Palladium-catalyzed regio- and stereoselective formate reduction of fluorine-containing allylic mesylates. A new entry for the construction of a tertiary carbon attached with a fluoroalkyl group

Article abstract of DOI:10.1021/jo0602120

The regioselective palladium-catalyzed formate reduction of γ-fluoroalkylated allylic esters is described. Reduction of the allylic esters under the influence of palladium with a monodentate phosphine ligand proceeded preferentially at the γ position, the corresponding reduction products with a fluoroalkyl group at the tertiary carbon being afforded in high yields. When the chiral allylic ester was employed, complete chirality transfer was observed, leading to the optically active materials in high yields.

Full text of DOI:10.1021/jo0602120

Palladium-Catalyzed Regio- and Stereoselective Formate Reduction
of Fluorine-Containing Allylic Mesylates. A New Entry for the
Construction of a Tertiary Carbon Attached with a Fluoroalkyl
Group
Tsutomu Konno,* Tsuyoshi Takehana, Makoto Mishima, and Takashi Ishihara
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki,
Sakyo-ku, Kyoto 606-8585, Japan
konno@chem.kit.ac.jp
ReceiVed February 1, 2006
The regioselective palladium-catalyzed formate reduction of γ-fluoroalkylated allylic esters is described.
Reduction of the allylic esters under the influence of palladium with a monodentate phosphine ligand
proceeded preferentially at the γ position, the corresponding reduction products with a fluoroalkyl group
at the tertiary carbon being afforded in high yields. When the chiral allylic ester was employed, complete
chirality transfer was observed, leading to the optically active materials in high yields.
Introduction
Introduction of a fluoroalkyl group into an asymmetric carbon
center (Figure 1) constitutes a major interest in organofluorine
chemistry owing to the recent outstanding applications of
optically active fluoroalkylated compounds in the medicinal,
pharmaceutical, and agricultural fields, such as Efavirenz (non-
nucleoside transcriptase inhibitor), KW-7158 (a agent for
treating urinary incontinence), and so on.1
Consequently, much effort has been put forth toward the
development of a new synthetic approach to various classes of
chiral fluoroalkylated compounds thus far.2 Herein, we wish to
describe a new entry to such chiral organic molecules 1 via
highly regio- and stereoselective palladium-catalyzed formate
reduction of γ-fluoroalkylated allylic esters 2 in detail (Scheme
1).3,4
FIGURE 1. Chiral fluoroalkylated compounds.
easily prepared as a mixture of E and Z isomers in four steps
from commercially available poly- or perfluoroalkanoic acid
ethyl esters 3 (Scheme 2).5 Thus, treatment of 3 with Grignard
reagents at -78 °C gave the corresponding polyfluoroalkyl
ketones 4 in good yields, which underwent the efficient Horner-
Wadsworth-Emmons reaction to afford the R,â-unsaturated
esters 5 in excellent yields. Reduction of 5 with DIBAL-H
followed by mesylation produced fluoroalkylated allyl mesylates
(2) (a) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. ReV. 2004, 104, 1-16.
(b) Konno, T.; Daitoh, T.; Ishihara, T.; Yamanaka, H. Tetrahedron:
Asymmetry 2001, 12, 2743-2748. (c) Lin, P.; Jiang, J. Tetrahedron 2000,
56, 3635-3671. (d) Konno, T.; Ishihara, T.; Yamanaka, H. Tetrahedron
Lett. 2000, 41, 8467-8472. (e) Iseki, K. Tetrahedron 1998, 54, 13887-
13914. (f) Konno, T.; Umetani, H.; Kitazume, T. J. Org. Chem. 1997, 62,
137-150. (g) Hiraoka, S.; Yamazaki, T.; Kitazume, T. Synlett 1997, 669-
670. (h) Konno, T.; Nakano, H.; Kitazume, T. J. Fluorine Chem. 1997, 86,
81-87. (i) Konno, T.; Kitazume, T. Tetrahedron: Asymmetry 1997, 8, 223-
230. (j) Yamazaki, T.; Hiraoka, S.; Kitazume, T. Tetrahedron: Asymmetry
1997, 8, 1157-1160. (k) Yamazaki, T.; Umetani, H.; Kitazume, T.
