Scope and limitations of the synthesis of functionalized quinolizidinones and related compounds by a simple precursor approach via addition of lithium allylmagnesates to 2-pyridones and RCM as key steps

Article abstract of DOI:10.1016/j.tet.2014.09.043

The scope and limitations of the simple synthesis of functionalized quinolizidin-4-ones by chemoselective N-alkenylation of NH pyridin-2(1H)-ones (2-pyridones), regioselective addition of lithium allyl(di-n-butyl)magnesates(1-) to N-alkenylpyridin-2(1H)-ones, followed by ring closing metathesis (RCM) is described. A number of functionalizations introduced into quinolizidin-4-one rings demonstrated the high prospect of the strategy proposed in scaffold synthesis. Their extension to the syntheses of pyrido[1,2-a]azepin-4-one and pyrido[1,2-a]azocin-4-one derivatives as well as to spiro-fused compounds is also presented.

Full text of DOI:10.1016/j.tet.2014.09.043

Tetrahedron 70 (2014) 8624e8635
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Scope and limitations of the synthesis of functionalized
quinolizidinones and related compounds by a simple precursor
approach via addition of lithium allylmagnesates to 2-pyridones
and RCM as key steps
a
,
a
a
b
*
ꢀ
Jacek G. Sosnicki , qukasz Struk , Tomasz Idzik , Gabriela Maciejewska
a
ꢀ
West Pomeranian University of Technology, Szczecin, Institute of Chemistry and Environmental Protection, Al. Piastow 42, 71-065 Szczecin, Poland
Wrocław University of Technology, Faculty of Chemistry, Wybrzeze Wyspianskiego 27, 50-370 Wrocław, Poland
b
_
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2014
Received in revised form 1 September 2014
Accepted 15 September 2014
Available online 20 September 2014
The scope and limitations of the simple synthesis of functionalized quinolizidin-4-ones by chemo-
selective N-alkenylation of NH pyridin-2(1H)-ones (2-pyridones), regioselective addition of lithium al-
lyl(di-n-butyl)magnesates(1-) to N-alkenylpyridin-2(1H)-ones, followed by ring closing metathesis
(RCM) is described. A number of functionalizations introduced into quinolizidin-4-one rings demon-
strated the high prospect of the strategy proposed in scaffold synthesis. Their extension to the syntheses
of pyrido[1,2-a]azepin-4-one and pyrido[1,2-a]azocin-4-one derivatives as well as to spiro-fused com-
pounds is also presented.
Keywords:
Quinolizidinones
Magnesates
Ó 2014 Elsevier Ltd. All rights reserved.
Regioselectivity
Nucleophilic addition
Metathesis
1. Introduction
methodology, consists of the introduction of an allyl group into C6
of d-lactam ring, as one of two adjacent allyl groups, by the addition
Quinolizidines make an important class of compounds first of all
because of their widespread occurrence in nature1,2 and because
they have been identified as valuable pharmacophores.3 A wide
range of biological activities associated with the quinolizidine
moiety still inspire synthetic organic chemists to develop more and
more advanced methods for the synthesis of these naturally oc-
curring compounds4 as well as to the design and assembly of
functionalized quinolizidines as drug candidates.5 However, in ac-
cordance with current recommendations for scaffold synthesis
based on natural products, the efforts in the synthetic strategy
development should be focused on their simplicity, accessibility of
starting materials, high degree of stereoselectivity, efficiency of
transformations in minimal number of steps and possible vast di-
versity in the ring systems.6
reaction of allyl nucleophiles to N-acyliminium ions followed by
annelation using ruthenium catalysts.4d,8a,f,r Despite undoubtedly
very high importance of the above methodologies their application
in scaffold synthesis is limited due to the lack of the attachment of
the optional substituents in the piperidinone ring of quinolizidin-
4-one. In order to avoid these restrictions we postulate to use
2-pyridones (pyridin-2(1H)-ones) as a functionable source of the
piperidin-2-one ring (Scheme 1).
nucleophilic
addition
R1
R1
2
RCM
(R )
H
R1
N
O
N
O
N
O
(R2)H ( )n = 1-3
(R2)H
( )n = 1-3
( )n = 1-3
R2
quinolizidin-4-ones
Amongst the variety of synthetic approaches to the synthesis of
quinolizidine skeleton,7 ring closing metathesis (RCM) has become
the most powerful annelation tool.3c,4d,e,l,m,q,ac,ae,5e,8 One of the
synthetic strategies towards quinolizidin-4-ones, based on RCM
2-pyridones
R1
R1
or
N
H
O
N
OMe
* Corresponding author. Tel.: þ48 91 4494798; fax: þ48 91 4494639; e-mail
Scheme 1. Retrosynthetic approach to quinolizidin-4-one scaffold.
ꢀ
addresses: sosnicki@zut.edu.pl, sosnicki@ps.pl (J.G. Sosnicki).
http://dx.doi.org/10.1016/j.tet.2014.09.043
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

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J.G. Sosnicki et al. / Tetrahedron 70 (2014) 8624e8635
8625
Exploring the concept of the synthesis of functionalized piperi-
din(e)-2(1H)-(thi)ones,9 we have hitherto published two pre-
liminary reports on a simple approach to substituted 3,6,9,9a-
tetrahydroquinolizin-4-ones, one achieved from pyridin-2(1H)-
ones10a and the second from 2-methoxypyridines as precursor of the
former10b (Recently, for the synthesis of substrates we also presented
some results on the noncryogenic 5-functionalization of 2-
methoxypyridine,11 which can be applied as a source of pyridin-
2(1H)-ones.). According to the strategy proposed, the regioselective
addition of lithium allyl(di-n-butyl)magnesate(1-)9e,f to ring-
functionalized N-allyl substituted pyridin-2(1H)-ones9i and ring
closing metathesis (RCM) were the key steps.10 To the best of our
knowledge the above-mentioned, preliminary reported method is
hitherto the only described access to both unsubstituted and
substituted 3,6,9,9a-tetrahydroquinolizin-4-ones, except a multistep
approach to enantiopure, unsubstituted 3,6,9,9a-tetrahy-
droquinolizin-4-one developed by Richards and Nomura in 2009.8l
As a continuation of our ongoing program aimed at scaffold assem-
blies based on quinolizidin-4-one, achieved from readily available
starting materials,10 we now report a detailed study on the scope and
limitations of the application of substituted derivatives of pyridin-
2(1H)-ones in nucleophilic addition of lithium allyl(di-n-butyl)
magnesate(1ꢀ) followed by RCM (Scheme 1). Within this study we
also present the attempts to apply lithium allyl(di-n-butyl)magne-
sates derived from 2-methylallylmagnesium chloride and 3,3-
dimethylallylmagnesium bromide and the results of further exami-
nation of usefulness of the investigated strategy for the synthesis of
bicyclic piperidin-2(1H)-ones with seven- and eight-membered
rings, which belong to pyrido[1,2-a]azepin-4-one and pyrido[1,2-a]
azocin-4-one systems, respectively. Finally, we will show the syn-
thesis of new spiro-fused quinolizidin-4-ones and related pyr-
idoazepin-4-one consisted in one-pot installation of three allyl arms
and one-pot double RCM. As an essential element of the worked out
strategy, we also include in this paper, the so far not described,
chemoselective procedure of N-alkylation of NH-substituted pyr-
idyn-2(1H)-ones, which comprises N-allylation and N-alkenylation.
As to reaction types applied, it should be emphasised that al-
though the RCM method is well established,8,12 the nucleophilic
addition to C6 of pyridin-2(1H)-ones still deserves more attention
because it was less studied, however, the reaction often leads to
valuable piperidin-2-one-like compounds.4j,13 Amid the nucleo-
philes used in the addition to pyridin-2(1H)-ones, developed and
applied by us, lithium allyl(di-n-butyl)magnesate(1ꢀ)9e,f,i,10 be-
longs to the relatively new and useful family of ‘ate’ complexes,
which have been recently reviewed.14 Besides, perusal of the lit-
erature reveals that from a synthetic point of view, the alkylation of
NH pyridin-2(1H)-ones is of fundamental importance as N-alky-
lated pyridin-2(1H)-ones are frequently used in the synthesis of
potential drugs15 and still remains a synthetic challenge in terms of
N- and O-chemoselectivity.4j,16 Furthermore, the synthesis of spiro-
fused compounds was dictated by the fact of their application in
medical chemistry.17
should be noted that the use of equimolar ratio of n-BuLi with re-
spect to NH pyridin-2(1H)-ones (2) in THF solution converted 2 into
colourless N-lithiated salt and the completion of NHeNLi exchange
can be easily identified due to the appearance of yellow or beige
colour upon addition of an excess of n-BuLi. This titration-like effect
was more or less intensively observed in all NH-pyridones used.
Furthermore, as the reaction with allylbromide occurs slowly at
room temperature, leading to complete conversion in a few days,
we decided to heat the reagents gently at 70 ꢁC, which allowed
a complete conversion within ca. 18e20 h. All N-lithiated pyridin-
2(1H)-ones used gave chemoselectively N-allylated products 3 in
good yields from both allylbromides and allyl chlorides, for the
latter in the presence of NaI (10e20 mol %). Complete chemo-
selectivity and reaction progress were concluded from the 1H NMR
spectra of crude reaction mixtures. The results and conditions
presented in Table 1 show that it is possible to prepare different
ring substituted N-allyl, N-2-methyl(or chloro or phenyl)allyl pyr-
idin-2(1H)-ones in a few grams scale and for liquid products simple
distillation can be applied for their purification. Most of NH pyridin-
2(1H)-ones used were commercially available and the other were
prepared from 2-methoxypyridines by simple transformations (for
details see Supplementary data).
Following these studies we also found that the above procedure
can be successfully applied for the chemoselective synthesis of N-
but-2-enyl and N-pent-2-enyl derivatives (Table 1, entries 21e23
and 24, respectively), however, in their syntheses more reactive
electrophiles, i.e., esters of sulfonic acids, instead of bromides or
iodides, should be used. In a group of sulfonates applied, only tri-
flates (Table 1, entries 21e24) allowed to obtain N-alkenylated
products within 3 h at room temperature, while the use of mesylate
(Table 1, entries 21 and 22) and besylate (Table 1, entry 21) required
7e8 or 2 days of heating to achieve reasonable conversion,
respectively.
As mentioned above, a few 5-substituted N-allylated pyridin-
2(1H)-ones 3 were obtained in good yields directly from 5-
functionalized 2-methoxypyridines by heating them at 55 ꢁC for
2 days in acetonitrile with 10-fold excess of allylbromide in the
presence of 2.2 equiv of NaI (Scheme 2).
At the next stage, functionalized N-alkenylpyridin-2(1H)-ones 3
were submitted to the reaction with lithium allyl(di-n-butyl)-
magnesates(1ꢀ) 6a and 6b (Table 2) at a low temperature (gener-
ally at ꢀ75ꢂ5 ꢁC). The results are summarized in Table 2. Lithium
allylmagnesate complexes 6a, 6b were prepared immediately be-
fore use, simply by mixing of allylMgCl (5a) or methallylMgCl (5b)
with 2 equiv of n-BuLi at 0 ꢁC. Subsequently, the whole mixture that
contained lithium allyl(di-n-butyl)magnesate and LiCl, was cooled
down and transferred to the solution of pyridin-2(1H)-one 3 in THF,
earlier cooled and held at ꢀ75ꢂ5 ꢁC (It should be noted that only
small excess of magnesate in relation to 3 was used (ca. 1.15 equiv)).
Stirring for 25 min led to obtain 6-allylated products 7 in good
yields in most reactions (Table 2). However, in the case of 5-CF3 (3f),
3-OBn (3k), 5-NO2 (3g, 3r), and 5-(4,4,5,5-tetramethyl-[1,3,2]
dioxaborolan-2-yl)- (3aa) substituted pyridin-2(1H)-ones un-
identified complex mixture formation or decomposition of the
substrate was observed. As far as regioselectivity of the addition of
6 to 3 is concerned all reactions proceed in regioselective manner
yielding mainly 6-allylated isomer 7. Only slight but essential in-
fluence of the substituent present at C5 of pyridin-2(1H)-one 3 on
the regioselective 1,6eaddition was observed. The lowest 1,6-
regioselectivity was found for C5eCl substituted substrates, better
for compounds 3 equipped with C5eH(D) or C5eSiMe3 or C5eMe
substituents. However, the best 1,6-regioselectivity was observed
for the addition of 6a to pyridin-2(1H)-ones, which posses C5-aryl
(3h, 3i, 3s, 3v) or C5-phenylsulfanyl- (3j, 3t, 3w) or C5-
phenylethynyl (3ab) substituents. An attempt to allylate 3-
methylpyridin-2(1H)-one (3d) allowed verification of the
2. Results and discussion
At the first stage of our study, we investigated the synthesis of
functionalized N-alkenyl substituted pyridin-2(1H)-ones. Accord-
ing to the first method (A) used, NH pyridin-2(1H)-ones (2) were
subjected to N-alkylation. The second method (B) applied consisted
in direct transformation of 5-functionalized 2-methoxypyridines
(1) into N-allyl derivatives 3 by adaptation of the method de-
veloped by Bowman and Bridge.18
While searching for an efficient and chemoselective method for
N-allylation of NH pyridin-2(1H)-ones (2) by varying solvents and
base, we found that the simply use of n-BuLi in THF and subsequent
use of allylbromide led to sole N-allylated products 3 (Table 1). It

