One-pot synthesis of trichloromethyl carbinols from primary alcohols

Article abstract of DOI:10.1021/jo300725v

Versatile trichloromethyl carbinols can be prepared in one pot from primary alcohols by treatment with Dess-Martin periodinane (DMP) in CHCl₃ followed by introduction of commercially available 1,5,7-triazabicyclo[4.4.0] dec-5-ene (TBD). A modification of the method was used to convert chiral primary alcohol (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol to the corresponding trichloromethyl carbinol with complete stereochemical fidelity, despite the reactant proceeding through a base-sensitive aldehyde intermediate.

Full text of DOI:10.1021/jo300725v

Note
pubs.acs.org/joc
One-Pot Synthesis of Trichloromethyl Carbinols from Primary
Alcohols
Manoj K. Gupta, Zhexi Li, and Timothy S. Snowden*
Department of Chemistry, The University of Alabama, P.O. Box 870336, Tuscaloosa, Alabama 35487-0336, United States
S
* Supporting Information
ABSTRACT: Versatile trichloromethyl carbinols can be
prepared in one pot from primary alcohols by treatment
with Dess−Martin periodinane (DMP) in CHCl3 followed by
introduction of commercially available 1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD). A modification of the
method was used to convert chiral primary alcohol (R)-
(−)-2,2-dimethyl-1,3-dioxolane-4-methanol to the correspond-
ing trichloromethyl carbinol with complete stereochemical
fidelity, despite the reactant proceeding through a base-
sensitive aldehyde intermediate.
richloromethyl carbinols (3) are useful precursors to α-
We considered two possibilities for conversion of 1 to 3
without isolation of 2 based upon the requirements for
trichloromethide formation and its addition to aldehydes. The
most significant factor is the solvent, in the case of
decarboxylation of sodium trichloroacetate, and the choice of
base, in the case of trichloromethide formation from chloro-
form. Pairing reliable oxidation methods with these require-
ments for trichloromethide formation would provide an
opportunity to bypass isolation of 2 in the preparation of 3.
Modifications of activated dimethyl sulfoxide-mediated11 or
Dess−Martin periodinane-based12 oxidations were appealing
options for evaluation of potential one-pot oxidation−
trichloromethylation reactions because of the generality of the
oxidation methods, and because both feature reaction
conditions that appeared amenable to modification for in situ
trichloromethylation of the aldehyde formed by the alcohol
oxidation process.
1
2
Tamino acids, α-substituted carboxylic acids, substituted
enoic acids,3 heterocycles,4 terminal alkynes,5 and 1,1-
dichloroalkenes,6 to name just a few compound classes.7 The
carbinols (3) are typically prepared by addition of weakly
nucleophilic trichloromethide to aldehydes (2). Trichlorome-
thide is formed by decarboxylation of sodium trichloroacetate
in DMF8 or DMSO9 or by treatment of chloroform with a base
(Scheme 1).1c,10 The latter method is generally restricted to
additions to hindered or nonenolizable aldehydes because of
the potential for side reactions resulting from enolate
formation.
Scheme 1. Preparation of Trichloromethyl Carbinols from
Primary Alcohols
We began our investigation by exploring modifications of the
Swern,13 Parikh−Doering,14 Albright−Goldberg,15 and related
oxidations.11 The employment of DMSO in these approaches
suggested that introduction of sodium trichloroacetate during,
or after completion of, the alcohol oxidation step might allow
for trichloromethide formation and subsequent addition to the
incipient aldehyde in a one-pot operation. However, systematic
changes to the amount of DMSO included, the DMSO
activator, the base used in the oxidation, and the amount of
time allowed for addition of sodium trichloroacetate did not
lead to satisfactory formation of 3 in a one-pot process. In most
cases, the oxidation step proceeded as expected; however,
trichloromethide formation or its addition to 2 was incomplete
under all conditions screened even after more than 48 h.
The instability of many aldehydes coupled with the attractive
potential of primary alcohols serving as direct precursors to
trichloromethyl carbinols led us to consider means of
converting 1 to 3 without isolating the intermediate aldehydes
2 (Scheme 1). Because many aldehydes used to prepare
trichloromethyl carbinols are formed by oxidation of the
corresponding alcohols, a convenient one-pot preparation of 3
from 1 would enhance step economy in the many applications
involving 3. The combination of oxidation and in situ
trichloromethylation would also obviate the need for isolation
and purification of aldehydes 2, many of which are difficult to
isolate or store without some decomposition.
Received: April 13, 2012
© XXXX American Chemical Society
A
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Note
Hence, only modest yields of 3 with isolation of unreacted 2
were encountered in even the best cases.
concentration. When we screened DBU and TBD at 0.67 M
aldehyde concentrations, we found that DBU was markedly less
effective under the more dilute reaction conditions needed to
allow for efficient DMP oxidation of a primary alcohol (Table
1, entry 8). However, TBD proved highly capable at both 2.5
and 0.67 M substrate concentrations (Table 1, entries 7 and 9),
thereby making it attractive for use in our desired one-pot
oxidation-trichloromethyl reactions. The cyclic guanidine even
permitted effective trichloromethylation of 4-methoxybenzalde-
hyde after 24 h (Table 1, entry 11), whereas DBU showed poor
conversion (Table 1, entry 10).
