Dithiocarbamate-substituted gem-difluorinated silicon reagent: generation and addition to aldehydes

Article abstract of DOI:10.1016/j.tetlet.2015.07.018

Abstract A new gem-difluorinated silicon reagent bearing a pyrrolidine dithiocarbamate substituent was prepared by the reaction of (bromodifluoromethyl)trimethylsilane with the corresponding potassium dithiocarbamate. The obtained reagent was employed in

Full text of DOI:10.1016/j.tetlet.2015.07.018

Tetrahedron Letters 56 (2015) 5048–5050
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dithiocarbamate-substituted gem-difluorinated silicon reagent:
generation and addition to aldehydes
Anton S. Maslov a,b, Vladimir O. Smirnov a, Marina I. Struchkova a, Dmitry E. Arkhipov c,
Alexander D. Dilman a,
⇑
a N. D. Zelinsky Institute of Organic Chemistry, Leninsky Prosp. 47, 119991 Moscow, Russian Federation
b Moscow State University, Department of Chemistry, Leninskie Gory 1-3, 119991 Moscow, Russian Federation
c A. N. Nesmeyanov Institute of Organoelement Compounds, Vavilov Str. 28, 119991 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A new gem-difluorinated silicon reagent bearing a pyrrolidine dithiocarbamate substituent was prepared
by the reaction of (bromodifluoromethyl)trimethylsilane with the corresponding potassium dithiocarba-
mate. The obtained reagent was employed in the nucleophilic addition to aldehydes and ketones.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 10 June 2015
Revised 1 July 2015
Accepted 6 July 2015
Available online 10 July 2015
Keywords:
Fluorine
Fluoroalkylation
Silicon reagents
Difluorocarbene
Direct introduction of a fluorinated fragment into organic mole-
cules constitutes an important approach in medicinal chemistry
and agrochemistry.1 Among the various methods of synthesizing
fluorinated building blocks,2 nucleophilic fluoroalkylation of car-
bonyl compounds and related substrates has emerged as a power-
ful and broadly applicable methodology.3 Correspondingly, many
organometallic derivatives have been evaluated as equivalents of
fluorinated carbanions,4 but only silicon reagents have found wide-
spread use. Indeed, the utility of fluorinated silanes stems from the
convenience of handling and mild conditions required to reveal
their nucleophilicity.3a–e
It has recently been noted that (bromodifluoromethyl)
trimethylsilane (Me3SiCF2Br, 1) may exchange bromine for
chlorine in an equilibrium reaction when exposed to a chloride
ion.12 We proposed that employment of the dithiocarbamate anion
would effect a similar bromine substitution. Gratifyingly, when
potassium dithiocarbamate 2 (K-dtc), easily obtained from pyrro-
lidine and carbon disulfide,13 was added to silane 1, a substitution
reaction occurred rapidly, and product 3 was isolated in 79% yield
(Scheme 2). We postulated that the reaction was initiated by attack
of the anionic species (X = dtc or Br) at the silicon atom to generate
difluorocarbene followed by its trapping by the dithiocarbamate
anion and subsequent silylation.
Besides the most widely used Ruppert–Prakash reagent
(Me3SiCF3),5 other silanes bearing
a
heteroatom substituent
Contrary to typical fluorinated silanes, compound 3 was
instead of one of the fluorine atoms have been prepared and
employed for carbonyl addition reactions and related processes6–9
(Scheme 1). Further extension of the palette of silicon reagents
with emphasis on new functional groups would be desirable.
Dithiocarbamates have displayed a diverse profile of biological
activities, including antifungal, antibacterial, antiviral, and anti-
cancer.10 Herein, we describe a new fluorinated silane bearing a
dithiocarbamate moiety, and demonstrate its utility in fluoroalky-
lation reactions.11
isolated as a crystalline material, and its structure was proved by
single crystal X-ray analysis14 (Fig. 1). Interestingly, it existed in
an eclipsed conformation along the Si–CF2 bond (see inset). Solid
silane 3 could be stored at 0 °C for weeks without visible changes
Me3Si
X
Previous work
This work
X =
F
F
X = SPh, SO2Ph
P(O)(OEt) 2
S
S
N
Cl, Br, I
OPh, N-azolyl
⇑
Corresponding author.
