Iron(II)-catalyzed trifluoromethylation of potassium vinyltrifluoroborates

Article abstract of DOI:10.1002/anie.201108267

Exchanging BF₃ by CF₃: The title reaction proceeds under exceedingly mild reaction conditions and provides 2-arylvinyl- and 2-heteroarylvinyl-substituted substrates with E/Z selectivities of more than 95:5. Experimental observations suggest that the reaction does not proceed through a transmetalation of the RBF₃K species to the iron catalyst. Copyright

Full text of DOI:10.1002/anie.201108267

Angewandte
Chemie
DOI: 10.1002/anie.201108267
Trifluoromethylation
Iron(II)-Catalyzed Trifluoromethylation of Potassium
Vinyltrifluoroborates**
Andrew T. Parsons, Todd D. Senecal, and Stephen L. Buchwald*
The incorporation of fluorinated functional groups in phar-
maceutical and agrochemical molecules has had a significant
impact on the discovery and development of biologically
active compounds.[1,2] Because of its metabolic stability,
lipophilicity, and electron-withdrawing character,[3] use of
the trifluoromethyl (CF3) substituent has gained considerable
attention in recent years. Several new methods for the direct
À
formation of C CF3 bonds have been reported recently, thus
highlighting the importance of this transformation.[4,5] Efforts
of our research group have focused on the development of
new fluorination[6] and trifluoromethylation[7] reactions
through the use of transition-metal catalysis and promotion.
À
Herein, we report a facile method to access vinyl CF3
functional groups through an iron(II)-catalyzed trifluorome-
thylation of potassium vinyltrifluoroborates (1) using Togniꢀs
reagent 2[8] [Eq. (1)].
Scheme 1. A) Observed chlorotrifluoromethylation of terminal olefins
when CuCl and 2 are used, and B) the proposed vinyl trifluoromethy-
lation of vinylboron reagents.
through the use of a functionalized vinyl substrate such as
a vinylboron reagent (Scheme 1B). Thus, trifluoromethyla-
tion of 7 would lead to formation of intermediate 6d. Loss of
the boron-based functional group would result in the gen-
À
Recently, we reported an oxidative trifluoromethylation
eration of the desired vinyl CF3 containing product.
À
of terminal olefins, which provides rapid access to allyl CF3
We commenced our studies by examining the trifluoro-
containing products of type 4.[9,10] During the course of our
studies, we observed the formation of 5, which is a side
product that results from the transfer of the chloride counter-
methylation of styryl BXn reagents with 2 by using various
À
metal catalysts. During our preliminary studies, we discovered
that both copper(I)[11] and iron(II) chloride provided a sat-
isfactory yield of product 3a (Table 1, entries 1–4). Because of
the low cost and cleaner reaction profile, we continued our
studies by examining various vinylboron reagents using
catalytic FeCl2 (Table 1, entries 2–4). Interestingly, the E/Z
product ratio varied significantly, depending on the identity of
À
ion from CuCl to the olefin substrate subsequent to C CF3
bond formation (Scheme 1A). We hypothesized several
possible intermediates (summarized as 6) that lead to the
formation of both 4 and 5. After consideration of these
possibilities, we surmised that regioisomeric products (i.e.
À
À
vinyl CF3 containing molecules) might be accessed through
a similar type of reactive intermediate. Toward this end, we
sought to evaluate the presumed product-forming step
the styryl BXn reagent employed. These variations suggest
that our proposed intermediate 6d is formed en route to the
À
vinyl CF3 products, since isomerization would be difficult to
explain if the olefin remained intact throughout the course of
the reaction. The ratios of E/Z isomers may be dependent on
the rate of elimination of the boron-based leaving group; the
Bpin and B(OH)2 moieties appear to eliminate rapidly to
provide a nearly equimolar ratio of isomers. The BF3-based
leaving group might be slow to eliminate, resulting in the high
E/Z product ratio observed.
[*] Dr. A. T. Parsons, T. D. Senecal, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[**] We thank the National Institutes of Health (GM46059) for financial
support of this project and for a postdoctoral fellowship to A.T.P.
(F32M093532). The Varian 300 MHz and Bruker 400 MHz NMR
spectrometers used in this work were supported by grants from the
National Science Foundation (CHE-9808061 and DBI-9729592) and
National Institutes of Health (1S10RR13886-01), respectively.
