 = Me, 70%
6r: R1 = Bn, R3 = Et, 68%
uncorrected. H and 13C-NMR spectra were recorded in
1
aReaction conditions: 1 (1.2 mmol), 2 (1.0 mmol), 5 (1.0 mmol),
InCl3 (10 mol %), MeOH (6 mL), 65 oC. bIsolated yields.
CDCl3 or DMSO-d6 at room temperature on a BruckerA-
vance 300 spectrometer operating at 300 MHz for 1H
and 75 MHz for 13C. Chemical shifts (δ) are expressed in
ppm using TMS as an internal standard and coupling
constants (J) are given in Hz. Infrared (IR) spectra were
obtained using an Agilent Cary630 FTIR Spectrometer
with a diamond ATR accessory for solid and liquid sam-
ples, requiring no sample preparation and the major fre-
quencies were reported in cm-1. Elemental analyses
were determined at the CAI de Microanálisis Elemental,
Universidad Complutense, by using a Leco 932 CHNS
combustion microanalyzer.
CONCLUSIONS
In conclusion, we have developed an efficient InCl3 cata-
lyzed three-component strategy for the synthesis of
bridged tetrahydroquinolines and chromanes in good
yields under mild reaction conditions. The reactions
showed high atom economy leaving only two molecules
of water as the side product and generated four new
bonds (1 C–C & 3 C–N or 1 C–C, 1 C–O & 2 C–N) and
two heterocyclic rings in a single operation. Mechanisti-
cally, the three-component reaction proceeds via
enamine formation, Michael addition, intramolecular cy-
clization and intramolecular iminium ion cyclization se-
quence. The bicyclic 2,6-methanobenzo[d][1,3]diazocine
and 2,6-methanobenzo[g][1,3]oxazocine scaffolds were
constructed via formation of 6-hydroxy-1,4,5,6-
tetrahydropyridine followed by intramolecular nucleo-
philic cyclization.
General Procedure for the Synthesis of Com-
pounds 3/5a-c.11b A stirred mixture of 2-amino or 2-
hydroxyarylaldehydes (3.0 mmol, 1.0 equiv.) and Wittig
ylide 2-(triphenyl-λ5-phosphanylidene)acetaldehyde (3.6
mmol, 1.2 equiv.) in toluene (10 mL) was heated at 90
oC in an oil bath for 3 h. After completion of the reaction,
the reaction mixture was cooled to room temperature,
solvent was evaporated to dryness, and the crude mix-
ture was purified by flash column chromatography elut-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 15
ing with petroleum ether-ethyl acetate mixture (90:10 to
80:20, v/v) to obtain compounds 3/5a-c.
solid; mp: 154-158 oC; yield: 0.394 g, 68%; 1H NMR (300
1
2
3
4
5
6
7
8
MHz, CDCl3/DMSO-d6): δ 9.71 (d, J = 7.8 Hz, 1H), 8.40
(d, J = 2.4 Hz, 1H), 8.12 (dd, J = 9.3, 27 Hz, 1H), 7.78 (d,
J = 16.2 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 6.92 (dd, J =
16.2, 7.8 Hz, 1H); 13C{1H} NMR (75 MHz, CDCl3/DMSO-
d6): δ 194.0, 162.6, 146.4, 140.2, 130.1, 127.2, 124.9,
121.3, 116.7.
(E)-4-Methyl-N-(2-(3-oxoprop-1-en-1-
yl)phenyl)benzenesulfonamide (3a).19a Purification by
flash column chromatography on silica gel eluting with
petroleum ether-ethyl acetate mixture (90:10 to 80:20,
v/v) afforded the title compound as off-white solid; mp:
147-148 oC; yield: 0.669 g, 74%; 1H NMR (300 MHz,
CDCl3): δ 9.50 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 2.1 Hz,
1H), 7.57 (d, J = 8.4 Hz, 2H), 7.40-7.48 (m, 2H), 7.25-
7.28 (m, 3H), 7.01 (d, J = 8.7 Hz, 1H), 6.43-6.53 (m, 2H),
2.40 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 193.9,
147.4, 144.5, 135.6, 134.8, 131.8, 131.3, 129.9, 128.2,
127.9, 127.4, 21.5.
General Procedure for the Synthesis of Bridged
Tetrahydroquinolines 4a-v. To a stirred solution of
primary amine 1 (1.2 mmol, 1.2 equiv.) in MeOH (6 mL)
was added β-ketoester 2 (1.0 mmol, 1.0 equiv.) and
InCl3 (10 mol%). The reaction mixture was stirred at
room temperature for 20 minutes. To this reaction
mixture 2-aminoarylaldehyde 3 (1.0 mmol, 1.0 equiv.)
was added, and the reaction mixture was stirred at 65 oC
in an oil bath for 1 h. After completion of the reaction, the
mixture was diluted with water (6 mL), extracted with
ethyl acetate (3 × 6 mL), and washed with brine (6 mL).
The organic layer was separated, dried over anhydrous
sodium sulphate, and concentrated in vacuum. The
crude product was purified through silica column
chromatography using petroleum ether-ethyl acetate as
eluent (90:10 to 85:15, v/v).
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10
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12
13
14
15
16
17
18
19
20
21
22
23
24
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26
27
28
29
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58
59
60
(E)-N-(4-Bromo-2-(3-oxoprop-1-en-1-yl)phenyl)-4-
methylbenzenesulfonamide (3b).27 Purification by flash
column chromatography on silica gel eluting with petro-
leum ether-ethyl acetate mixture (90:10 to 80:20, v/v)
afforded the title compound as off-white solid; mp: 168-
o
170 C; yield: 0.935 g, 82%;1H NMR (300 MHz, CDCl3):
δ 9.49 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.57
(d, J = 8.4 Hz, 2H), 7.40-7.48 (m, 2H), 7.26 (d, J = 8.1
Hz, 2H), 7.02 (d, J = 8.4 Hz, 1H), 6.70 (brs, 1H), 6.47
(dd, J = 15.9, 7.5 Hz, 1H), 2.40 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3): δ 193.2, 145.3, 144.8, 135.3, 134.5, 133.6,
133.2, 130.8, 130.2, 130.0, 129.7, 127.4, 121.7, 21.6.
(±)
Methyl-3-butyl-4-methyl-1-tosyl-1,2,3,6-
tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4a). Purification by flash column chromatog-
raphy on silica gel eluting with petroleum ether-ethyl ace-
tate mixture (90:10 to 85:15, v/v) afforded the title com-
tert-Butyl
(E)-(4-bromo-2-(3-oxoprop-1-en-1-
yl)phenyl)carbamate (3c).28 Purification by flash column
chromatography on silica gel eluting with petroleum
ether-ethyl acetate mixture (90:10 to 80:20, v/v) afforded
o
pound as off-white solid; mp: 140-142 C; yield: 0.377 g,
83%; IR (neat): 3423.9, 2922.6, 1717.3, 1681.6, 1629.5,
1458.9, 1367.3, 1286.2, 1206.3, 1106.9, 1082.8 cm-1; 1H
NMR (300 MHz, DMSO-d6): δ 7.82 (d, J = 8.4 Hz, 1H),
7.66 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.25 (d,
J = 7.2 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 7.2
Hz, 1H), 5.96 (s, 1H), 4.04 (s, 1H), 3.60 (s, 3H), 3.43 (t, J
= 7.5 Hz, 2H), 2.34 (s, 3H), 2.30 (s, 3H), 1.68-1.72 (m,
1H), 1.52-1.56 (m, 3H), 1.24-1.34 (m, 2H), 0.94 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 167.8,
153.3, 144.0, 136.1, 132.9, 132.6, 129.7, 129.0, 127.0,
126.4, 124.8, 122.4, 100.9, 67.5, 50.6, 47.7, 31.3, 30.0,
21.5, 20.1, 15.9, 13.9; Anal Calcd C25H30N2O4S: C,
66.05; H, 6.65; N, 6.16. Found: C, 65.70; H, 6.57; N,
6.08.
o
the title compound as off-white solid; mp: 142-144 C;
yield: 0.764 g, 78%; 1H NMR (300 MHz, CDCl3): δ 9.74
(d, J = 7.5 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.62-7.65
(m, 1H), 7.50-7.57 (m, 2H), 6.62-6.70 (m, 1H), 6.42 (brs,
1H), 1.53 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3): δ
193.0, 152.8, 145.5, 135.6, 134.4, 131.0, 130.1, 128.4,
125.4, 118.0, 81.8, 28.3.
(E)-3-(2-Hydroxyphenyl)acrylaldehyde (5a).29 Purifi-
cation by flash column chromatography on silica gel elut-
ing with petroleum ether-ethyl acetate mixture (90:10 to
80:20, v/v) afforded the title compound as white solid;
mp: 119-120 oC; yield: 0.324 g, 73 %; 1H NMR (300
MHz, CDCl3): δ 9.68 (d, J = 8.1 Hz, 1H), 7.50 (dd, J =
16.2 Hz, 1H), 7.31 (td, J = 8.1, 1.5 Hz, 1H), 7.07 (d, J =
8.1 Hz, 1H), 6.95-7.03 (m, 1H), 6.90 (d, J = 8.4 Hz, 1H),
6.80 (s, 1H); 13C{1H} NMR (75 MHz, CDCl3): δ 195.8,
155.8, 149.8, 132.8, 130.1, 129.1, 121.3, 120.9, 116.6.
