Organotitanium nucleophiles in asymmetric cross-coupling reaction: Stereoconvergent synthesis of chiral α-cf3 thioethers

Article abstract of DOI:10.1021/jacs.9b05671

Asymmetric Ni-catalyzed cross-coupling reactions have become a very attractive tool for the stereoselective construction of valuable organic chiral materials. While various nucleophiles are used in such transformation, organotitanium(IV) has not been used before. Herein we demonstrate, for the first time, that organotitanium species can serve as efficient coupling partners in asymmetric cross-couplings, which have proven to be beneficial, compared to the commonly used organomagnesium and organozinc counterparts. This principle is exemplified by the first asymmetric catalytic synthesis of CF₃-substituted thioethers via a Ni-catalyzed stereoconvergent cross-coupling reaction. Thioether moieties and their derivatives are common motifs in many biologically active compounds, and their enantioenriched fluorinated analogs should be of great interest in the search for novel drugs and agrichemicals.

Full text of DOI:10.1021/jacs.9b05671

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Communication
Organotitanium Nucleophiles in Asymmetric Cross-Coupling
3
Reaction: Stereoconvergent Synthesis of Chiral #-CF Thioethers
Andrii Varenikov, and Mark Gandelman
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 01 Jul 2019
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Organotitanium Nucleophiles in Asymmetric Cross-Coupling
Reaction: Stereoconvergent Synthesis of Chiral -CF3 Thioethers.
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Andrii Varenikov and Mark Gandelman*
Technion - Israel Institute of Technology, Technion City, Haifa 3200008, Israel
Supporting Information Placeholder
We anticipated that the use of organotitanium reagents could be
advantageous, since they possess a lower nucleophilicity and
basicity compared to their magnesium counterparts, allowing a
greater functional group tolerance; at the same time, these species
have higher transmetalation rates than organozinc compounds.
Knochel et al. demonstrated, that cross-couplings utilizing
organotitanium reagents are significantly faster than those
employing the corresponding organozinc counterparts.12
Interestingly, while organotitanium (IV) compounds were
extensively studied in nucleophilic addition to carbonyls,13, 14only
very few examples of the employment of such reagents in non-
asymmetric cross-coupling transformations are documented.12, 15
To the best of our knowledge, the utilization of organotitanium
nucleophiles in asymmetric cross-coupling reactions to create a
stereogenic center is unprecedented.
ABSTRACT:
Asymmetric
Ni-catalyzed
cross-coupling
reactions have become a very attractive tool for the stereoselective
construction of valuable organic chiral materials. While various
nucleophiles are used in such transformation, organotitanium (IV)
has not been used before. Herein we demonstrate, for the first
time, that organotitanium species can serve as efficient coupling
partners in asymmetric cross-couplings, which have proven to be
beneficial, compared to the commonly used organomagnesium
and organozinc counterparts. This principle is exemplified by the
first asymmetric catalytic synthesis of CF3-substituted thioethers
via a Ni-catalyzed stereoconvergent cross-coupling reaction.
Thioether moieties and their derivatives are common motifs in
many biologically-active compounds, and their enantioenriched
fluorinated analogs should be of great interest in the search for
novel drugs and agrichemicals.
Scheme 1. Nucleophiles in enantioconvergent cross-
coupling reactions
R-M
Cross-coupling reactions have become a major route for the
construction of carbon-carbon bonds in organic molecules and
materials. After a seminal work of Fu, the field of nickel-
catalyzed enantioselective cross-couplings has emerged as a
useful approach for the creation of stereo-defined chiral centers.1
In a quest for the perfect method, different nucleophiles were
employed under various conditions to incorporate the desired
moieties into the target molecule containing diverse sensitive
functional groups. Asymmetric cross-couplings are reported for
nucleophiles based on organo-zinc,2 boron,3 magnesium,4 silicon,5
aluminum,6 zirconium7 and indium.8 Between these species,
organo-magnesium and zinc nucleophiles are largely employed in
enantioselective cross-coupling reactions due to their fast
transmetalation rates and ease of preparation. Nevertheless, due to
their high basicity and nucleophilicity, organomagnesium reagents
suffer from low functional group compatibility.9 While
organozinc reagents possess a relatively high functional group
tolerance, in some cases the transmetalation from these
nucleophiles could present a rate limiting step of the catalytic
cycle.10 This could be detrimental for some reactions involving
alkyl-based electrophiles, since side processes such as β-H
elimination, dehydrohalogenation, or metal-F elimination (in the
species bearing fluoroalkyl substituents and involving an M-C-C-
F oxidative addition intermediate) are possible. Therefore,
attempts to utilize more selective, but less reactive,
transmetalating agents may result in significant changes to the
kinetics of the catalytic process,11 providing an opportunity for
undesired side reactions to occur. As such, the search for a
compromise between functional group compatibility and the rate
of transmetalation is essential for the success of the studied
transformation.
