Copper-catalyzed asymmetric conjugate addition of alkenyl- and alkylalanes to α,β-unsaturated lactams

Article abstract of DOI:10.1021/ol303505k

Alkenyl and alkyl groups have been successfully introduced to six-membered α,β-unsaturated lactams via a copper-catalyzed asymmetric 1,4-addition of the corresponding alanes. Moderate to good yields and good to excellent enantioselectivities are achieved by using a combination of the very cheap copper(II) naphthenate and a readily available phosphine amine ligand. The creation of an all-carbon quaternary stereogenic center, via Michael addition to a trisubstituted conjugated lactam, is also disclosed for the first time.

Full text of DOI:10.1021/ol303505k

ORGANIC
LETTERS
2013
Vol. 15, No. 4
828–831
Copper-Catalyzed Asymmetric Conjugate
Addition of Alkenyl- and Alkylalanes to
r,β-Unsaturated Lactams
€
Pierre Cottet, Daniel Muller, and Alexandre Alexakis*
Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30,
CH-1211 Geneva 4, Switzerland
alexandre.alexakis@unige.ch
Received December 21, 2012
ABSTRACT
Alkenyl and alkyl groups have been successfully introduced to six-membered R,β-unsaturated lactams via a copper-catalyzed asymmetric
1,4-addition of the corresponding alanes. Moderate to good yields and good to excellent enantioselectivities are achieved by using a combination
of the very cheap copper(II) naphthenate and a readily available phosphine amine ligand. The creation of an all-carbon quaternary stereogenic
center, via Michael addition to a trisubstituted conjugated lactam, is also disclosed for the first time.
Among the main reactions in organic synthesis, the
asymmetric conjugate addition (ACA) of organometallic
species is one of the most powerful tools for enantioselective
CꢀC bond formation. Highly effective Cu- and Rh-cata-
lyzed procedures have been reported on a wide range of
Michael acceptors and have been applied in the total synthe-
sis of natural products.1 However, some Michael acceptors
remain challenging substrates in ACA reactions, such as
R,β-unsaturated lactams, on which most efforts have been
dedicated to the introduction of aryl substituents. In 2001,
Hayashi was the first to describe the highly enantioselective
Rh-catalyzed 1,4-addition of arylboron reagents to 5,6-
dihydro-2(1H)-pyridinones.2 Later, various types of aryl
nucleophiles were successfully employed: arylsiloxanes,3
aryl[2-(hydroxymethyl)phenyl]dimethylsilanes,4 2-hetero-
arylzinc reagents,5 and arylboronic acids.6 In 2004, Feringa
reported the ACA of nonstabilized alkyl nucleophiles to
R,β-unsaturated lactams, allowing for the formation of
enantioenriched β-alkyl-substituted δ-lactams.7 Neverthe-
less, a limited number of alkyl groups could be introduced in
high enantioselectivity. Moreover, the use of alkenyl nu-
cleophiles in the context of Michael addition to conjugated
lactams is scarce in the literature.6b Based on our experience
in the field of alkenyl alanes chemistry,8 we decided to
(4) Nakao, Y.; Chen, J.; Imanaka, H.; Hiyama, T.; Ichikawa, Y.;
Duan, W.-L.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2007, 129,
9137.
(5) Smith, A. J.; Abbott, L. K.; Martin, S. F. Org. Lett. 2009, 11,
4200.
(1) For reviews on asymmetric conjugate additions, see: (a) Sibi, M. P.;
€
Manyem, S. Tetrahedron 2000, 56, 8033. (b) Krause, N.; Hoffmann-Roder,
A. Synthesis 2001, 171. (c) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem.
2002, 3221. (d) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.
(6) (a) Shao, C.; Yu, H.-J.; Wu, N.-Y.; Tian, P.; Wang, R.; Feng,
C.-G.; Lin, G.-Q. Org. Lett. 2011, 13, 788. (b) Lin, G.-Q.; Feng, C.-G.;
Tian, P.; Shao, C.; Yu, H.-J.; Wu, N.-Y. CN 101979378 A, 2011. (c) Jin,
S.-S.; Wang, H.; Xu, M.-H. Chem. Commun. 2011, 47, 7230. (d) Kuuloja,
€
(e) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rossle, M. Synthesis
€
ꢀ
2007, 1279. (f) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.;
ꢁ
Dieguez, M. Chem. Rev. 2008, 108, 2796. (g) Harutyunyan, S. R.; den
Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008,
108, 2824.
