Reactions of enamines with selectfluor: A straightforward route to difluorinated carbonyl compounds

Article abstract of DOI:10.1021/jo0506837

Reactions of enamines, preformed from β-dicarbonyl and monocarbonyl compounds, with Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2] octane bis(tetrafluoroborate) under mild conditions (triethylamine (TEA) or molecular sieves) easily led to the corresponding difluorinated carbonyl compounds in high yields.

Full text of DOI:10.1021/jo0506837

Reactions of Enamines with Selectfluor: A
Straightforward Route to Difluorinated
Carbonyl Compounds
1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Se-
lectfluor; F-TEDA-BF ), a commercially available, stable,
4
nonvolatile, nonhygroscopic, and easy to handle solid, is
more widely used for site-selective fluorination of a
9
variety of carbonyl compounds.
Weimin Peng and Jean’ne M. Shreeve*
Monocarbonyl compounds are difficult to difluorinate.10
Even when promoted by microwave irradiation in the
presence of a strong base, only minor amounts of mono-
fluorinated products were obtained. Derivatization of
monocarbonyl compounds to form metal enolates, enol
acetates, and trimethylsilyl enol ethers followed by
fluorination only produced the corresponding monoflu-
orinated products.11 A two-step procedure to obtain the
difluorinated derivative of 1-keto-5-tosylbenzazepine in-
cluded a double preparation of the corresponding enol
ether or enol acetate and twice fluorination of that
product with Selectfluor.12 Although â-dicarbonyl com-
pounds can be difluorinated with Selectfluor directly
under neutral conditions, because the difluorinating step
Department of Chemistry, University of Idaho,
Moscow, Idaho 83844-2343
jshreeve@uidaho.edu
Received April 7, 2005
3
was a much slower process than the first, these reactions
Reactions of enamines, preformed from â-dicarbonyl and
13
required a very long time to reach completion. Not
monocarbonyl compounds, with Selectfluor (1-chloromethyl-
surprisingly, fluorination occurred more rapidly with
compounds that exist (at least in part) in enolic form.
Since the monofluoro derivatives exist essentially as their
keto forms because of the electron withdrawing effect of
the fluorine atom, they are not readily fluorinated further
by Selectfluor. This indicates that the reaction occurred
via the enol or enolate form and is ionic in nature.
Although difluorinated products can be obtained in a very
4
-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluorobo-
rate) under mild conditions (triethylamine (TEA) or molec-
ular sieves) easily led to the corresponding difluorinated
carbonyl compounds in high yields.
The presence of two fluorine atoms adjacent to a
carbonyl functionality increases the electrophilicity of the
carbonyl carbon atom dramatically and consequently
facilitates the addition of nucleophiles. Nucleophilic
addition of an enzyme active site to the carbonyl group
of fluorinated ketones has been suggested as being
1
4
straightforward manner by using microwave, it was of
interest to find an alternate method of fluorination that
did not require special apparatus.
As nitrogen analogues of enols, enamines have proved
to be useful alternate reactive intermediates for the
introduction of fluorine on the carbon R to a carbonyl
group. With the greater ability of the nitrogen atom to
donate electrons to the double bond, the reactivity of the
enamines with some electrophilic fluorinating reagents
1
responsible for the inhibition of a variety of enzymes.
Numerous efforts have been made to prepare R,R-difluoro
carbonyl compounds by direct fluorination of the corre-
sponding nonfluorinated substrates through the use of a
2
3
2
variety of electrophilic fluorinating agents, such as F ,
4
5
6
7
15
XeF
2
, ClO
4
F, (CF
3
SO
2
)
2
NF, NF
3
O, etc. However, low
was enhanced relative to an enol ester. However, in
availability, disadvantage of hazardous and toxic char-
acteristics, and high reactivity of these reagents, along
with little or no selectivity, have curtailed their useful-
ness. While a variety of N-F electrophilic fluorinating
reagents are available, currently 1-chloromethyl-4-fluoro-
most cases, the reactions of enamines with electrophilic
fluorinating agents only gave the corresponding mono-
fluorinated carbonyl products. In only two instances was
8
16
a difluorinated product obtained in very low yield in the
17
reaction of a steroidal enamine with perchloryl fluoride.
The reactions of imines with N-fluorobis[(trifluorometh-
yl)sulfonyl]amine gave the corresponding difluorinated
(
1) (a) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; John Wiley and Sons: New York, 1991. (b) Schirlin, D.;
Baltzer, S.; VanDorsselaer, V.; Weber, F.; Weill, C.; Altenburger, J.