X
R
F.G.
R1
F.G.
R1
"NiLn*"
Known:
M = B, Zn, Si, Mg, Al, Zr, In
Ti
This work: M =
Scheme 2. Approaches towards α-CF3-benzyl (thio)ethers
R1
Our previous work
ArSi(OMe)3
"F-"
Cl
a)
R
*
NiCl2/ligand
F3C
O
R
F3C
O
Up to 96% yield
and 98% ee
32 expamles
This work
R1
ArTi(OiPr)3
tBuONa
Br
R
S
F3C
*
NiCl2/ligand
R
S
F3C
Previous approach:
enantiospecific
nucleophilic substitution
Our approach:
enantioconvergent
cross-coupling
R1
R1
b)
X
R
R
F3C
OTf
F3C
S
F3C
S
enantiopure
racemic
1
The site-selective introduction of fluorinated groups into drug
molecules or drug candidates frequently leads to a substantial
improvement in their biological properties.16 Therefore, efficient
methods for the regio- and stereoselective introduction of
fluorinated moieties into organic functional compounds are in
high demand in the search for new bioactive materials. Recently,
we initiated an active program of the utilization of CF3- and
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Page 2 of 7
Br
Ph
polyfluoroalkyl-substituted bisfunctionalized electrophiles in
1.3 equiv. Ph "M"
1
2
3
4
5
6
7
8
asymmetric cross-coupling transformations.5b Our approach
allows for a rapid synthesis of chiral organic compounds bearing
both a functional group and a fluoroalkyl substituent in the
stereogenic center. To initially exemplify this principle, we have
developed an approach towards enantioenriched α-trifluoromethyl
alcohols and ethers via an enantioconvergent nickel-catalyzed
Hiyama cross-coupling reaction, which provides the target
compounds in excellent yields and enantioselectivities (Scheme
2a). Inspired by these results, we sought to expand our approach
towards the corresponding sulfur analogues since thioether
moieties and their derivatives (such as sulfoxides and sulfones)
are common motifs in many biologically-active compounds.17,18
The preparation of enantioenriched thioethers usually relies on the
stereospecific nucleophilic substitution of stereodefined
electrophiles with sulfur-based nucleophiles.19 However,
stereospecific nucleophilic substitution at the benzylic position
bearing a trifluoromethyl group is challenging since the substrates
are susceptible to racemization, depending on the reaction
conditions and nature of the nucleophile (Scheme 2b).20
Employing our approach, the desired products could be prepared
via a stereoconvergent pathway starting from the racemic
precursor 1, which eliminates the need for the preparation of a
stereodefined precursor. Herein, we report on a novel preparation
of chiral (α-trifluoromethyl)benzyl thioethers in high yields and
enantioselectivities via an asymmetric cross-coupling reaction
utilizing aryltitanium nucleophiles. The approach can be extended
to the preparation of enantioenriched perfluoroalkyl substituted
thioethers. To the best of our knowledge, this is the first example
of the utilization of organotitanium nucleophiles in asymmetric
cross-coupling reactions.
