Single-step symmetrical double alkylation of β,γ-unsaturated δ-lactams via magnesium 'ate' complexes

Article abstract of DOI:10.1055/s-0029-1217354

An easy approach to symmetrically 3,3-dialkylated derivatives of 3,6-dihydro-1H-pyridin-2-one in a one-pot and a single-step procedure via magnesium 'ate' complex is described. [Bu3Mg]Li used as the base showed great basic potential as one equivalent of i

Full text of DOI:10.1055/s-0029-1217354

1812
LETTER
Single-Step Symmetrical Double Alkylation of b,g-Unsaturated d-Lactams
via Magnesium ‘Ate’ Complexes
S
ymmetric
a
al
D
ouble
c
A
lkylation
e
of
b
,
g
-
Unsa
k
turated
d
-
Lact am
s
G. Sośnicki,* Łukasz Struk
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 26 February 2009
3,6,9,9a-tetrahydro-quinolizin-4-ones by ring-closing
Abstract: An easy approach to symmetrically 3,3-dialkylated de-
rivatives of 3,6-dihydro-1H-pyridin-2-one in a one-pot and a single-
step procedure via magnesium ‘ate’ complex is described.
[Bu3Mg]Li used as the base showed great basic potential as one
equivalent of it allowed double proton abstraction from 3,6-dihy-
dro-1H-pyridin-2-one. Deprotonation at noncryogenic conditions
yielded stable magnesiates which on treatment with more than two
equivalents of alkyl halides provided 3,3-dialkylated products in
good yield. In some cases minor 3,5-dialkylated lactams were
formed due to allylic conjugation.
metathesis (RCM).13
In the preliminary studies on 3-alkylation of 1,6-diallyl-
3,6-dihydropyridin-2-ones in the reaction of the adduct,
formed from lithium allyldibutylmagnesiate and N-
allylpyridin-2-one, with 1.1 equivalents of BnBr at –70 °C,
the formation of minor 3,3-dibenzylated b,g-unsaturated
d-lactam apart from 3-monobenzylated derivatives was
observed (Scheme 1).13 This observation prompted us to
investigate the possibility of 3,3-dialkylation of b,g-unsat-
urated d-lactams using magnesiates. The goal seemed to
be interesting in the aspect of further disclosing applica-
tions of magnesiates as reagents and because the quater-
nization adjacent to the carbonyl group is still a
challenging problem in synthetic organic chemistry.14
Moreover, 3,3-dialkyl substituted d-lactams exhibited
interesting biological activity.15
Key words: lactams, magnesium ‘ate’ complex, alkylation, pipe-
ridines
Magnesium ‘ate’ complexes have been known since Wit-
tig and co-workers described formation of lithium triphe-
nylmagnesiate ([Ph3Mg]Li) from its homometallic
components (PhLi and Ph2Mg) in 1951.1 However their
application in the synthesis has been explored intensively
only in the past decade. The main interest has been fo-
cused on halogen–magnesium exchange reactions2 and
only little attention has been devoted to magnesiates as
alkylating agents.1,3 Recently, much work has been car-
ried out to explore [R3Mg]Li as bases.4 Deprotonative
property of magnesium ‘ate’ complexes has been used
mainly in proton abstraction from the aromatic com-
pounds like activated benzenes, pyridines,5 oxazoles,6
furans,7 and thiophenes.8 There are only few examples of
the use of the magnesium ‘ate’ complexes as deprotonat-
ing agents able to eliminate H from sp3 carbon site.9
Bu
Mg
Li
Bu
1. BnBr (1.1 equiv)
Bn
Bn
Bn
2. H+
(1.05 equiv)
+
THF
THF
–70 °C
N
O
–70 °C
N
O
N
O
molar ratio 2.8:1
Scheme 1
Among our recent efforts on the synthesis of functional-
ized d-lactams10 and d-thiolactams,11 we have previously
reported on nucleophilic properties of lithium allyldibu-
tylmagnesiate {[AllylBu2Mg]Li}. This magnesium ‘ate’
complex, prepared by mixing of allylmagnesium chloride
and n-butyllithum in 1:2 molar ratio at 0 °C, allowed a
regioselective introduction of an allyl substituent onto a
piperidine ring.11c,12,13 Addition of lithium allyldibutyl-
magnesiate to N-methylpyridin-2-one at 0 °C yielded
mainly 6-allyl-1-methyl-3,6-dihydro-1H-pyridin-2-one,12
while added to N-allylpyridin-2-ones at –70 °C led exclu-
sively to 1,6-diallyl-3,6-dihydro-1H-pyridin-2-ones.13
The synthesis of the latter allowed us to obtain racemic
The hitherto applied double alkylation of lactams at C-a
relative to carbonyl, also in the introduction of the same
substituents,16 was frequently realized by successive treat-
ment of lactam with organolithium bases like: s-BuLi,
LDA, or LiHMDS followed by addition of alkyl electro-
philes after each equivalent of base used.17 Symmetrical
dialkylation in one-step protocol using two equivalents of
lithium bases at once at the beginning of the reaction was
only sparingly applied.18 Moreover, double alkylation of
b,g-unsaturated d-lactams at C-a was not reported, while
monoalkylation was achieved by trapping of lithium19 or
cuprate20 dienolates with electrophiles.
