Asymmetric allylsilane additions to enantiopure N-acylhydrazones with dual activation by fluoride and In(OTF)3

Article abstract of DOI:10.1002/1521-3773(20011203)40:23<4491::AID-ANIE4491>3.0.CO;2-8

A mild, convenient, and stereoselective addition of allylsilanes to enantiopure N-acylhydrazones occurs at room temperature upon complementary activation of both the allylsilane and the hydrazone (see scheme; OTf = trifluoromethanesulfonate). The reaction

Full text of DOI:10.1002/1521-3773(20011203)40:23<4491::AID-ANIE4491>3.0.CO;2-8

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Previously we found that in the presence of ZnII or InIII
salts, chiral N-acylhydrazones (Scheme 1) underwent highly
stereoselective radical additions[4] inwhich Lewis acid activa-
tion and restriction of rotamer populations were key design
Mendonca, X.-Y. Xiao, Med. Res. Rev. 1999, 19, 451; f) K. Gordon, S.
Balasubramanian, Curr. Opin. Drug Discovery Dev. 1999, 2, 342; g) C.
Watson, Angew. Chem. 1999, 111, 2025; Angew. Chem. Int. Ed. 1999,
38, 1903; h) S. Kobayashi, Chem. Soc. Rev. 1999, 28, 1; i) S. Booth,
P. H. H. Hermkens, H. C. J. Ottenheijm, D. C. Rees, Tetrahedron 1998,
54, 15385; j) P. Hodge, Chem. Soc. Rev. 1997, 26, 417.
[2] a) F. Zaragoza, Angew. Chem. 2000, 112, 2158; Angew. Chem. Int. Ed.
2000, 39, 2077; b) A. B. Reitz, Curr. Opin. Drug Discovery Dev. 1999,
2, 358; c) C. J. Andres, D. L. Whitehouse, M. S. Deshpande, Curr.
Opin. Chem. Biol. 1998, 2, 353; d) I. W. James, Tetrahedron Lett. 1999,
55, 4855.
O
O
LA
NH2
R2
N
N
R1
CH2Ph
R1
[3] Y. Pan, C. P. Holmes, Org. Lett. 2001, 3, 2769.
¬
À
[4] C. Vanier, F. Lorge, A. Wagner, C. Mioskowski, Angew. Chem. 2000,
Scheme 1. Retrosynthetic carbon carbon bond disconnection of chiral a-
112, 1745; Angew. Chem. Int. Ed. 2000, 39, 1679.
[5] S. Br‰se, M. Schroen, Angew. Chem. 1999, 111, 1139; Angew. Chem.
Int. Ed. 1999, 38, 1071.
branched amines to
precursor.
a Lewis acid activated chiral N-acylhydrazone
[6] C. Pourbaix, F. Carreaux, B. Carboni, Org. Lett. 2001, 3, 803.
[7] W. Li, K. Burgess, Tetrahedron Lett. 1999, 40, 6527.
[8] J. K. Rueter, S. O. Nortey, E. W. Baxter, G. C. Leo, A. B. Reitz,
Tetrahedron Lett. 1998, 39, 975.
[9] a) K. Ritter, Synthesis 1993, 8, 735; b) W. J. Scott, J. E. McMurry, Acc.
Chem. Res. 1988, 21, 47; c) I. L. Baraznenok, V. G. Nenajdenko, E. S.
Balenkova, Tetrahedron 2000, 56, 3077.
elements. We sought to exploit this design further with other
reactiontypes that would broadenthe variety of accessible
chiral amines. An allyl group is particularly useful for
subsequent synthetic manipulations, so extensive efforts have
beendirected toward the stereoselective allylationof chiral
¬
[5]
[10] R. Franzen, Can. J. Chem. 2000, 78, 957; see also references compiled
ˆ
imines, iminium ions, and related C N electrophiles. We
inF. Zaragoza Dˆrwald, Organic Synthesis on Solid Phase, Chapter 5,
Wiley-VCH, Weinheim, 2000.
envisioned a novel dual activation protocol in which both the
allyl donor and acceptor would be activated in a comple-
[11] Support 1 bearing the PFS linker was prepared from Tentagel-NH2
resin(RAPP Polymere, loadign 0.43 mmolg À1) with the loading
À
mentary fashion to promote C C bond construction under
measured by elemental analysis being typically 0.33 mmolgÀ1
.
relatively mild conditions. We hypothesized that the fluoride-
[12] a) D. Stones, D. J. Miller, M. W. Beaton, T. J. Rutherford, D. Gani,
Tetrahedron Lett. 1998, 39, 4875; b) A. Svensson, K.-E. Bergquist, T.
