One-pot synthesis of fluoroalkanesulfonyl substituted amidines from ketone, amine and fluoroalkanesulfonyl azides in mild conditions

Article abstract of DOI:10.1055/s-2000-6360

A facile one-step method is presented for the synthesis of N- per(poly)fluoroalkanesulfonyl amidines in moderate to good yield by reactions of per(poly)fluoroalkanesulfonyl azides, ketone and secondary amine at room temperature. This synthetic methods pro

Full text of DOI:10.1055/s-2000-6360

PAPER
513
One-Pot Synthesis of Fluoroalkanesulfonyl Substituted Amidines from
Ketone, Amine and Fluoroalkanesulfonyl Azides in Mild Conditions
Yong Xu, Yanli Wang, Shizheng Zhu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Fax +86(21)64166128; Email: zhusz@pub.sioc.ac.cn
Received 12 October 1999; revised 20 December 1999
product 4 in good to moderate yield ranging from 48-
89% (Table 1). It was found that the use of cyclohexanone
led to much better yields, and required shorter reaction
times than that of cycloheptanone.9 Furthermore, the reac-
Abstract: A facile one-step method is presented for the synthesis of
N-per(poly)fluoroalkanesulfonyl amidines in moderate to good
yield by reactions of per(poly)fluoroalkanesulfonyl azides, ketone
and secondary amine at room temperature. This synthetic methods
provide an easy and simple access to N-per(poly)fluoroalkanesulfo- tion of cyclohexanone did not need the catalysis of acti-
nyl amidines.
vated MS 4A.
Key words: per(poly)fluoroalkanesulfonyl azides, ketone, second-
ary amine, amidine
Amidines, the nitrogen analogues of carboxylic acids, are
structural parts of numerous compounds of biological in-
terest and form important medical and biochemical
agents.1,2 It is well known that introduction of a fluorine
Rf = C H (1a); IC F OC F (1b)
n = 1 (2a); n = 2 (2b)
morpholine (3a); N-methylaniline (3b); diethylamine (3c)
atom or fluorine-containing group into an organic mole-
4
9
2 4
2 4
cule changes the chemical or biochemical properties of
the original molecule.3 Thus, fluorine-containing
amidines should be expected to be of particular impor-
tance.
Scheme 3
However, the preparation of fluorine-containing amidines
is rarely reported as yet.4 Niederprum et al. first reported
the synthesis of C4F9SO2N=CHNMe2 by two reaction
steps in very low yield (10%) (Scheme 1).5 Recently, we
prepared these compounds from the reaction of
RfSO2NHNa with Vilsmaier reagent.6 (Scheme 2)
Fusco et al. have shown that enamines derived from cyclic
ketones react with arenesulfonyl azides mainly under ring
contraction with formation of the corresponding
amidines.10,11 However, there are few reports about the
synthesis of amidines directly from azides, ketones and
amines until now. Enamines were generally prepared by
the condensation of ketones with secondary amines,9
therefore ketones mixed with secondary amines would
present an equilibrium between enamine and ketone. Due
to the strong electron-withdrawing properties of the fluo-
roalkanesulfonyl group, per(poly)fluoroalkanesulfonyl
azides are more reactive than other organic azides, espe-
cially in the reaction with electron-rich olefins.12,13 As flu-
oroalkanesulfonyl azides react quickly with enamines, the
equilibrium between enamine and ketone should shift to
enamines and form the triazoline intermediate by the 1,3-
dipolar cycloaddition.13 When the triazoline ring carries
an electron-withdrawing group at the 1-position, it is very
labile.13,14 Thus, the first formed triazolines are not readily
isolated, they decompose immediately after their forma-
tion to produce amidine 4 through rearrangement and loss
of the N2 at the same time.15
Scheme 1
Scheme 2
During our continuous study on the per(poly)fluoroal-
kanesulfonyl azides,7-8 we found that it reacts smoothly
with ketones and amines to afford N-per(poly)fluoroal-
kanesulfonyl amidines in good yield. Herein, we wish to
report these results.
