Stereocontrolled generation of nucleophilic (Z)- or (E)-α- fluoroalkenylchromium reagents via carbon-fluorine bond activation: Highly stereoselective synthesis of (E)- or (Z)-β-fluoroallylic alcohols

Article abstract of DOI:10.1039/c3cc47219a

Highly nucleophilic (Z)- or (E)-α-fluoroalkenylchromium species could be generated in a stereoselective manner via C-F bond activation of CBrF ₂-containing molecules, and they reacted smoothly with various aldehydes to give (E)- or (Z)-β-fluoroallylic alcohol derivatives in high yields, respectively. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc47219a

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Stereocontrolled generation of nucleophilic
(Z)- or (E)-a-fluoroalkenylchromium reagents
via carbon–fluorine bond activation:
highly stereoselective synthesis of (E)- or
(Z)-b-fluoroallylic alcohols†
Cite this: Chem. Commun., 2014,
50, 1543
Received 21st September 2013,
Accepted 30th November 2013
DOI: 10.1039/c3cc47219a
Takashi Nihei, Saya Yokotani, Takashi Ishihara and Tsutomu Konno*
www.rsc.org/chemcomm
Highly nucleophilic (Z)- or (E)-a-fluoroalkenylchromium species could species, via C–F bond activation with the early transition metal,
be generated in a stereoselective manner via C–F bond activation of Cr(II) 12
which react with a broad range of aldehydes, affording
CBrF2-containing molecules, and they reacted smoothly with various b-fluoroallylic alcohols (Table 1).
,
aldehydes to give (E)- or (Z)-b-fluoroallylic alcohol derivatives in high
Thus, treatment of 1A13 (1.0 equiv.) with 2.0 equiv. of benz-
yields, respectively.
aldehyde in the presence of 3.0 equiv. of Cr(II)Cl2 and 0.2 equiv. of LiI
in DMF at À20 1C for 4 h gave the corresponding b-fluoroallylic
Carbon–fluorine (C–F) bonds are the strongest single bonds in alcohol 2Aa in only 15% yield without recovery of 1A (entry 1). In this
organic substances. Therefore, the carbon–fluorine (C–F) bond case, any trace of fluorinated byproducts, including difluorinated
cleavage and its subsequent carbon–carbon (C–C) bond formation coupling adduct 3Aa, was not detected. While longer reaction time
have been one of the most attractive and challenging issues because was ineffective (entry 2), raising the reaction temperature from
such a process offers great potential in providing novel synthetic À20 1C to 0 1C significantly improved the efficacy of the reaction;
methodologies in synthetic organic chemistry.1
that is, 2Aa was obtained in 86% yield (entry 3). The reaction also
To date, there have been substantial efforts to develop such proceeded smoothly at ambient temperature (entry 4); however the
transformations, but most of preceding examples are the reactions reaction at 60 1C led to a significant decrease of the yield (entry 5).
mediated or catalyzed by late transition metals, such as Cu,2 Pd,3 Unfortunately, a slight decrease of the yield was observed using
Ni,4 Pt,5 Rh,6 Co,7 Ir,8 Fe.9 In these cases, under the influence of late a smaller equivalent of benzaldehyde (1.2 equiv.) (entry 7). In the
transition metals, the corresponding intermediary organometallics absence of LiI, the reaction yield was sharply decreased to only
are characterized as electrophilic, which can react with nucleophiles, 64% as well (entry 8). Finally the use of 4.0 equiv. of Cr(II)Cl2 led to
such as organolithium, Grignard reagent, organozinc, organoboronic the optimal reaction conditions (entry 9). To extend the scope of the
acid, etc., to afford the corresponding cross-coupling products
(Fig. 1, Path A).10 On the other hand, organometallic intermediates
Table 1 Investigation of the reaction conditions
generated through an early transition metal-mediated C–F bond
activation can be nucleophilic, and there are relatively few reports in
this research area. (Fig. 1, Path B).11
In this communication we disclose facile methods for highly stereo-
selective generation of nucleophilic (Z)- or (E)-a-fluoroalkenylmetal
Entrya
Temp. (1C)
Time (h)
Yieldb (%)
Recovery of 1Ab (%)
1
2
3
4
À20
À20
0
r.t.
60
0
4
20
4
4
4
4
4
4
4
15
18
86
84
27
13
76
64
89
Trace
Trace
Trace
0
0
21
4
9
5
6c
7d
8e
9f
0
0
0
Fig. 1 Classification of carbon–fluorine bond activation.
