Stereoselective CrCl2-mediated condensation of aldehydes with functionalized 1,1,1-trichlorides: Synthesis of trisubstituted (Z)-chloroolefins

Article abstract of DOI:10.1016/j.tetlet.2004.02.101

The CrCl₂-mediated condensation of aldehydes 1 with a variety of functionalized 1,1,1-trichlorides 2 affords trisubstituted chloroolefins 4 in excellent yields and generally high Z-stereoselectivity. The intermediate dichlorohydrin adducts 3 can be isolated in good yields under conditions of limited reagent and reduced temperature.

Full text of DOI:10.1016/j.tetlet.2004.02.101

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3039–3042
Stereoselective CrCl2-mediated condensation of aldehydes
with functionalized 1,1,1-trichlorides: synthesis of trisubstituted
(Z)-chloroolefins
J. R. Falck,* Anish Bandyopadhyay, D. K. Barma, Dong-Soo Shin, Abhijit Kundu
and R. V. Krishna Kishore
Department of Biochemistry, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA
Received 10 February 2004; accepted 19 February 2004
Abstract—The CrCl2-mediated condensation of aldehydes 1 with a variety of functionalized 1,1,1-trichlorides 2 affords trisubsti-
tuted chloroolefins 4 in excellent yields and generally high Z-stereoselectivity. The intermediate dichlorohydrin adducts 3 can be
isolated in good yields under conditions of limited reagent and reduced temperature.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
catalytic CrCl2 coupled to a Mn/TMSCl regeneration
system9 was also highly stereoselective, yields were
reduced (65–80%) and reaction times were significantly
longer (ꢀ16–24 h).
Recently, our laboratories described the efficient, stereo-
selective Cr(II)-mediated addition of 2,2,2-trihaloacetates
to carbonyls.1 The broad synthetic utility of the resultant
(Z)-a-haloacrylates2 prompted us to examine the scope of
this condensation using aldehydes 1 and a panel of rep-
resentative 1,1,1-trichlorides 23 for the preparation of
trisubstituted chloroolefins 4 (Eq. 1).4
Despite the presence of easily exchangeable protons,
both 2,2,2-trichloroacetamide (10) and 2-(trichloroacet-
yl)pyrrole (13) smoothly condensed with 5 and 8 giving
rise to all-Z 1110 (entry c), 12 (entry d), 14 (entry e), and
15 (entry f), correspondingly. a,a,a-Trichlorotoluene
(16) behaved analogously and stereoselectively gener-
ated 1711 (entry g) and 1812 (entry h) from 5 and 8,
respectively. In contrast, 2013 (entry i) was obtained in
good yield, but as an ꢀ1:1 mixture of E/Z-isomers, via
union of trichloroacetonitrile (19) with 5. The divergent
reactivity of 19 was even more apparent with aldehyde 8.
The anticipated adduct, chloroolefin 21, could be iso-
lated in low yield only under a variety of reaction con-
ditions.
ð1Þ
The results are summarized in Table 1. For typical aryl
and aliphatic aldehydes, exemplified by benzaldehyde
(5) and hydrocinnamaldehyde (8), respectively, stirring
with 1,1,1-trichloroacetone (6) and 5 equiv of commer-
cial5 CrCl2 at room temperature for 0.5 h generated (Z)-
3-chloroenones 76 (entry a) and 97 (entry b) in nearly
quantitative yields. None of the (E)-isomer8 could be
detected by NMR analysis of the crude reaction mix-
tures, indicating >99% stereochemical purity. While
By analogy with earlier studies,1 the preceding olefin-
ations most likely involve initial metalation of 2 and
addition of the nascent chromate anion to the aldehyde
carbonyl yielding Reformatsky-type adduct 3 (Eq. 1).
Reduction of a residual chloride and subsequent E2-
elimination evolves chloroolefin 4. Of the possible anti-
periplanar conformations, conformer A (Scheme 1) is
favored because it minimizes the steric interactions
between the trichloride R0 and aldehyde R groups.
Selective metalation of the chloride furthest from the
chromate ester ensures the observed Z-stereochemistry.
Keywords: Chromium; Condensations; Stereocontrol; Olefination.
* Corresponding author. Tel.: +1-214-648-2406; fax: +1-214-648-6455;
e-mail: j.falck@utsouthwestern.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.101

3040
J. R. Falck et al. / Tetrahedron Letters 45 (2004) 3039–3042
Table 1. (Z)-Chloroolefination of aldehydes
Entry
a
Aldehyde
Trichloride
Adduct
Yield (%)
99
5
6
6
7
9
b
99
8
5
c
95
92
10
10
11
12
d
8
e
f
5
8
89
91
13
13
14
15
17
g
5
8
Cl3C–Ph
95
93
16
h
16
18
i
j
5
8
Cl3C–CN
90
19
20
21
19
<10
When R0¼CN, this interaction is negligible and both
conformers are equally populated.
Consistent with the proposed mechanism, the corre-
sponding dihalohydrins 22–27 could be isolated in good
yield under conditions of limiting chromium and low
temperature (Table 2). Exposure of the dichlorohydrins
Scheme 1.
Table 2. Synthesis of Dichlorohydrins
Entry
Aldehyde
Trichloride
Adduct
Yield (%)
87
a
5
6
22
b
c
8
5
6
82
82
23
24
10

