Reactivity of γ-chloro-gem-trichloroalkanes with chromous chloride

Article abstract of DOI:10.1016/j.tetlet.2006.05.045

CrCl₂-mediated condensation of γ-chloro-gem-trichloroalkanes with aldehyde generates homoallylic alcohols through a hydride rearrangement followed by a Nozaki-Hiyama allylation.

Full text of DOI:10.1016/j.tetlet.2006.05.045

Tetrahedron Letters 47 (2006) 5177–5180
Reactivity of c-chloro-gem-trichloroalkanes with chromous chloride
a
a
a
b
b,
*
´
Steve Tisserand, Romain Bejot, Celia Billaud, De Run Li, J. R. Falck and
Charles Mioskowskia,*
a
`
´ ´
Laboratoire de Synthese Bio-Organique, UMR 7175-LC1, Faculte de Pharmacie, Universite Louis Pasteur de Strasbourg,
74 Route du Rhin, BP 24, 67401 Illkirch, France
bDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA
Received 14 March 2006; revised 19 April 2006; accepted 9 May 2006
Available online 5 June 2006
Abstract—CrCl2-mediated condensation of c-chloro-gem-trichloroalkanes with aldehyde generates homoallylic alcohols through a
hydride rearrangement followed by a Nozaki–Hiyama allylation.
Ó 2006 Elsevier Ltd. All rights reserved.
Organochromium reagents have emerged as versatile
synthetic intermediates due in large part to their unique
stereo-, regio- and chemo-selectivities. In the Hiyama–
Nozaki allylation, allylchromium(III) reagents, most
commonly made from allylic halides utilizing CrCl2,
have proven useful for the preparation of homoallylic
alcohols under mild conditions.1 On the other hand,
the initial dichlorochromium(III) carbenoid generated
from gem-trichlorides often undergoes further metalla-
tion to a chlorodichromium(III) species, which has
found considerable synthetic utility.2 As part of our
continuing investigation of organochromium methodol-
ogy, we report herein the preparation of homoallylic
alcohols from c-chloro-gem-trichloroalkanes with
chromous chloride in THF. The intramolecular rear-
rangement of chromium(III) c-chloro-alkylidene inter-
mediates was evidenced by isotopic labelling.
c-Halo-gem-trihaloalkanes are easily synthesized via
Kharasch addition of polyhaloalkanes to alkenes, cata-
lyzed by various metals.3 1-Chloro-2-trichloromethyl-
cyclohexane 2a was prepared from cyclohexene 1a and
tetrachloromethane in the presence of Fe(0) in 53% yield
as a mixture (2:1) of anti/syn isomers (Scheme 1).4 Puri-
fication by reversed-phase chromatography affords pure
anti-2a. 5-Chloro-6-trichloromethyldecane 2b was syn-
thesized under the same conditions in 48% yield as a
mixture (2:1) of anti/syn isomers.
The reaction of 1-chloro-2-trichloromethyl-cyclohexane
2a with chromous chloride in the presence of p-tolualde-
hyde 3 gives (E-2-chloromethylene-cyclohexyl)-p-tolyl-
methanol 4a as a mixture of diastereoisomers (70:30)
in 60% yield and 2-chloro-2-cyclohex-1-enyl-1-p-tolyl-
ethanol 5a in 3% yield (Scheme 1).5,6 Purification by
OH
Cl
RCHO
CrCl2, THF
CCl3
OH
Cl
CCl4, Fe0
R
Cl
R1
+
R1
R1
R
25˚C, 10 h
DMF, 80 ºC
R2
R1
R2
(53 %, anti/syn = 2:1)
2b (48 %, anti/syn = 2:1)
R2
R2
(3 %)
1a
R1, R2 = -(CH2)4-
2a
4a
5a
(R = Tol, 60 %, anti/syn = 70:30)
4b (R = i-Pr, 43 %, dr = 60:40)
5b (< 2 %)
4c (R = Tol, 54 %, ratio = 45:30:25) 5c (< 2 %)
1b R1 = R2 = n-Bu
Scheme 1. CrCl2-mediated condensation of c-chloro-gem-trichloroalkanes with aldehydes.
