The synthesis of fluoroheterocyclic ketene aminals

Article abstract of DOI:10.1081/SCC-100000578

The synthesis of fluoroheterocyclic ketene aminals was investigated. Fluorobenzyl ketene dithioacetals 1c reacted with nitric acid in the presence of concentrated sulfuric acid to give compound 2c. 1 reacted with diamines to afford 3-4. C-fluorobenzylatio

Full text of DOI:10.1081/SCC-100000578

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THE SYNTHESIS OF FLUOROHETEROCYCLIC KETENE
AMINALS
Zhan-Jiang Li a & Charles D. Smith b
a Department of Pharmacology , Pennsylvania State University, College of medicine ,
Hershey, PA, 17033, U.S.A.
b Department of Pharmacology , Pennsylvania State University, College of medicine ,
Hershey, PA, 17033, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Zhan-Jiang Li & Charles D. Smith (2001) THE SYNTHESIS OF FLUOROHETEROCYCLIC KETENE AMINALS,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:4,
527-533, DOI: 10.1081/SCC-100000578
To link to this article: http://dx.doi.org/10.1081/SCC-100000578
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SYNTHETIC COMMUNICATIONS, 31(4), 527–533 (2001)
THE SYNTHESIS OF
FLUOROHETEROCYCLIC KETENE
AMINALS
Zhan-Jiang Li and Charles D. Smith∗
Department of Pharmacology, Pennsylvania State
University, College of Medicine, Hershey, PA 17033
ABSTRACT
The synthesis of fluoroheterocyclic ketene aminals was in-
vestigated. Fluorobenzyl ketene dithioacetals 1c reacted with nitric
acid in the presence of concentrated sulfuric acid to give compound
2c. 1 reacted with diamines to afford 3–4. C-fluorobenzylation of
3–4 give the corresponding 5–8.
The synthesis and reactions of heterocyclic ketene aminals have attracted the
interest of organic chemists because these compounds are important intermediates
for the synthesis of a wide variety of new heterocycles and fused heterocycles
(1–10). Certain ketene aminals have antiviral activity (11,12); however, the syn-
thesis of fluoroheterocyclic analogs has not yet been reported. In this paper, we
disclose methods for the synthesis of fluoroheterocyclic ketene aminals.
Ketene dithioacetals 1 were prepared by the acetophenones with sodium
hydride and carbon disulfide, followed by methyl iodide according to a liter-
ature method (13). Fluorobenzyl ketene dithioacetals 1c (8) reacted with 90%
∗Corresponding author.
527
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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LI AND SMITH
nitric acid in the presence of concentrated sulfuric acid at −5◦C to give 1-(4ꢁ-
fluro-3ꢁ-nitro-phenyl)-3,3-bis-methanesulfinyl-propenone 2c by oxidation and ni-
tration reaction sequence. (1c spectra data: 1H NMR (CDCl3): δ 7.93 (d, J = 10Hz,
2H), 7.09 (d, J = 9.9 Hz, 2H), 6.71(s, 1H), 2.55 (s, 3H), 2.52 (s, 3H); 13C NMR
(CDCl3): δ 183.9, 166.8, 162.5, 135.0, 130.1, 129.9, 115.5, 115.1, 109.0, 17.2,
14.9. Anal. calcd. for C11H11FOS2 (242.33): C, 54.52; H, 4.58. Found: C, 54.52;
H, 4.61.) 1 reacted readily with diamines in anhydrous toluene to give com-
pounds 3–4. Fluorobenzylation of 3–4 only afforded C-alkylation products 5–8
(see Scheme 1). The reaction conditions, yields, and melting points of 2–8 are
listed in Table 1.
O
O
O
H3CS
H3CS
H3CS
H3CS
X
X
H
H
NO2
O
1
2
H
O
N
(CH2)n
X
N
H
H
3 n = 2 4 n = 3
H
H
H
O
O
N
(CH2)n
N
X
N
X
(CH2)n
CH2
N
CH2
H
F
F
7 n = 2 8 n = 3
5 n = 2 6 n = 3
1–8
a
b
c
Cl
F
X
H
Scheme 1.

