SN2′ reaction of allylic difluorides with lithium amides and thiolates

Article abstract of DOI:10.1021/ol302802r

The synthesis of monofluoroalkenes using an S_N2′ reaction of lithium amides derived from aromatic amines or lithium thiolates with 3,3-difluoropropenes is reported. This transformation features the use of fluoride as a leaving group.

Full text of DOI:10.1021/ol302802r

ORGANIC
LETTERS
SN20 Reaction of Allylic Difluorides with
Lithium Amides and Thiolates
2012
Vol. 14, No. 23
5888–5891
Maxime Bergeron, David Guyader, and Jean-Franc-ois Paquin*
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Canada Research Chair in Organic and Medicinal Chemistry, Departement de chimie,
Universite Laval, 1045 avenue de la Medecine, Quebec, Quebec G1V 0A6, Canada
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ꢀ
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jean-francois.paquin@chm.ulaval.ca
Received October 11, 2012
ABSTRACT
The synthesis of monofluoroalkenes using an SN20 reaction of lithium amides derived from aromatic amines or lithium thiolates with
3,3-difluoropropenes is reported. This transformation features the use of fluoride as a leaving group.
The pursuit of a new means of activating the CꢀF bond
isanactive field of research.1 This strong interestoriginates
from both the fundamental and practical aspects of such
transformations. Indeed, the CꢀF bond is the strongest
single carbonꢀhalogen bond2 and one of the least reactive
carbonꢀhalogen bonds in aliphatic substitution reac-
tions;1,3,4 however, its transformation may provide new
pathways to fluorinated motifs, privileged scaffolds in
pharmaceutical sciences.5
this reaction gave access to monofluoroalkenes, a useful
class of organofluorine compounds.7,8 We have also reported
a palladium-catalyzed allylic amination reaction from 3,3-
difluoropropenes as a new access to β-aminofluoroalkenes.9
This transformation worked well with secondary and pri-
mary aliphatic amines (Scheme 1B).10 However, under these
conditions, the use of aromatic amines led to low conversions
(<20%), and further optimization of the reaction conditions
was not successful.
We have recently described the activation of allylic
fluorides for SN20 displacement using organolithium re-
agents where we postulated that the lithium ion would
serve to enhance the leaving group ability of the fluorine
atom (Scheme 1A).6 Starting from 3,3-difluoropropenes,
In this context, we wondered if lithium amides derived
from aromatic amines would react directly with 3,3-
difluoropropenes. Indeed, while the reaction of lithium
amides with 3,3,3-trifluoropropenes is well documented,11
(8) For other synthetic approaches to monofluoroalkenes developed
in our group, see: (a) Landelle, G.; Champagne, P. A.; Barbeau, X.;
Paquin, J.-F. Org. Lett. 2009, 11, 681. (b) Landelle, G.; Turcotte-Savard,
M.-O.; Marterer, J.; Champagne, P. A.; Paquin, J.-F. Org. Lett. 2009,
11, 5406. (c) Landelle, G.; Turcotte-Savard, M.-O.; Angers, L.; Paquin,
J.-F. Org. Lett. 2011, 13, 1568.
(9) For selected recent examples of bioactive β-aminofluoroalkenes,
see: (a) O’Rourke, A. M.; Wang, E. Y.; Miller, A.; Podar, E. M.;
Scheyhing, K.; Huang, L.; Kessler, C.; Gao, H.; Ton-Nu, H.-T.;
MacDonald, M. T.; Jones, D. S.; Linnil, M. D. J. Pharmacol. Exp.
Ther. 2008, 324, 867. (b) Foot, J. S.; Deodhar, M.; Turner, C. I.; Yin, P.;
van Dam, E. M.; Silva, D. G.; Olivieri, A.; Holt, A.; McDonald, I. A.
Bioorg. Med. Chem. Lett. 2012, 22, 3935.
(1) For a review on CꢀF bond activation, see: Amii, H.; Uneyama,
K. Chem. Rev. 2009, 109, 2119.
(2) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255.
€
(3) Dorwald, F. Z. In Side Reactions in Organic Synthesis: A Guide to
Successful Synthesis Design; Wiley-VCH: Weinheim; 2005, p 66.
(4) For key examples of the use of fluoride as leaving group in SN2
reactions, see: (a) Tani, K.; Suwa, K.; Yamagata, T.; Otsuka, S. Chem.
Lett. 1982, 265. (b) Zhang, L.; Zhang, W.; Liu, J.; Hu, J. J. Org. Chem.
2009, 74, 2850.
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(5) Reviews: (a) Begue, J.-P.; Bonnet-Delphon, D. J. Fluorine Chem.
2006, 127, 992. (b) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013. (c)
€
Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (d)
Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (e) Purser, S.; Moore,
P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(6) Bergeron, N.; Johnson, T.; Paquin, J.-F. Angew. Chem., Int. Ed.
2011, 50, 11112.
(7) For reviews on the synthesis of monofluoroalkenes, see: (a)
Landelle, G.; Bergeron, M.; Turcotte-Savard, M.-O.; Paquin, J.-F.
Chem. Soc. Rev. 2011, 40, 2867. (b) Yanai, H.; Taguchi, T. Eur. J. Org.
Chem. 2011, 5939. (c) Hara, S. Top. Curr. Chem. 2012, 327, 59.
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(10) (a) Pigeon, X.; Bergeron, M.; Barabe, F.; Dube, P.; Frost, H. N.;
Paquin, J.-F. Angew. Chem., Int. Ed. 2010, 49, 1123. (b) Paquin, J.-F.
Synlett 2011, 289.
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(11) See, for example: (a) Begue, J.-P.; Bonnet-Delphon, D.; Rock,
ꢀ ꢀ
M. H. Synlett 1995, 659. (b) Begue, J.-P.; Bonnet-Delphon, D.; Rock,
ꢀ
ꢀ
M. H. Tetrahedron Lett. 1995, 36, 5003. (c) Begue, J.-P.; Bonnet-Delphon,
D.; Rock, M. H. J. Chem. Soc., Perkin Trans. 1 1996, 1409. (d) Mori, T.;
Iwai, Y.; Ichikawa, J. Chem. Lett. 2005, 34, 778.
r
10.1021/ol302802r
Published on Web 11/12/2012
2012 American Chemical Society

