Convenient synthesis of difluoromethyl alcohols from both enolizable and non-enolizable carbonyl compounds with difluoromethyl phenyl sulfone

Article abstract of DOI:10.1002/ejoc.200500101

A general and efficient nucleophilic difluoromethylation of carbonyl compounds (both enolizable and non-enolizable aldehydes and ketones) has been achieved by using a nucleophilic (phenylsulfonyl)difluoromethylation-reductive desul fonylation strategy. Di

Full text of DOI:10.1002/ejoc.200500101

SHORT COMMUNICATION
Convenient Synthesis of Difluoromethyl Alcohols from Both Enolizable and
Non-Enolizable Carbonyl Compounds with Difluoromethyl Phenyl Sulfone
G. K. Surya Prakash,*[a] Jinbo Hu,[a,b] Ying Wang,[a] and George A. Olah[a]
Keywords: Difluoromethyl phenyl sulfone / Nucleophilic reaction / Difluoromethylation / Fluorine / Reductive desulfo-
nylation
A general and efficient nucleophilic difluoromethylation of
carbonyl compounds (both enolizable and non-enolizable al-
dehydes and ketones) has been achieved by using a nucleo-
philic (phenylsulfonyl)difluoromethylation-reductive desul-
fonylation strategy. Difluoromethyl phenyl sulfone acts as a
difluoromethyl anion (“CF2H–”) equivalent.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
enolizable and non-enolizable aldehydes, it could not be ap-
plied to ketones.[6] Therefore, there is still lack of a general
and efficient difluoromethylation method applicable to both
enolizable and non-enolizable aldehydes and ketones. As
our continuing effort, herein we wish to disclose an efficient
nucleophilic difluoromethylation of both enolizable and
non-enolizable aldehydes and ketones, using difuoromethyl
phenyl sulfone as a difluoromethyl anion (“CF2H–”) equiv-
alent.
Introduction
Selective incorporation of difluoromethyl group (CF2H)
into organic molecules has attracted much interest since it
plays critical roles in the bioactive molecules as a lipophilic
isostere of hydroxy group (OH) as well as a hydrogen donor
through hydrogen bonding.[1] Although several methods are
available to introduce a difluoromethyl group into organic
substrates without an α-hydroxy group, few methods have
been reported for the preparation of α-difluoromethyl
alcohols.[2] Nucleophilic trifluoromethylation of carbonyl
compounds are well-developed and widely used, especially
with (trifluoromethyl)trimethylsilane (TMS–CF3), first de-
veloped by us in 1989.[3] However, its analogous nucleo-
philic difluoromethylation is more challenging regarding
the generality and efficiency. This is mainly due to the fact
that Si–CF2H (bond order 0.436) is less polarized than the
Si–CF3 bond (bond order 0.220), indicating that the cleav-
age of former bond is much more difficult.[4] Fuchikami
and co-workers have attempted the fluoride-induced difluo-
romethylation of carbonyl compounds with difluorometh-
ylsilane derivatives in DMF, and found that the reaction
requires high temperature (100 °C) and give poor yields
with ketones.[4] Stahly reported the difluoromethylation of
aldehydes with difuoromethyl phenyl sulfone, but the
method is only limited to non-enolizable aldehydes.[5] In
1997, we reported the fluoride-induced difluoromethylation
of carbonyl compounds with Me3SiCF2SiMe3 at room tem-
perature.[6] Although the reaction worked well with both
Results and Discussion
Previously, we have reported that difluoromethyl phenyl
sulfone (1)[7] can act as a selective difluoromethylene di-
–
anion equivalent (“–CF2 ”) in the one-pot stereoselective
synthesis of anti-2,2-difluoropropane-1,3-diols,[8] a difluo-
romethylidene equivalent (“=CF2”) in the synthesis of 1,1-
difluoro-1-alkenes,[9] and a difluoromethyl anion equivalent
(“CF2H–”) in the synthesis of difluoromethylsilanes[10] and
