Stereoselective monofluoromethylation of N-tert-butylsulfinyl ketimines using pregenerated fluoro(phenylsulfonyl)methyl anion

Article abstract of DOI:10.1021/ol802226k

(Chemical Equation Presented) Pregeneration of fluoro(phenylsulfonyl)methyl anion (PhSO₂CHF^-) paves the way for the efficient and highly stereoselective monofluoromethylation of (R)-N-tert-butylsulfinyl ketimines. The stereocontrol mode of the present diastereoselective monofluoromethylation of ketimines is different from the previously known nucleophilic fluoroalkylation of (R)-N-tert-butylsulfinyl aldimines, which suggests that a cyclic six-membered transition state (rather than a nonchelation controlled one) is involved in the current ketimine reaction.

Full text of DOI:10.1021/ol802226k

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5377-5380
Stereoselective Monofluoromethylation
of N-tert-Butylsulfinyl Ketimines Using
Pregenerated
Fluoro(phenylsulfonyl)methyl Anion
Jun Liu, Laijun Zhang, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
jinbohu@mail.sioc.ac.cn
Received September 24, 2008
ABSTRACT
Pregeneration of fluoro(phenylsulfonyl)methyl anion (PhSO2CHF-) paves the way for the efficient and highly stereoselective monofluoromethylation
of (R)-N-tert-butylsulfinyl ketimines. The stereocontrol mode of the present diastereoselective monofluoromethylation of ketimines is different
from the previously known nucleophilic fluoroalkylation of (R)-N-tert-butylsulfinyl aldimines, which suggests that a cyclic six-membered transition
state (rather than a nonchelation controlled one) is involved in the current ketimine reaction.
Recently, considerable attention has been directed toward
the synthesis of chiral R-fluoroalkyl amines, since fluorine
lowers the basicity of amines and thus enhances the metabolic
stability and bioactivity of a target drug.1 The most straight-
forward approach to synthesize chiral R-fluoroalkyl amines
is the stereocontrolled nucleophilic additions of fluoroalkyl
groups to imines. In 2001, Prakash and co-workers developed
a highly diastereoselective trifluoromethylation of enantio-
pure N-tert-butylsulfinyl aldimines using Me3SiCF3 reagent.2
Thereafter, similar diastereoselective trifluoromethylations of
sulfinyl aldimines were reported by the groups led by
Dolbier3 and Mukaiyama.4 We also successively demon-
strated the diastereoselective difluoromethylation, mono-
fluoromethylation, and difluoromethylenation of N-tert-
butylsulfinyl aldimines using PhSO2CF2H, PhSO2CH2F, and
Me3SiCF2SPh reagents.5 More recently, Shibata and co-
workers reported an enantioselective monofluoromethylation
of R-amido sulfones (as aldimine precursors) with
(PhSO2)2CFH.6 However, although these stereoselective tri-,
di-, and monofluoromethylations of aldimines have been
successfully accomplished, the corresponding nucleophilic
fluoroalkylations of ketimines are generally difficult (Scheme
1, eqs 1-3). As a result, the efficient and stereoselective
synthesis of R-fluoroalkyl tertiary carbinamines by nucleo-
philic fluoroalkylation of ketimines still remains a challenging
task.7,8
(1) (a) Be´gue´, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal
Chemistry of Fluorine; Wiley: Hoboken, NJ, 2008. (b) Hagmann, W. K.
J. Med. Chem. 2008, 51, 4359–4369. (c) Mu¨ller, K.; Faeh, C.; Diederich,
F. Science 2007, 317, 1881–1886. (d) McCarthy, J. R. Fluorine in Drug
Design: A Tutorial ReView; 17th Winter Fluorine Conference (St. Petersburg,
FL), Jan 9-14, 2005.
(2) (a) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem., Int.
Ed. 2001, 113, 609–610. (b) Prakash, G. K. S.; Mandal, M.; Olah, G. A.
Org. Lett. 2001, 3, 2847–2850. (c) Prakash, G. K. S.; Mandal, M. J. Am.
Chem. Soc. 2002, 124, 6538–6539.
(3) Xu, W.; Dolbier, W. R., Jr. J. Org. Chem. 2005, 70, 4741–4745.
(4) Kawano, Y.; Mukaiyama, T. Chem. Lett. 2005, 34, 894–895.
(5) (a) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882–5886. (b)
Li, Y.; Ni, C.; Liu, J.; Zhang, L.; Zheng, J.; Zhu, L.; Hu, J. Org. Lett.
2006, 8, 1693–1696. (c) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2007, 46,
2489–2492. (d) Liu, J.; Li, Y.; Hu, J. J. Org. Chem. 2007, 72, 3119–3121.
(6) Mizuta, S.; Shibata, N.; Goto, Y.; Furukawa, T.; Nakamura, S.; Toru,
T. J. Am. Chem. Soc. 2007, 129, 6394–6395.
10.1021/ol802226k CCC: $40.75
Published on Web 11/11/2008
2008 American Chemical Society

