Stereodivergent trifluoromethylation of: N -sulfinylimines by fluoroform with either organic-superbase or organometallic-base

Article abstract of DOI:10.1039/c8cc01526k

Here we have successfully demonstrated the first stereodivergent direct nucleophilic trifluoromethylation of N-sulfinylimines using the potent greenhouse gas "HFC-23, fluoroform" with an organic-superbase or an organometallic-base in high yields and selectivity.

Full text of DOI:10.1039/c8cc01526k

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: N. punna, T. Saito,
M. Kosobokov , E. Tokunaga, Y. Sumii and N. Shibata, Chem. Commun., 2018, DOI:
10.1039/C8CC01526K.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C8CC01526K
Journal Name
COMMUNICATION
Stereodivergent trifluoromethylation of N-sulfinylimines by
fluoroform with either organic-superbase or organometallic-base
Nagender Punna,a Takuya Saito,a Mikhail Kosobokov,a Etsuko Tokunaga,a Yuji Sumii,a and Norio
Shibata*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Here we have successfully demonstrated the first stereodivergent superbase (P4-tBu).2k,p In each case, stability of the substrate in
direct nucleophilic trifluoromethylation of N-sulfinylimines using the presence of a strong base played the crucial role.
šZꢀ ‰}šꢀvš PŒꢀꢀvZ}µ•ꢀ Pꢁ• ^IC/-îïU (oµ}Œ}(}Œu_ Á]šZ }ŒPꢁv]ꢂ-
Lv šZ]• ꢃ}všꢀÆšU r-trifluoromethyl amines have received
ample attention in the literature as key building blocks for many
active pharmacophores.5 During the last two decades,
nucleophilic trifluoromethylation of azomethines has increased
significantly to •ÇvšZꢀ•]• }( r-trifluoromethyl amines.6 Prakash
and co-workers pioneered the trifluoromethylation of diverse
sulfinylimines with CF3SiMe3 in good yields and
diastereoselectivities.6c-e,k Later on, several research groups
developed the trifluoromethylation of different kinds of
azomethine substrates with CF3SiMe3.6 However, until now,
there is no reported example of the trifluoromethylation of
azomethine substrates using fluoroform. As part of our ongoing
research program to develop the trifluoromethylation of
various substrates using fluoroform, here we have reported the
first stereodivergent trifluoromethylation of sulfinylimines with
high diastereoselectivities (dr) and yields (up to 90%) by using
fluoroform.
superbase or organometallic-base in high yields and selectivity.
Fluoroform (HFC-23, CF3H and trifluoromethane) is a stable,
nontoxic potent greenhouse gas (11,700-fold higher GWP than
carbon dioxide) and formed as a by-product during the
synthesis of poly tetrafluoroethylene (PTFE) in a huge amount,
and it is a very good source for trifluoromethyl (CF3) group.1,2
Trifluoromethyltrimethylsilane (CF3SiMe3, Ruppert-Prakash
reagent) is well known and most used nucleophilic
trifluoromethylating reagent, but the production of CF3SiMe3 is
expensive.3,1d To overcome this issue, fluoroform has attracted
as an inexpensive source for nucleophilic trifluoromethylation.
However, its high pKa (27), low boiling point (>82 °C) and lability
of the CF3 anion made trifluoromethylation quite challenging.2
In the past decades, fluoroform was successfully tamed by
different methods. Initially, trifluoromethylation of the carbonyl
compounds were disclosed by Shono, Normant and Langlois
using an electrogenerated bases and strong bases, here the CF3
anion was stabilized by trapping with DMF as a reservoir.2a,c,g
Later
on,
Grushin
demonstrated
the
productive
šŒ](oµ}Œ}uꢀšZÇoꢁš]}v }( ꢁŒÇoꢂ}Œ}v]ꢃ ꢁꢃ]ꢄ•U r-halo ketones and
aryl halides from fluoroform-derived CuCF3.4 Thereafter,
Prakash and co-workers tamed fluoroform with a common base
(potassium hexamethyldisilazide; KHMDS) and solvents (THF,
toluene and ether) in a stoichiometric manner.2i Our group also
made valuable contributions using fluoroform i.e.,
trifluoromethylation of aldehydes, sulfonyl fluorides, ketones
and sulfides using catalytic or stoichiometric amount of organic-
Scheme 1 Screening of the reaction of azomethines with CF3H. Reaction conditions:
azomethine (0.2 mmol), CF3H (excess), P4-tBu (1.1 equiv) in THF (1.0 mL) at room
temperature for 24 h. Yields were calculated by crude 19F NMR with PhCF3 as reference.
