Alkali base-initiated Michael addition/alkyne carbocyclization cascades

Article abstract of DOI:10.1021/ol2033674

A new cascade reaction involving an intramolecular Michael addition followed by an alkyne carbocyclization is presented. The reaction is promoted by a substoichiometric amount of KHMDS and represents one of the rare examples where the carbocyclization of

Full text of DOI:10.1021/ol2033674

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1016–1019
Alkali Base-Initiated Michael Addition/
Alkyne Carbocyclization Cascades
Christopher Kourra, Felix Klotter, Filippo Sladojevich, and Darren J. Dixon*
Chemistry Research Laboratory, Department of Chemistry, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, U. K.
darren.dixon@chem.ox.ac.uk
Received December 16, 2011
ABSTRACT
A new cascade reaction involving an intramolecular Michael addition followed by an alkyne carbocyclization is presented. The reaction is
promoted by a substoichiometric amount of KHMDS and represents one of the rare examples where the carbocyclization of an unactivated alkyne
is mediated by an alkali metal base, under mild conditions. The reaction allows the generation of functionally dense, stereochemically defined,
tricyclic structures possessing three adjacent stereocenters in good yields and with high stereoselectivity.
Cascade reactions are valuable tools in the hands of
organic chemists, allowing the generation of molecular
complexity from readily available starting materials. Dur-
ing a cascade process, several new carbonÀcarbon bonds
and stereogenic centers can be created inone pot ina highly
controlled fashion, thus facilitating the execution of short
and efficient reaction routes.1 The development of new
catalyzed cascade sequences represents an ultimate goal, in
terms of economy of resources, time, and reduction of
waste generation. Our group has developed several cata-
lytic cascade sequences involving activation of alkyne
functionalities toward nucleophilic addition via the use
of appropriate transition metal ions such as copper2 or
gold3 complexes.
We envisaged that compounds like structure 1 (Scheme 1),
bearing two electrophilic centers and two nucleophilic
centers, would represent an ideal substrate for a cascade
processinvolving aninitial Michael addition step, followed
by a carbocyclization of the newly formed ketone-enolate
onto the pendant alkyne functionality, as illustrated in
Scheme 1. We planned to realize this transformation by
means of a multicatalytic system comprising a combina-
tion of a Brønsted basic/secondary amine catalyst to
promote the Michael addition step and a transition metal
catalyst to promote the nucleophilic addition onto the
alkyne functionality.
(1) For reviews on cascade reactions see: (a) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186. (b) Tietze,
L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis;
Wiley-VCH: Weinheim, Germany, 2006; p 672. (c) Pellissier, H. Tetrahedron
2006, 62, 1619–1665. and 2143–2173.
(2) (a) Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon,
D. J. J. Am. Chem. Soc. 2009, 131, 9140–9141. (b) Wang, H.-F.; Yang,
T.; Xu, P.-F.; Dixon, D. J. Chem. Commun. 2009, 3916–3918. (c) Yang,
T.; Ferrali, A.; Campbell, L.; Dixon, D. J. Chem. Commun. 2008, 2923–
2925.
Inordertotestour hypothesis, wepreparedmalonamate
derivative 4a (Table 1), and we decided to first study the
Michael addition step using a series of organic/inorganic
catalysts. To our surprise, when compound 4a was treated
with inorganic bases such as KH, KHMDS, or NaHMDS,
the main product isolated from the reaction mixture was
not the expected Michael adduct 5 but compound 6a
(3) (a) Yang, T.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2007,
129, 12070–12071. (b) Muratore, M. E.; Holloway, C. A.; Pilling, A. W.;
Storer, R. I.; Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131,
10796–10797. (c) Barber, D. M.; Sanganee, H.; Dixon, D. J. Chem.
Commun. 2011, 47, 4379–4381.
(4) For reviews on carbocyclization to carbon-carbon multiple
ꢀ ꢁ
ꢀ
bonds, see: (a) Denes, F.; Perez-Luna, A.; Chemla, F. Chem. Rev.
2010, 110, 2366–2447. (b) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan,
R. J. Chem. Rev. 1996, 96, 635–662.
r
10.1021/ol2033674
Published on Web 01/31/2012
2012 American Chemical Society

