Highly diastereoselective zn/sncl2-mediated gem- difluoroallylation of chiral hydrazones

Article abstract of DOI:10.1021/ol802361p

Gem-Difuoroallylic zinc reacts with chiral hydrazones 1 in the presence of SnCl₂ to afford the versatile and chiral fluorinated building blocks, gem-difluorohomoallylic amines, in good yields and high diastereoselectivities.

Full text of DOI:10.1021/ol802361p

ORGANIC
LETTERS
2009
Vol. 11, No. 1
73-76
Highly Diastereoselective Zn/
SnCl2-Mediated gem-Difluoroallylation of
Chiral Hydrazones
Xuyi Yue,† Xingang Zhang,† and Feng-Ling Qing*,†,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China, and College
of Chemistry, Chemical Engineering and Biotechnology, Donghua UniVersity, 2999
North Renmin Lu, Shanghai 201620, China
flq@mail.sioc.ac.cn
Received October 13, 2008
ABSTRACT
gem-Difuoroallylic zinc reacts with chiral hydrazones 1 in the presence of SnCl2 to afford the versatile and chiral fluorinated building blocks,
gem-difluorohomoallylic amines, in good yields and high diastereoselectivities.
Fluorinated compounds play a very important role in life
sciences due to the introduction of one or a few fluorine atoms
into an organic molecule showing profound changes in its
chemical and biological nature.1 Among them, gem-difluori-
nated molecules constitute a distinct class of fluorinated
compounds.2 Incorporation of a gem-difluoromethylene group
(CF2) into an organic molecule can not only enhance its
neighboring group stability or acidity but also act as an
isopolar-isosteric substitute for oxygen.3 It has been used as
one strategy for modification of biologically active compounds,
such as enzyme inhibitors,4 and anticancer agents (e.g., Gem-
citabine5 and Vinflunine6 have been extensively used for
treatment of lung, ovarian, renal, pancreatic, head and, neck
cancers). Therefore, many efforts have been focused on the
synthesis of gem-difluorinated compounds.2,7 The most com-
monly used methods thus far are direct difluorination of
(4) (a) Furth, P. S.; Robinson, C. H. Biochemistry 1989, 28, 1254. (b)
Akahoshi, F.; Ashimori, A.; Sakashita, H.; Yoshimura, T.; Eda, M.; Imada,
T.; Nakajima, M.; Mitsutomi, N.; Kuwahara, S.; Ohtsuka, T.; Fukaya, C.;
Miyazaki, M.; Nakamura, N. J. Med. Chem. 2001, 44, 1297. (c) Cox, R. J.;
Hadfield, A. T.; Mayo-Martin, M. B. Chem. Commun. 2001, 18, 1710.
(5) Hertel, L. W.; Kroin, J. S.; Misner, J. W.; Tustin, J. M. J. Org. Chem.
1988, 53, 2406.
† Shanghai Institute of Organic Chemistry
‡ Donghua University
(6) Yun-San Yip, A.; Yuen-Yuen Ong, E.; Chow, L. W.-C Expert Opin.
InVestig. Drugs 2008, 17, 583.
(1) For recent reviews, see: (a) Smart, B. E. J. Fluorine Chem. 2001,
109, 3. (b) Maienfisch, P.; Hall, R. G. Chimia 2004, 58, 93. (c) Special
issue on “Fluorine in the Life Sciences”, ChemBioChem 2004, 5, 557. (d)
Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. ReV.
2008, 37, 320.
(7) For recent selected examples, see: (a) Li, Y.; Hu, J. Angew. Chem.,
Int. Ed. 2005, 44, 5882. (b) Xu, B.; Hammond, G. B. Angew. Chem., Int.
Ed. 2005, 44, 7404. (c) Xu, B.; Mashuta, M. S.; Hammond, G. B. Angew.
Chem., Int. Ed. 2006, 45, 7265. (d) Li, G.; van der Donk, W. A. Org. Lett.
2007, 9, 41. (e) Ni, C.; Liu, J.; Zhang, L.; Hu, J. Angew. Chem., Int. Ed.
2007, 46, 786. (f) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2007, 46, 2489. (g)
Codelli, J. A.; Baskin, J. M.; Agard, N. J.; Bertozzi, C. R. J. Am. Chem.
Soc. 2008, 130, 11486. (h) Schuler, M.; Silva, F.; Bobbio, C.; Tessier, A.;
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52, 8619. (b) Reddy, V. P.; Perambuduru, M.; Alleti, R. AdV. Org. Synth.
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Gouverneur, V. Angew. Chem., Int. Ed. 2008, 47, 7927
.
10.1021/ol802361p CCC: $40.75
Published on Web 12/08/2008
2009 American Chemical Society