The above one-pot reaction was also extended to the reac-
tion of acyclic ketone (Scheme 4). In the presence of flu-
oroalkanesulfonyl azides 1, pentan-3-one reacted with
morpholine or pyrrolidine and afforded amidines 7
through ethyl rearrangement. It is noteworthy that there is
a big difference between morpholine and pyrrolidine in
As shown in Scheme 3, per(poly)fluoroalkanesulfonyl
azides 1a-b were allowed to react with cyclohexanone or
cycloheptanone and various secondary amines 3 in abso-
lute diethyl ether to give the one-carbon ring contraction
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514
Y. Xu et al.
PAPER
Table 1
Entry
Azides
Ketones
Amines
Time (h)
Product
Yield %
1
2
3
4
5
6
7
8
1a
1b
1a
1b
1a
1b
1a
1b
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
cycloheptanone
cycloheptanone
morpholine
morpholine
5
5
4aaa
4baa
4aab
4bab
4aac
4bac
4aba
4bba
77
70
81
89
N-methylaniline
N-methylaniline
diethylamine
diethylamine
morpholine
72
72
48
48
12
12
48a
53a
53a
54a
morpholine
a 0.4 g of activated MS 4A was used for 1 mmol azides 1.
the reaction rate and product yield (Table 2). In the case
of pyrrolidine, the reaction time is about 1 hour and the
yield is 74-85%. However, the reaction of morpholine
with 1 needed 2 days under the catalysis of activated MS
4A, and gave lower yields. The difference should be at-
tributed to pyrrolidine being more nucleophilic than mor-
pholine.9
morpholine (3a); N-methylaniline (3b); diethylamine (3c)
Scheme 5
All reagents were of analytical grade. IR spectra were obtained with
a Perkin-Elmer 983G spectrophotometer using KBr disks. 1H
NMR and 19F NMR spectra were recorded on a Varian-360L or
Bruker AM-300 spectrometer instrument with TMS and CFCl3
(with upfield negative) as an internal and external standard, respec-
tively. NMR spectra were recorded using CHCl3 unless otherwise
stated. Mass spectra were obtained in a HP 5989a instrument. Ele-
mental analyses were performed at this Institute. Column chroma-
tography was performed using silica gel H, particle size 10-40m.
The per(poly)fluoroalkanesulfonyl azides 1 were prepared by our
previously described methods.7
morpholine (6a); pyrrolidine (6b)
Scheme 4
We have also tried the reaction of p-toluenesulfonyl azide
(TosN3) with cyclohexanone and amines 3a-c in the same
reaction conditions. Fortunately, it gave good reaction re-
sults (Scheme 5, Table 3). Because of the low reactivity of
TosN3, the reaction rate is slow compared to fluoroalkane-
N¢-Perfluorobutanesulfonyl-N, N-cyclo(ethyleneoxyethylene)-
cyclopentanamidine (4aaa); Typical Procedure for 4 and 7
To a solution of cyclohexanone 2a (0.118 g, 1.2 mmol) and mor-
sulfonyl azides. Furthermore, it is noteworthy that the pholine (0.113 g, 1.3 mmol) in absolute Et2O (5 mL), was added flu-
oroalkanesulfonyl azide 1a (0.325 g, 1.0 mmol) dropwise with
presence of MS 4A is indispensable in the case of N-me-
magnetic stirring at r.t. The reaction was completed after 5 h (mon-
thylaniline (Entries 3, 4)
itored by TLC). After removal of solvent, the residue obtained was
purified by column chromatography (petroleum ether/EtOAc, 6:1,
In conclusion, the reaction described herein provides a
novel, convenient and one-pot approach to N- Rf = 0.42) to give the pure product 4aaa (0.357 g, 77%). All of the
per(poly)fluoroalkanesulfonyl amidines. The easy proce-
dure and simple workup, availability of reagents and good
yield of the products make this method a useful addition
to the present methodologies.
