Oxidation of alkyl trifluoroborates: An opportunity for tin-free radical chemistry

Article abstract of DOI:10.1002/anie.201004513

Organotrifluoroborates have been oxidized by copper(II) salts and DessMartin periodinane via radical intermediates, as evidenced by TEMPO spin-trapping experiments. This new method of radical generation is compatible with functionalization and C-C bond fo

Full text of DOI:10.1002/anie.201004513

Angewandte
Chemie
DOI: 10.1002/anie.201004513
Radical Reactions
Oxidation of Alkyl Trifluoroborates: An Opportunity for Tin-Free
Radical Chemistry**
Geoffroy Sorin, Rocio Martinez Mallorquin, Yohan Contie, Alexandre Baralle, Max Malacria,
Jean-Philippe Goddard, and Louis Fensterbank*
Table 1: Oxidation of benzyl substrate 1a.
As a result of its unique attributes, radical chemistry offers
intriguing synthetic opportunities which are now fully recog-
nized and belong to mainstream chemistry.[1] Nowadays the
challenge is to develop more scalable and ecocompatible
reactions and to notably circumvent the use of tin reagents,
which has remained so far the traditional option.[2,3] In that
context, redox processes[4] have held great promise as recently
illustrated by several research groups through asymmetric
transformations and their applications to the synthesis of
natural products.[5]
While oxidation of classical organometallic compounds
such as Grignard or lithium reagents is well-known, this
approach suffers from the drawbacks associated with organ-
ometallic chemistry—stringent reaction conditions and poor
tolerance of a variety of function groups.[6] Inspired by the
seminal work of Kumada and co-workers on organopenta-
fluorosilicate compounds,[7] we reasoned that the oxidation of
softer organometallic derivatives was possible and we focused
our attention on the now well-developed organotrifluorobo-
rate compounds as precursors to radical species.[8] Moreover,
their oxidation chemistry has remained largely unex-
plored.[9,10]
Entry
Oxidant
Reaction conditions[a]
2a,
yield [%]
(1.2 equiv)
1
2
3
4
5
6
7
8
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(EH)2
FeCp2BF4
CuCl2
tBuOH, 808C, 20 h
DMSO, 1208C, 6 h
H2O/DMSO (9:1), 1008C, 14 h
DMSO, 1208C, 4.5 h
DMSO, 1208C, 3.5 h
DMSO, 1208C, 5 h
DMSO, 1208C, 3.5 h
Et2O,[b] RT, 14 h
34
88
72
85
73
28
66
72
49
CuCl2
CAN
DMSO, 508C, 24 h
[a] Entries 1–3: 0.5 equivalents of TEMPO; entries 4–6: 1.2 equivalents
of TEMPO; entries 7–9: 3 equivalents of TEMPO. [b] Concentration of
0.2m. CAN=ceric ammonium nitrate, Cp=cyclopentadienyl, Cu(EH)2 =
copper 2-ethylhexanoate, DMSO=dimethyl sulfoxide, TEMPO=2,2,6,6-
tetramethyl-1-piperidinyloxy, free radical.
To initially probe our design, we examined the behavior of
benzyl trifluoroborate 1a, bearing in mind that the benzyl
radical should be an easy one to generate and that trapping
with TEMPO[11] would give strong evidence for the radical
intermediate formation (adduct 2a; Table 1). A preliminary
screening of the reaction conditions provided valuable
information. We initially ran reactions with Cu(OAc)2 as the
oxidant and a default of 0.5 equivalents of TEMPO to easily
monitor the reactions by TLC. While the reaction did not
proceed in hydrocarbon solvents and was rather sluggish in
alcohols (34% of 2a in tBuOH; Table 1, entry 1), the use of
DMSO provided better results (Table 1, entry 2). Remark-
ably, a good yield of 2a was also observed in a H2O/DMSO
(9:1) mixture (Table 1, entry 3). In DMSO, copper salts
proved to be superior to ferrocenium salts or CAN. Interest-
ingly, CuCl2 was successful in Et2O at room temperature
(Table 1, entry 8).[12]
Having defined an appropriate set of reaction conditions,
we then studied the reactivity of other substrates (Table 2). As
expected, allyl substrate 1b provided good yields of TEMPO
adduct 2b in conditions similar to the oxidation of 1a
(Table 2, entries 1 and 2). We then looked at the alkyl
series. Hexenyl substrate 1c was oxidized under the same type
of conditions and gave, as the major product, linear adduct
2cL accompanied by about 10% of cyclized product 2cC.
Substrate 1c was also oxidized by Dess–Martin periodinane[13]
in Et2O at room temperature and delivered only 2cL. These
findings are consistent with a very rapid TEMPO trapping of
the hexenyl radical intermediate, which has little time to
cyclize,[14] especially at room temperature because of a lower
cyclization rate constant.[15] Secondary and tertiary substrates
proved to be easy to oxidize under mild conditions using
CuCl2 at room temperature or DMP (Table 2, entries 5–10).
