Three-component synthesis of 2-haloalk-2(Z)-en-1-ols via tandem haloalkylidenation-aldehyde addition

Article abstract of DOI:10.1016/S0040-4039(02)00206-X

Cr(II)-induced condensation of CCl₄ or CBr₄ with an aldehyde stereospecifically generates an (E)-α-haloalkylidene chromium carbenoid which adds in situ to a second equivalent of aldehyde furnishing 2-haloalk-2(Z)-en-1-ols in high yie

Full text of DOI:10.1016/S0040-4039(02)00206-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2179–2181
Three-component synthesis of 2-haloalk-2(Z)-en-1-ols via tandem
haloalkylidenation–aldehyde addition
Rachid Baati,a D. K. Barma,b J. R. Falckb,* and Charles Mioskowskia,*
aUniversite´ Louis Pasteur de Strasbourg, Faculte´ de Pharmacie, Laboratoire de Synthe`se Bio-Organique (UMR 7514),
67401 Illkirch, France
bDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA
Received 7 January 2002; revised 24 January 2002; accepted 28 January 2002
Abstract—Cr(II)-induced condensation of CCl4 or CBr4 with an aldehyde stereospecifically generates an (E)-a-haloalkylidene
chromium carbenoid which adds in situ to a second equivalent of aldehyde furnishing 2-haloalk-2(Z)-en-1-ols in high yield.
© 2002 Elsevier Science Ltd. All rights reserved.
sis indicating >95% stereochemical purity. Optimal
yields required 6 equiv. of CrCl2. This is consistent with
two single-electron transfers for each of the oxidative
additions of Cr(II) into the three CꢀCl bonds (Scheme
1).10 Yields were lower in most other solvents, inter
alia, DMF, CH2Cl2, Et2O, and C6H6. Likewise, a cata-
lytic system,11 using Mn powder to recycle Cr(III) to
Cr(II), proved disappointing.
Organochromium reagents have emerged as versatile
synthetic intermediates due in large part to their unique
stereo-, regio-, and chemo-selectivities.1 In particular,
alkenylchromiun(III) reagents, most commonly made
from alkenyl halides utilizing CrCl2 promoted by nickel
salts,2 have proven useful for the preparation of allyl
alcohols under exceptionally mild conditions.3 In fur-
therance of these observations, our laboratories
reported a broadly applicable and highly stereospecific
preparation
of
(E)-chlorovinylidene
chromium
Bromoalkenols are also readily accessible by starting
with CBr4 instead of CCl4 and replacing CrCl2 with
CrBr2 (conveniently prepared12 by LiAlH4 reduction of
commercial anhydrous CrBr3), e.g., bromide 713 from 5
(entry 2). If CrCl2 is used as the sole reductant in
combination with CBr4, one obtains an ꢀ1:1 mixture
of 6 and 7.
carbenoids4 leading to 2-chloropropenyl alcohols,5 2-
haloalk-2(Z)-en-1-ols6 as well as 1-chloro-1(Z)-alkenes
and 1-chloro-2-alkoxy-1(Z)-alkenes.7 Herein, we report
a three-component condensation involving initial gener-
ation of an (E)-chlorovinylidene chromium carbenoid
(3) via Cr(II)-induced addition/condensation of CCl4 or
CBr4 with an aldehyde (18“2) and subsequent in situ
vinylation of a second equivalent of aldehyde resulting
in 2-haloalk-2(Z)-en-1-ols (4) (Scheme 1).
Notably, the overall transformation proceeded
smoothly with conjugated systems such as cinnamalde-
hyde (8) to give 9 (entry 3) and intramolecularly with
benzene-1,2-dicarbaldehyde (10) furnishing indene 11
The results from subjecting a panel of representative
aldehydes to the tandem haloalkylidenation–addition
above are summarized in Table 1 and illustrate the
generality of the procedure. Simultaneous addition of
benzaldehyde (5) and CCl4 to a slurry of commercial
CrCl2 (Method A) in dry THF furnished the known9
(Z)-Chloroalkenol 6 in excellent yield (entry 1). None
OCrIII
CrIII
R
CrIII
OCrIII
CX3
2 CrX2
RCHO
4 CrX2
CX4
R
1
2
1
X
of the (E)-isomer could be detected by H NMR analy-
OH
-O(CrIII)2
CrIII
RCHO
R
R
R
X
X
Keywords: chromium; alkenylation; alcohols; vinylation; stereocon-
trol.
3
4
X = Cl, Br
* Corresponding authors. E-mail: j.falck@utsouthwestern.edu;
mioskow@aspirine.u-strasbg.fr
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00206-X

