Microwave-assisted tandem cross metathesis intramolecular Aza-Michael reaction: An easy entry to cyclic β-amino carbonyl derivatives

Article abstract of DOI:10.1021/ja0709829

Hoveyda-Grubbs catalyst in combination with BF3·OEt2 efficiently promotes tandem cross metathesis intramolecular aza-Michael reaction between enones and unsaturated carbamates resulting in the creation of β-amino carbonyl units. The use of microwave irradiation dramatically accelerates the process, enhancing the synthetic utility of this methodology for the preparation of these types of derivatives. When enantiomerically enriched ∞-branched amines were used as starting materials, the process was also very efficient, although with modest selectivity in the newly created stereocenter. The use of microwave irradiation led to an interesting effect, inverting the selectivity in the addition process. Copyright

Full text of DOI:10.1021/ja0709829

Published on Web 05/05/2007
Microwave-Assisted Tandem Cross Metathesis Intramolecular Aza-Michael
Reaction: An Easy Entry to Cyclic â-Amino Carbonyl Derivatives
Santos Fustero,*,†,‡ Diego Jime´nez,† Mar´ıa Sa´nchez-Rosello´,† and Carlos del Pozo†
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia, E-46100 Burjassot, Spain, and Laboratorio de
Mole´culas Orga´nicas, Centro de InVestigacio´n Pr´ıncipe Felipe, E-46013 Valencia, Spain
Received February 11, 2007; E-mail: santos.fustero@uv.es
Tandem or cascade processes1 have emerged as a powerful tool
to perform several chemical reactions in a single process, increasing
molecular complexity in only one operation and thus avoiding the
handling and isolation of intermediates. The design of a tandem
process is not generally obvious requiring two criteria: (1)
compatibility of reagents with each product formed in any single
reaction and (2) high conversion in each single reaction to obtain
a high-yielding sequence. Among all reagents used in tandem
processes, it is worth mentioning the use of ruthenium alkylidene
complexes.2 Their development in terms of stability and commercial
availability has led chemists to access a wide range of synthetic
applications and have extended their usefulness.
Scheme 1 . Synthetic Strategy for the Preparation of â-Amino
Carbonyl Units
Table 1. Optimization Conditions of the Tandem Protocol
In this sense, Grubbs et al.3 reported a very elegant straightfor-
ward synthesis of (R)-(-)-muscone via one-pot, three-component
RCM-transfer dehydrogenation-hydrogenation catalyzed by a
single Ru source. Several successful examples of tandem processes
have been described since then, involving a RCM-isomerization
sequence,4 a one-pot three-component tandem RCM-Diels-Alder
reaction,5 a tandem RCM-Kharasch addition,6 a RCM-dihydroxy-
lation sequence,7 a ROM-RCM reaction,8 a CM-allylic alcohol
isomerization process,9 a tandem enyne metathesis/Claisen rear-
rangement,10 or a tandem enyne metathesis followed by a cyclo-
propanation of the newly formed exo-cyclic double bond.11
To the best of our knowledge, no example of a CM-aza-Michael
tandem process has been described, and encouraged by recent
advances in tandem processes we decided to explore such a
sequence. The aza-Michael reaction leads to the creation of â-amino
carbonyl units, which are very important structures present in a
large number of natural products and pharmaceutical ingredients.
Although many examples of aza-Michael addition of N-protected
amines or their synthetic equivalents to R,â-unsaturated carbonyl
compounds have been described in its intermolecular variant, very
little is known about its intramolecular counterpart. All these reasons
prompted us to explore this tandem protocol that makes a rapid
access to Cbz-protected â-homoproline and â-pipecolic acid deriva-
tives in only one step, possible using readily available starting
materials (Scheme 1).
Initial screening reactions were conducted using carbamates as
nitrogen nucleophiles. Thus, the Cbz-protected starting amines 2
were obtained from the corresponding commercially available nitrile
by LiAlH4 reduction and nitrogen protection. A model reaction
between methyl vinyl ketone 1a and amine 2a was used to optimize
the reaction conditions. In the presence of second generation Grubbs
catalyst I (10 mol %) in dichloromethane (DCM) under reflux, the
only formed product after 5 h was 3a, the corresponding cross-
coupled product between both methyl vinyl ketone 1a and 2a in
45% yield. The corresponding tandem process product 4a was not
detected (Table 1, entry 1).
entry
catalyst
conditions
% 3a
% 4a
additive
1
2
3
4
5
I
DCM/∆/5 h
45
71
35
none
none
none
BF3‚OEt2
BF3‚OEt2
II
II
II
II
DCM/∆/5 h
3
21
99
96
toluene/∆/5 h
DCM/45 °C/4d
DCM/100 °C µwave/20 min
Scheme 2 . Reaction of Ruthenium Ligand with Enone 1a
The reduction of catalyst loading (5 mol %) and longer reaction
times did not produce any significant improvement in the process.
We then decided to check Hoveyda-Grubbs catalyst II since it
has been described to facilitate cross-coupling reactions between
olefins bearing EWG and terminal olefins.12 Using the aforemen-
tioned conditions, the use of catalyst II provided 71% of the CM
product together with a small amount of the tandem adduct (3%)
(Table 1, entry 2). We next explored the influence of the
temperature, and thus the reaction was carried out in toluene under
reflux giving rise to 21% of the tandem adduct and 35% of the
CM product (Table 1, entry 3). This result led us to consider the
possibility that catalyst II would be acting as a weak Lewis acid
