A remarkably efficient fluoroalkylation of cyclic sulfates and sulfamidates with PhSO2CF2H: Facile entry into β- difluoromethylated or β-difluoromethylenated alcohols and amines

Article abstract of DOI:10.1002/anie.200603983

(Chemical Equation Presented) On the fluor: Highly regioselective nucleophilic difluoromethylation of 1,2-cyclic sulfates and sulfamidates leads after selective desulfonylation to β-difluoromethylated and β-difluoromethylenated alcohols and amines (see sc

Full text of DOI:10.1002/anie.200603983

Communications
DOI: 10.1002/anie.200603983
Fluorine Chemistry
A Remarkably Efficient Fluoroalkylation of Cyclic Sulfates and
Sulfamidates with PhSO2CF2H: Facile Entry into b-
Difluoromethylated or b-Difluoromethylenated Alcohols and
Amines**
Chuanfa Ni, Jun Liu, Laijun Zhang, and Jinbo Hu*
Fluorine is increasingly recognized as a remarkable element
in the life sciences, based on the fact that incorporation of one
or a few fluorine atoms in an organic molecule can often
dramatically alter its stability, lipophilicity, bioavailability,
and biopotency. Currently, “as many as 30–40% of agro-
chemicals and 20% of pharmaceuticals on the market are
estimated to contain fluorine”.[1] Fluorination and fluoroal-
kylation are the two major synthetic methods to introduce
fluorine atoms or fluorine-containing moieties into organic
molecules.[2] While nucleophilic, electrophilic, and radical
trifluoromethylations have been extensively studied over the
past 30 years, the systematic exploration of the analogous
difluoromethylations and difluoromethylenations has
emerged more recently.[3] The difluoromethyl functionality
Scheme 1. Initial attempted preparation of b-difluoromethyl alcohols 4
and b-difluoromethylamines 5. P G=protecting group.
(CF2H) can act both as a more lipophilic biostere of the
carbinol group (CH2OH) and as a hydrogen donor through
hydrogen bonding,[3b,4] while 1,1-difluoroalkenyl functionality
can be used as a biostere of the carbonyl group with a
different reactivity pattern.[3i,5] In some cases, the difluoro-
methylated compounds exhibit increased bioactivity com-
pared with their trifluoromethylated counterparts.[6]
philes.[7] Although the negative fluorine effect was weakened
by using (PhSO2)2CHF, and both the b-monofluoromethyl
alcohols and amines were successfully prepared in one step,
this method was still not suitable for the synthesis of b-
difluoromethyl alcohols 4 and amines 5.[7] We surmised that
this problem might be solved by using the more electrophilic
epoxide and aziridine equivalents, the 1,2-cyclic sulfates 2 and
sulfamidates 3 (Scheme 1), to react with PhSO2CF2À. Com-
pounds 2 and 3 represent a versatile class of functionalized
and often enantiomerically pure electrophiles,[8] and their
application in organic synthesis has been widely studied,
especially since the development of osmium-catalyzed asym-
metric dihydroxylation and aminohydroxylation reactions by
Sharpless and co-workers.[9] However, the nucleophilic fluo-
roalkylation of 1,2-cyclic sulfates and sulfamidates have
scarcely been reported, with the only successful example
being the trifluoromethylation of 1,2-cyclic sulfates with CF3I/
TDAE (TDAE = tetrakis(dimethylamino)ethylene) to give a
b-trifluoromethyl alcohol in moderate yields (43–62%).[10]
Herein we disclose a remarkably efficient and highly regio-
selective fluoroalkylation of both 1,2-cyclic sulfates 2 and
sulfamidates 3 using difluoromethyl phenyl sulfone (1)[3] as
the fluoroalkylating agent. In addition to its high efficiency
and the simple experimental procedures involved, the major
advantage of this synthetic methodology is that it allows facile
entry to both b-difluoromethylated and b-difluoromethylen-
ated alcohols (4 and 6) and amines (5 and 7, Scheme 1), which
are important building blocks for drug design and for the
synthesis of bioactive target molecules.[11]
Previously, we successfully synthesized both a-difluoro-
methyl alcohols and a-difluoromethylamines from carbonyl
compounds and imines by using a direct nucleophilic di-
fluoromethylation strategy, orchestrated by TMSCF2SO2Ph
and PhSO2CF2H (1).[3a,b,d] However, the synthesis of b-
difluoromethyl alcohols and b-difluoromethylamines was
found to be more challenging. We studied the reactions
À
between PhSO2CF2 and epoxides (or aziridines), but the
expected products, the b-difluoromethyl alcohols 4 (or amines
5), were not observed (Scheme 1).[7] We ascribed the difficulty
of this ring-opening reaction to be the “negative fluorine
effect”, that is, fluorine substitution on the carbanion center
will dramatically decrease its nucleophilicity towards electro-
[*] C. Ni, J. Liu, L. Zhang, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Feng-Lin Road, Shanghai 200032 (P.R. China)
Fax: (+86)21-6416-6128
E-mail: jinbohu@mail.sioc.ac.cn
[**] Support of our work by the National Natural Science Foundation of
China (20502029), the Shanghai Rising-Star Program (06QA14063),
and the Chinese Academy of Sciences (Hundreds-Talent Program)
is gratefully acknowledged.
