Stereoselective transformations of trihalomethylcarbinols induced by chromous chloride

Article abstract of DOI:10.1002/anie.200461884

(Chemical Equation Presented) Reduction of trihalomethylcarbinols 1 with CrCl₂ affords good to excellent yields of (Z)-α-haloenol esters 2 and (Z)-β-haloenol ethers 3 through acyl or hydrogen migration, respectively. The reaction is proposed to

Full text of DOI:10.1002/anie.200461884

Communications
Organometallic Chemistry
Stereoselective Transformations of
Trihalomethylcarbinols Induced by Chromous
Chloride**
Romain Bejot, Steve Tisserand, L. Manmohan Reddy,
Deb K. Barma, Rachid Baati, J. R. Falck,* and
Charles Mioskowski*
Organochromium reagents are gaining greater prominence in
organic synthesis owing to their unique reactivities, high
stereoselectivities, compatibility with numerous functional
groups, and the recent introduction of regeneration systems
that only require catalytic chromium.[1–3] As part of our
continuing investigations into novel organochromium meth-
odology, we discovered that trihalomethylcarbinol esters and
ethers 1 undergo efficient, stereoselective intramolecular
rearrangements induced by chromous chloride in THF. The
resultant products, (Z)-a-haloenol esters 2 and (Z)-b-halo-
enol ethers 3, respectively, are potentially useful, yet highly
elusive synthetic intermediates (Scheme 1).[4] Esters 2 are
new, stable acyl halide enolate equivalents. They have only
been mentioned briefly in the literature as minor by-products
and their synthetic utility remains to be explored.[5] To help
Scheme 1. Reactivity of trihalomethylcarbinols esters and ethers with
CrCl2.
[*] Dr. L. M. Reddy, Dr. D. K. Barma, Prof. J. R. Falck
Department of Biochemistry
University of Texas Southwestern Medical Center
5323 Harry Hines Blvd., Dallas, TX 75235-9038 (USA)
Fax: (+ )214-648-6455
E-mail: j.falck@utsouthwestern.edu
R. Bejot, Dr. S. Tisserand, Dr. R. Baati, Dr. C. Mioskowski
Laboratoire de Synthꢀse Bioorganique, UMR 7514
Facultꢁ de Pharmacie
Universitꢁ Louis Pasteur
74 Route du Rhin, BP 24, 67401 Illkirch (France)
Fax: (+33)3-9024-4306
E-mail: mioskow@aspirine.u-strasbg.fr
[**] This work was supported by the Ministꢀre de la Jeunesse, de
l’Education Nationale et de la Recherche (to R. Bejot), the CNRS,
the Institut de Recherche Pierre Fabre (S.T.), the Robert A. Welch
Foundation, and the NIH (GM31278). We thank Euriso-Top SA for
18O2-labeled sodium acetate, Dr. T. G. LaCour for suggesting the
dyotropic rearrangement, and C. Antheaume and A. Valleix for NMR
spectroscopy and mass spectrometry measurements.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2008 ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200461884
Angew. Chem. Int. Ed. 2005, 44, 2008 –2011

