Reaction of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 2,4,6-tris(trifluoromethyl)-1,3,5-triazine: Planning and serendipity

Article abstract of DOI:10.1002/chem.201100379

Tri and you will succeed! A new type of formal [3+3] cyclization reaction of 2,4,6-tris(trifluoromethyl)-1,3,5-triazine with 1,3-bis(trimethylsilyloxy)-1, 3-butadienes has been discovered that provides a convenient approach to functionalized 2,6-bis(trifl

Full text of DOI:10.1002/chem.201100379

DOI: 10.1002/chem.201100379
Reaction of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes with 2,4,6-
Tris(trifluoromethyl)-1,3,5-triazine: Planning and Serendipity
Viktor O. Iaroshenko,*[a, b] Alina Bunescu,[a, c] Anke Spannenberg,[c] and
Peter Langer*[a, c]
Inverse electron-demand Diels–Alder (IEDDA) reactions
have gained a wide popularity as synthetic tool for the as-
sembly of complex carbocyclic and heterocyclic products,[1]
as well as natural products,[2] and drug-like scaffolds.[3] Elec-
tron-deficient heterocyclic azadienes have proven to be
useful reagents for IEDDA reactions with electron-rich di-
enophiles, providing a rapid access to a wide range of highly
substituted heterocyclic systems.[4]
which to date have only scarcely been reported in the litera-
ture.
In analogy to the known transformations of enol esters
and silyl enol ethers, it was expected that the reaction of
2,4,6-tris(trifluoromethyl)-1,3,5-triazine (2) with 1,3-bis(tri-
methylsilyloxy)-1,3-butadiene 1a would deliver pyrimidine
3. To our surprise, the reaction followed an unusual pathway
and led to the formation of g-pyridone 4a as the major
product in 78% yield (Table 1). The reaction was carried
Reactions of azadienes with classical enamines, enol
esters, and thioenol esters, as well as with amidines and gua-
nidines have been reported.[1] 1,2-Diazines, 1,2,4-triazines,
and 1,2,4,5-triazines can be regarded as masked azadienes.
Their reactions with dienophiles generally involve the for-
mation of a bridged intermediate and subsequent extrusion
of nitrogen (N2). In case of 1,3,5-triazines, elimination of a
nitrile is observed. For example, CF3-containing electron-
poor heterocyclic azadienes, such as 3,6-bis(trifluorometh-
yl)-1,2,4,5-tetrazine and 3,6-bis(trifluoromethyl)-1,2,4-tria-
zine, were recently explored for the assembly of heterocyclic
and carbocyclic frameworks.[5] We have reported the synthe-
sis of annulated 2,6-bis(trifluoromethyl)pyrimidines[6] and
the corresponding nucleosides of purine isosteres by the
IEDDA reaction of 2,4,6-tris(trifluoromethyl)-1,3,5-triazine
with electron-excessive heteroaromatic amines, anilines, and
enamines. Based on these results, and on our experience re-
lated to the chemistry of 1,3-bis(trimethylsilyloxy)-1,3-buta-
dienes,[7] we decided to study the reaction of the latter with
2,4,6-tris(trifluoromethyl)-1,3,5-triazine (2). We considered
that this reaction may produce a novel synthetic access to 2-
(2,6-bis(trifluoromethyl)pyrimidin-4-yl)acetate derivatives 3,
Table 1. Optimization of the synthesis of 4a.[a]
c (1)
[mmol]
c (2)
[mmol]
c (TMSOTf)
[mmol]
4a
G
E
U
[%][b]
1
1
2
2
0
1
30
78
[a] Reagents and conditions: trimethylsilyl trifluoromethanesulfonate
(TMSOTf), CH2Cl2, ꢀ78!208C; then 10% HCl; then EtOH, 50–608C,
10–25 h. [b] Yields of isolated products.
[a] Dr. V. O. Iaroshenko, A. Bunescu, Prof. Dr. P. Langer
Institut fꢀr Chemie, Universitꢁt Rostock
Albert-Einstein-Str. 3a, 18059 Rostock (Germany)
Fax : (+49)381-498-6412
out in three steps. In the first step, a CH2Cl2 solution of the
reaction mixture was stirred in the presence of trimethylsilyl
trifluoromethanesulfonate (TMSOTf, slow warming from
ꢀ78 to 208C during 12–14 h). Subsequently, hydrochloric
acid (10%) was added to the reaction mixture to cleave the
silyl groups. In the third step, an ethanol solution of the
crude product was heated at 50–608C to yield 4a (Table 1).
Stirring the ethanol solution and heating under reflux
(788C) instead of at 50–608C resulted in a dramatic de-
crease of the yield and the formation of several unidentified
products. The employment of TMSOTf proved to be impor-
tant; the yield decreased to 29% when the reaction was car-
ried out in the absence of TMSOTf (Table 1).
E-mail: viktor.iaroshenko@uni-rostock.de
[b] Dr. V. O. Iaroshenko
Department of Chemistry, National Taras Shevchenko University
62 Volodymyrska st., Kyiv-33, 01033 (Ukraine)
Fax : (+380)44-537-32-53
E-mail: iva108@googlemail.com
[c] A. Bunescu, Dr. A. Spannenberg, Prof. Dr. P. Langer
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock e.V.
Albert-Einstein-Str. 29a, 18059 Rostock (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100379.
7188
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Chem. Eur. J. 2011, 17, 7188 – 7192