M.; Neises, B.; Flynn, G.; Rimy, J. M.; Tarnus, C. Biorg. Med. Chem.
Lett. 1993, 3, 253-258.
(9) For reviews, see: (a) Singh, R. P.; Shreeve, J. M. Acc. Chem.
Res. 2004, 37, 31-44. (b) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.;
Vincent, S. P.; Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44, 192-
212. (c) Banks, R. E. J. Fluorine Chem. 1998, 87, 1-17.
(10) (a) Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2002, 2609-
2615. (b) Tsushima, T.; Kawada, K.; Tsuji, T. J. Org. Chem. 1982, 47,
1107-1110. (c) Stavber, S.; Zupan, M. Tetrahedron Lett. 1996, 37,
3591-3594.
(
2) (a) Lal, G. S.; Pez, G. P.; Syvret. R. G. Chem. Rev. 1996, 96,
1
737-1755. (b) Banks, R. E.; Talow, J. C. In Organofluorine Chemistry;
Banks, R. E., Smart, B. E., Tatlow, J. C., Eds: Plenum Press: New
York, 1994; pp 42-44. (c) Chambers, R. D. Fluorine in Organic
Chemistry; CRC Press LLC: Boca Raton, FL, 2004; pp 51-62.
(
3) Chambers, R. D.; Greenhall, M. P.; Hutchinson, J. Tetrahedron
1
996, 52, 1-8.
(11) (a) Resnati, G.; DesMarteau, D. D. J. Org. Chem. 1991, 56,
4925-4929. (b) Okonya, J. F.; Johnson, C. M.; Hoffman, R. V. J. Org.
Chem. 1998, 63, 6409-6413. (c) Nakanishi, S.; Morita, K.-I.; Jensen,
E. V. J. Am. Chem. Soc. 1959, 81, 5259-5260.
(
(
4) Zajc, B.; Zupan, M. J. Org. Chem. 1982, 47, 7, 573-575.
5) Inman, C. E.; Oesterling, R. E.; Tyczkowski, E. A. J. Am. Chem.
Soc. 1958, 80, 6533-6535.
(
6) Xu, Z. Q.; DesMarteau, D. D.; Gotoh, Y. Chem. Commun. 1991,
(12) Lal, G. S. Res. Disclosure 2001, 1498-1499.
1
2
1
79-181.
(13) Banks, R. E.; Lawrence, N. J.; Popplewell, A. L. Chem. Com-
mun. 1994, 343-344.
(
7) Gupta, O. D.; Shreeve, J. M. Tetrahedron Lett. 2003, 44, 2799-
801.
(14) Xiao, J. C.; Shreeve, J. M. J. Fluorine Chem. 2005, 126, 473-
476.
(
8) Tsushima, T.; Kawada, K.; Tsuji, T. J. Org. Chem. 1982, 47,
107-1110.
(15) Yakanis, S.; Jensen, E. V. J. Org. Chem. 1962, 27, 702-703.
10.1021/jo0506837 CCC: $30.25 © 2005 American Chemical Society
5760
J. Org. Chem. 2005, 70, 5760-5763
Published on Web 06/02/2005

SCHEME 1
TABLE 1. Fluorination of Enamine 1 with Selectfluor
enamine 1
yield,b 19F NMR
entry
R1
R2
X
producta
%
δ (ppm)
1
2
3
4
5
6
7
8
1a Me Me
1b Me OEt
1c Ph OEt
1d Ph Ph
CH2
CH2
CH2
CH2
CH2
CH2
2a
2b
2c
2d
2e
2f
50
47
88
81
71
97
95
89
-115.89
-114.81
-107.58
-102.61
-108.94
-108.21
-102.61
-108.94
1e Me Ph
1f Ph i-propyl
1g Ph 3-chloroPh CH2
2g
2e
1h Ph Me
OCH2
a
Known compounds except compound 2g; ref 21. b Isolated
products suggesting that the enamine intermediate plays
a key role in the reactions.18 Enamines, which have long
1
9
yields, except entries 1 and 2 which were determined by F NMR
spectroscopy by addition of R,R,R-trifluorotoluene as an internal
standard.
been recognized as valuable synthetic intermediates, are
easily prepared from amines and ketones or aldehydes,
and a variety of new methods have been added.19 Our
interest in development of a safer, more facile, milder
and cost-effective method for difluorinating carbonyl
compounds, especially monocarbonyl compounds, prompted
us to study the reactions of enamines with Selectfluor.
