Domino Reactions of Bis-Diazo Compounds: Rhodium(II) Acetate Catalyzed Diastereoselective Synthesis of Epoxy- and Epithio-Bridged Heterocycle-Fused Quinolizinone Analogues

Article abstract of DOI:10.1055/s-0035-1560441

Rhodium(II) acetate catalyzed domino reactions of bis-diazo compounds afford epoxy- and epithio-bridged heterocycle-fused quinolizinone systems in a stereoselective manner. The presence of an acceptor diazo functionality leads to a selective intermolecular X-H insertion reaction in a chemoselective manner, and the acceptor/acceptor diazo functionality subsequently participates in the formation of isomünchnone/thioisomünchnone 1,3-dipoles followed by intramolecular cycloaddition in a diastereoselective manner. This domino reaction is capable of constructing epoxy- and epithio-bridged heterocycle-fused quinolizinone ring systems with four stereogenic centers. The Bronsted acid induced reactions of oxa-bridged tricyclic compounds furnish ring-opened alcohol products in a regioselective manner.

Full text of DOI:10.1055/s-0035-1560441

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–M
paper
A
S. Muthusamy, C. Gangadurai
Paper
Synthesis
Domino Reactions of Bis-Diazo Compounds: Rhodium(II) Acetate
Catalyzed Diastereoselective Synthesis of Epoxy- and Epithio-
Bridged Heterocycle-Fused Quinolizinone Analogues
Sengodagounder Muthusamy*
Chinnakuzhanthai Gangadurai
chemoselective
insertion
H
X
N2
X
( )n
( )n
X
( )n
XH
XH
( )n
H
( )n
H
cat. Rh2(OAc)4
cat. Rh2(OAc)4
cat. PTSA
School of Chemistry, Bharathidasan University, Tiruchirappalli,
620024, India
muthu@bdu.ac.in
N
N
Y
N
Y
N
benzene, r.t.
3–4 h
benzene
60 °C then
reflux, 6–8 h
Y
CH2Cl2, r.t.
N2
N2
O
O
O
O
HO
R
R
R
retained intact at
room temperature
when Y = O
R
isomünchnone
cycloaddition
domino process
no excess catalyst
high diastereoselectivity
15 examples
R = COMe, CO2Me
X = NH, NPh, S, O; Y = O, S
n = 0,1
60–92% yield
Received: 18.12.2015
Accepted after revision: 26.02.2016
Published online: 13.04.2016
bonyl compounds catalyzed by transition metals have re-
ceived significant attention.3 The chemistry of such inter-
esting mesoionic oxazolium ylides (isomünchnones) and
their cycloaddition reactions with various dipolarophiles or
trapping with different nucleophiles to achieve a variety of
heterocycles have been documented.4 Other interesting
‘masked’ thiocarbonyl ylides (thioisomünchnones), generat-
ed from thioamides, undergo 1,3-dipolar cycloaddition re-
actions.5 The decomposition of diazo compounds bearing a
sulfur atom requires higher temperature because the metal
catalyst activity is generally poisoned by sulfur.6
DOI: 10.1055/s-0035-1560441; Art ID: ss-2015-n0726-op
Abstract Rhodium(II) acetate catalyzed domino reactions of bis-diazo
compounds afford epoxy- and epithio-bridged heterocycle-fused quin-
olizinone systems in a stereoselective manner. The presence of an ac-
ceptor diazo functionality leads to a selective intermolecular X–H inser-
tion reaction in a chemoselective manner, and the acceptor/acceptor
diazo functionality subsequently participates in the formation of
isomünchnone/thioisomünchnone 1,3-dipoles followed by intramolec-
ular cycloaddition in a diastereoselective manner. This domino reaction
is capable of constructing epoxy- and epithio-bridged heterocycle-
fused quinolizinone ring systems with four stereogenic centers. The
Brønsted acid induced reactions of oxa-bridged tricyclic compounds
furnish ring-opened alcohol products in a regioselective manner.
H
H
N
N
Key words bis-diazo compounds, domino reactions, diastereoselec-
tivity, X–H insertion, isomünchnones, rhodium(II) acetate
N
N
O
H
H
H
H
allomatridine
frog alkaloid (–)-205B
lycopodine
O
The construction of fused heterocycles through selec-
tive multiple-bond formation in a single synthetic step is of
particular interest in organic synthesis. Quinolizines consti-
tute a significant part of heterocyclic chemistry due to their
biological properties and their presence as structural fea-
tures of numerous alkaloids and drug candidates.1 For ex-
ample, quinolizine-fused carbo- and heterocyclic systems
such as allomatridine,1g,h frog alkaloid (–)-205B,1a lycopo-
dine,1d hydrojulolidine,1e and indoloquinolizine1f (Figure 1)
are existing alkaloids having potent biological activities
with utility of the lycopodine family of alkaloids in Chinese
folk medicine for the treatment of skin disorders.1d The syn-
thetic utilization of diazocarbonyl compounds has been
demonstrated to explore an array of reactions2 such as cy-
clopropanation, C–H insertion, heteroatom–H insertion and
ylide formation toward the synthesis of a wide range of
polycyclic systems and natural products. The multifarious
transformations of carbonyl ylides derived from diazocar-
H
N
N
H
N
(S)-indolo[2,3-a]quinolizine
hydrojulolidine
Figure 1 Examples of fused quinolizine alkaloids
However, the synthetic applications of bis-diazocarbon-
yl compounds are scarce, with reported methods utilizing
photolysis, thermolysis, ring contraction and metal cataly-
sis.7 Taking advantage of our interest in the chemistry of
bis-diazocarbonyl compounds,7f–h we herein report the
domino reactions of acceptor (A) and acceptor/acceptor
(A/A) substituted bis-diazo compounds in the presence of
rhodium(II) acetate for the construction of a range of ep-
oxy- and epithio-bridged heterocycle-fused quinolizinone
systems having different ring sizes. The reactions proceed
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

B
S. Muthusamy, C. Gangadurai
Paper
Synthesis
via X–H insertion/dipolar cycloaddition of isomünchnones
and thioisomünchnones in a regio-, chemo- and diastereo-
selective manner.
chemical behavior of the acceptor diazo functionality with
a bifunctional reaction partner in order to avoid the poten-
tial interference of the second A/A diazo functionality pres-
ent in bis-diazo compounds 3. Prior to assessing the reac-
tivity of bis-diazo compound 3, compound 2a was initially
utilized for the insertion reactions. Thus, diazo compound
2a was allowed to react with allyl alcohol 4a under mild re-
action conditions with a range of catalysts at different tem-
peratures. As diazo compounds are known to be potentially
explosive, and so as to ensure the complete conversion, the
reaction was performed by adding N-substituted diazo
compound 2a to allyl alcohol 4a over a period of 30 minutes
(flow rate of 0.1 mL/min via a syringe pump) in the pres-
ence of Cu(OTf)2 at room temperature to furnish the corre-
sponding product 5a in 21% yield (Table 1, entry 1). Under
similar conditions, the reaction catalyzed by Cu(acac)2 gave
a yield of only 17% (Table 1, entry 2). As the O–H insertion
reaction of α-diazocarbonyl compounds was feasible using
mild Lewis acids,9 the reaction of diazo compound 2a with
4a was performed in the presence In(OTf)3 to afford the de-
sired product in 34% yield (Table 1, entry 3). However, the
reaction using InCl3 as the catalyst failed to give the inser-
tion product, even after 12 hours (Table 1, entry 4). The re-
action of 2a and allyl alcohol 4a under similar conditions
using Rh2(OAc)4 as the catalyst afforded the insertion prod-
uct 5a in 76% yield (Table 1, entry 5). The product was ob-
tained in 54% yield when dichloroethane was used as the
solvent (Table 1, entry 6). The insertion reaction was pre-
ferred in benzene, as it was found to be a more suitable sol-
vent than dichloromethane for the dipole formation/cyc-
loaddition reactions in the second step. Thus, diazo com-
pound 2a was added slowly with the insertion partner, allyl
alcohol 4a, in the presence of Rh2(OAc)4 at 25 °C to furnish
the product 5a in 46% yield (Table 1, entry 7), when the re-
action was carried out in benzene. Next, the reaction was
repeated at 60 °C to furnish product 5a in 72% yield (Table 1,
entry 8).
In continuation of our earlier work7f–h on bis-diazocar-
bonyl compounds, we were motivated to investigate the
domino reactions of differently substituted bis-diazo com-
pounds 3 (Scheme 1). The required starting material, diazo
compound 1a, was synthesized8 from L-ornithine monohy-
drochloride. Thionation of the carbonyl group of 1a was
carried out using Lawesson’s reagent to furnish 1b. The bis-
diazo compounds were obtained quite conveniently by acy-
lation of 1a,b with 2,2,6-trimethyl-1,3-dioxin-4(H)-one or
methylmalonyl chloride in dry toluene under reflux condi-
tions. The second diazo functionality was introduced at the
active methylene group, with or without isolating the acy-
lated product, to furnish the bis-diazo compounds 3a–d
(Scheme 1). The various bifunctional reaction partners
used for the insertion/cycloaddition study are shown in Fig-
ure 2.
1. aq NaOH
alumina, toluene
reflux
O
Lawesson's
reagent
N2
O
N2
S
H2N
OH
O
2. isoamyl nitrite
AcOH, CHCl3
reflux, 20 min
toluene
50 °C, 5 h
N
N
H
NH2
H
·HCl
1a
1b
O
O
(or)
N2
Y
N2
MsN3, Et3N
toluene or benzene
reflux, 3–4 h
1a,b
N
N
Y
CH2Cl2, 0 °C to r.t.
10 h
N2
O
O
O
O
R
R
Cl
OCH3
2a R = COCH3; Y = O
2b R = CO2CH3; Y = O
2c R = COCH3; Y = S
2d R = CO2CH3; Y = S
3a R = COCH3; Y = O
3b R = CO2CH3; Y = O
3c R = COCH3; Y = S
3d R = CO2CH3; Y = S
Scheme 1 Synthesis of the mono- and bis-diazo compounds
A similar reaction was performed in dichloroethane to
furnish the product in 51% yield (Table 1, entry 9). To our
delight, the insertion reaction of N-substituted diazo com-
pound 2a with allyl alcohol 4a in the presence of Rh2(OAc)4
at 60 °C in benzene proved to be suitable conditions for the
insertion reactions as they could be used for further trans-
formations. Under these reaction conditions, other inser-
tion partners were reacted with the appropriate diazo com-
pounds yielding the corresponding products 5b–e in good
yields via O–H or S–H insertion reactions (Scheme 2). It was
observed that the unsubstituted diazo compound 1 afford-
ed the corresponding insertion products 5c–e in lower
yields; this might be due to the relatively poor solubility of
1 in benzene. It should be noted that S–H, N–H insertion re-
actions are generally less studied due to a reduction6b,10 in
HO
HO
HO
HS
4a
4b
4c
4d
H
N
H
N
H2N
4e
4f
4g
Figure 2 Various bifunctional reaction partners for the study
To study the reactions of the bis-diazocarbonyl com-
pounds, it was necessary to develop mild reaction condi-
tions in order to prevent uncontrolled thermal decomposi-
tion of the diazo functionalities. We began our study with
N-substituted mono-diazo compound 2a in order to opti-
mize the insertion reaction conditions and to ascertain the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