NR - no reaction.
Initially our investigation started by screening various
azomethine substrates using CF3H in our best reported
condition (reaction with organic-superbase (P4-tBu) in THF at
room temperature).2k In this primary screening, N-tosylimine
and N-sulfinylimine produced the desired trifluoromethylated
products in moderate to good yields (N-tosyl; 48% and N-
a. Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology,
Gokiso, Showa-ku, Nagoya 466-5888, Japan, E-mail: nozshiba@nitech.ac.jp
b. Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University,
688 Yingbin Avenue, 321004 Jinhua, China.
•9oꢀꢃšŒ}v]ꢃ
DOI: 10.1039/x0xx00000x
{µ‰‰oꢀuꢀvšꢁŒÇ
Lv(}Œuꢁš]}v
~9{L•
ꢁÀꢁ]oꢁꢂoꢀW
{ꢀꢀ
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
View Article Online
DOI: 10.1039/C8CC01526K
COMMUNICATION
Journal Name
sulfinyl; 73% with 20:1 dr), whereas other azomethine Œꢀ•µoš]vP ]v ꢁv ^Re_ (ꢁꢃꢀ ꢁššꢁꢃl š} (µŒv]•Z ‰Œꢀꢄ}u]vꢁšꢀoÇ ~Ss, S)
substrates (aldoxime, N-methylimine and azomethine imine) CF3-sulfinamides. In the P4-tBu trifluoromethylation reaction,
failed to produce the desired products. Details were shown in (oµ}Œ}(}Œu Áꢁ• ꢄꢀ‰Œ}š}vꢁšꢀꢄ ꢂÇ ꢂꢁ•ꢀ šZꢀv vꢁlꢀꢄ ^/C3_ ꢁv]}v
Scheme 1.
was stabilized by the phosphazene counter ion. Furthermore,
Encouraged by this result (Scheme 1, also see entry 1 in Table the phosphazene-•šꢁꢂ]o]Ìꢀꢄ ^/C3_ ꢁv]}v Zꢁ• ꢁššꢁꢃlꢀꢄ via open
1), we proceeded for further optimization studies with N- transition state TS3 ÁZ]ꢃZ Œꢀ•µošꢀꢄ ]v ꢁ oꢀ•• Z]vꢄꢀŒꢀꢄ ^Si_ (ꢁꢃꢀ
sulfinylimine
1 to make the reaction stereoselective. The attack to afford exclusively (Ss, R) CF3-sulfinamides (Figure 1).
reaction in catalytic amount of organic super base P4-tBu (0.2
equiv) with (Me3Si)3N as an additive in THF resulted no reaction
(Table 1, run 2). We then investigated the reaction in the
presence of other bases such as potassium tert-butoxide and in-
situ generated base ((Me3Si)3N + CsF), but these reactions did
not progress (Table 1, entries 3 and 4). Conversely, the reaction Figure 1 Transition states for trifluoromethylation reactions.