Table 1. Selected Optimization Resultsa
Scheme 1. (A) Activation of a CꢀF Bond through a CꢀF Li
3 3 3
Interaction (B) Synthesis of β-Aminofluoroalkenes from
3,3-Difluoropropenes
entry
conditions
THF, 0 °C, 1 h
THF, 21 °C, 16 h
THF, 21 °C, 16 h
hexane, 21 °C, 16 h
Et2O, 21 °C, 16 h
Et2O/toluene (1:1), 21 °C, 4 h
THF/toluene (1:1), 21 °C, 4 h
equiv conv (%)b yield (%)c
1
2
3
4
5
6
7
3
99
81
81
63
23d
ꢀ
2
1.2
2
52
0
2
100
68
77
38
79
2
2
100
a See the Supporting Information for details of the reaction condi-
tions. b Determined by 19F NMR analysis of the crude mixture. c Yield of
isolated 2. d Estimated by 1H and 19F NMR.
ring (entry 4) or a combination of both (entry 5) proceeded
well (63ꢀ98% yield). The lithium amide derived from
indoline could also be used (entry 6). In two cases, low
yields were obtained at room temperature (entry 3 and 6);
however, running the reaction at 60 °C allowed the isola-
tion of the corresponding products in improved yields. The
presence of an extra substituent on the alkene as found on
3,3-difluoropropene 3 considerably reduced the reactivity,
and as such, the desired β-aminofluoroalkene 14 was
obtained in low yield (entry 7). As conversion of 3 was
almost complete (ca. 91%) by 19F NMR, we imagine that
various side-reactions took place, although no specific
side-product could be isolated in pure form. Likewise,
reaction of 1-indanone-derived 3,3-difluoropropene 4 pro-
vided no desired product despite its full conversion (entry 8).
In this case, we presume that the methylene protons in 15,
which are both benzylic and allylic, can be easily abstracted
under the reaction conditions leading again to various side
reactions preventing its formation. 1-Benzosuberone-
derived 3,3-difluoropropene 5 reacted well providing 16
in 57% yield (entry 9). Finally, acyclic 3,3-difluoropro-
penes 6 and 7 could also be used providing trisubstituted
monofluoroalkenes in 60ꢀ79% as a mixture of Z/E iso-
mers (entries 10ꢀ12). Interestingly, products 17ꢀ19 struc-
turally resemble known MAO inhibitors.13
this transformation with 3,3-difluoropropenes has not
been explored. Overall, this transformation would not
only provide a route to β-aminofluoroalkenes that would
complement our palladium-catalyzed version, but would
also represent an additional example of the use of fluoride
as a competent leaving group in substitution reactions.1,4
Herein, we report the viability of this concept and also
show that it can be extended to S-based nucleophiles.
The initial optimization was performed on 3,3-difluoro-
propene 1, which is readily available from R-tetralone,
and the results are reported in Table 1. The first reaction,
which was conducted in THF at 0 °C using 3 equiv of the
lithium amide, led to complete conversion in 1 h with 81%
isolated yield of the β-aminofluoroalkene 2 (entry 1).
Attempts to use fewer equivalents of the lithium amide
only provided lower conversions and isolated yields
(entries 2ꢀ3), even if the reactions were conducted at room
temperature for a longer period of time (16 h). Switching to
hexane as the solvent completely shut down the reaction
(entry 4).12a Using Et2O provided full conversion with a
respectable 77% yield; however, some reproducibility
problems were encountered with these conditions. Finally,
the use of toluene as cosolvent was examined since this
solvent has been shown to potentially influence the struc-
ture and reactivity of organolithium reagents.12 Thus,
while using Et2O/toluene (1:1) gave a moderate conversion
and a low isolated yield (entry 6), using THF/toluene (1:1)
provided, in a reproducible fashion, full conversion and a
good isolated yield (entry 7).
This transformation was also explored using lithium
amides derived from aliphatic amines using 3,3-difluoro-
propene 1 (Scheme 2). The results varied greatly depending
on the amine used. Indeed, morpholine performed well
with an isolated yield of 91%, while N-methylbenzylamine
and pyrrolidine provided the corresponding monofluoro-
alkenes in 62 and 28% yield, respectively. Those results
confirm the complementarity between our two approaches
for the synthesis of β-aminofluoroalkenes. Indeed, for
aromatic amines, SN20 addition of their lithium amides,
The scope of this transformation was next examined using
these optimized conditions on various 3,3-difluoropropenes
and lithium amides derived from aromatic amines (Table 2).
Using 3,3-difluoropropene 1, the use of anilines substituted
either on the nitrogen atom (entries 1ꢀ3), on the aromatic
(12) (a) Armstrong, D. R.; Barr, D.; Clegg, W.; Hodgson, S. M.;
Mulvey, R. E; Reed, D.; Snaith, R.; Wright, D. S. J. Am. Chem. Soc.
1989, 111, 4719. (b) Remenar, J. F.; Collum, D. B. J. Am. Chem. Soc.
1998, 120, 4081.
(13) (a) Bey, P.; Fozard, J.; Lacoste, J. M.; McDonald, I. A.; Zreika,
M.; Palfreymanm, M. G. J. Med. Chem. 1984, 27, 9. (b) McDonald, I. A;
Lacoste, J. M.; Bey, P.; Palfreyman, M. G.; Zreika, M. J. Med. Chem.
1985, 28, 186.
Org. Lett., Vol. 14, No. 23, 2012
5889

