A novel synthesis of N-fluoroalkanesulfonylamidines using a three-component reaction

Article abstract of DOI:10.1139/v03-032

A novel, general, and efficient multicomponent reaction of fluoroalkanesulfonyl azides, secondary amines, and carbonyl compounds for the synthesis of N-fluoroalkanesulfonylamidines is presented. This reaction gave a good yield of products under very mild

Full text of DOI:10.1139/v03-032

265
A novel synthesis of N-fluoroalkanesulfonyl-
amidines using a three-component reaction
Shizheng Zhu, Yong Xu, and Guifang Jin
Abstract: A novel, general, and efficient multicomponent reaction of fluoroalkanesulfonyl azides, secondary amines,
and carbonyl compounds for the synthesis of N-fluoroalkanesulfonylamidines is presented. This reaction gave a good
yield of products under very mild reaction conditions.
Key words: multicomponent reactions, synthetic methods, N-fluoroalkanesulfonyl azide, N-fluoroalkanesulfonylamidine.
Résumé : On présente une nouvelle réaction générale, efficace et à plusieurs composants des azotures de fluoroalcane-
sulfonyles avec une amine primaire et des composés carbonylés qui permet de faire la synthèse de N-fluoroalcanesulfo-
nylamidines. Cette réaction s’effectue avec de bons rendements, dans des conditions réactionnelles très douces.
Mots clés : réactions à plusieurs composants, méthodes synthétiques, azoture de N-fluoroalcanesulfonyles, N-fluoroalca-
nesulfonylamidine.
[Traduit par la Rédaction] Zhu et al. 268
Introduction
fluoroalkanesulfonyl azide 1a (0.325 g, 1.0 mmol) was
added dropwise with magnetic stirring at room temperature.
The reaction was completed after 5 h (monitored by TLC).
After removal of solvent, the residue obtained was purified
by column chromatography (petroleum ether:EtOAc, 6:1,
Rf = 0.42) to give the pure product 4a (colorless oil)
(0.357 g, 77%).
Multicomponent reactions (MCRs), by virtue of their con-
vergence, productivity, facile execution, and generally high
yields of products, have attracted much attention from the
vantage point of combinatorial chemistry (1). Of pivotal im-
portance in this area are the isocyanide-based MCRs such as
the versatile Ugi reactions (2–3).
In the context of our ongoing studies on the reaction of
fluoroalkanesulfonylazide with the electron-rich olefines
such as vinyl ether, enamines appeared attractive from the
viewpoint of devising a novel MCR (4–5).
4a
FT-IR (KBr) (ν, cm–1): 1540 (C=N), 1478 (SO2), 1120–
1
1236 (C-F). H NMR (CDCl3) δ: 3.85 (m, 2H), 3.73 (m, 4H),
3.60 (m, 2H), 3.55 (m, 1H), 2.12 (m, 2H), 1.87 (m, 4H), 1.70
(m, 2H). 19F NMR (CDCl3) δ: –79.9 (s, 3F), –113.0 (m, 2F),
–120.8 (m, 2F), –125.8 (m, 2F). MS (70 eV) m/z (%): 465
([M+ + 1], 17.53), 245 ([M+ – Rf], 2.85), 181 ([M+ – SO2Rf],
3.63), 86 ([C4H8NO+], 100.00). Elemental anal. calcd. for
C14H17F9N2O3S (%): C 36.21, H 3.66, N 6.02; found:
C 36.14, H 3.78, N 5.87.
Prompted by the recent successful preparation of N-
fluoroalkanesulfonylamidines from the reaction of fluoro-
alkanesulfonyl azides 1 with the β-ketoester enamines or
1,2-dihydro-pyridines (6–8) (see Scheme 1), we reasoned
that a three-component reaction (3-CR, i.e., the azide,
amine, and the carbonyl substrate) would be workable.
It is well known that enamine compounds are formed by
treatment of the carbonyl compound with a secondary
amine; in this reaction, the equilibrium between the enamine
and the carbonyl compound should go forward if the added
azide 1 could react fast enough with the enamine.
6a
FT-IR (KBr) (ν, cm–1): 1542 (C=N), 1487 (SO2), 1123–
1
1274 (C-F). H NMR (CDCl3) δ: 3.82 (m, 2H), 3.76 (m,
6H), 3.48 (m, 1H), 1.82 (m, 1H), 1.70 (m, 1H), 1.38 (d,
3H, J = 11.0 Hz), 1.05 (t, 3H, J = 7.0 Hz). 19F NMR
(CDCl3) δ: –80.0 (s, 3F), –113.8 (m, 2F), –120.2 (m, 2F),
–125.3 (m, 2F). MS (70eV) m/z (%): 453 ([M+ + 1], 6.50),
424 ([M+ – C2H4], 2.71), 217 ([M+ – ORf], 4.29), 86
([C4H8NO]+, 100.00). Element anal. calcd. for
C13H17F9N2O3S (%): C 34.51, H 3.76, N 6.19; found: C
34.12, H 3.81, N 6.22.
Experiment section
Typical procedure for the preparation of 4 and 6
N′-Perfluorobutanesulfonyl-N,N-cyclo(ethyleneoxyethylene)-
cyclopentanamidine (4a)
To a solution of cyclohexanone 2a (0.118 g, 1.2 mmol)
and morpholine (0.113 g, 1.3 mmol) in absolute Et2O (5 ml),
Received 11 November 2002. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 31 March 2003.
Shizheng Zhu,1 Yong Xu, and Guifang Jin. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Lu, Shanghai 200 032, China.
1Corresponding author (e-mail: zhusz@pub.sioc.ac.cn).
Can. J. Chem. 81: 265–268 (2003)
doi: 10.1139/V03-032
© 2003 NRC Canada

