Organocatalytic asymmetric fluorination of α-chloroaldehydes involving kinetic resolution

Article abstract of DOI:10.3762/bjoc.10.30

In a previous study it was shown that the enantioselective α-fluorination of racemic α-chloroaldehydes with a chiral organocatalyst yielded the corresponding α-chloro-α-fluoroaldehydes with high enantioselectivity. It was also revealed that kinetic resolu

Full text of DOI:10.3762/bjoc.10.30

Organocatalytic asymmetric fluorination of
α-chloroaldehydes involving kinetic resolution
Kazutaka Shibatomi*, Takuya Okimi, Yoshiyuki Abe, Akira Narayama,
Nami Nakamura and Seiji Iwasa
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 323–331.
Department of Environmental and Life Sciences, Toyohashi University
of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580,
Japan
doi:10.3762/bjoc.10.30
Received: 25 October 2013
Accepted: 03 January 2014
Published: 04 February 2014
Email:
Kazutaka Shibatomi* - shiba@ens.tut.ac.jp
This article is part of the Thematic Series "Organo-fluorine chemistry III".
Guest Editor: D. O'Hagan
* Corresponding author
Keywords:
α-branched aldehyde; asymmetric catalysis; chlorination; fluorination;
© 2014 Shibatomi et al; licensee Beilstein-Institut.
License and terms: see end of document.
organocatalyst; organo-fluorine
Abstract
In a previous study it was shown that the enantioselective α-fluorination of racemic α-chloroaldehydes with a chiral organocatalyst
yielded the corresponding α-chloro-α-fluoroaldehydes with high enantioselectivity. It was also revealed that kinetic resolution of
the starting aldehydes was involved in this asymmetric fluorination. This paper describes the determination of the absolute stereo-
chemistry of a resulting α-chloro-α-fluoroaldehyde. Some information about the substrate scope and a possible reaction mechanism
are also described which shed more light on the nature of this asymmetric fluorination reaction.
Introduction
Fluorinated organic molecules are of considerable interest in α-chloro-α-fluoroaldehydes via the organocatalytic α-fluorin-
pharmaceutical and agricultural chemistry owing to the unique ation of α-alkyl-α-chloroaldehydes, a type of α-branched alde-
properties of the fluorine atom [1,2]. These compounds, espe- hyde, mediated by the Jørgensen–Hayashi catalyst 1 [8]. The
cially with one or more fluorinated stereogenic center(s), are reaction yielded the desired α-chloro-α-fluoroaldehydes with
fascinating building blocks for new drug candidates. Organocat- high enantioselectivity when the starting aldehyde was used in
alytic α-fluorination of aldehydes is known to be an efficient excess over N-fluorobenzenesulfonimide (NFSI) in the reaction.
strategy for the enantioselective construction of fluorinated However, when an excess NFSI with respect to the starting
chiral carbon centers [3-6]; however, very few successful aldehyde was used, poor asymmetric induction was observed. In
studies have been published on the fluorination of α-branched this paper, we describe the determination of the absolute stereo-
aldehydes [7]. During the course of our study on the enantiose- chemistry of a resulting α-chloro-α-fluoroaldehyde using this
lective construction of such fluorinated stereogenic centers, we methodology and discuss the possible reaction mechanism that
developed a method for the enantioselective synthesis of involves kinetic resolution.
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Beilstein J. Org. Chem. 2014, 10, 323–331.
Results and Discussion
our aim was to transform chlorofluoro ester 6 to 4a in order to
In our previous study [8], enantioselective fluorination of compare its optical rotation with that of 4a derived from 2a in
racemic 2-chloro-3-phenylpropanal (2a) was carried out with the presence of catalyst (S)-1. As shown in Scheme 3, β-keto
3 equiv of NFSI in the presence of organocatalyst (S)-1 to yield ester 6 was converted via the Barton–McCombie deoxygena-
the corresponding α-chloro-α-fluoroaldehyde 3a in good tion [13] into a simple ester 10, which was then reduced to the
conversion. Isolation of the product and determination of enan- primary alcohol 4a by treatment with LiAlH4. Comparison of
tiomeric purity were performed after reduction to primary the optical rotations and retention times on chiral HPLC clearly
alcohol 4a because 3a was unstable to silica gel chromatog- showed that the asymmetric fluorination of 2a catalyzed by
raphy. The reaction afforded 4a with high enantioselectivity (S)-1 yielded 4a having the R configuration (Scheme 1).
along with the monochloro alcohol 5a, whose enantiomeric
purity was determined to be 37% ee (Scheme 1) [8]. These An investigation of the substrate scope of the organocatalytic
results suggested that kinetic resolution of the starting alde- fluorination of α-chloroaldehydes was performed as shown in
hydes was involved in this asymmetric fluorination.