carbonyl with DAST8 and the Reformatsky reaction using
bromodifluoroacetate.9 However, to incorporate a gem-
difluoromethylene group to an organic molecule in a chemo-,
regio-, and stereo-manner is still a great challenge.10
Optically pure gem-difluorohomoallylic amines are very
important compounds. They can not only be transformed into
various new chiral fluorinated building blocks by function-
ization of alkene moiety, such as substituted alkenes, amino
acids, δ-lactams, and pyrrolidines, but also be applied to
biologically interesting compounds. In addition, allylic
fluorides are potent active-site-directed irreversible inhibitors
of isopentenyl-diphosphate isomerase.11 Surprisingly, only
two examples of preparation of gem-difluorohomoallylic
amines have been reported,12 despite that impressive progress
has been made on the development of asymmetric synthesis
of nonfluorinated homoallylic amines.13,14 One of these two
methods is through direct difluorination of allylic ketone with
DAST. But the yield was poor, intricate transformations were
required, and many functional groups were incompatible
under the harsh reaction conditions.12a The other one was
developed by our group. However, it required the conversion
of a chiral gem-difluorohomoallylic alcohol into an
amine.12b,c On the basis of a great demand for difluorinated
structures as well as the importance of optically pure gem-
difluorohomoallylic amines in biological chemistry and
natural product modification, a direct and efficient method
would thus facilitate their accessibility. Herein, we disclose
the first successful, efficient, highly stereoselective synthesis
of gem-difluorohomoallylic amines through the coupling of
the gem-difluoroallylic zinc with chiral hydrazones in the
presence of SnCl2 in good yields with high diastereoselec-
tivities (in many of the cases, only a single diastereoisomer
was obtained). Enantioselectivities up to >99% ee could be
achieved after removal of the chiral auxiliary.
Inspired by Cook’s indium-mediated diastereoselective
allylation of chiral hydrazones,15 initially we started the
selective synthesis of chiral gem-difluorohomoallylic amine
by coupling of gem-difluoroallylic indium with chiral hy-
drazone 1a in which the valinol-derived oxazolidinone was
employed as a chiral auxiliary. To our surprise, the reaction
between 1a and the 3-bromo-3,3-difluoropropene 2 in the
presence of indium powder did not afford any product, which
is in strong contrast to Cook’s nonfluorinated results15
(Scheme 1). Investigation of different solvent systems
Scheme 1
.
Metal-Mediated Non- and Difluorianted Allylation of
Chiral Valinol Hydrazone 1a
(DMSO, THF, or THF/H2O), metals (In, Al/Sn), or elevating
the reaction temperature did not give the desired product either.
We surmised that there might be two reasons for this
negative result. First, the strong electron-withdrawing effect
of fluorine dramatically reduces the nucleophilicity of gem-
difluoroallylic metal species toward electrophiles. Second,
compared to imines, the oxazolidinone-substituted hydra-
zones are weak electrophiles. Thus, we assumed that using
a Lewis acid to activate the chiral hydrazones or a bifunc-
tional catalyst16 to activate both a nucleophile and an
electrophile would promote this coupling reaction. On the
basis of these considerations, we then examined the indium-
mediated gem-difluoroallylation of 1a in DMF in the
presence of In(OTf)3 or InCl3 (Table 1, entries 1 and 2).
However, no desired product was formed. Switching solvent
to THF did not afford 3a (Table 1, entry 3). Since the gem-
difluoroallylic zinc generated in situ is more reactive than
its corresponding indium species, the zinc-mediated addition
of 2 to 1a in the presence of different Lewis acids was
screened. We discovered that when the reaction was per-
formed with zinc powder in THF at room temperature in
the presence of TMSCl trace 3a was provided (Table 1, entry
5). Encouraged by this result, other Lewis acids BiCl3, CeCl3,
and SnCl2 were tested, where SnCl2 was supposed to be a
bifunctional catalyst for the addition of allylic zinc to imines,
Sn (Lewis acid) toward imines, and Cl (Lewis base) toward
Zn of allylic zinc halide17 (Table 1, entries 6-8, Figure 1).
To our delight, when 2.0 equiv of SnCl2 was investigated,
41% yield of desired product 3a was afforded. More
gratifyingly, 19F NMR of the crude product showed that only
(8) (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574. (b) Hudlicky, M.
Org. React. 1988, 35, 513. (c) Takeo, T. J. Synth. Org. Chem. Jpn. 1990,
48, 1048.
(9) For recent examples, see: (a) Konas, D. W.; Pankuch, J. J.; Coward,
J. K. Synthesis 2002, 17, 2616. (b) Ocampo, R.; Dolbier, W. R., Jr.; Zuluaga,
F. J. Org. Chem. 2002, 67, 72. (c) Cozzi, P. G. Angew. Chem., Int. Ed.
2007, 46, 2568.
(10) Ma, J. -A.; Cahard, D. Chem. ReV. 2004, 104, 6119.
(11) Muehlbacher, M.; Poulter, C. D. Biochemistry 1988, 27, 7315.
(12) (a) Ohba, T.; Ikeda, E.; Takei, H. Bioorg. Med. Chem. Lett. 1996,
6, 1875. (b) Wu, Y.-Y.; Zhang, X.; Meng, W. -D.; Qing, F. -L. Org. Lett.
2004, 6, 3941. (c) Yue, X.; Wu, Y. -Y.; Qing, F. -L. Tetrahedron 2007,
63, 1560.
(13) For examples of enantioselective metal-catalyzed allylation of
imines, see: (a) Fernandes, R. A.; Stimac, A.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 14133. (b) Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc.
Chem. Res. 2003, 36, 10. (c) Hamada, T.; Manabe, K.; Kobayashi, S. Angew.
Chem., Int. Ed. 2003, 42, 3927. (d) Wada, R.; Shibuguchi, T.; Makino, S.;
Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7687
.
(14) For examples of asymmetric allylation of hydrazones, see: (a)
Kobayashi, S.; Ogawa, C.; Konishi, H.; Sugiura, M. J. Am. Chem. Soc.
2003, 125, 6610. (b) Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am.
Chem. Soc. 2003, 125, 9596. (c) Ogawa, C.; Sugiura, M.; Kobayashi, S.
Angew. Chem., Int. Ed. 2004, 43, 6491. (d) Berger, R.; Duff, K.; Leighton,
J. L. J. Am. Chem. Soc. 2004, 126, 5686. (e) Tan, K. L.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2007, 46, 1315. (f) Kargbo, R.; Takahashi, Y.; Bhor,
S.; Cook, G. R.; Lloyd-Jones, G. C.; Shepperson, I. R. J. Am. Chem. Soc.
2007, 129, 3846
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(15) Cook, G. R.; Maity, B. C.; Kargbo, R. Org. Lett. 2004, 6, 1741
.
(16) (a) Shibasaki, M.; Matsunaga, S. Chem. Soc. ReV. 2006, 35, 269.
(b) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300. (c) Paull,
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Chem. Res. 2008, 41, 655
.
74
Org. Lett., Vol. 11, No. 1, 2009