In this Letter we describe the preliminary results on a new
one-step symmetrical double alkylation of b,g-unsaturat-
ed d-lactams via magnesium ‘ate’ complexes, generated
by proton abstraction from b,g-unsaturated d-lactams us-
SYNLETT 2009, No. 11, pp 1812–1816
x
x
.x
x
.2
0
0
9
Advanced online publication: 12.06.2009
DOI: 10.1055/s-0029-1217354; Art ID: G05709ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Symmetrical
Double
Alkylation of
b
,
g
-Unsaturated4Symmetrical Double Alkylation of b,g-Unsaturated d-Lactams
d
-Lactam
s
1813
a
a
n-BuMgCl
MgCl
+ LiCl
+ 2 n-BuLi
+ 2 n-BuLi
[Bu3Mg] Li
[
(
1a
)
MgBu2] Li
(
1b)
+ LiCl
R2
R2
R2
R2
R2
R3
R3
–
R3
R3
Li+
MgBu2
R3X
e
1a
b
+
+
N
R1
O
N
R1
O
N
R1
5
O
N
R1
9
O
N
R1
O
4
3
10
R3X
R3X
c, d
c
1b
1b
R2
R2
R2
2a,b,e
R2
R3
MgBu
R3
BuMg
R3
•
LiX
+
O
MgBu2 • LiX
– n-BuH
N
R1
O
N
R1
O
N
R1
N
R1
O
2
6
7
8
Scheme 2 Reagents and conditions: (a) THF, 0 °C 5 min; (b) 1a (1.05 equiv), 0 °C, 0.5 h; (c) 1b (1.05 equiv), –72 °C, 15 min; (d) aq NH4Cl;
(e) R3X (> 2.0 equiv), 0 °C, 0.5–1 h.
ing [Bu3Mg]Li or by addition of [AllylBu2Mg]Li to pyri- Subsequently, addition of more than two equivalents of
din-2-ones.
primary alkyl halides (benzyl bromide, allyl bromide, and
n-propyl iodide) provided double 3,3-dialkylation (prod-
uct 9) within 30–60 minutes in good yields (Scheme 2,
Table 1).21 In the case of allyl bromide and propyl iodide,
formation of small quantity of 3,5-dialkylated products 10
was also observed.
At the first stage N-Me-, N-allyl-, N-Bn- and N-Ph-substi-
tuted 6-allyl-3,6-dihydro-1H-pyridin-2-ones 3a–d were
obtained as model compounds and were subsequently
submitted to the reaction with 1.05 equivalents of
[Bu3Mg]Li (Scheme 2, 1a) prepared simply by mixing of
n-BuMgCl and n-BuLi in 1:2 molar ratio. Deprotonations Substrates 3a–d were obtained according to the procedure
were performed at 0 °C for 0.5 hours in a THF solution.
described earlier,12,13 involving the addition of 1b to the
corresponding N-substituted pyridin-2-ones 2, however,
Table 1 Reaction Conditions, Yields, and Ratio of 9/10 Obtained in a Single-Step Dialkylation of 3 Using [Bu3Mg]Li (1a)
Entry
3a
R1
R3X (equiv)
BnBr (2.2)
AllBr (3.0)
n-PrI (2.3)
BnBr (2.2)
AllBr (3.0)
n-PrI (2.3)
BnBr (2.3)
AllBr (3.0)
n-PrI (2.3)
BnBr (2.3)
AllBr (3.0)
n-PrI (2.3)
9, 10
Ratio of 9/10b
>99:1
83:17
96:4
Yield of 9 and 10 (%)d
1
3a
3a
3a
3b
3b
3b
3c
3c
3c
3d
3d
3d
Me
Me
Me
Allyl
Allyl
Allyl
Bn
9a, 10a
9b, 10b
9c, 10c
9d, 10d
9e, 10e
9f, 10f
9g, 10g
9h, 10h
9i, 10i
94
76
81
72
60
70
98
89
87
98
94
72
2
3
4
>99:1
89:11
95:5
5
6
7
>99:1
90:10
97:3
8
Bn
9
Bn
10
Ph
9j, 10j
9k, 10k
9l, 10l
99:1
11
Ph
92:8
12
Ph
75:25c
a R2 = H.
b Ratio estimated by 1H NMR spectroscopy unless stated otherwise.
c Ratio estimated by 13C NMR spectroscopy.
d Total isolated yield.