Table 1. The reaction of 2a with 3 equiv of NFSI yielded 4a in
87% ee along with monochloro alcohol 5a in 37% ee (Table 1,
To collect further information on the reaction mechanism, we entry 2) as described above. On the other hand, the reaction
sought to determine the absolute configuration of 4a. Recently, with 2 equiv of NFSI against to 2a showed poor enantio-
we reported the enantioselective synthesis of α-chloro-α-fluoro- selectivity (31% ee, Table 1, entry 1). We also examined the
β-keto esters via the sequential chlorination–fluorination of reaction with 2 equiv of 2a based on NFSI. The reaction yielded
β-keto esters with the Cu(II) complex of SPYMOX [9], a spiro 4a in 75% ee (lower ee than that in Table 1, entry 2), and the
chiral oxazoline ligand developed by our research group [9-12]. enantiomeric purity of the recovered 5a was increased to
In that study, we succeeded in determining the absolute stereo- 52% ee (Table 1, entry 3). Similar trends were observed in the
chemistry of the α-chloro-α-fluoro-β-keto ester 6 by the X-ray fluorination with some other substrates 2b–2g (Table 1, entries
crystallographic analysis of its derivative 7 (Scheme 2). Here, 4–14). These results strongly suggested that the high asym-
Scheme 1: Organocatalytic enantioselective fluorination of α-chloroaldehyde 2a [8].
Scheme 2: Determination of absolute configuration of α-chloro-α-fluoro-β-keto ester 6 by X-ray analysis [9].
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Beilstein J. Org. Chem. 2014, 10, 323–331.
Scheme 3: Transformation of α-chloro-α-fluoro-β-keto ester 6 to chlorofluoro alcohol 4a.
Table 1: Enantioselective fluorination of α-chloroaldehydes.a
entry
R
2:NFSI
t (h)
% yield of 4b
% ee of 4c
% ee of 5c,d
1e
Bn (2a)
1:2
3:1
2:1
1:2
3:1
2:1
1:2
3:1
3:1
1:2
3:1
1:2
3:1
3:1
11
6
78
98
96
82
97
92
83
90
90
88
92
61
82
87
31 (R)
87 (R)
75 (R)
31
–
2e,f
3
Bn
37 (S)
52 (S)
–
Bn
6
4
n-Hex (2b)
n-Hex
11
10
19
19
10
4
5e,f
6
80
35 (S)
49 (S)
–
n-Hex
68
7
–(CH2)3OCH2OCH3 (2c)
–(CH2)3OCH2OCH3
–(CH2)3CO2Et (2d)
c-Hex (2e)
c-Hex
23
8f
78
33 (S)
20
9f
80
10g
11g
12
13e,f
14e,g
48
24
12
10
30
42
–
96
15
Ph (2f)
72
–
Ph
90
5
t-Bu (2g)
99
29
aReactions were carried out in t-BuOMe with 15 mol % of (S)-1 unless otherwise noted. bIsolated yield based on 2 or NFSI. cDetermined by chiral
HPLC or GC analysis. dMonochloro alcohol 5 was recovered in nearly quantitative yield. eSimilar result was reported in Ref. [8]. f10 mol % of (S)-1
was used. gReaction was carried out with 30 mol % of (S)-1 at 30 °C.
metric induction in this fluorination requires not only control of lyst (S)-1 reacts with (R)-2a to form iminium intermediate I,
enantiofacial selection during electrophilic fluorination of the which undergoes deprotonation from the side opposite to the
enamine intermediates, but also a high level of kinetic resolu- bulky substituent X (X = CAr2OTMS) of the pyrrolidine ring to
tion of the starting aldehydes.
afford enamine intermediate (Z)-11 (path A). Then, NFSI
attacks (Z)-11 from the side opposite to X to yield (R)-3a.
From these results, we proposed a reaction mechanism for the Although deprotonation may also occur from the same side as X
fluorination of α-chloroaldehydes, as shown in Scheme 4. Cata- to give (E)-11 (path B), the reaction through path B is consid-
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Beilstein J. Org. Chem. 2014, 10, 323–331.
