Unusual [2+2]-cycloaddition of carbodiimides to N-alkenylidenetriflamides

Article abstract of DOI:10.1016/j.tetlet.2016.08.078

An unusual [2+2]-cycloaddition to the C[dbnd]C bond of 1-azadienes has been observed for the first time using the example reaction of 1,3-N-trifluoromethylsulfonyl-1-azabutadienes with carbodiimides. The structure of N-{[2,2-dimethyl-1-cyclohexyl-4-(cyclo

Full text of DOI:10.1016/j.tetlet.2016.08.078

Accepted Manuscript
Unusual [2+2]-cycloaddition of carbodiimides to N-alkenylidenetriflamides
Bagrat A. Shainyan, Ljudmila L. Tolstikova, Irina V. Sterkhova
PII:
S0040-4039(16)31105-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.078
TETL 48049
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 June 2016
17 August 2016
23 August 2016
Please cite this article as: Shainyan, B.A., Tolstikova, L.L., Sterkhova, I.V., Unusual [2+2]-cycloaddition of
carbodiimides to N-alkenylidenetriflamides, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2
016.08.078
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Unusual [2+2]-cycloaddition of carbodiimides to N-alkenylidenetriflamides
*
Bagrat A. Shainyan, Ljudmila L. Tolstikova, Irina V. Sterkhova
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Division of Russian Academy of Sciences, 1 Favorsky Street
6
64033, Irkutsk, Russia
A B S T R A C T
____________________________________________________________________________
_
An unusual [2+2]-cycloaddition to the C=C bond of 1-azadienes has been observed for the first time using the
example reaction of 1,3-N-trifluoromethylsulfonyl-1-azabutadienes with carbodiimides. The structure of N-{[2,2-
dimethyl-1-cyclohexyl-4-(cyclohexylimino)azetidin-3-ylidene]methyl}trifluoromethanesulfonamide, formed from
dicyclohexylcarbodiimide and N-(3-methylbut-2-en-1-ylidene)trifluoromethanesulfonamide, was proved by single
crystal X-ray analysis.
_
____________________________________________________________________________________________
Keywords:
N-[1-Alkyl-4-(alkylimino)-3-azetanyliden]methyl(trifluoro)methanesulfonamides
2
1
,2-Dipolar cycloaddition reaction
,3-N-Trifluoromethylsulfonyl-1-azabutadienes
Single crystal X-ray
1
-Azadienes are reactive species which can act as heterodienes in the Diels-Alder reaction
with various dienophiles providing a straightforward and atom economical route to nitrogen-
1
–4
containing heterocycles possessing diverse biological activities. The simplest method for the
synthesis of 1-azadienes is the condensation of α,β-unsaturated carbonyl compounds with
4
amines. Of special interest are electron-deficient 1-azadienes, for which in a recent review two
methods were described. The first method uses the condensation of toluenesulfinimide
(
[
TolS(O)NH
2
) with β,γ-unsaturated α-ketoesters (ArCH=CHC(O)CO
2
Et) to give ethyl 5-aryl-3-
5
(tolylsulfinyl)imino]pent-4-enoates (ArCH=CHC(CO
2
Et)=NS(O)Tol), while the second uses
the Sonogashira reaction of aryl halides (ArX) with N-(1-arylprop-2-yn-1-yl)tosylamides
(
TsNHCH(Ar')C≡CH) followed by isomerization to give N-[1-aryl-3-arylprop-2-en-1-ylidene]-
6
tosylamides (TsN=C(Ar')CH=CHAr) (Scheme 1).
Scheme 1. Synthesis of electron-deficient 1-azadienes.
*
Corresponding author. Tel.: +39 5251 1425; fax: +39 5241 9346. E-mail address: bagrat@irioch.irk.ru.

