The Aza-ene Reaction of Heterocyclic Ketene Aminals with 4-Phenyl-1,2,4-triazoline-3,5-dione

Article abstract of DOI:10.1039/a801566j

Heterocyclic ketene aminals bearing a secondary enamine moiety underwent an efficient aza-ene reaction with 4-phenyl-1,2,4-triazoline-3,5-dione under very mild conditions, while no reaction was observed with their tertiary enamine analogues.

Full text of DOI:10.1039/a801566j

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486 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 486±487$
The Aza-ene Reaction of Heterocyclic Ketene
Aminals with 4-Phenyl-1,2,4-triazoline-3,5-dione$
Jian-Heng Zhang, Mei-Xiang Wang and Zhi-Tang Huang*
Institute of Chemistry, The Chinese Academy of Sciences, Beijing 100080, China
Heterocyclic ketene aminals bearing a secondary enamine moiety underwent an efficient aza-ene reaction with 4-phenyl-
1,2,4-triazoline-3,5-dione under very mild conditions, while no reaction was observed with their tertiary enamine
analogues.
The ene reaction has received much attention for a number
of decades because of its synthetic potential and its interest-
ing mechanistic aspects in organic chemistry.1 While the
ene reactions of an ole®n bearing an allylic hydrogen atom
(the `carba-ene') with activated alkenes and alkynes (the
`carba-enophiles') and with heteroenophiles, including
carbonyl, thiocarbonyl compounds, imines, nitroso and azo
compounds, are well documented,1 little is known of the
ene reactions involving hetero-ene components.2±4 This is
particularly true for those of hetero-ene systems contain-
ing
a
heteroatom at the 2-position (X ˆ heteroatom)
(Scheme 1).2,3 Nevertheless, we envisaged that hetero-ene
reactions of secondary enamines would provide novel and
valuable synthetic routes to imines 3 and to ketones, amines
and N-heterocycles, respectively, upon the hydrolysis,
reduction and cyclization of 3.
Scheme 1
Heterocyclic ketene aminals, also known as cyclic 1,1-ene-
diamines, are powerful and versatile synthons for various
types of compounds that are dicult to obtain by other
synthetic methods.5 Most noticeably, however, heterocyclic
ketene aminals bearing a secondary amino group have been
shown recently to be a unique aza-ene component, and the
aza-ene reaction proceeded readily when ethyl propiolate
was used as an enophile.6 To examine the scope and limi-
tations of this novel aza-ene component in organic synthesis,
we have extended the aza-ene reactions of heterocyclic
ketene aminals utilizing a range of carba- and heteroeno-
philes. Herein we report the reaction of aroyl-substituted
heterocyclic ketene aminals with 4-phenyl-1,2,4-triazoline-
3,5-dione (9, PTAD).
Scheme 2
pathway.6 In other words, a secondary enamine is a reactive
component and therefore the aza-ene reaction is most likely
involved (Scheme 2).
The reaction of imidazolidine-containing heterocyclic
ketene aminals 4 and 5 with 9 was rapid and ecient at
room temperature and the corresponding adducts (12) were
obtained immediately and the products 13 were formed
within one hour. Signi®cantly, when 1,3-dimethyl-2-aroyl-
methyleneimidazolidine 6 was employed, no reaction was
observed and the starting materials were recovered. It
should be noted that the only di€erence in structure between
4 or 5 and 6 is that the former has at least one secondary
amino group, being a secondary enamine species, while the
latter is a tertiary enamine compound. These results suggest
that the addition of heterocyclic ketene aminals to PTAD
does not proceed through a Michael addition mechanism, or
through a [2 ‡ 2] cycloaddition followed by rearrangement
Surprisingly, the reaction of six-membered heterocyclic
ketene aminals 7 with 9 under the same conditions did not
yield the desired aza-ene adducts. Instead, benzoylphenyl-
urea (PhCONHCONHPh) 15 was isolated as the sole pro-
duct. Only when the reaction temperature was lowered
to 60 8C, using dichloromethane (DCM) as solvent, was
the aza-ene reaction e€ected eciently. Aza-ene adduct 14
was found to decompose readily at room temperature when
treated with ethanol and other solvents, resulting in the
formation of 15. The instability of aza-ene products from
1-methylpyrimidine-substituted heterocyclic ketene aminals 8
inhibited their successful isolation, though the initial
formation of the aza-ene adducts was evident by thin-layer
chromatography. The reason for the fragmentation of 14
into 15 is not clear.