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FLUOROHETEROCYCLIC KETENE AMINALS
529
Table 1. Compounds 2–8 Prepared
Reaction Conditions
Yield
Mp
Products Temp (◦C) Time (h)
(%)
(◦C)
2c
3c
4c
5c
6a
6b
6c
7b
8a
8b
8c
−5
110
110
70
60
65
65
50
50
50
1
3
2
4
2
3
2
5
75
89
91
68
93
90
94
78
92
81
77
109–111
224–225
228–230
171–173
150–151
220–222
170–172
186–188
135–137
112–114
160–161
1
1.5
2
50
The structures of 2–8 were established by spectroscopic data. In IR spectra
of 2c, a nitro group absorption at ca. 1520 cm−1 and ca. 1340 cm−1 indicated
that aromatic nitration and oxidation of the methylsulfanyl group occurred in the
1
reaction of 1c with nitric acid-sulfuric acid. The H and 13C NMR spectra also
confirmed these aspects. In IR spectra of 3–8, there was an NH stretching absorp-
tion band at ca. 3400 cm−1 and a very strong carbonyl absorption of the aroyl
1
group of 3–8 at ca. 1615 cm−1. In the H NMR spectra, the signals of two ni-
trogen protons (9.25–11.04 ppm) and one ethylenic proton (5.15–5.24 ppm) of
3–4 were discovered, the signals of two nitrogen protons of 5–8 were shown
to still exist at 10.33–11.25 ppm. These data exclude either the N-alkylation
or O-alkylation of 3–4. Furthermore, the ethylenic proton signal of 5–8 disap-
peared, indicating that the fluorobenzylation took place at the ethylenic position
of 3–4.
EXPERIMENTAL
General Methods
Melting points were uncorrected. All reagents and solvents were obtained
from Aldrich, Acros, Fisher, or VWR. Reaction progress was monitored by an-
alytical thin-layer chromatography (Analtech scored 2.5 cm × 10 cm hard TLC
plates, glass). Silica gel used in flash chromatography was 60–200 mesh. Infrared
spectra were measured with an Avatar 360 ESP spectrometer and are expressed in
reciprocal centimeters. 1H NMR and 13C NMR spectra were obtained on a Bruker