Fex, J. Kihlberg, Tetrahedron Lett. 1998, 39, 7193.
[13] In the absence of a suitable nucleophile, reduction to the parent arene
is often observed during palladium-mediated reactions of aryl species.
[14] B. Ruhland, A. Bombrun, M. A. Gallop, J. Org. Chem. 1997, 62, 7820.
promoted additionof anallylsilane to
N-acylhydrazones in
the presence of a Lewis acid would achieve this goal with
excellent stereocontrol. There are surprisingly few examples
of the Sakurai-like fluoride-promoted additionof allylsilanes
[6]
ˆ
to C N bonds, perhaps because of a prevailing perception
that allylsilanes are rather unreactive toward imines without
the use of strong Lewis acids.[7] We report herein convenient,
highly stereoselective additions of allylsilanes to chiral N-
acylhydrazones at room temperature with dual activation by
fluoride and indium(iii) trifluoromethanesulfonate.
Our initial studies examined the reaction of allyltrimethyl-
silane with chiral hydrazone 2a[4] (Scheme 2). The use of a
fluoride ionsource required careful considerationof exper-
imental protocols to avoid its potential incompatibility with
Asymmetric Allylsilane Additions to
Enantiopure N-Acylhydrazones with Dual
Activation by Fluoride and In(OTf)3**
Gregory K. Friestad* and Hui Ding
O
O
O
Chiral a-branched amines are common features of bio-
logically active compounds. Direct asymmetric amine syn-
O
O
[Si]
O
RCHO
N
N
N
TBAT,
Lewis acid
H2N
N
HN
ˆ
thesis by additionto the C N bond of carbonyl imino
CH2Ph
CH2Ph
CH2Ph
derivatives holds promise for improved access to these
R
R
substructures by introducing a stereogenic center and a
1
2a–g
3a–g
À
carbon carbon bond in one step. However, the use of strongly
Scheme 2. Addition of allylsilanes to enantiopure hydrazones with dual
basic organometallic reagents for this purpose[1] canresult in
activationby Lewis acid and fluoride ion( a: R ˆ Ph; b: R ˆ p-tolyl; c: R ˆ
competitive metalloenamine formation.[2] Development of
ˆ
m-nitrophenyl; d: R ˆ 2-naphthyl; e: R ˆ 2-furyl; f: R ˆ CH CHPh; g:
R ˆ CH2CH3; for [Si] see Table 1).
À
alternative milder methods for the construction of C C bonds
is therefore of considerable importance.[3]
Lewis acids. Eventually, we found that the soluble, air-stable,
nonhygroscopic fluoride source tetrabutylammonium triphen-
yldifluorosilicate (TBAT)[8] could effectively promote allyl-
trimethylsilane addition to the complex formed by mixing 2a
with a Lewis acid, to provide 3a [Scheme 2] with good
stereoselectivity. The optimal protocol entailed mixing a slight
excess of allylsilane with TBAT in CH2Cl2 while preparing a
mixture of 2a and a Lewis acid in CH2Cl2. After 4 h, these
solutions were combined at room temperature, followed by a
[*] Prof. G. K. Friestad, H. Ding
Department of Chemistry, University of Vermont
Burlington, VT 05405 (USA)
Fax : (‡1)802-656-8705
E-mail: gregory.friestad@uvm.edu
[**] We thank the National Science Foundation (Vermont EPSCoR) and
the University of Vermont for generous support.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
Angew. Chem. Int. Ed. 2001, 40, No. 23
¹ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4023-4491 $ 17.50+.50/0
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normal workup after completion of the reaction. Indium(iii)
trifluoromethanesulfonate (In(OTf)3) was chosenfrom a broad
range of Lewis acids screened (ZnCl2, In C3l, In(OAc)3, TiCl4,
SnCl4, Sc(OTf)3, Yb(OTf)3, Cu(OTf)2, TMSOTf, BF3 ¥ OEt2).
