Efficient synthesis of 5-functionalised 2-methoxypyridines and their transformation to bicyclic d-lactams, both accessed using magnesium ?ate? complexes as key reagents

Article abstract of DOI:10.1055/s-0029-1217733

Simple and efficient synthesis of 5-functionalised ?2-methoxypyridines from 5-bromo-2-methoxypyridine using ?[n-Bu3Mg]Li performed in noncryogenic conditions is described. Application of 5-functionalised 2-methoxypyridines in the synthesis of 1-substitute

Full text of DOI:10.1055/s-0029-1217733

2508
LETTER
Efficient Synthesis of 5-Functionalised 2-Methoxypyridines and their
Transformation to Bicyclic d-Lactams, both Accessed Using Magnesium
‘Ate’ Complexes as Key Reagents
Synthesis
aof 5-Functi
c
onalised 2-M
e
ethoxypy
k
ridine
s
G. Sośnicki*
Institute of Chemistry and Environmental Protection, West Pomeranian University of Technology, Szczecin, Al. Piastów 42,
71065 Szczecin, Poland
Fax +48(91)4494639; E-mail: sosnicki@ps.pl
Received 18 June 2009
could be subsequently submitted to the synthesis of func-
Abstract: Simple and efficient synthesis of 5-functionalised
tionalised bicyclic d-lactams (e.g., 1-substituted quinoliz-
2-methoxypyridines from 5-bromo-2-methoxypyridine using
[n-Bu3Mg]Li performed in noncryogenic conditions is described.
Application of 5-functionalised 2-methoxypyridines in the synthesis
idin-4-ones10 according to the sequence of steps presented
in Scheme 1). Hitherto reported methods of 5-functional-
of 1-substituted 3,6,9,9a-tetrahydroquinolizin-4-ones and 3,5,8,8a- isation of 5-bromo-2-methoxypyridine via metal–halogen
tetrahydro-1H-quinolin-2-ones via allylation of the corresponding
5-functionalised N-allyl(or benzyl)pyridin-2-ones using [allyln-Bu2Mg]Li
followed by ring-closing metathesis is presented.
exchange comprised reactions with organolithium re-
agents performed at low temperature11 (typically from
–78 °C to –65 °C in THF). The necessity of application of
low-temperature standing as disadvantage of this method,
prompted us to find a more suitable protocol. The under-
Key words: magnesium ‘ate’ complexes, magnesiates, bromine–
magnesium exchange, allylation, quinolizidin-4-ones, RCM
taken elaboration of an easy procedure of 5-functionalisa-
tion of 2-methoxypyridine seemed to be an interesting
In the past decade organomagnesium ‘ate’ complexes of
the [R3Mg]Li type have attracted considerable attention as
useful reagents applied in the organic synthesis.1 The
main interest has been focused on halogen–magnesium
exchange reactions2 and much work has been carried out
to explore [R3Mg]Li as bases.3 Only little attention has
been devoted to magnesiates as alkylating agents.4 In the
synthesis of functionalised heterocycles the magnesiates
were successfully applied in the synthesis of functiona-
lised pyridines2g,2p–s,u,w,x,3c,i,4c and piperidines,3a com-
pounds widespread in nature and in biologically active
species.5
goal itself because, apart from their synthetic utility, com-
pounds with 5-substituted 2-alkoxypyridine moiety ex-
hibited broad spectrum of biological activity.11c,12
(Me)H
(Me)H
1. [Allyln-Bu2Mg]Li
2. H3O+
N
O
N
O
RCM
(Me)H
1
Among our recent efforts on the synthesis of functional-
ized d-lactams3a,6 and d-thiolactams,7 precursors of substi-
tuted piperidines, we have previously reported on
nucleophilic properties of lithium allyldibutylmagnesiate
([Allyln-Bu2Mg]Li).7c,8 We have demonstrated that addi-
tion of lithium allyldibutylmagnesiate to N-allylpyridin-2-
ones at –70 °C led mainly to 1,6-diallyl-3,6-dihydro-1H-
pyridin-2-ones.8b Submission of the product to the ring-
closing metathesis (RCM) allowed us to obtain 3,6,9,9a-
tetrahydroquinolizin-4-ones (Scheme 1).8b
N
O
Scheme 1 Synthesis of 1-H(Me) substituted quinolizidin-4-ones8b
0 °C, 5 min, THF
n-BuMgCl + 2 n-BuLi
Br
[n-Bu3Mg]Li (1a)
+ LiCl
R1
1. 1a (0.5 equiv) –2 °C, 0.5 h
2. E, 0 °C, 0.5 h then r.t., 1 h
During our research activities on the application of mag-
nesiates in the synthesis of functionalised piperidines we
have focused our attention on the synthesis of 5-function-
alised 2-methoxypyridines, potential substrates to obtain
5-substituted N-pyridin-2-ones.9 The idea was to obtain 5-
functionalised 2-methoxypyridines in order to convert
them into 5-substituted N-allylpyridin-2-ones, which
N
O
N
O
2
3
Scheme 2 Synthesis of 5-functionalised 2-methoxypyridines 3
(E = electrophile)
The result is an easy and noncryogenic synthesis of 5-
functionalised of 2-methoxypyridines via bromine–mag-
nesium exchange reaction using lithium magnesiate.
