Stereoselective α-aminoallylation of aldehydes with chiral tert -butanesulfinamides and allyl bromides

Article abstract of DOI:10.1021/jo101379u

Figure presented. The combination of an aldehyde, an allylic bromide, and tert-butanesulfinamide in the presence of indium metal and titanium tetraethoxide allows straightforward access to homoallylamine derivatives in high yields and stereoselectivities. Moreover, the synthetic utility of the enantioenriched homoallylamine derived from n-decanal was illustrated in a concise synthesis of (+)-isosolenopsin. In this context, similar homoallylamines has been recently used by other groups in the synthesis of naturally occurring alkaloids.

Full text of DOI:10.1021/jo101379u

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derivative, a process that typically requires about four syn-
Stereoselective r-Aminoallylation of Aldehydes with
Chiral tert-Butanesulfinamides and Allyl Bromides†
thetic operations.3 In this context, three-component reactions
involving carbonyl compounds, nitrogen nucleophiles, and
allylic nucleophiles are particularly attractive in assembling
both nitrogen-carbon and carbon-carbon bonds around the
carbonyl carbon. These reactions are referred to as R-amino-
allylations of carbonyl compounds,4 and several variations
have been reported for different nucleophiles.5 However, only
a few methods have been reported for the efficient preparation
of enantiomerically enriched homoallylic amines.6
ꢀ
ꢀ
ꢀ
Jose C. Gonzalez-Gomez,* Mohamed Medjahdi,
Francisco Foubelo,* and Miguel Yus
´
Departamento de Quımica Organica, Facultad de Ciencias
and Instituto de Sıntesis Organica (ISO), Universidad de
ꢀ
´
ꢀ
Alicante, Apdo. 99, 03080 Alicante, Spain
josecarlos.gonzalez@ua.es; foubelo@ua.es
Received July 13, 2010
Additions of nucleophiles to the CdN bond of enantio-
merically pure N-tert-butanesulfinyl imines are among the
most widely used approaches for the asymmetric synthesis of
amines.7 The ready availability of both enantiomers of tert-
butanesulfinamide in large-scale processes,8 the easy depro-
tection of the amine under acidic conditions, and a practical
procedure for recycling the chiral auxiliary have undoubt-
edly contributed to the widespread use of this approach.9 In
this context, the additions of allylmagnesium,10 allylzinc,11
and allylindium12 species to enantiopure N-tert-butanesulfi-
nylimines have also been exploited. We have been particu-
larly interested in the indium-mediated allylation reaction12b
due to the low toxicity of the metal and the high tolerance to a
wide range of functional groups, aqueous solvents, and
exposure to air.13 Continuing our interest in this topic, we
describe here the first one-pot R-aminoallylation of alde-
hydes with chiral tert-butanesulfinamide, allyl bromides,
and indium to provide homoallylic amines with high chemo-
and stereoselectivities (Scheme 1).
The combination of an aldehyde, an allylic bromide, and
tert-butanesulfinamide in the presence of indium metal
and titanium tetraethoxide allows straightforward access
to homoallylamine derivatives in high yields and stereo-
selectivities. Moreover, the synthetic utility of the enan-
tioenriched homoallylamine derived from n-decanal was
illustrated in a concise synthesis of (þ)-isosolenopsin. In
this context, similar homoallylamines has been recently
used by other groups in the synthesis of naturally occur-
ring alkaloids.
(3) For recent examples, see: (a) Kamal, A.; Vangala, S. R.; Reddy,
N. V. S.; Reddy, S. V. Tetrahedron: Asymmetry 2009, 20, 2589. (b) Kumar-G,
R. S. C.; Reddy, V.; Shankaraiah, G.; Babu, K. S.; Rao, J. M. Tetrahedron
Lett. 2010, 51, 1114.
€
(4) (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (b) von
€
€
Wangelin, A. J.; Neumann, H.; Gordes, D.; Klaus, S.; Strubing, D.; Beller,
M. Chem.;Eur. J. 2003, 9, 4286.
(5) For representative examples, see: (a) Veenstra, S. J.; Schmid, P.
Tetrahedron Lett. 1997, 38, 997. (b) Petasis, N. A.; Zavialov, I. A. J. Am.
Chem. Soc. 1997, 119, 445. (c) Sugiura, M.; Hirano, K.; Kobayashi, S. J. Am.
