Hafnium trifluoromethanesulfonate (hafnium triflate) as a highly efficient catalyst for chemoselective thioacetalization and transthioacetalization of carbonyl compounds

Article abstract of DOI:10.1021/jo8021988

(Chemical Equation Presented) A range of carbonyl compounds including aliphatic and aromatic aldehydes and ketones were converted to the corresponding thioacetals in high yields in the presence of a catalytic amount of hafnium trifluoromethanesulfonate (0.1 mol %, room temperature). The mild conditions tolerated various sensitive functional and protecting groups and were racemization-free when applied to α-aminoaldehydes. Transacetalization and chemoselective thioacetalization of aromatic aldehydes in the presence of aliphatic aldehydes and ketones were also documented.

Full text of DOI:10.1021/jo8021988

conditions, and stoichiometric amount of catalyst and failed to
protect deactivated aromatic substrates. Furthermore, many
reported methods were incompatible with sensitive functional
and protecting groups and displayed poor aldehydes versus
ketones chemoselectivity. We report herein that Hf(OTf)4 is a
highly efficient, racemization-free catalyst for the thioacetal-
ization of carbonyl compounds.
Hafnium Trifluoromethanesulfonate (Hafnium
Triflate) as a Highly Efficient Catalyst for
Chemoselective Thioacetalization and
Transthioacetalization of Carbonyl Compounds
Yan-Chao Wu and Jieping Zhu*
In connection with our synthetic program dealing with the
synthesis of tetrahydroisoquinoline-containing alkaloids,7,8 we
observed that hafnium trifluoromethanesulfonate [Hf(OTf)4] is
an efficient catalyst for transforming the aminal to aminothio-
ether, a key intermediate in the synthesis of antitumor antibiotic
(-)-quinocarcin.9 The high oxophilicity10 and low thiophilicity11
of Hf(OTf)4 led us to hypothesize that it could potentially act
as an efficient catalyst for the conversion of carbonyl compounds
to the corresponding thioacetals/thioketals. Indeed, simply
stirring a dichloromethane solution of 4-nitrobenzaldehyde (1a)
and ethanethiol (2a) at room temperature in the presence of 0.1
mol % of Hf(OTf)4 afforded the corresponding thioacetals (3a)
in 99% yield (Table 1). This reaction, completed within 5 min,
is extremely easy to perform without the need of using
anhydrous solvent and inert atmosphere.
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr
ReceiVed October 2, 2008
A range of carbonyl compounds including aliphatic and
aromatic aldehydes and ketones were converted to the
corresponding thioacetals in high yields in the presence of a
catalytic amount of hafnium trifluoromethanesulfonate (0.1
mol %, room temperature). The mild conditions tolerated
various sensitive functional and protecting groups and were
racemization-free when applied to R-aminoaldehydes. Transac-
etalization and chemoselective thioacetalization of aromatic
aldehydes in the presence of aliphatic aldehydes and ketones
were also documented.
This simple procedure turned out to be applicable to a wide
range of carbonyl compounds including racemization-prone
R-aminoaldehydes. The results are summarized in Table 1.
Reaction of ethanethiol with both electron-rich and electron-
poor aromatic aldehydes afforded the corresponding thioacetals
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9522 J. Org. Chem. 2008, 73, 9522–9524
10.1021/jo8021988 CCC: $40.75 2008 American Chemical Society
Published on Web 11/08/2008

TABLE 1. Hf(OTf)4-Catalyzed Thioacetalization of Aldehydes and Ketones to Thioacetalsa
a General conditions: 1 (1.0 mmol), 2a-2b (2.0 mmol) or 2c-2d (1.0 mmol), and Hf(OTf)4 (0.001 mmol) in CH2Cl2 (2 mL) at room temperature.
b Minutes. c One mole percent Hf(OTf)4 was used. TBS ) tert-butyldimethylsilyl; Bn ) benzyl; Boc ) tert-butylcarbonyl; Cbz ) benzyloxycarbonyl;
Alloc ) allyloxycarbonyl.
in excellent yields within less than 15 min (Table 1, entries
1-15). The highly deactivated and sterically hindered 2,4,6-
trimethoxybenzaldehyde (1i) that resisted most of the thioac-
etalization conditions was converted to thioacetal 3i in excellent
yield (97%, entry 9). Aliphatic aldehydes (1p,q, Table 1, entries
16 and 17) reacted equally well with EtSH to afford the
corresponding thioacetals (3p,q) in high yields. Other thiols such
as benzenethiol (PhSH, 2b), 1,2-ethanedithiol (2c), and 1,3-
propanedithiol (2d) participated in the thioacetalization of
aldehydes uneventfully (entries 18-20). Aromatic ketone (1r,
J. Org. Chem. Vol. 73, No. 23, 2008 9523

