A user-friendly procedure for the preparation of secondary alkyl chlorides

Article abstract of DOI:10.1055/s-0032-1317927

Secondary alkyl chlorides have been efficiently prepared from secondary alkyl sulfonates under mild and user-friendly conditions. The exchange reaction was generally performed by using benzyltributylammonium chloride in acetone (reflux, 30 min). Yields are excellent from functionalized, base-sensitive and hindered secondary alkyl sulfonates. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1317927

PAPER
▌231
paper
A User-Friendly Procedure for the Preparation of Secondary Alkyl Chlorides
User-Friendly Synthesis of Secondary Alkyl Chlorides
Gérard Cahiez,*a Nicolas Lefèvre,a Maël Poizat,b Alban Moyeuxb
a
Chimie ParisTech, UMR CNRS 7223, 11 rue Pierre et Marie Curie, 75005 Paris, France
E-mail: gerard-cahiez@chimie-paristech.fr
b
Université Paris 13, UMR CNRS 7244, 74 rue Marcel Cachin, 93017 Bobigny, France
Received: 19.11.2012; Accepted: 26.11.2012
change reaction lasts many hours under reflux and the
Abstract: Secondary alkyl chlorides have been efficiently prepared
yields are good, but not quantitative. Moreover, in the
from secondary alkyl sulfonates under mild and user-friendly con-
case of base-sensitive (Table 1, entries 1 and 2) or hin-
dered (Table 1, entry 3) secondary alkyl sulfonates, the
ditions. The exchange reaction was generally performed by using
benzyltributylammonium chloride in acetone (reflux, 30 min).
Yields are excellent from functionalized, base-sensitive and hin- yields are unsatisfactory.
dered secondary alkyl sulfonates.
OMs
Br
+
Key words: nucleophilic substitution, sulfonates, secondary alkyl
chlorides, quaternary ammonium halides, sulfonate–halogen ex-
change
LiBr
1 h
DMF, 120 °C:
THF, reflux:
72%
94%
17%
<1%
In recent years, we have reported new alkyl–alkyl, alkyl–
aryl and alkyl–alkenyl coupling procedures involving the
reaction of Grignard reagents with secondary alkyl
halides1 under iron2 or cobalt3 catalysis. To perform our
research in this field, we needed an efficient large-scale
preparative procedure to synthesize secondary alkyl ha-
lides. One of the classical ways to prepare alkyl halides is
to convert an alcohol into the corresponding alkyl sulfo-
nate which is then reacted with a metal halide such as LiX,
MgX2, KX or NaX (sulfonate–halogen exchange reac-
tion).4 These reactions, generally performed in polar sol-
vents like acetone, DMF or DMSO, are very inexpensive
and very easy to carry out; however, the synthetic scope
of these procedures suffers from some limitations, partic-
ularly for preparing secondary alkyl halides and especial-
ly chlorides. Recently, we reported that the sulfonate–
halide exchange reaction is advantageously achieved in
tetrahydrofuran.5 Primary alkyl iodides, bromides or chlo-
rides can thus be prepared in excellent yields under mild
conditions since the formation of elimination products is
not observed, or very limited, even in the case of highly
sensitive substrates such as homobenzylic sulfonates
(Scheme 1).
Scheme 1
OSO2Ph
6
LiCl
Cl
5
+
6
5
DMF, 120 °C, 12 h: 5%
THF, reflux, 72 h: 82%
93%
12%
12%
83%
20% MnCl2, THF, reflux, 8 h:
Scheme 2
We thus decided to continue our investigations to find a
faster and more efficient large-scale preparative proce-
dure to synthesize secondary alkyl chlorides.
The procedure is also efficient for preparing secondary al-
kyl bromides. On the other hand, the preparation of sec-
ondary alkyl chlorides is not as easy. Indeed, we showed
that, in tetrahydrofuran, LiCl reacts with secondary alkyl
sulfonates to give only a limited amount of olefins; how-
ever, the reaction is very slow. Fortunately, we discovered
that the exchange is clearly accelerated in the presence of
a catalytic amount of MnCl2 (Scheme 2).
