Thermal [2+2] cycloaddition of CF3-substituted allenynes: Access to novel cyclobutene-containing α-amino acids

Article abstract of DOI:10.1055/s-0030-1261217

An efficient approach for the preparation of novel CF₃- substituted cyclic α-amino acid derivatives fused with cyclobutene ring has been developed. The method is based on intramolecular thermal [2+2] cycloaddition of amino acid containing allen

Full text of DOI:10.1055/s-0030-1261217

LETTER
2321
Thermal [2+2] Cycloaddition of CF3-Substituted Allenynes: Access to Novel
Cyclobutene-Containing a-Amino Acids
[2+2]
C
ycloadditior3
n
of CF
t
-Subst
u
ituted Alleny
r
nes K. Mailyan,a Ivan M. Krylov,a Christian Bruneau,b Pierre H. Dixneuf,b Sergey N. Osipov*a
a
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
Vavilov Str. 28, 119991 Moscow, Russian Federation
Fax +7(499)1355085; E-mail: osipov@ineos.ac.ru
Institute Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France
b
Received 27 June 2011
processes, the thermal version of this reaction occurring in
the absence of any activation reagents or catalysts and
without creating any waste products is an ideal carbon–
carbon bond-forming process in terms of high atom econ-
Abstract: An efficient approach for the preparation of novel CF3-
substituted cyclic a-amino acid derivatives fused with cyclobutene
ring has been developed. The method is based on intramolecular
thermal [2+2] cycloaddition of amino acid containing allenynes
with internal triple bond obtained by successive [2,3]-sigmatropic omy and selectivity.
rearrangement of propargyl-containing nitrogen CF3-ylides and
Sonogashira derivatization of the triple bond.
However, the synthesis of allenynes bearing different
functionalities is not a trivial task requiring numerous syn-
thetic stages.4 Recently, we have developed an efficient
one-step method for the preparation of fluorinated a-ami-
nocarboxylic and a-aminophosphonic acid containing
enynes and the unique allenynes based on [2,3]-sigmatro-
pic rearrangement of allyl(propargyl) ylides. The synthet-
ic potential of those doubly unsaturated systems has been
further demonstrated in intermolecular cobalt-mediated
Pauson–Khand reaction to afford the corresponding bicy-
clic amino acid derivatives and their phosphorous ana-
logues (Scheme 1).5
Key words: allenynes, Sonogashira coupling, [2+2] cycloaddition,
cyclobutenes, amino acids
Transformation of acyclic functional molecules into bicy-
clic species is synthetically useful because bioactive com-
pounds typically comprise polycyclic structural
frameworks associated to the required functionality. In re-
cent decade, carbo- and heterocyclic compounds fused
with cyclobutene ring have attracted enhanced attention
since they are the key structural units frequently observed
in biologically relevant structures1 (Figure 1).
O
MeO
N
Me
F3C
X
OMe
OMe
CO2Me
CO2Me
OMe
X
F3C
MeO
H
N
[M]
– N2 [2,3]
N2
Me
N
MeO
Me
F3C
X
anticancer activity1a
H
PK
[M]
O
NHAc
O
OP(O)(OMe)2
N
anti-inflammatory and
antitumor activities1c
Me
[M] = Cu(F3-acac)2 for [2,3]
Co2(CO)8 for PK
X = CO2Me;
P(O)(OEt)2
Cl
AChE inhibitor1b
Scheme 1 Synthesis of functionalized CF3 heterocycles
Figure 1 Selected biologically active cyclobutene-containing com-
pounds
Fluorine-containing amino acids, especially their con-
strained cyclic derivatives, attract a considerable interest
as crucial targets in bioorganic and medicinal chemistry
for the design of potent and highly selective bioactive
compounds.6 Along with our current investigations direct-
ed towards the development of new methodologies for the
synthesis of trifluoromethylated cyclic a-amino acids,7 we
report now an efficient synthesis of a-CF3-a-amino acid
containing 1,6- and 1,7-allenynes with internal triple bond
and their subsequent intramolecular termal [2+2] cycload-
dition involving the terminal allene double bond to afford
the corresponding fused cyclobutene derivatives, which
are also potential bioactive compounds (Scheme 2).
The combination of high strain and unsaturation renders
cyclobutenes as versatile synthons for a number of useful
synthetic transformations such as electrocyclic ring open-
ing, metathesis-type reactions, epoxidation, or cyclopro-
panation.2 The intramolecular [2+2] cycloaddition of
allenynes represents the most prominent strategy for the
construction of fused cyclobutene derivatives just in one
step.3 With respect to environmentally friendly chemical
SYNLETT 2011, No. 16, pp 2321–2324
x
x
.x
x
.2
0
1
1
Advanced online publication: 08.09.2011
DOI: 10.1055/s-0030-1261217; Art ID: B12011ST
© Georg Thieme Verlag Stuttgart · New York