F3C
S
Ph
F3C
S
Ph
L
10% NiCl2•glyme/11%
THF
2
2a
1a
-10°C 15 min + 15 min to RT
Yield (conversion)
72% (100%)
67% (70%)
ee
"M" = ZnI•LiCl
MgBr
95%
92%
96%
MgBr + Ti(OiPr)4
88% (100%)
Promising preliminary results were obtained for organozinc
compounds. Thus, after an initial examination of the reaction
conditions, compound 2a was obtained in a moderate yield and a
high ee when the cross-coupling with PhZnBr was performed
employing a catalytic system of NiCl2 and ligand L2 (Scheme 4).
However, the reaction was accompanied by a substantial
production of homocoupled and other unidentified by-products.
On the other hand, an aryl Grignard reagent, utilized under the
same reaction conditions, led to a similar output, and the yield of
the product 2a was equivalent to the conversion (Scheme 4).
However, the reaction did not go to completion even after a
prolonged reaction time, presumably due to the deactivation of the
catalytic system with PhMgBr. The selectivity of the Grignard
reagent was improved by its prior mixing with Ti(OiPr)4, which,
in effect, was the formation of the organotitanium active species
(Scheme 4).12 This led us to examine independently prepared aryl
titanium (IV) compounds in this transformation.21 Notably,
PhTi(OiPr)3 gave significantly poorer results (55% yield and 61%
ee, Table 1, entry 2) than the titanate species presumably formed
in the mixture of PhMgBr and Ti(OiPr)4. Gratifyingly, when
PhTi(OiPr)3 was reacted in the presence of t-BuONa to form a
titanate complex, the thioether 2a was obtained in a 95% yield
and 97% ee (Table 1, entry 1). Notably, the high oxophilicity and
formation of a stable -ate complex preclude the presence of the
free alkoxide in the solution, which makes the reaction conditions
compatible with base-sensitive thioethers of type 2.
9
10
11
12
13
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21
22
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41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Hiyama cross-coupling reaction approach
1.3 equiv. ArSi(OMe)3
2.5 equiv. TBAT
Table 1. Optimization of the reaction conditions
Cl
Ar
F3C
S
Ph
F3C
S
Ph
10% NiCl2•glyme
L
11%
DMA, RT
1
2
1a'
1.3 equiv. PhTi(OiPr)3
Br
1.3 equiv. tBuONa
Ar = 4-MeOPh
Ph
2b
2a
2l
83% yield, 80% ee
25% yield
traces
F3C
S
Ph
F3C
S
Ph
L
9% NiCl2•glyme/10%
THF
2
1a
2a
3-CF3OPh
-10°C 15 min + 15 min to RT
O
O
O
O
Entry
1
2
3
4
5
6
7
8
Modification
None
yielda
93%
55%
81%
94%
87%
92%
66%
-
19%
70%
47%
26%
40%
6%
ee
Ph
Ph
N
N
N
N
-
TBAT = Bu4N+ Ph3SiF2
97%
61%
78%
94%
95%
89%
91%
-
Ph
Ph
Ph
Ph
Only PhTi(OiPr)3
LiCl instead of tBuONa
EtONa instead of tBuONa
PhMgBr + Ti(OiPr)4
PhMgBr + Ti(OBu)4
rt instead of -10°C
No NiCl2·glyme
L1
L2
Initially we attempted to prepare the desired thioether 2 by the
Hiyama reaction, under conditions that we developed for the
synthesis of the corresponding ethers.5b The model reaction of
substrate 1a’ with 4-methoxyphenyl(trimethoxy)silane furnished
the product 2b in a promising yield of 83% and 80% ee (Scheme
3). However, the reaction with phenyl(trimethoxy)silane resulted
in product 2a in 25% yield, while the reaction with 3-
trifluoromethoxyphenyl (trimethoxy)silane gave only traces of the
cross-coupling product 2l. Further analysis revealed that the target
thioethers, especially those bearing electron-deficient aryls, are
prone to the elimination of HF under basic Hiyama cross-coupling
conditions followed, by further decomposition of the elimination
product. This forced us to examine other nucleophiles for this
reaction.