difluoromethylalkanes.[11] The chemistry is mostly based on
the selective deprotonation of the acidic CF2H proton of
1 with a base (commonly tBuOK), to in situ generate a
–
(phenylsulfonyl)difluoromethyl anion (PhSO2CF2 ), and
the latter species further reacts with electrophiles.[8,9,11] We
attempted to apply a similar protocol in the difluoromethyl-
ation of carbonyl compounds (see Scheme 1), i.e., to synthe-
size the (phenylsulfonyl)difluoromethylated carbinols 3, fol-
lowed by selective desulfonylation to give difluoromethyl
carbinols 4. However, when 1/tBuOK reacted with benzal-
dehyde in DMF at –50 °C to room temp., 2,2-difluoro-1,3-
diphenyl-1,3-propanediol was formed as a byproduct in sig-
nificant amounts (30–40%), which decreased the product
yield. Obviously, here tBuOK also acts as a nucleophile to
further activate the C–S bond cleavage of the product 3.[8,12]
Furthermore, the reactions of 1/tBuOK system with enoliz-
able aldehydes and ketones at –50 °C to room temp. gave
[a] Loker Hydrocarbon Research Institute and Department of
Chemistry, University of Southern California,
University Park, Los Angeles, CA 90089-1661, USA
Fax: +1-213-740-6270
E-mail: gprakash@usc.edu
[b] Key Laboratory of Organofluorine Chemistry, Shanghai Insti-
tute of Organic Chemistry, Chinese Academy of Sciences,
354 Feng-Lin Rd., Shanghai, China 200032
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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DOI: 10.1002/ejoc.200500101
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Synthesis of Difluoromethyl Alcohols with Difluoromethyl Phenyl Sulfone
SHORT COMMUNICATION
very poor yields of product (10–30%). It soon became ap- atively lower yields of products were obtained (see Entries
parent that the use of a proper base is critical for this reac- 3 and 4). In the cases of Entries 3 and 4, after the reactions,
tion. The base has to satisfy the following two require- unreacted aldehydes were recovered and only small
ments: First, it should be a reasonably strong base (for de- amounts of aldol side-reaction products were observed. For
–
protonating 1 to generate PhSO2CF2 ) but a weak nucleo- the α,β-unsaturated aldehyde, only 1,2-addition product 3b
phile (unlike tBuOK), in order to avoid the C–S bond cleav- was observed (Entry 2). In the case of 4-(tert-butyl)cyclo-
age during the reaction; second, the base has to be able hexanone, both equatorial and axial addition products 3i
to kinetically effect the deprotonation of 1 rather than the and 3j were isolated in 5:8 ratio (see Entry 9). The reaction
unwanted enolization of the carbonyl compounds at low with benzophenone only gave 61% yield of product 3k (En-
temperature. We have scanned a variety of bases including try 10), probably due to the steric hindrance between the
–
triethylamine, pyridine, n-butyllithium, potassium hexa- PhSO2CF2 anion and two phenyl rings of benzophenone.
methyldisilazide
and
lithium
hexamethyldisilazide More remarkably, the chemistry also works with complex
(LHMDS), and finally found that LHMDS[13] is the base molecules such as steroids (see Table 1, Entries 11 and 12).
of choice. We have also noticed that McCarthy[14] and For 5α-cholestan-3-one, both axial and equatorial addition
Boger[15] have also applied LHMDS as a base in their prep- products 3l and 3m were obtained in 9:5 ratio (Table 1, En-
arations of 1,1-difluoroalkenes from carbonyl compounds. try 11). A high diastereoselective addition reaction was ob-
Others have also applied LDA[20] and LHMDS[21] for the served with pregnenolone acetate, to give the product 3n in
reactions between PhSO2CF2H and ketones.
81% yield with Ͼ 99% de (Table 1, Entry 12).