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LI AND SMITH
200-MHz spectrometer. The chemical shifts were reported in ppm downfield from
Me4Si. J values are given in Hz.
1-(4ꢁ-Fluoro-3ꢁ-nitro-phenyl)-3,3-bis-methanesulfinyl-propenone (2c)
Fluorobenzoyl ketene dithioacetals 1c (485 mg, 2 mmol) was added in por-
tions to a well-stirred solution of 90% nitric acid (8 mL) and 98% sulfuric acid
(10 mL) at −5◦C over a 1-h period. After stirring for a further 30 min, chloroform
(100 mL) was added. Then ice water (50 mL) was added dropwise. The organic
phase was separated, dried (MgSO4), and filtered. The solvent was removed under
reduced pressure to afford 2c as an oil, which was purified by flash chromatogra-
phy (chloroform-methanol, 25:1) to yield 2c (630 mg, 75%) as yellow needles, mp
109◦–111◦C; IR (KBr): 3428 (NH), 1645 (CO), 1594, 1571, 1520, 1340, 1058,
1022 cm−1; 1H NMR (CDCl3): δ 8.13 (m, 1H), 8.04 (s, 1H), 7.24 (m, 1H), 7.17 (s,
1H), 3.19 (s, 3H), 3.14 (s, 3H); 13C NMR (CDCl3): δ 185.7, 176.7, 169.2, 164.1,
132.1, 131.9, 125.4, 116.7, 116.3, 45.7, 43.2. Anal. calcd. for C13H18FNO5S2
(351.42): C, 44.43; H, 5.16; N, 3.99. Found: C, 44.80; H, 5.06; N, 3.97.
General Procedure for the Synthesis of Compounds 3 and 4
Asolutionofketenedithioacetals1(8mmol)andthecorrespondingdiamines
(10 mmol) in toluene (50 mL) was heated at reflux for 3 h, whereupon, a white
solid precipitated. The precipitate was filtered, washed with cold acetone, and dried
under vacuum. Spectra data corresponding to 3 and 4 are given below.
1-(4ꢁ-Fluoro-phenyl)-2-imidazolidin-2-ylidene-ethanone 3c
Yield 89%; mp 224◦–225◦C; IR (KBr): 3420 (NH), 3163, 1615 (CO), 1587,
1
1551, 922, 850 cm−1; H NMR (CDCl3): δ 9.25 (s, 2H), 7.76 (m, 2H), 7.17
(d, J = 8.9 Hz, 2H), 5.24 (s, 1H), 3.49 (m, 4H); 13C NMR (CDCl3): δ 180.0,
165.9, 161.1, 131.4, 130.5, 127.2, 116.8, 113.4, 74.8, 43.1, 42.4. Anal. calcd. for
C11H11FN2O (206.22): C, 64.07; H, 5.38; N, 13.58. Found: C, 64.17; H, 5.37; N,
13.42.
1-(4ꢁ-Fluoro-phenyl)-2-(tetrahydro-pyrimidin-2ꢁ-ylidene)-ethanone 4c
Yield 91%; mp 228◦–230◦C; IR (KBr): 3455 (NH), 3196, 1610 (CO), 1597,
1530, 1150, 845 cm−1; 1H NMR (DMSO-d6): δ 11.07 (s, 2H), 7.68 (m, 2H), 7.15
(m, 2H), 5.15 (s, 1H), 3.28 (t, 4H), 1.82 (m, 2H); 13C NMR (DMSO-d6): δ 178.5,

