One-pot in situ formation and reaction of trimethyl(trichloromethyl)silane: Application to the synthesis of 2,2,2-trichloromethylcarbinols

Article abstract of DOI:10.1021/jo3001063

2,2,2-Trichloromethylcarbinols are 1 are valuable synthetic intermediates with a multitude of uses. A scalable procedure for the synthesis of TMS-protected-2,2,2-trichloromethylcarbinols and 2,2,2-trichloromethylcarbinols 1 was developed that employs the in situ generation and reaction of trimethyl(trichloromethyl)silane (CCl₃-TMS). The procedure avoids the exposure of the carbonyl compounds to the strongly basic conditions typically used for this transformation and also avoids isolation of the difficult-to-handle CCl₃-TMS. This procedure was applied to diastereoselective trichloromethyl additions to 2-substituted 4-piperidinones and to reactions with a variety of structurally diverse aldehydes and ketones.

Full text of DOI:10.1021/jo3001063

Note
pubs.acs.org/joc
One-Pot in Situ Formation and Reaction of
Trimethyl(trichloromethyl)silane: Application to the Synthesis of
2,2,2-Trichloromethylcarbinols
Kevin E. Henegar* and Ricardo Lira
Pfizer Global Research and Development, Groton Laboratories Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: 2,2,2-Trichloromethylcarbinols are 1 are val-
uable synthetic intermediates with a multitude of uses. A
scalable procedure for the synthesis of TMS-protected-2,2,2-
trichloromethylcarbinols and 2,2,2-trichloromethylcarbinols 1
was developed that employs the in situ generation and reaction of trimethyl(trichloromethyl)silane (CCl3-TMS). The procedure
avoids the exposure of the carbonyl compounds to the strongly basic conditions typically used for this transformation and also
avoids isolation of the difficult-to-handle CCl3-TMS. This procedure was applied to diastereoselective trichloromethyl additions
to 2-substituted 4-piperidinones and to reactions with a variety of structurally diverse aldehydes and ketones.
alcohols and phenols,3d,13 hydride,13e thiols and selenides,13e,14
INTRODUCTION
2,2,2-Trichloromethylcarbinols 1 are useful synthetic inter-
mediates with many applications and are most commonly
prepared by the base-promoted addition of chloroform to
■
fluoride,13f,15 cyanide,13f thiocyanate,13f azide,16 amines,16i,17
pyrroles,18 and thiourea.19 Trichloromethylcarbinols can also be
converted to epoxides,20 vinyl dichlorides,21 alkynes,22,23 vinyl
dichlorides and chloroketones,22 2-haloalk-2(Z)-en-1-ols and 1-
aldehydes and ketones (Scheme 1). Bases which have been
chloro-1(Z)-alkenes,24 and ring-expanded ketones.25
As part of an ongoing project, we had a need for substantial
amounts of the diastereomerically pure 2,2,2-trichloromethyl-
Scheme 1. Formation of Trichloromethylcarbinols
carbinol 4 (Scheme 3). This had previously been prepared in
Scheme 3. Base-Promoted Reaction with (S)-2-Methyl-CBZ-
4-piperidinone
used for this reaction include amide bases,1 amidines,2 and
hydroxide.3 Reaction of CCl3CO2Na in CCl3CO2H-DMF also
yields trichloromethyl carbinols from aldehydes.4 2,2,2-
Trichloromethylcarbinols can also be prepared by the
formation of trimethylsilyl protected 2,2,2-trichloromethylcar-
binols using a variety of trichloromethyl-transferring reagents
followed by deprotection. Among the reagents used for these
additions are trimethyl(trichloromethyl)silane (CCl3-TMS)
with a variety of catalysts such as TASF,5 sodium formate,6
or thermally,7 and trimethylsilyl trichloroacetate with catalysis
by KF,8 K2CO3,9 or TBAF.10 The combination of TMS-Cl/
CCl4/Mg/HMPT has also been employed.11
Of the many uses of 2,2,2-trichloromethylcarbinols, one of
the most common and general reactions is the Jocic12 and
related reactions with nucleophiles to make α-substituted
carboxylic acids 2 (Scheme 2). Many nucleophiles that have
been used for these reactions; these include hydroxide,12
about 46% yield by adding LiHMDS to a mixture of (S)-2-
methyl-CBZ-4-piperidinone 3 and CHCl3 at less than −65
°C.16i The diastereomer ratio is about 2:1 at best under these
conditions; MgCl2 is added to this reaction to suppress
competing ketone enolization, but its presence does not alter
the diastereomer ratio. The addition of LiHMDS is very
exothermic, and to minimize competing ketone enolization, the
reaction temperature must be maintained at less than −65 °C,
which is difficult on scale. In addition, gumming and balling of
the poorly soluble MgCl2 during the reaction and the formation
of emulsions during product isolation create significant
operational challenges to scale-up. It should also be noted
Scheme 2. Generalized Jocic Reaction
Received: January 13, 2012
Published: February 15, 2012
© 2012 American Chemical Society
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Note
that little or no compound 4 is formed by reaction of 3 with
Table 1. Additions to 4-Piperidones
CHCl3 and either hydroxide or DBU.2,3
RESULTS AND DISCUSSION
■
Use of a bulkier trichloromethyl-transferring reagent should
provide better diastereoselectivity, and we found that trimethyl-
(trichloromethyl)silane (CCl3-TMS) with catalysis by sodium
formate using the procedure of Kister and Mioskowski6 gives
the desired diastereomer with about 9:1 selectivity. The
primary limitation to scale-up of this procedure is the need
for isolated CCl3-TMS, which is not commercially available and
is difficult to handle on scale due to its volatility and propensity
for sublimation. A number of methods have been reported for
the preparation of CCl3-TMS. The simplest procedure is by
amine-promoted decarboxylation of trimethylsilyl trichloroace-
tate,26 but we found that scale-up of this procedure was
complicated by erratic reaction rates and stalled reactions.