Scheme 4: Proposed reaction mechanism.
ered to be very slow because the steric repulsion between the employed in excess in the reaction, whereas an excess of NFSI
counter anion (OH–) and X would prevent deprotonation. led to poor asymmetric induction. In the former reaction, the
Further, the resulting (E)-11 would be a thermodynamically major enantiomer of the recovered 5a was the S-form (Table 1,
unfavorable product because of steric repulsion between the entries 2 and 3). This result also supports the proposed mecha-
methylene group on the pyrrolidine ring and the benzyl nism.
substituent on 2a. Alternatively, (S)-2a reacts with (S)-1 to form
iminium intermediate II, which also undergoes deprotonation to To test the proposed reaction mechanism, we carried out the
form (E)- or (Z)-11. In these cases, deprotonation from the side fluorination of enantioenriched 2a (61% ee, R favored) with
opposite to X (path C) is considered to be slow because the 2 equiv of NFSI in the presence of each enantiomer of catalyst
resulting (E)-11 is a thermodynamically unfavorable form, as 1. As expected from the mechanism, good enantioselectivity
described above, and deprotonation from the same side as X was observed when (S)-1 was employed in the reaction,
(path D) is also slow because of steric repulsion between the whereas the reaction proceeded more slowly to yield 4a with
counter anion (OH–) and X. Thus, it is difficult to control the poor enantioselectivity in the presence of (R)-1 (Scheme 5).
geometry of enamine intermediate 11 when starting from (S)-
2a, and hence, the enantioselectivity of the fluorination is Finally, we were curious to know whether a similar kinetic
significantly decreased because the fluorination occurs from the resolution would be observed in the fluorination of α,α-dialkyl-
side opposite to X, regardless of the geometry of 11. For these aldehydes. We examined the fluorination of racemic α,α-
reasons, high enantioselectivity was observed when 2a was dialkylaldehyde 12 in the presence of catalyst 1 (Scheme 6).
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Beilstein J. Org. Chem. 2014, 10, 323–331.
Scheme 5: Fluorination of the enantiomers of 2a.
Scheme 6: Enantioselective fluorination of α-branched aldehyde 12.
The reaction with 3 equiv of rac-12 based on NFSI afforded the Column chromatography was performed over silica gel
corresponding product 13 in higher enantioselectivity than that (40–100 μm). 1H, 13C, and 19F NMR spectra were acquired on
obtained in the reaction with 2 equiv of NFSI, along with a JEOL JNM-ECX500 spectrometer. Chemical shift values (δ)
27% ee of 14; however the enantiomeric excess of 13 was not are reported in ppm (1H: δ 0.00 for tetramethylsilane; 19F: δ
sufficiently high (47% ee). These results suggested that the 0.00 for trichlorofluoromethane; 13C: δ 77.0 for residual chloro-
reaction proceeded by a similar mechanism as shown in form). IR spectra were measured on a JASCO FT/IR-230 spec-
Scheme 4.
trometer. Elemental analysis was performed with a Yanaco
CHN CORDER MT-6. High-performance liquid chromatog-
raphy (HPLC) analyses were performed with a JASCO
PU-1586 with a UV-1575 UV–vis detector using a chiral
column. GC analysis was performed with a Shimadzu model
2014 instrument. Optical rotations were measured on a JASCO
P-1030 polarimeter.
Conclusion
In conclusion, we succeeded in the highly enantioselective fluo-
rination of α-chloroaldehydes to afford α-chloro-α-fluoroalde-
hydes mediated by chiral organocatalyst 1. It was revealed that
kinetic resolution of the racemic α-chloroaldehydes occurred
during this fluorination reaction, which played an important role
in the asymmetric induction.
α-Chloro aldehydes 2 were prepared with N-chlorosuccinimide
in the presence of organocatalyst according to the procedure
reported by Jørgensen [14] and were distilled before use.