Keywords: Carbene; Chromium; Nozaki–Hiyama allylation; Trichloroalkane.
*
Corresponding authors. E-mail addresses: j.falck@utsouthwestern.edu; mioskow@aspirine.u-strasbg.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.045

5178
S. Tisserand et al. / Tetrahedron Letters 47 (2006) 5177–5180
Cl
Cl
Cl
Cl
Cl
Cl
H
Cl
CrCl2
H
H
R1
R
CCl3
Cl
R1
R
R1
R
R1
R
α-elimination
1,2 hydride shift
2 CrCl2
2 CrCl2
H
CrCl3
2 H
2
2 H
2 H
2 H
6
8
7
Cl
Cl
H
γ
R1
OH
R1
R
3
H
Cl
β
CrCl2
CrCl2
H
α
R
R1
R2
H
CrCl2
2 H
5
9a
R
2 H
Cl
Cl
H
Cl
R1
R2
Cl
2 CrCl2
R1
R
Cl
H
CrCl2
H
OH
β
R1
R2
lit.19
3
α
2 H
γ
H
R
4
9b
10
Scheme 2. Proposed mechanism for the reaction of c-chloro-trichloroalkanes with chromous chloride.
n-Bu OH
silica gel chromatography afforded the isolated major
diastereoisomer 4a in 30% yield, which was character-
ized as the anti and E isomer by X-ray crystallography.7
The minor isomer 4a could not be isolated and crystal-
lized, but its E stereochemistry was determined by a
D
CCl3
n-Bu
CrCl2, THF
Cl
3
+
n-Bu
25 °C,10 h
D
D
n-Bu
Cl
D
2b-d2
4c-d2
1
2D H NOE NMR. Interestingly, the reaction of pure
Scheme 3. CrCl2-mediated condensation of isotopic labelled c-chloro-
gem-trichloroalkanes with an aldehyde.
anti-2a or a mixture (2:1) of anti/syn-2a isomers provides
the same ratio of 4a diastereomers (70:30). Under the
same conditions, with isobutyraldehyde 30, 1-chloro-2-
trichloromethyl-cyclohexane 2a gives a mixture of 4b
diastereomer (60:40) in 43% yield.8 5-Chloro-6-trichloro-
methyl-decane 2b in the presence of p-tolualdehyde 3
gives homoallylic alcohols 4c in 54% yield as a mixture
(45:30:25) of stereoisomers.9
as the g1 or g3 structure is not clear, it is likely to be g1
at least in the transition state of the reaction with carbonyl
compound. Allylic metal compounds normally react with
carbonyl compounds at the c position of the allyl metal
unit (9a ! 5 and 9b ! 4).17 The results suggest that the
alkyl substituents favour the metal at a-position of
chlorine to give 9b, which affords the major coupling
adduct 4. Because of the steric interaction between
ligands on chromium and the substituents on the allyl
fragment, the equilibrium lies towards the allylic
chromium species with less steric crowding of the
carbon–chromium bond.18 As equilibration between
two isomeric allylic metal compounds can occur, the
allylchromium(III) reagents 9 may also be obtained from
3,3-dichloropropene derivatives 10.19
Mechanistically, the formation of 4 and 5 probably pro-
ceeds initially through addition of chromium(II) into a
C–Cl bond (Scheme 2). Formally, the oxidative addition
of Cr(II) involves two consecutive single-electron trans-
fers, thus accounting for 2 equiv of CrCl2 needed for the
reduction of one C–Cl bond.10 Next, the coordination of
the c chlorine atom to the metal most likely induces
rehybridization of the dichlorocarbenoid species 6, thus
precluding oxidative addition of CrCl2 into a second
gem-C–Cl bond.2b,11 By placing a positive charge in a
p orbital, the organochromium produces a tight ion
pair, and the formation of a carbene complex 7 is postu-
lated.12,13 An intramolecular rearrangement involving a
1,2-migration of hydride then gives the allylic chloride
intermediate 8. The hydride migration was demon-
strated by reacting 5-chloro-6-trichloro-5,6-d2-methyl-
decane 2b-d2 under the standard conditions.14 Using p-
tolualdehyde and CrCl2, the coupling adduct 4c-d2 was
obtained (Scheme 3).15
In summary, c-chloro-gem-trichloroalkanes are precur-
sors of a,c-dichloroallyls and give homoallylic alcohols
after further Nozaki–Hiyama reaction. Interestingly,
final coupling adducts are obtained through two
organochromium intermediates, a dichloro-chromium(III)
alkane carbenoid and an allylchromium(III) species,
showing a different pattern of transformation owing to
the halide at the b position of the trichloromethyl group.
