Doubly dearomatising intramolecular coupling of a nucleophilic and an electrophilic heterocycle

Article abstract of DOI:10.1039/b901558b

Isonicotinamides carrying N-furanylmethyl, N-pyrrolylalkyl or N-thiophenylmethyl substituents at nitrogen undergo cyclisation induced by an electrophile, giving spirocyclic compounds or doubly spirocyclic compounds in which both the nucleophilic and elect

Full text of DOI:10.1039/b901558b

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Doubly dearomatising intramolecular coupling of a nucleophilic and an
electrophilic heterocyclew
Heloise Brice and Jonathan Clayden*
Received (in Cambridge, UK) 23rd January 2009, Accepted 18th February 2009
First published as an Advance Article on the web 12th March 2009
DOI: 10.1039/b901558b
Isonicotinamides carrying N-furanylmethyl, N-pyrrolylalkyl or
N-thiophenylmethyl substituents at nitrogen undergo cyclisation
induced by an electrophile, giving spirocyclic compounds or
doubly spirocyclic compounds in which both the nucleophilic
and electrophilic heterocycles are dearomatised.
Spirocyclic piperidines are present in many biologically active
compounds1 (including the alkaloids histrionicotoxin,
nakadomarin and cephalotaxine) and have been identified
as ‘‘privileged scaffolds’’ with respect to binding at
Fig. 1 Dearomatising additions to (a) electron-deficient and (b) electron-
G-protein coupled receptors.2 Compounds containing more
rich aromatic heterocycles; (c) tandem double dearomatisation.
than one adjacent spirocyclic centre are challenging to make,3
though bis-spirocyclic heterocycles feature in the Delphinium
and Aconitum alkaloids4 and other biologically active
compounds.5
In this paper we report a conceptually simple approach to
spirocycles in which a pair of tethered aromatic heterocycles—
one nucleophilic and one electrophilic—undergo a dearoma-
tising intramolecular coupling. The reaction allows the
synthesis of spirocyclic and doubly spirocyclic molecules by
a remarkable cascade of electrophilicity, governed by basicity,
effective concentration and steric hindrance.
Scheme 1 Spirocyclisations of 1- and 3-substituted pyrroles, furans
and thiophenes. a (CF3SO2)2O (1.0 equiv.), 2,6-lutidine (1.2 equiv.),
CH2Cl2, 0–20 1C, 30 min.
Both electron-deficient and electron-rich heterocycles may
be dearomatised with an appropriate electrophile–nucleophile
pair (Fig. 1). Pyridines, once acylated or alkylated at N to yield
pyridinium species, are electrophilic towards a variety of
anionic and neutral nucleophiles,6 including electron-rich
heterocycles (Fig. 1a).7 Likewise, bromination or nitration of
furan8 in the presence of a nucleophile may yield dihydrofuran
derivatives (Fig. 1b). We envisaged a tandem reaction in which
an activated pyridinium species would itself activate an electron-
rich heterocycle, potentially dearomatising both in one
reaction. In the face of challenging questions of regio- and
chemoselectivity, we decided to tether the nucleophilic hetero-
cycle to the pyridine, aiming to generate spirocyclic or even
doubly spirocyclic heterocycles (Fig. 1c).9
the resulting pyridinium species gave spirocyclic pyrrole 2,
furan 4 and thiophene 6 in moderate to good yield.
Pyrrole 7 and furan 9 tethered via their 2-positions behaved
differently. Intermediate 11a derived from pyrrole 7 cyclised
onto its 3-position (either by direct attack as shown, or by
rearrangement of an initial spirocyclic intermediate generated
by attack at the 2-position) to yield spirocyclic ring-fused
pyrrole 8 (Scheme 2). The oxonium ion 12 derived from the
furylpyridinium 11b, on the other hand, was trapped by
nucleophilic attack of water, so the product isolated from 9
Using standard methods for amide formation we made a
series of isonicotinamides 1, 3, 5 etc. carrying electron-rich
heterocyclic substituents (pyrroles, furans and thiophenes)
(Scheme 1). These were treated with trifluoromethanesulfonic
anhydride in order to activate the pyridine ring by N-sulfonyla-
tion:10 electrophilic attack on the 2-position of 1, 3 and 5 by
School of Chemistry, University of Manchester, Oxford Road,
Manchester, UK M13 9PL. E-mail: Clayden@man.ac.uk
w Electronic supplementary information (ESI) available: Experimental
details and characterisation data for all new compounds. CCDC
705273. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b901558b
Scheme 2 Spirocyclisations of 2-substituted pyrroles and furans.