SCHEME 1. Probing the Racemization Issue
SCHEME 3. Hf(OTf)4-Catalyzed Transthioacetalization
The Hf(OTf)4-catalyzed system is also suitable for transthio-
acetalization15 of acetals to thioacetals. Both aromatic acetal
(5a) and aliphatic acetal (5b) could be converted to the
corresponding thioacetals (3e and 3p) in high yields under
standard conditions (Scheme 3).
We emphasize that a variety of functional and protecting
groups such as nitro, cyano, dimethylamino, hydroxy, tert-
butyldimethylsilyl, benzyloxy, tert-butylcarbonyl (Boc), ben-
zyloxycarbonyl (Cbz), and allyloxycarbonyl (Alloc) are tolerated
under the present thioacetalization conditions.
SCHEME 2. Chemoselective Thioacetalization of Carbonyl
Compounds
In summary, Hf(OTf)4 is an excellent catalyst for the
thioacetalization of aldehydes and ketones. The reaction took
place at room temperature and displayed excellent functional
group compatibility. The protocol is also very effective for the
transthioacetalization of acetals to thioacetals and is racemiza-
tion-free when applied to chiral nonracemic R-aminoaldehyde.
Chemoselective thioacetalization of aromatic aldehyde in the
presence of aliphatic aldehyde and aromatic ketone was also
demonstrated.
Table 1, entry 21) and aliphatic ketone (1s, entry 22) were
similarly converted to the acetals under the standard conditions,
albeit with a longer reaction time.
Experiment Section
Finally, chiral nonracemic R-aminoaldehydes 1t, 1u, and 1v
were converted to the corresponding acetals 3w, 3x, and 3y in
excellent yields (entries 23-25). To verify if any racemization
took place during thioacetalization, the thioacetals 3w-y were
converted back to the corresponding aminoalcohols 4a-c via
a sequence of dethioacetalization12 and reduction (Scheme 1).
The optical rotation ([R]D) of these compounds matched with
those obtained by the direct reduction of chiral aldehydes 1t-v
(NaBH4, MeOH, 0 °C, 1 h), as well as those described in the
literature.13,14
We next examined the applicability of this protocol to the
selective thioacetalization of carbonyl groups. When an equimo-
lar mixture of benzaldehyde (1e) and phenylacetaldehyde (1p)
was allowed to react with EtSH under our established conditions
[0.1 mol % Hf(OTf)4, CH2Cl2, rt], only 1e was converted to
thioacetal 3e (98% yield) without a touch of 1p (Scheme 1, eq
1). Similarly, selective thioacetalization of benzaldehyde (1e)
was realized in the presence of equimolar amount of acetophe-
none (1s, Scheme 2, eq 2). We believed that such selective
thioacetalization procedure would be useful in the synthesis of
complex molecules.
Hf(OTf)4-Catalyzed Thioacetalization Procedure. A solution
of 4-tert-butyldimethylsilyloxy-3-methoxybenzaldehyde (1o, 266.4
mg, 1.0 mmol), EtSH (2a, 0.15 mL, 2.0 mmol), and Hf(OTf)4 (0.8
mg, 0.001 mmol) in CH2Cl2 (2 mL) was stirred at room temperature
for 5 min. The reaction mixture was filtered through a short pad of
Celite, and the filtrate was concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel to afford thioacetal 3o (365.2 mg) in 98% yield as a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 7.00 (d, 1H, J ) 2.1 Hz), 6.84
(dd, 1H, J ) 8.1, 2.1 Hz), 6.75 (d, 1H, J ) 8.1 Hz), 4.88 (s, 1H),
3.81 (s, 3H), 2.62-2.48 (m, 4H), 1.21 (t, 6H, J ) 7.4 Hz), 0.99 (s,
9H), 0.14 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 151.0, 144.6,
133.7, 120.3, 120.1, 111.3, 55.4, 52.4, 26.3, 25.7, 18.4, 14.3, -4.7;
FTIR (film) 2956, 2927, 2855, 1508, 1463, 1415, 1282, 1249, 1236,
1206, 1148, 1122, 1036, 903, 838, 822, 804, 780, 746, 701 cm-1
;
MS 372 (M+), 311; HRMS (TOF MS ES+) m/z calcd for
C18H32O2NaSiS2 [M + Na]+ 395.1511, found 395.1511.
Acknowledgment. Financial support from CNRS and this
institute (ICSN) are gratefully acknowledged.
Supporting Information Available: Experimental proce-
dures; characterization data; and copies of H and 13C NMR
1
(12) For selected examples of dethioacetalizations, see: (a) Corey, E. J.;
Erickson, B. W. J. Org. Chem. 1971, 36, 3553–3560. (b) Ravindranathan, T.;
Chavan, S. P.; Tejwani, R. B.; Varghese, J. P. J. Chem. Soc., Chem. Commun.
1991, 1750–1751. (c) Komatsu, N.; Taniguchi, A.; Uda, M.; Suzuki, H. Chem.
Commun. 1996, 1847–1848. (d) Komatsu, N.; Taniguchi, A.; Uda, M.; Suzuki,
H. AdV. Synth. Catal. 2001, 343, 473–480. (e) Wang, E. C.; Wu, C. H.; Chien,
S. C.; Chiang, W. C.; Kuo, Y. H. Tetrahedron Lett. 2007, 48, 7706–7708.
(13) For authentic alcohol 4a, see: (a) Varala, R.; Nuvula, S.; Adapa, S. R.
J. Org. Chem. 2006, 71, 8283–8286. (b) Chankeshwara, S. V.; Chakraborti, A. K.
Org. Lett. 2006, 8, 3259–3262.
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO8021988
(15) For selected examples of transthioacetalization, see: (a) Fieser, L. F.
J. Am. Chem. Soc. 1954, 76, 1945–1947. (b) Muthusamy, S.; Babu, S. A.;
Gunanathan, C. Tetrahedron Lett. 2001, 42, 359–362. (c) Yadav, J. S.; Reddy,
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9524 J. Org. Chem. Vol. 73, No. 23, 2008