It was reported previously that the reaction of enami-
nones with bis(pyridine) iodonium(I) tetrafluoroborate (a
electrophilic iodating regeant) resulted in the preparation
of R-iodo enaminones in almost quantitative yields
through a monoiodation pyrrolidinium intermediate
nated pyrrolidinium salt A in a way which is a key to
this difluorination transformation of enamine.
It was very encouraging to find when even a single
equivalent of Selectfluor was reacted with enamine 1a
as a example of enamines prepared from 1, 3 dicarbonyl
compounds), a mixture of difluorinated and monofluori-
nated products was obtained in a 3:2 ratio. Unfortu-
nately, increasing the amounts of Selectfluor beyond 2
equiv did not cause the reaction to give only the diflu-
orinated product. Although Selectfluor can be decom-
posed by base, it was found that when a weak base, such
(
2
0
(
Scheme 1). An enamine can easily be reacted with
Selectfluor to give the monofluorinated pyrrolidinium salt
A. But in our case, the difluorination of the enamine was
our intended transformation. If the monofluorinated
enamine B, which is equivalent to R-iodo enaminone, can
be regenerated from A, it could be readily fluorinated by
another equivalent of Selectfluor to give the difluorinated
pyrrolidinium salt C. Then aqueous hydrolysis could
readily lead to a difluorinated carbonyl compound in a
one-pot reaction of enamine with Selectfluor (Scheme 1).
This result suggested that the monofluorinated enamine
B was generated in a similar manner from monofluori-
2 3
as triethylamine (TEA) or Na CO , was added to the
reaction system, no monofluorinated product was de-
tected by 19F NMR spectroscopy. In this case, Selectfluor
was not decomposed by base. This was attributed to the
rapid reaction rate between the enamine and Selectfluor.
Finally, we observed that only 1 equiv of TEA was
needed for the high-yield formation of the difluorinated
product without concomitant formation of the monoflu-
orinated species (Table 1) (see the Experimental Sec-
21
1
tion). When the R group bonded directly to the enamine
moiety is alkyl (1a,b,e), the yield is lower than when R
is aryl (1c,d,1f-h). The higher yield with R bonded
1
1
(
16) Enamines with N-F agents: (a) Banks, R. E.; Mohialdin-
Khaffaf, S. N.; Lal, G. S.; Sharifa, I.; Syvret, R. G. J. Chem. Soc., Chem.
Commun. 1992, 595-596. (b) Poss, A. J.; Van Der Puy, M.; Nalewajek,
D.; Shia, G. A.; Wagner, W. J.; Frenette, R. L. J. Org. Chem. 1991, 56,
directly to the enamine is also demonstrated by compar-
ing the yield of enamine 1e to that of 1h since both
enamines gave the same product 2e (Table 1, entries 5
and 8). When the reaction of Selectfluor with the monof-
luorinated product of benzoyl ethyl acetate was at-
tempted in the presence of TEA, no difluorinated product
was formed and the Selectfluor was decomposed. There-
fore, the fluorinated enamine intermediate B (Scheme
), that was regenerated from the pyrrolidinium salt A
under the effect of base, plays a crucial role in the
process.
Given the success of the difluorination of the enamines
obtained from 1,3-dicarbonyl compounds, this methodol-
ogy was applied to the difluorination of the enamine
5
962-5964. (c) Banks, R. E.; Du Boisson, R. A.; Morton, W. D.;
Tsiliopoulos, E. J. Chem. Soc., Perkin Trans. 1 1988, 2805-2811. (d)
Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada, K.;
Tomital, K. J. Am. Chem. Soc. 1990, 112, 563-575. (e) Alkhathlan,
H. Z. Tetrahedron 2003, 59, 8163-8170. (f) Purrington, S. T.; Jones,
W. A. J. Fluorine Chem. 1984, 26, 43-46. With fluoroxy compounds:
(
g) Barton, D. H. R.; Godinho, L. S.; Hesse, R. H.; Pechet, M. M. Chem.
Commun. 1968, 804-806. With perchloryl fluoride: (h) Njar, V. C. O.;
Arunachalam, T.; Caspi, E. J. Org. Chem. 1983, 48, 1007-1011.