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J.G. Sosnicki et al. / Tetrahedron 70 (2014) 8624e8635
8626
Table 1
Synthesis of N-alkenylpyridin-2(1H)-ones 3 by chemoselective N-alkylation of 2
1. n-BuLi, THF
R2
2.
X
R1
R1
R1
R1
R2
( )n = 1-3
( )n = 1-3
N
O
N
O
4
not observed
N
1
O
N
O
method A
( )n = 1-3
R2
H
2
3
Entry
1
R1
H
R2
n
X
3
T [ꢁC];
t [h];
RX [equiv]
Conversion of 2a [%]
3 Yieldb [%]
H
1
Br
a
70
22
70
70
70
22
70
22
70
22
70
70
70
70
70
70
70
70
70
70
70
70
70
70
65
70
70
22
70
22
22
68
70
22
18
144
18
18
19
96
18
72
18
24
20
20
17
20
20
20
20
20
20
20
20
20
20
20
9
1.3
3.0
1.3
1.3
1.3
2.5
2.0
3.0
1.3
3.0
1.3
1.2
1.2
1.3
1.3
2.0
1.3
1.3
1.3
1.2
1.2
1.2
1.2
1.2
1.3
1.2
1.2
1.2
1.2
1.2
1.2
1.3
1.3
1.2
>99
98
95c (99)2
81c (81)2
82c (85)2
84c (84)2
86c (90)2
82c
2
3
4
5-Me
4-Me
3-Me
H
H
H
1
1
1
Br
Br
Br
b
c
d
>99
>99
>99
>99
>99
>99
>99
99
>99
>99
>99
>99
>99
>99
>99
86
5
5-Cl
H
1
Br
e
86c (94)2
84c (94)1
85c (93)1
72d
6
7
8
9
10
11
12
5-CF3
5-NO2
5-Ph
5-(4-FC6H4)
5-SPh
3-OBn
H
H
H
H
H
H
H
Me
1
1
1
1
1
1
1
Br
Br
Br
Br
Br
Br
f
g
h
i
j
k
l
91d
86d
92d
86d
Br
78c (86)1
91c (97)2
82c (89)2
70c (76)2
73c (82)2
90d (91)2
95d (99)2
81d (83)2
85d (87)2
78d (78)2
33h
Cle
Clf
13
14
15
16
17
18
19
20
21
5-Cl
H
4-Me
H
5-Cl
5-NO2
5-Ph
5-SPh
H
Me
Cl
Cl
Ph
Ph
Ph
Ph
Ph
H
1
1
1
1
1
1
1
1
2
m
n
o
p
q
r
s
t
u
Clf
Clf
98
Br
Br
Br
Br
>99
>99
>99
>99
w92
w88
w94
>99
>99
94
>99
>99
w90
w72
>99
Br
Brg
OMs
SO3Ph
OTf
OMs
OTf
OTf
Brg
Bri
OTf
168
48
2.5
192
2.5
3.0
5.5
96
1.5
79c
71c (84)2
91d (94)2
82d
22
5-Ph
H
2
v
87d
23
24
5-SPh
H
H
H
2
3
w
x
95d
36d,h
53c (56)2
93j (97)1
a
Conversion estimated using 1H NMR spectroscopy of crude reaction mixture.
b
c
d
e
f
Isolated yields. Yields estimated by 1H NMR spectroscopy using internal reference are given in the parenthesis. The number of determinations is given in the upper index.
Product was isolated in pure state by distillation.
Product was isolated in pure state by column chromatography.
NaI (20 mol %) was added.
NaI (10 mol %) was added.
K2CO3 (1.3 equiv) and anhydrous acetone were used instead of n-BuLi and THF.
In this reaction additionally 9% of O-alkylated isomer was formed.
NaI (30 mol %) was added.
g
h
i
j
Product was isolated in pure state by distillation and the residue was purified by column chromatography.
stereoselectivity at C-3. In this reaction, low stereoselectivity was
observed yielding trans and cis isomers of 7f, quoted further as 7f-
trans and 7f-cis, in the ratio of 6:4, respectively. Fortunately, these
compounds were obtained in diastereoisomerically pure state by
separation using flash column chromatography. For the sake of
comparison 3a, 3b and 3j were exposed to allylMgCl (5a) under the
same temperature as for allyl(n-Bu2)MgLi (6a). The results con-
firmed a lower reactivity of allylMgCl in relation to that of allyl(n-
Bu2)MgLi9e,f and also showed that reactions conducted with the use
of magnesates 6 led to the pure products, while the application of
sole Grignard reagent produced impurities, probably of CeC cou-
pling origin, which were difficult to remove (e.g., Table 2, entry 12).
In the light of the recent investigation on the structure and re-
activity of allylmagnesates,19 the explanation of the improved re-
activity of 6 in relation to 5 can be considered in terms of
coordination modes of allyl moieties. However, to support this
hypothesis, more detailed studies on complexes of 6 are required.
Finally, functionalized N-alkenyl,6-allyl
b,g-unsaturated d-lac-
tams 7 were annelated by RCM (Table 3), employing, in general,
Grubbs first (GI) and/or more efficient Grubbs second (GII) gener-
ation catalyst, with the exception of 6-allyl-N-(2-phenylallyl) de-
rivatives 7q, 7r, 7t and 7u, for which StewarteGrubbs catalyst
(SeG) was used. (The attempt to apply GII for 7q brought much
worse outcome [see Table 3, entry 18]). The optimal conditions
found for SeG cat., required 1.6e1.9 mol % loading of catalyst,
temperature 75 ꢁC and reaction time up to 140 min (TLC-control)
(Table 3, entries 18e21). It should be noted that StewarteGrubbs
catalyst (SeG) was hitherto used to increase the efficiency in cross-
metathesis (CM)20 and RCM reactions of sterically hindered olefins
(except phenylvinyl derivatives)21 or in ring-rearrangement

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J.G. Sosnicki et al. / Tetrahedron 70 (2014) 8624e8635
8627
of two adjacent 3-allyl groups in one step,9i we decided to apply
this reaction as the first step of the planned synthesis of spiro-
fused derivatives. However, because the reactions described
were not fully regioselective, yielding 3,3-diallylation and 3,5-
diallylation products in ca. 8:2 ratio,9i we used 5-phenyl and 5-
phenysulfanyl derivatives (3h, 3v, 3w) with occupied C5 posi-
tion. Besides, the selected compounds led to the highest regiose-
lectivity in the reaction with allyl(di-n-butyl)magnesate 6a. The
second step comprised one-pot double RCM. As a result, the
syntheses of spiroquinolizidin-4-ones 15ae15c were accom-
plished only in two steps starting from 3 leading to both tetraal-
kenylated intermediates 14 and spiro-compounds 15 in good
yields as depicted in Scheme 4.
In the overall assessment, the protocol described seemed to be
useful for quinolizidin-4-ones scaffold synthesis as well as for re-
lated bicyclic piperidinones and spiro-fused compounds, in spite of
medium tolerance of functional groups during the addition and the
annelation step. In the light of search for potential drugs, from
among the achievements obtained, the most valuable seemed to be
the synthesis of derivatives 9 and 15 equipped with aryl groups as
their presence often enhances biological activities.27
method B
Br
(10 eq.)
R1
R1
N
O
CH3CN,
N
O
NaI (2.2 eq.)
1
3
55oC, 2 days
PhS
Cl
Ph
N
O
N
O
N
O
3j 81%
3h 85%
3e 74%*
Ph
O
B
D
Me3Si
O
N
O
N
O
N
O
N
O
3ab 72%
3aa 70%
3y 78%
3z 77%
Scheme 2. Direct synthesis of N-allylpyridin-2(1H)-ones from 2-methoxypyridines ( 5
*
days of heating was applied).
metathesis (RRM).22 Only recently, StewarteGrubbs catalyst was
used in the RCM synthesis, in which 2-phenyacryloyl arm partici-
pated.23 Furthermore, the extension of the above methodology for
the synthesis of derivatives with newly formed seven- (9ve9x,
Table 3, entries 22e24) and eight-membered (9y, Table 3, entry 25)
rings was successful. Bicyclic compounds 9ve9x were obtained in
good yields, however, in the case of formation of eight-membered
ring (9y, Table 3) 10% of E isomer was also formed.
The structures of compounds 3, 7, 9, 10a, 12a, 13e15 were elu-
cidated with the aid of 1D NMR (1H,13C, 13C-DEPT-135) and 2D NMR
spectroscopy (1H,1H COSY; 1H,13C HETCOR), IR spectroscopy, mass
spectra and HRMS analyses. The configurations of products 7f-trans,
7-cis and 9f, 9g were determined on the basis of 1D NOE experi-
ments and 2D 1H,1H NOESY spectra, respectively. Compounds 7 and
8 were easily analyzed by TLC and because of their different polarity
were separated by column chromatography without problems.
However, due to low yields of regioisomers 8, only six of them (8a,
8b, 8c, 8g, 8z, 8ab) were isolated in purity permitting their structural
analyses by NMR, IR and GCeMS methods. As far as distinction of
regioisomers 7 and 8 is concerned, the inspection of 1H and 13C NMR
spectra (including routine 13C DEPT-135 experiments) of both
regioisomers 7 and 8 (see Supplementary data), showed that in
general,13C NMR chemical shifts of CH-6 groups found in the spectra
of regioisomers 7 in w61e56 ppm region, in comparison to 13C NMR
chemical shifts of CH-4 groups observed in spectra of regioisomers
8, appearing in the range w39e30 ppm, are the best criteria for
simple distinction of both regioisomers. This observation is sup-
ported by 13C NMR and 13C DEPT-135 NMR spectra of 4-(1,1-
dimethylallyl) substituted, major regioisomer 10a, in which the
resonance signal assigned to CH-4 appears at 41.5 ppm. Further-
more, although the 1H NMR spectra of both regioisomers 7 and 8 are
less useful for their distinction because the resonance positions and
multiplicities of 1H NMR signals are strongly affected by sub-
stituents, the most characteristic differences appear in the reso-
nance positions of signals originating from NCH2 of N-allyl groups.
For 6-allylated isomers 7 diastereotopic NCHH protons give reso-
nance signals distant from each other by w1.1e1.8 ppm, while for
compounds 8 the difference between chemical shifts of NCHH is
much smaller, of about w0.1 ppm with average chemical shits of
NCHH at w4.1 ppm for both isomers.
Regrettably, two diallylated d-lactams 7p, 7ad give no positive
results in RCM. One lactam possesses N-(2-chloroallyl) moiety (7p)
and other one has 5-phenylethynyl substituent (7ad). Although, on
the basis of the literature reports, the connection of allyl and
chlorovinyl arms can be expected to occur,24 three attempts to
obtain product 9q from 7p failed (Table 3, entry 17), albeit, traces of
the product formation were observed when larger amount of cat-
alyst GII was used. When using 5-phenylethynyl-1,6-diallyl de-
rivative 7ad, RCM product was not observed and the substrate was
recovered in 70% (Table 3, entry 14). Although difficulties in
annelation of vinylchlorides by RCM have been well established,25
no annelation process observed for 5-phenylethynyl 1,6-diallyl
derivative 7ad was surprising. This lack of reactivity may result
from Fischer-type carbene complex formation, which, being
‘locked’ by coordination of alkyne
p-electrons, failed to react fur-
ther. Similar, unsuccessful RCM annelation of adjacent alkenyl
groups in the presence of alkynyl moiety was observed in
boline synthesis.26
b-car-
As previously mentioned we wanted to expand the allylation
step for using lithium di-n-butyl(3,3-dimethylallyl)magnesate 6c
but the attempt partly failed, because in the reaction with 3a
mainly 4-allylated isomer 10a was formed in 63% yield together
with only small amounts (15% yield) of 1:1 mixture of 6-allylated
isomers 11a and 11b (Scheme 3, upper part). Albeit, forcing the
reaction towards 6-allylation by submission of 6c to the reaction
with 4-methylpyridin-2(1H)-one (3c), resulted in the addition at C6
in moderate yields, but still as 1:1 inseparable mixture of isomers
(12a, 12b) (Scheme 3, lower part). Fortunately, treatment of this
mixture with catalyst GI succeeded in accomplishing 9-dimethyl-
substituted quinolizidin-4-one 13 from the corresponding 1,1-
dimethylallyl isomer 12b, while isomer 12a remained unchanged.
At the end of our study, we also briefly explore the possibilities
of the synthesis of quinolizidin-4-ones and its bicyclic analogs
equipped with spiro-fused five-membered rings in two steps
starting from 3 (Scheme 4). Because addition of lithium allyl(di-n-
butyl)magnesates to N-alkylated pyridin-2(1H)-ones followed by
the reaction with excess of allylbromide allowed the introduction
3. Conclusions
In conclusion, we have demonstrated that the 1,6 regioselective
addition
of
lithium
allyl(or
2emethylallyl)(di-n-butyl)
magnesate(1ꢀ) reagent to substituted in the ring N-alkenylpyridin-
2(1H)-ones, followed by RCM, provided easy access to racemic,
functionalized 3,6,9,9a-tetrahydroquinolizin-4-ones, having sub-
stituents and CeC double bonds in both rings. The protocol de-
scribed, enables their extension for the synthesis of substituted
bicyclic piperidin-2-ones (pyridoazepin-4-ones and pyridoazocin-
4-one) and of spiro-functionalized quinolizidin-4-ones and pyr-
idoazepin-4-ones. Both, typical and extended procedures