Experimental
Experiments involving moisture- and/or air-sensitive com- Racemic forms were synthesized with DL-proline catalyst, and
pounds were performed in oven-dried flasks under an atmos- optically active 2a was synthesized with L-prolinamide catayst,
phere of dry argon. All reactions were magnetically stirred and whose enantiopurity was slightly decreased during the distilla-
monitored by thin-layer chromatography (TLC) using pre- tion.
coated silica gel plates with F254 indicator. Visualization was
accomplished with UV light (254 nm), or phosphomolybdic We confirmed that the optical purity of fluorinated products 4
acid, potassium permanganate, or anisaldehyde staining. did not change even after chromatographic purification using
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Beilstein J. Org. Chem. 2014, 10, 323–331.
achiral silica gel and subsequent solvent evaporation. Therefore, A flame-dried flask under argon was charged with 10
we concluded that the enantiomers did not undergo self-dispro- (0.07 mmol) and Et2O (0.2 mL). LiAlH4 (0.11 mmol) was
portionation during the purification process [15-19].
added to this solution at −78 °C, and the mixture was stirred for
1 h at room temperature. The reaction mixture was quenched
with saturated aqueous NH4Cl and the mixture was extracted
Transformation of 6 to (R)-4a
Compound 8 was synthesized from 6 (94% de) according to the with Et2O. The organic layer was dried over Na2SO4 and
procedure reported in [9]. A flame-dried flask under argon was concentrated under reduced pressure. The crude mixture was
charged with 8 (anti/syn = 10:1, 0.35 mmol) and 1,2- purified by silica gel column chromatography (5:1 hexane/
dichloroethane (2 mL). 1,1′-Thiocarbonyldiimidazole EtOAc) to give (R)-4a in 74% yield, with an enantiomeric
(0.6 mmol) was added to this solution, and the mixture was purity of 94% ee.
stirred for 16 h at ambient temperature. The mixture was
quenched by adding saturated aqueous NaHCO3 and extracted 4a: [α]D = −2.8 (c 1.5, CHCl3). HPLC (99:1 hexane/2-propanol;
with CH2Cl2. The organic layer was dried over Na2SO4 and 1 mL/min; using a CHIRALPAK IC column (0.46 cm Ø ×
concentrated under reduced pressure. The crude mixture was 25 cm)): 11.4 min (major) and 11.9 min (minor). These analyt-
purified by silica gel column chromatography (1:1 hexane/ ical data were identical to those of 4a synthesized from 2a with
Et2O) to give 9 in 98% yield (anti/syn = 10:1).
(S)-1.
General procedure for the asymmetric fluorin-
9: 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.83–7.72 (m,
6H), 7.06 (s, 1H), 6.74 (d, J = 21.6 Hz, 1H), 4.87 (td, J = 10.8, ation of α-chloroaldehydes 2
4.4 Hz, 1H), 2.01–1.94 (m, 1H), 1.74–1.56 (m, 4H), 1.55–1.36 To a solution of α-chloroaldehyde 2 (1.5 mmol) in t-BuOMe
(m, 2H), 1.18–0.96 (m, 2H), 0.92 (d, J = 6.4 Hz, 3H), 0.74 (d, J (2 mL) was added catalyst 1 (0.05 mmol) and NFSI (0.5 mmol).
= 7.2 Hz, 3H), 0.52 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, The reaction mixture was stirred at room temperature for the
CDCl3) δ 180.6, 163.6 (d, J = 29.4 Hz), 137.1, 131.4, 130.3, time given in Table 1 and then poured into MeOH/CH2Cl2 (1:4,
129.9, 129.8, 128.8, 128.6, 117.8, 103.3 (d, J = 262.8 Hz), 84.5 5 mL) at 0 °C. To this solution, NaBH4 (5 mmol) was added,
(d, J = 19.8 Hz), 78.8, 46.8, 40.1, 33.9, 31.5, 26.2, 22.8, 22.0, and the mixture was stirred at room temperature for 1 h. The
20.7, 15.2; 19F NMR (376 MHz, CDCl3) δ −132.1 (d, J = 21.4 reaction was quenched with saturated aqueous NH4Cl, and the
Hz); FTIR (neat) υmax: 2955, 1762, 1464, 1395, 1288, 1212, mixture was extracted with Et2O. The organic layer was dried
1102, 992, 952, 742, 475 cm−1; anal calcd (%) for over Na2SO4, concentrated, and chromatographed on silica gel
C23H28ClFN2O3S: C, 59.15; H, 6.04; N, 6.00; found: C, 59.18; to give 4, along with monochloro alcohol 5.
H, 5.96; N, 6.40.