Crude solutions containing CCl3-TMS from this reaction work,
but these have a low DSC thermal onset (87 °C, 399 J/g),
which precludes scale-up. The other reported methods for the
synthesis of CCl3-TMS all have critical features that limit their
practicality for large-scale synthesis: photochemical chlorination
of trichloromethylsilane,27CHCl3/TMS-Cl/n-BuLi/-110 °C,28
TMS-Cl/CCl4/Mg/HMPT,29 and CHCl3/TMS-Cl/P-
(NEt2)3.30
We found that CCl3-TMS is rapidly and cleanly formed by
the direct treatment of CHCl3 and TMS-Cl with LiHMDS in
THF at less than −60 °C. The characteristic 1H NMR
resonance of CCl3-TMS at δ 0.37 is observable in these
solutions. Formation of CCl3-TMS is further demonstrated by
its isolation as a crystalline solid. Temperature control is
important, and the reagent does not form properly above about
−60 °C. In contrast to the reaction of ketone 3 with CHCl3 and
LiHMDS, the addition of LiHMDS to the mixture of CHCl3
and TMS-Cl is not particularly exothermic, and the required
temperatures that are easily within the range of conventional
mechanical chillers. The unprocessed solutions containing
CCl3-TMS yield TMS protected 2,2,2-trichloromethyl carbinols
upon reaction with aldehydes and ketones. In the absence of
any additive, the reaction is slow; for example, ketone 3
undergoes about 20% conversion after 18 h. Addition of tetra n-
butylammonium acetate markedly accelerates the reaction.
Other potential catalysts such as sodium formate, cesium
acetate, or betaine are ineffective due to poor solubility.
Reaction of ketone 3 with the in situ generated CCl3-TMS
gives the same product diastereomer ratio as with the isolated
CCl3-TMS, which is about 9:1 at 0 °C. The reaction becomes
sluggish at lower temperatures, and the diastereomer ratio does
not substantially improve. The slow non-tetra n-butylammo-
nium acetate-promoted background reaction is somewhat less
selective and gives a diastereomer ratio of about 4:1. The
intermediate TMS ether formed is remarkably stable. Acid-
promoted desilylation was slow with partial loss of the CBZ
group with HCl in methanol; accordingly, the silyl group was
removed with TBAF. Control reactions showed that some
reversion of the 2,2,2-trichloromethylcarbinol 4 to the ketone 3
occurs with TBAF alone, and AcOH was added to prevent this.
The isolated yield of 4 was 78% by crystallization on a 1 kg
scale with less than 0.1% of the undesired diastereomer.
The in situ generated CCl3-TMS undergoes reaction with a
number of 4-piperidinones to give the expected products in
good to excellent yield (Table 1). CBZ 4-piperidinone (entry
1) gave the TMS-protected trichloromethylcarbinol 5a in high
yield. The other entries gave varying amounts of recovered
starting ketone after the desilylation, presumably due to
competing silyl enol ether formation during the trichloromethyl
addition. In these cases, all of the ketone was consumed in the
reaction with CCl3-TMS, but ketone was recovered after the
desilylation; as noted above, control reactions showed the
product trichloromethylcarbinols are stable to TBAF/AcOH.
The diastereoselectivity in the additions to the 2-substituted 4-
piperidones in entries 3, 4, and 5 is good to excellent.
Assignments of the relative configurations of the major
diastereomers for 6b, 6c, and 6d are based on analogy with
the reaction of ketone 3 to yield 4. Product diastereomer ratios
were determined by 1H NMR integrations of the crude
products, and the yields given in Table 2 are for the purified
diastereomer mixtures. Partial separation of the 6b and 6c
diastereomers was possible by either chromatography or
crystallization.
Additions of CCl3-TMS to a diverse array of aldehydes and
ketones are summarized in Table 2 and generally proceed in
high yield. The two low-yielding entries (4 and 6) in the
trichloromethyl addition are both with readily enolized
substrates. Benzyloxyacetaldehyde (entry 4) gave substantial
amounts of recovered starting material after the desilylation,
and the reaction with 2-indanone (entry 6) gave tars in addition
to the intended product. Entry 7 proceeded with high
diastereoselectivity to give the product 8h as a single
stereoisomer, identified by comparison with reported data,25
where as expected the trichloromethyl addition occurred trans
to the phenyl group. Under conventional conditions (CHCl3−
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warm to rt. The mixture was concentrated by rotary evaporation (40
°C bath) to a slurry, and then 20 mL of water and 50 mL of pentane
were added. The aqueous phase was separated and extracted with 50
mL of pentane. The combined pentane solutions were washed with 20
mL of water, dried briefly over Na2SO4, and evaporated (40 °C bath)
to yield a colorless syrup that formed white solids on standing.
Filtration gave 3.5 g (44% yield) of a white solid. The solids were
mostly pure trimethyl(trichloromethyl)silane containing a small
amount of hexamethyldisilazane by 1H NMR. The solids were
sublimed to yield 2.0 g of trimethyl(trichloromethyl)silane as a
colorless waxy solid: mp 131−133 °C (lit. mp 130−132 °C);26 1H
NMR (400 MHz, CDCl3) δ 0.37 (s); 13C NMR (100 MHz, CDCl3) δ
−3.87, 95.41. LRMS-ACPI m/z 73, 93, 95, 113, 115, 117.