Easily accessible 5-substituted 2-methoxypyridines en-
couraged us also to check the idea of the synthesis of
SYNLETT 2009, No. 15, pp 2508–2512
x
x
.x
x
.2
0
0
9
Advanced online publication: 27.08.2009
DOI: 10.1055/s-0029-1217733; Art ID: G20309ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 5-Functionalised 2-Methoxypyridines
2509
bicyclic d-lactams using lithium allyldibutylmagnesiate
and RCM. Thus, preliminary results on the synthesis of 1-
functionalised quinolizidin-4-ones are also presented.
Table 1 Synthesis of 5-Functionalised 2-Methoxypyridines 3
Entry Electrophile
(equiv)
3
Yield
(%)a–c
R1
In the synthesis of 5-functionalised 2-methoxypyridine
lithium tributylmagnesiate {[n-Bu3Mg]Li, 1a} was ap-
plied as bromine–magnesium exchange agent
(Scheme 2). [n-Bu3Mg]Li, prepared simply by mixing of
0.5 equivalents of n-BuMgCl and 1.0 equivalent of
n-BuLi for 5 minutes at 0 °C in THF, was able to ex-
change bromine in 5-bromo-2-methoxypyridine (1 equiv)
in 30 minutes at temperatures from –2 °C to 0 °C. Accord-
ing to the earlier described protocols2h,p,r,s,u,x all three alkyl
groups in [R3Mg]Li are replaced with three molecules of
Br–Ar during exchange process, indicating that formally
0.33 equivalents of 1a with respect to Br–Ar should be
used. However, in our experiments application of 0.5
equivalents of 1a gave the best results of the exchange re-
actions. Optimisation of the amount of electrophiles
required for quenching of 2-methoxy-5-pyridinyl magne-
siate indicated that in these conditions at least 2 equiva-
lents of the electrophiles should be applied. However, in
the case of (PhS)2 and C2Cl6, the 1.0 and 1.3 equivalents,
respectively, were sufficient amount for complete conver-
sion. Thus, according to the simple procedure13 broad
spectrum of 5-functionalised 2-methoxypyridines was ob-
tained in good or in very good yields (Scheme 2, Table 1).
Majority of the products were prepared in a few gram
scales and were purified by distillation. It’s worth empha-
sising that most of the introduced functional groups could
be transformed to other functionalities including the pro-
tected functional groups.