E-mail address: adil25@mail.ru (A.D. Dilman).
Scheme 1. Fluorinated silicon reagents.
http://dx.doi.org/10.1016/j.tetlet.2015.07.018
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

A. S. Maslov et al. / Tetrahedron Letters 56 (2015) 5048–5050
5049
S
Under the optimized conditions, a series of aldehydes 4 were
examined in the dithiocarbamate initiated fluoroalkylation reac-
Me3Si
S
S
MeCN
Me3Si
Br
+
KS
N
F
F
N
tion (Table 2). Aromatic, heteroaromatic, and
a,b-unsaturated
—35 to 0 °C,
40 min
F
F
aldehydes gave alcohols 6 in high yields. Addition to an aldehyde
bearing an electron withdrawing ester group proceeded rapidly
and was complete with 5 min (entry 3). Notably, in the reaction
of an aldehyde bearing a methallyl group, no products of double
bond difluorocyclopropanation were observed15 (entry 4). An eno-
lizable aldehyde, hydrocinnamaldehyde, also gave the addition
product in high yield (entry 9). However, branched aliphatic alde-
hydes reacted sluggishly, and an increased loading of reagents 1
(3.0 equiv) and 2 (3.3 equiv) was required (entries 10–12).
1, 1.1 equiv
2 (K-dtc)
3, 79%
Me3SiX
X
dtc
Me3Si
dtc
Me3Si
Br
C
F
F
F
dtc
F
F
F
F
F
3
1
Scheme 2. Synthesis of silane 3.
Table 2
Addition to aldehydesa
OH
0 °C, 2 h
MeCN
O
Me3Si
Br
S
S
+
+
K-dtc
R
F
F
R
F
F
N
4
1
2
5
No.
1
Aldehyde
5
Yield of 5b (%)
O
5b
80
Ph
O
Figure 1. X-ray structure of silane 3.
2
5c
5d
5e
5f
84
81
68
76
Cl
and could be conveniently handled in air. However, when the
reagent was kept at room temperature it slowly underwent
decomposition. Given that silane 3 is rapidly formed from shelf-
stable precursors, it is convenient to generate this silicon reagent
in situ.
O
3c
MeO2C
O
Anisaldehyde 4a was selected as a model substrate and its
reaction with silane 3 in acetonitrile was evaluated (Table 1). No
reaction occurred in the absence of a Lewis basic activator. Use
of K-dtc (0.1 equiv) as an activator gave after desilylative
work-up (with KHF2/TFA), alcohol 5a in 70% yield within 1 h at
0 °C (entry 2). Increasing the reaction time to 2 h, and generating
silane 3 in situ from 1.3 equiv of Me3SiCF2Br and 1.4 equiv of K-
dtc provided product 5a in 81% yield (entry 5). It is worth noting
that although the reaction could be initiated by the poorly Lewis
basic bromide ion, the reaction proceeded at a decreased rate
(entry 6).
4
O
O
5
Br
O
6
7
5g
5h
64
81
O
O
Table 1
O
Optimization studies
8
9
5i
5j
79
73
Ph
Ph
OH
O
O
activator
Me3Si
dtc
S
S
+
Ar
5a
MeCN
then KHF2/TFA
Ar
F
F
F
F
N
O
4a
3, 1.3 equiv
10d
11d
12d
5k
5l
74
80
82
Ar = 4-MeOC6H4
O
Entry
Activator (equiv)
Temp
Time (h)
Yield of 5aa (%)
Ph
1
2
3
—
rt
2
1
2
1
2
3
—
K-dtc (0.1)
K-dtc (0.1)
K-dtc (0.1)
K-dtc (0.1)
Bu4NBr (1.0)
0 °C
0 °C
rt
0 °C
rt
70
80
75
81
17c
O
5m
4
BzO
5b
6
a
b
c
Standard conditions: 1 (1.3 equiv), 2 (1.4 equiv).
Isolated yield.
Reaction time 5 min.
a
b
c
Isolated yield.
Silane 3 generated in situ from 1 and K-dtc.
Yield determined by 19F NMR.
