Acid-catalyzed synthesis of functionalized arylthio cyclopropane carbaldehydes and ketones

Article abstract of DOI:10.1039/c8cc07571a

A general strategy for the synthesis of arylthio cyclopropyl carbaldehydes and ketones via a Br?nsted acid catalyzed arylthiol addition/ring contraction reaction sequence has been exploited. The procedure led to a wide panel of cyclopropyl carbaldehydes in generally high yields and with broad substrate scope. Mechanistic aspects and synthetic applications of this procedure were investigated.

Full text of DOI:10.1039/c8cc07571a

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Acid-catalyzed synthesis of functionalized arylthio
cyclopropane carbaldehydes and ketones†
Cite this: Chem. Commun., 2018,
54, 13547
a
a
Stefania Porcu, ‡a Alberto Luridiana, ‡a Alberto Martis,
Angelo Frongia,
b
c
c
c
Received 18th September 2018,
Accepted 12th November 2018
Giorgia Sarais,
David J. Aitken,
Thomas Boddaert,
Regis Guillot
and
a
Francesco Secci
*
DOI: 10.1039/c8cc07571a
rsc.li/chemcomm
A general strategy for the synthesis of arylthio cyclopropyl carbaldehydes reactions have been documented for 2-halocyclobutanones, leading
and ketones via a Brønsted acid catalyzed arylthiol addition/ring to cyclopropane carboxylic acid derivatives,11 while cyclobutanediols
contraction reaction sequence has been exploited. The procedure undergo Lewis acid induced ring contraction to provide cyclo-
led to a wide panel of cyclopropyl carbaldehydes in generally high propane carbaldehyde or ketone derivatives.12
yields and with broad substrate scope. Mechanistic aspects and
synthetic applications of this procedure were investigated.
The synthesis of arylthiocyclopropyl carbaldehydes or carbinols,
however, is limited mainly to stoichiometric metalation of arylthio
ethers followed by trapping with formamides or aldehydes
Due to the ease of its preparation1 and its extensive chemical (Scheme 1(a and b))13–15 or to hydrolysis of cyclopropane carbo-
reactivity2 2-hydroxycyclobutanone 1a constitutes a powerful nitriles (path c).13b To evaluate our hypothesis we first examined
building block for organic synthesis. Recent applications in the reaction between 2-hydroxycyclobutanone 1a and benzenethiol
ring cleavage reactions,3 Wittig reaction acetalization,4 preparation 2a, conducted under neat conditions at room temperature for
of methylenecyclobutane nucleoside analogues,5 synthesis of func- 24 hours using 20 mol% of PTSA as the catalyst. We were delighted
tionalized tryptamines or dioxins,6 stereoselective aldol reactions7 to find that the desired product 3a could be isolated from the
and catalytic a-amination reactions underline the synthetic value of reaction mixture in 48% yield, accompanied by a secondary
this molecule.8,9 Recently, we initiated studies on the preparation product (10% yield), identified as the cyclopropanol thioketal 4a
and reactivity of a related series of compounds, 2-(arylthio)- (Table 1, entry 1). The use of a panel of solvents toluene, n-hexane,
cyclobutanones.10 Their synthesis was achieved through the EtOAc and THF had a deleterious effect (entries 2, 4–6), so it was
organocatalyzed a-sulfanylation of cyclobutanone using diaryl gratifying to observe a significantly higher yield of 3a (93%), along
disulfides.10a Given the reactivity of 1a with other nucleophiles, with traces amount of compound 4a, after only 2 hours reaction
it might appear plausible that it could serve as a convenient pre- time when the reaction was performed in CH2Cl2 (entry 3). A series
cursor for 2-(arylthio)cyclobutanones through substitution reac-
tions with arylthiols 2. However, we hypothesized that the reaction
between 1a and 2 in the presence of a Brønsted acid would result in
the formation of a phenylsulfanyl-cyclobutanediol intermediate I
and therefrom the sulfur-stabilized cationic intermediate II,
which would evolve by ring contraction to furnish cyclopropyl
carbaldehydes 3 (Scheme 1d). Indeed, analogous ring contraction
a
`
Dipartimento di Scienze Chimiche e Geologiche, Universita degli Studi di Cagliari,
S.S. 554, bivio per Sestu, 09042, Monserrato (Ca), Italy. E-mail: fsecci@unica.it
b
`
Dipartimento di Scienze della Vita e dell’Ambiente, Universita degli Studi di
Cagliari, via Ospedale 82, 09124 Cagliari, Italy
c CP3A Organic Synthesis Group & Services Communs, ICMMO (UMR 8182), CNRS,
´
´
Universite Paris Sud, Universite Paris Saclay, 15 rue Georges Clemenceau,
91405 Orsay, cedex, France
† Electronic supplementary information (ESI) available: Full experimental proce-
dures, NMR spectra and X-ray analysis. CCDC 1575152. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c8cc07571a
‡ These authors contributed equally to this work.