1
(17) (a) Nagerlein, B. J.; Pike, J. E.; Jackson, R. W.; Vandenberg,
G. E.; Kagan, F. J. Am. Chem. Soc. 1964, 29, 2982-2986. (b)
Nakanishi, S.; Morgan, R. L.; Jensen, E. V. Chem. Ind. 1960, 1136-
1
5
2
137.
(
18) Ying, W. W.; DesMarteau, D. D.; Gotoh, Y. Tetrahedron 1996,
2, 15-22.
(
19) For reviews: (a) Hickmott, P. W. Tetrahedron 1982, 38, 1975-
050. (b) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277-294. For recent
developments: (c) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun.
(21) The spectra of all the known compounds confirmed their
structures. For the procedure to prepare 2a, 2e, and 2f, see: Xu, Z.
Q.; DesMarteau, D. D.; Gotoh, Y. J. Fluorine Chem. 1992, 58, 71-79.
For the procedure to prepare 2b, 2c, and 2d, see ref 14.
2
005, 973-986 and references therein.
20) Campos, P. J.; Arranz,J.; Rodriguez, M. A. Tetrahedron Lett.
997, 38, 8397-8400.
(
1
J. Org. Chem, Vol. 70, No. 14, 2005 5761

SCHEME 2
TABLE 2. Fluorination of Enamine 4 with Selectfluor
prepared from a monocarbonyl compound since this had
not been possible earlier through direct fluorination.
Preparation of the corresponding enamine by condensa-
tion of acetophenone and morpholine in the presence of
a Brønsted acid using the conventional Dean-Stark trap
technique was not successful. The acetophenone re-
mained in large amounts and required separation using
high vacuum and high-temperature distillation which
resulted in loss of product. The literature method which
employed titanium tetrachloride as reaction promoter
and as a water scavenger to prepare these enamines22
enamine 4
R1
19F NMR
a
5/6b
entry
R2 product yield, % δ (ppm)
1
2
3
4
5
4a
H
H
5ac
74
64
95
72
89
-121.9
-121.3
11:1
2.8:1
c
4b MeO
4c NO2
4d EtOOC
H
5b
d
H
H
Me
5c
-121.5 100:0
-122.0 100:0
d
5d
c
e
4e
H
6e
-181.2
1:19
a
Isolated yield except entry 1, in which the yield was deter-
19
mined by F NMR by addition of R,R,R-trifluorotoluene as internal
b
19
did not work well because the preformed sticky TiCl
4
-
standard. Determined by F NMR of the reaction mixture.
c
d
Known compounds confirmed by spectral data; ref 18. New
amine complex made stirring difficult precluding com-
plete reaction of the acetophenone. This method was
e
compound. One equivalent of Selectfluor was used.
4
modified by adding a solution of TiCl in hexane dropwise
into the solution of acetophenone and morpholine in
presence of 4 Å MS in anhydrous acetonitrile for 7-8 h
to give the corresponding difluorinated products 5a-d
in good yields (Table 2, entries 1-4).
hexane (because acetophenone 3b-d did not dissolve well
in hexane, some benzene could be added). The TiCl -
4
amine complex produced in situ reacted with the ac-
etophenone immediately, and fine particles of TiO
The ratios of the difluorinated to the monofluorinated
products formed, which can be readily separated by flash
chromatography, were a function of the 4-substituent on
the phenyl ring. When the latter was an electron-
withdrawing group, no monofluorinated product was
formed (Table 2, entries 3-4), while the electron-donating
methoxy substituted enamine 4b gave the two products
in a ratio of 2.8:1 (Table 2, entry 2). After the reaction
was completed, the reaction mixture had become acidic
and all of the starting enamine substrate had been
hydrolyzed to regenerate the starting acetophenone. The
enamines themselves are liable to hydrolysis, e.g., if the
sample in the NMR tube was held at ambient tempera-
ture for 1 day, about one-third of the enamine had
hydrolyzed. It was very curious that the reaction of
enamine 4e,26 synthesized from propiophenone 3e, with
Selectfluor under analogous conditions gave the monof-
luorinated product 6e as the major product in high yield
(Table 2, entry 5). Even when two equivalents of Select-
fluor were used, only a trace of the difluorinated product
5e could be detected by 19F NMR spectroscopy. Thus, a
methyl group attached to the position at which fluorina-
tion was to occur has a significant effect on the reaction
result by reducing the acidity of the proton of pyrroli-
dinium salt A (Scheme 1), precluding enolization and
resulting in hydrolysis of A.