C
S. Muthusamy, C. Gangadurai
Paper
Synthesis
Table 1 Insertion Reactionsa of Diazo Compound 2a
quinolizinone system 7a in 79% yield. Alternatively, bis-di-
azo compound 3a, synthesized from compound 2a using
MsN3/Et3N, was subjected to an insertion reaction with allyl
alcohol 4a in CH2Cl2 at room temperature catalyzed by
Rh2(OAc)4 to afford the clean O–H insertion product 6a in
86% yield (Scheme 3, path B). Interestingly, the IR spectrum
of compound 6a confirmed the presence of a second diazo
group without any decomposition. Next, it was intended to
investigate the chemical behavior of the second diazo group
for the formation of isomünchnone dipoles toward synthet-
ic applications. In order to utilize the chemistry of the sec-
ond diazo functionality, the reaction of 6a in the presence
of Rh2(OAc)4 as the catalyst was performed in benzene at
reflux temperature. Based on the TLC analysis, the reaction
mixture was concentrated and purified by column chroma-
tography to afford product 7a in 79% yield (Scheme 3). The
1H NMR spectrum of compound 7a exhibited two multi-
plets for Ha and Hb in the range of 3.67–3.61 ppm and 3.49–
3.44 ppm, respectively. The high-resolution mass spectrum
showed the required molecular ion peak.
N2
O
O
HO
4a
N
O
O
N
O
conditions
O
O
2a
5a
Entry
Catalyst
Solvent
Temp (°C) Time (h) Yield (%)c
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(acac)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
25
25
25
25
25
25
25
60
60
4
4
21
17
34
–
b
In(OTf)3
4
b
InCl3
12
3
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
76
54
46
72
51
3
benzene
benzene
DCE
3
2
3
a Reaction conditions: slow addition of 2a (0.42 mmol, 0.1 mL/min), 4a (0.42
mmol), catalyst (1 mol% of copper or rhodium catalyst), solvent (3 mL).
b 10 mol% of the indium catalyst was used.
path C
Rh2(OAc)4
Ha
N2
O
HO
c Yield of isolated product.
4a
N
O
N
O
Hb
O
PhH
60 °C then reflux
6 h, 92%
N2
MsN3, Et3N
0 °C to r.t., 10 h
97%
O
O
O
the activity of the rhodium catalyst, and there was no for-
mation of the corresponding cyclopropane11 derivative
with olefinic alcohols 4.
3a
7a
N2
HO
4a
path B
N
O
O
Rh2(OAc)4
Rh2(OAc)4
PhH, reflux
79%
N2
CH2Cl2, r.t.
86%
X
O
O
O
XH
path A
N
R
O
cat. Rh2(OAc)4
PhH, 60 °C
N
R
O
N
H
O
O
HO
2a
4a
MsN3, Et3N
1, 2
5b R = COCH2COCH3, X = S; 74%
5c R = H, X = O; 59%
5d R = H, X = S; 54%
5e 51%
Rh2(OAc)4
CH2Cl2, r.t., 68%
N
O
O
N
O
N2
0 °C to r.t., 10 h
97%
O
O
remains
unscathed
(via path B)
Scheme 2 Survey of bifunctional reaction partners
O
6a
5a
Scheme 3 Stepwise and one-pot insertion/cycloaddition sequences
In continuation of the above insertion reactions of diazo
compounds 1 and 2, our ultimate aim was to develop a pro-
cess utilizing bis-diazo compounds 3 in the presence of
Rh2(OAc)4 as the catalyst, avoiding the isolation of any in-
termediates. Hence, the possibility of subsequent ylide-
forming reactions was explored. Reaction of the N-substi-
tuted mono-diazo compound 2a with 4a in the presence of
Rh2(OAc)4 afforded the corresponding product 5a (Table 1
and Scheme 3, path A). To continue the sequence, the sec-
ond A/A diazo functionality was introduced by subjecting
compound 5a to the diazo transfer reaction using
MsN3/Et3N. The presence of a diazo functionality in 6a was
confirmed based on the characteristic peak at 2137 cm–1 in
the IR spectrum. Utilizing compound 6a for possible 1,3-di-
pole formation, the reaction in the presence of Rh2(OAc)4
was performed to afford the epoxy-bridged furan-fused
Other insertion reactions of bis-diazo compounds 3a,b
with bifunctional partners 4c,d were carried out to furnish
the corresponding products 6b–f (Scheme 4). Following the
stepwise reaction of compound 3a, bis-diazo compound 3b
was reacted with allyl alcohol 4a to give product 6b in 64%
yield. The insertion product 6c was obtained in 89% yield
when bis-diazo compound 3a was reacted with propargyl
alcohol (4c). Similarly, propargyl alcohol (4c) and bis-diazo
compound 3b underwent the insertion reaction to yield
product 6d. The insertion product 6e was obtained from
the reaction of 3a with 4d. In addition, the reaction of bis-
diazo compound 3b and allyl mercaptan (4d) yielded the
insertion product 6f.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

D
S. Muthusamy, C. Gangadurai
Paper
Synthesis
Table 2 Optimization of the Reaction Conditionsa
N2
X
XH
cat. Rh2(OAc)4
insertion
N
O
O
N
O
Ha
O
CH2Cl2, r.t.
N2
O
OH
N2
N2
O
4a
catalyst
R
R
N
O
O
N
O
Hb
3a,b
6b R = CO2CH3; X = O, 64%
6c R = COCH3; X = O, 89%
6d R = CO2CH3; X = O, 89%
6e R = COCH3; X = S, 91%
6f R = CO2CH3; X = S, 64%
conditions
N2
O
O
isomünchnone
cycloaddition
3a
7a
Scheme 4 Insertion reactions of other bifunctional partners with bis-
diazo compounds
Entry
Catalystb
Solvent
Time (h)
Yield (%)c
1d
2d
3d
4
Cu(OTf)2
CuCl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
14
24
11
10
36
16
12
7
13
–
The successful O–H insertion reaction of an acceptor
carbenoid followed by 1,3-dipolar cycloaddition reactions
of an acceptor/acceptor carbenoid prompted us to investi-
gate the domino reaction of bis-diazo compounds 3. Thus,
we next planned to test the feasibility of the one-pot reac-
tion of 3a with allyl alcohol 4a by coupling both the above
reaction processes. Hence, the reaction of bis-diazo com-
pound 3a and allyl alcohol 4a in the presence of Rh2(OAc)4
in anhydrous benzene, initially at 60 °C and then at reflux
temperature, until complete conversion of the starting ma-
terial furnished product 7a in 92% yield (Scheme 3, path C).
The lower yield obtained in the stepwise reaction may be
due to the involvement of the isolation of two compounds,
5a and 6a. The optimization of the intermolecular X–H in-
sertion and the subsequent intramolecular cycloaddition
reactions of bis-diazo compound 3a and bifunctional part-
ner 4a was carried out with various metal catalysts and the
obtained results are summarized in Table 2. The use of ru-
thenium-based catalysts, effective in cyclopropanation and
ylide formation,12 failed to yield the desired product (Table
2, entries 11 and 12).
Under the above optimized conditions, the reaction of
bis-diazo compound 3b with chosen partner 4a furnished
the epoxy-bridged furan-fused quinolizinone 7b in 83%
yield via O–H insertion followed by isomünchnone cycload-
dition. The reaction of 3a with propargyl alcohol (4c) yield-
ed the expected furan-fused quinolizinone 7c, having a
double bond, in 67% yield. Subsequently, bis-diazo com-
pound 3b was reacted with propargyl alcohol (4c) to yield
62% of product 7d. The reaction of homoallyl alcohol 4b and
bis-diazo compound 3a afforded the epoxy-bridged pyran-
fused quinolizinone 7e in 73% yield. Having successfully
demonstrated the domino reaction of O–H insertion and
isomünchnone cycloaddition, it was next planned to exploit
the N–H and S–H insertion and cycloaddition reactions us-
ing bifunctional reaction partners for this synthetic study.
Thus, reaction of 3a with N-allylaniline (4f) afforded the de-
sired pyrrolidine-fused quinolizinone 7f in 85% yield. The
reaction of N-propargyl aniline (4g) with bis-diazo com-
pound 3a yielded the expected product 7g in 60% yield.
Next, the reaction of allyl mercaptan (4d) with 3a was per-
formed using the optimized conditions to afford epoxy-
Cu(acac)2
Cu(OTf)2
Cu(OAc)2
Cu(OTf)2
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
trace
21
–
5
DCE
6
benzene
CH2Cl2
DCE
26
29
53
92
81
–
7d
8
9
benzene
benzene
benzene
benzene
6
10
11
12
Rh2(CF3CF2CO2)4
Ru(PPh3)3Cl2
RuCl3
7
24
24
–
a Reaction conditions: 3a (0.42 mmol), 4a (0.42 mmol), catalyst, solvent (3
mL), 60 °C then reflux.
b 1 mol% of copper, rhodium or ruthenium catalyst was used.
c Yield of isolated product.
d Reflux conditions.
bridged tetrahydrothiophene-fused quinolizinone 7h in
76% yield. Similar reaction conditions were employed for
the reaction of 3b and allyl mercaptan (4d), which afforded
the product 7i in 70% yield (Scheme 5).
Thioisomünchnones generated from diazothioamides13
have also proved to be interesting precursors to sulfur-con-
taining heterocyclic compounds. The successful intramolec-
ular 1,3-dipolar cycloaddition reactions of isomünchnones
formed in the presence of rhodium(II) acetate as the cata-
lyst motivated us to envisage the tandem process of bis-di-
azo compounds 3c,d owing to their potential to generate
less studied thioisomünchnone dipoles, the reactions of
which would result in epithio-bridged heterocyclic com-
pounds. The bis-diazo compound 3c was subjected to reac-
tion with allyl alcohol 4a under similar reaction conditions
to furnish the epithio-bridged furan-fused quinolizinone
system 7j in 71% yield via an O–H insertion, subsequent
thioisomünchnone formation and cycloaddition. Similarly,
the bifunctional reaction partner 4a reacted with the ap-
propriate bis-diazo compound 3d to give the epithio-
bridged heterocyclic system 7k. The reaction of 3c with bi-
functional propargyl alcohol (4c) gave the epithio-bridged
product 7l, having a double bond, in 60% yield. In continua-
tion, the possible S–H or N–H insertion reactions followed
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