9
No ligand
-
10
11
12
13
14
15
Under air in closed vial
0.1 equiv. of H2O
Ligand L1 instead of L2
Ligand L3 instead of L2
Ligand L4 instead of L2
Ligand L5 instead of L2
95%
89%
27%
51%
-
17%
6%
a – determined by 19F NMR (with internal standard).
Scheme 4. Choice of organometallic nucleophiles
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Journal of the American Chemical Society
a
b
CN
– isolated yields (average of two runs); – 1.5 equiv. of
O
O
O
O
O
O
ArTi(OiPr)3 and 1.5 equiv. of tBuONa; c – the ate complex was
prepared in situ by a halogen-magnesium exchange with methyl
4-iodobenzoate followed by transmetalation to Ti(OiPr)4; – the
1
2
Ph
Ph
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
d
3
4
5
6
L1
L2
L3
ate complex was prepared in situ by a halogen-magnesium
exchange with 4-bromobenzonitrile followed by transmetalation
Ph
Ph
NH
NH
e
f
O
O
to Ti(OiPr)4; – reaction on 5 mmol scale(1.4 g) of starting 1a;
N
– EtONa was used instead of tBuONa; g – without alkoxide.
N
N
Ph
Ph
7
L4
L5
8
9
Having established the optimal conditions, we subjected the
substrate 1a to the reaction with different aryl titanium
nucleophiles (Table 2). To our delight, the scope of this
transformation is significantly broad. The reaction proceeds
smoothly with electron-rich and electron-poor aryl titanates,
bearing various functional groups such as alkoxy, thioalkoxy,
trimethylsilyl, tertiary anilines, halogens, trifluoromethoxy,
protected aldehydes, nitriles and esters. While aryl Ti(IV) bearing
meta and para- substituents on the aromatic ring performs
excellently in this transformation, their counterparts with the
ortho- substitution provides very low yields. Aryltitanium
nucleophiles, bearing the electron-donating group in the para-
position (see entries 2, 14, 20) show a diminished performance,
giving rise to the formation of unidentified side products. The
reaction can be improved by using slightly increased excess of the
reagents (1.5 instead of 1.3 equivalents of both the aryl titanium
and sodium tert-butoxide). In the case of highly electron poor
aryltitaniums (entries 13, 15, 17), ate complex exhibits poor
stability and hence an altered reactivity, what could be overcome
by utilizing a sodium ethoxide suspension instead of soluble
sodium tert-butoxide.22 Aryl Ti(IV) bearing functional groups,
such as ester23 and nitrile, proved to be compatible with this cross-
coupling reaction, however, under slightly midified conditions,
since isolation of such ArTi(OR)3 is problematic.24 Heterocyclic
aryl(triisopropoxy)titanium nucleophiles (entries 21-23) undergo a
Any changes from the optimized conditions (entry 1) led to
detrimental results. Thus, attempts to prepare the titanate complex
by addition of LiCl to PhTi(OiPr)3 furnished product 2a in a 81%
yield and 78% ee (entry 3). Sodium ethoxide provides similar
results to those of tBuONa (94% yield and 94% ee; entry 4). The -
ate complex can be prepared in situ from the corresponding
Grignard reagent and titanium tetraisopropoxide or tetrabutoxide,
furnishing slightly poorer yields and enantioselectivities (entries 5
and 6). The reaction performed at room temperature is
significantly faster, providing substantially inferior results (entry
7). The presence of both the nickel salt and the ligand are
necessary for the performance of the reaction (entries 8 and 9).
While the reaction is moderately air sensitive, the addition of 0.1
equivalents of water significantly decreases the yield (entries 10
and 11).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Scope of the aryl titanium partners
1.3 equiv. ArTi(OiPr)3
1.3 equiv. tBuONa
Br
Ar
Ph
F3C
S
F3C
S
Ph
L
9% NiCl2•glyme/10%
THF
2
1a
2a-w
-10°C, 2h
Entry
Ar
R
Yield a
ee
cross-coupling
reaction,
although
the
yields
and
2a
1
2
3
4
5
6
7
H
OMe
Ph
SiMe3
Br
CO2Me
CN
87%
97%
93%
98%
96%
98%
96%
94%
enantioselectivities of the products are moderate.