Gratifyingly, other functionalized organotrifluoroborate com-
pounds[16] 1h–j were amenable to this oxidation process, as
illustrated in Scheme 1 by the formation of TEMPO adducts
such as 2h bearing a benzyl ether group, the fragile ketone
2i,[17] and the very intriguing allylsilane 2j. Thus, this process
is compatible with function groups that are susceptible to
nucleophilic attack and oxidation.
[*] Dr. G. Sorin, Dr. R. Martinez Mallorquin, Y. Contie, A. Baralle,
Prof. Dr. M. Malacria, Dr. J.-P. Goddard, Prof. Dr. L. Fensterbank
Institut Parisien de Chimie Molꢀculaire
(UMR CNRS 7201)—FR 2769, UPMC Univ Paris 06
C. 229, 4 place Jussieu, 75005 Paris (France)
Fax: (+33)1-44-27-73-60
E-mail: louis.fensterbank@upmc.fr
Homepage: http://www.ipcm.fr/
[**] This work was supported by the CNRS, UPMC, ANR (grant
no. BLAN0309, “Radicaux Verts”) and IUF (L.F., M.M.). R.M.M.
thanks the Fondation de l’ICSN for a PhD grant. We thank Prof. E.
Hasegawa (Niigata University) for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004513.
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Table 2: Oxidation of trifluoroborates 1.
opening of 1g to give cylohexene 2g. We also examined the
À
possibility of applying this method for C C bond formation.
Entry
Substrate
Oxidant,
Product, yield [%]
conditions[a]
Thus, heating a 0.5m solution of 1a in the presence of
Cu(OAc)2 at 1208C provided 70% of 1,2-diphenylethane,
which resulted from the dimerization of the benzyl radical,
accompanied by oxidation by-products (benzyl alcohol,
benzaldehyde).
1
2
1b
1b
Cu(EH)2, A
Cu(OAc)2, A
2b, 75
2b, 72
However, more meaningful from a synthetic point of view
is the possibility of operating Giese-type reactions with the
addition of MVK on secondary trifluoroborates to produce
ketones 3d or 3e (Scheme 2). In the latter case, only one
diastereomer was isolated.[19] Furthermore, allylation to give
acrylate 4 was also achieved.
3
4
1c
1c
Cu(EH)2, A
DMP, B
2cL/2cC (89:11), 57
2cL/2cC (100:0), 50
5
6
1d
1d
CuCl2, B
DMP, B
2d, 63
2d, 64
7
8
1e
1e
CuCl2, B
DMP, B
2e, 64
2e, 82
9
10
1 f
1 f
CuCl2, B
DMP, B
2 f, quant.
2 f, 85
À
Scheme 2. Formation of C C bonds. MVK= methyl vinyl ketone.
Although a plausible mechanism is still speculative, we
think that a single-electron transfer from the oxidant gen-
erates a transient radical species RC that can be trapped by
TEMPO to generate adducts 2 or trapped by MVK to
produce ketones 3 (Scheme 3). In the latter case, we found the
role of water to be highly beneficial to guarantee good yields.
A possible rationalization would be an in situ well-controlled
hydrolysis of the copper enolate species.[7]
11
1g
CuCl2, B
2g, 67
[a] Conditions A: 1.2 equivalents of TEMPO, DMSO (0.1m), 1208C,
20 h; conditions B: 3 equivalents of TEMPO, Et2O (0.2m), RT, 24–48 h.
DMP=Dess–Martin periodinane.
Scheme 1. Fuctionalized organotrifluoroborate compounds. Bn=ben-
zyl.
We then sought further confirmation on the radical
character of these transformations. A primary indication
came from the observed formation of cyclopentyl product
2cC, which presumably originates from a 5-exo-trig radical
cyclization process. Running the reaction in a more dilute
medium (0.01m in DMSO at 1208C, 72 h) resulted in an
increased formation of 2cC (2cL/2cC (73:27), 29% yield),
thus suggesting a closer competition between the TEMPO
trapping and the 5-exo-trig cyclization. Along the same lines,
the stereoselectivity in the formation of 2e is consistent with
the intervention of a radical intermediate[18] as is the ring
Scheme 3. Mechanism proposal.
In conclusion, we have shown that it is possible to oxidize
allyl and alkyl trifluoroborates with copper(II) salts and DMP.
Appropriate reaction conditions have been developed for
each class of substrates (primary to tertiary). This new
method of radical generation is compatible with functional-
À
ization and C C bond formation and augurs well for further
elaborations, and these results will be report in due course.
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[6] For TEMPO-mediated oxidations, see: a) M. S. Maji, T. Pfeifer,
Experimental Section
A. Studer, Angew. Chem. 2008, 120, 9690 – 9692; Angew. Chem.
Int. Ed. 2008, 47, 9547 – 9550; b) T. Nagashima, D. P. Curran,
Synlett 1996, 330 – 332; c) see also: M. Pouliot, P. Renaud, K.
Schenk, A. Studer, T. Vogler, Angew. Chem. 2009, 121, 6153 –
6156; Angew. Chem. Int. Ed. 2009, 48, 6037 – 6040, and
references therein.
