Nucleophilic substitution of optically active 1-alkoxypolyfluoroalkyl sulfonates

Article abstract of DOI:10.1039/a801847b

Reaction of l-alkoxypolyfluoroalkyl sulfonates with lithium tetraalkylaluminates gives stereospecifically alkylated products with a high degree of inversion of configuration; in contrast, the ces of the resulting ethers are slightly reduced in the reactio

Full text of DOI:10.1039/a801847b

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Nucleophilic substitution of optically active 1-alkoxypolyfluoroalkyl sulfonates
Hiroshi Matsutani,a Herve´ Poras,a Tetsuo Kusumoto*a† and Tamejiro Hiyamab
a Sagami Chemical Research Center, Nishiohnuma, Sagamihara, Kanagawa 229-0012, Japan
b Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Yoshida, Kyoto 606-8501, Japan
Reaction of 1-alkoxypolyfluoroalkyl sulfonates with lithium
tetraalkylaluminates gives stereospecifically alkylated pro-
ducts with a high degree of inversion of configuration; in
contrast, the ees of the resulting ethers are slightly reduced
in the reaction with trialkylaluminium reagents.
not react with Bu2CuLi·LiI/BF3·OEt2. However, treatment of
(R)-(2)-3a (61% ee) with AlEt3 in toluene at 220 °C gave
(2)-2-benzyloxy-1,1,1-trifluorobutane 4a in 66% yield with
46% ee [eqn. (1) and Table 1, entry 1]. Since the absolute
Rf
Rf
'AlR' (2.5 equiv.)
toluene
Chiral acetals are versatile building blocks for the synthesis of
biologically active agents and functional materials.1 However,
few optically pure compounds are known whose acetal carbon
only is chiral.2 We have recently reported that the Baeyer–
Villiger reaction of optically active a-alkoxyalkyl ketones
affords optically active 1-alkoxyalkyl carboxylates. The result-
ing acetals undergo the substitution reaction with lithium
dialkylcuprates in the presence of BF3·OEt2 to give optically
active alkoxyalkanes with inversion of configuration.3 We
undertook to expand the concept to trifluoroacetaldehyde
because fluorinated chiral compounds are receiving increasing
attention in view of their remarkable biological and physical
properties.4 Furthermore, the nucleophilic C–C bond-forming
substitution reaction at a carbon bearing a trifluoromethyl group
with inversion of configuration is unprecedented.5,6 We report
herein a nucleophilic substitution of optically active 1-alkoxy-
polyfluoroalkyl sulfonates with an organoaluminium reagent7
to give optically active alkoxypolyfluoroalkanes with a high
degree of inversion of configuration.
Optically active 1-alkoxypolyfluoroalkyl sulfonates were
prepared according to Scheme 1. Trifluoroacetaldehyde or
heptafluorobutanal was liberated in situ from hemiacetal 1a or
hydrate 1b, respectively, and allowed to react with benzyl
alcohol to give racemic hemiacetal 2a or 2b, which was
converted to the corresponding sulfonate with alkane- or arene-
sulfonyl chloride, triethylamine and DMAP.5a,8 The resulting
hemiacetal derivatives were resolved by HPLC (Daicel CHIR-
ALPAK AD or CHIRALCEL OD) to afford (+)- and (2)-3a–d.
Alternatively, (S)-(+)-3a (79% ee‡) was prepared by asym-
metric addition of benzyl alcohol to trifluoroacetaldehyde using
an (R)-binaphthol–titanium(iv) complex9 followed by mesyla-
tion at 0 °C.10
(1)
BnO
OSO2R2
BnO
R
*
*
3a–d
4a Rf = CF3, R = Et
b Rf = CF3, R = Me
c Rf = CF3, R = Bun
d Rf = CF3, R = Bui
e Rf = n-C3F7, R = Bui
configuration of ether (2)-4a is S and that of mesylate (2)-3a
is R,§ we conclude that the reaction has proceeded with
inversion of configuration. This is the first observation of a
stereospecific nucleophilic substitution reaction giving C–C
bond formation at a CF3-substituted carbon with inversion of
configuration, although the enantiomeric excess (ee) of 3a was
slightly lost in 4a. This observation suggests that Lewis acid
AlEt3 induced the formation of an oxocarbenium ion inter-
mediate, which led to racemization to some extent.3 After some
trials, we were delighted to find that the use of LiAlEt412 instead
of AlEt3 gave (R)-(+)-4a in 59% yield with 83% ee, starting
from (S)-(+)-3a (83% ee).¶ It is noteworthy that the ster-
eochemical integrity of the substrate was completely main-
tained (Table 1, entry 2). Thus, the Lewis acidity of the
organometallic reagent affects significantly the stereochemical
course of the reaction.
