Iron-catalyzed regio- and stereoselective conjugate addition of aryl-grignard reagents to α,β,γ,δ-unsaturated sulfones and its synthetic application

Article abstract of DOI:10.1002/adsc.201201124

The iron-catalyzed δ-addition of aryl-Grignard reagents to α,β,γ,δ-unsaturated sulfones proceeded in a regio- and stereoselective manner to give cis-4-aryl-2-alkenyl sulfones. Allylic alkylation of the resultant products was performed without isomerization of the cis-olefin to give cis-4-aryl-1,1-dialkyl-2-alkenyl sulfones, which upon intramolecular Friedel-Crafts reaction with aluminum chloride gave 1,4-dihydronaphthalenes having a quaternary carbon center. Copyright

Full text of DOI:10.1002/adsc.201201124

COMMUNICATIONS
DOI: 10.1002/adsc.201201124
Iron-Catalyzed Regio- and Stereoselective Conjugate Addition of
Aryl-Grignard Reagents to a,b,g,d-Unsaturated Sulfones and its
Synthetic Application
Takeshi Hata,a Takuya Nakada,a Yun Taek Oh,a Naoki Hirone,a
and Hirokazu Urabea,*
a
Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of
Technology, 4259-B-59 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
Fax : (+81)-(0)45-924-5849; e-mail: hurabe@bio.titech.ac.jp
Received: December 25, 2012; Revised: April 26, 2013; Published online: June 5, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201201124.
Abstract: The iron-catalyzed d-addition of aryl-
Grignard reagents to a,b,g,d-unsaturated sulfones
proceeded in a regio- and stereoselective manner to
give cis-4-aryl-2-alkenyl sulfones. Allylic alkylation
of the resultant products was performed without
isomerization of the cis-olefin to give cis-4-aryl-1,1-
dialkyl-2-alkenyl sulfones, which upon intramolecu-
lar Friedel–Crafts reaction with aluminum chloride
gave 1,4-dihydronaphthalenes having a quaternary
carbon center.
dition, the cis-alignment of the incoming aryl group
and the sulfonyl group at another allylic terminus in
product 2 prompted us to investigate the intramolecu-
lar Friedel–Crafts reaction between these two
groups,[1f,8] giving bicyclic compound 3, which is also
shown in Eq. (1).
Keywords: allyl sulfones; conjugate addition; Frie-
del–Crafts reaction; Grignard reagents; iron cata-
lysts
We first examined the iron-catalyzed conjugate ad-
While there are numerous reports on the nucleophilic dition of aryl-Grignard reagents to dienyl sulfones.
addition to a,b-unsaturated sulfones,[1] similar reac- Thus, alkadienyl sulfone 4 was treated with PhMgBr
tions to a,b,g,d-unsaturated sulfones have been rarely in the presence of 10 mol% of FeCl2 to afford virtual-
documented.[2] This may come from the fact that the ly the single cis-allylic sulfone 5 after hydrolysis
latter reaction is accompanied by additional difficulty (Scheme 1, ds=diastereoselectivity).[9] Alternatively,
in controlling the regioselection (b- vs. d-addition)
and stereoselection (E or Z of the resultant olefin).[3]
We have recently reported that an iron-catalyzed 1,6-
addition of aryl-Grignard reagents to a,b,g,d-unsatu-
rated esters or amides took place in a highly regio-
and stereoselective manner to give stereodefined bi-
functional building blocks, cis-4-aryl-2-alkenoates or
-amides.[4–7] The exclusive formation of the cis-olefinic
bond in these products, presumably arising from the
intermediate s-cis-diene-iron complex, is a characteris-
tic feature of this reaction.[4] We had conceived that
this reaction might be applicable to a,b,g,d-unsaturat-
ed sulfones 1 as well, and found that they are actually
Scheme 1. Iron-catalyzed selective d-addition of PhMgBr to
a promising substrate as formulated in Eq. (1). In ad- dienyl sulfone 4.
1736
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1736 – 1740

Iron-Catalyzed Regio- and Stereoselective Conjugate Addition of Aryl-Grignard Reagents
deuteriolysis or treatment with alkyl halides gave 5-d participated in the addition as well, to give allylic sul-
with a high deuterium incorporation or the alkylated fones 12 and 13 as single isomers (entries 5 and 6). 3-
products 6 and 7, respectively, in good yields.
