Concise syntheses of nonracemic γ-fluoroalkylated allylic alcohols and amines via an enantiospecific palladium-catalyzed allylic substitution reaction

Article abstract of DOI:10.1021/jo011013d

α-Fluoroalkylated allyl mesylates reacted with various carboxylates and amines in the presence of tetrakis(triphenylphosphine)palladium(0) catalyst to give the corresponding γ-fluoroalkylated (E)-allylic alcohol derivatives and amines, respectively, in excellent yields. In almost all cases, no other regio- and stereoisomers were produced. Application of this palladium-catalyzed allylic substitution reaction to various nonracemic mesylates afforded chiral γ-fluoroalkylated allylic alcohol derivatives and amines without any loss of enantiomeric excess through the reaction.

Full text of DOI:10.1021/jo011013d

1768
J . Org. Chem. 2002, 67, 1768-1775
Con cise Syn th eses of Non r a cem ic γ-F lu or oa lk yla ted Allylic
Alcoh ols a n d Am in es Via a n En a n tiosp ecific P a lla d iu m -Ca ta lyzed
Allylic Su bstitu tion Rea ction
Tsutomu Konno,* Kensuke Nagata, Takashi Ishihara, and Hiroki Yamanaka
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Sakyo-ku,
Matsugasaki, Kyoto 606-8585, J apan
konno@chem.kit.ac.jp
Received October 18, 2001
R-Fluoroalkylated allyl mesylates reacted with various carboxylates and amines in the presence of
tetrakis(triphenylphosphine)palladium(0) catalyst to give the corresponding γ-fluoroalkylated (E)-
allylic alcohol derivatives and amines, respectively, in excellent yields. In almost all cases, no other
regio- and stereoisomers were produced. Application of this palladium-catalyzed allylic substitution
reaction to various nonracemic mesylates afforded chiral γ-fluoroalkylated allylic alcohol derivatives
and amines without any loss of enantiomeric excess through the reaction.
In tr od u ction
The synthesis of regio- and stereoselective poly- or
perfluoroalkylated molecules has become important in
the field of phamaceutical research, owing to their unique
physiological and biological properties imparted by a
fluoroalkyl group.1 In many cases, the substitution of an
alkyl group by a poly- or perfluoroalkyl group results in
increased metabolic stability and lipophilicity, which may
improve pharmacokinetic properties of drug candidates.2
Although much effort has been devoted to developing
convenient and practical methods for the preparation of
such poly- or perfluoroalkylated compounds,3 the stereo-
selective synthesis of optically active compounds has
received much less attention.4
F igu r e 1. Optically active γ-fluoroalkylated allylic alcohols
(1) and amines (2).
organofluorine chemistry, and their syntheses in enan-
tiomerically and geometrically pure forms should present
significant challenges for the synthetic chemist.
Among several reported methods, the enzymatic ki-
netic resolution of the racemic propargyl alcohols 3,
followed by stereoselective reduction of the triple bond,
is well-known as one of the most reliable synthetic
methods to obtain both enantiomers of 1 with high optical
purities (Scheme 1).5 However, this method suffers from
at least two serious disadvantages. First, the yields of
the desired chiral alcohols are not more than 50%.
Second, the enzyme has a high substrate-specificity, and
a little structural change in the substrate sometimes
prevents the reaction from proceeding and often results
in a large decrease of enantioselectivity. On the other
hand, an enantiospecific synthesis would have great
advantages, such as the fact that the transformation can
be carried out to completion (i.e., 100% maximum yield)
and that a little structural change in the substrate does
not necessarily influence the reaction.
γ-Fluoroalkylated allylic alcohols 15 and amines 2,
shown in Figure 1, are recognized as the most important
synthetic intermediates for the preparation of structur-
ally complex poly- or perfluoroalkylated molecules in
(1) (a) McAtee, J . J .; Schinazi, R. F.; Liotta, D. C. J . Org. Chem.
1998, 63, 2161-2167. (b) Fluorine-Containing Amino Acids: Synthesis
and Properties; Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley & Sons:
New York, 1995. (c) Resnati, G. Tetrahedron 1993, 49, 9385-9445.
(d) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry;
Wiley & Sons: New York, 1991. (e) Be´gue´, J .-P.; Bonnet-Delpon, D.
Tetrahedron 1991, 47, 3207-3258. (f) Welch, J . T. Tetrahedron 1987,
43, 3123-3197.
(2) (a) Arnone, A.; Bernardi, R.; Blasco, F.; Cardillo, R.; Resnati,
G.; Gerus, I. I.; Kukhar, V. P. Tetrahedron 1998, 54, 2809-2818. (b)
Tan, L.; Chen, C.-Y.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J .
Tetrahedron Lett. 1998, 39, 3961-3964.
(3) (a) Darses, S.; Pucheault, M.; Geneˆt, J .-P. Eur. J . Org. Chem.
2001, 1121-1128. (b) Singh, R. P.; Shreeve, J . Tetrahedron 2000, 56,
7613-7632. (c) Lin, P.; J iang, J . Tetrahedron 2000, 56, 3635-3671.
(d) Brown, H. C.; Chen, G.-M.; J ennings, M. P.; Ramachandan, P. V.
Angew. Chem., Int. Ed. 1999, 38, 2052-2054. (e) Kitazume, T.;
Yamazaki, T. Experimental Methods in Organic Fluorine Chemistry;
Kodansha: Tokyo, 1998. (f) J enneings, M. P.; Cork, E. A.; Ramachan-
dran, P. V. J . Org. Chem. 2000, 65, 8763-8766. (g) McClinton, M. A.;
McClinton, D. A. Tetrahedron 1992, 48, 6555-6666. (h) Burton, D. J .;
Yang, Z.-Y. Tetrahedron 1992, 48, 189-275.
(4) Several general synthetic methods for the preparation of optically
active poly- or perfluoroalkylated compounds have been reported. (a)
Kumar, D. J . S.; Madhavan, S.; Ramachandran, P. V.; Brown, H. C.
Tetrahedron: Asymmetry 2000, 11, 4629-4632. (b) Resnati, G.; Brabo,
P. Tetrahedron: Asymmetry 1990, 1, 661-692. (c) Iseki, K. Tetrahedron
1998, 54, 13887-13914. (d) Matsutani, H.; Poras, H.; Kusumoto, T.;
Hiyama, T. Chem. Commun. 1998, 1259-1260.
In this contribution, we report the convenient synthesis
of nonracemic γ-fluoroalkylated allylic alcohols 1 and
amines 2 via an enantiospecific palladium-catalyzed
(5) (a) Yamazaki, T.; Umetani, H.; Kitazume, T. Tetrahedron Lett.
1997, 38, 6705-6708. (b) Konno, T.; Kitazume, T. Tetrahedron:
Asymmetry 1997, 8, 223-230. (c) Konno, T.; Umetani, H.; Kitazume,
T. J . Org. Chem. 1997, 62, 137-150. (d) Konno, T.; Kitazume, T. Chem.
Commun. 1996, 2227-2228. (e) Yamazaki, T.; Mizutani, K.; Kitazume,
T. J . Org. Chem. 1995, 60, 6046-6056. (f) Konno, T.; Nakano, H.;
Kitazume, T. J . Fluorine Chem. 1997, 86, 81-87. (g) Hanzawa, Y.;
Kawagoe, K.; Yamada, A.; Kobayashi, Y. Tetrahedron Lett. 1985, 26,
219-222. (h) Kitazume, T.; Ishikawa, N. J . Fluorine Chem. 1985, 29,
431-444. (i) Hanzawa, Y.; Kawagoe, K.; Tanahashi, N.; Kobayashi,
Y. Tetrahedron Lett. 1984, 25, 4749-4752.
10.1021/jo011013d CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/28/2002

Concise Syntheses of Alcohols and Amines
J . Org. Chem., Vol. 67, No. 6, 2002 1769
Sch em e 1. En zym a tic Kin etic Resolu tion
Sch em e 3. P a lla d iu m -Ca ta lyzed Allylic
Su bstitu tion Rea ction
Sch em e 2. Gen er a l Ou tlin e for th e Syn th esis of
Ch ir a l γ-F lu or oa lk yla ted Allylic Alcoh ols (1) a n d
Am in es (2)
Ta ble 1. In vestiga tion of th e Rea ction Con d ition s for
th e P d (0)-Ca ta lyzed Allylic Su bstitu tion Rea ction
yieldb (%)
4c
temp/ time/
or
5c 4d
6c
(E:Z)
entrya
catalyst
°C
h
1c
2c
3
4
5
none
Pd(PPh3)4
Pd(PPh3)4
reflux
reflux
0
0
0
3
0
0
99
0
99
99
0
99
2
0
0
0
0
3
3
3
3
1/2Pd2(dba)3‚CHCl3
1/2Pd2(dba)3‚CHCl3 +
4(PhO)3P
86
12
(100:0)
0
6
7
8
9
1/2Pd2(dba)3‚CHCl3 +
4Bu3P
0
3
14
3
16 84
42 54
1/2Pd2(dba)3‚CHCl3 + room
0
0
4Bu3P
allylic substitution reaction of nonracemic R-fluoroalky-
lated allylic alcohol derivatives 4, as described in Scheme
2.