Reductive desulfonylation is a widely used method in or-
ganic synthesis.[17] However, the reductive desulfonylation
of gem-difluorinated sulfones are scarce. Stahly has used
Na/EtOH system to desulfonate 2,2-difluoro-1-(4-meth-
ylphenyl)-2-(phenylsulfonyl)ethanol in low yield (49%).[5]
Inspired by the previous report,[18] we have found that
Na(Hg)/MeOH/Na2HPO4 is a much better desulfonylating
system for the gem-difluorinated sulfones.[11] In the process
of desulfonylation of above-obtained sulfones 3, sodium/
mercury amalgam (10 wt.-% Na in Hg, 5 equiv.) and
Na2HPO4 (5 equiv., used to control the pH of the solution)
in methanol were used, and the reaction was carried out
at –20 to –10 °C over a period of 1–3 h. The reactions were
monitored by 19F NMR spectroscopy, and quantitative
conversions were observed with high selectivity in most
Scheme 1. Difluoromethylation of carbonyl compounds using 1.
A typical reaction was carried out as follows: LHMDS cases. The results are summarized in Table 2. Various di-
(2 equiv., dissolved in THF) was slowly added into a mix- fluoromethyl alcohols 4 were obtained in good to excellent
ture of 1 (1 equiv.) and carbonyl compounds (2 equiv.) in yields. Both equatorial and axial 4-tert-butyl-1-(difluo-
THF/HMPA (10:1) at –78 °C, and the reaction mixture was romethyl)cyclohexanols 4h/4i and 3-(difluoromethyl)-5α-
kept at this temperature and stirred for 1.5–8.0 h. The ad- cholestan-3-ols 4l/4k were obtained selectively in high yields
dition of hexamethylphosphoramide (HMPA)[16] as a co- (see Entries 8, 9, 11, and 12). Interestingly, the reductive
solvent was found to be helpful in shortening the reaction desulfonylation reaction condition was found to be also ef-
time and enhancing the yields. A variety of structurally di- fective for the deacetylation. As a result, 20-(difluo-
verse carbonyl compounds (both enolizable and non-enoliz- romethyl)pregn-5-ene-3,20-diol (4m) was obtained in one
able aldehydes and ketones) have been used for this reac- step from 20-[difluoro(phenylsulfonyl)methyl]pregn-5-ene-
tion, and the results are summarized in Table 1. As shown 3,20-diol 3-acetate (3n) in 93% yield (Table 2, Entry 13). It
in Table 1, the reaction works equally well with most alde- is worthwhile to mention that in most reactions as shown
hydes and ketones to give the (phenylsulfonyl)difluo- in Table 2, simple standard work-up is sufficient to give di-
romethyl carbinols 3 in high yields. It is remarkable that fluoromethyl products 4 with high purity.
with the enolizable substrates, such as acetone (see Table 1,
Entry 5), the expected product 3e was formed in 92% yield.
This indicates that at –78 °C, both reaction rates of depro-
Conclusions
tonation of 1 with LHMDS and nucleophilic addition of
–
PhSO2CF2 into carbonyl group are much faster than that
In this communication, we have demonstrated a general
of the unwanted enolization reaction. When the same reac- and efficient nucleophilic difluoromethylation of carbonyl
tion was carried out at room temperature, much poorer compounds (both enolizable and non-enolizable aldehydes
yield of product was obtained, indicating that the kinetic and ketones) by using a nucleophilic (phenylsulfonyl)difluo-
resolution plays a key role for the success of the reaction romethylation-reductive desulfonylation strategy under
at –78 °C. Enolizable aldehydes as expected showed more mild conditions. Difluoromethyl phenyl sulfone acts as a
sensitivity to LHMDS than the enolizable ketones, and rel- difluoromethyl anion (“CF2H–”) equivalent. This method-
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G. K. Surya Prakash, J. Hu, Y. Wang, G. A. Olah
SHORT COMMUNICATION
Table 1. Nucleophilic reaction of sulfone 1 (1.0 equiv.) with carbonyl compounds 2 (2.0 equiv.) in the presence of LHMDS (2.0 equiv.)
in THF/HMPA (10:1 v/v) at –78 °C.