Scheme 1 Rational design for the acid-catalyzed synthesis of arylthio
cyclopropyl derivatives.
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Table 1 Solvent and catalyst studiesa,b
Entry
Catalyst (%)
Solvent
Time (h)
3a, (4a) yields (%)
1
2
3
4
5
6
7
8
PTSA (20)
PTSA (20)
PTSA (20)
PTSA (20)
PTSA (20)
PTSA (20)
H2SO4 (20)
MSA (20)
CSA (20)
—
24
24
2
48 (10)
36 (—)
93 (o5)
10 (8)
12 (—)
36 (—)c
68 (10)
66 (5)
49 (—)
23 (—)
— (—)
72 (o5)c
85 (11)
Toluene
CH2Cl2
Hexane
EtOAc
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
24
24
24
24
24
24
24
24
12
2
9
10
11
12
13
TFA (20)
BF3–OEt2 (20)
PTSA (10)
PTSA (30)
a
Reactions were performed with 0.58 mmol of 1a, 2a (1.0 equiv.),
catalyst (10–30 mol%), solvent (2.0 mL) at room temperature, and
b
c
followed by GC-MS. Isolated yield after flash chromatography. Entries
6 and 12 where repeated in the presence of molecular sieves (3 Å) without
yields or selectivity improvement.
of Brønsted acid catalysts were evaluated in CH2Cl2ꢀH2SO4 (entry 7)
gave the phenylthiocyclopropyl carbaldehyde in acceptable
yield (68%), whereas MSA, CSA, and TFA performed less well
(entries 8–10). BF3–OEt2 was ineffective (entry 11).
Catalyst loading was also evaluated (entries 12 and 13) showing
that the optimum yield of 3a was afforded using 20 mol% of
PTSA. With these optimized reaction conditions in hand, we next
examined the reaction scope using a series of substituted
arylthiols (Scheme 2). A high substituent tolerance in arylthiols
2 emerged, allowing access to a good variety of functionalized
carbaldehydes 3. Methyl-substituted arylthiols 2b–g, independently
of their substitution pattern, furnished the corresponding adducts
3b–g in uniformly high yields (92–96%). Similarly, carbaldehyde 3h
was isolated in 92% yield. EDG-substituted p-, m-methoxyarylthiols
2i–j and p-N-acylaminoarylthiol 2k gave good conversions and
yields of the corresponding compounds 3i–k. The reaction with
Scheme 2 Substrate scope exploration. a Reactions were performed with
0.58 mmol of 1a, 2a–r, 2t–v (1.0 equiv.), PTSA 20 mol%, CH2Cl2 (2.0 mL) at
room temperature and followed by GC-MS. b Reaction was carried-out
the more bulky 2-naphthylthiol 2l as the substrate afforded with 0.58 mmol of 1a, benzene selenol 2s (1.0 equiv.), PTSA 20 mol%,
CH2Cl2 (2.0 mL). c Diphenyldiselenide was isolated in 22% yield after
carbaldehyde 3l in 87% yield. Reactions of 1a with haloarylthiols
2m–n ( p-, o-F), 2o ( p-Cl), 2p ( p-Br) and 2q (o-Br) all proceeded
chromatography.
efficiently to afford the adducts 3m–q in excellent yields. The
acid catalyzed ring-contraction of 1a worked well even with the cyclopropyl carbaldehydes 3x and 3y; the predominant reaction
EWG-substituted arylthiols 2r and 2s which provided 3r and 3s products were identified as the cyclobutanones 5x–y.16 To test
in 78% and 84% yields, respectively. Unsatisfactory results were the ring contraction protocol for the synthesis of arylthio-
achieved with 2-pyridylthiol 2t and the carbaldehyde 3t was only cyclopropyl ketones, functionalized 2-hydroxycyclobutanone
observed in trace amounts by 1H NMR analysis of its crude derivatives 1b–e17 were treated with thiophenol 2a in the
reaction mixture. Nevertheless, 2-thiophenethiol 2u was effi- presence of PTSA at room temperature. Pleasingly, as shown
ciently converted into the corresponding adduct 3u in 93% yield. in Scheme 3, ketone 6b was isolated in 90% yield after 8 hours
In order to evaluate further extensions of this procedure, benzene- reaction time.