1/2Pd2(dba)3‚CHCl3 +
0
0
4
99
2dppe
1/2Pd2(dba)3‚CHCl3 + room
14
51 35
(79:21)
2dppe
a
Resu lts a n d Discu ssion
(R-Trifluoromethyl)allyl mesylate 4d was employed as a
b
starting material, unless otherwise noted. Determined by 19F
NMR. c As the starting material, (R-trifluoromethyl)allyl benzoate
4c was employed. Benzoic acid and triethylamine were not used.
Rea ction of r-F lu or oa lk yla ted Allyl Mesyla tes
w ith Va r iou s Ca r boxyla tes. At first, we attempted the
thermal allylic rearrangement using (R-trifluoromethyl)-
allyl benzoate 4c, which was readily accessible from ethyl
trifluoroacetate in three steps6 (Scheme 3). Thus, 4c was
heated in refluxing THF but was recovered unchanged
quantitatively (Table 1, entry 1). Even when the reaction
was carried out in the presence of a catalytic amount of
tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) at
the reflux temperature of THF, no desired product was
detected (entry 2). Next, we attempted the Pd-catalyzed
reaction by using R-(trifluoromethyl)allyl mesylate 4d as
the starting material, which was prepared readily from
ethyl trifluoroacetate in a manner similar to that for the
preparation of 4c. Thus, using 5 mol % Pd(PPh3)4 in THF
at 0 °C, the starting material 4d was completely con-
sumed after 3 h, and the desired compound 5c was
formed as the sole product in 99% NMR yield without
any formation of the R-product7 (entry 3). We also
examined the influence of the palladium catalyst upon
this reaction, as shown in entries 4-9. The use of Pd2-
(dba)3 as the catalyst resulted in the complete suppres-
sion of the reaction (entry 4), while the use of triphenyl
phosphite as the ligand afforded the desired allylic
alcohol derivative 5c in 86% yield together with a 12%
yield of the diene 6c (entry 5). The latter may be formed
via the â-elimination of Pd-H from an intermediary
π-allylpalladium complex.8 When the reaction was carried
out with the tributylphosphine or bis(diphenylphosphi-
no)ethane (dppe) ligand, a large amount of the starting
material remained unchanged (84-99% recovered, en-
tries 6 and 8). On the other hand, the use of Bu3P and
dppe as ligands at room temperature for 14 h led to 5c
in 42% yield and to a mixture of 6c (35% yield) and 5c
(4% yield), respectively (entries 7 and 9). As a result,
triphenylphosphine was found to be the ligand of choice
in the present reaction.
Next, our attention was directed to the allylic substitu-
tion reactions of various types of mesylates 4. The results
(7) The reaction of the trifluoromethylated π-allylpalladium complex
with the carbanion derived from diethyl malonate has been reported.
(a) Hanzawa, Y.; Ishizawa, S.; Ito, H.; Kobayashi, Y.; Taguchi, T. J .
Chem. Soc., Chem. Commun. 1990, 394-395. (b) Hanzawa, Y.; Ish-
izawa, S.; Kobayashi, Y. Chem. Pharm. Bull. 1988, 36, 4209-4212.
(8) Tsuji, J .; Yamakawa, T.; Kaito, M.; Manda, T. Tetrahedron Lett.
1978, 2075-2078.
(6) (a) Ramachandran, P. V.; Teodorovic’ A. V.; Gong, B.; Brown, H.
C. Tetrahderon: Asymmetry 1994, 5, 1075-1086. (b) Ramachandran,
P. V.; Gong, B.; Teodorovic, A. V.; Brown, H. C. Tetrahderon: Asym-
metry 1994, 5, 1061-1074.

1770 J . Org. Chem., Vol. 67, No. 6, 2002
Konno et al.
Ta ble 2. P d (0)-Ca ta lyzed Rea ction of F lu or in a ted Allyl
Mesyla te w ith Va r iou s Ca r boxyla tes
Ta ble 3. P d (0)-Ca ta lyzed Rea ction of F lu or in a ted Allyl
Mesyla te w ith Va r iou s Am in es
sub-
pro- yieldb,c
sub-
pro- yieldb,c
entrya strate
Rf
R1R2NH
duct
(%)
entrya strate
Rf
CH2F
CHF2
CF3
CF3
CF3
CF3
CF3
CF3
CF3
R
R′OH
duct
(%)
1
4b
4d
4d
4d
4d
4d
4d
4d
4d
4d
4d
4d
4g
4h
CHF2
CF3
BnNH2
BnNH2
BnNH2
allylamine
PhNH2
p-NO2C6H4NH2
EtOOCCH2NH2‚HCl
Me2NH‚HCl
Bn2NH
10a
88
0
1
2
3
4
5
6
7
8
9
4a
4b
4d
4d
4d
4d
4d
4e
4f
n-C6H13 BzOH
n-C6H13 BzOH
n-C6H13 BzOH
n-C6H13 CH3CO2H
5a
5b
5c
5d
56d
89
91
80
74
99
96
93e
0
2d
3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
10b
10c
10d
10e
10f
10g
10h
10i
96
81
99
99
90
92
70
88
95
83
99
99
4
5
n-C6H13 CH2CH2CO2H 5e
n-C6H13 ClCH2CO2H 5f
n-C6H13 MeOCH2CO2H 5g
6
7e
8
BnOCH2 BzOH
t-Bu BzOH
n-C6H13 BzOH
5h
9
10
11
12
13
14
EtOOCCH2NHBn
10
11
4g
4h
CF3CF2
CF3(CF2)2 n-C6H13 BzOH
5i
5j
87
99
CF3
CF3
EtOOCCH2CH2NHBn 10j
cyclohexylamine
BnNH2
10k
10l
10m
a
All reactions were performed at 0 °C by using 2 equiv each of
CF3CF2
CF3(CF2)2 BnNH2
b
Et3N, carboxylic acid, and 5 mol % Pd(PPh3)4. Isolated yields.
c The (E)-isomer was produced exclusively in all cases, unless
a
All reactions were performed at room temperature for 3 h by
d
otherwise noted. Two-step yield from a monofluoromethylated
using 2 equiv of both the amine and 5 mol % Pd(PPh3)4, unless
allylic alcohol. e The (E)- and (Z)-stereoisomers were obtained in
otherwise noted. Isolated yields. c The (E)-isomer was produced
b
a ratio of 94:6.
d
exclusively. The reaction was carried out in the absence of
Pd(PPh3)4. e Stirred for 24 h.
Sch em e 4. P a lla d iu m -Ca ta lyzed Su bstitu tion
Rea ction in th e Non -flu or in a ted System
was treated with 5 mol % Pd(PPh3)4 and 2 equiv of
benzoic acid at room temperature for 24 h. HPLC
analysis of the reaction mixture indicated that a large
amount of 7 remained unchanged and that the R- and
γ-products, 8 and 9, were obtained in only 16% combined
yield in a ratio of 87:13, respectively. It should be
emphasized that the R-product was obtained preferen-
tially instead of the γ-product. This result is totally
different from the results of the reaction of the fluori-
nated substrates 4.10
are summarized in Table 2. Monofluorinated mesylate
4a (Rf ) CH2F) was too unstable to be purified by silica
gel column chromatography and was used in the follow-
ing allylic substitution reaction without any purification.