E
S. Muthusamy, C. Gangadurai
Paper
Synthesis
by cycloadditions of bis-diazo compounds were further
planned. Toward this goal, the reaction of allyl mercaptan
(4d) with 3c furnished epithio-bridged tetrahydrothio-
phene-fused quinolizinone product 7m, having two sulfur
atoms, in 71% yield (Scheme 5) via S–H insertion, subse-
quent thioisomünchnone formation and cycloaddition.
Similarly, the reaction of 3d and bifunctional partner 4d
was performed to furnish the corresponding thiophene-
fused quinolizinone 7n, again having two sulfur atoms, in
72% yield.
yield. However, the use of allylamine (4e) did not yield the
desired product 7p (Scheme 5), even with an excess amount
of catalyst; instead we observed unidentified products. The
structures and stereochemistries of products 7b and 7h
were determined unequivocally by single-crystal X-ray
analysis (Figure 3). The Ha and Hb protons of the epoxy- and
epithio-bridged heterocycle-fused quinolizinones 7 are anti
to each other due to endo-cycloaddition during the second
step with regard to the tethered pendent dipole. This obser-
vation is in full accord with molecular mechanics calcula-
tions14 that indicate that endo-products 7b,h are more sta-
ble than the corresponding exo-isomers. The stereochemis-
try of the other products was assigned based upon analogy
with products 7b,h.
Toward N–H insertion/cycloaddition reactions, the rep-
resentative reaction of 3c with N-allylaniline (4f) furnished
epithio-bridged pyrrole-fused quinolizinone 7o in 69%
Mechanistically, the rhodium(II) carbenoid derived
from bis-diazo compounds 3 undergoes intermolecular in-
sertion into the polar X–H bond of the alcohol, thiol or
amine 4 in a concerted or stepwise fashion to give the in-
sertion products 6 in a chemoselective manner. Next, the
second diazo functionality present in the same molecule
forms the reactive isomünchnone dipoles 10 in the pres-
ence of the Rh2(OAc)4 catalyst in the reaction mixture. Sub-
sequent intramolecular 1,3-dipolar cycloaddition reaction
with the tethered pendent olefin unit affords heterocycle-
fused quinolizinones 7 with complete diastereoselectivity
(Scheme 6).
insertion
Ha
( )
n
N2
XH
X
Rh2(OAc)4
(1 mol%)
( )n
Hb
N
Y
N
Y
R
PhH
60 °C to reflux
6–8 h
N2
O
O
X = NH, NPh, S, O
Y = O, S
n = 0,1
R
isomünchnone
cycloaddition
3a–d
7a–o
Ha
Ha
O
Ha
Ha
O
O
O
N
N
N
N
O
Hb
Hb
O
O
O
O
O
O
O
O
H3CO
O
O
H3CO
O
(AcO)4Rh2
H
7a, 6 h, 92%
7b, 6 h, 83%
7c, 7.5 h, 67%
7d, 7 h, 62%
X
N
O
Ph
Ha
N
Ph
Ha
N
Ha
O
Ha
S
N2
X
O
N2
R
N
N
N
O
N
N
Y
XH
Hb
Hb
8 (concerted)
O
Hb
O
O
+
4a
N2
N
Y
H
(AcO)4Rh2
X
O
O
O
O
O
+
N2
Rh2(OAc)4
R
O
O
O
O
O
6
R
7g, 7.5 h, 60%
7e, 6.5 h, 73%
7f, 6.7 h, 85%
7h, 8 h, 76%
N
Y
3
cat.
Rh2(OAc)4
reflux
N2
O
Ha
S
Ha
O
Ha
O
Ha
O
R
9 (stepwise)
N
N
S
N
S
N
H
Hb
O
Hb
H
X
S
X
1,3-dipolar
cycloaddition
O
O
O
O
N
N
Y
H
H3CO
O
O
H3CO
O
O
Y
O
7j, 7.5 h, 71%
7i, 7.3 h, 70%
7k, 7.8 h, 64%
7l, 7.3 h, 60%
O
R
R
isomünchnone
ylides
Ph
Ha
N
7
10
H
H
Ha
S
Ha
S
N
Scheme 6 Mechanistic pathway for the domino insertion/[3+2] cyc-
loaddition reactions
N
N
O
N
S
N
Hb
H
Hb
Hb
S
S
O
O
O
O
We were further interested in carrying out the ring-
opening reactions of the synthesized tricyclic systems 7 to
give hydroxy compounds. To this end, a representative ring-
opening reaction of epoxy-bridged furan-fused quinoliz-
inone 7a in the presence of p-toluenesulfonic acid was car-
O
O
H3CO
O
O
7n, 8 h, 72%
7o, 7.5 h, 69%
7p 0%
7m, 8 h, 71%
Scheme 5 Scope of the insertion/cycloaddition reactions of bis-diazo
compounds
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

F
S. Muthusamy, C. Gangadurai
Paper
Synthesis
All reactions were carried out in oven-dried glassware under an at-
mosphere of argon. Dry dichloromethane (dried over phosphorus
pentoxide) and dry benzene (stored over sodium wire) were freshly
prepared for each reaction. Analytical thin-layer chromatography
(TLC) was performed on Merck 60 F254 silica gel plates and the compo-
nents of mixtures were made visual by observation under iodine or
UV light, or by sulfuric acid charring. Column chromatography was
performed on Merck silica gel (100–200 mesh). Melting points were
obtained using a Veego VMP-D instrument and are uncorrected. FT-IR
spectra were recorded using a Bruker Alpha-T spectrophotometer us-
ing the ATR technique. 1H and 13C NMR spectra (400 MHz and 100
MHz, respectively) were obtained using a Bruker Avance 400 spec-
trometer and are referenced to TMS. Multiplicities are indicated as
singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), or vari-
ants thereof. Coupling constants (J) are reported in hertz (Hz). Carbon
types were determined from DEPT 13C NMR experiments. Low- and
high-resolution mass spectra were determined on Thermofisher LTQ
XL and Waters QTof Micromass spectrometers, respectively, using the
ESI method. Elemental analyses were determined using a Vario Micro
Cube instrument.
Figure 3 X-ray crystal structures (ORTEP views) of compounds 7b (left)
and 7h (right)
ried out in benzene at room temperature. Interestingly, the
reaction furnished smoothly the furan-fused quinolizinone
11a in moderate yield and in a regioselective manner. Un-
der similar conditions, the reaction of compound 7e afford-
ed pyran-fused quinolizinone 11b in 63% yield (Scheme 7).
The ring-opening reaction might occur via initial protona-
tion of the ethereal oxygen by the catalytic acid, followed by
cleavage of the C–O bond in a regioselective manner.
3-Diazopiperidine-2-one (1a)8a
To a stirred solution of 3-aminopiperidin-2-one (1.6 g, 14.0 mmol) in
anhydrous CHCl3 (30 mL) were added dropwise isoamyl nitrite (1.98
g, 16.8 mmol) and glacial AcOH (126 mg, 2.1 mmol) sequentially un-
der an Ar atm. The reaction mixture was then heated at reflux tem-
perature for 20 min, cooled in ice-bath and washed with sat. NaHCO3
solution (10 mL). The organic layer was separated, dried over MgSO4,
and the solvent was evaporated under vacuum. The red solid was pu-
rified by column chromatography using alumina to give 1a as an or-
ange solid (1.07 g, 60%).
H
O
O
( )n
H
( )n
H
PTSA (cat.)
N
N
O
Mp 117–120 °C.
benzene, r.t.
3–4 h
O
O
HO
IR (ATR): 3270, 3181, 3033, 2949, 2879, 2087, 1638, 1480, 1461, 1413,
1293, 1177, 1077, 993 cm–1
.
O
O
7a n = 0
7e n = 1
11a n = 0, 49% yield
11b n = 1, 63% yield
1H NMR (400 MHz, CDCl3): δ = 7.69 (br s, 1 H, NH), 2.78 (s, 2 H, NCH2),
2.76 (t, J = 6.7 Hz, 2 H, CH2), 1.89–1.84 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 167.2 (C=O), 68.7 (C=N2), 41.2 (CH2),
Scheme 7 Ring-opening reactions of tricyclic systems 7a,e
21.8 (CH2), 20.9 (CH2).
In conclusion, the rhodium(II) acetate catalyzed trans-
formations of bis-diazo compounds have been demonstrat-
ed to proceed via an intermolecular X–H insertion reaction,
without affecting other diazo functionality present in the
same molecule, in a chemoselective manner. Subsequently,
the dipole formation–cycloaddition reaction furnished the
corresponding epoxy- or epithio-bridged heterocycle-fused
quinolizinone systems with complete diastereoselectivity
via isomünchnone or thioisomünchnone dipoles. In addi-
tion, representative ring-opening reactions afforded fused
heterocyclic alcohols in a regioselective manner. No excess
catalyst was required for these domino reactions of bis-di-
azo compounds. Further investigation of these interesting
bis-diazo compounds is currently in progress in our labora-
tory and the results will be reported in due course.
3-Diazopiperidine-2-thione (1b)
To a stirred solution of 3-diazopiperidin-2-one (1a) (1 g, 8.0 mmol) in
anhydrous toluene (20 mL) was added Lawesson’s reagent (1.6 g, 4
mmol) under an Ar atm. The yellow reaction mixture was heated at
50 °C for 5 h. After completion of the reaction (monitored by TLC), the
mixture was concentrated under reduced pressure and the residue
purified by flash column chromatography to afford 1b as a yellow sol-
id (710 mg, 63%).
Mp 124–126 °C.
IR (ATR): 3209, 3124, 3021, 2936, 2281, 2025, 1638, 1472, 1428, 1293,
1119, 1098, 985 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.72 (br s, 1 H, NH), 2.74 (s, 2 H, NCH2),
2.69 (t, J = 6.4 Hz, 2 H, CH2), 1.87–1.83 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 169.8 (C=O), 69.4 (C=N2), 41.5 (CH2),
21.6 (CH2), 20.5 (CH2).
MS (ESI): m/z = 142.0 [M + H]+.
Anal. Calcd for C5H7N3S: C, 42.53; H, 5.00; N, 29.76. Found: C, 42.33;
H, 5.02; N, 29.79.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