Table 3
Entry Azides Amines
Product
Yield (%)
1
1c
1c
1c
1c
morpholine
8a
8b
−
76
57
0
Table 2
2a
3b
4a
N-methylaniline
N-methylaniline
diethylamine
c
Entry Azides Amines
Time (h) Product Yield (%)
8c
59
1
2
3
4
1a
1b
1a
1b
morpholine
morpholine
pyrrolidine
pyrrolidine
48
48
1
7aa
7ba
7ab
7bb
53
a 0.4 g of activated MS 4A was used for 1 mmol azides 1.
b No MS 4A was used.
43
83a
74a
c The structures of all compounds prepared were confirmed by spec-
troscopic methods and elemental analysis. The IR spectra of com-
pounds 4 and 7 showed strong absorption of C=N at 1560 cm–1.
1
a 0.4 g of activated MS 4A is used for 1 mmol azides 1.
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One-Pot Synthesis of Fluoroalkanesulfonyl Substituted Amidines
515
products 4 and 7 are oily compounds except product 4aba, which is
a white crystalline solid.
MS: m/z (%) = 575 (M++1, 0.37), 231 (M+-Rf, 3.18), 167 (M++1-
SO2Rf, 3.54), 72 (Et2N+, 100.00), 69 (CF3 , 66.25).
+
4aaa
4aba: mp 97-98 °C
IR (KBr): n = 1540 (C=N), 1478 (SO2), 1120-1236 (C-F) cm-1.
IR (KBr): n = 1541 (C=N), 1475 (SO2), 1005-1295 (C-F) cm-1.
1H NMR (CDCl3): d = 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).
1H NMR (CDCl3): d = 3.76 (s, 8H), 3.10 (m, 1H), 2.16 (s, 2H), 1.95
(m, 4H), 1.73 (m, 2H), 1.27 (m, 2H).
19F NMR (CDCl3): d = -79.9 (s, 3F), -113.0 (m, 2F), -120.8 (m,
2F), -125.8 (m, 2F).
19F NMR (CDCl3): d = -79.8 (s, 3F), -112.2 (m, 2F), -120.0 (m,
2F), -125.2 (m, 2F).
MS: m/z (%) = 465 (M++1, 17.53), 245 (M+-Rf, 2.85), 181 (M+-
MS: m/z (%) = 479 (M++1, 17.60), 259 (M+-Rf, 2.34), 195 (M+-
SO2Rf, 3.63), 86 (C4H8NO+, 100.00), 69 (CF3+ or C5H9 , 25.54).
SO2Rf, 4.21), 86 (C4H8NO+, 100.00), 69 (CF3 , 25.54).
+
+
4baa
4bba
IR (KBr): n = 1540 (C=N), 1478 (SO2), 1080-1360 (C-F) cm-1.
IR (KBr): n = 1541 (C=N), 1449 (SO2), 1094-1230 (C-F) cm-1.
1H NMR (CDCl3): 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).
1H NMR (CDCl3): d = 3.76 (s, 8H), 3.10 (m, 1H), 2.16 (s, 2H), 1.95
(m, 4H), 1.73 (m, 2H), 1.27 (m, 2H).
19F NMR (CDCl3): d = -62.8 (s, 2F), -80.4 (t, 2F, 4JFF = 17 Hz), -
19F NMR (CDCl3): d = -64.8 (s, 2F), -80.3 (t, 2F, 4JFF = 17 Hz), -
84.7 (t, 2F, 4JFF = 17 Hz), -116.0 (s, 2F).
84.6 (t, 2F, 4JFF = 17 Hz), -125.7 (s, 2F).