N
N
OMe
OMe
D
1
2
3
4
5
D2O (5.0)
3a 75a (85)
3b 92a (96)
TMS
Cl
TMSCl (3.0)
C2Cl6 (1.3)
PhSSPh (1.0)
N
OMe
3c
63a (65)
N
OMe
PhS
3d 89a (92)
N
OMe
3e
3f
63a,d (65)
74a,e (76)
Br
(3.0)
N
OMe
O
O
Me
Me
6
7
N
Cl
N
Me
Me
N
OMe
(3.0)
O
B
O
B
3g 72a (93)
O
O
Oi-Pr
(2.0)
N
OMe
OH
In order to check the potential application of 5-functiona-
lised 2-methoxypyridine in the synthesis of bicyclic d-lac-
tams, compounds 3a–e, as representatives of 5-
functionalised 2-methoxypyridines with functional
groups rather resistant to nucleophilic attack, were trans-
formed to 5-substituted N-allylpyridin-2-ones 4a–e, using
NaI/allylBr in MeCN (Scheme 3, Table 2),14 according to
the slightly modified procedure described by Bowman
and Bridge.9a As a result, we observed that in order to ob-
tain the satisfactory yields of the products 4 the reaction
required 1–6 days of heating at 55 °C14 and that in the case
of 5-Cl derivative 4c the reaction was the slowest. At the
next stage14 pyridones 4a–e were submitted to the reaction
with lithium allyldibutylmagnesiate (1b) at –72 °C. Under
these conditions, the reactions proceeded smoothly with
complete conversion after 20 minutes to give the 6-allyla-
tion products 5a–e in good yields and regioselectivities
(Scheme 3, Table 2). Only in the case of 5-chloropyridin-
2-one (4c) slightly lower regioselectivity was observed
(5c/6c = 87:13). Finally, 5-functionalised N,6-diallyl d-
lactams 5a–e were annulated by RCM, performed in tolu-
ene at 70 °C, using Grubbs first- or second-generation cat-
alyst 8 and 9, respectively.14 Because in these reactions
catalyst 9 was found more effective and more tolerant to
the functional groups, this catalyst was applied in the ma-
jority of cases. Generally, 1-functionalised quinolizidin-
4-ones were obtained in good yields (Scheme 3, Table 2).
8
9
PhCHO (2.0)
DMF (3.0)
3h 93a (98)
Ph
N
OMe
O
3i
3j
89a (92)
96b (97)
H
N
OMe
O
Ph
10
11
PhNCO (2.0)
N
H
N
OMe
OMe
+
N
Me
Me
3k 83a,f (86)
N
I–
Me
Me
N
(2.0)
a Isolated yields after distillation.
b Isolated yields after column chromatography.
c Yields estimated by 1H NMR spectroscopy using internal reference
are given in parentheses.
d Reaction time was prolonged for 2 d.
e At the end of the reaction 0.5 mL of Et3N were added, and the reac-
tion was prolonged for 2 h at r.t.
f H2O instead of NH4Cl was added for quenching the reaction.
Only in the case of N,5,6-triallyl derivative 5e the yield of
1-allylquinolizidin-4-one was lower due to competitive
annulation leading to N-allyl-3,5,8,8a-tetrahydro-1H-
Synlett 2009, No. 15, 2508–2512 © Thieme Stuttgart · New York

2510
J. G. Sośnicki
LETTER
0 °C, 5 min, THF
Mgn-Bu2] Li
[
+ LiCl
MgCl
+ 2 n-BuLi
1b
Br
R1
R1
R1
R1
R1
a
b
c
d
e
D
TMS
Cl
PhS
Allyl
NaI
1. 1b
+
2. H3O+
MeCN
55 °C
N
O
N
O
N
O
N
O
5a–e
6a–e
3a–e
4a–e
RCM
PhH, 70 °C
(cat. 8 or 9)
R1
1
N
N
PCy3
Mes
Mes
Ph
Cl
Cl
Cl
Ru
Ph
+
N
O
Ru
N
O
Cl
PCy3
PCy3
8
10e
9
7a–e
Scheme 3 Transformation of 5-functionalised 2-methoxypyridines 3a–e to bicyclic d-lactams 7a–e and 10e
Table 2 Yields and Reaction Conditions for the Synthesis of Compounds 4–7 and 10e
Entry
Synthesis of 4
Yield (%) and reaction temp (°C) (d)
Time
Addition of 1b to 4
RCM of 5
Yield of 5/6 (%) and ratioa
Yield of 7 and 10 (%); cat., mol%, time (h)
1
2
3
4
5
4a (75)
4b (68)
4c (69)
4d (76)
4e (80)
2
2
6
2
1
5a/6a (82), 95:5
5b/6b (81), 93:7
5c/6c (66), 87:13
5d/6d (76), 98:2
5e/6e (72), 92:8
7a (82); 9, 1.4, 0.5
7b (73); 8, 7.0, 0.3
7c (94); 9, 2.5, 0.3
7d (83); 9, 4.0, 0.3
7e (25); 9, 0.4, 0.5
10e (25)
a Estimated by 1H NMR spectroscopy of crude reaction mixture.