Tetrahedron Lett. 1997, 38, 6705-6708. (l) Konno, T.; Yamazaki, T.;
Kitazume, T. Tetrahedron 1996, 52, 199-208. (m) Shinohara, N.; Haga,
J.; Yamazaki, T.; Kitazume, T.; Nakamura, S. J. Org. Chem. 1995, 60,
4363-4374. (n) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron: Asymmetry
1994, 5, 961-974. (o) Resnati, G. Tetrahedron 1993, 49, 9385-9445. (p)
Yamazaki, T.; Haga, J.; Kitazume, T. Chem. Lett. 1991, 2175-2178. (q)
Bravo, P.; Resnati, G. Tetrahedron: Asymmetry 1990, 1, 661-692. (r)
Yamazaki, T.; Ishikawa, N.; Iwatsubo, H.; Kitazume, T. J. Chem. Soc.,
Chem. Commun. 1987, 1340-1342.
Results and Discussion
Palladium-Catalyzed Formate Reduction of Nonchiral
Allyl Mesylates. Our initial studies were performed using
nonchiral allyl mesylates 2a-f,h as a substrate which could be
(1) (a) Young, S. D.; Britcher, S. F.; Tran, L. O.; Linda, L. S.; Lumma,
W. C.; Lyle, T. A.; Hyff, J. R.; Anderson, P. S.; Olson, D. B.; Carrol, S.
S.; Pettibone, Z. D.; Obrien, J. A.; Ball, R. G.; Balani, S. K.; Lin, J. H.;
Chen, I. W.; Schleif, W. A.; Sardana, V. V.; Long, W. J.; Brynes, V. W.;
Emni, Antimicrob. Agents Chemother. 1995, 39, 2602. (b) Pierce, M. E.;
Parsons, R. L., Jr.; Radesca, L. A.; Lo, Y. S.; Silverman, S.; Moore, J. R.;
Islam, Q.; Choudhury, A.; Fortunak, J. M. D.; Nguyen, D.; Luo, C.; Mogan,
S. J.; Davis, W. P.; Confalone, P. N.; Chen, C.; Tillyer, R. D.; Frey, L.;
Tan, L.; Xu, F.; Zhao, D.; Thompson, A. S.; Corley, E. G.; Grabowski, E.
J. J.; Reamer, R.; Reider, P. J. J. Org. Chem. 1998, 63, 8536-8543.
10.1021/jo0602120 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/24/2006
J. Org. Chem. 2006, 71, 3545-3550
3545

Konno et al.
SCHEME 1
SCHEME 2
SCHEME 3
In particular, the use of Pd2(dba)3CHCl3 + 4PPh3 led to
optimum regioselectivity (entry 10). On the contrary, a bulky
and monodentate trialkylphosphine ligand, like PCy3, decreased
the regioselectivity significantly. More interestingly, bidentate
ligands, such as dppe, dppf, and BINAP, resulted in a high
reverse regioselectivity, the R-product 7a being afforded in 75-
97% yields.
With the optimized reaction conditions (Table 1, entry 10),
we investigated the present palladium-catalyzed formate reduc-
tion of various types of allyl mesylates 2 as shown in Scheme
4 and Table 2.
Generally, all substrates could participate nicely in the
reaction to give the reduction products 1 and 7 in excellent
combined yields. The reaction of allyl mesylate bearing para-
and meta-substituted aromatic rings as R1 proceeded in a highly
regioselective manner (entries 1, 2, and 4); however, ortho-
substitution on the aromatic ring in R1 slightly decreased the
regioselectivity (entries 3 and 5). The use of an alkyl group as
R1 also led to a high regioselectivity. It should be noted that
various types of fluoroalkyl groups did not influence on the
yield and regioselectivity.
Formate Reduction of R-Substituted-Allyl Mesylates. We
next investigated the palladium-catalyzed formate reduction of
(R-substituted)allyl esters 2i-o, which could be easily prepared
as described in Schemes 5 and 6. Thus, 2i,j,l-n could be
prepared from 3 by a similar procedure as shown in Scheme 2,
though phosphonium salts 8 were used for the Wittig reaction,
instead of Horner-Wadsworth-Emmons reagents (Scheme 5).