Reagents: 1 (3.0 equiv), 2 (3.3 equiv).
d

5050
A. S. Maslov et al. / Tetrahedron Letters 56 (2015) 5048–5050
Me3Si
Br
, K-dtc
References and notes
Me3SiO
S
S
O
1
2
F
F
R
R
1. (a) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369; (b) Wang, J.; Sanchez-
Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok,
V. A.; Liu, H. Chem. Rev. 2014, 114, 2432–2506.
F
F
N
R
R
6a
7a
2. (a) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975–996; (b) Schlosser, M.
Angew. Chem., Int. Ed. 2006, 45, 5432–5446; (c) Shimizu, M.; Hiyama, T. Angew.
Chem., Int. Ed. 2005, 44, 214–231.
, R = Ph
6b, R = Me
, R = Ph, 43%
7b, R = Me, <5%
3. (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757–786; (b) Liu, X.; Xu,
C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683–730; (c) Dilman, A. D.; Levin, V.
V. Eur. J. Org. Chem. 2011, 831–841; (d) Singh, R. P.; Shreeve, J. M. Tetrahedron
2000, 56, 7613–7632; (e) Uneyama, K. J. Fluorine Chem. 2008, 129, 550–576; (f)
Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921–930; (g) Hu, J.; Zhang, W.;
Wang, F. Chem. Commun. 2009, 7465–7478; (h) Medebielle, M.; Dolbier, W. R.,
Jr. J. Fluorine Chem. 2008, 129, 930–942.
4. (a) Burton, D. J.; Yang, Z.-Y. Tetrahedron 1992, 48, 189–275; (b) Burton, D.; Lu, L.
Top. Curr. Chem. 1997, 193, 45–89.
5. For a pioneering work, see: Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am.
Chem. Soc. 1989, 111, 393–395.
Scheme 3. Reactions of ketones.
Me3Si Rf
Rf
O
Me
Me
Rf
Si Me
Me
Me
R
O
Si Me
O
K-dtc
4
S
S
Me3Si Rf
R
Rf
3
8
N
Me3Si-dtc
R
O
Rf
6. For thia-substituted silicon reagents, see: (a) Ni, C.; Hu, J. Tetrahedron Lett.
2005, 46, 8273–8277; (b) Soorukram, D.; Kuhakarn, C.; Reutrakul, V.;
Pohmakotr, M. Synlett 2014, 2558–2573; (c) Ni, C.; Hu, M.; Hu, J. Chem. Rev.
2015, 115, 765–825.
Rf =
dtc
OSiMe3
Rf
F
F
R
R
7. For
a phosphoryl-substituted reagent, see: Alexandrova, A. V.; Beier, P. J.
Fluorine Chem. 2009, 130, 493–500.
Scheme 4. Proposed mechanism.
8. For halogenated silanes, see: (a) Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.;
Bradley, M.; Bau, R.; Olah, G. A. J. Am. Chem. Soc. 1997, 119, 1572–1581; (b)
Kosobokov, M. D.; Dilman, A. D.; Levin, V. V.; Struchkova, M. I. J. Org. Chem.
2012, 77, 5850–5855; (c) Li, L.; Wang, F.; Ni, C.; Hu, J. Angew. Chem., Int. Ed.
2013, 52, 12390–12394.
9. For O- and N-substituted silanes, see: (a) Guidotti, J.; Metz, F.; Tordeux, M.;
Wakselman, C. Synlett 2004, 1759–1762; (b) Bissky, G.; Staninets, V. I.;
Kolomeitsev, A. A.; Röschenthaler, G.-V. Synlett 2001, 374–378.
The reactions of ketones were also evaluated (Scheme 3). Using
a three-fold excess of reagents 1 and 2, benzophenone gave the
expected product 7a, albeit in moderate yield. At the same time,
in the reaction of acetone, no addition product was observed by
19F NMR, while GC MS analysis suggested the formation of acetone
self-condensation products.
Concerning the mechanism, the reaction likely proceeds
through the Lewis base initiated generation of alkoxide 8 which
subsequently drives the chain process typical of fluorinated silicon
reagents (Scheme 4).3a
Finally, we attempted to investigate the reactivity of the
obtained products. However, Swern oxidation of alcohol 5a under
the conditions suitable for trifluoromethylated alcohols,16 was
unsuccessful. When compound 5a was subjected to the typical
Zard’s free-radical atom transfer chemistry17 (e.g., reaction with
N-allylphthalimide and dilauroyl peroxide), complex mixtures
were formed.
