Study of fluorocarbonyls for the Baylis-Hillman reaction

Article abstract of DOI:10.1021/jo025591l

A study of the effect of fluorine substitution in Baylis-Hillman reactions of various fluorocarbonyl partners with acrolein, methyl vinyl ketone, ethyl acrylate, and acrylonitrile has been made.

Full text of DOI:10.1021/jo025591l

We chose acrolein (1a ), methyl vinyl ketone (1b), ethyl
acrylate (1c), and acrylonitrile (1d ) as the olefin partners
in the reaction. Acrolein is also known to polymerize in
the presence of amines, similar to the case of fluoral.8
Michael-type dimerization of methyl vinyl ketone in the
presence of DABCO has also been reported.9 We were
faced with the difficult task to find conditions to react
these amine-sensitive olefins with fluorinated aldehydes
and ketones. Optimum yields of the fluorinated allyl
alcohol products are obtained by matching the reactivities
of the olefin and carbonyl partners, whereas a mismatch
results in the decomposition or side reaction of the faster
reacting partner. The reactions are discussed below
according to the class of fluorocarbonyl studied.
F lu or oa ld eh yd es. The reactions of fluoral (2) with
1a -d were examined first. As feared, mixing 2 with 1a
at room temperature (rt) under neat conditions resulted
in the polymerization of both reactants. Addition of THF
as a solvent for the reaction provided a very low yield of
the expected product along with the polymers of the
starting materials. With the hope of arresting the poly-
merization, we lowered the reaction temperature to -25
°C and obtained a 40% yield of the BH product, 3a (eq
3). However, we could not suppress the polymerization
Stu d y of F lu or oca r bon yls for th e
Ba ylis-Hillm a n Rea ction
M. Venkat Ram Reddy, Michael T. Rudd, and
P. Veeraraghavan Ramachandran*
Department of Chemistry, Purdue University,
W. Lafayette, Indiana 47907-1393
chandran@purdue.edu
Received February 5, 2002
Abstr a ct: A study of the effect of fluorine substitution in
Baylis-Hillman reactions of various fluorocarbonyl partners
with acrolein, methyl vinyl ketone, ethyl acrylate, and
acrylonitrile has been made.
Fluorine substitution in organic molecules often influ-
ences the biological properties of medicinal compounds1
and the physical properties of several optoelectronic
devices.2 Fluorinated allylic alcohols are important build-
ing blocks in synthetic fluoroorganic chemistry.3 The
possibility to synthesize novel functionalized fluorinated
allylic alcohols in a single step led us to the investigation
of the operationally simple, atom-economical, environ-
mentally friendly Baylis-Hillman (BH) reaction4 of fluo-
rocarbonyls. Unfortunately, a literature search revealed
that the simplest fluorocarbonyls, fluoral and 1,1,1-
trifluoroacetone, polymerize instantaneously in the pres-
ence of amines (eqs 1 and 2).5,6 Our desire to find
completely. Further lowering of the temperature to -78
°C had a deleterious effect on the BH reaction, since
polymerization of both reactants was faster than the BH
reaction at this temperature.
Reaction of 2 with 1b provided the product 3b in 35%
yield under neat conditions, at rt, 1 h, and 65% yield in
THF at -25 °C (eq 3). Reaction with 1c provided a 20%
yield of the product 3c at rt under neat conditions (eq
3). However, decreasing the reaction temperature sup-
pressed the BH reaction completely, and only polymeric
fluoral was obtained. Olefin 1d did not yield any BH
product 3d at rt or at lower temperature.
Reaction of 2,2,3,3,4,4,4-heptafluorobutanal (4) showed
identical reaction patterns with slightly improved yields
of the allylic alcohols. While acrolein and methyl vinyl
ketone provided 50% and 70% yield, respectively, of
products at -25 °C, ethyl acrylate provided only 18%
yield of the product 5c and acrylonitrile failed to provide
any product at rt.
conditions to suppress the polymerization and obtain the
products led to a systematic study achieving the reaction
of both of these compounds with activated olefins under
controlled conditions.7
(1) For several recent reviews, see: Biomedical Frontiers of Fluorine
Chemistry; Ojima, I., McCarthy, J . R., Welch, J . T., Eds.; ACS
Symposium Series 639; American Chemical Society: Washington, DC,
1996.
