Trifluoromethylation of Secondary Nitroalkanes

Article abstract of DOI:10.1021/acs.orglett.7b01196

Using a commercially available Umemoto's reagent, the metal-free trifluoromethylation of nitroalkanes is now possible. This method provides a general, high-yielding synthesis of α-(trifluoromethyl)nitroalkanes. The quaternary α-(trifluoromethyl)nitroalkanes obtained from this transformation can be elaborated to a variety of complex nitrogen-containing molecules, including α-(trifluoromethyl)amines.

Full text of DOI:10.1021/acs.orglett.7b01196

Letter
pubs.acs.org/OrgLett
Trifluoromethylation of Secondary Nitroalkanes
Amber A. S. Gietter-Burch,‡ Vijayarajan Devannah,‡ and Donald A. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716 United States
S
* Supporting Information
ABSTRACT: Using a commercially available Umemoto’s
reagent, the metal-free trifluoromethylation of nitroalkanes is
now possible. This method provides a general, high-yielding
synthesis of α-(trifluoromethyl)nitroalkanes. The quaternary α-
(trifluoromethyl)nitroalkanes obtained from this transformation
can be elaborated to a variety of complex nitrogen-containing
molecules, including α-(trifluoromethyl)amines.
rganofluorine compounds play a vital role in the chemical
enterprise, including in pharmaceuticals, agrochemicals,
conditions for trifluoromethylation of secondary nitroalkanes.
These conditions provide high-yielding access to fully
substituted α-(trifluoromethyl)nitroalkanes, which can be
readily converted into the corresponding α-(trifluoromethyl)-
amines.
In analogy to our prior studies, our initial efforts focused on
the use of copper catalysts in combination with a variety of
reagents known to generate trifluoromethyl radicals.10 Using
nitroalkane 1 as a model substrate, we were initially pleased to
find that the combination of catalytic CuBr and a diketiminate
ligand with Umemoto’s reagent (2) and base led to detectable
levels of the desired product 3 (Table 1, entry 1).11 Control
O
liquid crystals, dyes, and polymers.1 Trifluoromethyl groups, in
particular, have been shown to impart unique physiological
properties, including modulation of binding affinity, metabolic
stability, lipophilicity, and bioavailability when introduced into
small molecules.2 For example, the introduction of a
trifluoromethyl group α to nitrogen has been shown to
modulate the biological properties of numerous small
molecules compared to their nonfluorinated analogues.3
A potentially efficient entry into such α-(trifluoromethyl)-
amino compounds would involve the trifluoromethylation of a
nitroalkane.4 In 2007, Togni reported that α-nitroesters can be
trifluoromethylated in reasonable yields under copper catalysis
(Figure 1, top).5 Unfortunately, this method is not applicable to
Table 1. Optimization of Reaction Conditions
a
entry
base
additive
temp (°C)
yield 3 (%)
b
1
2
3
4
5
NaOSiMe3
NaOSiMe3
DBU
20 mol % Cu/L
none
40
40
22
24
52
58
90
none
40
DBU
none
rt
DBU
none
−25
a
1.3 equiv of 2; yields determined by 1H NMR using 1,3,5-
trimethoxybenzene as an internal standard. 20 mol % of CuBr, 20
mol % of bis-N,N′-(2,6-dimethylphenyl)-2,4-diiminopentane added to
reaction.
b
Figure 1. Trifluoromethylation of nitroalkanes.
nitroalkanes lacking the adjacent activating ester group. A
general protocol for the trifluoromethylation of nitroalkanes has
not yet been described.6
experiments, however, quickly revealed that the reaction did
not require the catalytic additives (entry 2). Switching the base
from sodium trimethylsilanolate to DBU increased the yield to
52% (entry 3). The reaction proved most efficient when
conducted in methylene chloride.10 Finally, lowering the
temperature from +40 to −25 °C afforded optimal amounts
of the desired product 3 (entries 3−5).