Table 1. Optimization of the Reaction Conditions
Scheme 1. Concept for the Michael Addition/Alkyne Carbocy-
clization Cascade
entry
1
base
solvent temp (°C)/ time concn (M) yield (%)a
(Table 1), derived from an initial intramolecular Michael
addition followed by an alkyne carbocyclization and an
isomerization step.
Although numerous examples of carbocyclizations of
nucleophiles onto unactivated alkynes are known,4 less
common are those mediated by alkali metal bases, espe-
cially under catalytic conditions.5
Herein, we report the discovery, optimization and the
substrate scope of this new catalyzed cascade reaction,
promoted by alkali metal bases.
When a solution of precursor 4a in tetrahydrofuran was
treated with a stoichiometric amount of potassium bis-
(trimethylsilyl)amide (KHMDS) (15% w/w solution in
toluene),6 the only product present in the reaction mixture
was tricycle 6a, which was isolated in 43% yield (entry 1,
Table 1) as a single diastereoisomer.7
KHMDS
THF
0 °C/10 min
20 °C/2 h
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
43
44
43
(1.00 equiv)
KHMDS
2
3
4
5
6
7
8
9
toluene 0 °C/10 min
20 °C/24 h
(1.00 equiv)
KHMDS
dioxane 0 °C/10 min
20 °C/2.5 h
(1.00 equiv)
t-BuOK
b
THF
THF
THF
THF
THF
THF
THF
0 °C/45 min
40 °C/4 h
0 °C/45 min
40 °C/4 h
0 °C/45 min
40 °C/4 h
0 °C/45 min
40 °C/20 h
0 °C/45 min
40 °C/72 h
0 °C/45 min
40 °C/4 h
À
(0.50 equiv)
NaHMDS
(0.50 equiv)
KHMDS
59
51
81
(0.50 equiv)
KH
(0.5 equiv)
LHMDS
b
À
(0.50 equiv)
KHMDS
79
(0.25 equiv)
c
10 KHMDS
(0.25 equiv)
0 °C/45 min
20 °C/9.5 h
À
The reaction outcome proved similar when tetrahydro-
furan was replaced with toluene, but a longer reaction time
was required (entry 2, Table 1). When 1,4-dioxane was
used as solvent, a comparable result to the use of tetra-
hydrofuran was obtained (entry 3, Table 1).
a Isolated yield. b Only the Michael adduct intermediate was isolated.
c An inseparable mixture of Michael adduct 5 and 6 was obtained in a
0.84:1.00 ratio as determined by 1H NMR analysis of the crude reaction
mixture.
We hypothesized that the low yield obtained in entries 1À3
was due to partial decomposition under the reaction condi-
tions, rather than to lack of reactivity (no starting material 4a
or Michael adduct 5 were observed by NMR analysis of the
crude reaction mixture for entries 1À3 in Table 1). When
sodium and potassium bis-(trimethylsilyl)amides were used
in substoichiometric amount (0.5 equiv), the reaction yield
was increased respectively to 59 and 51% (entries 5 and 6,
Table 1), while t-BuOK and LHMDS were unable to
promote the cascade process and yielded Michael adduct 5
(entry 4 and 8, Table 1).8 Further reduction of the amount of
base to 0.25 equiv led to a satisfactory 79% yield of the
desired tricycle 6a (entry 9, Table 1). Decrease of the reaction
temperature from 40 to 20 °C did not result in a full
consumption of the intermediate Michael adduct 5. Similarly,
a decrease of the amount of KHMDS from 0.25 to 0.10 equiv
resulted in incomplete consumption of intermediate 5 after
heating in THF at 40 °C for 24 h. We therefore identified
optimal reaction conditions as those reported in entry 9 in
Table 1: initially, a solution of precursor 4 was treated with
KHMDS at 0 °C and stirred at this temperature for 45 min, in
order to let the Michael addition take place. Subsequently,
the reaction mixture was transferred to a preheated oil bath at
40 °C and stirred until all intermediate 5 was converted to
product 6. It should be noted that a rigorous exclusion of air
(5) (a) Eglinton, G.; Whiting, M. C. J. Chem. Soc. 1953, 3052–3059.
(b) Kitagawa, O.; Suzuki, T.; Fujiwara, H.; Fujita, M.; Taguchi, T.
Tetrahedron Lett. 1999, 40, 4585–4588. (c) Gao, K.; Wu, J. Org. Lett.
2008, 10, 2251–2254. (d) Dumez, E.; Durand, A.-C.; Guillaume, M.;
ꢁ
Roger, P.-Y.; Faure, R.; Pons, J.-M.; Herbette, G.; Dulcere, J.-P.;
Bonne, D.; Rodriguez, J. Chem.;Eur. J 2009, 15, 12470–12488. (e)
ꢁ
Guillaume, M.; Dumez, E.; Rodriguez, J.; Dulcere, J.-P. Synlett 2002,
11, 1883–1885.
(6) Several different batches of KHMDS solutions were tested.
KHMDS solutions in THF and toluene from Aldrich, Alfa Aesar, and
Acros were tested, and in all cases, comparable results were obtained.
(7) The stereochemistry of 6a was assigned by analogy to the product
of the intramolecular Michael addition/enolate alkylation reaction
shown below, which was established via single crystal X-ray analysis.
(8) At present, the effect of the nature of the alkali base on the
reaction outcome remains unclear. However, when KH is used as
promoter, turnover is observed, therefore suggesting that enolate 13
(c.f. Scheme 3) is competent as the reaction promoter.
For details, see: Sladojevich, F.; Michaelides, I. N.; Darses, B.; Ward, J. W.;
Dixon, D. J. Org. Lett. 2011, 13, 5132–5135.
Org. Lett., Vol. 14, No. 4, 2012
1017

