Highly stereoselective synthesis of (Z,E)-1-halo-1,3-dienol esters via rearrangement of Fischer chromium chloro-carbenes using microwave irradiation

Article abstract of DOI:10.1039/b903244b

Functionalized (Z,E)-1-halo-1,3-dienol esters are synthesized in a highly stereoselective manner via CrCl₂-mediated rearrangement of allylic trihalomethylcarbinol esters induced by microwave irradiation.

Full text of DOI:10.1039/b903244b

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COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Highly stereoselective synthesis of (Z,E)-1-halo-1,3-dienol esters
via rearrangement of Fischer chromium chloro-carbenes using
microwave irradiation†‡
Dhurke Kashinath,a Charles Mioskowski,§a J. R. Falck,b Mohan Goli,b Ste´phane Meunier,*a Rachid Baati*a
and Alain Wagnera
Received 16th February 2009, Accepted 6th March 2009
First published as an Advance Article on the web 19th March 2009
DOI: 10.1039/b903244b
Functionalized (Z,E)-1-halo-1,3-dienol esters are synthesized
in a highly stereoselective manner via CrCl2-mediated rear-
rangement of allylic trihalomethylcarbinol esters induced by
microwave irradiation.
The development of stereoselective molecular rearrangements is
an emerging area in organic synthesis for the preparation of
halogenated olefins.1,2 While numerous examples for the prepa-
Scheme 1 Preparation of (Z,E)-1-halo-1,3-dienol esters.
ration of (Z)-1-haloenol esters, (Z)-2-haloenol ethers,2 (Z,Z)-1-
chloro-1,3-dienes and Z-chloroalkenes exist,3 (Z,Z)- and (Z,E)-
standard procedures6 and treated with chromous chloride. Facing
1-halo-1,3-dienol esters are uncommon and remain highly elusive
the challenge of achieving high stereoselectivity, we first examined
the reactivity of compound 1 using reported conditions, i.e., with 3
equiv of CrCl2 in THF under reflux for 3.5 h.2a Initial results were
rather encouraging since the expected (Z,E)-1-chloro-1,3-dienol
acetate 27 was isolated in 84% yield, along with 16% of starting ma-
terial (Table 1, entry 1). However, we observed that exposure of the
p-chloroarene 3 to the same experimental conditions failed to give
the desired product 4 in an acceptable yield (30%), due to the low
conversion of the starting material 3 (Table 1, entry 2). Prolonged
reaction times proved to be unsatisfactory since the degradation
of the rearranged product 4 and the formation of side products
took place predominantly. Gratifyingly, it was eventually found,
through an assay of diverse reaction conditions, that treatment of 3
with 3.5 equiv of CrCl2, under microwave irradiation, enabled clean
and rapid (25 min) formation of 4 as the sole (Z,E) isomer, in 74%
of isolated yield (Table 1, entry 2). NOE experiments, corroborated
by a single-crystal X-ray diffraction analysis, assessed unam-
biguously the (Z,E)-stereochemistry of the 1-chloro-1,3-dienol
acetate 4.8
The benefit of the microwave irradiation proved to be a generally
advantageous alternative to the initial thermal reaction,2a and the
yield of 2 could be improved up to 92% of the major (Z,E) product
(Table 1, entry 1), along with 5% of the minor (E,E) isomer. While
enhancing drastically the kinetic of the rearrangement,9 these new
conditions did not affect the high stereoselectivity of the reaction,
and more importantly, the stability and the viability of the reactive
intermediate.
intermediates, despite their obvious synthetic utility. Indeed, quite
recently, halo-1,3-butadienyl esters have been successfully used
in combination with alkylsulfonyl cyanides for the preparation
of halogenopyridines.4 This report represents the sole example
reported so far in the literature, but provides a tantalizing
glimpse into the vast potential class of synthetic intermediates.
Additionally, it has been found that (Z)-1-haloenol esters are
potential prodrugs for Alzheimer disease.5 Considering the syn-
thetic and biological relevance of 1-haloenols, a general strate-
gic approach for the stereoselective preparation of 1-halo-1,3-
dienol esters is highly desirable. Inspired by our recent discovery
that chromium (II) chloride in THF induces trihalomethyl-
carbinol esters and ethers to undergo efficient, stereoselective
intramolecular rearrangement, to (Z)-a-haloenol esters and (Z)-
b-haloenol ethers, respectively, we became interested in the pos-
sibility of applying this reaction to allylic trihalomethylcarbinol
substrates.2a
Herein, we describe the optimization of this reaction and
its application in the first general method for the stereoselec-
tive preparation of (Z,E)-1-halo-1,3-dienol esters from allylic
1,1,1-trihalomethylcarbinol esters using microwave irradiation
(Scheme 1). Relying upon our prior experience, various substi-
tuted allylic trihalomethylcarbinol esters were synthesized using
aLaboratoire de Chimie des Syste`mes Fonctionnels, UMR 7199, Faculte´ de
Pharmacie, Universite´ de Strasbourg, 74 Route du Rhin, B. P. 24, 67401
Illkirch, France. E-mail: baati@bioorga.u-strasbg.fr, meunier@bioorga.