Á]šZ YIa5{ ]v ÇIC ꢁš >óô £/ ‰Œ}PŒꢀ••ꢀꢄ •u}}šZoÇ ꢁvꢄ PꢁÀꢀ ꢁv
excellent yield of 91% with 2:1 diastereomeric ratio (Table 1,
entry 8). To improve the diastereoselectivity we screened
various solvents using KHMDS as a base, and finally found that
toluene is the best solvent to furnish the desired product with
good yield and excellent diastereoselectivity (dr 1: 20, Table 1,
entry 10). After that, an attempt with P4-tBu base in toluene at
>78 °C slightly increased the yield and further excellent
diastereoselectivity (86%, dr 34:1, Table 1, entry 11) compared
to entry 1 in Table 1. Noteworthy is the reaction in the presence
of KHMDS which produced the (Ss, S) diastereomer whereas P4-
tBu gave the (Ss, R) diastereomer exclusively. The configuration
of these diastereomers were confirmed by the hydrolysis of CF3-
Table 2 Substrate scope in presence of KHMDS.a
Entry
R
Sulfinamide (Ss, S)
Yield (%)b
drc
1
2
4-OCH3C6H4
Ph
2a
2b
2c
2d
2e
2f
79 (84)
60 (72)
60 (68)
45 (48)
55 (61)
42 (48)
52 (56)
70 (78)
78 (83)
74 (81)
36 (40)
64 (70)
61 (66)
68 (68)
45 (48)
34 (35)
78 (79)
1:20
1:18
1:18
1:2
3
4-ClC6H4
4
4-NO2C6H4
tBu
5
1:4
sulfinamides followed by
a
comparison with previous
6
4-CF3C6H4
4-BrC6H4
1:5
chiroptical data in the literature (see later part, Table 4).6c
7
2g
2h
2i
1:13
1:14
1:13
1:14
1:5
8
4-N(Me)2C6H4
2-Napthyl
3,4-(OCH3)2C6H3
3-CF3C6H4
3-OCH3C6H4
2-OCH3C6H4
4-CH3C6H4
2-CH3C6H4
Styrenyl
Table 1 Optimization of solvent and base.a
9
10
11
12
13
14
15
16
17
2j
2k
2l
1:11
1:9
2m
2n
2o
2p
2q
1:8
1:7
Yield [%]b
drc
1:13
1:7
Entry
Base (equiv)
Solvent
T [°C]
1-Napthyl
a
1
2c
3
P4-tBu (1.1)
P4-tBu (0.2)
THF
25
25
73
traces
0
20:1
-
Reaction conditions: azomethine (0.2 mmol), CF3H (excess), KHMDS in toluene
b
THF
(2.0 ꢀ‹µ]À• ]v š}oµꢀvꢀ ~íXì u[• ꢁš >óô £/ }ÀꢀŒv]PZšX Yields are isolated yields of
total diastereomeric mixture and yields in parentheses were calculated by crude
19F NMR with reference PhCF3. Diastereomeric ratios were determined by 19F
tBuOK (2.0)
THF
>óô
>óô
>óô
>óô
>óô
-
c
4
5
(Me3Si)3N (1.5)e
KHMDS (1.5)
KHMDS (2.0)
KHMDS (2.5)
THF/toluene
THF/toluene
THF/toluene
THF/toluene
0
27
-
NMR spectroscopy of the crude reaction mixture.
1:2
1:2
1:5
6
80
Having the optimized trifluoromethylation reaction
7
61
conditions in hand, we next screened the substrate scope of (S)-
8
KHMDS (2.0)
THF
>óô
91
2:1
N-sulfinylimines
1
]v šZꢀ ‰Œꢀ•ꢀvꢃꢀ }( YIa5{ ~>óô £/ ]v š}oµꢀvꢀU
having
9
KHMDS (2.0)
KHMDS (2.0)
P4-tBu (1.1)
Et2O
toluene
toluene
>óô
>óô
>óô
71
84
89
1:20
1:20
34:1
10
11
Table 2). Most of the (S)-N-sulfinylimine substrates
1
different electronic properties were tolerated to produce good
yields with moderate to excellent diastereoselectivities (Ss, S).