It is well known that the rate of nucleophilic substitution
(SN2) by a chloride anion, in a polar aprotic solvent like
acetone, clearly depends on the degree of dissociation;
thus, Bu4NCl (TBACl) is more efficient than LiCl.6 De-
spite this, the use of quaternary ammonium chlorides for
preparing secondary alkyl chlorides has not been fre-
quently reported. Only a few isolated examples have been
described and all involve an excess of Bu4NCl, an expen-
sive reagent compared to LiCl.7 We thought that quaterna-
ry ammonium chlorides could be interesting candidates to
prepare secondary alkyl chlorides and we decided to start
a more detailed study.
Nevertheless, the preparation of secondary alkyl chlorides
could still be improved since the MnCl2-catalyzed ex-
SYNTHESIS 2013, 45, 0231–0236
Advanced online publication: 19.12.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317927; Art ID: SS-2012-Z0894-OP
© Georg Thieme Verlag Stuttgart · New York

232
G. Cahiez et al.
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BnEt3NCl, an industrial product which is 10 times less ex-
pensive than Bu4NCl and available on a large scale, also
afforded a quantitative yield of 5 under similar reaction
conditions (Table 2, entry 2); however, the reaction was
slower (20 h instead of 1 h) as BnEt3NCl is not very solu-
ble in tetrahydrofuran. This can be circumvented by using
BnBu3NCl which is slightly more expensive but also more
soluble; a quantitative yield of 5 was then obtained in one
hour (Table 2, entry 3). The reaction can even be per-
formed at room temperature, however, in this case, a reac-
tion time of 72 hours is required (Table 2, entry 4).
Interestingly, excellent results were obtained when only
1.1 equivalents of BnBu3NCl was used (Table 2, entry 5).
It should be emphasized that BnBu3NCl is more user-
friendly than lithium halides6 since it is much less hygro-
scopic.
Table 1 Challenging Secondary Alkyl Chloride Targets
MnCl2 (20 mol%)
LiCl (2 equiv)
OSO2Ph
R2
Cl
R1
R1
R2
THF, reflux
Entry
Product
Time (h) Yield (%)
Cl
1
4
4
60
48
1
O
Cl
2
3
2
Cl
H
Table 3 Scope of the Reaction
48
traces
H
H
BnBu3NCl
(1.1 equiv)
O
OSO2Ph
R
Cl
3
(FG)
(FG)
R
acetone,
reflux, 0.5 h
n
n
Our first results were very encouraging since the reaction
of tridec-6-yl benzenesulfonate (4) with Bu4NCl (2 equiv)
in refluxing tetrahydrofuran afforded quantitative yields
of 6-chlorotridecane (5) in one hour (Table 2, entry 1);8
however, the price of Bu4NCl limits the interest of this re-
action for a large-scale preparative use. Accordingly, we
tried to replace Bu4NCl by a less expensive quaternary
ammonium chloride.7 We were able to show that
Entry
Product
Yielda (%)
97
Cl
1
2
10
6
Cl
96
6
Table 2 Reaction of the Secondary Alkyl Sulfonate 4 with Quater-
nary Ammonium Chlorides: Influence of Various Parameters
5
7
Cl
OSO2Ph
R1R2R3R4NCl
solvent, reflux
Cl
3
4
5
92b
82
6
6
4
5
Cl
N
Entry R1R2R3R4NCl
Solvent
Time (h) Yielda (%)
1
1
2
Bu4NCl (2 equiv)
THF
1
20
1
98
Cl
Boc
BnEt3NCl (2 equiv)
BnBu3NCl (2 equiv)
BnBu3NCl (2 equiv)
BnBu3NCl (1.1 equiv)
BnEt3NCl (2 equiv)
BnBu3NCl (2 equiv)
BnBu3NCl (1.1 equiv)
py·HCl (2 equiv)
THF
99
89
3
THF
99
8
9
72b
1
99
Cl
Cl
4
THF
N
5
THF
94
6
99
6
6
acetonec
acetonec
acetonec
acetonec
acetonec
acetonec
2
97
O
7
0.5
97
8
0.5
1
97
OEt
7
8
88
92
6
9
22d
7d
10
2
O
Cl
10
11
Me2NH·HCl (2 equiv)
NH4Cl (2 equiv)
1
1
traces
a GC yield using decane as an internal standard.
b Reaction was performed at room temperature.
a Isolated yield.
b From the sulfonate of (S)-(+)-octan-2-ol; (R)-7: [α]D20 –37.4 (neat)
[Lit.10 [α]D20 –37.3 (neat)].
c Technical grade acetone (up to 2% H2O) was used.
d Reaction mainly gives elimination products.