MS: m/z (%) = 589 (M++1, 55.87), 245 (M+-Rf, 2.76), 181 (M+-
MS: m/z (%) = 603 (M++1, 17.60), 259 (M+-Rf, 3.09), 195 (M+-
SO2Rf, 2.62), 86 (C4H8NO+, 100.00), 69 (C5H9 , 13.57).
SO2Rf, 4.20), 86 (C4H8NO+, 100.00), 83 (C6H10+, 8.53).
+
4aab
7aa
IR (KBr): n = 1540 (C=N), 1478 (SO2), 1140-1238 (C-F) cm-1.
IR (KBr): n = 1542 (C = N), 1487 (SO2), 1123-1274 (C-F) cm-1.
1H NMR (CDCl3): d = 7.52 (m, 3H), 7.18 (m, 2H), 3.35 (s, 3H),
2.72 (m, 1H), 2.20 (m, 2H), 1.85 (m, 2H), 1.70 (m, 2H), 1.38 (m,
2H).
1H NMR (CDCl3): d = 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 Hz), 1.05 (t, 3H,
J = 7.0 Hz).
19F NMR (CDCl3): d = -80.1 (s, 3F), -112.2 (m, 2F), -120.8 (m,
2F), -125.3 (m, 2F).
19F NMR (CDCl3): d = -80.0 (s, 3F), -113.8 (m, 2F), -120.2 (m,
2F), -125.3 (m, 2F).
MS: m/z (%) = 485 (M++1, 8.52), 265 (M+-Rf, 4.26), 201 (M+-
MS: m/z (%) = 453 (M++1, 6.50), 424 (M+-C2H4, 2.71), 217 (M+-
+
+
SO2Rf, 100.00), 106 (C7H8N+, 62.66), 69 (CF3+ or C5H9 , 66.25).
ORf, 4.29), 86 (C4H8NO+, 100.00), 69 (CF3 , 66.25).
4bab
7ba
IR (KBr): n = 1538 (C=N), 1474 (SO2), 1080-1230 (C-F) cm-1.
IR (KBr): n = 1541 (C=N), 1489 (SO2), 1095-1226 (C-F) cm-1.
1H NMR (CDCl3): d = 7.52 (m, 3H), 7.18 (m, 2H), 3.35 (s, 3H),
2.72 (m, 1H), 2.20 (m, 2H), 1.85 (m, 2H), 1.70 (m, 2H), 1.38 (m,
2H).
1H NMR (CDCl3): d = 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 Hz), 1.05 (t, 3H,
J = 7.0 Hz).
19F NMR (CDCl3): d = -61.9 (s, 2F), -79.6 (t, 2F, 4JFF = 17 Hz), -
19F NMR (CDCl3): d = -62.9 (s, 2F), -80.3 (t, 2F, 4JFF = 17 Hz), -
83.8 (t, 2F, 4JFF = 17 Hz), -116.8 (s, 2F).
84.8 (t, 2F, 4JFF = 17 Hz), -116.3 (s, 2F).
MS: m/z (%) = 609 (M++1, 1.82), 265 (M+-Rf, 7.90), 201 (M+-
MS: m/z (%) = 577 (M++1, 3.76), 548 (M+-C2H4, 6.54), 233 (M+-
+
+
SO2Rf, 100.00), 106 (C7H8N+, 36.37), 69 (C5H9 , 24.63).
Rf, 7.48), 86 (C4H8NO+, 100.00), 56 (C4F8 , 23.65).
4aac
7ab
IR (KBr): n = 1542 (C=N), 1490 (SO2), 1140-1227 (C-F) cm-1.
IR (KBr): n = 1542 (C=N), 1487 (SO2), 1123-1274 (C-F) cm-1.
1H NMR (CDCl3): d = 3.55 (q, 2H, J = 7.1 Hz), 3.48 (q, 2H, J = 7.1
Hz), 3.30 (m, 1H), 2.22 (m, 2H), 1.95 (m, 4H), 1.65 (m, 2H), 1.33
(t, 3H, J = 7.1 Hz), 1.21 (t, 3H, J = 7.1 Hz).
