Convenient preparation of (Z)-α-halo-α,β-unsaturated aldehydes: synthesis of a Laurencia flexilis toxin

Article abstract of DOI:10.1016/j.tetlet.2008.05.026

The CrCl₂-mediated two-carbon halo-homologation of aryl, alkenyl, and aliphatic aldehydes with chloral ethyl hemiacetal or bromal affords (Z)-α-chloro- and (Z)-α-bromo-α,β-unsaturated aldehydes, respectively, in good to excellent yields and high stereoselectivity. The utility of this methodology was illustrated by a synthesis of 2-chloropentadec-2(Z)-enal, a toxin isolated from the marine red alga Laurencia flexilis.

Full text of DOI:10.1016/j.tetlet.2008.05.026

Tetrahedron Letters 49 (2008) 4359–4361
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient preparation of (Z)-a-halo-a,b-unsaturated aldehydes:
synthesis of a Laurencia flexilis toxin
b
a,
Deb K. Barma a, Biao Lu a, Rachid Baati b, , Charles Mioskowski , J. R. Falck
*
*
a Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
b Université Louis Pasteur de Strasbourg, Faculté de Pharmacie UMR 7175-LC1, Laboratoire de Synthèse Bio-Organique, 74 route du Rhin, 67 401 Illkirch-Graffenstaden, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The CrCl2-mediated two-carbon halo-homologation of aryl, alkenyl, and aliphatic aldehydes with chloral
ethyl hemiacetal or bromal affords (Z)-a-chloro- and (Z)-a-bromo-a,b-unsaturated aldehydes, respec-
tively, in good to excellent yields and high stereoselectivity. The utility of this methodology was illus-
Received 3 April 2008
Revised 21 April 2008
Accepted 7 May 2008
Available online 10 May 2008
trated by
a
synthesis of 2-chloropentadec-2(Z)-enal,
a
toxin isolated from the marine red alga
Laurencia flexilis.
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to the memory of Charles
Mioskowski who passed away on June 2,
2007
Keywords:
Homologation
Chromium
Aldehydes
Enals
1. Introduction
ð1Þ
In many instances, organochromium intermediates offer che-
mo-, regio-, and/or stereoselectivities not achievable with tradi-
tional organometallic reagents.1 For example, our laboratories
have reported efficient, stereocontrolled condensations of a,a-
di-2/a,a,a- trihalo-esters,3 -amides, -ketones, -nitriles, and -methyl-
benzene with aldehydes and ketones4 induced by Cr(II)-salts.
Herein, we describe a convenient, stereoselective synthesis of
(Z)-a-chloro- and (Z)-a-bromo-a,b-unsaturated aldehydes in good
to excellent yields via the CrCl2-mediated two-carbon halo-homol-
ogation of aldehydes with chloral ethyl hemiacetal or bromal (Eq.
1). a-Halo-a,b-unsaturated aldehydes are useful synthetic inter-
mediates5 as well as structural elements in natural products.6
However, they are generally accessible only via multi-step
sequences or using highly reactive reagents and are often obtained
as E/Z-mixtures in reduced yields.7
The scope and limitations of this facile transformation were
explored using a panel of representative aldehydes as summarized
in Table 1. The simplest aryl aldehyde, benzaldehyde (1), was read-
ily converted into the corresponding (Z)-a-chlorocinnamaldehyde8
(2) using chloral ethyl hemiacetal9 and CrCl2 under the standard
reaction conditions, that is, THF at room temperature (entry 1).10
Catalytic CrCl2 regenerated in situ by Mn(0)11 or Fe(0)12 resulted
in lower yields of 2 as did the use of solvents other than THF.13
By conducting the reaction at 0 °C, the somewhat labile bromal gave
rise to (Z)-a-bromocinnamaldehyde7c (3) from 1 in synthetically
useful yield (entry 2). The halo-homologations were relatively
insensitive to the nature of the aryl moiety. Electron-rich substrates,
viz., 1-naphthaldehyde (4), p-tolualdehyde (6), and piperonal (8),
and electron-poor 4-trifluoromethylbenzaldehyde (10) furnished
adducts 514 (entry 3), 77b (entry 4), 9 (entry 5), and 11 (entry 6),
respectively, in comparable yields. Importantly, the reaction was
compatible with a wide variety of functional groups. Benzyl/methyl
bis-ether 12, p-bromobenzaldehyde (14), and the reduction prone
p-nitrobenzaldehyde (16) reacted smoothly and accordingly led
to a-chloroenals 13 (entry 7), 157b (entry 8), and 17 (entry 9),
* Corresponding authors. Tel.: +33 (0)39 024 4301; fax: +33 (0)39 024 4306
(R.B.); tel.: +214 648 2406; fax: +214 648 6455 (J.R.F.).
E-mail addresses: baati@bioorga.u-strasbg.fr (R. Baati), j.falck@utsouthwestern.
edu (J. R. Falck).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.026