COMMUNICATION
Encouraged by this finding, we decided to investigate the
scope, limitations, and the mechanism of the new cyclization
reaction. Therefore, we have studied, following the opti-
mized conditions, the reaction of triazine 2 with 1,3-bis (tri-
methylsilyloxy)-1,3-butadienes 1a–n (Table 2). The reaction
Table 2. Yields of 2,6-bis(trifluoromethyl)-1,4-dihydro-4-oxopyridines
4a–j.[a]
1
R1
R2
4
[%][b]
Figure 1. Crystal structure of 4b as a monohydrate.
1a
1b
1c
1d
1e
1 f
1g
1h
1i
H
H
H
H
H
H
H
H
Me
Et
Me
Et
iPr
Bn
4a
4b
4c
4d
4e
4 f
4g
4h
4i
78
95
64
57
77
69
40
54
35
23
0
The new product was isolated by using flash chromatogra-
phy and its structural elucidation revealed that the bridged
heterocycle 5a had been formed (Table 3).
AHCTUNGRTEG(NNUN CH2)2OMe
iBu
iPent
nOct
Me
Me
Me
1j
1k
1l
4j
4k
4l
Table 3. Yields of compounds 5a–e.[a]
A
Me
0
1m
1n
U
Me
Me
4m
4n
0
0
[a] Reagents and conditions: TMSOTf, CH2Cl2, ꢀ78!208C, 12 h; then
10% HCl; then EtOH, 50–608C, 10–25 h. [b] Yields of isolated products.
of 2 with dienes 1a–j afforded products 4a–j. The reactions
of dienes 1a–h, containing no substituent located at carbon
C4 of the diene, proceeded in good yields and with very
good regioselectivity. In fact, no isomeric structures, such as
3, were detected under the reaction conditions studied. The
yields decreased for dienes 1i and 1j containing a methyl
and an ethyl group, respectively (Table 2). For dienes 1k–n,
no product could be isolated (due to formation of complex
mixtures). The reaction of 2 with 2-substituted 1,3-bis(trime-
thylsilyloxy)-1,3-butadienes again resulted in the formation
of a complex mixture.
1
5
R1
R2
6
[%][a]
1a
1i
1k
1m
1n
5a
5b
5c
5d
5e
H
Me
ACHTUNGTRENNUNG
Me
Me
Me
Me
Me
6a
6b
6c
6d
6e
43
54
42
71
48
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a] Reagents and conditions: a) CH2Cl2, ꢀ78 to 208C, 12 h; then HCl
(10%); b) EtOH, 50–608C, 10–25 h. [b] Yields of isolated products.
The structure of product 4b was independently confirmed
by X-ray crystal structure analysis (Figure 1).[8] Product 4b
is, as expected, a flat molecule, which crystallized as a mon-
ohydrate.
The structure of 5a was independently confirmed by X-
ray crystal structure analysis (Figure 2).[8] The pure com-
pound 5a could be successfully transformed to pyridone 4a
by simple heating in ethanol at 50–608C (See Table 3 and
Table 4). Likewise, reaction of 2 with diene 1i afforded the
bridged compound 5b, which was isolated and could be
transformed into 4i. The reaction of dienes 1k–n with 2
gave products 5c–e; however, the thermal transformation of
the latter into products 4 failed. The stereochemical out-
come of the cycloaddition was determined by the X-ray
crystal structure analysis of 5d. The ORTEP plot shows that
5d possesses an endo configuration and it also shows the rel-
We next focused our attention on the isolation of the in-
termediate formed in the first step of the reaction. The reac-
tion, which was carried out in the absence of TMSOTf, was
followed by TLC. At the beginning of the reaction, we ob-
served a single spot of a product that was not identical to
4a. Once the temperature of the slowly warmed reaction
mixture reached ꢀ208C (after stirring for 6–8 h), we ob-
served an increase of the intensity of this spot and a de-
crease of the intensity of the spot of starting material 2. Fur-
ther warming of the reaction mixture to 208C resulted in a
complete consumption of triazine 2 (as judged by TLC).
Chem. Eur. J. 2011, 17, 7188 – 7192
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7189