Variations to the substituents on the silicon atom were
examined next (Table 1). Although allyltrialkoxysilanes and
various allylchlorosilanes were ineffective under these con-
ditions, allyl(diisopropylamino)dimethylsilane led to a sig-
nificant improvement and provided 3a inhigh yield adn
stereoselectivity. Commercially available tetraallylsilane
proved to be a superior allyl donor and gave 3a in78% yield
with excellent stereocontrol (d.r. > 99:1).
optical rotationto have the S configuration.[9] Saturationof
the allyl group of 3g (H2, Pd/C) gave a known derivative of
(R)-3-aminohexane.[10] For insight into the mechanism, con-
trol experiments were conducted with 2a:
1) Reaction in the absence of In(OTf)3: 15% yield, d.r. 67:33.
2) Reactionwithout TBAT: 30% yield, d.r. 94:6.
3) Neither In(OTf)3 nor TBAT: no reaction.
4) Additional In(OTf)3 inthe TBAT/allylsilane mixture prior
to mixing with the In(OTf)3 hydrazone complex: 66%
yield, d.r. > 99:1.
5) However, after >12 h, the mixture of In(OTf)3, TBAT,
and allylsilane behaves differently: 22% yield, dr 95:5.
Accordingly, 1H NMR spectroscopy experiments
(500 MHz, CD2Cl2, 278C) showed that tetraallylsilane is
essentially unchanged after 4 h in the presence of TBAT, and
Table 1. Variation of Silicon Substituents in TBAT/In(OTf)3-Promoted
Addition of Allylsilanes to Hydrazone 2a (Scheme 2).
whenIn(OTf) is added, consumption of the tetraallylsilane
3
[Si] of allylsilane
Yield of 3a[a]
d.r.[b]
94:6
requires at least a further 14 h. Transmetallation to an
allylindium species therefore appears to be slow, and hence
the reactionof a hypervalent silicate with the Lewis acid
complexed hydrazone seems more likely.[11] Furthermore, the
variation in the reactivity and selectivity upon changing the
silicon ligands suggests the presence of silicon in the transition
state of the addition. The improved yield and selectivity with
tetraallylsilane over allyltrimethylsilane may be attributed to
a more electrophilic siliconatom, which leads to greater
fluoride ion affinity, increased hypervalent silicate population,
and a later transition state.[12] Stereochemical results are
consistent with the chelate structure in Scheme 1, in which
restriction of rotamer populations facilitates steric blocking of
the Re face.
Insummary, highly stereoselective allylsilane additionto
enantiopure N-acylhydrazones occurs in the presence of
easily handled, air-stable TBAT and In(OTf)3, which appear
to induce complementary dual activation of both reactants. To
our knowledge, these are the first examples of useful auxiliary
acyclic stereocontrol in allylsilane addition to stable, isolable
imino derivatives. Considering the ubiquity of chiral amines
and the synthetic versatility of the allyl group, applications to
complex targets may be envisioned.
SiMe3
SiPh3
58%
n.r.
n.r.
n.r.
n.r.
n.r.
81%
78%
Si(OMe)3
SiCl3
SiMeCl2
SiMe2Cl
SiMe2N(iPr)2
Si(allyl)3
95:5
> 99:1
[a] Yields of isolated purified diastereomer mixtures (n.r.: no reaction).
[b] Diastereomer ratio determined by means of HPLC (Microsorb-MV C8,
2-PrOH/hexane).
With effective reaction conditions in hand, a brief survey of
the scope of the reaction was undertaken by using a series of
hydrazones prepared from the corresponding aldehydes
(Table 2). Aromatic aldehyde hydrazones 2b e generally
gave homoallylic amines in good yield with excellent stereo-
selectivity, and a,b-unsaturated hydrazone (E)-2 f underwent
chemoselective additionto the C N bond. Although propio-
naldehyde hydrazone 2g[4] also participated inthe reaction,
the stereoselectivity was modest.