(2) For several recent reviews, see: Asymmetric Fluoroorganic
Chemistry; Ramachandran, P. V., Ed.; ACS Symposium Series 746;
American Chemical Society: Washington, DC, 1999.
(3) For a review on fluorinated allylic alcohols as building blocks,
see: Allmendinger, T.; Angst, C.; Karfunkel, H. J . Fluorine Chem.
1995, 72, 247.
We then studied a perfluorinated aldehyde that does
not undergo polymerization under the BH reaction condi-
(4) For recent reviews, see: (a) Basavaiah, D.; Rao, P. D.; Hyma, R.
S. Tetrahedron 1996, 52, 8001. (b) This reaction is also known as the
Morita-Baylis-Hillman reaction. Ciganek, E. In Organic Reactions;
Paquette, L. A., Ed.; J ohn Wiley: New York, 1997; Vol. 51, p 201.
(5) Busfield, W. K.; Whalley, E. Polymer 1966, 7, 541.
(6) Dhingra, M. M.; Tatta, K. R. Org. Magn. Reson. 1977, 9, 23.
(7) Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T. Chem.
Commun. 2001, 757.
(8) Yamashita, N.; Yoshihara, M.; Maeshima, T. J . Macromol. Sci.,
Chem. 1973, 7, 569.
(9) Basavaiah, D.; Gowriswari, V. V. L.; Bharathi, T. K. Tetrahedron
Lett. 1987, 28, 4591.
10.1021/jo025591l CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/29/2002
5382
J . Org. Chem. 2002, 67, 5382-5385

TABLE 1. Ba ylis-Hillm a n Rea ction s of F lu or oa ld eh yd es
aldehyde, RFCHO H2CdCH-EWG
reaction conditions
temp, °C
product
isol yld, %
no.
RF
no.
EWG
solvent
time, h
no.
2
2
2
2
4
4
4
4
6
6
6
6
CF3
CF3
CF3
CF3
C3F7
C3F7
C3F7
C3F7
C6F5
C6F5
C6F5
C6F5
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
CHO
COCH3
CO2Et
CN
CHO
COCH3
CO2Et
CN
CHO
COCH3
CO2Et
CN
THF
THF
none
none
THF
THF
none
none
THF
none
none
none
-25
-25
25
1
1
4
4
1
1
4
4
3a
3b
3c
3d
5a
5b
5c
5d
7a
7b
7c
7d
40
65
20a
0
50
70
18a
0
95
70
70b
75b
25
-25
-25
25
25
0
25
25
25
0.25
48
96
96
a
b
Two minor products accounting for a total of ∼20% mass balance were not characterized. On the basis of the recovered aldehyde.
tions (in the presence of a tertiary -amine). Accordingly,
we tested pentafluorobenzaldehyde (6) for BH reaction
with 1a -d . While the reactions of 1b-d under neat
with 1d was faster, complete within 24 h, and provided
94% yield of the product 11d (eq 6).
2-Trifluoroacetylthiophene (12) underwent reaction
with 1c within 7 days, providing the product 13c in 65%
yield, and with 1d within 24 h, providing the product
allylic alcohol 13d in 82% yield (eq 6). Again, 1a and 1b
did not undergo BH reaction.
3-Trifluoroacetylindole (14) was included in the study
to determine whether the Baylis-Hillman reaction com-
petes with the possible Michael reaction under the
conditions. We limited the olefins to 1c and 1d . As feared,
the Michael addition was faster than the BH reaction
with these olefins. We isolated 80% and 82% of the
corresponding Michael addition products 15c and 15d ,
respectively (eq 7).
conditions at rt took 2-4 days to afford 70-75% of the
products 7b-d , 1a polymerized under these conditions.
However, it reacted in THF at 0 °C within 0.25 h to
provide 7a in near quantitative yield (eq 4). All of the
Baylis-Hillman reactions of fluorinated aldehydes are
summarized in Table 1.
F lu or ok eton es. Although 1,1,1-trifluoroacetone (8) is
also known to trimerize in the presence of amines (eq
2),6 our partial success with fluoral persuaded us to
undertake the reaction at low temperatures. We obtained
a 10-12% yield of the products 9a with 1a in THF at
-25 °C and 9d with 1d at rt (eq 5). However, only a
polymeric material was isolated during the reaction of
olefins 1b and 1c with 8.