*To receive any correspondence.
From the above ®ndings it can be concluded that hetero-
cyclic ketene aminals are e€ective aza-ene components. The
aza-ene reaction between them and the hetero-enophile
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1998 487
l
max/nm (log e in ethanol) 228 (4.25) and 296 (4.18); dH 11.30 (s, br,
PTAD takes place easily under very mild thermal con-
ditions.
1 H), 9.60 (s, 1 H), 7.40 (d), 7.40±7.30 (m, 5 H), 7.12 (d, 2 H), 3.60
(s, 4 H) and 2.95 (s, 3 H); dC 187.6, 161.8, 150.4, 149.5, 140.6,
133.2, 131.8, 128.8, 127.9, 127.8, 127.6, 126.2, 88.2, 51.9, 41.7 and
33.4; m/z (EI) 411 (M , 2%), 327 (4), 292 (4), 273 (4), 214 (6), 139
(45) and 119 (100).
‡
Experimental
For general experimental details see our previous paper.6
General Procedure for the Preparation of 14.ÐA suspension of
PTAD (1 mmol) in CH2Cl2 (5 cm3) was added to a stirred solution
of heterocyclic ketene aminals 7 (1 mmol) in CH2Cl2 (10 cm3) at
60 8C. The colour of PTAD faded within 0.5 h and white solid
products precipitated from the solution. After being ®ltered o€ and
washed thoroughly with ethanol, pure products 14 were obtained.
14a. Yield: 58%, mp 156±158 8C (white solid from ethanol)
(Found: C, 63.4; H, 5.1; N, 18.3. C20H19N5O3 requires C, 63.65;
General Procedure for the Synthesis of 12 and 13.ÐTo the
solution of heterocyclic ketene aminals 4 or 5 (1.0 mmol) in 1,4-
dioxane (20 cm3) was added dropwise a solution of 4-phenyl-1,2,4-
triazoline-3,5-dione (9)7 (1.0 mmol) in 1,4-dioxane (5 cm3) at room
temperature. Product 12 precipitated immediately after the addition
of 3 while 13 was formed after another 0.5±1 h. Recrystallization
from the appropriate solvent gave pure 12 and 13.
12a. Yield: 75%, mp 203±205 8C (white solid from ethanol);
(Found: C, 63.0; H, 4.6; N, 19.2. C19H17N5O3 requires C, 62.80; H,
1
H, 5.07; N, 18.56%); ꢀmax/cm 3420, 3230, 1755 and 1690; lmax/nm
1
(log e in ethanol) 290 (4.03); dH 10.85 (s, 1 H), 10.82 (s, br, 1 H),
7.62 (s, 1 H), 7.62 (s, 1 H), 7.10±7.50 (m, 10 H), 3.38 (t, 4 H), 1.86
(quin, 2 H); dC 186.4, 158.4, 151.3, 151.2, 142.5, 132.7, 130.0, 129.5,
129.2, 128.3, 127.0, 126.4, 91.2, 41.1, 38.5 and 20.1; m/z (FAB) 378
4.72; N, 19.28%); ꢀmax/cm 3430, 3300, 1740 and 1675; lmax/nm
(log
e in ethanol) 226 (4.21) and 292 (4.04). dH [200 MHz,
(CD3)2SO] 10.95 (s, 1 H), 9.05 (s, 1 H), 8.00 (s, 1 H), 7.50±7.15
(m, 10 H), 3.75 (t, 2 H) and 3.55 (t, 2 H); dC [50 MHz, (CD3)2SO]
186.4, 163.6, 150.2, 149.6, 141.5, 132.3, 128.4, 128.3, 127.3, 127.1,
‡
(M ‡ 1) ; m/z (EI) 359 (29%), 317 (23), 243 (54) and 227 (100).
