Stereoselective difluoromethylenation using Me3SiCF 2SPh: Synthesis of chiral 2,4-disubstituted 3,3-difluoropyrrolidines

Article abstract of DOI:10.1002/anie.200604783

A radical synthon: Nucleophilic (phenylthio)difluoromethylation of (R)-N-(tert-butylsulfinyl)imines with 1, a difluoromethylene radical anion equivalent, afforded the corresponding products in good yields and with high diastereoselectivity (d.r. ≥ 98:2).

Full text of DOI:10.1002/anie.200604783

Angewandte
Chemie
DOI: 10.1002/anie.200604783
Difluoromethylenation
Stereoselective Difluoromethylenation Using Me3SiCF2SPh:
Synthesis of Chiral 2,4-Disubstituted3,3-Difluoropyrrolidines**
Ya Li and Jinbo Hu*
As the most electronegative element, fluorine has attracted
enormous attention recently in the fields of agricultural and
medicinal chemistry as well as in materials science.[1] Nowa-
days, the efficient and selective incorporation of fluorine
atom(s) or fluorine-containing moieties into organic mole-
cules to modulate their biological properties has become a
routine and powerful strategy in drug design. Asymmetric
fluorination and fluoroalkylation are two categories of
fascinating reactions in organofluorine chemistry, and enan-
tioselective electrophilic fluorinations and enantioselective
nucleophilic monofluoromethylation represent the state-of-
the-art achievements.[2] Currently, enantioselective trifluoro-
methylation and difluoromethylation are still very challeng-
ing topics with respect to stereoselectivity and generality,
while highly diastereoselective trifluoromethylations and
difluoromethylations have been achieved by using suitable
chiral auxiliaries.[2a,3,4] In 2001 Prakash et al. reported an
elegant diastereoselective nucleophilic trifluoromethylation
of N-(tert-butylsulfinyl)imines using the Ruppert–Prakash
reagent (TMSCF3),[5] and recently we described highly
diastereoselective nucleophilic difluoromethylations and
monofluoromethylations using PhSO2CF2H and PhSO2CH2F
as the di- and monofluoromethylating agents, respectively.[4]
The pyrrolidine unit is ubiquitous in natural products, and
recently it was found that the 3,3-difluoropyrrolidine moiety
plays very important roles in a variety of enzyme inhibitors
such as coagulation factor Xa (or thrombin) inhibitors[6c] and
cathepsin inhibitors,[6d] among others.[6e–g] It was rationalized
that fluorine substitution on the pyrrolidine moiety can
decrease the basicity of the amine functionality and inhibit
the enzymatic recognition processes and associated metabolic
pathways, resulting in the enhanced biological activity and
metabolic stability of a drug candidate.[6] However, we are not
aware of any reports of the efficient synthesis of chiral 2,4-
disubstituted 3,3-difluoropyrrolidines. As part of our con-
tinuing efforts in the development of efficient fluoroalkyla-
tion methodologies, herein we report a highly diastereoselec-
tive difluoromethylenation method using [difluoro(phenyl-
thio)methyl]trimethylsilane (1, TMSCF2SPh)[7] as a difluoro-
methylene radical anion equivalent. Using this appraoch, we
effectively synthesized chiral 2,4-disubstituted 3,3-difluoro-
pyrrolidines 7 from N-(tert-butylsulfinyl)imines 2 following a
selective nucleophilic addition/radical cyclization strategy
(Scheme 1).
Scheme 1. Use of TMSCF2SPh (1) as a difluoromethylene radical anion
equivalent. TMS=Me3Si.
First, we carried out the diastereoselective nucleophilic
(phenylthio)difluoromethylation of (R)-(tert-butylsulfinyl)-
imines 2 with reagent 1. Compound 2a was used as a model
compound to study the reaction, and the reaction conditions
were carefully tuned as shown in Table 1. We tried LiOAc,
Table 1: Optimization of reaction conditions.
Entry
Reaction conditions[a]
d.r.[b]
Yield[%] [c]
1
2
3
4
5
6
LiOAc (1.1 equiv), DMF
CsF (1.1 equiv), DMF
TBAT (0.5 equiv), DMF
TBAT (0.5 equiv), THF
TBAT (0.3 equiv), DMF
TBAT (0.2 equiv), DMF
ꢀ99:1
ꢀ99:1
ꢀ99:1
ꢀ99:1
ꢀ99:1
ꢀ99:1
30
67
75
57
71
64
[a] For entries 1 and2, the reaction mixture was maintainedat À408C for
2 h then at À208C for 4 h; for entries 3–6, the reaction was maintainedat
À408C for 1 h then at À208C for 4 h. [b] d.r.=(Rs,S)/(Rs,R), determined
by 19F NMR spectroscopy on a sample from the crude product mixture.