To demonstrate the generality of the substitution reaction,
optically active sulfonates 3a–c were allowed to react with
various organoaluminium reagents. The results are summarized
in Table 1. The chirality transfer, i.e. the ratio of (% ee of 4)/(%
ee of 3), is shown also. Using AlEt3, benzenesulfonate
(R)-(2)-3b∑ gave ether (S)-(2)-4a with 76% chirality transfer
(entry 3). On the other hand, the same substrate reacted
stereospecifically with LiAlEt4 with 97% chirality transfer
(entry 4). Similar results were obtained with optically active
tosylate 3c (entry 5 and 6). Reaction of (S)-(+)-3c∑ (100% ee)
with LiAlEt4 gave (R)-(+)-4a with 98% ee. Similarly, AlMe3,
With sulfonates 3a–d in hand, we then studied C–C bond-
forming reactions using various organometallic reagents. In
contrast to the corresponding acetaldehyde acetals,3,11 3a did
AlBun , and AlBui3 reacted stereospecifically with optically
3
active tosylate 3c, while the corresponding aluminates
(LiAlMe4, LiAlBun4 and LiAlBui4) reacted with higher stereo-
specificity (entries 8, 10 and 12 vs. entries 7, 9 and 11). The low
yield of ether 4b may be attributed to the poor solubility of
LiAlMe4 in toluene (entry 8, Table 1).
Rf
Rf
(1) polyphosphoric acid, ∆
R1O
OH
(2) BnOH
BnO
OH
1a Rf = CF3, R1 = Et
b Rf = n-C3F7, R1 = H
2a Rf = CF3
b Rf = n-C3F7
Optically active 1-benzyloxy-2,2,3,3,4,4,4-heptafluorobutyl
toluene-p-sulfonate 3d derived from heptafluorobutanal also
reacted with organoaluminium reagents stereospecifically (en-
tries 12 and 13). Treatment of 3d with AlBui3 afforded optically
active ether 4e with 23% chirality transfer in low yield. In
contrast, 3d reacted with LiAlBui4 with 84% chirality transfer.
Although the absolute configurations of sulfonate 3d and ether
4e remain to be determined, the reaction may be assumed to
have proceeded with inversion of configuration as in the cases
of 3a–c.
(1) R2SO2Cl, NEt3, DMAP
(2) resolution by HPLC
Rf
BnO
OSO2R2
*
3a Rf = CF3, R2 = Me
b Rf = CF3, R2 = Ph
c Rf = CF3, R2 = p-Tol
d Rf = n-C3F7, R2 = p-Tol
Scheme 1
Chem. Commun., 1998
1259

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Table 1 Nucleophilic substitution of optically active 1-alkoxypolyfluoroalkyl sulfonates using organoaluminium reagents
Chirality
Entry
Substrate
Ee (%)
‘AlR’
T/°C
t/h
Product
Yield (%)
Ee (%)
transfer (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(R)-(2)-3ab
(S)-(+)-3ab,c
(R)-(2)-3bf
(R)-(2)-3bf
(S)-(+)-3cf
(S)-(+)-3cf,g
(R)-(2)-3cf
(R)-(2)-3cf
(R)-(2)-3cf
(S)-(+)-3cf
(R)-(2)-3cf
(S)-(+)-3cf
(2)-3d
61
83
93
AlEt3
LiAlEt4
AlEt3
LiAlEt4
AlEt3
220
0
0.5
1.5
0.5
1.5
0.5
1.5
0.5
2.5
0.5
1.0
0.5
1.5
0.5
2.0
(S)-(2)-4ad
(R)-(+)-4ad,e
(S)-(2)-4ad
(S)-(2)-4ad
(R)-(+)-4ad
(R)-(+)-4ad,h
(S)-(2)-4bi
(S)-(2)-4bi,j
(S)-(2)-4ck
(R)-(+)-4ck,l
(S)-(2)-4dm
(R)-(+)-4dm,n
(2)-4e
66
59
57
61
75
69
66
26
67
62
76
46
17
43
46
83
71
95
82
98
69
78
72
90
61
93
23
84
75
100
76
97
82
98
76
87
78
90
65
93
23
84
220
98
0
100
100
91
90
92
100
94
100
98
220
0
220
0–40
220
r.t.
