Trichloromethanesulfonyl chloride: A chlorinating reagent for aldehydes

Article abstract of DOI:10.1021/acs.joc.5b02543

Trichloromethanesulfonyl chloride (CCl₃SO₂Cl), a commercially available reagent, has been found to perform efficiently in the α-chlorination of aldehydes, including its catalytic asymmetric version, under very mild reaction conditions. Under our reaction conditions, this compound outperforms typical chlorinating reagents for organic synthesis, facilitates workup and purification of the product, and minimizes the formation of toxic, chlorinated organic waste.

Full text of DOI:10.1021/acs.joc.5b02543

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Note
Trichloromethanesulfonyl chloride: a chlorinating reagent for aldehydes
Ciril Jimeno, Lidong Cao, and Philippe Renaud
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02543 • Publication Date (Web): 08 Jan 2016
Downloaded from http://pubs.acs.org on January 14, 2016
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Trichloromethanesulfonyl chloride: a chlorinating reagent for aldehydes
a
b
b*
Ciril Jimeno, Lidong Cao and Philippe Renaud
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a
Department of Biological Chemistry and Molecular Modelling. IQAC-CSIC. c/Jordi Girona 18-
24. E08034 Barcelona, Spain.
b
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012
Bern, Switzerland.
E-mail: philippe.renaud@dcb.unibe.ch
3 2
Abstract. Trichloromethanesulfonyl chloride (CCl SO Cl), a commercially available reagent,
has been found to perform efficiently in the α-chlorination of aldehydes, including its
catalytic asymmetric version, under very mild reaction conditions. Under our reaction
conditions, this compound outperforms typical chlorinating reagents for organic synthesis,
facilitates work-up and purification of the product, and minimizes the formation of toxic,
chlorinated organic waste.
α-Chlorinated aldehydes are very useful building blocks for synthesis of a of
1
pharmaceutically important compounds. They can be prepared via a variety of reactions,
among them, the direct catalytic α-chlorination of ketones and aldehydes is the most
established procedure (Scheme 1). The catalysts used for this transformation are metal
derivatives and secondary amines. By using chiral secondary amine catalysts,
enantioselective α-chlorinations of aldehydes and ketones have been reported.
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Scheme 1. General representation of the α-chlorination of ketone and aldehydes.
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The selection of the chlorinating agent is also a key element of the process since it
determines the nature of the by-products. It also strongly influences the mechanism of the
chlorination reaction and therefore the yield as well as the level of enantioselectivity of the
2
process. Numerous different chlorinating reagents have been used, ranging from inorganic
compounds to polychlorinated organic molecules. Molecular chlorine may be considered the
most atom economical, but its high reactivity and the difficulties associated with handling of
this gas make it often impractical. No asymmetric version is known using gaseous chlorine,
but a clever approach using lithium chloride combined with a strong oxidant like sodium
5
persulfate and copper(II) salts has been described. Enantioselective catalytic chlorination
are typically run with a chlorinated organic compound such as N-chlorosuccinimide (NCS)
6-10
11-18
and a metal- or an organocatalyst.
Other useful reagents include hypervalent iodine
1
9
20
21
compounds, N-chlorophthalimide, 2,2,6,6-tetrachlorocyclohexanone,
2
2-25
26
hexachlorocyclohexadienone,
and trichloroquinolinone, They have been widely used in
combination with organocatalysts or metal catalysts. In any case, organic waste in the form
of succinimide, phthalimide, chlorocyclohexanones and chlorophenols are generated
27
requiring a careful purification of the products. Sulfuryl chloride and p-toluenesulfonyl
2
8
chloride (TsCl) have also been employed with some success. Trichloromethylsulfonyl
chloride had been also used as a chlorinating reagent of preformed silyl enol ethers in a
29
3 2
ruthenium-catalyzed process. Interestingly, trifluoromethanesulfonyl fluoride (CF SO F)
3
0
have been used in both non-catalyzed and asymmetric metal-catalyzed fluorination
3
1
reactions.
Recently, we described how the commercially available trichloromethanesulfonyl chloride,
32,33
was an extremely efficient reagent for radical carbochlorination reactions.
