Diastereoselective allylation and crotylation of N-tert-butanesulfinyl imines with allylic alcohols

Article abstract of DOI:10.1039/c4cc02317j

The palladium-catalyzed allylation of N-tert-butanesulfinyl imines with allylic alcohols in the presence of InI as reducing reagent takes place with high diastereoselectivity in reasonable yields. The reaction with crotyl alcohol is totally regioselective

Full text of DOI:10.1039/c4cc02317j

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Diastereoselective allylation and crotylation of
N-tert-butanesulfinyl imines with allylic alcohols†‡
Cite this: Chem. Commun., 2014,
50, 6898
Olga Soares do Rego Barros,§ Juan Alberto Sirvent, Francisco Foubelo* and
Received 28th March 2014,
Accepted 23rd April 2014
Miguel Yus*
DOI: 10.1039/c4cc02317j
www.rsc.org/chemcomm
The palladium-catalyzed allylation of N-tert-butanesulfinyl imines stereoselective allylation of imine derivatives with allylic halides in the
with allylic alcohols in the presence of InI as reducing reagent takes presence of reducing metals under Barbier-type reaction conditions
place with high diastereoselectivity in reasonable yields. The reaction (metalation in the presence of the electrophile) is also of interest,
with crotyl alcohol is totally regioselective, leading to the anti- because this strategy circumvents the need of isolating allyl metal
diastereomer as the main reaction product.
species (the real nucleophiles), which usually are sensitive, and in
many cases also toxic. The most commonly used metals in these
The stereoselective allylation of imines using organometallic transformations are chromium,6 indium7 and zinc.8 Particularly
compounds is of great interest in synthetic organic chemistry noteworthy is the use of allylic alcohols as allylating reagents of
because the resulting homoallylic amines are valuable building carbonyl compounds and imines under palladium catalysis in the
blocks.1 For instance, the double bond of the allylic moiety presence of a reducing reagent.9 More recently, the use of the
can participate in a number of further synthetically useful Kulinkovich reagent in the coupling of allylic alcohols with aldimines
transformations: hydroboration, hydration, epoxidation, hydro- provides an alternative approach to regio-and stereodefined homo-
formylation, ozonolysis, olefin metathesis, etc.2 Among the allylic amines.10 On the other hand, in the growing field of the
stereoselective methodologies, the catalytic enantioselective synthetic applications of chiral N-tert-butanesulfinyl derivatives,11 we
allylations3 rely on the use of chiral Lewis acids or chiral Lewis reported the diastereoselective allylation12 of N-tert-butanesulfinyl
bases. In addition, double activation could be also achieved by aldimines13 and ketimines14 with in situ generated allylindium
using chiral bifunctional catalysts4 by the simultaneous activation of reagents, and the first one-pot a-aminoallylation of aldehydes
both electrophilic and nucleophilic reaction partners through a with chiral tert-butanesulfinamide, allylic bromides, and
cooperative action of different functionalities of the ligand. How- indium, which provides homoallylic amines with high chemo-
ever, and in spite of the rapid evolution of catalytic methods in and stereoselectivities.15 The chiral auxiliary is easily accessible
recent years, the use of stoichiometric reagents (including substrates in both enantiomeric forms in large-scale processes16 and can
and/or allylic organometallic partners) is still the favourite choice of be easily removed under acidic conditions. Continuing our
organic chemists in the synthesis of key intermediates of natural studies on the diastereoselective allylation of chiral sulfinyl
products. In these diastereoselective allylations,5 the stereochemical imines, we report herein the use for the first time of allylic
information can be transferred by substrate control, including chiral alcohols as allylating reagents of these chiral imines.
auxiliaries, or through the use of chiral reagents (reagent control).
The chiral imine 1a derived from (R)-tert-butanesulfinamide
Sometimes a double induction could also be involved in the and 3-phenylpropanal was taken as the imine model for the
process, a match/mismatch effect being possible. Performing the optimization of the reaction conditions in the palladium catalyzed
allylation with allylic alcohols and derivatives. Although many assays
were undertaken, only the most significant ones are compiled in
Table 1. Thus, the reaction of allyl alcohol (2a) with imine 1a in the
´
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Departamento de Quımica Organica, Facultad de Ciencias and Instituto de Sıntesis
´
Organica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain.
presence of InCl3 (1 equiv.), In (2 equiv.) and a substoichiometric
E-mail: foubelo@ua.es, yus@ua.es
† This paper is dedicated to Professor Richard J. K. Taylor on occasion of his amount of Pd(PPh3)4 (5 mol%), in a 1 : 1 mixture of THF and water,17
65 birthday.
led to the expected reaction product 3a (84%) along with the
homoallylic alcohol 4 resulting from the allylation of the aldehyde
after hydrolysis of the starting imine (Table 1, entry 1). However, the
‡ Electronic supplementary information (ESI) available: Experimental proce-
dures, full characterization, and copies of 1H and 13C NMR spectra of compounds
3 and 6. See DOI: 10.1039/c4cc02317j
allylation with allyl acetate (2b) under the same reaction conditions
gave alcohol 4 as the major reaction product and only a small
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§ Permanent address: Instituto de Quımica, Universidade Federal de Goias,
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Campus Samambaia, CEP 74001-970, Goiana, Goias, Brazil.