J. R. Falck et al. / Tetrahedron Letters 45 (2004) 3039–3042
3041
Table 2 (continued)
Entry
Aldehyde
Trichloride
Adduct
Yield (%)
75
d
8
10
25
e
f
5
8
13
13
75
79
26
27
to the original reaction conditions led exclusively to (Z)-
chloroolefins in yields comparable to those in Table 1.
References and notes
1. Barma, D. K.; Kundu, A.; Zhang, H.; Mioskowski, C.;
Falck, J. R. J. Am. Chem. Soc. 2003, 125, 3218.
2. (a) Kakehi, A.; Ito, S. J. Org. Chem. 1974, 39, 1542; (b)
Dollt, H.; Zabel, V. Aust. J. Chem. 1999, 52, 259; (c)
Mironiuk-Puchalska, E.; Kolaczkowska, E.; Sas, W.
Tetrahedron Lett. 2002, 43, 8351; (d) Tanaka, K.; Kat-
sumura, S. Org. Lett. 2000, 2, 373; (e) Dai, W.-M.; Wu, J.;
Fong, K. C.; Lee, M. Y. H.; Lau, C. W. J. Org. Chem.
1999, 64, 5062; (f) Qing, F.-L.; Zhang, X. Tetrahedron
Lett. 2001, 42, 5929.
2. General procedures
2.1. Stoichiometric CrCl2
A mixture of trichloride (1 mmol) and aldehyde
(1 mmol) in dry THF (2 mL) was added to a stirring,
room temperature suspension of anhydrous CrCl2
(5.0 mmol) in THF (8 mL) under an argon atmosphere.
After 0.5–2 h, the resultant reddish reaction mixture was
quenched with water, extracted thrice with ether, and
the combined ethereal extracts were evaporated in
vacuo. Chromatographic purification of the residue on
silica gel furnished pure chloroolefin in the indicated
yields (Table 1).
5
3. Poor yields of olefin and/or complex product mixtures
were observed using trichloronitromethane, hexachloro-
acetone, and 1,1,1-trichlorotrifluoroethane.
4. For additional examples of recent CrCl2-based methodol-
ogy see: (a) Baati, R.; Barma, D. K.; Falck, J. R.;
Mioskowski, C. J. Am. Chem. Soc. 2001, 123, 9196; (b)
Barma, D. K.; Baati, R.; Valleix, A.; Mioskowski, C.;
Falck, J. R. Org. Lett. 2001, 3, 4237; (c) Falck, J. R.;
Barma, D. K.; Baati, R.; Mioskowski, C. Angew. Chem.,
Int. Ed. 2001, 40, 1281; (d) Barma, D. K.; Kundu, A.;
Baati, R.; Mioskowski, C.; Falck, J. R. Org. Lett. 2002,
4, 1387; (e) Baati, R.; Barma, D. K.; Falck, J. R.;
Mioskowski, C. Tetrahedron Lett. 2002, 43, 2179.
5. Available from Omm Scientific, Inc. (www.ommscientific.
com).
2.2. Catalytic CrCl2
A mixture of trichloride (1 mmol) and aldehyde
(1 mmol) in dry THF (3 mL) was added to a stirring,
room temperature suspension of anhydrous CrCl2
(0.5 mmol), Mn powder (4 mmol), and freshly distilled
TMS–Cl (4 mmol) in THF (7 mL) under an argon
atmosphere. After 16–24 h, the reaction was quenched
and the product was purified as described above to give
chloroolefin in the indicated yields (Table 1).
5
6. Depres, J. P.; Navarro, B.; Greene, A. E. Tetrahedron
1989, 45, 2989.
7. Spectral data for 9: 1H NMR (CDCl3, 300 MHz): d 2.38 (s,
3H), 2.68–2.76 (m, 2H), 2.79–2.86 (m, 2H), 6.95 (t, 1H,
J ¼ 6:9 Hz), 7.91–7.34 (m, 5H); 13C NMR (CDCl3,
75 MHz): d 22.66, 31.45, 33.89, 126.60, 128.50, 128.80,
134.38, 140.58, 140.67, 192.21; MS m=z 208 (Mþ), 210
1
(Mþþ2). 12: H NMR (CDCl3, 400 MHz): d 2.58 (q, 2H,
J ¼ 7:3 Hz), 2.81 (q, 2H, J ¼ 7:3 Hz), 5.63 (b s, 1H), 6.46
(b s, 1H), 7.16–7.33 (m, 6H). 14: 1H NMR (CDCl3,
300 MHz): d 6.41–6.50 (m, 1H), 7.03–7.12 (m, 2H), 7.31–
7.42 (m, 3H), 7.64 (s, 1H), 7.75–7.81 (m, 2H), 9.71 (s, 1H);
13C NMR (CDCl3, 75 MHz): d 111.26, 119.38, 126.10,
128.54, 128.95, 129.66, 129.91, 130.46, 133.24, 135.84,
179.01; MS m=z 231 (Mþ), 233 (Mþþ2). 15: 1H NMR
(CDCl3, 300 MHz): d 2.67–2.83 (m, 4H), 6.17–6.21 (m,
1H), 6.73–6.80 (m, 2H), 7.01–7.03 (m, 1H), 7.16–7.27 (m,
5H), 9.71 (b s, 1H); 13C NMR (CDCl3, 75 MHz): d 31.13,
34.11, 77.47, 111.39, 119.15, 125.87, 126.61, 128.63,
128.85, 129.92, 132.02, 139.50, 140.84, 178.91; MS m=z
2.3. Dichlorohydrins
A mixture of trichloride (1 mmol) and aldehyde
(1 mmol) in dry THF (2 mL) was added to a stirring,
0 °C suspension of anhydrous CrCl2 (2.5 mmol) in THF
(8 mL) under an argon atmosphere. After 12 h, the
reaction was quenched and the product was purified as
described above to give dichlorohydrin in the indicated
yields (Table 1).
5
1
259 (Mþ), 261 (Mþþ2). 21: H NMR (CDCl3, 300 MHz):
Acknowledgements
d 2.61–2.70 (m, 2H), 2.80 (t, 2H, J ¼ 3:5 Hz), 6.50 (t, 1H,
J ¼ 4:5 Hz), 7.36–7.40 (m, 3H), 7.51–7.56 (m, 2H). 22: 1H
NMR (CDCl3, 300 MHz): d 2.57 (s, 3H), 3.39 (d, 1H,
J ¼ 4:2 Hz), 5.38 (d, 1H, J ¼ 4:5 Hz), 7.36–7.42 (m, 3H),
Financial support provided by the CNRS, the Robert A.
Welch Foundation, and NIH (GM31278, DK38226).