The fluoroalkylated allylic mesylate with a phenyl group as R2
was too unstable to be prepared, so that the corresponding allyl
acetate 2k was used for the next formate reduction. On the other
hand, propargylic alcohol 9, which could be prepared from
2-bromo-3,3,3-trifluoropropene 10 according to the literature,6
was reduced with an excess amount of Red-Al followed by
treatment of I2, leading to vinyl iodide 11. The Suzuki-Miyaura
cross-coupling reaction of 117 and the subsequent mesylation
of the resultant allylic alcohol 12 gave the desired allylic
mesylate 2o in good yield (Scheme 6).
2 in good combined yields. Difluoromethylated allyl mesylate
was too unstable to be prepared, so that the corresponding allyl
carbonate 2g was used for the next reaction.
Treatment of 2a (E/Z ) 76/24) with HCO2-NEt3H+ (1.2
equiv) in the presence of Pd(PPh3)4 in THF at room temperature
for 24 h afforded the desired γ-product 1a in 66% yield
preferentially, together with 20% of the R-product 7a (Scheme
3, Table 1, entry 1). The reaction in benzene resulted in a slight
increase of the chemical yield (entry 2). In contrast to these
solvents, more polar solvents, such as 1,4-dioxane and DMF,
were found to be less effective for the reaction at room
temperature, 1a being obtained in only 45% and 25% yields,
respectively (entries 3 and 4). Interestingly, higher reaction
temperatures caused a significant increase of the yield as shown
in entries 5-8. In particular, the reaction in DMF at 80 °C for
2 h gave 1a in 89% yield (entry 8).
We also examined the effect of the ligand on palladium as
shown in entries 9-17. When a phosphine ligand was not
employed, 7a was formed preferentially (entry 9). A series of
monodentate phosphine ligands, such as PPh3, P(o-Tol)3,
P(OPh)3, and P(n-Bu)3, were found to be very effective to afford
the desired 1a in high yields with a satisfactory regioselectivity.
(3) For the study of the fluorine-containng π-allylpalladium complex,
see: (a) Konno, T.; Takehana, T.; Ishihara, T.; Yamanaka, H. Org. Biomol.
Chem. 2004, 2, 93-98. (b) Okano, T.; Matsubara, H.; Kusukawa, T.; Fujita,
M. J. Organomet. Chem. 2003, 676, 43-46. (c) Konno, T.; Nagata, K.;
Ishihara, T.; Yamanaka, H. J. Org. Chem. 2002, 67, 1768-1775. (d) Konno,
T.; Ishihara, T.; Yamanaka, H. Tetrahedron Lett. 2000, 41, 8467-8472.
(e) Hanzawa, Y.; Ishizawa, S.; Kobayashi, Y. Chem. Pharm. Bull. 1988,
36, 4209-4212. (f) Hanzawa, Y.; Ishizawa, S.; Ito, H.; Kobayashi, Y.;
Taguchi, T. J. Chem. Soc., Chem. Commun. 1990, 394-395.
(6) (a) Yamazaki, T.; Mizutani, K.; Kitazume, T. J. Org. Chem. 1995,
60, 6046-6056. (b) Mizutani, K.; Yamazaki, T.; Kitazume, T. J. Chem.
Soc., Chem. Commun. 1995, 51-52.
(4) For the transition-metal-catalyzed formate reduction, see: (a) Lautens,
M.; Paquin, J.-F. Org. Lett. 2003, 5, 3391-3394. (b) Hayashi, T. J.
Organomet. Chem. 1999, 576, 195-202. (c) Fuji, K.; Sakurai, M.; Kinoshita,
T.; Kawabata, T. Tetrahedron Lett. 1998, 39, 6323-6326. (d) Tsuji, J.;
Manda, T. Synthesis 1996, 1-24. (e) Hayashi, T.; Iwamuara, H.; Uozumi,
Y.; Matsumoto, Y.; Ozawa, F. Synthesis 1994, 526-532.