ꢀ
J.G. Sosnicki et al. / Tetrahedron 70 (2014) 8624e8635
8628
Table 2
Synthesis of 6-allyllactams 7 by regioselective addition of lithium (meth)allyl(di-n-butyl)magnesates 6 to N-alkenylpyridin-2(1H)-ones 3
5a (R3=H)
+
2n-BuLi
MgCl
5b (R3=CH3)
R3
5
6a (R3=H)
1.
LiCl
Mgn-Bu2Li +
R3
6b (R3=CH3)
R3
6
R1
R1
R1
THF, -75 5oC, 25 min.
R3
+
N
O
N
O
N
O
( )n = 1-3
R2
( )n = 1-3
R2
( )n = 1-3
R2
2. NH4Cl aq.
7
3
8
Entry
1
R1
H
R2
H
R3
H
n
5, 6
7, 8
T [ꢁC]
7/8a
Conversion of 3a
7 Yieldb [%]
1
5ac
5ad
6a
6b
5ac
6a
6a
6b
6a
6a
6a
6a
6a
6a
5ad
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
a
ꢀ70
ꢀ80
ꢀ70
ꢀ72
ꢀ80
ꢀ80
ꢀ65
ꢀ72
ꢀ70
ꢀ72
ꢀ78
ꢀ78
ꢀ74
ꢀ74
ꢀ78
ꢀ78
ꢀ80
ꢀ80
ꢀ80
ꢀ80
ꢀ80
ꢀ80
ꢀ80
ꢀ80
ꢀ78
ꢀ72
ꢀ78
ꢀ80
ꢀ72
ꢀ72
ꢀ78
76:24
88:12
99:1
94:6
68:32
92:8
100:0
100:0
92:e8
87:13
d:df
d:df
>99:1
>99:1
99:1
>99:1
d:df
94:6
87:13
96:4
54
92
>99
92
85
>99
>99
93
>99
89
27
49
81
74
44
93
90
81
82
58
0f
2
3
H
5-Me
H
H
Me
H
1
1
b
c
4
5
6
7
8
9
10
11
12
4-Me
4-Me
3-Me
5-Cl
5-CF3
5-NO2
5-Ph
5-(4-FC6H5)
5-SPh
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
1
1
1
1
1
1
1
1
1
d
e
f
g
h
i
j
k
l
99
99
0f
>99
>99
w95
>99
>99
>99
>99
97
>99
>99
>99
>99
>99
>99
>99
>99
96
88
90
58g
75
0f
74
67
73
87
79
0f
82
90
82
83
81
84
79
76
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
3-OBn
H
5-Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1
1
1
1
1
1
1
1
1
2
2
2
3
1
1
m
n
o
p
q
r
s
t
u
v
x
Me
Me
Cl
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
95:5
5-Cl
5-NO2
5-Ph
5-SPh
H
5-Ph
5-SPh
H
88:12
d:df
>99:1
>99:1
>99:1
>99:1
>99:1
94:6
y
z
aa
ab
5-D
5-TMS
95:5
95:5
>99
>99
H
O
28
5-(
H
H
1
6a
6a
ac
ꢀ80
d:d
>99
>99
0h
B
)
O
29
5-Ph-C^C
H
H
1
ad
ꢀ74
>99:1
84
a
Estimated using 1H NMR spectroscopy of crude reaction mixture.
Isolated yields.
1.5 equiv was used.
2.0 equiv was used and stirred 1 h.
Product 7f was isolated as trans (7f (trans))/cis (7f (cis)) mixture of isomers in 6:4 ratio.
The complex mixture was obtained.
b
c
d
e
f
g
h
Product can not be obtained in pure state.
Decomposition of substrate.
comprised the synthesis of the intermediate
b
,
g
-unsaturated
d
-
4. Experimental section
4.1. General
lactams, in which the substituent originated from the starting N-
alkenylpyridin-2(1H)-ones, which in turn were obtained by che-
moselective N-alkenylation. Due to great basic potential of mag-
nesate complexes, novel spiro-fused compounds were obtained
from N-alkenylpyridin-2(1H)-ones only in two steps. The relatively
high degree of functionalization and potentially possible further
derivatization of RCM products28 indicate high prospect of 3,6,9,9a-
tetrahydroquinolizin-4-ones and related bicyclic compounds in
scaffold synthesis. Design and synthesis of functionalized quinoli-
zidines on the basis of the above procedure, aimed at obtaining
derivatives showing anticancer activity are currently under way.
Melting points were determined on a Boetius hot stage appa-
ratus. 1H, 13C NMR spectroscopic measurements were performed
on a Bruker DPX 400 spectrometer equipped with a 5 mm 1H/
BB-inverse probehead, operating at 400.1 and 100.6 MHz. TMS was
used as internal reference. For resolving of multiplets in 1H NMR
spectra ACD/SpecManager program (version 12.01) was used. For
detailed peak assignments, 2D spectra were acquired using stan-
dard Bruker software (COSY, HETCOR). In the 1He1H NOESY

ꢀ
J.G. Sosnicki et al. / Tetrahedron 70 (2014) 8624e8635
8629
Table 3
RCM of 7
H3C
CH
H3C
3 N
N
N
N
Cy
RCM
Conditions: Table 3
R1
Cy
Cy
R1
H3C
Cl
CH3
CH3
P
R3
H3C
CH3
Cl
cat.
Cl
Ru
Ru
Ru
N
O
N
O
cat.
Cl
Ph
Cy
Cl
Cl
Ph
( )n = 1-3
R2
( )n = 1-3
R2
R3
P
O
P
Cy
H3C
Cy
Cy
Cy
CH3
Cy
7
9
S-G
GI
GII
Entry
1
9
a
9
Cat.a (mol %) Temp (ꢁC) Time (min.) Yieldb (%) Entry
9
9
Cat.a (mol %) Temp (ꢁC) Time (min.) Yieldb (%)
Ph
GI (6)
22
70
60
20
83
89
14
n
GII (2.0)
70
120
0d
N
O
GII (1.0)
N
O
N
O
2
3
b
c
GII (0.7)
70
15
87
15
16
o
p
GII (1.1)
GII (1.4)
70
70
20
20
79
93
N
O
Cl
GI (8)
GII (0.9)
22
70
60
20
75
83
N
O
N
N
O
O
4
5
d
e
GI (6)
GII (1.1)
22
70
60
20
75
85
17
18
q
r
GII (3.5)
GII (7)
SeG (3.5)
75
70
75
60
120
1200
0e
N
O
O
Tracesf
0e
Cl
GII (0.7)
70
20
80
GII (10)
SeG (1.7)
70
75
120
120
16
80
N
N
O
Ph
Cl
6
7
f
GI (7)
GII (1.0)
22
70
45
20
82
83
19
20
s
t
SeG (1.6)
SeG (1.9)
75
75
140
80
91
66
N
O
N
N
O
O
Ph
g
GI (4)
GII (1.2)
22
70
60
20
75
80
N
O
Ph
S
D
N
O
8
9
h
i
GII (1.4)
GI (7)c
70
70
30
20
82
73
21
22
u
v
SeG (1.7)
75
100
76
N
O
Ph
Me3Si
GI (7)
GII (1.5)
22
70
45
30
73
82
N
O
N
O
Cl
10
j
GII (2.5)
70
20
95
23
w
GII (1.0)
70
30
83
N
O
N
O
S
11
12
k
l
GII (2.5)
GII (1.9)
70
70
15
20
78
87
24
25
x
y
GII (1.1)
GII (1.0)
70
70
30
45
91
N
O
N
O
F
75g
N
O
N
O
(continued on next page)