0
a
b
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan. E-mail: konno@kit.ac.jp;
Fax: +81 75-724-7580
In every case, the E-isomer was obtained exclusively. Determined by
19F NMR. Two equiv. of CrCl2 was used. The reaction was carried out
in the presence of 1.2 equiv. of benzaldehyde. Without LiI. Four
equiv. of CrCl2 was used.
c
d
e
f
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc47219a
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Table 2 Reductive coupling of 1A with various aldehydes
Table 3 Reductive coupling of 1B with various aldehydes
method, a broad range of aldehydes was tested for the present
reductive coupling reaction. The results are summarized in Table 2.
Aromatic aldehydes having an electron-donating group (Me
and MeO) on the benzene ring could participate in the reaction
to afford the desired products with high E stereoselection.14 Also,
p-fluorobenzaldehyde, which has an electron-withdrawing substi-
tuent, could be successfully applied for this reaction; however, a
stronger electron-withdrawing CF3 group as a substituent on the
benzene ring led to a significant decrease of the yield. In the case
of aliphatic aldehydes, the reaction with butanal, isobutyralde-
hyde, and pivalaldehyde took place very smoothly, regardless of
the bulkiness of the substituent R in aldehydes, to obtain the
corresponding alcohols in high to excellent yields. Disappoint-
ingly, crotonaldehyde was found to be unsuitable for the reaction,
though its stereoselectivity was still high.
Scheme 1 Screening of the substrates.
one-carbon elongated framework compared with 1C, could partici-
pate in the reaction very nicely to give the corresponding adduct
2Da in good yield. Additionally, 1E was also found to be a good
substrate for the reaction. In both cases, the b-fluoroallylic alcohols
were obtained exclusively in a Z selective manner.
Although the detailed reaction mechanism must require for
further investigation, our experimental results allow us to propose
the following plausible reaction mechanism (Scheme 2).20,21 Thus, the
starting substrate 1 can be converted into difluorinated chromium
species Int-1 through the single electron transfer mechanism,
followed by b-elimination, to give the corresponding difluoro-
alkene 5 (Path A). Again, single electron transfer takes place to
We also examined the reductive coupling reaction using the
substrate 1B15 under similar reaction conditions as tabulated
in Table 2. The results are listed in Table 3.
In sharp contrast to the results in Table 2, the reductive
coupling proceeded in a highly Z selective fashion.16 Thus, various
aromatic aldehydes, such as benzaldehyde, p-tolualdehyde,
p-anisaldehyde, and p-fluorobenzaldehyde, were all found to be
good substrates as a reaction partner to give the corresponding
(Z)-alcohols in acceptable yields. Similarly to the results shown in
Table 2, the aromatic aldehyde with a CF3 group at its para position
is not suitable for this reaction. Various aliphatic aldehydes, such
as butanal, isobutyraldehyde, and pivalaldehyde, could also be
successfully applied for the reaction. However, a,b-unsaturated
aldehyde showed poor yield in spite of the complete consumption
of the starting compound 1B. In all cases, a small amount of the
byproduct 4B was detected.
We also investigated the reductive coupling using other sub-
strates, 1C,15 1D,17 and 1E18 as shown in Scheme 1. It was revealed
that 1C gave b,b-difluoroacrylate 5C in 18% yield as the sole
product.19 Very surprisingly, the substrate 1D, which has just
Scheme 2 A plausible reaction mechanism. (Halogen ligands on Cr were
omitted.)
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7 T. J. Korn, M. A. Schade, S. Wirth and P. Knochel, Org. Lett., 2006, 8,
725–728.
8 (a) R. P. Hughes, R. B. Laritchev, L. N. Zakharov and A. L. Rheingold,
J. Am. Chem. Soc., 2005, 127, 6325–6334; (b) P. K. Chan and
W. K. Leong, Organometallics, 2008, 27, 1247–1253.
´
9 (a) R. Rumin, K. Guennou, R. Pichon, F. Y. Ptiilone, K. W. Muir and
D. S. Yufitt, J. Organomet. Chem., 1997, 533, 177–185; (b) Z. Mo,
Q. Zhang and L. Deng, Organometallics, 2012, 31, 6518–6521.
10 There have been several reports on nucleophilic intermediates generated
in the presence of late transition metals. See, (a) J. Terao, S. A. Begum,
A. Oda and N. Kambe, Synlett, 2005, 1783–1786; (b) S. Yamada,
T. Takahashi, T. Konno and T. Ishihara, Chem. Commun., 2007,
3679–3681; (c) B. C. Bailey, J. C. Huffman and D. J. Mindiola, J. Am.