ˆ
Table 2. Preparationof Various Aldehyde Hydrazoens
In(OTf)3-Promoted Additionof Tetraallylsilane (Scheme 2).
2 and TBAT/
Hydrazone
Yield[a]
Allyl adduct
Yield[b]
d.r.[c]
Experimental Section
2b
2c
2d
2e
(E)-2 f
2g
94%
91%
92%
92%
97%
92%
3b
3c
3d
3e
3 f
3g
94%
71%
82%
58%
60%
51%
98:2
> 99:1
98:2
96:4
95:5
Allyl addition: A solution of allylsilane (3 equiv) and TBAT (3 equiv) in
CH2Cl2 (0.75m), and a solution of In(OTf)3 (1.3 equiv) and hydrazone 2a in
CH2Cl2 (0.1m) were prepared separately. After 4 h at approximately 258C,
the allylsilane/TBAT mixture was transferred by syringe to the hydrazone/
In(OTf)3 mixture. After 2 d at approximately 258C, the reactionmixture
was washed with water, dried (MgSO4), concentrated, and purified by flash
chromatography.
82:18
[a] Yield of isolated hydrazone. [b] Yields of isolated purified diastereomer
mixtures. [c] Diastereomer ratio determined by means of HPLC.
Hydrazone formation: Aldehyde (0.4 mmol),
1 (0.25 mmol), MgSO4
(200 mg), p-toluenesulfonic acid (catalytic amount) were heated in toluene
(10 mL) at reflux for 10 min.
To determine the stereochemistry, the auxiliary was re-
moved reductively from the N-benzoyl derivative of 3a to
give benzamide 4 [Eq. (1)], which was shownby means of
Received: August 1, 2001 [Z17653]
O
[1] Reviews: a) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069; b) R.
Bloch, Chem. Rev. 1998, 98, 1407; c) D. Enders, U. Reinhold,
Tetrahedron Asymmetry 1997, 8, 1895; d) S. E. Denmark, O. J.-C.
Nicaise, Chem. Commun. 1996, 999.
[2] a) Aza-enolization of imines with Grignard reagents: G. Stork, S. R.
Dowd, J. Am. Chem. Soc. 1963, 85, 2178; G. Wittig, H. D. Frommeld, P.
Suchanek, Angew Chem. 1963, 75, 978; Angew. Chem. Int. Ed. Engl.
1) nBuLi
(PhCO)2O
(81%)
O
O
O
NHCOPh
N
HN
Ph
+
HN
(1)
Ph
CH2Ph
2) SmI2
HMPA
CH2Ph
3a
5 (96%)
4 (93%)
4492
¹ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4023-4492 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 23

COMMUNICATIONS
1963, 2, 683; b) less basic organocerium reagents also exhibit aza-
enolization: D. Enders, E. Diez, R. Fernandez, E. Martin-Zamora,
J. M. Munoz, R. R. Pappalardo, J. M. Lassaleta, J. Org. Chem. 1999,
64, 6329.
Molecular Insight Into Surface Organometallic
Chemistry Through the Combined Use of 2D
HETCOR Solid-State NMR Spectroscopy and
Silsesquioxane Analogues**
[3] For selected recent examples, see: a) review of asymmetric Strecker-
type reactions: L. Yet, Angew. Chem. 2001, 113, 900; Angew. Chem.
Int. Ed. 2001, 40, 875; b) for asymmetric Mannich reactions, see: W.
Notz, K. Sakthivel, T. Bui, G. Zhong, C. F. Barbas III, Tetrahedron
Lett. 2001, 42, 199; B. List, J. Am. Chem. Soc. 2000, 122, 9336; S. Saito,
K. Hatanaka, H. Yamamoto, Org. Lett. 2000, 2, 1891; K. Miura, K.
Tamaki, T. Nakagawa, A. Hosomi, Angew. Chem. 2000, 112, 2034;
Angew. Chem. Int. Ed. 2000, 39, 1958.