ꢀ
J.G. Sosnicki et al. / Tetrahedron 70 (2014) 8624e8635
8630
Table 3 (continued )
Entry
9
9
Cat.a (mol %) Temp (ꢁC) Time (min.) Yieldb (%) Entry
9
9
Cat.a (mol %) Temp (ꢁC) Time (min.) Yieldb (%)
S
13
m
GII (4.0)
GII (2.0)
70
70
20
20
83
79
N
O
a
For GI, CH2Cl2 at 22 ꢁC, for GII, toluene at 70 ꢁC and for SeG, toluene at 75 ꢁC were used unless stated otherwise.
Isolated yields.
b
c
d
e
f
Toluene was used as solvent.
Not detected by GCeMS nor 1H NMR. Substrate was recovered in 70%.
Substrate was unchanged. Not detected by GCeMS.
Detected by GCeMS.
g
Product contained 10 mol % of isomer trans.
4.2. Compounds and reagents
Amongst NH pyridin-2(1H)-one used 3-benzyloxypyridin-
2(1H)-one was obtained from 3-hydroxypyridin-2(1H)-one,29 while
pyridin-2(1H)-one their 3-methyl-, 4-methyl-, 5-methyl-, 5-chloro-,
5-trifluoro- and 5-nitrosubstituted derivatives were supplied from
commercial sources. AllMgCl (2.0 M in THF), metallMgCl (0.5 M in
THF), n-BuLi (2.5 M in hexane) and ruthenium catalysts as well as 3-
bromopropene, 4-bromobut-1-ene, 5-bromopent-1-ene, 3-bromo-
2-methyl-propene, 2,3-dichloropropene were purchased from
Aldrich. (1-Bromo-methylvinyl)benzene30 and but-3-en-1-yl-,
pent-4-en-1-sulfonates,31 3,3-dimethylallylmagnesium bromide9f
and 5-deuterium-, 5-chloro-, 5-phenylsulfanyl-, 5-trimethy
lsilanyl- and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
substituted 2-methoxypyridines11 were prepared according to
procedure described earlier.
MgCl
+ 2n-BuLi
5c
1.
Mgn-Bu2Li
+ LiCl
6c
+
+
N
O
THF, -72oC, 15 min.
N
O
N
O
N
O
2. NH4Cl aq.
3a
11b
11a 1 : 1
10a
63%
15%
GI (9 mol%) PhMe, 70oC, 30 min.
1. 6c
THF, -72oC,
15 min.
2. NH4Cl aq.
N
O
+
12a
+
N
O
N
O
N
O
3c
13
90%
12b
12a 1 : 1
60%
Scheme 3. An attempt to apply magnesate 6c in the synthesis of quinolizidin-4-ones.
4.3. General procedure for N-chemoselective alkenylation of
2
To a cooled (w0 ꢁC) and stirred solution of NH pyridin-2(1H)-
one 2 (7.8 mmol) in anhydrous THF (50 mL) in a 100 mL Schlenk
flask equipped with septum and argon balloon, n-BuLi (7.8 mmol,
3.2 mL, 2.5 M in hexane) was added via syringe over a few minutes
and the mixture was stirred for 5 min.y To a cooled (ꢀ2 to 0 ꢁC)
solution alkyl halides or sulfonates [9.4e15.6 mmol (see Table 1)]
were added via syringe. The resulting solution was stirred for
10 min. Subsequently, in most reactions (see Table 1) the septum
was removed and the flask was equipped with condenser crowned
with argon balloon and placed in oil bath at 70ꢂ1 ꢁC. The mixture
was continuously stirred for appropriate time (Table 1). After
cooling to rt and addition of aqueous saturated NH4Cl (15 mL), the
aqueous layer was extracted with ethyl acetate (3ꢃ80 mL) and
combined organic layersz were dried over MgSO4. Filtration, con-
centration in vacuo and purification by distillation or flash column
chromatography (see Table 1) yielded 3.
1. 6a -80oC
THF 30 min
PhMe 70oC
(30 min.)
then AllBr (3 eq.)
-80oC to rt
R
R
R
GII (4.5 mol%)
N
O
N
O
N
O
( )n = 1-2
( )n = 1-2
( )n = 1-2
15a (R=Ph, n=1) 62%
3h
3v
3w
14a (R=Ph, n=1) 84%
15b (R=Ph, n=2) 88%
15c (R=SPh, n=1) 88%
14b (R=Ph, n=2) 79%
14c (R=SPh, n=1) 90%
Scheme 4. Two-step synthesis of spiro-fused compounds 15.
experiments a mixing time of 0.75 s was used. The abbreviation
‘dm’ in description of 1H NMR spectra means doublet of multiplet. It
describes more complex couplings including one large coupling
constant. Gas chromatographyemass spectrometry (GCeMS)
measurements were carried out on a HewlettePackard instrument
model HP 6890 equipped with a mass detector HP 5973. Infrared
spectra were taken with a Specord M80 or ALPHA FT-IR in-
struments. HRMS analyses (ESIþ) were performed on a Waters LCT
premier XE (TOF) using acetonitrile as solvent. Low temperature
was generated by Julabo FT902 immersion cooler. Reactions in
tetrahydrofuran (THF) solution were performed under argon in
flame-dried flasks and liquid components were added by syringe.
THF, toluene were purified over sodium, CH2Cl2 over calcium hy-
dride, both in argon atmosphere according to a standard procedure
prior to use. Products were purified by flash column chromatog-
raphy on silica gel (0.04e0.063 mm, Merck).
4.4. General procedure for addition of lithium allyl(di-n-bu-
tyl)magnesates to pyridin-2(1H)-ones. Synthesis of 7, 8, 10, 12
and 14
On stirring, to a cooled (0 ꢁC) solution of allylMgCl (4.9 mmol,
2.45 mL, 2.0 M in THF) in dry THF (10 mL) in a Schlenk flask, n-BuLi
(9.8 mmol, 3.9 mL, 2.5 M in hexane) was added via syringe over
3 min under argon. A pale yellow solution was stirred for 5 min and
cooled to ꢀ75ꢂ5 ꢁC. The suspension containing lithium allyl(di-n-
y
n-BuLi was added until the solutions become permanently pale yellow or beige.
For sulfonates, the combined organic extracts were additionally washed with
z
saturated aqueous NaHCO3.

ꢀ
J.G. Sosnicki et al. / Tetrahedron 70 (2014) 8624e8635
8631
butyl)magnesate was next transferred via syringe to a cooled
(ꢀ75ꢂ5 ꢁC) solution of N-alkenylpyridin-2(1H)-one 3 (4.25 mmol)
in THF (40 mL). The resulting brown-orange solution was stirred for
25 min at ꢀ75ꢂ5 ꢁC. After quenching with aqueous saturated NH4Clx
(10 mL) and warming up to rt, the aqueous layer was extracted with
ethyl acetate (3ꢃ75 mL) and the combined organic layers were dried
over MgSO4. Filtration, concentration in vacuo and purification by
flash column chromatography yielded target product.
(37), 53 (24), 39 (27); IR (film):
n
¼3032, 2908, 2884, 2844, 1664,
1638, 1466, 1250, 1070, 808, 662 cmꢀ1. HRMS (ESI-TOF): m/z
[MþþH] calculated for C10H14NO, 164.1075; found 164.1088.
4.5.4. (ꢂ)-2-Methyl-3,6,9,9a-tetrahydroquinolizin-4-one
(9d). Colourless oil (138 mg, 85% yield). The crude product was
purified by column chromatography (SiO2, diethyl ether); 1H NMR
(400 MHz, CDCl3, 23 ꢁC):
d
¼1.73 (s, 3H, CH3), 2.01e2.13 (m, 1H,
CHH-9), 2.25 (dm, J¼ca. 17.1 Hz, 1H, CHH-9), 2.83e2.99 (m, 2H, CH2-
3), 3.49 (d, J¼18.8 Hz, 1H, NCHH), 4.02 (br dm, J¼ca. 6.4 Hz, 1H, CH-
9a), 4.87 (d, J¼18.8 Hz, 1H, NCHH), 5.42 (br s, 1H, ]CH-1),
5.68e5.75 (m, 1H, ]CH), 5.77e5.83 (m, 1H, ]CH); 13C NMR
4.5. General procedure for RCM. Synthesis of compounds 9,
13, 15
(100.6 MHz, CDCl3):
d
¼21.8, 33.7, 36.3, 41.9, 54.1, 119.3, 124.2, 124.2,
Detailed conditions for RCM synthesis are collected in Table 3. To