Chem. Soc., 2007, 129, 5302–5303; (d) S. Yamada, E. Ishii, T. Konno and
T. Ishihara, Tetrahedron, 2008, 64, 4215–4223; (e) S. Yamada, K. Shimoji,
T. Takahashi, T. Konno and T. Ishihara, Chem.–Asian J., 2010, 5,
1846–1853; ( f ) S. Yamada, T. Takahashi, T. Konno and T. Ishihara,
J. Fluorine Chem., 2013, 149, 95–103.
11 For the generation of nucleophilic intermediates via early transition
metal-mediated C–F bond activation, see, M. Fujiwara, J. Ichikawa,
T. Okauchi and T. Minami, Tetrahedron Lett., 1999, 40, 7261–7265.
12 For Cr-mediated reaction, see, (a) K. Takai, K. Kimura, T. kuroda,
T. Hiyama and H. Nozaki, Tetrahedron Lett., 1983, 24, 5281–5284;
(b) H. Jin, J. Uenishi, W. J. Christ and Y. Kishi, J. Am. Chem. Soc.,
1986, 108, 5644–5646; (c) K. Takai, Org. React., 2004, 64, 253–612.
13 T. Shimada, T. Konno and T. Ishihara, Chem. Lett., 2007, 636–637.
14 Assignment of the stereochemistry of 2 was made by NMR spectroscopy.
The coupling constants between vinyl-H and F were 21–23 Hz for 2A and
35–38 for 2B–E, which indicate that the 2A and 2B–E possess E and Z
configuration, respectively. The detail was shown in ESI†.
15 For the preparation of 1C, see S. Peng, F. Qing, Y. Li and C. Hu,
J. Org. Chem., 2000, 65, 694–700. 1B was easily prepared from 1C in
two steps (1. DIBAL-H, 2. TBDPS-Cl/Imidazole).
16 When the reaction with benzaldehyde was carried out under the
same reaction conditions as employed in Table 2, the coupling
product was obtained in only 44%, together with 40% recovery of
the starting material.
17 J. Chen and C.-M. Hu, J. Chem. Soc., Perkin Trans. 1, 1994, 1111–1114.
18 M. D. Bartberger, W. R. Dolbier, Jr., J. Lusztyk and K. U. Ingold,
Tetrahedron, 1997, 53, 9857–9880.
19 When the reaction was carried out at À40 1C for 16 h in the presence
of 2.0 equiv. of Ti(OiPr)4, instead of a catalytic amount of LiI, 5C was
obtained in 40% yield.
Fig. 2 Chelation control.
afford the anion radical Int-2, which undergoes a smooth
elimination of fluoride to provide a monofluorovinyl radical
Int-3. Then a subsequent single electron transfer results in the
formation of a thermokinetically stable (E)-fluorovinylchromium
reagent Int-4, which can react with various aldehydes to yield
the corresponding (Z)-b-fluoroallylic alcohol derivatives 2,
whereas unreacted vinylchromium provides (Z)-fluoroalkene 4
after quenching the reaction with H2O.
In the case of the reaction with 1A, however, b-elimination of
1 by the chromium alkoxide Int-5 may play a role to provide
difluoroalkene 5 due to a highly acidic a-proton of the carbonyl
(Path B). Additionally, the Lewis acidic chromium metal can
coordinate with the carbonyl oxygen of the oxazolidinone moiety to
form a stable 7-membered intermediate Int-6 (Fig. 2), which can
react with aldehydes to produce (E)-b-fluoroallylic alcohols 2Aa–Ai.
In summary, this communication reports the convenient
Cr(II)Cl2-mediated generation of (E)- or (Z)-a-fluorovinylchromium
species via C–F bond activation. These intermediates are very
nucleophilic, which can react smoothly with various aldehydes,
and b-fluoroallylic alcohols are afforded in moderate yields.
Notably, the present methodology makes it possible to prepare
both (E)- and (Z)-fluoroalkenes in a highly stereoselective
manner.22 Further studies on the reductive coupling are now
underway in our laboratory.
20 It has been reported that trichloroalkanes in the presence of 4 equiv.
of CrCl2 can be converted into the corresponding chlorovinylidene
chromium(III) carbenoids. See, (a) R. Baati, D. K. Barma, J. R. Falck
and C. Mioskowski, J. Am. Chem. Soc., 2001, 123, 9196–9197;
(b) D. K. Barma, R. Baati, A. Valleix, C. Mioskowski and
J. R. Falck, Org. Lett., 2001, 3, 4237–4238; (c) R. Baati,
D. K. Barma, U. M. Krishna, C. Mioskowski and J. R. Falck, Tetra-
hedron Lett., 2002, 43, 959–961.
