Addition of amines to the triple bond in α, α α-trichloromethylpropargyl mesylate: Synthesis of α,α- dichloromethylenaminones and preparation of 2-phenyl-4-dichloromethylquinolines

Article abstract of DOI:10.1021/jo048101t

Addition of amines to the triple bond in α,α,α,- trichloromethylpropargyl mesylate to give α,α- dichloromethylenaminones and its use in the preparation of 2-phenyl-4- dichloromethylquinolines in good yields are reported.

Full text of DOI:10.1021/jo048101t

tribromomethylpropargylic alcohol into versatile building
blocks of vinyl triflates was also described. The vinyl
triflates are important in a vast array of palladium-
catalyzed cross-coupling reactions for the development
of functional molecular architecture.9
Addition of Amines to the Triple Bond in
r,r,r-Trichloromethylpropargyl Mesylate:
Synthesis of
r,r-Dichloromethylenaminones and
Preparation of
Alkynylation of chloral and bromal with phenylacety-
lene gave propargyl alcohol 1a and 1b in 95% and 83%
yield, respectively, in the presence of ZnCl2 and Et3N
according to our previously reported procedure.10 Initially
we envisioned that treatment of the trichloromethylpro-
pargyl mesylate 2a with benzylamine might lead to the
transformation of the trichloromethylpropargyl mesylate
into the corresponding propargylamine via the nucleo-
philic substitute of mesyl with an amine. However, when
trichloromethylpropargyl mesylate 2a was treated with
benzylamine (1.1 equiv) in DMF in the presence of Et3N
(1.5 equiv) at 35 °C for 4 h, an unexpected addition
product enaminone 3a was isolated in 71% yield after
workup (Scheme 1). Further experimental optimization
showed that the yield of enaminone 3a could be increased
to 90% by treatment of trichloromethylpropargyl mesy-
late with benzylamine (1.5 equiv) in DMF in the presence
of Et3N (2.5 equiv) at 55-60 °C for 8 h.
2-Phenyl-4-dichloromethylquinolines
Yu-Gui Si, Song-Po Guo, Wan-Jun Wang, and
Biao Jiang*
Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, People’s Republic of China
jiangb@mail.sioc.ac.cn
Received October 27, 2004
Under the above normal conditions, a variety of
primary, secondary, and aromatic amines added to the
trichloromethylpropargyl mesylate 2a giving the corre-
sponding enaminones 3 in good to excellent yields
(Scheme 2). The results revealed the electron-rich aro-
matic amines gave higher yields than the electron-
deficient aromatic amines in the enaminone formation
reaction. The structures of these compounds were sup-
ported by NMR spectroscopy, elemental analysis, and/or
high-resolution mass spectrometry. A single-crystal X-ray
analysis of enaminone 3d showed that these compounds
exist in the (E)-configuration (see the Supporting Infor-
mation). To demonstrate the utility of these kinds of
enaminones, treatment of the enaminones which derived
from some aromatic amine and trichloromethylpropargyl
mesylate with PPA at 100-110 °C gave the desired
cyclization compounds 2-phenyl-4-dichloromethylquino-
lines 4 in excellent yields (Scheme 3).11
To understand the mechanism of the reaction, we
conducted the reaction without the addition of the
nucleophilic amine. Treatment of the trichloromethyl-
propargyl mesylate 2a with 1.1 equiv of Et3N in DMF at
30 °C for 2 h gave the hydrogen chloride elimination
product 5a isolated in quantitative yield (Scheme 4).
Under other basic conditions, K2CO3/DMF, Py/CH2Cl2,
the reaction gave a similar result. Treating the elimina-
tion product 5a with benzylamine in DMF also gave the
3a enaminone. Proparglic alcohol 1 underwent mesyla-
tion and elimination to give the vinyl mesylate compound
5a and 5b in high yield in the presence of 1.2 equiv of
MsCl and 2.5 equiv of Et3N. Proparglic alcohol 1b
Addition of amines to the triple bond in R,R,R-trichloro-
methylpropargyl mesylate to give R,R-dichloromethylen-
aminones and its use in the preparation of 2-phenyl-4-
dichloromethylquinolines in good yields are reported.
Enaminones are important synthetic intermediates,
particularly in heterocyclic chemistry.1 Heterocycles pre-
pared from enaminones include carbazolequinone alka-
loids,2 prrroles,3 pyrimidinones,4 pyrazoles,5 and quino-
lines.6 The preparation of enaminones has been docu-
mented.1 A common method for the synthesis of enami-
nones involves reaction between ammonia or a primary
or secondary amine and a 1,3-diketone or 3-keto ester.
Alternatively imine anion can be acylated at the â-carbon
to give enaminones.7 In an ongoing project in our labora-
tory on the alkynylation of CdO and CdN bonds,8 an
unexpected addition of amines to the triple bond in R,R,R-
trichloromethylpropargyl mesylate to produce R,R-dichlo-
romethylenaminones was discovered. We herein report
the details about this reaction and its use in the prepara-
tion of 2-phenyl-4-dichloromethylquinolines. In addition,
the efficient transformation of the trichloromethyl- or
(1) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277.
(2) Murphy, W. S.; Bertrand, M. J. Chem. Soc., Perkin Trans. 1 1998,
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(3) Trautwein, A. W.; Jung, G. Tetrahedron Lett. 1998, 39, 8263.
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F. C.; Zanatta, N.; Martins, M. A. P. Tetrahedron Lett. 2002, 43, 9315.
(5) Cvetovich, R. J.; Pipik, B.; Hartner, F. W.; Grabowski, E. J. J.
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(8) (a) Jiang, B.; Chen, Z. L.; Tang, X. X. Org. Lett. 2002, 4, 3451.
(b) Jiang, B.; Chen, Z. L.; Xiong, W. N. Chem. Commun. 2002, 1524.
(c) Jiang, B.; Si, Y.-G. Tetrahedron Lett. 2003, 44, 6767.
(9) Diederich, F. Chem. Commun. 2001, 219.
(10) (a) Jiang, B.; Si, Y.-G. Tetrahedron Lett. 2002, 43, 8323. (b)
Jiang, B.; Si, Y.-G. Adv. Synth. Catal. 2004, 346, 669.
(11) (a) Soulen, R. L.; Kundiger, D. G.; Searles, S.; Sanchez, R. A.
J. Org. Chem. 1967, 32, 2661. (b) Roedig, A.; Ritschel, W. Chem. Ber.
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10.1021/jo048101t CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/21/2005
1494
J. Org. Chem. 2005, 70, 1494-1496