Synlett 2009, No. 11, 1812–1816 © Thieme Stuttgart · New York

1814
J. G. Sośnicki, Ł. Struk
LETTER
in the present study low temperatures (–72 °C) were ap- formed from 3 and 1a or 2 and 1b, being stable near 0 °C,
plied (Scheme 2, Table 2). Since the low temperature ap- led to monoalkylated product 6 in the reaction with the
plied in the above reactions provided 3a, 3b, and 3e first equivalent of RX. Dibutyl magnesium (MgBu2)
regioselectively, the synthesis of 9a–f and 9m–s formed in this reaction together with LiX,22 also present in
(Scheme 2, Table 3) was possible in a one-pot procedure the reaction mixture, is basic enough23 to abstract proton
starting from 2a, 2b, and 2e. Thus, magnesium ‘ate’ com- from monoalkylated lactam 6 producing butylmagnesiat-
plexes of 2a, 2b, and 2e generated as a result of addition ed lactam 7 and 8 due to allylic conjugation. Since 7 is
of 1.05 equivalent of lithium allyldibutylmagnesiate (1b) well stabilized by carbonyl conjugation (not seen) product
at –72 °C and trapped with alkyl halides (>2.0 equiv), af- 9 is obtained in great majority as a result of the reaction
ter stirring at 0 °C provided double alkylated products in with second equivalent of alkyl halide.
good yields (Scheme 2, Table 3). At this stage, in order to
With respect to the 3,3- or 3,5-dialkylation regioselectivi-
check the generality of the proposed strategy, the broader
ty, BnBr and decyl iodide reacted the most regioselective-
spectrum of alkyl halides was used in the reaction with
ly and provided mainly 3,3-dialkylated product. However,
magnesium ‘ate’ complex obtained from 2a (Table 3, en-
it should be noted that 4-methyl substituent in 2e dimin-
ished 3,3-dibenzylation, yielding 3,3- (9p) and 3,5-di-
tries 1–6).
The reaction course of the worked-out synthesis of 9 is benzylated (10p) products in 91:9 molar ratio (Table 3,
presented in Scheme 2. Dibutylmagnesiated lactam 5, entry 10).
As far as the basicity of [Bu3Mg]Li is concerned the above
Table 2 Preparation of 3 According to the Procedure Presented in
Scheme 2
investigations led to the conclusion that trialkylmagne-
sium ‘ate’ complex has great basic potential because it en-
ables twice repeated proton abstraction. The preferred
monoalkylation at a low temperature (ca. –70 °C,
Scheme 1) and dialkylation possible near 0 °C indicated
different nucleophilic power of 5 and 7, 8 after the first
and the second deprotonation steps.
Entry
2
R1
R2
3, 4
Ratio of Yield of
3/4a
3 and 4 (%)b
1
2
3
4
5
2a
2b
2c
2d
2e
Me
H
3a, 4a
3b, 4b
3c, 4c
3d, 4d
3e, 4e
100:0
99:1
95:5
81
79
83
Allyl
Bn
H
Structures of 3, 9, and 10 were determined on the basis of
H
1D NMR (1H, 13C, 13C-DEPT), 2D NMR (1H, 1H COSY,
1
13C, H COSY) spectroscopy.24 Additionally, conforma-
Ph
H
69:31 93
100:0 91
tional analysis of 10p using the coupling constants and
Allyl
Me
1
molecular modelling as well as H,1H NOESY spectrum
a Ratio estimated by 1H NMR spectroscopy.
b Total isolated yield.