(7) (a) Konno, T.; Daitoh, T.; Noiri, A.; Chae, J.; Ishihara, T.; Yamanaka,
H. Tetrahedron 2005, 61, 9391-9404. (b) Konno, T.; Daitoh, T.; Noiri,
A.; Chae, J.; Ishihara, T.; Yamanaka, H. Org. Lett. 2004, 6, 933-936. (c)
Wang, J.-J.; Ling, W.; Lu, L. J. Fluorine Chem. 2001, 111, 241-246. (d)
Qing, F.-L.; Ying, J.; Zhang, Y. J. Fluorine Chem. 2000, 101, 31-33. (e)
Pan, R.-Q.; Liu, X.-X.; Deng, M.-Z. J. Fluorine Chem. 1999, 95, 167-
170. (f) Prie´, G.; Thibonnet, J.; Abarbri, M.; Ducheˆne, A.; Parrain, J.-L.
Synlett 1998, 839-840.
(5) Kimura, M.; Yamazaki, T.; Kitazume, T.; Kubota, T. Org. Lett. 2004,
6, 4651-4654.
3546 J. Org. Chem., Vol. 71, No. 9, 2006

Pd-Catalyzed Reduction of Fluorine-Containing Allylic Mesylates
TABLE 1. Investigation of the Reaction Conditions Using 2a
entrya
Pd(0)/(Pd ) 5 mol %)
Pd(PPh)4
Pd(PPh)4
Pd(PPh)4
Pd(PPh)4
Pd(PPh)4
Pd(PPh)4
Pd(PPh)4
solvent
THF
PhH
1,4-dioxane
DMF
THF
PhH
1,4-dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
yieldd/% of 1a
yieldd/% of 7a (E/Z)
1b
2b
3b
4b
5c
66
70
45
25
66
86
79
89
29
86 (82)c
85
77
80
47
0
20 (100:0)
12 (99:1)
15 (93:7)
6 (67:33)
16 (100:0)
7 (100:0)
6 (100:0)
9 (100:0)
69 (90:10)
7 (100:0)
12 (86:14)
20 (95:5)
16 (88:12)
50 (90:10)
97 (82)c (97:3)
83 (94:6)
75 (91:9)
6c
7c
8
9
Pd(PPh)4
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3 + 4PPh3
Pd2(dba)3‚CHCl3 + 8P(o-Tol)3
Pd2(dba)3‚CHCl3 + 8P(OPh)3
Pd2(dba)3‚CHCl3 + 8P(n-Bu)3
10
11
12
13
14
15
16
17
f
Pd2(dba)3‚CHCl3 + 8PCy3
Pd2(dba)3‚CHCl3 + 4dppeg
Pd2(dba)3‚CHCl3 + 4dppfh
Pd2(dba)3‚CHCl3 + 4(S)-BINAPi
0
7
a Unless otherwise noted, the reaction was carried out at 80 °C. b Stirred at rt for 24 h. c Stirred at the reflux temperature for 2 h. d Determined by 19F
NMR. e Isolated yields. f Cy ) cyclohexyl. g dppe ) 1,2-bis(diphenylphosphino)ethane. h 1,1′-Bis(diphenylphosphino)ferrocene. i BINAP ) 2,2′-bis(diphe-
nylphosphino)-1,1′-binaphthyl.
SCHEME 4
SCHEME 5
TABLE 2. Palladium-Catalyzed Formate Reduction of Various
Mesylates
entry
substrate (E/Z)
yielda/% of 1
yieldb/% of 7 (E:Z)
1
2
3
4
5
6
7c
8
2a (76/24)
2b (95/5)
2c (88/12)
2d (97/3)
2e (31/69)
2f (94/6)
86 (82)
86 (46)
61 (54)
73 (52)
69 (26)
84
7 (100:0)
8 (100:0)
12 (100:0)
10 (100:0)
22 (59:41)
9 (100:0)
0
2g (16/84)
2h (95/5)
91 (88)
78 (62)
13 (100:0)
a Determined by 19F NMR. Values in parentheses are of isolated yield.
b Determined by 19F NMR. c Difluoromethylated allyl carbonate was used.