V. O. Iaroshenko, P. Langer et al.
Figure 2. Crystal structure of 5a.
Table 4. Synthesis of 4a and 4b starting from 5a and 5b, respectively.
5
R1
R2
4
[%][a]
5a
5b
H
Me
Me
Me
4a
4i
62
77
[a] Yields of isolated products.
ative configuration of all four asymmetric carbon atoms
(Figure 3).[8]
Based on the results discussed above, we believe that the
one-pot synthesis of pyridones 4 proceeds by reaction of
dienes 1 with triazine 2 to give intermediate D, which can
be regarded as a silylated analogue of 5 (Scheme 1). Inter-
mediate D then undergoes subsequent desilylation and ex-
trusion of 2,2,2-trifluoroacetamidine. The formation of D
can be explained by two different pathways (Scheme 1); the
first path is a pericyclic cycloaddition via transition state E,
which implies the simultaneous migration of the TMS-
groups to the neighbouring nitrogen atoms. Alternatively,
Scheme 1. Proposed reaction mechanism. a) CH2Cl2, ꢀ78 to 208C, 12 h;
b) HCl (10%); c) EtOH, 50–608C, 10–25 h.
the reaction can proceed by a sequential process that in-
volves a nucleophilic attack (Scheme 1). Intermediate A,
which might exist in an equilibrium with s-complex B, is
formed by nucleophilic attack of the terminal carbon atom
of diene 1 to the C=N double bond of 2. The latter is pre-
sumably activated by interaction with the Lewis acid
TMSOTf to give the highly electrophilic 1,3,5-triazonium tri-
flate 6. In fact, the use of TMSOTf resulted in an increase
of the yield (Table 1).
As mentioned above, products of type 5 are exclusively
formed as endo isomers. Therefore, we believe that the reac-
tion proceeds sequentially via the intermediates A, B, C,
and D (Scheme 1). It is worth noting that zwitterions 7 and
8 have been previously isolated and characterized (see
below),[9] which supports the proposed intermediates A and
B.
Figure 3. Crystal structure of 5d.
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Chem. Eur. J. 2011, 17, 7188 – 7192