a
(CF3SO2)2O (1.0 equiv.), 2,6-lutidine (1.2 equiv.), CH2Cl2,
0–20 1C, 30 min.
ꢀc
This journal is The Royal Society of Chemistry 2009
1964 | Chem. Commun., 2009, 1964–1966

View Online
hindered face of the dihydrofuran, was established by X-ray
crystallography (Fig. 2).11
The two adjacent spirocyclic centres arise from direct
coupling between the 4-position of the pyridine and the
2-position of the furan, and 10b represents a rare12 doubly
dearomatised structure arising from the coupling of two
aromatic heterocycles. The chemoselectivity evident in the
cascade of electrophilicity leading from 9 to 10b is also
noteworthy, with each of three nucleophiles (the pyridine via
its nitrogen atom, the furan ring and the trityl alcohol) waiting
its turn to react selectively with each of three electrophiles
(the sulfonic anhydride, the pyridinium 11b and the oxonium
ion 12b).
Scheme 3 Nucleophilic trapping of the doubly dearomatised inter-
mediate. a (CF3SO2)2O (1.0 equiv.), 2,6-lutidine (1.2 equiv.), CH2Cl2,
À20 1C, 1 min then NuH, À20 1C, 1 h.
Diisopropylamine was also successful as a nucleophilic trap,
giving 10c, but less hindered nucleophiles were less effective
(for example, methanol and furan gave only 26% and 25%
yield, respectively, of the trapped products) presumably
because of competing attack on electrophilic species other
than 12 within the reaction mixture.
Nonetheless, by chemoselectively reducing the dihydro-
furan 10b to the tetrahydrofuran 13 and re-subjecting this
acetal to a mixture of Lewis acid and nucleophile,13 it
was possible to derivatise the doubly spirocyclic scaffold
with a range of nucleophiles to yield 14a–f (Scheme 4 and
Table 1).
Fig. 2 X-Ray crystal structure of anti-10b.11
was the doubly dearomatised, doubly spirocyclic dihydro-
pyridine-g-lactam-dihydrofuran 10a.
Initial yields of 10a were low, probably due to the instability
of the intermediate oxonium ion 12. However, we found that
adding a nucleophile to the reaction mixture allowed intercep-
tion of the intermediate 12 to yield derivatives 10b and 10c
(Scheme 3). For example, addition of triphenylmethanol to the
reaction mixture immediately after the trifluoromethane-
sulfonic anhydride allowed formation of the doubly dearomatised
acetal 10b in good yield and with excellent (430 : 1)
diastereoselectivity. The stereochemistry of the major diastereo-
isomer of 10b, in which the trityloxy group occupies the less
In this paper we have demonstrated that molecules containing
tethered electron-deficient and electron-rich heteroaromatic
rings may be activated towards intramolecular coupling by
addition of a sufficiently mutually unreactive electrophile–
nucleophile pair (for example, triflic anhydride and triphenyl-
methanol). In common with other bicyclic systems made by
dearomatisation, many of which have been used in the syn-
thesis of biologically important structures,14 the products
display rich functionality amenable to further elaboration.
The doubly dearomatised products are bis-spirocyclic, and
we envisage such reactions, especially if applied as part of a
diversity orientated synthetic strategy,15 as being of value for
the generation of new spirocyclic scaffolds for the discovery of
biologically active molecules.