R-product was formed in 28% yield. Then the γ-product 1i was
afforded in 57% yield when P(p-Tol)3 was employed. Eventu-
ally, the best yield was given when more electron-donating
ligand, P(p-MeOC6H4)3, was used. In this case, the γ-product
was obtained in 72% yield as a mixture of E and Z isomer in
With allylic mesylate 2i (Rf ) CF3, R1 ) Ph, R2 ) Me), the
palladium-catalyzed formate reduction was attempted under the
same reaction conditions as in the case of 2a (Scheme 7). Thus,
to a solution of formic acid (1.2 equiv) and Et3N (1.4 equiv) in
the presence of Pd2(dba)3CHCl3 (2.5 mol %) and PPh3(10 mol
%) in DMF was added the starting ester 2i, and then the whole
was heated at 80 °C for 2 h. As a result, the desired γ-product
1i was formed in only 47% yield as an E and Z mixture in a
ratio of 83:17, together with 5% of the R-product 7i. Addition-
ally, fluoroalkylated diene 13i was given in 46% yield (Table
3, entry 1). The unsatisfactory results prompted us to reexamine
the reaction of 2i in detail as described in entries 2-10.
As shown in entry 2, the reaction at room temperature for
24 h did not give rise to any change in the ratio of 1i/7i/13i,
the starting material being recovered in only 16% yield. Even
use of 20 mol % of PPh3 did not lead to a satisfactory result
(entry 3). On the other hand, P(o-Tol)3 caused an increase of
the yield of 1i and a decrease of the yield of 13i, though the
SCHEME 6
J. Org. Chem, Vol. 71, No. 9, 2006 3547

Konno et al.
SCHEME 7
FIGURE 2. A byproduct.
SCHEME 9
TABLE 3. Palladium-Catalyzed Formate Reduction of 2i
yield/% of 1i
(E/Z)a
yield/%
yield/%
entry
ligand (10 mol %)
of 7ia,b
of 13ia
1
2c
3d
4
5
6
7
8
9
10
PPh3
PPh3
PPh3
P(o-Tol)3
P(p-Tol)3
P(p-MeOC6H4)3
P(n-Bu)3
PCy3
47 (83:17)
37 (100:0)
41 (93:7)
59 (83:17)
57 (82:18)
72 (84:16)
36 (100:0)
45 (100:0)
29 (100:0)
15 (100:0)
5
3
4
28
6
5
21
55
35
64
46
32
51
6
37
23
0
0
21
17
dppe
bpy
a Determined by 19F NMR. b The stereochemistry was not determined.
c Stirred at rt for 24 h. d Twenty mol % of ligand was employed.
SCHEME 8
the R-product in 38% yield (entry 3), while the high regio-
selectivity was observed in the case of a phenyl group as R2
(entry 4).
It was also found that the R1 group influenced the present
reaction significantly. Thus, when an alkyl group, such as the
n-C10H21 substituent, was employed as R1, the R- or γ-product
was afforded in only 45 or 3% yield, respectively, together with
the byproduct 14 (entry 6, Figure 2), though changing the R1
group from a phenyl to a 4-(t-Bu)C6H4 group did not affect the
reaction (entry 5). Use of a pentafluoroethyl group as a
fluoroalkyl group did not influence the reaction significantly
(entry 7).
Synthesis of Optically Active Fluorine-Containing Materi-
als. Our attention was thus directed to the preparation of
optically active compounds as described in Scheme 9. The
optically active starting ester (R)-2i or (S)-2k was easily pre-
pared via the enantioselective reduction of 5i or 5k, followed
by the usual mesylation or acetylation according to the litera-
ture method.8 The optical purity of (R)-6i or (S)-6k was
determined as 88% ee or 76% ee by HPLC using a chiral column
(DAICEL, CHIRALPAK AD-H, and CHIRALPAK OD). When
the nonracemic fluoroalkylated ester, (R)-2i or (S)-2k, was
subjected to the palladium-catalyzed formate reduction as
described above, the corresponding γ-product (S)-1i or (S)-1k
was obtained in 72% or 80% yield, respectively. The stereo-
chemical assignment of 1k was made as follows. The ozono-
lysis of 1k produced crude R-trifluoromethyl aldehyde, which
TABLE 4. Palladium-Catalyzed Formate Reduction of Various
Mesylates
yield/% of 1
entry
substrate
(E/Z)a
yield/% of 7a,b
yield/% of 13a,b
1
2
3
4
5
6
7
2i
2o
2j
2k
2l
2m
2n
72 (84:16)
62 (100:0)
48 (100:0)
80 (89:11)
68 (87:13)
45 (100:0)
67c
5
22
38
9
23
16
7
21
3
11
11d
23d
a Determined by 19F NMR. b The stereochemistry was not determined.