selenol 2v and some alkylthiols (2w–y) were tested. Reaction of
On the other hand, 1c, bearing a 2-phenyl group, afforded
1a with 2v proceeded smoothly yielding the selenyl-adduct 3v in the corresponding cyclopropane 6c as a 10 : 90 mixture with the
68% yield after 4 hours reaction. Moreover, methyl thioglycolate cyclobutanone 6c0 in a 81% overall yield. A similar result was
2w, afforded 3w in 72% yield. On the other hand, reaction achieved when 2-hydroxy-3-methyl-2-phenyl-cyclobutanone 1d
carried out with 2x and 2y, gave poor yields of the corresponding (50 : 50 cis/trans) was submitted to acid-catalyzed ring-contraction
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Scheme 3 Acid catalyzed formal thiophenol-addition–ring contraction
of 2-hydroxycyclobutanones 1b–1f.
in the presence of thiophenol leading to a 10 : 90 mixture of the
corresponding compounds 6d and 6d0 (70% yield). Finally, with
the aim to investigate the stereochemical tendency of this reaction,
3-benzyloxy-2-ethyl-2-hydroxy-cyclobutanone cis-1e and trans-1e
were submitted to reaction with 2a. Interestingly, both cyclo-
butanones allowed to isolate in appreciable yields the compound
trans-6e as a single diastereoisomer. Analog results were
achieved when 3-benzyloxy-2-hydroxy-2-propyl-cyclobutanone 1f
was treated under the same operational conditions (Scheme 3).
Based on the above results, a plausible mechanism for the acid-
catalyzed ring-contraction is proposed in Scheme 4. As described
on Scheme 1d, protonation of 1a followed by nucleophilic
Scheme 4 Proposed mechanism for the synthesis of compounds 3a–w,
6b, 6c and 6e (see also ESI†).
addition of 2a leads to the formation of the intermediate trans-cyclopropane 6e in good yields (superimposable results were
cyclobutane-1,2-diol-species I.11d,12
obtained by using the cyclobutanone 1f).21
Further loss of water would give the aryl cyclobutylthionium
In an application of this methodology, we carried out the
carbocation II. Ring contraction of this intermediate leads to gram scale preparation of cyclopropylcarbaldehyde 3l, now
the obtainment of carbaldehydes 3 and cyclopropyl ketone 6b obtained in 90% yield, which was used as the starting material for
(Scheme 4, path a). This mechanism has been also investigated using the formal synthesis of the B1-bradykinin receptor antagonist22,23
18O-1a allowing to isolate 18O-3a in 92% yield (18O-incorporation (BK-B1). This was accomplished in four synthetic steps starting from
78%).18 Moreover, cyclobutanones bearing a phenyl group on the 1a (instead of the 14 steps required in the original synthesis)23 as
2-position, might generate two possible carbocation species shown in Scheme 5. In our first approach, aldehyde 3l was treated
(Scheme 4, path b); The first one having a positive charge with the lithium-enolate of ethyl acetate to furnish b-hydroxyester 7
stabilized by the sulfanyl-group (thionium-ion) II0 would prefer- in 79% yield. Oxidation of this compound to sulfone 8 was
entially lead to the formation of the compound 6c. On the other ineffective and the starting material was recovered unchanged after
hand, the protonation of the hydroxy-group and the loss of a several days of treatment with m-CPBA. To circumvent this problem,
molecule of water from the position-2, would generate a benzylic we inversed the order of events: 3l was oxidized efficiently to
carbocation III which would undergo phenylthio [1,2]-shift sulfone 9, obtained in 94% as a white crystalline solid. Addition
through the intermediacy of an episulfonium ion IV and leading of the lithium-enolate of ethyl acetate to this compound
to the prevalent formation of the 2-phenyl-2-phenylsulfanyl- furnished 8 in 82% yield. Finally, facile basic hydrolysis of
cyclobutanone 6c0. Analog result might be achieved by phenyl the ester function gave the sulfone 10 in 88% yield, after
[1,2]-shift from the adduct II0.19 Finally (Scheme 4, path c), crystallization from chloroform.