Scheme 4 Derivatives of the spirocycles. a H2, 10% Pd/C, EtOAc,
EtOH (continuous flow). b Lewis acid, NuH (see Table 1).
Table 1 Nucleophilic substitution of the trityl group
Entry
1
Nu =
OH
Conditions
Product
Yield (%)
Ratio anti-14 : syn-14
CF3CO2H, Et3SiH
or Et3AlCl
AllylSiMe3, InCl3, Me3SiBr
Et3SiH, InCl3, Me3SiBr
PhC(OSiMe3)QCH2, InCl3, Me3SiBr
HCO2H
14a
14a
14b
14c
14d
14e
14f
15
100
87
85
98
51
55
88
81
2 : 1a
2 : 1a
5 : 4a
—
2
3
4
5
6
7
Allyl
H
CH2C(QO)Ph
OCHO
OAc
4 : 3b
2 : 1a
5 : 4b
1 : 1a
Ac2O, py (on 14a)
AllylSnBu3, Et2AlCl
—
a
b
Inseparable mixture of diastereoisomers. Separable mixture of diastereoisomers.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 1964–1966 | 1965

View Online
2003, 14, 469; D. Comins, L. King, E. Smith and F. Fevrier, Org.
Notes and references
Lett., 2005, 7, 5059; D. L. Comins, X. Zheng and R. R. Goehring,
Org. Lett., 2002, 4, 1622; A. B. Charette, M. Grenon, A. Lemire,
M. Pourashraf and J. Martel, J. Am. Chem. Soc., 2001, 123, 11829;
F. Rezgui, P. Mangeney and A. Alexakis, Tetrahedron Lett., 1999,
40, 6241; M. L. Bennasar, C. Juan and J. Bosch, Tetrahedron Lett.,
2001, 42, 585; M. Bennasar, J.-M. Jimenez, B. Vidal, A. Sufi and
J. Bosch, J. Org. Chem., 1999, 64, 9605; M. L. Bennasar, C. Juan
and J. Bosch, Tetrahedron Lett., 1998, 39, 9275; R. Lavilla,
1 A. A. Krafft, A. Kurt, A. Maier, A. W. Thomas and D. Zimmerli,
Synthesis, 2005, 3245; G. C. Bignan, K. Battista, P. J. Connolly,
M. J. Orsini, J. Liu, S. A. Middleton and A. B. Reitz, Bioorg. Med.
Chem. Lett., 2005, 15, 5022; R. W. DeSimone, K. S. Currie,
S. A. Mitchell, J. W. Darrow and D. A. Pippin, Comb. Chem. High
Throughput Screening, 2004, 7, 473; J.-S. Xie, C. Q. Huang,
Y.-Y. Fang and Y.-F. Zhu, Tetrahedron, 2004, 60, 4875; T. Guo
and D. W. Hobbs, Assay Drug Dev. Technol., 2003, 1, 579;
R. A. Glennon, K. Metwally, M. Dukat, A. M. Ismaiel, J. de los
Angeles, J. Herndon, M. Teitler and N. Khorana, Curr. Top. Med.