Because of limited success in modifications of activated
DMSO-mediated oxidations, we shifted our attention to
modifying the Dess−Martin periodinane (DMP)-based oxida-
tion of 1 to develop a one-pot approach to 3. We reasoned that
substituting chloroform for the dichloromethane typically
employed as the solvent in DMP oxidations and then adding
a base capable of deprotonating chloroform to form
trichloromethide should promote the formation of 3 from 1.
The key to this approach was identifying a base capable of
deprotonating weakly acidic chloroform (pKa = 13.6),16 thereby
potentially allowing the poorly nucleophilic trichloromethide to
add to the intermediate aldehyde.
With TBD identified as the optimal base, we evaluated its
ability to promote trichloromethylation of a series of aldehyde
intermediates generated by initial DMP oxidation of the
corresponding primary alcohols in CHCl3 (Table 2). The
alcohol oxidations did not proceed in high yields when DMP
and TBD were combined with the alcohol substrates in CHCl3,
perhaps because of the guanidine competing with the primary
alcohol for coordination to the acetoxyperiodinane intermedi-
ates.17 However, by combining the oxidant and the alcohol in
CHCl3 and then adding 3.3 equiv of TBD when the oxidation
was judged complete by TLC analysis (4−8 h), the desired
trichloromethyl carbinols were afforded in yields comparable to
those resulting from separate alcohol oxidation and aldehyde
trichloromethylation reactions (vide infra). The method
necessitates the use of at least 3 equiv of base, since 2 equiv
of acetic acid are generated from DMP during the oxidation
step. Addition of 2 equiv of NaOH to neutralize the generated
acetic acid and 1.3 equiv of TBD to promote the
trichloromethylation after the alcohol oxidation did not afford
the desired trichloromethyl carbinols. Also, replacement of
TBD with commercially available 1,5,7-triazabicyclo[4.4.0]dec-
5-ene bound to polystyrene afforded products 3 in very low
yields (5−15%), even after reaction times of greater than 48 h.
The one-pot oxidation−trichloromethylation strategy
worked well with both electron-rich and electron-poor
functionalized benzyl alcohols (1a−1d) and with 2-naphthale-
nemethanol (1e). It also provided yields of 70% with 2-
furylmethanol (1j) and 61% with 2-thienylmethanol (1k),
compounds which form sensitive aldehydes that are difficult to
oxidize, isolate, and trichloromethylate in high yields. Similarly,
allylic alcohols 1l and 1m were trichloromethylated in good
yields. Substrates proceeding through enolizable aldehydes
(1f−1i) were trichloromethylated in yields ranging from 60 to
75%, although these compounds generally required longer
reaction times than most of the nonenolizable substrates for the
trichloromethylations to reach completion. Propargylic alcohols
1n and 1o were not compatible substrates, since several
byproduct were formed upon addition of base to the
intermediate ynals.
Several commercially available bases were screened for their
ability to form trichloromethide from chloroform and to
promote addition to benzaldehyde and to less electrophilic 4-
methoxybenzaldehyde (Table 1). As expected, triethylamine
Table 1. Screening of Bases for Trichloromethylation of
Benzaldehydes in Chloroform
a
b
entry
R
[2] (M)
base
time (h)
3:2 (%)
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2.5
Et3N
DBU
DBU
TMG
TMG
TBD
TBD
DBU
TBD
DBU
TBD
24
1
<5:95
2
2.5
82:18
>98:2
23:77
86:14
90:10
>98:2
45:55
>98:2
26:74
87:13
3
2.5
16
1
4
2.5
5
2.5
24
1
6
2.5
7
2.5
3
8
0.67
0.67
0.67
0.67
24
3
9
10
11
4-CH3OPh
4-CH3OPh
24
24
a
Reactions were conducted by treating 2 (0.50 mmol) with the
b
corresponding base (0.60 mmol) in CHCl3. Relative percentages of 3
and 2 were determined by 1H NMR analyses of crude reaction
mixtures.
was insufficiently basic to form useful quantities of trichlor-
omethide (Table 1, entry 1), and 1,1,3,3-tetramethylguanidine
(TMG) gave inferior results (Table 1, entries 4−5). Aggarwal
and co-workers reported that DBU may be used to deprotonate
CHCl3 in a convenient procedure for the trichloromethylation
of aldehydes. They also reported one example of 7-methyl-
1,5,7-triazabicyclo[4.4.0]dec-5-ene serving a comparable func-
tion.10b In comparing the trichloromethylation yields and
reaction times between DBU and 1,5,7-triazabicyclo[4.4.0]dec-
5-ene (TBD), we noted that the reaction with the latter was
faster than with DBU, although both bases ultimately proved
effective in highly concentrated solutions of substrate (2.5 M)
(Table 1, entries 3 and 7). Dess−Martin periodinane shows
incomplete solubility in CH2Cl2 and CHCl3 at 2.5 M
concentration, but it is fully soluble at a 0.67 M substrate
We compared the traditional two step oxidation−trichlor-
omethylation strategy to the one-pot sequential procedure
outlined herein with four varied primary alcohols (Table 3).
