SYNLETT0936-52141437-2096
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 135–136
spotlight
Syn lett
135
Spotlight
P. R. Mears
Paul R. Mears
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
[email protected]
Published online: 03.12.2014
DOI: 10.1055/s-0034-1379732; Art ID: st-2014-v0502-v
Introduction
With the virtues of installing fluorine into organic compounds with potential pharmaceutical uses known,1 methods for introducing a CF2 group under milder conditions are
desirable and are more likely to find use in installing fluorine into advanced organic fragments of natural products
and their analogues. One such reagent is 3,3,3-bromodifluoro-1-propene,2 which was first prepared in 1955 by a radical reaction of CF2Br2 and ethylene before base-mediated
elimination.3 This (hazardous!) procedure was rediscovered
by Seyferth et al.4 Lithiation of 3,3,3-bromodifluoro-1-propene gives difluoroallyllithium which reacts with electrophiles in the form of aldehydes, ketones or trialkylsilyl chlo-
Paul Mears graduated with a first class honours
degree in Applied Chemistry from the University of Leeds, UK in 2010. He subsequently moved
to the University of Manchester, UK to pursue
graduate studies under the supervision of Prof.
Jim Thomas. His work is focused on natural
product total synthesis, specifically of the bryostatin macrolides, as well as routes towards difluorinated analogues of these and related compounds.
rides. The instability of difluoroallyllithium at temperatures
>–95 °C has led to milder alternatives being developed, including work by Burton et al. where a screen of transitionmetal-mediated coupling reactions with aldehydes and ketones concluded with zinc powder identified as the reagent
of choice.5 More recently, the indium-mediated coupling6
has become the most widely used reaction for addition of
(now widely commercially available) 3,3,3-bromodifluoro1-propene to aldehydes and ketones in the preparation of
difluorohomoallylic alcohols. The regioselectivity of these
reactions is marked by the fact that the CF2 terminus always
forms the C–E bond (E = electrophile), resulting in a general
formula (ECF2CH=CH2).
Table 1 Use of 3,3,3-Bromodifluoro-1-propene
(A) Qing et al. used the indium-mediated difluoroallylation reaction
as a starting point in their synthesis of novel geminal-difluorinated
sugar nucleosides.7 In fact, the reaction was diastereoselective and
gave the anti-homoallylic alcohol as the major product. Further
steps were used to prepare N1-(3-deoxy-3,3-difluoro-D-arabinofuranosyl)cytosine.
O
O
H
O
OH
In powder
O
N
O
HO
N
DMF, r.t., 90% O
O
F
F
NH2
F
F
F
OH
F
anti/syn = 7.7:1
Br
(B) Taguchi and co-workers used the indium-mediated coupling
conditions to prepare difluorohomoallylic alcohols before developing a reagent system to effect a defluorinative allylic alkylation
transformation.8 The resulting fluoro-olefin structures are known
isosteres for peptidic bonds.
(C) Zhao, Wang and co-workers reported the first preparation of
difluorohomoallylic amines using their protocol of zinc-mediated
coupling of 3,3,3-bromodifluoro-1-propene to α-amido sulfones.9
F
RCHO
In powder
F
Br
H2O–THF, 60 °C R
OH
F
OH
Et3Al (3 equiv)
F
R
CH2Cl2, 1–5 h, r.t.
R = Ar, Alk
F
11 examples;
79–97% yield
Z/E > 20:1
NHR1
R2
Et
SO2Ph
NHR1
F
+
Zn powder
F
Br
R1 = Boc, Cbz; R2 = Ar, Alk
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 135–136
DMF, 3 h, r.t.
R2
F
F
11 examples, 76–99% yield
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3,3,3-Bromodifluoro-1-propene: The Mild Introduction of CF2
136
Syn lett
Spotlight
P. R. Mears
(D) Qing and co-workers found that the use of a zinc-mediated coupling of 3,3,3-bromodifluoro-1-propene in the presence of catalytic
SnCl2 gave the resulting homoallylic hydrazine in good yield and
with high diastereoselectivity.10 Cleavage of the hydrazine enables
facile accessibility to chiral difluorohomoallylic amines.
O
O
O
Zn powder (5 equiv)
SnCl2 (0.4 equiv)
F
N
N
F
i-Pr
THF, 48 h, r.t.