G
S. Muthusamy, C. Gangadurai
Paper
Synthesis
1-(3-Diazo-2-oxopiperidin-1-yl)butane-1,3-dione (2a)8b
IR (ATR): 3201, 2089, 1719, 1698, 1686, 1594, 1341, 1327, 1238, 1136,
961 cm–1
.
To an oven-dried 25 mL round-bottom flask fitted with a reflux con-
denser was added a solution of 1a (300 mg, 2.4 mmol) in anhydrous
toluene (15 mL) under an N2 atm and the mixture was heated to re-
flux temperature. 2,2,6-Trimethyl-1,3-dioxin-(4H)-one (340 mg, 2.4
mmol) was added and the mixture stirred for 3 h. After completion of
the reaction as indicated by TLC, the mixture was cooled to r.t. and
the solvent was evaporated to dryness. The residue was purified via
column chromatography to furnish compound 2a as a pale yellow oil
(410 mg, 81%).
1H NMR (400 MHz, CDCl3): δ = 4.11–4.08 (m, 2 H, CH2), 3.92–3.87 (m,
2 H, CH2), 3.52 (s, 3 H, CH3), 2.79 (t, J = 6.4 Hz, 2 H, CH2), 2.09–1.89 (m,
2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 199.4 (C=O), 169.3 (NC=O), 168.1
(C=S), 66.2 (C=N2), 51.3 (CH3), 44.6 (CH2), 33.8 (CH2), 29.4 (CH2), 20.8
(CH2).
MS (ESI): m/z = 242.1 [M + H]+.
Anal. Calcd for C9H11N3O3S: C, 44.80; H, 4.60; N, 17.42. Found: C,
43.84; H, 4.58; N, 17.44.
IR (ATR): 3119, 2089, 1711, 1659, 1631, 1374, 1356, 1320, 1251, 1143,
936 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.05 (s, 2 H, OCH2), 3.69–3.66 (m, 2 H,
CH2), 2.81 (t, J = 6.4 Hz, 2 H, CH2), 2.45 (s, 3 H, CH3), 2.03–1.97 (m, 2 H,
CH2).
13C NMR (100 MHz, CDCl3): δ = 202.3 (C=O), 169.3 (C=O), 168.9 (C=O),
64.9 (C=N2), 47.8 (CH2), 44.4 (CH2), 33.3 (CH2), 29.9 (CH3), 21.3 (CH2).
2-Diazo-1-(3-diazo-2-oxopiperidin-1-yl)butane-1,3-dione (3a)
To a stirred solution of 2a (100 mg, 0.47 mmol) in anhydrous CH2Cl2
(30 mL) under an Ar atm were added methanesulfonyl azide (MsN3)
(57 mg, 0.47 mmol) and anhydrous Et3N (52 mg, 0.51 mmol) sequen-
tially via a syringe at 0 °C. The reaction mixture was allowed to stir at
r.t. for 10 h. After completion of the reaction (monitored by TLC), the
mixture was quenched with ice-cold H2O, the organic layer was sepa-
rated and dried over anhydrous Na2SO4, and the solvent was evapo-
rated to dryness under vacuum. The crude residue was purified by
flash column chromatography to give 3a as a deep red solid (218 mg,
97%).
Methyl 3-(3-Diazo-2-oxopiperidin-1-yl)-3-oxopropanoate (2b)
To a flame-dried 25 mL round-bottom flask fitted with a reflux con-
denser was added anhydrous benzene (15 mL) followed by 1a (300
mg, 2.4 mmol). The mixture was heated to reflux temperature and
then methylmalonyl chloride (360 mg, 2.6 mmol) was added and the
mixture allowed to stir at reflux temperature for 4 h. The mixture was
cooled to r.t. and the solvent was removed under vacuum to dryness.
The residue was purified via column chromatography to give 2b as a
yellow oil (418 mg, 77%).
Mp 147–149 °C.
IR (ATR): 3178, 2095, 2089, 1726, 1689, 1638, 1385, 1351, 1316, 1269,
1152, 939 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 3.40–3.33 (m, 2 H, CH2), 2.43 (s, 3 H,
CH3), 2.16–2.13 (m, 1 H, CH2), 1.99–1.82 (m, 3 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 201.4 (C=O), 173.2 (C=O), 168.7 (C=O),
64.9 (C=N2), 54.3 (C=N2), 41.7 (CH2), 30.1 (CH3), 26.4 (CH2), 19.1 (CH2).
IR (ATR): 3111, 2096, 1729, 1692, 1656, 1374, 1341, 1329, 1240, 1136,
928 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.04–4.00 (m, 2 H, CH2), 3.99–3.90 (m,
2 H, CH2), 3.65 (s, 3 H, CH3), 2.83 (t, J = 6.4 Hz, 2 H, CH2), 2.07–1.99 (m,
2 H, CH2).
MS (ESI): m/z = 236.0 [M + H]+.
13C NMR (100 MHz, CDCl3): δ = 201.1 (C=O), 169.9 (C=O), 169.7 (C=O),
65.7 (C=N2), 51.2 (CH3), 44.6 (CH2), 33.5 (CH2), 29.9 (CH2), 21.2 (CH2).
Anal. Calcd for C9H9N5O3: C, 45.96; H, 3.86; N, 29.78. Found: C, 46.07;
H, 3.88; N, 29.71.
MS (ESI): m/z = 226.1 [M + H]+.
Methyl 2-Diazo-3-(3-diazo-2-oxopiperidin-1-yl)-3-oxopropa-
noate (3b)
Anal. Calcd for C9H11N3O4: C, 48.00; H, 4.92; N, 18.66. Found: C, 47.85;
H, 4.90; N, 18.70.
The title compound was synthesized using the procedure described
for 3a.
1-(3-Diazo-2-thioxopiperidin-1-yl)butane-1,3-dione (2c)
Yield: 102 mg (92%); yellow oil.
IR (ATR): 3270, 2137, 1659, 1363, 1316, 1289, 1264, 1164, 735 cm–1
.
The title compound was synthesised using the procedure described
for 2a. Yield: 390 mg (78%); viscous yellow oil.
IR (ATR): 2197, 2103, 1718, 1661, 1627, 1374, 1355, 1342, 1237, 1129,
1H NMR (400 MHz, CDCl3): δ = 3.77–3.66 (m, 2 H, CH2), 3.28 (s, 3 H,
CH3), 3.15–3.07 (m, 1 H, CH), 2.23–1.87 (m, 4 H, CH2), 1.49–1.18 (m, 1
H, CH).
13C NMR (100 MHz, CDCl3): δ = 201.3 (C=O), 173.0 (C=O), 169.0 (C=O),
75.2 (C=N2), 75.0 (CH2), 64.9 (C=N2), 54.3 (CH2), 30.1 (CH2), 19.1 (CH3).
974 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.07 (s, 2 H, OCH2), 3.66–3.62 (m, 2 H,
CH2), 2.83 (t, J = 6.8 Hz, 2 H, CH2), 2.37 (s, 3 H, CH3), 1.99–1.95 (m, 2 H,
CH2).
13C NMR (100 MHz, CDCl3): δ = 202.0 (C=O), 169.6 (NC=O), 167.7
(C=S), 64.9 (C=N2), 47.8 (CH2), 44.0 (CH2), 33.7 (CH2), 30.0 (CH3), 21.1
(CH2).
MS (ESI): m/z = 252.0 [M + H]+.
Anal. Calcd for C9H9N5O4: C, 43.03; H, 3.61; N, 27.88. Found: C, 43.12;
H, 3.59; N, 27.96.
MS (ESI): m/z = 226.1 [M + H]+.
2-Diazo-1-(3-diazo-2-thioxopiperidin-1-yl)butane-1,3-dione (3c)
Anal. Calcd for C9H11N3O2S: C, 47.99; H, 4.92; N, 18.65. Found: C,
47.83; H, 4.89; N, 18.68.
The title compound was synthesized using the procedure described
for 3a.
Methyl 3-(3-diazo-2-thioxopiperidin-1-yl)-3-oxopropanoate (2d)
Yield: 97 mg (87%); orange solid; mp 136–138 °C.
The title compound was synthesised using the procedure described
for 2b. Yield: 403 mg (76%); thick, deep-yellow oil.
IR (ATR): 2095, 2089, 1726, 1689, 1638, 1385, 1351, 1316, 1269, 1152,
939 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