LiAlEt4
AlMe3
LiAlMe4
AlBun
3
LiAlBun
4
AlBui3
220
LiAlBui4
AlBui3
0
220
45
(+)-3do
100
LiAlBui4
(+)-4ep
a See text. b The absolute configuration was assigned on the basis of the optical rotation of (S)-(+)-3a prepared using an (R)- binaphthol–titanium(iv) complex
(ref. 9 and 10). c [a]2D0 +46 (c 1.0, CHCl3). d The (S)-isomer prepared from (S)-3,3,3-trifluoro-1,2-epoxypropane 5 showed [a]2D0 240 (c 1.0, CHCl3). e [a]2D0
+41 (c 1.0, CHCl3). f The absolute configuration was estimated by analogy with entries 1 and 2. g [a]2D0
20 +51 (c 1.0, CHCl3). i The
+38 (c 1.0, CHCl3). h [a]D
(S)-isomer prepared from 5 showed [a]2D0 215 (c 1.0, CHCl3). j [a]2D0 214 (c 1.0, CHCl3). k The (S)-isomer prepared from 5 showed [a]2D0 237 (c 1.1, CHCl3).
20
20
20
[a]D +43 (c 1.1, CHCl3). The (S)-isomer prepared from 5 showed [a]D 239° (c 1.0, CHCl3). [a]D +49 (c 1.0, CHCl3). [a]2D0 +33 (c 1.1, CHCl3).
l
m
n
o
p [a]2D0 +25 (c 1.0, CHCl3).
1986, vol. 4, pp. 125–259; J. K. Whitesell, Chem. Rev., 1989, 89, 1581;
T. Mukaiyama and M. Murakami, Synthesis, 1987, 1043.
2 Synthesis of an optically active 1-alkoxy-2,2,2-trichloroethyl ester has
been achieved enzymatically: R. Cheˆnevert, M. Desjardins and
R. Gagnon, Chem. Lett., 1990, 33.
The versatility of the present reaction is demonstrated by the
transformation of the products to optically active 1,1,1-tri-
fluoroalkan-2-ols [eqn. (2)]. Hydrogenolysis of benzyl ether
3 H. Matsutani, S. Ichikawa, J. Yaruva, T. Kusumoto and T. Hiyama,
J. Am. Chem. Soc., 1997, 119, 4541 and refs. therin.
CF3
CF3
Bun
5% Pd–C / H2
(2)
BnO
(R)-(+)-4c (91% ee)
Bun
HO
4 See, for example: M. Hudlicky and A. E. Pavlath, ed., Chemistry of
Organic Fluorine Compounds II, ACS Monograph 187, American
Chemical Society, Washington, DC, 1995; Organofluorine Chemicals
and their Industrial Applications, ed. R. E. Banks, Ellis Harwood,
Chichester, 1979; B. E. Smart, Chem. Rev., 1996, 96, 1555.
5 For substitution at the carbon bearing a trifluoromethyl group by a
heteroatom nucleophile, see: (a) P. J. Casara, M. T. Kenny and
K. C. Jund, Tetrahedron Lett., 1991, 32, 3823; (b) T. Hagiwara,
K. Tanaka and T. Fuchikami, Tetrahedron Lett., 1996, 37, 8187; (c)
K. Mikami, T. Yajima, M. Terada, S. Kawauchi, Y. Suzuki and
I. Kobayashi, Chem. Lett., 1996, 861; (d) T. Katagiri, H. Thara,
M. Takahashi, S. Kashino, K. Furuhashi and K. Uneyama, Tetrahedron:
Asymmetry, 1997, 8, 2933; (e) E. C. Tongco, G. K. S. Prakash and
G. A. Olah, Synlett, 1997, 1193; (f) A. Ishii, F. Miyamoto, K. Higa-
shiyama and K. Mikami, Chem. Lett., 1998, 119.