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FLUOROHETEROCYCLIC KETENE AMINALS
531
165.4, 160.5, 138.9, 128.3, 128.1, 114.9, 114.5, 76.7, 37.8(2C), 20.5. Anal. calcd.
for C12H13FN2O (220.24): C, 65.44; H, 5.95; N, 12.72. Found: C, 65.24; H, 5.95;
N, 12.68.
General Procedure for the Synthesis of Compounds 5–8
To a mixture of 3 or 4 (1 mmol) in toluene (15 mL) was added fluoroben-
zyl chloride (1.5 mmol), then the reaction mixture was heated at 50◦–70◦C for
1–5 h until no starting material 3 or 4 was detected by TLC (CHCl3: CH3OH,
10 : 1). The solvent was removed under reduced pressure. The crude product was
purified by flash silica gel chromatography (CHCl3 : CH3OH, 50 : 1) to give the
corresponding product (see Table 1). Spectra data of 5–8 are given below.
3-(3ꢁ-Fluoro-phenyl)-1-(4ꢁ-fluoro-phenyl)-2-imidazolidin-2-ylidene-
propan-1-one 5c
Yield 68%; mp 171◦–173◦C; IR (KBr): 3405 (NH), 3126, 1692 (CO), 1614,
1
1588, 1092, 947, 839 cm−1; H NMR (DMSO-d6): δ 11.25 (s, 2H), 7.10–8.24
(m, 8H), 3.48 (m, 4H), 3.20 (s, 2H); 13C NMR (DMSO-d6): δ 192.5, 167.6, 164.3,
139.4, 133.0, 132.8, 132.3, 131.2, 131.1, 125.6, 117.1, 116.3, 114.6, 114.4, 46.9,
44.9(2C), 36.5. Anal. calcd. for C18H16F2N2O (314.33): C, 68.78; H, 5.13; N,
8.91. Found: C, 68.86; H, 5.22; N, 8.98.
3-(3ꢁ-Fluoro-phenyl)-1-phenyl-2-(tetrahydro-pyrimidin-2ꢁ-ylidene)-
propan-1-one 6a
Yield 93%; mp 150◦–151◦C; IR (KBr): 3426 (NH), 3109, 1685 (CO), 1615,
1586, 1314, 948 cm−1 1H NMR (DMSO-d6): δ 10.41 (s, 2H), 7.03–8.29
;
(m, 9H), 3.37 (m, 4H), 3.21 (s, 2H), 1.58 (m, 2H); 13C NMR (DMSO-d6): δ 193.8,
164.8, 159.4, 139.7, 135.4, 134.4, 130.4, 130.3, 129.2, 125.5, 116.3, 115.8, 114.1,
113.7, 50.9, 39.2(2C), 34.8, 17.7. Anal. calcd. for C19H19FN2O (310.37): C, 73.53;
H, 6.17; N, 9.03. Found: C, 73.04; H, 6.17; N, 9.06.
1-(4ꢁ-Chloro-phenyl)-3-(3ꢁ-fluoro-phenyl)-2-(tetrahydro-pyrimidin-2ꢁ-
ylidene)-propan-1-one 6b
Yield 90%; mp 220◦–222◦C; IR (KBr): 3400 (NH), 3129, 1692 (CO), 1614,
1588, 1319, 947, 836 cm−1 1H NMR (DMSO-d6): δ 10.42 (s, 2H), 8.20
;
(d, J = 9.0 Hz, 2H), 7.60 (d, J = 9.2 Hz, 2H), 7.04–7.37 (m, 4H), 3.37 (m, 4H), 3.21
(s, 2H), 1.57 (m, 2H); 13C NMR (DMSO-d6): δ 193.6, 164.8, 159.4, 139.5, 134.0,