Although the crude mesylate 4a was employed as such
for the Pd-catalyzed process, the desired allylic alcohol
derivative 5a was obtained in 56% yield in a two-step
process as a single isomer (entry 1). As shown in entries
2, 3, 10, and 11, the Rf groups of 4 did not exert any
influence on the regio- and stereochemical courses of the
reaction, all of which led efficiently to γ-products with
the (E) configuration. A variety of carboxylic acids such
as benzoic acid, acetic acid, propionic acid, and chloro-
and methoxyacetic acid participated nicely in the reac-
tion, giving rise to the corresponding γ-products 5
exclusively (entries 3-7). It was found that differences
in the R component of the side chain greatly affected the
reaction. Thus, the stereoselectivity at the newly formed
olefinic bond was slightly decreased when the benzyl-
oxymethyl group was R (entry 8).9 Furthermore, the tert-
butyl group completely prevented the reaction from
proceeding (entry 9).
Rea ction of r-F lu or ola lk yla ted Allyl Mesyla tes
w ith Va r iou s Am in es. We also investigated the Pd-
catalyzed allylic substitution reaction of 4 with various
amines. The results are summarized in Table 3. As shown
in entries 1, 3, 13, and 14, various fluoroalkylated
mesylates 4 gave the corresponding allylamines 10 in
excellent yields, indicating that using different Rf groups
did not affect the present reaction at all. The fact that
the reaction did not proceed at all in the absence of the
palladium catalyst (entry 2) strongly suggests that the
direct SN2′ reaction of the allyl mesylate with amine does
not occur. The primary amines, such as benzylamine and
allylamine, could participate nicely in the reaction to give
the corresponding γ-trifluoromethylated allylamine de-
rivatives 10b and 10c in 96 and 81% yields, respectively
(entries 3 and 4). The reaction with less-nucleophilic
amines, such as aniline and p-nitroaniline, also proceeded
smoothly to afford the corresponding allylamines 10d and
10e quantitatively (entries 5 and 6). Free glycine ethyl
ester or dimethylamine, which was generated in situ by
treating its hydrochloride salt with an equimolar amount
of triethylamine, reacted efficiently with the mesylate 4d
in the presence of the Pd(0) catalyst to produce 10f and
10g in excellent yields (entries 7 and 8). As shown in
entries 8-12, various secondary and cyclic amines could
also be employed for the present reaction, leading to
To evaluate the effect of an Rf group on the reaction,
we examined the reaction of a nonfluorinated counterpart
(Scheme 4). Ethyl carbonate 7 was employed as the
starting ester because the corresponding allyl mesylate
was so thermally labile that it could not be obtained. 7
(10) The regioselectivity in the palladium-catalyzed allylic substitu-
tion reaction in the nonfluorinated system has been discussed in detail.
(a) Frost, C. G.; Howarth, J .; Williams, J . M. Tetrahedron: Asymmetry
1992, 3, 1089-1122. (b) Keinan, E.; Sahai, M. J . Chem. Soc., Chem.
Commun. 1984, 648-650.
(9) The effect that the side chain has on the regioselectivity in the
allylic substitution reaction has been reported. Kaffit, M. E.; Fu, Z.;
Procter, M. J .; Wilson, A. M.; Dasse, O. A.; Hirosawa, C. Pure Appl.
Chem. 1998, 70, 1083-1090.

Concise Syntheses of Alcohols and Amines
J . Org. Chem., Vol. 67, No. 6, 2002 1771
Sch em e 5. Syn th esis of Op tica lly Active γ-Tr iflu or om eth yla ted Allylic Alcoh ol Der iva tives a n d Th eir
Ster eoch em ica l Assign m en ts
Sch em e 6. Syn th esis of Ch ir a l γ-F lu or oa lk yla ted
satisfactory results. In all cases, the newly formed olefinic
bonds were of the E configuration; no product with (Z)
configuration was detected. Furthermore, the regioisomer
R-product could not be observed.
Allylic Alcoh ol a n d Am in e Der iva tives
P r ep a r a tion of Non r a cem ic Allylic Alcoh ol a n d
Am in e Der iva tives. The synthesis of nonracemic γ-fluo-
roalkylated allylic alcohol derivatives 5 was undertaken
as outlined in Scheme 5. Thus, on treating the nonrace-
mic (E)-substrate (S)-4d -E6 (82% ee) with benzoic acid
and triethylamine under the same conditions as de-
scribed above, the optically active product (S)-5c was
obtained in 91% yield. The ester (S)-5c, after hydrolysis,
was converted into the MTPA ester (S)-11c,11 whose
diastereomeric excess was determined to be 84% by gas
chromatography. This result clearly indicates that the
reaction proceeds without any loss of enantiomeric excess
throughout the reaction. Similarly, the reaction of the
nonracemic (Z)-substrate (S)-4d -Z (92% ee) was con-
ducted under the same reaction conditions, leading to the
corresponding nonracemic allylic alcohol derivative (R)-
5c in 88% yield. This ester was transformed into the
MTPA ester (R)-11c, whose diastereomeric excess was
determined to be 89% by gas chromatography. This fact
indicates that even the reaction of the (Z)-substrate takes
place in an enantiospecific fashion.
The stereochemical assignment of (S)- or (R)-5c was
made as follows. The ozonolysis of 5c obtained from (S)-
4d -E produced the crude R-alkoxy aldehyde, which was
immediately reduced by an excess amount of lithium
aluminum hydride to give the known compound (S)-12.
The comparison of the observed optical rotation of (S)-
12 with its literature value12 made it possible to deter-
mine the absolute configuration of 5c from (S)-4d -E as
S. On the other hand, the optical rotation of 5c obtained
from (S)-4d -Z was opposite to that of the (S)-enantiomer,
(S)-5c, indicating that its absolute configuration was R.
The chiral mesylate possessing a pentafluoroethyl
group, (S)-4g-E, could also be converted into the corre-
sponding nonracemic allylic alcohol derivative (S)-5i in
87% yield, as shown in Scheme 6.
In a similar way, nonracemic γ-trifluoromethylated and
γ-pentafluoroethylated allylic amine derivatives (S)-10b
and (S)-10l could be obtained in 99% yields with high
enantiomeric excesses (96% ee), which were measured
by HPLC using a chiral column (DAICEL, CHIRALPAK
AD). This fact indicates that the reaction of the mesylate
with amine also proceeds without any loss of enantio-
meric excess throughout the reaction. To the best of our
knowledge, this is the first example of the synthesis of
nonracemic allylamines having a fluoroalkylated group
at the γ-position.
Mech a n ism . The proposed mechanism for the present
reaction is outlined in Scheme 7. Thus, when the Pd
complex coordinates on the face of the olefin distal to the
mesyloxy group, the Pd species displaces the mesylate
with inversion to give a π-allyl complex 13. The carbox-
ylate nucleophile attacks 13 on the face opposite to that
occupied by Pd. The double inversion results in a net
retention for these processes.13 In this case, the Pd moiety
might be closer to the Rf group than to the R because of
(11) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
(12) Moussou, P.; Archelas, A.; Furstoss, R. Tetrahedron 1998, 54,
1563-1572.

1772 J . Org. Chem., Vol. 67, No. 6, 2002
Konno et al.
Sch em e 7. Mech a n ism of th e P a lla d iu m -Ca ta lyzed Allylic Su bstitu tion Rea ction s
MHz) FT-NMR spectrometer was used to obtain 19F NMR
spectra in CDCl3 solution with an internal standard of trichlo-
rofluoromethane. High-resolution mass spectra (HRMS) were
taken on a Hitachi M-80B mass spectrometer by electron
impact (EI) or chemical ionization (CI) methods. Gas-liquid
chromatography (GLC) was performed on a Shimazdu GC-7AG
chromatograph equipped with a flame ionization detector and
nitrogen carrier gas using a Shimazdu capillary column
(HiCap CBP-5-M25-025, 25 m × 0.2 mm). High-performance
liquid chromatography (HPLC) was carried out on a Shimazdu
LC-3A chromatograph equipped with a UV detector using a
chiral column (CHIRALPAK AD, DAICEL CHEMICAL IND.