Table 2. Additions to Aldehydes and Ketones
(2S,4S)-Benzyl 4-hydroxy-2-methyl-4-(trichloromethyl)-
piperidine-1-carboxylate (4).16i Chloroform (810 mL, 10.1 mol)
and chlorotrimethylsilane (990 mL, 7.8 mol) were dissolved in 3.75 L
of THF and cooled to about −65 °C internal. LiHMDS solution (1 M
in THF, 7.4 L, 7.4 mols) was added over about 20 min, keeping the
internal temp between −60 and −70 °C. The mixture was stirred
between −60 and −70 °C for 20 min and then allowed to warm to
about −20 °C. A solution of (S)-benzyl 2-methyl-4-oxopiperidine-1-
carboxylate (3) (1.00 kg, 4.04 mols) dissolved in 3.16 L of DMF was
added over about 30 min, and then a solution of tetra n-
butylammonium acetate (110 g, 0.37 mol) dissolved in 810 mL of
DMF was added. The mixture was allowed to stir at less than 0 °C
until complete and then warmed to rt, and 2.8 L of water and 2.8 L of
MTBE were added. The organic phase was washed with 2.8 L of water,
2.8 L of 1 M HCl, and 2 × 2.8 L of water. The organic solution was
distilled under vacuum to a low volume, 2-MeTHF (12.2 L) was
added, and the mixture was distilled under vacuum to a volume of
about 4 L. AcOH (240 mL, 4 mol) was added. Tetra n-
butylammonium fluoride solution (1 M in THF, 4.04 L, 4.04 mol)
was added, and the mixture was stirred for 30 min. A solution of 650 g
of K2CO3 in 4 L of water was added, and the mixture was stirred for 30
min. The phases were separated, and the organic phase was washed
with water (3 × 4 L). The organic solution was distilled under vacuum
to a volume of about 4 L. Dichloromethane (8 L) was added, and the
solution was filtered through 1 kg of Florisil. The filtrate was distilled
under vacuum to a volume of about 4 L, then 5 L of MTBE was added,
and the distillation was continued under atmospheric pressure, adding
MTBE to maintain the volume at about 7 L, until the head temp was
greater than 54 °C. The slurry was cooled to 0 °C for 12 h and then
filtered. Yield: 1164 g (78.9%) of 4 as a white solid: mp 146.8−147.9
°C; 1H NMR (400 MHz, CDCl3) δ 7.30−7.42 (m, 5H), 5.16 (s, 2H),
4.55−4.75 (m, 1H), 4.08−4.28 (m, 1H), 3.21−3.38 (m, 1H), 2.40 (s,
1H), 2.30−2.38 (m, 1H), 1.87−2.24 (m, 3H), 1.36−1.40 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 155.1, 154.7, 136.6, 128.5, 128.0, 127.9,
127.8, 109.1, 81.1, 67.2, 45.7, 45.5, 34.8, 34.5, 34.3, 31.4, 31.1, 18.5,
17.9.
Procedure A. General Procedure for the One-Step in Situ
Generation and Reaction of Trimethyl(trichloromethyl)silane
To Form Trimethylsilyl-Protected 2,2,2-Trichloromethylcarbi-
nols 5 and 7. Chloroform (4.5 mL, 56.2 mmol) and chlorotrime-
thylsilane (4.9 mL, 38.6 mmol) were dissolved in 20 mL of THF and
cooled to about −65 °C internal. LiHMDS solution (1 M in THF, 36
mL, 36 mmol) was added over about 20 min, keeping the internal
temp between −60 and −70 °C. The mixture was stirred between −60
and −70 °C for 30 min and then allowed to warm to about −20 °C.
The carbonyl compound (21.4 mmol) dissolved in 10 mL of DMF was
added over 10 min, and then a solution of tetra n-butylammonium
acetate (0.56 g, 1.9 mmol) in 5 mL of DMF was added. The mixture
was allowed to stir at less than 0 °C until complete and then warmed
to rt, and 15 mL of water and 15 mL of MTBE were added. The
organic phase was washed with 15 mL of water, 15 mL of 1 M HCl,
and 2 × 15 mL of water, and then dried over Na2SO4. The organic
solution was filtered through a short plug of silica or Florisil and
concentrated to yield the trimethylsilyl protected intermediate.
Procedure B. General Procedure for the Trimethylsilyl
Deprotection To Yield 2,2,2-Trichloromethylcarbinols 6 and
8. The trimethylsilyl protected intermediate was dissolved in 2-
LiHMDS, −78 °C), 5:1 selectivity was observed for this
reaction.25 The desilylation reactions in Table 2 were generally
uneventful and gave the desilylated products in high yield.
Exceptions were entry 5, where some unidentified nonpolar
byproduct were formed in the desilylation (only a trace of
mesitylaldehyde was formed), and entry 8, which showed
significant loss of the trichloromethyl group during the
desilylation (about 10% 4-methoxyacetophenone was recov-
ered), even with the addition of AcOH.31
CONCLUSIONS
■
In conclusion, we have demonstrated the one-pot in situ
formation and reaction of trimethyl(trichloromethyl)silane with
a wide variety of aldehydes and ketones to yield trichlor-
omethylcarbinols and their trimethylsilyl ethers. This expands
the utility of this reagent, which is difficult to isolate, and
provides a procedure which can be run on a large scale.
EXPERIMENTAL SECTION
■
Trimethyl(trichloromethyl)silane. Chloroform (5.0 mL, 62.3
mmol) and chlorotrimethylsilane (5.2 mL, 40.9 mmol) were dissolved
in 25 mL of THF and cooled to −65 °C internal. LiHMDS solution (1
M in THF, 40 mL, 40 mmol) was added over about 20 min, keeping
the internal temp between −60 and −70 °C (mostly about −62 °C).
The mixture was stirred at −65 °C for 20 min and then allowed to
3001
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The Journal of Organic Chemistry
Note
MeTHF (10 mL/g), and AcOH (1.2 mL, 21.5 mmol) was added.