as reported herein, is preferred, whereas for aliphatic
amines, the Pd-catalyzed version10a is ideal.14
Table 2. SN20 Reaction of Lithium Amides Derived from
Aromatic Aminesa
Scheme 2. SN20 Reaction of Lithium Amides Derived from
Aliphatic Amines with 3,3-Difluoropropene 1
Another complementary aspect of the present transfor-
mation is the possibility of synthesizing monofluoroalk-
enes bearing a primary amine, especially since the use
of aqueous ammonia15 as nucleophile in the palladium-
catalyzed version failed. While initial experiments with
LiNH2 (2 equiv, THF, 21 °C, 16 h) were not successful,
the use of benzophenone imine, which has been reported as
a synthetic equivalent to ammonia,16 provided encoura-
ging results. Indeed, reaction of 3,3-difluoropropene1 with
a combination of benzophenone imine and n-BuLi under
the standard conditions furnished, after an acidic workup,
the primary amine 23 in 53% for the two steps (Scheme 3).
Scheme 3. Synthesis of Primary Amine 23 from 1
We next explored the possibility of preparing β-mercap-
tomonofluoroalkenes (Scheme 4).17 Thus, performing the
reaction with lithium benzenethiolate or lithium 4-meth-
oxybenzenethiolate provided the desired monofluoro-
alkenes 2418 and 25 in 87 and 63% yield, respectively.
Good yields were also observed for n-butylthiol (70%)
and t-butylthiol (94%). Unfortunately, investigations
using other substratesrevealeda narrower scope compared
to lithium amides derived from aromatic amines.19 Finally,
this transformation could not be extended to O-based
nucleophiles. Indeed, using lithium phenoxide or lithium
methoxide gavelittle or no conversion, and no product was
observed in both cases.
At the moment, we believe that the transformation
reported herein proceeds through a mechanism similar to
a See the Supporting Information for details of the reaction condi-
tions. b Yield after purification by flash chromatography. c Reaction was
performed at 60 °C. d NMR yield for the reaction conducted at 21 °C.
e E and Z configuration could not be assigned unambiguously.
(15) Nagano, T.; Kobayashi, S. J. Am. Chem. Soc. 2008, 131, 4200.
˚
(16) Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald,
S. L. Tetrahedron Lett. 1997, 38, 6367.
(17) McDonald, I. A.; Bey, P. Tetrahedron Lett. 1985, 26, 3807.
(18) Alternatively, the reaction can be performed under less basic
conditions, using LiOH (2 equiv) in DMF at 66 °C for 16 h. In this case,
the desired product 24 is isolated in 92% yield.
(14) For example, with substrate 1, reaction of pyrrolidine under the
Pd conditions (ref 10a) allowed the isolation of product 22 in 64% (as
opposed to 28% with its lithium amide). Likewise, reaction of the same
substrate with N-methylaniline under the Pd conditions gave 8 in <3%
yield instead of 79% using its lithium amide (Table 2, entry 1).
(19) See the Supporting Information for details.
5890
Org. Lett., Vol. 14, No. 23, 2012