Table 1. Metal-Mediated Addition of
3-Bromo-3,3-difluoropropene 2 to Chiral Hydrazone 1a in the
Presence of Lewis Acid
Table 2. Zinc-Mediated Addition of
3-Bromo-3,3-difluoropropene 2 to Chiral Hydrazones 1 in the
[a]
Presence of SnCl2
entry
metal
solvent
Lewis acid
In(OTf)3
InCl3
In(OTf)3
SnCl2
TMSCl
BiCl3
CeCl3
SnCl2 (2.0equiv)
SnCl2 (0.4equiv)
yield [%][a]
1
2
3
4
5
6
7
8
9
In
In
In
In
Zn
Zn
Zn
Zn
Zn
DMF
DMF
THF
THF
THF
THF
THF
THF
THF
NR[b]
NR[b]
NR[b]
NR[b]
trace[c]
trace[c]
trace[c]
41%
92%
[a] Determined by gas chromatography. [b] No reaction. [c] Determined
by 19F NMR.
Figure 1. Mechanistic proposal on stereocontrol.
[a] Reaction conditions: 1 (1 equiv), 2 (7 equiv), Zn (5 equiv), SnCl2
(0.25 M in THF, 0.4 equiv), room temperature, 0.1 M in THF. [b] Yield of
isolated product. [c] Yield based on the conversion. [d] 300 mg of 4 Å
molecular sieves/mmol substrate was added. [e] Determined by 19F NMR
a single diastereoisomer of 3a was formed. Further optimiz-
ing reaction conditions, we found that using 0.4 equiv of
SnCl2 and 5 equiv of zinc powder the reaction could be
conducted in 92% yield without erosion of the diastereose-
lectivity (Table 1, entry 9). The amount of SnCl2 has a
notable effect on the reaction. Overloading or reducing the
amount of SnCl2 would lead to decreased yield, but high
stereoselectivities remained (for details, see Supporting
Information Table 1, S10). On the contrary, when SnCl2 was
used for the indium-mediated addition of 2 to 1a, no desired
product was detected (Table 1, entry 4).
Under the optimized condition, the scope of gem-difluoro-
homoallylation of chiral hydrazones 1 with gem-difluoroallylic
zinc in the presence of SnCl2 was investigated (Table 2), and
the hydrazones included those bearing electron-withdrawing and
electron-donating substituents on the aryl ring and aliphatic and
functional hydrazones. High diastereoselectivities (de 12/1 to
single, determined by 19F NMR) and yields ranging from 42%
to 86% were observed for all the hydrazones tested. For all the
aryl substituted hydrazones, the yields depend on the electronic
[f]
before column chromatography. 19F NMR showed only a single diaste-
reoisomer was detected.
features of the substituents, and 4 Å molecular sieves were
required to facilitate the reaction (Table 2, entries 1-9).
Generally, moderate to good yields could be achieved for the
aromatic hydrazones, despite that the starting materials could
not be consumed completely. Electron-rich aryl hydrazones
provided moderate yields with high de values (Table 2, entries
3 and 4), while electron-deficient aryl substituents afforded good
yields with good to excellent diastereoselectivities (Table 2,
entries 5-9). Hydrazones bearing a naphthyl, furyl, or thienyl
group also furnished 3j-3l in good yields with high diastereo-
selectivity (Table 2, entries 10-12), but a slightly decreased
selectivity for substrate 1k (Table 2, entry 11). Notably, all alkyl-
substituted hydrazones underwent complete reaction in good
yields, and only a single diastereoisomer of desired product was
detected by 19F NMR (Table 2, entries 14-16). Functional
hydrazones 1q-1s also tolerated the reaction with de 12/1 to
single (Table 2, entries 17-19), and only the 1,2-addition
product was obtained for cinnamyl-substituted hydrazone 1m
(17) (a) Olah, G. A.; Kobayashi, S.; Tashiro, M. J. Am. Chem. Soc.
1972, 94, 7448. (b) Mine, N.; Fujiwara, Y.; Taniguchi, H Chem. Lett. 1986,
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Org. Lett., Vol. 11, No. 1, 2009
75