(±)
Methyl-3-hexyl-4-methyl-1-tosyl-1,2,3,6-
tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4b). Purification by flash column chroma-
tography on silica gel eluting with petroleum ether-ethyl
acetate mixture (90:10 to 85:15, v/v) afforded the title
compound as pale yellow solid; mp: 88-90 oC; yield:
0.347 g, 72%; IR (neat): 3426.1, 2926.8, 1711.4, 1686.2,
1631.0, 1456.3, 1361.9, 1284.5, 1204.8, 1101.8, 1082.2
(E)-3-(5-Bromo-2-hydroxyphenyl)acrylaldehyde
(5b).29 Purification by flash column chromatography on
silica gel eluting with petroleum ether-ethyl acetate mix-
ture (90:10 to 80:20, v/v) afforded the title compound as
1
cm-1; H NMR (300 MHz, CDCl3): δ 8.00 (d, J = 8.4 Hz,
o
pale brown solid; mp: 145-146 C; yield: 0.525 g, 77 %;
1H), 7.51 (d, J = 8.1 Hz, 2H), 7.29-7.34 (m, 1H), 7.18 (d,
J = 8.1 Hz, 2H), 7.08-7.14 (m, 1H), 6.97-7.02 (m, 1H),
5.83 (s, 1H), 4.11 (s, 1H), 3.70 (s, 3H), 3.33-3.69 (m,
2H), 2.36 (s, 3H), 2.32 (s, 3H), 1.60-1.63 (m, 4H), 1.25-
1.51 (m, 6H), 0.91-0.93 (m, 3H); 13C{1H} NMR (75 MHz,
CDCl3): δ 167.8, 153.3, 144.0, 136.1, 132.9, 132.6,
129.7, 129.0, 127.0, 126.4, 124.7, 122.4, 100.9, 67.5,
50.6, 48.0, 31.5, 30.0, 29.2, 26.6, 25.1, 22.6, 21.5, 16.0,
14.0; Anal Calcd for C27H34N2O4S: C, 67.19; H, 7.10; N,
5.80. Found: C, 66.86; H, 6.89; N, 5.64.
1H NMR (300 MHz, CDCl3): δ 9.69 (d, J = 7.8 Hz, 1H),
7.69 (d, J = 15.9 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.38
(dd, J = 8.7, 2.4 Hz, 1H), 6.88 (dd, J = 16.2, 7.8 Hz, 1H),
6.76 (d, J = 8.7 Hz, 1H); 13C{1H} NMR (75 MHz,
CDCl3/DMSO-d6): δ 193.9, 155.8, 147.1, 134.3, 130.5,
128.5, 122.6, 118.0, 110.9.
(E)-3-(2-Hydroxy-5-nitrophenyl)acrylaldehyde (5c).29
Purification by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 80:20, v/v) afforded the title compound as pale brown
ACS Paragon Plus Environment

Page 7 of 15
The Journal of Organic Chemistry
Methyl-3-benzyl-4-methyl-1-tosyl-1,2,3,6-
o
(±)
pound as off-white solid; mp: 128-132 C; yield: 0.400 g,
82%; IR (neat): 3282.3, 2940.9, 1684.5, 1577.5, 1481.0,
1331.6, 1211.1, 1156.1, 1080.9 cm-1; 1H NMR (300 MHz,
CDCl3): δ 7.70 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 8.4 Hz,
1H), 7.40 (dd, J = 7.2, 1.5 Hz, 1H), 7.34 (d, J = 8.4 Hz,
2H), 7.21 (d, J = 8.1 Hz, 2H), 7.02-7.13 (m, 4H), 6.93 (d,
J = 8.4 Hz, 1H), 6.20 (s, 1H), 4.29 (s, 1H), 3.74 (s, 3H),
2.40 (s, 3H), 2.37 (s, 3H), 2.35 (s, 3H), 1.89-2.03 (m,
2H); 13C{1H} NMR (75 MHz, CDCl3): δ 167.8; 153.1,
143.7, 143.6, 137.5, 136.8, 136.2, 135.2, 133.9, 133.0,
132.5, 129.8, 129.6, 129.2, 127.3, 127.1, 126.4, 124.8,
122.4, 122.3, 103.6, 69.8, 50.9, 30.3, 26.4, 21.5, 21.2,
20.9, 18.9; Anal Calcd for C28H28N2O4S: C, 68.83; H,
5.78; N, 5.73. Found: C, 68.46; H, 5.83; N, 5.54.
1
tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
2
3
4
5
6
7
8
9
carboxylate (4c). Purification by flash column chromatog-
raphy on silica gel eluting with petroleum ether-ethyl ace-
tate mixture (90:10 to 85:15, v/v) afforded the title com-
o
pound as off-white solid; mp: 166-168 C; yield: 0.395 g,
81%; IR (neat): 3426.8, 2977.8, 2926.6, 1676.1, 1578.7,
1
1451.7, 1348.5, 1208.9, 1166.3, 1109.8 cm-1; H NMR
(300 MHz, CDCl3): δ 7.94 (d, J = 8.4 Hz, 1H), 7.45 (d, J
= 8.4 Hz, 2H), 7.28-7.38 (m, 4H), 7.11-7.22 (m, 5H), 7.00
(t, J = 7.5 Hz, 1H), 5.74 (s, 1H), 4.83 (d, J = 17.7 Hz,
1H), 4.72 (d, J = 17.7, 1H), 4.20 (s, 1H), 3.72 (s, 3H),
2.34 (s, 3H), 2.32 (s, 3H), 1.73 (dt, J = 12.3, 2.4 Hz, 1H),
1.51 (dt, J = 12.3, 2.4 Hz, 1H); 13C{1H} NMR (75 MHz,
CDCl3): δ 167.8, 153.3, 144.1, 137.7, 135.9, 132.3,
129.9, 129.7, 129.1, 128.9, 127.3, 127.0, 126.6, 126.5,
126.1, 124.9, 122.6, 101.5, 68.0, 50.8, 30.1, 24.9, 21.5,
16.2; Anal Calcd for C28H28N2O4S: C, 68.83; H, 5.78; N,
5.73. Found: C, 68.67; H, 5.73; N, 5.65.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(±)
Methyl-3-(4-methoxyphenyl)-4-methyl-1-tosyl-
1,2,3,6-tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4g). Purification by flash column chroma-
tography on silica gel eluting with petroleum ether-ethyl
acetate mixture (90:10 to 85:15, v/v) afforded the title
compound as brown gummy solid; yield: 0.343 g, 65%;
IR (neat): 3287.1, 2941.6, 1686.4, 1579.3, 1489.8,
1337.9, 1210.8, 1156.7, 1080.7 cm-1; 1H NMR (300 MHz,
CDCl3): δ 7.72 (d, J = 8.1 Hz, 1H), 7.35-7.41 (m, 3H),
7.01-7.22 (m, 4H), 6.94-6.97 (m, 1H), 6.70-6.83(m, 3H),
6.15 (s, 1H), 4.28 (s, 1H), 3.80 (s, 3H), 3.74(s, 3H), 2.35
(s, 3H), 1.91-2.05 (m, 5H); 13C{1H} NMR (75 MHz,
CDCl3): δ 167.7, 158.9, 153.2, 143.7, 136.8, 135.2,
133.0, 132.5, 129.6, 129.5, 129.2, 127.1, 126.4, 124.8,
122.4, 114.9, 103.3, 70.0, 55.4, 50.8, 30.2, 26.4, 21.5,
18.8; Anal Calcd for C28H28N2O5S: C, 66.65; H, 5.59; N,
5.55. Found: C, 66.44; H, 5.65; N, 5.45.
(±)
Methyl-4-methyl-3-phenethyl-1-tosyl-1,2,3,6-
tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4d). Purification by flash column chroma-
tography on silica gel eluting with petroleum ether-ethyl
acetate mixture (90:10 to 85:15, v/v) afforded the title
compound as off-white solid; mp: 160-162 oC; yield:
0.402 g, 80%; IR (neat): 3426.9, 2938.9, 1676.8, 1561.1,
1430.9, 1349.9, 1260.3, 1213.0, 1159.0, 1056.8 cm-1; 1H
NMR (300 MHz, CDCl3): δ 8.01 (d, J = 8.1 Hz, 1H), 7.47
(d, J = 8.4 Hz, 2H), 7.28-7.37 (m, 6H), 7.18 (d, J = 8.1,
2H), 7.11 (td, J = 7.5, 1.8 Hz, 1H), 6.98-7.03 (m, 1H),
5.73 (s, 1H), 4.10 (s, 1H), 3.79-3.89 (m, 1H), 3.59-3.73
(m, 4H), 2.82-3.02 (m, 2H), 2.36 (s, 3H), 2.35 (s, 3H),
1.53-1.58 (m, 1H), 1.35 (dt, J = 12.6, 2.1 Hz, 1H);
13C{1H} NMR (75 MHz, CDCl3): δ 167.7, 153.0, 144.1,
138.3, 136.1, 132.9, 132.5, 129.8, 129.1, 129.0, 128.7,
127.0, 126.6, 126.5, 124.8, 122.5, 101.4, 67.7, 50.7,
49.6, 35.9, 30.0, 24.8, 21.6, 15.9; Anal Calcd for
C29H30N2O4S: C, 69.30; H, 6.02; N, 5.57. Found: C,
68.91; H, 5.95; N, 5.51.
(±)
Methyl-3-(4-chlorophenyl)-4-methyl-1-tosyl-
1,2,3,6-tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4h). Purification by flash column chroma-
tography on silica gel eluting with petroleum ether-ethyl
acetate mixture (90:10 to 85:15, v/v) afforded the title
o
compound as pale yellow solid; mp: 194-195 C; yield:
0.356 g, 70%; IR (neat): 3301.1, 2910.7, 1665.4, 1566.2,
1
1489.7, 1338.6, 1216.5, 1140.0, 1076.6 cm-1; H NMR
(±)
Methyl-4-methyl-3-phenyl-1-tosyl-1,2,3,6-
(300 MHz, CDCl3): δ 7.70 (d, J = 8.1 Hz, 1H), 7.35-7.40
(m, 5H), 7.17-7.24 (m, 2H), 7.13 (d, J = 7.8 Hz, 2H),
6.98-7.10 (m, 2H), 6.16 (s, 1H), 4.30 (s, 1H), 3.75 (s,
3H), 2.37 (s, 3H), 1.95-2.00 (m, 5H); 13C{1H} NMR (75
MHz, CDCl3): δ 167.6, 152.1, 143.9, 141.0, 136.5, 133.4,
132.8, 132.3, 129.4, 129.3, 129.2, 127.2, 127.0, 126.6,
125.0, 122.6, 104.9, 69.5, 51.0, 30.2, 26.3, 21.5, 18.9;
Anal Calcd for C27H25ClN2O4S: C, 63.71; H, 4.95; N,
5.50. Found: C, 63.52; H, 4.89; N, 5.33.
tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4e). Purification by flash column chromatog-
raphy on silica gel eluting with petroleum ether-ethyl ace-
tate mixture (90:10 to 85:15, v/v) afforded the title com-
o
pound as pale brown solid; mp: 131-133 C; yield: 0.384
g, 81%; IR (neat): 3296.3, 2955.4, 2919.7, 1676.8,
1567.8, 1489.7, 1338.4, 1211.1, 1163.8, 1071.3 cm-1; 1H
NMR (300 MHz, CDCl3): δ 7.62-7.68 (m, 2H), 7.36-7.44
(m, 5H), 7.33 (d, J = 8.4 Hz, 1H), 7.22 (dd, J = 8.1, 2.4
Hz, 1H), 7.13 (d, J = 5,4 Hz, 2H), 7.04-7.09 (m, 2H), 6.26
(s, 1H), 4.30 (s, 1H), 3.75 (s, 3H), 2.34 (s, 3H), 1.96-2.01
(m, 5H); 13C{1H} NMR (75 MHz, CDCl3): δ 167.7, 152.7,
143.7, 142.5, 136.8, 132.4, 129.6, 129.3, 127.7, 127.3,
127.0, 126.5, 125.3, 124.8, 122.3, 121.6, 104.0, 69.7,
50.9, 30.3, 26.4, 21.5, 19.0; Anal Calcd for C27H26N2O4S:
C, 68.33; H, 5.52; N, 5.90. Found: C, 68.02; H, 5.65; N,
5.70.