Recent studies from our group have demonstrated a variety
of reactions for the alkylation of nitroalkanes using copper
catalysis and radical-stabilizing alkyl halide electrophiles.7 Given
the variety of recent examples of transformations involving
trifluoromethyl radicals8 and the broad utility of nitroalkanes,9
we were inspired to investigate the trifluoromethylation of
nitroalkanes as a potential entry into α-(trifluoromethyl)amino
compounds. Herein we report simple, transition-metal-free
Received: April 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01196
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With optimized conditions in hand, the scope of the
transformation was investigated (Scheme 1). The reaction is
ester products could also be prepared (17−19), albeit with
slightly lower levels of diastereoselection. These results mirror
the selectivities previously observed in Michael additions of β-
nitrocarbonyls.14 Henry reaction products (20),9a as well as
those from conjugate addition of nitroalkenes (21),15 could
both be trifluoromethylated with good to excellent levels of
diastereoselectivity. In the latter case, stereoselectivity is
consistent with addition of the CF3 group away from the
large aromatic ring.
Scheme 1. Scope of the Trifluoromethylation of Secondary
Nitroalkanes
The functional group tolerance of the reaction is very high.
In addition to those already mentioned, tolerated functional
groups include aryl halides (3 and 15), heterocycles (4, 7, 8,
and 20), alkenes (10), aryl ethers (5), nitriles (9), ketones (6),
protected and free alcohols (7, 17, 18, and 20), sulfones (11),
and protic nitrogen functional groups (14 and 15).
The method does show some limitations with respect to
nitroalkanes bearing acidic and sterically accessible β-protons.
In such cases, elimination of an equivalent of nitrous acid from
the trifluoromethylated product can be observed. For example,
under standard conditions using DBU as base, reaction of 22
did not lead to the trifluoromethyl nitroalkane 23 (Scheme 2,
Scheme 2. Competitive Alkene Formation and Role of Base
top). Instead, the trifluormethyl alkene 24 was observed in
moderate yield. In some cases, the use of the bulkier base,
tetramethylguanidine (TMG), enabled access to the desired
product without significant elimination, albeit with less than
ideal conversion and yield. In other cases, such as with ester 25,
elimination could not be avoided regardless of the base used
(Scheme 2, bottom).
Interestingly, the (trifluoromethyl)alkenes described in
Scheme 2 all formed with significant selectivity for the E-
isomer (as determined by 1H−19F HOSEY NMR).10 We
attribute this selectivity to the larger steric size of the CF3 group
compared to an n-alkyl group.2f Recognizing the possible utility
of this process for preparing (trifluoromethyl)alkenes,16 we
investigated if this base-promoted process can be triggered in
less acidic products. Using substrate 3 as a model system, we
found that exposure to KOtBu at 40 °C led to a nearly
quantitative yield of the corresponding vinyl (trifluoromethyl)-
alkene 28 with modest E/Z selectivity (eq 1). This method
potentially provides a mild, high-yielding, two-step synthesis of
vinyl (trifluoromethyl)alkenes from a variety of complex
nitroalkanes.
a
Isolated yields unless otherwise noted. Diastereomeric ratios (dr)
b
1
determined by H NMR analysis of crude reaction. 1.5 equiv of 2
c
d
used. 18 h. Yield determined by 1H NMR using 1,3,5-
e
f
trimethoxybenzene as an internal standard. 48 h. 24 h.
general for a broad range of secondary nitroalkanes. The model
substrate was isolated in 83% yield (3).7a Other homobenzylic
nitroalkanes (4) led to similar results. Both benzylic substrates
(5−8)12 and Michael reaction adducts (e.g., 9−12) were also
well tolerated. Sterically demanding substrates could also be
used. For example, even neopentylic substrates led to
appreciable yields of products (14) containing vicinal fully
substituted centers. In contrast to secondary substrates, primary
nitroalkanes provide very little reactivity. For example, only
traces of 13 were observed. Further studies will be directed at
expanding the scope of the reaction to primary nitroalkanes.