2
precipitated quickly. After completing the addition, the
reaction mixture was refluxed gently to complete the
conversion of acetophenone. Filtration gave the corre-
sponding essentially pure enamine in nearly quantitative
yield. No further purification was required (Scheme 2).
When the method used to fluorinate enamine 1 was
employed in the reaction of enamine 4a with Selectfluor,
a mixture of difluorinated and monofluorinated products
was obtained in low yield in a ratio of 1:2. Since a large
amount of nonfluorinated acetophenone was recovered,
most of the Selectfluor was apparently consumed in
reaction with TEA. However, the reaction of enamine 4a23
with 2 equiv of Selectfluor in anhydrous acetonitrile gave
the difluorinated acetophenone 5a in moderate yield
(50%). The monofluorinated acetophenone 6a was also
formed in 13% yield. Addition of molecular sieves (MS)
to the reaction system increased the yield of the diflu-
orinated product to ∼60% but the product ratio (di:mono)
was changed dramatically (9:1). It may be that MS can
facilitate the regeneration of the fluoro enamine inter-
mediate B (Scheme 1). After optimizing the reaction
conditions by balancing the yield of the difluorinated
product and the chemoselectivity, enamines 4a-d2
were reacted with two equivalents of Selectfluor in the
3-25
We have developed a practical and straightforward
method to obtain difluorinated carbonyl compounds in
high yields from readily available enamines via fluorina-
tion with Selectfluor without requiring a strong base to
generate the corresponding anion. However, a base, such
as TEA, or molecular sieves was crucial to regenerate
(
(
22) Carlson, R.; Nilsson, A. Acta Chem. Scand. B 1984, 38, 49-53.
23) (a)Pine, S. H.; Pettit, R. J.; Geib, G. D.; Cruz, S. G.; Gallego, C.
H.; Tijerina, T.; Pine, R. D. J. Org. Chem. 1985, 50, 1212-1216. (b)
Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes, C. Chem. Commun.
2
004, 1400-1401.
(
24) Carlson, R.; Nilsson, A. Acta Chem. Scand., Ser. B: Org. Chem.
Biochem. 1984, B38, 49-53.
25) (a) Funabiki, K.; Matsunaga, K.; Nojiri, M.; Hashimoto, W.;
Yamamoto, H.; Shibata, K.; Matsui, M. J. Org. Chem. 2003, 68, 2853-
860. (b) Funabiki, K.; Nojiri, M.; Matsui, M.; Shibata, K. Chem.
Commun. 1998, 2051-2052.
(
(26) (a) Kawai, N.; Shioiri, T. Chem. Pharm. Bull. 1983, 31, 2564-
2573. (b) Seebach, D.; Golinski, J. Helv. Chim. Acta 1981, 64, 1413-
1423.
2
5762 J. Org. Chem., Vol. 70, No. 14, 2005

the monofluorinated enamine, the key intermediate in
obtaining the difluorinated carbonyl compound. Since this
method uses a commercially available and easily handled
reagent and has wide functional group tolerance, it offers
a promising alternative in the synthesis of some highly
functionalized bioactive difluorinated compounds.
morpholine (9.2 mmol, 0.8 g, 0.8 mL). Then TiCl
4
(1.4 mmol,
0
.26 g, 0.15 mL) in 5 mL of anhydrous n-hexane was added
dropwise over 20 min. Fine particles of TiO
2
precipitated. The
reaction mixture was heated at reflux for 10 min to 1 h after
TiCl
4
addition to the solution depending on the acetophenone
, the filtrate was
used. After cooling and filtration of TiO
2
evaporated in vacuo to give the enamine nearly quantitatively
and essentially pure (traces of acetophenone may remain).
General Procedure Fluorination of Enamine 4 To Form
Monocarbonyl Compounds. To the mixture of Selectfluor (2
mmol, 746 mg) and 4 Å MS (2 g) in 20 mL of anhydrous
acetonitrile cooled at -10 °C under nitrogen was added a single
portion of enamine 4 (1 mmol) in 5 mL of anhydrous acetonitrile.
After the reaction mixture was stirred for 7-8 h at -10 °C, it
was filtered and 2.5 g of silica gel was added to the filtrate. The
solvent was removed under vacuum, and the remaining solid
was chromatographed using n-hexanes-ethyl acetate as eluent
to give the difluorinated product 5.
Experimental Section
See the Supporting Information for general methods and
analytical and spectral data.
