Stereoselective Alkylation of (S)-N-Acyl-4-isopropyl-1,3-thiazolidine-2-thiones Catalyzed by (Me3P)2NiCl2

Article abstract of DOI:10.1021/acs.orglett.5b01626

The structurally simple (Me₃P)₂NiCl₂ complex catalyzes S_N1-type alkylations of chiral N-acyl thiazolidinethiones with diarylmethyl methyl ethers and other stable carbenium cations. The former can contain a varie

Full text of DOI:10.1021/acs.orglett.5b01626

Letter
pubs.acs.org/OrgLett
Stereoselective Alkylation of (S)‑N‑Acyl-4-isopropyl-1,3-thiazolidine-
2-thiones Catalyzed by (Me3P)2NiCl2
Javier Fernandez-Valparís,† Juan Manuel Romo,† Pedro Romea,*,† Felix Urpí,*,† Hubert Kowalski,†
́
̀
and Merce Font-Bardia‡
̀
†Departament de Química Organ
Carrer Martí i Franques
‡Unitat de Difraccio
̀
ica and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona,
́
1-11, 08028 Barcelona, Catalonia, Spain
́
de RX. CCiTUB. Universitat de Barcelona, Carrer Sole i Sabarís 1-3, 08028 Barcelona, Catalonia, Spain
́
S
* Supporting Information
ABSTRACT: The structurally simple (Me3P)2NiCl2 complex
catalyzes SN1-type alkylations of chiral N-acyl thiazolidinethiones
with diarylmethyl methyl ethers and other stable carbenium cations.
The former can contain a variety of functional groups and
heteroatoms at the α-position. The resultant adducts are isolated as
single diastereomers in high yields and can be converted into
enantiomerically pure derivatives in a straightforward manner.
Scheme 1. Direct SN1-Type Alkylations
he asymmetric C-α-alkylation of carbonyl compounds is
Tone of the most valuable tools for the stereoselective
construction of carbon−carbon bonds.1 Conventional alkyla-
tions proceed through an SN2-type mechanism and thus require
highly nucleophilic species, such as metal enolates or enamines,
together with sterically nonhindered and activated alkyl halides
or sulfonates. Despite the tremendous accomplishments
achieved in this area, the need to expand the scope of such
transformations has recently triggered the introduction of a
variety of new concepts. Indeed, MacMillan devised highly
enantioselective α-alkylations of aldehydes based on a new
SOMO activation mode,2 which was later enhanced by merging
photoredox catalysis with organocatalysis.3,4 Zakarian exploited
the biradical character of titanium enolates5 for dual Ti−Ru
catalysis in the direct radical haloalkylation of chiral oxazolidi-
nones.6 In turn, Jacobsen reported enantioselective SN1-type
additions of silyl ketene acetals to prochiral oxocarbenium
intermediates generated catalytically by anion binding of chiral
thioureas to glycosyl chlorides.7,8 Besides this, Jacobsen,9
Melchiorre,10 and Cozzi11 also reported organocatalytic
alkylations of aldehydes with diarylmethyl derivatives, which
presumably proceed through an SN1-type mechanism.12 More
recently, Jorgensen has devised an insightful strategy for the
asymmetric alkylation of aldehydes based on the 1,6-conjugated
addition of chiral enamines to p-quinone methides, which
permits the simultaneous installation of two new stereo-
centers.13,14
required partners for the desired alkylations. If such a reaction
occurs, the outstanding stereocontrol imparted by the
thiazolidinethione scaffold on the configuration of the α-chiral
center18 could produce a single diastereomer of the alkylated
adduct that could eventually be converted into a plethora of
enantiomerically pure derivatives by removal of the chiral
auxiliary.19
Preliminary experiments with (S)-4-isopropyl-N-propanoyl-
1,3-thiazolidine-2-thione (1), 4,4′-dimethoxybenzhydrol,
(Me3P)2NiCl2 as the catalyst, TESOTf as the Lewis acid, and
2,6-lutidine as the base did not furnish the desired alkylated
adduct even after long reaction times (entry 1 in Table 1).
