Alternative coupling reaction with unactivated furan derivatives

Article abstract of DOI:10.1002/ejoc.200900542

Treatment of various dienimides in the presence of a Lewis acid and (trimethylsiloxy)furan leads to the corresponding aniline furan-2(5H)-ones. The same treatment with furan yields a triaryl product and, surprisingly, a byproduct with a pent;acyclo[5.4.0.

Full text of DOI:10.1002/ejoc.200900542

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900542
Alternative Coupling Reaction with Unactivated Furan Derivatives
Marc-André Giroux,[a] Kimiaka C. Guérard,[a] Marc-André Beaulieu,[a] Cyrille Sabot,[a] and
Sylvain Canesi*[a]
Keywords: Oxygen heterocycles / Michael addition / Aromaticity / Cross-coupling / Sulfonamides
Treatment of various dienimides in the presence of a Lewis
acid and (trimethylsiloxy)furan leads to the corresponding
aniline furan-2(5H)-ones. The same treatment with furan
yields a triaryl product and, surprisingly, a byproduct with a
pentacyclo[5.4.0.0.0.0]undecane main core. The formation of
this birdcage system containing nine stereogenic centres was
produced with complete diastereoselectivity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Formation of novel C–C bonds in chemical synthesis is
still a major challenge, especially in the coupling of two
aromatic units as an avenue to biaromatics or to introduce Figure 1. Possible avenue to compounds 3.
an alkyl moiety onto an aromatic unit. These transforma-
tions have received attention due to the large number of
natural compounds that incorporate these systems,[1] the
use of axially chiral biaryls as ligands in asymmetric reac-
Results and Discussion
tions[2] and the potential of bi- and polyaryls in materials
chemistry and nanotechnology.[3] Different strategies have
been developed to construct such systems; the first practical
methods involve the Ullmann reaction[4] and variants
thereof.[5] The scope of these transformations was greatly
extended with the advent of nickel-[6] and, especially, palla-
dium-mediated[7] reactions. Moreover, the development of
new, efficient and environmentally benign methods for aryl–
aryl or aryl–alkyl coupling remains an active field of re-
search.[8] In this connection, techniques for the direct cou-
pling of aromatic rings, that is, one technique that elimin-
ates the need to prepare halogen or metal derivatives of the
aryl fragments prior to their actual union, would be quite
useful. New developments using hypervalent iodine rea-
gents have recently been developed; important aspects of
these reagents are their low toxicity compared to heavy met-
als and their abilities to directly achieve cross coupling of
unfunctionalised arenes.[9] Ongoing work in our laboratory
required rapid access to compounds of type 3 (Figure 1).
Compounds such as 1 (X = O) or 2 (X = NSO2Me) are
easily synthesized by the oxidation of the corresponding
phenols[10] and sulfonamides[11] with diacetoxyiodobenzene
(DIB)[12] in methanol. These transformations produce de-
sired compounds 1 and 2 in high yield (71–89%). This
method provides easy and efficient access to dienones or
dienimides. In addition, another hypervalent iodine reagent
such as phenyliodine bis(trifluoroacetate) (PIFA)[12] can
promote such transformations. First, we investigated the re-
activity of compound 2 as a Michael acceptor. Although
the behaviour of such dienones[13] has already been deter-
mined, a similar transformation on dienimides is poorly de-
veloped; only a few examples of Diels–Alder transforma-
tions have been related.[14] The differences in reactivities be-
tween dienones and dienimides were compared by oxidation
of para-cresol and its mesylamide analogue 7 with DIB in
ethylene glycol to produce alcohols 5[13c,13f] and 8. At this
point, the behaviour of these alcohols in an intramolecular
Michael process to produce bicycles 6 and 9 was compared
(Scheme 1).
[a] Département de chimie, Université du Québec à Montréal, La-
boratoire de Méthodologie et Synthèse de Produits Naturels,
C.P. 8888, Succ. Centre-Ville, Montréal, H3C 3P8, Québec,
Canada
It has been observed that the cyclisation of intermediate
8 occurs faster than that of 5. In addition, compound 8 is
too reactive to be isolated. On the basis of this observation,
we deduced that dienimide 8 seemed to be a very good
Michael acceptor. Moreover, a diastereoselectivity of 2:1 for
the double bond cis to the methanesulfonyl group was ob-
Fax: +1-514-987-4054
E-mail: canesi.sylvain@uqam.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900542.
Eur. J. Org. Chem. 2009, 3871–3874
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M.-A. Giroux, K. C. Guérard, M.-A. Beaulieu, C. Sabot, S. Canesi
SHORT COMMUNICATION
Table 1. A novel Michael-rearomatisation tandem process.
Scheme 1. Intramolecular Michael addition.
served.[15] An indication for understanding the diastereo-
1
selectivity observed is provided by H NMR spectroscopy;
indeed, the hydrogen atom close to the methanesulfonyl
group in compounds 2 or 9 has a higher chemical shift than
that of the hydrogen atom trans to the sulfonyl group (close
to 1 ppm difference). A withdrawing effect generated by the
cis-sulfonyl group may explain the diastereoselectivity ob-
served. The behaviour of such structures is poorly devel-
oped, probably due to the difficulty in synthesizing them.
The oxidative process[11] is currently the best method for
producing such cores (Figure 2).
This reaction tolerates functionalities such as a protected
alcohol (Table 1, Entry e) or a mesylate (Table 1, Entry g)
on the aliphatic side chain, suggesting that the new process
may tolerate a range of spectator functional groups. The
reaction with a free methyl alcohol (Table 1, Entry f) occurs
in lower yield to produce the fragile benzyl alcohol func-
tionality. This alternative cross-coupling reaction also oc-
curs with furan (1–2 equiv.). It should be noted than furan
is a poorer nucleophile than compound 10. Under these
conditions, we observed the formation of dimer 13 resulting
in the bis(arylation) of furan; only a small amount of
monoaddition was observed (≈5%). This result can be ex-
plained if we consider that the monosubstituted furan de-
rivative is more electron rich than regular furan and reacts
faster with a second molecule of dienimide 2. A summary
of representative experiments appears in Table 2.
1
Figure 2. H NMR chemical shift.
To develop a strategy for the rapid generation of struc-
tures such as 3 through a tandem Michael–aromatisation
process, furan derivatives (1.5–2 equiv.) were used. It should
be noted that such processes would require only the elimi-
nation of methanol as a byproduct. Although the reaction
failed with dienone 1, trace amounts of wanted compound
11 were isolated. However, we were pleased to observe the
formation of desired compound 12 in good yield from dien-
imide 2. This result demonstrates that the sulfonamide
group appears to be a more efficient Michael acceptor than
its oxygenated analogue (Scheme 2).
Table 2. Formation of bicyclic compound 13.
This reaction in the presence of furan also tolerates func-
tionalities such as a protected alcohol (Table 2, Entry e), a
mesylate (Table 2, Entry g) or an ester (Table 2, Entry h) on
the aliphatic side chain, suggesting that the new process
may tolerate a range of spectator functional groups. This
Scheme 2. Dienone vs. sulfonamide.
To exemplify this transformation, different dienimides method is a novel benign avenue to the formation of C–C
such as 2 were treated under the same conditions. A sum- bonds through a C–H/C–H cross-coupling reaction. This
mary of representative experiments with (trimethylsiloxy)- result suggests that this reaction could be performed with
furan[16] 10 appears in Table 1.
different electron-rich furan derivatives. In this process, the
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Eur. J. Org. Chem. 2009, 3871–3874