‡
14b. Yield: 72%, mp 158±160 8C (white solid from ethanol)
(Found: C, 64.1; H, 5.5; N, 17.7. C21H21N5O3 requires C, 64.43;
126.0, 125.9, 88.1, 44.2 and 41.8; m/z (FAB) 363 (M ); m/z (EI) 303
(4%), 201 (24), 180 (53), 105 (54) and 44 (100).
1
H, 5.41; N, 17.89%); ꢀmax/cm 3420, 3230, 1755 and 1690; lmax/nm
12b. Yield: 65%, mp 205±207 8C (white solid from ethanol);
(Found: C, 63.5; H, 5.0; N, 18.9. C20H19N5O3 requires C, 63.65;
(log e in ethanol) 292 (4.06); dH 10.92 (s, br, 1 H), 10.82 (s, 1 H),
7.60 (s, 1 H), 7.43 (d, 2 H), 7.16 (d, 2 H), 7.06±7.38 (m, 5 H), 3.32
(t, 4 H), 2.26 (s, 3 H) and 1.88 (quin, 2 H); dC 185.4, 157.7, 150.5,
150.2, 139.4, 137.5, 132.5, 128.6, 128.0, 127.3, 126.1, 125.9, 89.8,
40.8, 37.7, 21.0 and 19.6; m/z (EI) 373 (3%), 331 (2), 257 (38), 227
(30) and 119 (100).
1
H, 5.07; N, 18.56%); ꢀmax/cm 3420, 3280, 1740 and 1675; lmax/nm
(log e in ethanol) 228 (4.22) and 296 (4.11); dH 10.95 (s, 1 H), 9.10
(s, 1 H), 7.90 (s, 1 H), 7.43 (d, 2 H), 7.12 (d, 2 H), 7.40±7.20
(m, 5 H), 3.65 (t, 2 H), 3.62 (t, 2 H), 2.30 (s, 3 H); dC 186.3, 163.7,
150.4, 149.5, 138.7, 138.1, 132.3, 128.6, 128.1, 127.4, 126.1, 126.0,
‡
14c. Yield: 61%, mp 153±155 8C (white solid from ethanol)
(Found: C, 61.7; H, 5.1; N, 17.1. C21N21N5O4 requires C, 61.90;
88.1, 44.3, 41.9 and 20.9; m/z (EI) 377 (M , 2%), 317 (27), 258 (6),
215 (19), 194 (92) and 119 (100).
1
H, 5.20; N, 17.19%); ꢀmax/cm 3420, 3230, 1755 and 1690; lmax/nm
12c. Yield: 70%, mp 187±189 8C (white solid from ethanol);
(Found: C, 60.4; H, 4.97; N, 17.7. C20H19N5O4 requires C, 61.06;
(log e in ethanol) 298 (3.89); dH 11.00 (s, 1 H), 10.84 (s, br, 1 H),
7.58 (s, 1 H), 7.40 (d, 2 H), 7.20±7.36 (m, 5 H), 6.82 (d, 2 H), 3.72
(s, 3 H), 3.38 (t, 4 H) and 1.88 (quin, 2 H); dC 184.8, 157.7, 150.5,
150.1, 159.4, 134.6, 132.6, 128.6, 127.6, 127.4, 126.2, 112.8, 89.6,
55.1, 37.9, 37.6 and 19.7; m/z (EI) 389 (4%), 347 (4), 273 (77), 27
(23) and 135 (100).