(2) Senda, T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66,
6852.
(3) Gini, F.; Hessen, B.; Feringa, B. L.; Minnaard, A. J. Chem.
Commun. 2007, 710.
ꢁ
N.; Vaismaa, M.; Franzen, R. Tetrahedron 2012, 68, 2313. (e) Jin, S.-S.;
Wang, H.; Zhu, T.-S.; Xu, M.-H. Org. Biomol. Chem. 2012, 10, 1764. (f)
He, Z.-T.; Wei, Y.-B.; Yu, H.-J.; Sun, C.-Y.; Feng, C.-G.; Tian, P.; Lin,
G.-Q. Tetrahedron 2012, 68, 9186.
(7) Pineschi, M.; Del Moro, F.; Gini, F.; Minnaard, A. J.; Feringa,
B. L. Chem. Commun. 2004, 1244.
r
10.1021/ol303505k
Published on Web 01/29/2013
2013 American Chemical Society

reinvestigate R,β-unsaturated lactams as substrates for
ACA reactions (during the course of our study, Feng, Lin,
et al. published the enantioselective rhodium-catalyzed 1,4-
addition of potassium alkenyltrifluoroborates to R,β-unsa-
turated lactams).9 Herein, we describe the asymmetric
copper-catalyzed Michael addition of alkenyl- and alkyla-
lanes to six-membered conjugated lactams, leading to valu-
able building blocks for the preparation of optically active
nitrogen-containing heterocycles.
Table 1. Optimisation of the Reaction Conditionsa
Very recently, we reported optimized conditions for the
copper-catalyzed 1,4-addition to 2,3-dehydro-4-piperidones.8g
The reaction, promoted by a chiral monodentate phosphine
amineꢀcopper complex, is highly enantioselective, what-
ever the nature of the organoaluminum reagent (alkenyl,
alkyl, and aryl). Assuming that 2,3-dehydro-4-piperidones
and R,β-unsaturated lactams might have similar reactivity,
we decided to start with the same reaction conditions in this
study, on 1a as substrate of choice (prepared from the
commercially available δ-valerolactam, by a three steps
sequence: protection, R-selenation, elimination).7,10 Ac-
cording to the study of Feringa, the right protecting-activat-
ing group had to be selected in his case, in order to get full
conversion and high enantioselectivity.7 The benzyloxycar-
bonyl (Cbz) group was chosen for our test substrate 1a
because it could be cleaved without touching the lactam
function, contrary to other protecting groups.11 As shown in
Table 1, the original conditions developed for 2,3-dehydro-
4-piperidones could be applied on 1a, affording the desired
product 2a with acceptable isolated yield (58%) and a
promising enantioselectivity of 80% (entry 1). The reaction
was catalyzed by the combination of copper(II) naphthe-
nate (CuNp) and a SimplePhos ligand L1, which can be
easily prepared on a multigram scale.8f Coactivation with
Me3Al was also employed for the reaction to proceed, as
previously reported for challenging substrates in the context
of tandem hydroalumination/Cu-catalyzed 1,4-additions.8f,g
The enantiomeric excess could be increased by lowering the
reaction temperature. Unfortunately, it caused a decrease of
the isolated yield, even if the reactions went to completion in
both examples (entries 2 and 3). Running the reaction in
toluene (entry 4) or THF (entry 5) led mainly to a degrada-
tion of the starting material. Interestingly, good results were
obtained when the lactam 1a was added to the reaction
mixture in a toluene solution. These conditions allowed for
the formation of the 1,4-adduct in acceptable isolated yield
(53%) and good enantioselectivity (86%) while preserving
the reaction temperature at a more practical value (entry 6).
entry lactam Cu saltb
solvent
temp (°C) yieldc (%) eed (%)
1
1a
1a
1a
1a
1a
1a
1b
1a
CuNp Et2O
ꢀ10
ꢀ30
ꢀ50
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
58
55
42
80
84
89
2
CuNp Et2O
3
CuNp Et2O
4e
5e
6
CuNp toluene
CuNp THF
CuNp Et2O/toluene
CuNp Et2O/toluene
CuTC Et2O/toluene
53
42
50
86
66
87
7
8
a Reactions performed on a 0.2 mmol scale, under an Ar atmosphere.