Notes and references
1 For review, see, (a) H. Amii and K. Uneyama, Chem. Rev., 2009, 109,
2119–2183; (b) E. Clot, O. Eisenstein, N. Jasim, S. A. Macgregor,
J. E. Mcgrady and R. N. Perutz, Acc. Chem. Res., 2011, 44, 333–348.
2 (a) N. Yoshikai, H. Mashima and E. Nakamura, J. Am. Chem. Soc.,
2005, 127, 17978–17979; (b) C. Yu, C. Zhang and X. Shi, Eur. J. Org.
Chem., 2012, 1953–1959.
21 It has been discussed that LiI play an important role in solubility of
CrCl2 in DMF. See, L. Wessjohann and T. Gabriel, J. Org. Chem.,
1997, 62, 3772–3774.
3 (a) A. Hazari, V. Gouverneur and J. M. Brown, Angew. Chem., Int. Ed.,
2009, 48, 1296–1299; (b) X. Pigeion, M. Berferon, F. Barabe, P. Dube,
´
´
H. F. Frost and J.-F. Paquin, Angew. Chem., Int. Ed., 2010, 49, 22 To our best of knowledge, there has been no reports on highly
1123–1127; (c) M. Ohashi, T. Kambara, T. Hatanaka, H. Saijo,
R. Doi and S. Ogoshi, J. Am. Chem. Soc., 2011, 133, 3256–3259;
(d) D. Yu, Q. Shen and L. Lu, J. Org. Chem., 2012, 77, 1798–1804;
(e) M. Ohashi, H. Saijo, M. Shibata and S. Ogoshi, Eur. J. Org. Chem.,
2013, 443–447.
4 (a) J. Terao, H. Watabe and N. Kambe, J. Am. Chem. Soc., 2005, 127,
3656–3657; (b) T. Schaub, M. Backes and U. Radius, J. Am. Chem.
Soc., 2006, 128, 15964–15965; (c) M. Tobisu, T. Xu, T. Shimasaki and
N. Chatani, J. Am. Chem. Soc., 2011, 133, 19505–19511; (d) W.-J. Guo
and Z.-X. Wang, J. Org. Chem., 2013, 78, 1054–1061.
5 (a) T. Wang, B. J. Alfonso and J. A. Love, Org. Lett., 2007, 9,
5629–5631; (b) H. L. Buckley, T. Wang, O. Tran and J. A. Love,
Organometallics, 2009, 28, 2356–2359.
6 (a) S. T. Belt, M. Helliwell, W. D. Jones, M. G. Partridge, R. N. Perutz
and M. K. Whittleesey, Chem. Commun., 1996, 961–962; (b) T. Braun,
stereoselective synthesis of both (E)- and (Z)-fluoroalkene using
the same methodology. As the preparation of fluoroalkenes,
for example, see, (a) T. Dubuffet, C. Bidon, P. Martinet,
ˆ
R. Sauvetre and J. F. Normant, J. Organomet. Chem., 1990, 393,
161–172; (b) T. Allmendinger, E. Felder and E. Hungarbu¨hler,
Tetrahedron Lett., 1990, 31, 7301–7304; (c) M. Shimizu, T. Hata
and T. Hiyama, Tetrahedron Lett., 1999, 40, 7375–7378; (d) Y.
Nakamura, M. Okada, H. Horikawa and T. Taguchi, J. Fluorine
Chem., 2002, 117, 143–148; (e) G. Dutheuil, X. Lei, X. Pannecoucke
and J.-C. Quirion, J. Org. Chem., 2005, 70, 1911–1914;
( f ) G. S. Nikolova and G. Haufe, Beilstein J. Org. Chem., 2008,
4, 12; (g) H. Yanai and T. Taguchi, Eur. J. Org. Chem., 2011,
5939–5954; (h) M. Bergeron, T. Hohnson and J. F. Paquin, Angew.
Chem., Int. Ed., 2011, 50, 11112–11116; (i) H. Yanai, H. Okada,
A. Sato, M. Okada and T. Taguchi, Tetrahedron Lett., 2011, 52,
2997–3000; ( j) C. Schneider, D. Masi, S. Couve-Bonnaire,
X. Pannecoucke and C. Hoarau, Angew. Chem., Int. Ed., 2013, 52, 1–5.
¨
M. A. Salomon, K. Altenhoner, M. Teltewskoi and S. Hinze, Angew.
Chem., Int. Ed., 2009, 48, 1818–1822.
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