quinolin-2-one (10e, Scheme 3). To support facile forma- product 10f was obtained in 50% and 72% yields using
tion of 3,5,8,8a-tetrahydroquinolin-2-one ring system and catalyst 8 and 9, respectively.
in order to confirm the structure of 10e, the same allyla-
tion–RCM sequence of reactions was repeated for N-ben-
zyl-5-allyl-2-methoxypyridine, obtained from 3e using
The structures of all compounds were determined on the
basis of 1D NMR (1H, 13C, 13C-DEPT) and 2D NMR (1H,
BrBn and NaI (Scheme 4). In this case the final annulated
1b
+
–72 °C
N
O
N
O
N
O
Bn
Bn
Bn
5f/6f = 91:9
85% yield
64%
4f
reflux
5 h
NaI, BnBr
MeCN
RCM
Grubbs I (8): 7 mol%, Ph, 70 °C,
0.5 h, 50% yield
3e
N
O
Grubbs II (9): 6 mol%, CH2Cl2,
r.t., 2 h, 72% yield
Bn
10f
Scheme 4 Synthesis of N-benzyl-3,5,8,8a-tetrahydroquinolin-2-one 10f
Synlett 2009, No. 15, 2508–2512 © Thieme Stuttgart · New York

LETTER
Synthesis of 5-Functionalised 2-Methoxypyridines
2511
1
1H COSY, 13C, H COSY) spectroscopy, IR spectrosco-
6884. (r) Dumouchel, S.; Mongin, F.; Trécourt, F.;
Quéguiner, G. Tetrahedron Lett. 2003, 44, 3877.
py, mass spectra, and elemental analysis or HRMS.15
(s) Dumouchel, S.; Mongin, F.; Trécourt, F.; Quéguiner, G.
Tetrahedron Lett. 2003, 44, 2033. (t) Inoue, A.; Kondo, J.;
Shinokubo, H.; Oshima, K. Chem. Eur. J. 2002, 8, 1730.
(u) Mase, T.; Houpis, I. N.; Akao, A.; Dorziotis, I.; Emerson,
K.; Hoang, T.; Iida, T.; Itoh, T.; Kamei, K.; Kato, S.; Kato,
Y.; Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres, P.;
Molina, A.; Nemoto, T.; Okada, S.; Reamer, R.; Song, J. Z.;
Tschaen, D.; Wada, T.; Zewge, D.; Volante, R. P.; Reider,
P. J.; Tomimoto, K. J. Org. Chem. 2001, 66, 6775.
(v) Kondo, J.; Inoue, A.; Shinokubo, H.; Oshima, K. Angew.
Chem. Int. Ed. 2001, 40, 2085. (w) Inoue, A.; Kitagawa, K.;
Shinokubo, H.; Oshima, K. J. Org. Chem. 2001, 66, 4333.
(x) Iida, T.; Wada, T.; Tomimoto, K.; Mase, T. Tetrahedron
Lett. 2001, 42, 4841. (y) Kitagawa, K.; Inoue, A.;
In summary, a practical (noncryogenic) method was de-
veloped for the synthesis of 5-functionalised 2-methoxy-
pyridines starting from 5-bromo-2-methoxypyridine,
using [n-Bu3Mg]Li as Mg–Br exchange reagent. The con-
venient synthesis of a variety of 5-substituted 2-methoxy-
pyridines possibly obtained using different electrophiles,
and easy transformation of the products to pyridone deriv-
atives, open access to a broad range of starting materials
for the synthesis of derivatives containing a piperidine
ring. As an example, the synthesis of bicyclic d-lactams in
addition of [allyln-Bu2Mg]Li to the corresponding 5-func-
tionalised N-allyl(or benzyl)pyridin-2-ones followed by
RCM was demonstrated. The strategy proposed allowed
obtaining 1-functionalised quinolizidin-4-one and N-sub-
stituted unsaturated quinolin-2-one systems, both existing
in naturally occurring alkaloids. Further research on the
synthesis of alkenyl-substituted pyridin-2-ones via func-
tionalised 2-alkoxypyridines, their application to the syn-
thesis of 1-functionalised quinolizidin-4-ones and to other
bicyclic d-lactams according to allylation–RCM proce-
dure is currently under way.