When trying to
extend this reaction to the carbochlorination of enamines with trichloromethylsulfonyl
chloride, we discovered that instead of the desired reaction, an electrophilic chlorination
was taking place. Based on this initial observation, we report here a fast and clean method
for the α-monochlorinations of aldehydes using pyrrolidine-type catalysts and
34-38
trichloromethanesulfonyl chloride.
This reagent proved to behave also very well in an
enantioselective version of this reaction outperforming other well-established chlorinating
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agents.
The reaction conditions were optimized for the chlorination of 3-phenylpropanal (1a) using
pyrrolidine as a catalyst in different solvents in the presence and in the absence of a base
2 2
and water (eq. 1). Results are summarized in Table 1. Reaction in dry CH Cl without base
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was disappointing, the conversion just reached only 31% and a mixture of mono- (2a) and
dichlorinated (2a') aldehydes was obtained (entry 1, Table 1). In 1,2-dimethoxyethane (DME),
the conversion was even lower (entry 2, Table 1). Gratifyingly, when two equivalents of a
base, 2,6-lutidine, was added, the conversion reached 98% but 1:1 mixture of mono- and
dichlorinated products were obtained. When three equivalents H O was added in the
2
absence of a base, only the monochlorinated aldehyde 2a was detected, but the reaction
was very slow (entry 4, Table 1). The combination of 2,6-lutidine (2 equivalents) and H
equivalents) gave the best results (Table 1, entry 5). After reduction of the crude chlorinated
aldehyde 2a with NaBH , the stable 2-chloroalcohol 3a was obtained in 95% yield (entry 5,
Table 1). The use of dichloromethane in the presence of 2,6-lutidine and H O led to full
2
O (3
4
2
conversion but lower chemoselectivity (Table 1, entry 6), which, after reductive work up, led
to alcohol 3a in lower yield.
Table 1. Optimization of the chlorination reaction of 1a according to Equation 1.
a
b
Entry
Solvent 2,6-Lutidine
H
2
O
Conversion
2a/2a' Yield 3a
1
2
3
4
5
CH Cl2
-
-
31
1:1
-
2
DME
DME
DME
DME
-
-
<20
>98
49
1:1
-
2 equiv
-
-
1:1
-
3 equiv
3 equiv
>99:1
>99:1
-
2 equiv
>99
95%
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CH
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2 equiv
3 equiv
>99
4:1
74%
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1
b
Determined by H-NMR on the crude mixture. Isolated yield after flash chromatography.
The scope and limitation of the method was then examined with a range of aliphatic
aldehydes (Scheme 2). Unsubstituted aldehydes 1a–1d provided the desired β-chloro
alcohols 3a–3d in ≥89% yield. Substrates containing double bonds such as 1d and 1f reacted
smoothly too. Phenylacetaldehyde 1g provided the desired product 3g in moderate yield
together with some dichlorinated product. This result may be explained by the increased
acidity of this system that favors a rapid isomerization of the α-chloroiminium ion to the
chloroenamine competing with the hydrolysis step. Then, sterically more demanding α-
substituted aldehydes were tested. Reaction of 2-phenylpropanal 1h was slower, and the
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amount of CCl SO Cl had to be increased to 1.4 equivalents and the temperature to 60 °C.
Under these conditions, the desired aldehyde was isolated in 61% yield. In the course of the
reaction, a white precipitate appeared that we identified as the result of reaction of 2,6-
lutidine with CCl SO Cl. The structure of this precipitate could not be characterized but it
3
2
showed a complex oligomeric nature. We rationalized that the rate of enamine formation
from aldehydes and pyrrolidine decreased with α-substitution of the aldehydes and
therefore the reaction between the base and the trichloromethylsulfonyl chloride can
proceed, thus reducing the efficacy of the process. To avoid this competing reaction, the
bulkier 2,6-di-tert-butylpyridine was used as a base and the yield increased to 80% after 5
hours. This procedure was then applied with success to other α-disubstituted aldehydes
such as 1i and 1j.
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a
Scheme 2. α-Chlorination of aldehydes with CCl
Dichloro-2-phenyl-ethan-1-ol (16%) is also formed. ) Using 2,6-di-tert-butylpyridine instead
of 2,6-lutidine and 1.3 equivalents of CCl SO Cl.