(±)
Ethyl
-3-benzyl-4-methyl-1-tosyl-1,2,3,6-
tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4i). Purification by flash column chromatog-
raphy on silica gel eluting with petroleum ether-ethyl ace-
tate mixture (90:10 to 85:15, v/v) afforded the title com-
o
pound as pale brown solid; mp: 169-170 C; yield: 0.402
g, 80%; IR (neat): 3423.9, 2976.6, 2938.9, 1676.8,
1570.7, 1450.2, 1348.6, 1206.2, 1160.9, 1106.9, 1050.0
1
cm-1; H NMR (300 MHz, CDCl3/DMSO-d6): δ 8.00 (d, J
(±)
Methyl-4-methyl-3-(p-tolyl)-1-tosyl-1,2,3,6-
= 8.4 Hz, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.40 (dd, J = 7.8,
1.8 Hz, 1H), 7.28-7.37 (m, 3H), 7.11-7.16 (m, 5H), 7.03
(td, J = 7.5, 1.2 Hz, 1H), 5.74 (s, 1H), 4.83 (d, J = 17.7
Hz, 1H), 4.77 (d, J = 17.7 Hz, 1H), 4.11-4.24 (m, 3H),
2.34 (s, 3H), 2.33 (s, 3H), 1.73 (dt, J = 12.6, 2.7 Hz, 1H),
tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4f). Purification by flash column chromatog-
raphy on silica gel eluting with petroleum ether-ethyl ace-
tate mixture (90:10 to 85:15, v/v) afforded the title com-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 15
1.47-1.54 (m, 1H), 1.33 (t, J = 7.2 Hz, 3H); 13C{1H} NMR
67.8, 49.5, 35.9, 30.2, 28.7, 24.8, 21.6, 15.9; Anal Calcd
for C32H36N2O4S: C, 70.56; H, 6.66; N, 5.14. Found: C,
70.33; H, 6.69; N, 5.03.
1
2
3
4
5
6
7
8
(75 MHz, CDCl3/DMSO-d6): δ 172.8, 157.6, 149.0,
142.5, 140.5, 137.7, 137.2, 134.6, 133.8, 133.6, 132.0,
131.1, 130.7, 129.6, 127.2, 106.5, 72.9, 64.0, 55.6, 34.6,
29.6, 26.3, 20.8, 19.4; Anal Calcd for C29H30N2O4S: C,
69.30; H, 6.02; N, 5.57. Found: C, 68.93; H, 5.97; N,
5.44.
(±) Methyl-8-bromo-3-butyl-4-methyl-1-tosyl-1,2,3,6-
tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4m). Purification by flash column chroma-
tography on silica gel eluting with petroleum ether-ethyl
acetate mixture (90:10 to 85:15, v/v) afforded the title
(±)
Ethyl-4-methyl-3-phenethyl-1-tosyl-1,2,3,6-
o
tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
compound as pale brown solid; mp: 122-124 C; yield:
carboxylate (4j). Purification by flash column chromatog-
raphy on silica gel eluting with petroleum ether-ethyl ace-
tate mixture (90:10 to 85:15, v/v) afforded the title com-
0.464 g, 87%; IR (neat): 3427.4, 2929.6, 1719.4, 1689.8,
1463.9, 1359.5, 1286.2, 1209.4, 1103.2, 1082.9 cm-1; 1H
NMR (300 MHz, CDCl3): δ 7.88 (d, J = 9.0 Hz, 1H), 7.50
(d, J = 8.1 Hz, 2H), 7.45 (d, J = 2.1 Hz, 1H), 7.19-7.23
(m, 3H), 5.79 (s, 1H), 4.07 (s, 1H), 3.71 (s, 3H), 3.33-
3.58 (m, 2H), 2.38 (s, 3H), 2.33 (s, 3H), 1.54-1.60 (m,
3H), 1.36-1.43 (m, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (75 MHz, CDCl3): δ 153.6, 144.3, 135.8, 134.7,
132.2, 131.7, 129.9, 129.3, 127.0, 124.1, 117.9, 100.4,
67.4, 50.7, 47,7, 31.3, 30.0, 24.8, 21.6, 20.1, 15.9, 13.9;
Anal Calcd for C25H29BrN2O4S: C, 56.29; H, 5.48; N,
5.25. Found: C, 55.92; H, 5.51; N, 5.11.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
pound as off-white solid; mp: 155-156 C; yield: 0.423 g,
82%; IR (neat): 3426.8, 2936.4, 1677.3, 1562.0, 1436.8,
1
1351.4, 1268.4, 1210.3, 1160.9, 1058.3 cm-1; H NMR
(300 MHz, CDCl3): δ 8.02 (d, J = 8.4 Hz, 1H), 7.47 (d, J
= 8.4 Hz, 2H), 7.29-7.37 (m, 6H), 7.17 (d, J = 8.4 Hz,
2H), 7.11 (td, J = 8.7, 1.8 Hz, 1H), 7.00 (t, J = 7.5 Hz,
1H), 5.73 (s, 1H), 4.07-4.22 (m, 3H), 3.78-3.89 (m, 1H),
3.49-3.68 (m, 1H), 2.81-3.02 (m, 2H), 2.36 (s, 6H), 1.54-
1.56 (m, 1H), 1.25-1.38 (m, 4H); 13C{1H} NMR (75 MHz,
CDCl3): δ 167.3, 152.8, 144.1, 138.3, 136.1, 132.9,
132.5, 129.7, 129.1, 129.0, 128.7, 127.0, 126.6, 124.8,
122.5, 67.7, 59.3, 49.5, 35.9, 29.9, 24.8, 21.6, 14.7; Anal
Calcd for C30H32N2O4S: C, 69.74; H, 6.24; N, 5.42.
Found: C, 69.39; H, 6.11; N, 5.33.
(±)
Methyl-3-benzyl-8-bromo-4-methyl-1-tosyl-
1,2,3,6-tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4n). Purification by flash column chroma-
tography on silica gel eluting with petroleum ether-ethyl
acetate mixture (90:10 to 85:15, v/v) afforded the title
compound as off-white solid; mp: 186-187 oC; yield:
0.482 g, 85%; IR (neat): 3428.8, 2945.7, 2917.7, 2257.3,
1717.3, 1561.1, 1428.9, 1354.7, 1208.2, 1160.9, 1106.9
(±)
tert-Butyl-3-benzyl-4-methyl-1-tosyl-1,2,3,6-
tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4k). Purification by flash column chromatog-
raphy on silica gel eluting with petroleum ether-ethyl ace-
tate mixture (90:10 to 85:15, v/v) afforded the title com-
1
cm-1; H NMR (300 MHz, CDCl3): δ 7.88 (d, J = 9.0 Hz,
1H), 7.50 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H),
7.28-7.38 (m, 3H), 7.21-7.26 (m, 1H), 7.18 (d, J = 8.1
Hz, 2H), 7.12 (d, J = 6.3 Hz, 2H), 5.71 (s, 1H), 4.82 (d, J
= 17.4 Hz, 1H), 4.72 (d, J = 17.4 Hz, 1H), 4.16 (s, 1H),
3.74 (s, 3H), 2.36 (s, 3H), 2.34 (s, 3H), 1.71 (dt, J = 12.9,
2.7 Hz, 1H), 1.40-1.47 (m, 1H); 13C{1H} NMR (75 MHz,
CDCl3): δ 167.5, 153.5, 144.4, 137.5, 135.6, 134.4,
132.3, 131.8, 129.9, 129.4, 128.9, 127.4, 127.0, 126.0,
124.3, 118.0, 101.0, 67.9, 50.9, 50.8, 30.1, 24.6, 21.6,
16.2; Anal Calcd for C28H27BrN2O4S: C, 59.26; H, 4.80;
N, 4.94. Found: C, 58.95; H, 4.76; N, 4.88.
o
pound as off-white solid; mp: 146-148 C; yield: 0.403 g,
76%; IR (neat): 3426.9, 2967.4, 2924.5, 1659.9, 1565.8,
1
1476.4, 1346.0, 1267.4, 1138.6, 1100.4 cm-1; H NMR
(300 MHz, CDCl3): δ 8.01 (d, J = 8.1 Hz, 1H), 7.41-7.46
(m, 3H), 7.28-7.38 (m, 3H), 7.11-7.17 (m, 5H), 7.01-7.06
(m, 1H), 5.72 (s, 1H), 4.81 (d, J = 17.7 Hz, 1H), 4.69 (d,
J = 17.7 Hz, 1H), 4.17 (s, 1H), 2.34 (s, 3H), 2.30 (s, 3H),
1.73 (dt, J = 12.6, 3.0 Hz, 1H), 1.46-1.57 (m, 10H);
13C{1H} NMR (75 MHz, CDCl3): δ 166.9, 152.0, 144.1,
137.9, 136.1, 133.1, 132.5, 128.9, 128.8, 127.2, 127.0,
126.4, 126.1, 124.7, 122.7, 103.1, 79.1, 68.0, 50.6, 30.3,
28.7, 25.0, 21.5, 16.2; Anal Calcd for C31H34N2O4S: C,
70.16; H, 6.46; N, 5.28. Found: C, 69.93; H, 6.35; N,
5.14.