In a first trial, we chose propane 1,2-cyclic sulfate 2a,
which is readily prepared from propane-1,2-diol according to
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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the procedure of Gao and Sharpless,[9a] as a model compound.
The initial reaction of the anion PhSO2CF2À (generated in situ
from PhSO2CF2H and LHMDS) with 2a was carried out in
THF/HMPA at À788C over 2 h (molar ratio 2a/1/LHMDS
1.2:1:1.2), and the (phenylsulfonyl)difluoromethylated prod-
uct 8a was obtained in 77% yield after subsequent hydrolysis
(Scheme 2). A brief optimization of the reaction conditions
revealed that an excellent yield (98%) of product 8a was
obtained when the ratio of reactants was 2a/1/LHMDS
1.0:1.1:1.2 and the reaction time reduced (less than 30 min,
Scheme 2). The addition of HMPA significantly enhanced
Table 1: (Phenylsulfonyl)difluoromethylation of 1,2-cyclic sulfate 2.
Entry Sulfate 2
Product 8
Yield [%][a]
98
1
2
94
3
4
5
94
89
Scheme 2. (Phenylsulfonyl)difluoromethylation of 1,2-cyclic sulfate 2a.
HMPA=hexamethyl phosphoramide, LHMDS=lithium hexamethyl-
disilazanide.
92[b]
6
7
87
99
both the reaction rate and the yield. The propane 1,2-cyclic
sulfite (the precursor to the preparation of 2a) was also
examined as a substrate under the similar reaction conditions.
However, no product 8a was formed, and longer reaction
times resulted in the decomposition of the PhSO2CF2H
reagent.
We examined the scope of the nucleophilic (phenylsulfo-
nyl)difluoromethylation of 2 with 1 under these optimized
reaction conditions (Table 1). The reaction proved to be
8
9
Ar=P h (2h)
Ar=p-MeOC6H4
(2i)
Ar=P h (8h)
Ar=p-MeOC6H4 (8i)
93
99
À
general and highly regioselective, with the PhSO2CF2 ion
attacking at the less-hindered-carbon atom of the cyclic
sulfates 2 to provide the secondary alcohols 8. In all cases, as
shown in Table 1, the yields of 8 were excellent (87–99%).
The reaction was found to be compatible with other func-
tional groups such as OTs and Cl (Table 1, entries 4and 5),
which shows the high reactivity of PhSO2CF2À towards cyclic
sulfates 2. Notably, high reaction rates meant that in all cases
the reaction had reached completion as soon as the dropwise
addition of the base (LHMDS) had finished (usually within
30 min at À788C). The nucleophilic fluoroalkylation of 1,2-
cyclic sulfates 2 with 1 was remarkable, especially when
compared with the previously reported nucleophilic tri-
fluoromethyations of 2 using CF3I/TDAE which proceed in
much lower yields (< 62%).[10]
10
11
Ar=o-MeOC6H4
(2j)
Ar=m-MeC6H4
(2k)
Ar=o-MeOC6H4 (8j)
Ar=m-MeC6H4 (8k)
97[b]
94[b]
[a] Yield of isolated product. [b] Purified after silylation of the hydroxy
group. Bn=benzyl, Ts=toluene-4-sulfonyl.