Synthesis 2013, 45, 231–236
© Georg Thieme Verlag Stuttgart · New York

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User-Friendly Synthesis of Secondary Alkyl Chlorides
233
The reaction can also be performed successfully in ace-
tone (Table 2, entries 6 and 7), since the formation of
elimination products was not observed.9 The yields are
similar to those obtained in tetrahydrofuran but, interest-
ingly, the reaction is much faster (10 times faster in the
case of BnEt3NCl; Table 2, entry 6). It should be empha-
sized that anhydrous acetone is not required to perform
the reaction. Excellent results were achieved by using
commercial technical grade acetone (H2O ≤2%). This is
interesting for a large-scale procedure since this solvent is
less expensive than tetrahydrofuran. Finally, some at-
tempts of this reaction with various amine hydrochlorides
led to failure (Table 2, entries 9–11).
Cl
OSO2Ph
H
H
H
H
H
H
O
O
3
LiCl, 20% MnCl2, THF, 2 d: < 1%
BnBu3NCl, MEK, reflux, 5 d: 96%
Scheme 3 Synthesis of 17α-chloroandrost-4-en-3-one
SN1 substitution (94%; LiCl, MeCN, reflux) or the 3α-epi-
mer 12 (SN2 substitution) but only in moderate yield
(42%; Bu4NCl, TMU, acetone).11c Thus, it should be not-
ed that the synthesis of 12 generally involves multistep
procedures.12 Under our conditions and after complete
consumption of the 3β-tosylate derivative 11 (R = 4-Tol),
we obtained only 57% yield of 12 contaminated with large
amounts of elimination products (Table 4, entry 1).
In the light of these promising results, we decided to study
the scope of the reaction. The results presented in Table 3
show that many functional groups (FG), a Boc-protected
amine, a nitrile, an ester or a ketone, are tolerated under
our reaction conditions (Table 3, entries 5–8). Excellent
yields were also obtained from challenging base-sensitive
sulfonates (Table 3, entries 4 and 8; cf. Table 1, entries 1
and 2). Noteworthy, as in the case of the manganese-
catalyzed reaction,5 the reaction proceeds with complete
inversion of configuration (Table 3, entry 3). It should be
noted that the crude product is generally pure enough to be
used directly for further synthetic uses.
In methyl ethyl ketone, it is possible to operate at a higher
temperature and the reaction is faster, but the yield was
not improved (Table 4, entry 2). It is commonly accepted
that mesylate derivatives are slightly more reactive than
the corresponding tosylates;13 accordingly, we decided to
use the 3β-mesylate 11 (R = Me). Our first attempt, in
methyl ethyl ketone at reflux, mainly led to elimination
products (Table 4, entry 4). As it is well established that
polar solvents can favor elimination reactions,14 we then
tried to perform the reaction in toluene in place of acetone.
To our delight, the reaction proceeded with an excellent
yield in only two hours (Table 4, entry 5). Noteworthy,
only two equivalents of BnBu3NCl are enough to perform
the reaction efficiently (Table 4, entry 6).
As expected, the procedure described herein is superior to
the MnCl2-catalyzed procedure for the challenging prepa-
ration of 17α-chloroandrost-4-en-3-one (3) from the cor-
responding hindered 17β-sulfonate (Scheme 3).