Alternative Coupling Reaction with Unactivated Furan Derivatives
electrophilic character of dienimide 2 is trapped by an elec-
tron-rich furan derivative in a manner consistent with elec-
trophilic substitution of furans. This transformation also
succeeds with polysubstituted dienimide 14 in the presence
of furan (Scheme 3).
Experimental Section
General Procedure for the Oxidative Process: To a stirred solution
of sulfonamide (0.5 mmol) in methanol (5 mL) at 20 °C was added
PhI(OAc)2 (DIB, 0.6 mmol, 1.2 equiv.) dissolved in methanol
(2 mL) over 10 s. The reaction was stirred for 10 min, concentrated
and then purified by chromatography (hexane/ethyl acetate as re-
quired).
General Procedure for the Coupling Process with 2-(Trimethylsiloxy)-
furan: To a stirred solution of compound 2 (0.1 mmol) and 2-(tri-
methylsiloxy)furan (0.15–0.2 mmol, 1.5–2 equiv.) in dry dichloro-
methane (2 mL) at –78 °C was added BF3·OEt2 (0.2 mmol,
2 equiv.). The mixture was stirred and kept at –78 °C until the reac-
tion was complete as indicated by TLC (1–1.5 h) and then
quenched with saturated aqueous NaHCO3 (5 mL). The aqueous
phase was extracted with EtOAc (3ϫ8 mL), and the combined or-
ganic layer was washed with brine (2ϫ5 mL), dried with Na2SO4
and concentrated. The crude product was purified under vacuum
then purified by chromatography (hexane/ethyl acetate as required).
The compound requires rapid purification to avoid potential iso-
merisation of the double bond.
Scheme 3. Polysubstituted dienimide.
The reaction with compound 14 leads to intriguing by-
product 19 in 13% yield. The structure produced contains
a pentacyclo[5.4.0.0.0.0]undecane[17] main core. Formation
of such a compound can be explained if we consider that a
double formal cycloaddition tandem process occurred. In-
deed, we assume that intermediate 16 was trapped by the
mesylenamide group to generate 17 through a formal [4+2]
cycloaddition. The Lewis acid should activate the remain-
ing enimide functionality that would be trapped by the
double bond of the dihydrofuran moiety to generate species
18, assimilated into a Prins reaction. Intermediate 18 would
be intercepted by the mesylenamide segment to produce 19
through a formal [2+2] cycloaddition. This tandem process
reaction yields unique structure 19 containing nine stereo-
genic centres produced in only one step and with complete
diastereoselectivity verified by NOE NMR spectroscopic
analysis (Scheme 4).
General Procedure for the Coupling Process with Furan: To a stirred
solution of compound 2 (0.1 mmol) and furan (0.2 mmol, 2 equiv.)
in dichloromethane (2 mL) at –78 °C was added BF3·OEt2
(0.2 mmol, 2 equiv.). The mixture was stirred and kept at –78 °C
until the reaction was complete as indicated by TLC (1–1.5 h) and
then quenched with saturated aqueous K2CO3 (3 mL). The aque-
ous phase was extracted with EtOAc (3ϫ8 mL), and the combined
organic layer was washed with brine (2ϫ5 mL), dried with Na2SO4
and concentrated. The crude product was purified by chromatog-
raphy (hexane/ethyl acetate as required).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for all new
1
compounds along with copies of the H and 13C NMR spectra.
Acknowledgments
Acknowledgment is made to the donors of the American Chemical
Society Petroleum Research Fund (ACS PRF) for support of this
research. We are also very grateful to the Natural Sciences and
Engineering Research Council of Canada (NSERC), the Canada
Foundation for Innovation (CFI), the Provincial Government of
Quebec (FQRNT) and to Boehringer Ingelheim (Canada) Ltd. for
their financial support.
Scheme 4. Formation of a birdcage system.
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Received: May 16, 2009
Published Online: June 30, 2009
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