We then compared the reactivity of the chlorine
analogue of 10. 2,2,2-Trichloroacetophenone (16) failed
to react with all of the above four olefins, 1a -d . The
reaction was too slow to be of any practical value, and
the thin layer chromatogram of the reaction mixture
revealed several minor products along with the starting
material. However, 2-chloro-2,2-difluoroacetophenone (17)
has a reactivity similar to that of the trifluoromethyl
analogue. Ethyl acrylate reacted within 7 days, providing
To avoid the polymerization initiated by abstraction
of the R-hydrogen atom, we focused our attention on aryl
trifluoromethyl ketones. The treatment of 2,2,2-trifluo-
roacetophenone (10) with 2 equiv of 1a in the presence
of 10% DABCO, under neat conditions, at rt, did not
provide any product. Decreasing the reaction tempera-
ture to -25 °C yielded 15% of acrolein dimer along with
its polymer. Olefin 1b also did not provide any of the
expected BH product at rt, although we obtained a 30%
yield of the dimer. Lowering the temperature resulted
only in the suppression of the dimerization. In contrast,
a slow reaction (7 days) between 10 and 1c resulted in
71% yield of the expected allylic alcohol 11c. The reaction
J . Org. Chem, Vol. 67, No. 15, 2002 5383

TABLE 2. Ba ylis-Hillm a n Rea ction s of F lu or oa lk yl Keton es
ketone, RCORF
R
H2CdCH-EWG
no. EWG
CHO
reaction condition
temp, °C
product
yld, %
12
0a
no.
RF
solvent
time
no.
8
8
8
Me
Me
Me
Me
Ph
Ph
2-thioph
2-thioph
3-indolyl
3-indolyl
Ph
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF2Cl
CF2Cl
1a
1b
1c
1d
1c
1d
1c
1d
1c
1d
1c
1d
THF
none
none
THF
none
none
none
none
THF
THF
none
none
-25
-25
-25
rt
rt
rt
rt
rt
rt
rt
1 h
1 h
1 h
1 h
7 d
1 d
7 d
1 d
9a
9b
9c
COMe
CO2Et
CN
CO2Et
CN
CO2Et
CN
CO2Et
CN
0
10
70
94
65
82
80b
82b
68
90
8
9d
10
10
12
12
14
14
17
17
11c
11d
13c
13d
15c
15d
18c
18d
10 h
10 h
7 d
CO2Et
CN
rt
rt
Ph
1 d
a
b
30% of MVK dimer was formed at rt. Only 1,4-addition took place.
TABLE 3. Ba ylis-Hillm a n Rea ction of r-Acetylen ic
r′-P er flu or oa lk yl Keton es
the corresponding allylic alcohol 18c in 68% yield, and
acrylonitrile provided the product 18d within 24 h, in
90% yield (eq 8).The reactions of fluoroalkyl ketones are
summarized in Table 2.
Ph-CtC-CORF
H2CdCH-EWG
product
yld, %
no.
RF
no.
EWG
no.
r-Acetylen ic r′-Tr iflu or oa lk yl Keton es. We ex-
pected a fast Baylis-Hillman reaction of R-acetylenic R′-
perfluoroalkyl ketones because of the increased electro-
philic nature of the carbonyl carbon. However, the
extreme amine sensitivity of these ketones was a concern.
During our projects involving the asymmetric reduction
of the above ketones, we observed that they decompose
very rapidly in the presence of amines.10 Indeed, the
reactions of 1,1,1-trifluoro-4-phenyl-3-butyn-2-one (19)
and 4,4,5,5,6,6,6-heptafluoro-1-phenyl-2-hexyn-3-one (21)
with 1a -d were found to be extremely sensitive to the
reaction conditions. Every parameter, such as tempera-
ture, solvent concentration, amount of catalyst, and so
forth influenced the reaction drastically. After repeated
attempts, we arrived at the optimal conditions and
achieved the fastest Baylis-Hillman reaction at very low
temperatures.