(±)
Methyl-8-bromo-4-methyl-3-phenethyl-1-tosyl-
1,2,3,6-tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4o). Purification by flash column chroma-
tography on silica gel eluting with petroleum ether-ethyl
acetate mixture (90:10 to 85:15, v/v) afforded the title
compound as off-white solid; mp: 145-147 oC; yield:
0.494 g, 85%; IR (neat): 3427.8, 2971.4, 2921.6, 1677.8,
1566.3, 1480.3, 1339.4, 1259.4, 1223.2, 1158.7, 1068.5
(±)
tert-Butyl-4-methyl-3-phenethyl-1-tosyl-1,2,3,6-
tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4l). Purification by flash column chromatog-
raphy on silica gel eluting with petroleum ether-ethyl ace-
tate mixture (90:10 to 85:15, v/v) afforded the title com-
1
cm-1; H NMR (300 MHz, CDCl3): δ 7.91 (d, J = 9.0 Hz,
o
pound as off-white solid; mp: 123-125 C; yield: 0.408 g,
1H), 7.46 (dd, J = 5.4, 2.7 Hz, 1H), 7.27-7.38 (m, 6H),
7.19-7.24 (m, 4H), 5.66 (s, 1H), 4.06 (s, 1H), 3.59-3.87
(m, 5H), 2.82-3.00 (m, 2H), 2.38 (s, 3H), 2.37 (s, 3H),
1.51-1.57 (m, 1H), 1.23-1.30 (m, 1H); 13C{1H} NMR (75
MHz, CDCl3): δ 167.5, 153.2, 144.4, 138.1, 135.7, 134.6,
132.2, 131.7, 129.9, 129.4, 129.1, 128.7, 127.0, 126.7,
124.2, 118.0, 100.9, 67.6, 50.8, 49.6, 35.9, 29.9, 24.4,
21.6, 15.8; Anal Calcd for C29H29BrN2O4S: C, 59.90; H,
5.03; N, 4.82. Found: C, 59.70; H, 4.89; N, 4.73.
75%; IR (neat): 3431.7, 2971.8, 2932.2, 1671.9, 1580.4,
1450.21352.8, 1216.0, 1163.8, 1104.0 cm-1; 1H NMR
(300 MHz, CDCl3): δ 8.02 (d, J = 8.4 Hz, 1H), 7.48 (d, J
= 8.4 Hz, 2H), 7.40 (dd, J = 7.5, 1.8 Hz, 1H), 7.25-7.36
(m, 5H), 7.18 (d, J = 8.1 2H), 7.08 (td, J = 7.2, 1.5 Hz,
1H), 7.01 (td, J = 7.5, 1.2 Hz, 1H), 5.74 (s, 1H), 4.07 (s,
1H), 3.75-3.86 (m, 1H), 3.56-3.66 (m, 1H), 2.81-3.00 (m,
2H), 2.36 (s, 3H), 2.34 (s, 3H), 1.52-1.55 (m, 10H), 1.33-
1.38 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3): δ 167.0,
151.7, 144.0, 138.4, 136.2, 133.0, 132.7, 129.7, 129.1,
128.7, 127.0, 126.6, 126.4, 124.7, 122.6, 103.1, 79.0,
(±)
Methyl-8-bromo-4-methyl-3-phenyl-1-tosyl-
1,2,3,6-tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4p). Purification by flash column chroma-
ACS Paragon Plus Environment

Page 9 of 15
The Journal of Organic Chemistry
tography on silica gel eluting with petroleum ether-ethyl
1476.2, 1336.5, 1258.3, 1219.8, 1160.9, 1066.7 cm-1; 1H
1
2
3
4
5
6
7
8
acetate mixture (90:10 to 85:15, v/v) afforded the title
compound as off-white solid; mp: 167-168 oC; yield:
0.443 g, 80%; IR (neat): 3431.7, 2962.1, 2934.1, 1679.6,
1563.0, 1476.2, 1349.9, 1215.9, 1170.6, 1078.0 cm-1; 1H
NMR (300 MHz, CDCl3): δ 7.59 (d, J = 9.0 Hz, 1H), 7.53
(d, J = 2.4 Hz, 1H), 7.32-7.48 (m, 6H), 7.20 (dd, J = 8.7,
2.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.22 (s, 1H), 4.26
(s, 1H), 3.76 (s, 3H), 2.36 (s, 3H), 1.99-2.05 (m, 4H),
1.87 (dq, J = 12.6, 2.1 Hz, 1H); 13C{1H} NMR (75 MHz,
DMSO/CDCl3): δ* 167.4; 153.0, 144.0, 142.3, 134.6,
132.3, 131.9, 129.8, 129.5, 127.8, 127.0, 123.9, 117.9,
103.5, 69.5, 51.0, 30.2, 26.0, 21.5, 19.0; Anal Calcd for
C27H25BrN2O4S: C, 58.59; H, 4.55; N, 5.06. Found: C,
58.24; H, 4.63; N, 5.02. *Two aromatic carbons merged
with others.
NMR (300 MHz, CDCl3): δ 7.91 (d, J = 9 Hz, 1H), 7.52
(d, J = 3.6 Hz, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.27-7.38
(m, 4H), 7.19-7.22 (m, 3H), 5.66 (s, 1H), 4.23-4.28 (m,
1H), 4.05-4.20 (m, 3H), 3.60-3.84 (m, 2H), 2.82-2.96 (m,
2H), 2.39 (s, 3H), 2.38 (s, 3H), 1.52-1.60 (m, 1H), 1.35 (t,
J = 7.2 Hz, 3H), 1.23-1.29 (m, 1H); 13C{1H} NMR (75
MHz, CDCl3): δ 167.0, 153.1, 144.4, 138.1, 135.7, 134.7,
132.2, 131.8, 129.9, 129.3, 129.1, 128.7, 127.0, 126.7,
124.2, 117.9, 101.0, 67.7, 59.4, 49.6, 35.9, 29.8, 24.3,
21.6, 15.7, 14.7; Anal Calcd for C30H31BrN2O4S: C,
60.50; H, 5.25; N, 4.70. Found: C, 60.19; H, 5.12; N,
4.59.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(±)
tert-Butyl-3-benzyl-8-bromo-4-methyl-1-tosyl-
1,2,3,6-tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4t). Purification by flash column chromatog-
raphy on silica gel eluting with petroleum ether-ethyl ace-
tate mixture (90:10 to 85:15, v/v) afforded the title com-
(±)
Methyl-8-bromo-3-(4-chlorophenyl)-4-methyl-1-
tosyl-1,2,3,6-tetrahydro-2,6-
o
methanobenzo[d][1,3]diazocine-5-carboxylate (4q). Puri-
fication by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 85:15, v/v) afforded the title compound as off-white
pound as off-white solid; mp: 153-154 C; yield: 0.463 g,
76%; IR (neat): 3427.7, 2971.6, 1671.4, 1566.3, 1480.8,
1351,0, 1266.6, 1147.9, 1103.7 cm-1; 1H NMR (300 MHz,
CDCl3): δ 7.89 (d, J = 9 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H),
7.43 (d, J = 8.4 Hz, 2H), 7.29-7.38 (m, 3H), 7.23 (dd, J =
8.7, 2.4 Hz, 1H), 7.13-7.19 (m, 4H), 5.69 (s, 1H), 4.79 (d,
J = 17.7 Hz, 1H), 4.70 (d, J = 17.7 Hz, 1H), 4.09 (s, 1H),
2.36 (s, 3H), 2.31 (s, 3H), 1.73 (dt, J = 12.6, 2.7 Hz, 1H),
1.55 (s, 9H), 1.42 (dt, J = 12.6, 2.1 Hz, 1H); 13C{1H} NMR
(75 MHz, CDCl3): δ 166.6, 152.4, 144.3, 137.7, 135.7,
134.6, 132.3, 131.7, 129.8, 129.1, 128.9, 127.3, 127.0,
126.1, 124.4, 117.9, 102.5, 79.4, 67.9, 50.6, 30.3, 28.7,
24.5, 21.6, 16.0; Anal Calcd for C31H33BrN2O4S: C,
61.08; H, 5.46; N, 4.60. Found: C, 60.77; H, 5.38; N,
4.52.
o
solid; mp: 176-178 C; yield: 0.452 g, 77%; IR (neat):
3391.7, 2958.0, 2917.1, 1679.3, 1566.2, 1493.3, 1336.2,
1211.3, 1159.8, 1069.3 cm-1. 1H NMR (300 MHz, CDCl3):
δ 7.61 (d, J = 9.0 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.35-
7.38 (m, 4H), 7.22 (dd, J = 9.0, 2.7 Hz, 1H), 7.16 (d, J =
8.1 Hz, 2H), 6.12 (s, 1H), 4.25 (s, 1H), 3.76 (s, 3H), 2.38
(s, 3H), 1.96-2.03 (m, 4H), 1.86-1.93 (m, 1H); 13C{1H}
NMR (75 MHz, CDCl3): δ* 167.3, 152.3, 144.3, 140.7,
136.1, 134.4, 133.6, 132.0, 131.9, 129.8, 129.6, 127.0,
124.1, 118.0, 104.4, 69.4, 51.1, 30.1, 26.0, 21.6, 18.9;
Anal Calcd for C27H24BrClN2O4S: C, 55.16; H, 4.11; N,
4.76. Found: C, 55.89; H, 4.10; N, 4.67. *Two aromatic
carbons merged with others.