Notably, the one-pot process offered yields comparable or
superior to the two-step approach with substrates 1b and 1k,
although the overall yields were slightly lower using the one-pot
approach with cinnamyl alcohol (1l) and hydrocinnamyl
alcohol (1f). However, even with the latter compounds, the
new procedure obviates the need for isolation and purification
of the intermediate aldehydes and, hence, offers advantages in
terms of total materials costs and overall preparation time.
Next we examined the ability to oxidize−trichloromethylate a
primary alcohol (1p) possessing an α-stereocenter that is prone
B
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Note
mixture of diastereomers (S,S)-3p, and (S,R)-3p in 72%
combined yield. Notably, the combined yield of (S,S)-3p and
(S,R)-3p was slightly higher using the one-pot method under
the buffered conditions than that reported for the trichlor-
omethylation of (S)-isopropylideneglyceraldehyde alone
(68%).2d Conversion of the diastereomeric mixture to Mosher
ester derivatives18 confirmed that each was a single stereo-
isomer.19 Hence, no racemization of the stereogenic center
occurred in the intermediate aldehyde under the modified
buffered conditions. Despite the successful employment of the
buffered conditions in the oxidation−trichloromethylation of
1p, this procedure did not improve the yields of 3f, 3g, 3k, 3l,
or 3n relative to the use of TBD in CHCl3, although the
buffered system did allow for generation of 3o, albeit in poor
yield, where TBD failed (Table 2). These results suggest that
the basicity of TBD is not solely responsible for the moderate
yields of these products in the reactions involving the guanidine
base.
Table 2. One-Pot Oxidation−Trichloromethylation of
Primary Alcohols
The introduction of a sequential oxidation−trichloromethy-
lation of primary alcohols now makes it possible to convert
such alcohols to one-carbon homologated carboxylic acids in
two operational steps. Combining the outlined approach with
our previously reported homologation−functionalization pro-
cedure,2f representative alcohols 1e, 1f, 1j, and 1m were
homologated to carboxylic acids 4−7 in 65−79% overall yields
in two steps (Scheme 3). A similar strategy may be employed to
prepare any member of the vast array of products derived from
trichloromethyl carbinols1−7 in just two operational steps
starting from primary alcohols.
In summary, we devised a conversion of primary alcohols to
trichloromethyl carbinols in a convenient one-pot operation.
The approach obviates the isolation and purification of sensitive
aldehydes and is compatible with a wide range of primary
alcohol substrates. Functionalized aryl and heteroaryl meth-
anols and hindered aliphatic alcohols are particularly suitable
for the outlined method. The approach can be combined with
any of the several one-pot transformations of trichloromethyl
carbinols1−7 to rapidly elaborate primary alcohols in a step-
economical fashion.
EXPERIMENTAL SECTION
■
1
General Information. The H spectra were recorded at 500 or
360 MHz as indicated. The 13C NMR spectra were recorded at 125
MHz. High-resolution mass spectra were recorded on an EBE sector
instrument using electron ionization (EI) at 70 eV. Dess−Martin
periodinane was prepared by the method of Boeckman et al.20
General Procedure for the Preparation of Trichloromethyl
Carbinols from Primary Alcohols. Method A. To a solution of
primary alcohol (1.0 mmol) in anhydrous CHCl3 (1.5 mL) was added
Dess−Martin periodinane (509 mg, 1.2 mmol) at 0 °C under an argon
atmosphere. The reaction mixture was brought to room temperature
and allowed to stir until starting alcohol was consumed, as determined
by TLC analysis. TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) (446 mg,
3.2 mmol) was added in 3 portions and stirred very rapidly at 0 °C.
After 6−8 h, the mixture was monitored by TLC. If corresponding
aldehyde remained, 1 equiv of TBD was added with vigorous stirring.
Once the reaction was judged complete, the mixture was diluted with
aqueous NaHCO3 (5 mL) and CH2Cl2 (5 mL). The precipitated
solids were filtered through a bed of diatomaceous earth, the filter cake
was rinsed with CH2Cl2, and the biphasic filtrate was separated. The
aqueous layer was extracted with CH2Cl2 (3 × 10 mL), and then the
combined organic layers were dried (Na2SO4), and the solvent was
evaporated. The resulting residue was eluted through a plug of silica
gel with indicated ratios of EtOAc/hexanes to afford the
corresponding trichloromethyl carbinols.
a
b
All reactions were conducted on a 1 mmol scale. Method A: 1.2
equiv of DMP, CHCl3, 4−8 h, and then 3.3 equiv of TBD, 0 °C to rt,
c
6−48 h. Method B: 1.2 equiv of DMP, DMF, 4−8 h, and then 3.3
equiv of Cl3CCO2Na, 3.3 equiv of Cl3CCO2H, 0 °C to rt, 16−48 h.
d
Yield of purified product.