Tetra n-butylammonium fluoride solution (1 M in THF, 21 mL, 21
mmol) was added, and the mixture was stirred for 10 min. One molar
aqueous K2CO3 solution (24 mL) was added, and the mixture was
stirred for 30 min. The phases were separated, and the organic phase
was washed with water (3 × 25 mL). The organic solution was dried
over anhydrous Na2SO4 and evaporated to yield the product, which
was purified by chromatography or crystallized.
butylpiperidine yielded 0.58 g (65.8%) of 6d as a single diastereomer
as an oil after chromatography on silica (8:1 heptane/EtOAc): FT-IR
(SB-DC) cm−1 3379, 1661, 814; 1H NMR (400 MHz, CDCl3) δ
4.24−4.44 (m, 1H), 4.19−3.93 (m, 1H), 3.23−3.03 (m, 1H), 2.93−
2.76 (m, 1H), 2.29−2.18 (m, 1H), 2.17−1.84 (m, 4H), 1.69−1.49 (m,
1H), 1.44 (s, 9H), 1.37−1.15 (m, 4H), 0.94−0.88 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 154.7, 154.4, 109.3, 81.2, 81.2, 79.7, 79.6, 50.0,
49.0, 35.1, 33.9, 33.0, 32.4, 31.6, 31.5, 31.2, 29.1, 28.3, 22.5, 22.3, 14.0;
HRMS (GC-ESI) calcd for C10H19Cl3NO [(M − BOC + H)+] m/z
274.0532, found 274.0523.
Benzyl 4-(Trichloromethyl)-4-(trimethylsilyloxy)piperidine-
1-carboxylate (5a). Following Procedure A, 5.0 g (21.4 mmol) of
CBZ-4-piperidinone yielded 8.92 g (98%) of 5a after filtration through
a short plug of silica with 2:1 heptane/EtOAc as an oil that crystallized
Trimethyl(1,1,1-trichloro-4-phenylbutan-2-yloxy)silane
(7a).6 Following Procedure A, 0.94 g (7 mmol) of hydro-
cinnamaldehyde yielded 1.95 g (85.5%) of 7a as a colorless oil after
chromatography on silica eluting with 98:2 heptane/EtOAc: FT-IR
1
on standing: mp 71.4−74.7 °C; FT-IR (SB-DC) cm−1 1700, 838; H
NMR (400 MHz, CDCl3) δ 7.29−7.44 (m, 5H), 5.16 (s, 2H), 4.13−
4.36 (m, 2H), 2.90−3.08 (m, 2H), 1.92−2.20 (m, 4H), 0.27 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 154.8, 136.5, 128.4, 127.9, 84.6, 67.2,
1
(SB-DC) cm−1 863, 837; H NMR (400 MHz, CDCl3) δ 7.36−7.26
(m, 5H), 4.17 (dd, J = 9.3, 1.9 Hz, 1H), 2.98 (ddd, J = 14.0, 10.6, 5.0
Hz, 1H), 2.69 (ddd, J = 13.7, 10.3, 6.5 Hz, 1H), 2.53−2.42 (m, 1H),
2.13−2.00 (m, 1H), 0.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
140.8, 128.5, 128.3, 126.2, 103.8, 83.7, 34.6, 32.4, 0.8; LRMS-EI calcd
for C13H20Cl3OSi [(M + H)+] m/z 325, found 325.
40.0, 31.8, 31.6, 2.4; HRMS (GC-ESI) calcd for C17H25Cl3NO3Si [(M
+ H)+] m/z 424.0669, found 424.0664.
Benzyl 4-Hydroxy-4-(trichloromethyl)piperidine-1-carboxy-
late (6a). Following Procedure B, 8.53 g of 5a yielded 7.12 g (97%) of
6a as an oil that crystallized on standing: mp 146.4−148.6 °C; FT-IR
(SB-DC) cm−1 3368, 1670, 820; 1H NMR (400 MHz, CDCl3) δ
7.30−7.50 (m, 5H), 5.15 (s, 2H), 4.12−4.34 (m, 2H), 3.06−3.24 (m,
2H), 3.03 (s, 1H), 2.05−2.11 (m, 2H), 1.89−2.05 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 155.1, 136.5, 128.5, 127.8, 108.8, 80.3, 77.2,
67.3, 39.8, 31.1; HRMS (GC-ESI) calcd for C14H17Cl3NO3 [(M +
H)+] m/z 352.0274, found 352.0272.
1-tert-Butyl 2-Methyl 4-hydroxy-4-(trichloromethyl)-
piperidine-1,2-dicarboxylate (6b). Following Procedure A, without
isolation of 6a and Procedure B, 2.79 g (10.84 mmol) of methyl 1-
BOC-4-oxopiperidine-2-carboxylate was chromatographed on silica
(2:1 heptane/EtOAc) to yield the product as a colorless oil that
partially solidified on standing. 1.15 g of the major diastereomer was
obtained as a solid and 1.28 g of a mixture of diastereomers was
isolated as an oil. Total yield 2.43 g (59%). 0.53 g of the starting
ketone was recovered. Major diastereomer: mp 166.7−168.0 °C; FT-
IR (SB-DC) cm−1 3380, 1747, 167, 818; 1H NMR (400 MHz, CDCl3)
δ 4.81−4.85 and 5.0−5.05 (2 multiplets, total 1H), 3.96−4.04 and
4.07−4.14 (2 multiplets, total 1H), 3.73 and 3.75 (2 singlets, total
3H), 3.15−3.38 (m, 1H), 2.71−2.87 (m, 1H), 2.29−2.40 (m, 1H),
1.94−2.16 (m, 2H), 1.43 and 1.48 (2 singlets, total 9H); 13C NMR
(100 MHz, CDCl3) δ 172.4, 172.2, 155.2, 154.9, 108.0, 80.67, 80.65,
80.1, 80.0, 52.49, 52.45, 52.41, 51.3, 37.7, 36.8, 32.2, 32.0, 30.2, 30.0,
28.3; HRMS (GC-ESI) calcd for C8H13Cl3NO3 [(M-BOC+H)+] m/z
275.9961, found 275.9961.