Ltd., 0.46 cm L × 25 cm).
the electron-withdrawing effect of the Rf group.14 There-
fore, the nucleophile attacks preferentially at the less-
hindered γ-carbon to give the γ-fluoroalkylated allylic
alcohol or amine derivatives 5 or 10.
On the other hand, oxidative addition of Pd(0) to the
(Z)-substrate 4-Z generates the π-allylpalladium complex
14, which is less stable than 15 because of 1,3A strain.15
Therefore, 14 could be converted into 15 via π-σ-π
equilibrium16 with inversion. The attack of the nucleo-
phile occurs with inversion, as mentioned for the (E)-
substrate. Thus, the reaction of the (Z)-substrate involves
three inversion processes, resulting in a net inversion.
Typ ica l P r oced u r e for th e P r ep a r a tion of Allyl Mesy-
la tes 4. To a solution of R-fluoroalkylated allylic alcohol6 (1
mmol) and methansulfonyl chloride (1.2 mmol) in CH2Cl2 (5
mL) was added dropwise triethylamine (1.2 mmol) at 0 °C.
The reaction mixture was allowed to warm to room temper-
ature and was stirred for several hours. Then, the reaction
mixture was poured into saturated NH4Cl(aq) and extracted
three times with CH2Cl2. The combined organic layers were
washed with water, dried over anhydrous Na2SO4, and con-
centrated in vacuo. The crude materials were purified by silica
gel column chromatography to give the corresponding allyl
mesylate in over 90% yield. Monofluorinated allyl mesylate
4a could not be isolated because of thermal instability;
therefore, the crude mixture was used for the next reaction
without purification.
Con clu sion s
In summary, we have described the reaction of R-fluo-
roalkylated allylic mesylates 4 with various carboxylates
and amines in the presence of a palladium catalyst to
give the corresponding γ-fluoroalkylated allylic alcohol
(5) and amine (10) derivatives in excellent yields. Only
γ-products with (E) stereochemistry were obtained in
these reactions. Moreover, the reaction using nonracemic
substrates afforded the corresponding nonracemic prod-
ucts without any loss of enantiomeric excess.
Exp er im en ta l Section
1-(Diflu or om eth yl)-(2E)-n on en yl Meth an esu lfon ate (4b):
1H NMR (CDCl3) δ 0.85 (t, J ) 6.60 Hz, 3H), 1.20-1.42 (m,
8H), 2.05-2.15 (m, 2H), 3.02 (s, 3H), 5.04 (ddt, J ) 3.45, 8.25,
10.80 Hz, 1H), 5.49 (dd, J ) 8.25, 15.30 Hz, 1H), 5.77 (dt, J )
3.45, 54.90 Hz, 1H), 6.07 (dt, J ) 6.60, 15.30 Hz, 1H); 13C NMR
(CDCl3) δ 13.96, 22.47, 28.24, 28.64, 31.48, 32.31, 39.29, 79.62
(t, J ) 26.74 Hz), 112.84 (t, J ) 246.61 Hz), 118.75, 142.81;
19F NMR (CDCl3) δ -130.31 (ddd, J ) 10.80, 54.90, 288.25
Hz, 1F), -126.33 (ddd, J ) 10.80, 54.90, 288.25 Hz, 1F); IR
Gen er a l Meth od s. NMR spectra were recorded with 500
and 300 MHz spectrometers. A J EOL J NM-EX90A (84.21
(13) Trost, B. M. Acc. Chem. Res. 1980, 13, 385-393.
(14) It has been reported that the palladium atom in the η3
intermediate lies closer to the carbon attached to the electron-
withdrawing group. See (a) Keinan, E.; Pereta, M. J . Org. Chem. 1983,
48, 5302-5309. (b) Keinan, E.; Roth, Z. J . Org. Chem. 1983, 48, 1769-
1772.
(15) (a) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1860. (b) Cha,
J . K.; Christ, W. J .; Kishi, Y. Tetrahedron 1984, 40, 2247-2255. (c)
Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron Lett. 1983, 24, 3947-
3950. (d) Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron Lett. 1983,
24, 3943-3946.
(16) Kawatsura, M.; Uozumi, Y.; Ogasawara, M.; Hayashi, T.
Tetrahedron 2000, 56, 2247-2257.
(neat) 1670, 1366 cm-1
.
(1S)-1-(Tr iflu or om et h yl)-(2E)-n on en yl Met h a n esu l-
1
fon a te ((S)-4d -E): H NMR (CDCl3) δ 0.88 (t, J ) 5.10 Hz,
3H), 1.20-1.50 (m, 8H), 2.10-2.20 (m, 2H), 3.08 (s, 3H), 5.24
(dq, J ) 8.20, 6.30 Hz, 1H), 5.54 (dd, J ) 8.20, 15.45 Hz, 1H),
6.17 (dt, J ) 15.45, 6.50 Hz, 1H); 13C NMR (CDCl3) δ 13.94,

Concise Syntheses of Alcohols and Amines
J . Org. Chem., Vol. 67, No. 6, 2002 1773
22.46, 28.08, 28.58, 31.45, 32.22, 39.45, 77.80 (q, J ) 34.12
Hz), 117.78, 122.25 (q, J ) 279.94 Hz), 144.10; 19F NMR
(CDCl3) δ -77.38 (d, J ) 6.30 Hz, 3F); IR (neat) 1670, 1373
129.92, 133.123, 136.92 (t, J ) 10.94 Hz), 165.54; 19F NMR
(CDCl3) δ -112.80 to (approx.) -112.670 (m, 1F), -112.00 to
(approx.) -111.80 (m, 1F). IR (neat): 1720 cm-1; HRMS m/ z
(M+) calcd for for C17H22F2O2, 296.1588; found, 296.1591; Anal.
Calcd for C17H22F2O2: C, 68.90; H, 7.48. Found: C, 68.60; H,
7.60.
cm-1; [R]20 +38.9 (c 0.82, CHCl3) (82% ee); HRMS m/z: (M+)
D
calcd for C11H19F3O3S, 288.1007; found, 288.0990; Anal. Calcd
for C11H19F3O3S: C, 45.82; H, 6.64. Found: C, 45.47; H, 6.59.
(1S)-1-(Tr iflu or om et h yl)-(2Z)-n on en yl Met h a n esu l-
(1S)-1-(Tr iflu or o-(1E)-p r op en yl)h ep tyl Ben zoa te ((S)-
1
1
fon a te ((S)-4d -Z): H NMR (CDCl3) δ 0.89 (t, J ) 6.50 Hz,
5c): H NMR (CDCl3) δ 0.88 (t, J ) 6.31 Hz, 3H), 1.20-1.50
3H), 1.20-1.50 (m, 8H), 2.13-2.30 (m, 2H), 3.08 (s, 3H), 5.45
(m, 1H), 5.64 (dq, J ) 9.50, 6.00 Hz, 1H), 6.05 (dt, J ) 11.00,
7.50 Hz, 1H); 13C NMR (CDCl3) δ 13.97, 22.51, 28.08, 28.80,
28.82, 31.52, 39.46, 72.74 (q, J ) 34.92 Hz), 117.24, 122.46 (q,
J ) 280.82 Hz), 143.01; 19F NMR (CDCl3) δ -77.22 (d, J )
(m, 8H), 1.75-1.90 (m, 2H), 5.60-5.70 (m, 1H), 5.87 (ddq,
J ) 1.50, 15.75, 6.00 Hz, 1H), 6.44 (ddq, J ) 5.10, 15.75, 2.10
Hz, 1H), 7.45-7.52 (m, 2H), 7.55-7.65 (m, 1H), 8.05-8.10 (m,
2H); 13C NMR (CDCl3) δ 13.94, 22.46, 24.79, 28.89, 31.51,
33.82, 72.07, 119.03 (q, J ) 34.71 Hz), 122.74 (q, J ) 268.44
Hz), 128.46, 129.60, 129.69, 133.26, 138.24 (q, J ) 5.72 Hz),
165.40; 19F NMR (CDCl3) δ -64.77 (d, J ) 6.00 Hz, 3F); IR
(neat): 1724 cm-1; HRMS m/ z (M+) calcd for C17H21F3O2,
6.00 Hz, 3F); IR (neat) 1659, 1373 cm-1; [R]25 -34.2 (c 0.95,
D
CHCl3) (92% ee).