We have also tried to prepare 3α-chlorocholest-5-ene (12)
from the 3β-sulfonate 11. It is challenging11 since it has
been described that, according to the conditions, the sul-
fonate–chloride exchange reaction gives either the 3β-
chlorocholest-5-ene epimer in good yield according to an
Table 4 Synthesis of 3α-Chlorocholest-5-ene
BnBu3NCl
solvent, reflux
11
12
RO2SO
Cl
Entry
R
BnBu3NCl (equiv)
Solventb
Time (h)
Yielda (%)
1
2
3
4
5
6
4-Tol
4-Tol
4-Tol
Me
10
10
5
acetone
MEK
24
1
57
53
52
39
95
89
MEK
2
5
MEK
6
Me
5
toluene
toluene
2
Me
2
4
a NMR yield using 1,3,5-trimethoxybenzene as an internal standard.
b MEK = methyl ethyl ketone.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 231–236

234
G. Cahiez et al.
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1H NMR (400 MHz, CDCl3): δ = 8.04–8.00 (m, 2 H), 7.76–7.60 (m,
3 H), 4.72–4.63 (m, 1 H), 1.68–1.62 (m, 4 H), 1.37–1.27 (m, 16 H),
0.99–0.90 (m, 6 H).
13C NMR (101 MHz, CDCl3): δ = 137.6, 133.26, 128.9, 127.5, 84.8,
34.0, 31.5, 31.3, 29.1, 28.9, 24.6, 24.2, 22.5, 22.3, 13.9, 13.8.
In conclusion, we have described herein a fast and effi-
cient method to prepare secondary alkyl chlorides from
the corresponding sulfonate derivatives and BnBu3NCl.
To the best of our knowledge, this is the first use of
BnBu3NCl for this purpose. Functionalized or hindered
alkyl sulfonates afford excellent yields. This method is es-
pecially interesting for preparative purposes since high
yields can be obtained by using commercial non-anhy-
drous acetone and inexpensive BnBu3NCl. Moreover, the
latter can be used and stored without special precautions,
in contrast to the very hygroscopic lithium halides. It
should be emphasized that, in simple cases, it is possible
to synthesize the alkyl chloride in high yield directly from
the corresponding primary or secondary alkanol in a one-
pot reaction (Scheme 4).
Sulfonate–Halide Exchange Reaction (Tables 2 and 3); General
Procedure
Solvent (5 mL), an alkyl sulfonate (5 mmol) and a tertiary ammoni-
um halide (5.5 mmol, 1.1 equiv) were introduced into a 20-mL flask
under a nitrogen atmosphere and the reaction mixture was refluxed
for 0.5 h. Then, the reaction was quenched with H2O (20 mL) and
the product was extracted with petroleum ether (2 × 40 mL). The
combined extract was dried over MgSO4, filtered and concentrated
under reduced pressure; the product was distilled or purified by
chromatography on a silica gel column.
One-Pot Reaction (Scheme 4); General Procedure
Pyridine (5 mL), an alkanol (5 mmol), benzenesulfonyl chloride
(7.5 mmol) and BnBu3NCl (5 mmol, 1.1 equiv) were introduced
into a 20-mL flask under a nitrogen atmosphere and the reaction
mixture was refluxed for the specified time. Then, the reaction was
quenched with H2O (20 mL) and the product was extracted with pe-
troleum ether (2 × 40 mL). The combined extract was dried over
MgSO4, filtered and concentrated under reduced pressure; the prod-
uct was distilled or purified by chromatography on a silica gel col-
umn.
PhSO2Cl (1.5 equiv)
BnBu3NCl (1.1 equiv)
OH
Cl
pyridine, reflux, 1 h
97%
PhSO2Cl (1.5 equiv)
BnBu3NCl (1.1 equiv)
Cl
HO
10
10
pyridine, reflux, 10 min
(2-Chloropropyl)benzene (1)
96%
Solvents were distilled under atmospheric pressure, then the trace
solvents were carefully eliminated by evaporation under 8 mmHg
(purity of the crude product ≥ 97% by GC); yield: 634 mg (82%);
colorless oil.
Scheme 4 One-pot procedure
1H NMR (400 MHz, CDCl3): δ = 7.34–7.10 (m, 5 H), 4.19 (sept,
J = 6.7 Hz, 1 H), 3.05 (dd, J = 13.9, 7.0 Hz, 1 H), 2.93 (dd, J = 13.9,
6.9 Hz, 1 H), 1.51–1.40 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 138.3, 129.7 (2 C), 128.7 (2 C),
127.1, 58.8, 47.0, 25.0.
We are confident that this method is a reliable and eco-
nomical large-scale preparative procedure for the synthe-
sis of secondary alkyl chlorides.