Shinokubo, H.; Oshima, K. Angew. Chem. Int. Ed. 2000, 39,
2481.
(3) (a) Sośnicki, J. G.; Struk, Ł. Synlett 2009, 1812.
(b) Bentabed-Ababsa, G.; Blanco, F.; Derdour, A.; Mongin,
F.; Trécourt, F.; Quéguiner, G.; Ballesterous, R.; Abarca, B.
J. Org. Chem. 2009, 74, 163. (c) Hawad, H.; Bayh, O.;
Hoarau, C.; Trécourt, F.; Quéguiner, G.; Marsais, F.
Tetrahedron 2008, 64, 3236. (d) Mulvey, R. E.; Mongin, F.;
Uchiyama, M.; Kondo, Y. Angew. Chem. Int. Ed. 2007, 46,
3802. (e) Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.;
Bischoff, L.; Trécourt, F.; Quéguiner, G.; Marsais, F.;
Blanco, F.; Abarca, B.; Ballesteros, R. J. Org. Chem. 2005,
70, 5190. (f) Mongin, F.; Bucher, A.; Bazureau, J. P.; Bayh,
O.; Awad, H.; Trécourt, F. Tetrahedron Lett. 2005, 46,
7989. (g) Awad, H.; Mongin, F.; Trécourt, F.; Quéguiner,
G.; Marsais, F.; Blanco, F.; Abarca, B.; Ballesteros, R.
Tetrahedron 2005, 61, 4779. (h) Awad, H.; Mongin, F.;
Trécourt, F.; Quéguiner, G.; Marsais, F. Tetrahedron Lett.
2004, 45, 7873. (i) Awad, H.; Mongin, F.; Trécourt, F.;
Quéguiner, G.; Marsais, F.; Blanco, F.; Abarca, B.;
Ballesteros, R. Tetrahedron Lett. 2004, 45, 6697. (j) Ide,
M.; Nakata, M. Bull. Chem. Soc. Jpn. 1999, 72, 2491.
(k) Ide, M.; Yasuda, M.; Nakata, M. Synlett 1998, 936.
(l) Yasuda, M.; Ide, M.; Matsumoto, Y.; Nakata, M. Bull.
Chem. Soc. Jpn. 1998, 71, 1417.
(4) (a) Hatano, M.; Miyamoto, T.; Ishihara, K. Curr. Org.
Chem. 2007, 11, 127. (b) Hatano, M.; Matsumura, T.;
Ishihara, K. Org. Lett. 2005, 7, 573. (c) Faraks, J. Jr.;
Richey, H. G. Jr. Organometallics 1990, 9, 1778.
(d) Richery, H. G. Jr.; DeStephano, J. Tetrahedron Lett.
1985, 26, 275. (e) Ashby, E. C.; Chao, L.-C.; Laemmle, J.
J. Org. Chem. 1974, 39, 3258. (f) Wittig, G.; Meyer, F. J.;
Lange, G. Justus Liebigs Ann. Chem. 1951, 571, 167.
(5) See, for example: Rubiralta, M.; Giralt, E.; Diez, A.
Piperidines. Structure, Preparation, Reactivity and
Synthetic Application of Piperidines and its Derivatives;
Elsevier: Amsterdam, 1991.
Acknowledgment
The support by the Ministry of Science and Higher Education of Po-
lish State (Grant No.N N204 014136) is gratefully acknowledged.
References and Notes
(1) Yorimitsu, H.; Oshima, K. The Chemistry of
Organomagnesium Ate Complexes In The Chemistry of
Organomagnesium Compounds; Rappoport, Z.; Marek, I.,
Eds.; Wiley: Chichester, 2008, Chap. 15, 681–716.
(2) (a) Stefan, M. C.; Javier, A. E.; Osaka, I.; McCullough, R. D.
Macromolecules 2009, 42, 30. (b) Shinozuka, T.;
Yamamoto, Y.; Hasegawa, T.; Saito, K.; Naito, S.
Tetrahedron Lett. 2008, 49, 1619. (c) Gallou, F.; Haenggi,
R.; Hirt, H.; Marterer, W.; Schaefer, F.; Seeger-Weibel, M.