3 2
SO Cl and pyrrolidine as a catalyst. ) 2,2-
b
3
2
Next, the chlorination of cyclohexanone 4 was examined (eq. 3). When 1.1 equivalents of
CCl SO Cl were used under the optimized conditions developed for aldehydes (see above),
3
2
the major product was the dichlorinated cyclohexanone. However, when using
cyclohexanone in excess and longer reaction time (36 h), the desired α-chlorocyclohexanone
5
was obtained in a modest 43% yield together with some polychlorinated products. All
attempts to improve this yield by using bases such as 2,6-di-tert-butylpyridine were
unsuccessful (Scheme 3).
Scheme 3. α-Chlorination of cyclohexanone.
The efficient pyrrolidine catalyzed α-chlorination of aldehydes using CCl SO Cl as an
3
2
electrophilic source of chlorine atom offers the possibility of developing an organocatalytic
asymmetric version of this reaction. The α-chlorination of 3-phenylpropanal 1a and n-octanal
1b was investigated (equation 4, Table 2). 2,6-Lutidine was used as a base and DME as a
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solvent. A rapid initial screening of commercial asymmetric organocatalysts showed that the
3
9,40
simple diarylprolinol silyl ether 6 is a suitable catalyst for this reaction.
Surprisingly, this
commercially available and general catalyst has not been used in chlorination reaction at the
2
exception of the mechanistic work of Blackmond. The addition of a small amount of water
41,42
(
3 equiv.) was essential for the reaction to proceed efficiently.
To avoid racemization, the
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chlorinated aldehydes (S)-2a and (S)-2b were not isolated but directly reduced with sodium
borohydride to the corresponding alcohol (S)-3a and (S)-3b. The alcohol (S)-3a was obtained
in 74% yield and 81% ee (Table 2, entry 1). Aldehyde 1b was converted to (S)-3b in 98% yield
and 93% ee under the same reaction conditions (Table 2, entry 5). The absolute
configuration of (S)-3a and (S)-3b were attributed based on comparison of measured optical
5
rotations with literature values (See SI). Both yields and ee's compare well with the results
5
,14,17,24
14
described in the literature.
Higher ee's were only reported by Jorgensen (2 × 95% ee)
24
and MacMillan (92% and 52% ee) for the chlorination of aldehydes 1a and 1b, respectively.
The ee's and yields obtained under our conditions are noticeably higher than the one
obtained by Blackmond with the same catalyst and NCS for the chlorination of 3-
2
methylpropanal. For comparison purposes, the chlorination of 1a with NCS was performed
with and without 2,6-lutidine. Both reaction conditions afforded low enantioselectivities and
low to moderate yields (Table 2, entries 2 and 3). Other chlorinating agents were also tested
under our reaction conditions: hexachlorocyclohexadienone and trifluoromethanesulfonyl
chloride gave with both substrates lower yields and enantioselectivities, (Table 2, entries 4, 6
and 7) but always the same absolute configuration of product.
Table 2. Enantioselective chlorination of aldehydes according to equation 4.
Entry Aldehyde 1
Reagent
Yield
Ee's
b
c
(
S)-3a/3b (S)-3a/3b
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1a (R = Ph)
1a (R = Ph)
1a (R = Ph)
1a (R = Ph)
CCl
3
SO
2
Cl
74%
81% ee
26% ee
NCS
NCS
<10%
a
a
a
a
a
50%
6% ee
76%
69% ee
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1b (R = n-C
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H
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)
CCl
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SO
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Cl
95%
66%
93% ee
82% ee
1b (R = n-C H )
5
11
7
1b (R = n-C
5
H
11
)
CF
3
SO
2
Cl
57%
84% ee
a
)
2 b
Without 2,6-lutidine according to Blackmond's conditions. ) Isolated yield after flash
c
chromatography. ) Determined by HPLC or GC on chiral stationary phases.