Br
R
O
N
HN
i-Pr
R
R = Ar, Alk
F
F
18 examples
59–86% yield
de > 12:1
X
R1
R2ZnBr
F
F
(6 equiv)
X
Pd(OAc)2 (5 mol%)
Zn(OTf)2 (1 equiv)
benzoquinone (4 equiv), air
dioxane–DMA (2:1), 5 h, r.t.
X = OH, OBn, NBn2; R2 = Bn, Ar, Alk, Hetar; R2 = Alk
(F) Zhang and co-workers directly coupled 3,3,3-bromodifluoro-1propene to arylboronic acids with high regioselectivity (α-substitution) and chemoselectivity (aldehydes were unreacted under the reaction conditions).12
F
F
22 examples
59–91% yield
Pd2(dba)3 (0.4 mol%)
K2CO3 (3 equiv)
F
ArB(OH)2
R2
R1
Ar
F
H2O (0.48 equiv), dioxane, 80 °C
Br
(1.5 equiv)
F
F
γ-product
24 examples
60–93% yield
α/γ > 8:1
(G) Ichikawa and co-workers found conditions for a selective γ-attack (SN2′) of 3,3,3-bromodifluoro-1-propene by 1,2-bromoheteroarenes to give 3,3-difluoroallylic compounds which could
undergo an intramolecular radical cyclisation to gain access to 3-difluoromethylated dihydrobenzoheteroles.13
R
Br
F
Cs2CO3 (1 equiv)
R
Br
CF2
F
NMP, 0.5 h, 80 °C
Y
Br [for Y = NH ; n-BuLi (1 equiv),
2
(2 equiv)
THF, 10 min, –78 °C]
γ-product
R = various; Y = OH, SH, NH2
Y
CF2H
AIBN (10 mol%) R
Bu3SnH (1.2 equiv)
hexane, 4 h, 80 °C
Y
11 examples; 61–94% yield
References
(1) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem.
Rev. 2014, 114, 2432.
(2) CAS no. 420-90-6
(3) Tarrant, P.; Lovelace, A. M.; Lilyquist, M. R. J. Am. Chem. Soc.
1955, 77, 768.
(4) (a) Seyferth, D.; Wursthorn, K. R. J. Organomet. Chem. 1979, 182,
455. (b) Seyferth, D.; Simon, R. M.; Sepelak, D. J.; Klein, H. A.
J. Org. Chem. 1980, 45, 2273. (c) Seyferth, D.; Simon, R. M.;
Sepelak, D. J.; Klein, H. A. J. Am. Chem. Soc. 1983, 105, 4634.
(5) (a) Yang, Z.-Y.; Burton, D. J. J. Fluorine Chem. 1989, 44, 339.
(b) Yang, Z.-Y.; Burton, D. J. J. Org. Chem. 1991, 56, 1037.
(6) (a) Kirihara, M.; Takuwa, T.; Takizawa, S.; Momose, T. Tetrahedron Lett. 1997, 38, 2853. (b) Kirihara, M.; Takuwa, T.; Takizawa,
S.; Momose, T.; Nemoto, H. Tetrahedron 2000, 56, 8275.
(7) Zhang, X.; Xia, H.; Dong, X.; Jin, J.; Meng, W.-D.; Qing, F.-L. J. Org.
Chem. 2003, 68, 9026.
(8) Yanai, H.; Okada, H.; Sato, A.; Okada, M.; Taguchi, T. Tetrahedron
Lett. 2011, 52, 2997.
(9) Xie, Z.-F.; Chai, Z.; Zhao, G.; Wang, J.-D. Synthesis 2008, 3805.
(10) Yue, X.; Zhang, X.; Qing, F.-L. Org. Lett. 2009, 11, 73.
(11) Lin, X.; Qing, F.-L. Org. Lett. 2013, 15, 4478.
(12) Min, Q.-Q.; Yin, Z.; Feng, Z.; Guo, W.-H.; Zhang, X. J. Am. Chem.
Soc. 2014, 136, 1230.
(13) Fujita, T.; Sanada, S.; Chiba, Y.; Sugiyama, K.; Ichikawa, J. Org.
Lett. 2014, 16, 1398.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 135–136
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
(E) Lin and Qing showed that the difluorohomoallylic alcohols and
amines (prepared from the reactions shown above) could undergo
an anti-Markovnikov hydroalkylation in the presence of an organozincate under palladium catalysis with an oxidant (benzoquinone
under an air atmosphere).11