EtOH
65% yield
(R)-(+)-6
[a]D20 +25 (c 1.4, MeOH)
(R)-(+)-4c removed the benzyl moiety to furnish
(R)-(+)-1,1,1-trifluorohexan-2-ol 613 which is a key chiral
building block of antiferroelectric liquid crystalline materi-
als.14
Notes and References
† E-mail: kus-scrc@ppp.bekkoame.or.jp
‡ Enantiomeric excess (ee) was analyzed by HPLC with CHIRALCEL or
CHIRALPAK (both available from Daicel).
§ The absolute configuration of ethers 4a–d was assigned on the basis of the
optical rotation of a corresponding authentic sample prepared from
(S)-3,3,3-trifluoro-1,2-epoxypropane 5.
¶ Typical procedure. A toluene (2.0 ml) solution of lithium tetraalkyl-
aluminate prepared in situ from the corresponding alkyllithium (0.63 mmol)
and trialkylaluminum (0.63 mmol) was added dropwise to a stirred solution
of 3 (0.25 mmol) in toluene (2.5 ml). The reaction mixture was stirred for
the indicated period and quenched with dilute HCl. The resulting mixture
was extracted with Et2O. The organic layer was washed with aq. NaCl, dried
and concentrated. The residue was purified by silica gel column chromatog-
raphy. All new compounds were fully characterized by IR, mass and NMR
spectroscopy and elemental analysis.
6 A substitution reaction of a cyclic diastereomeric O,N-acetal having a
trifluoromethyl group with organolithium reagents with retention of
configurations been reported recently: A. Ishii, F. Miyamoto, K. Higa-
shiyama and K. Mikami, Tetrahedron Lett., 1998, 39, 1199.
7 Organoaluminium reagents cleave acetals: A. Mori, J. Fujiwara,
K. Maruoka and H. Yamamoto, J. Organomet. Chem., 1985, 285, 83.
8 J. Crank, D. R. K. Harding and S. S. Szinai, J. Med. Chem., 1970, 13,
1212.
9 Diastereo- and enantio-selective ene reaction and aldol reaction of
trifluoroacetaldehyde using a chiral binaphthol–titanium(iv) complex:
K. Mikami, T. Yajima, T. Takasaki, S. Matsukawa, M. Terada,
T. Uchimaru and M. Maruta, Tetrahedron, 1996, 52, 85.
10 H. Poras, H. Matsutani, J. Yaruva, T. Kusumoto and T. Hiyama, Chem.
Lett., in the press. Assignment of the absolute configuration of mesylate
(S)-(+)-3a is also discussed.
11 Organocopper or cuprate reagents associated with BF3 cleave acetals.
See, for example: A. Ghribi, A. Alexakis and J. F. Normant,
Tetrahedron Lett., 1984, 25, 3075.
∑ The absolute configurations of sulfonates 3b,c were estimated on the basis
of the configurations of products 4a–d as well as the stereochemical course
of the reaction.
12 E. B. Baker and H. H. Sisler, J. Chem. Soc., 1953, 5193.
13 T. Yonezawa, Y. Sakamoto, K. Nogawa, T. Yamazaki and T. Kitazume,
Chem. Lett., 1996, 855.
14 For a review, see: A. Fukuda, Y. Takanishi, T. Isozaki, K. Ishikawa and
H. Takezoe, J. Mater. Chem., 1994, 4, 997.
1 H. Fujioka and Y. Kita, in Studies in Natural Products Chemistry, ed.
A.-U. Rahman, Elsevier, Amsterdam, The Netherlands, 1994, vol. 14,
pp. 469–516; R. J. Ferrier, R. Blattner, R. H. Furneaux, P. C. Tyler,
R. H. Wightman and N. R. Williams, in Carbohydrate Chemistry, The
Royal Society of Chemistry, Cambridge, 1991, vol. 23, ch. 7;
D. Seebach, R. Imwinkelried and T. Weber, in Modern Synthetic
Methods 1986, ed. R. Scheffold, Springer Verlag, Berlin, Heidelberg,
Received in Cambridge, UK, 6th March 1998; 8/01847B
1260
Chem. Commun., 1998