[a] Isolated yields. [b] Both axial addition product 3l and equatorial addition product 3m were obtained in 9:5 ratio. [c] Only one
diastereomer was obatined with de Ͼ 99%.
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Synthesis of Difluoromethyl Alcohols with Difluoromethyl Phenyl Sulfone
SHORT COMMUNICATION
Table 2. Reductive desulfonylation of carbinols 3 using Na(Hg) amalgam (10 wt.-% Na in Hg, 5 equiv.) and Na2HPO4 (5 equiv.) in
methanol at –20 to –10 °C.
[a] Isolated yields. [b] 10 wt.-% Na/Hg amalgam (6 equiv.) was applied, and MeOH/THF (1:1) was used as the solvent.
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G. K. Surya Prakash, J. Hu, Y. Wang, G. A. Olah
SHORT COMMUNICATION
bined ether phase was dried with MgSO4, and the ether was re-
moved to give the crude product, which was further purified by
silica gel chromatography to give product 4a as a colorless liquid,
yield 79% (62 mg). 1H NMR (CDCl3): δ = 3.15 (br., 1 H), 4.78 (td,
J = 10.2 Hz, 4.7 Hz, 1 H), 5.76 (td, J = 55.6 Hz, 4.7 Hz, 1 H), 7.41
(m, 5 H) ppm. 13C NMR (CDCl3): δ = 73.5 (t, J = 24 Hz), 115.7
(t, J = 246 Hz), 127.1, 128.6, 128.9, 135.8 (t, J = 3.5 Hz) ppm. 19F
NMR (CDCl3): δ = –127.7 (ddd, J = 284 Hz, 56 Hz, 9 Hz, 1 F),
–128.2 (ddd, J = 284 Hz, 57 Hz, 11 Hz, 1 F) ppm. MS (EI): m/z =
158 [M+], 107, 79, 77. The data are consistent with the previous
ology requires only inexpensive reagents and standard lab
setups, and it promises to be a highly useful synthetic tool
for many potential applications. Further elaboration and
study of this new difluoromethylation method, including
the control of stereoselectivity using modified arylsulfonyl
or arylsulfinyl groups, the stereoselectivity with carefully se-
lected (mono- or bicyclic) examples to explore its scope (or
limitations), searching for new desulfonylation methods
with broader compatibility with other functional groups,
and applying this method to other readily enolizable car- report.[19]
bonyl compounds, are still under investigations in our lab-
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic and analytical data of synthesized compounds
ratory.
3 and 4.
Experimental Section
Acknowledgments
General Remarks: Unless otherwise mentioned, all other chemicals
were purchased from commercial sources. THF was freshly distilled
from sodium. Difluoromethyl phenyl sulfone (1) was prepared
using known procedures.[7] Silica gel column chromatography was
used to isolate the products using 60–200 mesh silica gel (from J. T.
Support of our work by Loker Hydrocarbon Research Institute
is gratefully acknowledged (see footnote on the first page of this
article).
1
Baker), mostly using hexane/ethyl acetate (9:1) as eluent. H, 13C
and 19F NMR spectra were recorded on 500 MHz or 400 MHz
NMR spectrometer. 1H NMR chemical shifts were determined rel-
ative to internal (CH3)4Si (TMS) at δ = 0.0 ppm or to the signal
of a residual protonated solvent: CDCl3 δ = 7.26 ppm. 13C NMR
chemical shifts were determined relative to internal TMS at δ = 0.0
or to the 13C signal of solvent: CDCl3 δ = 77.0 ppm. 19F NMR
chemical shifts were determined relative to internal CFCl3 at δ =
0.0. GC-MS data were recorded on a GC-MS spectrometer with a
mass selective detector at 70 eV. High-resolution mass data were
recorded on a high-resolution mass spectrometer in the EI or CI
mode.
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[3] a) G. K. S. Prakash, R. Krishnamurti, G. A. Olah, J. Am.
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PhSNa and CF2HCl followed by simple oxidation, see: a) J.