a solution of diallyllactam 7 or tetraalkenyllactam 14 (1.0 mmol) in
dry, degassed solvent (8 mL), adequate ruthenium catalyst GI
(4e5 mol %, w33e66 mg) or GII (0.7e4 mol %, w6e34 mg) or SeG
(1.6e1.9 mol %, w9e11 mg) (see Table 3) was added and the re-
action mixture was stirred under slowly bubbled stream of argon at
temperature and time indicated in Table 3. Then the solvent was
evaporated at reduced pressure and the residue was left standing
for 48 h followed by purification on column chromatography.
124.2, 129.1, 166.8; GCeMS (70 eV): 163 (100) [Mþ], 162 (79), 148
(67), 134 (21), 120 (22), 110 (25), 94 (18), 81 (39), 80 (89), 54 (49), 53
(34), 41 (22), 39 (36); IR (film):
n
¼3036, 2892, 2840, 1640, 1448,
1408, 1356, 1298, 1248, 816 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH]
calcd for C10H14NO, 164.1075; found 164.1070.
4.5.5. (ꢂ)-2,8-Dimethyl-3,6,9,9a-tetrahydroquinolizin-4-one
(9e). Colourless oil (142 mg, 80% yield). The crude product was pu-
rified by column chromatography (SiO2, n-hexane/ethyl acetate, 1:1
then 4:6); 1H NMR (400 MHz, CDCl3, 23 ꢁC):
d¼1.70 (s, 3H, CH3), 1.73
4.5.1. (ꢂ)-3,6,9,9a-Tetrahydroquinolizin-4-one (9a). Colourless oil
(133 mg, 89% yield). The crude product was purified by column
chromatography (SiO2, diethyl ether); 1H NMR (400 MHz, CDCl3,
(s, 3H, CH3), 2.01e2.10 (m, 2H, CH2-9), 2.80e2.95 (m, 2H, CH2-3), 3.42
(br d, J¼18.3 Hz, 1H, NCHH), 3.95e4.05 (m, 1H, CH-9a), 4.82 (dm,
J¼18.3 Hz, 1H, NCHH), 5.38e5.43 (m, 2H, ]CH-1, ]CH-7); 13C NMR
23 ꢁC):
d
¼2.04e2.20 (m, 1H, CHH-9), 2.28 (1H, dquint, J¼16.9,
(100.6 MHz, CDCl3):
d
¼21.9, 22.9, 36.5, 38.4, 41.6, 54.0, 118.0, 119.4,
2.5 Hz, CHH-9), 3.00 (br s, 2H, CH2-3), 3.49 (br d, J¼ca. 18.6 Hz, 1H,
NCHH), 4.04e4.10 (m, 1H, CH-9a), 4.90 (dm, J¼ca. 18.6 Hz, 1H,
NCHH), 5.66e5.85 (m, 4H, 4ꢃ]CH); 13C NMR (100.6 MHz, CDCl3):
129.2,131.8,166.4; GCeMS (70 eV): 177 (100) [Mþ],176 (38),162 (49),
148 (12),134 (18),110 (51), 94 (12), 80 (17), 68 (18), 67 (22), 53 (11); IR
(film):
n
¼2964, 2912, 1642, 1448, 1408, 1298, 1112, 820 cmꢀ1. HRMS
d
¼31.8, 33.5, 41.8, 54.2, 121.2, 124.1, 124.4, 125.0, 166.4; GCeMS
(ESI-TOF): m/z [MþþH] calculated for C11H16NO, 178.1232; 178.1231.
(70 eV): 149 (100) [Mþ], 148 (67), 134 (8), 120 (27), 106 (12), 96 (13),
80 (18), 67 (32), 54 (30), 39 (24); IR (film):
n
¼3036, 2896, 2844,
4.5.6. (ꢂ)-trans-3-Methyl-3,6,9,9a-tetrahydroquinolizin-4-one
(9f). Colourless oil (135 mg, 83% yield). The crude product was
purified by column chromatography (SiO2, diethyl ether/n-hexane
1662, 1632, 1462, 1448, 1408, 1356, 1328, 1252, 1168, 760, 722,
662 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH] calcd for C9H12NO,
150.0919; found 150.0926.
7:3); 1H NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼1H NMR (400.1 MHz,
CDCl3):
d
¼1.34 (d, J¼7.5 Hz, 3H, 3-CH3), 2.04e2.16 (m, 1H, CHH-9),
4.5.2. (ꢂ)-8-Methyl-3,6,9,9a-tetrahydroquinolizin-4-one
(9b). Colourless oil (142 mg, 87% yield). The crude product was
purified by column chromatography (ethyl acetate); 1H NMR
2.26 (dm, J¼16.7 Hz,1H, CHH-9), 2.96e3.07 (m,1H, CH-3), 3.49 (dm,
J¼18.8 Hz, 1H, NCHH), 4.02e4.14 (m, 1H, CH-9a), 4.90 (dm,
J¼18.8 Hz, 1H, NCHH), 5.65e5.85 (m, 4H, 4ꢃ]CH); 13C NMR
(400 MHz, CDCl3, 23 ꢁC):
d
¼1.70e1.73 (m, 3H, 8-CH3), 2.10 (dm,
(100.6 MHz, CDCl3):
d
¼19.1, 33.4, 35.5, 41.9, 54.0, 123.7, 124.0, 124.6,
J¼7.6 Hz, 2H, CH2-9), 2.97e3.01 (m, 2H, CH2-3), 3.43 (dm, J¼18.3 Hz,
1H, NCHH), 4.02e4.11 (m, 1H, CH-9a), 4.85 (dm, J¼18.3 Hz, 1H,
NCHH), 5.38e5.43 (m, 1H, ]CH-7), 5.67e5.78 (m, 2H, ]CH-1, ]
127.6, 170.0; GCeMS (70 eV): 163 (43) [Mþ], 148 (100), 134 (7), 120
(8), 80 (28), 54 (19), 53 (18), 39 (15); IR (film):
n
¼3016, 2928, 2840,
1664,1642, 1464, 1444, 1356, 1324, 1248 cmꢀ1. HRMS (ESI-TOF): m/z
[MþþH] calcd for C10H14NO, 164.1075; found 164.1073.
CH-2); 13C NMR (100.6 MHz, CDCl3):
d
¼22.9, 31.9, 38.1, 41.6, 54.1,
118.1, 121.2, 125.0, 131.7, 166.2; GCeMS (70 eV): 163 (100) [Mþ], 162
(31), 148 (22), 134 (15), 120 (22), 96 (31), 80 (11), 68 (25), 67 (32), 53
4.5.7. (ꢂ)-cis-3-Methyl-3,6,9,9a-tetrahydroquinolizin-4-one
(9g). Colourless oil (130 mg, 80% yield). The crude product was
purified by column chromatography (SiO2, diethyl ether); 1H NMR
(11), 41 (11), 39 (11); IR (film):
n
¼3072, 2952, 1642, 1446, 1408,
1356, 1328, 1248, 1108, 788, 732 cmꢀ1. HRMS (ESI-TOF): m/z
[MþþH] calculated for C10H14NO, 164.1075; found 164.1077.
(400 MHz, CDCl3, 23 ꢁC):
d
¼1.32 (d, J¼7.4 Hz, 3H, 3-CH3), 2.02e2.14
(m, 1H, CHH-9), 2.29 (dm, J¼16.5 Hz, 1H, CHH-9), 2.98 (ddq, J¼11.1,
7.3, 3.7 Hz, 1H, CH-3), 3.49 (dm, J¼18.7 Hz, 1H, NCHH), 4.03 (dq,
J¼11.3, 3.4 Hz, 1H, CH-9a), 4.86 (dm, J¼18.7 Hz, 1H, NCHH),
4.5.3. (ꢂ)-1-Methyl-3,6,9,9a-tetrahydroquinolizin-4-one
(9c). Colourless oil (135 mg, 83% yield). The crude product was
purified by column chromatography (SiO2, diethyl ether); 1H NMR
5.65e5.84 (m, 4H, 4ꢃ]CH); 13C NMR (100.6 MHz, CDCl3):
¼20.6,
d
(400 MHz, CDCl3, 23 ꢁC):
d
¼1.76 (d, J¼1.7 Hz, 3H, CH3), 2.00e2.11
34.1, 36.3, 42.1, 54.3, 123.7, 124.1, 124.6, 127.8, 170.3; GCeMS
(m, 1H, CHH-9), 2.47 (dm, J¼ca. 16.9 Hz, 1H, CHH-9), 2.97 (d,
J¼1.7 Hz, 2H, CH2-3), 3.44 (dm, J¼18.5 Hz, 1H, NCHH), 3.90 (dq,
J¼11.3, 3.6 Hz, 1H, CH-9a), 4.98 (dm, J¼18.5 Hz, 1H, NCHH), 5.44 (br
s, 1H, ]CH-2), 5.70e5.76 (m, 1H, ]CH), 5.79e5.86 (m, 1H, ]CH);
(70 eV): 163 (34) [Mþ], 148 (100), 134 (5), 120 (8), 105 (7), 91 (7), 80
(30), 54 (23), 53 (19), 41 (15), 39 (22); IR (film):
n
¼3040, 2964, 2928,
2892, 2840, 1662, 1638, 1464, 1446, 1356, 1328, 1250, 766, 722,
660 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH] calcd for C10H14NO,
164.1075; found 164.1070.
13C NMR (100.6 MHz, CDCl3):
d
¼19.7, 31.7, 32.1, 41.9, 57.9, 116.9,
124.4, 124.6, 131.1, 166.5; GCeMS (70 eV): 163 (100) [Mþ], 162 (70),
148 (30), 134 (13), 120 (16), 110 (12), 94 (12), 81 (27), 80 (67), 54
4.5.8. (ꢂ)-1-(2 H)-3,6,9,9a-Tetrahydroquinolizin-4-one
(9h). Colourless oil (123 mg, 82% yield). The crude product was
purified by column chromatography (SiO2, n-hexane/ethyl acetate,
x
In the synthesis of 14aec, allylbromide (1.11 mL, 12.8 mmol) instead of NH4Cl
1
6:4 then 1:1); H NMR (400 MHz, CDCl3, 23 ꢁC):
d¼2.06e2.17 (m,
was added and the solution was warmed to 0 ꢁC over 30 min and stirred at 0 ꢁC for
over 30 min then at rt 1 h.
1H, CHH-3), 2.28 (dm, J¼ca. 17.1 Hz, 1H, CHH-3), 2.97e3.02 (m, 2H,