In the above examples, the electron withdrawing group is either the TolSO (in 1) or
TolSO group (in 2). The interest in electron-deficient 1-azadienes is connected with their ability
to react as electrophiles in 1,4-additions and to enter the reactions with electron-rich dienophiles
2
3,5,7,8
in the inverse electron-demand hetero Diels-Alder reactions.
Recently, we have reported the synthesis of alkenylidenetriflamides (TfN=CH–
CR=CR'CH
3
) via the reaction of N-sulfinyltriflamide (TfNSO) with the corresponding α,β-
9
unsaturated aldehydes, which provided the opportunity to investigate these new electron-
deficient 1-azadienes in cycloaddition reactions (Scheme 2).
Scheme 2. Synthesis of 1-trifluoromethylsulfonyl-1-azadienes.
Electron-deficient 1-azadienes are known to react with different dienophiles, such as
1
8
1,10
2
2
11
ketene acetals, enamines, vinyl ethers,
vinyl esters, alkenes, methyl vinyl ketones,
1
2
13
14
8
sulfenes (CH
2
=SO ), ketenes, and enolizable ketones or undergo dimerization via a [4+2]-
2
cycloaddition mechanism. The regioselectivity of cycloaddition is determined by the polarization
of the dienophile C=C bond.
Much less common is the [2+2]-cycloaddition reaction of 1-azadienes. As summarized in a
2
review by Mahajan and co-workers, 1-azadienes usually form four-membered cycloadducts
with ketenes as the second addends, and it was specially noted that ‘only the C=N double bond
2
of the azadienes is involved in these [2+2]-cycloadditions’. It is also worth noting that alkenes
enter
the
[2+2]-cycloaddition
reaction
with
keteneiminium
triflates
+
–
15
(
[RR'C=C=N(CH
2
CH=CH
2
) ] TfO ) only with participation of the C=C bond of the latter.
2
1
6
Taking into account the unique behavior of the triflamide derivatives, which often
demonstrate patterns of reactivity different from those of arenesulfonamides and to which our
new N-triflyl 1-azadienes obviously belong, we tried the reaction of 1-azadienes (TfN=CH–
CH=C(R)Me, R = Me (3), H (4)) with carbodiimides (R'N=C=NR', R' = c-C
6
H
11 (6), i-C
3
7
H (7)).
Carbodiimides as addends were used, taking into account their ability to enter into cycloaddition
reactions; in particular, we have found that N-sulfinyltriflamide (TfNSO) gives N-triflyl-1,2,4-
thiadiazetidin-3-imine 1-oxides via a [2+2]-cycloaddition/ring opening/ring closure sequence of
1
7
transformations. As far as we are aware, there are no reports of the reactions of 1-azadienes
with carbodiimides.

The reaction of 1-azadienes 3, 4 with carbodiimides 6, 7 may proceed either as a [4+2] or
[
2+2]-cycloaddition, and in the latter case, either with the C=C or C=N bond.
Scheme 3. Possible pathways for the cycloaddition of carbodiimides to alkenylidenetriflamides.
Since N-triflyl-1-azadienes (TfN=CH–CR=CR'R'') were shown to be hydrolytically
9
unstable, decomposing to the starting enals and triflamide, for the reaction with carbodiimide 6
we used the in situ formed 1-azadiene 3, without its isolation from the reaction mixture. For this,
a solution of N-sulfinyltriflamide in CH
2
Cl was added to a solution of 3-methyl-2-butenal in the
2
same solvent under an inert atmosphere at –40 to –30 °С, stirred for 1 h and allowed to stand
overnight at 4 °С to complete the first reaction step (Scheme 4). Then, to the obtained solution of
1
-azadiene 3, carbodiimide 6 was added at a temperature not exceeding –20 °С, stirred for 30
min and left to stand overnight in a refrigerator at –18 °С. After 16 h, the crystalline product 8
1
8
was precipitated.
It is important to note that the two steps in Scheme 4 must be performed separately,
otherwise TfNSO can react with carbodiimide 6 resulting in formation of N-
1
7
trifluoromethanesulfonyl-2,4-dicyclohexyl-1,2,4-thiadiazetidin-3-imine 1-oxide 9, which is
what occurred when the enal, TfNSO and carbodiimide were mixed simultaneously or when
excess TfNSO was present in the reaction mixture. The 1,2,4-thiadiazetidin-3-imine 1-oxide 9
was further hydrolyzed to give N-triflylguanidine 10. This route was proved by isolation of a
crystalline product from the reaction with simultaneous mixing of the reagents; its single crystal
19
X-ray structure coincided with that earlier obtained for compound 10 by our research group.
Scheme 4. Reaction of the in situ formed 1-azadiene 3 with dicyclohexylcarbodiimide 6
catalyzed by Y(OTf)
3
.