The reaction of 1,1,1-trifluoro-4-phenyl-3-butyn-2-one
(19) with 1c, neat, was very vigorous at rt and was
conducted at 0 °C, complete within 15 min providing a
75% isolated yield of the product 20c (eq 9). Prolonged
reaction times had a deleterious effect. We observed that
19 by itself decomposed in the presence of DABCO to
provide a mixture of compounds.
19
19
19
19
21
21
CF3
CF3
CF3
CF3
C3F7
C3F7
1a
1b
1c
1d
1a
1b
CHO
20a
20b
20c
20d
22a
22b
54
COCH3
CO2Et
CN
CHO
COCH3
50a
75
40
50a
46b
a
b
On the basis of the 10% of recovered ketone. On the basis of
the 40% of recovered ketone. Longer reaction times resulted in
decomposition of 21.
in the decomposition of the ketone. Acrolein provided a
54% yield of the product within 10 min, and methyl vinyl
ketone yielded 50% of product 20b, along with 10% of
the starting material, within the same time (eq 9). Again,
prolonging the reaction had a destructive effect.
4,4,5,5,6,6,6-Heptafluoro-1-phenyl-1-hexyn-3-one (21)
decomposed faster than 19 in the presence of DABCO.
Yet, we obtained 50% and 46% of the products 22a and
22b with 1a and 1b, respectively, at -25 °C (eq 9). The
reactions of R-acetylenic R′-perfluoroalkyl ketones are
summarized in Table 3.
In conclusion, a study of the effect of fluorine substitu-
tion in the Baylis-Hillman reaction of various fluoro-
carbonyl partners with acrolein, methyl vinyl ketone,
ethyl acrylate, and acrylonitrile has been made. We
succeeded in preparing multifunctionalized fluorinated
allyl alcohols with amine-sensitive aldehydes and olefins
by balancing their reactivities.
The results suggest that when the olefin is capable of
reacting with itself in the presence of an amine (e.g.
acrolein), the electrophile has to be very reactive as well
(e.g. fluoral) to obtain a modest to good yield of BH
products. The reaction of a moderately reactive olefin (e.g.
ethyl acrylate or acrylonitrile) and a very reactive elec-
trophile (e.g. fluoral) results in self-reaction of the elec-
trophile or very low yield of the allylic alcohol product.
A moderately reactive electrophile (e.g. trifluoroacetophe-
none) provides a good yield of products with moderately
reactive olefins (e.g. ethyl acrylate and acrylonitrile).
Thus, a match between the reactivities of the olefin and
carbonyl partners is essential for obtaining reasonable
yields of the products.
The reaction of 19 with 1d was even more vigorous at
rt and at 0 °C. We conducted the reaction under con-
trolled conditions, at -25 °C, and isolated a 40% yield of
the product 20d after 10 min. With the more reactive
olefin partner 1a or 1b, we had to carry out the reaction
in 2 M THF at -25 °C. A reaction at 0 °C or rt resulted
(10) Ramachandran, P. V.; Gong, B. Q.; Teodorovic, A. V.; Brown,
H. C. Tetrahedron Asymmetry 1994, 5, 1061.
5384 J . Org. Chem., Vol. 67, No. 15, 2002

Gen er a l P r oced u r e for Ba ylis-Hillm a n Rea ction of
P er flu or oa lk yl- a n d -a r yl Keton es. The reaction of 2,2,2-
trifluoroacetophenone with acrylonitrile is representative. To a
stirred solution of acrylonitrile (0.53 g, 10 mmol, 0.66 mL) and
2,2,2-trifluoroacetophenone (0.87 g, 5 mmol, 0.70 mL) was added
DABCO (0.056 g, 0.5 mmol) at rt. The reaction was complete
within 24 h. In the case of ethyl acrylate, the reaction was
complete in 7 days. The volatiles were removed under vacuum,
and the crude reaction mixture was purified by silica gel
chromotography (hexanes/ethyl acetate 95:5) to obtain 1.07 g
(94%) of the pure compound.
Exp er im en ta l Section
Ma ter ia ls. Tetrahydrofuran was distilled from benzophenone
ketyl prior to use. 2,2,2-Trifluoroacetaldehyde and 2,2,3,3,4,4,4-
heptafluorobutyraldehyde hydrates were prepared from the
corresponding carboxylic acids by reduction with 0.5 molar equiv
of lithium aluminum hydride in ethyl ether at -10 °C for 4 h,
followed by quenching with water and concd sulfuric acid.11 The
aldehydes were obtained by the dehydration of the corresponding
hydrates using phosphorus pentoxide in concentrated sulfuric
acid at 90 °C and were distilled twice at rt prior to use.