The imines with an electron-donating group 1a (4-OCH3) and 1h
(4-N(Me)2) produced the corresponding trifluoromethylated
sulfinamides in excellent yields (2a: 79%; 2h: 70%) with high
diastereoselectivities (dr 1:20 and 1:14, Table 2, entries 1 and
8). The electron-withdrawing group substituted (S)-N-
sulfinylimines 1d (4-NO2), 1f (4-CF3) and 1k (3-CF3) furnished the
desired products 2d (45%), 2f (42%) and 2k (36%) in moderate
yields with average diastereoselectivities (dr up to 1:5, Table 2,
a
Reaction conditions: 1a (0.2 mmol), CF3H (excess) in solvent (1.0 mL) at given
b
temperature overnight. Yields were calculated by crude 19F NMR with the
reference compound PhCF3. dr calculated from crude 19F NMR. (Me3Si)3N (1.5
equiv) used as an additive. e 1.5 equiv of CsF was used
c
d
The phenomena of the reversal of diastereoselectivities are
explained by the chelated and open transition states.7 In the
case of KHMDS, diastereoselectivity is explained by the
formation of a chelated transition state TS1 with (S)-N-
sulfinylimine and KHMDS; subsequently, TS1 transforms to TS2
,
entries 4,
6
and 11). The halogen-substituted (S)-N-
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 4
View Article Online
DOI: 10.1039/C8CC01526K
Journal Name
COMMUNICATION
sulfinylimines 1c (4-Cl) and 1g (4-Br) tolerated the reaction well afford the desired product 3e in 61% yield with excellent
and afforded CF3-sulfinamides in good yields 2c (60%) and 2g diastereoselectivity (dr 49:1, Table 3, entry 4). More
(52%) with high selectivities (dr 1:18 and 1:13, Table 2, entries, interestingly, the (S)-N-sulfinylimine having the electron-
3 and 7). The tert-butyl (S)-N-sulfinylimine 1e proceeded the withdrawing group 1f (4-CF3) furnished the corresponding
reaction with moderate yield 2e (55%) and diastereoselectivity trifluoromethylated product 3f in 80% yield with excellent
~ꢄŒ íWðU Çꢁꢂoꢀ îU ꢀvšŒÇ ñ•U ÁZꢀŒꢀꢁ• rU t-unsaturated selectivity (dr 21:1, Table 3, entry 5). In the case of P4-tBu, we
sulfinylimine 1p furnished the corresponding product in low observed that substrates with different electron properties did
yield 2p (34%) with very good diastereoselectivity (dr 1:13, not show the any significant differences in yields and
Table 2, entry 16). We have observed the slight decrease in diastereoselectivities.
diastereoselectivity, when the substitution was present at the
Spurred by these results, the obtained (Ss, S)-sulfinamides
2
ortho position of the phenyl ring in (S)-N-sulfinylimine 1o (2- and (Ss, R)-sulfinamides
3
in the presence of KHMDS and P4-tBu
CH3) and 1q (napthyl) in Table 2, entries 13 and 17. These were further hydrolyzed with 4 M HCl in dioxane, and endured
phenomena can be explained by steric hindrance of the group šZꢀ ꢃ}ŒŒꢀ•‰}vꢄ]vP ꢀvꢁvš]}‰µŒꢀ r-trifluoromethyl amines with
present at the ortho position which disturbs the chelated good yields. These results were outlined in Table 4. The absolute
transition state.
configuration of these compounds was determined by
comparing with the chiroptical values of previously reported
compounds.6c
Table 3 Substrate scope in presence of P4-tBu Base.a
Table 4 Hydrolysis of CF3-sulfinamides 2 and 3.a
Entry
R
Sulfinamide (Ss, R)
Yield (%)b
drc
1
2
4-OCH3C6H4
Ph
3a
3b
3c
3e
3f
85 (89)
64(66)
79 (83)
61 (61)
80 (89)
80 (84)
79 (84)
75 (80)
87 (90)
86 (96)
81 (88)
88 (89)
96 (97)
70 (75)
79 (92)
70 (71)
34:1
23:1
41:1
49:1
21:1
24:1
6:1
(S)-amine;
(R)-amine;
Entry
R
ee
ee
Yield [b,d]
Yield [b,d]
3
4-ClC6H4
tBu
4
1
2
3
4
OCH3
H
4a: 82%
4b: 91%
4c: 87%
4f: 70%
99%
99%
99%
97%
5a: 92%
5b: 93%
5c: 94%
5f: 94%
99%
99%
99%
99%
5
4-CF3C6H4
4-BrC6H4
6
3g
3h
3i
Cl
7
4-N(Me)2C6H4
2-Napthyl
3,4-(OCH3)2C6H3
3-CF3C6H4
3-OCH3C6H4
2-OCH3C6H4
4-CH3C6H4
2-CH3C6H4
Styrenyl
CF3
8
20:1
44:1
23:1
63:1
23:1
48:1
35:1
14:1
13:1
a
Reaction conditions: sulfinamide (0.2 mmol), 4 M HCl in dioxane (0.4 mmol) in
9
3j
b
methanol (4 mL) at room temperature. Configurations were determined by
c
10
11
12
13
14
15
16
3k
3l
comparison with reported values of optical rotations. Optical rotations were
measured in methanol. d Yields are isolated yields.