[c] Yieldof isolatedproduct. DMF =N,N-dimethylformamide.
[*] Y. Li, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Feng-Lin Road, Shanghai, 200032 (China)
Fax: (+86)21-64166128
E-mail: jinbohu@mail.sioc.ac.cn
CsF, and tetrabutylammonium triphenyldifluorosilicate
(TBAT) as the Lewis base initiators for the reaction and
found that in all cases excellent diastereoselectivities (d.r.
ꢀ 99:1) were observed and that the use of 0.3–0.5 equivalents
of TBAT in DMF solution gave the best yield of 3a (Table 1,
entries 3 and 5).
[**] Support of our work by the National Natural Science Foundation of
China (20502029), Shanghai Rising-Star Program (06A14063), and
the Chinese Academy of Sciences (Hundreds Talent Program) is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Eventually, we chose the reaction conditions listed under
nylthio)difluoromethylation reaction with imines 2 is orien-
tated by a non-chelation-controlled addition mode.[4] Indeed,
the present diastereoselective (phenylthio)difluoromethyla-
tion of N-(tert-butylsulfinyl)imines 2 provides an alternative
approach for the preparation of
entry 3 (Table 1) as the standard conditions to study the scope
of the reaction between imines 2 and 1. The results are
summarized in Table 2. High diastereoselectivity was
homochiral
a-difluoromethyl
Table 2: Stereoselective (phenylthio)difluoromethylation of sulfinylimines 2 with TMSCF2SPh.
amines, which we previously syn-
thesized by using PhSO2CF2H.[4a]
We transformed the above-
obtained sulfinamides 3 to the N-
allylated products 5 in good yields
by acid-catalyzed alcoholysis to
remove the tBuS(O) group, fol-
lowed by N-allylation with allyl
bromide. The results are summar-
ized in Table 3. With the expect-
Entry
Sulfinylimine 2
Product 3
Yield
[%][a]
d.r.[b]
1
2
3
75
85
89
ꢀ99:1
ꢀ98:2
ꢀ99:1
À
ation that the F2C S bond could be
cleaved homolytically under radical
conditions,[8] we carried out the
intramolecular radical cyclization
reaction of 5 under thermal initia-
tion in the presence of Bu3SnH and
a catalytic amount of AIBN. The
cyclization reaction proceeded
smoothly, and both trans products
7 and cis products 7’ were obtained
in good yields, with 5-exo cycliza-
tion being favored exclusively
(Table 3). 19F NMR spectroscopic
analysis of the crude mixture indi-
cated that the diastereoselectivity
(7/7’) was up to 11:1 (Table 3,
entry 5). The absolute configuration
of the major trans product 7a
(Table 3, entry 1) was confirmed
by NOESY experiments (Scheme 3
and Supporting Information) and
was consistent with our prediction
based on a Beckwith–Houk transi-
4
5
85
72
75
74
58
ꢀ98:2
ꢀ98:2
ꢀ99:1
ꢀ99:1
ꢀ99:1
ꢀ99:1
ꢀ99:1
6
7
8
30
9
(45[c])
10
71
[a] Yields of isolated analytically pure material. [b] Diastereomeric ratios were determined by 19F NMR
spectroscopy of the crude reaction mixture. [c] 1.0 equivalent of TBAT was used. Bn=benzyl.
observed in each case, and good yields were obtained with
non-enolizable imines (Table 2, entries 1–5 and 10) and with
imines that bear only one a-hydrogen atom (entries 6–8).
However, relatively lower yields (30–45%) were obtained in
the case of imine 2i, which bears two a-hydrogen atoms
(Table 2, entry 9). Careful TLC analysis revealed that imine
2i disappeared shortly after the reaction was performed and
indicates a labile enolization of 2i under such basic con-
ditions. Note that products 3 are useful precursors for the
preparation of chiral a-difluoromethyl amines. For instance,
(phenylthio)difluoromethylated sulfinamide 3d was treated
with Bu3SnH/AIBN in toluene at 908C and the mixture was
subjected to acid-catalyzed alcoholysis with HCl/MeOH to
afford a-difluoromethyl 2-naphthalenemethanamine 4 (in salt
form) in 85% yield (Scheme 2). The specific rotation of 4 was
consistent with that of the (S)-a-difluoromethyl 2-naphtha-
lenemethanamine salt we reported earlier.[4a] The result
demonstrates that the stereochemical outcome of the (phe-
Scheme 2. Preparation of a-difluoromethyl amine salt 4 from 3d.