was applied to establish 5,6-trans configuration in 10. Al-
though a distinct cross-peak found in the NOESY spec-
Table 3 Reaction Conditions, Yields, and Ratio of 9/10 Obtained in a One-Pot Sequentional Addition of 1b to 2 Followed by Dialkylation
Entry
2
R1
R2
R3X (equiv)
9, 10
Ratio of
Yield of
9/10a
9 and 10 (%)c
1
2
2a
2a
2a
2a
2a
2a
2b
2b
2b
2e
2e
2e
Me
H
BnBr (2.2)
AllylBr (2.9)
n-PrI (2.3)
MeI (3.0)
9a, 10a
9b, 10b
9c, 10c
9m, 10m
9n, 10n
9o, 10o
9d, 10d
9e, 10e
9f, 10f
>99:1
85:15
97:3b
95:5
92
76
64
69
72
72
84
71
73
88
62
66
Me
H
3
Me
H
4
Me
H
5
Me
H
i-Bu (2.2)
83:17b
>99:1
>99:1
86:14
97:3
6
Me
H
n-DecylI (2.2)
BnBr (2.2)
AllylBr (3.0)
n-PrI (2.2)
BnBr (3.0)
AllylBr (3.0)
n-PrI (2.5)
7
Allyl
Allyl
Allyl
Allyl
Allyl
Allyl
H
8
H
9
H
10
11
12
Me
Me
Me
9p, 10p
9r, 10r
9s, 10s
91:9
80:20
95:5
a Ratio estimated by 1H NMR spectroscopy unless stated otherwise.
b Ratio estimated by 13C NMR spectroscopy.
c Total isolated yield (%).
Synlett 2009, No. 11, 1812–1816 © Thieme Stuttgart · New York

LETTER
Symmetrical
Double
Alkylation of
b
,
g
-Unsaturated4Symmetrical Double Alkylation of b,g-Unsaturated d-Lactams
d
-Lactam
s
1815
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trum between H-5 and H-6 of 10p indicated a short
distance between them in the molecule, the routine 1H, 1H
COSY spectra gave no visible cross-peak indicating the
absence or a small value of the vicinal coupling constants.
3
Indeed, JH-5,H-6 coupling constant refined from Lorentz-
ian to Gaussian resolution enhancement spectra was
established as ca. 1 Hz. According to the Haasnoot
equation25 this value corresponds to H-5/H-6 dihedral an-
gle of 79° and is in good agreement with the angle of 83°
present in 5,6-trans-disubstituted structure of 10p opti-
mized by PM3 calculation.26
In conclusion, we have demonstrated new and efficient
single-step, double-alkylation protocol of N-substituted
6-allyl-3,6-dihydro-2H-pyridin-2-ones performed in non-
cryogenic conditions using lithium tributylmagnesiate
(1a) as a base followed by treatment with primary alkyl
halides (> 2.0 equiv). Double proton abstraction achieved
by using of one equivalent of tributyl magnesium ‘ate’
complex revealed its great basic potential. It should be
emphasized that due to the combination of highly convert-
ible amide and alkenyl groups present in lactam, as well
as a broad range of electrophiles potentially used for the
dialkylation, the method proposed stand as valuable ap-
proach to functionalized piperidines. Investigation of the
possibilities and limitations of the 3,3-dialkylation of lac-
tams via trialkylmagnesium ‘ate’ complexes as well as the
possible synthesis of spirofunctionalized d-lactams in the
reaction with 1,n-dihalogenoalkanes and by 3,3-dialkenyl-
ation–RCM is currently under way.
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Acknowledgment
The authors thank West Pomeranian University of Technology,
Szczecin for financial support of this investigation.
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1816
J. G. Sośnicki, Ł. Struk
LETTER
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of aq sat. NH4Cl (5 mL), the aqueous layer was extracted
with EtOAc (2 × 50 mL) and the combined organic layers
were dried over MgSO4. Filtration, concentration in vacuo,
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2006, 3069. (b) Hanessian, S.; Tremblay, M.; Marzi, M.;
Del Ville, J. R. J. Org. Chem. 2005, 70, 5070. (c) Barberis,
M.; Garcia-Losada, P.; Pleite, S.; Rodriguez, J. R.; Soriano,
J. F.; Mendiola, J. Tetrahedron Lett. 2005, 46, 4847.
(17) See, for example: (a) Amat, M.; Lozano, O.; Escolano, C.;
Molins, E.; Bosch, J. J. Org. Chem. 2007, 72, 4431.
(b) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56,
9843. (c) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake,
J. F.; Williard, P. G. J. Am. Chem. Soc. 1998, 120, 7429.
(d) Meyers, A. I.; Seefeld, M. A.; Lefker, B. A.; Blake, J. F.
J. Am. Chem. Soc. 1997, 119, 4565. (e) Meyers, A. I.;
Lefker, B. A.; Wanner, K. T.; Aitken, R. A. J. Org. Chem.
1986, 51, 1936.
(18) (a) Brimble, M. A.; Trzoss, M. Tetrahedron 2004, 60, 5613.
(b) Colombo, L.; Di Giacomo, M.; Vinci, V.; Colombo, M.;
Manzoni, L.; Scolastico, C. Tetrahedron 2003, 59, 4501.