2
0
The structure of heterocyclization product 8 was confirmed by spectroscopic methods
21
and proved by single crystal X-ray analysis (Fig. 1).
Figure 1. Single crystal X-ray structure of N-{[2,2-dimethyl-1-cyclohexyl-4-
cyclohexylimino)azetidin-3-ylidene]methyl}trifluoromethanesulfonamide 8.
(
Taking into account the moderate yield (~35%) and the fact that heterocyclization
3
,8,10
reactions of 1-azadienes are often catalyzed by Lewis acids,
performed the reaction of the in situ formed azadiene 3 in the presence of 1 mol% Yb(OTf)
which was added to the reaction mixture before the addition of carbodiimide 6. Notably, the use
in particular, metal triflates, we
3
,
of Yb(OTf)
3
may change the course of the reaction, directing it to the dimerization of the 1-
8
azadiene and the formation of tetrahydropyridines. In our case, however, the use of Yb(OTf)
substantially increased the yield, to 83%, and no dimer was formed.
3
The more stable 1-azadiene 4 directly reacted with either carbodiimides 6 or 7 at –5 °С,
stirred at this temperature for 20 min and left to stand overnight in a refrigerator (–18 °С); to
1
7
give the corresponding azetidines after 18 h (Scheme 5).
Scheme 5. Reaction of 1-azadiene 4 with carbodiimides 6, 7.
Therefore, the reaction of 1,3-N-trifluoromethylsulfonyl-1-azabutadienes with
carbodiimides represents the first example of a [2+2]-cycloaddition reaction to the C=C bond of

1
-azadienes. Although the detailed mechanism remains to be elucidated, the following tentative
scheme can be proposed (Scheme 6).
Scheme 6. Tentative mechanism for the [2C=C + 2C=N] cyclization of 1-azadienes with
carbodiimides.
The proposed mechanism is supported by the observation that the IR spectra of the reaction
–
1
mass before crystallization (apart from the bands of products 8, 11, 12 at 1689 and 1645 cm )
–
1
consists of intense bands at 1584–1594 cm , which can be assigned to the intermediate
azetidines containing the TfN=C moiety, and coincide with the band in the IR spectra of the
2
3
earlier obtained N-triflylimines (TfN=CRR').
The reason why N-alkenylidenetriflamides react with carbodiimides via their C=C double
2
bond, while ketenes react with 1-azadienes via addition to the C=N double bond is evident: the
latter reactions include nucleophilic 1-azadienes, bearing no electron-withdrawing groups at
nitrogen, so, the reaction proceeds as a nucleophilic addition of the N-nucleophile to the C=O
group. N-Alkenylidenetriflamides act as electrophiles and, at first glance, the attack of
carbodiimide should be directed to the most electrophilic C=N carbon. However, in this case, the
incipient negative charge would be located on the triflamide nitrogen, while for attack on the
terminal Csp2 atom, as depicted in Scheme 6, it is delocalized over the
thus stabilizing the system.
tryad,
In summary, we have found that the reaction of 1,3-N-trifluoromethylsulfonyl-1-
azabutadienes with carbodiimides proceeds as a [2+2]-cycloaddition reaction leading to 2-
substituted N-{[1-alkyl-4-(alkylimino)azetidin-3-ylidene]methyl}trifluoromethanesulfonamides
and represents the first example of addition to 1-azadienes involving the C=C rather than the
C=N bond. The structure of the products was proved by IR and NMR spectroscopy as well as
single crystal X-ray analysis. Taking into account the strong acceptor character of the triflyl
group, a mechanism was proposed to explain the unusual course of the reaction.
References and notes
1
2
.
.
Behforouz, M.; Ahmadian, M. Tetrahedron 2000, 56, 5259.
Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379.