3m
3n
3o
3p
3q
To explore our methodology, we examined the isatin-derived
ketimines using our optimized conditions (Scheme 2).
Previously, Xu and co-workers reported that a reaction using
CF3SiMe3 furnished corresponding CF3-derivatives in 66% yield
with poor selectivity (dr 1:4).8 In our case, the KHMDS base
produced the desired product in low yield (39%), but the
reaction in the presence of P4-tBu resulted in good yield (79%),
in both cases selectivity was poor (dr 1:1.2, Scheme 2). The
extensive screening of solvents and substituents were
summarized in supporting information (Table S1, SI). Further
screening is ongoing in our laboratory to improve the
diastereoselectivity and yield with CF3SiMe3.
1-Napthyl
a Reaction conditions: azomethine (0.2 mmol), CF3H (excess), P4-tBu in hexane (1.1
ꢀ‹µ]À• ]v š}oµꢀvꢀ ~íXì u[• ꢁš >óô £/ }ÀꢀŒv]PZšX b Yields are isolated yields of total
diastereomeric mixture and yields in parentheses were calculated by crude 19F
NMR with reference PhCF3. c Diastereomeric ratios were determined by 19F NMR
spectroscopy of the crude reaction mixture.
We also examined the generality of trifluoromethylation
reaction with (S)-N-sulfinylimines
1 in the presence of P4-tBu
base and the results were summarized in Table 3. The
trifluoromethylation of (S)-N-sulfinylimines with P4-tBu base
proceeded well for all the kind of substrates to furnish the
corresponding CF3-sulfinamides in excellent yields and
diastereoselectivities (Ss, R; Table 3) including (S)-N-
sulfinylimine 1f (4-CF3). Substrate
1 with various donating
groups (1a: OCH3; 1j: di-OCH3) and halogen substituents (1c: 4-
Cl; 1g: 4-Br) exhibited good reactivity and produced the
expected products in good yields 3a (85%), 3j (87%), 3c (79%)
and 3g (80%) with very high diastereoselectivities (dr up to 44:1,
Table 3, entries 1, 3, 6 and 9). Gratifyingly, tert-butyl (S)-N-
sulfinylimine substrate 1e also tolerated the reaction well to
Scheme 2 Trifluoromethylation of Isatin-derived ketimines.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
View Article Online
DOI: 10.1039/C8CC01526K
COMMUNICATION
Journal Name
L, Huazhang, J. Fluorine Chem., 2012, 140, 7; (e) V. V. Grushin,
Chim. Oggi., 2014, 32, 81.
(a) T. Shono, M. Ishifune, T. Okada and S. Kashimura, J. Org.
Chem., 1991, 56, 2; (b) R. Barhdadi, M. Troupel and J. Perichon,
Chem. Commun., 1998, 0, 1251; (ꢃ• .X C}oo as, I. Marek, J. -F.