2b
2c
2d
2e
2f
86% b
90%
Notably, the reaction can be performed on a gram-scale with
no significant difference in its effectiveness. Thus, when 5
mmol(1.43 g) of 1a was cross-coupled with 3-MeOPhTi(OiPr)3
under our standard conditions, the thioether 2b was obtained in
91% yield and 98% ee (entry 10).
After exploring the scope of nucleophiles, we examined
electrophiles bearing various thioether motifs (Scheme 5). To our
delight, numerous functionalities are compatible with Ti (IV)
nucleophiles in the cross-couplings under our reaction conditions.
Esters, amides, silyl ethers, ketones and protected aldehydes
having different distances from the reaction center, and even
unfunctionalized substrates (see product 8a) react efficiently to
furnish products with excellent enantioselectivities and good
yields. Benzylic thioethers exhibit faster reaction rates compared
to alkyl substituted ones. While the reaction is complete within 2
hours for products 2a, 3a, 4b and 15a, approximately 5 hours are
required to reach a full conversion for other products.
81%
R
82%
81% c
72% d
2g
2h
2i
2j
2k
2l
8
9
10
11
12
CH(OCH2)2
SMe
OMe
NMe2
OCF3
86%
96%
99%
R
R
90%
83% (91%)e
92%
97%(98%)e
97%
83%
94%
85% f
81% b
82% f
96%
92%
96%
2m
2n
2o
13
14
15
Cl, Cl
OCH2O
OCF2O
R
R
R
2p
2q
16
17
Me, Me
CF3, CF3
87%
97%
97%
82% f
2r
18
19
93%
92%
99%
99%
The reaction is not significantly sensitive to the steric bulk of
the thioether substituent. Thus, the yields are high when the
tertiary carbon center is located in either the β- or γ- positions
(products 5a and 6a, correspondingly). However, in the case of a
tertiary -carbon, the desired product 7a is obtained in only a
13% yield, although with an excellent ee. The main outcome of
the reaction in the latter case is a homocoupled product. It should
be noted that electrophiles derived from secondary thioethers
perform efficiently in this cross-coupling reaction (15a). Aryl
thioethers could also be prepared by this method, but in
diminished yields and ee (product 13a). Interestingly, it is
possible to extend our approach to substrates bearing
perfluoroalkyl chains instead of trifluoromethyl group in the
2s
N
O
2t
20
21
22
23
86% b
76% f
48% g
47% g
96%
95%
56%
71%
Ph
2u
2v
2w
N
OMe
S
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Journal of the American Chemical Society
Page 4 of 7
stereogenic center. The resulting compounds were obtained with
substrate-unrelated cross-coupling reactions, as well as the
mechanistic studied of the presented method are under
investigation in our labs.
1
2
3
4
excellent enantioselectivities, although the yields were only
moderate (2b` and 2b``). More complex compounds, for example
derivatives of captopril (14a) and thiogluocose (15a) bearing
multiple stereocenters in proximity to the thioether linkage could
be efficiently utilized in this reaction, resulting in products with a
high diastereomeric purity.
ASSOCIATED CONTENT
Supporting Information
5
6
7
Scheme 5. Scope of thioethers
The Supporting Information is available free of charge on the
OMe
ACS
Publications
website.
8
9
1.3 equiv. 3-MeOPhTi(OiPr)3
Br
1.3 equiv. tBuONa
R
F3C
S
Experimental procedures, characterization data, NMR and HPLC
spectra of new compounds (PDF).
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
L
9% NiCl2•glyme/10%
THF, -10°C, 4h
F3C
S
2
1a, 3-15
2b, 3a-15a
AUTHOR INFORMATION
OMe
OMe
OMe
Corresponding Author
O
* E-mail: chmark@technion.ac.il
F3C
S
F3C
S
F3C
S
CF3
2b
3a
4a
Notes
83% yield
97% ee
94% yield
98% ee
84% yield
95% ee
The authors declare no competing financial interests.
OMe
OMe
OMe
ACKNOWLEDGMENT
O
The authors acknowledge financial support from the Israel
Science Foundation (grant no. 1890_/15). We are grateful to Dr.