4-Ben zyloxy-1-(t r iflu or om et h yl)-(2E)-b u t en yl Met h -
a n esu lfon a te (4e): H NMR (CDCl3) δ 3.10 (s, 3H), 4.11 (d,
314.1494; found, 314.1489; [R]28 +33.8 (c 0.60, CHCl3) (84%
1
D
J ) 3.75 Hz, 2H), 4.55 (s, 2H), 5.33 (quint., J ) 7.00 Hz, 1H),
5.89 (dd, J ) 7.00, 15.75 H, 1H), 6.25 (dt, J ) 15.75, 3.75 Hz,
1H), 7.28-7.40 (m, 5H); 13C NMR (CDCl3) δ 39.40, 68.53, 72.72,
76.78 (q, J ) 34.91 Hz), 118.77, 122.18 (q, J ) 280.84 Hz),
127.72, 127.86, 128.47, 137.58, 138.49; 19F NMR (CDCl3) δ
de); Anal. Calcd for C17H21F3O2: C, 64.96; H, 6.73. Found: C,
64.91; H, 6.80.
1-(Tr iflu or o-(1E)-pr open yl)h eptyl Acetate (5d): 1H NMR
(CDCl3) δ 0.82 (t, J ) 6.50 Hz, 3H), 1.15-1.28 (m, 8H), 1.50-
1.65 (m, 2H), 2.04 (s, 3H), 5.05-5.35 (m, 1H), 5.72 (ddq, J )
1.00, 16.00, 6.50 Hz, 1H), 6.25 (ddq, J ) 5.50, 16.00, 1.50 Hz,
1H); 13C NMR (CDCl3) δ 13.93, 20.90, 22.44, 24.69, 28.84,
31.50, 33.67, 71.60, 119.03 (q, J ) 34.08 Hz), 122.72 (q, J )
269.75 Hz), 138.09 (q, J ) 6.29 Hz), 169.92; 19F NMR (CDCl3)
-77.17 (d, J ) 7.00 Hz); IR (neat) 1690, 1315 cm-1
.
(1S)-1-(P en t a flu or oet h yl)-(2E)-n on en yl Met h a n esu l-
fon a te ((S)-4 g): 1H NMR (CDCl3) δ 0.88 (t, J ) 6.50 Hz, 3H),
1.20-1.34 (m, 6H), 1.38-1.45 (m, 2H), 2.16 (q, J ) 6.82 Hz,
2H), 3.06 (s, 3H), 5.34 (q, J ) 10.00 Hz, 1H), 5.56 (dd, J )
10.00, 15.50 Hz, 1H), 6.17 (dt, J ) 15.50, 6.82 Hz, 1H); 13C
NMR (CDCl3) δ 13.95, 22.50, 28.14, 28.61, 31.49, 32.29, 39.66,
77.66 (dd, J ) 17.51, 27.98 Hz), 110.0-114.0 (m), 117.53,
118.40 (tq, J ) 35.07, 286.70 Hz), 144.68; 19F NMR (CDCl3) δ
δ -64.87 (d, J ) 6.50 Hz). IR (neat) 1747 cm-1
.
1-(Tr iflu or o-(1E)-p r op en yl)h ep tyl P r op ion a te (5e): 1H
NMR (CDCl3) δ 0.81 (t, J ) 7.00 Hz, 3H), 1.10 (t, J ) 7.50 Hz,
3H), 1.15-1.30 (m, 8H), 1.50-1.65 (m, 2H), 2.31 (q, J ) 7.50
Hz, 2H), 5.27 (m, 1H), 5.71 (ddq, J ) 1.00, 15.50, 6.25 Hz, 1H),
6.25 (ddq, J ) 5.00, 15.50, 2.00 Hz, 1H); 13C NMR (CDCl3) δ
9.10, 13.93, 22.44, 24.69, 27.55, 28.84, 31.50, 33.70, 71.34,
118.90 (q, J ) 34.46 Hz), 122.74 (q, J ) 269.37 Hz), 138.25 (q,
J ) 6.16 Hz), 173.35; 19F NMR (CDCl3) δ -64.82 (d, J ) 6.25
Hz); IR (neat) 1744 cm-1. HRMS m/ z (M+) calcd for C13H21F3O2,
266.1494; found, 266.1475.
-124.13 (m, 2F), -81.66 (s, 3F); IR (neat) 1670, 1373 cm-1
;
[R]22 +27.4 (c 0.82, CHCl3) (96% ee); Anal. Calcd for
D
C
12H19F5O3S: C, 42.60; H, 5.66. Found: C, 42.57; H, 5.60.
1-(Hepta flu or op r op yl)-(2E)-n on en yl Meth a n esu lfon a te
(4h ): 1H NMR (CDCl3) δ 0.81 (t, J ) 6.50 Hz, 3H), 1.15-1.27
(m, 6H), 1.30-1.40 (m, 2H), 2.06-2.14 (m, 2H), 2.99 (s, 3H),
5.34 (q, J ) 9.25 Hz, 1H), 5.51 (dd, J ) 9.25, 15.00 Hz, 1H),
6.12 (dt, J ) 15.00, 7.00 Hz, 1H); 13C NMR (CDCl3) δ 13.96,
22.50, 28.16, 28.62, 31.50, 32.32, 39.76, 77.67 (dd, J ) 24.20,
28.65 Hz), 117.55, 106-120 (m), 144.82; 19F NMR (CDCl3) δ
-125.90 to (approx.) -125.30 (m, 2F), -121.30 to (approx.)
-120.70 (m, 2F), -81.29 (t, J ) 9.25 Hz, 3F); IR (neat) 1670,
1373 cm-1; Anal. Calcd for C13H19F7O3S: C, 40.21; H, 4.93.
Found: C, 40.72; H, 5.02.
1-(Tr iflu or o-(1E)-p r op en yl)h ep tyl Ch lor oa ceta te (5f):
1H NMR (CDCl3) δ 0.88 (t, J ) 6.31 Hz, 3H), 1.20-1.40 (m,
8H), 1.70-1.80 (m, 2H), 4.09 (s, 2H), 5.35-5.50 (m, 1H), 5.75-
5.90 (m, 1H), 6.25-6.40 (m, 1H); 13C NMR (CDCl3) δ 13.95,
22.46, 24.61, 28.80, 31.49, 33.59, 40.71, 73.66, 119.88 (q, J )
34.46 Hz), 122.57 (q, J ) 269.75 Hz), 137.11 (q, J ) 6.29 Hz),
166.36; 19F NMR (CDCl3) δ -65.00 (d, J ) 6.64 Hz, 3F); IR
(neat) 1763 cm-1; HRMS m/ z (M+) calcd for C12H18ClF3O2,
286.0947; found, 286.0927; Anal. Calcd for C12H18ClF3O2: C,
50.27; H, 6.33. Found: C, 50.87; H, 6.54.
1-(Tr iflu or o-(1E)-pr open yl)h eptyl Meth oxyacetate (5g):
1H NMR (CDCl3) δ 0.88 (t, J ) 6.60 Hz, 3H), 1.20-1.40 (m,
8H), 1.65-1.80 (m, 2H), 3.46 (s, 3H), 4.07 (s, 2H), 5.40-5.55
(m, 1H), 5.81 (ddq, J ) 1.50, 15.90, 6.30 Hz, 1H), 6.32 (ddq,
J ) 5.70, 15.90, 1.80 Hz, 1H); 13C NMR (CDCl3) δ 13.89, 22.41,
24.65, 28.77, 31.46, 33.62, 59.32, 69.62, 72.14, 119.54 (q, J )
34.68 Hz), 122. 59 (q, J ) 269.25 Hz), 137.56 (q, J ) 6.16 Hz),
169.25; 19F NMR (CDCl3) δ -64.96 (d, J ) 6.30 Hz, 3F); IR
(neat) 1763 cm-1; HRMS m/ z (M+) calcd for C13H21F3O3,
282.1443; found, 282.1446; Anal. Calcd for C13H21F3O3: C,
55.31; H, 7.50. Found: C, 54.98; H, 7.60.