PhSO2CHF- and ketimine 2a gave product 4a in low yields
(Scheme 1, eqs 2 and 3). An aza-enolization of 2a caused
by the strong base lithium hexamethyldisilazide (LiHMDS)
or n-BuLi may account for the low product yield, and we
envisaged that a pregeneration of anion PhSO2CHF- could
improve this monofluoromethylation reaction. Furthermore,
during our previous study of “negative fluorine effect” of
fluorinated carbanions,10 we found that anion PhSO2CHF-
possesses good thermal stability and is suitable for pregen-
eration. Based on these considerations, we pregenerated
PhSO2CHFLi (5) by mixing PhSO2CH2F (1) and n-BuLi at
-78 °C for 30 min and then allowed 5 to react with ketimine
2a at the same temperature (Scheme 1, eq 4). To our delight,
product 4a was produced in 97% yield (determined by 19F
NMR), which encouraged us to further investigate this
chemistry.
Scheme 1.
Attempted Fluoroalkylation of Ketimine 2a9
We envisioned that the difficulty of the fluoroalkylation
of ketimines could be caused by the relatively low electro-
philicity of ketimines (compared to aldimines2-6 ) and the
relatively low nucleophilicity of fluorinated carbanions Rf-
(due to the “negative fluorine effect”10). Nucleophilic fluoro-
alkylation usually requires an in situ generation of the Rf-
species in the presence of an electrophilic reaction partner
because many fluorinated carbanions are thermally unstable
and their pregeneration and storage often result in decom-
position (usually via R-elimination of a fluoride ion).11 In
the course of our previous study of diastereoselective
fluoroalkylation of N-tert-butylsulfinyl aldimines,5 we real-
ized that the reactions between in situ generated anion
As shown in Table 1, by using ketimine 2a as a model
compound, we first examined the effects of different bases,
reactant molar ratios, solvents, and reaction times on the
chemical yield and the stereoselectivity of the product. It
turned out that, when n-BuLi was used as a base in THF,
excellent yield (92%) and good facial selectivity (dr ) 95:
5) were obtained (entry 6); and when KHMDS was used as
a base, excellent facial selectivity (dr ) 99:1) and satisfactory
yield (72%) were achieved (entry 13). It should be noted
that we applied several Lewis acids such as Me3Al, ZnBr2,
and BF3·Et2O for the n-BuLi-mediated reaction, but no
improvement of stereoselectivity was observed.
Table 1. Optimization of Reaction Conditions
molar ratio
(2a:1:base)
facial selectivityb
[(4a′+4a′′):4a′′′]
yield (%)c
(4a′ + 4a′′)
entrya
base
solvent
time (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
n-BuLi
LiHMDS
NaHMDS
KHMDS
LDA
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
KHMDS
KHMDS
KHMDS
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1:1.2:1.4
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1:1.4:1.5
1:1.1:1.2
1:2:2.2
THF
THF
THF
THF
THF
THF
THF
toluene
Et2O
CH2Cl2
THF
THF
THF
2
2
2
2
2
1
1
1
1
1
2
2
2
95:5
94:6
97:3
99:1
96:4
95:5
95:5
87:13
83:17
87:13
99:1
99:1
99:1
92
37
17
67
57
92
87
76
75
89
64
51
72
a In all cases, 1 and base were stirred in solvent at -78 °C for 30 min first, and then 2a was added to react with the pregenerated carbanion at -78 °C
for the period of time as shown. b Diastereomeric ratios were determined by 19F NMR of the crude reaction mixture. c Determined by 19F NMR using PhCF3
as internal standard.
5378
Org. Lett., Vol. 10, No. 23, 2008

