Amidine-Promoted Addition of Chloroform to Carbonyl Compounds

Full text of DOI:10.1021/jo000584n

J . Org. Chem. 2000, 65, 7211-7212
7211
Ta ble 1. Am id in e Ca ta lyzed Ad d ition of Ch lor ofor m to
Ben za ld eh yd ea
Am id in e-P r om oted Ad d ition of Ch lor ofor m
to Ca r bon yl Com p ou n d s
entry
catalyst
equiv
time (h)
yield (%)c
Varinder K. Aggarwal*,‡ and Andrea Mereu
1
2
3
4
5
6
DBU
1
1
0.1
1
0.1
1
3
36
2
3
24
3
98
95
12
98
4
DBUb
Department of Chemistry, University of Sheffield,
Sheffield S3 7HF, U.K.
DBU
DBN
DBN
guanidine 6
98
v.aggarwal@sheffield.ac.uk
Received April 17, 2000
a
Reaction performed in absence of solvent using a PhCHO:
CHCl3 ratio of 1:2. PhCHO:CHCl3 ) 1:10. c Isolated yields.
b
Trihalocarbinols are useful intermediates in organic
synthesis as they can be readily converted into R-amino,
R-hydroxy, and R-thio acids.1,2 They are usually prepared
by base-promoted addition of chloroform to aldehydes/
ketones, but to date relatively strong bases have been
employed.3 Potassium tert-butoxide in liquid ammonia at
-78 °C,3a sodium in liquid ammonia,3b or powdered
potassium hydroxide in various solvents3c-d,4 are the most
commonly used conditions. However, in all these reac-
tions low temperatures were required to minimize the
extent of the Cannizzaro reaction, which gave the main
side product.3c Perhaps the best method to date for
preparing trichloromethyl carbinols is due to Wyvratt,
who found that when using methanolic KOH in DMF at
-5 °C, essentially no Cannizzaro reaction occurred and
good yields of the desired carbinols were obtained,
although only a limited range of examples was reported.4
Corey has also reported the decarboxylation of sodium
trichloroacetate and subsequent addition to carbonyl
compounds as an alternative route to trichloromethyl
carbinols that avoids the use of strong base.5
In this paper we describe our discovery that the
reaction between chloroform and carbonyl compounds can
be promoted under milder conditions, in high yields,
using less basic catalysts such as cyclic amidines.6
After screening a broad range of amines (most of which
were ineffective), we discovered that amidines and
guanidines were extremely active promoters of the reac-
tion between chloroform and benzaldehyde (Table 1).
Using 1 equiv of DBU or DBN with a slight excess of
CHCl3 without solvent provided a quantitative yield of
the trichlorocarbinol 3 [entry 1 (optimum condition) and
entry 4]. Using a larger excess of chloroform 2 resulted
in longer reaction times, but similar yields could be
achieved (entry 2). Catalytic amounts of DBU or DBN
were much less effective, suggesting that some decom-
position/protonation of the amidine had occurred (entries
3, 5). Guanidine 6 was also an effective catalyst for this
Ta ble 2. DBU-Ca ta lyzed Ad d ition of Ch lor ofor m to
Ca r bon yl Com p ou n d sa
entry
carbonyl compounds
benzaldehyde
2-chlorobenzaldehyde
2-anisaldehyde
time (h)
yield (%)b
1
2
3
3
4
6
98
94
95
4
4-anisaldehyde
6
95
5
6
7
8
2-nitrobenzaldehyde
4-nitrobenzaldehyde
mesitaldehyde
10 min
10 min
1
2
98
98
25c
80
propanaldehyde
9
isobutyraldehyde
cyclohexanecarboxaldehyde
trimethylacetaldehyde
acetone
2
7
2
24
24
80
10
11
12
13
98
30c
75c
84c
cyclohexanone
a
Reactions performed in absence of solvent using a carbonyl
compound:CHCl3:DBU ratio of 1:2:1. b Isolated yields. c Remainder
is starting material. Longer reaction times did not improve yield.
transformation (entry 6). In none of these cases were
there any products derived from the Cannizzaro reaction,
even from those employing electron-withdrawing aromat-
ics (these are particularly prone to such side reactions)
(Table 2, entries 5,6).
The reaction was applied to a range of aromatic and
aliphatic aldehydes and ketones (Table 2). High yields
were obtained using stoichiometric amounts of DBU in
all cases except those involving exceptionally hindered
carbonyl groups (entries 7, 11). In these cases, and
reactions with ketones, a significant amount of the
carbonyl compound remained. The high yields with
aliphatic aldehydes and ketones bearing enolizable pro-
tons are noteworthy (entries 8-10, 12, 13) as the use of
chloroform and strong base results in extensive aldol side
reactions in such cases.5 The mild conditions were further
exemplified in the reaction of the highly base sensitive
substrate p-acetoxybenzaldehyde 7, which certainly can-
not be employed using the conventional treatment with
strong base. This substrate reacted cleanly to give the
intermediate tricarbinol, but this was rapidly acylated
by the starting aldehyde to give 8 in 50% yield together
‡ Current address: School of Chemistry, University of Bristol,
Bristol BS8 1TS; v.aggarwal@bristol.ac.uk.
(1) Corey, E. J .; Link, J . O. J . Am. Chem. Soc. 1992, 114, 1906-
1908.
(2) For a review, see: Reeve, W. Synthesis 1971, 131-138.
(3) (a) Bal’on, Y. G.; Paranyuk, V. E.; Shul’man, M. D. Zh. Obshch.
Chim. 1974, 44, 2633. (b) Viehe, H. G.; Franchimont, E.; Valange, P.
Chem. Ber. 1963, 96, 426-431. (c) Bergmann, E. D.; Ginsburg, D.
Lavie, D. J . Am. Chem. Soc. 1950, 72, 5012. (d) Merz, A.; Tomahogh,
R. Chem. Ber. 1977, 110, 96-106.
(4) Wyvratt, J . M.; Hazen, G.; Weinstock, L. M. J . Org. Chem. 1987,
52, 944-945.
(5) Corey, E. J .; Link, J . O.; Shao, Y. Tetrahedron Lett. 1992, 3435-
3438.
(6) (a) Oediger, H.; Moller, F.; Eiter, K. Synthesis 1972, 591-598.
(b) Barton, D. H. R.; Elliott, J . D.; Gero, S. D. J . Chem. Soc., Perkin
Trans. 1 1982, 2085-2090.
10.1021/jo000584n CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/28/2000

7212 J . Org. Chem., Vol. 65, No. 21, 2000
Notes
ketones were distilled prior to use except for 4-nitrobenzalde-
hyde, which was used as supplied.
Sch em e 1
Gen er a l P r oced u r e, r-(Tr ich lor om eth yl)ben zyl Alcoh ol.
To a mixture of benzaldehyde (200 µL, 1.97 mmol) and chloro-
form (310 µL, 3.94 mmol) was added dropwise under nitrogen 1
equiv of DBU (300 µL, 1.97 mmol). The reaction was stirred for
2 h and then diluted with chloroform (20 mL) and washed with
2 N HCl (3 × 10 mL) to remove the catalyst. The organic phase
was then dried (Na2SO4) and evaporated to yield the trichloro-
carbinol (430 mg, 98% yield).
Sch em e 2
2-Acetoxy-2-(4-a cetoxyp h en yl)-1,1,1-tr ich lor oeth a n e (8).
1H NMR (CDCl3) 2.21 (3H, s), 2.30 (3H, s), 6.38 (1H, s), 6.90-
7.15 (2H, m), 7.59-7.66 (2H, m); 13C NMR 20.8, 21.2, 81.8, 95.1,
101.2, 121.2, 130.5, 130.9, 151.7, 168.6, 169.7; MS m/z (EI+) 324
[M+(3 × 35Cl), 25%, Cl3 isotope pattern], 165 (75), 123 (100)
(Found M+, 323.9711. C12H11O4Cl3 requires M+, 323.9722)
(Found C, 44.34; H, 3.49. C12H11O4Cl3 requires C, 44.27; H, 3.41).
1,1,1-(Tr ich lor om eth yl)ben zen e Meth a n ol 4-Meth ylben -
zen esu lfon a te (10).7a To a mixture of benzaldehyde (500 µL,
4.92 mmol) and chloroform (790 µL, 9.84 mmol) was added
dropwise under nitrogen 1 equiv of DBU (740 µL, 4.92 mmol).
The reaction was stirred for 3 h and cooled to 0 °C, and a solution
of p-toluenesulfonyl chloride (1.125 g, 5.9 mmol) and triethy-
lamine (680 µL, 4.92 mmol) in chloroform (20 mL) was added
dropwise. After 12 h the reaction was diluted with ether (50 mL)
and washed with saturated NH4Cl (3 × 30 mL). The organic
phase was dried over Na2SO4, filtered, and evaporated to give a
solid which was purified by chromatography (petrol-60/80:ether
) 8:1, Rf ) 0.3) to give 1,1,1-(trichloromethyl)benzene methanol
4-methylbenzenesulfonate as a white solid (1.8 g, 95% yield):
1H NMR (CDCl3) 2.38 (3H, s), 5.85 (1H, s), 7.15 (2H, d, J ) 8.3
Hz), 7.18-7.32 (3H, m), 7.42 (2H, d, J ) 8.3 Hz), 7.60 (2H, d, J
) 8.3 Hz); 13C NMR (CDCl3) 21.9, 88.8, 99.0, 127.8, 128.4, 128.8,
129.0, 129.3, 1296.