Chem., 2002, 2, 539; B. L. Palucki, S. D. Feighner, S.-S. Pong,
K. K. McKee, D. L. Hrenick, C. Tab, A. D. Howard, L. H. Van der
Ploeg, A. A. Patchett and R. P. Nargund, Bioorg. Med. Chem. Lett.,
2001, 11, 1955; T. G. Dhar, R. P. Nagarathnam, M. R. Marzabadi,
B. Lagu, W. C. Wong, G. Chiu, S. Tyagarajan, S. W. Miao,
F. Zhang, W. Sun, D. Tian, Q. Shen, J. Zhang, J. M. Wetzle,
C. Firray, R. Chang, T. P. Broten, T. W. Schorn, T. B. Chen,
S. O’Malley, R. Ransom, K. Schneck, R. Bendesky, C. M. Harrell,
K. P. Vyas, K. Zhang, J. Gilbert, D. J. Pettibone, M. A. Patane,
M. G. Bock, R. M. Freidinger and C. Gluchowski, J. Med. Chem.,
1999, 42, 4778; A. Metwally, M. Dukat, C. T. Egan, C. Smith,
A. DuPre, C. B. Gauthier, K. Herrick-David, M. Teitler and
R. A. Glennon, J. Med. Chem., 1998, 41, 5084; J. M. Elliott,
H. Broughton, M. A. Cascieri, G. Chicchi, I. T. Huscroft,
M. Kurtz, A. M. MacLeod, S. Sadowski and G. I. Stevenson,
Bioorg. Med. Chem. Lett., 1998, 8, 1851; J. M. Elliott,
M. A. Cascieri, G. Chicchi, S. Davies, F. J. Kelleher, M. Kurtz,
T. Ladduwahetty, R. T. Lewis, A. M. MacLeod, K. J. Merchant,
S. Sadowski and G. I. Stevenson, Bioorg. Med. Chem. Lett., 1998, 8,
1845; S. M. Efange, A. P. Kamath, A. B. Khare, M.-P. Kung,
R. H. Mach and S. M. Parsons, J. Med. Chem., 1997, 40, 3905;
M. S. Chambers, R. Baker, D. C. Billington, A. K. Knight,
D. N. Middlemiss and E. H. Wong, J. Med. Chem., 1992, 35,
2033; R. H. Mach, J. R. Jackson, R. R. Luedtke, K. J. Ivins,
P. B. Molinoff and R. L. Ehrenkaufer, J. Med. Chem., 1992, 35,
423.
2 J. A. Pfefferkorn and C. Choi, Tetrahedron Lett., 2008, 49, 4372;
A. A. Patchett, R. P. Nargund, J. R. Tata, M. H. Chen,
K. J. Barakat, D. B. R. Johnston, K. Cheng, W. W. S. Chan,
B. Butler, B. Hickey, T. Jacks, K. Schleim, S. S. Pong, L. Y.
P. Chaung, H. Y. Chen, E. Frazier, K. H. Leung, S. H. L. Chui and
R. G. Smith, Proc. Natl. Acad. Sci. U. S. A., 1995, 92, 7001;
K. Bondensgaard, M. Ankersen, H. Thogerson, B. S. Hansen,
B. S. Wulff and R. P. Bywater, J. Med. Chem., 2004, 47, 888.
3 M. Sannigrahi, Tetrahedron, 1999, 55, 9007.
4 K. Wada, M. Hazawa, K. Takahashi, T. Mori, N. Kawahara and
I. Kashiwakura, J. Nat. Prod., 2007, 70, 1854–4853; J. Xiong,
N.-H. Tan, C.-J. Ji, Y. Lu and N.-B. Gong, Tetrahedron Lett.,
2008, 49, 4851–4853; K. E. Panter, G. D. Manners,
B. L. Stegelmeier, S. Lee, D. R. Gardner, M. H. Ralphs,
J. A. Pfister and L. F. James, Biochem. Syst. Ecol., 2002, 30,
113–4853.
G. Gotsens, M. Guero, C. Masdeu, C. Santano, C. Minguillon
¨
and J. Bosch, Tetrahedron, 1997, 53, 13959; J. Bosch and
M.-L. Bennasar, Synlett, 1995, 587; X. Wang, A. Kauppi,
R. Olsson and F. Almqvist, Eur. J. Org. Chem., 2003, 4586;
S. Yamada and C. Morita, J. Am. Chem. Soc., 2002, 124, 8184;
J. Pabel, C. Ho
¨
Chem., 2000, 65, 9272; C. Ho
sl, M. Maurus, M. Ege and K. Wanner, J. Org.
sl, M. Maurus, J. Pabel, K. Polborn
¨
and K. Wanner, Tetrahedron, 2002, 58, 6757.
7 V. O. Illi, Synthesis, 1979, 136; R. Lavilla, T. Gotsens and J. Bosch,
Synthesis, 1991, 842; E. J. Corey and Y. Tian, Org. Lett., 2005, 7,
5535.