Conversion = 100%, determined by 1H NMR of the crude mixture.
b CuNp = solution of copper(II) naphthenate in pentane; CuTC =
Cu(II) thiophene-2-carboxylate. c Isolated yields. d Determined by
supercritical fluid chromatography (SFC) on a chiral stationary phase.
e A degradation of the starting material was mainly observed by 1H NMR
of the crude reaction mixture.
Then, lactam 1b,12 bearing a tert-butoxycarbonyl (Boc)
moiety as an alternative protecting group, was subjected
to this Michael addition. Unfortunately, the corresponding
product 2b was isolated in lower yield and poorer enantio-
selectivity (entry 7). Finally, the reaction was performed in
the presence of copper(I) thiophene-2-carboxylate (CuTC)
on 1a (entry 8). This copper salt and CuNp gave similar
results. However, the reaction is slightly cleaner in the
presence of the latter. Moreover, the fact that CuNp can
be used as a stock solution and is the cheapest commercially
available organic copper source urged us to choose CuNp
for the following study.
With the optimized conditions in hand, we studied the
nucleophile scope of the reaction (Table 2). Efficient
methodologies were selected for the preparation of the
requisite aluminum-based reagents: either by hydroalumi-
nation of terminal alkynes with DIBAL-H (method A),
which can affordthe branchedvinylalaneinthe presenceof
the right Ni complex (method C) or by lithiumꢀhalogen
exchange from the corresponding alkenyl bromide, fol-
lowed by transmetalation with Me2AlCl (method B).13 As
shown in Table 2, alkyl β-substituted alkenylalanes, made
via hydroalumination with DIBAL-H, could be intro-
duced to 1a effectively, providing the desired 1,4-adducts
in good enantioselectivities and practical yields (entries 1
and 3), which could be improved by increasing the reaction
scale (entry 2). However, a more sterically demanding
alkenylalane, bearing a tert-butyl group, led to a lower
(8) (a) Alexakis, A.; Albrow, V.; Biswas, K.; d’Augustin, M.; Prieto,
O.;Woodward, S. Chem. Commun. 2005, 2843. (b)Vuagnoux-d’Augustin,
M.; Alexakis, A. Chem.;Eur. J. 2007, 13, 9647. (c) Hawner, C.; Li, K.;
Cirriez, V.; Alexakis, A. Angew. Chem., Int. Ed. 2008, 47, 8211. (d) Palais,
€
L.; Alexakis, A. Chem.;Eur. J. 2009, 15, 10473. (e) Muller, D.; Hawner,
€
C.; Tissot, M.; Palais, L.; Alexakis, A. Synlett 2010, 1694. (f) Muller, D.;
€
Tissot, M.; Alexakis, A. Org. Lett. 2011, 13, 3040. (g)Muller, D.;Alexakis,
€
A. Org. Lett. 2012, 14, 1842. (h) Muller, D.; Alexakis, A. Chem. Commun.
2012, 48, 12037.
(9) Yu, H.-J.; Shao, C.; Cui, Z.; Feng, C.-G.; Lin, G.-Q. Chem.;Eur.
J. 2012, 18, 13274.
(10) (a) Casamitjana, N.; Lopez, V.; Jorge, A.; Bosch, J.; Molins, E.;
Roig, A. Tetrahedron 2000, 56, 4027. (b) Foti, C. J.; Comins, D. L.
J. Org. Chem. 1995, 60, 2656.
(11) As stated in the Supporting Information of ref 7.
ꢁ
ꢁ
´
nguez, G.; Perez-Castells, J.
(12) del Villar, I. S.; Gradillas, A.; Domı
Tetrahedron Lett. 2010, 51, 3095.
(13) For details about these methodologies (advantages and
limitations), see ref 8g and references cited therein.