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Can. J. Chem. Vol. 81, 2003
Scheme 1.
Scheme 2.
Scheme 3.
Scheme 4.
zene, THF, and ether were also suitable for this reaction, and
it was found that the reaction gave the best yield in diethyl
ether. For example, when the reaction of 1a with 2a and 3a
were carried out in Et2O, the yield could be increased to
77%.
The three component reactions were found to be general
and efficient. The amine used could be cyclic, such as
morpholine and pyrrolidine, or acyclic, such as N-methyl an-
iline or diethylamine, etc. It should be noted that the less re-
active tosyl azide 1c can also react with 2 and 3 to give the
corresponding N-tosyl-substituted amidine in the presence of
actived 4 Å molecular sieves (see Scheme 2).
6e
FT-IR (KBr) (ν, cm–1): 2981 (C-H), 1546 (C=N), 1455
1
(SO2), 1321 (C-F). H NMR (CDCl3) δ: 3.71–3.64 (m, 4H),
3.22 (m, 1H), 2.09 (m, 2H), 1.95 (m, 2H), 1.28 (d, 6H, J =
7.1 Hz). 19F NMR (CDCl3) δ: –79.7 (s, 2F), –109.3 (s, 2F),
–116.7 (s, 2F), –122.1 (s, 2F). MS (70eV) m/z (%): 423
([M+ + 1], 31.08), 203 ([M+ – C4F9], 16.40), 70 ([C4H8N]+,
100.0). Element anal. calcd. for C12H15F9N2O2S (%):
C 34.12, H 3.55, N 6.64; found: C 34.36, H 3.66, N 6.69.
Results and discussion
The result of our investigations are presented here.
Initially, fluoroalkanesulfonyl azide 1a was added slowly
to a solution of morpholine 2a and cyclohexanone 3a in dry
toluene at room temperature; TLC analysis showed that the
reaction was finished in 5 h. The one-carbon ring contrac-
tion condensation product 4a was obtained in 66% yield (see
Scheme 2). Its structure was fully characterized by spectral
methods and elemental analysis. Other solvents such as ben-
To further explore the scope of this reaction, we have ex-
tended it to other carbonyl substrates. We found that the
acyclic ketone and aldehydes such as 3-pentanone and iso-
butylaldehyde were readily present in this reaction; in the
case of the aldehyde, the reaction occurred more rapidly: it
finished in 1 h (Scheme 3).
A possible reaction pathway is shown in Scheme 4.
All the reaction results are summarized in Table 1.
© 2003 NRC Canada

Zhu et al.
267
Table 1. Preparation of N-fluoroalkanesulfonyl amides using a three-component reaction.
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Can. J. Chem. Vol. 81, 2003
Table 1 (concluded).
In conclusion, we uncovered a novel and efficient multi-
component reaction of fluoroalkanesulfonyl azides, second-
ary amines, and carbonyl compounds for the synthesis of N-
fluoroalkanesulfonylamidines. This reaction also conforms
to the principle of green chemistry and atom economics, as
the by-products are water and nitrogen gas and, also, the sol-
vent can be reused.
Reference
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3. A. Domling and I. Ugi. Angew. Chem. Int. Ed. 39, 3168 (2000).
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(2001).
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Acknowledgment
7. S.Z. Zhu, Y. Xu, Y.L. Wang, and G.Y. Zhu. J. Fluorine Chem.
106, 133 (2000).
8. S.Z. Zhu and Y. Xu. Tetrahedron, 57, 3909 (2001).
This work was supported by the National Natural Science
Foundation of China (NNSFC) (No. 20 072 049 and
No. 20 032 010) and the Innovation Foundation of Chinese
Academy of Science.
© 2003 NRC Canada