Table 2. Diastereoselective Monofluoromethylation of Ketimines
facial selectivity
[4′ + 4′′):4′′′]b
yield (%)c
(4′ + 4′′)
entry
ketimines (2)
conditiona
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
95:5
99:1
96:4
99:1
91:9
97:3
96:4
99:1
95:5
99:1
94:6
98:2
94:6
99:1
95:5
94:6
87:13
99:1
95:5
94:6
95:5
99:1
91:9
99:1
90
64
81
65
86
60
85
62
93
68
77
69
72
68
81
77
81
74
81d
73d
77d
47d
88
67
1
2
R1 ) Ph, R2 ) CH3 (2a)
R1 ) 4-FC6H4, R2 ) CH3 (2b)
R1 ) 4-CF3C6H4, R2 ) CH3 (2c)
R1 ) 4-CH3OC6H4, R2 ) CH3 (2d)
R1 ) 4-CH3C6H4, R2 ) CH3 (2e)
R1 ) 4-ClC6H4, R2 ) CH3 (2f)
R1 ) 2-naphthyl, R2 ) CH3 (2g)
R1 ) 2-furyl, R2 ) CH3 (2h)
R1 ) pyridyl, R2 ) CH3 (2i)
R1 ) i-Pr, R2 ) CH3 (2j)
3
4
5
6
7
8
9
10
11
12
R1 ) t-Bu, R2 ) CH3 (2k)
R1 ) Ph, R2 ) nBu (2l)
a Condition A: Using reaction conditions as mentioned in entry 6 of Table 1 (n-BuLi as a base). Condition B: using reaction conditions as mentioned in
b
entry 13 of Table 1 (KHMDS as a base). Diastereomeric ratios were determined by 19F NMR of the crude reaction mixture. The isomeric ratios between
d
4′ and 4′′ are 1:1-4:1 (see the Supporting Information). c Isolated yield. Determined by 19F NMR using PhCF3 as internal standard.
Based on these optimization results, we finally decided to
choose the reaction conditions of entry 6 using n-BuLi as
base (condition A) and entry 13 using KHMDS as base
(condition B) as the standard to study the scope of nucleo-
philic monofluoromethylation of ketimines 2. The results are
shown in Table 2. A variety of structurally diverse (R)-N-
tert-butylsulfinyl ketimines 2 were able to readily react with
the pregenerated anion PhSO2CHF- to give the correspond-
ing chiral sulfinamide 4 in good to excellent yields and with
high diastereoselectivity (up to 99:1). The reaction with
sterically demanding ketimine 2k also gave product 4k (4k
) 4k′ + 4k′′) in good yield and with satisfactory facial
selectivity (Table 2, entries 11). When R1 ) phenyl and R2
) n-butyl group, the ketimine 2l still gave a high yield of
product with excellent diastereoselectivity (entry 12). The
absolute configurations of products 4a′ (entry 1) and 4k′′
(entry 11) were determined by single-crystal X-ray analysis
(see the Supporting Information), and the configurations of
other products were assigned by analogy. It is particularly
interesting that the stereocontrol mode of current diastereo-
selective (phenylsulfonyl)monofluoromethylation is com-
pletely opposite to the previously reported similar reactions
with aldimines.2-5 While the previously known fluoroalky-
lations of (R)-N-tert-butylsulfinyl aldimines prefer Rf- species
attacking the Re face of the aldimines (Scheme 2, TS-1),
the current reaction with ketimines 2 prefers PhSO2CHF-
(7) Sorochinsky and co-workers examined the addition reaction between
lithium diethyl difluoromethylphosphonate and the acetophenone-derived
sulfinyl ketimine (with or without Lewis acid activation), and they found
that the product yields (36-42%) were not satisfactory. See: Ro¨schenthaler,
G.-V.; Kukhar, V. P.; Belik, M. Y.; Mazurenko, K. I.; Sorochinsky, A. E.
Tetrahedron 2006, 62, 9902–9910.
(8) Enantiocontrolled Synthesis of Fluoroorganic Compounds: Stereo-
chemical Challenges and Biomedical Targets; Soloshonok, V. A., Ed.;
Wiley: New York, 1999.
(9) The yields for eqs 1-4 were determined by 19F NMR using internal
standard. The reactant ratio for eq 1 was 2a/Me3SiCF3/TBAT ) 1:1.2:1.1,
and the reactant ratios for eqs 2-4 were 2a/1/base ) 1:1.2:1.3.
(10) (a) Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829–6833. (b)
Ni, C.; Liu, J.; Zhang, L.; Hu, J. Angew. Chem., Int. Ed. 2007, 46, 786–
789. (c) Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699–5713.
(11) Farnham, W. B. Chem. ReV. 1996, 96, 1633–1640. (b) Prakash,
G. K. S.; Yudin, A. K. Chem. ReV. 1997, 97, 757–786. (c) Prakash, G. K. S.;
Hu, J. Acc. Chem. Res. 2007, 40, 921–930. (d) Gassman, P. G.; O’Reilly,
N. J. J. Org. Chem. 1987, 52, 2481–2490.
Org. Lett., Vol. 10, No. 23, 2008
5379