(±) tert-Butyl-8-bromo-4-methyl-3-phenethyl-1-tosyl-
1,2,3,6-tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4u). Purification by flash column chroma-
tography on silica gel eluting with petroleum ether-ethyl
acetate mixture (90:10 to 85:15, v/v) afforded the title
compound as off-white solid; mp: 158-160 oC; yield:
0.480 g, 77%; IR (neat): 3426.9, 2969.8, 2924.5, 1670.0,
1565.9, 1476.2, 1349.9, 1265.0, 1146.5, 1102.1 cm-1; 1H
NMR (300 MHz, CDCl3): δ 7.91 (d, J = 9.0 Hz, 1H); 7.59
(d, J = 2.1 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.29-7.35
(m, 4H), 7.20 (d, J = 8.4 Hz, 4H), 5.66 (s, 1H), 4.00 (s,
1H), 3.74-3.84 (m, 1H), 3.56-3.66 (m, 1H), 2.90-3.00 (s,
3H), 2.37 (s, 3H), 2.36 (s, 3H), 1.54-1.58 (m, 10H), 1.23-
1.28 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3): δ 166.6,
152.1, 144.3, 138.2, 135.8, 134.8, 132.2, 131.7, 129.9,
129.1, 128.7, 127.0, 126.6, 124.3, 117.8, 102.5, 79.3,
67.7, 49.5, 35.9, 30.1, 28.7, 24.3, 21.6, 15.7; Anal Calcd
for C32H35BrN2O4S: C, 61.63; H, 5.66; N, 4.49. Found: C,
61.33; H, 5.54; N, 4.33.
(±) Ethyl-3-benzyl-8-bromo-4-methyl-1-tosyl-1,2,3,6-
tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4r). Purification by flash column chromatog-
raphy on silica gel eluting with petroleum ether-ethyl ace-
tate mixture (90:10 to 85:15, v/v) afforded the title com-
o
pound as colourless solid; mp: 178-180 C; yield: 0.494
g, 85%; IR (neat): 3427.6, 2944.5, 2257.1, 1717.9,
1559.3, 1429.4, 1332.1, 1209.3, 1168.1, 1106.6 cm-1; 1H
NMR (300 MHz, CDCl3): δ 7.88 (d, J = 8.7 Hz, 1H), 7.57
(d, J = 2.4 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.28-7.38
(m, 3H), 7.23 (dd, J = 8.7, 2.4 Hz, 1H), 7.12-7.19 (m,
4H), 5.71 (s, 1H), 4.81 (d, J = 17.4 Hz, 1H), 4.72 (d, J =
17.7 Hz, 1H), 4.21-4.30 (m, 1H), 4.10-4.18 (m, 2H), 2.36
(s, 3H), 2.35 (s, 3H), 1.72 (dt, J = 12.6, 3.3 Hz, 1H),
1.40-1.47 (m, 1H), 1.36 (t, J = 7.2 Hz, 3H); 13C{1H} NMR
(75 MHz, CDCl3): δ 167.0, 153.4, 144.4, 137.5, 135.6,
134.5, 132.3, 131.9, 128.9, 127.4, 127.0, 126.1, 124.3,
117.9, 101.1, 67.9, 59.5, 50.8, 30.0, 24.6, 21.6, 16.1,
14.7; Anal Calcd for C29H29BrN2O4S: C, 59.90; H, 5.03;
N, 4.82. Found: C, 59.53; H, 4.92; N, 4.71.
(±)
1-(tert-Butyl)
5-methyl-3-benzyl-8-bromo-4-
methyl-3,6-dihydro-2,6-methanobenzo[d][1,3]diazocine-
1,5(2H)-dicarboxylate (4v). Purification by flash column
chromatography on silica gel eluting with petroleum
ether-ethyl acetate mixture (90:10 to 85:15, v/v) afforded
(±)
Ethyl-8-bromo-4-methyl-3-phenethyl-1-tosyl-
1,2,3,6-tetrahydro-2,6-methanobenzo[d][1,3]diazocine-5-
carboxylate (4s). Purification by flash column chromatog-
raphy on silica gel eluting with petroleum ether-ethyl ace-
tate mixture (90:10 to 85:15, v/v) afforded the title com-
o
the title compound as off-white solid; mp: 110-114 C;
yield: 0.348 g, 66%; IR (neat): 3397.9, 2979.5, 2932.2,
1710.6, 1679.7, 1570.7, 1390.4, 1369, 1315.2, 1213.0,
o
1
pound as off-white solid; mp: 144-146 C; yield: 0.512 g,
1165.8, 1094.4 cm-1; H NMR (300 MHz, CDCl3): δ 7.62
86%; IR (neat): 3423.9, 2974.6, 2924.5, 1671.9, 1570.7,
(d, J = 9.0 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.24-7.33
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 15
(m, 3H), 7.18 (dd, J = 9.0, 2.4 Hz, 1H), 7.02 (d, J = 6.6 (±) Methyl-3-hexyl-4-methyl-3,6-dihydro-2H-2,6-
1
2
3
4
5
6
7
8
Hz, 2H), 5.90 (s, 1H), 4.74 (d, J = 17.7 Hz, 1H), 4.66 (d,
J = 17.7 Hz, 1H), 4.37 (s, 1H), 3.79 (s, 3H), 2.35 (s, 3H),
2.13 (dt, J = 12.3, 2.1 Hz, 1H), 1.95 (dt, J = 12.3, 2.7 Hz,
1H), 1.30 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3): δ
167.7, 154.2, 152.5, 137.8, 133.8, 133.7, 131.2, 128.7,
128.6, 127.2, 125.6, 124.5, 116.2, 101.6, 82.3, 65.3,
51.6, 50.9, 30.6, 28.1, 26.7, 16.0; Anal Calcd for
C26H29BrN2O4 C, 60.82; H, 5.69; N, 5.46. Found: C,
60.61; H, 5.50; N, 5.33.
methanobenzo[g][1,3]oxazocine-5-carboxylate (6b). Pu-
rification by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 85:15, v/v) afforded the title compound as brown solid;
mp: 76-77 oC; yield: 0.227 g, 69%; IR (neat): 3434.8,
2974.1, 2958.0, 1684.4, 1588.9, 1427.9, 1329.0, 1208.1,
1
1157.3, 1106.5 cm-1; H NMR (300 MHz, CDCl3): δ 7.33
(dd, J = 7.2, 1.5 Hz, 1H), 7.06 (td, J = 8.1, 1.5 Hz, 1H),
6.80-6.86 (m, 2H), 5.35 (s, 1H), 4.19 (s, 1H), 3.75 (s,
3H), 3.46-3.57 (m, 1H), 3.20-3.37 (m, 1H), 2.39 (s, 3H),
2.11 (dt, J = 12.6, 3.0 Hz, 1H), 1.56-1.82 (m, 5H), 1.25-
1.29 (m, 4H), 0.87-0.91 (m, 3H); 13C{1H} NMR (75 MHz,
CDCl3): δ 168.1, 153.1, 150.8, 128.8, 127.8, 127.0,
120.5, 116.2, 102.0, 81.3, 50.7, 49.7, 31.5, 30.0, 28.0,
26.6, 25.9, 22.6, 15.7, 14.0; Anal Calcd for C20H27NO3:
C, 72.92; H, 8.26; N, 4.25. Found: C, 72.70; H, 8.17; N,
4.24.
9
Procedure for the Synthesis of Compound 4a in 3
mmol Scale. To a stirred solution of n-butylamine 1a
(3.6 mmol, 0.263 g) in MeOH (20 mL) was added methyl
acetoacetate 2a (3.0 mmol, 0.348 g) and InCl3 (10 mol%,
0.066 g). The reaction mixture was stirred at room
temperature for 20 minutes. To this reaction mixture, (E)-
4-methyl-N-(2-(3-oxoprop-1-en-1-
yl)phenyl)benzenesulfonamide 3a (3.0 mmol, 0.904 g)
was added, and the reaction mixture was stirred at 65 oC
in an oil bath for 1 h. After completion of the reaction, the
mixture was diluted with water (20 mL), extracted with
ethyl acetate (3 × 15 mL), and washed with brine. The
organic layer was separated, dried over anhydrous
sodium sulphate, and concentrated in vacuum. The
crude product 4a was purified through silica column
chromatography using petroleum ether-ethyl acetate as
eluent (90:10 to 85:15, v/v). Yield: 79% (1.08 g).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(±)
Methyl-3-benzyl-4-methyl-3,6-dihydro-2H-2,6-
methanobenzo[g][1,3]oxazocine-5-carboxylate (6c). Puri-
fication by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 85:15, v/v) afforded the title compound as brown solid;
o
mp: 99-101 C; yield: 0.275 g, 82%; IR (neat): 3426.9,
2938.9, 1674.9, 1564.9, 1456.9, 1424.2, 1328.7, 1224.6,
1165.8, 1118.5, 1056.8 cm-1; 1H NMR (300 MHz,
CDCl3/DMSO-d6): δ 7.25-7.40 (m, 4H), 7.14 (d, J = 6.9
Hz, 2H), 7.07 (td, J = 7.8, 1.5 Hz, 1H), 6.87 (dd, J = 7.2,
0.9 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 5.34 (s, 1H), 4.76
(s, 2H), 4.28 (s, 1H), 3.76 (s, 3H), 2.34 (s, 3H), 2.16 (dt,
J = 12.9, 2.7 Hz, 1H), 1.93 (dt, J = 12.6, 2.4 Hz, 1H);
13C{1H} NMR (75 MHz, CDCl3/DMSO-d6): δ 167.2, 152.4,
150.2, 137.3, 128.5, 128.2, 127.0, 126.6, 126.5, 125.3,
120.0, 115.7, 102.0, 80.5, 51.5, 50.4, 27.3, 25.2, 15.4;
Anal Calcd for C21H21NO3: C, 75.20; H, 6.31; N, 4.18.
Found: C, 75.05; H, 6.23; N, 4.09.
General Procedure for the Synthesis of Bridged
Chromanes 6a-r. To a stirred solution of primary amine
1 (1.2 mmol, 1.2 equiv.) in MeOH (6 mL) was added β-
ketoester 2 (1.0 mmol, 1.0 equiv.) and InCl3 (10 mol%).
The reaction mixture was stirred at room temperature for
20
minutes.
