Stereoselective thia-Michael 1,4-Addition to Acyclic 2,4-Dienones and 2-En-4-ynones

Article abstract of DOI:10.1002/adsc.201501138

Organocatalyzed highly stereoselective 1,4-thia-Michael addition of mercaptans to linear 2,4-dienones and 2-en-4-ynones was developed using Cinchona alkaloid-based squaramides. Application of only 0.5-1 mol % loading afforded products in up to 98:2 e.r. and above 99:1 after a single recrystallization. The adducts of allyl mercaptan can be conveniently further transformed to new chiral 2-substituted 2,5-dihydrothiophenes by ring-closing metathesis.

Full text of DOI:10.1002/adsc.201501138

FULL PAPERS
DOI: 10.1002/adsc.201501138
Stereoselective thia-Michael 1,4-Addition to Acyclic 2,4-Dienones
and 2-En-4-ynones
a,
a
´
Rafał Kowalczyk * and Przemysław J. Boratynski
a
Department of Organic Chemistry, Wrocław University of Technology, 50-370 Wrocław, Poland
Fax: (+48)-713202427; Phone: +4871 3203302; e-mail: rafal.kowalczyk@pwr.wroc.pl
Received: December 14, 2015; Revised: January 21, 2016; Published online: March 2, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501138.
Abstract: Organocatalyzed highly stereoselective 1,4- tion. The adducts of allyl mercaptan can be conven-
thia-Michael addition of mercaptans to linear 2,4-di- iently further transformed to new chiral 2-substituted
enones and 2-en-4-ynones was developed using Cin- 2,5-dihydrothiophenes by ring-closing metathesis.
chona alkaloid-based squaramides. Application of
only 0.5–1 mol% loading afforded products in up to Keywords: conjugate addition; dienones; enynones;
98:2 e.r. and above 99:1 after a single recrystalliza- organic catalysis; squaramides; thia-Michael addition
Introduction
sired mixture of regioisomers. So far there are no re-
ported examples of enantioselective 1,4-additions of
The enantioselective thia-Michael reaction, that is, ad- thiols to either 1 or 2.
dition of thiols to a,b-unsaturated carbonyl com-
pounds, is one of the most valuable synthetic methods
in organosulfur chemistry.[1] Products of this transfor-
mation include many biologically active compounds
and top-selling medicines.[2] Although the use of
simple Michael acceptors is now well-established,[3]
the reactions of multiply functionalized analogues
remain challenging.[4] For example, additions to
a,b,g,d-diunsaturated carbonyl compounds are expect-
ed to produce allylic sulfides[5] that could serve as at-
tractive
intermediates
in
targeted
synthesis
(Scheme 1). Nevertheless, there are few reported ap-
plications of such reactions.[6] The extension of the p-
system of the Michael acceptor with an additional
double or triple bond comes at the cost of ambiguous
regioselectivity, and may be beyond the scope of
asymmetric catalysts routinely used for simple accept-
ors.
In acyclic conjugated dienone 1, the presence of
a substituent at the end of the p-system (i.e., R1 is dif-
ferent than a hydrogen atom in Scheme 1) generally
renders 1,6-addition unfavorable.[7] It was only recent-
ly shown, that the use of a specially tailored iron(III)-
salen complex could provide such regioselectivity.[8]
On the other hand, conjugated ynenone 2 was shown
to react with strongly nucleophilic thiophenol[9] or
even phosphines[10] at the end of the conjugated
system, despite the substitution (Scheme 1). Also pos-
Scheme 1. Conjugate 1,4- and 1,6-Michael additions to 1 and
sible is a non-selective reaction producing an unde- 2 and subsequent reactions of the products.
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Rafal Kowalczyk et al.