Chem. Soc. 2004, 126, 7182. (d) Narsaiah, A. V.; Kumar, J. K.; Narsimha, P.
Synthesis 2010, 1609.
Chiral homoallylic amines are of great value as building
blocks in organic synthesis because the carbon-carbon
double bond can be readily converted to a variety of func-
tional groups and the free amine moiety can be diversely
functionalized. The importance of these versatile intermedi-
ates is emphasized by the prevalence of chiral R-branched
amines in natural products, biologically active molecules,
and ligands.1 The addition of allylmetals to CdN double
bonds is a useful synthetic method for the formation of
homoallylic amine derivatives.2 However, chiral homoallylic
amines are still very commonly prepared by enantioselective
allylation of carbonyl compounds and subsequent transfor-
mation of the resulting alcohol into the corresponding amine
(6) For a leading reference, see: Sugiura, M.; Mori, C.; Kobayashi, S.
J. Am. Chem. Soc. 2006, 128, 11038.
(7) For reviews on the asymmetric synthesis of amines via N-tert-buta-
nesulfinylimines, see: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem.
Res. 2002, 35, 984. (b) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62,
ꢀ
8869. (c) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. Chem. Soc.
Rev. 2009, 38, 1162.
(8) (a) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317. (b) Weix, D. J.;
Ellman, J. A. Org. Synth. 2005, 82, 157.
(9) (a) Wakayama, M.; Ellman, J. A. J. Org. Chem. 2009, 74, 2646.
(b) Aggarwal, V. K.; Barbero, N.; McGarrigle, E. M.; Mickle, G.; Navas, R.;
ꢀ
Suarez, J. R.; Unthank, M. G.; Yar, M. Tetrahedron Lett. 2009, 50, 3482.
(10) (a) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883.
(b) Grainger, R. S.; Welsh, E. J. Angew. Chem., Int. Ed. 2007, 46, 5377.
(11) (a) Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979.
(b) Kolodney, G.; Sklute, G.; Perrone, S.; Knochel, P.; Marek, I. Angew.
Chem., Int. Ed. 2007, 46, 9291. (c) Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q.
Org. Lett. 2008, 10, 1259.
(12) (a) Cooper, I. R.; Grigg, R.; MacLachlan, W. S.; Thornton-Pett, M.;
Sridharan, V. Chem. Commun. 2002, 1372. (b) Foubelo, F.; Yus, M. Tetra-
hedron: Asymmetry 2004, 15, 3823.
(13) For reviews, see: (a) Chauhan, K. K.; Frost, C. G. J. Chem. Soc.,
Perkin Trans. 1 2000, 3015. (b) Ranu, B. C. Eur. J. Org. Chem. 2000, 2347.
(c) Podlech, J.; Maier, T. C. Synthesis 2003, 633. (d) Nair, V.; Ros, S.; Jayan,
N. C.; Pillai, B. S. Tetrahedron 2004, 60, 1959.
†
ꢀ
Dedicated to Professor Carmen Najera on occasion of her 60th birthday.
(1) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kesseler, M.;
Stuermer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788.
(2) (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069. (b) Puentes,
C. O.; Kouznetsov, V. J. Heterocycl. Chem. 2002, 39, 595. (c) Kobayashi, S.;
Sugiura, M.; Ogawa, C. Adv. Synth. Catal. 2004, 346, 1023.
6308 J. Org. Chem. 2010, 75, 6308–6311
Published on Web 08/19/2010
DOI: 10.1021/jo101379u
r
2010 American Chemical Society

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Gonzalez-Gomez et al.
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JOCNote
SCHEME 1. R-Aminoallylation Using Chiral tert-Butanesul-
finamide
compounds 4a and 5a (Table 1, entry 3).17 It was found that
2 equiv of Ti(OEt)4 promoted the reaction to afford homo-
allylamine 4a with excellent chemoselectivity (>95:5, entry 5).18
In an additional control experiment, the use of zinc instead of
indium, under otherwise identical optimized conditions, gave
less than 20% conversion of 2 into compound 4a.
Since the reaction was conducted in the presence of indium
and titanium, both species that could act as Lewis acids, as
well as water and/or ethanol, which can act as Lewis bases,
the stereoselectivity of the reaction was a major concern at
the outset.19 Given these precedents, we were pleased to find
the same diastereoselectivity (91:9) was obtained as pre-
viously observed for the indium-mediated allylation of the
preformed N-sulfinylimine.12b The generality of the sub-
strate was screened, and some problems were encountered
in obtaining good chemoselectivity for different substrates.
The results were more consistent in all cases when all reac-
tants except allyl bromide (3a) were stirred for 1 h at room
temperature, and after the addition of 3a, the reaction
mixture was heated at 60 °C for a further 5 h. Notably, full
conversion of the aldehyde into the N-sulfinimine was not
necessary. Different aldehydes were examined in conjunction
with this minor modification (Table 2).
Notably, aromatic aldehydes gave lower stereoselectivi-
ties and isolated yields than 3-phenylpropanal regardless of
whether the substituent was electron-withdrawing or -donat-
ing (4b-4d, Table 2, entries 2-4). Interestingly, R,β-con-
jugated aldehydes gave exclusive 1,2-addition in syntheti-
cally useful isolated yields and diastereoselectivities (4e-g,
Table 2, entries 5-7). More importantly, aliphatic aldehydes
that commonly complicate the reaction with organometallic
reagents due to enamine formation perform cleanly in the
R-aminoallylation reaction (4h-k, Table 2, entries 8-11).
Unfortunately, homoallylamine formation was not observed
for the more sterically hindered pivalaldehyde or for acet-
ophenone under the conditions studied. The stereochemical
outcome of the R-aminoallylation reaction was determined
by comparison of spectroscopic data with those of previously
characterized diastereomers of amines 4a,b,i,j.20
TABLE 1. Screening Conditions for R-Aminoallylation
entry
additive (mol %)
4aa (%)
5aa (%)
1
none
27
0c
51
24
91d
70c
69
2b
3
CF3CO2H (600)
In(OTf)3 (10)
In(OTf)3 (20)
Ti(OEt)4 (200)
Ti(OEt)4 (100)
100c
40
4
5
6
60
0
30c
aIsolated yield of analytically pure compounds. bThe reaction was run
at 23 °C. cDetermined by 1H NMR analysis of the crude reaction
mixture. d91:9 dr relative to sulfur was determined by 1H NMR.
Since the formation of homoallyl alcohols from the reac-
tion of aldehydes or ketones with allylindium species is well
precedented,14 chemoselectivity was the first issue to address
in order to develop the R-aminoallylation. An important
limitation for the chemoselectivity was imposed by the fact
that only 1 equiv of chiral tert-butanesulfinamide should be
used for practical reasons, and it was not obvious how to
minimize the concentration of aldehyde in the equilibrium.15
In a preliminary experiment, a mixture of 3-phenylpropanal
(1a, 0.55 mmol), (S)-N-tert-butanesulfinamide (2, 0.50mmol),
allyl bromide (3a, 0.60 mmol), and indium metal (0.50 mmol)
was heated in THF (1 mL) at 60 °C over 5 h. To our surprise,
apart from homoallyl alcohol 5a, homoallylsulfinylamine
derivative 4a was isolated in 27% yield (Table 1, entry 1).
Following this lead, we examined different additives in an
effort to improve the chemoselectivity in favor of compound
4a. The addition of TFA16 afforded exclusively homoallyl
alcohol 5a and In(OTf)3 led to an almost 1:1 mixture of
The reaction of 3-phenylpropanal was also investigated
with methallyl bromide (3b), prenyl bromide (3c), and cyclo-
hexenyl bromide 3d, with very good chemo- and stereose-
lectivities obtained in all cases (Figure 1). Importantly, high
γ-addition selectivity was also observed for 3c, and excellent
anti addition selectivity was observed for cyclohexenyl bro-
mide. The absolute stereochemistry of 4n was confirmed by
X-ray analysis22 and is in accordance with the addition of
the allylindium reagent over the Re face of the CdN in
the (SS)-sulfinyl imine. This stereochemical outcome can be
explained in terms of a chairlike transition-state model, where
the indium atom is coordinated to both the nitrogen and
(14) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831.
(15) It is worth noting that in the R-aminoallylation with ammonia, a
large excess of ammonia was crucial to obtain high chemoselectivity. See:
(a) Reference 5c. (b) Kobayashi, S.; Hirano, K.; Sugiura, M. Chem. Commun.
2005, 104.