Tetrahedron Lett. 2008, 49, 5024. (d) Lau, S. Y. W.;
Hughes, G.; O’Shea, P. D.; Davies, I. W. Org. Lett. 2007, 9,
2239. (e) Fleming, F. F.; Gudipati, S.; Anh Viet, V.; Mycka,
R. J.; Knochel, P. Org. Lett. 2007, 9, 4507. (f) Dolman,
S. J.; Gosselin, F.; O’Shea, P. D.; Davies, I. W. Tetrahedron
2006, 62, 5092. (g) Kii, S.; Akao, A.; Iida, T.; Mase, T.;
Yasuda, N. Tetrahedron Lett. 2006, 47, 1877. (h)Buron, F.;
Plé, N.; Turck, A.; Marsais, F. Synlett 2006, 1586.
(i) Thomas, G. L.; Böhner, C.; Ladlow, M.; Spring, D. R.
Tetrahedron 2005, 61, 12153. (j) Trost, B. M.; Frederiksen,
M. U.; Papillon, J. P.; Harrington, P. E.; Shin, S.; Shireman,
B. T. J. Am. Chem. Soc. 2005, 127, 3666. (k) Xu, J.; Jain,
N.; Sui, Z. Tetrahedron Lett. 2004, 45, 6399.
(6) (a) Sośnicki, J. G. Synlett 2003, 1673. (b) Sośnicki, J. G.;
Westerlich, S. Tetrahedron Lett. 2002, 43, 1325.
(7) (a) Sośnicki, J. G. Tetrahedron 2009, 65, 1336.
(b) Sośnicki, J. G. Tetrahedron Lett. 2009, 50, 178.
(c) Sośnicki, J. G. Tetrahedron 2007, 63, 11862.
(l) Therkelsen, F. D.; Rottländer, M.; Thorup, N.; Pedersen,
E. B. Org. Lett. 2004, 6, 1991. (m) Tsuji, T.; Nakamura, T.;
Yorimitsu, H.; Shinokubo, H.; Oshima, K. Tetrahedron
2004, 60, 973. (n) Ito, S.; Kubo, T.; Morita, N.; Matsui, Y.;
Watanabe, T.; Ohta, A.; Fujimori, K.; Murafuji, T.;
Sugihara, Y.; Tajiri, A. Tetrahedron Lett. 2004, 45, 2891.
(o) Shinokubo, H.; Oshima, K. Eur. J. Org.Chem. 2004,
2081. (p) Dumouchel, S.; Mongin, F.; Trécourt, F.;
Quéguiner, G. Tetrahedron 2003, 59, 8629. (q) Fukuhara,
K.; Takayama, Y.; Sato, F. J. Am. Chem. Soc. 2003, 125,
(8) (a) Sośnicki, J. G. Tetrahedron Lett. 2005, 46, 4295.
(b) Sośnicki, J. G. Tetrahedron Lett. 2006, 47, 6809.
(9) (a) Bowman, W. R.; Bridge, C. F. Synth. Commun. 1999, 29,
4051. (b) Kunishima, M.; Friedman, J. E.; Rokita, S. E.
J. Am. Chem. Soc. 1999, 121, 4722. (c) Shiao, M.-J.; Lai,
L.-L.; Ku, W.-S.; Lin, P.-Y.; Hwu, J. R. J. Org. Chem. 1998,
58, 4742. (d) Hwu, J. R.; Wong, F. F.; Huang, J.-J.; Tsay,
S.-C. J. Org. Chem. 1997, 62, 4097. (e)Hongo, H.; Nakano,
Synlett 2009, No. 15, 2508–2512 © Thieme Stuttgart · New York

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J. G. Sośnicki
LETTER
H.; Okuyama, Y. Heterocycles 1995, 40, 831.
(f) Newkome, G. R.; Kohli, D. K.; Kawato, T. J. Org. Chem.
1980, 45, 4508.
bromide (38.5 mmol) was heated in MeCN (30 mL) at 55 °C
for 1–6 d (see Table 2). Subsequently, the solvent was
evaporated and brine containing 1% Na2S2O3 was added.