In this paper we describe organocatalyzed Michael mixture of mono and di-addition products as con-
1,4-addition to carbonyl compounds of extended con- firmed by NMR and ESI-MS. Nevertheless, at lower
jugate p-systems 1 and 2. Also we aim to prove the excess of the mercaptan the reaction remained highly
utility of the adducts of allyl mercaptan to 1 in further selective, and only the 1,4-adduct was formed. The
modifications.
preferential attack of benzyl mercaptan at the b-posi-
tion (double bond) but not at the d-position (triple
bond) in 2 may be ascribed to the differences in polar-
izability between these units. The alkene is more po-
larizable compared to the alkyne, and the proximity
Results and Discussion
Additions of benzyl thiol to Michael acceptors with of the alkene to the carbonyl group results in greater
two conjugated double bonds (1) or a triple and inductive activation.
double bonds (2) were studied. Initial experiments
Several chiral organic catalysts were screened in
showed that reactions of both acceptors catalyzed the reaction. Chalcones as well as cyclic dienones un-
either by simple bases or bifunctional organocatalysts dergo addition of benzylthiol with high enantioselec-
proceeded solely toward 1,4-addition. However, the tivity using covalent catalysis (iminium ion cataly-
two extended Michael acceptor classes 1 and 2 differ sis).[13] However, this strategy provided only poor
significantly in terms of reactivity. Diene 1a is much enantioselectivity for the transformations of both
less reactive than simple acceptors. In a competitive 1 and 2. Nevertheless, much better stereocontrol was
experiment the transformation of 1a was approxi- achieved for bifunctional catalysts possessing both
mately 5 times slower than that of chalcone. Also the a hydrogen-bond donor and tertiary amine. Out of
conversion of 1a was never complete, and in a typical the assayed catalysts (Figure 1, Table 1) the Cinchona
reaction an excess of thiol was required to obtain an alkaloid-derived squaramides[14] were particularly ef-
acceptable yield. In contrast, the yn-ene 2a was signif- fective for both additions to 1 and 2. The structurally
icantly more reactive providing consistently near com- related thioureas as well as catalysts of a different
plete conversions.
chiral scaffold were less selective. However, variation
In a competitive experiment monitored by NMR, in the achiral amide residue in squaramides C7–C10
an equimolar mixture of 1a and 2a was treated with did not influence the stereochemical outcome of the
a half equivalent of benzyl mercaptan in the presence reaction leading to almost the same enantioselectivity
of a bifunctional squaramide catalyst. Nearly exclu- as C6. This was confirmed for both electron-rich and
sive addition to 2a was observed within 24 h.[11] The
addition to 1a remaining in the mixture was observed
after applying an excess of thiol. The differences in
site selectivity between Michael acceptors 1 and 2
were also demonstrated in response to a varying
excess of benzyl mercaptan. Less active dienone 1 re-
acted in a 1,4-mode regardless of the amount of nu-
cleophile, while the outcome of addition to ynenone
2[9] was strongly dependent on the quantity of thiol
(Scheme 2). When used in three-fold excess, the mer-
captan reacts unselectively,[12] forming an inseparable
Scheme 2. Base and organocatalyzed conjugate addition to
1 and 2
Figure 1. Organocatalysts
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Stereoselective thia-Michael 1,4-Addition
Table 1. Catalyst screening for addition of benzyl mercaptan
to 1 and 2[a]
C14 and C6 gave different enantiomers of products in
similar enantioselectivity.
The enantioselectivities of the reactions of 2 were
more affected by small variations in the structure of
catalyst than that of 1. The highest ee in addition to 2
was achieved with the catalyst C14 having a quinidine
core. On the other hand, reaction of 1 was best cata-
lyzed by a cinchonidine-derived C13.
Entry
Catalyst
Loading
Yield (%)[b]
e.r.[c]
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C7
C8
10 mol%
10 mol%
10 mol%
20 mol%
10 mol%
1 mol%
1 mol%
2 mol%
2 mol%
2 mol%
5 mol%
2 mol%
1 mol%
5 mol%
1 mol%
88
26:74[d]
55:45
79:21[d]
42:58[d]
70:30
93:7
94:6
93:7
93:7
93:7
50:50
88:12
7:93
95:5
96:4
14
n.d.[e]
89
The influence of catalyst loading was examined for
the two most effective catalysts C13 and C14. The
model reaction of benzyl mercaptan and diene 1a cat-
alyzed by C13 revealed that 1 mol% of the catalyst in
dichloromethane led to the product in good yield and
92% ee. Surprisingly, an increase in loading led to
worse results. Interestingly, 0.5 mol% of squaramide
C13 gave adduct 3a with better ee (93%), at the cost
of fairly diminished yield (56%). Further decrease in
loading to 0.2 mol% resulted in a decline of both the
yield (30%) and ee (86%).[11] Also, lowering the tem-
perature to À208C led to an unexpected deterioration
of stereoselectivity down to 66% ee and seriously af-
fected the yield (23–29%). Similar effects of catalyst
loading on the stereochemical outcome of reaction
were noted for acceptor 2a.