1
H, 4.87; N, 17.80%); ꢀmax/cm 3400, 3300, 1745 and 1670; lmax/nm
(log e in ethanol) 225 (sh) and 302 (4.13); dH 10.95 (s, 1 H),
9.10 (s, 1 H), 7.88 (s, 1 H), 7.43 (d, 2 H), 7.40±7.25 (m, 5 H), 6.86
(d, 2 H), 3.75 (s, 3 H), 3.70 (t, 2 H) and 3.55 (t, 2 H); dC 185.6,
163.8, 159.7, 150.4, 149.7, 133.7, 132.3, 128.5, 127.9, 127.3, 126.1,
‡
14d. Yield: 75%, mp 171±173 8C (white solid from ethanol)
(Found: C, 58.2; H, 4.8; N, 16.7. C20H18ClN5O3 requires C, 58.32;
112.8, 87.9, 55.1, 44.3 and 41.9; m/z (EI) 393 (M , 2%), 333 (13),
231 (10), 210 (43) and 135 (100).
1
H, 4.40; N, 17.01%); ꢀmax/cm 3420, 3230, 1760 and 1690; lmax/nm
12d. Yield: 80.5%, mp 208±210 8C (white solid from ethanol);
(Found: C, 57.3; H, 4.3; N, 17.2. C19H16ClN5O3 requires C, 57.36;
(log e in ethanol) 292 (4.05); dH 10.90 (s, 1 H), 10.76 (s, br, 1 H),
7.70 (s, br, 1 H), 7.40 (d, 2 H), 7.18±7.36 (m, 5 H), 7.17 (d, 2 H),
3.36 (t, 4 H) and 1.86 (quin, 2 H); dC 183.9, 157.4, 150.4, 150.1,
140.8, 132.7, 132.3, 128.5, 127.7, 127.4, 127.3, 126.0, 89.7, 37.6, 37.5
and 19.4; m/z (EI) 393 (19%), 351 (9), 277 (30) and 227 (100).
Reaction of Heterocyclic Ketene Aminal 7a with PTAD at Room
Temperature.ÐThis followed the same procedure for the synthesis
of 12 and 13, reaction of 7a with 9 gave a viscous yellow solution.
After the removal of solvent, the residue was recrystallized in
ethanol to give benzoylphenylurea as white needles. Yield: 73%,
1
H, 4.05; N, 17.61%); ꢀmax/cm 3400, 3300, 1745 and 1670; lmax/nm
(log e in ethanol) 228 (4.30) and 296 (4.20); dH 10.95 (s, 1 H),
9.02 (s, 1 H), 8.02 (s, 1 H), 7.42 (d, 2 H), 7.40±7.30 (m, 5 H), 7.24
(d, 2 H), 3.75 (t, 2 H), 3.55 (t, 2 H); dC 185.0, 163.6, 150.5, 149.8,
140.4, 133.4, 132.3, 128.7, 128.0, 127.7, 127.4, 126.1, 88.2, 44.4 and
‡
41.9; m/z (FAB) 398 (M ‡ 1) ; m/z (EI) 337 (6%), 235 (20), 214
(30) and 139 (100).
13a. Yield: 53%, mp 162±164 8C (colourless needles from
ethanol); (Found C, 63.8; H, 5.1; N, 18.4. C20H19N5O3 requires
1
mp 208±210 8C (lit.8 208±209 8C); ꢀmax/cm 3210 and 1685; ꢁH
1
C, 63.65; H, 5.07; N, 18.56%); ꢀmax/cm 3410, 3210, 1740 and
10.96 (s, 1 H), 9.72 (s, br, 1 H), 7.10±8.10 (m, 10 H); ꢁC 168.7,
152.2, 137.2, 133.3, 132.1, 129.0, 128.8, 128.1, 124.4 and 120.5.
1680; lmax/nm (log e in ethanol) 226 (4.19) and 294 (4.16); dH 11.25
(s, 1 H), 9.65 (s, 1 H), 7.45±7.08 (m, 10 H), 3.65 (s, 4 H), 2.95
(s, 3 H); dC 188.9, 161.7, 150.2, 149.3, 141.8, 131.8, 128.5, 128.1,
127.5, 127.2, 126.0, 125.6, 88.0, 51.7, 41.5 and 33.2; m/z (EI) 377
We thank the National Natural Science Foundation of
China for ®nancial support.