1,1,1-Trichloro-4-phenylbutan-2-ol (8a).23 Following Proce-
dure B, 0.326 g (1.0 mmol) of 7a yielded 0.225 g (91%) of 8a as a
colorless oil after chromatography on silica eluting with 93:7 heptane/
EtOAc: FT-IR (SB-DC) cm−1 3400, 807; 1H NMR (400 MHz,
CDCl3) δ 7.30−7.35 (m, 2H), 7.21−7.27 (m, 3H), 4.00 (ddd, J = 10.0,
5.5, 2.0 Hz, 1H), 3.02 (ddd, J = 13.7, 9.0, 4.7 Hz, 1H), 2.75−2.83 (m,
1H), 2.76 (dd, J = 5.5, 1.8 Hz, 1H), 2.36−2.44 (m, 1H), 1.95−2.06
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 140.6, 128.6, 128.5, 126.3,
104.1, 82.0, 32.9, 31.9; LRMS-CI calcd for C10H11Cl3O [M+] m/z 252,
found 252.
Trimethyl(2,2,2-trichloro-1-cyclohexylethoxy)silane (7b).9
Following Procedure A, 0.79 g cyclohexanecarboxaldehyde (7.1
mmol) yielded 2.1 g (98%) of 7b as a colorless oil after
chromatography on silica eluting with 98:2 heptane/EtOAc: FT-IR
1
(SB-DC) cm−1 835; H NMR (400 MHz, CDCl3) δ 3.88 (d, J = 2.2
Hz, 1H), 2.02−2.13 (m, 2H), 1.72−1.80 (m, 2H), 1.64−1.70 (m, 2H),
1.08−1.40 (m, 5H), 0.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
104.0, 87.9, 40.7, 33.5, 27.2, 26.8, 26.3, 26.1, 0.6; LRMS-CI calcd for
C11H22Cl3OSi [(M + H)+] m/z 303, found 303.
2,2,2-Trichloro-1-cyclohexylethanol (8b).2 Following Proce-
dure B, 0.304 g (1.0 mmol) of 7b yielded 0.217 g (94%) of 8b as a
colorless oil after chromatography on silica eluting with 92:8 heptane/
EtOAc: FT-IR (SB-DC) cm−1 3500, 806; 1H NMR (400 MHz,
CDCl3) δ 3.88 (dd, J = 6.6, 2.7 Hz, 1H), 2.70 (d, J = 6.6 Hz, 1H),
2.02−2.13 (m, 2H), 1.73−1.83 (m, 3H), 1.65−1.72 (m, 1H), 1.14−
1.50 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 104.2, 86.4, 39.9, 32.3,
26.7, 26.6, 26.1, 25.9; LRMS-CI calcd for C8H14Cl3O [(M + H)+] m/z
231, found 231.
Benzyl 4-Hydroxy-2-phenyl-4-(trichloromethyl)piperidine-
1-carboxylate (6c). Following Procedure A, without isolation of
5c, and Procedure B, 4.0 g (12.9 mmol) of 1-CBZ-4-oxo-2-
phenylpiperidine yielded after chromatography on a silica eluting
with 85:15 heptane/EtOAc, 2.82 g of the major diastereomer as an oil
that solidified on standing and 1.63 g of the minor diastereomer as a
solid. Total yield 4.45 g (80.2%). Major diastereomer: mp 130.1−
Trimethyl(1,1,1-trichlorodecan-2-yloxy)silane (7c). Following
Procedure A, 1.01 g (7.1 mmol) of nonaldehyde yielded 2.29 g (96%)
of 7c as a colorless oil after chromatography on silica eluting with 98:2
heptane/EtOAc: FT-IR (SB-DC) cm−1 881, 839; 1H NMR (400
MHz, CDCl3) δ 4.04 (dd, J = 9.4, 2.0 Hz, 1H), 2.00−2.08 (m, 1H),
1.63−1.73 (m, 1H), 1.50−1.59 (m, 1H), 1.25−1.36 (m, 11H), 0.90 (t,
J = 6.6 Hz, 3H), 0.25 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 104.1,
84.3, 32.3, 31.9, 29.44, 29.37, 29.2, 29.0, 26.3, 22.7, 14.11, 14.08, 0.7;
LRMS-CI calcd for C13H28Cl3OSi [(M + H)+] m/z 333, found 333;
HRMS (GC-ESI) calcd for C13H27Cl2SiO [(M + H − HCl)+] m/z
297.1208, found 297.1202.
1
131.9 °C; FT-IR (SB-DC) cm−1 3380, 1662, 814; H NMR (400
MHz, CDCl3) δ 7.18−7.53 (m, 10H), 5.82−5.66 (m, 2H), 5.29−5.12
(m, 2H), 4.43−4.26 (m, 1H), 3.50−3.33 (m, 1H), 2.89−2.76 (m, 1H),
2.72−2.62 (m, 1H), 2.29−2.12 (m, 1H), 2.08−1.94 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 155.6, 155.5, 128.6, 126.5, 125.0, 108.7,
80.4, 67.5, 67.3, 52.0, 51.6, 36.7, 33.9, 33.2, 30.9, 30.6; HRMS (GC-
ESI) calcd for C20H21Cl3NO3 [(M + H)+] m/z 428.0587, found
428.0583. Minor diastereomer: mp 156.6−157.6 °C; FT-IR (SB-DC)
1,1,1-Trichlorodecan-2-ol (8c).23 Following Procedure B, 0.325
g (1.0 mmol) of 7c yielded 0.24 g (94%) of 8c as a colorless oil after
chromatography on silica eluting with 95:5 heptane/EtOAc: FT-IR
(SB-DC) cm−1 3400, 812; 1H NMR (400 MHz, CDCl3) δ 4.01 (ddd, J
= 9.8, 5.9, 2.0 Hz, 1H), 2.69 (dd, J = 5.5, 1.6 Hz, 1H), 2.00−2.10 (m,
1H), 1.60−1.71 (m, 2H), 1.24−1.51 (m, 11H), 0.89 (t, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 104.4, 83.0, 31.8, 31.5, 29.4,
29.3, 29.2, 26.1, 22.7, 14.1; LRMS-CI calcd for C10H20Cl3O [(M +
H)+] m/z 261, found 261.