Allylic halides in the presence of CrCl2are known to give
coupling adducts with aldehydes.1 Compound 8 reacts
with chromium(II) to give the allylchromium(III)
reagents 9 and in the presence of an aldehyde, 9 adds to
the carbonyl group to furnish homoallylic alcohols 4
and 5.16 Whether allylchromium(III) species 9a(b) exists
Acknowledgements
This work was supported by the CNRS and the Institut
de Recherche Pierre Fabre (S.T.), the Ministere delegue
`
´ ´
´
`
´
`
a l’Enseignement superieur et a la Recherche (R.B.), the
Robert A. Welch Foundation and the NIH (GM31278).

S. Tisserand et al. / Tetrahedron Letters 47 (2006) 5177–5180
5179
column chromatography (n-hexane/Et2O = 95:5) afforded
4 and 5. Analytical data for anti-(E)-4a: 1H NMR
(300 MHz, CDCl3) d 7.26 (d, 2H, 3J = 8.1 Hz), 7.20 (d,
We thank Dr. B. Rousseau and the CEA for hydrogena-
tion of 5-decyne with D2, C. Antheaume and Dr. A. De
Cian for NMR and X-ray spectroscopy.
3
4
2H, J = 8.1 Hz), 6.10 (d, 1H, J = 1.5 Hz), 4.75 (d, 1H,
3J = 10.3 Hz), 2.80 (dt, 1H, 3J = 4.0 Hz, 2J = 14.1 Hz),
2.44 (dt, 1H, 3J = 4.0 Hz), 2.38 (s, 3H), 2.17 (ddt, 1H,
3J = 4.8 Hz, 4J = 1.5 Hz), 1.86 (dquin, 1H, 3J1 =
3J2 = 4,0 Hz, 2J = 12.8 Hz), 1.64–1.56 (m, 1H), 1.49
(dquin, 1H, 3J1 = 3J2 = 4.0 Hz, 2J = 13.4 Hz), 1.41 (dquin,
References and notes
1. (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am.
Chem. Soc. 1977, 99, 3179–3181; (b) Hiyama, T.; Okude,
Y.; Kimura, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1982,
55, 561–568; (c) Cintas, P. Synthesis 1992, 248–257; (d)
Wessjohann, L. A.; Scheid, G. Synthesis 1999, 1–36; (e)
Baati, R.; Gouverneur, V.; Mioskowski, C. J. Org. Chem.
2000, 65, 1235–1238; (f) Semmelhack, M. F. In Organo-
metallics in Synthesis: A Manual; 2nd ed.; Schlosser,
Manfred, Ed., John Wiley & Sons, 2004; (g) Lee, J. Y.;
Miller, J. J.; Hamilton, S. S.; Sigman, M. S. Org. Lett.
2005, 7, 1837–1839.
2. (a) Falck, J. R.; Barma, D. K.; Mioskowski, C.; Schlama,
T. Tetrahedron Lett. 1999, 40, 2091–2094; (b) Baati, R.;
Barma, D. K.; Falck, J. R.; Mioskowski, C. J. Am. Chem.
Soc. 2001, 123, 9196–9197; (c) Barma, D. K.; Baati, R.;
Valleix, A.; Mioskowski, C.; Falck, J. R. Org. Lett. 2001,
3, 4237–4238; (d) Bejot, R.; Tisserand, S.; Reddy, L. M.;
Barma, D. K.; Baati, R.; Falck, J. R.; Mioskowski, C.