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Table 1 Optimization of the reaction conditionsa
Productsb
Entry Reaction conditions
1a : 3ac : 4
1
2
3
4
5
6
7
2a (X = H, 1.0 mmol), In (0.4 mmol), InCl3 (0.20 mmol), Pd(PPh3)4 (0.01 mmol), THF/H2O (0.3 mL/0.3 mL), 23 1C (14 h)
2b (X = Ac, 1.0 mmol), In (0.4 mmol), InCl3 (0.20 mmol), Pd(PPh3)4 (0.01 mmol), THF/H2O (0.3 mL/0.3 mL), 23 1C (14 h)
2b (X = Ac, 0.8 mmol), In (0.4 mmol), InCl3 (0.20 mmol), Pd(PPh3)4 (0.04 mmol), THF (1.0 mL), 23 1C (14 h)
0 : 84 : 16
0 : 12 : 88
92 : 8 : 0
2c (X = CO2CH2CHQCH2, 0.8 mmol), In (0.4 mmol), InCl3 (0.20 mmol), Pd(PPh3)4, (0.04 mmol), THF (1.0 mL), 23 1C (14 h) 75 : 15 : 10
2b (X = Ac, 0.8 mmol), In (0.4 mmol), InCl3 (0.20 mmol), Pd(PPh3)4 (0.04 mmol), THF (1.0 mL), 60 1C (14 h)
2a (X = H, 0.8 mmol), InI (0.4 mmol), Pd(PPh3)4 (0.01 mmol), THF (1.0 mL), 23 1C (14 h)
2b (X = Ac, 0.8 mmol), InI (0.4 mmol), Pd(PPh3)4 (0.01 mmol), THF (1.0 mL), 23 1C (14 h)
0 : 95 : 5
0 : 100 : 0
0 : 79 : 21
a
b
c
Reactions were carried out with 0.2 mmol of 1a. Ratio was determined from 1H NMR spectrum of the crude reaction mixture. Major
diastereoisomer is shown.
Table 2 Allylation of chiral imines 1
amount of the desired homoallylamine derivative 3a (Table 1,
entry 2). It seems that allyl acetate (2b) is less reactive than allyl
alcohol (2a) and hydrolysis occurred faster than allylation of the
imine. On the other hand, the allylation with allyl acetate (2b) or
diallyl carbonate (2c) proceeded very slowly when it was performed
exclusively in THF at room temperature, and after 14 hours, 92 and
75%, respectively, of the starting material 1a remained unreacted
(Table 1, entries 3 and 4). Total conversion was observed when the
allylation with allyl acetate (2b) was performed in THF at 60 1C,
producing in this case 3a and 4 in 95 : 5 ratio (Table 1, entry 5).
Fortunately, we were please to find that switching from the combi-
nation In/InCl3 to InI18 as reducing reagent, the palladium catalyzed
allylation of 1a with allyl alcohol (2a) occurred with total conversion
and selectivity at room temperature (Table 1, entry 6), meanwhile
with allyl acetate (2b) an almost 4:1 mixture of the desired amine
derivative 3a and the homoallyl alcohol 4 was obtained (Table 1,
entry 7). We studied next the scope of the allylation of N-tert-
butylsulfinyl imines 1 with different allylic alcohols 2 by applying
the optimized conditions depicted in Table 1, entry 6. The expected
homoallylamine derivatives 3 were obtained in good yields for
aliphatic aldimines and moderate-to-good yields in the case of
aromatic aldimines using allyl (2a) and methallyl alcohol (2d) as
allylating reagents (Table 2). It was also possible to carry out the
allylation of the ketimine derived from butanone with allyl alcohol
(2a) but under more demanding reaction conditions, 60 1C instead
a
b
Major diastereoisomer is shown. Yields were determined for iso-
c
lated compounds after column chromatography. Diastereomeric
ratios were determined by lH NMR analysis of the crude reaction
d
of room temperature in this case (Table 2, compound 3i). Regarding mixture. For comparison, yield and dr reported for compound 3a
obtained by an indium mediated allylation with allyl bromide in THF at
aromatic imines, electron-rich derivatives seemed to perform better
than the electron-poor ones (Table 2, compare compounds 3f and
60 1C.13 e The reaction was performed at 60 1C.