and moisture was required in order to obtain acceptable
results, and the use of Schlenk line techniques was found ideal
for guaranteeing the reproducibility of the reaction.
Table 3. Preparation of Cascade Precursors 4iÀ4l
Table 2. Preparation of Cascade Precursors 4aÀ4h
entry
1
7
8
4 yield (%)
4a, 74
7a, R = PMB,
R1 = Me
8a, R2 = Me,
n = 1
2
3
4
5
6
7
8
7b, R = Bn,
R1 = Me
8a, R2 = Me,
n = 1
4b, 64
4c, 63
4d, 79
4e, 86
4f, 70
4g, 84
4h, 81
7c, R = CH2CHdCH2,
R1 = Me
8a, R2 = Me,
n = 1
7d, R = CH2CH(OMe)2,
R1 = Me
8a, R2 = Me,
n = 1
7e, R = PMB,
R1 = n-pentyl
7a, R = PMB,
R1 = Me
8a, R2 = Me,
n = 1
Scheme 2. Scope of the Reaction
8b, R2 = t-Bu,
n = 1
7a, R = PMB,
R1 = Me
8c, R2 = Bn,
n = 1
8d, R2 = Me,
n = 2
7a, R = PMB,
R1 = Me
Oncethe optimal reactionconditionswere identified, the
reaction scope was surveyed. For this purpose, a series of
precursors 4aÀ4h were readily prepared using standard
amide coupling of amines 7aÀe with acid chlorides 8aÀd,
as detailed in Table 2. Further precursors 4iÀ4l, bearing an
internal acetylenic function, were prepared via Sonoga-
shira coupling of 4a or 4d with iodo-derivatives 9aÀ9d, as
shown in Table 3. With12substrates 4aÀ4l, presenting five
diversification points (RÀR3 and n) in hand, the carbocy-
clization cascade was tested using optimal conditions, and
the results are presented in Scheme 2. Substitution on the
amine was well tolerated, and various groups could be
introduced in this position without affecting the diaster-
eoselectivity or yield of the cyclization process: tricyclic
compounds 6aÀ6d were obtained in good yields ranging
from 79 to 86%, and all of them were obtained as single
diastereoisomers. Substitutionon the cyclohexene ring was
investigated through introduction of a n-pentyl chain on
the β-carbon (R1 group in compound 4e). Pleasingly, also
in this case the expected product 6e was obtained in good
yield upon exposure to the optimized reaction conditions.
We then investigated substitution on the ester group and
prepared substrates incorporating a t-butyl ester and a
benzyl ester (substrates 4f and 4g). Steric hindrance on the
ester group was found to have no effect on the diastereos-
electivity, and tricyclic products 6f and 6g were isolated in
respectively 75 and 72% yield as single diastereoisomers.
a The reaction was performed with 0.5 equiv of KHMDS.
b Only the intermediate Michael adduct was isolated.
1018
Org. Lett., Vol. 14, No. 4, 2012