In summary, we have synthesised a novel silicon reagent
bearing a dithiocarbamate fragment and demonstrated its utility
for the nucleophilic fluoroalkylation of carbonyl compounds. The
opportunity for in situ generation of the silane from readily avail-
able and shelf-stable precursors makes this a convenient procedure
for synthetic applications.
10. (a) Li, R.-D.; Wang, H.-L.; Li, Y.-B.; Wang, Z.-Q.; Wang, X.; Wang, Y.-T.; Ge, Z.-M.;
Li, R.-T. Eur. J. Med. Chem. 2015, 93, 381–391; (b) Carta, F.; Aggarwal, M.;
Maresca, A.; Scozzafava, A.; McKenna, R.; Masini, E.; Supuran, C. T. J. Med. Chem.
2012, 55, 1721–1730; (c) Imamura, H.; Ohtake, N.; Jona, H.; Shimizu, A.;
Moriya, M.; Sato, H.; Sugimoto, Y.; Ikeura, C.; Kiyonaga, H.; Nakano, M.;
Nagano, R.; Abe, S.; Yamada, K.; Hashizume, T.; Morishima, H. Bioorg. Med.
Chem. 2001, 9, 1571–1578; (d) Len, C.; Boulogne-Merlot, A.-S.; Postel, D.;
Ronco, G.; Villa, P.; Goubert, C.; Jeufrault, E.; Mathon, B.; Simon, H. J. Agric. Food
Chem. 1996, 44, 2856–2858.
11. Recent results from our group on the use of functionalized silicon reagents,
see: (a) Levin, V. V.; Zemtsov, A. A.; Struchkova, M. I.; Dilman, A. D. Org. Lett.
2013, 15, 917–919; (b) Kosobokov, M. D.; Levin, V. V.; Zemtsov, A. A.;
Struchkova, M. I.; Korlyukov, A. A.; Arkhipov, D. E.; Dilman, A. D. Org. Lett. 2014,
16, 1438–1441; (c) Kosobokov, M. D.; Levin, V. V.; Struchkova, M. I.; Dilman, A.
D. Org. Lett. 2014, 16, 3784–3787; (d) Tsymbal, A. V.; Kosobokov, M. D.; Levin,
V. V.; Struchkova, M. I.; Dilman, A. D. J. Org. Chem. 2014, 79, 7831–7835; (e)
Zemtsov, A. A.; Kondratyev, N. S.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. J.
Org. Chem. 2014, 79, 818–822; (f) Kosobokov, M. D.; Levin, V. V.; Struchkova, M.
I.; Dilman, A. D. Org. Lett. 2015, 17, 760–763; (g) Fedorov, O. V.; Kosobokov, M.
D.; Levin, V. V.; Struchkova, M. I.; Dilman, A. D. J. Org. Chem. 2015, 80, 5870–
5876.
12. Wang, F.; Li, L.; Ni, C.; Hu, J. Beilstein J. Org. Chem. 2014, 10, 344–351.
13. Potassium salt 2 derived from pyrrolidine was selected since it can be readily
prepared in anhydrous form, see: Ramos, L. A.; Cavalheiro, E. T. G. Braz. J. Therm.
Anal. 2013, 2, 38–44.
14. Crystallographic data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre (CCDC 1405909) and are available
free of charge at CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ca.uk).
Acknowledgement
This work was supported by the Russian Science Foundation
(project 14-13-00034).
15. This fact suggests the very fast interaction of an intermediate difluorocarbene
with the dithiocarbamate anion, which was reported to be
a strong
nucleophile, see: Duan, X.-H.; Maji, B.; Mayr, H. Org. Biomol. Chem. 2011, 9,
8046–8050.
16. Tanaka, Y.; Ishihara, T.; Konno, T. J. Fluorine Chem. 2012, 137, 99–104.
17. (a) Quiclet-Sire, B.; Zard, S. Z. Chem. Eur. J. 2006, 12, 6002–6016; (b) Quiclet-
Sire, B.; Zard, S. Z. Pure Appl. Chem. 2011, 83, 519–551.
Supplementary data
Supplementary data (experimental procedures, product charac-
terization, NMR spectra) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.
018.