To
this
reaction
mixture
2-
hydroxyarylaldehyde 5 (1.0 mmol, 1.0 equiv.) was added
o
and the reaction was stirred at 65 C in an oil bath for 1
h. After completion of the reaction, the reaction mixture
was diluted with water (6 mL), extracted with ethyl
acetate (3 × 6 mL), and washed with brine (6 mL). The
organic layer was separated, dried over anhydrous
sodium sulphate, and concentrated in vacuum. The
crude product was purified through silica column
chromatography using petrolium ether-ethyl acetate as
eluent (90:10 to 85:15, v/v).
(±) Methyl-4-methyl-3-phenethyl-3,6-dihydro-2H-2,6-
methanobenzo[g][1,3]oxazocine-5-carboxylate (6d). Pu-
rification by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 85:15, v/v) afforded the title compound as off-white
o
solid; mp: 122-123 C; yield: 0.286 g, 82%; IR (neat):
3443.3, 3023.8, 2942.8, 1681.6, 1561.2, 1482.9, 1423.2,
1251.6, 1158.0, 1115.6, 1046.2 cm-1; 1H NMR (300 MHz,
CDCl3): δ 7.31-7.35 (m, 2H), 7.22-7.29 (m, 2H), 7.17-
7.20 (m, 2H), 7.04-7.09 (m, 1H), 6.82-6.87 (m, 2H), 5.25
(s, 1H), 4.19 (s, 1H), 3.72-3.83 (m, 4H), 3.54-3.64 (m,
1H), 2.93-3.02 (m, 1H), 2.75-2.85 (m, 1H), 2.40 (s, 3H),
2.07 (dt, J = 12.6, 2.7 Hz, 1H), 1.77 (dt, J = 12.6, 2.7 Hz,
1H); 13C{1H} NMR (75 MHz, CDCl3): δ 168.1, 152.7,
150.8, 138.5, 128.9, 128.7, 127.8, 127.1, 126.7, 120.6,
116.3, 102.8, 81.7, 51.4, 50.8, 36.8, 28.0, 25.8, 15.6;
Anal Calcd for C22H23NO3: C, 75.62; H, 6.63; N, 4.01.
Found: C, 75.54; H, 6.59; N, 4.03.
(±)
Methyl-3-butyl-4-methyl-3,6-dihydro-2H-2,6-
methanobenzo[g][1,3]oxazocine-5-carboxylate (6a). Puri-
fication by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 85:15, v/v) afforded the title compound as off-white
o
solid; mp: 104-105 C; yield: 0.223 g, 74%; IR (neat):
3433.6, 2945.7, 2927.4, 1674.9, 1559.2, 1484.9, 1428.9,
1248.7, 1222.6, 1115.6, 1087.7 cm-1; 1H NMR (300 MHz,
CDCl3): δ 7.33 (dd, J = 7.5, 1.5 Hz, 1H), 7.06 (td, J = 7.8,
1.8 Hz, 1H), 6.81-6.86 (m, 2H), 5.35 (s, 1H), 4.19 (s,
1H), 3.75 (s, 3H), 3.47-3.57 (m, 1H), 3.27-3.38 (m. 1H),
2.38 (s, 3H), 2.11 (dt, J = 12.9, 3.0 Hz, 1H), 1.79 (dt, J =
12.6, 2.7 Hz, 1H), 1.50-1.66 (m, 2H), 1.25-1.39 (m, 2H),
0.94 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ
168.1, 153.1, 150.8, 128.9, 127.8, 127.1, 102.1, 81.3,
50.7, 49.5, 32.2, 28.0, 25.9, 20.1, 15.7, 13.9; Anal Calcd
for C18H23NO3 C, 71.73; H, 7.69; N, 4.65. Found: C,
71.35; H, 7.68; N, 4.57.
(±)
Methyl-4-methyl-3-phenyl-3,6-dihydro-2H-2,6-
(6e).
methanobenzo[g][1,3]oxazocine-5-carboxylate
Purification by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 85:15, v/v) afforded the title compound as off-white
o
solid; mp: 161-162 C; yield: 0.247 g, 77%; IR (neat):
3417.2, 2945.7, 1676.8, 1563.0, 1484.9, 1406.8, 1321.9,
1211.0, 1104.4, 1073.2 cm-1; 1H NMR (300 MHz, CDCl3):
ACS Paragon Plus Environment

Page 11 of 15
The Journal of Organic Chemistry
δ 7.31-7.42 (m, 4H), 7.07-7.13 (m, 3H), 6.88 (td, J = 7.2,
(±)
Ethyl-4-methyl-3-phenethyl-3,6-dihydro-2H-2,6-
1
2
3
4
5
6
7
8
1.2 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 5.62 (s, 1H), 4.30
(s, 1H), 3.79 (s, 3H), 2.26 (dt, J = 12.6, 2.7 Hz, 1H),
2.04-2.11 (m, 4H); 13C{1H} NMR (75 MHz, CDCl3): δ*
168.1, 152.2, 150.9, 143.7, 129.5, 128.9, 127.8, 127.6,
127.2, 120.7, 116.4, 104.2, 82.5, 50.9, 28.1, 26.2, 18.7;
Anal Calcd for C20H19NO3: C, 74.75; H, 5.96; N, 4.36.
Found: C, 74.39; H, 5.99; N, 4.32. *One aromatic carbon
is merged with others.
methanobenzo[g][1,3]oxazocine-5-carboxylate (6i). Puri-
fication by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 85:15, v/v) afforded the title compound as pale yellow
o
solid; mp: 108-109 C; yield: 0.305 g, 84%; IR (neat):
3443.3, 3028.8, 2949.3, 1684.4, 1561.3, 1480.3, 1428.6,
1253.2, 1154.6, 1116.0, 1096.8, 1076.3 cm-1; H NMR
1
(300 MHz, CDCl3/DMSO-d6): δ 7.18-7.35 (m, 6H), 7.03-
7.08 (m, 1H), 6.81-6.85 (m, 2H), 5.27 (s, 1H), 4.12-4.28
(m, 3H), 3.73-3.83 (m, 1H), 3.57-3.65 (m, 1H), 2.93-3.02
(m, 1H), 2.75-2.85 (m, 1H), 2.39 (s, 3H), 2.06 (dt, J =
12.6, 2.7 Hz, 1H), 1.79 (dt, J = 12.3, 2.4 Hz, 1H), 1.38 (t,
J = 7.2 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3/DMSO-
d6): δ 167.3, 152.2, 150.6, 138.4, 128.6, 128.5, 127.7,
126.9, 126.5, 120.3, 116.0, 102.7, 81.5, 59.1, 51.2, 36.6,
27.7, 25.5, 15.4, 14.6; Anal Calcd for C23H25NO3: C,
76.01; H, 6.93; N, 3.85. Found: C, 75.76; H, 6.83; N,
3.76.
(±)
Methyl-3-(4-methoxyphenyl)-4-methyl-3,6-
9
dihydro-2H-2,6-methanobenzo[g][1,3]oxazocine-5-
carboxylate (6f). Purification by flash column chromatog-
raphy on silica gel eluting with petroleum ether-ethyl ace-
tate mixture (90:10 to 85:15, v/v) afforded the title com-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
pound as colourless solid; mp: 178-180 C; yield: 0.239
g, 68%; IR (neat): 3436.5, 2943.8, 1674.9, 1561.1,
1
1509.0, 1321.9, 1219.8, 1110.8, 1076.1 cm-1; H NMR
(300 MHz, CDCl3): δ 7.39 (dd, J = 7.5, 1.5 Hz, 1H); 7.10
(td, J = 8.1, 1.8 Hz, 1H), 6.88-7.02 (m, 4H), 6.84 (d, J =
8.1 Hz, 2H), 5.54 (s, 1H), 4.29 (s, 1H), 3.83 (s, 3H), 3.78
(s, 3H), 2.24 (dt, J = 12.6, 3.0 Hz, 1H), 2.03-2.09 (m,
4H); 13C{1H} NMR (75 MHz, CDCl3): δ 168.1, 158.8,
152.7, 150.9, 136.4, 128.9, 127.9, 127.2, 120.7, 116.4,
114.6, 103.7, 82.7, 55.5, 50.8, 28.1, 26.2, 18.5; Anal
Calcd for C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found:
C, 71.85; H, 5.90; N, 3.89.
(±) Ethyl-3-(4-methoxyphenyl)-4-methyl-3,6-dihydro-
2H-2,6-methanobenzo[g][1,3]oxazocine-5-carboxylate
(6j). Purification by flash column chromatography on
silica gel eluting with petroleum ether-ethyl acetate mix-
ture (90:10 to 85:15, v/v) afforded the title compound as
o
off-white solid; mp: 150-151 C; yield: 0.270 g, 74%; IR
(neat): 3426.9, 2979.9, 2945.7, 1676.8, 1561.1, 1484.9,
1320.0, 1211.1, 1108.8, 1064.5 cm-1; 1H NMR (300 MHz,
CDCl3): δ 7.42 (dd, J = 7.5, 1.5 Hz, 1H); 7.07-7.12 (m,
3H), 6.83-6.92 (m, 4H), 5.55 (s, 1H), 4.18-4.30 (m, 3H),
3.83 (s, 3H), 2.23 (dt, J = 12.6, 3.0 Hz, 1H), 2.04-2.10
(m, 4H), 1.39 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (75 MHz,
CDCl3): δ* 167.7, 158.8, 152.5, 150.9, 136.5, 128.9,
128.0, 127.2, 120.6, 116.4, 114.6, 103.8, 82.7, 59.5,
55.5, 28.1, 26.2, 18.5, 14.7; Anal Calcd for C22H23NO4: C,
72.31; H, 6.34; N, 3.83. Found: C, 71.95; H, 6.31; N,
3.79. *One aromatic carbon is merged with others.