(16) Very recently, it has been shown that TFA promotes efficiently the
intramolecular indium-mediated allylation of chiral hydrazones. See:
Samanta, D.; Kargbo, R. B.; Cook, G. R. J. Org. Chem. 2009, 74, 7183.
(17) It is known that In(OTf)3 increases both the stereoselectivity and
the rate of the indium-mediated allylation of chiral hydrazones. See: Cook,
G. R.; Maity, B. C.; Kargbo, R. Org. Lett. 2004, 6, 1741.
(19) It is known that the stereochemical outcome of the Zn/In-mediated
allylation of N-tert-butanesulfinyl imines can be highly dependent on the
presence of Lewis acids or bases. See: Lin, G.-Q.; Xu, M.-H.; Zhong, Y. W.;
Sun, X.-W. Acc. Chem. Res. 2008, 41, 831.
(20) (a) Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979.
ꢀ
ꢀ
(b) Medjahdi, M.; Gonzalez-Gomez, J. C.; Foubelo, F.; Yus, M. J. Org.
Chem. 2009, 74, 7859.
(18) (a) Ti(OEt)4 it is an excellent water scavenger and catalyst for the
formation of N-tert-butanesulfinylimines, see: Liu, G.; Cogan, D. A.;
Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278.
(b) Ti(OEt)4 has also been successfully used in a one-pot protocol for the
formationandreductionofN-tert-butanesulfinylketoimines,see: Tanuwidjaja,
J.; Peltier, H. M.; Ellman, J. A. J. Org. Chem. 2007, 72, 626.
(21) NMR analysis by comparison to diastereomer mixture standards
prepared according to: Brak, K.; Barret, K. T.; Ellman, J. A. J. Org. Chem.
2009, 74, 3606.
(22) Crystal data (excluding structure factors) deposited at the Cam-
bridge Crystallographic Data Centre as supplementary publication no.
CCDC 779151.
J. Org. Chem. Vol. 75, No. 18, 2010 6309

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Gonzalez-Gomez et al.
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JOCNote
TABLE 2. R-Aminoallylation of Aldehydes 1
FIGURE 1. Reaction with allylic bromides 3b-dand model approach
of cyclohexenylindium intermediate to the aldimine and X-ray structure
of 4n.
similar rates under the conditions studied. Treatment of
homoallyl alcohol 5a in the absence of allyl bromide, under
otherwise optimized conditions, did not afford any homo-
allylamine derivative 4a, thus ruling out interconversion
between these two products.24 With the present data, we
speculate that indium(III) salts formed in situ should accel-
erate both the formation of the N-sulfinylimine and its
allylation, a situation that would account for the good
chemoselectivity observed (Table 1, entry 3).
Following our previously reported route, amine 4i was
used in a concise synthesis of the natural (þ)-isosolenopsin
(7).25 Cross-metathesis of amine 4i with methyl vinyl ketone
afforded intermediate 6, which after conjugate reduction,
amine deprotection, and iminium reduction afforded the
expected (þ)-isosolenopsin (7) in very good overall yield
and diastereoselectivity (Scheme 2). Notably, only four syn-
thetic operations and three purification steps were required
to prepare efficiently this natural piperidine from n-decanal.
To further illustrate the synthetic utility of homoallylamine
4i in the field of alkaloid natural products, Wolfe and co-
workers have developed a seven-step synthesis from ent-4i of
(þ)-preussin and several analogs.26 Moreover, Rao and co-
workers recently used the N-Cbz analogue of amine 4i in a
four-step synthesis of the alkaloid (þ)-241D.3b
aYields and diastereoselectivities (1H NMR analysis)21 were deter-
mined for isolated pure compounds after column chromatography. bThe
corresponding imine was isolated in 40% yield. The C-4 epimer was
c
isolated pure in 8% yield; see the Supporting Information. dSimilar
results were obtained on a 5 mmol scale.
the oxygen of the sulfinyl imine moiety in the s-trans confor-
mation. Interestingly, this latter example complements the
recently reported addition of racemic cyclohexenyl zinc
chloride to (SS)-N-tert-butanesulfinyl imines, where the op-
posite configuration was observed for the two newly created
stereocenters.23
In an attempt to understand the scope of the reaction, even
without the necessity of full conversion of the aldehyde
into the sulfinyl imine, we considered several alternatives. In
a competition experiment, we observed that allylation of
3-phenylpropanal and the corresponding sulfinyl imine have
In summary, one-pot reactions of commercially available
aldehydes, allyl bromides, indium, and chiral tert-butane-
sulfinamide were found to afford enantioenriched homo-
allylic amines in high yields and with high chemo- and ster-
eoselectivities. The reaction performs better when aliphatic
(24) Although formation of an allyltitanium species can not be excluded
at present, we believe that allylindium is the actual nucleophile because the
same stereoinduction is achieved when the allylation of the preformed imine
is conducted in the absence of Ti(OEt)4.