Angewandte
Chemie
Table 1: Conversion of trihalomethylcarbinol esters into (Z)-a-haloenol esters.
expedite access to these highly functional-
ized olefins and to better understand their
formation, we report herein the results of
treating a series of representative trihalo-
methylcarbinol esters and ethers with CrCl2
as well as insights from mechanistic studies.
When trihalomethylcarbinol ester 1a
was stirred with commercial CrCl2
(3 equiv) for 3 h with heating at reflux in
THF under an argon atmosphere, a-halo-
enol ester 2a was obtained as the principal
product in 76% yield (Table 1, entry 1).
Applying Fꢀrstnerꢁs catalytic system, which
utilizes Mn0 powder to recycle chromium-
(iii) to chromium(ii), also gave rise to 2a,
though in lower but acceptable yield
(entry 2).[6] The scope of the reaction was
explored by using various esters: cinnamate
(entry 3), benzoate (entry 4), and acetate
(entry 5); all of these primarily undergo 1,2-
migration of the acyloxy group. Likewise,
trichloromethylcarbinol and dibromofluoro-
methylcarbinol esters derived from ali-
phatic aldehydes (entries 6, 8, and 11), aryl
aldehydes (entries 5 and 10), a cyclic ketone
(entry 7), and (formally) formaldehyde
(entry 9) behaved analogously to furnish
good to excellent yields of (Z)-a-haloenol
esters. In contrast, dichloromethyl- and
dichlorofluoromethylcarbinols are refrac-
tory under the standard conditions
(entries 12 and 14). Addition of TMEDA
(N,N,N’,N’-tetramethylethylenediamine) as
donor ligand, which enhances the reduction
power of chromium(ii), did not improve this
result (entry 13). On the other hand, tribro-
momethylcarbinols, which are more reac-
tive toward chromous chloride, only fur-
nished complex mixtures of products; for
example, 2,2,2-tribromoethyl benzoate gave
a mixture of 1-bromoethyl benzoate, 1-
chloroethyl benzoate, 2,2-dibromoethyl
benzoate, and several unidentified com-
pounds.[7]
Entry
Trihalomethyl
Product(s)
Yield [%][a]
carbinol ester 1
1
76
7[b]
2[c]
1a
2a
3a
1k
53
5
2[b]
85
3
4[b]
84
4
5
(Z/E=78:22)
75
(Z/E=87:13)
80
6
7
(Z/E>99:1)[d]
82
84
8
(Z/E>99:1)[d]
9
80[e]
98
10
11
(Z/E>99:1)[d]
98
(Z/E>99:1)[d]
12
[f]
[f]
[f]
0
0
0
13[g]
14
1k
The data in Table 1 also indicate that the
carbinol substitution pattern influences the
stereoselectivity of the rearrangement. For
instance, the hydrocinnamyl adducts 1e,g,
and j, and dibromofluoromethylcarbinol
derivative 1i afforded exclusively the
Z isomers 2e,g, and j, and 2i, respectively,
whereas the p-tolyl-trichloromethylcarbi-
nols 1c and d yielded 2c and d as mixtures
of Z and E isomers.[8]
[a] Yields for isolated materials after purification by column chromatography, unless otherwise stated.
[b] Yields calculated from 1H NMR spectrum of isolated mixture of 2 and 3. [c] Reaction was conducted
using catalytic chromium and excess Mn0 powder. [d] Only one isomer was detected by 1H NMR and/or
GC analysis of crude material. [e] Crude purity greater than 97%; volatile compound not purified by
column chromatography. [f] Starting material was recovered in 100% yield. [g] Two equivalents of
TMEDA added. Bz=benzoyl, Ac=acetyl, TBDPS=tert-butyldiphenylsilyl.
The isolation in some cases of minor amounts of (Z)-b-
haloenol ester, such as 3a,b, is consistent with the expectation
that acyloxy groups have a significantly better migratory
aptitude relative to hydrogen. This also prompted an exami-
nation of the reactivity of trichloromethylcarbinol ethers.[9]
As anticipated, when treated with commercial CrCl2 under
the standard conditions these ethers exclusively formed (Z)-
b-chlorovinyl ethers 3 in good yields and with good stereo-
selectivities (Table 2, entries 1–5).[10]
Angew. Chem. Int. Ed. 2005, 44, 2008 –2011
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2009