(±) Methyl-3-(4-fluorophenyl)-4-methyl-3,6-dihydro-
2H-2,6-methanobenzo[g][1,3]oxazocine-5-carboxylate
(6g). Purification by flash column chromatography on
silica gel eluting with petroleum ether-ethyl acetate mix-
ture (90:10 to 85:15, v/v) afforded the title compound as
colourless solid; mp: 152-153 oC; yield: 0.244 g, 72%; IR
(neat): 3437.8. 2931.3, 1684.3, 1571.2, 1509.8, 1326.4,
1219.7, 1108.6, 1079.2 cm-1; 1H NMR (300 MHz, CDCl3):
δ 7.39 (dd, J = 7.5, 1.5 Hz, 1H), 7.08-7.13 (m, 5H), 6.89
(td, J = 7.5, 1.2 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 5.55 (s,
1H), 4.29 (s, 1H), 3.79 (s, 3H), 2.25 (dt, J = 12.9, 3.0 Hz,
1H), 2.03-2.10 (m, 4H); 13C{1H} NMR (75 MHz, CDCl3): δ
168.0; 161.7 (d, J = 246 Hz), 151.9, 150.7, 139.6 (d, J =
3.0 Hz), 130.6, 128.9, 127.8, 127.3, 120.8, 116.4, 116.3
(d, J = 22.5 Hz), 104.6, 82.6, 50.9, 28.1, 26.2, 18.6; Anal
Calcd for C20H18FNO3: C, 70.78; H, 5.35; N, 4.13. Found:
C, 70.53; H, 5.40; N, 4.04.
(±) Ethyl-3-(4-fluorophenyl)-4-methyl-3,6-dihydro-2H-
2,6-methanobenzo[g][1,3]oxazocine-5-carboxylate (6k).
Purification by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 85:15, v/v) afforded the title compound as off-white
o
solid; mp: 154-155 C; yield: 0.265 g, 74%; IR (neat):
3436.5, 2981.3, 1681.6, 1570.7, 1507.1, 1323.8, 1211.1,
1106.9, 1071.3 cm-1; H NMR (300 MHz, CDCl3): δ 7.41
1
(±) Methyl-3-(4-bromophenyl)-4-methyl-3,6-dihydro-
2H-2,6-methanobenzo[g][1,3]oxazocine-5-carboxylate
(6h). Purification by flash column chromatography on
silica gel eluting with petroleum ether-ethyl acetate mix-
ture (90:10 to 85:15, v/v) afforded the title compound
(dd, J = 7.5, 1.5 Hz, 1H), 7.07-7.13 (m, 5H), 6.89 (td, J =
7.5, 1.2 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 5.56 (s, 1H),
4.18-4.31 (m, 3H), 2.25 (dt, J = 12.6, 2.7 Hz, 1H), 2.03-
2.11 (m, 4H), 1.39 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (75
MHz, CDCl3): δ 167.5, 161.7 (d, J = 246 Hz), 151.7,
150.8, 139.6 (d, J = 3.0 Hz), 128.9, 127.8, 127.3, 120.8,
116.4, 116.3 (d, J = 22.5 Hz), 104.8, 82.6, 59.6, 28.1,
26.2, 18.5, 14.7; Anal Calcd for C21H20FNO3: C, 71.37;
H, 5.70; N, 3.96. Found: C, 71.03; H, 5.50; N, 3.74.
o
asoff-white solid; mp: 127-128 C; yield: 0.304 g, 76%;
IR (neat): 3419.6, 2944.3, 1676.8, 1566.3, 1481.3,
1
1408.7, 1328.1, 1210.5, 1101.8, 1071.6 cm-1; H NMR
(300 MHz, CDCl3): δ 7.52 (d, J = 8.7 Hz, 2H), 7.38 (dd, J
= 7.5, 1.5 Hz, 1H), 7.10 (td, J = 7.8, 1.5 Hz, 1H), 7.00 (d,
J = 7.8 Hz, 2H), 6.89 (dd, J = 7.5, 1.2 Hz, 1H), 6.81 (d, J
= 8.1 Hz, 1H), 5.58 (s, 1H), 4.29 (s, 1H), 3.79 (s, 3H),
2.25 (td, J = 12.6, 2.7 Hz, 1H), 2.03-2.10 (m, 4H); 13C{1H}
NMR (75 MHz, CDCl3): δ 167.9, 151.5, 150.7, 142.7,
132.7, 130.6, 128.9, 127.6, 127.4, 121.4, 120.9, 116.4,
105.2, 82.4, 51.0, 28.1, 26.2, 18.7; Anal Calcd for
C20H18BrNO3: C, 60.01; H, 4.53; N, 3.50. Found: C,
59.85; H, 4.60; N, 3.49.
(±) tert-Butyl-3-benzyl-4-methyl-3,6-dihydro-2H-2,6-
methanobenzo[g][1,3]oxazocine-5-carboxylate (6l). Puri-
fication by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 85:15, v/v) afforded the title compound as off-white
solid; mp: 76-78 oC; yield: 0.294 g, 78%; IR (neat):
3422.1, 2974.7, 2960.2, 1684.5, 1570.7, 1428.9, 1336.4,
1222.6, 1118.5, 1052.0 cm-1; 1H NMR (300 MHz, CDCl3):
δ 7.41 (dd, J = 7.5, 1.5 Hz, 1H), 7.24-7.36 (m, 3H), 7.15
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(d, J = 7.2 Hz, 2H), 7.09 (td, J = 8.1, 1.8 Hz, 1H), 6.88 C22H22BrNO3: C, 61.69; H, 5.18; N, 3.27. Found: C,
1
2
3
4
5
6
7
8
(dd, J = 7.2, 1.2 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 5.29
(s, 1H), 4.72 (s, 2H), 4.26 (s, 1H), 2.32 (s, 3H), 2.14 (dt,
J =12.9, 3.0 Hz, 1H), 1.92 (dt, J = 12.6, 2.7 Hz, 1H), 1.58
(s, 9H); 13C{1H} NMR (75 MHz, CDCl3): δ 167.2, 150.9,
138.2, 128.8, 127.8, 127.2, 127.1, 126.0, 120.6, 116.4,
104.3, 80.9, 79.1, 51.7, 28.8, 28.3, 25.9, 16.0; Anal
Calcd for C24H27NO3: C, 76.36; H, 7.21; N, 3.71. Found:
C, 76.15; H, 7.16; N, 3.49.
61.44; H, 5.07; N, 3.08.
(±) Ethyl-8-bromo-4-methyl-3-phenethyl-3,6-dihydro-
2H-2,6-methanobenzo[g][1,3]oxazocine-5-carboxylate
(6p). Purification by flash column chromatography on
silica gel eluting with petroleum ether-ethyl acetate mix-
ture (90:10 to 85:15, v/v) afforded the title compound as
off-white solid; mp: 79-80 oC; yield: 0.367 g, 83%; IR
(neat): 3448.6, 2969.4, 2947.3, 1681.7, 1566.8, 1430.3,
1338.4, 1203.6, 1169.0, 1129.1, 1106.8, 1054.3 cm-1; 1H
NMR (300 MHz, CDCl3): δ 7.49 (d, J = 2.4 Hz, 1H), 7.23-
7.34 (m, 3H), 7.17-7.22 (m, 2H), 7.14 (dd, J = 8.7, 2.4
Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 5.23 (s, 1H), 4.14-4.32
(m, 3H), 3.70-3.79 (m, 1H), 3.53-3.63 (m, 1H), 2.91-3.00
(m, 1H), 2.76-2.84 (m, 1H), 2.42 (s, 3H), 2.02 (dt, J =
12.6, 2.7 Hz, 1H), 1.77 (dt, J = 12.9, 2.7 Hz, 1H), 1.40 (t,
J = 7.2 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3): δ 167.4,
152.7, 150.1, 138.4, 131.5, 129.9, 129.8, 128.8, 128.7,
126.7, 118.0, 112.6, 102.5, 81.9, 59.5, 51.5, 36.8, 27.9,
25.4, 15.5, 14.7; Anal Calcd for C23H24BrNO3: C, 62.45;
H, 5.47; N, 3.17. Found: C, 62.13; H, 5.42; N, 3.18.
(±) tert-Butyl-4-methyl-3-phenethyl-3,6-dihydro-2H-
2,6-methanobenzo[g][1,3]oxazocine-5-carboxylate (6m).
Purification by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 85:15, v/v) afforded the title compound as off-white
solid; mp: 83-84 oC; yield: 0.297g, 76%; IR (neat):
3427.6, 2977.8, 1688.4, 1570.8, 1429.7, 1331.8, 1221.8,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1114.5, 1058.7 cm-1; H NMR (300 MHz, CDCl3): δ 7.38
(d, J = 7.2 Hz, 1H), 7.29-7.34 (m, 2H), 7.18-7.23 (m, 3H),
7.06 (td, J = 7.8, 1.5 Hz, 1H), 6.82-6.87 (m, 2H), 5.24 (s,
1H), 4.16 (s, 1H), 3.71-3.81 (m, 1H), 3.51-3.61 (m, 1H),
2.91-3.01 (m, 1H), 2.73-2.83 (m, 1H), 2.38 (s, 3H), 2.05
(dt, J = 12.6, 2.7 Hz, 1H), 1.78 (dt, J = 12.6 Hz, 1H), 1.57
(s, 9H); 13C{1H} NMR (75 MHz, CDCl3): δ 167.3, 151.5,
150.8, 138.7, 128.8, 128.7, 127.9, 127.1, 126.6, 120.5,
116.3, 104.6, 81.8, 79.1, 51.3, 36.9, 28.8, 28.3, 25.9,
15.6; Anal Calcd for C25H29NO3: C, 76.70; H, 7.47; N,
3.58. Found: C, 76.47; H, 7.42; N, 3.51.
(±) Methyl-3-benzyl-4-methyl-8-nitro-3,6-dihydro-2H-
2,6-methanobenzo[g][1,3]oxazocine-5-carboxylate (6q).
Purification by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 85:15, v/v) afforded the title compound as yellow solid;
o
mp: 146-148 C; yield: 0.266 g, 70%; IR (neat): 3426.9,
(±)
Methyl-3-benzyl-8-bromo-4-methyl-3,6-dihydro-
2979.5, 2943.8, 1658.5, 1570.7, 1510.9, 1421.3, 1333.5,
1232.3, 1108.9, 1084.8 cm-1; 1H NMR (300 MHz, CDCl3):
δ 8.28 (d, J = 2.7 Hz, 1H), 8.0 (dd, J = 9.0, 3.0 Hz, 1H),
7.29-7.38 (m, 3H), 7.12 (d, J = 6.9 Hz, 2H), 6.87 (d, J =
9.0 Hz, 1H), 5.43 (s, 1H), 4.76 (s, 2H), 4.36 (s, 1H), 3.83
(s, 3H), 2.39 (s, 3H), 2.15 (dt, J = 12.9, 3.0 Hz, 1H), 2.02
(dt, J = 12.9, 2.7 Hz, 1H); 13C{1H} NMR (75 MHz,
CDCl3/DMSO-d6): δ 167.0, 156.6, 152.6, 140.8, 137.0,
128.5, 128.0, 127.0, 125.5, 124.5, 122.8, 116.5, 101.7,
81.7, 52.0, 50.6, 27.6, 24.7, 15.4; Anal Calcd for
C21H20N2O5: C, 66.31; H, 5.30; N, 7.36. Found: C, 66.05;
H, 5.40; N, 3.49.