The results of all spectroscopic analyses of compounds 4a, 4b,
A flame-dried flask under argon was charged with 9 4f, 4g, and 5a–5f were identical to those described in our
(0.22 mmol) and benzene (3.6 mL). Tributyltin hydride previous report [8] and in references [20,21]. Absolute
(0.45 mmol) was added to this solution, and the mixture was configuration of 5a–5c was confirmed by comparing their
stirred for 30 min at room temperature. The solvent was optical rotation to that reported in the above-mentioned litera-
removed under reduced pressure and the crude mixture was ture [20].
purified by silica gel column chromatography (5:1 hexane/
CH2Cl2) to give 10 in 42% yield.
(R)-2-Chloro-2-fluoro-3-phenylpropan-1-ol (4a, 87% ee):
1H NMR (500 MHz, CDCl3) δ 7.35–7.30 (m, 5H), 3.88–3.71
10: 1H NMR (400 MHz, CDCl3) δ 7.35–7.25 (m, 5H), 4.74 (td, (m, 2H), 3.46 (dd, J = 32.3, 15.0 Hz, 2H), 2.15 (br, 1H);
J = 10.8, 4.4 Hz, 1H), 3.65 (d, J = 6.8 Hz, 1H), 3.59 (d, J = 3.2 13C NMR (125 MHz, CDCl3) δ 133.3 (d, J = 3.8 Hz), 130.7,
Hz, 1H), 1.85–1.76 (m, 2H), 1.72–1.63 (m, 2H), 1.50–1.41 (m, 128.4, 127.6, 114.8 (d, J = 247 Hz), 67.2 (d, J = 26.4 Hz), 44.6
2H), 1.37–1.19 (m, 1H), 1.09–0.98 (m, 1H), 0.95–0.91 (m, 1H), (d, J = 21.4 Hz); 19F NMR (470 MHz, CDCl3) δ −114.2 (m);
0.89 (d, J = 2.4 Hz, 3H), 0.87 (dd, J = 3.2 Hz, 3H), 0.74 (dd, J [α]D = −2.7 (c 1.5, CHCl3). The enantiopurity was determined
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.3 (d, J = by HPLC (99:1 hexane/2-propanol; 1 mL/min; using a
27.4 Hz), 132.3, 130.7, 130.6, 128.5, 127.9, 106.1 (d, J = 257.9 CHIRALPAK IC column (0.46 cm Ø × 25 cm)): 11.4 min
Hz), 77.9, 46.8, 40.0, 34.0, 31.4, 26.1, 23.3, 22.0, 20.8, 16.1; (major) and 11.9 min (minor).
19F NMR (376 MHz, CDCl3) δ −116.6 (dd, J = 22.9, 19.6 Hz);
FTIR (neat) υmax: 2954, 1754, 1458, 1282, 1216, 1145, 1043, 2-Chloro-2-fluorooctan-1-ol (4b, 80% ee): 1H NMR (500
952, 704, 624, 471 cm−1; anal calcd (%) for C19H26ClFO2: C, MHz, CDCl3) δ 3.91–3.78 (m, 2H), 2.14–2.05 (m, 3H),
66.95; H, 7.69; found: C, 67.02; H, 7.96.
1.59–1.54 (m, 2H), 1.37–1.29 (m, 6H), 0.90 (t, J = 7.0 Hz, 3H);
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Beilstein J. Org. Chem. 2014, 10, 323–331.
13C NMR (125 MHz, CDCl3) δ 116.1 (d, J = 245 Hz), 68.3 (d, Hz), 14.2; 19F NMR (470 MHz, CDCl3) δ −114.0 (m); [α]D13 =
J = 26.4 Hz), 38.5 (d, J = 21.3 Hz), 31.5, 28.9, 23.3 (d, J = 3.8 −1.48 (c 1.1, CHCl3); anal calcd (%) for C8H14ClFO3: C,
Hz), 22.5, 14.0; 19F NMR (470 MHz, CDCl3) δ −113.9 (br); 45.19; H, 6.64; found: C, 44.65; H, 6.67. The enantiopurity was
[α]D = +2.0 (c 0.5, CHCl3). The enantiopurity was determined determined after conversion into the corresponding 2-naph-
by GC (100–150 °C, 3 °C/min; using a Chiral DEX B-DM thoate 15d by a procedure similar to that employed for the syn-
column): 12.4 min (major) and 13.3 min (minor).