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J.G. Sosnicki et al. / Tetrahedron 70 (2014) 8624e8635
8632
CH2-9), 3.49 (dm, J¼18.8 Hz, 1H, NCHH), 4.04e4.12 (m, 1H, CH-9a),
4.90 (dm, J¼18.8 Hz, 1H, NCHH), 5.69e5.85 (m, 3H, ]CH-2, ]CH-7,
32.7, 42.1, 56.5, 115.6 (d, J¼22.0 Hz), 119.3, 124.6, 124.6, 128.0 (d,
J¼7.3 Hz), 134.3 (d, J¼2.9 Hz), 135.4, 162.4 (d, J¼247.4 Hz), 167.8;
GCeMS (70 eV): 243 (100) [Mþ], 242 (50), 161 (59), 147 (14), 134
(27), 133 (42); IR (KBr pellet): 3088, 2888, 2848, 1668, 1634, 1510,
1468, 1448, 1400, 1328, 1300, 1250, 1220, 1164, 1144, 1104, 1056,
964, 850, 820, 812, 756, 672 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH]
calculated for C15H15FNO, 244.1138; found 244.1138.
]CH-8); 13C NMR (100.6 MHz, CDCl3):
d
¼31.8, 33.5, 41.8, 54.1, 121.1,
124.1, 124.1, 124.5, 124.7 (t, JCD¼24.9 Hz, C-1), 166.3; GCeMS
(70 eV): 150 (100) [Mþ], 149 (65), 121 (22), 107 (9), 97 (11), 81 (12),
68 (26), 54 (27), 39 (11). IR (film):
n
¼3036, 2968, 2892, 2840, 1632
br, 1462, 1448, 1408, 1324, 1302, 1252, 1104, 1070, 756, 700,
664 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH] calcd for C9H11DNO,
151.0981; found 151.0997.
4.5.13. (ꢂ)-1-Phenylsulfanyl-3,6,9,9a-tetrahydroquinolizin-4-one
(9m). Colourless oil (214 mg, 83% yield). The crude product was
purified by column chromatography (SiO2, n-hexane/ethyl acetate,
4.5.9. (ꢂ)-1-Trimethylsilanyl-3,6,9,9a-tetrahydroquinolizin-4-one
(9i). Colourless oil (161 mg, 73% yield). The crude product was
purified by column chromatography (SiO2, n-hexane/ethyl acetate,
1:1); 1H NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼2.08e2.19 (m, 1H, CHH-
9), 2.72 (dm, J¼ca. 17.1 Hz, 1H, CHH-9), 3.04e3.20 (m, 2H, CH2-3),
3.38 (dm, J¼18.3 Hz,1H, NCHH), 3.96 (dq, J¼11.2, 3.7 Hz, 1H, CH-9a),
4.98 (dm, J¼18.3 Hz, 1H, NCHH), 5.65 (dm, J¼10.0 Hz, 1H, ]CH),
5.74e5.81 (m, 1H, ]CH), 6.04 (ddd, J¼ca. 4.1, 3.2, 0.7 Hz, 1H, ]CH-
1:1); 1H NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼0.15 (s, 9H, Me3Si),
2.00e2.10 (m, 1H, CHH-9), 2.34 (dm, J¼ca. 17.1 Hz, 1H, CHH-9),
2.90e3.07 (m, 2H, CH2-3), 3.42 (dm, J¼ca. 18.3 Hz, 1H, NCHH), 4.16
(dq, J¼11.5, 3.4 Hz, 1H, CH-9a), 5.06 (dm, J¼18.3 Hz, 1H, NCHH),
5.69e5.76 (m, 1H, ]CH-7), 5.76e5.83 (m, 1H, ]CH-8), 6.02 (ddd,
2), 7.24e7.39 (m, 5H, C6H5); 13C NMR (100.6 MHz, CDCl3):
d
¼32.8,
33.1, 42.1, 56.8, 124.4, 124.6, 127.4, 127.5, 129.4, 130.4, 130.7, 133.1,
165.2; GCeMS (70 eV): 257 (100) [Mþ], 224 (9), 203 (13), 174 (9),
J¼4.2, 3.2,1.0 Hz,1H, ]CH-2); 13C NMR (100.6 MHz, CDCl3):
¼ꢀ1.1,
d
161 (14), 148 (21), 104 (14), 71 (10); IR (film):
n
¼3040, 2896, 2844,
32.9, 34.1, 41.7, 57.6, 124.8, 125.0, 131.1, 137.2, 166.1; GCeMS (70 eV):
1664, 1642, 1476, 1440, 1248, 1110, 746, 692, 692 cmꢀ1. HRMS (ESI-
TOF): m/z [MþþH] calculated for C15H16NOS, 258.0953; found
258.0945.
221 (79) [Mþ], 220 (100), 206 (12), 152 (14), 148 (23), 124 (23), 100
(34), 73 (28); IR (film):
n
¼3036, 2960, 1666, 1644, 1468, 1444, 1404,
1296, 1254, 1116, 840, 760 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH]
calculated for C12H20NOSi, 222.1314; found 222.1319.
4.5.14. (ꢂ)-7-Methyl-3,6,9,9a-tetrahydroquinolizin-4-one
(9o). Colourless oil (129 mg, 79% yield). The crude product was
purified by column chromatography (SiO2, n-hexane/ethyl acetate,
4.5.10. (ꢂ)-1-Chloro-3,6,9,9a-tetrahydroquinolizin-4-one
(9j). Colourless oil (175 mg, 95% yield). The crude product was
purified by column chromatography (SiO2, n-hexane/ethyl acetate,
6:4 then 1:1); 1H NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼1.71 (t, J¼1.2 Hz,
3H, 7-CH3), 2.00e2.12 (m, 1H, CHH-9), 2.18e2.28 (m, 1H, CHH-9),
3.00 (t, J¼2.3 Hz, 2H, CH2-3), 3.38 (d, J¼18.8 Hz, 1H, NCHH),
3.95e4.05 (m, 1H, CH-9a), 4.76 (d, J¼18.8 Hz, 1H, NCHH), 5.47e5.52
(m, 1H, ]CH-8), 5.67e5.77 (m, 2H, ]CH-1, ]CH-2); 13C NMR
1
1:1 then 4:6); H NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼2.10e2.22 (m,
1H, CHH-9), 2.73 (dm, J¼17.1 Hz, 1H, CHH-9), 3.08 (t, J¼3.9 Hz, 2H,
CH2-3), 3.47 (dm, J¼18.6 Hz, 1H, NCHH), 4.08 (dq, J¼11.2, 3.9 Hz, 1H,
CH-9a), 4.96 (dm, J¼18.6 Hz, 1H, NCHH), 5.73 (dm, J¼10.6 Hz, 1H, ]
CH-8), 5.81e5.85 (m, 1H, ]CH-7), 5.86 (td, J¼3.7, 0.7 Hz, 1H, ]CH-
(100.6 MHz, CDCl3):
d
¼20.5, 31.9, 33.4, 45.3, 54.0, 118.5, 121.1, 125.0,
131.6, 166.3; GCeMS (70 eV): 163 (100) [Mþ], 162 (39), 148 (13), 134
2); 13C NMR (100.6 MHz, CDCl3):
d
¼31.9, 32.4, 42.2, 57.9, 119.6,
(12), 120 (11), 96 (40), 68 (31), 67 (35), 53 (11), 41 (13), 39 (16); IR
123.9, 124.3, 128.0, 164.5; GCeMS (70 eV): 185 (31) [Mþþ2], 184
(thin film):
n
¼3040, 2972, 2912, 2836, 1676, 1646, 1460, 1408, 1334,
(Mþ1, 21), 183 (Mþ, 100), 148 (14), 120 (15), 105 (14), 101 (18), 54
1248, 1174, 1152, 1072, 956, 832, 798, 732, 694 cmꢀ1; HRMS (ESI-
TOF): m/z [MþþH] calcd for C10H14NO, 164.1075; found 164.1073.
(41), 39 (16); IR (film):
n
¼3040, 2892, 2852, 1666, 1644, 1464, 1420,
1408, 1320, 1248, 1108, 1020, 968, 932, 884, 820, 720 cmꢀ1. HRMS
(ESI-TOF): m/z [MþþH] calculated for C9H11ClNO, 184.0529; found
184.0534.
4.5.15. (ꢂ)-1-Chloro-7-methyl-3,6,9,9a-tetrahydroquinolizin-4-one
(9p). Colourless oil (184 mg, 93% yield). The crude product was
purified by column chromatography (SiO2, n-hexane/ethyl acetate
1:1); 1H NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼1.70e1.73 (m, 3H, 7-CH3),
4.5.11. (ꢂ)-1-Phenyl-3,6,9,9a-tetrahydroquinolizin-4-one (9k). Pale
green oil (175 mg, 78% yield). The crude product was purified by
column chromatography (SiO2, n-hexane/ethyl acetate, 1:1 then
2.05e2.17 (m, 1H, CHH-9), 2.62e2.72 (m, 1H, CHH-9), 3.08 (td,
J¼3.9, 0.8 Hz, 2H, CH2-3), 3.36 (d, J¼18.1 Hz, 1H, NCHH), 4.01 (dq,
J¼11.3, 3.9 Hz, 1H, CH-9a), 4.81 (dsxt, J¼18.1, 1.0 Hz, 1H, NCHH), 5.53
(dquint, J¼6.1, 1.7 Hz, 1H, ]CH-8), 5.85 (td, J¼3.9, 0.9 Hz, 1H, ]CH-
4:6); 1H NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼1.99e2.10 (m, 1H, CHH-9),
2.18e2.27 (m, 1H, CHH-9), 3.17 (q, J¼3.6 Hz, 2H, CH2-3), 3.56 (dm,
J¼ca. 18.5 Hz, 1H, NCHH), 4.61 (dq, J¼11.2, 3.6 Hz, 1H, CH-9a), 5.08
(dm, J¼ca. 18.5 Hz, 1H, NCHH), 5.70e5.78 (m, 2H, ]CH-7, ]CH-8),
5.89 (t, J¼3.6 Hz, 1H, ]CH-2), 7.29e7.42 (m, 5H, C6H5); 13C NMR
2); 13C NMR (100.6 MHz, CDCl3):
d
¼20.3, 31.8, 32.5, 45.7, 57.8, 118.2,
119.4, 128.1, 131.5, 164.5; GCeMS (70 eV): 199 (34) [Mþ2], 198
(18) [Mþ1], 197 [Mþ], 182 (12), 130 (21), 68 (61), 67 (44), 53 (14), 39
(20); IR (thin film):
n
¼2972, 2932, 2840, 1682, 1644, 1460, 1408,
(100.6 MHz, CDCl3):
d
¼32.1, 32.7, 42.1, 56.4, 119.1, 124.6, 124.7, 126.3,
127.9, 128.7, 136.3,138.2,166.0; GCeMS (70 eV): 225 (100) [Mþ], 224
(54), 196 (7), 182 (7), 171 (9), 156 (8), 143 (53), 134 (14), 129 (19), 128
(20), 115 (57), 102 (8), 91 (10), 77 (10), 63 (8), 51 (10), 39 (13); IR
1328, 1312, 1300, 1246, 1202, 1104, 1022, 984, 956, 894, 836, 816,
662, 638 cmꢀ1
;
HRMS (ESI-TOF): m/z [MþþH] calculated
C10H13ClNO, 198.0686; found 198.0676.
(film):
n
¼3036, 2892, 2848, 1660, 1640, 1472, 1444, 1406, 1332, 1302,
1252,1208,1104, 830, 764, 732, 700, 664 cmꢀ1. HRMS (ESI-TOF): m/z
4.5.16. (ꢂ)-7-Phenyl-3,6,9,9a-tetrahydroquinolizin-4-one (9r). Pale
green oil (180 mg, 80% yield). The crude product was purified by
column chromatography (SiO2, n-hexane/ethyl acetate, 1:1); 1H
[MþþH] calculated for C15H16NO, 226.1232; found 226.1230.
NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼2.24e2.34 (m, 1H, CHH-9),
4.5.12. (ꢂ)-1-(4-Fluorophenyl)-3,6,9,9a-tetrahydroquinolizin-4-one
(9l). White solid (211 mg, 87% yield). Mp 124e126 ꢁC (n-hexane).
The crude product was purified by column chromatography (SiO2,
2.44e2.52 (dm, 1H, CHH-9), 3.00e3.09 (m, 2H, CH2-3), 3.79 (dm,
J¼17.8 Hz, 1H, NCHH), 4.09e4.17 (m, 1H, CH-9a), 5.42 (dt, J¼17.8,
1.4 Hz, 1H, NCHH), 5.74e5.82 (m, 2H, ]CH-1, ]CH-2), 6.17 (dq,
J¼6.1, 2.0 Hz, 1H, ]CH-8), 7.26e7.31 (m, 1H, C6H5), 7.32e7.37 (m,
2H, C6H5), 7.39e7.44 (m, 2H, C6H5); 13C NMR (100.6 MHz, CDCl3):
1
ethyl acetate); H NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼1.98e2.09 (m,
1H, CHH-9a), 2.15e2.24 (m, 1H, CHH-9a), 3.08e3.24 (m, 2H, CH2-3),
3.55 (dm, J¼ca. 19 Hz, 1H, NCHH), 4.56 (dq, J¼11.2, 3.8 Hz, 1H, CH-
9a), 5.09 (dm, J¼ca. 19 Hz, 1H, NCHH), 5.72e5.77 (m, 2H, ]CH-7, ]
CH-7), 5.85 (ddd, J¼4.0, 3.2, 0.8 Hz, 1H, ]CH-2), 7.02e7.09 (m, 2H,
d
¼31.9, 34.0, 43.2, 53.9, 120.9, 121.4, 124.8, 125.2, 127.7, 128.5, 134.7,
138.5, 166.4; GCeMS (70 eV): 225 (83) [Mþ], 130 (100), 129 (96), 115
(49), 102 (10), 91 (14), 77 (12), 51 (15), 39 (12); IR (film):
¼3044,
ArF), 7.26e7.32 (m, 2H, ArF); 13C NMR (100.6 MHz, CDCl3):
d
¼32.1,
n