Reaction of 1,3-Bis(trimethylsilyloxy)-1,3-Butadienes
COMMUNICATION
The final step of the transformation involves the desilyla-
tion of D to give 5. As illustrated in Table 2, the synthesis of
compounds 4k–n failed. Analyzing the reaction mixture by
HPLC, we were unable to identify any major side products
besides the desired products 4. Analysis by 19F NMR spec-
troscopy showed that prolonged heating of 5a–e led to the
formation of complex product mixtures with predominating
signals in the range of d=ꢀ72, ꢀ75, and ꢀ80 ppm, with an
integral ratio of 1:1:1. These results suggested that a stable
major product had been formed. Our efforts to isolate this
product proved to be successful only in case of 5a (with
R1 =H). The structure of the product, methyl 5,5-bis(2,2,2-
trifluoroacetamido)-6,6,6-trifluoro-3-oxohexanoate
(9a),
could be unambiguously identified by X-ray crystal structure
analysis (Figure 4). A detailed investigation of the reaction
Scheme 2. Proposed reaction mechanism. a) EtOH, 50–608C, 10–25 h.
In conclusion, the domino reaction of 1,3-bis(trimethylsi-
lyloxy)-1,3-butadienes
1
with 2,4,6-tris(trifluoromethyl)-
1,3,5-triazine 2 was investigated in detail. This reaction pro-
vides a set of 2,6-bis(trifluoromethyl)-1,4-dihydro-4-oxopyri-
dones 4. The reaction proceeds by formation of the bicyclic
adduct 5 and its subsequent conversion to the final product
upon heating. The cyclization reaction reported herein is dif-
ferent to known modes of cycloadditions and constitutes a
novel type of reaction. The products are not readily avail-
able by other methods and the scope and limitations of the
reactions have been studied.
Experimental Section
Figure 4. Crystal structure of methyl 5,5-bis(2,2,2-trifluoroacetamido)-
6,6,6-trifluoro-3-oxohexanoate 9a.
General procedure for the synthesis of compounds 4: Compound 2
(2.0 mmol) was added to a CH2Cl2 solution of 1 (2 mL, 1.0 mmol of 1)
and subsequently, Me3SiOTf (0.18 mL, 1.0 mmol) was added at ꢀ788C.
The temperature of the solution was allowed to warm to 208C during 12–
14 h with stirring. To the solution was added HCl (10%, 10 mL) and the
organic and the aqueous layers were separated. The latter was extracted
with CH2Cl2 (2ꢃ10 mL). The combined organic layers were dried
(Na2SO4), filtered, and the filtrate was concentrated in vacuo. The resi-
due was heated at 50–608C in EtOH (20 mL, 1 mmol of 1) during 10–
25 h. The solvent was removed in vacuo and the product was washed
with CH2Cl2.
mixture revealed that, besides unidentified products, pyri-
dines 4 and compounds 9 were present in the ratio given in
Table 5. Mechanistically, this transformation might proceed
Table 5. Ratio of 4 to 9 in the reaction mixture (by 19F NMR spectro-
scopic analysis).
For full experimental and characterization please see the Supporting In-
formation.
5
R1
R2
Ratio 4/9
5a
5b
5c
5d
5e
H
Me
G
Me
Me
Me
Me
Me
4:1
7:1
1:23
1:21
1:25
ACHTUNGTRENNUNG
Keywords: cyclization
·
cycloaddition
·
fluorine
·
ACHTUNGTRENNUNG
heterocycles · pyridones · triazine
via intermediate F, which is formed by nucleophilic attack of
a water molecule on position 1 of 1,5,7-tris(trifluoromethyl)-
3-oxo-6,8,9-triaza-bicycloACHTNUTRGNE[UNG 3.3.1]non-7-ene (4) with subse-
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Received: February 2, 2011
Published online: May 12, 2011
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Chem. Eur. J. 2011, 17, 7188 – 7192