The aqueous solution was extracted with EtOAc (2 × 75
mL), and the combined organic layers were dried over
MgSO4. Filtration, concentration in vacuo, and purification
by flash column chromatography yielded 4. To a cooled
(0 °C) and stirred solution of allylMgCl (4.9 mmol, 2.45 mL,
2.0 M in THF) in dry THF (4 mL) in a Schlenk flask n-BuLi
(9.8 mmol, 3.9 mL, 2.5 M in hexane) was added via syringe
under argon, the mixture was stirred for 5 min and then
cooled to –72 °C. The mixture containing 1b was next
transferred via syringe to a cooled (–72 °C) solution of
N-allylpyridin-2-one (4, 9.0 mmol) in THF (20 mL). The
resulting solution was stirred for 20 min at –72 °C, and then
aq sat. NH4Cl (10 mL) was added. The aqueous layer was
extracted with EtOAc (2 × 75 mL), and the combined
organic layers were dried over MgSO4. Filtration,
concentration in vacuo, and separation by flash column
chromatography yielded 5. To a solution of 1,6-diallyl
lactam 5 (1.0 mmol) in dry, degassed toluene (10 mL),
ruthenium catalyst 8 or 9 was added, and the reaction
mixture was stirred under slowly bubbled stream of argon at
70 °C. After the reaction was complete (Table 2), the solvent
was evaporated at reduced pressure, and the residue was left
standing for 48 h followed by purification on column
chromatography.
(10) 1-Substituted quinolizidin-4-ones are biologically active
species. See, for example: (a) Casagrande, M.; Basilico, N.;
Parapini, S.; Romeo, S.; Taramelli, D.; Sparatore, A. Bioorg.
Med. Chem. 2008, 16, 6813. (b) Vazanna, I.; Budriesi, R.;
Terranowa, E.; Ioan, P.; Ugenti, M. P.; Tasso, B.; Chiarini,
A.; Sparatore, F. J. Med. Chem. 2007, 50, 334. (c) Kim,
D.-I.; Deutsch, H. M.; Ye, X.; Schwerei, M. M. J. Med.
Chem. 2007, 50, 2718.
(11) (a) Mahiout, Z.; Lomberget, T.; Goncalves, S.; Barret, R.
Org. Biomol. Chem. 2008, 6, 1364. (b) Boros, E. E.;
Burova, S. A.; Erickson, G. A.; Johns, B. A.; Koble, C. S.;
Kurose, N.; Sharp, M. J.; Tabet, E. A.; Thompson, J. B.;
Toczko, M. A. Org. Process Res. Dev. 2007, 11, 899.
(c) Denton, T. T.; Zhang, X.; Cashman, J. R. J. Med. Chem.
2005, 48, 224. (d) Manoso, A. S.; Ahn, C.; Soheili, A.;
Handy, C. J.; Correia, R.; Seganish, W. M.; DeShong, P.
J. Org. Chem. 2004, 69, 8305. (e) Hodgson, D. M.;
Maxwell, C. R.; Wisedale, R.; Matthews, I. R.; Carpenter,
K. J.; Dickenson, A. H.; Wonnacott, S. J. Chem. Soc., Perkin
Trans. 1 2001, 3150. (f) Giblin, G. M. P.; Jones, C. D.
Synlett 1997, 589.
(12) See, for example: (a) Humphries, P. S.; Do, T. Q.-Q.;
Wilhite, D. M. Tetrahedron Lett. 2009, 50, 1765.
(b) Wroblewski, B.; Wigglesworth, M. J.; Szekeres, P. G.;
Smith, G. D.; Rahman, S. S.; Nicholson, N. H.; Muir, A. I.;
Hall, A.; Heer, J. P.; Gerland, S. L.; Coates, W. J. J. Med.
Chem. 2009, 52, 818. (c) Brown, A.; Brown, L.; Brown, B.;
Calabrese, A.; Ellis, D.; Puhalo, N.; Smith, C. R.; Wallace,
O.; Watson, L. Bioorg. Med. Chem. Lett. 2008, 18, 5242.
(d) Ebdrup, S.; Hoffmann, H.; Refsgaard, F.; Fledelius, C.;
Jacobsen, P. J. Med. Chem. 2007, 50, 5449. (e) Qu, W.;
Kung, M.-P.; Hou, C.; Benedum, T. E.; Kung, H. F. J. Med.