2H-2,6-methanobenzo[g][1,3]oxazocine-5-carboxylate
(6n). Purification by flash column chromatography on
silica gel eluting with petroleum ether-ethyl acetate mix-
ture (90:10 to 85:15, v/v) afforded the title compound
o
asoff-white solid; mp: 165-166 C; yield: 0.348 g, 84%;
IR (neat): 3440.4, 2960.2, 2944.8, 1679.7, 1576.5,
1471.4, 1421.3, 1333.5, 1201.4, 1167.7, 1123.3, 1102.1
1
cm-1; H NMR (300 MHz, CDCl3): δ 7.47 (d, J = 2.4 Hz,
1H), 7.29-7.36 (m, 3H), 7.17 (dd, J = 8.7, 2.4 Hz, 1H),
7.11 (d, J = 6.9 Hz, 2H), 6.69 (d, J = 8.4 Hz, 1H), 5.31 (s,
1H), 4.73 (s, 2H), 4.25 (s, 1H), 3.80 (s, 3H), 2.36 (s, 3H),
2.12 (dt, J = 12.9, 2.7 Hz, 1H), 1.91 (dt, J = 12.9, 2.7 Hz,
1H); 13C{1H} NMR (75 MHz, CDCl3): δ 167.8, 153.4,
150.1, 137.8, 131.5, 130.0, 129.7, 128.9, 127.4, 125.9,
118.2, 112.8, 102.3, 81.1, 52.1, 51.0, 28.0, 25.6, 16.0;
Anal Calcd for C21H20BrNO3: C, 60.88; H, 4.87; N, 3.38.
Found: C, 60.36; H, 4.81; N, 3.35.
(±)
Ethyl-3-benzyl-4-methyl-8-nitro-3,6-dihydro-2H-
2,6-methanobenzo[g][1,3]oxazocine-5-carboxylate (6r).
Purification by flash column chromatography on silica gel
eluting with petroleum ether-ethyl acetate mixture (90:10
to 85:15, v/v) afforded the title compound as yellow
gummy solid; yield: 0.268g, 68%; IR (neat): 3428.6,
2978.0, 2944.5, 2848.6, 1656.4, 1571.8, 1514.6, 1422.4,
1329.4, 1109.1, 1088.5 cm-1; 1H NMR (300 MHz, CDCl3):
δ 8.35 (d, J = 2.7 Hz, 1H), 8.00 (dd, J = 9.0, 2.7 Hz, 1H),
7.29-7.38 (m, 3H), 7.13 (d, J = 6.9 Hz, 2H), 6.87 (d, J =
9.0 Hz, 1H), 5.43 (s, 1H), 4.75 (s, 2H), 4.18-4.37 (m,
3H), 2.40 (s, 3H), 2.15 (dt, J = 12.9, 3.0 Hz, 1H), 2.03
(dt, J = 12.9, 2.7 Hz, 1H), 1.47 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3): δ 167.0, 157.0, 152.9,
141.4, 137.5, 129.0, 128.4, 127.6, 126.0, 125.2, 123.2,
116.8, 102.4, 82.1, 60.0, 52.3, 28.0, 25.2, 15.8, 14.6;
Anal Calcd for C22H22N2O5: C, 66.99; H, 5.62; N, 7.10.
Found: C, 66.63; H, 5.50; N, 7.14.
(±)
Methyl-8-bromo-4-methyl-3-phenethyl-3,6-
dihydro-2H-2,6-methanobenzo[g][1,3]oxazocine-5-
carboxylate (6o). Purification by flash column chroma-
tography on silica gel eluting with petroleum ether-ethyl
acetate mixture (90:10 to 85:15, v/v) afforded the title
compound as off-white solid; mp: 114-116 oC; yield:
0.351g, 82%; IR (neat): 3444.6, 2969.3, 2948.8, 1684.7,
1576.6, 1427.3, 1336.6, 1203.0, 1168.1, 1121.8, 1102.4,
1056.1 cm-1; H NMR (300 MHz, CDCl3): δ 7.44 (d, J =
1
2.4 Hz, 1H), 7.23-7.34 (m, 2H), 7.13-7.22 (m, 4H), 6.71
(d, J = 8.7 Hz, 1H); 5.22 (s, 1H), 4.15 (s, 1H), 3.71-3.88
(m, 4H), 3.53-3.64 (m, 1H), 2.91-3.00 (m, 1H), 2.74-2.84
(m, 1H), 2.41 (s, 3H), 2.02 (dt, J = 12.9, 3.0 Hz, 1H),
1.76 (dt, J = 12.9, 2.7 Hz, 1H); 13C{1H} NMR (75 MHz,
CDCl3): δ 167.8, 152.9, 150.0, 138.4, 131.4, 130.0,
129.9, 128.8, 128.7, 126.8, 118.1, 112.7, 102.3, 81.8,
51.4, 50.9, 36.8, 27.9, 25.4, 15.6; Anal Calcd for
ASSOCIATED CONTENT
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The Journal of Organic Chemistry
nelli, P. Ueber Aldehyduramide des Acetessigäthers. II. Chem.
Ber. 1891, 24, 2962–2967.
(7) Mannich, C.;
Kondensationsprodukt aus Formaldehyd, Ammoniak und
Antipyrin. Arch. Pharm. 1912, 250, 647–667.
(8) Passerini, M. Sopra gli Isonitrili (I). Composto del p-
Isonitril-azobenzolo con Acetone ed Acido Acetico. Gazz.
Chim. Ital. 1921, 51, 126–129.
(9) Ugi, I.; Meyr, R.; Fetzer U.; Steinbrückner, C.
Versammlungsberichte. Angew. Chem. 1959, 71, 373–388.
(10) For some recent examples of multicomponent reactions
for the synthesis of heterocycles, see: (a) Vivekanand, T.;
Vachan, B. S.; Karuppasamy, M.; Muthukrishnan, I.; Mahe-
swari, C. U.; Nagarajan, S.; Bhuvanesh, N.; Sridharan, V.
Diastereoselective ABB′ Three-Component Synthesis of Highly
Functionalized Spirooxindoles Bearing Five Consecutive
Asymmetric Carbons. J. Org. Chem. 2019, 84, 4009–4016. (b)
Muthukrishnan, I.; Vachan, B. S.; Karuppasamy, M.; Eniyaval,
A.; Maheswari, C. U.; Nagarajan, S.; Menéndez, J. C.; Sri-
dharan, V. Heterogeneous Amberlyst-15-Catalyzed Synthesis
of Complex Hybrid Heterocycles Containing [1,6]-Naphthyridine
Under Metal-Free Green Conditions. Org. Biomol. Chem. 2019,
17, 6872–6879. (c) Echemendía, R.; Silva, G. P.; Kawamura,
M. Y.; de la Torre, A. F.; Corrêa, A. G.; Ferreira, M. A. B.; Rive-
The Supporting Information is available free of charge on
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8
the ACS Publications website at DOI:
1
Copies of H and 13C NMR spectra of all compounds,
Krösche,
W.
Ueber
ein
and X-ray crystallographic data of compound 4n (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: umamaheswaric@scbt.sastra.edu or
uma.cchem@gmail.com
*E-mail: vesridharan@gmail.com or
sridharan.che@cujammu.ac.in
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ORCID
C. Uma Maheswari: 0000-0002-7855-2193
Vellaisamy Sridharan: 0000-0002-3099-4734
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final ver-
sion of the manuscript.
ra, D. G.; Paixão, M. W.
A Stereoselective Sequential
Organocascade and Multicomponent Approach for the
Preparation of Tetrahydropyridines and Chimeric Derivatives.
Chem. Commun. 2019, 55, 286–289. (d) Samala, S.; Ryu, D.
H.; Song, C. E.; Yoo, E. J. Multicomponent Dipolar
Cycloadditions: Efficient Synthesis of Polycyclic Fused
Pyrrolizidines via Azomethine Ylides. Org. Biomol. Chem. 2019,
17, 1773–1777. (e) Liu, Y.-Y.; Yu, X.-Y.; Chen, J.-R.; Qiao, M.-
M.; Qi, X.; Shi, D.-Q.; Xiao, W.-J. Visible-Light-Driven Aza-
ortho-quinone Methide Generation for the Synthesis of Indoles
in a Multicomponent Reaction. Angew. Chem. Int. Ed. 2017, 56,
9527–9531. (f) Wang, C.; Lai, J.; Chen, C.; Li, X.; Cao, H. Ag-
Catalyzed Tandem Three-Component Reaction Toward the
Synthesis of Multisubstituted Imidazoles J. Org. Chem. 2017,
82, 13740–13745. (g) Qiu, G.; Wang, Q.; Zhu, J. Palladium-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the Department of Science and
Technology–Science and Engineering Research Board,
DST-SERB (EMR/2016/001619 & EMR/2016/002485) is
gratefully acknowledged.
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O
R4
R2
O
R4
CO2R3
R2
CO2R3
R2
NH
OH
InCl3 (10 mol %)
H
H
PG
R3O2C
InCl3 (10 mol %)
N
R4
R4
O
N
+
R1
R1
new bonds
MeOH, 65 oC, 1 h
(68-84%)
MeOH, 65 oC, 1 h
(65-87%)
N
O
H
H
H2N
R1
PG
new bonds
(1 C–C and 3 C–N)
(22 examples)
(1 C–C, 1 C–O, 2 C–N)
(18 examples)
One-pot, Sequential Three-component Reaction
High atom economy (–2H2O)
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