Natalia Fridman for the X-ray analysis and structure solution of
compounds 2s and 15a.
F3C
F3C
F3C
S
F3C
F3C
F3C
S
F3C
F3C
F3C
S
Ph
O
5a
6a
7a
76% yield
95% ee
75% yield
93% ee
13% yield
89% ee
OMe
OMe
OMe
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Jarvo, E. R. Asymmetric transition metal-catalyzed cross-coupling
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C12H25
S
S
OAc
S
OTBDMS
6
6
8a
9a
10a
74% yield
94% ee
83% yield
95% ee
76% yield
96% ee
OMe
OMe
OMe
OMe
OMe
O
Ph
S
S
S
5
5
O
O
11a
12a
13a
75% yield
91% ee
80% yield
92% ee
37% yield
74% ee
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of Racemic Secondary Benzylic Halides. J. Am. Chem. Soc. 2005, 127,
10482-10483. (b) Fischer, C.; Fu, G. C. Asymmetric Nickel-Catalyzed
Negishi Cross-Couplings of Secondary α-Bromo Amides with Organozinc
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That Bear an Oxygen Leaving Group. J. Am. Chem. Soc. 2012, 134, 2966-
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Nickel/Bis(oxazoline)-Catalyzed Asymmetric Negishi Arylations of
Racemic Secondary Benzylic Electrophiles to Generate Enantioenriched
1,1-Diarylalkanes. J. Am. Chem. Soc. 2013, 135, 16288-16291. (j) Choi,
J.; Martín-Gago, P.; Fu, G. C. Stereoconvergent Arylations and
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OMe
OMe
OAc
O
N
O
O
O
AcO
S
AcO
F3C
S
CF3
OAc
14a
15a
L
L
L
(R,R) 2: 84% 90% de
(S.S) 2: 93% 98% de
(R,R) 2: 62% yield, 88% de
(S.S) 2: 60% yield, 86% de
L
OMe
OMe
C4F9
S
C7F15
S
2b`
2b``
37% yield
93% ee
43% yield
91% ee
In conclusion, we have developed a novel asymmetric catalytic
synthesis of CF3-substituted thioethers by a Ni-catalyzed cross-
coupling reaction, employing aryl titanium (IV) as a nucleophilic
reagent. The method is compatible with various functional groups
and the resulting products are usually obtained in high yields and
enantioselectivities. To the best of our knowledge, this is the first
example of the utilization of organotitaniums as nucleophiles in
asymmetric cross-coupling reactions. Aryl titanium proved to be
superior as a coupling partner in this particular transformation,
compared to its closely related organomagnesium and organozinc
counterparts. The added value of the organotitanium species in
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hexane. Concentration and cooling of the hexane extracts furnished
precepitation of the aryl(triisopropoxy)titanium. For the detailed
procedure see supporting information.
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18. For example, ones of the most selling drugs – Diltiazem, Montelukast,
Tazobactam – possess a thioether function in the stereogenic center.
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22. Persumably, sodium ethoxide is poorly soluble in tetrahydrofuran, but
reacts selectively with an aryltitanium furnishing the corresponding ate
complex in situ.
23. During the reaction was observed partial transesterification of methyl
ester to isopropyl ester in extent of 5%
24. The whole three-step sequence was performed as one-pot procedure
starting from the corresponding aryl halides: (1) halogen-magnesium
exchange by the reaction of an aryl halide with i-PrMgCl·LiCl; (2)
transmetallation of the resulting aryl Grignard reagent to Ti(OiPr)4 to form
aryl-titanate, and (3) Ni-catalyzed cross-coupling of the resulting aryl-
titanate with the electrophile 1a. This indicates that the procedure is highly
efficient (entries 6, 7) and tolerates the co-products of each step of the
sequence, including secondary alkyl halides (formed in the first step).
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21.
The
aryltitaniums
were
prepared
by
reaction
of
chloro(triisopropoxy)titanium with corresponding arylmagnesium bromide
in THF, followed by evaporation of the solvent and extraction with
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