Scheme 3. (Phenylsulfonyl)difluoromethylation of 1,3-cyclic sulfate 9.
We also investigated the reaction of 1,3-cyclic sulfate 9
À
with PhSO2CF2 as shown in Scheme 3. We found that
À
compound 9 showed lower reactivity towards PhSO2CF2
,
with high regioselectivity under similar reaction conditions as
for 2, and the corresponding homochiral b-(phenylsulfonyl)-
difluoromethylated amines 11 were obtained in 90–99%
yields (Table 2). Stereochemical deterioration at the stereo-
genic center is negligible as demonstrated by the high ee value
(> 99.5%) determined for product 11a by HPLC on a chiral
stationary phase (see the Supporting Information).
and a longer reaction time (8 h) was required to afford the
g-difluoroalkylated product 10 in 63% yield.
Encouraged by these results, we predicted that the 1,2-
cyclic sulfamidates 3 could also undergo the nucleophilic ring-
opening reaction with PhSO2CF2À. Thus, the optically pure
1,2-cyclic sulfamidates 3 were prepared from the correspond-
ing amino alcohols. A variety of structurally diverse 1,2-cyclic
To demonstrate the synthetic utility of this highly efficient
fluoroalkylation reaction, b-(phenylsulfonyl)difluoromethyl
À
sulfamidates 3 were found to react readily with PhSO2CF2
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Communications
Table 2: (Phenylsulfonyl)difluoromethylation of cyclic sulfamidates 3.
Entry
1
Sulfamidate 3
Product 11[a]
Yield [%][b]
96
2
3
4
5
98
99
98
93
Scheme 4. Prepration of b-difluoromethylated and b-difluoro-
methylenated alcohols 12 and 14, and amines 13 and 15.
DMF=N,N-dimethylformamide.
6
90
Experimental Section
Typical procedure for the nucleophilic difluoromethylation of 1,2-
cyclic sulfates using difluoromethyl phenyl sulfone: A solution of
LHMDS (1.0m, 1.2 mmol) in THF (1.2 mL) was added over 10 min to
a 20-mL Schlenk flask containing 2a (138 mg, 1.0 mmol) and 1
(211 mg, 1.1 mmol) in THF (5 mL) and HMPA (0.5 mL) at À788C
under N2. The reaction mixture was stirred at this temperature for
another 20 min, and then 20% aqueous sulfuric acid (5 mL) was
added. The mixture was stirred at room temperature overnight, and
then extracted with Et2O (10 mL ” 3). The combined organic phase
was washed with saturated NaHCO3 solution and then dried over
MgSO4. After removal of volatile solvents under vacuum, the crude
product was purified by column chromatography through silica gel to
give 8a as a colorless oil (245 mg, 98% yield).
[a] An ee value of >99.5% was determined for 11a by using HPLC
analysis on a chiral stationary phase. The configurations of other
products 11b–f were assigned based on the fact that no racemization
occurred during the reactions. [b] Yield of isolated product. PMB=para-
methoxybenzyl.
alcohol 8h and amine 11a were further transformed into their
corresponding b-difluoromethylated and b-difluoromethylen-
ated products 12–15 (Scheme 4), by taking advantage of the
property of the sulfone functionality as a “chemical chame-
leon”.[12] Reductive desulfonylations of 8h and 11a were
carried out in DMF solution at room temperature by using
our previously developed Mg/HOAc/NaOAc system.[3a] The
corresponding b-difluoromethylated alcohol 12 and amine 13
were obtained in 83% and 81% yield, respectively
(Scheme 4). Another important transformation of 8h and
11a is the base-mediated a,b-elimination of a molecule of
phenylsulfinic acid to give the corresponding b-difluoro-
methylenated alcohol 14 and amine 15 in 82% and 70% yield,
respectively.
Received: September 28, 2006
Published online: December 13, 2006
Keywords: cyclic sulfates · fluorine · fluoroalkylation ·
.
nucleophilic addition · sulfamidates
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In summary, we have demonstrated a highly regioselective
synthesis of b-difluoromethylated and b-difluoromethylen-
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methylation strategy. Nucleophilic (phenylsulfonyl)difluoro-
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