Highly diastereoselective indium-mediated allylation of chiral hydrazones

Article abstract of DOI:10.1021/ol0496172

Matrix presented. The indium-mediated allylation of chiral hydrazones was investigated. Essentially complete diastereoselectivity and quantitative yields were obtained for substrates derived from both aromatic and aliphatic aldehydes.

Full text of DOI:10.1021/ol0496172

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1741-1743
Highly Diastereoselective
Indium-Mediated Allylation of Chiral
Hydrazones
Gregory R. Cook,* Bikash C. Maity, and Robert Kargbo
North Dakota Network in Catalysis, Department of Chemistry and Molecular Biology,
North Dakota State UniVersity, Fargo, North Dakota 58105-5516
gregory.cook@ndsu.nodak.edu
Received March 1, 2004
ABSTRACT
The indium-mediated allylation of chiral hydrazones was investigated. Essentially complete diastereoselectivity and quantitative yields were
obtained for substrates derived from both aromatic and aliphatic aldehydes.
Chiral amines have found great utility in the preparation of
ligands for asymmetric catalysis, and are important building
blocks for the synthesis of biologically important compounds.
One of the most direct methods for their preparation is the
addition of carbon nucleophiles to CdN bonds. However,
relative to carbonyls, imine derivatives are generally less
reactive, and nucleophilic addition to them usually demands
the use of very strong organometallic reagents.1 Thus,
enolization and functional group tolerance are common
impediments in these processes.
In the past decade, allylindium has emerged as a mild and
effective reagent for the allylation of carbonyl compounds.2
Several examples of indium-mediated allylation of CdN
bonds have also been reported,3 thus affording an alternative
to highly basic nucleophiles. The use of chiral auxiliaries to
effect a diastereoselective addition has met with some
success. Examples include chiral sulfinimine derivatives4 and
imines derived from valine.5 Imines prepared from R-keto
chiral sultams6 have provided the best examples to date.
These methods generally suffer from modest yields, poor
diastereoselectivity, auxiliaries that are difficult to cleave,
or relatively long reaction times. New methods for the
asymmetric indium-mediated allylation of CdN bonds that
are procedurally simple, have easily removable auxiliaries,
and are general in scope are desirable.
Recently, Friestad reported the allylation of chiral hydra-
zones utilizing fluoride-induced allylation with allylsilane
(3) (a) Beuchet, P.; Le Marrec, N.; Mosset, P. Tetrahedron Lett. 1992,
33, 5959. (b) Chan, T. H.; Lu, W. Tetrahedron Lett. 1998, 39, 8605. (c)
Lu, W.; Chan, T. H. J. Org. Chem. 2000, 65, 8589. (d) Kumar, H. M. S.;
Anjaneyulu, S.; Reddy, E. J.; Yadav, J. S. Tetrahedron Lett. 2000, 41, 9311.
(e) Lu, W.; Chan, T. H. J. Org. Chem. 2001, 66, 3467. See also: (f)
Prajapati, D.; Laskar, D. D.; Gogoi, B. J.; Devi, G. Tetrahedron Lett. 2003,
44, 6755. (g) Banik, B. K.; Ghatak, A.; Becker, F. F. J. Chem. Soc., Perkin
Trans. 1 2000, 2179. (h) Ghatak, A.; Becker, F. F.; Banik, B. K.
Heterocycles 2000, 53, 2769. (i) Skaanderup, P. R.; Madsen, R. J. Org.
Chem. 2003, 68, 2115.
(4) (a) Cooper, I. R.; Grigg, R.; MacLachlan, W. S.; Thornton-Pett, M.;
Sridharan, V. Chem. Commun. 2002, 1372. (b) Cooper, I. R.; Grigg, R.;
Hardie, M. J.; MacLachlan, W. S.; Sridharan, V.; Thomas, W. A.
Tetrahedron Lett. 2003, 44, 2283.
(5) (a) Basile, T.; Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J. Org.
Chem. 1994, 59, 7766. (b) Loh, T.-P.; Ho, D. S.-C.; Xu, K.-C.; Sim, K.-Y.
Tetrahedron Lett. 1997, 38, 865.
(6) (a) Lee, J. G.; Choi, K. I.; Pae, A. N.; Koh, H. Y.; Kang, Y.; Cho,
Y. S. J. Chem. Soc., Perkin Trans. 1 2002, 1314. (b) Miyabe, H.; Nishimura,
A.; Ueda, M.; Naito, T. Chem. Commun. 2002, 1454. (c) Miyabe, H.;
Yamaoka, Y.; Naito, T.; Takemoto, Y. J. Org. Chem. 2003, 68, 6745. (d)
Miyabe, H.; Yamaoka, Y.; Naito, T.; Takemoto, Y. J. Org. Chem. 2004,
69, 1415.
(1) Reviews: (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
(b) Bloch, R. Chem. ReV. 1998, 98, 1407. (c) Enders, D.; Reinhold, U.
Tetrahedron: Asymmetry 1997, 8, 1895. (d) Denmark, S. E.; Nicaise, O.
J.-C. Chem. Commun. 1996, 999.
(2) Reviews: (a) Nair, V.; Ros, S.; Jahan, C. N.; Pillai, B. S. Tetrahedron
2004, 60, 1959. (b) Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149. (c)
Ranu, B. C. Eur. J. Org. Chem. 2000, 2347. (d) Pae, A. N.; Cho, Y. S.
Curr. Org. Chem. 2002, 6, 715.
10.1021/ol0496172 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/04/2004