Angew. Chem., Int. Ed. 2005, 44, 2008–2011.
1H, J1 = 3J2 = 4.0 Hz, J = 12.8 Hz), 1.37–1.27 ppm (m,
2H); 13C (50 Hz, CDCl3), d 142.3, 139.6, 138.1, 129.7,
127.2, 112.3, 73.2, 51.3, 29.6, 27.0, 25.9, 22.6, 21.7 ppm; IR
m 3442, 2928, 2857, 1743, 1703, 1685, 1607, 1514, 1449,
1296, 1175, 1041, 890, 820, 803, 561, 509 cmꢀ1; MS (TOF)
m/z 273 ([M+Na]+). Analytical data for syn-(E)-4a: 1H
NMR (300 MHz, CDCl3) d 7.33 (d, 2H, 3J = 8.1 Hz), 7.21
(d, 2H, 3J = 8.1 Hz), 6.12 (d, 1H, 4J = 1.3 Hz), 4.81 (d,
3
2
3
1H, J = 10.3 Hz), 3.38–3.30 (m, 1H), 2.49–2.30 (m, 4H),
2.30–1.80 (m, 2H), 1.70–0.95 ppm (m, 5H). Analytical
1
data for 5a: H NMR (300 MHz, CDCl3) d 5.95 (s, 1H),
3
4
3
5.56 (dd, 1H, J = 7.8 Hz, J = 4.0 Hz), 4.50 (d, 1H, J =
7.8 Hz), 2.78 ppm (m, 1H); 3C (50 Hz, CDCl3), d 142.8,
140.4, 138.5, 129.6, 127.4, 113.3, 74.1, 44.7, 30.4, 27.4,
27.1, 23.5, 21.6 ppm.
7. Crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 295551. Copies of the
data can be obtained free of charge, on applicationto
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
8. Compound 4b was obtained as a mixture (60:40) of
diastereomers. Analytical data for 4b: major isomer: 1H
NMR (200 MHz, CDCl3) d 5.94 (d, 1H, 4J = 1.5 Hz), 3.68
(dd, 1H, 3J = 9.8 Hz, 3J = 2.2 Hz), 2.79–2.75 (m, 1H),
2.72–2.68 (m, 1H), 2.27–2.21 (m, 1H), 2.12–1.25 (m, 7H),
3. Kharasch, M. S.; Jensen, E. V.; Urry, W. H. J. Am. Chem.
Soc. 1947, 69, 1100–1105.
4. Bellesia, F.; Forti, L.; Ghelfi, F.; Pagnoni, U. M. Synth.
Commun. 1997, 27, 961–971, General procedure for the
preparation of c-halo-trihaloalkanes 2a and 2b: alkene
(22 mmol), iron powder (1.2 g, 44 mmol) and tetrachloro-
methane (18 mL, 176 mmol) in anhydrous DMF (5 mL)
were carefully warmed to 90 °C in a 250 mL round bottom
flask, fitted with a condenser (CAUTION: very exother-
mic reaction). After the reaction started violently, the dark
reaction mixture was stirred at 80 °C for 2 h. The reaction
was quenched with 5% HCl at rt and extracted with n-
hexane. The combined organic extracts were washed with
brine, dried over MgSO4 and concentrated in vacuo.
Purification of the crude product by reversed-phase
chromatography (H2O/EtOH = 2:8) afforded 2a and 2b
as a mixture (2:1) of anti/syn isomers. Analytical data for
2b: 1H NMR (300 MHz, CDCl3) d 4.75–4.60 (m, 1H),
3.08–2.90 (m, 1Hanti), 2.59–2.53 (m, 1Hsyn), 2.3–1.2 (m,
12H), 0.96 ppm (t, J = 7 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 104.1 (Csyn), 103.1 (Canti), 65.4 (Canti), 63.3
(Csyn), 62.6 (Canti), 62.3 (Csyn), 39.0 (Csyn), 32.7 (Canti), 32.2
(Csyn), 31.9 (Canti), 29.4 (Canti), 29.1 (Csyn), 28.5 (Csyn), 27.5
(Canti), 22.9, 22.0, 14.0, 13.8 ppm; MS (CI, NH3) m/z 295
([M+H]+), 312 ([M+NH4]+).