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LI AND SMITH
131.0, 130.5, 129.3, 130.3, 125.5, 116.3, 115.9, 114.2, 113.7, 50.9, 39.1(2C), 34.8,
17.7. Anal. calcd. for C19H18ClFN2O (344.81): C, 66.18; H, 5.26; N, 8.12. Found:
C, 66.06; H, 5.02; N, 8.15.
3-(3ꢁ-Fluoro-phenyl)-1-(4ꢁ-fluoro-phenyl)-2-(tetrahydro-pyrimidin-
2ꢁ-ylidene)-propan-1-one 6c
Yield 94%; mp 170◦–172◦C; IR (KBr): 3400 (NH), 3129, 1689 (CO), 1610,
1588, 1320, 945, 845 cm−1 1H NMR (DMSO-d6): δ 10.43 (s, 2H), 8.20
;
(d, J = 8.8 Hz, 2H), 7.66 (d, J = 9.2 Hz, 2H), 7.00–7.47 (m, 4H), 3.39 (m, 4H), 3.21
(s, 2H), 1.58 (m, 2H); 13C NMR (DMSO-d6): δ 193.8, 168.9, 165.2, 163.8, 159.4,
140.1, 132.7, 132.6, 130.6, 125.9, 116.9, 116.3, 114.6, 114.1, 51.2, 39.2(2C), 35.4,
18.1. Anal. calcd. for C19H18F2N2O (328.36): C, 69.50; H, 5.53; N, 8.53. Found:
C, 69.87; H, 5.22; N, 8.51.
1-(4ꢁ-Chloro-phenyl)-3-(4ꢁ-fluoro-phenyl)-2-imidazolidin-2-ylidene-
propan-1-one 7b
Yield 78%; mp 186◦–188◦C; IR (KBr): 3410 (NH), 3034, 1682 (CO), 1586,
1
1402, 1091, 949, 848 cm−1; H NMR (DMSO-d6): δ 10.86 (s, 2H), 7.58–8.22
(m, 4H), 7.03–7.33 (m, 4H), 3.75 (m, 4H), 3.31 (s, 2H); 13C NMR (DMSO-d6): δ
193.3, 166.9, 164.7, 139.7, 133.7, 131.1, 130.6, 130.4, 129.3, 125.3, 116.2, 115.8,
114.2, 113.8, 46.6, 44.4(2C), 34.7. Anal. calcd. for C18H16ClFN2O (330.78): C,
65.36; H, 4.88; N, 8.47. Found: C, 65.81; H, 4.63; N, 8.42.
3-(4ꢁ-Fluoro-phenyl)-1-phenyl-2-(tetrahydro-pyrimidin-2ꢁ- ylidene)-
propan-1-one 8a
Yield 92%; mp 135◦–137◦C; IR (KBr): 3426 (NH), 3127, 1690 (CO), 1615,
1588, 1319, 947 cm−1; 1H NMR (DMSO-d6): δ 10.33 (s, 2H), 7.55–8.24 (m, 4H),
7.00–7.38(m, 5H), 3.34(m, 4H), 3.21(s, 2H), 1.59(m, 2H);13CNMR(DMSO-d6):
δ 194.7, 164.7, 159.6, 139.7, 135.4, 134.4, 130.4, 130.3, 129.2, 125.5, 116.3, 115.8,
114.1, 113.7, 50.8, 39.2(2C), 34.9, 17.7. Anal. calcd. for C19H19FN2O (310.37):
C, 73.53; H, 6.17; N, 9.03. Found: C, 73.80; H, 6.10; N, 9.00.
1-(4ꢁ-Chloro-phenyl)-3-(4ꢁ-fluoro-phenyl)-2-(tetrahydro-pyrimidin-
2ꢁ- ylidene)-propan-1-one 8b
Yield 81%; mp 112◦–114◦C; IR (KBr): 3407 (NH), 3129, 1687 (CO), 1610,
1575, 1319, 945 cm−1; 1H NMR (DMSO-d6): δ 10.48 (s, 2H), 7.83–8.52 (m, 4H),

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533
7.08–7.65 (m, 4H), 3.36 (m, 4H), 3.21 (s, 2H), 1.61 (m, 2H); 13C NMR
(DMSO-d6): δ 193.7, 163.5, 159.1, 139.1, 133.7, 132.6, 132.5, 130.9, 130.6,
128.8, 115.1, 114.7, 114.1, 113.7, 50.8, 39.2(2C), 34.0, 17.3. Anal. calcd. for
C19H18ClFN2O (344.81): C, 66.18; H, 5.26; N, 8.12. Found: C, 66.50; H, 5.09; N,
8.15.
1,3-Bis-(4ꢁ-fluoro-phenyl)-2-(tetrahydro-pyrimidin-2ꢁ-ylidene)-propan-1-one 8c
Yield 77%; mp 160◦–161◦C; IR (KBr): 3400 (NH), 3120, 1685 (CO), 1612,
1578, 1317, 940 cm−1; 1H NMR (DMSO-d6): δ 10.40 (s, 2H), 7.10–8.42 (m, 8H),
3.35 (m, 4H), 3.21 (s, 2H), 1.62 (m, 2H); 13C NMR (DMSO-d6): δ 194.0, 168.9,
164.3, 163.6, 159.5, 133.4, 132.8, 132.6, 131.8, 131.5, 116.9, 116.5, 115.9, 115.5,
51.5, 39.1(2C), 35.0, 18.1. Anal. calcd. for C19H18F2N2O (328.36): C, 69.50; H,
5.53; N, 8.53. Found: C, 69.57; H, 5.17; N, 8.74.
ACKNOWLEDGMENTS
This work was supported by NIH grant R01 CA 64983 from the National
Cancer Institute and the Innovative Biotechnology Research Fund of the
Pennsylvania State University.
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Received in the USA May 19, 2000

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