u-strasbg.fr; Fax: (+33)3-9024-4306; Tel: (+33)3-9024-4301; (+33)3-
9024-4295
Table 1 summarizes the evaluation of the reaction scope under
the optimized conditions. Importantly, all reactions proceeded to
completion within short reaction times (25 min), regardless of
the olefin substitution of the starting allylic trihalomethylcarbinol
esters, or the nature of the migratory acyl group. A survey of
electronically and sterically varied aryl, heteroaryl and olefinic
substituents on the allylic trihalomethylcarbinol esters showed,
similarly to 1 and 3, a high degree of stereospecificity in the
bDepartment of Biochemistry, University of Texas Southwestern Medical
Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9038, USA
† Electronic supplementary information (ESI) available: Experimental
procedures, spectral, and crystallographic data. CCDC reference numbers
715259 and 715260. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b903244b
‡ Dedicated to the memory of Dr. Charles Mioskowski
§ Passed away on 2nd June 2007
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Table 1 Synthesis of Z-1-halo-1,3-dienol esters
Entry
1
Trihalocarbinol ester
a-Halo-1,3-dienol ester
Yield (%)a
92 (84)b
2
74 (30)b
3
4
5
6
5 = R = CH3
6 = R = CH3
90c
68
81
85
7 = R = Ph
8 = R = Ph
9 = R = 2-thienyl
11 = R = 2-pentenyl
10 = R = 2-thienyl
12 = R = 2-pentenyl
7
8
13 = R = CH3
15 = R = Ph
14 = R= CH3
16 = R = Ph
90c
77
9
10
11
17 = R = CH3
18 = R = CH3
90
83
64
19 = R = p-OCH3-C6H4
20 = R = p-OCH3-C6H4
12
13
74
68
a Isolated yields by microwave irradiation reaction; b Yields in parentheses are from conventional heating for 10–12 h.2a c Yields are calculated based on
the crude 1H NMR spectra.
rearrangement step, and in most cases, excellent yields were
obtained (Table 1). Interestingly, even low molecular weight
substrates such as 5 and 13 were specifically converted to the
corresponding (Z)-1-chlorodienol acetates 6 and 14, however,
isolation of the compounds was tedious due to their high
volatility (entries 3, 7).10 These practical problems were easily
overcome by substitution of the acetyl group by a heavier
migratory benzoyl (Bz) substituent. Accordingly, analogues 7
and 15 afforded, without any complications, the expected (Z)-
1-chloro-1,3-dienol benzoates 8 and 16 in good isolated yields
(entries 4, 8). For both cases, 8 to 12% of the minor (E)-
1-chloro-1,3-dienol benzoate isomers were also identified in a
complex inseparable mixture. It is worthwhile mentioning that
the rearrangement conditions also tolerate thienoyl and pentenoyl
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moieties as migratory groups; substrates 9 and 11 were smoothly,
and exclusively converted to (Z)-10 and (Z)-12, respectively, in
excellent isolated yields (entries 5, 6). Disubstituted (E)-allylic
trichloromethylcarbinol esters 17 and 19 also behaved well and
provided the corresponding (Z,E)-1-chloro-1,3-dienol acetate 18
and benzoate 20 almost exclusively (entries 9, 10). For these
reagents (17 and 19) the formations of the minor (E,E)-1-chloro-
1,3-dienol esters isomers were observed in low quantities, based
upon the analysis of the 1H NMR spectrum of the crude reaction
mixture (<5%).
It was also found that the rearrangement of the citral deriva-
tive 21, provided 64% of the desired (Z,E)-1-chloro-1,3-dienol
acetate 22, accompanied with 12% of the (E,E)-isomer (Entry
11). Extension of our methodology to the formation of (Z,E)-
1-fluoro-1,3-dienol acetate 24 was successfully achieved when
1-fluorodibromomethylcarbinol 23 was subjected to the same
optimized conditions (Entry 12). The stereochemistry of the
resulting (Z,E)-1-fluoro-1,3-dienol acetate 24 (single isomer)
was assigned and confirmed by 19F-NMR spectroscopy. Finally,
the substrate survey showed also that E-furan trichloromethyl
carbinol 25 reacted with chromium(II) chloride in similar fashion.
The expected (Z,E)-1-chloro-1,3-dienol acetate 26 was isolated in
pure form with 68% of yield, along with 24% of a 60:40 mixture
of minor (E,E)-1-chloro-1,3-dienol acetate, and an unidentified
product (Entry 13).11
ester 30.13 Interestingly, the reactions of Fischer chromium(III)
carbene complexes (FCCs) under microwave irradiation are
unknown. Moreover, only one report can be found in the liter-
ature involving Fischer chromium(0) alkoxy carbene complexes.