Substituted and even 3,4-disubstituted dienyl sulfones
Other products prepared from various dienyl sul- 10 and 11 reacted smoothly with a Grignard reagent
fones, Grignard reagents, and electrophiles are sum- to produce the corresponding allylic sulfones 14 and
marized in Table 1. Besides methyl-substituted dienyl 15 in good yields (entries 7 and 8). As aryl-Grignard
sulfone 4, propyl and cyclohexyl derivatives 8 and 9 reagents, 3-methoxyphenyl-, 4-methoxyphenyl-, and
Table 1. Preparation of various allylic sulfones.
[a]
1
The stereochemistry of the olefin was confirmed by H NMR NOESY experiments.
Adv. Synth. Catal. 2013, 355, 1736 – 1740
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1737

Takeshi Hata et al.
COMMUNICATIONS
Table 2. Cyclization of allylic sulfones with AlCl3.
3,5-dimethoxyphenylmagnesium bromides afforded
single allylic sulfones and their alkylated homologues
16–23 with a cis-olefin in good yields (entries 9–16).
(Acetylamino)phenyl-Grignard reagent (prepared
from the corresponding iodide and isopropylmagnesi-
um bromide in situ[10]) afforded the desired product
24 as well (entry 17). Even halogenated Grignard re-
agents took part in the addition to give 25 and 26,
with their halogen moieties remaining unattacked
(entries 18 and 19). In addition, aryl-Grignard re-
agents having an electron-withdrawing group such as
4-(piperidinocarbony)- or 4-(ethoxycarbonyl)phenyl-
magnesium halides underwent the addition to dienyl
sulfone 4 to give the desired products 27 and 28 (en-
tries 20 and 21), showing the good compatibility of
functional groups in this transformation.
Although many synthetic applications are possible
from allylic sulfones,[1] we focused our attention on
their allyl transfer ability under the Friedel–Crafts
To attest the feasibility of the Friedel–Crafts reac-
conditions as shown in Eq. (1), where the cis olefinic tion shown in Eq. (1), we executed the cyclization of
structure should be crucial to the smooth ring closure the allylic sulfones prepared above (Table 2). The at-
between the aryl group and the allylic sulfone. In ad- tempted cyclization of 18 or 19 with AlCl3 did not
dition to products 18 and 19 directly obtained from afford the desired products even under forcing condi-
the conjugate addition (entries 11 and 12 in Table 1), tions (entries 1 and 2), due perhaps to an insufficient
more substituted allylic sulfones are readily prepared stabilization at the primary or secondary allylic cation
by deprotonation and alkylation of these products as to initiate the Friedel–Crafts reaction. However, grati-
shown in Scheme 2. For example, treatment of 19 or fyingly, a,a-dialkylated allylic sulfones 29–31 afforded
20 with BuLi,[11a–c] followed by methyl iodide, gave 1,4-dihydronaphthalenes 32–34 in good yields (en-
product 29 or 30 having a fully substituted carbon tries 3–5).[8,13] These bicyclic skeletons having a quater-
a to the sulfone in good yields [Scheme 2, Eqs. (2) nary carbon adjacent to the ring junction are often
and (3)].[12] On the other hand, 31 was prepared via found in naturally occurring products.[14]
the dianion of 18 (2.2 equiv. of BuLi)[11a–c] in the simi-
In conclusion, we have reported the iron-catalyzed
lar way [Scheme 2, Eq. (4)]. In any case, it should be selective d-addition of aryl-Grignard reagents to
emphasized that olefin isomerizaion from cis to trans a,b,g,d-unsaturated sulfones and its synthetic utility.
was not observed.[11c–i]
In these transformations, the sulfonyl group plays
a triple role: (i) to effect the selective conjugate addi-
tion, (ii) to enable alkylation at its a position, and (iii)
to work as a leaving group in the Friedel–Crafts reac-
tion. Further investigation on the utility of these reac-
tions is now in progress.