In general, the use of 1 to 2 mol% of catalysts C13
and C14 provided optimum results in terms of yield
and ee. The observation that higher catalyst concen-
trations induced deterioration of their efficiency sug-
gests significant self-association of the catalyst. How-
ever, it turned out that the reactions were affected by
the choice of solvent only to a minor extent. Among
several tested solvents, the best results were achieved
by application of dichloromethane for 1a and toluene
for 2a (Table 1, entry 29, Tables S1-S2, SI).
The optimized conditions were used to evaluate the
scope of sulfur nucleophiles in the Michael addition
to acceptors 1a and 2a (Figure 2). Several benzyl
mercaptans and allyl thiol reacted with diene 1a and
afforded products in good yield and enantiomeric
ratios close to 95:5. The highest selectivity (97% ee)
was achieved for tert-butylbenzyl mercaptan. Substitu-
tion of the benzene ring in the mercaptan did not in-
terfere with the yield or stereochemical outcome
through steric interactions, as exemplified by the reac-
tions of a few ortho-substituted benzyl mercaptans.
n.d.[e]
82
54
40
47
9
C9
10
11
12
13
14
15
C10
C11
C12
C14
C13
C13
51
n.d.[e]
61
68
61
70
16
17
18
19
20
21
22
23
24
25
26
27
28
29
C1
C5
C6
C6
C7
C8
C9
C10
C11
C12
C13
C14
C14
C14
5 mol%
5 mol%
5 mol%
1 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
1 mol%
1 mol%
99
81
43
92
90
85
99
99
92
99
84
99
90
86
70:30
70:30
22:78
13:87
11:89
11:89
13:87
14:86
37:63
16:84
7.5:92.5
94:6
94:6
97.5:2.5[d]
[a]
Reaction was performed in a 0.3–0.25 mmol scale apply-
ing 1.2–1.5 equiv of benzyl mercaptan in dichlorome-
thane (0.1M) for 20 h at r.t.
After column chromatography.
Determined by HPLC.
[b]
[c]
[d]
[e]
Reaction run in toluene.
Not determined.
electron-poor aryls, as well as a tert-butyl group. Nev- On the other hand, the presence of electron-donating
ertheless, with one particular flexible residue (3,5-bis- substituents, such as in 4-methoxybenzyl mercaptan
trifluoromethylbenzylamine) in C11, the reactions led to a significant decrease in the yield, but not enan-
gave racemic or nearly racemic products.
tioselectivity (91% ee). These results suggest that the
Modification of the Cinchona alkaloid residue at retro-addition of electron rich mercaptans to 1a may
the 2’-position of quinoline ring was previously re- be a serious limitation. Also, no product was isolated
ported to improve catalyst efficiency.[15] However, in the reaction of 1a and lauryl mercaptan. On the
such modification in C12 only deteriorated the enan- other hand, the use of aromatic thiols was detrimental
tioselectivity in the reactions of 1 and 2.
for the enantioselectivity. Thiophenol and 1a gave ad-
Both antipodes of addition products were obtaina- dition products in e.r. of up to 73:27. It is noteworthy
ble through proper choice of catalyst diastereomer. that other Cinchona alkaloids and their dimeric
Application of quinidine- and quinine-based catalysts ethers, provided even lower degree of enantioselectiv-
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Rafal Kowalczyk et al.
tems, that is, at the carbonyl group and at the d-posi-
tions. The acceptors were tested in the addition of
benzyl mercaptan under previously optimized condi-
tions for 1a and 2a (Table 2). In all the studied cases
only the 1,4-addition products were formed. The
nature of the substituent at the d-position had no no-
ticeable effect on the reaction outcome. Small but
Table 2. Scope of Michael acceptors[a]
Entry Acceptor, R1, R2
Yield
(%)[b]
e.r.[c]
1
2
3
4
5
1a, Ph
1c, Ph
1d, Ph
1e, Ph
1 f, Ph
Ph
4-FC6H4
4-ClC6H4
4-CH3C6H4 51
4-
67
51
59
96:4
93:7
97:3
97:3
91:9
57
MeOC6H4
4-PhC6H4
2-naphthyl 73
3-NO2C6H4 65
2-NO2C6H4 61
2-ClC6H4
2-BrC6H4
2-thienyl
CH3
6
7
8
9
10
11
12
13
14
15
1g, Ph
1h, Ph
1i, Ph
1j, Ph
1k, Ph
1l, Ph
1m, Ph
1b, Ph
51
97:3(99:1)
96:4(99:1)
95:5
89:11
92:8
90:10
95:5
90:10
95.5:4.5
92:8
44
77[d]
64
15[e]
81
Figure 2. Scope of the thiols in the reaction with acceptors
1a and 2a catalyzed by C13 and C14, respectively. Values in
parentheses correspond to e.r. after a single recrystalliza-
tion.