AIBN=azobis(isobutyronitrile).
tion-state model.[9] As shown in Table 3, the radical cycliza-
tion reaction gave good product yields and good diastereo-
selectivity with aryl-substituted substrates (Table 3, entries 1–
3). With a 2-furyl group, the yield of 7d was moderate and the
diastereoselectivity dropped (Table 3, entry 4). For the alkyl-
substituted substrates, a longer reaction time was required
and afforded the cyclization products 7e and 7 f in reasonable
yields and with high diastereoselectivity (Table 3, entries 5
and 6). The present intramolecular cyclization reaction
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Table 3: Stereoselective synthesis of 2,4-substituted 3,3-difluoropyrrolidines 7.
Experimental Section
Typical procedures for the stereoselec-
tive (phenylthio)difluoromethylation of
sulfinylimines 2 with TMSCF2SPh (1):
TBAT (702 mg, 1.3 mmol) was added
under N2 atmosphere to
a 30-mL
Schlenkflaskcontaining
sulfinyl)aldimine (2a;
N-(tert-butyl-
Entry
Product 5
Yield
Product 7
Yield
d.r.
548 mg,
(5) [%][a]
(7) [%][a]
(7/7’)[b]
2.6 mmol) and PhSCF2TMS (734 mg,
3.0 mmol) in DMF (10 mL) at À408C.
The reaction mixture was stirred at this
temperature for 2 h, and then the tem-
perature was raised to À208C and the
reaction mixture was stirred for another
4 h. Aqueous saturated NH4Cl solution
(10 mL) was then added to the mixture
at this temperature, and the mixture was
extracted with EtOAc (25 mL ” 3). The
combined organic phase was dried over
MgSO4, and the volatile solvents were
removed under reduced pressure. The
crude product was further purified by
silica gel column chromatography with
ethyl acetate/petroleum ether (1:3 v/v)
to give product 3a as a white solid
(721 mg, 75% yield).
Typical procedure for preparation of
the N-allylated products 5: HCl/dioxane
(4n; 0.3 mL) was added under N2 atmos-
phere into a 10-mL flaskcontaining 3a
(443 mg, 1.2 mmol) in anhydrous meth-
anol (5 mL). The reaction mixture was
stirred at room temperature for 1 h, and
then the solvent was removed to give the
intermediate product, which was used in
the next step without further purifica-
tion. A mixture of the intermediate
product and anhydrous K2CO3 (332 mg,
2.4 mmol) in DMF (5 mL) was stirred at
room temperature until the intermedi-
1
2
3
4
5
6
78
76
75
72
72
61
75
71
77
43
52
50
11:1
9:1
10:1
5:1
11:1
10:1
[a] Yield of isolated product. [b] Diastereomeric ratios were determined by 19F NMR spectroscopy of the
crude reaction mixture.
ate product was consumed. Then H2O (10 mL) was added, and the
mixture was extracted with Et2O. The combined organic phase was
dried over MgSO4, and the solvent was removed to give the crude
product, which was further purified by silica gel column chromatog-
raphy with ethyl acetate/petroleum ether (1:30 v/v) to give product 5a
as an oil (286 mg, 78% yield).
Typical procedure for the intramolecular radical cyclization
reaction of N-allylated compounds 5: Bu3SnH (0.38 mmol, 0.10 mL)
and catalytic AIBN (2.0 mg) were added under N2 atmosphere to a
10-mL Schlenkflaskcontaining 5a (76 mg, 0.25 mmol) in toluene
(2 mL) at 908C, and the reaction mixture was then stirred at this
temperature for 2 h. Then, another portion of AIBN (2.0 mg) was
added and the reaction mixture was stirred for another 3 h. Aqueous
saturated KF solution (10 mL) was then added to the mixture at room
temperature, and the solution mixture was extracted with Et2O
(25 mL ” 3). The combined organic phase was dried over MgSO4, and
the volatile solvents were removed under reduced pressure. The crude
product was purified by silica gel column chromatography with ethyl
acetate/petroleum ether (1:5 v/v) to give product 7a as an oil (37 mg,
75% yield).
Scheme 3. Determination of configurations of 7a and 7a’ with NOESY
experiments.
provides a new method for the synthesis of pyrrolidines that
contain a midchain gem-difluoromethylene (CF2) moiety.
In summary, we have successfully developed a new
synthetic application of TMSCF2SPh as a difluoromethylene
radical anion synthon based on the selective ionic cleavage of
À
À
its F2C Si bond and radical cleavage of its F2C S bond.
Nucleophilic (phenylthio)difluoromethylation of (R)-(N-tert-
butylsulfinyl)imines with TMSCF2SPh affords the corre-
sponding products in good yields and with high diastereose-
lectivity (d.r. ꢀ 98:2). The obtained PhSCF2-containing sulfi-
namides can be further transformed into chiral 2,4-trans-
disubstituted 3,3-difluoropyrrolidines through an intramolec-
ular radical cyclization methodology.
Received: November 24, 2006
Published online: February 27, 2007
Keywords: enantioselectivity · fluoroalkylation · pyrrolidines ·
.
radical reactions · synthetic methods
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Communications
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