The use of lithium thiolates as nucleophiles was also
presented. Overall, this transformation represents one of
the rare cases where fluoride acts as a competent leaving
group in a nucleophilic substitution reaction.
Scheme 4. SN20 Reaction of Lithium Thiolates with
3,3-Difluoropropene 1
Acknowledgment. This work was supported by the
Canada Research Chairs Program, the Natural Sciences
and Engineering Research Council of Canada, the Canada
Foundation for Innovation, the FQRNT Centre in Green
Chemistry and Catalysis (CGCC), Pfizer Global Research
ꢀ
& Development, and the Universite Laval. We thank
Xavier Pigeon (Universite Laval) for performing some
preliminary experiments.
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the reaction of organolithium reagents with 3,3-difluoro-
propenes (Scheme 1A).6 This is evidenced by the fact that
not only do reactions occur under comparable conditions,
but also both transformations share analogous reactivity
profiles in terms of substrate scope and the requirement for
the use of lithium-based nucleophiles.19
In conclusion, we have reported the synthesis of
β-aminofluoroalkenes using a SN20 reaction of lithium am-
ides derived from aromatic amines with 3,3-difluoropropenes.
Supporting Information Available. General experimen-
tal procedures, specific details of representative reactions,
and the isolation and spectroscopic information of the
new compounds prepared. This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
5891