through its axial coordination site (oxygen ligand). Once the first
catalytic cycle is completed, the styrene moiety leaves the metal
coordination sphere, and the ruthenium acts as a Lewis acid through
its empty d orbital. This assumption was supported by the fact that
compound 6 was isolated as a byproduct in the CM reaction
(Scheme 2). At the same time it might explain why catalyst II works
better than I in the tandem protocol, since the axial phosphine ligand
remains bonded to the ruthenium in catalyst I, avoiding the
activation of the aza-Michael step.
At this point, we decided to evaluate the use of some additives
to activate the cyclization step. It is well-known that carbamates
are weak nucleophiles in aza-Michael reactions, and either a basic13
† Universidad de Valencia.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
9
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J. AM. CHEM. SOC. 2007, 129, 6700-6701
10.1021/ja0709829 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Tandem Protocol
In summary, we have developed the first cross metathesis
intramolecular aza-Michael tandem reaction, catalyzed by a Hov-
eyda-Grubbs second generation catalyst (II)/BF3‚OEt2 system, that
allows rapid access to protected 2,5-substituted pyrrolidine and
2-substituted piperidine heterocyles with excellent overall yields.
Microwave irradiation effectively accelerates the tandem process,
producing an inversion of the selectivity when R-substituted amines
were used as starting materials. These â-amino carbonyl units are
very interesting building blocks for the synthesis of several
alkaloids. In addition, the tandem protocol constitutes one of the
few intramolecular aza-Michael reactions of Cbz-protected amines
reported in the literature, thus becoming a straightforward meth-
odology to access such compounds. New applications of this
methodology are currently under study.
1
2
R1
n
R2
(
±
)-4,5
% yielda
1a
1a
1b
1b
1c
1c
1a
2a
2b
2a
2b
2a
2b
2c
Me
Me
n-Pr
n-Pr
n-Pn
n-Pn
Me
1
2
1
2
1
2
1
H
H
H
H
H
H
F
4a
5a
4b
5b
4c
5c
4d
99 (96)
82 (93)
73 (65)
79 (72)
81 (70)
83 (61)
60 (55)
a In brackets are the yields obtained when the reaction was performed
under microwave irradiation.
Acknowledgment. The authors thank the Ministerio de Edu-
cacio´n y Ciencia (BQU2003-01610) and the Generalitat Valenciana
(GR03-193) of Spain for financial support. D.J. and M.S. express
their thanks for predoctoral fellowships, and C.P. acknowledges a
Ramo´n y Cajal contract.
Table 3. Tandem Protocol with Substituted Amines 7
Supporting Information Available: Experimental procedures and
NMR spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
7
R
8,9
% yield (8/9)a,b
% yield (8/9)a,c
(µwave)
References
a
b
c
i-Pr
Ph
a
b
c
97 (3/1)
98 (6/1)
78 (4/1)
76 (5/1)
81 (1/4)
86 (1/2)
97 (1/2)
97 (1/3)
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PMPd
CF3
d
d
a Diastereomeric ratios were determined by GC-MS. b Thermal reaction.
c Microwave irradiation reaction. d PMP ) 4-MeO-C6H4.
or acidic14 activation is needed. It has been previously described
that boron compounds efficiently promote CM reactions of enones
in the presence of catalyst II.15 Furthermore, these substrates have
also been employed in the intermolecular aza-Michael addition of
carbamates.16 Since BF3‚OEt2 has shown its compatibility with both
types of processes, we decided to use it as the additive. We per-
formed the tandem protocol with catalyst II (5 mol %) in the
presence of BF3‚OEt2 (1 mol %). To our delight, the expected prod-
uct 4a was isolated in 99% yield, after continuous heating of the
reaction mixture at 45 °C in a sealed tube for 4 days (Table 1,
entry 4). The reaction time was dramatically reduced (20 min) when
microwave irradiation was employed (Table 1, entry 5). Once rea-
ction conditions had been optimized, we extended this tandem
process to other alkyl vinyl ketones and protected amines. The
results are summarized in Table 2. It is noteworthy that the tandem
process is independent of the ketone substitution affording good
to excellent chemical yields in the formation of both five- and six-
membered rings.
The next step of our study was the extension of the tandem
protocol to enantiomerically enriched substituted amines 7. With
this purpose, we prepared a set of R-branched Cbz-protected amines
following known protocols (see Supporting Information), which
were subjected to the tandem process, applying the optimized
reaction conditions using methyl vinyl ketone 1a as the enone
component. The obtained results are summarized in Table 3.
Once again the overall process was very efficient, providing
excellent chemical yields in all cases albeit with moderate selectivity
in the formation of the newly created stereocenter.17 After continu-
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(with trans relative disposition) are formed to a major extent.
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the reaction was performed under microwave irradiation, was
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the major diastereoisomers.18
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(17) The relative stereochemistry of the newly created stereocenter was
determined by NOESY experiments over compounds 8a and 9a (see
Supporting Information).
(18) A solvent study over substrate 7a was performed (with the process under
microwave irradiation). The reaction was carried out in DCM, toluene,
THF, and acetonitrile. The best results in terms of selectivity and yield
were obtained in DCM.
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