Since the potassium trifluoroborate salt provided an
excellent E/Z ratio of > 95:5, optimization was continued by
À
using styryl BF3K as a model substrate. Additional increases
in yield were achieved through a lowering of catalyst loading
and the use of acetonitrile as the solvent. Furthermore,
employing 2 as the limiting reagent prevented the formation
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108267.
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Table 1: Optimization studies for the trifluoromethylation of styryl-based
vinylboron reagents.[a,b]
Entry Cat. (mol%) BXn
2 [equiv] Solvent E/Z
Yield [%]
1
2
3
4
5
6
7
CuCl (25)
FeCl2 (25)
FeCl2 (25)
FeCl2 (25)
FeCl2 (10)
FeCl2 (10)
FeCl2 (10)
FeCl2 (10)
FeCl3 (10)
none
BF3K
BF3K
B(OH)2 1.2
Bpin
BF3K
BF3K
BF3K
BF3K
BF3K
BF3K
1.2
1.2
MeOH
MeOH
MeOH
MeOH
96:4
94:6
50:50 74
55:45 73
75
80
1.2
1.2
1.2
0.9
0.9
0.9
0.9
MeOH >95:5
77
88
86
89
9
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
98:2
99:1
99:1
8[c]
9
10
n.d.[d]
–
0
[a] Reaction conditions: 1 (0.20 mmol), 2 (0.24 or 0.18 mmol), and
catalyst in 0.50 mL solvent at room temperature for 24 hours. [b] Yield
and E/Z ratio were determined by 19F NMR spectroscopy. [c] Ultrapure
FeCl2 (99.998% based on trace metals, Sigma–Aldrich) was used.
[d] n.d.=not determined. pin=pinacolato.
of side products. Use of ultrapure FeCl2 (99.998% based on
trace metals) resulted in an equally efficient trifluoromethy-
lation of 1, thus suggesting that the catalyst system is iron-
based (Table 1, entry 8). No detectable amounts of b-
trifluoromethylstyrene product 3a were formed in the
absence of a metal catalyst (Table 1, entry 10).
With an optimized protocol in hand, we examined the
range of potassium vinyltrifluoroborates that are capable of
undergoing iron(II)-catalyzed trifluoromethylation with 2
Scheme 2. Scope of the iron(II)-catalyzed trifluoromethylation of potas-
sium vinyltrifluoroborates using 2. Reaction conditions: 1 (1.1–
0.55 mmol, 1.1 equiv), 2 (1.0–0.50 mmol, 1.0 equiv), FeCl2 (10 mol%),
[2]t=0 =0.40m. The reaction time was not optimized, and the yields of
isolated products are given as average of two independent trials.
Yields in parentheses were determined by 19F NMR spectroscopy. E/Z
ratios were determined by 19F and 1H NMR spectroscopy. [a] Contains
10–15 mol% of a protodeboronated side product. [b] 15 mol% FeCl2
was used.
À
À
(Scheme 2). 2-Arylvinyl BF3K and 2-heteroarylvinyl BF3K
salts were excellent substrates for this method and provided
the products in good yields and high E/Z product ratios.
Since potassium (E)-2-arylvinyltrifluoroborates, such as
1b, provide high selectivity for the E isomer, we were
interested in determining whether this was a stereospecific
trifluoromethylation. Thus, we prepared potassium 4-methyl-
phenylvinyltrifluoroborate 1b in > 95:5 Z-isomeric purity.
Subjecting (Z)-1b to the standard reaction conditions fur-
nished b-trifluoromethylstyrene derivative 3b exclusively as
the E isomer [Eq. (2)]. We conducted an analogous experi-
ment by using (Z)-1j and obtained identical results when
À
Linear aliphatic substrates furnished vinyl CF3 products in
high yields, but with poor E/Z selectivity. Isomeric ratios were
improved when branched aliphatic substrates were used, but
remained modest at 83:17 E/Z for a cyclohexyl-substituted
substrate (product 3k). The mild reaction conditions allow for
the trifluoromethylation of substrates that are not suitable for
many copper- or palladium-based systems. Notably, all
reactions could be set up on the bench top (run under an
inert atmosphere) and carried out at room temperature.
During the course of this study, we found that this reaction
has some limitations. For example, electron-deficient sub-
strates give trifluoromethylated products in poor yields.
À
Trisubstituted vinyl BF3K salts were also poor substrates
and furnished only trace amounts of trifluoromethylated
product.[12] We are currently working to address these issues
in order to expand the generality of this transformation.