3-benzyloxycyclobutanones 1e once reacted with 2a can be
In summary, a new Brønsted acid-catalyzed C4–C3 ring
involved in the formation of zwitterionic-like species VI20 contraction reaction has been established which allows access to
by Brønsted acid intermediacy and promoting a ring-opening arylthio- and arylselenyl-functionalized cyclopropyl carbaldehydes
ring-closing donor–acceptor cyclobutane-rearrangement. This and ketones from 2-hydroxycyclobutanone derivatives. The trans-
reactivity has been evoked to justify the stereochemical outcome formation is achieved via a cascade, metal-free process under mild
of this reaction. In fact, both pure cis- and trans-1e independently conditions in which electronic effects of the cyclobutanone species
by their stereochemistry, provided exclusively the corresponding play a crucial role in the ring-contraction/ring opening process.19–21
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7 (a) D. J. Aitken, F. Capitta, A. Frongia, J. Ollivier, P. P. Piras and
F. Secci, Synlett, 2011, 712; (b) D. J. Aitken, F. Capitta, A. Frongia,
J. Ollivier, P. P. Piras and F. Secci, Synlett, 2012, 727.
8 (a) D. J. Aitken, P. Caboni, H. Eijsberg, A. Frongia, R. Guillot, J. Ollivier,
P. P. Piras and F. Secci, Adv. Synth. Catal., 2014, 356, 941; (b) A. Frongia,
N. Melis, I. Serra, F. Secci, P. P. Piras and P. Caboni, Asian J. Org. Chem.,
2014, 3, 378; (c) N. Melis, L. Ghisu, R. Guillot, P. Caboni, F. Secci,
D. J. Aitken and A. Frongia, Eur. J. Org. Chem., 2015, 4358.
9 L. Ghisu, N. Melis, F. Secci, P. Caboni and A. Frongia, Tetrahedron,
2016, 72, 8201.
10 (a) A. F. Vaquer, A. Frongia, F. Secci and E. Tuveri, RSC Adv., 2015,
5, 96695; (b) A. Luridiana, A. Frongia, D. J. Aitken, R. Guillot,
G. Sarais and F. Secci, Org. Biomol. Chem., 2016, 14, 3394.
11 (a) H. Stadler, Helv. Chim. Acta, 2015, 98, 1189; (b) B. B. Snider and
M. Walner, Tetrahedron, 1989, 45, 3171; (c) K. E. Harding,
J. B. Strickland and J. Pommerville, J. Org. Chem., 1988, 53, 4877;
(d) J. M. Conia and J. Salaun, Acc. Chem. Res., 1972, 5, 33.
12 (a) J. P. Barnier, J. M. Denis, J. Salaun and J. M. Conia, Tetrahedron,
1974, 30, 1397; (b) V. Ghembus, L. Karmazin, S. Pira and D. Uguen,
Bull. Chem. Soc. Jpn., 2018, 91, 319.
13 (a) B. M. Trost, W. C. Vladuchick and A. J. Bridges, J. Am. Chem. Soc.,
1980, 102, 3548; (b) B. M. Trost and L. Jungheim, J. Am. Chem. Soc.,
1980, 102, 7910.
Scheme 5 Formal synthesis of the anti-inflammatory BK-B1 receptor
antagonist, 11.
14 (a) T. Cohen, W. M. Daniewski and R. B. Weisenfeld, Tetrahedron
Lett., 1978, 47, 4665; (b) A. M. Bernard, A. Frongia, P. P. Piras,
F. Secci and M. Spiga, Org. Lett., 2005, 7, 4565.
To the best of our knowledge, there is no literature precedent for
this transformation; most known synthetic methods proceed via
pre-formed arylthiocyclopropane intermediates.11–13 The efficient
access to compound 10, the known precursor of a biologically
active compound, suggests that this synthetic methodology may be
of interest for the preparation of other multifunctional cyclopro-
pane derivatives as building blocks in medicinal chemistry.
15 (a) K. Tanaka, H. Uneme, S. Matsui, R. Tanikaga and A. Kaji, Chem.
Lett., 1980, 287; (b) A. M. Bernard, E. Cadoni, A. Frongia, P. P. Piras
and F. Secci, Org. Let., 2002, 4, 2565; (c) A. M. Bernard, A. Frongia,
R. Guillot, P. P. Piras, F. Secci and M. Spiga, Org. Lett., 2007, 9, 541.
16 Regarding the tendency of alkylthiols to produce of 2-
sulfanylcyclobutanones 5 (Scheme 2), we suppose that kinetic
effects and differences in the ability of alkyl and aryl sulfur deriva-
tives to stabilize a positive charge in cyclobutylthionium ions are
consequential in this transformation.