With these results in hand, we have successfully prepared the
trifluoromethylated drug analogues NPS R-568 (
7; Scheme 3a)
2
and Cinacalcet (8; Scheme 3b). Initially, the desulfonylation of
the compounds (Ss, S)-2l and (Ss, S)-2q furnished the desired
ꢀvꢁvš]}‰µŒꢀ r-trifluoromethyl amines in good yields (4l: 96%;
4q: 87%, Scheme 3). Further, these compounds were treated
with corresponding aldehydes for reductive amination in the
presence of sodium triacetoxyborohydride to afford the
required trifluoromethylated drug analogues in quantitative
Normant and L. Saint-Jalmes, Tetrahedron Lett., 1998, 39
2973; (d) J. Russell and N. Roques, Tetrahedron, 1998, 54
,
,
13771; (e) C. Mispelaere and N. Roques, Tetrahedron Lett.,
1999, 40, 6411; (f) B. Folleas, I. Marek, J. -F. Normant and L.
Saint-Jalmes, Tetrahedron, 2000, 56, 275; (g) S. Large, N.
Roques and B. R. Langlois, J. Org. Chem., 2000, 65, 8848; (h) T.
yields (7: 83%; 8: 80%) and enantioselectivities (7: 99%; 8: 99%).
B. Billard, S. Bruns and B. R. Langlois, Org. Lett., 2000,
(i) G. K. S. Prakash and G. A. Olah, Science, 2012, 338, 1324; (j)
C. S. Thomoson and W. R. Dolbier, Jr. J. Org. Chem., 2013, 78
2, 2101;
,
8904; (k) H. Kawai, Z. Yuan, E. Tokunaga and N. Shibata, Org.
Biomol. Chem., 2013, 11, 1446; (l) S. Potash and S. Rozen, J.
Org. Chem., 2014, 79, 11205; (m) C. S. Thomoson, L. Wang and
W. R. Dolbier, J. Fluorine Chem., 2014, 168, 34; (n) S. Okusu, E.
Tokunaga and N. Shibata, Org. Lett., 2015, 17, 3802; (o) K.
Aikawa, K. Maruyama, K. Honda and K. Mikami, Org. Lett.,
2015, 17, 4882; (p) S. Okusu, K. Hirano, E. Tokunaga and N.
Shibata, ChemistryOpen, 2015, 4, 581.
3
4
(a) G. K. S. Prakash, D. Denis, A. K. Yudin and G. A. Olah, Synlett,
1994, 12, 1057; (b) G. K. S. Prakash, A. K. Yudin, D. Deffieux
and G. A. Olah, Synlett, 1996, 151.
(a) A. Zanardi, M. A. Novikov, E. Martin, J. Benet-Buchholz and
V. V. Grushin, J. Am. Chem. Soc., 2011, 133, 20901; (ꢂ• tX
b}Àꢅk, A. Lishchynskyi and V. V. Grushin, Angew. Chem., Int.
Ed., 2012, 51, 7767; (ꢃ• tX b}Àꢅk, A. Lishchynskyi and V. V.
Grushin, J. Am. Chem. Soc., 2012, 134, 16167; (d) A.
[]•ZꢃZÇv•lÇ]U aX !X b}À]l}ÀU 9X aꢁŒš]vU 9X /X 9•ꢃµꢄꢀŒ}r!ꢄꢅvU tX
b}Àꢅk and V. V. Grushin, J. Org. Chem., 2013, 78, 11126; (e) A.
Lishchynskyi, G. Berthon and V. V. Grushin, Chem. Commun.,
2014, 50, 10237.
Scheme 3 Preparation of CF3 drug analogues. a) NPS R-568; b) Cinacalcet.
In conclusion, we have synthesized enantio-Œ]ꢃZ r-
trifluoromethyl amines in a stereodivergent manner by the
]vꢀƉꢀv•]Àꢀ ‰}šꢀvš PŒꢀꢀvZ}µ•ꢀ Pꢁ• ^(oµ}Œ}(}Œu_X9 The
trifluoromethylation of (S)-N-sulfinylimines in the presence of
KHMDS produced (Ss, S)-trifluoromethylated N-sulfinamides
whereas the P4-tBu super base furnished (Ss, R)-
trifluoromethylated N-sulfinamides. This phenomenon was
explained by the formation of chelated and non-chelated
transition states with bases. By this methodology we
successfully synthesized the enantiopure trifluoromethylated
analogues of known drugs Cinacalcet and NPS R-568 in high
yields. These enantio-Œ]ꢃZ r-trifluoromethyl amines are very
useful precursors for the preparation of chiral ligands and
biologically active compounds.