3042
J. R. Falck et al. / Tetrahedron Letters 45 (2004) 3039–3042
7.52–7.57 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 24.89,
(m, 1H), 2.25–2.37 (m, 1H), 2.71–2.82 (m, 1H), 2.98–3.09
(m, 1H), 3.44–3.48 (m, 1H), 4.33–4.39 (m, 1H), 6.34–6.39 (m,
1H), 7.18–7.34 (m, 6H), 7.42–7.46 (m, 1H), 9.36 (br s, 1H).
8. Kim, K. M.; Chung, K. H.; Kim, J. N.; Ryu, E. K.
Synthesis 1993, 283.
77.68, 89.19, 127.94, 129.21, 129.38, 135.91, 198.74. 23: 1H
NMR (CDCl3, 300 MHz): d 1.95–2.07 (m, 1H), 2.18–2.29
(m, 1H), 2.54 (s, 3H), 2.70–2.81 (m, 1H), 2.92–3.01 (m,
1
2H), 4.19–4.26 (m, 1H), 7.20–7.36 (m, 5H). 24: H NMR
€
(CDCl3, 300 MHz): d 3.38 (d, 1H, J ¼ 5:4 Hz), 4.25–4.32
(br s, 1H), 5.89 (br s, 1H), 6.69 (br s, 1H), 7.17–7.33 (m,
5H). 25: 1H NMR (CDCl3, 300 MHz): d 1.90–2.02 (m,
1H), 2.15–2.27 (m, 1H), 2.68–2.79 (m, 1H), 2.94–3.04 (m,
1H), 3.38 (d, 1H, J ¼ 5:4 Hz), 4.25–4.32 (m, 1H), 5.89 (br
9. Furstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349.
10. Berkovitch-Yellin, Z.; Van Mil, J.; Addadi, L.; Idelson,
M.; Lahav, M.; Leiserowitz, L. J. Am. Chem. Soc. 1985,
107, 3111.
11. Kodomari, M.; Nagaoka, T.; Furusawa, Y. Tetrahedron
Lett. 2001, 42, 3105.
1
s, 1H), 6.69 (br s, 1H), 7.17–7.33 (m, 5H). 26: H NMR
(CDCl3, 300 MHz): d 3.99 (d, 1H, J ¼ 3:9 Hz), 5.54 (d, 1H,
J ¼ 3:6 Hz), 6.38–6.40 (m, 1H), 7.11–7.15 (m, 1H), 7.36–
7.42 (m, 3H), 7.45–7.49 (m, 1H), 7.58–7.63 (m, 2H), 9.42
12. Reich, I. L.; Haile, C. L.; Reich, H. J. J. Org. Chem. 1978,
43, 2402.
13. Kim, J. N.; Son, J. S.; Kim, H. R.; Ryu, E. K. Bull. Korean
Chem. Soc. 1998, 19, 812.
1
(br s, 1H). 27: H NMR (CDCl3, 300 MHz): d 2.01–2.19