Mathieu Chabanas, Elsje Alessandra Quadrelli,
¬
Bernard Fenet, Christophe Coperet,*
JeanThivolle-Cazat, Jean-Marie Basset,*
Anne Lesage, and Lyndon Emsley*
[4] a) G. K. Friestad, J. Qin, J. Am. Chem. Soc. 2000, 122, 8329; b) G. K.
The structural characterizationof heterogeneous catalysts
remains difficult. In the late eighties, Feher and later others
showed that polyhedral oligomeric silsesquioxanes (POSS)
canbe used to model the surface structure of partially
dehydroxylated silica and therefore infer information about
the coordination sphere of metal complexes directly support-
Friestad, J. Qin, J. Am. Chem. Soc. 2001, 123, 9922.
ˆ
[5] For reviews of allyl organometallic addition to C N bonds, see: Y.
Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207; E. F. Kleinman, R. A.
Volkmann in Comprehensive Organic Synthesis, Vol. 2 (Eds.: B. M.
Trost, I. Fleming), Pergamon, New York, 1991, pp. 975 1006; see also
ref. [1]. For selected recent examples, see:a) allyltin: H. Nakamura, K.
Aoyagi, J.-G. Shim, Y. Yamamoto, J. Am. Chem. Soc. 2001, 123, 372;
F. M. Guerra, M. R. Mish, E. M. Carreira, Org. Lett. 2000, 2, 4265;
J. A. Marshall, K. Gill, B. M. Seletsky, Angew. Chem. 2000, 112, 983;
Angew. Chem. Int. Ed. 2000, 39, 953; b) allylboron: K. Watanabe, S.
Kuroda, A. Yokoi, K. Ito, S. Itsuno, J. Organomet. Chem. 1999, 581,
103; c) allyltitanium: X. Teng, Y. Takayama, S. Okamoto, F. Sato, J.
Am. Chem. Soc. 1999, 121, 11916; d) allylmagnesium: S. Maiorana, C.
Baldoliu, P. D. Buttero, E. Licandro, A. Papagni, M. Lanfranchi, A.
Tiripicchio, J. Organomet. Chem. 2000, 593 594, 380; A. G. Steinig,
D. M. Spero, J. Org. Chem. 1999, 64, 2406; e) allylsamarium: R.
Yanada, M. Okaniwa, A. Kaieda, T. Ibuka, Y. Takemoto, J. Org.
Chem. 2001, 66, 1283; f) allylindium: H. M. S. Kumar, S. Anjaneyulu,
E. J. Reddy, J. S. Yadav, Tetrahedron Lett. 2000, 41, 9311; T. H. Chan,
W. Lu, Tetrahedron Lett. 1998, 39, 8605; g) allylgermanium: T.
Akiyama, J. Iwai, Y. Onuma, H. Kagoshima, Chem. Commun. 1999,
2191.
[1]
ed onoxides such as silica. This approach canalso provide
mechanistic insights on surface chemistry processes. However,
no direct comparison between these models and their related
surface complexes has beenreported.
We have recently shown that the reaction of tris(neopen-
ˆ
tyl)neopentylidene tantalum, [Ta( CHtBu)(CH2tBu)3] (1)
ꢀ
ˆ
with SiO2-(500) gives a mixture of mono-[ SiO-Ta( CHtBu)-
(CH2tBu)2]
and
bisgrafted
surface
complexes
[2a]
ꢀ
ˆ
[( SiO)2Ta( CHtBu)(CH2tBu)], while its reactionwith a
SiO2-(700) provides the monografted species [ SiO-Ta-
( CHtBu)(CH2tBu)2] (2s) as the sole surface species. The
characterization was based on elemental analysis, the evolu-
tion of neopentane during grafting of 1, and solvolysis of 2s as
well as infrared (IR) spectroscopy.[2b]
ꢀ
ˆ
[6] a) X. Fang, M. Johannsen, S. Yao, N. Gathergood, R. G. Hazell, K. A.
Jorgensen, J. Org. Chem. 1999, 64, 4844; b) D.-K. Wang, Y.-G. Zhou,
Y. Tang, X.-L. Hou, L.-X. Dai, J. Org. Chem. 1999, 64, 4233; c) A. S.
Pilcher, P. DeShong, J. Org. Chem. 1996, 61, 6901.