Typ ica l P r oced u r e for th e Syn th esis of γ-F lu or oa lk y-
la ted Allylic Alcoh ol Der iva tives 5. To a solution of Pd-
(PPh3)4 (5 mol %, 58 mg) in THF (2 mL) was added R-fluoro-
alkylated allyl mesylate 4 (1 mmol) at 0 °C. After stirring the
reaction mixture at that temperature for 10 min, 2 equiv each
of carboxylic acid and triethylamine were added to the mixture,
followed by stirring at 0 °C for 3 h. The reaction was quenched
with saturated NH4Cl(aq) and extracted with ethyl acetate
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 chroma-
tography to give the corresponding γ-fluoroalkylated allyl ester
5 in 74-99% yield.
1-(3-F lu or o-(1E)-p r op en yl)h ep t yl Ben zoa t e (5a ): 1H
NMR (CDCl3) δ 0.88 (t, J ) 7.00 Hz, 3H) 1.20-1.47 (m, 8H),
1.69-1.87 (m, 2H), 4.87 (dd, J ) 5.50, 47.51 Hz, 2H), 5.50 (m,
1H), 5.85-6.00 (m, 2H), 7.40-7.60 (m, 3H), 8.00-8.10 (m, 2H);
13C NMR (CDCl3) δ 14.01, 22.54, 25.02, 29.02, 31.65, 34.34,
73.97, 82.43 (d, J ) 164.12 Hz), 126.72 (d, J ) 16.79 Hz),
128.35, 129.57, 130.36, 132.60 (d, J ) 11.93 Hz), 132.94,
165.76; 19F NMR (CDCl3) δ -215.10 (dt, J ) 7.74, 47.51 Hz,
1-(Ben zyloxym eth yl)-4,4,4-tr iflu or o-(2E)-bu ten yl Ben -
1
zoa te (5h ): H NMR (CDCl3) δ 3.71 (dd, J ) 5.00, 10.75 Hz,
1H), 3.76 (dd, J ) 6.50, 10.75 Hz, 1H), 4.57 (d, J ) 12.00 Hz,
1H), 4.63 (d, J ) 12.00 Hz, 1H), 5.81-5.88 (m, 1H), 5.96 (ddq,
J ) 1.50, 16.00, 6.00 Hz, 1H) 6.53 (ddq, J ) 4.50, 16.00, 2.00
Hz, 1H), 7.25-7.35 (m, 5H), 7.45-7.51 (m, 2H), 7.57-7.63 (m,
1H), 8.05-8.12 (m, 2H); 13C NMR (CDCl3) δ 70.26, 70.86, 73.34,
120.34 (q, J ) 34.50 Hz), 122.65 (q, J ) 268.92 Hz), 125.86,
127.66, 127.89, 128.46, 128.52, 129.79, 133.48, 135.50 (q, J )
6.21 Hz), 137.46, 165.27; 19F NMR (CDCl3) δ -64.92 (d, J )
6.00 Hz, 3F); IR (neat) 1724 cm-1; HRMS m/ z (M+) calcd for
1F); IR (neat) 1720 cm-1; HRMS m/ z (M+) calcd for C17H23
-
FO2, 278.1682; found, 278.1678.
1-(3,3-Diflu or o-(1E)-p r op en yl)h ep tyl Ben zoa te (5b): 1H
NMR (CDCl3) δ 0.87 (t, J ) 6.90 Hz, 3H), 1.20-1.50 (m, 8H),
1.70-1.90 (m, 2H), 5.55 (m, 1H), 5.80 (m, 1H), 6.10 (dt, J )
5.25, 55.50 Hz, 1H), 6.17 (ddt, J ) 15.90, 5.25, 3.00 Hz, 1H),
7.43-7.50 (m, 2H), 7.55 (m, 1H), 8.05-8.10 (m, 2H); 13C NMR
(CDCl3) δ 13.96, 22.48, 24.85, 28.93, 31.55, 33.97, 72.75, 114.18
(t, J ) 233.22 Hz), 123.91 (t, J ) 24.27 Hz), 128.40, 129.57,
C
19H17F3O3, 350.1130; found, 350.1137.
(1S)-1-(3,3,4,4,4-P en ta flu or o-(1E)-bu ten yl)h ep tyl Ben -
1
zoa te ((S)-5i): H NMR (CDCl3) δ 0.80 (t, J ) 6.50 Hz, 3H),
1.15-1.40 (m, 8H), 1.65-1.80 (m, 2H), 5.50-5.65 (m, 1H), 5.77
(dt, J ) 15.50, 12.00 Hz, 1H), 6.35-6.45 (m, 1H), 7.40 (t, J )
7.50 Hz, 2H), 7.53 (t, J ) 7.50 Hz, 1H), 8.00 (d, J ) 7.50 Hz,

1774 J . Org. Chem., Vol. 67, No. 6, 2002
Konno et al.
2H); 13C NMR (CDCl3) δ 13.98, 22.50, 24.76, 28.93, 31.55,
33.88, 72.42, 117.42 (t, J ) 23.64 Hz), 120˜140 (m), 128.52,
129.65, 129.74, 133.32, 140.53 (t, J ) 8.44 Hz), 165.42; 19F
NMR (CDCl3) δ -116.18 (d, J ) 11.02 Hz, 2F), -85.71 (s, 3F);
IR (neat) 1724 cm-1; HRMS m/ z (M+) calcd for C18H21F5O2,
(d, J ) 4.37 Hz, 3F); IR (neat) 1605 cm-1; HRMS m/ z (M+)
calcd for C16H22F3N, 285.1704; found, 285.1660.
N-{1-(3,3,3-Tr iflu or o-(1E)-p r op en yl)h ep t yl}-p -n it r o-
1
a n ilin e (10e): H NMR (CDCl3) δ 0.89 (t, J ) 6.75 Hz, 3H),
1.26-1.78 (m, 10H), 4.0-4.1 (m, 1H), 4.56 (d, J ) 6.50 Hz,
1H), 5.78 (ddq, J ) 1.00, 15.88, 6.50 Hz, 1H), 6.36 (dq, J )
15.88, 2.25 Hz, 1H), 6.52 (d, J ) 9.00 Hz, 2H), 8.10 (d, J )
9.00 Hz, 2H); 13C NMR (CDCl3) δ 13.95, 22.48, 25.73, 28.90,
31.52, 35.04, 53.71, 116.63, 119.20 (q, J ) 34.02 Hz), 122.84
(q, J ) 269.57 Hz), 126.36, 138.61, 139.89 (q, J ) 5.87 Hz),
152.04; 19F NMR (CDCl3) δ -64.16 (d, J ) 6.50 Hz, 3F); IR
(neat) 1600 cm-1; HRMS m/ z (M+) calcd for C16H21F3N2O2,
330.1555; found, 330.1559.
364.1462; found, 364.1466; [R]30 +29.4 (c 0.88, CHCl3).
D
1-(3,3,4,4,5,5,5-Hep ta flu or o-(1E)-p en ten yl)h ep tyl Ben -
zoa te (5j): 1H NMR (CDCl3) δ 0.88 (t, J ) 6.60 Hz, 3H), 1.25-
1.50 (m, 8H), 1.75-1.85 (m, 2H), 5.60-5.70 (m, 1H), 5.86 (dt,
J ) 12.60, 16.05 Hz, 1H), 6.48 (ddt, J ) 5.10, 16.05, 2.40 Hz,
1H), 7.45-7.50 (m, 2H), 7.55-7.65 (m, 1H), 8.05-8.10 (m, 2H);
13C NMR (CDCl3) δ 13.92, 22.44, 24.69, 28.88, 31.50, 33.83,
72.38, 117.45 (t, J ) 23.77 Hz), 120˜140 (m) 128.46, 129.58,
129.69, 133.25, 140.55 (t, J ) 8.68 Hz) 165.36; 19F NMR
(CDCl3) δ -128.28 (s, 2F), -113.51 (m, 2F), -80.87 (t, J )
11.02 Hz, 3F); IR (neat) 1728 cm-1; HRMS m/ z (M+) calcd for
Eth yl-2-{1-(3,3,3-tr iflu or o-(1E)-pr open yl)h eptyl}am in o-
1
a ceta te (10f): H NMR (CDCl3) δ 0.88 (t, J ) 6.50 Hz, 3H),
1.26-1.59 (m, 13H), 1.78 (s, 1H), 3.13 (dt, J ) 7.25, 6.50 Hz,
1H), 3.28 (d, J ) 7.25 Hz, 1H), 3.37 (d, J ) 7.25 Hz, 1H), 4.19
(q, J ) 7.20 Hz, 2H), 5.76 (dq, J ) 15.50, 7.00, Hz, 1H), 6.15
(ddq, J ) 15.50, 7.25, 2.00 Hz, 1H); 13C NMR (CDCl3) δ 13.99,
14.13, 22.53, 25.53, 29.15, 31.61, 35.14, 48.50, 59.16, 60.90,
119.51 (q, J ) 33.60 Hz), 122.84 (q, J ) 269.18 Hz), 142.28 (q,
J ) 6.06 Hz), 172.43; 19F NMR (CDCl3) δ -64.03 (d, J ) 7.00
Hz, 3F); IR (neat) 1740 cm-1; HRMS m/ z (M+) calcd for
C
C
19H21F7O2, 414.1430; found, 414.1408; Anal. Calcd for
19H21F7O2: C, 55.07; H, 5.11. Found: C, 55.32; H, 5.21.
Typ ica l P r oced u r e for th e Syn th esis of γ-F lu or oa lk y-
la ted Allylic Am in es 10. To a solution of Pd(PPh3)4 (5 mol
%) in THF (2 mL) was added the R-fluoroalkylated allyl
mesylate 4 at 0 °C. After the reaction mixture was stirred for
5 min, 2 equiv of amine was added at 0 °C, and the reaction
mixture was warmed to room temperature and then stirred
for 3-24 h. The reaction was quenched with saturated NH4-
Cl(aq), extracted three times with ethyl acetate, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude
material was purified by silica gel column chromatography
(ethyl acetate/hexane 1:3) to give the corresponding γ-fluoro-
alkylated allylamine 10.
C
14H24F3NO2, 295.1759; found, 295.1753.
N,N-Dim eth yl-1-(3,3,3-tr iflu or o-(1E)-p r op en yl)h ep tyl-
1
a m in e (10g): H NMR (CDCl3) δ 0.88 (t, J ) 6.50 Hz, 3H),
1.20-1.35 (m, 8H), 1.40-1.50 (m, 1H), 1.63-1.68 (m, 1H), 2.25
(s, 6H), 2.81-2.85 (m, 1H), 5.70 (dq, J ) 15.88, 6.35 Hz, 1H),
6.25-6.31 (m, 1H); 13C NMR (CDCl3) δ 14.38, 22.59, 26.01,
29.28, 31.68, 31.70, 41.50, 65.98, 120.73 (q, J ) 33.45 Hz),
122.71 (q, J ) 268.01 Hz), 139.37 (q, J ) 5.68 Hz); 19F NMR
N-Benzyl-1-(3,3-difluoro-(1E)-propenyl)heptylamine (10a):
1H NMR (CDCl3) δ 0.87 (t, J ) 6.50 Hz, 3H), 1.20-1.35 (m,
8H), 1.35-1.60 (m, 3H), 3.13 (q, J ) 7.25 Hz, 1H), 3.63 (d,
J ) 13.25 Hz, 1H), 3.80 (d, J ) 13.25 Hz, 1H), 5.75 (ddt, J )
5.75, 15.75, 8.00 Hz, 1H), 5.90 (ddt, J ) 7.25, 15.75, 3.50 Hz,
(CDCl3) δ -64.01 (t, J ) 6.35 Hz, 3F); IR (neat) 1678 cm-1
;
HRMS m/ z (M+) calcd for C12H22F3N, 237.1704; found, 237.1683.
N,N-Diben zyl-1-(3,3,3-tr iflu or o-(1E)-p r op en yl)h ep tyl-
1
a m in e (10h ): H NMR (CDCl3) δ 0.87 (t, J ) 6.75 Hz, 3H),
1.20-1.80 (m, 10H), 3.10-3.20 (m, 1H), 3.38 (d, J ) 13.75 Hz,
2H), 3.81 (d, J ) 13.75 Hz, 2H), 5.64 (dq, J ) 15.80, 6.31 Hz,
1H), 6.30-6.40 (m, 1H), 7.20-7.30 (m, 2H), 7.30-7.40 (m, 8H);
13C NMR (CDCl3) δ 14.06, 22.62, 26.20, 29.10, 31.07, 31.71,
53.63, 58.40, 120.74 (q, J ) 33.07 Hz), 126.98, 127.10 (q, J )
306.35 Hz), 128.31, 128.56, 138.86 (q, J ) 5.78 Hz), 139.62;
19F NMR (CDCl3) δ -64.14 (d, J ) 6.31 Hz, 3F); IR (neat) 1674
cm-1; HRMS m/ z (M+) calcd for C24H30F3N, 389.2330; found,
389.2336.
1H), 6.09 (dt, J ) 5.75, 56.01 Hz, 1H), 7.23-7.35 (m, 5H); 13
C
NMR (CDCl3) δ 14.04, 22.57, 25.63, 29.21, 31.69, 35.35, 51.36,
58.96, 115.03 (t, J ) 233.74 Hz), 124.23 (t, J ) 24.12 Hz),
127.00, 128.10, 128.44, 140.22, 142.22 (t, J ) 11.23 Hz); 19F
NMR (CDCl3) δ -110.46 (dd, J ) 56.01, 8.00 Hz, 2F); IR (neat)
1678 cm-1; HRMS m/ z (M+) calcd for C17H25F2N, 281.1955;
found, 281.1955.
(1S)-N-Ben zyl-1-(3,3,3-tr iflu or o-(1E)-p r op en yl)h ep tyl-
a m in e ((S)-10b): 1H NMR (CDCl3) δ 0.80 (t, J ) 6.75 Hz, 3H),
1.10-1.20 (m, 10H), 1.40 (m, 1H), 3.08 (q, J ) 7.17 Hz, 1H),
3.56 (d, J ) 13.00 Hz, 1H), 3.72 (d, J ) 13.00 Hz, 1H), 5.69
(dq, J ) 15.65, 6.33 Hz, 1H), 6.14 (ddq, J ) 15.65, 7.17, 2.00
Hz, 1H), 7.20 (m, 5H); 13C NMR (CDCl3) δ 13.97, 22.51, 25.50,
29.12, 31.61, 35.10, 51.32, 58.37, 119.12 (q, J ) 33,45 Hz),
123.00 (q, J ) 268.87 Hz), 127.02, 128.01, 128.48, 139.99,
142.87 (q, J ) 6.29 Hz); 19F NMR (CDCl3) δ -64.27 (d, J )
6.33 Hz, 3F); IR (neat) 1678 cm-1; HRMS m/ z (M+) calcd for
E t h yl N-Ben zyl-2-{1-(3,3,3-t r iflu or o-(1E)-p r op en yl)-
1
h ep tyl}a m in oa ceta te (10i): H NMR (CDCl3) δ 0.88 (t, J )
6.75 Hz, 3H), 1.20-1.50 (m, 12H), 1.60-1.75 (m, 1H), 3.24 (d,
J ) 13.50 Hz, 1H), 3.29 (q, J ) 7.30 Hz, 1H), 3.35 (d, J )
13.50 Hz, 1H), 3.68 (d, J ) 13.50 Hz, 1H), 3.87 (d, J ) 13.50
Hz, 1H), 4.13 (q, J ) 7.00 Hz, 2H), 5.73 (dq, J ) 15.50, 6.00
Hz, 1H), 6.25-6.35 (m, 1H), 7.20-7.40 (m, 5H); 13C NMR
(CDCl3) δ 14.04, 22.59, 26.00, 29.14, 31.42, 31.70, 50.99, 54.93,
60.47, 60.82, 120.38 (q, J ) 33.24 Hz), 122.86 (q, J ) 269.52
Hz), 127.19, 128.34, 128.70, 138.88, 139.60 (q, J ) 5.78 Hz),
171.73; 19F NMR (CDCl3) δ -64.31 (d, J ) 6.00 Hz, 3F); IR
(neat) 1736 cm-1; HRMS m/ z (M+) calcd for C21H30F3N,
385.2229; found, 385.2233.
C
17H24F3N, 299.1861; found, 299.1875; [R]31 +1.6 (c 1.23,
D
CHCl3, 96% ee). The retention time in HPLC (hexane only,
0.7 mL/min) is as follows: (R) isomer, 9.4 min; (S) isomer,
9.8 min.
N-Allyl-1-(3,3,3-t r iflu or o-(1E)-p r op en yl)h ep t yla m in e
(10c): 1H NMR (CDCl3) δ 0.88 (t, J ) 6.75 Hz, 3H), 1.27-1.61
(m, 11H), 3.11-3.21 (m, 2H), 3.25-3.29 (m, 1H), 5.11-5.20
(m, 2H), 5.74 (dq, J ) 15.75, 6.50 Hz, 1H), 5.83-5.91 (m, 1H),
6.18 (ddq, J ) 15.75, 8.00, 2.00 Hz, 1H); 13C NMR (CDCl3) δ
14.00, 22.34, 25.60, 29.17, 31.64, 34.99, 49.75, 58.51, 116.53,
119.53 (q, J ) 33.58 Hz), 122.92 (q, J ) 269.13 Hz), 136.03,
142.35 (q, J ) 5.53 Hz); 19F NMR (CDCl3) δ -64.40 (d, J )
6.50 Hz, 3F); IR (neat) 1678 cm-1; HRMS m/ z (M+ + H) calcd
for C13H23F3N, 250.1783; found, 250.1774.
N-{1-(3,3,3-Tr iflu or o-(1E)-pr open yl)h eptyl}an ilin e (10d):
1H NMR (CDCl3) δ 0.88 (t, J ) 6.75 Hz, 3H), 1.20-1.50 (m,
10H), 3.60 (s, 1H), 3.90 (s, 1H), 5.78-5.86 (m, 1H), 6.37 (ddq,
J ) 15.82, 6.81, 2.08 Hz, 1H), 6.55 (d, J ) 7.68 Hz, 2H), 6.72
(t, J ) 7.68 Hz, 1H), 7.17 (t, J ) 7.68 Hz, 2H); 13C NMR (CDCl3)
δ 14.0, 22.55, 25.84, 29.08, 31.63, 35.37, 54.06, 117.84, 118.49
(q, J ) 33.83 Hz), 118.90, 122.20, 123.28 (q, J ) 269.76 Hz),
124.35, 141.78 (q, J ) 5.78 Hz); 19F NMR (CDCl3) δ -64.10
E t h yl N-Ben zyl-3-{1-(3,3,3-t r iflu or o-(1E)-p r op en yl)-
h ep tyl}a m in op r op ion a te (10j): H NMR (CDCl3) δ 0.79 (t,
1
J ) 7.00 Hz, 3H), 1.12-1.23 (m, 11H), 1.37 (m, 1H), 1.53-
1.58 (m, 1H), 2.31-2.41 (m, 2H), 2.60 (dt, J ) 13.00, 6.50 Hz,
1H), 2.91 (dt, J ) 13.00, 7.50 Hz, 1H), 2.95-3.05 (m, 1H), 3.36
(d, J ) 14.00 Hz, 1H), 3.71 (d, J ) 14.00 Hz, 1H), 4.04 (m,
2H), 5.57 (dq, J ) 15.80, 6.30 Hz, 1H), 6.21-6.27 (m, 1H),
7.15-7.25 (m, 5H); 13C NMR (CDCl3) δ 14.03, 14.50, 22.59,
26.25, 29.08, 31.19, 31.73, 34.84, 45.55, 54.70, 60.03, 60.38,
120.50 (q, J ) 33.62 Hz), 122.83 (q, J ) 269.69 Hz), 127.02,
128.27, 128.52, 138.89 (q, J ) 5.01 Hz), 139.50, 172.40; 19F
NMR (CDCl3) δ -64.18 (d, J ) 6.30 Hz, 3F); IR (neat) 1736
cm-1; HRMS m/ z (M+) calcd for C22H32F3NO2, 399.2385; found,
399.2393.
1-(3,3,3-Tr iflu or o-(1E )-p r op e n yl)h e p t ylc yc loh e xy-
1
a m in e (10k ): H NMR (CDCl3) δ 0.88 (t, J ) 6.75 Hz, 3H),
1.22-1.31 (m, 10H), 1.35-1.50 (m, 3H), 1.51-1.70 (m, 5H),
2.39-2.41 (m, 2H), 2.48-2.50 (m, 2H), 2.80-2.84 (m, 1H), 5.67

Concise Syntheses of Alcohols and Amines
J . Org. Chem., Vol. 67, No. 6, 2002 1775
(dq, J ) 15.57, 6.33 Hz, 1H), 6.30 (ddq, J ) 15.57, 8.50, 2.0
Hz, 1H); 13C NMR (CDCl3) δ 14.03, 22.59, 24.63, 26.27, 26.32,
29.27, 31.23, 31.69, 50.56, 66.39, 122.16 (q, J ) 32.19 Hz),
122.84 (q, J ) 269.89 Hz), 140.16 (q, J ) 4.78 Hz); 19F NMR
for C18H24F5N: C, 61.88; H, 6.92; N, 4.01. Found: C, 61.89;
H, 7.07; N, 3.71.
N-Ben zyl-1-(3,3,4,4,5,5,5-h ep t a flu or o-(1E)-p en t en yl)-
h ep tyla m in e (10m ): 1H NMR (CDCl3) δ 0.87 (t, J ) 6.50 Hz,
3H), 1.20-1.35 (m, 8H), 1.40-1.60 (m, 3H), 3.20 (q, J ) 7.50
Hz, 1H), 3.62 (d, J ) 13.25 Hz, 1H), 3.79 (d, J ) 13.25 Hz,
1H), 5.76 (dt, J ) 15.75, 12.00 Hz, 1H), 6.25 (ddt, J ) 15.75,
7.50, 2.00 Hz, 1H), 7.23-7.35 (m, 5H); 13C NMR (CDCl3) δ
14.01, 22.53, 25.52, 29.16, 31.65, 35.24, 51.33, 58.80, 110-120
(m), 117.49 (t, J ) 23.09 Hz), 127.10, 128.06, 128.49, 133.66,
133.82, 140.02, 145.47 (t, J ) 8.35 Hz); 19F NMR (CDCl3) δ
-128.25 (s, 2F), -113.20 to (approx.) -112.50 (m, 2F), -80.82
(CDCl3) δ -64.19 (d, J ) 6.33 Hz, 3F); IR (neat) 1739 cm-1
.
(1S)-N-Ben zyl-1-(3,3,4,4,4-p en t a flu or o-(1E)-b u t en yl)-
1
h ep tyla m in e ((S)-10l): H NMR (CDCl3) δ 0.88 (t, J ) 6.50
Hz, 3H), 1.20-1.35 (m, 8H), 1.45-1.55 (m, 3H), 3.20 (q, J )
7.25 Hz, 1H), 3.63 (d, J ) 13.25 1H), 3.80 (d, J ) 13.25 Hz,
1H), 5.74 (dt, J ) 15.75, 12.00 Hz, 1H), 6.26 (ddt, J ) 15.75,
7.25, 2.00 Hz, 1H), 7.24-7.36 (m, 5H); 13C NMR (CDCl3) δ
14.01, 22.52, 25.50, 29.13, 31.64, 35.11, 51.29, 58.75, 110.00-
125.00 (m), 117.63 (t, J ) 24.00 Hz), 127.13, 128.09, 128.49,
131.95-132.13 (m), 139.83, 145.10-145.20 (m); 19F NMR
(CDCl3) δ -85.84 (s, 3F), -115.63 (d, J ) 12.00 Hz, 2F); IR
(neat) 1739 cm-1; HRMS m/ z (M+) calcd for C18H24F5N,
349.1829; found, 349.1824; [R]33D +1.1 (c 0.71, CHCl3, 96% ee).
The retention time in HPLC (hexane only, 0.7 mL/min) is as
follows: (R)-isomer, 8.0 min; (S)-isomer, 8.5 min; Anal. Calcd
(t, J ) 8.83 Hz, 3F); IR (neat) 1670 cm-1
.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O011013D