3
3
1.05 (d, 3H, J = 6.6 Hz), 0.85 ppm (d, 3H, J = 6.6 Hz);
13C (50 Hz, CDCl3) d 142.5, 111.4, 72.9, 46.8, 29.0, 28.9,
1
26.7, 25.6, 22.2, 20.9, 13.7 ppm; minor isomer: H NMR
(200 MHz, CDCl3) d 6.00 (s, 1H), 3.74 (dd, 1H, 3J =
10.5 Hz, 3J = 2.0 Hz), 3.13–3.06 (m, 1H), 2.24–1.33
(m, 9H), 1.07 (d, 3H, 3J = 6.8 Hz), 0.92 ppm (d, 3H,
3J = 6.8 Hz).
9. Compound 4c was obtained as a mixture (a/b/c =
45:30:25) of stereoisomers. Configuration of stereoisomers
could not be determined. Analytical data for 4c: 1H NMR
(300 MHz, CDCl3) d 7.5–7.2 (m, 4H, ArH), 6.12 (s, 1H,
C@CCClHc), 5.99 (s, 1H, C@CClHa), 5.79 (s, 1H,
C@CCClHb), 4.61 (d, J = 5.6 Hz, 1H, CHOHb), 4.47 (d,
J = 8.6 Hz, 1H, CHOHa and c), 3.3 (m, 1H, CH–CHOHc),
2.4–2.0 (m, 1H, CH–CHOHa and b), 2.34 (s, 3H, ArCH3),
2.0–0.7 ppm (m, 22H, CH3–(CH2)4); 13C (50 Hz, CDCl3),
d 142.83, 142.80, 141.8, 140.1, 139.9, 139.5, 137.6, 137.5,
137.0, 129.1, 129.0, 128.8, 127.0, 126.8, 126.1, 125.5,
5. CrCl2 prepared from CrCl3 via reduction with Mn0
powder. General procedure for the preparation of CrCl2:
anhydrous CrCl3 (481 mg, 3.0 mmol) and Mn0 (109 mg,
2.0 mmol) in anhydrous MeCN (4 mL) were stirred at rt
for 0.5 h under an argon atmosphere and ultrasound
irradiation. The grey and viscous reaction mixture was
then concentrated in vacuo and CrCl2 as a grey powder
was used for further reaction.
6. General procedure for the preparation of homoallylic
alcohols 4 and 5: to a suspension of CrCl2 (prepared from
CrCl3, 3.0 mmol) in anhydrous THF, was added
p-tolualdehyde (120 mL, 1.0 mmol) and 2 (0.5 mmol),
under argon atmosphere at rt. After 10 h stirring at rt, the
reaction mixture was quenched with 5% HCl and extracted
with Et2O. The ethereal extract was washed with brine,
dried over MgSO4, filtered through a small pad of
FlorisilÒ and concentrated in vacuo. Purification by
116.4c, 116.2a, 115.8b, 75.93, 75.87, 75.7, 54.5a or b
,
52.8a or b, 48.4c, 31.9, 31.1, 30.3, 29.7, 29.5, 29.34, 29.25,
29.17, 29.1, 28.9, 28.3, 27.5, 23.3, 22.9, 22.84, 22.81, 22.54,
22.45, 21.15, 21.08, 14.1, 14.0, 13.9, 13.7 ppm; MS (TOF)
m/z 331 ([M+Na]+).
10. (a) Kochi, J. K.; Davis, D. D. J. Am. Chem. Soc. 1964, 86,
5264–5271; (b) Kochi, J. K.; Singleton, D. M. J. Am.
Chem. Soc. 1968, 90, 1582–1589; (c) Furstner, A. Chem.
Rev. 1999, 99, 991–1045.
11. Alternatively the rehybridization may occur because the
adjacent carbon is disubstituted and therefore more
crowded than a simple methylene.