species attacking the Si face of 2 (Scheme 2, TS-2). Although
a full understanding of this unexpected “turn-over” of facial
selectivity between the (phenylsulfonyl)monofluoromethy-
lation of aldimines5b and ketimines 2 needs further study,
we speculate that a cyclic six-membered transition state13
TS-2 (rather than a nonchelation-controlled transition state
TS-1 that was proposed for aldimine reactions2-5 ) may
predominate in the current monofluoromethylation reaction
with ketimines 2 (see Scheme 2).
Scheme 3. Various Transformations
Scheme 2. Depiction of the Transition States
As a comparison, we also examined the nucleophilic
addition reaction between the pregenerated PhSO2CH2Li and
ketimine 2a under the reaction condition A (Scheme 3, eq
5). It was found that the corresponding product 7 was
obtained in 58% isolated yield with high diastereoselectivity.
Single-crystal X-ray analysis showed that the absolute
configuration of major isomer of product 7 is (Rs,S) (see
Supporting Information), which indicates that the reaction
proceeded via a similar cyclic transition state as above-
mentioned ketimine reactions. The low chemical yield may
be due to the R-deprotonation of ketimine 2a caused by
which confirms that the current monofluoromethylation
methodology is reliable for the preparation of enantiomeri-
cally pure R,R-dibranched monofluoromethyl amines. Fur-
thermore, (phenylsulfonyl)monofluoromethylated sulfin-
amides4b-gwerealsosuccessfullyconvertedtocorresponding
fluoromethyl amines 11b-g in 65-80% isolated yields
(Scheme 3, eq 8).
In summary, we have achieved the first efficient and highly
diastereoselective synthesis of R,R-dibranched monofluoro-
methyl amines via nucleophilic monofluoromethylation of
(R)-N-tert-butylsulfinyl ketimines. The pregeneration of
PhSO2CHF- anion from PhSO2CH2F and a base plays a key
role in this reaction, and the relatively high thermal stability
and good nucleophilicity of PhSO2CHF- anion account for
the overall chemical outcome of the reaction. The stereo-
control mode of the current diastereoselective monofluoro-
methylation of ketimines is opposite to the other known
nucleophilic fluoroalkylation of (R)-N-tert-butylsulfinyl al-
dimines, which suggests that a cyclic six-membered transition
state is involved in the reaction.
PhSO2CH2 , which is a stronger base than PhSO2CHF-. It
-
is also noteworthy to mention that we attempted a similar
pregeneration protocol for the (phenylsulfonyl)difluoro-
methylation of ketimine 2a (Scheme 3, eq 6), but no addition
product 9 was formed (only partial decomposition of
PhSO2CF2H (8) was observed). These results clearly indicate
that the thermal stability, good nucleophilicity, and relatively
weak basicity of PhSO2CHF- anion play important roles in
the current efficient and highly stereoselctive (phenylsulfon-
yl)monofluoromethylation of ketimes 2.
Upon reductive desulfonylation using Mg/HOAc/NaOAc
reagent,14 followed by acid-catalyzed alcoholysis and benz-
oylation, compound 4a (from the reaction as shown in Table
2, entry 1, condition B) was successfully converted to
benzamide derivative 10 (Scheme 3, eq 7). The high optical
purity of 10 (98.6% ee) was determined by chiral HPLC,
Acknowledgment. Support of our work by the National
Natural Science Foundation of China (20502029, 20772144,
20825209) and the Chinese Academy of Sciences (Hundreds-
Talent Program and Knowledge Innovation Program) is
gratefully acknowledged.
(12) Fluoromethyl phenyl sulfone (PhSO2CH2F) is commercially avail-
able, and it can also be prepared using known methods. See: (a) Matthews,
D. P.; Persichetti, R. A.; McCarthy, J. R. Org. Prep. Proced. Int. 1994, 26,
605–608. (b) Inbasekaran, M.; Peet, N.; McCarthy, J. R. J. Chem. Soc.,
Chem. Commun. 1985, 678–679.
(13) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984–995. (b) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39–46. (c)
Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallon, E.
Aldrichim. Acta 2005, 38, 93–103. (d) Daniel, M.; Stockman, R. A.
Tetrahedron 2006, 62, 8868–8905. (e) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-
W.; Sun, X.-W. Acc. Chem. Res. 2008, 41, 831–840.
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) Ni, C.; Hu, J. Tetrahedron Lett. 2005, 46, 8273–8277.
OL802226K
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Org. Lett., Vol. 10, No. 23, 2008