Experimental Section
Typical Procedure for the Preparation of Allyl
Sulfones: (Z)-4-Phenyl-2-pentenyl Phenyl Sulfone (5)
To a solution of (1E,3E)-1,3-pentadienyl phenyl sulfone 4
(41.7 mg, 0.200 mmol) and FeCl2 (2.5 mg, 0.020 mmol) in
2 mL of THF was added phenylmagnesium bromide
(0.330 mL, 1.09M solution in THF, 0.360 mmol) at À458C
under argon. After the mixture had been stirred at À45 to
À308C for 3 h, the reaction was terminated by the addition
of 1N HCl solution (1 mL). The organic layer was separated
and the aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed successively with
aqueous saturated NaHCO3 solution and brine, dried over
Na2SO4, and concentrated under vacuum to give a crude oil,
Scheme 2. Alkylation
(MeO)2C6H3].
of
allylic
sulfones
[Ar=3,5-
1738
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1736 – 1740

Iron-Catalyzed Regio- and Stereoselective Conjugate Addition of Aryl-Grignard Reagents
1H NMR analysis of which did not show the presence of
regio- and olefinic stereoisomers. The crude product was
chromatographed on silica gel (hexane-ethyl acetate) to
afford the title compound as a white solid; yield: 46.9 mg
(82%).
Hartog, S. R. Harutyunyan, D. Font, A. J. Minnaard,
B. L. Feringa, Angew. Chem. 2008, 120, 404–407;
Angew. Chem. Int. Ed. 2008, 47, 398–401; b) H. Hꢄnon,
M. Mauduit, A. Alexakis, Angew. Chem. 2008, 120,
9262–9264; Angew. Chem. Int. Ed. 2008, 47, 9122–9124;
c) K. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2010,
132, 2898–2900; d) J. Wencel-Delord, A. Alexakis, C.
Crꢄvisy, M. Mauduit, Org. Lett. 2010, 12, 4335–4337;
e) M. Tissot, A. P. Hernꢁndez, D. Mꢆller, M. Mauduit,
A. Alexakis, Org. Lett. 2011, 13, 1524–1527. Under Rh
or Ir catalysis: f) G. De La Herrꢁn, A. G. Csꢁkꢅ, Synlett
2009, 585–588; g) T. Nishimura, Y. Yasuhara, T.
Sawano, T. Hayashi, J. Am. Chem. Soc. 2010, 132,
7872–7873. With organocatalyst: h) C. G. Oliva,
A. M. S. Silva, F. A. A. Paz, J. A. S. Cavaleiro, Synlett
2010, 1123–1127. Without catalyst: i) M. Ocejo, L. Car-
rillo, D. Badꢃa, J. L. Vicario, N. Fernꢁndez, E. Reyes, J.
Org. Chem. 2009, 74, 4404–4407.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search (B) (21350027) and a Grant-in-Aid for Young Scien-
tists (B) (23750102, to T. H.) from JSPS, Japan.
References
[1] For reviews, see: a) The Chemistry of Organic Sulfur
Compounds, (Eds.: N. Kharasch, C. Y. Meyers), Perga-
mon Press, Oxford, 1966; b) E. Block, Reactions of Or-
ganosulfur Compounds, Academic Press, New York,
1978; c) S. Oae, Organic Sulfur Chemistry: Structure
and Mechanism, CRC Press, Boca Raton, 1991; d) N. S.
Simpkins, Sulphones in Organic Synthesis, Pergamon
Press, Oxford, 1993; e) The Syntheses of Sulphones,
Sulphoxides and Cyclic Sulphides, (Eds.: S. Patai, Z.
Rappoport), Wiley, Chichester, 1994; f) B. M. Trost,
Bull. Chem. Soc. Jpn. 1988, 61, 107–124; g) C. Nꢁjera,
M. Yus, Tetrahedron 1999, 55, 10547–10658; h) A. El-
Awa, M. N. Noshi, X. Mollat du Jourdin, P. L. Fuchs,
Chem. Rev. 2009, 109, 2315–2349; i) A.-N. R. Alba, X.
Companyꢂ, R. Rios, Chem. Soc. Rev. 2010, 39, 2018–
2033; j) M. Nielsen, C. B. Jacobsen, N. Holub, M. W.
Paix¼o, K. A. Jørgensen, Angew. Chem. 2010, 122,
2726–2738; Angew. Chem. Int. Ed. 2010, 49, 2668–2679.
[2] Regio- and stereoselection in the addition to a,b,g,d-
unsaturated sulfones has not been amply elucidated:
the following reports mention only the b-addition to
dienyl sulfones; a) J. P. Marino, J. K. Long, J. Am.
Chem. Soc. 1988, 110, 7916–7917; b) J. L. Garcꢃa Rua-
no, C. Schçpping, C. Alvarado, J. Alemꢁn, Chem. Eur.