to racemization upon oxidation (Scheme 2). Treatment of (R)-
(−)-2,2-dimethyl-1,3-dioxolane-4-methanol 1p with DMP in
CHCl3 followed by introduction of 3.3 equiv of TBD after the
alcohol was consumed afforded a complex mixture of polar
materials. We altered the reaction conditions to test an
approach that might allow for sequential oxidation−trichlor-
omethylation of 1p without decomposition or racemization of
the intermediate aldehyde. Conducting the reaction with DMP
in DMF followed by addition of 3.3 equiv of both sodium
trichloroacetate and trichloroacetic acid8 afforded a 63:37
C
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Note
Table 3. Comparative Study of Conventional Two-Step vs Outlined One-Pot Preparations of Trichloromethyl Carbinols from
Varied Primary Alcohols
a
b
DMP oxidation
trichloromethylation
c
entry
compd
R
time (h)
yield (%)
time (h)
yield (%)
product
combined yield / one-pot yield (%)
1
2
3
4
1b
1f
Ph
6
8
4
4
96
94
72
81
18
24
48
12
93
87
78
84
3b
3f
89/87
82/71
56/61
68/62
PhCH2CH2
1k
1l
thiophen-2-yl
E-PhCHCH
3k
3l
a
b
1.2 equiv of DMP, CH2Cl2, 4−8 h, followed by flash chromatography purification. 1.5 equiv of Cl3CCO2Na, DMF, 0 °C to rt, 12−48 h, followed
by flash chromatography purification. Reactions were conducted on a 1.0 mmol scale.
c
Scheme 2. One-Pot Trichloromethylation−Oxidation of a Chiral Alcohol (1p)
Scheme 3. Two-Step One-Carbon Homologation−Functionalization of Primary Alcohols
1
Method B. To a solution of primary alcohol (1.0 mmol) in
anhydrous DMF (1.5 mL) was added Dess−Martin periodinane (509
mg, 1.2 mmol) at 0 °C under an atmosphere of argon. The reaction
mixture was brought to room temperature and allowed to stir until
starting primary alcohol was consumed, as determined by TLC
analysis. The reaction was cooled to 0 °C, then trichloroacetic acid
(539 mg, 3.3 mmol) and sodium trichloroacetate (604 mg, 3.3 mmol)
were quickly added. The reaction was allowed to warm to room
temperature and stir until the corresponding aldehyde was consumed
(12−48 h). After the reaction was judged complete, the mixture was
diluted with aqueous NaHCO3 (5 mL) and ethyl acetate (10 mL), and
the precipitated solids were filtered through a bed of diatomaceous
earth. The filter cake was rinsed with EtOAc, and the biphasic filtrate
was separated. The aqueous layer was extracted with EtOAc (3 × 10
mL), and then the combined organic layers were dried (Na2SO4), and
the solvent was evaporated. The resulting residue was eluted through a
plug of silica gel with indicated ratios of EtOAc/hexanes to afford the
corresponding trichloromethyl carbinols.
mg): H NMR (CDCl3, 360 MHz) δ 7.71−7.53 (m, 2H), 7.50−7.34
(m, 3H), 5.22 (s, 1H), 3.28 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ
134.8, 129.4, 129.2, 127.8, 103.0, 84.4; HRMS m/z calcd for
C8H7Cl3O, 223.9562; found 223.9563.
2,2,2-Trichloro-1-(4-nitrophenyl)-ethanol (3c).2f The crude ma-
terial (prepared following Method A) was purified by flash
chromatography through a plug of silica gel using 8:2 hexane/
EtOAc as the eluant. The indicated compound was obtained as an off-
white solid in 85% yield (230 mg): mp 107−108 °C; 1H NMR
(CDCl3, 500 MHz) δ 8.23 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.8 Hz,
2H), 5.34 (d, J = 3.5 Hz, 1H), 3.64 (d, J = 3.5 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ 148.4, 141.5, 130.4, 122.8, 102.0, 83.4; HRMS
m/z calcd for C8H6Cl3NO3, 268.9413; found 268.9406.
2,2,2-Trichloro-1-(4-(trifluoromethyl)phenyl)ethanol (3d).22 The
crude material (prepared following Method A) was purified by flash
chromatography through a plug of silica gel using 95:5 hexane/EtOAc
as the eluant. The indicated compound was obtained as a white solid
in 86% yield (253 mg): mp 34−35 °C; 1H NMR (CDCl3, 360 MHz) δ
7.76 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 5.28 (d, J = 3.8 Hz,
1H), 3.38 (d, J = 3.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 138.4,
131.4 (q, J = 35.8 Hz), 129.7, 124.7 (q, J = 3.7 Hz), 122.8 (q, J = 270.4
Hz), 102.5, 83.8; 19F NMR (CDCl3, 360 MHz) δ −62.7; HRMS m/z
calcd for C8H6F3O, 175.0371; found 175.0373, which corresponds to
[M − CCl3]+.
2,2,2-Trichloro-1-(4-methoxyphenyl)ethanol (3a).2f The crude
material (prepared following Method A) was purified by flash
chromatography through a plug of silica gel using 9:1 hexane/
EtOAc as the eluant. The indicated compound was obtained as a white
1
solid in 83% yield (212 mg): mp 44−45 °C; H NMR (CDCl3, 500
MHz) δ 7.53 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 5.14 (d, J =
4.1 Hz, 1H), 3.82 (s, 3H), 3.61 (d, J = 4.1 Hz, 1H); 13C NMR (CDCl3,
125 MHz) δ 160.2, 130.3, 127.0, 113.1, 103.3, 84.0, 55.2; HRMS m/z
calcd for C9H9O2Cl3, 253.9668; found 253.9665.