Org. Lett., Vol. 15, No. 4, 2013
829

Table 2. Cu-Catalyzed ACA of Alkenylalanes to Lactam 1aa
Table 3. Cu-Catalyzed ACA of Alkyl- and Arylalanes to
Lactam 1aa
entry
R
yieldb (%)
eec (%)
1
2
3
4
Med
Etd
i-Bud
Phe
54 (2j)
45 (2k)
42 (2l)
51 (2m)
94
96
86
86
alkenylalane
entry methodb R1
R2
R3
yieldc (%) eed (%)
1
Ae
Ae
Ae
Ae
Ae
Bg
Bg
Ch
Ae
H
n-Bu
H
H
H
H
H
H
H
H
53 (2a)
70 (2a)
54 (2c)
66 (2d)
58 (2e)
69 (2f)
54 (2g)
30 (2h)
86
86
82
72
84
90
74
51
12
a Reactions performed on a 0.2 mmol scale, under an Ar atmosphere.
Conversion = 100%, determined by 1H NMR or TLC. b Isolated yields.
c Determined by SFC on a chiral stationary phase. d Commercially
available R3Al were used. e Alane made by lithiumꢀhalogen exchange
from bromobenzene, followed by transmetalation with Me2AlCl; coac-
tivation with 1.0 equiv of Me3Al.
2f
3
H
n-Bu
Cy
H
4
H
t-Bu
(CH2)3Cl
Ph
5f
6
H
H
7
Me
n-Bu
H
H
8
9i
H
inappropriate to promote the 1,4-addition of a Z-alkenyla-
lane, prepared by hydroalumination of tert-butyl propargyl
ether.8g,15 Under the standard reaction conditions, Me and
i-Bu transfer were mainly observed. The same issue was
encountered with 2,3-dehydro-4-piperidones, and special
conditions were developed (Et2O was replaced by THF to
suppress Me- and i-Bu-transfer; 20 mol % of Kubas salt
[Cu(MeCN)4]BF4 and 22 mol % of ligand L1 were used; 3
equiv of alane was added).8g These modifications allowed us
actually to isolate 47% of the desired product 2i. Unfortu-
nately, almost no enantioselectivity was observed (entry 9).
Since a limited number of alkyl chains have been success-
fully introduced selectively to R,β-unsaturated lactams,7
it was interesting to test our conditions in the presence of
various trialkylaluminum reagents (Table 3). To our delight,
under the same conditions, the reaction afforded the product
2j in a high enantioselectivity of 94%, which was a great
improvement for the methyl group (entry 1). The reaction
worked equally well with triethylaluminum (entry 2). A good
enantiomeric excess was obtained for the isobutyl derivative
2l (entry 3). The reaction was also extended to the 1,4-
addition of an arylalane, leading to the product 2m in a
moderate yield and a good enantioselectivity (entry 4).
Interestingly, the CuTC/L2 complex, known to be
highly efficient for Michael additions with organoalumi-
num reagents,8b,c gave excellent results for the 1,4-addition
of trimethylaluminum to the N-Boc derivative 1b (eq 1).16
H
CH2O-t-Bu 47 (2i)
a Reactions performed on a 0.2 mmol scale, under an Ar atmosphere.
Conversion = 100%, determined by 1H NMR or TLC. b The letter
indicated refers to the general procedure which was used for the
preparation of the corresponding alane; see the Supporting Information
for details. c Isolated yields. d Determined by SFC on a chiral stationary
phase. e Alanes made by hydroalumination of terminal alkynes with
DIBAL-H (R = iBu).8g f Reaction performed on a 0.4 mmol scale.
g Alanes made by lithiumꢀhalogen exchange from the corresponding
alkenyl bromides, followed by transmetalation with Me2AlCl (R =
Me).8e,g h Alane made by Ni-catalyzed R-hydroalumination of 1-hexyne
(R = iBu).8g,14 i Et2O was replaced by THF, 20 mol % of Kubas salt
[Cu(MeCN)4]BF4, and 22 mol % of ligand L1 were used; 3 equiv of alane
was added.8g
enantiomeric excess (entry 4). Interestingly, good results
were obtainedwith a functionalized alane, allowing further
transformations on the corresponding product (entry 5).