J. 2010, 16, 8968–8971; c) T. Nishimura, Y. Takiguchi, T.
Hayashi, J. Am. Chem. Soc. 2012, 134, 9086–9089. See
also: d) J. J. Murphy, A. Quintard, P. McArdle, A.
Alexakis, J. C. Stephens, Angew. Chem. 2011, 123,
5201–5204; Angew. Chem. Int. Ed. 2011, 50, 5095–5098;
e) M. C. Bernabeu, R. Chinchilla, C. Nꢁjera, Tetrahe-
dron Lett. 1995, 36, 3901–3904; f) C. E. Houlden, C. D.
Bailey, J. G. Ford, M. R. Gagnꢄ, G. C. Lloyd-Jones,
K. I. Booker-Milburn, J. Am. Chem. Soc. 2008, 130,
10066–10067.
[6] For reviews on iron-catalyzed and mediated organic re-
actions, see: a) Iron Catalysis in Organic Chemistry,
(Ed.; B. Plietker), Wiley-VCH, Weinheim, 2008; b) A.
Correa, O. G. MancheÇo, C. Bolm, Chem. Soc. Rev.
2008, 37, 1108–1117; c) E. B. Bauer, Curr. Org. Chem.
2008, 12, 1341–1369; d) S. Enthaler, K. Junge, M.
Beller, Angew. Chem. 2008, 120, 3363–3367; Angew.
Chem. Int. Ed. 2008, 47, 3317–3321; e) C. Bolm, J.
Legros, J. Le Paih, L. Zani, Chem. Rev. 2004, 104,
6217–6254. For enyne cyclization, see: f) V. Michelet,
P. Y. Toullec, J.-P. GenÞt, Angew. Chem. 2008, 120,
4338–4386; Angew. Chem. Int. Ed. 2008, 47, 4268–4315.
For coupling reactions, see: g) B. Plietker, Synlett 2010,
2049–2058; h) B. Plietker, A. Dieskau, Eur. J. Org.
Chem. 2009, 775–787; i) W. M. Czaplik, M. Mayer, J.
ˇ
Cvengros, A. Jacobi von Wangelin, ChemSusChem
2009, 2, 396–417; j) B. D. Sherry, A. Fꢆrstner, Acc.
Chem. Res. 2008, 41, 1500–1511; k) A. Fꢆrstner, R.
Martin, Chem. Lett. 2005, 34, 624–629. For iron carbon-
yl complexes, see: l) M. F. Semmelhack, in: Organome-
tallics in Organic Synthesis. A Manual, 2nd edn., (Ed.;
M. Schlosser), John Wiley & Sons, Chichester, 2002,
pp 1006–1121;
m) Comprehensive
Organometallic
Chemistry, Vol. 4, (Eds.; G. Wilkinson, F. G. A. Stone,
E. W. Abel), Pergamon Press, Oxford, 1982, pp. 243–
649. For selected reports on iron-catalyzed addition re-
actions, see: n) M. Nakamura, A. Hirai, E. Nakamura,
J. Am. Chem. Soc. 2000, 122, 978–979; o) A. Fꢆrstner,
M. Mꢄndez, Angew. Chem. 2003, 115, 5513–5515;
Angew. Chem. Int. Ed. 2003, 42, 5355–5357; p) Z. Lu,
G. Chai, S. Ma, J. Am. Chem. Soc. 2007, 129, 14546–
14547; q) A. Fꢆrstner, K. Majima, R. Martꢃn, H.
Krause, E. Kattnig, R. Goddard, C. W. Lehmann, J.
Am. Chem. Soc. 2008, 130, 1992–2004; r) B. D. Sherry,
A. Fꢆrstner, Chem. Commun. 2009, 7116–7118.
[3] a) A. G. Csꢁkꢅ, G. de La Herrꢁn, M. C. Murcia, Chem.
Soc. Rev. 2010, 39, 4080–4102; b) E. M. P. Silva,
A. M. S. Silva, Synthesis 2012, 44, 3109–3128.
[4] a) S. Okada, K. Arayama, R. Murayama, T. Ishizuka,
K. Hara, N. Hirone, T. Hata, H. Urabe, Angew. Chem.
2008, 120, 6966–6970; Angew. Chem. Int. Ed. 2008, 47,
6860–6864; b) K. Fukuhara, H. Urabe, Tetrahedron
Lett. 2005, 46, 603–606.