2,2,2-Trichloro-1-napthalen-2-yl-ethanol (3e).2f The crude ma-
terial (prepared following Method A) was purified by flash
chromatography through a plug of silica gel using 9:1 hexane/
EtOAc as the eluant. The indicated compound was obtained as an off-
white solid in 84% yield (232 mg): mp 93−94 °C; 1H NMR (CDCl3,
360 MHz) δ 8.09 (s, 1H), 7.94−7.83 (m, 3H), 7.74 (dd, J = 8.6, 1.8
Hz, 1H), 7.58−7.49 (m, 2H), 5.40 (d, J = 3.9 Hz, 1H), 3.37 (d, J = 3.9
2,2,2-Trichloro-1-phenylethanol (3b).2f,21 The crude material
(prepared following Method A) was purified by flash chromatography
through a plug of silica gel using 9:1 hexane/EtOAc as the eluant. The
indicated compound was obtained as a colorless oil in 87% yield (196
D
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The Journal of Organic Chemistry
Note
Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 133.6, 132.4, 132.2, 129.2,
128.3, 127.6, 127.3, 126.8, 126.3, 126.0, 103.1, 84.5; HRMS m/z calcd
for C12H9OCl3, 273.9712; found 273.9713.
1,1,1-Trichloro-4-methylpent-3-en-2-ol (3m).2f,25 The crude ma-
terial (prepared following Method A) was purified by flash
chromatography through a plug of silica gel using 95:5 hexane/
EtOAc as the eluant. The indicated compound was obtained as a white
1,1,1-Trichloro-4-phenylbutan-2-ol (3f).2f The crude material
(prepared following Method A) was purified by flash chromatography
through a plug of silica gel using 9:1 hexane/EtOAc as the eluant. The
indicated compound was obtained as a colorless oil in 71% yield (180
mg): 1H NMR (CDCl3, 500 MHz) δ 7.41−7.12 (m, 5H), 3.98 (ddd, J
= 10.0, 5.5, 1.8 Hz, 1H), 2.99 (ddd, J = 13.8, 9.1, 4.7 Hz, 1H), 2.86−
2.71 (m, 2H), 2.47−2.31 (m, 1H), 2.04−1.91 (m, 1H); 13C NMR
(CDCl3, 125 MHz) δ 140.7, 128.6, 128.5, 126.3, 104.1, 82.0, 32.9,
31.9; HRMS m/z calcd for C10H11Cl3O, 251.9875; found 251.9885.
1,1,1-Trichloroundecan-2-ol (3g). The crude material (prepared
following Method A) was purified by flash chromatography through a
plug of silica gel using 95:5 hexane/EtOAc as the eluant. The indicated
compound was obtained as a colorless oil in 60% yield (165 mg): IR
1
solid in 80% yield (163 mg): mp 85−86 °C; H NMR (CDCl3, 500
MHz) δ 5.36 (dd, J = 8.3, 1.2 Hz, 1H), 4.78 (dd, J = 8.3, 6.0 Hz, 1H),
2.67 (d, J = 6.0 Hz, 1H), 1.83 (s, 3H), 1.81 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 142.5, 119.5, 103.6, 79.5, 26.1, 19.2; HRMS m/z
calcd for C5H9O, 85.0653; found 85.0650, which corresponds to [M −
CCl3]+.
1,1,1-Trichloro-4-phenylbut-3-yn-2-ol (3n).23 The crude material
(prepared following Method A) was purified by flash chromatography
through a plug of silica gel using 95:5 hexane/EtOAc as the eluant.
The indicated compound was obtained as a colorless oil in 34% yield
1
(85 mg): H NMR (CDCl3, 500 MHz) δ 7.54−7.47 (m, 2H), 7.42−
7.29 (m, 3H), 5.04 (d, J = 9.0 Hz, 1H), 3.10 (d, J = 9.0 Hz, 1H); 13C
NMR (CDCl3, 125 MHz) δ 132.0, 129.4, 128.4, 121.2, 101.1, 88.1,
83.0, 75.8; HRMS m/z calcd for C10H7Cl3O, 247.9562; found
247.9559.
1
(film) 3431, 2926, 2856, 1461, 1266 cm−1; H NMR (CDCl3, 360
MHz) δ 4.00 (ddd, J = 9.4, 5.6, 1.9 Hz, 1H), 2.65 (dd, J = 5.6, 1.5 Hz,
1H), 2.11−1.98 (m, 1H), 1.74−1.56 (m, 2H), 1.50−1.41 (m, 1H),
1.37−1.21 (m, 12H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 104.4, 83.0, 31.9, 31.5, 29.5, 29.4, 29.3, 29.2, 26.1, 22.7, 14.1;
HRMS m/z calcd for C10H21O, 157.1592; found 157.1586, which
corresponds to [M − CCl3]+.
1,1,1-Trichloronon-3-yn-2-ol (3o). The crude material (prepared
following Method B) was purified by flash chromatography through a
plug of silica gel using 98:2 hexane/EtOAc as the eluant. The indicated
compound was obtained as a colorless oil in 18% yield (45 mg): IR
(film) 3387, 2932, 2860, 1621, 1379 cm−1; 1H NMR (500 MHz,
CDCl3) δ 4.78 (dt, J = 8.8, 1.9 Hz, 1H), 2.95 (d, J = 8.8 Hz, 1H), 2.26
(td, J = 7.1, 1.9 Hz, 2H), 1.60−1.49 (m, 2H), 1.43−1.26 (m, 4H), 0.90
(t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 101.6, 89.8, 75.4,
74.6, 30.9, 27.7, 22.1, 18.6, 13.9; HRMS m/z calcd for C8H13O [M −
CCl3]+, 125.0966; found 125.0968.