ꢀ
J.G. Sosnicki et al. / Tetrahedron 70 (2014) 8624e8635
8633
2888, 2844, 1658, 1638, 1462, 1444, 1328, 1254, 1162, 840, 756,
696 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH] calculated for C15H16NO,
226.1232; found 226.1223.
(16), 44 (22), 39 (26); IR (film):
n
¼3016, 2920, 2908, 1640, 1468,
1432, 1368, 1322, 718 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH] calcd for
C10H14NO, 164.1075; found 164.1069.
4.5.17. (ꢂ)-1-Chloro-7-phenyl-3,6,9,9a-tetrahydroquinolizin-4-one
(9s). Colourless solid (237 mg, 91% yield). Mp 97e99 ꢁC (n-hexane/
ethyl/acetate). The crude product was purified by column chro-
matography (SiO2, n-hexane/ethyl acetate, 6:4 then 1:1 then 4:6);
4.5.21. (ꢂ)-1-Phenyl-6,7,10,10a-tetrahydro-3H-pyrido[1,2-a]azepin-
4-one (9w). Pale yellow solid (198 mg, 83% yield). Mp 101e103 ꢁC
(n-hexane/ethyl acetate). The crude product was purified by col-
umn chromatography (SiO2, diethyl ether); 1H NMR (400 MHz,
1H NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼2.34 (dddd, J¼17.4, 11.3, 6.3,
CDCl3, 23 ꢁC):
d¼2.14e2.26 (m, 1H, CHH-10), 2.31e2.41 (m, 2H,
2.8 Hz, 1H, CHH-9), 2.92 (ddt, J¼17.4, 6.2, 2.5 Hz, 1H, CHH-9), 3.14 (t,
J¼3.8 Hz, 2H, CH2-3), 3.77 (dm, J¼17.8 Hz, 1H, NCHH), 4.15 (dq,
J¼11.3, ca. 3.7 Hz, 1H, CH-9a), 5.46 (dt, J¼17.8, 1.2 Hz, 1H, NCHH),
5.90 (td, J¼3.8, 0.7 Hz, 1H, ]CH-2), 6.17e6.21 (m, 1H, ]CH-8),
CHH-10, CHH-7), 2.45e2.57 (m, 1H, CHH-7), 2.77 (ddd, J¼13.4, 11.2,
2.4 Hz, 1H, NCHH), 3.09e3.25 (m, 2H, CH2-3), 4.40 (dq, J¼10.9,
2.1 Hz, 1H, CH-10a), 4.65 (dt, J¼13.4, 4.0 Hz, 1H, NCHH), 5.69 (ddt,
J¼11.4, 8.1, 2.9 Hz, 1H, ]CH-8), 5.91 (ddt, J¼11.4, 7.8, 3.2 Hz, 1H, ]
CH-9), 6.03 (dd, J¼4.9, 3.1 Hz, 1H, ]CH-2), 7.29e7.42 (m, 5H, C6H5);
7.27e7.43 (m, 5H, C6H5); 13C NMR (100.6 MHz, CDCl3):
43.6, 57.7, 119.6, 120.5, 125.2, 127.9, 127.9, 128.6, 134.6, 138.1, 164.6;
GCeMS (70 eV): 261 (19) [Mþþ2] 260 (10) [Mþþ1] 259 (Mþ, 52),
130 (100), 129 (78), 115 (46), 102 (11), 91 (12), 77 (16), 51 (14), 39
d
¼32.4, 32.6,
13C NMR (100.6 MHz, CDCl3):
d
¼29.1, 33.0, 36.8, 46.7, 61.7, 119.3,
125.9, 127.9, 128.3, 128.8, 131.5, 137.7, 138.4, 167.3; GCeMS (70 eV):
239 (25) [Mþ], 185 (22), 172 (24), 171 (90), 157 (26), 156 (100), 128
(12); IR (KBr pellet):
n
¼3056, 3024, 2956, 2888, 1660, 1640, 1404,
(32), 115 (22); IR (KBr pellet):
n
¼3060, 3008, 2916, 1648, 1492, 1472,
1328,1252,1020, 974, 892, 844, 812, 800, 756, 696, 654 cmꢀ1. HRMS
(ESI-TOF): m/z [MþþH] calcd for C15H15ClNO, 260.0842; found
260.0835.
1428, 1368, 1348, 1292, 1270, 1176, 1056, 960, 932, 836, 760,
696 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH] calcd for C16H18NO,
240.1388; found 240.1383.
4.5.18. (ꢂ)-1,7-Diphenyl-3,6,9,9a-tetrahydroquinolizin-4-one
(9t). Pale yellow oil (198 mg, 66% yield). The crude product was
purified by column chromatography (SiO2, n-hexane/ethyl acetate
4.5.22. (ꢂ)-1-Phenylsulfanyl-6,7,10,10a-tetrahydro-3H-pyrido-[1,2-
a]azepin-4-one (9x). White solid (246 mg, 91% yield). Mp
111e113 ꢁC (n-hexane). The crude product was purified by column
chromatography (SiO2, n-hexane/ethyl acetate, 1:1); 1H NMR
1
1:1 then 4:6); H NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼2.16e2.27 (m,
1H, CHH-9), 2.43 (dquint, J¼17.6, 2.9 Hz, 1H, CHH-9), 3.14e3.30 (m,
2H, CH2-3), 3.86 (br d, J¼17.6 Hz,1H, NCHH), 4.68 (dq, J¼11.5, 3.9 Hz,
1H, CH-9a), 5.60 (dt, J¼17.8, 1.5 Hz, 1H, NCHH), 5.94 (t, J¼3.7 Hz, 1H,
]CH-2), 6.11 (dq, J¼6.1, 1.7 Hz, 1H, ]CH-8), 7.25e7.44 (m, 10H,
(400 MHz, CDCl3, 23 ꢁC):
d
¼2.16e2.28 (m, 2H, CHH-7, CHH-10),
2.37e2.48 (m, 1H, CHH-10), 2.53 (ddd, J¼12.8, 11.3, 2.2 Hz, 1H,
NCHH), 2.83 (ddd, J¼16.6, 7.8, 2.2 Hz, 1H, CHH-7), 3.07 (dt, J¼21.7,
2.7 Hz, 1H, CHH-3), 3.16 (dd, J¼21.7, 5.1 Hz, 1H, CHH-3), 3.73 (dq,
J¼11.1, 1.3 Hz, 1H, CH-10a), 4.51 (dt, J¼12.9, 3.9 Hz, 1H, NCHH),
5.69e5.76 (m, 1H, ]CH-9), 5.80e5.87 (m, 1H, ]CH-8), 6.03 (dd,
J¼5.1, 2.7 Hz, 1H, ]CH-2), 7.24e7.27 (m, 5H, C6H5); 13C NMR
2ꢃC6H5); 13C NMR (100.6 MHz, CDCl3):
¼32.3, 33.2, 43.5, 56.1,
d
119.1, 121.5, 125.2,126.3, 127.8, 128.0, 128.5, 128.8,134.8,136.1, 138.1,
138.4, 166.0; GCeMS (70 eV): 301 (98) [Mþ], 130 (100), 129 (76), 115
(65), 102 (10), 91 (13), 77 (11); IR (thin film):
n
¼3056, 3032, 2888,
(100.6 MHz, CDCl3):
d
¼28.9, 34.0, 36.4, 46.4, 62.0, 127.4, 127.5,
1656,1638,1496,1472,1444,1406,1304,1254,1198,1066,1020, 910,
128.0, 129.4, 130.3, 131.2, 132.5, 133.4, 166.8; GCeMS (70 eV): 271
844, 758, 730, 698 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH] calcd for
(64) [Mþ], 217 (12), 203 (92), 188 (100), 162 (17), 160 (20), 109 (14),
C
21H20NO, 302.1545; found 302.1551.
80 (11), 67 (11); IR (KBr pellet):
n
¼3056, 3016, 2920, 2880, 1648,
1580, 1474, 1428, 1364, 1264, 1172, 1024, 932, 828, 736, 716,
692 cmꢀ1; HRMS (ESI-TOF): m/z [MþþH] calculated for C16H18NOS,
272.1109; found 272.1110.
4.5.19. (ꢂ)-7-Phenyl-1-phenylsulfanyl-3,6,9,9a-tetrahy-
droquinolizin-4-one (9u). Colourless solid (254 mg, 76% yield). Mp
158e160 ꢁC (n-hexane/ethyl acetate). The crude product was pu-
rified by column chromatography (SiO2, n-hexane/ethyl acetate
4.5.23. (ꢂ)-3,6,7,8,11,11a-Hexahydropyrido[1,2-a]azocin-4-one
(þ10% trans) (9y). Colourless oil (133 mg, 75% yield). The crude
product was purified by column chromatography (SiO2, diethyl
1
1:1 then 4:6); H NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼2.25e2.36 (m,
1H, CHH-9), 2.90 (dm, J¼17.5 Hz, 1H, CHH-9), 3.09e3.26 (m, 2H,
CH2-3), 3.68 (br d, J¼17.5 Hz, 1H, NCHH), 4.02 (dq, J¼11.5, 3.5 Hz,
1H, CH-9a), 5.49 (dt, J¼17.6, 1.2 Hz, 1H, NCHH), 6.08 (dd, J¼3.8,
3.5 Hz, 1H, ]CH-2), 6.13 (dq, J¼6.1, 1.8 Hz, 1H, ]CH-8), 7.23e7.42
ether); 1H NMR (400 MHz, toluene-d8, 23 ꢁC):
d
¼0.83e0.93 (m, 1H,
CHH-7), 1.51e1.61 (m, 2H, CHH-8, CHH-11), 1.99 (ddd, J¼13.3, 12.2,
3.4 Hz, 1H, NCHH), 2.17e2.29 (m, 1H, CHH-7), 2.40 (td, J¼3.5, 1.9 Hz,
2H, CH2-3), 3.00e3.07 (m, 1H, CH-11a), 3.85 (ddd, J¼13.3, 4.0,
2.6 Hz, 1H, NCHH), 4.86 (ddt, J¼10.0, 3.8, 2.0 Hz, 1H, ]CH), 5.01
(dtd, J¼10.0, 3.4, 1.2 Hz, 1H, ]CH), 5.16 (td, J¼9.5, 7.0 Hz, 1H, ]CH),
5.36 (td, J¼9.5, 7.2 Hz, 1H, ]CH); 13C NMR (100.6 MHz, toluene-d8):
(m, 10H, 2ꢃC6H5); 13C NMR (100.6 MHz, CDCl3):
¼32.2, 33.3, 43.5,
d
56.5, 121.2, 125.2, 127.4, 127.6, 127.8, 128.5, 129.4, 130.2, 130.7,
133.0, 134.6, 138.2, 165.3; GCeMS (70 eV): 333 (100) [Mþ], 224
(10), 203 (34), 130 (52), 129 (40), 128 (20), 115 (29), 104 (11), 91
(11), 77 (10); IR (pellet KBr):
n
¼3036, 2928, 1660, 1640, 1584, 1496,
d
¼23.2, 25.2, 30.9, 32.5, 46.2, 60.4, 120.9, 124.8, 125.3, 132.3, 165.1;
1468, 1442, 1424, 1392, 1356, 1330, 1260, 1190, 1024, 844, 752, 736,
690 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH] calcd for C21H20NOS,
334.1266; found 334.1266.
GCeMS (70 eV): 177 (16) [Mþ], 176 (21), 122 (31), 109 (100), 96 (33),
82 (22), 81 (40), 80 (31), 67 (39), 53 (11), 41 (16), 39 (16); IR (film):
n
¼3020, 2932, 1642, 1468, 1430, 1408, 1364, 1334, 818, 764, 740,
714 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH] calculated for C11H16NO,
4.5.20. (ꢂ)-6,7,10,10a-Tetrahydro-3H-pyrido[1,2-a]azepin-4-one
(9v). Colourless oil (134 mg, 82% yield). The crude product was
purified by column chromatography (SiO2, diethyl ether); 1H NMR
178.1232; found 178.1234.
4.5.24. (ꢂ)-2,9,9-Trimethyl-3,6,9,9a-tetrahydroquinolizin-4-one
(13). Colourless oil (85.6 mg, 90% yield{). The crude product was
(400 MHz, CDCl3, 23 ꢁC):
d
¼2.10e2.21 (m, 1H, CHH-10), 2.29e2.46
(m, 3H, CH2-7, CHH-10), 2.79 (ddd, J¼13.5, 10.1, 2.9 Hz, 1H, NCHH),
2.97e3.01 (m, 2H, CH2-3), 3.97e4.04 (m, 1H, CH-10a), 4.53 (ddd,
J¼13.5, 4.9, 3.9 Hz, 1H, NCHH), 5.68e5.81 (m, 3H, ]CH-1, ]CH-2,
]CH-8), 5.85e5.93 (m, 1H, ]CH-9); 13C NMR (100.6 MHz, CDCl3):
purified by column chromatography (SiO2, n-hexane/ethyl acetate,
1
6:4 then 1:1); H NMR (400 MHz, CDCl3, 23 ꢁC):
d¼0.83 (s, 3H, 9-
d
¼28.6, 31.7, 37.4, 46.4, 59.4, 121.6, 126.6, 127.7, 131.4, 168.2; GCeMS
(70 eV): 163 (8) [Mþ], 109 (26), 96 (63), 81 (48), 80 (100), 68 (26), 53
From the 1:1 mixture of compounds 12a and 12b.
{