1
c The stereochemistry was not determined. d Determined by H NMR.
a ratio of 84:16, together with 5% of 7i and 23% of 13i (entry
6). Additional studies on the ligand effect revealed that
trialkylphosphines and bidentate phosphine were not suitable
for obtaining the γ-product largely (entries 7-9) and that the
use of bpy ligand gave the R-product preferentially (entry 10).
With the best reaction conditions (entry 6 in Table 3), we
performed the reaction of various allyl mesylates having a
side chain R2 at the R position (Scheme 8). The results are
summarized in Table 4.
Switching the side chain R2 from a methyl group to an n-hexyl
group led to a decrease of the R-/γ-product ratio, 1 and 7 being
obtained in 62% and 22% yield, respectively (entry 2) (Scheme
8). Furthermore, a t-Bu group resulted in the formation of
(8) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6709-6706.
3548 J. Org. Chem., Vol. 71, No. 9, 2006

Pd-Catalyzed Reduction of Fluorine-Containing Allylic Mesylates
SCHEME 10
was immediately reduced with an excess amount of lithium
aluminum hydride to give the known compound 15. Comparison
of the observed optical rotation of (R)-15 with its literature
value9 made it possible to determine the absolute configura-
tion of 15 as R. Analysis of the optical purity of reduction
products by HPLC revealed that (S)-1i or (S)-1k had 83% ee
or 55% ee. Of great synthetic value is that almost no loss of
the optical purity occurs in the reaction of (R)-2i, strongly
suggestive of the present reaction proceeding in an almost
complete stereoselective manner. However, the formate reduc-
tion of (S)-2k resulted in a significant decrease of the chirality
transfer
Mechanism. A possible reaction mechanism for the Pd(0)-
catalyzed formate reduction is outlined in Scheme 10. Thus,
the oxidative addition of allyl mesylate to Pd(0), followed by
the attack of formate to a palladium center, gives the corre-
sponding π-allylpalladium complex Int-A1. In the case of a
monodentate ligand as L, the subsequent decarbonation (Int-
A2) followed by the reductive elimination affords the reduction
product. In this process, a palladium metal would be closer to
the γ-carbon attached with an Rf group than the R-carbon, due
to an extremely electron-withdrawing Rf group.10 Accordingly,
the reductive elimination takes place at the γ-carbon preferen-
tially to give the corresponding γ-product 1. In the case of a
bidentate ligand as L, on the other hand, the palladium has
already four ligands, indicating that the double bond in the allylic
part cannot coordinate with the palladium anymore, the pal-
ladium complex being in a σ-allyl form. In this case, Int-A3 is
more stable than Int-A4 due to a large steric repulsion between
a bulky CF3, R groups and a palladium moiety. Accordingly,
Int-A3 can be transformed into Int-A5 via decarbonation,
followed by the reductive elimination, giving the corresponding
R-product 7 preferentially.
In the case of the substrate 2i-o (except 2j,k) carrying a
side chain R2 (R2 ) CH2R3), a cationic π-allylpalladium
complex may easily be converted into the diene 13 via
â-elimination before the attack of the formate ion to the
palladium center, when the electron-donating ability of the
ligand L on palladium is weak (i.e., L ) PPh3). The use of
(9) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron: Asymmetry 1994,
5, 961-974.
(10) The similar effect was observed in our previous work. See ref 3a,b.
J. Org. Chem, Vol. 71, No. 9, 2006 3549

Konno et al.
ddd, J ) 7.4, 10.4, 17.3 Hz), 6.89 ∼ 6.90 (2H, m), 7.23 ∼ 7.25
(2H, m); 13C NMR (CDCl3) δ 53.1 (q, J ) 27.6 Hz), 55.2, 114.1,
120.4, 126.0 (q, J ) 279.9 Hz), 126.4 (q, J ) 1.5 Hz), 130.1, 131.7
(q, J ) 2.3 Hz), 159.4; 19F NMR (CDCl3) δ -70.0 (3F, d, J ) 9.2
Hz); HRMS (EI) calcd for C11H11F3O (M+) 216.0762, found
P(4-MeOC6H4)3 as the ligand L, on the other hand, makes the
cationic π-allylpalladium complex stable due to its strongly
electron-donating ability. As a result, the nucleophilic attack
of the formate ion to the palladium center proceeds smoothly,
followed by decarbonation and reductive elimination, the R- or
γ-product being afforded in good yield.