6-[(tert-Butyldimethylsilyl)oxy]-1,1,1-trichlorohexan-2-ol (3h).2f
The crude material (prepared following Method A) was purified by
flash chromatography through a plug of silica gel using 95:5 hexane/
EtOAc as the eluant. The indicated compound was obtained as a
1
colorless oil in 62% yield (208 mg): H NMR (CDCl3, 500 MHz) δ
4.01 (ddd, J = 9.0, 5.6, 1.8 Hz, 1H), 3.69−3.63 (m, 2H), 2.89 (s, 1H),
2.14−2.04 (m, 1H), 1.78−1.48 (m, 5H), 0.90 (s, 9H), 0.06 (s, 6H);
13C NMR (CDCl3, 125 MHz) δ 104.3, 83.1, 63.0, 32.2, 31.2, 22.8,
19.2, 18.4, −5.3; HRMS m/z calcd for C8H16Cl3SiO2 [M − C4H9]+,
276.9985; found 276.9977.
(S)-(−)-2,2,2-Trichloro-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-
ethanol ((S,S)-3p). The crude material (prepared following Method
B) was purified by flash chromatography through a plug of 1%
pyridine-saturated silica gel using 95:5 hexane/EtOAc as the eluant. A
67:33 mixture of diastereomers ((S,S)-3p) and ((S,R)-3p),
respectively, was afforded in combined 72% yield (178 mg). Pure
((S,S)-3p) was obtained as a white crystal. No racemization was
indicated in the NMR spectra of the Mosher ester derivative; see
theSupporting Information for details: mp 80−82 °C; [α]D20 −21.3 (c
2,2,2-Trichloro-1-cyclohexylethanol (3i).2f The crude material
(prepared following Method A) was purified by flash chromatography
through a plug of silica gel using 95:5 hexane/EtOAc as the eluant.
The indicated compound was obtained as a colorless oil in 73% yield
1
(169 mg): H NMR (CDCl3, 360 MHz) δ 3.86 (d, J = 2.2 Hz, 1H),
1
2.78 (d, J = 6.0 Hz, 1H), 2.15−1.96 (m, 2H), 1.82−1.64 (m, 4H),
1.48−1.14 (m, 5H); 13C NMR (CDCl3, 125 MHz) δ 104.2, 86.4, 39.9,
32.9, 26.7, 26.5, 26.0, 25.9; HRMS m/z calcd for C7H13O [M −
CCl3]+, 113.0966; found 113.0965.
3.8, CHCl3); H NMR (CDCl3, 500 MHz) δ 4.59 (ddd, J = 3.0, 6.5,
6.5 Hz, 1H), 4.36 (dd, J = 4.0, 3.5 Hz, 1H), 4.27 (dd, J = 6.5, 9.0 Hz,
1H), 4.10 (dd, J = 6.5, 9.0 Hz, 1H), 3.06 (d, J = 4.0 Hz, 1H), 1.47 (s,
3H), 1.39 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 109.2, 100.6, 82.4,
75.1, 64.7, 26.3, 25.3; HRMS m/z calcd for C6H11O3, 131.0708; found
131.0711, which corresponds to [M − CCl3]+.
2,2,2-Trichloro-1-furan-2-yl-ethanol (3j).2f The crude material
(prepared following Method A) was purified by flash chromatography
through a plug of silica gel using 95:5 hexane/EtOAc as the eluant.
The indicated compound was obtained as a white solid in 70% yield
(151 mg): mp 34−35 °C; 1H NMR (CDCl3, 500 MHz) δ 7.47 (d, J =
1.7 Hz, 1H), 6.61 (d, J = 3.3 Hz, 1H), 6.44 (dd, J = 3.3, 1.7 Hz, 1H),
5.24 (d, J = 7.3 Hz, 1H), 3.34 (d, J = 7.3 Hz, 1H); 13C NMR (CDCl3,
125 MHz) 148.4, 143.1, 110.9, 110.7, 101.2, 79.3; HRMS m/z calcd
for C6H5Cl3O2, 213.9355; found 213.9352.
(R)-(−)-2,2,2-Trichloro-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-
ethanol ((S,R)-3p). The crude material (prepared following Method
B) was purified by flash chromatography through a plug of 1%
pyridine-saturated silica gel using 95:5 hexane/EtOAc as the eluant. A
67:33 mixture of diastereomers ((S,S)-3p) and ((S,R)-3p),
respectively, was afforded in 72% combined yield (178 mg). Pure
((S,R)-3p) was obtained as a colorless oil. No racemization was
indicated in the NMR spectra of the Mosher ester derivative; see the
2,2,2-Trichloro-1-thiophen-2-ylethanol (3k).2f The crude material
(prepared following Method A) was purified by flash chromatography
through a plug of silica gel using 95:5 hexane/EtOAc as the eluant.
