An improved preparation and a new application of trichloromethylcarbinols from enolizable ketones

Article abstract of DOI:10.1016/j.tetlet.2014.03.118

We report an improved method for the preparation of trichloromethylcarbinols from enolizable ketones. Trichloromethylcarbinols were obtained in good to excellent yields by using of a combination of CHCl ₃, n-BuLi, and chlorotitanium (IV) triiso

Full text of DOI:10.1016/j.tetlet.2014.03.118

Tetrahedron Letters 55 (2014) 3137–3139
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Tetrahedron Letters
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An improved preparation and a new application of
trichloromethylcarbinols from enolizable ketones
⇑
⇑
Jing Li , Brenden Derstine, Takahiro Itoh, Jaume Balsells
Department of Process Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report an improved method for the preparation of trichloromethylcarbinols from enolizable
ketones. Trichloromethylcarbinols were obtained in good to excellent yields by using of a combination
of CHCl3, n-BuLi, and chlorotitanium (IV) triisopropoxide. Hydrolysis of the trichloromethylcarbinol to
Received 27 January 2014
Revised 25 March 2014
Accepted 26 March 2014
Available online 5 April 2014
an a,b-unsaturated ester was also explored.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Trichloromethylcarbinols
Enolizable ketones
Low-valent titanium
Addition reaction
a,b-Unsaturated ester
Introduction
to suppress the ketone enolization. However, the poor solubility of
MgCl2 salts also introduced significant operational challenges, such
as gumming and balling of salts and formation of emulsions during
work up.13 As an alternative, he developed an in situ formation of
the otherwise difficult to handle trimethyl (trichloromethyl)
silane and its application to the synthesis of TMS-protected
trichloromethylcarbinols which, after deprotection, can provide
trichloromethylcarbinols.13
Trichloromethylcarbinols are very versatile intermediates in
organic synthesis. It has been used for over a century to afford
substituted carboxylic acids upon treatment with base and an
a
-
appropriate nucleophile. Various nucleophiles have been explored
in this Jocic-type process1 such as hydroxide,1 alcohol and phenol,2
azide,3 amine,3i,4 fluoride,2g,5 cyanide,
hydride,2f and thiols.2f
2g
Other applications of trichloro-methylcarbinol include the forma-
tion of epoxides,6 vinyl dichlorides7, terminal alkynes,8 and ring
expanded ketones.9
In this Letter, we describe a simple and straightforward one-
step method to synthesize trichloromethylcarbinols from sterically
hindered and enolizable ketones by adding triisopropoxytitanium
chloride. We also found further hydrolysis of the trichloromethyl-
carbinol moiety could lead to a,b-unsaturated esters, a new appli-
cation for this versatile functional group.
The preparation of trichloromethylcarbinols usually involves
base-promoted addition of chloroform to carbonyl compounds.
Strong bases, such as n-BuLi, LiHMDS, potassium tert-butoxide in
liquid ammonia, sodium in liquid ammonia, or powdered potas-
sium hydroxide are commonly used.10 Competing enolization is a
major cause of low yield for enolizable ketone or aldehyde sub-
strates. Although it has been reported that some mild amidine
bases (like DBU) can promote the reaction between chloroform
and carbonyl compounds, particularly aldehydes, this method
has limited application on ketone substrates.11 Corey’s method of
using decarboxylation of sodium trichloroacetate for addition reac-
tions is also limited to aldehyde substrates.12 MgCl2 has been tried
Results
In the course of our research program, we were required to
develop a scalable synthesis of trihalomethylcarbinol 2a from
ketone 1a (Scheme 1). Several different conditions, such as CHCl3/
O
HO
CCl3
Bn2N
N
Bn2N
N
⇑
Corresponding authors. Tel.: +1 215 652 6603; fax: +1 215 652 7310 (J.L.);
1a
2a
tel.: +1 215 652 6659; fax: +1 215 652 7310 (J.B.).
E-mail addresses: jing_li9@merck.com (J. Li), jaume_balsells@merck.com
(J. Balsells).