SCHEME 1. Formation of Enaminone 3a
SCHEME 2. Synthesis of Enaminones 3
SCHEME 3. Synthesis of
2-Phenyl-4-dichloromethyl Quinolines 4
SCHEME 4. Formation of the Vinyl Mesylate and
Triflate 5
underwent trifluoromesylation and elimination to give
the vinyl triflate compound 5c in high yield in the
presence of 1.2 equiv of trifluoromethanesulfonic anhy-
dride and 2.5 equiv of Et3N at -70 °C. On the basis of
these results, the reaction can be understood by the
following postulated mechanism as shown in Scheme 5.
At first, hydrogen chloride was eliminated from the
trichloromethylpropargyl mesylate 2 to give the phenyl-
ethynylvinyl mesylate 5. The amine then attacked the
triple bond in 5 through 1,4-addition to form the allene.
The mesyl group left from the allene to give the allenol
anion. The allenol anion was protonated and followed by
isomerization to give the enaminone 3.
In summary, an unexpected addition reaction of amines
to the triple bond in trichloromethylpropargyl mesylate
to give R,R-dichloromethylenaminones and its use in the
preparation of 2-phenyl-4-dichloromethylquinolines were
reported. The intermediate phenylethynyldichlorovinyl
mesylate or triflate 5 produced in the reaction also can
serve as an important, highly unsaturated synthetic
building block. Synthesis of such mesylates or triflates
cannot be easily accomplished with previously described
methodology.12
Experimental Section
General Procedure for the Preparation of Enaminones
3. To a solution of 1-trichloromethyl-3-phenyl-2-propyn-1-ol
mesylate (1.63 g, 5 mmol) in DMF (10 mL) was added Et3N (1.8
mL, 12.5 mmol). The amine (5.5 mmol) was added after the
resulting mixture was stirred for 1 h at room temperature. The
reaction mixture was stirred at 55-60 °C for 10 h. After cooling
(12) Rankin, T.; Tykwinshi, R. R. Org. Lett. 2003, 5, 213.
J. Org. Chem, Vol. 70, No. 4, 2005 1495