216.0769; IR (neat) ν 1612, 1516, 1252, 1167 cm-1
.
Typical Procedure for the Palladium-Catalyzed Formate
Reduction of R-Substituted Fluoroalkylated Allyl Mesylates. To
a DMF solution of palladium catalyst, prepared in situ by mixing
Pd2(dba)3‚CHCl3 (65 mg, 0.063 mmol) and P(p-MeOC6H4)3 (88
mg, 0.25 mmol), was added (R)-(E)-5,5,5-trifluoro-4-phenyl-3-
penten-2-yl methansulfonate ((R)-2i) (736 mg 2.5 mmol) at 0 °C.
After the reaction mixture was stirred for 10 min at that temperature,
a DMF solution of triethylammonium formate, prepared from formic
acid (138 mg, 3.0 mmol) and triethylamine (0.49 mL, 3.5 mmol),
was added to the reaction mixture, and the solution was stirred for
2 h at 80 °C. The reaction was quenched with NH4Cl aq and the
whole was extracted with ether three times. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated in Vacuo. The residue was purified by silica gel column
chromatography using hexane to give 5,5,5-trifluoro-4-phenyl-2-
pentene ((S)-1i) in 72% yield.
Conclusion
In summary, we have developed the palladium(0)-catalyzed
formate reduction of various allyl mesylates 2, leading to the
desired compounds 1 attached with a fluoroalkyl group at the
tertiary carbon. More significantly, the use of chiral allyl
mesylate (R)-2i resulted in the formation of chiral (S)-1i with
almost complete chiralty transfer.
Experimental Section
Typical Procedure for the Palladium-Catalyzed Formate
Reduction of Fluoroalkylated Allyl Mesylates. To a DMF solution
of palladium catalyst prepared in situ by mixing Pd2(dba)3‚CHCl3
(8 mg, 0.008 mmol) and PPh3 (8 mg, 0.032 mmol) was added 4,4,4-
trifluoro-3-(4-methoxyphenyl)-2-butenyl mesylate 2a (100 mg, 0.32
mmol) at 0 °C. After the reaction mixture was stirred for 10 min
at that temperature, a DMF solution of triethylammonium formate,
prepared from formic acid (18 mg, 0.38 mmol) and triethylamine
(0.06 mL, 0.45 mmol), was added to the reaction mixture, and the
solution was stirred for 2 h at 80 °C. The reaction was quenched
with NH4Cl aq, and the whole was extracted with ether three times.
The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated in Vacuo. The residue was
purified by silica gel column chromatography with hexane/benzene
(10/1) as an eluent to give 1,1,1-trifluoro-2-(4-methoxyphenyl)-3-
butene 1a (57 mg, 82%).
(S)-(E)-5,5,5-Trifluoro-4-phenyl-2-pentene (1i): yield 72%
1
(determined by 19F NMR); H NMR (CDCl3) δ 1.74 (3H, d, J )
5.6 Hz), 3.89-3.96 (1H, m), 5.67-5.79 (2H, m), 7.30-7.38 (5H,
m); 13C NMR (CDCl3) δ 18.0, 53.3 (q, J ) 18.2 Hz), 124.4 (q, J
) 2.7 Hz), 126.2 (q, J ) 279.9 Hz), 128.0, 128.7, 128.8, 132.0,
135.3; 19F NMR (CDCl3) δ -69.8 (3F, d, J ) 9.3 Hz); HRMS
calcd for C11H10F3 (M - H) 199.0735, found 199.0735; IR (neat)
ν 3036, 2922, 1499, 1456 cm-1. This compound was found to be
very volatile, so that it could not be purified completely. Therefore,
the optical rotation value could not be measured.
Supporting Information Available: 1H NMR and 13C NMR
spectra of all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
4,4,4-Trifluoro-3-(4-methoxyphenyl)-1-butene (1a): yield 82%.
1H NMR (CDCl3) δ 3.81 (3H, s), 3.94 (1H, dq, J ) 7.4, 9.2 Hz),
5.27 (1H, d, J ) 17.3 Hz), 5.35 (1H, d, J ) 10.4 Hz), 6.11 (1H,
JO0602120
3550 J. Org. Chem., Vol. 71, No. 9, 2006