ꢀ
(25) Gonzalez-Gomez, J. C.; Foubelo, F.; Yus, M. Synlett 2008, 2777.
(26) Bertrand, M. B.; Wolfe, J. P. Org. Lett. 2006, 8, 2353.
ꢀ
(23) Reddy, L. R.; Hu, B.; Prashad, M.; Prasad, K. Org. Lett. 2008, 10,
3109.
6310 J. Org. Chem. Vol. 75, No. 18, 2010

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SCHEME 2. Synthesis of (þ)-Isosolenopsin (7)
brine (2 mL), and diluted with EtOAc. The resulting suspension
was filtered through a short pad of Celite and concentrated in
vacuo (15 Torr). The residue was purified by column chromatog-
raphy (silica gel), eluting with hexane/EtOAc (4:1, then 3:1) to
afford 277 mg (87%, 96:4 dr) of compound 4n as a colorless solid:
mp 72-73 °C; [R]20 þ44 (c 0.86, CH2Cl2); Rf 0.25 (hexane/
D
EtOAc 2:1); 1H NMR (400 MHz, CDCl3) δ = 7.29 (m, 2H), 7.19
(m, 3H), 5.84 (ddd, J = 9.9, 6.4, 3.2, 1H), 5.52 (d, J = 10.1, 1H),
3.31 (d, J = 7.6, 1H), 3.21 (ddd, J = 11.8, 7.9, 4.0, 1H), 2.78 (m,
1H), 2.58 (m, 2H), 1.98 (m, 2H), 1.89 - 1.69 (m, 4H), 1.51 (m,
2H), 1.25 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 142.0 (C), 130.9
(CH), 128.53 (CH), 128.46 (CH), 127.0 (CH), 126.0 (CH), 60.1
(CH), 56.3 (C), 40.8 (CH), 35.7 (CH2), 32.9 (CH2), 25.3 (CH2),
24.9 (CH2), 23.0 (CH3), 22.0 (CH2); IR (neat, cm-1) 3300, 2935,
2863, 1452, 1047; HRMS (EI) calcd for C15H21NOS (M - C4H8)
263,1344, found 263.1352. Crystallization from hexane/CH2Cl2
afforded crystals of a single isomer suitable for X-ray analysis.
aldehydes are used and is well-suited for allyl-, methalyl-,
prenyl-, and cyclohexenyl bromides.
Acknowledgment. This work was generously supported
ꢀ
by the Spanish Ministerio de Ciencia e Innovacion (Grant
Experimental Section
No. CTQ2007-65218 and Consolider Ingenio 2010-CSD-
2007-00006) and the Generalitat Valenciana (Grant No.
PROMETEO/2009/039). We also thank Medalchemy S.L.
for a gift of enantiopure (S)-tert-butanesulfinamide.
Representative Procedure for the r-Aminoallylation of Alde-
hydes: (3R,10S,Ss)-N-(tert-Butanesulfinyl)-3-(1-amino-3-phenyl-
propyl)cyclohexene (4n). A mixture of indium powder (173 mg,
1.50 mmol), (SS)-N-tert-butanesulfinamide (2, 121 mg, 1.00 mmol),
phenylpropanal (1a, 150 μL, 1.15 mmol), and Ti(OEt)4 (450 μL,
2.00 mmol) in THF (2 mL) was stirred under argon for 1 h at
23 °C. At this time, allylic bromide 3d (254 mg, 1.50 mmol) was
added and the reaction mixture heated for 5 h at 60 °C. The
mixture was allowed to cool to room temperature, quenched with
Supporting Information Available: Experimental proce-
1
dures, full characterization, and copies of H and 13C NMR
spectra of all compounds and X-ray crystal data for compound
4n. This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 18, 2010 6311