Significantly, nitroalkanes bearing a tertiary stereocenter β to
the nitro group proved to be excellent substrates.7b In these
cases, good to excellent levels of diastereoselection were
observed. For example, amide 15 was formed with greater than
>95:5 selectivity favoring the diastereomer shown.13 Similar
selectivity was observed for the Weinreb amides (16). Related
(Trifluoromethyl)nitroalkanes are readily reduced to α-
(trifluoromethyl)amines. As shown in Scheme 3 (top and
middle), both Zn/AcOH reduction and hydrogenolysis can be
effective. However, we note that with α-aryl nitroalkanes, which
are prone to denitration,17 hydrogenolysis is the preferred
method for reduction (Scheme 3, bottom).
B
DOI: 10.1021/acs.orglett.7b01196
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Preparation of α-(Trifluoromethyl)amines
Figure 2. Proposed mechanism for nitroalkane trifluoromethylation.
electron transfer. Rapid recombination of the two radicals
results in the formation of the observed product 3.20,21
In conclusion, we have developed mild reaction conditions
for the trifluoromethylation of secondary nitroalkanes using a
commercially available trifluoromethylating reagent. This
procedurally simple protocol allows rapid access to highly
complex quaternary α-(trifluoromethyl)nitroalkanes in good
yields and diastereoselectivity. The wide functional group
tolerance highlights the power of this transformation as a
method for late-stage installation of a trifluoromethyl group. In
addition, we have demonstrated that these products can be
reduced to medicinally interesting α-(trifluoromethyl)amines.
Finally, we have also shown that, in at least some cases, base-
induced elimination of HNO2 allows the products to be
converted to highly substituted trifluoromethylalkenes with
good levels of stereocontrol. Further studies will be aimed at
expanding the scope of these transformations.
Consistent with our earlier results,7 preliminary mechanistic
studies suggest that the trifluoromethylation reaction proceeds
via a radical mechanism. When the radical inhibitor TEMPO is
introduced into the reaction, no desired trifluoromethylated
1
product was observed (eq 2). Further, in situ H NMR studies
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01196.
■
in CD2Cl2 have revealed many of the details of the reaction
mechanism. First, combining DBU and nitroalkane 1 at low
temperature reveals that a significant equilibrium concentration
of nitronate anion 32 is produced and that the deprotonation is
relatively slow (it takes about 10 min for a 2:1 mixture of DBU
and 1 to reach equilibrium at −25 °C). Second, when DBU and
2 are combined at −25 °C, 2 is instantly consumed and a new
complex bearing related aromatic signals is produced. Prior
studies have shown that 2 forms electron-donor−acceptor
(EDA) complexes with basic amines,18 and we have tentatively
assigned this as the EDA complex 2·DBU. Third, monitoring
the trifluoromethylation reaction by 1H NMR of 1 under
slightly modified conditions (−25 °C, half optimal concen-
tration) reveals an initially fast rate of production of 3 that
slows considerably as the reaction progresses. Under these
conditions, two reactive intermediates are observed. The first,
which is maximally present at the first observation point (ca. 2
min) and then decays as the reaction proceeds, has signals that
match 2·DBU. The second builds in early in the reaction and
S
X-ray data for compound 21 (CIF)
X-ray data for compound s12 (CIF)
X-ray data for compound 15 (CIF)
Experimental procedures; crystallographic and spectral
data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dawatson@udel.edu.
ORCID
Donald A. Watson: 0000-0003-4864-297X
Author Contributions
‡A.A.S.G.-B. and V.D. contributed equally to this work.
Notes
1
then decays as the reaction progresses. This complex bears H
NMR signals that are related both to 1 and 2. We tentatively
assign this as the associated ion pair 33.19
The authors declare no competing financial interest.
Based upon these observations, we propose the following
reaction mechanism (Figure 2). Early in the reaction, DBU and
2 form the EDA complex 2·DBU. As the nitronate anion 32 is
formed, 2·DBU is consumed and the ion pair 33 is formed. The
salt complex 33 then undergoes slow decomposition to a
nitronate radical 34, CF3-radical, and dibenzothiophene via
ACKNOWLEDGMENTS
■
The University of Delaware (UD), the University of Delaware
Research Foundation, the Research Corp. Cottrell Scholars
Program, and the NIH NIGMS (R01 GM102358) are
gratefully acknowledged for support. Dr. Peter Gildner (UD)
C
DOI: 10.1021/acs.orglett.7b01196
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Commun. 2016, 52, 152−155. (k) Vara, B. A.; Johnston, J. N. J. Am.