19F NMR (CDCl3): d = -79.9 (s, 3F), -112.2 (m, 2F), -119.9 (m,
2F), -125.0 (m, 2F).
1H NMR (CDCl3): d = 3.75 (m, 2H), 3.55 (m, 6H), 2.10-1.85 (m,
4H), 1.70 (m, 2H), 1.42 (d, 3H, J = 7.0 Hz), 0.98 (t, 3H, J = 7.4 Hz).
19F NMR (CDCl3): d = -79.4 (s, 3F), -110.3 (m, 2F), -116.7 (m,
2F), -122.1 (s, 2F).
MS: m/z (%) = 437 (M++1, 34.96), 217 (M+-Rf, 7.19), 153 (M+-
MS: m/z (%) = 451 (M++1, 9.90), 167 (M++1-SO2Rf, 3.37), 72
SO2Rf, 2.68), 70 (C4H8N+, 100.00), 69 (CF3 , 20.41).
+
+
+
(Et2N+, 100.00), 69 (CF3 , 66.25), 67 (C5H7 , 6.10).
7bb
4bac
IR (KBr): n = 1542 (C=N), 1487 (SO2), 1123-1274 (C-F) cm-1.
1H NMR (CDCl3): d = 3.75 (m, 2H), 3.55 (m, 6H), 2.10-1.85 (m,
4H), 1.70 (m, 2H), 1.42 (d, 3H, J = 7.0 Hz), 0.98 (t, 3H, J = 7.4 Hz).
19F NMR (CDCl3): d = -63.8 (s, 2F), -80.0 (t, 2F, 4JFF = 17 Hz), -
85.1 (t, 2F, 4JFF = 17 Hz), -116.6 (s, 2F).
IR (KBr): n = 1542 (C = N), 1490 (SO2), 1140-1227 (C-F) cm-1.
1H NMR (CDCl3): d = 3.55 (q, 2H, J = 7.1 Hz), 3.48 (q, 2H, J = 7.1
Hz), 3.30 (m, 1H), 2.22 (m, 2H), 1.95 (m, 4H), 1.65 (m, 2H), 1.33
(t, 3H, J = 7.1 Hz), 1.21 (t, 3H, J = 7.1 Hz).
19F NMR (CDCl3): d = -62.6 (s, 2F), -80.3 (t, 2F, 4JFF = 17Hz), -
MS: m/z (%) = 561 (M++1, 40.55), 532 (M+-C2H4, 3.07), 217 (M+-
84.7 (t, 2F, 4JFF = 17 Hz), -115.8 (s, 2F).
Rf, 10.34), 153 (M+-SO2Rf, 3.21), 70 (C4H8N+, 100.00).
Synthesis 2000, No. 4, 513–516 ISSN 0039-7881 © Thieme Stuttgart · New York

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Y. Xu et al.
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Acknowledgement
White solid: mp 148-149 °C (Lit10 145 °C).
The authors thank the National Natural Science Foundation of
China (NNSFC) (No. 2972051 and No. 29672041) for financial
support.
IR (KBr): n = 2965 (C–H), 1597 (m), 1541 (C=N), 1475 (SO2)
cm-1.
1H NMR (CDCl3): d = 7.79 (d, 2H, J = 8.2 Hz), 7.25 (d, 2H, J = 8.2
Hz), 4.12 (m, 1H), 3.71 (m, 4H), 3.46 (m, 4H), 2.40 (s, 3H), 2.10
(m, 2H), 1.26 (m, 6H).
References
MS: m/z (%) = 337 (M++1, 3.15), 295 (M++1-C3H6, 6.91), 181
(1) Shriner, R. L.; Neuman, F. W. Chem. Rev. 1944, 35, 351.
(2) The Chemistry of Amidines and Imidates; Patai, S.,
Rappoport, Z., Eds.; Interscience: London, 1991.