1n, 4-ClC6H4 Ph
1o, 2-
NO2C6H4
1p, 2-furyl
Ph
Ph
73
16
88[d]
95:5
ity (up to 34:66 e.r. for the (DHQ)2AQN), despite
their successful applications in addition of thiophenol
to simple chalcones.[16] In contrast the reaction of this
thiol with more reactive acceptors 2 resulted in nearly
racemic products (9% ee for 2d). The marked differ-
ences in enantioselectivity obtained for aliphatic mer-
captans and aromatic thiols were reported previously
for other types of Michael acceptors as well.[17]
In general, the thia-Michael reaction of the tested
mercaptans with acceptor 2a occurred with high
enantioselectivity regardless of the nucleophileꢁs
structure. The greater reactivity of this acceptor re-
sulted in efficient transformations even using mercap-
tans unreactive with 1a, that is, 4-methoxybenzyl mer-
captan and 2-phenylethane thiol. Also, better yields
of the adducts were obtained in comparison to the
corresponding reactions of dienone 1a. However, the
lower yields achieved for acceptors 1 are to some
extent attributable to the difficulty in separating the
products from unreacted starting material.
17
18
19
20
21
22
2a, Ph
2c, Ph
2d, Ph
2e, Ph
2 f, Ph
2g, Ph
Ph
86
92
95
99
97.5:2.5
98:2
98:2
96:4
96:4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4 74
4-
MeOC6H4
CH3
Ph
Ph
Ph
72
97:3
23
24
25
26
27
28
29
2b, Ph
43[f]
94
94
54
99
97
88
22:78
98:2
98:2
96.5:3.5
98:2
96:4
2h, 4-FC6H4
2i, 4-ClC6H4
2j, 2-ClC6H4
2k, 2-naphthyl Ph
2l, 2-thienyl
2m, nBu
Ph
Ph
97:3
[a]
Reaction was performed using 1 mol% of catalysts in
a 0.25–0.3 mmol scale applying 1.2–1.5 equiv of benzyl
mercaptan for 20 h at r.t.
After column chromatography.
Determined by HPLC. Values in parentheses correspond
to e.r. after single recrystallization.
Reaction run with 3-fold excess of thiol.
Catalyzed by C6.
Performed using 5 mol% of C6.
[b]
[c]
In an attempt to better understand the nature of
the interactions between the Michael acceptor and
the catalyst, a series of analogues of 1 and 2 were ob-
tained with different groups at the ends of the p-sys-
[d]
[e]
[f]
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Stereoselective thia-Michael 1,4-Addition
visible differences were observed for compounds with
differently substituted aryl groups adjacent to the car-
bonyl. Poorer enantioselectivities were obtained for
ortho-substituted derivatives of 1. However, particu-
larly worse results in terms of both the yield and
enantioselectivity were obtained for alkyl-substituted
carbonyl derivatives 1b and 2b.
Interestingly, no deterioration of stereoselectivity
was observed when a mixture of isomers (Z and E) of
Michael acceptor 2 was applied, compared to purely
E material. Notably, reaction of (E)-2 f gave the prod-
uct with 92% ee, while the mixture of isomers (E/Z
9:1 by NMR) subjected to an analogous reaction led
to the same product with identical yield and 94% ee.