We originally felt that the vinyl trifluoromethylation of
1 might proceed through the cleavage of the p bond of the
olefin in a homo- or heterolytic manner. After our synthetic
studies, however, the mechanistic details of this transforma-
tion were unclear. We could not rule out the possibility that
a mechanism including transmetalation and reductive elim-
ination is occurring. We sought to gain insight into the details
of this transformation through the examination of selected
substrates as mechanistic probes.
compared to (E)-1j [Eq. (3)]. The stereoconvergence of the E
and Z substrate isomers causes us to disfavor a mechanism
that proceeds through a transmetalation/reductive elimina-
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potassium vinyltrifluoroborate (1.1 equiv), Togni reagent
2
tion sequence. We believe these experiments suggest a mech-
anism involving generation of a radical or carbocationic
intermediate, similar to 6a or 6b (Scheme 1).
The results shown in Equations (2) and (3) led us to
investigate whether product formation may be achieved by
using Lewis acid catalysis (through the direct formation of
a cationic intermediate, see Scheme 1). Thus, we conducted
the trifluoromethylation of (E)-1b in the presence of various
Lewis acids. We found that a range of other catalysts provided
(1.0 equiv), and iron(II) chloride (0.10 equiv). The tube was sealed
with a PTFE-lined screw cap, evacuated, and backfilled with argon
(repeated three times). The vial was then charged with acetonitrile
(2.5 mLmmolÀ1 2) and the reaction mixture was stirred at room
temperature for 24 hours. The contents of the vial were then
transferred to
a separatory funnel that contained saturated
NaHCO3 ( ꢀ 10 mL) by using CH2Cl2. The aqueous layer was
extracted with CH2Cl2 (3 ꢁ 15 mL). The combined organic extracts
were washed with brine (20 mL), dried over Na2SO4, and adsorbed
onto silica gel. The products were purified by flash chromatography
using the solvent system indicated in the Supporting Information.
À
an appreciable amount of vinyl CF3 product. Sn(OTf)2 was
the most efficient Lewis acid of those examined and afforded
(E)-3b in 80% yield and high E/Z ratio. To further examine
the transformation catalyzed by Sn(OTf)2, we also conducted
trifluoromethylations of (Z)-1b and (E/Z)-1j (Scheme 3).
Received: November 23, 2011
Published online: February 10, 2012
Keywords: fluorine · homogeneous catalysis · iron ·
.
trifluoromethylation
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Scheme 3. Evidence that Lewis acid activation resulting in direct
formation of a cationic intermediate is a viable pathway that leads to
À
vinyl CF3 product formation.
Trifluoromethylation of these substrates provided identical
E/Z ratios and yields regardless of the geometry of the
potassium vinyltrifluoroborate starting material. These
results further suggest that the trifluoromethylation is not
proceeding through a transmetalation/reductive elimination
pathway. It should be noted that while the yields of 3b and 3j
(determined by 19F NMR spectroscopy) are satisfactory when
Sn(OTf)2 is used, the formation of numerous trifluoromethy-
lated side products causes us to prefer FeCl2 as the catalyst for
this transformation.
In summary, we have developed an iron(II)-catalyzed
trifluoromethylation of potassium vinyltrifluoroborates. 2-
Arylvinyl substrates in particular provide products in good
yields and excellent E/Z ratios. The reactions are amenable to
a bench top set up and proceed under exceedingly mild
reaction conditions. Preliminary mechanistic analyses suggest
the reaction proceeds through a carbocationic intermediate
by Lewis acid catalysis, but we are currently unable to rule out
a radical-type mechanism. Future efforts of our research
group will aim to further elucidate the mechanistic details and
expand the scope of this transformation.
Experimental Section
General Procedure for the FeCl2-catalyzed trifluoromethylation of
À
vinyl BF3K reagents. An oven-dried reaction tube was charged with
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16410.
[12] For example potassium (E)-(4-(trifluoromethyl)styryl)trifluoro-
borate and potassium (1-(tert-butoxycarbonyl)-1,2,3,6-tetra-
hydropyridin-4-yl)trifluoroborate provided < 5% yield of the
À
desired vinyl CF3 product when subjected to the reaction
conditions described in Scheme 2.
[11] For examples of CuI-catalyzed trifluoromethylation of aryl and
vinylboronic acids, see: a) T. Liu, Q. Shen, Org. Lett. 2011, 13,
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