6-Chlorononan-2-one (2)
Purification by chromatography on silica gel (PE–EtOAc, 96:4);
yield: 856 mg (92%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 3.97–3.84 (m, 1 H), 2.46 (td,
J = 6.8, 1.7 Hz, 2 H), 2.14 (s, 3 H), 1.90–1.33 (m, 8 H), 0.92 (t,
J = 7.4 Hz, 3 H).
LiCl and LiBr were purchased from Acros and were dried for 8 h at
150 °C under vacuum. Anhydrous THF (H2O <5 ppm) was directly
obtained from a commercial source and stored under a nitrogen at-
mosphere. All other solvents (analytical grade) were used without
further purification. All reactions were carried out with mechanical
stirring under a nitrogen atmosphere. 1H and 13C NMR spectra were
recorded at 400 and 101 MHz, respectively, with a Jeol ECX-400
NMR spectrometer using CDCl3 as a solvent. Mass spectra were re-
corded on a Hewlett Packard HP 5973 mass spectrometer via
GC/MS coupling with a Hewlett Packard HP 6890 gas chromato-
graph equipped with a capillary column (HP-5MS, 50 m × 0.25
mm × 0.25 μm). Ionization was performed by electron impact (EI,
70 eV). Yields refer to isolated compounds; purity was >96%, as de-
termined by GC analysis (Hewlett Packard HP 6890 gas chromato-
graph equipped with a HP-5 column). The analytical data for all
compounds match the literature data.
13C NMR (101 MHz, CDCl3): δ = 208.6, 63.5, 43.1, 40.6, 37.9,
30.0, 20.9, 19.8, 13.7.
HRMS (ESI): m/z calcd for C9H17ClO: 176.0968; found: 176.0966.
17α-Chloroandrost-4-en-3-one (3)
Purification by chromatography on silica gel (PE–CH2Cl2–EtOAc,
7:1:2); yield: 1.472 g (96%); white solid.
1H NMR (400 MHz, CDCl3): δ = 5.73 (d, J = 1.7 Hz, 1 H), 4.10–
4.03 (m, 1 H), 2.52–2.20 (m, 5 H), 2.09–0.91 (m, 14 H), 1.45 (s, 3
H), 0.84 (d, J = 0.5 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 199.6, 171.1, 124.1, 70.9, 53.3,
47.9, 46.2, 38.7, 36.1, 35.8, 34.3, 34.1, 33.6, 32.9, 32.3, 24.7, 20.9,
18.0, 17.6.
Tridec-6-yl Benzenesulfonate (4); Typical Procedure
Tridecan-6-ol (2 g, 10 mmol) and CH2Cl2 (10 mL) were introduced
into a 100-mL flask. Pyridine (1.58 g, 20 mmol) was added at r.t.,
then benzenesulfonyl chloride (2.65 g, 15 mmol) was added at 0 °C
and the reaction mixture was stirred at r.t. for 24 h. The reaction
mixture was quenched with H2O (20 mL) and the organic layer was
washed with 1 M HCl soln (20 mL), sat. Na2CO3 soln (20 mL) and
finally with H2O (30 mL). The organic layer was dried over MgSO4,
filtered and concentrated under reduced pressure. The product was
purified by flash chromatography on a silica gel column (cyclohex-
ane–EtOAc, 95:5) to give 4 as a yellowish oil; yield: 3.17 g (93%).
6-Chlorotridecane (5)
Purification by distillation (bp 124 °C/2 mmHg); yield: 1.050 g
(96%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 3.95–3.83 (m, 1 H), 1.78–1.62 (m,
4 H), 1.59–1.46 (m, 2 H), 1.46–1.20 (m, 14 H), 0.88 (t, J = 6.6 Hz,
6 H).
13C NMR (101 MHz, CDCl3): δ = 64.6, 38.7, 31.9, 29.0, 26.6, 22.7,
14.2.