2-Acetoxy-2-p h en yl-1,1,1-tr ich lor oeth a n e (12).7b To a mix-
ture of benzaldehyde (500 µL, 4.92 mmol) and chloroform (790
µL, 9.84 mmol) was added dropwise under nitrogen 1 equiv of
DBU (740 µL, 4.92 mmol). The reaction was stirred for 3 h and
cooled to 0 °C and acetic anhydride (490 µL, 5.2 mmol) was added
dropwise. After 2 h, the reaction mixture was diluted with ethyl
acetate (50 mL) and washed with 2N HCl (3 × 30 mL) and
aqueous saturated Na2CO3 (3 × 30 mL). The organic phase was
dried over Na2SO4, filtered, and evaporated to give 2-acetoxy-
2-phenyl-1,1,1-trichloroethane (1.28 g, 98% yield) pure by NMR:
1H NMR (CDCl3) 2.22 (3H, s), 6.37 (1H, s), 7.3-7.45 (3H, m),
7.50-7.70 (2H, m); 13C NMR (CDCl3) 20.8, 82.7, 99.5, 128.1,
128.3, 129.8, 133.2, 168.6; MS m/z (EI+) 266 (M+, 15%), 149 (55),
107 (100) (Found M+, 265.9657. C10H9O2Cl3 requires M+,
265.9668).
with 4-hydroxybenzaldehyde 9 (Scheme 1). None of the
intermediate trichlorocarbinol was detected, indicating
that an extremely fast in situ acylation occurred.
Trichlorocarbinols have recently been used as inter-
mediates in the synthesis of acetylenes7a and vinyl
dichlorides,7b thus extending their utility. In each case
the trichlorocarbinol, which was derived from the corre-
sponding aldehyde, was first converted into the corre-
sponding tosylate or acetate, followed by treatment with
MeLi or Zn/AcOH.7 We have found that the DBU-
promoted method for formation of the trichlorocarbinol
can also be coupled with tosylation or acylation, leading
to a highly efficient one-pot synthesis of intermediates
10 and 12 (Scheme 2). Thus, aldehydes can now be
converted into acetylenes and vinyl dichlorides in two
steps using mild conditions which, in particular, are
amenable to scale-up.
The reaction protocol for formation of the trichloro-
carbinols is exceptionally simple: reactions are conducted
at ambient temperature and pressure, and in the absence
of solvent. Washing with water removes the amidine and
gives the product in high yield, which in many cases is
pure by 1H/13C NMR. This probably represents the
simplest and best method to date to prepare these useful
compounds.
Registr y Nu m ber s (p r ovid ed by th e a u th or s). R-(trichlo-
romethyl)benzyl alcohol, 2000-43-3; 2-chloro-R-(trichlorometh-
yl)benzyl alcohol, 10291-39-1; 2-methoxy-R-(trichloromethyl)-
benzyl alcohol, 58369-59-8; 4-methoxy-R-(trichloromethyl)benzyl
alcohol, 14337-31-6; 2-nitro-R-(trichloromethyl)benzyl alcohol,
62798-94-1; 4-nitro-R-(trichloromethyl)benzyl alcohol, 54075-
25-1; 2,4,6-trimethyl-R-(trichloromethyl)benzyl alcohol, 172649-
86-4; 1,1,1-trichloro-2-butanol, 6111-61-1; 1,1,1-trichloro-3-
methyl-2-butanol, 32766-45-3; 2,2,2-trichloro-1-cyclohexyl-
ethanol, 57741-12-5; 1,1,1-trichloro-3,3-dimethyl-2-butanol,
41262-30-0; 1,1,1-trichloro-2-methyl-2-propanol, 57-15-8;
1-(trichloromethyl)-1-cyclohexanol, 3508-84-7; 2-acetoxy-2-(4-
acetoxy-phenyl)-1,1,1-trichloro-ethane, 83671-16-3.
Exp er im en ta l Section
R ea gen t s. DBN and guanidine 6 were used as purchased
from Aldrich. DBU, chloroform, and all the aldehydes and
Su p p or tin g In for m a tion Ava ila ble: Spectral data for all
listed compounds including spectra (1H/13C) for compounds 8,
10, and 12. This material is available free of charge via the
Internet at http://pubs.acs.org.
(7) (a) Wang, Z.; Campagna, S.; Yang, K.; Xu, G.; Pierce, M. E.;
Fortunak, J . M.; Confalone, P. N. J . Org. Chem. 2000, 65, 1889-1891.
(b) Wang, Z.; Campagna, S.; Xu, G.; Pierce, M. E.; Fortunak, J . M.;
Confalone, P. N. Tetrahedron Lett. 2000, 41, 4007-4009.
J O000584N