Indeed, recently, Barluenga et al. have successfully used Fischer
alkoxy carbene complexes, generated with microwave irradiation,
for the diastereoselective cyclopropanation of electron-deficient
alkenes.14
To the best of our knowledge, the reactions reported herein,
are the first examples of highly stereoselective intramolecular
rearrangement of homoallylic Fischer chloro carbenes, in situ
generated under microwaves irradiation, and affording stere-
oselectively, (Z,E)-1-halo-1,3-dienol esters of valuable synthetic
interest.
Conclusion
In conclusion, we have developed a novel, simple and versatile
method for the stereoselective preparation of (Z,E)-1-halo-1,3-
dienol esters which are useful intermediates in organic synthesis.
Further studies on the use of Fischer chromium(III) carbene
complexes (FCCs) as intermediates in chemistry, are under
progress in our laboratories.
Acknowledgements
It is important to point out that for all substrates evaluated the
stereochemistry of the starting allylic trihalomethylcarbinol esters
(1,3 and 17–25) did not suffer from any competitive isomerization,
in our experimental conditions. Mechanistically, all the results
described in this communication can be accommodated by the
rational considerations depicted in Scheme 2.
We gratefully acknowledge the French National Research Agency
(L¢Agence Nationale de la Recherche: ANR Proteasome) for
financial support to DK, NIH GM31278, and the Robert A. Welch
Foundation.
Notes and references
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Falck and C. Mioskowski, Angew. Chem., Int. Ed., 1998, 37, 2085–2087.
2 (a) R. Bejot, S. Tisserand, L. M. Reddy, D. K. Barma, R. Baati, J. R.
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2011; (b) M. B. Boxer and Y. Yamamoto, Org. Lett., 2008, 10, 453–455;
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3 (a) M. S. Karatholuvhu and P. L. Fuchs, J. Am. Chem. Soc., 2004,
126, 14314–14315; (b) R. Baati, D. K. Barma, J. R. Falck and C.
Mioskowski, J. Am. Chem. Soc., 2001, 123, 9196–9197; (c) R. Baati,
D. K. Barma, U. M. Krishna, C. Mioskowski and J. R. Falck,
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3858.
Scheme 2 Plausible mechanism for the formation of 30.
4 K. Tomoya, I. Shinichi, A. Goro, S. Manzo, WO 9811071, 1998.
5 M. Yoshimatsu, M. Sakai and E. Moriura, Eur. J. Org. Chem., 2007,
498–507.
6 (a) H. Tanaka, S. Yamashita, M. Yamanoue and S. Torii, J. Org. Chem.,
1989, 54, 444–450; (b) D. Yang, G.-S. Jiao, Y.-C. Yip, T.-H. Lai and
M.-K. Wong, J. Org. Chem., 2001, 66, 4619–4624.
7 The (Z,E)-stereochemistry of 2 was unambiguously assigned by NOE
experiments.
8 See supporting information for the X-ray crystal structure and addi-
tional data for 4.
As reported earlier,2a it is believed that the reaction of 27
proceeds through the initial formation of the dihalocarbenoid
intermediate 28, that undergoes a rapid a-elimination of CrCl2X
through metal-assisted ionization,12 to afford the postulated ho-
moallylic Fischer chloro carbene 29. An intramolecular suprafa-
cial nucleophilic rearrangement involving the nonbonded (n)
electrons of the carbonyl group takes place, converting this
highly reactive species into the observed (Z,E)-1-chloro-1,3-dienol
9 A. Loupy, in Microwaves in Organic Synthesis, Wiley-VCH, Weinheim,
2006.
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10 For both substrates
5
and 13, 85 to 90% of conversion was
Rachon, V. Goedken and H. M. Walborsky, J. Am. Chem. Soc., 1986,
108, 7435–7436.
13 The Z stereochemistry of the products may be rationalized if one
takes into account the possible conformations of the postulated
Fisher carbene 29. See reference 2a for a detailed explanation for the
stereochemical model for the migration.
achieved, and rearranged products
6 and 14 were formed as
single isomers based on the analysis of the crude 1H-NMR
spectra.
11 X-Ray crystal structure of 26 is provided in supporting information.
12 (a) The organochromium species undergo a rehybridization by placing
a positive charge in a p orbital to produce a tight ion pair: M. Duraisamy
and H. M. Walborsky, J. Am. Chem. Soc., 1984, 106, 5035–5037; (b) J.
14 J. Barluenga, M. A. Ferna´ndez-Rodr´ıguez, P. Garc´ıa-Garc´ıa, E. Aguilar
and I. Merino, Chem.–Eur. J., 2006, 12, 303–313.
1774 | Org. Biomol. Chem., 2009, 7, 1771–1774
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©