(Table 2, entry 13). It should be mentioned that the optically
pure 3r resulting from 1r is a very important building block to
access many bioactive ꢀ-fluorinated amino acids18 via the
transformation of an alkene moiety (Table 2, entry 18).
Scheme 2. Cleavage of the Hydrazine N-N Bond
The absolute configurations of the hydrazines were as-
signed by X-ray crystallographic analysis of optically pure
3e (for details see Supporting Information S27), which
indicated that the selectivity of the addition of hydrazones
with gem-difluoroallylic zinc should be induced from the less
hindered Si face of the hydrazones to generate the R
configuration. The greater reactivity of the substrates and
high stereoselectivity of the reaction probably could be
explained by the coordination of SnCl2 with substrates in a
highly restricted chair transition state in which Sn coordinates
C)N of hydrazone, and carbonyl group of oxazolidinone to
activate the hydrazone and Cl of SnCl2 chelates with Zn to
activate the gem-difluoroallylic zinc, which allows higher
reactivity of both the electrophile and nucleophile and
induces the gem-difluoroallylic zinc to attack the steric less
hindered Si face of hydrazone in a high stereoselective
manner (Figure 1).
In conclusion, we have developed a highly diastereose-
lective Zn/SnCl2 mediated gem-difluoroallylation of chiral
hydrazones. The bifunctional catalyst SnCl2 plays an im-
portant role in the reaction. The reaction scope can be
extended to a series of aromatic, heteroaromatic, aliphatic,
and functional hydrazines in good yields with high diaste-
reoselectivities. In many of the cases (both aromatic and
aliphatic hydrazones), only a single diastereoisomer could
be detected by 19F NMR. To the best of our knowledge, this
represents the first example of highly asymmetric gem-
difluoroallylation of stable, isolable imine equivalents. The
potential synthetic utility of this highly stereoselective gem-
difluoroallylation reaction is in progress.
The optical pure primary gem-difluorohomoallylic amines
could be efficiently obtained by Friestad’s procedure for
cleavage of the N-N bond of hydrazides.19 As shown in
Scheme 2, compound 3a was trifluoroacylated with trifluoro-
acetic anhydride (TFAA), and the resulting N-trifluoroacylated
hydrazine 4a was exposed to SmI220 to afford gem-difluoro-
homoallylic amide 5 in 55% yield with up to >99% ee.
Acknowledgment. This paper is dedicated to Prof. Qin-
Yun Chen on the occasion of his 80th birthday. The National
Natural Science Foundation of China and Shanghai Munici-
pal Scientific Committee are greatly acknowledged for
funding this work.
(18) (a) Kukhar, V. P.; Soloshonok, V. A. Fluorine Containing Amino
Acids: Synthesis and Properties; Wiley: New York, 1995. For recent
reviews, see: (b) Sutherland, A.; Willis, C. L. Nat. Prod. Rep. 2000, 17,
621. (c) Qiu, X. -L.; Meng, W. -D.; Qing, F. -L. Tetrahedron 2004, 60,
6711.
Supporting Information Available: Detailed experimen-
tal procedures and analytical data for all new compounds
and crystallographic data for compound 3e. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637.
(20) Souppe, J.; Danon, L.; Namy, J. L.; Kagen, H. B. J. Organomet.
Chem. 1983, 250, 227.
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