Chem. Soc. 2016, 138, 13794−13797.
is acknowledged for initial experiments in this area, as are Dr.
Glenn Yap (UD) and Dr. Shi Bai (UD) for assistance with X-
ray crystallography and NMR analysis. Data was acquired at
UD on instruments obtained with the assistance of NSF and
NIH funding (NSF CHE0421224, CHE0840401,
CHE1229234, and CHE1048367; NIH S10 OD016267-01,
S10 RR026962-01, P20GM104316, P30GM110758).
(10) See the Supporting Information.
(11) (a) Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993, 115,
2156−2164. (b) Zhang, C. Org. Biomol. Chem. 2014, 12, 6580−6589.
(12) (a) Vogl, E. M.; Buchwald, S. L. J. Org. Chem. 2002, 67, 106−
111. (b) Walvoord, R. R.; Kozlowski, M. C. J. Org. Chem. 2013, 78,
8859−8864.
(13) The relative configuration of 15 was established by single-crystal
X-ray analysis.
(14) Gietter-Burch, A. A. S.; Mitrut, R. E.; Watson, D. A. Org. Lett.
REFERENCES
■
(1) Kirsch, D. P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity,
Applications. Wiley-VCH: Weinheim, 2013.
2015, 17, 5468−5471.
(15) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000,
122, 10716−10717.
(2) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320−330. (b) Kirk, K. L. Org. Process Res. Dev.
2008, 12, 305−321. (c) Hagmann, W. K. J. Med. Chem. 2008, 51,
(16) For recent examples of their preparation, see: (a) Kathiravan, S.;
Nicholls, I. A. Org. Lett. 2015, 17, 1874−1877. (b) Ramachandran, P.
V.; Mitsuhashi, W. Org. Lett. 2015, 17, 1252−1255.
(17) Fessard, T. C.; Motoyoshi, H.; Carreira, E. M. Angew. Chem., Int.
Ed. 2007, 46, 2078−2081.
(18) (a) Cheng, Y.; Yuan, X.; Ma, J.; Yu, S. Chem. - Eur. J. 2015, 21,
8355−8359. (b) Cheng, Y.; Yu, S. Org. Lett. 2016, 18, 2962−2965.
(19) A similar reaction profile is observed at −25 °C under optimized
reaction conditions; however, the reaction is too fast to be adequately
observed by NMR over the first half-life and is complicated by initial
heterogeneity during the first minutes of the reactions. See the
Supporting Information.
(20) Radical substitution mechansims are well precedented for nitro
compounds. For an early example, see: Kornblum, N.; Swiger, R. T.;
Earl, G. W.; Pinnick, H. W.; Stuchal, F. W. J. Am. Chem. Soc. 1970, 92,
5513−5514.
(21) We cannot exclude the possibilty of an alternative radical-chain
mechanism.
4359−4369. (d) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317,
̈
1881−1886. (e) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432−
5446. (f) Smart, B. E. J. Fluorine Chem. 2001, 109, 3−11.
(3) (a) Lim, J.; Taoka, B.; Otte, R. D.; Spencer, K.; Dinsmore, C. J.;
Altman, M. D.; Chan, G.; Rosenstein, C.; Sharma, S.; Su, H.-P.;
Szewczak, A. A.; Xu, L.; Yin, H.; Zugay-Murphy, J.; Marshall, C. G.;
Young, J. R. J. Med. Chem. 2011, 54, 7334−7349. (b) Gauthier, J. Y.;
Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L. T.; Falgueyret, J.-
P.; Kimmel, D. B.; Lamontagne, S.; Leg
Masse, F.; McKay, D. J.; Nicoll-Griffith, D. A.; Oballa, R. M.; Palmer, J.
T.; Percival, M. D.; Riendeau, D.; Robichaud, J.; Rodan, G. A.; Rodan,
S. B.; Seto, C.; Therien, M.; Truong, V.-L.; Venuti, M. C.; Wesolowski,
́
er, S.; LeRiche, T.; Li, C. S.;
́
́
G.; Young, R. N.; Zamboni, R.; Black, W. C. Bioorg. Med. Chem. Lett.
