Geminal silicon/zinc reagent as an equivalent of difluoromethylene bis-carbanion

Article abstract of DOI:10.1021/ol5002297

A new difluorinated reagent, [difluoro(trimethylsilyl)methyl]zinc bromide, bearing C-Zn and C-Si bonds is described. The reagent is conveniently prepared by cobalt-catalyzed halogen/zinc exchange. It can be coupled with two different C-electrophiles in a stepwise manner (with allylic halides for C-Zn bond and aldehydes for C-Si bond) affording products containing a difluoromethylene fragment.

Full text of DOI:10.1021/ol5002297

Letter
pubs.acs.org/OrgLett
Geminal Silicon/Zinc Reagent as an Equivalent of Difluoromethylene
Bis-carbanion
Mikhail D. Kosobokov,† Vitalij V. Levin,† Artem A. Zemtsov,† Marina I. Struchkova,†
Alexander A. Korlyukov,‡ Dmitry E. Arkhipov,‡ and Alexander D. Dilman*,†
†N. D. Zelinsky Institute of Organic Chemistry, Leninsky prosp. 47, 119991 Moscow, Russian Federation
‡A. N. Nesmeyanov Institute of Organoelement Compounds, Vavilov str. 28, 119991 Moscow, Russian Federation
S
* Supporting Information
ABSTRACT: A new difluorinated reagent, [difluoro(trimethylsilyl)-
methyl]zinc bromide, bearing C−Zn and C−Si bonds is described. The
reagent is conveniently prepared by cobalt-catalyzed halogen/zinc
exchange. It can be coupled with two different C-electrophiles in a
stepwise manner (with allylic halides for C−Zn bond and aldehydes for C−Si bond) affording products containing a
difluoromethylene fragment.
Scheme 2. Equivalents of CF2 Bis-carbanion Synthon
he ability of fluorine to affect biological properties of
1
Torganic compounds has led to the discovery and successful
use of numerous fluorine-containing drugs.1,2 In the majority of
these molecules, the fluorine is present either as a substituent or
in the form of a trifluoromethyl group. At the same time,
compounds bearing difluoromethylene units are less frequent
among marketed medicines, but interest in this structural motive
is growing. Indeed, it has been noted that the CF2 fragment is
isosteric to ethereal oxygen1a,b,3 and, in some cases, even to
carbonyl or gem-dimethylmethylene groups4 (Scheme 1).
Scheme 1. Bioisosterism of CF2 Fragment
C−Si bonds being sequentially involved in coupling with suitable
electrophiles.
In the initial experiment, (bromodifluoromethyl)trimethyl-
silane (Me3SiCF2Br, 1)14 was treated with zinc dust. Reagent 2
was detected in small amounts along with homocoupling product
3, as determined by 19F NMR spectroscopy15 (Scheme 3).
Attempts to improve this reductive protocol failed despite
extensive variation of reaction conditions.16,17
Typically, synthesis of CF2-containing products either involves
a deoxofluorination reaction, which requires harsh reagents,5 or
relies on a building block approach, which is laborious.6,7
Recently, we described a strategy for assembling gem-
difluorinated compounds from difluorocarbene, nucleophile,
and electrophile.8 Herein, we report a reagent for coupling of
binucleophilic CF2 unit with two electrophilic species.
Scheme 3. Attempted Reductive Zincation of 1
Previously, sulfur9 and phosphorus10 reagents were shown to
act as equivalents of −CF2− synthon in reactions with two
aldehydes affording 1,3-diols (Scheme 2). However, the use of
fluorinated silanes would be desirable, since the carbon−silicon
bond is readily cleaved by fluoride anion or even weaker bases.11
To this end, the bis-silicon reagent (TMS)2CF2 was reported but
failed to serve as the bis-carbanion in reaction with aldehydes.12
Concerning polar organometallics, preparation of α-lithiated and
α-magnesiated silanes was attempted but was unsuccessful.13 In
this work, we describe the silicon/zinc reagent with C−Zn and
Then, the generation of organozinc species 2 was evaluated by
means of bromine/zinc exchange using isopropylzinc iodide
(Table 1). The reaction of silane 1 with 1.6 equiv of i-PrZnI was
slow at room temperature, providing modest yields of 2 (entries
Received: January 22, 2014
Published: February 19, 2014
© 2014 American Chemical Society
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Letter
Table 1. Preparation of Reagent 2
b
b
no.