Scheme 1. Initial substrate for ketone to trihalomethylcarbinol transformation.
http://dx.doi.org/10.1016/j.tetlet.2014.03.118
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3138
J. Li et al. / Tetrahedron Letters 55 (2014) 3137–3139
Table 1
Table 2
Impact of TiCl(OiPr)3 to CHCl3/ketone addition reactionsa
Chlorotitanium (IV) triisopropoxide promoted addition of chloroform to ketonesa
Product 2
Assay yieldb
no additive
(%)
Isolated yieldc Isolated yieldc
Entry
Ketones
Products
Isolated
with MgCl2
(%)
with TiCl(OiPr)3
(%)
yieldb (%)
HO
CCl3
HO
CCl3
1
2
3
1c
95
93
91
0
—
91
78
2c
N
Bn2N
HO
N
2a
HO CCl3
1d
CCl3
28
41
2d
2b
HO
CCl3
a
Reaction conditions: CHCl3 (5 equiv), n-BuLi (5 equiv), TiCl(OiPr)3 or MgCl2
1e
(0 equiv or 2 equiv), THF (0.5 M).
2e
b
Assay yield was determined by HPLC comparison with a standard solution of
HO
HO
purified product.
c
CCl3
Purified by flash chromatography on silica gel.
4
5
1f
84
93
2f
CCl3
HO
R1
O
TiCl(Oi-Pr)3, CHCl3, THF
then n-BuLi, -60 °C
CCl3
R2
1g
R1
R2
2g
2
HO CCl3
1
6
7
8
1h
1i
88
96
71
Scheme 2. Titanium promoted synthesis of trihalomethylcarbinol.
2h
HO CCl3
DBU, CHBr3/LiOH, CHBr3/LiHMDS, and CHCl3/n-BuLi were investi-
gated unsuccessfully. Most of the starting ketone remained unre-
acted under these conditions suggesting the reaction suffered
from poor reactivity and stability of the chloroform carbanion as
well as ketone enolization, which was apparent in the case of
2i
HO CCl3
1j
2j
CHBr3/LiHMDS, where trace amounts of
observed as a byproduct of the reaction.
a-bromination were
HO CCl3
Scouting for an experimentally simple solution to suppress
the enolization problem that would be amenable to the gener-
ation of multiple and diverse analogs, we turned our attention
to the use of organotitanium reagents. Organotitanium reagents
have been shown to be superior to traditional Grignard reagents
for additions to sterically hindered and/or enolizable ketones.14
Treatment of chloroform carbanion with TiCl(OiPr)3 at a low
temperature (À60 °C) followed by addition of the ketone start-
ing material 1a led to a clean conversion to the desired triha-
lomethyl-carbinol 2a. Looking for the simplest possible
experimental procedure, we explored the order of addition of
the reagents and found that simply combining the ketone,
CHCl3, and TiCl(OiPr)3 in cold THF and adding n-BuLi slowly
provided a similar result. The drastic improvement on substrate
1a encouraged us to explore the scope of this transformation.
We started by carrying out the same comparison of reaction
conditions on indanone 1b. By comparison, the reaction without
any additive only gave 28% assay yield, the reaction with
2 equiv MgCl2 gave 41% isolated yield, while the reaction with
2 equiv TiCl(OiPr)3 provided 83% assay yield and 78% isolated
yield (Table 1).
9
1k
1l
83c
45
2k
OH
CCl3
10
2l
a
Reaction conditions: CHCl3(5 equiv), n-BuLi (5 equiv), TiCl(OiPr)3 (2 equiv), THF
(0.5 M).
b
Purified by flash chromatography on silica gel.
Relative stereochemistry determined by comparision of 1H NMR with literature
c
data9b (dr > 9:1 by 1H NMR).
Cl
Cl
HO
CCl3
1) H2SO4, THF
NaOMe
Bn2N
N
Bn2N
N
2a
3a
OMe
2) NaOMe, MeOH,
then HCl
MeO
OMe
CO2Me
H+
The success of these experiments prompted us to examine the
improved reaction conditions on a variety of other enolizable
ketones (Scheme 2). The results summarized in Table 2 indicate
that the titanium-promoted addition reaction works well on a
number of ketones, including alkyl-aryl (entries 1–6), bisalkyl
Bn2N
N
4a
Bn2N
N
5a
Scheme 3. Dehydration and hydrolysis of trihalomethylcarbinol. Reagents and
conditions: (1) H2SO4, THF, 70 °C; (2) NaOMe, MeOH, 60 °C, then aq HCl, 80% for two
steps.
(entries 8–9), and
a,b-unsaturated ketones (entry 7), to give the
expected products in satisfactory yields. The presence of more ste-
rically demanding branched alkyl groups (entries 4, 5, and 9) had
no effect on the product formation as high yields were achieved
in all of these examples. This protocol was also applied to a highly
enolizable substrate, 2-indanone, to give desired trichloromethyl-
carbinol in moderate yield (entry 10).