R-Acetylenic R′-fluoroalkyl ketones were prepared according to
a literature procedure.12
The reaction conditions varied depending on the alkene and
fluorocarbonyl compound. General procedures for different
classes of carbonyl compounds are described below. The reaction
yields and physical data of individual reactions are provided in
the Supporting Information.
Gen er a l P r oced u r e for Ba ylis-Hillm a n Rea ction of
P er flu or oa lk yl Ald eh yd es. The reaction of a methyl vinyl
ketone with fluoral is representative. To a stirred solution of
methyl vinyl ketone (0.70 g, 10 mmol, 0.83 mL) in THF (5 mL)
was added 2,2,2-trifluoroacetaldehyde (0.49 g, 5 mmol) at -25
°C. To this was added DABCO (0.056 g, 0.5 mmol) in 0.5 mL of
THF. The reaction mixture was stirred at this temperature for
an additional hour (in the case of ethyl acrylate, the reaction
was carried out at rt, under neat conditions for 4 h). The solvent
was evaporated under vacuum, and the crude reaction mixture
was purified by silica gel chromatography (hexanes/ethyl acetate
9:1) to yield 0.55 g (65%) of the pure product.
Gen er a l P r oced u r e for Ba ylis-Hillm a n Rea ction of
F lu or oa r yl Ald eh yd es. The reaction of 2′,3′,4′,5′,6′-pentafluo-
robenzaldehyde with methyl vinyl ketone is representative. To
a stirred solution of methyl vinyl ketone (0.7 g, 10 mmol, 0.83
mL) and pentafluorobenzaldehyde (0.98 g, 5 mmol, 0.62 mL) was
added DABCO (0.056 g, 0.5 mmol) at rt. The reaction was
complete in 2 days. Following the evaporation of the volatiles,
the crude reaction mixture was purified by silica gel chroma-
tography (hexanes/ethyl acetate 9:1) to yield 0.93 g (70%) of the
pure product.
Gen er a l P r oced u r e for Ba ylis-Hillm a n Rea ction of
r-Acetylen ic r′-F lu or oa lk yl Keton es. The reaction of 4-phen-
yl-1,1,1-trifluoro-3-butyn-2-one with acrolein is representative.
To a stirred solution of acrolein (0.56 g, 10 mmol, 0.67 mL) and
THF (5 mL) at -25 °C was added 4-phenyl-1,1,1-trifluoro-3-
butyn-2-one (0.99 g, 5 mmol). DABCO (0.056 g, 0.5 mmol) was
then added, and the reaction was mixed for 10 min at this
temperature. The crude reaction mixture was directly purified
by silica gel chromotography (hexanes/ethyl acetate 9:1) to yield
the pure product 20a (0.70 g, 54%).
In the case of methyl vinyl ketone, 10-mmol-scale reactions
were conducted in 2.5 mL of THF at -25 °C with 0.14 g (1.25
mmol) of DABCO.
In the case of ethyl acrylate, the reactants were mixed under
neat conditions at 0 °C in the presence of 0.056 g (0.5 mmol) of
DABCO and kept at rt for 15 min.
In the case of acrylonitrile, the reactants were mixed at -25
°C in the presence of 0.14 g (1.25 mmol) of DABCO, and the
mixture was maintained for 10 min and filtered through a silica
gel column (hexanes/ethyl acetate 9:1).
Ack n ow led gm en t. Financial assistance from East-
man Kodak Co. is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: The spectral data
and other physical characteristics of all of the compounds
described (5 pages). 1H, 13C, and 19F NMR spectra of all
compounds (74 pages). This material is available free of charge
via the Internet at http://pubs.acs.org.
(11) Braid, M.; Iserson, H.; Lawlor, F. E. J . Am. Chem. Soc. 1954,
76, 4027.
(12) Lindermann, R. J .; Lonikar, M. S. J . Org. Chem. 1988, 53, 6013.
J O025591L
J . Org. Chem, Vol. 67, No. 15, 2002 5385