These results most likely stem from the reversibility
of the addition. The stereoconvergence of the reac-
tion alleviates the need for the isomeric purity of Mi-
chael acceptors, and makes the transformation practi-
cal even for reactants for which isomers are too diffi-
cult to separate (e.g., 2m). In contrast, the additions
of mercaptans to unsymmetrically substituted fuma-
rate and maleate gave enantioenriched and racemic
products, respectively.[4b]
Figure 3. X-ray structure of 3g. Ellipsoids are set at 30%
probability, the terminal ring of biphenyl group is disordered
equally between two positions.[18]
A single recrystallization of some adducts resulted
in an enhancement of optical purity, providing sam-
ples of e.r. close to 99:1. As a further extension of the
studied reactions, we developed an alternative proto-
Figure 4. Plausible approach of the nucleophile to 1a (for
col for the reactions of dienones. The troublesome pu- a computational approach, see Figure S3, SI)
rification step via column chromatography was re-
placed with a brief filtration through a plug of silica
gel to remove catalyst, and subsequent recrystalliza- the basic center of the quinuclidine directs the ap-
tion from methanol. For compound 3g, the crystalline proach of the nucleophile (Figure 4).[14]
product was obtained in 99:1 e.r. and 78% yield.
The products of stereoselective monoadditions to
However, the same reaction mixture processed acceptors 1 and 2 have a remaining double or triple
through standard column chromatography (requiring bond. Extra functionalities could be introduced with
careful separation from unreacted starting material) a proper choice of nucleophile. Also, the nucleophilic
gave the product in only 51% yield and 97:3 e.r.
sulfur atom in sulfides is known to coordinatively pro-
The structures of all the products were confirmed mote ruthenium-catalyzed metathesis reaction[19] and
in NMR experiments. The crystals of 3g (obtained is tolerated in palladium-catalyzed transformations.[20]
using catalyst C13) undergo reversible phase transi- As a result the products are prone to further modifi-
tion observed in DSC between 17 and 218C. In an X- cations. Consequently, the synthetic utility of obtained
ray study at 300 K the asymmetric unit of P21 space allyl sulfides was exemplified in an intramolecular
group contained one molecule in the asymmetric part. ring-closing methathesis reaction. The adduct of allyl
At a lower temperature the crystals changed and the mercaptan was transformed to a chiral 2-substituted
unit cell volume nearly quadrupled. Based on the X- dihydrothiophene[19b,21] in modest yield (Scheme 3).
ray diffraction data at 300 K the (R)-configuration for Among the tested RCM catalysts, a modified Hovey-
the product 3g was assigned unequivocally (Figure 3) da–Grubbs catalyst (Green-cat)[22] offered the best
with an appropriate value of Flack parameter yield of the cyclic product. The reaction operated in
(À0.04(8)). Tentatively, the same configuration was commercial grade, non-degassed ethyl acetate with
ascribed to all the dienone adducts, and the (S)-con- full substrate conversion. The catalyst was easy to
figuration to the en-ynones adducts catalyzed by the remove from the crude reaction mixture.
pseudoenantiomeric catalyst C14.
The configuration observed in the X-ray structure
is consistent with the stereochemical outcomes ob- Conclusions
served for simple Michael acceptors and similar cata-
lysts. The catalyst most likely forms hydrogen bonds We have developed catalytic systems for asymmetric
with the ketone group of the Michael acceptor while 1,4-thia-Michael addition of mercaptans to challeng-
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Experimental Section
A solution of catalyst C13 or C14 (1.0 mol%) and acceptor
1 or yn-enone 2 (0.3 mmol for 1 and 0.25 mmol for 2) in di-
chloromethane or toluene (0.1M) was stirred at r.t. for 15–
20 min. Then a solution of thiol (1.2–1.5 equiv) in the same
solvent (0.6M) was added dropwise and the resulting homo-
genous mixture was stirred for 20 h at r.t. The reaction mix-
ture was then diluted with about an equal volume of chloro-
form and passed through a plug of silica gel (5–10 g). Elu-
tion by a total volume of 100 mL chloroform afforded crude
product, which was further purified using column chroma-
tography (silica gel, hexanes/AcOEt, 15:1, v/v). Enantiomer-
ic excess was determined using HPLC on chiral stationary
phase (AD-H, OD-H).
Acknowledgements
We thank National Science Center (NCN) Poland for fund-
ing, grant No. 2011/03/D/ST5/05766. We are grateful to Prof.
Tadeusz Lis for X-ray study of 3g, Miss. Aleksandra J.
Wierzba for preparation of catalyst C3 and Dr. Małgorzata
Serwadczak for the DSC analysis of 3g.
1294
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Adv. Synth. Catal. 2016, 358, 1289 – 1295

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