Trichloromethanesulfonic chloride is a very potent source of electrophilic chlorine atom. Its
reactivity may be rationalized by the acidity of the trichloromethanesulfinic acid (pKa 2.19)
that lies very close to trifluoromethanesulfinic acid (pKa 2.09). Trichloromethanesulfinic acid
is several orders of magnitude more acidic that pentachlorophenol (pKa 4.68) and
succinimide (pKa 9.62), the conjugated acids of the anion generated when
hexachlorocyclohexadienone and N-chlorosuccinimide are used as source of electrophilic
chlorine atom. Concerning the mechanism of this process, we believe that the reaction
involves a conventional enamine formation, chlorination, and hydrolysis pathway (Scheme
13
2
4). In contrast to the work of Jorgensen and Blackmond, no formation of an adduct
1
between the iminium ion B and the trichloromethylsulfinate could be detected by H-NMR.
Either such an adduct decomposes rapidly in the presence of 2,6-lutidine or it is not formed.
Indeed, it seems reasonable to have a direct and possibly reversible conversion of the
iminium B to the chloroenamine C in presence of 2,6-lutidine. A second chlorination of
chloroenamine C rationalize the formation of the 2,2-dichloroaldehyde 2' side product. In
the asymmetric version of the reaction, the stereocontrol is set either during the chlorination
of enamine A or during the protonation of enamine C. If, as expected based on minimization
of dipole–dipole interactions, enamine C exists preferentially in a E geometry, both reactions
should lead to the same enantiomer of 2. However, if a fast reversible formation of enamine
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C from iminium B is reached, the situation becomes more complex and the rate of hydrolysis
of the diastereomeric forms of iminium ion B may also influence the stereochemical
outcome of the reaction. The N-chlorination–sigmatropic rearrangement mechanism
1
3
proposed by Jorgensen cannot be ruled out but it is inconsistent with the observed
influence of the chlorinating agent on the level of enantioselectivity.
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Scheme 4. Proposed mechanism for the chlorination reaction
In conclusion, an efficient procedure for the α-chlorination of aldehydes using
trichloromethylsulfonyl chloride as source of electrophilic chlorine atom has been
developed. The reaction takes place in the presence of 2,6-lutidine to neutralize the
trichloromethanesulfonic acid generated during the reaction. Due to the ionic nature of the
2,6-lutidinium trichloromethanesulfonate by-product , the pure β-chloroalcohols are easily
obtained after acid washing and flash chromatography through silica gel.
Experimental Section
General. Commercially available solvents and reagents were used as received. Reactions
were performed in standard laboratory glassware under atmospheric conditions, without
any special caution. Silica gel 60 Å (40-63 μm) was used for flash column chromatography
1
13
1
(FC). H and C NMR spectra were recorded on a spectrometer operating at 300 MHz for H
1
3
and 75 MHz for C at 22 °C unless otherwise stated. Chemical shift data are reported in units
1
of δ (ppm) using residual CHCl
3
as the internal standard (δ = 7.26 for H NMR spectra and δ =
1
3
7
7.0 for C NMR spectra). Multiplicities are given as s (singlet), d (doublet), t (triplet), q
1
(
quartet), m (multiplet), and br (broad) for H spectra. Coupling constants, J, are reported in
Hz. GC-MS were obtained with gas chromatograph coupled to a single quadrupole mass
spectrometry detector (EI, 70 ev). HRMS were measured on a double-focusing magnetic
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sector mass spectrometer in EI mode at 45 eV. Determination of enantiomeric excesses by
HPLC analyses were performed on a Chiralcel IA column, with a 90:10 mixture of
hexanes/isopropanol at 0.9 mL/min flow. Determination of enantioselective excess by GC
analyses were performed on a Chiraldex Tau column, at 90 °C isothermal.
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Experimental procedures for the α-chlorination of aldehydes:
General Procedure A: Pyrrolidine catalyzed chlorination. A 10 mL two-necked flask was
charged with the aldehyde (1.0 mmol), DME (2 mL), pyrrolidine (16 µL, 0.2 mmol), 2,6-
lutidine (230 µL, 2.0 mmol) and H O (54 µl, 3.0 mmol). Cl CSO Cl (240 mg, 1.1 mmol) was
2
3
2
added to this mixture and the solution was stirred at rt for 2 to 4 h. After the aldehyde was
completely consumed (NMR monitoring), the reaction mixture was diluted with MeOH (4
o
mL), cooled to 0 C and NaBH
4
(150 mg, 4.0 mmol) was added. After 25 min, the reaction
Cl , was added followed by
Cl , the organic phases were
washed with diluted HCl and brine successively, dried over anhydrous Na SO , filtered and
mixture was warmed to room temperature for 5 min and CH
2
2
saturated NH
4
Cl (10 mL). The solution was extracted with CH
2
2
2
4
finally concentrated in vacuo. Purification of the resulting oil by FC with pentane/TBME
afforded the desired 2-chloroalcohol.