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B. R. Langlois, J. Fluorine Chem. 1988, 41, 247–261; c) Ref.[4]
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Typical Procedure for Nucleophilic (Phenylsulfonyl)difluoromethyla-
tion of Carbonyl Compounds: A THF solution (3 mL) of (TMS)2-
NLi (LHMDS, 334 mg, 2 mmol) was added dropwise to a 50-mL
Schlenk flask containing benzaldehyde (212 mg, 2 mmol) and
PhSO2CF2H (192 mg, 1 mmol) in THF (5 mL)/HMPA (0.5 mL)
at –78 °C under N2. The reaction mixture was then stirred vigor-
ously at –78 °C for 2 h, followed by adding a saturated aq. NaCl
solution (10 mL) at this temperature. The solution mixture was ex-
tracted with Et2O (20 mL×3), and the combined organic phase
was dried with MgSO4. After the removal of volatile solvents under
vacuum, the crude product was further purified by silica gel column
chromatography to give product 3a as a white solid, yield 83%
1
(247 mg). H NMR (CDCl3): δ = 3.92 (d, J = 4.4 Hz, 1 H), 5.60
(dd, J = 21 Hz, 2.3 Hz, 1 H), 7.36 (m, 3 H), 7.48 (m, 2 H), 7.56 (t,
[9] G. K. S. Prakash, J. Hu, Y. Wang, G. A. Olah, Angew. Chem.
2004, 116, 5315; Angew. Chem. Int. Ed. 2004, 43, 5203–5206.
J = 8 Hz, 2 H), 7.70 (t, J = 8 Hz, 1 H), 7.98 (d, J = 8 Hz, 2 H) [10] G. K. S. Prakash, J. Hu, G. A. Olah, J. Org. Chem. 2003, 68,
ppm. 19F NMR (CDCl3): δ = –106.4 (dd, J = 238 Hz, 3 Hz, 1 F),
–121.5 (dd, J = 238 Hz, 21 Hz, 1 F) ppm. MS (EI): m/z = 298 [M+],
156, 140, 127, 107, 77. The data are consistent with the previous
report.[5]
4457–4463.
[11] G. K. S. Prakash, J. Hu, Y. Wang, G. A. Olah, Org. Lett. 2004,
6, 4315–4317.
[12] G. K. S. Prakash, J. Hu, G. A. Olah, Org. Lett. 2003, 5, 3253–
3256.
Typical Procedure for Reductive Desulfonylation: Na/Hg amalgam [13] LHMDS (97% purity) was obtained from the commercial
source and used without further purification. For the previous
use of LHMDS, see: M. Gray, V. Snieckus, in: Encyclopedia of
Reagents for Organic Synthesis (Ed.: R. A. Paquette); Wiley:
New York, 1995, p. 3127.
(10 wt.-% Na in Hg, net sodium content 3 mmol) was added under
N2 into a 50-mL Schlenk flask containing sulfone compound 3a
(149 mg, 0.5 mmol) and Na2HPO4 (3 mmol) in 5 mL anhydrous
methanol at –20 °C. The reaction mixture was stirred at –20 °C to
0 °C for 1 h. The liquid phase was decanted, and the solid residue
was washed with Et2O. The solids were then treated with elemental
sulfur powder to destroy the mercury residue. The solvent of com-
bined organic phase was removed under vacuum, and 20 mL brine
was added, followed by extracting with Et2O brine thrice. The com-
[14] J. S. Sabol, J. R. McCarthy, Tetrahedron Lett. 1992, 33, 3101–
3104.
[15] D. L. Boger, T. J. Jenkins, J. Am. Chem. Soc. 1996, 118, 8860–
8870.
[16] R. B. Dykstra, in: Encyclopedia of Reagents for Organic Synthe-
sis (Ed.: R. A. Paquette); Wiley: New York, 1995, p. 2668.
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Synthesis of Difluoromethyl Alcohols with Difluoromethyl Phenyl Sulfone
SHORT COMMUNICATION
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Received: February 08, 2005
Published Online: April 25, 2005
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