(c) Ezquerra, J.; Pedregal, C.; Rubio, A.; Vaquero, J. J.;
Matia, M. P.; Martin, J.; Diaz, A.; Navio, J. L. G.; Deeter,
J. B. J. Org. Chem. 1994, 59, 4327.
(22) Due to a well documented enhancement effect of LiCl on the
reactivity of Grignard reagents it is possible that the presence
of LiX (X = Cl, I) in the reaction environment influenced
basicity of MgBu2, see: Rauhut, C. B.; Vu, A. V.; Fleming,
F. F.; Knochel, P. Org. Lett. 2008, 10, 1187; and references
cited therein, see also ref. 23a.
(23) (a) Kerr, W. J.; Watson, A. J. B.; Hayes, D. Chem. Commun.
2007, 5049; and references cited therein. (b) Richey, H. G.
Jr.; King, B. A. J. Am. Chem. Soc. 1982, 104, 4672.
(24) Selected Spectroscopic Data
6-Allyl-3,3-dibenzyl-1-methyl-3,6-dihydro-1H-pyridin-
2-one (9a)
Colorless solid (0.62 g, 94%), mp 61–63 °C (from n-
hexane). IR (KBr pellet): n = 3028 (w), 2912 (w), 1628 (s),
1496 (w), 1456 (w), 1398 (w), 1348 (w), 1230 (w), 916 (w),
756 (m), 744 (m), 702 (m), 696 (m) cm–1. 1H NMR (400.1
MHz, CDCl3): d = 1.03 (1 H, dt, J = 14.0, 8.3 Hz, 6-CHH),
1.86 (1 H, dm, J = 14.0 Hz, 6-CHH), 2.65 (2 H, d, J = 12.6
Hz, 2 × 3-CHH), 2.69 (3 H, s, NCH3), 3.14–3.20 (1 H, m,
CH-6), 3.44 (1 H, d, J = 12.6 Hz, 3-CHH), 3.47 (1 H, d, J =
12.6 Hz, 3-CHH), 4.70–4.80 (2 H, m, =CH2), 4.92–5.05 (1
H, m, =CH), 5.42 (1 H, dd, J = 10.3, 3.2 Hz, =CH-5), 5.54 (1
H, dd, J = 10.3, 1.6 Hz, =CH-4), 7.08–7.27 (10 H, m,
2 × C6H5). 13C NMR (100.6 MHz, CDCl3): d = 32.46
(NCH3), 38.20 (6-CH2), 45.93, 46.58 (2 × 3-CH2), 50.54 (C-
3), 59.03 (CH-6), 117.86 (=CH2), 125.33 (=CH-5), 128.80
(=CH-4), 126.20, 126.35, 127.54, 127.79, 130.30, 130.66,
137.61, 137.82 (2 × C6H5), 132.61 (=CH), 170.80 (C-2).
GC-MS (EI, 70eV): m/z = 331 (<1) [M+], 290 (100), 198
(28), 122 (37), 91 (63). Anal. Calcd for C23H25NO: C, 83.34;
H, 7.60; N, 4.23. Found: C, 83.25; H, 7.69; N, 4.13.
(25) Haasnoot, C. A. G.; DeLeeuw, F. A. A. M.; Altona, A.
Tetrahedron 1980, 36, 2783.
(19) Anderson, T. F.; Knight, J. G.; Tchabanenko, K.
Tetrahedron Lett. 2003, 44, 757.
(20) Niida, A.; Mizumoto, M.; Narumi, T.; Inokuchi, E.; Oishi,
S.; Ohno, H.; Otaka, A.; Kitaura, K.; Fujii, N. J. Org. Chem.
2006, 71, 4118.
(21) Typical Procedure for the Dialkylation of 3 Using
[Bu3Mg]Li (1a)
To a cooled (0 °C) and stirred solution of BuMgCl (2.1
mmol, 1.05 mL, 2.0 M in THF) in dry THF (2 mL) in a
Schlenk flask, n-BuLi (4.2 mmol, 1.68 mL, 2.5 M in hexane)
was added via syringe over 1 min under argon. A yellow
suspension formed was stirred for 5 min and was next
transferred via syringe to a cooled (0 °C) solution of 6-allyl-
1-methyl-3,6-dihydro-1H-pyridin-2-ones (3a, 0.3 g, 2.0
mmol) in THF (10 mL). The resulting yellow solution was
stirred for 30 min at 0 °C, and then benzyl bromide (0.75 g,
(26) PM3 calculations were performed using the HyperChem
program (7.52 release).
Synlett 2009, No. 11, 1812–1816 © Thieme Stuttgart · New York