thesis of 15c. The crude mixture was purified by silica gel
column chromatography (hexane/EtOAc = 10:1) to give 81%
2-Chloro-2-fluoro-5-(methoxymethoxy)pentan-1-ol (4c, 78% yield of 15d.
ee): 1H NMR (500 MHz, CDCl3) δ 4.63 (s, 2H), 3.99–3.79 (m,
2H), 3.66–3.55 (m, 2H), 3.37 (s, 3H), 2.40–2.12 (m, 3H), 2-Chloro-6-ethoxy-2-fluoro-6-oxohexyl 2-naphthoate (15d,
2.01–1.82 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 115.8 (d, J 80% ee): 1H NMR (500 MHz, CDCl3) δ 8.65 (s, 1H), 8.07 (d, J
= 245 Hz), 96.4, 68.4 (d, J = 26.4 Hz), 66.8, 55.3, 35.4 (d, J = = 8.8 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.92–7.89 (m, 2H),
21.6 Hz), 23.9 (d, J = 4.8 Hz); 19F NMR (470 MHz, CDCl3) δ 7.64–7.55 (m, 2H), 4.79–4.66 (m, 2H), 4.13 (q, J = 7.0 Hz, 2H),
−114.3 (m); [α]D22 = +4.6 (c 0.16, CHCl3); anal calcd (%) for 2.48–2.38 (m, 2H), 2.37–2.17 (m, 2H), 2.09–1.95 (m, 2H), 1.24
C7H14ClFO3: C, 41.91; H, 7.03; Cl, 17.67; F, 9.47; O, 23.92; (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.7,
found: C, 44.91; H, 7.51. The enantiopurity was determined 165.6, 135.7, 132.4, 131.6, 129.5, 128.6, 128.4, 127.8, 126.8,
after conversion into the corresponding 2-naphthoate 15c.
126.2, 125.1, 112.5 (d, J = 247.6 Hz), 67.9 (d, J = 27.6 Hz),
60.5, 38.4 (d, J = 22.8 Hz), 33.4, 18.9 (d, J = 4.8 Hz), 14.2;
A flame-dried flask under argon was charged with 4c 19F NMR (470 MHz, CDCl3) δ −111.8 (m); [α]D21 = +7.1 (c
(0.10 mmol) and CH2Cl2 (1.0 mL). Triethylamine (0.20 mmol), 0.31, CHCl3); anal calcd (%) for C19H20ClFO4: C, 62.21; H,
2-naphthoyl chloride (0.15 mmol), and 4-dimethylaminopyri- 5.50; found: C, 62.92; H, 6.07. The enantiopurity was deter-
dine (0.01 mmol) were added to this solution, and the mixture mined by HPLC (50:1 hexane/2-propanol; 1.0 mL/min; using a
was stirred for 2 h at 0 °C. The mixture was diluted by satu- CHIRALPAK IB-3 column (0.46 cm Ø × 25 cm)): 19.5 min
rated aqueous NaHCO3, and extracted with CH2Cl2. The (minor) and 24.9 min (major).
organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The crude mixture was purified by silica gel 2-Chloro-2-cyclohexyl-2-fluoroethan-1-ol (4e, 96% ee):
column chromatography (hexane/ethyl acetate 5:1) to give the 1H NMR (500 MHz, CDCl3) δ 4.02–3.83 (m, 2H), 2.19–2.08
desired 2-naphthoate 15c in 82% yield.
(m, 1H), 1.98–1.92 (m, 1H), 1.89–1.78 (m, 3H), 1.74–1.66 (m,
1H), 1.39–1.11 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 119.0
2-Chloro-2-fluoro-5-(methoxymethoxy)pentyl 2-naphthoate (d, J = 247 Hz), 66.8 (d, J = 26.4 Hz), 44.5 (d, J = 20.4 Hz),
(15c, 78% ee): 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 27.3 (d, J = 6.0 Hz), 26.1 (d, J = 3.6 Hz), 25.9, 25.7, 25.6;
8.08 (d, J = 10.4 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.93–7.86 19F NMR (470 MHz, CDCl3) δ −117.8 (m); [α]D22 = −6.2 (c
(m, 2H), 7.67–7.53 (m, 2H), 4.83–4.66 (m, 2H), 4.61 (s, 2H), 0.64, CHCl3); anal calcd (%) for C8H14ClFO: C, 53.19; H,
3.62 (t, J = 5.80 Hz, 2 H), 3.34 (s, 3H), 2.49–2.19 (m, 2H), 7.81; Cl, 19.62; F, 10.52; O, 8.86; found: C, 52.52; H, 7.88. The
2.11–1.88 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.6, enantiopurity was determined after conversion into the corres-
135.8, 132.4, 131.6, 129.4, 128.6, 128.4, 127.8, 126.8, 126.3, ponding 2-naphthoate 15e by a procedure similar to that
125.2, 112.8 (d, J = 247 Hz), 96.4, 68.1 (d, J = 26.8 Hz), 66.6, employed for the synthesis of 15c. The crude mixture was puri-
55.2, 36.2 (d, J = 22.0 Hz), 23.9 (d, J = 3.83 Hz); 19F NMR fied by silica gel column chromatography (hexane/ethyl acetate
(470 MHz, CDCl3) δ −111.7 (m); [α]D22 = +7.5 (c 0.36, = 20:1) to give 81% yield of 15e.
CHCl3); anal calcd (%) for C18H20ClFO4: C, 60.93; H, 5.68;
Cl, 9.99; F, 5.35; O, 18.04; found: C, 60.95; H, 5.85. The enan- 2-Chloro-2-cyclohexyl-2-fluoroethyl 2-naphthoate (15e, 96%
tiopurity was determined by HPLC (50:1 hexane/2-propanol; ee): 1H NMR (500 MHz, CDCl3) δ 8.65 (s, 1H), 8.08 (d, J =
0.5 mL/min; using a CHIRALPAK ID column (0.46 cm Ø × 10.32 Hz, 1H), 7.99 (d, J = 8.41 Hz, 1H), 7.94–7.87 (m, 2H),
25 cm)): 25.1 min (major) and 30.5 min (minor).
7.66–7.54 (m, 2 H), 4.75 (br d, J = 17.5 Hz, 1H), 4.75 (br d, J =
19.0 Hz, 1H), 2.25–2.16 (m, 1H), 2.09–2.00 (m, 1H), 1.96–1.80
Ethyl 5-chloro-5-fluoro-6-hydroxyhexanoate (4d, 80% ee): (m, 3H), 1.76–1.66 (m, 1H), 1.49–1.35 (m, 1H), 1.36–1.15 (m,
1H NMR (500 MHz, CDCl3) δ 4.14 (q, J = 7.3 Hz, 2H), 4H); 13C NMR (100 MHz, CDCl3) δ 165.6, 135.7, 132.4, 131.6,
3.94–3.80 (m, 2H), 2.58 (s, 1H), 2.44–2.34 (m, 2H), 2.28–2.07 129.5, 128.6, 128.4, 127.8, 126.8, 126.5, 125.2, 116.0 (d, J =
(m, 2H), 1.95–1.86 (m, 2H), 1.26 (t, J = 7.3 Hz, 3H); 13C NMR 248.2 Hz), 66.7 (d, J = 25.9 Hz), 45.4 (d, J = 20.1 Hz), 27.4 (d,
(125 MHz, CDCl3) δ 173.1, 115.4 (d, J = 246.5 Hz), 68.1 (d, J J = 5.8 Hz), 26.1 (d, J = 2.8 Hz), 25.8, 25.7, 25.6; 19F NMR
= 26.5 Hz), 60.6, 37.4 (d, J = 22.8 Hz), 33.3, 18.9 (d, J = 4.8 (470 MHz, CDCl3) δ −114.3 (m); [α]D24 = −13.7 (0.36,
329

Beilstein J. Org. Chem. 2014, 10, 323–331.
CHCl3); anal calcd (%) for C19H20ClFO2: C, 68.16; H, 6.02; using a CHIRALPAK AS-H column (0.46 cm Ø × 25 cm)):
Cl, 10.59; F, 5.67; O, 9.56; found: C, 68.03; H, 5.98. The enan- 7.2 min (major) and 8.3 min (minor).
tiopurity was determined by HPLC (200:1 hexane/2-propanol;
0.5 mL/min; using a CHIRALCEL OJ-H column (0.46 cm Ø × 2-Fluoro-3-(4-isopropylphenyl)-2-methylpropan-1-ol (13,
25 cm)): 22.5 min (major) and 25.4 min (minor).