H
S. Muthusamy, C. Gangadurai
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 3.40–3.33 (m, 2 H, CH), 2.43 (s, 3 H,
CH3), 2.16–2.13 (m, 1 H, CH2), 1.99–1.82 (m, 3 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 201.4 (C=O), 168.7 (C=S), 173.2 (C=O),
64.9 (C=N2), 54.3 (C=N2), 41.7 (CH2), 30.1 (CH3), 26.4 (CH2), 19.1 (CH2).
13C NMR (100 MHz, CDCl3): δ = 201.3 (C=O), 173.2 (C=O), 168.7
(NC=O), 134.0 (CH), 117.9 (CH2), 75.9 (SCH), 71.7 (SCH2), 54.3 (CH2),
41.7 (CH2), 30.1 (CH3), 26.4 (CH2), 19.1 (CH2).
MS (ESI): m/z = 256.1 [M + H]+.
MS (ESI): m/z = 252.0 [M + H]+.
Anal. Calcd for C12H17NO3S: C, 56.45; H, 6.71; N, 5.49. Found: C, 56.55;
H, 6.69; N, 5.47.
Anal. Calcd for C9H9N5O2S: C, 43.02; H, 3.61; N, 27.87. Found: C, 42.90;
H, 3.59; N, 27.80.
3-(Prop-2-en-1-yloxy)piperidin-2-one (5c)
Yield: 24 mg (59%); colorless solid; mp 114–116 °C.
Methyl 2-Diazo-3-(3-diazo-2-thioxopiperidin-1-yl)-3-oxopropa-
noate (3d)
IR (ATR): 2953, 2822, 1730, 1495, 1437, 1416, 1210, 1172, 735, 700
The title compound was synthesized using the procedure described
cm–1
.
for 3a.
1H NMR (400 MHz, CDCl3): δ = 6.96 (s, 1 H, NH), 5.88–5.83 (m, 1 H,
CH), 5.11 (ddd, J1 = 4.6 Hz, J2 = 3.2 Hz, J3 = 2.0 Hz, 2 H, CH2), 4.33–4.28
(m, 1 H, CH), 4.15–4.10 (m, 1 H, CH), 3.77–3.73 (m, 1 H, CH2), 3.25–
3.19 (m, 2 H, CH2), 1.87–1.83 (m, 4 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 173.2 (C=O), 131.7 (CH), 115.8 (CH2),
85.1 (CH), 71.3 (CH2), 38.2 (CH2), 32.1 (CH2), 19.3 (CH2).
Yield: 93 mg (84%); yellow oil.
IR (ATR): 3270, 2137, 1659, 1363, 1316, 1289, 1264, 1164, 735 cm–1
1H NMR (400 MHz, CDCl3): δ = 3.77–3.66 (m, 2 H, CH2), 3.28 (s, 3 H,
CH3), 3.15–3.07 (m, 1 H, CH), 2.23–1.87 (m, 2 H, CH2), 1.49–1.18 (m, 1
H, CH).
.
MS (ESI): m/z = 156.0 [M + H]+.
13C NMR (100 MHz, CDCl3): δ = 201.3 (C=O), 173.0 (C=O), 169.0 (C=S),
75.2 (C=N2), 75.0 (CH2), 64.9 (C=N2), 54.3 (CH2), 30.1 (CH2), 19.1 (CH3).
MS (ESI): m/z = 268.0 [M + H]+.
Anal. Calcd for C8H13NO2: C, 61.91; H, 8.44; N, 9.03. Found: C, 61.79;
H, 8.42; N, 9.06.
Anal. Calcd for C9H9N5O3S: C, 40.45; H, 3.39; N, 26.20. Found: C, 40.54;
H, 3.37; N, 26.16.
3-(Prop-2-en-1-ylsulfanyl)piperidin-2-one (5d)
Yield: 32 mg (54%); yellowish-green solid; mp 157–159 °C.
IR (ATR): 2953, 2822, 1730, 1495, 1437, 1416, 1210, 1172, 735, 700
1-[2-Oxo-3-(prop-2-en-1-yloxy)piperidin-1-yl]butane-1,3-dione
(5a); Typical Procedure
cm–1
.
N-Substituted diazo compound 2a (40 mg, 3.2 mmol) and allyl alco-
hol 4a (18 mg, 3.2 mmol) were dissolved in anhydrous benzene (20
mL) and stirred for 5 min at r.t. To this stirred solution was added
Rh2(OAc)4 (1 mol%) and the resulting mixture was stirred at 60 °C for
2 h. After cooling, the mixture was concentrated under reduced pres-
sure. Purification of the residue by column chromatography on silica
gel gave the title compound 5a as a pale yellow oil (31 mg, 72%).
1H NMR (400 MHz, CDCl3): δ = 6.96 (s, 1 H, NH), 5.88–5.83 (m, 1 H,
CH), 5.11 (ddd, J1 = 4.6 Hz, J2 = 3.2 Hz, J3 = 1.4 Hz, 2 H, CH2), 4.33–4.28
(m, 1 H, CH), 4.15–4.10 (m, 1 H, CH), 3.77–3.73 (m, 1 H, CH2), 3.25–
3.19 (m, 2 H, CH2), 1.87–1.83 (m, 4 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 174.7 (C=O), 133.1 (CH), 117.2 (CH2),
51.7 (CH), 37.5 (CH2), 37.3 (CH2), 31.6 (CH2), 21.9 (CH2).
MS (ESI): m/z = 172.0 [M + H]+.
IR (ATR): 2815, 1685, 1691, 1495, 1455, 1420, 1384, 1354, 965 cm–1
.
Anal. Calcd for C8H13NOS: C, 56.11; H, 7.65; N, 8.18. Found: C, 56.19;
H, 7.67; N, 8.15.
1H NMR (400 MHz, CDCl3): δ = 5.85–5.80 (m, 1 H, CH), 5.24 (ddd,
J1 = 8.2 Hz, 1 H, J2 = 5.4 Hz, J3 = 4.0 Hz, CH), 5.13 (ddd, J1 = 8.0 Hz,
J2 = 5.8 Hz, J3 = 3.8 Hz, 1 H, CH), 4.24–4.19 (m, 1 H, CH), 4.05 (dd,
J1 = 3.2 Hz, J2 = 2 Hz, 4 H, CH2), 3.98–3.94 (m, 1 H, CH2), 3.92–3.81 (m,
1 H, CH2), 2.20 (s, 3 H, CH3), 2.09 (d, J = 5.6 Hz, 1 H, CH2), 1.96–1.78 (m,
3 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 201.4 (C=O), 173.2 (C=O), 168.7
(NC=O), 134.0 (CH), 117.9 (CH2), 75.9 (CH), 71.7 (CH2), 54.3 (C=N2),
41.7 (CH2), 30.1 (CH3), 26.4 (CH2), 19.1 (CH2).
3-(Prop-2-yn-1-yloxy)piperidin-2-one (5e)
Yield: 24 mg (51%); colorless liquid.
IR (ATR): 3416, 2931, 1718, 1651, 1601, 1389, 1322, 1035, 815, 753
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.01 (s, 1 H, NH), 4.57–4.48 (m, 2 H,
CH2), 4.03–4.00 (m, 1 H, CH), 3.33–3.24 (m, 2 H, CH2), 2.44 (t, J = 2.4
Hz, 1 H, CH), 2.12–1.88 (m, 3 H, CH2), 1.80–1.75 (m, 1 H, CH).
13C NMR (100 MHz, CDCl3): δ = 172.0 (C=O), 80.0 (quat-C), 75.0 (CH),
73.0 (CH), 58.2 (CH2), 42.0 (CH2), 28.0 (CH2), 20.0 (CH2).
MS (ESI): m/z = 240.0 [M + H]+.
Anal. Calcd for C12H17NO4: C, 60.24; H, 7.16; N, 5.85. Found: C, 60.13;
H, 7.14; N, 5.83.
HRMS (ESI): m/z [M + Na]+ calcd for C8H11NO2Na: 176.0687; found:
176.0680.
1-[2-Oxo-3-(prop-2-en-1-ylsulfanyl)piperidin-1-yl]butane-1,3-di-
one (5b)
2-Diazo-1-[2-oxo-3-(prop-2-en-1-yloxy)piperidin-1-yl]butane-
1,3-dione (6a)
Yield: 36 mg (74%); yellow oil.
IR (ATR): 1723, 1685, 1634, 1391, 1294, 1152, 990, 922 cm–1
1H NMR (400 MHz, CDCl3): δ = 5.85–5.80 (m, 1 H, CH), 5.18 (ddt,
J1 = 38.8 Hz, J2 = 17.2 Hz, J3 = 1.6 Hz, 2 H, CH2), 4.21 (ddt, J1 = 12.4 Hz,
J2 = 5.2 Hz, J3 = 1.6 Hz, 1 H, CH), 4.09–3.81 (m, 5 H, CH2), 3.61–3.55 (m,
1 H, CH), 3.58 (t, J = 5.2 Hz, 1 H, CH), 2.20 (s, 3 H, CH3), 2.10–1.85 (m, 1
H, CH2), 1.84–1.78 (m, 2 H, CH2).
.
Yield: 73 mg (86%); yellow viscous oil.
IR (ATR): 2137, 1723, 1687, 1638, 1385, 1351, 1316, 1269, 1152, 931
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.74–5.69 (m, 1 H, CH), 5.22–5.12 (m,
2 H, CH2), 3.62–3.60 (m, 2 H, CH), 3.40–3.33 (m, 2 H, CH), 3.19 (dd,
J1 = 6.4 Hz, J2 = 2.7 Hz, 1 H, CH2), 2.43 (s, 3 H, CH3), 2.16–2.13 (m, 1 H,
CH2), 1.99–1.82 (m, 3 H, CH2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