2322
A. K. Mailyan et al.
LETTER
Table 1 Synthesis of Allenynes 4 and 5 via Sonogashira Reaction
1.
Me N
F3C
MeO2C
n
Entry
n
1
1
1
1
1
1
1
2
2
2
Ar
Product
4a
Yield (%)a
Cu(F3-acac)2, 100 °C
F3C
CO2Me
•
N
1
2
Ph
82
74
81
77
73
80
82
84
65
80
2. ArI, PdCl2(PPh3)2
CuI, r.t.
Me
N2
Ar
n
4-MeC6H4
2-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-O2NC6H4
2-O2NC6H4
Ph
4b
n = 1, 2
3
4c
F3C
MeO2C
N
[2+2]
4
4d
Δ
Me
5
4e
n
Ar
n = 1, 2
6
4f
Scheme 2 Access to cyclobutene-containing a-CF3-a-amino acid
7
4g
derivatives
8
5a
Thus, we found that 1,6- and 1,7-allenynes 4 and 5 can be
readily obtained in good yields by the two-step sequence
involved [2,3]-sigmatropic rearrangement and Pd-cata-
lyzed Sonogashira coupling reaction. For the rearrange-
ment stage proceeding through the formation of
propargyl-containing ylides,5 methyl-2-diazocarboxylate
(1) was heated with N,N-dipropargyl-N-methylamine or
N-homopropargyl-N-propargyl-N-methylamine in the
presence of 5–10 mol% of copper trifluoroacetylacetonate
in toluene to give the corresponding 1,6- and 1,7-allen-
ynes with terminal triple bond in 71% (2) and 60% (3)
yields, respectively (Scheme 3).
9
4-MeOC6H4
4-O2NC6H4
5b
10
5c
a After column chromatography on silica gel (hexanes–EtOAc).
pound 3 has proved to be completely inert even under
heating in xylenes at 185 °C (plugged Schlenk tube) for
24 hours. The data obtained are in agreement with litera-
ture examples published for the related [2+2] thermal re-
actions of simple allenynes.3 At the same time, it is known
that the mechanism of this cycloaddition involves the for-
mation of diradical intermediates8 and any substituent on
triple bond of allenyne, which can effectively stabilize
these biradicals, is expected to be extremely essential for
successful conversion.3e
F3C
Me N
MeO2C
•
F3C
CO2Me
n
N
Me
Cu(F3-acac)2, toluene, 100 °C
N2
Indeed, 1,6-allenynes 4a–g comprising radical-stabilizing
aryl groups on triple bond were successfully transformed
into the corresponding bicyclo[4.2.0]octa-1,6-dienes 6 in
excellent yields under refluxing in toluene for 2 hours
(Scheme 4, Table 2, entries 1–7). It is significant that the
formation of cyclobutene ring proceeds upon distal dou-
ble bond of allene moiety exclusively. The nature of the
substituents on the benzene ring did not significantly af-
fect the outcome of the reaction.
n
1
2 (n = 1), 3 (n = 2)
F3C
ArI, PdCl2(PPh3)2
CuI
MeO2C
N
Me
Ar
DMF, Et3N, r.t.
n
4a–g (n = 1), 5 a–c (n = 2)
Scheme 3 Synthesis of CF3-allenynes with internal triple bond
F3C
MeO2C
F3C
MeO2C
[2+2]
To synthesize allenynes 4 and 5 with internal triple bond
the palladium-catalyzed cross-coupling of 2 and 3 with
different aryl iodides was successfully performed using 5
mol% PdCl2(PPh3)2/CuI catalytic system in the mixture of
N,N-dimethylformamide and triethylamine at room tem-
perature. In each case the desired allenynes 4 and 5 were
isolated in good yields (Table 1).
N
N
Me
Me
Δ
n
Ar
Ar
n
4a–g (n = 1)
5a–c (n = 2)
6a–g (n = 1)
7a–c (n = 2)
Scheme 4 Thermal [2+2] cycloaddition of allenynes 4 and 5
Thermal [2+2] cycloaddition of 1,7-allenynes 5a–c re-
quires more drastic conditions. Thus, in this case the full
conversion was achieved only under heating in xylenes at
185 °C (plugged Schlenk tube) for 36 hours to afford the
target CF3-substituted azepine-2-carboxylates fused with
cyclobutene ring 7a–c in high yields (Scheme 4, Table 2,
entries 8–10).
The investigation of intramolecular [2+2] cycloaddition
of synthesized allenynes commenced with the reactions of
1,6- and 1,7-allenynes 2 and 3 bearing terminal alkyne
unit. For this purpose they were heated in toluene or xy-
lenes for 3–24 hours.
As a result, only decomposition of 2 has been detected un-
der refluxing in toluene for 3 hours. In contrast, the com-
Synlett 2011, No. 16, 2321–2324 © Thieme Stuttgart · New York