SCHEME 5. Proposed Mechanism for the Formation of Enaminone 3
to room temperature, the reaction mixture was quenched with
saturated NH4Cl aqueous. The mixture was extracted with
EtOAc (2 × 40 mL). After removal of solvent, the crude product
was purified by flash chromatography on silica gel (hexane:
EtOAc ) 15:1) to afford the enaminones 3.
1,1-Dichloro-4-benzylamino-4-phenylbut-3-en-2-one (3a).
FTIR (neat) 3197, 1604, 1586, 1570, 1487, 1339 cm-1; 1H NMR
δ 11.12 (br s, 1H), 7.50-7.18 (m, 10H), 5.90 (s, 1H), 5.49 (s, 1H),
4.43 (d, J ) 6.3 Hz, 2H); 13C NMR δ 185.0, 169.7, 137.5, 134.4,
130.5, 129.1, 129.0, 128.0, 127.8, 127.2, 91.2, 70.8, 49.1; MS (EI)
m/e 319 (M+, 7.6), 284 (8.6), 248 (10.7), 236 (100), 91 (93.3). Anal.
Calcd for C17H15NCl2O: C, 63.95; H, 4.70; N, 4.38. Found: C,
64.12; H, 4.82; N, 4.28.
4-Dicholromethyl-2-phenylquinoline (4a). FTIR (KBr)
2970, 1599, 1350, 765 cm-1; 1H NMR δ 8.29-8.20 (m, 5H), 7.83
(m, 1H), 7.66 (m, 1H), 7.54 (m, 3H), 7.40 (s, 1H); 13C NMR δ
156.1, 147.8, 142.7, 137.8, 129.7, 128.9, 128.7, 127.9, 126.4, 126.0,
121.6, 121.2, 115.4, 67.3; MS (EI) m/e 287 (M+, 100), 252 (84.6),
217 (64.8), 189 (14.4), 108 (26.3). Anal. Calcd for C16H11NCl2:
C, 66.90; H, 3.83; N, 4.88. Found: C, 66.58; H, 3.86; N, 4.60.
Acknowledgment. This work was financially sup-
ported by the Shanghai Municipal Committee of Science
and Technology, The Shanghai Oversea Scholarship,
and the National Natural Science Foundation of China.
General Procedure for the Preparation of Quinolines
4. Enaminone (1 mmol) and 3 g of PPA were warmed to 110 °C
for 4-8 h and then cooled to room temperature. The resulted
mixture was poured into 10 mL of ice water and extracted with
EtOAc (3 × 10 mL). The combined organic layer was washed
with brine and dried with Na2SO4. After removal of solvent, the
crude product was purified by flash chromatography on silica
gel (hexane:EtOAc ) 20:1) to afforded the quinolines 4.
Supporting Information Available: Detailed experi-
mental procedures, spectral characterization data for com-
pounds 3, 4, and 5, and X-ray analysis of compound 3d. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO048101T
1496 J. Org. Chem., Vol. 70, No. 4, 2005