47% ee) [7]: 1H NMR (500 MHz, CDCl3) δ 7.16 (s, 4H),
3.61–3.56 (m, 2H), 2.96 (br d, J = 16.5 Hz, 1H), 2.96 (br d, J =
2-Chloro-2-fluoro-2-phenylethanol (4f, 90% ee): 1H NMR 20.5 Hz, 1H), 2.91–2.85 (m, 1H), 1.82 (br s, 1H), 1.27 (d, J =
(500 MHz, CDCl3) δ 7.59–7.53 (m, 2H), 7.46–7.40 (m, 3H), 21.8 Hz, 3H), 1.24 (d, J = 6.9 Hz, 6H); 13C NMR (125 MHz,
4.15–4.04 (m, 2H), 2.15 (t, J = 7.3 Hz, 1H); 13C NMR (125 CDCl3) δ 147.3, 133.2 (d, J = 4.8 Hz), 130.3, 126.3, 97.4 (d, J =
MHz, CDCl3) δ 137.7 (d, J = 22.6 Hz), 129.8, 128.6, 125.3 (d, J 170 Hz), 67.5 (d, J = 22.8 Hz), 41.9 (d, J = 22.8 Hz), 33.7, 24.0,
= 7.5 Hz), 112.9 (d, J = 247 Hz), 70.2 (d, J = 26.4 Hz); 20.9 (d, J = 22.8); 19F NMR (470 MHz, CDCl3) δ −154.7 (m);
19F NMR (470 MHz, CDCl3) δ −118.2 (t, J = 18.8 Hz); [α]D = [α]D25 = −7.0 (c 0.60, CHCl3); The enantiopurity was deter-
−76.5 (c 0.6, CHCl3). The enantiopurity was determined by mined by HPLC (99:1 hexane/2-propanol; 1 mL/min; using a
HPLC (99:1 hexane/2-propanol; 1 mL/min; using a CHIRALCEL OJ column (0.46 cm Ø × 25 cm)): 17.4 min
CHIRALPAK IC column (0.46 cm Ø × 25 cm)): 19.1 min (major) and 21.8 min (minor).
(major) and 21.1 min (minor).
3-(4-Isopropylphenyl)-2-methylpropan-1-ol (14, 27% ee)
2-Chloro-2-fluoro-3,3-dimethylbutan-1-ol (4g) and [22]: 1H NMR (500 MHz, CDCl3) δ 7.15 (d, J = 8.0 Hz, 2H),
2-Chloro-3,3-dimethylbutan-1-ol (5g): 4g and 5g were insepa- 7.10 ( d, J = 8.0 Hz, 2H), 3.54 (dd, 5.0, 5.7 Hz, 1H), 3.47 (dd, J
rable by column chromatography. Therefore, isolation and = 4.6, 6.1 Hz, 1H), 2.88 (m, 1H), 2.71 (dd, J = 6.5, 6.9 Hz, 1H),
determination of their enantiopurity were performed after the 2.41 (dd, J = 5.3, 8.1 Hz, 1H), 1.93 (m, 1H), 1.24 (d, J = 6.9 Hz,
conversion into the corresponding 2-naphthoates 15g and 16g 6H), 0.92 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
by a procedure similar to that employed for the synthesis of 15c. 146.4, 137.8, 129.0, 126.3, 67.8, 39.3, 37.8, 33.7, 24.1, 16.6;
The crude mixture was purified by silica gel column chroma- [α]D25 = −2.3 (c 0.15, CHCl3); The enantiopurity was deter-
tography (hexane/CH2Cl2 = 3:1) to give 87% yield of 15g, mined by HPLC (99:1 hexane/2-propanol; 1 mL/min; using a
along with 80% yield of 16g.
CHIRALPAK IC-3 column (0.46 cm Ø × 25 cm)): 17.6 min
(minor) and 19.9 min (major).
2-Chloro-2-fluoro-3,3-dimethylbutyl 2-naphthoate (15g,
99% ee): 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.12 (d, J Acknowledgements
= 8.9 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.92–7.88 (m, 2H), This study was supported by the Tatematsu Foundation and a
7.63–7.54 (m, 2H), 4.89–4.78 (m, 2H), 1.26 (s, 9H); 13C NMR Grant-in-Aid for Scientific Research (C) (25410113) from
(125 MHz, CDCl3) δ 166.0, 135.7, 132.4, 131.6, 129.5, 128.5, Japan Society for the Promotion of Science.
128.3, 127.8, 126.7, 126.6, 125.2, 119.1 (d, J = 251.9 Hz), 66.0
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