3
4
5
6
7
8
9
1
1
1
1
1
1
.
.
.
.
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.
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Jiang, X.; Wang, R. Chem. Rev. 2013, 113, 5515.
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Schramm, O. G.; Oeser, T.; Müller, T. J. J. J. Org. Chem. 2006, 71, 3494.
He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 26, 8418.
Vicario, J.; Aparicio, D.; Palacios, F. Tetrahedron Lett. 2011, 52, 4109.
Shainyan, B. A.; Tolstikova, L. L. Russ. J. Org. Chem. 2016, 52, 499.
0. Esquivias, J.; Alonso, I.; Arrayás, R. G.; Carretero., J. C. Synthesis 2009, 113.
1. Wang, G.; Rexiti, R.; Sha, F.; Wu, X.-Y. Tetrahedron 2015, 71, 4255.
2. Singh, P.; Bisetty, K. Int. J. Org. Chem. 2012, 2, 121.
3. Jian, T.-Y.; Shao, P.-L.; Ye, S. Chem. Commun. 2011, 2381.
4. Li, J.-L.; Liu, T.-Y.; Chen, Y.-C. Acc. Chem. Res. 2012, 45, 1491.
5. Kolleth, A.; Lumbroso, A.; Tanriver, G.; Catak, S.; Sulzer-Mossé, S.; De Mesmaeker, A.
Tetrahedron Lett. 2016, 57, 2697.
1
1
1
6. Shainyan, B. A.; Tolstikova, L. L. Chem. Rev. 2013, 113, 699.
7. Shainyan, B. A.; Tolstikova, L. L. J. Fluor. Chem. 2012, 140, 59.
8. When stored at room temperature, the reaction mixture polymerized, did not crystallize, and the yield
of 8 decreased. The same occurred for products 11, 12.
1
2
9. Shainyan, B. A.; Tolstikova, L. L.; Schilde, U. J. Fluor. Chem. 2012, 135, 261.
0. N-{[2,2-Dimethyl-1-cyclohexyl-4-(cyclohexylimino)azetidin-3-ylidene]methyl}trifluoromethanesulfon-
amide 8; yield 83% (from the Y(OTf)
IRνmax: 3242, 2936, 2859, 1689, 1645, 1366, 1299, 1255, 1196, 1178, 1110, 953, 884, 607 cm ; H
NMR (400 MHz, DMSO-d ) : 8.64 (1Н, br.s, NH), 7.15 (1H, s, CH=N), 3.62 (1H, m, =NCH), 3.22
3
-catalyzed reaction), m.p. 212 °C (white crystals, from EtOH);
–
1 1
6
13
(1H, m, NCH), 1.53 (6H, s, CH
3
), 1.93–1.70, 1.65–1.40, 1.40–1.05 (20H, m, CH
2
); C NMR (100
MHz, DMSO-d
6
) : 157.3 (С=N), 139.8 (CH=С), 120.8 q (CF , J = 326.6 Hz), 112.8 (CH=С), 72.4
3
(
=NCH), 54.2 (CMe
CH ), 24.5 (CH ), 24.10 (=NCHCH
) : –77.73. Anal. calcd for C19
С 54.11; Н 7.28; N 9.46; S 7.50.
N-{[2-Methyl-1-cyclohexyl-4-(cyclohexylimino)azetidin-3-ylidene]methyl}trifluoromethanesulfonamide
2
), 53.8 (NCH), 32.5 (=NCHCH
2
), 30.7 (NCHCH
4
2
), 25.1 (NCHCH
2
CH ), 24.6
2
19
(
3
3
2 2
CH ), 24.06 (C in cyclohexyl rings); F NMR (376 MHz,
DMSO-d
6
H
30
F
3
N
3
O S, %: С 54.14; Н 7.17; N 9.97; S 7.61; found, %:
2
1
1
7
1; yield 32%, m.p. 163 °C (colorless crystals, from EtOH); IRνmax: 3250, 2935, 2860, 1683,
–
1 1
645, 1372, 1307, 1259, 1196, 1119, 969, 888, 610 cm . H NMR (400 MHz, CD
.37 (br.s, 1Н, NH), 6.78 (s, 1H, CH=N), 4.60 (q, J = 6.0 Hz, 1Н, CHCH ), 3.45 (m, 1Н), 3.37
), 1.81 (m, 6H), 1.65 (m, 2H), 1.35 (m,
CN) : 160.1 (C=N), 143.4 (C=CH), 121.8 (q, J = 324.4,
3
CN) :
3
(
m, 1Н), 2.17 (m, 2H), 1.51 (d, J = 6.0, 3H, CHCH
3
1
3
1
0Н); C NMR (100 MHz, CD
3
1
9
CF
3
), 108.2 (C=CH), 62.0, 55.0, 33.5, 33.4, 32.4, 30.6, 25.7, 25.6, 25.5, 25.2, 19.0; F NMR