preferential formation a stable conjugated system is neces-
sary for the reaction to occur. Although a detailed
mechanistic investigation has not been carried out, we hy-
pothesize the scenario illustrated in Scheme 3, where the
alkali base acts as a promoter, initiating the cascade
process via an initial and irreversible deprotonation of
the CRÀH of malonamate 4a. A subsequent Michael
addition of the potassium enolate with the cyclohexenone
generates a second enolate 11 that undergoes carbocycliza-
tion with the pendant alkyne group to give 12. A final series
of proton transfer steps leads to the formation of extended
enolate 13. A final protonation of 13 from a molecule of
starting material results in product 6a and the regeneration
of malonamate enolate 10.
Scheme 3. Plausible Mechanistic Hypothesis
In summary, we have discovered and developed a new
cascade process involving a Michael addition/alkyne car-
bocyclization cascade initiated using substoichiometric
quantities of alkali metal base. The reaction takes place
under mild conditions and gives access to stereochemically
defined, tricyclic structures in good yields and high stereo-
selectivity. Further investigation of this transformation, as
well as application to total synthesis, is currently under
investigation in our laboratories.
Notably, non-terminal alkynes were also effective sub-
strates for the cyclization. Substituted aromatic groups could
be introduced at the terminal acetylenic position: com-
pounds 4iÀ4k were successfully cyclized with good yield,
independently of the substitution on the aromatic ring.
Precursors 4j and 4k, bearing respectively a p-Me and a p-Cl
substituted aromatic ring were both cyclized with comparable
yield (70 and 71%). Also, alkene groups could be introduced at
the terminal acetylenic position via Sonogashira coupling: 4a
was coupled with (E)-(2-iodovinyl)benzene (9d) to give 4l,
which was successfully converted to tricycle 6l in 55% yield
when treated under optimizedreaction conditions. Interestingly,
for compounds bearing an internal acetylene group, a single
regioisomer bearing the newly formed double bond in con-
jugation with the ketone, not the arene or alkene, was obtained.
The fact that for all examples reported in Scheme 2 the
final products possess a conjugated enone suggests that the
Acknowledgment. We thank the EPSRC (Leadership
Fellowship to D.J.D., postdoctoral fellowships to F.S), the
EC [IEF to F.S. (PIEF-GA-2009-254068)], Andrew Kyle,
David Barber of the Department of Chemistry, University
of Oxford, for X-ray analysis, and the Oxford Chemical
Crystallography Service for the use of the instrumentation.
Supporting Information Available. Experimental pro-
cedures and spectral data for compounds 4aÀ4l, 5a,
6aÀ6g, 6iÀ6l, 7aÀ7e, and all intermediates required for
their preparation, and experimental procedures for
8aÀ8d. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
1019