[7] a) Sluggish reactivity of allylsilanes toward neutral imines has been
noted: see refs. [1] and [5a]; b) although allylsilane addition to
iminium ions is effective, a strong Lewis acid such as TiCl4 or BF3 ¥
Et2O is often required; for a review, see: I. Fleming, J. Dunogus, R.
Smithers, Org. React. 1989, 37, 57; recent examples: J. V. Schaus, N.
Jain, J. S. Panek, Tetrahedron 2000, 56, 10263; T. Akiyama, M. Sugano,
H. Kagoshima, Tetrahedron Lett. 2001, 42, 3889.
We report here the use of high-resolutionsolid-state one-
dimensional (1D) and two-dimensional (2D) NMR spectros-
copy to study 2s and the use of high-resolution solution-state
1D and 2D NMR spectroscopy of its molecular analogue
À À
ˆ
[(c-C5H9)7Si7O12Si O Ta( CHtBu)(CH2tBu)2] (2m) to define
the structure of 2s at a molecular level and to investigate the
reactionpathway leading to the grafted species.
[8] A. S. Pilcher, H. L. Ammon, P. DeShong, J. Am. Chem. Soc. 1995, 117,
5166; C. J. Handy, Y.-F. Lam, P. DeShong, J. Org. Chem. 2000, 65,
3542.
[9] The optical rotationof 4 ([a]2D0 ˆ À2.0 (c ˆ 3.4 inCHCl 3)) was within
experimental error of an authentic sample ([a]2D0 ˆ À2.2 (c ˆ 3.4 in
CHCl3)) prepared from the known homoallylic amine: T. Basile, A.
Bocoum, D. Savoia, A. Umani-Ronchi, J. Org. Chem. 1994, 59, 7766.
[10] Hydrogenation of 3g gives 6, identical to that from n-propyl radical
additionto 2g [Eq. (2)]. See ref. [4b].
¬
[*] Dr. C. Coperet, Dr. J.-M. Basset, M. Chabanas, Dr. J. Thivolle-Cazat
¬
Laboratoire de Chimie Organometallique de Surface
UMR-9986 CNRS ESCPE Lyon, 43 blvd du 11 Novembre 1918
69626 Villeurbanne Cedex (France)
Fax : (‡33)4-7243-1795
Dr. E. A. Quadrelli
Dipartimento di Chimica e Chimica Industriale
Via Risorgimento 35, 56100 Pisa (Italy)
B. Fenet
O
O
Centre de RMN UCB Lyon 1 ESCPE Lyon
43 bd du 11 Novembre 1918, 69626 Villeurbanne Cedex (France)
H2 (1 atm)
nPr•
N
2g
(2)
3g
HN
Et
Pd/C
Dr. L. Emsley, Dr. A. Lesage
Laboratoire de Stereochimie et des Interactions Moleculaires
radical
addition
CH2Ph
(100%)
¬ ¬
¬
nPr
¬
UMR-117 CNRS ENS Lyon, Ecole Normale Superieure de Lyon
69364 LyonCedex (France)
6
[**] We are also indebted to the CNRS, ENS Lyon, and ESCPE Lyon for
financial support. M.C. is grateful to the French ministry of education,
research, and technology (MENRT) for a pre-doctoral fellowship.
[11] The allylsilane addition fails in 10:1 CH2Cl2/water, which would not
likely interfere with allylindium addition (see ref. [5f]).
[12] Similar explanations have been advanced regarding the enhanced
reactivity of bis(allyl)silanes. A. Shibato, Y. Itagaki, E. Tayama, Y.
Hokke, N. Asao, K. Maruoka, Tetrahedron 2000, 56, 5373.
¡
E.A.Q. gratefully acknowledges Universita di Pisa and S.N.A.M. for
financial support. 2D HETCOR ˆ two-dimensional heteronuclear
correlation.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
Angew. Chem. Int. Ed. 2001, 40, No. 23
¹ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4023-4493 $ 17.50+.50/0
4493