1
cm−1 3380, 1667; H NMR (400 MHz, CDCl3) δ 7.0−7.4 (m, 10H),
5.14−5.18 (m, 1H), 5.1 (d, J = 12.5 Hz, 1H), 5.02 (d, J = 12.5 Hz,
1H), 4.40−4.07 (m, 1H), 3.36−3.47 (m, 1H), 3.04 (s, 1H), 2.39−2.54
(m, 3H), 2.02−2.14 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 156.0,
143.0, 136.4, 128.7, 128.3, 127.5, 125.5, 108.5, 81.1, 67.2, 53.1, 39.5,
37.1, 34.0; HRMS (GC-ESI) calcd for C20H21Cl3NO3 [(M + H)+] m/
z 428.0587, found 428.0584.
tert-Butyl 2-Butyl-4-hydroxy-4-(trichloromethyl)piperidine-
1-carboxylate (6d). Following Procedure A without isolation of 5d
and then Procedure B, 0.6 g (2.53 mmol) of 1-CBZ-4-oxo-2-
(3-(Benzyloxy)-1,1,1-trichloropropan-2-yloxy)-
trimethylsilane (7d). Following Procedure A, 2.02 g (6.9 mmol) of
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The Journal of Organic Chemistry
Note
2-(benzyloxy)acetaldehyde yielded 0.85 g (36%) of 7d as a colorless
oil after chromatography on silica eluting with 92:8 heptane/EtOAc:
FT-IR (SB-DC) cm−1 836, 836; 1H NMR (400 MHz, CDCl3) δ 7.32−
7.41 (m, 5H), 4.61 (dd, J = 15.4, 11.9 Hz, 2H) 4.35 (dd, J = 7.2, 2.0
Hz, 1H), 4.12 (dd, J = 9.8, 2.0 Hz, 1H), 3.63 (dd, J = 10.0, 7.2 Hz,
1H), 0.27 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 137.7, 128.4,
127.7, 127.6, 100.8, 83.0, 73.6, 72.1, 0.4; LRMS-CI calcd for
C13H20Cl3O2Si [(M + H)+] m/z 341, found 341; HRMS (GC-ESI)
calcd for C13H19Cl3O2Si [M+] m/z 340.0220, found 340.0219.
3-(Benzyloxy)-1,1,1-trichloropropan-2-ol (8d). Following Pro-
cedure B, 0.35 g (1.02 mmol) of 7d yielded 0.24 g (86%) of 8d as a
white solid after chromatography on silica eluting with 1:1 heptane/
heptane/EtOAc: mp 57.3−59.2 °C; FT-IR (SB-DC) cm−1 3400, 798;
1H NMR (400 MHz, CDCl3) δ 7.39−7.20 (m, 5H), 3.39 (dd, 1H, J =
12.7, 3.7 Hz). 2.49−2.41 (m, 1H), 2.17−2.05 (m, 1H), 2.03−1.93 (m,
1H), 1.89−1.79 (m, 3H), 1.76−1.69 (m, 1H), 1.47−1.33 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 142.6, 128.4, 126.9, 109.2, 83.6, 48.3, 33.8,
32.49, 25.9, 22.4; LRMS-EI calcd for C13H16Cl3O [(M + H)+] m/z
293, found 293.
Trimethyl(1,1,1-trichloro-2-(4-methoxyphenyl)propan-2-
yloxy)silane (7h). Following Procedure A, 3.25 g (21.6 mmol) of 4-
methoxyacetophenone yielded 7.04 g (95%) of 7h as an oil after
chromatography a short plug of silica eluting with 8:1 heptane/EtOAc:
1
FT-IR (SB-DC) cm−1 881, 833; H NMR (400 MHz, CDCl3) δ 7.61
1
EtOAc: mp 105.4−106.3 °C; FT-IR (SB-DC) cm−1 3389, 807; H
(d, J = 8.9 Hz, 2H), 6.87 (d, J = 8.9 Hz, 2H), 3.83 (s, 3H), 2.09 (s,
3H), 0.17 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 159.46, 132.32,
130.39, 112.28, 108.51, 85.41, 55.14, 24.74, 1.94; HRMS (GC-ESI)
calcd for C13H20Cl3O2Si [(M + H)+] m/z 341.0298, found 341.0296.
1,1,1-Trichloro-2-(4-methoxyphenyl)propan-2-ol (8h). Fol-
lowing Procedure B, 6.8 g (19.9 mmol) of 7h yielded 4.45 g (83%)
of 8h after chromatography eluting with 95:5 heptane/EtOAc as a
colorless oil that solidified on standing: mp 71.8−73.5 °C; FT-IR (SB-
DC) cm−1 3472, 832, 792; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J =
8.9 Hz, 2H), 6.9 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H), 2.94 (s, 1H), 2.07
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.5, 130.4, 129.7, 112.6,
108.4, 83.1, 55.2, 25.8; HRMS (GC-ESI) calcd for C10H12Cl3O2 [(M +
H)+] m/z 268.9903, found 268.9901.
NMR (400 MHz, CDCl3) δ 7.31−7.41 (m, 5H), 4.65 (dd, J = 16.0,
12.1 Hz, 2H), 4.36 (m, 1H), 4.04 (dd, J = 10.2, 3.1 Hz, 1H), 3.77 (dd,
J = 10.2, 6.6 Hz, 1H), 3.51 (d, 4.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 137.1, 128.6, 128.1, 127.8, 100.5, 80.9, 73.7, 69.6; LRMS-CI
calcd for C10H11Cl3O2 [M+] m/z 268, found 268; HRMS (GC-ESI)
calcd for C10H11Cl3O2 [M+] m/z 267.9825, found 267.9824.