solvent
THF
RZnI (equiv)
additive (equiv)
none
temp (°C)
conv of 1 (%)
yield of 2 (%)
1
1.6
1.6
1.6
1.2
1.2
1.2
1.2
1.2
1.0
1.0
1.2
1.2
1.2
1.2
1.2
20
20
20
5
65
65
30
15
0
2
THF/NMP
THF
none
3
LiCl (1.6)
100
29
4
THF
Ni(acac)2 (0.01)
NiBr2·(PPh3)2 (0.01)
CoBr2·(PPh3)2 (0.01)
CoBr2·dppe (0.01)
CoBr2·dppe (0.01)
CoBr2·dppe (0.01)
CoBr2·dppe (0.01)
CoBr2·dppe(0.005)
CoBr2·dppp (0.01)
CoBr2·dppb (0.01)
CoBr2 (0.01)
12
24
38
30
90
88
87
88
60
63
28
34
5
THF
5
49
6
THF
5
62
7
THF
5
95
8
THF/DG
THF/DG
THF/DG
THF/DG
THF/DG
THF/DG
THF/DG
THF/DG
5
100
95
95
9
5
c
10
11
12
13
14
15
5
5
97
5
86
5
78
5
43
d
CoBr2·dppe (0.01)
5
69
a
b
c
THF: tetrahydrofuran. NMP: N-methylpyrrolidone. DG: diglyme. Determined by 19F NMR using PhCF3 as internal standard. Reaction time 48
d
h. i-PrZnBr was used.
1 and 2). Then, the effect of various catalysts was evaluated.18
The significant rate acceleration was observed by adding 1 mol %
of CoBr2·dppe complex (dppe, 1,2-bis(diphenylphosphino)-
ethane), which allowed the temperature to decrease as well the
amount of i-PrZnI (to 1.2 equiv, entry 7). Rewardingly, the
addition of diglyme as a cosolvent (THG/diglyme, 1/1) led to
complete conversion together with 90% yield of 2 (entry 8). The
use of a precisely stoichiometric amount of i-PrZnI afforded
almost the same yield of 2 at 95% conversion (entry 9). Other
evaluated cobalt and nickel salts and complexes were notably less
efficient. When isopropylzinc bromide was employed instead of
isopropylzinc iodide, the reaction was slow (entry 15).
Figure 1. X-ray structure of 2·diglyme. Hydrogen atoms are omitted for
We also investigated the stability, composition, and structure
of organozinc reagent 2. The obtained THF/diglyme solutions
of 2 are reasonably stable and can even be stored at low
temperatures. For example, after 72 h at −30 °C, no decrease of
reagent concentration was noted, whereas after the same time at
room temperature only 25% of 2 decomposed (19F NMR
control).
clarity.
Scheme 4. Proposed Mechanism of Halogen/Zinc Exchange
19F NMR analysis of 2 in THF/diglyme solution showed two
close signals (−130.4 and −130.7 in a ratio 93:7, respectively),
likely owing to Schlenk equilibrium. Interestingly, when isolated
crystals of 2·diglyme (vide infra) were dissolved in CD3CN, only
one signal was observed.
It was surprising to find that reagent 2 contains bromide at zinc
despite using isopropylzinc iodide for the halogen/zinc exchange.
Indeed, such a halogen distribution pattern was established by
identification of isopropyl iodide byproduct.19 Furthermore, we
were fortunate to obtain highly air-sensitive crystals of 2
coordinated with diglyme, and X-ray analysis unambiguously
demonstrated the presence of bromide (Figure 1).
bond. The final step involves Co/Zn transmetalation providing
reagent 2.
We suggest a tentative mechanism of bromine/zinc exchange
accounting for unusual halogen redistribution (Scheme 4). At
first, the cobalt(II) complex is reduced to generate catalytically
active Co(I) iodide species.20 Subsequently, oxidative addition
leads to Co(III) intermediate,21 which serves as iodinating
reagent with respect to isopropylzinc iodide. At the latter step the
isopropyl iodide is formed along with generation of the Zn−Br
Having developed a method for the preparation of reagent 2,
we proceeded with exploration of its properties as equivalent of
difluoromethylene bis-carbanion. Given the greater polarity of
C−Zn bond compared to that of C−Si bond, reactions of 2 as
organozinc species were first evaluated. For fluorinated organo-
zinc reagents, copper(I)-catalyzed arylation22 and allylation8b,23
have been reported. Since arylations are performed under harsh
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Letter
conditions (elevated temperatures, long times), we focused on
allylation reactions. Thus, reagent 2 was coupled with allylic
halides in the presence of 5 mol % of copper cyanide24 (Table 2).
Table 3. Reaction of Silanes 5 with Aldehydes
a
Table 2. Allylation of Reagent 2
a
Ratio 2:4 is equal to 1:1.2 (entries 1 and 2) or 1:1 (entries 3−5).
b
c
d
Isolated yield based on reagent 2. E/Z mixture 13:1. Combined
yield of α and γ regioisomers, ratio 1:1. The α-regioisomer is formed as
E/Z mixture in a ratio of 13:1.