12. (a) Walborsky, H. M.; Duraisamy, M. J. Am. Chem.
Soc. 1984, 106, 5035–5037; (b) Walborsky, H. M.;
Rachon, J.; Goedken, V. J. Am. Chem. Soc. 1986, 108,
7435–7436.

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S. Tisserand et al. / Tetrahedron Letters 47 (2006) 5177–5180
13. For an example of a rehybridization induced by the
coordination of a b oxygen atom to the metal, and the
formation of a Fischer carbene complex, see Ref. 2d.
14. Procedure for the preparation of 5-chloro-6-trichloro-5,6-
d2-methyl-decane 2b-d2: a solution of 5-decyne (5 mL,
28 mmol), Lindlar catalyst (Pd/CaCO3/PbOAc) (148 mg)
and quinoline (1 mL, 8.4 mmol) in Et2O was stirred for
1.5 h at rt under a D2 atmosphere (1 bar). The reaction
mixture was then filtered over CeliteÒ. The ethereal
filtrate was dried over MgSO4 and concentrated in vacuo.
Purification by column chromatography (n-hexane) affor-
ded 5,6-d2-dec-5-ene in 81% yield. Analytical data for 5,6-
15. 2-Butyl-2-d1-3-chloro-d1-methylene-1-p-tolyl-heptan-1-ol
4c-d2 was prepared according to the procedure of Ref. 6.
Analytical data for 4c-d2: 1H NMR (300 MHz, CDCl3) d d
7.5–7.2 (m, 4H, ArH), 4.64 (br s, 1H, CHOHc), 4.50 (br s,
1H, CHOHa/b), 2.34 (s, 3H, ArCH3), 2.0–0.7 ppm (m,
22H, CH3–(CH2)4); 13C NMR (50 MHz, CDCl3) d 142.8,
142.7, 141.8, 140.3, 140.1, 139.7, 137.7, 137.6, 137.1, 129.2,
129.1, 129.0, 127.2, 127.0, 126.3, 125.6, 115.7 (t,
J = 30 Hz), 76.00, 75.95, 75.8, 54.0 (t, J = 19 Hz), 52.4
(t, J = 20 Hz), 48.0 (t, J = 20 Hz), 32.1, 31.2, 30.4, 30.04,
30.02, 29.8, 29.6, 29.5, 29.4, 29.24, 29.20, 29.0, 28.3, 27.6,
23.5, 23.04, 22.98, 22.96, 22.8, 22.7, 22.6, 21.29, 21.27,
21.2, 14.0, 13.9, 13.8; MS (TOF) m/z 333 ([M+Na]+).
16. Mulzer, J.; Strecker, A. R.; Kattner, L. Tetrahedron Lett.
2004, 45, 8867–8870.
1
d2-dec-5-ene: H NMR (300 MHz, CDCl3) d 2.1–1.9 (m,
4H), 1.4–1.2 (m, 8H), 1.0–0.8 ppm (m, 6H). 5-chloro-6-
trichloro-5,6-d2-methyl-decane 2b-d2 was then prepared
according to the general procedure of Ref. 4. Analytical
data for 2b-d2: 1H NMR (300 MHz, CDCl3) d 2.3–1.3 (m,
12H), 0.90–0.99 ppm (m, 6H); 13C NMR (50 MHz,
17. Via a Zimmerman–Traxler 6-membered transition state;
see: Takai, K. In Organic Reactions; Overman, L. E., Ed.;
John Wiley & Sons, 2004; Vol. 64, pp 253–612.
CDCl3)
d
103.0, 64.8 (t, J = 20 Hz), 62.3 (t, J =
18. Takai, K.; Nitta, K.; Utimoto, K. Tetrahedron Lett. 1988,
29, 5263–5266.
19. Takai, K.; Kataoka, Y.; Utimoto, K. Tetrahedron Lett.
1989, 30, 4389–4392.
22.5 Hz), 32.6, 31.9, 29.3, 27.4, 22.9, 22.0,14.0,
13.8 ppm; MS (CI, NH3) m/z 297 ([M+H]+), 314
([M+NH4]+).