Preparation of 4-isopinocamphenyl-2-butanone (3e): A mixture of
potassium trifluoroborate salt 1e (244 mg, 1 mmol), CuCl2 (161 mg,
1.2 mmol, 1.2 equiv), and methyl vinyl ketone (0.4 mL, 5 mmol,
5 equiv) in DMSO/water (9:1; 5 mL) was heated at 1208C for 20 h.
The reaction mixture was cooled to room temperature, diluted with
water (20 mL), and extracted with Et2O (2 ꢀ 20 mL). The combined
extracts were dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel to afford 3e as a colorless oil (176 mg, 84%). IR (neat):
[7] K. Tamao, J.-I. Yoshida, H. Yamamoto, T. Kakui, H. Matsumoto,
M. Takahashi, A. Kurita, M. Murata, M. Kumada, Organo-
metallics 1982, 1, 355 – 368.
n = 2918, 2359, 2341, 1716, 1366 cmÀ1; H NMR (CDCl3, 400 MHz):
1
[8] a) H. A. Stefani, R. Cella, A. S. Vieira, Tetrahedron 2007, 63,
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288 – 325.
d = 0.70 (d, J = 9.7 Hz, 1H, H7), 0.96 (s, 3H, H11 or H12), 0.99 (d, J =
7.0 Hz, 3H, H13), 1.16 (s, 3H, H12 or H11), 1.34–1.45 (m, 2H, H3 and
H9), 1.50–1.68 (m, 2H, H4 and H5), 1.70–1.85 (m, 2H, H3’ and H6),
1.85–1.91 (m, 1H, H8), 2.06–2.15 (m, 1H, H9’), 2.13 (s, 3H, H13),
2.22–2.30 (m, 1H, H7’), 2.34 (ddd, 1H, J = 16.5, 10.4, 5.1 Hz, H2),
2.46 ppm (ddd, 1H, J = 16.5, 10.1, 5.9 Hz, 1H, H2’); 13C NMR
(CDCl3, 100 MHz): d = 21.7 (C13), 23.0 (C11 or C12), 28.1 (C11 or
C12), 30.0 (C14), 34.1 (C7), 34.5 (C9), 34.8 (C3), 36.1 (C4), 38.8 (C10),
42.0 (C8), 42.3 (C2), 43.7 (C5), 48.2 (C6), 209.5 ppm (C1). HRMS
calcd for C14H25O ([M+H]+): 209.1899, found: 209.1900.
[9] CuII oxidation of boranes in halogenation reactions is known,
see: a) C. Ollivier, P. Renaud, Chem. Rev. 2001, 101, 3415 – 3434,
and references therein, notably: b) C. F. Lane, J. Organomet.
Chem. 1971, 31, 421 – 431.
[10] Electrochemical oxidation of polyphenyltrifluoroborate anions
is known, see: a) L. A. Shundrin, V. V. Bardin, H.-J. Z. Frohn, Z.
Anorg. Allg. Chem. 2004, 630, 1253 – 1257; for PET oxidation of
allyl- and benzyltrifluoroborates, see: b) Y. Nishigaichi, T.
Orimi, A. Takuwa, J. Organomet. Chem. 2009, 694, 3837 –
3839; see also for other borates: c) G. B. Schuster, Pure Appl.
Chem. 1990, 62, 1565 – 1572; for the oxidation of arylboronic
acids with Mn(OAc)3, see: d) A. Dickschat, A. Studer, Org. Lett.
2010, 12, 3972 – 3974, and references therein; see also: e) I. B.
Seiple, S. Su, R. A. Rodriguez, R. Gianatassio, Y. Fujiwara, A. L.
Sobel, P. S. Baran, J. Am. Chem. Soc. 2010, 132, 13194 – 13196;
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Lemaire, Tetrahedron Lett. 2009, 50, 6855 – 6857.
[11] For a review on the use of TEMPO, see: T. Vogler, A. Studer,
Synthesis 2008, 1979 – 1993.
[12] Under these conditions, an excess amount of TEMPO (3 equiv)
was used. TEMPO and CuCl2 are known to form a complex, see:
J. Laugier, J.-M. Latour, A. Caneschi, P. Rey, Inorg. Chem. 1991,
30, 4474 – 4477.
[13] For the oxidation of hydroxy-substituted trifluoroorganoborates
with hypervalent iodine derivatives, see: G. A. Molander, D. E.
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[14] a) See Ref. [6b]; b) V. W. Bowry, K. U. Ingold, J. Am. Chem. Soc.
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[15] C. Chatgilialoglu, K. U. Ingold, J. C. Scaiano, J. Am. Chem. Soc.
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[16] For examples of functionalized organotrifluoroborates, see:
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b) G. A. Molander, W. Febo-Ayala, M. Ortega-Guerra, J. Org.
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Received: June 22, 2010
Published online: October 7, 2010
Keywords: boron · copper · electron transfer · oxidation ·
.
radical reactions
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[19] The stereochemistry of 3e is assigned by analogy with product
2e.
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