(
376 MHz, CD
0.31; S 7.87; found, %: С 52.93; Н 6.92; N 10.25; S 7.55.
N-{[1-Isopropyl-2-methyl-4-(isopropylimino)azetidin-3-ylidene]methyl}trifluoromethanesulfonamide
3
CN) : –78.67. Anal. calcd for C18
H
28
F
3
N
3
O S, %: С 53.05; Н 6.93; N
2
1
12; yield 38%, m.p. 183 °C (white crystals, from EtOH); IRνmax: 3263, 2978, 2935, 1682, 1645,
–
1 1
1
373, 1257, 1197, 1181, 1117, 958, 881, 604 cm ; H NMR (400 MHz, CD
), 3.82 (m, 2Н, CHMe
); C NMR (100 MHz, CD
), 108.7 (C=CH), 61.9 (C=NCH), 48.3 (NCHCH
3
CN) : 7.41 (br.s, 1Н,
), 1.51 (d, J = 6.1, 3Н,
NH), 6.84 (s, 1Н, CH=N), 4.62 (q, J = 6.1, 1Н, CHCH
3
2
13
CHCH
3
), 1.24 (m, 12H, CH(CH
22.1 (q, J = 122.1, CF
2.8, 21.7, 19.9, 19.0 (CH
)
3 2
3
CN) : 160.5 (C=N), 143.43 (C=CH),
), 47.8 (NCHMe ), 22.9,
) : –79.00. HRMS, m/z: calcd for
S [(M+H) ] 328.1307, found 328.1330; Anal. calcd for C12 S, %: С
4.03; Н 6.16; N 12.84; S 9.80; found, %: С 44.09; Н 6.09; N 12.90; S 9.79.
1
2
3
3
2
1
9
3
); F NMR (376 MHz, DMSO-d
6
+
C
12
H
21
F
3
N
3
O
2
H
20
F
3 3
N O
2
4
2
1. Crystal data for 8: C19
30
H F
3
N
3
O S, M 421.52, colorless plates, m.p. 212 °C, 0.500×0.400×0.030
2
3
mm , triclinic, space group P-1, cell parameters: a 9.8847(6), b 10.5093(7), c 11.5856(8) Å, α
3
7
7.624(2), β 67.468(2), γ 88.073(2), V 1084.25(12), Z 2, dcalc 1.291 g/cm . 58125 reflections
collected on a Bruker D8 Venture diffractometer with MoK

radiation ( = 0.71073) in the range
 = 3.90 to 60.74°, of which 6476 are unique. 369 variables refined: R = 0.0468, wR = 0.1178 [I
= 0.1269 [all data]. CCDC 1478264 contains the supplementary
2
1
2
22
>
2(I)] and R
1
= 0.0637, wR
2
crystallographic data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK. Fax: +44
1223 336033.
2
2
2. Sheldrick, G. M. Acta Cryst. Sect. A 2008, 64, 112–122.
3. Shainyan, B. A.; Tolstikova, L. L. Russ. J. Org. Chem., Engl.Transl. 2005, 41, 984.

Graphical abstract

Highlights
>
Unusual [2+2]-cycloaddition of carbodiimides to 1,3-N-trifluoromethylsulfonyl-1-
azabutadienes was first observed.
>
The
structure
of
the
formed
N-{[1-alkyl-4-(alkylimino)azetidin-3-
ylidene]methyl}triflamides was proved by single crystal X-ray analysis.
>
The mechanism of the reaction was proposed.