17 W. H. Urry and D. J. Trecker, J. Am. Chem. Soc., 1961, 84, 118.
18 18O-1a was prepared as described in the ESI.† Reaction of this
compound with thiophenol 2a (1.0 equiv.) in the presence of PTSA
(20 mol%) afforded the corresponding carbaldehyde 18O-3a in 92%
yield (18O incorporation 78%). See ESI† for details.
Conflicts of interest
19 L. A. Paquette and J. E. Hofferberth, The a-Hydroxy Ketone (a Ketol)
and Related Rearrangements, 2003, pp. 477–567.
There is no conflict of interest regarding this paper.
20 (a) H.-U. Reissig and R. Zimmer, Chem. Rev., 2003, 103, 1151; (b) J.-I.
Matsuo, Tetrahedron Lett., 2014, 55, 2589; (c) Y. A. Volkova, E. M.
Budynina, A. E. Kaplun, O. A. Ivanova, A. O. Chagarovskiy, D. A.
Skvortsov, V. B. Rybakov, I. V. Trushkov and M. Y. Melni-kov, Chem. –
Eur. J., 2013, 19, 6586; (d) O. A. Ivanova, E. M. Budynina, A. O.
Chagarovskiy, I. V. Trushkov and Y. Melnikov, J. Org. Chem., 2011,
76, 8852; (e) J.-I. Matsuo, S. Sasaki, T. Hoshikawa and H. Ishibashi, Org.
Lett., 2009, 17, 3822; ( f ) J.-I. Matsuo, R. Okado and H. Ishibashi, Org. Lett.,
2010, 12, 3266; (g) A. M. Bernard, A. Frongia, P. P. Piras, F. Secci and
M. Spiga, Org. Lett., 2005, 7, 4565; (h) G. Alberti, A. M. Bernard, C. Floris,
A. Frongia, P. P. Piras, F. Secci and M. Spiga, Org. Biomol. Chem., 2009,
7, 3512.
Notes and references
1 J. J. Bloomfield and J. M. Nelke, Org. Synth., 1988, 6, 167.
2 (a) J. C. Namsylo and D. E. Kaufmann, Chem. Rev., 2003, 103, 1485;
(b) E. Lee-Ruff and G. Mladenova, Chem. Rev., 2003, 103, 1449;
(c) E. Lee-Ruff, The Chemistry of Cyclobutanes, ed. Z. Rappoport and
J. F. Liebman, Wiley, Chichester, 2005, p. 281; (d) J. Salau¨n, Sci.
Synth., 2004, 26, 557; (e) F. Secci, A. Frongia and P. P. Piras,
Molecules, 2013, 18, 15541; ( f ) S. Chen, G. Shan, P. Nie and
Y. Rao, Asian J. Org. Chem., 2015, 4, 16.
3 M. Ohno, L. Oguri and E. Shoji, J. Org. Chem., 1992, 64, 8995.
4 R. W. Saalfrank, W. Hafner, J. Markmann, A. Welch, K. Peters, 21 Ring contraction of cyclobutanone 1e was carried out by using CSA
G. Hans and Z. Naturforsch, J. Chem. Sci., 1994, 49, 389.
5 S. Danappe, A. Pal, C. Alexandre, A. M. Aubertin, N. Bourgougnon
and F. Huet, Tetrahedron, 2005, 61, 5782.
6 (a) N. Melis, F. Secci, T. Boddaert, D. J. Aitken and A. Frongia, Chem.
Commun., 2015, 51, 15272; (b) A. Martis, A. Luridiana, A. Frongia,
(ee 4 99%) as a catalyst, yielding the corresponding cyclopropyl-
derivative trans-6e as a racemic mixture.
22 (a) For reviews on bradykinin receptors and therapeutic targets see:
J. Howl and S. J. Payne, Expert Opin. Ther. Targets, 2003, 7, 277;
´
(b) D. Regoli and J. Barabe, Pharmacol. Rev., 1980, 32, 1.
M. Arca, G. Sarais, D. J. Aitken, R. Guillot and F. Secci, Org. Biomol. 23 B. C. Askew, T. Aya, K. Biswas, J. J. Chen, H. J. Brooks and Q. Wenyuan,
Chem., 2017, 15, 10053.
Substituted sulfones and methods of use, WO 2006041888, 2006.
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