2180
R. Baati et al. / Tetrahedron Letters 43 (2002) 2179–2181
Table 1. Tandem synthesis of 2-haloalk-2(Z)-en-1-ols
Entry
1
Aldehyde
CHO
Product
OH
Yield (%)
95
Cl
Br
Cl
5
5
6
7
9
OH
OH
65
2
CHO
3
4
91
85
8
OH
CHO
CHO
Cl
11
13
10
OH
CHO
12
CHO
14
CHO
16
CHO
5
94
Cl
H3CO
F3C
H3CO
F3C
OCH3
CF3
OH
OH
OH
6
7
93
85
Cl
Cl
15
17
O2N
O2N
NO2
8
9
93
94
Cl
Cl
18
19
21
Br
Br
Br
OH
OH
CHO
20
BnO
BnO
OBn
H3CO
H3CO
OCH3
CHO
22
89
85
92
10
11
12
O
O
O
Cl
23
25
27
OH
OH
CHO
Cl
Cl
24
CHO
O
O
O
O
O
O
26
(4:1)
(entry 4). Neither the reaction rate nor yield were
significantly influenced by electron donating or with-
drawing substituents, i.e. 12 and 14 gave rise to 13
(entry 5) and 15 (entry 6), respectively, in good yield in
10 h. The compatibility of the general procedure with a
variety of common functionality was demonstrated by
the conversion of nitro 16 (entry 7), aryl bromide 18
(entry 8), benzyl/methyl diether 20 (entry 9), and bis-
methyleneoxy ether 22 (entry 10) to 17, 19, 21, and 23,
respectively.
Application of the Barbier-type conditions (Method A)
to aliphatic aldehydes was complicated by competitive
aldol condensation resulting in depressed yields of
chloroalkenol. However, brief pre-incubation of CCl4
with CrCl2 before addition of the aldehyde (Method B)
obviated side reactions and restored overall efficiency.
For instance, chloroalkenol 25 was efficiently evolved
from dihydrocinnamaldehyde (24) (entry 11). Even acid
sensitive acetonide 26 yielded 27 without incident as a
4:1 mixture of diastereomers (entry 12).