J. Li et al. / Tetrahedron Letters 55 (2014) 3137–3139
3139
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It is reported that trihalomethylcarbinols can be reductively
eliminated to vinyl dihalides by a reducing metal halide.15 Under
non-reductive acidic condition, SOCl2 can dehydrate a trihalometh-
ylcarbinol into a mixture of isomeric forms, such as vinyl trichloro-
methyl- and chloro- vinyl dichloride.16 We wondered whether
under more forceful acidic conditions we could drive the reaction
into a more thermodynamically stable isomer and then through
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basic hydrolysis to provide and a,b-unsaturated ester. To test this
idea, we treated trichloromethylcarbinol 2a with excess sulfuric
acid in warm THF. A major product 3a was formed after a few
hours of heating as determined by LCMS. After work up, the crude
product 3a was directly subjected to NaOMe in MeOH. Based on
LCMS data, trimethoxy analog 4a was gradually formed upon heat-
ing. Upon acidic work up,
a,b-unsaturated ester 5a was formed and
isolated in 80% overall yield from 2a.
a
,b-Unsaturated esters are a
substrate for asymmetric hydrogenation, making this synthetic
approach a potential route for enantioselective carbon homologa-
tion of ketones (Scheme 3).
9. (a) Taguchi, H.; Yamamoto, H.; Nozaki, H. J. Am. Chem. Soc. 1974, 96, 3010; (b)
Falck, J. R.; He, A.; Reddy, L. M.; Kundu, A.; Barma, D. K.; Bandyopadhyay, A.;
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Summary and conclusions
In summary, chlorotitanium (IV) triisopropoxide mediated
addition of chloroform to enolizable ketones offers
a facile,
convenient, and efficient method for the synthesis of trichlorom-
ethylcarbinols.17 We also demonstrated the conversion of
trihalomethylcarbinol 2a to provide an a
,b-unsaturated ester.18
15. Wolf, R.; Steckhan, E. J. Chem. Soc., Perkin Trans. 1 1986, 5, 733–739.
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Acknowledgments
We thank C. Ross, S. Ceglia, and J. Brouillette for structure con-
firmation on selected products using HRMS and NMR. We also
thank Cameron Cowden and Michael Kress for helpful comments
on the manuscript.
17. General procedure for the preparation of trihalomethylcarbinols: A 50 mL round
bottomed dry flask containing 2,3-dihydro-1H-inden-1-one (1b, 200 mg,
1.5 mmol), CHCl3 (0.61 mL, 7.8 mmol), chlorotitanium (IV) triisopropoxide
(790 mg, 3.0 mmol), and THF (3.0 mL) was cooled with dry ice acetone bath
(internal temperature about À60 °C). n-BuLi (2.5 M in hexane, 3.0 mL,
7.5 mmol) was added slowly over 20 min. The reaction was stirred cold for
four hours before quenching with saturated NH4Cl (3 mL) and water (5 mL).
After warm to room temperature, the mixture was extracted with EtOAc
(10 mL Â 3). The combined organics were dried over anhydrous MgSO4 and
concentrated in vacuo. The crude oil was purified by ISCO silica gel
chromatography (EtOAC/Hexane, 0–10% gradient) to give product 2b as a
colorless oil (298 mg, 78% yield).
Supplementary data
Supplementary data (spectroscopic data of selected entries
from Table 1 and Table 2) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
03.118.
18. Conversion of trihalomethylcarbinol 2a to a,b-unsaturated ester 5a: A mixture of
2-(dibenzylamino)-5-(trichloromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-
5-ol (2a, 5.6 g, 12.5 mmol) and concentrated sulfuric acid (21.0 mL, 375 mmol)
in THF (56.0 mL) was heated at 70 °C for 15 h. The mixture was cooled to room
temperature, the pH was adjusted to ꢀ10 with 5 N NaOH, and extracted with
EtOAc. The EtOAc layer was stirred with anhydrous MgSO4 and activated
charcoal (Darco KB-B) for one hour at room temperature before being filtered
and concentrated. The orange solid 3a (6.6 g) was taken up in MeOH (168 mL)
and DMF (56 mL) and added NaOMe (20.2 g, 375 mmol). The mixture was
stirred at 60 °C for one hour, and added slowly into a mixture of EtOAc, concd.
HCl (35 ml), and water. The separated aqueous layer was extracted again with
EtOAc and the combined organic layer was concentrated and purified by ISCO
silica gel chromatography (EtOAC/Hexane, 0–60% gradient) to give the final
product 5a (3.7 g, 80% yield).
References and notes
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