in the presence of a Lewis acid with high selectivity. The
hydrazine products were readily cleaved with SmI2 to afford
homoallylic amine derivatives.7 Although the chemistry is
quite elegant and worked well for most cases, the selectivity
with substrates derived from aliphatic aldehydes (∼4:1) was
lower than that with aromatic substrates. In addition, reaction
times were quite long, requiring 2 days to reach completion.
To the best of our knowledge, there are no reports of the
application of allylindium with chiral hydrazone auxiliaries.
We envisioned these reagents would offer improvements in
rate, selectivity, and overall ease of the process as compared
with allylsilane. Herein we report the results of our inves-
tigation of the indium-mediated allylation of Friestad chiral
hydrazones.
reacted in quantitative yield (entry 1); however, the diaste-
reoselectivity was poor. Substrates prepared from phenyla-
laninol (1b), valinol (1c), and aminoindanol (1d) all proceed
with complete diastereoselectivity as indicated by careful
proton NMR analysis. The isolated yields in all cases were
excellent.
We settled on the smallest auxiliary based on valinol to
study the substrate scope of the indium-mediated allylation
reaction. Our results are summarized in Table 2. Reaction
Table 2. Allylation of Chiral Hydrazones Substratesa
We first examined the conditions required for the allylation
reaction. Interestingly, addition of 1 equiv of indium and 1
equiv of allyl iodide to the substrate in THF was completely
unreactive and the starting material was recovered intact.
Adding 1.5 equiv of allyl iodide afforded an 86% conversion
after 8 h. This could be increased to 95% conversion with
1.5 equiv of In(0) and 3 equiv of allyl idodide. We found
the use of 2 equiv of indium and 3 equiv of allyl iodide in
THF was optimal and afforded complete conversion within
3 h. Utilizing more of the reagents gave no additional
benefits. The use of less reagent was practical but some
starting material always remained after 3 h. The stoichiom-
etry requirements suggest that an allylindium sesquihalide
species2 was necessary for the reaction to take place.
We next focused our attention on the chiral auxiliary. Thus,
we scrutinized several oxazolidinones with the p-tolyl
hydrazones 1 (Table 1). The phenylglycinol-derived 1a
Table 1. Allylation of Chiral Hydrazones Auxiliary Screena
a Conditions: allyl iodide (3 equiv), In(0) (2 equiv), 100 mg of substrate
in 3 mL of THF, rt, 3h. b Isolated yields. c Diastereomer ratios determined
by careful proton NMR spectroscopy. d In(OTf)3 (1.3 equiv) added, reaction
run for 1 h. e Reaction run for 8 h; 48% of the starting material was
recovered.
with aromatic aldehyde-derived substrates (entries 1-7) with
allyl iodide and indium in THF gave overall excellent yields
and excellent diastereoselectivities. There were a couple of
exceptions. The p-nitro derivative 3f (entry 6) afforded
complete selectivity; however, the reactivity was quite low
a Conditions: allyl iodide (3 equiv), In(0) (2 equiv), 100 mg of substrate
in 3 mL of THF, rt, 3 h. b Isolated yields. c Diastereomer ratios determined
by careful proton NMR spectroscopy.
1742
Org. Lett., Vol. 6, No. 11, 2004