Trimethyl(2,2,2-trichloro-1-mesitylethoxy)silane (7e). Fol-
lowing Procedure A, 3.22 g (21.7 mmol) of mesitylaldehyde yielded
7.2 g (97%) of 7e as a white solid after passing through a short plug of
silica eluting with 8:1 heptane/EtOAc: mp 73.6−75.6 °C; FT-IR (SB-
1
DC) cm−1 3483, 853, 815; H NMR (400 MHz, CDCl3) δ 6.88 (s,
1H), 6.84 (s, 1H), 5.72 (s, 1H), 2.70 (s, 3H), 2.50 (s, 3H), 2.27 (s,
3H), 0.14 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 138.8, 138.0,
137.9, 132.2, 130.1, 129.2, 104.2, 83.7, 22.6, 22.4, 20.8, −0.2; HRMS
(GC-ESI) calcd for C14H20Cl3OSi [(M − H)+] m/z 337.0349, found
337.0351.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra (1H and 13C) for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
2,2,2-Trichloro-1-mesitylethanol (8e).2 Following Procedure B,
6.4 g (18.8 mmol) of 7e yielded 3.97 g (78%) of 8e as a colorless oil
after chromatography on silica eluting with 95:5 heptane/EtOAc: FT-
1
IR (SB-DC) cm−1 881, 833; H NMR (400 MHz, CDCl3) δ 6.94 (s,
AUTHOR INFORMATION
■
1H), 6.91 (s, 1H), 5.83 (d, J = 4.6 Hz, 1H), 3.41 (d, J = 4.6 Hz, 1H),
2.77 (s, 3H), 2.53 (s, 3H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 138.8, 138.6, 138.4, 132.2, 129.4, 128.1, 104.7, 83.5, 22.8, 20.8, −0.2;
HRMS (GC-ESI) calcd for C11H13Cl2O [(M + H − HCl)+] m/z
231.0343, found 231.0340.
Corresponding Author
*E-mail: kevin.e.henegar@pfizer.com.
Notes
The authors declare no competing financial interest.
Trimethyl(2-(trichloromethyl)-2,3-dihydro-1H-inden-2-
yloxy)silane (7f). Following Procedure A, 2.83 g (21.4 mmol) of 2-
indanone yielded 2.90 g (42%) of 7f as a white solid after
chromatography on silica eluting with 8:1 heptane/EtOAc: mp
38.1−39.8 °C; FT-IR (SB-DC) cm−1 869, 838; 1H NMR (400
MHz, CDCl3) δ 7.20−7.27 (m, 4H), 3.85 (d, J = 17.1 Hz, 1H), 3.17
(d, J = 17.1, 1H), −0.05 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
139.8, 127.1, 124.8, 106.6, 94.2, 44.1, −1.6; HRMS (GC-ESI) calcd for
C10H10Cl3O [(M − TMS + H)+] m/z 250.9797, found 250.9790.
2-(Trichloromethyl)-2,3-dihydro-1H-inden-2-ol (8f). Follow-
ing Procedure B, 2.05 g (6.3 mmol) of 7f yielded 1.55 g (78%) of 8f as
a colorless solid after clarification through a plug of Florisil eluting
with 95:5 heptane/EtOAc: mp 97.5−99.5 °C; FT-IR (SB-DC) cm−1
ACKNOWLEDGMENTS
■
We thank David Pattavina, Angel Diaz, and Ronald Morris for
determining the mass spectra. We also thank Professor David
Collum for a helpful discussion.
REFERENCES
■
(1) (a) Taguchi, H.; Yamamoto, H.; Nozaki, H. J. Am. Chem. Soc.
1974, 96, 3010−3011. (b) Taguchi, H.; Yamamoto, H.; Nozaki. Bull.
Chem. Soc. Jpn. 1977, 50, 1588−1591.
1
(2) Aggarwal, V. K.; Mereu, A. J. Org. Chem. 2000, 65, 7211−7212.
(3) (a) Korger, G.; Koenig, J. Chem. Ber. 1963, 96, 10−37.
(b) Wyvratt, J. M.; Hazen, G. G.; Weinstock, L. M. J. Org. Chem. 1987,
52, 944−945. (c) Boesch, R. Bull. Soc. Chim. France 1953, 1050−1056.
(d) Weizmann, C.; Bergmann, E.; Sulzbacher, M. J. Am. Chem. Soc.
1948, 70, 1189−1191. (e) Merz, A.; Tomahogh, R. Chem. Ber. 1977,
110, 96−106.
(4) Corey, E. J.; Link, J. O.; Shao, Y. Tetrahedron Lett. 1992, 33,
3435−3438.
(5) Fujita, M.; Hiyama, T. J. Am. Chem. Soc. 1985, 107, 4085−4087.
(6) Kister, J.; Mioskowski, C. J. Org. Chem. 2007, 72, 3925−3928.
(7) Gisch, J. F.; Landgrebe, J. A. J. Org. Chem. 1985, 50, 2050−2054.
(8) de Jesus, M. A.; Prieto, J. A.; del Valle, L.; Larson, G. L. Syn.
Commun. 1987, 17, 1047−1051.
3543, 832; H NMR (400 MHz, DMSO) δ 7.20−7.26 (m, 4H), 6.51
(s, 1H), 3.62 (d, J = 16.8 Hz, 1H), 3.14 (d, J = 16.8 Hz, 1H); 13C
NMR (100 MHz, DMSO) δ 140.1, 127.0, 125.0, 107.7, 90.8, 43.7;
HRMS (GC-ESI) calcd for C10H10Cl3O [(M + H)+] m/z 250.9797,
found 250.9792.
erythro-Trimethyl-2-phenyl-1-(trichloromethyl)-
cyclohexyloxy)silane (7g). Following Procedure A, 1.21 g (7 mmol)
of 2-phenylcyclohexanone yielded 2.45 g (96%) of 7g as a colorless oil
after chromatography on silica eluting with 98:2 heptane/EtOAc: FT-
1
IR (SB-DC) cm−1 836; H NMR (400 MHz, CDCl3) δ 7.34 (br s,
2H), 7.16−7.27 (m, 3H), 3.25 (dd, J = 12.5, 3.3 Hz, 1H), 2.45 (m,
1H), 1.92−2.03 (m, 2H), 1.80−1.91 (m, 2H), 1.64−1.78 (m, 2H),
1.36−1.48 (m, 1H), 0.35 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
143.4, 129.6, 127.6, 126.3, 108.9, 88.2, 50.4, 33.10, 33.07, 26.0, 23.0,
2.5; HRMS (GC-ESI) calcd for C16H23Cl3OSi [M+] m/z 364.0584,
found 364.0582.