The indicated compound was obtained as an off-white solid in 61%
20
1
Supporting Information for details: [α]D −10.5 (c 2.0, CHCl3); H
NMR (CDCl3, 500 MHz) δ 4.57 (ddd, J = 2.5, 6.5, 6.5 Hz, 1H), 4.25
(dd, J = 6.5, 8.5 Hz, 1H), 3.98 (dd, J = 2.5, 8.5 Hz, 1H), 3.91 (dd, J =
7, 8.5 Hz, 1H), 3.72 (d, J = 8.5 Hz, 1H), 1.49 (s, 3H), 1.44 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 110.9, 101.3, 81.1, 73.2, 68.4, 26.1,
1
yield (140 mg): mp 29−30 °C; H NMR (CDCl3, 500 MHz) δ 7.41
(dd, J = 5.1, 1.2 Hz, 1H), 7.33−7.31 (m, 1H), 7.05 (dd, J = 5.1, 3.6 Hz,
1H), 5.48 (d, J = 4.7 Hz, 1H), 3.30 (d, J = 4.7 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ 137.3, 129.1, 127.1, 126.3, 102.5, 81.6; HRMS
m/z calcd for C6H5Cl3SO, 229.9127; found 229.9122.
25.7; HRMS m/z calcd for C7H11O3Cl3, 246.9696; found 246.9701.
General Procedure for the Preparation of One-Carbon
Homologated Carboxylic Acids from Trichloromethyl Carbi-
nols. Diphenyl diselenide (374 mg, 1.2 mmol) was added under a
blanket of argon to a dry round-bottom flask equipped with a stir bar.
Absolute ethanol (4 mL) was added, the system was cooled to 0 °C,
and the solution was deoxygenated by passing argon through a needle
submersed in the EtOH. After 30 min, NaBH4 (95 mg, 2.5 mmol) was
added rapidly in one portion. Once the yellow solution became
colorless (<5 min), the ice bath was removed, and the solution was
stirred for an additional 30 min. Neat trichloromethyl carbinol (1.0
mmol) was quickly added, followed by powdered NaOH (240 mg, 6.0
mmol). The solution purge needle was removed, and the reaction was
(E)-1,1,1-Trichloro-4-phenylbut-3-en-2-ol (3l).24 The crude ma-
terial (prepared following Method A) was purified by flash
chromatography through a plug of silica gel using 95:5 hexane/
EtOAc as the eluant. The indicated compound was obtained as an off-
white solid in 62% yield (156 mg): mp 62−63 °C; 1H NMR (CDCl3,
500 MHz) δ 7.45 (d, J = 7.2 Hz, 2H), 7.29−7.38 (m, 3H), 6.91 (d, J =
15.9 Hz, 1H), 6.38 (dd, J = 15.9, 5.9 Hz, 1H), 4.78 (t, J = 5.9 Hz, 1H),
2.98 (d, J = 5.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 136.8, 135.6,
128.7, 128.6, 126.9, 122.6, 102.8, 83.4; HRMS m/z calcd for
C10H9Cl3O, 249.9719; found 249.9729.
E
dx.doi.org/10.1021/jo300725v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
heated to 40 °C under argon and allowed to mix for 24−36 h while
being monitored for consumption of starting material by TLC. (Note:
diphenyl diselenide rapidly reforms if oxygen is introduced into the
system. Leaving the argon purge needle submersed in the EtOH until
all components are added can improve product yields.) After
completion, the ethanol was removed by rotary evaporation, and the
amorphous solids were dissolved in 5 mL of ethyl acetate and 5 mL of
H2O. The resulting solution was cooled to 0 °C and adjusted to pH 1
with 1 N HCl. The product was extracted with ethyl acetate (5 × 10
mL), dried (Na2SO4), and then concentrated by rotary evaporation.
The crude material was purified by flash chromatography through a
small plug of silica using the specified eluants, affording the pure
carboxylic acid.
REFERENCES
■
(1) For select examples, see: (a) Reeve, W.; Fine, L. W. J. Org. Chem.
1964, 29, 1148−1150. (b) Corey, E. J.; Link, J. O. J. Am. Chem. Soc.
1992, 114, 1906−1908. (c) Dominguez, C.; Ezquerra, J.; Baker, S. R.;
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1897, 29, 97−103. (b) Reeve, W.; McKee, J. R.; Brown, R.;
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(4) For select examples, see: (a) Tennyson, R. L.; Cortez, G. S.;
Galicia, H. J.; Kreiman, C. R.; Thompson, C. M.; Romo, D. Org. Lett.
2002, 4, 533−536. (b) Blanchet, J.; Zhu, J. Tetrahedron Lett. 2004, 45,
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Naphthalen-2-ylacetic Acid (4).27 The crude material was purified
by flash chromatography through a plug of silica gel using hexane to
remove diphenyldiselenide and then 8:2 hexane/EtOAc as the eluant.
The indicated compound was obtained as a white solid in 94% yield
1
(175 mg): mp 142−143 °C; H NMR (CDCl3, 500 MHz) δ 11.00
(brs, 1H), 7.84−7.79 (m, 3H), 7.74 (s, 1H), 7.49−7.45 (m, 2H), 7.41
(dd, 1H, J = 4.5 Hz, 13.5 Hz), 3.82 (s, 2H); 13C NMR (CDCl3, 125
MHz) δ 177.4, 133.4, 132.6, 130.7, 128.3, 128.2, 127.7, 127.7, 127.3,
126.2, 125.9, 41.1; HRMS m/z calcd for C12H10O2, 186.0681; found
186.0683.