Chem. 2007, 50, 2157.
(15) Selected Spectroscopic Data
2-Methoxy-5-trimethylsilanylpyridine (3b)
Colorless oil. IR (film): 2956, 1586, 1556, 1488, 1352, 1286,
1250, 1116, 1026, 840 cm–1. MS (EI, 70 eV):
m/z (%) = 181 (32) [M+], 180 (17), 166 (100), 136 (7). 1H
NMR (400.1 MHz, CDCl3): d = 0.26 (9 H, s, Me3Si), 3.94 (3
H, s, OCH3), 6.74 (1 H, dd, J = 8.3, 0.8 Hz, =CH-3), 7.65 (1
H, dd, J = 8.3, 1.9 Hz, =CH-4), 8.24 (1 H, dd, J = 1.8, 0.8
Hz, =CH-6). 13C NMR (100.6 MHz, CDCl3): d = –1.1
(Me3Si), 53.3 (OCH3), 110.6 (CH-3), 126.3 (C-5), 143.5
(CH-4), 151.6 (CH-6), 164.8 (C-2). HRMS (EI): m/z calcd
for C9H15NOSi: 181.0923; found: 181.0922.
(13) Typical Procedure of 5-Functionalisation of 2-Methoxy-
pyridine
To a cooled (0 °C) and stirred solution of n-BuMgCl (4.2
mmol, 2.1 mL, 2.0 M in THF) in dry THF (4 mL) in a
Schlenk flask, n-BuLi (8.4 mmol, 3.4 mL, 2.5 M in hexane)
was added via syringe over 1 min under argon, and the
mixture was stirred for 5 min. To a yellow, cooled (–2 to
0 °C) solution 5-bromo-2-methoxypyridine (8.4 mmol, 1.09
mL) was added via syringe. The resulting solution was
stirred for 30 min at –2 to 0 °C, then the electrophile was
added (Table 1), and the mixture was continuously stirred
for 30 min at 0 °C and 1 h at r.t. After addition of aq sat.
NH4Cl (5 mL), the aqueous layer was extracted with EtOAc
(2 × 75 mL), and the combined organic layers were dried
over MgSO4. Filtration, concentration in vacuo, and
purification by distillation or flash column chromatography
yielded compound 3.
1-Trimethylsilanyl-3,6,9,9a-tetrahydroquinolizin-4-one
(7b)
Colorless oil. IR (film): 3036, 2960, 1666, 1644, 1468, 1444,
1404, 1296, 1254, 1116, 840, 760 cm–1. MS (EI, 70 eV): m/
z (%) = 221 (79) [M+], 220 (100), 206 (12), 152 (14), 148
(23), 124 (23), 100 (34), 73 (28). 1H NMR (400.1 MHz,
CDCl3): d = 0.15 (9 H, s, Me3Si), 2.00–2.10 (1 H, m, CHH-
9), 2.34 (1 H, dm, J = ca. 17.1 Hz, CHH-9), 2.97–3.01 (2 H,
m, CH2-3), 3.42 (1 H, dm, J = ca. 18.3 Hz, CHH-6), 4.16 (1
H, dq, J = 11.5, 3.4 Hz, CH-9a), 5.06 (1 H, dm, J = 18.3 Hz,
CHH-6), 5.69–5.76 (1 H, m, =CH-7), 5.76–5.83 (1 H, m,
=CH-8), 6.02 (1 H, ddd, J = 4.2, 3.2, 1.0 Hz, =CH-2). 13
C
NMR (100.6 MHz, CDCl3): d = –1.1 (Me3Si), 32.9 (CH2-3),
34.1 (CH2-9), 41.7 (CH2-6), 57.6 (CH-9a), 124.8 (=CH-8),
125.0 (=CH-7), 131.1 (=CH-2), 137.21 (C-1), 166.1 (C-4).
HRMS (EI): m/z calcd for C12H19NOSi: 221.1236; found:
221.1234.
(14) Typical Procedure of Transformation of 3 to Bicyclic
Lactams 7
The mixture of 3 (5.5 mmol), NaI (11 mmol), and allyl
Synlett 2009, No. 15, 2508–2512 © Thieme Stuttgart · New York

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