General Procedure B: Pyrrolidine catalyzed chlorination. A 10 mL two-necked flask was
charged with aldehyde (1.0 mmol), DME (2 mL), pyrrolidine (16 µL, 0.2 mmol), 2,6-tert-butyl-
pyridine (450 µL, 2.0 mmol) and H
2
3 2
O (54 µL, 3.0 mmol). Cl CSO Cl (305 mg, 1.4 mmol) was
o
added and the reaction mixture was stirred at 60 C for 5 h. After the aldehyde was
completely consumed (NMR monitoring), CH Cl and saturated NH Cl (10 mL) were added.
2
2
4
The solution was extracted with CH Cl , the combined organic phases were washed with
2
2
diluted HCl and brine, dried (Na SO ), filtered and then concentrated in vacuo. Purification of
2
4
the resulting oil by FC with pentane/TBME afforded the desired α-chloroaldehyde or α-
chloroketone.
General Procedure C: Enantioselective Chlorination. The chlorinating reagent (0.55 mmol)
was dissolved in DME (1 mL) and then the aldehyde (0.5 mmol) and 2,6-lutidine (117 μl, 1
mmol) were successively added followed by the chiral amine 6 (60 mg, 0.1 mmol) and by
water (27 μl, 1.5 mmol). The mixture was stirred at rt for 2 h and then treated with H
acidified with 0.2 M HCl and extracted with Et O. The combined organic layers were washed
with 0.5 M HCl (2 ×), dried (MgSO ), filtered, and concentrated in vacuo. The crude product
was dissolved in MeOH (2 mL) and NaBH (83 mg, 2.2 mmol) was added at 0 °C. After 30 min,
the reaction was treated with sat. aq. NH Cl and extracted with CH Cl . The product was
2
O,
2
4
4
4
2
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purified by FC eluting with mixture of pentane/TBME of increasing polarity.
2-Chloro-3-phenyl-propan-1-ol 3a. Prepared according to the General Procedure A from 3-
1
phenylpropanal 1a (130 µL, 1 mmol), 2 h reaction time. Colorless oil, 162 mg (95% yield). H
NMR (300 MHz, CDCl
3
) δ 7.40-7.26 (m, 5H), 4.31-4.23 (m, 1H), 3.88-3.81 (m, 1H), 3.77-3.69
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(m, 1H), 3.14 (qd, J = 7.2, 14.1 Hz, 2H), 2.10 ( t, J = 7.2 Hz, 1H) ppm. C NMR (75.4 MHz,
CDCl
3
) δ 137.1, 129.4, 128.6, 127.0, 65.9, 64.9, 40.8 ppm. In accordance to reported
5
literature data.
2-Chloro-octan-1-ol 3b. Prepared according to the General Procedure A from 1-octanal (160
1
µL, 1 mmol), 2 h reaction time. Colorless oil, 147 mg (89% yield). H NMR (300 MHz, CDCl ) δ
3
4
1
6
.06-3.98 (m, 1H), 3.82-3.74 (m, 1H), 3.70-3.61 (m, 1H), 2.12 ( dd, J = 5.7, 7.8 Hz, 1H), 1.83-
1
3
.64 (m, 2H), 1.57-1.28 (m, 8H), 0.88 (t, J = 6.9 Hz, 3H) ppm. C NMR (75.4 MHz, CDCl
3
) δ
5
7.1, 65.4, 34.3, 31.6, 28.8, 26.3, 22.6, 14.0 ppm. In accordance to reported literature data.
2-Chloro-3-methyl-butan-1-ol 3c. Prepared according to the General Procedure A from
1
isovaleraldehyde (107 µL, 1 mmol), 4 h reaction time. Colorless oil, 118 mg (96% yield). H
NMR (300 MHz, CDCl ) δ 3.95-3.89 (m, 1H), 3.85-3.69 (m, 2H), 2.11-2.03 (m, 1H), 2.00-1.93
3
1
3
(
3
m, 1H), 1.03 (d, J = 6.0 Hz, 3H), 1.01 (d, J = 6.0 Hz, 3H) ppm. C NMR (75.4 MHz, CDCl ) δ
43,44
7
1.9, 65.5, 31.5, 20.0, 18.2 ppm. In accordance to reported literature data.