2008, 18, 923−928. (c) Black, W. C.; Bayly, C. I.; Davis, D. E.;
́ ́
Desmarais, S.; Falgueyret, J.-P.; Leger, S.; Li, C. S.; Masse, F.; McKay,
D. J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou, N.; Zamboni,
R. Bioorg. Med. Chem. Lett. 2005, 15, 4741−4744. (d) Dal Pozzo, A.;
Ni, M.; Muzi, L.; de Castiglione, R.; Mondelli, R.; Mazzini, S.; Penco,
S.; Pisano, C.; Castorina, M.; Giannini, G. J. Med. Chem. 2006, 49,
1808−1817. (e) Ojima, I.; Slater, J. C.; Pera, P.; Veith, J. M.;
Abouabdellah, A.; Beg
1997, 7, 133−138.
́ ́
ue, J.-P.; Bernacki, R. J. Bioorg. Med. Chem. Lett.
(4) Electrophiliic fluoronitration of difluoroalkenes has previously
been shown to allow limited access to these compounds; see:
Knunyants, I. L.; German, L. S.; Rozhkov, I. N. Bull. Acad. Sci. USSR,
Div. Chem. Sci. 1963, 12, 1794−1797.
(5) (a) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem., Int. Ed.
2007, 46, 754−757. (b) Charpentier, J.; Fruh, N.; Togni, A. Chem. Rev.
̈
2015, 115, 650−682.
(6) Also see: (a) Umemoto, T.; Kuriu, Y. Tetrahedron Lett. 1981, 22,
5197−5200. (b) Feiring, A. E. J. Org. Chem. 1983, 48, 347−354.
(7) (a) Gildner, P. G.; Gietter, A. A. S.; Cui, D.; Watson, D. A. J. Am.
Chem. Soc. 2012, 134, 9942−9945. (b) Gietter, A. A. S.; Gildner, P. G.;
Cinderella, A. P.; Watson, D. A. Org. Lett. 2014, 16, 3166−3169.
(c) Shimkin, K. W.; Gildner, P. G.; Watson, D. A. Org. Lett. 2016, 18,
988−991.
(8) (a) Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950−8958.
(b) Barata-Vallejo, S.; Lantano, B.; Postigo, A. Chem. - Eur. J. 2014, 20,
̃
16806−16829. (c) Alonso, C.; Martínez de Marigorta, E.; Rubiales, G.;
Palacios, F. Chem. Rev. 2015, 115, 1847−1935. (d) Wang, S.-M.; Han,
J.-B.; Zhang, C.-P.; Qin, H.-L.; Xiao, J.-C. Tetrahedron 2015, 71,
7949−7976.
(9) (a) Ono, N. The Nitro Group In Organic Synthesis; John Wiley
and Sons: New York, 2001. (b) Ooi, T.; Takada, S.; Doda, K.;
Maruoka, K. Angew. Chem., Int. Ed. 2006, 45, 7606−7608. (c) Dobish,
M. C.; Johnston, J. N. Org. Lett. 2010, 12, 5744−5747. (d) Grenning,
A. J.; Tunge, J. A. Org. Lett. 2010, 12, 740−742. (e) Noole, A.; Lippur,
K.; Metsala, A.; Lopp, M.; Kanger, T. J. Org. Chem. 2010, 75, 1313−
1316. (f) Noble, A.; Anderson, J. C. Chem. Rev. 2013, 113, 2887.
(g) Qian, H.; Yu, X.; Zhang, J.; Sun, J. J. Am. Chem. Soc. 2013, 135,
18020−18023. (h) Li, J.; Lear, M. J.; Kawamoto, Y.; Umemiya, S.;
Wong, A. R.; Kwon, E.; Sato, I.; Hayashi, Y. Angew. Chem., Int. Ed.
2015, 54, 12986−12990. (i) Manna, M. S.; Mukherjee, S. J. Am. Chem.
Soc. 2015, 137, 130−133. (j) Schwieter, K. E.; Johnston, J. N. Chem.
D
DOI: 10.1021/acs.orglett.7b01196
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