General Procedure for Synthesis of a 1,3-Dicarbonyl
Compound from Enamine 1 via Fluorination. To a solution
of Selectfluor (2 mmol, 746 mg) in 20 mL of acetonitrile cooled
to -10 °C was added triethylamine (1 mmol, 101 mg, 0.14 mL).
A solution of the preformed enamine 1 (1 mmol) in 5 mL of
acetonitrile was added dropwise over 10 min. It was stirred for
3
0 min with continued cooling. Silica gel (2.5 g) was added to
2
,2-Difluoro-1-(4-ethoxycarbonylphenyl)ethanone (5d):
white solid (mp 57-58 °C; n-hexane/CH Cl /AcOEt (2/1/0.1), R
.2); H NMR δ 8.22-8.12 (AB system, J ) 8.7 Hz, 4H), 6.30 (t,
J ) 53.4 Hz, 1H), 4.44 (q, J ) 7.1 Hz, 2H), 1.44 (t, J ) 7.1 Hz,
the reaction mixture, and the solvent was evaporated to dryness.
2
2
f
The mixture was chromatographed on silica gel (60-200 micron,
1
0
6
0 Å) with n-hexanes-ethyl acetate as eluent to give the
difluorinated product 2. (For determination of reaction yield, in
some cases, 1 mmol R,R,R-trifluorotoluene was added to the
19
13
3
)
)
(
2
1
H); F NMR δ -122.0 (d, J ) 53.7 Hz); C NMR δ 188.1 (t, J
25.9 Hz), 166.2, 136.6, 135.3 (t, J ) 2.0 Hz), 130.8, 130.4 (t, J
2.4 Hz), 112.0 (t, J ) 254.0 Hz), 62.5, 15.1; GC-MS (EI) 228
1
9
reaction mixture, and the F NMR spectrum was obtained.)
2
,2-Difluoro-1-phenyl-3-(3-chlorophenyl)-1,3-propanedi-
0.5);
H NMR δ 8.20-7.90 (m, 4H), 7.80-7.40 (m, 5H); F NMR δ
+
M ), 213, 207, 183, 177, 155, 149, 127, 121, 104, 93; IR (KBr)
one (2g): pale yellow heavy oil (n-hexane/AcOEt (10/1), R
f
989, 1711, 1610, 1471, 1398, 1371, 1291, 1239, 1181, 1137,
1
19
-1
112, 1059, 1021, 971, 883, 843, 769, 726, 694, 661, cm . Anal.
: C, 57.90; H, 4.42. Found: C, 57.66; H,
1
3
1
1
1
02.6; C NMR δ 188.0 (t, J ) 27.1 Hz), 187.3 (t, J ) 25.4 Hz),
36.2, 136.0, 135.8, 134.0 (t, J ) 1.4 Hz), 132.3 (t, J ) 1.6 Hz),
31.1 (t, J ) 2.7 Hz), 131.1, 130.8 (t, J ) 2.6 Hz), 129.8, 129.2
Calcd for C11
.43.
10 2 3
H F O
4
(
(
t, J ) 3.2 Hz), 113.4 (t, J ) 266.6 Hz); GC-MS (EI) 294/296
+
Acknowledgment. We are grateful to the NSF
M ), 139/141, 111/113, 105, 77, 51; IR (KBr) 3395, 3072, 1702,
(
CHE-0315275), the ONR (N00014-02-1-0600), and the
1
7
6
595, 1570, 1475, 1448, 1425, 1294, 1242, 1163, 1111, 965, 898,
88, 748, 713, 684, 577 cm . Anal. Calcd for C15
-
1
AFOSR (F49620-03-1-0209) for support of this work.
9 2 2
H F O : C,
1.14; H, 3.08. Found: C, 61.40; H, 3.26.
General Procedure for Preparing Enamine 4 from
Supporting Information Available: Analytical and spec-
Acetophenone 3. Into a nitrogen-filled three necked flask
equipped with a dropping funnel, a reflux condenser, and a
magnetic stirrer, and cooled to 0 °C, was added 20 mL of
anhydrous n-hexane (10 mL anhydrous benzene was also needed
in the case of acetophenone 3b-d), acetophenone 3 (2 mol), and
1
tral data for 4c, 4d, and 5c. H NMR spectra for compounds
2
c-f, 4a,b,e, 5b, and 6e. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0506837
J. Org. Chem, Vol. 70, No. 14, 2005 5763