(
Z)-2-Chloro-non-6-en-1-ol 3d. Prepared according to the General Procedure A from cis-6-
1
nonenal (170 µL, 1 mmol), 2 h reaction time. Colorless oil, 164 mg (93% yield). H NMR (300
MHz, CDCl
3
) δ 5.45-5.25 (m, 2H), 4.06-3.98 (m, 1H), 3.83-3.75 (m, 1H), 3.70-3.62 (m, 1H),
13
2
.13-1.98 (m, 5H), 1.83-1.42 (m, 4H), 0.96 (t, J = 7.5 Hz, 3H) ppm. C NMR (75.4 MHz, CDCl )
3
δ 132.5, 128.1, 67.0, 65.2, 33.8, 26.5, 26.4, 20.6, 14.3 ppm. EI-MS: m/z (rel. intensity) 176
+
(
M , 0.7), 140 (7), 123 (11), 109 (16), 93 (22), 81 (42), 67 (96), 41 (100). EI-HRMS cacld. for
+
5
M (C
9
H17ClO): 176.0969, found 176.0968. In accordance to reported literature data.
2-Chloro-3,3-dimethyl-butan-1-ol 3e. Prepared according to the General Procedure A from
3,3-dimethylbutanal (125 µL, 1 mmol), 4 h reaction time. Colorless oil, 128 mg (94% yield).
1
H NMR (300 MHz, CDCl
3
) δ 4.03-3.86 (m, 2H), 3.69-3.61 (m, 1H), 2.05-2.01 (m, 1H), 1.04 (s,
1
3
9
H) ppm. C NMR (75.4 MHz, CDCl ) δ 76.9, 64.0, 34.9, 27.0 ppm. In accordance to reported
3
1
4
literature data.
2-Chloro-3,7-dimethyloct-6-en-1-ol 3f. Prepared according to the General Procedure A from
rac-citronellal (180 µL, 1 mmol), 4 h reaction time. Colorless oil, 160 mg (84% yield). Mixture
1
of diastereomers (The ratio is about 55:45). H NMR (300 MHz, CDCl
3
) δ 5.07 (m, 1H), 4.07
(m, 0.55 H, diast. A), 3.97 (m, 0.45 H, diast. B), 3.86-3.69 (m, 2H), 2.11-1.84 (m, 4H), 1.68 (s,
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3H), 1.60 (s, 3H), 1.47 (m, 1H), 1.32 (m, 1H), 1.02 (d, J = 6.9 Hz, 1.4H, diast. B), 0.95 (d, J = 6.9
1
3
Hz, 1.6H, diast. A) ppm. C NMR (75.4 MHz, CDCl
3
, diast. A and B) δ 132.1(A), 132.0(B),
1
2
1
23.9(A), 123.8(B), 71.1(A), 70.1(B), 65.8(B), 64.9(A), 36.4(A), 35.3(B), 34.3(B), 32.8(A),
5.7(A and B), 25.3(A and B), 17.7(A and B), 16.3(A), 14.6(B) ppm. EI-MS: m/z (rel. intensity)
+
90 (M , 1), 172 (2), 137 (8), 121 (12), 95 (15), 82 (28), 69 (100), 55 (65), 41 (75). EI-HRMS
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11
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19
20
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22
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26
27
28
29
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47
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49
50
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52
53
54
55
56
57
58
59
60
+
cacld. for M (C10
H
19ClO): 190.1126, found 190.1124. In accordance to reported literature
4
5
data.
2
-Chloro-2-phenyl-ethan-1-ol 3g. Prepared according to the General Procedure A from
phenylacetaldehyde (115 µL, 1 mmol), 2 h reaction time. Colorless oil, 92 mg (59% yield). H
NMR (300 MHz, CDCl ) δ 5.00 (dd, J = 5.7, 7.2 Hz, 1H), 3.96-3.92 (m, 2H), 2.17 (br, 1H) ppm.