3h). Interestingly, this methodology is compatible with both the use
of functionalized allylic alcohols, such as ethyl 2-(hydroxymethyl)-
The crotylation of chiral imines 1 was also investigated. The
acrylate (2e) (Table 2, compound 3n), and the presence of an active reaction of our imine model compound 1a with crotyl alcohol (2f)
sp2 C–Br bond in palladium catalysis (Table 2, compound 3g). On under the standard conditions produced compound 3o in a regio-
Table 2, yield and diastereomeric ratio for the allylation of chiral selective process with almost total face selectivity and low anti :syn
imine 1a with allyl bromide in the presence of indium metal are also diastereoselectivity (63 : 37), meanwhile, the indium mediated croty-
given in order to compare both methodologies. It could be said that lation of 1a using crotyl bromide (5) occurred with high face-addition
palladium-catalyzed allylation of chiral imines 1 with allylic alcohols selectivity and a similar anti :syn ratio of 61 : 39 (Table 3). Surpris-
is superior to that using allylic halides taking into account stereo- ingly, the palladium-catalyzed crotylation of a-substituted (Table 3,
selectivities. Anyway, in both cases, they show the same sense of the compound 3p) and aromatic imines occurred with high anti-
stereochemical induction which is controlled by the configuration of diastereoselectivity in all cases (Table 3, compounds 3q–v). On the
the sulfur atom of the sulfinyl unit.
other hand, the reaction of these aldimines with crotyl bromide (5)
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Table 3 Crotylation of chiral imines 1
Scheme 2 Desulfinylation of 3q.
the chair-like one III (in this case the syn-isomer would be produced),
due to the steric repulsion between the methyl group and the
substituent of the aldimine (Scheme 1).19 Higher diastereo-
selectivities are obtained for the palladium-catalyzed allylations with
alcohols when the processes are performed at room temperature,
instead of 60 1C. On the other, and according with the proposed
working model, the bulkier the substituent of the starting aldimine
1, the higher diastereoselectivity is obtained (Table 3).
Finally, the tert-butanesulfinyl group was easily removed
from compounds 3q after treatment with a 6 M HCl aqueous
solution in THF to give the known homoallylic amine 620 with
anti-relative configuration (Scheme 2).
In summary, allylation of N-tert-butanesulfinyl imines was per-
formed with high diastereoselectivity with allylic alcohols under
palladium-catalysis. The reaction with crotyl alcohol occurred also in
reasonable yields and high anti-diastereoselectivity in a regioselective
manner. In addition, and comparing to allylic halides, allylic alcohols
are preferable allylating reagents by taking into account environ-
mental (less toxic), economic (less expensive) and availability (numerous
allylic alcohols are commercially available) considerations.
a
b
Major diastereoisomer is shown. Yields were determined for iso-
c
lated compounds after column chromatograph. anti : syn ratios were
determined by 1H NMR analysis of the crude reaction mixture. For
d
comparison, yield and dr reported for compounds 3 obtained by an
indium mediated allylation with crotyl bromide in THF at 60 1C.
proceeded also with better diastereoselectivities than for 1a. A
mechanism has been proposed for this palladium catalyzed allyla-
tions. First a p-allylpalladium complex I is formed. Indium salts
facilitate the process by converting the hydroxy a better leaving group
after coordination.17 Then, the initially formed p-allylpalladium(II)
complex I is reductively transmetalated with indium(I) salts to give
allylindium(III) species II, which is the real allylating reagent.18 Face
selectivity could be explained by considering six-membered cyclic
transition states III (R2 = H) or IV (R = Me) where the indium is
coordinated to both the nitrogen and the oxygen atom of the sulfinyl
imine, taking place a Si-face attack for imines with R-configuration at
the sulfur atom. Regarding the regiochemistry and the diastereo-
selectivity in the crotylation reactions, the indium atom located at
the terminal position in the allyl indium intermediate with
E-configuration, the most stable carbanion, reacts at the g-position
through a cyclic boat-like six-membered transition state IV to
produce the anti-isomer (Scheme 1). This kind of boat-like transition
state IV has been proposed in a similar process to be preferred over
´
We thank the Spanish Ministerio de Ciencia e Innovacion
(Grant No. CTQ2011-24165), the Generalitat Valenciana (Grant No.
PROMETEO/2009/039 and FEDER) and the University of Alicante
for financial support. OSRB thanks CNPq of Brazil for a fellowship.
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