Considering that the lack of reactivity could be due to the poor
nature of the OH as the leaving group, parallel alkylations with a
variety of derivatives were next assessed. Silyl protected 4,4′-
dimethoxybenzhydrol also proved to be completely unreactive
(entry 2 in Table 1); but we were pleased to observe that the
corresponding methyl ether afforded alkylated adduct 2a in a
94% yield, as a single diastereomer (entry 3 in Table 1). Having
Taking advantage of these precedents and our own experience
in this field,15 we envisaged that chiral N-acyl thiazolidinethiones
might undergo highly stereoselective SN1 direct type alkylations
catalyzed by structurally simple, commercially available, and easy
to handle nickel(II) complexes.16,17 As shown in Scheme 1, the
parallel generation of putative nickel(II) enolates by the action of
(R3P)2NiL2 catalysts and carbocationic intermediates by Lewis
acid treatment of appropriate E−X substrates might provide the
Received: June 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01626
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Once the synthetic potential of such an alkylation was
established, the optimized conditions were then applied to a wide
range of diarylmethyl methyl ethers. The outcome of these
alkylations proved to be strongly dependent on the substituents
on the aromatic rings; so the conditions reported in entry 3 of
Table 1 were applied. As represented in Scheme 3, the reaction
Table 1. Preliminary Studies on the Alkylation of 1
Scheme 3. Alkylation of 1 with Ar2CHOMe
a
entry
X
(Me3P)2NiCl2 (mol %)
time (h)
yield 2a (%)
b
1
H
5
15
15
15
1
nr
nr
94
94
93
92
92
b
2
TES
Me
Me
Me
Me
Me
Me
Me
5
b
3
5
b
4
5
c
5
2.5
1
15
15
5
c
6
c
7
1
c
d
8
0.5
48
72
71
c
9
nr
a
b
Isolated yield after chromatographic purification. 1.2 equiv of
c
d
TESOTf. 1.15 equiv of TESOTf. 25% of 1 was recovered.
identified the appropriate leaving group, we then examined the
influence of catalyst loading and reaction time.20 The reaction
turned out to be much faster than expected: alkylated adduct 2a
was isolated in an excellent yield after just 1 h (compare entries
3−4 in Table 1). It should be noted that the reaction was also
completed using 2.5 and 1 mol % and afforded 2a in a yield of up
to 93% after 15 h (entries 5−6 in Table 1) and indeed at shorter
reaction times (entry 7 in Table 1). Smaller amounts of catalyst
were unable to mediate quantitative conversions even after long
reaction times, but a tiny 0.5 mol % load was enough to produce
2a in a remarkable 71% yield after 48 h (entry 8 in Table 1). This
indicates that the catalyst attains an outstanding turnover value of
ca. 140. Finally, the reaction did not take place in absence of
(Me3P)2NiCl2 (entry 9 in Table 1). All together, these results
prove that alkylation of 1 with 4,4′-dimethoxybenzhydryl methyl
ether is catalyzed by 1−5 mol % of (Me3P)2NiCl2 to produce
adduct 2a as a single diastereomer in 92−94% yield in a simple
and very efficient manner.
All these reactions were carried out at a 0.5 mmol scale; but
they could easily be scaled-up. Indeed, alkylated adduct 2a was
prepared in a 92% yield at the 5 mmol scale (2.05 g) from 1.2
equiv of the methyl ether after keeping the reaction mixture in
the freezer (−20 °C). Moreover, the chiral auxiliary was removed
in a straightforward manner to obtain enantiomerically pure
alcohol and morpholine amide derivatives in high yields, as
shown in Scheme 2.21
gives excellent yields, provided that the electrophile contains
electronically rich aromatic rings. Indeed, substrates containing
one or two ether, thioether, or amine groups on the aryl moiety
produced the alkylated adducts 2 as single diastereomers in yields
of up to 96%.22 The less stabilized methyl substituted
counterpart in contrast just afforded adduct 2e in a poor 10%
yield, and the simple benzhydryl methyl ether did not react at all.