ꢀ
J.G. Sosnicki et al. / Tetrahedron 70 (2014) 8624e8635
8634
CH3), 1.06 (s, 3H, 9-CH3), 1.78 (3H, s, 2-CH3), 2.84 (dm, J¼ca. 21.7 Hz,
1H, CHH-3), 2.95 (dm, J¼ca. 21.6 Hz, 1H, CHH-3), 3.39 (d, J¼18.4 Hz,
1H, NCHH), 3.76e3.81 (m, 1H, CH-9a), 4.90 (d, J¼18.4 Hz, 1H,
NCHH), 5.51 (br s, 1H, ]CH-1), 5.55e5.57 (m, 2H, ]CH-7, CH-8);
946, 910, 726, 690, 652 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH] cal-
culated C19H20NOS, 310.1266; found 310.1254.
Acknowledgements
13C NMR (100.6 MHz, CDCl3):
d
¼21.8, 22.2, 25.8, 36.4, 38.1, 41.7,
63.5, 115.7, 121.0, 131.7, 136.9, 167.0 (C-4); GCeMS (70 eV): 191
Financial support by the National Science Center (Grant N N204
219640) is gratefully acknowledged.
(12) [Mþ], 110 (100), 92 (10), 82 (33), 67 (38), 53 (10), 41 (14), 39
(12); IR (film):
n
¼2964, 1648 br, 1262, 1100 br, 1020 br, 804 cmꢀ1
.
HRMS (ESI-TOF): m/z [MþþH] calculated for C12H18NO, 192.1388;
Supplementary data
found 192.1380.
Experimental procedures and spectroscopic data for 3, some 2-
methoxypyridines and NH pyridin-2(1H)-ones as precursors of 3 as
well as for 7, 8g, 10a, 12a, 13, 14. 1H and 13C NMR spectra of com-
pounds 3 (except 3a), 7, 8a, 8b, 8c, 8g, 8z, 8ab, 9, 10a, 12a, 13, 14, 15,
1H,1H NOESY spectra of 9f, 9g. Supplementary data associated with
this article can be found in the online version, at http://dx.doi.org/
10.1016/j.tet.2014.09.043.
4.5.25. (ꢂ)-10-Phenyl-40,60,90,9a0-tetrahydrospiro(cyclopentane-1,30-
quinolizin)-3-en-40-one (15a). Colourless oil (173 mg, 62% yield).
The crude product was purified by column chromatography (SiO2,
n-hexane: ethyl acetate, 7:3 then 6:4); 1H NMR (400 MHz, CDCl3,
23 ꢁC):
d
¼1.93e2.04 (m, 1H, CHH-90), 2.20e2.29 (m, 1H, CHH-90),
2.35 (dq, J¼16.2, 2.1 Hz, 1H, CHH), 2.45 (dq, J¼16.5, 2.1 Hz, 1H, CHH),
3.02 (dquint, J¼16.5, 2.2 Hz, 1H, CHH), 3.30 (dquint, J¼16.5, 2.2 Hz,
1H, CHH), 3.59 (dm, J¼18.0 Hz, 1H, NCHH), 4.61 (dd, J¼11.2, 3.4 Hz,
1H, CH-9a0), 5.09 (br d, J¼18.0 Hz, 1H), 5.62e5.67 (m, 1H, ]CH),
5.68e5.72 (m, 1H, CH), 5.74 and 5.75 (twos, 2H, ]CH-70, ]CH-80),
5.96 (s, 1H, ]CH-20), 7.29e7.38 (m, 5H, C6H5); 13C NMR (100.6 MHz,
References and notes
1. (a) Michael, J. P. Nat. Prod. Rep. 2000, 17, 579e602; (b) Michael, J. P. Nat. Prod.
Rep. 2004, 21, 625e649; (c) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603e626; (d)
Michael, J. P. Nat. Prod. Rep. 2007, 24, 191e222; (e) Michael, J. P. Nat. Prod. Rep.
2008, 25, 139e165.
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Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556e1575.
CDCl3):
d
¼33.4, 42.7, 46.1, 47.2, 48.5, 56.2, 124.6, 125.9, 126.3, 127.3,
127.3, 128.7, 128.8, 130.0, 132.5, 138.0, 172.4; GCeMS (70 eV): 277
(100) [Mþ], 223 (56), 222 (70), 208 (25), 194 (67), 165 (19), 152 (10),
3. (a) Fitch, R. W.; Garraffo, H. M.; Spande, T. F.; Yeh, H. J. C.; Daly, J. W. J. Nat. Prod.
2003, 66, 1345e1350; (b) Kanakubo, A.; Gray, D.; Innocent, N.; Wonnacottb, S.;
Gallagher, T. Bioorg. Med. Chem. Lett. 2006, 16, 4648e4651; (c) Toyooka, N.;
Kobayashi, S.; Zhou, D.; Tsuneki, H.; Wada, T.; Sakai, H.; Nemoto, H.; Sasaoka, T.;
Garraffo, H. M.; Spandeb, T. F.; Daly, J. W. Bioorg. Med. Chem. Lett. 2007, 17,
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Biomed. Anal. 2008, 47, 892e898; (e) Lin, Z.; Huang, C.-F.; Liu, X.-S.; Jiang, J.
Basic Clin. Pharmacol. Toxicol. 2010, 108, 304e309; (f) Konrath, E. L.; dos Santos
115 (10); IR (thin film, ATR):
n
¼3054, 3032, 2912, 2842, 1660, 1631,
1462, 1443, 1300, 1234, 1206, 948, 908, 760, 727, 698, 656 cmꢀ1
.
HRMS (ESI-TOF): m/z [MþþH] calculated C19H20NO, 278.1545;
found 278.1552.
4.5.26. (ꢂ)-10-Phenyl-60,70,100,10a0-tetrahydrospiro(cyclopentane-
1,30-pyrido[1,2-a]azepin)-3-en-40-one (15b). White solid (256 mg,
88% yield). Mp 115e117 ꢁC (n-hexane). The crude product was
ꢀ
Passos, C. L.; Klein-Junior, C.; Henriques, A. T. J. Pharm. Pharmacol. 2013, 65,
1701e1725.
4. For selected examples see: (a) Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.;
Gramain, J.-C. Tetrahedron: Asymmetry 1998, 9, 4361e4368; (b) Padwa, A.;
Heidelbaugh, T. M.; Kuethe, J. T. J. Org. Chem. 2000, 65, 2368e2378; (c) iLi, Z.;
Jin, Z.; Huang, R. Synthesis 2001, 16, 2365e2378; (d) Chen, B.-F.; Tasi, M.-R.;
Yang, C.-Y.; Chang, J.-K.; Chang, N.-C. Tetrahedron 2004, 60, 10223e10231; (e)
Wijdeven, M. A.; Botman, P. N. M.; Wijtmans, R.; Schoemaker, H. E.; Rutjes, F. P.
J. T.; Blaauw, R. H. Org. Lett. 2005, 7, 4005e4007; (f) Katoh, M.; Mizutani, H.;
Honda, T. Tetrahedron Lett. 2005, 46, 5161e5163; (g) Goodenough, K. M.; Moran,
W. J.; Raubo, P.; Harrity, J. P. A. J. Org. Chem. 2005, 70, 207e213; (h) Back, T. G.;
Hamilton, M. D.; Lim, V. J. J.; Parvez, M. J. Org. Chem. 2005, 70, 967e972; (i)
Suyama, T. L.; Gerwick, W. H. Org. Lett. 2006, 8, 4541e4543; (j) Gray, D.; Gal-
lagher, T. Angew. Chem., Int. Ed. 2006, 45, 2419e2423; (k) Huang, P.-Q.; Guo, Z.-
Q.; Ruan, Y.-P. Org. Lett. 2006, 8, 1435e1438; (l) Liu, S.; Fan, Y.; Peng, X.; Wang,
W.; Hua, W.; Akberb, H.; Liao, L. Tetrahedron Lett. 2006, 47, 7681e7684; (m)
Nishikawa, Y.; Kitajima, M.; Takayama, H. Org. Lett. 2008, 10, 1987e1990; (n)
Wijdeven, M. A.; Wijtmans, R.; van den Berg, R. J. F.; Noorduin, W.; Schoemaker,
H. E.; Sonke, T.; van Delft, F. L.; Blaauw, R. H.; Fitch, R. W.; Spande, T. F.; Daly, J.
W.; Rutjes, F. P. J. T. Org. Lett. 2008, 10, 4001e4003; (o) Zhang, Y.; Gerasyuto, A.
I.; Long, Q. A.; Hsung, R. P. Synlett 2009, 237e240; (p) Perreault, S.; Rovis, T.
Chem. Soc. Rev. 2009, 38, 3149e3159; (q) Srivastava, A. K.; Das, S. K.; Panda, G.
Tetrahedron 2009, 65, 5322e5327; (r) Santos, L. S.; Mirabal-Gallardo, Y.;
Shankaraiah, N.; Simirgiotis, M. J. Synthesis 2011, 51e56; (s) Saha, N.; Biswas, T.;
purified by column chromatography (SiO2, n-hexane/ethyl acetate,
1
7:3 then 6:4); H NMR (400 MHz, CDCl3, 23 ꢁC):
d¼2.07e2.17 (m,
1H, CHH-100), 2.31e2.54 (m, 5H, CHH-100, CH2-70, 2ꢃCHH), 2.79
(ddd, J¼13.3, 11.2, 2.5 Hz, 1H, NCHH), 3.00 (dquint, J¼16.1, 2.4 Hz,
1H, CHH), 3.38 (dquint, J¼16.5, 2.5 Hz, 1H, CHH), 4.42 (dd, J¼10.7,
2.0 Hz, 1H, CH-10a0), 4.66 (ddd, J¼13.3, 4.9, 3.7 Hz, 1H, NCHH),
5.62e5.76 (m, 3H, 3ꢃ]CH), 5.90e5.97 (m, 1H, ]CH), 6.06 (s, 1H, ]
CH-20), 7.28e7.42 (m, 5H, C6H5); 13C NMR (100.6 MHz, CDCl3):
d
¼29.0, 38.1, 45.7, 47.0, 47.9, 48.9, 61.4, 126.1, 127.1, 127.8, 128.3,
128.7, 129.1, 130.9, 132.0, 134.9, 137.8, 173.2; GCeMS (70 eV): 291
(100) [Mþ], 274 (19), 262 (12), 237 (88), 236 (94), 222 (26), 209 (31),
208 (81), 194 (32), 178 (16), 165 (27), 152 (15), 128 (13), 115 (21), 77
(12), 67 (12); IR (KBr pellet):
n
¼3060, 3020, 2920, 2860, 1630, 1600,
1472, 1428, 1374, 1344, 1336, 1252, 1220, 952, 936, 876, 766, 720,
702 cmꢀ1. HRMS (ESI-TOF): m/z [MþþH] calculated C20H22NO,
292.1701; found 292.1700.
ꢀ
Chattopadhyay, S. K. Org. Lett. 2011, 13, 5128e5131; (t) Fustero, S.; Moscardo, J.;
ꢀ
ꢀ
4.5.27. (ꢂ)-10-Phenylsulfanyl-40,60,90,9a0-tetrahydrospir-
o(cyclopentane-1,30-quinolizin)-3-en-40-one (15c). Colourless oil
(320 mg, 88% yield). The crude product was purified by column
chromatography (SiO2, n-hexane/ethyl acetate, 7:3 then 6:4); 1H
Sanchez-Rosello, M.; Flores, S.; Guerola, M.; del Pozo, C. Tetrahedron 2011, 67,
7412e7417; (u) Chou, S.-S. P.; Chung, Y.-C.; Chen, P.-A.; Chiang, S.-L.; Wu, C.-J. J.
Org. Chem. 2011, 76, 692e695; (v) Wong, H.; Garnier-Amblard, E. C.; Liebeskind,
L. S. J. Am. Chem. Soc. 2011, 133, 7517e7527; (w) Pansare, S. V.; Dyapa, R. Org.
Biomol. Chem. 2012, 10, 6776e6784; (x) Chou, S.-S. P.; Huang, J.-L. Tetrahedron
ꢁ
Lett. 2012, 53, 5552e5554; (y) Chausset-Boissarie, L.; Arvai, R.; Cumming, G. R.;
NMR (400 MHz, CDCl3, 23 ꢁC):
d
¼2.02e2.12 (m, 1H, CHH-90), 2.38
ꢀ
ꢀ
€
Guenee, L.; Kundig, E. P. Org. Biomol. Chem. 2012, 10, 6473e6479; (z) Tsukano,
C.; Oimura, A.; Enkhtaivan, I.; Takemoto, Y. Org. Lett. 2012, 14, 1902e1905; (aa)
Trinh, T. T. H.; Nguyen, K. H.; de Aguiar Amaral, P.; Gouault, N. Beilstein J. Org.
Chem. 2013, 9, 2042e2047; (ab) Chou, S.-S. P.; Huang, J.-L. Molecules 2013, 18,
8243e8256; (ac) Chou, S.-S. P.; Zhang, J.-W.; Chen, K.-H. Tetrahedron 2013, 69,
1499e1508; (ad) Thorat, R. G.; Pansare, S. V. Eur. J. Org. Chem. 2013, 7282e7285;
(ae) Jansen, D. J.; Shenvi, R. A. J. Am. Chem. Soc. 2013, 135, 1209e1212; (af) Chou,
S.-S. P.; Yang, K.-S.; Chiu, T.-H. Heterocycles 2014, 89, 679e691.
(dm, J¼ca. 16.4 Hz, 2H, 2ꢃCHH), 2.73 (dm, J¼16.8 Hz, 1H, CHH-90),
2.94 (dquint, J¼16.1, 2.6 Hz, 1H, CHH), 3.31 (dquint, J¼16.4, 2.4 Hz,
1H, CHH), 3.39 (dsxt, J¼18.3, 2.20 Hz, 1H, NCHH), 3.93 (dd, J¼11.2,
3.4 Hz, 1H, CH-9a0), 4.99 (dm, J¼18.3 Hz, 1H, NCHH), 5.58e5.62 (m,
1H, ]CH), 5.63e5.71 (m, 2H, 2ꢃ¼CH), 5.73e5.80 (m, 1H, ]CH),
6.19 (s, 1H, ]CH-20), 7.23e7.36 (m, 5H, C6H5); 13C NMR (100.6 MHz,
5. For selected examples see: (a) Ercoli, M.; Mina, L.; Boido, C. C.; Boido, V.;
Sparatore, F.; Armani, U.; Piana, A. Farmaco 2004, 59, 101e109; (b) Sparatore, A.;
Novelli, F.; Sparatore, F. Helv. Chim. Acta 2004, 87, 580e591; (c) Jong, L.; Zaveri,
N.; Toll, L. Bioorg. Med. Chem. Lett. 2004, 14, 181e185; (d) Sparatore, A.; Basilico,
N.; Parapini, S.; Romeo, S.; Novelli, F.; Sparatorec, F.; Taramelli, D. Bioorg. Med.
Chem. 2005, 13, 5338e5345; (e) Le Bourdonnec, B.; Goodman, A. J.; Michaut,
M.; Ye, H.-F.; Graczyk, T. M.; Belanger, S.; Herbertz, T.; Yap, G. P. A.; DeHaven, R.
CDCl3):
d
¼33.3, 42.7, 45.7, 47.7, 47.9, 48.7, 56.7, 124.4, 124.6, 126.8,
127.2, 128.6, 129.3, 129.9, 133.7, 139.4, 171.6; GCeMS (70 eV): 309
(100) [Mþ], 255 (98), 240 (17), 226 (48), 200 (28), 145 (16), 128 (19),
117 (18), 91 (16), 77 (17), 65 (14); IR (thin film, ATR): 3055, 2913,
2842, 1661, 1635, 1580, 1475, 1440, 1334, 1294, 1230, 1205, 1024,

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J.G. Sosnicki et al. / Tetrahedron 70 (2014) 8624e8635
8635
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