The lithiumꢀbromine exchange/transmetalation sequence
was used to generate the pure trans-styryl alane, which
underwent the ACA with good yield and good enantio-
selectivity (entry 6). The same strategy was used to prepare
isopropenylalane from 2-bromopropene. It went through
a clean 1,4-addition, albeit with a relatively lower level of
stereoinduction (entry 7). Then, a second alkyl R-substi-
tuted alkenylalane was made by Ni-catalyzed R-hydroalu-
mination of 1-hexyne.8g,14 However, the corresponding
product 2h was obtained in a low isolated yield and a poor
enantioselectivity (entry 8). The presence of THF, required
for the preparation of this aluminum reagent, should be
incompatible with the catalytic system (as seen in Table 1,
entry 5). The steric hindrance of the R-substituted alkenyl
alane could also be responsible for the low selectivity. In
addition, the presence of Ni derivatives in the reaction
mixture may not explain this result because it has been shown
that nickel salts could catalyze with a very low efficiency the
conjugate addition of alkenylalanes to 2,3-dehydro-4-
piperidones.8g Finally, the catalytic system proved to be
Finally, we investigated the ability of our catalytic
system for promoting ACA to trisubstituted conjugated
lactams. The substrate 1c was prepared by protection of the
(14) Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10961.
830
Org. Lett., Vol. 15, No. 4, 2013

intermediate in the synthesis of a family of herbicides, whose
general strucure is depicted in Scheme 1.19
Table 4. Cu-Catalyzed ACA of Triethylaluminum to the
β-Substituted Conjugated Lactam 1ca
Scheme 1. Synthetic Utility of Lactam 3
entry
L
Cu saltb
temp (°C)
yieldc (%)
eed (%)
1
2
3
L1
L2
L2
CuNp
CuTC
CuTC
ꢀ10
ꢀ10
ꢀ30
33
58
53
64 (þ)
78 (ꢀ)
87 (ꢀ)
a Reactions performed on a 0.2 mmol scale, under an Ar atmosphere.
Conversion = 100%, determined by 1H NMR or TLC. b CuNp =
solution of copper(II) naphthenate in pentane; CuTC = Cu(II) thio-
phene-2-carboxylate. c Isolated yields. d Determined by SFC on a chiral
stationary phase.
a Properties observed for the racemic form of the corresponding
compounds.
known 4-methyl-5,6-dihydropyridin-2(1H)-one.17 By ap-
plying the optimized reaction conditions in the presence of
triethylaluminum, we were pleased to obtain the desired
product 3 in 33% of isolated yield and a promising enantio-
meric excess of 64% (Table 4, entry 1). Then, a nice
improvement could be achieved by the use of the CuTC/
L2 complex (entry 2). By lowering the reaction temperature
to ꢀ30 °C, the product 3 could be formed in practical yield
(53%) and good optical purity (87% ee) (entry 3).
It should be noted that lactam 3 could serve as a precursor
for the preparation of compounds with interesting properties
(Scheme 1). Its deprotection by hydrogenation was carried
out to form the product 4, of which the racemic form showed
biological activities (partial agonist in the central nervous
system).18 The lactam 4 could also be considered as an
In conclusion, a series of alkenyl groups have been
successfully introduced to an R,β-unsaturated lactam, af-
fording valuable building blocks in the synthesis of enan-
tioenriched nitrogen-containing heterocycles. The chiral
SimplePhos/copper complex proved to also be highly effi-
cient to promote the 1,4-addition of trialkylaluminum
reagents. β-Methyl-substituted δ-lactams were formed in
very high optical purity. By slightly modifying the general
procedure, the first example of ACA to β-substituted con-
jugated lactams is reported, allowing the formation of an all-
carbon quaternary stereogenic center. Extension of this
methodology is ongoing in our laboratory.
Acknowledgment. We thank the Swiss National Research
Foundation (Grant No. 200020_144344) for financial sup-
port. Chiral amines were kindly provided by BASF.
(15) Alexakis, A.; Duffault, J. M. Tetrahedron Lett. 1988, 29, 6243.
(16) Unfortunately, the CuTC/L2 catalytic system gave no satisfying
results for the introduction of alkenyl substituents to both compounds
1a and 1b.
(17) Kawanaka, Y.; Kobayashi, K.; Kusuda, S.; Tatsumi, T.;
Murota, M.; Nishiyama, T.; Hisaichi, K.; Fujii, A.; Hirai, K.; Nishizaki,
M.; Naka, M.; Komeno, M.; Nakai, H.; Toda, M. Bioorg. Med. Chem.
2003, 11, 689.
Supporting Information Available. Experimental proce-
dures, NMR spectra, and chiral separations for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Laycock, G. M.; Shulman, A. Nature 1963, 200, 849.
(19) Kudou, T.; Tanima, D.; Masuzawa, Y.; Yano, T. WO
2010026989 A1, 2010.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
831