(3) Organofluorine Chemistry, Principles and Commerical
Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.;
Plenum Press: New York, 1994.
(4) Leonov, O. N.; Kryukova, L. Y.; Anferteva, M. V.; Kryukov,
L. N. Zh. Obshch. Khim. 1992, 62(7), 1592.
(5) Niederprum, H.; Voss, P.; Beyl, V. Liebigs Ann. Chem. 1973,
767, 20.
+
(M+-Tos, 8.44), 169 (TosN+, 3.47), 155 (Tos+, 25.36), 91 (C7H7 ,
+
53.69), 86 (C4H8NO+, 100.00), 69 (C5H9 , 12.08).
8b
White solid: mp 91-92 °C.
IR (KBr): n = 2947 (C–H), 1597 (m), 1541 (C=N), 1471 (SO2)
cm-1.
1H NMR (CDCl3): d = 7.91 (d, 2H, J = 8.2 Hz), 7.41 (m, 3H), 7.26
(d, 2H, J = 7.8 Hz), 7.18 (d, 2H, J = 8.2 Hz), 3.35 (s, 3H), 2.88 (m,
1H), 2.40 (s, 3H), 2.28 (m, 2H), 1.73 (m, 4H), 1.35 (m, 2H).
(6) Xu, G. L.; Xu, B.; Qin, C. Y.; Zhu, S. Z. J. Fluorine Chem.
1997, 84, 25.
(7) Zhu, S. Z. J. Chem. Soc., Perkin Trans. I. 1994, 2077.
(8) Xu, Y.; Xu, G. L.; Zhu, S. Z. J. Fluorine Chem. 1999, 96, 79.
(9) Stork, G. J. Am. Chem. Soc. 1963, 85, 207.
(10) Fusco, R.; Bianchetti, G.; Pocar, D. Gazz. Chim. Ital. 1961,
91, 933.
(11) Scribner, R. M. Tetrahedron Lett. 1967, 4737.
(12) Cipollene, A.; Lorete, M. A.; Pellacani, L.; Tardella, P. A. J.
Org. Chem. 1987, 52, 2584.
MS: m/z (%) = 356 (M+, 0.52), 250 (M+-C7H8N+, 5.43), 201 (M+-
Tos, 37.19), 155 (Tos+, 100.00), 106 (C7H8N+, 41.87), 91 (C6H5N+,
+
97.18), 77 (C6H5 , 16.13).
8c
White solid: mp 83-84 °C.
IR (KBr): n = 2975 (C–H), 1540 (C=N), 1478 (SO2) cm-1.
1H NMR (CDCl3): d = 7.82 (d, 2H, J = 8.1 Hz), 7.25 (d, 2H, J = 8.1
Hz), 3.81 (m, 1H), 3.38 (m, 4H), 2.39 (s, 3H), 2.02 (m, 2H), 1.98
(m, 4H), 1.67 (m, 2H), 1.21 (m, 3H), 1.10 (m, 3H).
(13) Lwowski, W. In 1,3-Dipolar Cycloaddition Chemistry; Vol.
1, Chap. 5; Padwa, A., Ed.; John-Wiley: New York, 1984.
(14) Bourgois, J.; Mathieu, A.; Texier, F. J. Heterocycl. Chem.
1984, 21, 513.
MS: m/z (%) = 323 (M++1, 43.41), 250 (M+-C4H10N+, 5.85), 215
(15) Croce, P. D.; Stradi, R. Tetrahedron 1977, 33, 865.
(M+-OC7H7, 3.21), 167 (M+-Tos, 11.47), 155 (Tos+, 23.08), 91
+
(C7H7 , 51.55), 72 (C4H10N+, 100.00).
Article Identifier:
1437-210X,E;2000,0,04,0513,0516,ftx,en;F06699SS.pdf
Synthesis 2000, No. 4, 513–516 ISSN 0039-7881 © Thieme Stuttgart · New York