4-Phenylbutanoic Acid (5).26 The crude material was purified by
flash chromatography through a plug of silica gel using hexane to
remove diphenyldiselenide and then 85:15 hexane/EtOAc as the
eluant. The indicated compound was obtained as a colorless crystal in
(5) Li, J.; Xu, X.; Zhang, Y. Tetrahedron Lett. 2003, 44, 9349−9351.
(6) (a) Villieras, J.; Bacquet, C.; Normant, J. F. J. Organomet. Chem.
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Pierce, M. E.; Fortunak, J. M.; Confalone, P. N. J. Org. Chem. 2000, 65,
1889−1891.
1
90% yield (148 mg): mp 50−51 °C; H NMR (CDCl3, 500 MHz) δ
10.70 (brs, 1H), 7.29 (dd, 2H, J = 7.5, 7.5 Hz), 7.22−7.17 (m, 3H),
2.68 (t, 2H, J = 7.5 Hz), 2.39 (t, 2H, J = 7.5 Hz), 2.01−1.95 (m, 2H);
13C NMR (CDCl3, 125 MHz) δ 179.5, 141.2, 128.5, 128.4, 126.0, 35.0,
33.3, 26.2; HRMS m/z calcd for C10H12O2, 164.0842; found 164.0837.
2-(Furan-2-yl)acetic Acid (6).2f,28 The crude material was purified
by flash chromatography through a plug of silica gel using hexane to
remove diphenyldiselenide and then 85:15 hexane/EtOAc as the
eluant. The indicated compound was obtained as a white solid in 92%
yield (116 mg): mp 60−61 °C; 1H NMR (CDCl3, 500 MHz) δ 10.96
(brs, 1H), 7.38 (dd, 1H, J = 1.8, 0.7 Hz), 6.37 (dd, 1H, J = 3.2, 1.8
Hz), 6.28 (dd, 1H, J = 3.2, 0.7 Hz), 3.77 (s, 2H); 13C NMR (CDCl3,
125 MHz) δ 173.7, 146.9, 142.3, 110.6, 108.4, 33.5; HRMS m/z calcd
for C6H6O3, 126.0321; found 126.0317.
(7) For reviews concerning preparations and reactions of
trichloromethyl carbinols, see: (a) Gukasyan, A. O.; Galstyan, L. K.;
Avetisyan, A. A. Russ. Chem. Rev. 1991, 60, 1318−1330. (b) Menezes,
F. G.; Gallardo, H.; Zucco, C. Quim. Nova 2010, 33, 2233−2244.
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3435−3438.
(9) Atkins, P. J.; Gold, V.; Marsh, R. J. Chem. Soc., Perkin Trans. 2
1984, 7, 1239−1245.
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K.; Mereu, A. J. Org. Chem. 2000, 65, 7211−7212.
4-Methylpent-3-enoic Acid (7).2f,29 The crude material was purified
by flash chromatography through a plug of silica gel using hexane to
remove diphenyldiselenide and then 9:1 hexane/EtOAc as the eluant.
The indicated compound was obtained as a yellow oil in 95% yield
(11) Tidwell, T. T. Org. React. 1990, 39, 297−572 and references
therein.
(12) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155−
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957−962. (b) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651−
1660.
1
(108 mg): H NMR (CDCl3, 500 MHz) δ 5.31−5.29 (m, 1H), 3.07
(d, 2H, J = 7 Hz), 1.75 (s, 3H), 1.64 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 178.7, 136.3, 115.0, 33.5, 25.6, 17.9; HRMS m/z calcd for
C6H10O2, 114.0681; found 114.0678.
ASSOCIATED CONTENT
■
(14) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89,
S
* Supporting Information
5505−5507.
NMR spectra (1H and 13C) of all products, 19F spectra of 3d,
and Mosher ester derivatives of 3p. This material is available
free of charge via the Internet at http://pubs.acs.org
(15) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89, 2416−
2423.
(16) Scharlin, P. Acta Chem. Scand., Ser. A 1986, A40, 207−209.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: snowden@bama.ua.edu. Phone: 205-348-8550. Fax:
205-348-9104.
■
(18) (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543. (b)
For preparation of the Mosher ester derivatives, we
followed: Myers, A. G.; Bryant, H. Y.; Chen, H. Organic Syntheses;
Wiley & Sons: New York, 2004; pp 509−516.
Notes
The authors declare no competing financial interest.
(19) Absolute configurations were assigned on the basis of
correlations of specific rotation data with that reported in reference 2d.
(20) Boeckman, R. K., Jr.; Shao, P.; Mullins, J. J. Organic Syntheses;
Wiley & Sons: New York, 2004; pp 696−707.
ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation CAREER
program (CHE-0847686) for financial support. We also thank
Dr. Qiaoli Liang for acquiring the mass spectrometry data.
(21) Kryshtal, G. V.; Bogdanov, V. S.; Yanovskaya, L. A. Tetrahedron
Lett. 1982, 23, 3607−3610.
F
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The Journal of Organic Chemistry
Note
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G
dx.doi.org/10.1021/jo300725v | J. Org. Chem. XXXX, XXX, XXX−XXX