5
6
(a) W. S. Faraci and C. T. Walsh, Biochemistry, 1989, 28, 431;
(b) G. L. Grunewald, J. Lu, K. R. Criscione and C. O. Okoro,
Bioorg. Med. Chem. Lett., 2005, 15, 5319; (c) S. Leger, C. I.
Bayly, W. C. Black, S. Desmarais, J.-P. Falgueyret, F. Masse, M.
D. Percival and J.-F. Truchon, Bioorg. Med. Chem. Lett., 2007,
17,
ChemMedChem, 2007,
4328; (d) M. Sani, A. Volonterio and M. Zanda,
, 1693;
2
(a) A. D. Dilman and V. V. Levin, Eur. J. Org. Chem., 2011, 831;
(b) G. K. S. Prakash, M. Mandal and G. A. Olah, Synlett, 2001,
77; (c) G. K. S. Prakash, M. Mandal and G. A. Olah, Angew.
Chem., Int. Ed., 2001, 40, 589; (d) G. K. S. Prakash, M. Mandal
and G. A. Olah, Org. Lett., 2001, 3, 2847; (e) G. K. S. Prakash
and M. Mandal, J. Am. Chem. Soc., 2002, 124, 6538; (f) Y.
Kawano and T. Mukaiyama, Chem. Lett., 2005, 34, 894; (g) Y.
Conflicts of interest
There are no conflicts to declare
Kawano, H. Fujisawa and T. Mukaiyama, Chem. Lett., 2005, 34
,
422; (h) Y. Kawano, N. Kaneko and T. Mukaiyama, Bull. Chem.
Soc. Jpn., 2006, 79, 1133; (i) H. Kawai, A. Kusuda, S. Nakamura,
M. Shiro and N. Shibata, Angew. Chem., Int. Ed., 2009, 121
,
6442; Angew. Chem. Int. Ed., 2009, 48, 6324; (j) G. K. S.
Prakash, Y. Wang, R. Mogi, J. Hu, T. Mathew and G. A. Olah,
Org. Lett., 2010, 12, 2932; (k) H. Rodríguez, T. C. Hernández
and K. E. T. Huizar, Synthesis, 2011, 17, 2817.
(a) N. Shibata, T. Nishimine, N. Shibata, E. Tokunaga, K.
Kawada, T. Kagawa, J. L. Aceña, A. E. Sorochinsky and V. A.
Soloshonok, Org. Biomol. Chem., 2014, 12, 1454; (b) N.
Shibata, T. Nishimine, N. Shibata, E. Tokunaga, K. Kawada, T.
Kagawa, A. E. Sorochinsky and V. A. Soloshonok, Chem.
Commun., 2012, 48, 4124.
Acknowledgements
This work was supported by the Asahi Glass Foundation, the
Public Foundation of Chubu Science and Technology Center,
and ACT-C from the JST (JPMJCR12Z7). We also would like to
thank Tosoh Finechem Corporation for support.
7
Notes and references
1
(a) J. T. Houghton, L. G. Meira Filho, B. A. Callander, N. Harris,
A. Kattenberg and K. Maskell, Climate Change 1995. The
Science of Climate Change, Cambridge University Press,
Cambridge, 1996; (b) D. E. Oram, W. T. Sturges, S. A. Penkett,
8
9
D. Chen and M. tH. Xu, J. Org. Chem., 2014, 79, 7746.
(a) J. B. Geri and N. K. Szymczak, J. Am. Chem. Soc., 2017, 139
,
9811; (b) J. B. Geri, M. M. W. Wolfe and N. K. Szymczak, Angew.
Chem., Int. Ed., 2018, 57, 1.
A. McCulloch and P. J. Fraser, Geophys. Res. Lett., 1998, 25
,
35t38; (c) A. McCulloch and A. A. Lindley, Atmos. Environ.,
2007, 41, 1560t1566; (d) H. Wenfeng, L. Ying, T. Haodong and
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins