tert-Butyldimethylsilyloxytrichloromethylmethane-readily accessible and robust protecting group for (hetero)aryl aldehydes

Article abstract of DOI:10.1016/j.tetlet.2008.02.072

The tert-butyldimethylsilyloxytrichloromethylmethane (TBSTCM) substituent serves as a readily accessible masking group for aromatic and heteroaromatic aldehydes. The TBSTCM substituent is compatible with a range of common reagents and offers several strategic advantages over alternative aldehyde protecting groups.

Full text of DOI:10.1016/j.tetlet.2008.02.072

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Tetrahedron Letters 49 (2008) 2844–2847
tert-Butyldimethylsilyloxytrichloromethylmethane—readily accessible
and robust protecting group for (hetero)aryl aldehydes
Lauren R. Cafiero, Timothy S. Snowden *
The University of Alabama Department of Chemistry, 250 Hackberry Lane, Tuscaloosa, AL 35487-0336, United States
Received 16 January 2008; revised 11 February 2008; accepted 13 February 2008
Available online 19 February 2008
Abstract
The tert-butyldimethylsilyloxytrichloromethylmethane (TBSTCM) substituent serves as a readily accessible masking group for
aromatic and heteroaromatic aldehydes. The TBSTCM substituent is compatible with a range of common reagents and offers several
strategic advantages over alternative aldehyde protecting groups.
Ó 2008 Elsevier Ltd. All rights reserved.
TBSTCM
During our recent investigations into new synthetic
applications involving trichloromethylcarbinols,1 we found
that detrichloromethylation of aryl and alkenyl trichloro-
methyl carbinols could occur under specific reaction condi-
tions, thereby revealing the corresponding aldehyde (Fig. 1,
from 3 to1).2 With this in mind, we reasoned that if the
chemically vulnerable carbinol hydroxyl group could be
shielded as a silyl ether, the resultant silyloxytrichloro-
methylmethane might serve as a stable masked aldehyde
with strategic applications in multistep synthesis. Such a
role would require that the silyloxytrichloromethylmethane
be readily installed and efficiently converted back to the
original aldehyde.
OTBS
CCl3
O
?
H
Masked
Aldehyde?
1
2
?
-
F
-
Cl3C
-
O
CCl3
3
Kister and Mioskowski recently reported a method for
the single-step preparation of trimethylsilyl-protected tri-
chloromethylcarbinols using trichloromethyl-trimethyl-
silane under mild conditions.3 Although this method offers
excellent yields of the TMS-protected trichlorocarbinols,
the susceptibility of the TMS ether to common reagents
makes these products undesirable as potential masked
aldehydes in most common reactions. We reasoned that
the TBS analog would offer superior durability along with
a comparable propensity for an unprecedented one-pot
Fig. 1. Considerations in the installation and removal of the tert-
butyldimethylsilyloxytrichloromethylmethane (TBSTCM) group.
desilylation–detrichloromethylation to regenerate the alde-
hyde in the presence of a fluoride source (Fig. 1).
All classes of aldehydes are efficiently converted to tert-
butyldimethylsilyloxytrichloromethylmethane (TBSTCM)
analogs using a modification of the Corey–Link aldehyde
trichloromethylation procedure.4 Addition of sodium
trichloroacetate, TBSCl, and imidazole to the aldehyde in
DMF affords the desired compounds in excellent
yields (Fig. 2). This approach serves as an alternative to
the Mioskowski procedure, but offers the advantage of
*
Corresponding author. Tel.: +1 205 348 8550; fax: +1 205 348 9104.
E-mail address: snowden@bama.au.edu (T. S. Snowden).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.072

L. R. Cafiero, T. S. Snowden / Tetrahedron Letters 49 (2008) 2844–2847
2845
Table 1
Cl3CCO2Na, TBSCl, Imid,
DMF, rt, 8-12 h
O
OTBS
CCl3
Yields for the protection of aldehydes 6a–h and deprotection of aryl
TBSTCM derivatives 7a–h
(90-98%)
R
H
R
5
Protection yielda (%)
Deprotection yielda (%)
4
Entry
Aldehyde
R = aliphatic, alkenyl, aryl
1
2
3
4
5
6
7
8
a
6a
6b
6c
6d
6e
6f
96
97
97
96
95
90
90
94
92
94
92
92
93
90
91
95
Fig. 2. One-step conversion of aldehydes to TBSTCM derivatives.
commercially available reagents. It is notable that aldol
reactions of enolizable substrates do not occur under these
conditions.
6g
6h
We screened numerous solvents and reaction tempera-
tures in the presence of TBAF in THF, HF–pyridine, or tri-
ethylamine trihydrofluoride to evaluate the capacity of
aryl, alkenyl, and aliphatic TBSTCM groups to undergo
deprotection to the corresponding aldehydes. As expected,
aliphatic TBSTCM groups were readily desilylated, how-
ever the ensuant saturated trichloromethylalkoxides were
stable to all attempted detrichloromethylation conditions.
Trichloromethylallylic alkoxides, furnished by the desilyl-
ation of the alkenyl substrates, also proved resistant to tri-
chloromethide elimination. These compounds undergo
significant but incomplete detrichloromethylation only in
tert-butanol at elevated temperature over several days.
However, aryl TBSTCM groups were rapidly and cleanly
converted to the corresponding aldehydes by simply treat-
ing the substrates with 1.1 equiv of TBAF (1 M in THF) in
DMF at 50 °C for 9–12 h (Fig. 3). The enhanced pro-
pensity of aryl TBSTCM substituents to undergo detri-
chloromethylation is presumably due to their greater
thermodynamic driving force for extending conjugation
relative to alkenyl substrates.
Isolated yield of chromatographically purified product.
6–8) proceed smoothly.5,6 The resultant products are sub-
jected to a simple aqueous workup, then readily purified
by passing through a short plug of silica.
Having established optimal conditions for the protec-
tion and deprotection of aryl aldehydes, we investigated
the compatibility of the TBSTCM substituent in 7a toward
a variety of common reaction conditions (Table 2). The
TBSTCM group possesses excellent thermal stability (entry
1) and is compatible with common reductants (entries 4–6)
and oxidants (entries 7 and 8). We were pleased to find that
the TBSTCM functionality shows resistance to both Bro¨n-
sted acidic and basic conditions (entries 2 and 3) despite the
presence of the silyloxy group. The reduced Lewis basicity
of the TBSTCM oxygen atom, resulting from the proximal
trichloromethyl group, may contribute to the hydrolytic
stability and diminished propensity for trans-silylation.
The protecting group is also suitable in reactions involving
LDA, Grignard reagents, and organocuprates (entries
9–11). The only investigated conditions incompatible with
the TBSTCM substituent were those involving fluoride,
which generates the corresponding trichloromethyl
carbinol, and alkyl lithium reagents7 or Lewis acids that
result in decomposition (entries 12 and 13).
Protection and deprotection of both activated and deac-
tivated benzaldehydes (Table 1, entries 1–4), naphthalde-
hyde (entry 5), and heteroaromatic aldehydes (entries
Cl3CCO2Na
TBSCl, Imid,
DMF, rt, 8-12 h
O
OTBS
Ar
6a-
H
Ar
CCl3
7a-h
h
Table 2
Reagent compatibility of 7a
TBAF, DMF,
50 oC, 9-12 h
Entry Reagent
Equiv Conditions
Recoverya
(%)
CHO
CHO
1
2
3
4
5
6
7
8
9
NA
NA
4
4
2.0
1.2
1.5
2.5
1.3
1.1
1.2
DMF, reflux, 12 h
98
99
97
96
97
96
88b
98
98
96
I
CHO
1 N HCl
2 N NaOH
LiAlH4
MeOH, rt, 24 h
THF, rt, 24 h
THF, rt, 12 h
PhCH3, À78 °C
Et2O, rt, 24 h
DCM, rt, 12 h
DMF, rt, 6 h
H3CO
6c
CHO
6b
6a
DIBAL
BH3ÁDMS
CHO
PCC
DMP
LDA
MeMgBr (3 M in
Et2O)
Bu2Cu(CN)Li2ÁLiCl
F3C
THF, À78 °C, 2 h
6e
6d
10
THF, rt, 12 h
O
S
N
CHO
CHO
CHO
11
1.5
THF, À40 °C to rt, 97
4 h
12
13
a
n-BuLi
AlCl3
1.2
1.5
THF, À78 °C, 1 h
Decomp.
Decomp.
6f
6g
6h
DCM, rt, 12 h
Fig. 3. Established conditions for the protection and deprotection of aryl
aldehydes 6a–h.
Isolated recovery of chromatographically purified 7a.
No conversion to other materials or decomposition was detected.
b

2846
L. R. Cafiero, T. S. Snowden / Tetrahedron Letters 49 (2008) 2844–2847
Given the stability of TBSTCM substituent to a variety
deprotection process could prove particularly advanta-
geous in the late stages of complex molecule syntheses.
Aldehyde 10 is smoothly converted to 1,3-dioxane 13
under standard conditions (Fig. 4B). The resulting acetal
may be selectively removed by treatment with 1 N HCl in
THF–H2O over 24 h. The TBSTCM group shows no deg-
radation under these conditions, thereby exemplifying its
hydrolytic stability. Alternatively, the TBSTCM substitu-
ent may be converted to aryl aldehyde 14 using TBAF in
DMF without affecting the acetal. These results highlight
the orthogonality of the TBSTCM and acetal carbonyl
protecting groups. Another advantage of the outlined
method is the high selectivity of the weakly nucleophilic tri-
chloromethide, generated from the decarboxylation of
sodium trichloroacetate in DMF, for aldehydes relative
to unhindered ketones (16, Fig. 4C). Hence, the aryl
TBSTCM group may be installed without competition
from resident non-aldehyde carbonyl functionalities.
Although we have featured the aryl TBSTCM substi-
tuent as a masked aldehyde, it is important to note that
silyl-protected trichloromethyl carbinols are used directly
in several synthetic transformations. The increased stability
of the TBS-protected trichloromethyl carbinols reported
herein, relative to the typical TMS analogs, allows the
former to be prepared, carried through numerous synthetic
steps, then converted directly to, for example, (Z)-2-chlo-
roenol ethers,7,9 (Z)-1-chloroalk-1-enes, 2-chloroketones,
vinyl dichlorides, terminal alkynes,10 or 2-aryl-2-fluoro-
1,1,1-trichloroethanes.11 As such, the TBSTCM group
may serve as a valuable synthetic handle or stable latent
functionality independent of its application as a capable
protecting group for aromatic and heteroaromatic
aldehydes.
of reaction conditions and the means by which the group is
removed to reveal the corresponding aldehyde, we consid-
ered several strategic advantages offered by its employ-
ment. Protected compounds 10 and 11 were prepared
from 88 as shown in Figure 4. It is notable that the selection
of the TBSTCM group allows for the protection of both
the aldehyde and the resident hydroxyl or phenol groups
in an efficient single operation (e.g., conversion of 8 to 9).
Product 11 features a TBS-protected primary alcohol, phe-
nol, and a TBSTCM masked aldehyde. Treatment of 11
with 3.5 equiv of TBAF in DMF at 50 °C affords globally
deprotected 12 in excellent yield (Fig. 4A). An analogous
OH
OTBS OTBS
CCl3
Cl3CCO2Na,
TBSCl, Imid,
DMF, rt, 12 h
CHO
(93%)
8
9
OTBS
OTBS
O3, MeOH, -60 oC, 1 h
(79%)
OHC
CCl3
10
OTBS OTBS
1. NaBH4, EtOH
2. TBSCl, Imid, DMF
TBSO
CCl3
(87%)
11
A. Global Deprotection:
OH
3.5 equiv TBAF,
DMF, 50 oC, 12 h
HO
CHO
11
(94%)
The facile installation and removal, coupled with broad
reagent compatibility, make the tert-butyldimethylsilyl-
oxytrichloromethylmethane group an attractive option
for aryl aldehyde protection. Its possible employment in
global silylation–desilylation protocols, applications
requiring orthogonal carbonyl protecting groups, or the
selective monoprotection of ketoaldehydes offers strategic
synthetic options unavailable to many alternatives. Such
masked aldehydes may also prove useful in direct transfor-
mations to unrelated functional groups.
12
OTBS OTBS
CCl3
B. Orthogonal Protection/Deprotection:
HO OH
O
PhH, cat. TsOH,
Dean-Stark
10
(89%)
O
13
2.2 equiv TBAF,
DMF, 50 oC, 12 h
(93%)
1 N HCl, THF-H2O,
rt, 24 h
(91%)
OH
O
CHO
OTBS OTBS
CCl3
Acknowledgment
O
OHC
Acknowledgment is made to the Donors of the
American Chemical Society Petroleum Research Fund
for the support of this research.
14
15
C. Selective Carbonyl Protection:
OTBS
CCl3
Cl3CCO2Na,
CHO
Supplementary data
TBSCl, Imid,
DMF, rt, 12 h
Preparative experimental procedures, characterization
(91%)
1
data, and H and 13C spectra of compounds 7a–h, 9–15
O
O
16
17
and 17 are available. Supplementary data associated with
this article can be found, in the online version, at doi:
10.1016/j.tetlet.2008.02.072.
Fig. 4. Preparation of TBS-protected masked aryl aldehydes 10 and 11
and strategic applications/advantages of the TBSTCM group.

L. R. Cafiero, T. S. Snowden / Tetrahedron Letters 49 (2008) 2844–2847
2847
chloride solution and once with brine. The organic phase was dried
with anhydrous sodium sulfate and evaporated under reduced
pressure. The resulting residue was eluted through a plug of silica
gel with hexane/ethyl acetate to afford the corresponding mono-
protected aryl aldehyde.
References and notes
1. (a) Shamshina, J. L.; Snowden, T. S. Org. Lett. 2006, 8, 5881–5884;
(b) Cafiero, L. R.; Snowden, T. S., submitted for publication.
2. Other authors have reported detrichloromethylation of unsaturated
trichloromethylcarbinols under highly basic conditions: (a) Hull, R. J.
Chem. Soc. 1957, 4845–4857; (b) Crochemore, M. French Patent FR
2663321, 1991.; (c) Bonneau, I.; Gubelmann, M.; Tirel, P. J. Eur.
Patent EP 428979, 1992.
3. Kister, J.; Mioskowski, C. J. Org. Chem. 2007, 72, 3925–3928.
4. Corey, E. J.; Link, J. O.; Shao, Y. Tetrahedron Lett. 1992, 33, 3435–
3438.
6. General procedure for the deprotection of monoprotected aryl aldehydes
(6a–h). To a solution of monoprotected aryl aldehyde (1 mmol) in
2 mL of DMF with stirring at room temperature was added a 1 M
solution of TBAF in THF (1.1 mmol). After heating for 9–12 h at
50 °C, the reaction mixture was cooled to room temperature and
eluted through a plug of silica gel with hexane/ethyl acetate to afford
the corresponding aryl aldehyde.
7. Pirrung, M. C.; Hwu, J. R. Tetrahedron Lett. 1983, 24, 565–568.
8. Marshall, W. S.; Goodson, T.; Cullinan, C. J.; Swanson-Bean, D.;
Haisch, K. D.; Rinkema, L. E.; Fleisch, J. H. J. Med. Chem. 1987, 30,
682–689.
9. (a) Takai, K.; Kokumai, R.; Nobunaka, T. Chem. Commun. 2001,
1128–1129; (b) Bejot, R.; Tisserand, S.; Reddy, L. M.; Barma, D. K.;
Baati, R.; Falck, J. R.; Mioskowski, C. Angew. Chem., Int. Ed. 2005,
44, 2008–2011.
10. Villieras, J.; Bacquet, C.; Normant, J. F. J. Organomet. Chem. 1975,
97, 355–374.
11. Ayi, A. I.; Condom, R.; Wade, T. N.; Guedj, R. J. Fluorine Chem.
1979, 14, 437–454.
5. General procedure for the preparation of monoprotected aryl aldehydes
(7a–h). To a solution of aldehyde (1 mmol) in 3.3 mL of anhydrous
DMF was added sodium trichloroacetate (2 mmol) with stirring at
room temperature. Initially, rapid evolution of CO2 was observed.
After 40 min, imidazole (1.5 mmol) and TBSCl (1.4 mmol) were
added. After 8 h, the reaction mixture was monitored by TLC. [If
starting material remained, additional sodium trichloroacetate
(1 mmol) was added and the suspension was mixed rapidly for an
additional 4–6 h.] The mixture was diluted with 5 mL of diethyl ether
and washed with
a saturated aqueous solution of ammonium
chloride. Any precipitate was filtered and washed with diethyl ether
(3 Â 10 mL). The filtrate was washed two more times with ammonium