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D. K. Barma et al. / Tetrahedron Letters 49 (2008) 4359–4361
Table 1
2. General procedure: a-chloro-a,b-unsaturated aldehydes
Synthesis of a-halo-a, b-unsaturated aldehydes
Entry
Aldehyde
Adduct
Yield(%)
91
A mixture of aldehyde (1 mmol) and 2,2,2-trichloro-1-ethoxy-
ethanol (chloral ethyl hemiacetal, 1 mmol) in anhydrous THF
(1 mL) was added to a stirring, room temperature suspension of
1
15
anhydrous CrCl2 (4 mmol, Aldrich Chem. Co.) in anhydrous THF
(10 mL) under an argon atmosphere. After 10 h, the reaction mix-
ture was quenched with aqueous 5% HCl (10 mL), stirred for an
additional 10 min and then extracted with ether (3 ꢀ 25 mL). The
combined ethereal extracts were washed with brine, dried over
anhydrous Na2SO4, and the solvent was evaporated under reduced
pressure. The residue was purified by column chromatography to
give a-chloro-a,b-unsaturated aldehyde in the indicated yields
(Table 1).
2
3
1
69
81
4
91
2.1. a-Bromo-a,b-unsaturated aldehydes
5
6
82
89
Same as above except a mixture of aldehyde (1 mmol) and bro-
mal (2 mmol, Fluka Chem. Co.) was added to a 0 °C suspension of
CrCl2 and kept at this temperature for 1 h before quenching and
purification as described above.
Acknowledgment
7
85
Financial support provided by the CNRS, the Robert A. Welch
Foundation, and NIH (DK38226, GM31278) is gratefully
acknowledged.
8
9
77
71
References and notes
1. Reviews (a) Fürstner, A. Chem. Rev. 1999, 99, 991–1045; (b) Hodgson, D. M. J.
Organomet. Chem. 1994, 476, 1–5.
2. Barma, D. K.; Kundu, A.; Bandyopadhyay, A.; Kundu, A.; Sangras, B.; Briot, A.;
Mioskowski, C.; Falck, J. R. Tetrahedron Lett. 2004, 45, 5917–5920.
3. Barma, D. K.; Kundu, A.; Zhang, H.; Mioskowski, C.; Falck, J. R. J. Am. Chem. Soc.
2003, 125, 3218–3219.
4. Falck, J. R.; Bandyopadhyay, A.; Barma, D. K.; Shin, D.-S.; Kundu, A.; Kishore, R.
V. K. Tetrahedron Lett. 2004, 45, 3039–3042.
10
11
87
71a
5. (a) Nagamitsu, T.; Takano, D.; Marumoto, K.; Fukuda, T.; Furuya, K.; Otoguro, K.;
Takeda, K.; Kuwajima, I.; Harigaya, Y.; Omura, S. J. Org. Chem. 2007, 72, 2744–
2756; (b) Simpkins, S. M. E.; Weller, M. D.; Cox, L. R. Chem. Commun. 2007,
4035–4037; (c) Timmons, C.; Chen, D.; Cannon, J. F.; Headley, A. D.; Li, G. Org.
Lett. 2004, 6, 2075–2078.
12
87
82
6. de Nys, R.; König, G. M.; Wright, A. D.; Stricher, O. Phytochem. 1993, 34, 725–
728.
13
7. Typical examples: (a) Chen, S.; Wang, J. J. Org. Chem. 2007, 72, 4993–4996; (b)
Nenajdenko, V. G.; Reznichenko, A. L.; Lenkova, O. N.; Shastin, A. V.; Balenkova,
E. S. Synthesis 2005, 605–609; (c) Kim, K.-M.; Park, I.-H. Synthesis 2004, 2641–
2644; (d) Mitani, M.; Kobayashi, Y. Bull. Chem. Soc. Jpn. 1994, 67, 284–286; (e)
Satoh, T.; Kitoh, Y.; Onda, K.-i.; Takano, K.; Yamakawa, K. Tetrahedron 1994, 50,
4957–4972; (f) Ley, S.; Whittle, A. J. Tetrahedron Lett. 1981, 22, 3301–3304; (g)
Masure, D.; Chuit, C.; Sauvêtre, R.; Normant, J. F. Synthesis 1978, 458–460; (h)
Poutsma, M. L.; Ibarbia, P. A. J. Org. Chem. 1970, 35, 4038–4054; (i) Jedlinski, Z.;
Majnusz, J. Tetrahedron 1969, 25, 699–705; (j) Märkl, G. Chem. Ber. 1962, 95,
3003–3007.
8. Adduct 2 was identical in all respects with an authentic sample of (Z)-a-
chlorocinnamaldehyde from Aldrich Chem. Co. and the spectral data of 25
corresponded closely with literature values (see Ref. 6). All other products were
assigned (Z)-stereochemistry in analogy.
9. Anhydrous chloral, prepared by distillation of chloral hydrate from P2O5 under
reduced pressure, gave 2 in only 56% yield. The superior yields obtained with
chloral ethyl hemiacetal may result from the slow release of free chloral. A low
steady state concentration of free chloral would minimize side reactions, thus
improving overall halo-homologation yields.
a
5–7% of the E-isomer was also obtained.
respectively, without complications. It was also gratifying to find
conjugated (18?19, entry 10), aliphatic (20?21, entry 11), and
a-branched aliphatic aldehydes (22?23, entry 12) behaved analo-
gously. The utility of this methodology was further demonstrated
using commercial tridecanal (24) for the one-step synthesis of
2-chloropentadec-2(Z)-enal (25, entry 13), a toxin isolated from
the marine red alga Laurencia flexilis.6
In concert with earlier mechanistic proposals,3 CrCl2 likely acts
as a multiple one-electron reductant generating chromium(III)-
enolate 26 from chloral/bromal which is intercepted by aldehyde
(Eq. 2). The resultant Reformatsky-type adduct 27 undergoes fur-
ther reductive metallation with concomitant E2-elimination to
give the final a-halo-a,b-enal adduct.
10. Organochromium intermediates of the type described here belong to a small
but growing class of organometallics, for example, indium reagents, that are
tolerant of water, alcohols and hydroxylic solvents, yet are still capable of
reaction with organic electrophiles such as aldehydes.
ð2Þ