Synthesis 2013, 45, 231–236
© Georg Thieme Verlag Stuttgart · New York

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User-Friendly Synthesis of Secondary Alkyl Chlorides
235
2-Chlorotridecane (6)
Solvents were carefully evaporated under 20 mmHg (purity ≥ 97%
by GC); yield: 1.061 g (97%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 3.88–3.75 (m, 1 H), 1.86–1.58 (m,
4 H), 1.52–1.33 (m, 2 H), 1.33–1.18 (m, 14 H), 1.01 (t, J = 7.3 Hz,
3 H), 0.92–0.80 (m, 3 H).
Acknowledgment
The authors thank the CNRS for financial support and the Ministère
de l’Education Nationale et de la Recherche for financial support
and a grant to M.P.
13C NMR (101 MHz, CDCl3): δ = 66.1, 38.3, 32.1, 31.6, 29.8, 29.7,
29.7, 29.5, 29.4, 26.7, 22.8, 14.3, 11.1.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
(R)-2-Chlorooctane (7)
Due to high volatility of the product, the solvent was carefully evap-
orated under 150 mmHg; yield: 683 mg (92%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 4.04 (sept, J = 6.5 Hz, 1 H), 1.79–
1.62 (m, 2 H), 1.51 (d, J = 6.5 Hz, 3 H), 1.44–1.22 (m, 8 H), 0.96–
0.86 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 59.1, 40.5, 31.9, 28.9, 26.8, 25.5,
22.7, 14.2.
References
(1) For general reviews on cross-coupling reactions with alkyl
halides, see: (a) Frisch, A. C.; Beller, M. Angew. Chem. Int.
Ed. 2005, 44, 674. (b) Netherton, M. R.; Fu, G. C. Adv.
Synth. Catal. 2004, 346, 1525. (c) Càrdenas, D. J. Angew.
Chem. Int. Ed. 2003, 42, 384. (d) Westrum, L. J. Fine
Chemistry 2002, November/December, 10. (e) Luh, T.-Y.;
Leung, M.-K.; Wong, K.-T. Chem. Rev. 2000, 100, 3187.
(2) (a) Cahiez, G.; Habiak, V.; Duplais, C.; Moyeux, A. Angew.
Chem. Int. Ed. 2007, 46, 4364. (b) Cahiez, G.; Habiak, V.;
Duplais, C.; Moyeux, A. Org. Lett. 2007, 9, 3253.
(3) (a) Cahiez, G.; Chaboche, C.; Duplais, C.; Giulliani, A.;
Moyeux, A. Adv. Synth. Catal. 2008, 350, 1484. (b) Cahiez,
G.; Chaboche, C.; Duplais, C.; Moyeux, A. Org. Lett. 2009,
11, 277.
tert-Butyl 4-Chloropiperidine-1-carboxylate (8)
Purification by chromatography on silica gel (PE–EtOAc, 98:2);
yield: 977 mg (89%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 4.18 (tt, J = 7.6, 3.7 Hz, 1 H), 3.69
(ddd, J = 13.2, 7.2, 3.7 Hz, 2 H), 3.28 (ddd, J = 13.6, 7.7, 3.6 Hz, 2
H), 2.07–1.95 (m, 2 H), 1.79 (ddt, J = 15.7, 11.7, 5.6 Hz, 2 H), 1.45
(s, 9 H).
13C NMR (101 MHz, CDCl3): δ = 154.7, 79.9, 57.1, 35.0, 28.6, 9.2.
(4) (a) Bohlmann, R. In Comprehensive Organic Synthesis; Vol.
6; Trost, B. M.; Fleming, I.; Winterfeldt, E., Eds.; Pergamon
Press: Oxford, 1991, 203. (b) Comprehensive Organic
Transformations; Larock, R. C., Ed.; Wiley-VCH:
Weinheim, 1999, 689.
HRMS (ESI): m/z calcd for C10H18ClNO2: 219.1026; found:
219.1022.
5-Chlorododecanenitrile (9)
Purification by chromatography on silica gel (PE–EtOAc, 98:2);
yield: 1.068 g (99%); colorless oil.
(5) Cahiez, G.; Gager, O.; Moyeux, A.; Delacroix, T. Adv.
Synth. Catal. 2012, 354, 1519.
(6) Winstein, S.; Savedoff, L. G.; Smith, S.; Stevens, I. D. R.;
Gall, J. S. Tetrahedron Lett. 1960, 24.