(9) Renga, J. M.; Wang, P.-C. Tetrahedron Lett. 1985, 26, 1175−
1178.
(10) Wang, P. -C. U.S. Patent 4634787, 1987.
(11) Brunner, H.; Wimmer, P. J. Organomet. Chem. 1986, 309, C4−
C6.
erythro-2-Phenyl-1-(trichloromethyl)cyclohexanol (8g).25
Following Procedure B, 0.366 g (1.0 mmol) of 7g yielded 0.28 g
(95%) of 8g as a white solid after chromatography eluting with 90:10
3003
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Note
(12) (a) Jocic, J. Z. Zh. Russ. Fiz. Khim. Ova. 1897, 29, 97−103.
(b) Reeve, W.; McKee, J. R.; Brown, R.; Lakshamanan, S.; McKee, G.
Can. J. Chem. 1980, 58, 485−493.
(13) (a) Bergmann, E. D.; Ginsburg, D.; Lavie, D. J. Am. Chem. Soc.
1950, 70, 5012−5014. (b) Reeve, W.; Woods, C. W. J. Am. Chem. Soc.
1960, 82, 4062−4066. (c) Compere, E. L. Jr.; Shockravi, A. J. Org.
Chem. 1978, 43, 2702−2703. (d) Corey, E. J.; Link, J. O. Tetrahedron
Lett. 1992, 33, 3431−3434. (e) Shamshina, J. L.; Snowden, T. S. Org.
Lett. 2006, 8, 5881−5884. (f) Scaffidi, A.; Skelton, B. W.; Stick, R. V.;
White, A. H. Aust. J. Chem. 2006, 59, 426−433.
(14) Cafiero, L. R.; Snowden, T. S. Org. Lett. 2008, 10, 3853−3856.
(15) (a) Oliver, J. E.; Waters, R. M.; Lusby, W. R. Synthesis 1994,
273−275. (b) Khrimian, A. P.; Oliver, J. E.; Waters, R. M.; Panicker,
S.; Nicholson, J. M.; Klun, J. A. Tetrahedron: Asymmetry 1996, 7, 37−
40.
(16) (a) Corey, E. J.; Link, J. O. J. Am. Chem. Soc. 1992, 114, 1906−
1908. (b) Dominguez, C.; Ezquerra, J.; Baker, S. R.; Borrelly, S.;
Prieto, L.; Espada, C. M.; Pedregal, C. Tetrahedron Lett. 1998, 39,
9305−9308. (c) Sorensen, M. H.; Nielsen, C.; Nielsen, P. J. Org. Chem.
2001, 66, 4878−4886. (d) Scaffidi, A.; Skelton, B. W.; Stick, R. V.;
White, A. H. Aust. J. Chem. 2004, 57, 723−732. (e) Habay, S. A.;
Schafmeister, C. E. Org. Lett. 2004, 6, 3369−3371. (f) Forman, G. S.;
Scaffidi, A.; Stick, R. V. Aust. J. Chem. 2004, 57, 25−28. (g) Finke, P.
E.; Loebach, J. L.; Parker, K. A.; Plummer, C. W.; Mills, S. G. U.S.
Patent 20050070609. (h) Gupta, S.; Schafmeister, C. E. J. Org. Chem.
2009, 74, 3652−3658. (i) Brodney, M. A.; Efremov, I. V.; Helal, C. J.;
O’Neill, B. T. Patent WO 2010058333.
(17) Reeve, W.; Fine, L. W. J. Org. Chem. 1964, 29, 1148−1150.
(18) Pliushchev, M. A.; Wodka, D.; Sorensen, B. K.; Link, J. T. U.S.
Patent 20100222316.
(19) Blanchet, J.; Zhu, J. Tetrahedron Lett. 2004, 45, 4449−4452.
(20) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1993, 34, 5227−5230.
(21) Li, J.; Xu, X.; Zhang, Y. Tetrahedron Lett. 2003, 44, 9349−9351.
(22) Villieras, J.; Bacquet, C.; Normant, J. F. J. Organomet. Chem.
1975, 97, 355−374.
(23) Wang, Z.; Campagna, S.; Yang, K.; Xu, G.; Pierce, M. E.;
Fortunak, J. M.; Confalone, P. N. J. Org. Chem. 2000, 65, 1889−1891.
(24) Baati, R.; Barma, D. K.; Falck, J. R.; Mioskowski, C. Tetrahedron
Lett. 2002, 43, 2183−2185.
(25) Falck, J. R.; He, A.; Reddy, L. M.; Kundu, A.; Barma, D. K.;
Bandyopadhyay, A.; Kamilia, S.; Akella, R.; Bejot, R.; Mioskowski, C.
Org. Lett. 2006, 8, 4645−4647.
(26) Hergott, H. H.; Simchen, G. Synthesis 1980, 626−627.
(27) Spier, J. L. J. Am. Chem. Soc. 1951, 73, 824−826.
(28) Bamford, W. R.; Pant, B. C. J. Chem. Soc. C 1967, 1470−1472.
(29) Dunogues, J.; Jousseaume, E.; Calas, R. J. Organomet. Chem.
1974, 71, 377−392.
(30) Koidan, G. N.; Marchenko, A. P.; Pinchuk, A. M. Zh. Obshch.
Khim. 1990, 60, 709−710.
(31) Cafiero, L. R.; Snowden, T. S. Tetrahedron Lett. 2008, 49, 2844−
2847.
3004
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