and only a 50% yield was obtained (97% based on recovered
starting material). The p-methoxy substrate 3g demonstrated
good reactivity, but the selectivity dropped to 86:14. Ally-
lation of the cinnamaldehyde hydrazone 3h (entry 8)
proceeded with essentially no selectivity. Aliphatic substrates
3i-k (entries 9-11) also reacted with poor selectivity.
Interestingly, we observed that the selectivity changed for
these substrates depending on the scale of the reaction. We
determined that excess allylindium reagents in more dilute
conditions favored better selectivity. Thus, when 50 mg of
3h was treated with 4 equiv of In(0) and 6 equiv of allyl
indium in 7.5 mL of THF, the selectivity jumped from 55:
45 to 98:2. The same increase in selectivity was observed
for 3j giving >95:5 under these conditions. Changing either
the concentration or the amount of reagents independently
had much less influence on the diastereoselectivity. These
observations are difficult to rationalize and we are currently
investigating this unusual phenomenon.
Figure 1. Hydrazone rotamers.
failed to react with hydrazone substrates. We are currently
exploring the scope of allylic systems that can be incorpo-
rated into this reaction and our results will be reported in
due course.
The chiral auxiliary was readily cleaved as reported by
Friestad.7 As shown below in Scheme 1, 4a was acylated
with benzoic anhydride and the hydrazine was cleaved via
reduction with SmI2.
The unusual dependence of the diastereoselectivity on the
concentration and amount of allylindium reagent suggested
that excess In(III) in solution was coordinating the substrate
as a Lewis acid.8 Thus, we examined the influence of added
Lewis acid on the reaction. We were very pleased to see
that the addition of 1.3 equiv of In(OTf)3 to the chiral
hydrazones increased both the selectivity and the rate of the
reaction. In all cases, the reaction was complete within 1 h.
Even the sluggish p-nitro substrate afforded 4f in 95%
isolated yield. As shown in entries 7-11, diastereoselectivity
was nearly complete in the presence of In(OTf)3 for the
substrates that were previously problematic. Presumably, the
Lewis acid coordinates the hydrazone in a chelating fashion
to both activate the substrate as well as restrict the confor-
mational mobility allowing for greater reactivity and selec-
tivity.9
Scheme 1. Removal of the Chiral Auxiliary
In summary, we have demonstrated the highly diastereo-
selective indium-mediated allylation of chiral hydrazones.
Reactions were operationally simple and reaction times were
short. With the employment of In(OTf)3 Lewis acid diaste-
reoselectivity was controlled for both aromatic and aliphatic
substrates. The enantioselective variant of this allylation
reaction is currently being pursued.
The use of allylic bromides proved to be problematic.
While the simple allyl bromide performed equally well as
allyl iodide upon reaction with 3a, it would only do so in
the presence of added In(OTf)3 (90% yield, >99:1 dr).
Surprisingly, cinnamyl bromide, crotyl bromide, prenyl
bromide, 3-bromocyclohexene, and propargyl bromide all
Acknowledgment. We are grateful to the National
Science Foundation (NSF-CHM-0316618) and the ND-
EPSCoR Network in Catalysis program (NSF-EPS-0132289)
for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) Friestad, G. K.; Ding, H. Angew. Chem., Int. Ed. 2001, 40, 4491.
Recently Friestad and co-workers have improved on the hydrazine cleavage
method. See: Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637.
(8) Recently, Loh has reported on the influence of in situ generated In-
(III) salts on allylation reactions. Tan, K.-T.; Chng, S.-S.; Cheng, H.-S.;
Loh, T. P. J. Am. Chem. Soc. 2003, 125, 2958.
(9) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 122, 8329.
OL0496172
Org. Lett., Vol. 6, No. 11, 2004
1743