Running parallel to these reactions, N-acyl thiazolidinethiones
5−13 shown in Scheme 4 were smoothly alkylated with 4,4′-
dimethoxybenzhydryl methyl ether to afford adducts 14a−22a as
single diastereomers in excellent yields. The alkylation was not
affected by the steric hindrance of R, and even thiazolidinethione
7, which possesses a bulky isopropyl group, produced adduct 16a
in a 94% yield. The presence of neither an alkene nor an ester
group in R was not a problem, and adducts 17a and 18a were
obtained in similar yields. Importantly, the alkylation also
succeeded with thiazolidinethiones containing heteroatoms at
the α-position, and adducts 19a−22a were isolated in a yield of
up to 95%, which represents a new and highly appealing way to
prepare enantiomerically pure α-oxygenated and α-nitrogenated
carbonyl compounds. Finally, X-ray analysis of 14a permitted us
to firmly establish the absolute configuration of all these
adducts.23
A plausible mechanism for the above alkylations is outlined in
Scheme 5. Since Sodeoka uncovered the formation of nickel(II)
triflate complexes by treatment of the corresponding nickel(II)
chlorides with TESOTf,24 (Me3P)2Ni(OTf)2 may be the true
catalyst of the alkylation reaction. Thus, addition of this complex
to 1 gives rise to complex I, which can be deprotonated by 2,6-
lutidine to produce chelated Z enolate II. The crucial step in the
overall cycle involves the production of the carbenium
intermediate, [R1]+. If such a species can be generated in situ
from R1−OMe and TESOTf, the isopropyl group at C4 hinders
the approach of the Re face of the enolate to the [R1]+ cation and
Scheme 2. Removal of the Chiral Auxiliary from 2a
B
DOI: 10.1021/acs.orglett.5b01626
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Scheme 4. Alkylation of (S)-N-Acyl-4-isopropyl-1,3-thiazolidine-2-thiones
Scheme 5. Plausible Mechanism for the Stereocontrolled
Catalytic Alkylation of 1
Scheme 6. Stereoselective Alkylations of 1
22% yield, far below the common yields reported in Scheme 4,
but acceptable if one considers the steric bulk of trityl
carbocation. In turn, diastereomerically pure tropylium adduct
2h was isolated in a 74% yield, which proves that the alkylation
described here can be extended to different substrates provided
that the corresponding carbenium intermediates are generated in
situ or added to the reaction mixture.
In summary, the structurally simple and easy to handle
(Me3P)2NiCl2 complex catalyzes SN1-type alkylations of chiral
N-acyl thiazolidinethiones with methyl ethers activated by
TESOTf. Importantly, just 1−5 mol % of the nickel(II) complex
is enough to achieve excellent yields. The acyl group can contain
a variety of alkyl substituents, functional groups, and
heteroatoms at the α-position. In turn, the electrophile
encompasses diarymethyl or trityl methyl ether, and stable
carbenium cations such as the tropylium carbocation. The
resultant adducts are isolated as single diastereomers, usually in
high yields, and can easily be converted into enantiomerically
pure derivatives by the removal of the chiral auxiliary under mild
conditions.
facilitates the stereocontrolled construction of the carbon−
carbon bond in III. Finally, product dissociation regenerates the
catalyst and furnishes diastereomerically pure alkylated adduct
2.25
As the stability of [R1]+ species can be anticipated by
application of Mayr’s scale,26 other carbenium ions were then
identified as potential candidates to undergo the aforementioned
reactions. Taking advantage of such a predictive tool and aiming
to expand the scope of the process, we examined the alkylation of
N-propanoyl thiazolidinethione 1 with methyl trityl ether and
tropylium tetrafluoroborate (C7H7BF4). The former substrate
involves a bulky electrophile, the trityl cation, which represents a
challenging case for any asymmetric alkylation; whereas the
second reagent is a commercially available salt that does not
require further activation. The results shown in Scheme 6 met
our expectations. The trityl derived adduct 2g was isolated with a
C
DOI: 10.1021/acs.orglett.5b01626
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(14) For related additions of β-diketones to o-quinone methides
catalyzed by chiral phosphoric acids, see El-Sepelgy, O.; Haseloff, S.;
Alamsetti, S. K.; Schneider, C. Angew. Chem., Int. Ed. 2014, 53, 7923.