D. K. Barma et al. / Tetrahedron Letters 49 (2008) 4359–4361
4361
11. Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349–12357.
12. Falck, J. R.; Bejot, R.; Barma, D. K.; Bandyopadhyay, A.; Joseph, S.; Mioskowski,
C. J. Org. Chem. 2006, 71, 8178–8182.
13. When 1 equiv of CrCl2 was used along with 5 equiv of Mn(0) or 5 equiv of
Fe(0), only 10% and 21% of 2 were obtained, respectively, at room temperature
after 24 h. Increasing the temperature to 45 °C did not improve the yields. The
use of other solvents such as DMF (no formation of 2), EtOAc (5–10% of 2), or
DME (less than 10% of 2) was also disappointing.
11: 1H NMR (CDCl3, 400 MHz) d 7.59 (s, 1H), 7.72–7.75 (d, 1H, J = 12.0 Hz),
8.02–8.05 (d, 1H, J = 12.0 Hz), 9.54 (s, 1H). 13: 1H NMR (CDCl3, 400 MHz) d 3.95
(s, 3H), 5.24 (s, 2H), 6.94–6.97 (d, 1H, J = 12.0 Hz), 7.30–7.74 (m, 7H), 7.74 (s,
1H), 9.45 (s, 1H). 19: 1H NMR (CDCl3, 400 MHz) d 7.10–7.25 (m, 1H), 7.29–7.49
(m, 5H), 7.53–7.64 (m, 2H), 9.50 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 122.9,
128.4, 129.5, 130.7, 132.9, 135.9, 144.9, 145.9, 185.9; IR: 3012, 1685, 1613,
1584, 1546, 1263, 1166 cmꢁ1; MS (DCI/NH3) m/z (M+NH4)+ 210; mp 64–66 °C.
21: 1H NMR (CDCl3, 400 MHz) d 2.86–2.88 (m, 4H), 6.87 (t, 1H, J = 6.4 Hz), 7.20–
7.26 (m, 3H), 7.30–7.34 (m, 2H), 9.33 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 30.9,
33.5, 126.6, 128.3, 128.7, 139.9, 185.6; IR: 3027, 1701, 1624, 1496, 1454,
1123 cmꢁ1; MS (DCI/NH3) m/z (M+NH4)+ 212. 23: 1H NMR (CDCl3, 300 MHz) d
1.50–1.53 (d, 1H, J = 9.0 Hz), 4.22–4.32 (m, 4H), 6.90–6.93 (d, 1H, J = 9.0 Hz),
7.25–7.35 (m, 5H), 9.35 (s, 1H).
14. Spectral/physical data for 5: 1H NMR (CDCl3, 400 MHz) d 7.56–7.62 (m, 3H).
7.92–8.01 (m, 3H), 8.17– 8.19 (d, 1H, J = 8.0 Hz), 8.30 (s, 1H), 9.71 (s, 1H); 13C
NMR (CDCl3, 75 MHz) d 186.6, 142.9, 134.6, 133.7, 131.6, 131.5, 129.3, 128.8,
128.6, 127.5, 126.7, 125.3, 123.3. 9: 1H NMR (CDCl3, 400 MHz) d 6.07 (s, 2H),
6.90–6.92 (d, 1H, J = 8.0 Hz), 7.36–7.39 (dd, 1H, J = 1.6, 8.4 Hz), 7.43 (s, 1H),
7.70 (s, 1H), 9.45 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 101.9, 108.7, 109.9, 126.7,
128.2, 129.9, 145.2, 148.2, 150.5, 186.5; IR: 3002, 1684, 1611, 1593, 1504,
1455, 1271, 1128, 1038 cmꢁ1; MS (DCI/NH3) m/z (M+NH4)+ 218; mp 87–89 °C.
15. Commercial, anhydrous CrCl2 was transferred to a tared flask under an argon
atmosphere and dried in vacuo with a heat-gun or low flame for 3–5 min, then
cooled to room temperature prior to weighing and use.