C NMR (75.4 MHz, CDCl ) δ 137.9, 128.9, 128.8, 127.5, 67.9, 64.9 ppm. In accordance to
1
3
1
3
3
46
reported literature data.
2
-Chloro-2-phenyl-propan-1-al 2h. Prepared according to the General Procedure B from 2-
1
phenylpropionaldehyde (134 µL, 1 mmol). Colorless oil, 135 mg (80% yield). H NMR (300
1
3
MHz, CDCl
3
3
) δ 9.45 (s, 1H), 7.49-7.36 (m, 5H), 1.98 (s, 3H) ppm. C NMR (75.4 MHz, CDCl ) δ
47
1
91.7, 129.0, 128.9, 126.7, 77.0, 25.5 ppm. In accordance to reported literature data.
1
-Chloro-cyclohexanecarbaldehyde 2i. Prepared according to General Procedure B from
1
cyclohexanecarboxaldehyde (105 µL, 1 mmol). Colorless oil, 106 mg (72% yield). H NMR
(
300 MHz, CDCl
3
) δ 9.40 (s, 1H), 1.93-1.89 (m, 4H), 1.86-1.71 (m, 2H), 1.64-1.58 (m, 3H),
1
3
1
.40-1.29 (m, 1H) ppm. C NMR (75.4 MHz, CDCl ) δ 195.3, 74.4, 33.6, 24.9, 21.7 ppm. In
3
48
accordance to reported literature data.
2-Chloro-2-methyl-undecan-1-al 2j. Prepared according to the General Procedure B from 2-
1
methylundecanal (220 µL, 1 mmol). Colorless oil, 173 mg (79% yield). H NMR (300 MHz,
3
CDCl ) δ 9.43 (s, 1H), 1.98-1.78 (m, 2H), 1.58 (s, 3H), 1.43-1.26 (m, 14H), 0.88 (t, J = 6.6 Hz,
1
3
3
H) ppm. C NMR (75.4 MHz, CDCl
3
) δ 195.9, 73.6, 38.7, 31.9, 29.6, 29.5, 29.4, 29.3, 24.2,
+
2
3.6, 22.7, 14.1 ppm. EI-MS: m/z (rel. intensity) 218 (M , 0.5), 142 (3), 111 (18), 97 (53), 92
4
9
(52), 83 (39), 69 (61), 55 (100), 43 (53).
(
S)-2-Chloro-3-phenyl-propan-1-ol (S)-3a. Prepared according to General Procedure C from
trichloromethane sulfonyl chloride (120 mg, 0.55 mmol) and 3-phenylpropanal 1a (65 µL, 0.5
mmol). (S)-3a was isolated as a colorless oil, 58 mg (74% yield). Chiral HPLC analysis of the p-
2
D
5
25
D
nitrobenzoate derivative afforded 81% ee. [α]
= –18.2 (c=1.0, CH
2
Cl
2
). Lit. [α]
= –21.67
5
(
3
c=1.0, CHCl , 95% ee).
(
S)-2-Chloro-octan-1-ol (S)-3b. Prepared according to General Procedure C from
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trichloromethane sulfonyl chloride (120 mg, 0.55 mmol) and 1-octanal 1b (80 µL, 0.5 mmol).
(S)-3b was isolated as a colorless oil, 79 mg (95% yield), Chiral GC analysis of (S)-3b afforded
2
D
5
25
5
9
3% ee. [α]
= –36.7 (c = 1.4, CH
2
Cl
2
). Lit. [α]
D
3
= –25.30 (c=1.0, CHCl , 96% ee).
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Associated Content
Supporting Information
The supporting information is available free of charge on the ACS Publications website at
DOI:
1
13
Determination of ee's of compounds 3a and 3b. H- and C- NMR spectra of all chlorinated
products.
Author Information
Corresponding Author* Email: philippe.renaud@dcb.unibe.ch
Notes
The authors declare no competing financial interest.
Acknowledgments
We thank the Swiss National Science Foundation (project 20020_152782) and the University
of Bern for financial support. C.J. thanks the Ministerio de Economia y Competitividad
(CTQ2012-38594-C02-02 and RYC-2010-06750) for his "Ramón y Cajal" fellowship.
References
(
(
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