1H NMR (400 MHz, CDCl3): δ = 3.96–3.83 (m, 1 H), 2.40 (t,
J = 6.3 Hz, 2 H), 2.06–1.64 (m, 6 H), 1.60–1.18 (m, 10 H), 0.88
(sept, J = 4.2 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 119.4, 62.8, 38.7, 37.2, 31.9,
29.3, 29.2, 26.6, 22.8, 22.6, 16.9, 14.2.
(7) Indicative prices (Acros Chemicals): Bu4NCl: 662 €/mol,
BnEt3NCl: 42 €/mol, BnBu3NCl: 102 €/mol, LiCl: 10 €/mol.
(8) (a) Tetrabutylammonium chloride has already been used to
perform sulfonate–halide exchange reactions; however, uses
for the preparation of secondary alkyl chlorides are quite
rare. Moreover, the reaction is restricted to activated alkyl
sulfonates like α-keto benzylic sulfonates,8a,b or to steroid8c
or sugar8d derivatives. No general method has been reported
for the conversion of unactivated secondary alkyl sulfonates
into secondary alkyl halides with quaternary ammonium
halides. (b) Choi, D.; Stables, J. P.; Kohn, H. Bioorg. Med.
Chem. 1996, 4, 2105. (c) Effenberger, F.; Kremser, A.;
Stelzer, U. Tetrahedron: Asymmetry 1996, 7, 607.
(d) Henbest, H. B.; Jackson, W. R. J. Chem. Soc. 1962, 954.
(e) Panday, N.; Meyyappan, M.; Vasella, A. Helv. Chim.
Acta 2000, 83, 513. For some immobilized tertiary
ammonium derivatives, see: (f) Colonna, S.; Re, A.;
Gelbard, G.; Cesarotti, E. J. Chem. Soc., Perkin Trans. 1
1979, 2248.
Ethyl 5-Chlorododecanoate (10)
Purification by chromatography on silica gel (PE–EtOAc, 98:2);
yield: 1.156 g (88%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 4.13 (q, J = 7.1 Hz, 2 H), 3.89 (dq,
J = 5.4, 2.4 Hz, 1 H), 2.32 (t, J = 6.8 Hz, 2 H), 1.93–1.63 (m, 6 H),
1.57–1.35 (m, 2 H), 1.35–1.20 (m, 11 H), 0.91–0.84 (m, 3 H).
13C NMR (101 MHz, CDCl3): δ = 173.5, 63.7, 60.5, 38.6, 37.8,
33.8, 31.9, 29.3, 29.2, 26.6, 22.8, 22.1, 14.4, 14.2.
HRMS (ESI): m/z calcd for C14H27ClO2: 262.1700; found:
262.1705.
3α-Chlorocholest-5-ene (12)
Purification by chromatography on silica gel (PE); yield: 1.944 g
(95%); white solid.
1H NMR (400 MHz, CDCl3): δ = 5.42–5.33 (m, 1 H), 4.53–4.41 (m,
1 H), 2.87–2.66 (m, 1 H), 2.27 (dt, J = 15.2, 2.5 Hz, 1 H), 2.06–1.79
(m, 5 H), 1.70–1.00 (m, 21 H), 1.00 (s, 3 H), 0.92 (d, J = 6.6 Hz, 3
H), 0.87 (dd, J = 6.6, 1.9 Hz, 6 H), 0.68 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 137.5, 123.7, 60.7, 56.8, 56.3,
49.9, 42.5, 40.5, 39.9, 39.7, 37.1, 36.3, 36.0, 33.1, 31.9, 31.9, 30.1,
28.4, 28.2, 24.4, 24.0, 23.0, 22.7, 20.9, 19.3, 18.9, 12.0.
(9) When the reaction is performed with LiCl, it has been
observed that the use of polar solvents favors the formation
of elimination products; for instance, see ref. 5.
(10) Filippo, J. S.; Silbermann, J. J. Am. Chem. Soc. 1981, 103,
5588.
(11) (a) Madaeva, O. S. J. Gen. Chem. USSR (Engl. Transl.)
1955, 25, 1373. (b) Aneja, R.; Davies, A. P.; Knaggs, J. A.
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R.; Anderson, R. L. J. Org. Chem. 1976, 41, 381. For metal
salt catalyzed procedures, see: (d) Lepore, S. D.; Bhunia, A.
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