(15) (a) Cosp, A.; Romea, P.; Talavera, P.; Urpí, F.; Vilarrasa, J.; Font-
Bardia, M.; Solans, X. Org. Lett. 2001, 3, 615. (b) Larrosa, I.; Romea, P.;
Urpí, F.; Balsells, D.; Vilarrasa, J.; Font-Bardia, M.; Solans, X. Org. Lett.
2002, 4, 4651. (c) Larrosa, I.; Romea, P.; Urpí, F. Org. Lett. 2006, 8, 527.
ASSOCIATED CONTENT
* Supporting Information
Physical and spectroscopic data for adducts 2a−d and 2g−h,
derivatives 3−4, N-acyl thiazolidinethiones 5−13, and adducts
14a−22a as well as X-ray of 14a. The Supporting Information is
available free of charge on the ACS Publications website at DOI:
10.1021/acs.orglett.5b01626.
■
S
́ ́
(d) Checa, B.; Galvez, E.; Parello, R.; Sau, M.; Romea, P.; Urpí, F.; Font-
Bardia, M.; Solans, X. Org. Lett. 2009, 11, 2193.
(16) For an inspiring precedent of direct reactions of nickel(II) enolates,
see Evans, D. A.; Thomson, R. J. J. Am. Chem. Soc. 2005, 127, 10506.
(17) For a copper-catalyzed asymmetric alkylation of β-keto esters, see
AUTHOR INFORMATION
Corresponding Authors
■
Trillo, P.; Baeza, A.; Naj
(18) Baiget, J.; Cosp, A.; Gal
F. Tetrahedron 2008, 64, 5637.
(19) For an early proof of concept, see Romo, J. M.; Gal
́
era, C. Adv. Synth. Catal. 2013, 355, 2815.
*E-mail: pedro.romea@ub.edu.
*E-mail: felix.urpi@ub.edu.
Notes
́
vez, E.; Gomez-Pinal, L.; Romea, P.; Urpí,
́
́
vez, E.;
Nubiola, I.; Romea, P.; Urpí, F.; Kindred, M. Adv. Synth. Catal. 2013,
355, 2781.
The authors declare no competing financial interest.
(20) Other nickel(II) complexes as (Chx3P)2NiCl2, (Bu3P)2NiCl2,
(Ph3P)2NiCl2, dpppNiCl2, and ddpeNiCl2 were also tested but none of
them improved the results provided by (Me3P)2NiCl2.
(21) Morpholine amides are key intermediates for the synthesis of
derived ketones, see Martín, R.; Romea, P.; Tey, C.; Urpí, F.; Vilarrasa, J.
Synlett 1997, 1997, 1414.
ACKNOWLEDGMENTS
Financial support from the Spanish Ministerio de Economia y
■
́
Competitividad (Grant No. CTQ2012-31034), and the General-
itat de Catalunya (2014SGR586) as well as doctorate student-
ships to J.F.-V. (APIF−IBUB) and J.M.R. (FPU, Ministerio de
(22) The lower yield for methyl thioxanthydryl ether was due to the
poor stability of 2d.
́
Educacion) are acknowledged.
(23) Crystallographic data for 14a has been deposited at the
Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC 1401881. A copy of the data can be obtained free of charge
on application to CCDC (E-mail: deposit@ccdc.cam.ac.uk).
(24) (a) Suzuki, T.; Hamashima, Y.; Sodeoka, M. Angew. Chem., Int. Ed.
2007, 46, 5435. (b) Hamashima, Y.; Nagi, T.; Shimizu, R.; Tsuchimoto,
T.; Sodeoka, M. Eur. J. Org. Chem. 2011, 2011, 3675.
(25) For a related mechanism, see ref 16.
(26) (a) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker,
B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel, H. J.
Am. Chem. Soc. 2001, 123, 9500. (b) Mayr, H.; Kempf, B.; Ofial, A. R.
Acc. Chem. Res. 2003, 36, 66.
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DOI: 10.1021/acs.orglett.5b01626
Org. Lett. XXXX, XXX, XXX−XXX