LETTER
[2+2] Cycloaddition of CF3-Substituted Allenynes
2323
Table 2 Thermal [2+2] Cycloaddition of 1,6- and 1,7-Allenynes:
Synthesis of Cyclobutenes 6 and 7
Table 2 Thermal [2+2] Cycloaddition of 1,6- and 1,7-Allenynes:
Synthesis of Cyclobutenes 6 and 7 (continued)
Entry Producta Structure
Yield (%)b
Entry Producta Structure
Yield (%)b
F3C
F3C
MeO2C
MeO2C
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
80
N
N
N
Me
Me
10
7c
91
F3C
NO2
MeO2C
a Conditions for 6: refluxing in toluene for 2 h; conditions for 7: heat-
ing in xylenes at 185 °C for 36 h (plugged Schlenk tube).
b Isolated yield after flash column chromatography on silica gel (hex-
anes–EtOAc).
80
90
86
74
87
93
87
Me
Me
F3C
MeO2C
In conclusion, the present study first demonstrated that
allenynes possessing a-CF3-a-amino acid skeleton can re-
gioselectively undergo intramolecular [2+2] cycloaddi-
tion of the distal double bond of the allene moiety leading
to a hitherto unknown class of CF3-substituted cyclic a-
amino acid fused with cyclobutene ring. This simple and
environmentally benign process would extend the poten-
tial application of bicyclic amino acid derivatives in syn-
thetic and medicinal chemistry. We are continuing our
studies into the scope and limitations of this new method
and also investigating the synthetic utility of these func-
tional cyclobutenes.
Me
N
N
Me
F3C
MeO2C
Me
OMe
F3C
MeO2C
OMe
N
N
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
experimental details and NMR spectra for all new compounds.
Me
F3C
MeO2C
Acknowledgment
Me
This work was financially supported by RFBR-PICS and GDRI
grants (No 07-03-92171, 08-03-92504) in the frame of bilateral col-
laboration between CNRS France and Russian Academy of Sci-
ences.
NO2
F3C
MeO2C
NO2
6g
7a
N
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Me
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LETTER
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