R. Baati et al. / Tetrahedron Letters 43 (2002) 2179–2181
2181
General procedure
9. Kadota, J.; Komori, S.; Fukumoto, Y.; Murai, S. J. Org.
Chem. 1999, 64, 7523–7527.
Method A: A solution of aldehyde (2 mmol) and CCl4
(1 mmol) in THF (1 mL) was added to a stirring, 0°C
suspension of CrCl2 (6 mmol; Strem Chem., 99.9%) in
THF (9 mL) under an argon atmosphere. After 10 h at
room temperature, the resultant reddish reaction mix-
ture was quenched with water, extracted thrice with
ether, and the combined ethereal extracts were evapo-
rated in vacuo. The residue was purified by SiO2 chro-
matography affording 2-haloalk-2(Z)-en-1-ols in the
indicated yields (Table 1).
10. (a) Kochi, J. K.; Davis, D. D. J. Am. Chem. Soc. 1964,
86, 5264; (b) Kochi, J. K.; Singleton, D. M. J. Am. Chem.
Soc. 1968, 90, 1582.
11. Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118,
12349–12357.
12. (a) Hiyama, T.; Okude, Y.; Kimira, K.; Nozaki, H. Bull.
Chem. Soc. Jpn. 1982, 55, 561–568; (b) Okude, Y.;
Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc.
1977, 99, 3179.
1
13. Spectral data for 7: H NMR (CDCl3, 300 MHz) l 2.56
(d, 1H, J=5.1 Hz), 5.45 (d, 1H, J=4.2 Hz), 7.26 (s, 1H),
7.31–7.52 (m, 8H), 7.60–7.70 (m, 2H). Compound 9: H
1
Method B: CCl4 (1 mmol) was stirred with a slurry of
CrCl2 (6.5 mmol) in dry THF (9 mL) at 0°C under
argon. After 15 min, a solution of aldehyde (2 mmol) in
THF (1 mL) was added and the stirring was continued
at ambient for 10 h. Isolation and purification as
described above gave the adduct in the indicated yields
(Table 1).
NMR l 7.45–6.90 (m, 10H), 5.61 (t, 1H, J=8.0 Hz),
4.47–4.35 (m, 1H), 2.57 (s, 1H), 2.55–2.35 (m, 6H),
2.20–1.80 (m, 2H); 13C NMR l 144.1, 141.2, 135.1, 131.1,
130.5, 129.1, 128.6, 127.8, 127.1, 123.9, 79.9, 36.1, 34.2,
32.1, 30.4. Compound 13: 1H NMR l 7.62 (d, 2H, J=9.3
Hz), 7.36 (d, 2H, J=8.7 Hz), 6.84–6.92 (m, 5H), 5.33 (d,
1H, J=4.5 Hz), 3.79 (s, 3H), 3.78 (s, 3H), 2.64 (d, 1H,
J=5.1 Hz); 13C NMR (CDCl3, 75 MHz) l 159.66,
159.51, 133.08, 132.75, 130.95, 128.19, 126.93, 124.69,
Acknowledgements
1
114.05, 113.84, 77.91, 55.44. Compound 15: H NMR l
7.56–7.78 (m, 8H), 7.06 (s, 1H), 5.50 (d, 1H, J=3.3 Hz),
2.67 (d, 1H, J=4.5 Hz). Compound 17: 1H NMR
(CD3COCD3) l 7.44–7.50 (m, 4H), 7.14–7.20 (m, 2H),
7.20–7.07 (m, 2H), 6.60 (s, 1H), 4.29 (s, 2H); 13C NMR l
149.76, 149.05, 148.48, 142.27, 140.17, 131.59, 129.38,
Financial support provided by Robert A. Welch Foun-
dation, NIH (GM31278, DK38226), CNRS, Instituts
de Recherches Pierre Fabre (to R.B.), and an unre-
stricted grant from Taisho Pharmaceutical Co. Ltd. Dr.
E. R. Fogel is warmly thanked for insightful
discussions.
1
125.30, 124.77, 124.65, 77.75. Compound 19: H NMR l
7.79 (s, 1H), 7.61 (s, 1H), 7.55 (d, 1H, J=5.7 Hz), 7.45
(dd, 2H, J=6.0, 10.5 Hz), 7.37 (d, 1H, J=6.0 Hz), 7.24
(dd, 2H, J=5.7, 11.7 Hz), 6.91 (s, 1H), 5.36 (d, 1H,
J=2.4 Hz), 2.62 (d, 1H, J=3.3 Hz); 13C NMR l 142.3,
136.02, 135.67, 132.28, 131.76, 131.50, 130.36, 130.02,
129.97, 128.13, 125.55, 124.65, 122.94, 122.56, 77.54.
References
1. Reviews: (a) Hodgson, D. M. J. Organomet. Chem. 1994,
476, 1–5; (b) Fu¨rstner, A. Chem. Rev. 1999, 99, 991–1045.
2. Guo, J.; Duffy, K. J.; Stevens, K. L.; Dalko, P. I.; Roth,
R. M.; Hayward, M. M.; Kishi, Y. Angew. Chem., Int.
Ed. 1998, 37, 187–192.
3. Gonza´lez, I. C.; Forsyth, C. J. Tetrahedron Lett. 2000, 41,
3805–3807.
4. Baati, R.; Barma, D. K.; Falck, J. R.; Mioskowski, C. J.
1
Compound 21: H NMR l 7.26–7.46 (m, 11H), 7.12 (dd,
1H, J=1.2, 6.0 Hz), 7.01 (d, 1H, J=1.2 Hz), 6.80–6.92
(m, 4H), 5.30 (d, 1H, J=2.1 Hz), 5.15 (s, 2H), 5.13 (s,
2H), 3.87 (s, 6H), 2.60 (d, 1H, J=2.1 Hz); 13C NMR l
149.80, 149.22, 148.29, 148.28, 137.18, 137.03, 133.59,
133.12, 128.74, 128.71, 128.06, 128.02, 127.54, 127.42,
127.38, 124.94, 122.84, 119.30, 113.74, 113.46, 112.87,
110.53, 78.08, 71.12, 70.98, 56.20, 56.15. Compound 23:
1H NMR l 7.33 (d, 1H, J=1.8 Hz), 7.05 (dd, 1H, J=1.8,
8.1 Hz), 6.89–6.96 (m, 2H), 6.85 (s, 1H), 6.79 (d, 2H,
J=8.1 Hz), 5.96 (s, 2H), 5.95 (s, 2H), 5.28 (d, 1H, J=3.3
Hz), 2.52 (d, 1H, J=4.5 Hz); 13C NMR l 148.06, 147.76,
147.71, 147.63, 134.46, 133.13, 128.26, 124.93, 124.42,
120.64, 109.27, 108.37, 108.35, 107.34, 101.41, 101.39,
78.06. Compound 25: 1H NMR l 7.51–7.20 (m, 10H),
7.13 (dd, 1H, J=16, 10 Hz), 6.81–6.57 (m, 3H), 6.32 (dd,
1H, J=16, 6 Hz), 4.97 (t, 1H, J=6.0 Hz), 2.22 (d, 1H,
J=6.0 Hz); 13C NMR l 138.2, 137.8, 136.2, 135.3, 128.7,
128.5, 128.3, 128.1, 127.7, 126.7, 126.5, 126.1, 123.2, 76.1.
Am. Chem. Soc. 2001, 123, 9196–9197.
5. Falck, J. R.; Barma, D. K.; Mioskowski, C.; Schlama, T.
Tetrahedron Lett. 1999, 40, 2091–2094.
6. Barma, D. K.; Baati, R.; Valleix, A.; Mioskowski, C.;
Falck, J. R. Org. Lett. 2001, 3, 4237–4238.
7. Baati, R.; Barma, D. K.; Krishna, U. M.; Mioskowski,
C.; Falck, J. R. Tetrahedron Lett. 2002, 43, 959–961.
8. For additional evidence that 1 is an intermediate as well
as its utility in the preparation of ‘unsymmetrical’
chloroalkenols using different aldehydes, see: Baati, R.;
Barma, D. K.; Falck, J. R.; Mioskowski, C. Tetrahedron
Lett. 2002, 43, 2183–2185.