‡
(M , 6%), 293 (11), 229 (20), 180 (32) and 119 (100).
13b. Yield: 68%, mp 169±171 8C (colourless needles from ethyl
acetate/light petroleum, bp 60±90 8C); (Found: C, 64.3; H, 5.4;
N, 18.3. C21H21N5O3 requires C, 64.43; H, 5.41; N, 17.89%);
Received, 24th February 1998; Accepted, 8th April 1998
Paper E/8/01566J
1
ꢀ
max/cm 3410, 3200, 1745 and 1690; lmax/nm (log e in ethanol)
228 (4.17) and 296 (4.16); dH 11.30 (s, 1 H), 9.85 (s, 1 H), 7.40
(d, 2 H), 7.38±7.16 (m, 5 H), 7.14 (d, 2 H), 3.63 (t, 2 H) 3.58
(t, 2 H), 2.95 (s, 3 H), 2.35 (s, 3 H); dC 190.6, 162.4, 151.1, 151.0,
138.7, 138.1, 131.5, 128.9, 128.4, 127.9, 126.0, 125.8, 89.1, 52.1,
41.5, 33.6 and 21.2; m/z (EI) 391 (M , 2%), 307 (11), 229 (24), 194
(34) and 119 (100).
References
1 For reviews of ene reactions, see (a) W. Carruthers, Cycloaddition
Reactions in Organic Synthesis, Pergamon Press, Oxford, 1990;
(b) B. B. Snide, Ene Reactions With Alkenes as Enophiles in
Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon Press, Oxford, 1991, vol. 5, ch. 1.1.
2 P. C. Montevecchi and M. L. Navacchia, J. Org. Chem., 1995,
60, 6455.
3 J. Cossy, A. Bouzide and M. Pfau, J. Org. Chem., 1997, 62, 7106.
4 J. E. Baldwin, R. M. Adlington, A. U. Jain, J. N. Kolhe and
M. W. D. Perry, Tetrahedron, 1986, 42, 4247.
5 M.-X. Wang and Z.-T. Huang, J. Org. Chem., 1995, 60, 2807 and
references therein.
6 Z.-T. Huang and M.-X. Wang, J. Chem. Soc., Perkin Trans. 1,
1993, 1085.
7 Org. Synth., 1988, Coll. Vol. 6, p. 936.
‡
13c. Yield: 70%, mp 120±122 8C (colourless needles from light
petroleum, bp 60±90 8C/1,4-dioxane) (Found: C, 61.7; H, 5.5;
N, 17.1. C21H21N5O4 requires C, 61.90; H, 5.20; N, 17.19%);
1
ꢀ
max/cm 3400, 3220, 1740 and 1685; lmax/nm (log e in ethanol)
225 (sh) and 300 (4.20); dH 11.15 (s, br, 1 H), 9.75 (s, 1 H), 7.42
(d, 2 H), 7.45±7.10 (m, 5 H), 6.88 (d, 2 H), 3.75 (s, 3 H), 3.60
(s, 4 H), 2.95 (s, 3 H); dC 188.3, 161.9, 159.5, 150.3, 149.5, 134.1,
131.9, 128.7, 128.3, 127.5, 126.2, 112.8, 88.0, 55.1, 51.9, 41.6 and
‡
33.4; m/z (EI) 407 (M , 2%), 323 (11), 229 (14), 210 (15) and 135
(100).
13d. Yield: 92%, mp 165±167 8C (colorless white needles from
ethanol) (Found: C, 58.4; H, 4.5; N, 16.6. C20H18ClN5O3 requires
8 M.-Z. Deng, P. Caubere, J. P. Senet and S. Lecolier, Tetrahedron,
1988, 44, 6079.
1
C, 58.32; H, 4.40; N, 17.01%); ꢀmax/cm 3410, 3200, 1745, 1680;