Communications
Table 2: Conversion of trichloromethylcarbinol ethers into (Z)-b-chloro-
enol ethers.
reactivity of trihalomethylcarbinol esters with chromium(ii)
is a result of coordination of the b oxygen atom to the metal
which induces rehybridization of the organochromium spe-
Entry
Trichloromethyl ether 1
Product
Yield [%][a]
cies 4, thus precluding oxidative addition of CrCl2 into a
[14]
À
second C X bond.
1
89
The observed Z stereochemistry of products 2c–e,g,i, and
j may be rationalized if one takes into account the possible
2
3
4
77
76
75
conformations of the postulated Fischer carbene
5
(Scheme 3).[15] Of both possible conformations of the
5
75
[a] Yields for isolated materials after purification by column chromatog-
raphy. Bn=benzyl, TBDMS=tert-butyldimethylsilyl.
Mechanistically, the formation of 2 from 1 probably
proceeds initially through oxidative addition of chromium
À
into a C X (X = Cl, Br) bond through two consecutive single-
electron transfers (Scheme 2).[11] Next, the dichlorocarbenoid
Scheme 3. Stereochemical model for the migration.
chromium(iii) carbene complex, conformer 5a is much more
favored than 5b because of steric interactions between
hexacoordinated chromium and the large group L (R2).
Secondary steric repulsion between L and the halogen atom
in 5a might be responsible for the formation of minor
amounts of the E stereoisomer. Interestingly, when the latter
steric interaction is decreased by using less-bulky substituents
such as cinnamyl (versus p-tolyl) or fluoride (versus chloride),
the reaction provides exclusively and stereospecifically the
Z isomers in good isolated yields (Table 1, entries 6, 8, 10, and
11).
Scheme 2. Proposed mechanism for the rearrangement of
trichloromethylcarbinol esters and ethers.
The 1,2-migration of hydride in chlorocarbene
5
(Scheme 2) rationalizes the origin of the ethers in Table 2.
A pathway proceeding through the b-oxy-vinylidene carbe-
noid 6 is disproved.[16] Quenching with D2O the reduction of
1m by CrCl2 did not lead to 2-chloro-2-d-vinyloxybenzyl: 3m
was obtained instead.[16,17] Moreover, the deuterated com-
pound 2,2,2-trichloro-1,1-d2-ethoxybenzyl 1n gives exclu-
sively (Z)-2-chloro-1,2-d2-vinyloxybenzyl 3n, consistent with
a 1,2-migration of a deuterium atom (Table 2, entry 2). As
above, the Z stereochemistry of ethers 3 can be rationalized if
the possible conformations of the proposed Fischer carbene
are taken into account (Scheme 3).
4 species undergoes an a elimination of CrCl2X through
metal-assisted ionization[12] to give the proposed carbene 5.
Then, intramolecular nucleophilic rearrangement involving
the nonbonded (n) electrons of the carbonyl group converts
this highly reactive intermediate into ester 2. This suprafacial
rearrangement is most likely a concerted 2,3-shift mechanism
through a five-center cyclic transition state: CrCl2 reduction
of 18O-labeled substrate 1r indicates a complete exchange of
the carbonyl and carboxyl oxygens [Eq. (1)]. This trans-
This intriguing new reactivity, observed for carboxylic
esters and ethers of trihalomethylcarbinols, led us finally to
study sulfonic and phosphoric esters. Unfortunately, no
rearrangement was observed. Fragmentation occured prefer-
entially to lead to 1,1-dichloroalkenes.[18]
In conclusion, we have demonstrated that (Z)-a-haloenol
esters 2 and (Z)-b-haloenol ethers 3 can be efficiently
obtained from trihalomethylcarbinol esters and ethers,
respectively, with chromous chloride in THF. A mechanism
has been proposed which accounts for both the nature of the
formation is comparable to the Surzur–Tanner rearrange-
ment, which involves intramolecular 1,2-suprafacial migra-
tion of the acyloxy group of b-acyloxyalkyl halides under
radical conditions.[4,13] We postulate that this particular
2010
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2005, 44, 2008 –2011