Silanes 5a−e were obtained in good yields after purification of
crude material either by distillation or by chromatography.25 At
the same time, the reaction of unsymmetrical substrate 4f bearing
an ester group afforded a 1:1 mixture of regioisomers (entry 6).
It should be pointed out that gem-difluorinated silanes
Me3SiCF2R, where R is a nonfluorinated group, are difficult to
synthesize, and only a limited number of examples were
documented.26 The use of reagent 2 as a source of nucleophilic
silyldifluoromethyl group opens up opportunities for the
synthesis of novel partially fluorinated silanes.
Silanes 5a−e were employed as nucleophilic reagents with a
range of aldehydes (Table 3). Aromatic and α,β-unsaturated, as
well as tertiary and α-branched aliphatic aldehydes, gave gem-
difluorinated alcohols 6 in high yields. However, hydro-
cinnamaldehyde afforded product in moderate yield (entry 5),
presumably owing to facile enolization under basic conditions.
Reactions of ketones with silane 5a were also briefly
investigated. Under standard conditions, benzophenone afforded
the expected alcohol 6m in modest yield along with fluorodiene 7
(Scheme 5). It is likely that diene 7 is formed by elimination of
HF from the primary product. In the reaction of acetophenone, a
enolizable ketone, neither conventional gem-difluorinated
alcohol, nor fluorodiene was detected.
a
b
Isolated yield. Mixture of diastereoisomers 1:1.
Scheme 5. Reaction of Benzophenone
In summary, a new fluorinated organometallic reagent serving
as an equivalent of difluoromethylene bis-carbanion is described.
The key feature of the reagent is Si−CF2−Zn functionality,
which enables successive coupling with two different electro-
philes by exploiting nucleophilic reactivities of C−Zn and C−Si
bonds. Furthermore, the intermediate silanes Me3SiCF2R,
produced after coupling with a first electrophile, may find their
own use in synthesis of organofluorine compounds.
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Letter
Org. Chem. 2012, 77, 5850−5855. (b) Li, L.; Wang, F.; Ni, C.; Hu, J.
Angew. Chem., Int. Ed. 2013, 52, 12390−12394.
(15) Compound 3 was previously described; see ref 12a.
ASSOCIATED CONTENT
■
S
* Supporting Information
(16) Various additives, which were expected to affect reductive
metalation (such as LiCl or copper(I) salts), had an even greater
deleterious effect. See: (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.;
Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 6040−6044. (b) Metzger,
A.; Schade, M. A.; Knochel, P. Org. Lett. 2008, 10, 1107−1110.
(17) For preparation of nonfluorinated reagent Me3SiCH2ZnX, see:
(a) Jones, P.; Reddy, C. K.; Knochel, P. Tetrahedron 1998, 54, 1471−
1490. (b) Charette, A. B.; Beauchemin, A.; Marcoux, J.-F. Tetrahedron
Lett. 1999, 40, 33−36. (c) Hatakeyama, T.; Nakagawa, N.; Nakamura,
M. Org. Lett. 2009, 11, 4496−4499.
Experimental procedures, compound characterization data,
copies of NMR spectra for all compounds, and X-ray data for
2·diglyme (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: adil25@mail.ru.
Notes
(18) Transition-metal catalysts are used for accelerating halogen/zinc
exchange using diethylzinc or triorganozincate as metallating reagents;
The authors declare no competing financial interest.
see: (a) Stadtmuller, H.; Lentz, R.; Tucker, C. E.; Stuedemann, T.;
̈
Doerner, W.; Knochel, P. J. Am. Chem. Soc. 1993, 115, 7027−7028.
ACKNOWLEDGMENTS
(b) Stadtmuller, H.; Vaupel, A.; Tucker, C. E.; Studemann, T.; Knochel,
̈
̈
■
P. Chem.Eur. J. 1996, 2, 1204−1220. (c) Vaupel, A.; Knochel, P. J.
Org. Chem. 1996, 61, 5743−5753. (d) Melzig, L.; Diene, C. R.;
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(19) A solution of 2 was concentrated under vacuum collecting the
volatiles in a cold trap. NMR analysis of condensed material indicated i-
PrI and i-PrBr in a ratio 94:6.
This work was supported by the Ministry of Science (project
MD-1151.2011.3), Russian Foundation for Basic Research
(projects 13-03-12074, 14-03-00293, 14-03-31253_mol_a, 14-
03-31265_mol_a), and the Russian Academy of Sciences. We are
grateful to R. Novikov (N. D. Zelinsky Institute of Organic
Chemistry) for 2D-NMR measurements and to G. Ivanov
(Higher Chemical College, Russian Academy of Sciences) for
experimental assistance.
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known; see: Harrison, D. J.; Gorelsky, S. I.; Lee, G. M.; Korobkov, I.;
Baker, R. T. Organometallics 2013, 32, 12−15 and reference cited
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