I
S. Muthusamy, C. Gangadurai
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 201.4 (C=O), 173.2 (C=O), 168.7
(NC=O), 134.0 (CH), 117.9 (CH2), 75.9 (CH), 71.7 (CH2), 54.3 (C=N2),
41.7 (CH2), 30.1 (CH3), 26.4 (CH2), 19.1 (CH2).
1H NMR (400 MHz, CDCl3): δ = 5.74–5.69 (m, 1 H, CH), 5.22–5.12 (m,
2 H, CH2), 3.62–3.60 (m, 2 H, CH), 3.40–3.33 (m, 2 H, CH), 3.19 (dd,
J1 = 5.8 Hz, J2 = 1.8 Hz, 1 H, CH2), 2.43 (s, 3 H, CH3), 2.16–2.13 (m, 1 H,
CH2), 1.99–1.82 (m, 3 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 201.4 (C=O), 173.2 (C=O), 168.7
(NC=O), 134.0 (=CH), 117.9 (=CH2), 75.9 (SCH), 71.7 (SCH2), 54.3
(C=N2), 41.7 (CH2), 30.1 (CH3), 26.4 (CH2), 19.1 (CH2).
MS (ESI): m/z = 266.1 [M + H]+.
Anal. Calcd for C12H15N3O4: C, 54.33; H, 5.70; N, 15.84. Found: C,
54.21; H, 5.68; N, 15.81.
MS (ESI): m/z = 282.1 [M + H]+.
3-(3-Allyloxy-2-oxo-piperidin-1-yl)-2-diazo-3-oxo-propionic Acid
Methyl Ester (6b)
Anal. Calcd for C12H15N3O3S: C, 51.23; H, 5.37; N, 14.94. Found: C,
51.09; H, 5.34; N, 14.92.
Yield: 68 mg (64%); yellow oil.
IR (ATR): 3270, 2137, 1659, 1363, 1316, 1289, 1264, 1164, 735 cm–1
.
Methyl 2-Diazo-3-oxo-3-[2-oxo-3-(prop-2-en-1-ylsulfanyl)piperi-
din-1-yl]propanoate (6f)
1H NMR (400 MHz, CDCl3): δ = 5.97–5.87 (m, 1 H, CH), 5.35–5.13 (m,
2 H, CH2), 4.38 (q, J = 6.4 Hz, 1 H, CH), 4.11–3.81 (m, 1 H, CH), 3.77–
3.66 (m, 2 H, CH2), 3.28 (s, 3 H, CH3), 3.15–3.07 (m, 1 H, CH), 2.23–1.87
(m, 4 H, CH2), 1.49–1.18 (m, 1 H, CH).
Yield: 173 mg (64%); yellow viscous oil.
IR (ATR): 2133, 1654, 1357, 1314, 1288, 1082, 1160, 964 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 201.3 (C=O), 173.0 (C=O), 169.0 (C=O),
79.0 (quat-C), 75.2 (C=N2), 75.0 (CH2), 58.0 (CH2), 54.3 (CH2), 42.0
(CH2), 30.1 (CH2), 26.4 (CH2), 19.1 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C12H16N3O5: 282.1090; found:
282.1092.
1H NMR (400 MHz, CDCl3): δ = 5.93–5.90 (m, 1 H, =CH), 5.35–5.13 (m,
2 H, C=CH2), 4.39–4.08 (m, 1 H, CH), 3.89–3.58 (m, 3 H, CH2), 3.27 (s, 3
H, OCH3), 3.08–2.93 (m, 1 H, CH), 2.23–2.03 (m, 1 H, CH), 2.00–1.87
(m, 2 H, CH2), 1.22 (td, J1 = 5.6 Hz, J2 = 1.3 Hz, 1 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 19.1 (CH2), 26.4 (CH2), 30.1 (CH3), 41.7
(CH2), 54.3 (C=N2), 71.7 (SCH2), 75.9 (SCH), 117.9 (=CH2), 134.0 (=CH),
168.7 (NC=O), 173.2 (C=O), 201.4 (C=O).
2-Diazo-1-[2-oxo-3-(prop-2-yn-1-yloxy)piperidin-1-yl]butane-
1,3-dione (6c)
MS (ESI): m/z = 298.1 [M + H]+.
Yield: 76 mg (89%); yellow oil.
IR (ATR): 3270, 2955, 2139, 1718, 1653, 1437, 1331, 1160, 1128 cm–1
Anal. Calcd for C12H15N3O4S: C, 48.47; H, 5.08; N, 14.13. Found: C,
48.33; H, 5.05; N, 14.11.
.
1H NMR (400 MHz, CDCl3): δ = 4.48–4.37 (m, 2 H, CH2), 4.23 (q, J = 6.0
Hz, 1 H, CH), 3.68 (q, J = 7.6 Hz, 2 H, CH2), 2.51 (t, J = 5.6 Hz, 1 H, CH),
2.45 (s, 3 H, CH3), 2.23–2.18 (m, 1 H, CH2), 2.06–2.00 (m, 1 H, CH2), (m,
1 H, CH).
13C NMR (100 MHz, CDCl3): δ = 200.1 (C=O), 169.1 (NC=O), 102.0
(quat-C), 95.0 (quat-C), 72.0 (CH2), 70.2 (CH), 46.2 (CH), 39.0 (CH2),
31.0 (CH2), 30.0 (CH2), 27.2 (CH3), 20.0 (CH2).
Epoxy- and Epithio-Bridged Heterocycle-Fused Quinolizinones
7a–o; General Procedure
In an oven-dried flask, a solution containing the appropriate bis-diazo
compound 3 (100 mg, 0.42 mmol) and the selected bifunctional reac-
tion partner 4 (0.42 mmol), rhodium(II) acetate dimer (1 mol%) in an-
hydrous benzene (dried over Na wire) was degassed under Ar. After
loading the catalyst, the reaction was kept stirring under reflux for
the appropriate amount of time (see Scheme 5) until complete con-
sumption of starting material had occurred as monitored by TLC. Af-
ter completion of the reaction, the solvent was removed under re-
duced pressure and the resulting crude residue was purified by flash
column chromatography (hexanes–EtOAc) to afford epoxy- or epi-
thio-bridged heterocycle-fused quinolizinones 7a–o.
HRMS (ESI): m/z [M + H]+ calcd for C12H14N3O4: 264.0984; found
264.0981.
Methyl 2-Diazo-3-oxo-3-[2-oxo-3-(prop-2-yn-1-yloxy)piperidin-1-
yl]propanoate (6d)
Yield: 76 mg (89%); yellow oil.
IR (ATR): 2093, 1723, 1687, 1638, 1384, 1351, 1314, 1150, 728 cm–1
.
4-Acetyloctahydro-5H-4,9b-epoxyfuro[2,3,4-ij]quinolizin-5-one
(7a)
1H NMR (400 MHz, CDCl3): δ = 4.49 (dd, J1 = 16 Hz, J2 = 6.1 Hz, 1 H,
CH), 4.43–4.35 (m, 2 H, CH2), 4.32–4.21 (m, 2 H, CH2), 3.87 (d, J = 5.6
Hz, 1 H, CH), 3.78 (s, 3 H, CH3), 2.56–2.54 (m, 2 H, CH2), 2.31–2.19 (m,
2 H, CH2).
Yield: 93 mg (92%); colorless solid; mp 140–142 °C.
IR (ATR): 1733, 1719, 1415, 1361, 1265, 1148, 1083, 953, 889 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 200.1 (C=O), 169.1 (NC=O), 102.0
(quat-C), 95.0 (quat-C), 72.0 (CH2), 70.2 (CH), 46.2 (CH), 39.0 (CH2),
31.0 (CH2), 30.0 (CH2), 27.2 (CH3), 20.0 (CH2).
1H NMR (400 MHz, CDCl3): δ = 4.17–4.09 (m, 2 H, OCH2), 3.67–3.61
(m, 1 H, OCH), 3.49–3.44 (m, 1 H, CH), 2.84 (ddd, J1 = 15.2 Hz, J2 = 11.2
Hz, J3 = 3.6 Hz, 1 H, CH2), 2.67–2.61 (m, 1 H, CH2), 2.33 (s, 3 H, CH3),
2.29–2.25 (m, 1 H, CH2), 2.16–2.11 (m, 1 H, CH2), 1.85 (dd, J1 = 12.4 Hz,
J2 = 3.6 Hz, 1 H, CH), 1.82–1.76 (m, 1 H, CH2), 1.61–1.50 (m, 1 H, CH2),
1.37–1.27 (m, 1 H, CH).
13C NMR (100 MHz, CDCl3): δ = 200.1 (C=O), 169.1 (NC=O), 102.0
(quat-C), 94.5 (quat-C), 72.0 (OCH2), 70.2 (OCH), 46.2 (CH), 38.7 (CH2),
30.7 (CH2), 29.5 (CH2), 27.3 (CH3), 19.7 (CH2).
MS (ESI): m/z = 280.1 [M + H]+.
Anal. Calcd for C12H13N3O5: C, 51.61; H, 4.69; N, 15.06. Found: C,
51.48; H, 4.66; N, 15.03.
2-Diazo-1-[2-oxo-3-(prop-2-en-1-ylsulfanyl)piperidin-1-yl]bu-
tane-1,3-dione (6e)
HRMS (ESI): m/z [M + H]+ calcd for C12H16NO4: 238.1079; found:
238.1078.
Yield: 253 mg (91%); yellow oil.
IR (ATR): 2095, 1723, 1687, 1638, 1385, 1351, 1316, 1269, 1152, 931
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

J
S. Muthusamy, C. Gangadurai
Paper
Synthesis
Methyl 5-Oxohexahydro-2H-4,9b-epoxyfuro[2,3,4-ij]quinolizine-
4(5H)-carboxylate (7b)
Anal. Calcd for C12H13NO5: C, 57.37; H, 5.22; N, 5.58. Found: C, 57.48;
H, 5.20; N, 5.56.
Yield: 83 mg (83%); colorless solid; mp 149–151 °C.
5-Acetyloctahydro-5,10b-epoxypyrano[2,3,4-ij]quinolizin-6(2H)-
one (7e)
IR (ATR): 2944, 2816, 2779, 1687, 1454, 1382, 1353, 1317, 1297, 1243,
1153, 964 cm–1
.
Yield: 78 mg (73%); colorless solid; mp 163–165 °C.
1H NMR (400 MHz, CDCl3): δ = 4.17–4.12 (m, 2 H, OCH2), 3.85 (s, 3 H,
OCH3), 3.67–3.62 (m, 1 H, OCH), 3.49 (dd, J1 = 10.4 Hz, J2 = 3.7 Hz, 1 H,
CH), 2.89–2.82 (m, 1 H, CH), 2.66–2.62 (m, 1 H, CH), 2.28–2.16 (m, 2
H, CH2), 2.00 (dd, J1 = 12.8 Hz, J2 = 3.6 Hz, 1 H, CH), 1.81–1.76 (m, 1 H,
CH), 1.57–1.53 (m, 1 H, CH2), 1.34–1.30 (m, 1 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 168.7 (C=O), 165.7 (NC=O), 102.0
(quat-C), 89.9 (quat-C), 71.9 (OCH2), 70.2 (OCH), 53.2 (CH), 46.3
(OCH3), 38.9, (CH2), 31.0 (CH2), 29.6 (CH2), 19.7 (CH2).
IR (ATR): 3328, 2967, 1719, 1656, 1624, 1479, 1438, 1321, 1211, 1074,
866 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.18–4.13 (m, 1 H, CH), 3.72–3.68 (m,
1 H, CH), 3.65–3.61 (m, 2 H, CH2), 2.59 (td, J1 = 13.2 Hz,J2 = 3.6 Hz, 1 H,
CH), 2.34 (s, 3 H, CH3), 2.24–2.13 (m, 2 H, CH2), 1.93–1.79 (m, 4 H,
CH2), 1.65–1.56 (m, 3 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 200.7 (NC=O), 170.0 (C=O), 91.2 (quat-
C), 90.5 (quat-C), 70.5 (CH), 59.7 (CH2), 38.5 (CH2), 36.0 (CH2), 35.2
(CH3), 31.7 (CH2), 27.4 (CH), 24.6 (CH2), 22.0 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C12H16NO5: 254.1028; found:
254.1025.
HRMS (ESI): m/z [M + H]+ calcd for C13H18NO4: 252.1236; found:
Crystal Data for Compound 7b
252.1230.
The product was recrystallized using EtOAc and hexanes. C12H15NO5,
M = 254.10, crystal size 0.8 × 0.15 × 0.10 mm, orthorhombic, space
group P-212121, with a = 8.203(1) Å, b = 10.630(2) Å, c = 13.417(2) Å,
a = 90°, b = 90°, g = 90°, V = 1170.0(3) Å3; T = 296 K, R1 = 0.0357,
4-Acetyl-1-phenyloctahydro-4,9b-epoxypyrrolo[2,3,4-ij]quinoliz-
in-5(1H)-one (7f)
Yield: 115 mg (85%); white solid; mp 141–143 °C.
wR2 = 0.1112 on observed data, Z = 4, Dcalcd = 1.438
g
cm–3
,
IR (ATR): 3319, 3127, 3064, 2987, 2130, 1826, 1612, 1509, 1394, 1104,
F(000) = 536, absorption coefficient = 0.113 mm–1
,
l = 0.71073 Å,
913 cm–1
.
1418 reflections were collected on a Smart Apex CCD single-crystal
diffractometer, 2131 observed reflections [I ≥ 2σ(I)]. The largest dif-
ference peak and hole was 0.18 and –0.19 eÅ–3, respectively. The
structure was solved by direct methods and refined by full-matrix
least squares on F2 using SHELXL-97 software (CCDC 1432164).
1H NMR (400 MHz, CDCl3): δ = 7.26–7.22 (m, 2 H, ArH), 6.74 (t, J = 7.2
Hz, 1 H, ArH), 6.59 (d, J = 8.0 Hz, 1 H, ArH), 3.94 (q, J = 6.0 Hz, 1 H, CH),
3.87–3.81 (m, 2 H, CH2), 2.98–2.81 (m, 3 H, CH2), 2.76–2.71 (m, 1 H,
CH2), 2.37 (s, 3 H, CH3), 2.33–2.28 (m, 1 H, CH2), 2.04 (dd, J1 = 12.8 Hz,
J2 = 3.6 Hz, 1 H, CH), 1.94–1.91 (m, 1 H, CH2), 1.76–1.71 (m, 1 H, CH2),
1.34–1.24 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 200.3 (NC=O), 169.3 (C=O), 146.7 (CH),
129.5 (CH), 117.0 (CH), 111.7 (CH), 99.3 (quat-C), 93.7 (quat-C), 54.6
(CH), 52.6 (CH2), 42.7 (CH3), 39.0 (CH2), 33.1 (CH2), 29.1 (CH2), 27.4
(CH2), 20.8 (CH2).
4-Acetyl-2,4,7,8,9,9a-hexahydro-5H-4,9b-epoxyfuro[2,3,4-ij]quin-
olizin-5-one (7c)
Yield: 67 mg (67%); pale white solid; mp 143–145 °C.
IR (ATR): 2952, 2926, 1730, 1437, 1416, 1361, 1209, 1171, 1008, 957
cm–1
.
MS (ESI): m/z = 313.1 [M + H]+.
1H NMR (400 MHz, CDCl3): δ = 5.92 (s, 1 H, CH), 5.11 (t, J = 0.8 Hz, 2 H,
CH2), 4.79–4.73 (m, 1 H, CH), 4.13 (ddd, J1 = 14.4 Hz, J2 = 6.8 Hz,
J3 = 2.0 Hz, 1 H, CH), 3.74–3.66 (m, 1 H, CH2), 2.67 (s, 3 H, CH3), 2.47–
2.34 (m, 2 H, CH2), 2.29–2.22 (m, 1 H, CH), 1.98–1.86 (m, 1 H, CH2).
Anal. Calcd for C18H20N2O3: C, 69.21; H, 6.45; N, 8.97. Found: C, 69.04;
H, 6.42; N, 8.95.
4-Acetyl-1-phenyl-2,4,7,8,9,9a-hexahydro-4,9b-epoxypyrro-
lo[2,3,4-ij]quinolizin-5(1H)-one (7g)
13C NMR (100 MHz, CDCl3): δ = 198.3 (C=O), 159.8 (NC=O), 147.7
(quat-C), 133.4 (quat-C), 118.8 (CH2), 112.7 (CH), 96.1 (CH), 43.0
(CH2), 32.0 (CH2), 30.0 (CH2), 27.2 (CH3), 20.0 (CH2).
Yield: 79 mg (60%); colorless solid; mp 153–155 °C.
HRMS (ESI): m/z [M + H]+ calcd for C12H14NO4: 236.0923; found:
236.0912.
IR (ATR): 3416, 2931, 1718, 1651, 1601, 1466, 1440, 1369, 1252, 1088,
815 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.19 (m, 2 H, ArH), 6.74 (t, J = 7.6
Hz, 1 H, CH), 6.60 (d, J = 7.6 Hz, 2 H, ArH), 6.52 (t, J = 2.4 Hz, 1 H, CH),
4.53 (t, J = 4.0 Hz, 1 H, CH), 4.20 (t, J = 2.4 Hz, 2 H, CH2), 3.38–3.31 (m,
1 H, CH2), 3.21–3.18 (m, 1 H, CH2), 2.31 (s, 3 H, CH3), 2.17–2.11 (m, 1
H, CH2), 2.01–1.67 (m, 3 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 200.3 (C=O), 169.3 (NC=O), 146.7
(quat-C), 129.4 (quat-C), 117.0 (CH2), 111.6 (CH), 99.3 (CH2), 93.7
(CH2), 54.6 (CH2), 52.6 (CH3), 42.7 (CH2), 39.0 (CH2), 33.1 (CH2), 29.1
(CH2), 27.4 (CH), 20.7 (CH2).
Methyl 5-Oxo-7,8,9,9a-tetrahydro-2H-4,9b-epoxyfuro[2,3,4-
ij]quinolizine-4(5H)-carboxylate (7d)
Yield: 63 mg (62%); pale yellow semi-solid; mp 158–160 °C.
IR (ATR): 3417, 2935, 1717, 1653, 1601, 1466, 1440, 1369, 1252, 1088,
815 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.52–6.48 (m, 1 H, CH), 4.69–4.51 (m,
3 H, CH2), 3.94 (s, 3 H, CH3), 3.33–3.28 (m, 2 H, CH2), 2.03–1.99 (m, 1
H, CH2), 1.94–1.86 (m, 1 H, CH2), 1.84–1.76 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 171.7 (C=O), 164.1 (C=O), 159.7 (quat-
C), 123.0 (CH), 103.6 (CH2), 97.7 (CH), 71.0 (CH), 63.8 (CH2), 53.3
(CH3), 39.5 (CH2), 25.8 (CH2), 17.1 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C18H19N2O3: 311.1396; found:
311.1387.
4-Acetyloctahydro-5H-4,9b-epoxythieno[2,3,4-ij]quinolizin-5-one
(7h)
MS (ESI): m/z = 252.0 [M + H]+.
Yield: 81 mg (76%); pale yellow solid; mp 167–169 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

K
S. Muthusamy, C. Gangadurai
Paper
Synthesis
IR (ATR): 2813, 2776, 1661, 1485, 1483, 1455, 1435, 1357, 1318, 1112,
964 cm–1
Methyl 5-Oxooctahydro-2H-2a,1,4-epithiofuro[2,3,4-ij]quino-
lizine-4-carboxylate (7k)
.
1H NMR (400 MHz, CDCl3): δ = 3.77 (dd, J1 = 12.8 Hz, J2 = 2 Hz, 1 H,
CH), 3.44–3.41 (m, 1 H, CH), 3.10–3.05 (m, 1 H, CH), 2.81–2.75 (m, 2
H, CH2), 2.68–2.63 (m, 1 H, CH), 2.32 (s, 3 H, CH3), 2.28–2.16 (m, 2 H,
CH2), 1.91–1.80 (m, 2 H, CH2), 1.59–1.52 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 200.2 (C=O), 169.1 (NC=O), 103.4
(quat-C), 92.6 (quat-C), 47.5 (CH), 40.3 (CH), 39.0 (CH2), 35.0 (CH2),
34.7 (CH2), 33.3 (CH2), 27.4 (CH3), 22.3 (CH2).
Yield: 64 mg (64%); viscous oil.
IR (ATR): 3106, 2869, 1752, 1713, 1429, 1398, 1324, 1211, 1203, 1163,
968 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.17–4.12 (m, 2 H, CH2), 3.85 (s, 3 H,
CH3), 3.64 (dt, J1 = 12.8 Hz, J2 = 4.0 Hz, 1 H, CH), 3.49 (q, J = 2.0 Hz, 1 H,
CH), 2.89–2.82 (m, 1 H, CH), 2.68–2.61 (m, 1 H, CH), 2.29–2.16 (m, 2
H, CH2), 2.00 (dd, J1 = 12.8 Hz, J2 = 3.6 Hz, 1 H, CH), 1.81–1.76 (m, 1 H,
CH), 1.57–1.53 (m, 1 H, CH2), 1.37–1.27 (m, 1 H, CH2).
HRMS (ESI): m/z [M + H]+ calcd for C12H16NO3S: 254.0851; found:
13C NMR (100 MHz, CDCl3): δ = 168.6 (C=O), 165.7 (C=O), 102.0 (quat-
C), 89.9 (quat-C), 71.9 (CH2), 70.2 (CH), 53.2 (CH), 46.3 (CH3), 38.9,
(CH2), 31.4 (CH2), 29.6 (CH2), 19.7 (CH2).
254.0886.
Crystal Data for Compound 7h
HRMS (ESI): m/z [M + H]+ calcd for C12H16NO4S: 270.0800; found:
270.0812.
The product was recrystallized using EtOAc and hexanes. C12H15NO3S,
M = 253.31, crystal size 0.09 × 0.08 × 0.07 mm, orthorhombic, space
group Pna21, with a = 15.716(3) Å, b = 8.797(2) Å, c = 8.520(2) Å,
a = 90°, b = 90°, g = 90°, V = 1178.0(10) Å3, T = 296 K, R1 = 0.0415,
4-Acetyl-7,8,9,9a-tetrahydro-2H-2a,1,4-epithiofuro[2,3,4-ij]quino-
lizin-5(4H)-one (7l)
wR2 = 0.1080 on observed data, Z = 4, Dcalcd = 1.428
g
cm–3
,
F(000) = 536, absorption coefficient = 0.270 mm–1
,
l = 0.71073 Å,
Yield: 64 mg (60%); viscous oil.
4089 reflections were collected on a Smart Apex CCD single crystal
diffractometer, 3326 observed reflections [I > 2σ(I)]. The largest dif-
ference peak and hole are 0.30 and –0.27 eÅ–3, respectively. The struc-
ture was solved by direct methods and refined by full-matrix least
squares on F2 using SHELXL-97 software (CCDC 1432165).
IR (ATR): 2955, 2924, 1752, 1719, 1440, 1398, 1333, 1268, 1203, 1160,
1074 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.92 (s, 1 H, CH), 5.11 (d, J = 3.6 Hz, 2 H,
CH2), 4.79–4.73 (m, 1 H, CH), 4.13 (ddd, J1 = 14.8 Hz, J2 = 6.8 Hz,
J3 = 2.4 Hz, 1 H, CH), 3.74–3.66 (m, 1 H, CH), 2.67 (s, 3 H, CH3), 2.47–
2.34 (m, 2 H, CH2), 2.29–2.22 (m, 1 H, CH2), 1.98–1.86 (m, 1 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 198.0 (C=O), 159.3 (NC=O), 147.2
(quat-C), 133.0 (quat-C), 118.3 (CH2), 112.2 (CH), 73.0 (quat-C), 72.8
(CH2), 42.5 (CH2), 31.5 (CH2), 26.4 (CH3), 19.1 (CH2).
Methyl 5-Oxohexahydro-2H-4,9b-epoxythieno[2,3,4-ij]quino-
lizine-4(5H)-carboxylate (7i)
Yield: 74 mg (70%); white solid; mp 162–164 °C.
IR (ATR): 2955, 2924, 1752, 1719, 1440, 1398, 1333, 1268, 1203, 1160,
1076 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C12H14NO3S: 252.0694; found:
252.0642.
1H NMR (400 MHz, CDCl3): δ = 4.17–4.12 (m, 2 H, SCH2), 3.85 (s, 3 H,
OCH3), 3.64 (dt, J1 = 12.8 Hz, J2 = 4.0 Hz, 1 H, SCH), 3.49 (q, J = 2.0 Hz, 1
H, CH), 2.84 (dt, J1 = 14.8 Hz, J2 = 1.2 Hz, 1 H, CH), 2.67–2.61 (m, 1 H,
CH), 2.29–2.16 (m, 2 H, CH2), 2.00 (dd, J1 = 12.8 Hz, J2 = 3.6 Hz, 1 H,
CH), 1.81–1.75 (m, 1 H, CH), 1.60–1.53 (m, 1 H, CH2), 1.37–1.27 (m, 1
H, CH2).
13C NMR (100 MHz, CDCl3): δ = 168.7 (C=O), 165.7 (NC=O), 102.0
(quat-C), 89.9 (quat-C), 71.9 (OCH2), 70.2 (OCH), 53.2 (CH), 46.3
(OCH3), 38.9 (CH2), 31.0 (CH2), 29.6 (CH2), 19.7 (CH2).
4-Acetyloctahydro-5H-4,9b-epithiothieno[2,3,4-ij]quinolizin-5-
one (7m)
Yield: 76 mg (71%); fluffy solid; mp 140–142 °C.
IR (ATR): 2964, 2715, 1733, 1719, 1415, 1361, 1265, 1148, 1083, 953,
889 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.17–4.09 (m, 2 H, CH2), 3.67–3.61 (m,
1 H, CH), 3.46 (q, J = 2.0 Hz, 1 H, CH), 2.84 (ddd, J1 = 15.2 Hz, J2 = 11.2
Hz, J3 = 3.6 Hz, 1 H, CH2), 2.68–2.61 (m, 1 H, CH2), 2.33 (s, 3 H, CH3),
2.31–2.23 (m, 1 H, CH2), 2.14 (dd, J1 = 12.8 Hz, J2 = 7.6 Hz, 1 H, CH2),
1.87–1.77 (m, 2 H, CH2), 1.61–1.50 (m, 1 H, CH2), 1.37–1.27 (m, 1 H,
CH2).
MS (ESI): m/z = 270.1 [M + H]+.
Anal. Calcd for C12H15NO4S: C, 53.52; H, 5.61; N, 5.20. Found: C, 53.66;
H, 5.58; N, 5.18.
13C NMR (100 MHz, CDCl3): δ = 200.1 (C=O), 169.2 (NC=O), 101.6
(quat-C), 94.5 (quat-C), 72.0 (CH2), 70.2 (CH), 46.2 (CH), 38.7 (CH2),
30.7 (CH2), 29.5 (CH2), 27.3 (CH3), 19.7 (CH2).
4-Acetyloctahydro-5H-4,9b-epithiofuro[2,3,4-ij]quinolizin-5-one
(7j)
Yield: 71 mg (71%); colorless solid; mp 144–146 °C.
MS (ESI): m/z = 270.1 [M + H]+.
IR (ATR): 1733, 1719, 1415, 1361, 1265, 1148, 1083, 953, 889 cm–1
.
Anal. Calcd for C12H15NO2S2: C, 53.50; H, 5.61; N, 5.20. Found: C,
53.65; H, 5.59; N, 5.18.
1H NMR (400 MHz, CDCl3): δ = 4.23–4.17 (m, 2 H, CH2), 3.74–3.67 (m,
1 H, CH), 3.54 (q, J = 2.0 Hz, 1 H, CH), 2.91 (ddd, J1 = 14.8 Hz, J2 = 11.2
Hz, J3 = 3.6 Hz, 1 H, CH), 2.74–2.67 (m, 1 H, CH), 2.35 (s, 3 H, CH3),
2.35–2.31 (m, 1 H, CH2), 2.13 (dd, J1 = 12.8 Hz, J2 = 7.6 Hz, 1 H, CH2),
1.94–1.82 (m, 2 H, CH2), 1.68–1.57 (m, 1 H, CH2), 1.44–1.39 (m, 1 H,
CH2).
Methyl 5-Oxooctahydro-2H-2a,1,4-epithiothieno[2,3,4-ij]quino-
lizine-4-carboxylate (7n)
Yield: 76 mg (72%); yellow solid; mp 162–164 °C.
13C NMR (100 MHz, CDCl3): δ = 200.1 (C=O), 169.2 (C=O), 101.7 (quat-
C), 94.6 (quat-C), 72.0 (CH2), 70.3 (CH), 46.3 (CH), 38.8 (CH2), 30.7
(CH2), 29.6 (CH2), 27.3 (CH3), 19.7 (CH2).
IR (ATR): 2955, 2924, 1752, 1719, 1440, 1398, 1333, 1268, 1203, 1160,
1076 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C12H16NO3S: 254.0851; found:
254.0852.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

L
S. Muthusamy, C. Gangadurai
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 4.20 (q, J = 7.6 Hz, 2 H, CH2), 3.91 (s, 3
H, CH3), 3.72–3.69 (m, 1 H, CH), 3.55 (t, J = 10.0 Hz, 1 H, CH), 2.94–
2.88 (m, 1 H, CH), 2.74–2.67 (m, 1 H, CH), 2.34–2.23 (m, 2 H, CH2),
2.07 (dd, J1 = 12.8 Hz, J2 = 3.2 Hz, 1 H, CH), 1.86–1.83 (m, 1 H, CH),
1.66–1.56 (m, 2 H, CH2), 1.38 (q, J = 12.4 Hz, 1 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 168.7 (C=O), 165.7 (C=O), 102.0 (quat-
C), 89.9 (quat-C), 71.9 (OCH2), 70.2 (CH), 53.2 (CH), 46.3 (CH3), 38.9,
(CH2), 31.0 (CH2), 29.6 (CH2), 19.7 (CH2).
Yield: 38 mg (63%); thick greenish oil.
IR (ATR): 3312, 3178, 2964, 1739, 1721, 1430, 1384, 1321, 1257, 1211,
1065 cm–1
1H NMR (400 MHz, CDCl3): δ = 4.48 (s, 1 H, OH), 4.25 (dt, J1 = 13.2 Hz,
J2 = 4.0 Hz, 1 H, CH), 4.08 (dq, J1 = 11.2 Hz, J2 = 4 Hz, J3 = 2.4 Hz, 1 H,
CH), 3.80–3.74 (m, 1 H, CH), 3.15–3.08 (m, 1 H, CH), 2.66–2.60 (m, 1
H, CH), 2.25 (s, 3 H, CH3), 2.22–2.15 (m, 2 H, CH2), 1.91–1.82 (m, 2 H,
CH2), 1.65–1.51 (m, 4 H, CH2).
.
MS (ESI): m/z = 286.1 [M + H]+.
13C NMR (100 MHz, CDCl3): δ = 209.0 (C=O), 166.1 (NC=O), 137.4
(quat-C), 113.6 (quat-C), 79.0 (quat-C), 65.0 (CH2), 41.0 (CH2), 35.3
(CH2), 29.5 (CH2), 26.4 (CH), 25.1 (CH3), 24.6 (CH), 21.0 (CH2).
Anal. Calcd for C12H15NO3S2: C, 50.50; H, 5.30; N, 4.91. Found: C,
50.35; H, 5.29; N, 4.89.
HRMS (ESI): m/z [M + Na]+ calcd for C13H17NO4Na: 274.1055; found:
274.1050.
4-Acetyl-1-phenyloctahydro-4,9b-epithiopyrrolo[2,3,4-ij]quino-
lizin-5(1H)-one (7o)
Yield: 90 mg (69%); pale yellow solid; mp 134–136 °C.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.22 (m, 2 H, ArH), 6.74 (t, J = 7.2
Hz, 1 H, ArH), 6.59 (d, J = 8.0 Hz, 2 H, ArH), 2.98–2.81 (m, 3 H, CH2),
2.76–2.71 (m, 1 H, CH), 2.37 (s, 3 H, CH3), 2.33–2.28 (m, 1 H, CH),
2.06–2.02 (m, 1 H, CH), 2.04 (dd, J1 = 12.8 Hz, J2 = 3.6 Hz, 3 H, CH2),
1.94–1.91 (m, 1 H, CH), 1.76–1.71 (m, 1 H, CH), 1.34–1.24 (m, 1 H,
CH2).
13C NMR (100 MHz, CDCl3): δ = 197.7 (C=O), 166.8 (NC=O), 144.1
(quat-C), 127.0 (CH), 114.5 (CH), 109.1 (CH), 96.8 (CH2), 91.1 (CH2),
52.0 (CH), 50.0 (CH2), 40.1 (CH), 36.5 (CH2), 30.5 (CH2), 26.5 (CH2),
24.8 (CH3), 18.2 (CH2).
Acknowledgment
We thank the Department of Science and Technology (DST), India, for
providing the 400 MHz NMR facility under the FIST program and for
supporting this research work [No. SR/S1/OC-11/2011(G)]. C.G.
thanks the University Grants Commission, New Delhi, for a fellow-
ship.
Supporting Information
MS (ESI): m/z = 329.1 [M + H]+.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560441.
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Anal. Calcd for C18H20N2O2S: C, 65.83; H, 6.14; N, 8.53. Found: C,
65.70; H, 6.12; N, 8.55.
References
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tion of epoxy-bridged tricyclic compound 7a (60 mg, 0.25 mmol) in
benzene (2 mL). The reaction mixture was allowed to stir at r.t. for 3 h.
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chromatography to give 11a as a thick, pale yellow oil (33 mg, 49%).
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.
1H NMR (400 MHz, CDCl3): δ = 4.77 (s, 1 H, OH), 4.57–4.52 (m, 1 H),
4.39–4.35 (m, 1 H), 4.09–4.03 (m, 1 H), 3.44–3.37 (m, 1 H), 2.95–2.88
(m, 1 H), 2.54 (s, 3 H), 2.51–2.41 (m, 2 H), 2.20–2.04 (m, 4 H).
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MS (ESI): m/z = 238.1 [M + H]+.
Anal. Calcd for C12H15NO4: C, 60.75; H, 6.37; N, 5.90. Found: C, 60.61;
H, 6.35; N, 5.88.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M

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Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–M