Angewandte
Chemie
[9] The reduction of 2 with CrCl2 in aqueous media was reported by
observed products and their preferred Z stereochemistry.
This contribution to organochromium chemistry affords new
insight into b-oxy-alkylidene carbenoids and chlorochro-
mium(iii)–carbene complexes as proposed key intermediates.
Finally, we also established a reactivity scale of gem-poly-
halide compounds with chromous chloride: CBr3 > CCl3 and
CBr2F @ CCl2F and CCl2H (not reactive). Further extensions
are underway in our laboratory, including the use of (Z)-a-
haloenol esters 2 as unique ketene precursors.
Steckhan and gave (Z)-chloroalkenes: R. Wolf, E. Steckhan, J.
Chem. Soc. Perkin Trans. 1 1986, 733.
[10] The Z stereochemistry of 3m,p, and q was determined by 2D 1H
nOe NMR spectroscopy.
[11] a) J. K. Kochi, D. D. Davis, J. Am. Chem. Soc. 1964, 86, 5264;
b) J. K. Kochi, D. M. Singleton, J. Am. Chem. Soc. 1968, 90, 1582;
c) J. Mulzer, A. R. Strecker, L. Kattner, Tetrahedron Lett. 2004,
45, 8867.
[12] The organochromium species undergo a rehybridization by
placing a positive charge in a p orbital to produce a tight ion pair:
a) H. M. Walborsky, M. Duraisamy, J. Am. Chem. Soc. 1984, 106,
5035; b) H. M. Walborsky, J. Rachon, V. Goedken, J. Am. Chem.
Soc. 1986, 108, 7435.
Experimental Section
CrCl2 was purchased from Strem. Tetrahydrofuran (THF) was
distilled from Na/benzophenone ketyl before use.
[13] For a review on this and related reactions, see: A. L. J. Beckwith,
D. Crich, P. J. Duggan, Q. Yao, Chem. Rev. 1997, 97, 3273.
[14] Another possible mechanism would proceed through a dyo-
General Procedure: Compound 1 (0.39 mmol)[19] in THF (2 mL)
was added to a stirring suspension of chromium(ii) chloride (145 mg,
1.17 mmol) in anhydrous THF (3 mL) at RT under argon. The
mixture was heated at reflux for 3 h, cooled to RT, quenched with 5%
HCl, and diluted with Et2O. The layers were separated, and the
aqueous phase was extracted twice with Et2O. The combined organic
extracts were washed twice with brine, dried over MgSO4, and filtered
over Florisil. Alternatively, the reaction mixture can be diluted with
Et2O and filtered through a small pad of SiO2. After concentration of
the organic extract under vacuum, the crude product was purified by
chromatography on silica gel to give 2 and/or 3.
À
tropic rearrangement, that is to say a process in which C Cl and
1
À
C OR s bonds of the dichlorocarbenoid species simultaneously
migrate intramolecularly, followed by a b elimination of CrCl2X.
However, this mechanism is unlikely as the formation of 2 f
(Table 1, entry 7) would require rearrangement to a quaternary
center. For a review of the dyotropic rearrangement, see: M. T.
Reetz, Tetrahedron 1973, 29, 2189.
[15] For an example of a postulated chromium(iii)–carbene complex,
see: M. H. Voges, C. Romming, M. Tilset, Organometallics 1999,
18, 529.
[16] R. Baati, D. K. Barma, J. R. Falck, C. Mioskowski, J. Am. Chem.
Soc. 2001, 123, 9196.
Received: September 3, 2004
Revised: November 26, 2004
Published online: February 23, 2005
[17] The non-incorporation of a deuterium atom could be explained
by the internal proton return phenomenon, that is, the delivery
of a proton from coordinated water triggered by the addition of
D2O. See: a) P. L. Creger, J. Am. Chem. Soc. 1970, 92, 1396; b) D.
Seebach, M. Boes, R. Naef, W. B. Schweizer, J. Am. Chem. Soc.
1983, 105, 5390.
[18] The fragmentation of b-sulfonate- and b-phosphate-substituted
alkyl radicals is known to compete with the Surzur–Tanner
rearrangement. See ref. [13].
[19] The starting 2-alkoxy-substituted 1,1,1-trihaloalkanes were pre-
pared according to: a) E. J. Corey, J. O. Link, Y. Shao, Tetrahe-
dron Lett. 1992, 33, 3435; b) J. Russell, N. Roques, Tetrahedron
1998, 54, 13771; c) M. Shimizu, N. Yamada, Y. Takebe, T. Hata,
M. Kuroboshi, T. Tamejiro Hiyama, Bull. Chem. Soc. Jpn. 1998,
71, 2903.
Keywords: carbenes · chromium · isotopic labeling ·
.
rearrangement · synthetic methods
[1] a) J. R. Falck, D. K. Barma, R. Baati, C. Mioskowski, Angew.
Chem. 2001, 113, 1321; Angew. Chem. Int. Ed. 2001, 40, 1281;
b) D. K. Barma, A. Kundu, H. M. Zhang, C. Mioskowski, J. R.
Falck, J. Am. Chem. Soc. 2003, 125, 3218.
[2] a) A. Fꢀrstner, Chem. Rev. 1999, 99, 991; b) L. A. Wessjohann,
G. Scheid, Synthesis 1999, 1, 1.
[3] M. Bandini, P. G. Cozzi, A. Umani-Ronchi, Angew. Chem. 2000,
112, 2417; Angew. Chem. Int. Ed. 2000, 39, 2327.
[4] 2,2,2-Trichloroethyl esters undergo rearrangement to 1-halo-
vinyl esters through a radical pathway known as a Surzur–
Tanner rearrangement with a mixture of CuCl and bipyridine
(1:1). See: R. N. Ram, N. K. Meher, Org. Lett. 2003, 5, 145.
[5] K. Takai, R. Kokumai, T. Nobunaka, Chem. Commun. 2001,
1128.
[6] a) A. Fꢀrstner, N. Shi, J. Am. Chem. Soc. 1996, 118, 2533; b) A.
Fꢀrstner, N. Shi, J. Am. Chem. Soc. 1996, 118, 12349.
[7] 1-Chloroethyl benzoate probably arises through halide scram-
bling, see: M. B. Smith, J. March, Marchꢀs Advanced Organic
Chemistry : Reactions, Mechanisms, and Structure, 5th ed., Wiley,
New York, 2001.
[8] The Z stereochemistry of the major isomers of 2c and g was
determined by X-ray crystallography. CCDC-234464 and
CCDC-254732 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif. The Z stereochemistry of 2d was
determined by 2D 1H nOe NMR spectroscopy. The Z stereo-
chemistry of 2i and j was determined from the coupling constant
3JHF by 1H NMR spectroscopy. The stereochemistry of 2e could
not be determined by spectroscopy, but by analogy with the
other compounds it is assumed that (Z)-2e is obtained.
Angew. Chem. Int. Ed. 2005, 44, 2008 –2011
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2011