[7] For a relevant iron-catalyzed 1,6-addition to 2-alken-4-
ynoates or -amides, see: T. Hata, S. Iwata, S. Seto, H.
Urabe, Adv. Synth. Catal. 2012, 354, 1885–1889.
[8] a) B. M. Trost, M. R. Ghadiri, J. Am. Chem. Soc. 1984,
106, 7260–7261; b) B. M. Trost, M. R. Ghadiri, J. Am.
Chem. Soc. 1986, 108, 1098–1100.
[9] Recently, copper impurities contained in iron reagents
have been reported to be the actual promoter in cer-
tain iron-catalyzed reactions: S. L. Buchwald, C. Bolm,
[5] For latest examples of the selective conjugate addition
to a,b,g,d-unsaturated carbonyl compounds reported
from other groups, see: under Cu catalysis: a) T. den
Adv. Synth. Catal. 2013, 355, 1736 – 1740
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1739

Takeshi Hata et al.
COMMUNICATIONS
Angew. Chem. 2009, 121, 5694–5695; Angew. Chem.
Int. Ed. 2009, 48, 5586–5587. Thus, we carried out some
control experiments to negate such a possibility in the
present reaction. First, FeCl2 of the purity 99.998%
showed virtually the same yield and selectivity of 5 as
the routinely used FeCl2 (99.9% pure, Scheme 1 or
entry 1 in Table 1). On the other hand, in the similar
reaction, the attempted use of a typical copper catalyst,
CuBr·SMe2 (10 mol%), afforded a 28:72 mixture of b-
and d-adducts in a moderate yield.
ing, J. Chem. Soc. Perkin Trans. 1 1975, 897–913; e) M.
Julia, D. Uguen, Bull. Soc. Chim. Fr. 1976, 513–518;
f) M. Harmata, C. B. Gamlath, C. L. Barnes, Tetrahe-
dron Lett. 1990, 31, 5981–5984; g) D. Craig, C. J. Ether-
idge, A. M. Smith, Tetrahedron Lett. 1992, 33, 7445–
7446; h) B. M. Trost, M. R. Ghadiri, Bull. Soc. Chim.
Fr. 1993, 130, 433–442; i) T. Balasubramanian, A. Hass-
ner, Tetrahedron: Asymmetry 1998, 9, 2201–2205.
[12] a-Alkylated allylic sulfone 19 or 20 was also prepared
by the deprotonation (BuLi) and alkylation (MeI or
BuI) of sulfone 18 without isomerization of the olefinic
stereochemistry. Analogously, 29 or 30 was also ob-
tained from 18 (2.2 equiv. of BuLi, MeI) or 19 (BuLi,
BuI), respectively. For details, see the Supporting Infor-
mation.
[13] The yields of 32 remained lower with other Lewis acids
(BF3·OEt2: 0%, FeCl3: trace, TiCl4: 34%, and Et2AlCl:
40%).
[14] T. K. Devon, A. I. Scott, in: Handbook of Naturally
Occurring Compounds, Academic Press, New York,
1972, Vol. II, pp 154–156, 201–235, 240–243, 248, 270–
271, and 283–294.
[10] a) A. Boudier, L. O. Bromm, M. Lotz, P. Knochel,
Angew. Chem. 2000, 112, 4584–4606; Angew. Chem.
Int. Ed. 2000, 39, 4414–4435; b) T. Delacroix, L. Bꢄril-
lon, G. Cahiez, P. Knochel, J. Org. Chem. 2000, 65,
8108–8110; c) W. Dohle, D. M. Lindsay, P. Knochel,
Org. Lett. 2001, 3, 2871–2873.
[11] a) J. Vollhardt, H.-J. Gais, K. L. Lukas, Angew. Chem.
1985, 97, 607–609; Angew. Chem. Int. Ed. Engl. 1985,
24, 610–611; b) D. J. Knight, P. Lin, S. T. Russell, G. H.
Whitham, J. Chem. Soc. Perkin Trans. 1 1987, 2701–
2705; c) B. M. Trost, C. A. Merlic, J. Org. Chem. 1990,
55, 1127–1129; d) R. V. M. Campbell, L. Crombie,
D. A. R. Findley, R. W. King, G. Pattenden, D. A. Whit-
1740
asc.wiley-vch.de
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1736 – 1740