8 J. G. Michels and K. J. Hayes, J. Am. Chem. Soc., 1958, 80, 1114;
G. Balina, P. Kesler, J. Petre, D. Pham and A. Vollmar, J. Org.
Chem., 1986, 51, 3811; S. D. Ross, M. Finkelstein and J. Uebel,
J. Org. Chem., 1969, 34, 1018; H. Chen, R. Liu, W. H. Myers and
W. D. Harman, J. Am. Chem. Soc., 1998, 120, 509.
9 For a spirocyclisation initiated by a related attack of furan on an
acyliminium ion, see: K. Tokumaru, S. Arai and A. Nishida, Org.
Lett., 2006, 8, 27; A bis-spirocycle has been made by reductive
coupling of pyridinium species: T. Muramatsu, A. Toyota,
M. Kudou, Y. Ikegami and M. Watanabe, J. Org. Chem., 1999,
64, 7249.
10 G. Arnott, H. Brice, J. Clayden and E. Blaney, Org. Lett., 2008, 10,
3089.
11 X-Ray crystallographic data for anti-10b. C38H31F3N2O5S; Mr =
ꢀ
684.71; crystal dimensions 0.20 Â 0.15 Â 0.10 mm; triclinic, P1;
a = 11.4401(18) A, b = 11.6862(19)(10) A, c = 13.896(2) A; V =
1585.2(4) A3; a = 71.474(4)1, b = 67.306(4)1, g = 71.622(3)1;
Z = 2; rcalcd = 1435 kg mÀ3; m = 0.170 mmÀ1; wavelength
0.71073 A; T = 100(2) K; reflections collected/unique: 9330/6339
[Rint = 0.0718]; R1 = 0.0605; wR2 = 0.0955. CCDC number
705273.
12 Some double dearomatisation was observed on cyclisation of an
imidazolylalkyl pyridine, see: J. Winter and J. Retey, Chem.–Eur.
J., 1997, 3, 410.
13 Indium chloride in the presence of trimethylsilyl bromide generally
proved to be an effective Lewis acid in these transformations, see:
T. Saito, Y. Nishimoto, M. Yasuda and A. Baba, J. Org. Chem.,
2006, 71, 8516.
14 J. Clayden, F. E. Knowles and I. R. Baldwin, J. Am. Chem. Soc.,
2005, 127, 2412; J. Clayden, F. E. Knowles and C. J. Menet,
Tetrahedron Lett., 2003, 44, 3397; J. Clayden, C. J. Menet and
K. Tchabanenko, Tetrahedron, 2002, 58, 4727; J. Clayden and
K. Tchabanenko, Chem. Commun., 2000, 317; A. Ahmed,
R. A. Bragg, J. Clayden and K. Tchabanenko, Tetrahedron Lett.,
2001, 42, 3407; R. A. Bragg, J. Clayden, M. Bladon and
O. Ichihara, Tetrahedron Lett., 2001, 42, 3411J. Clayden,Total
synthesis of kainoids by dearomatising anionic cyclisation, in Stra-
tegies and Tactics in Organic Synthesis, ed. M. Harmata, Academic
Press, New York, 2004, vol. 4, pp. 72–96.
5 R. R. Kumar, S. Perumal, P. Senthilkumar, P. Yogeeswari and
D. Sriram, Tetrahedron, 2008, 64, 2962.
6 For a review, see: R. Lavilla, J. Chem. Soc., Perkin Trans. 1,
2002, 1141, Other leading references: G. Arnott, J. Clayden and
S. D. Hamilton, Org. Lett., 2006, 8, 5325; J. T. Kuethe and
D. L. Comins, J. Org. Chem., 2004, 69, 5219; M.-L. Bennasar,
E. Zulaica, Y. Alonso and J. Bosch, Tetrahedron: Asymmetry,
15 M. D. Burke and S. L. Schreiber, Angew. Chem., Int. Ed., 2004, 43, 46.
ꢀc
This journal is The Royal Society of Chemistry 2009
1966 | Chem. Commun., 2009, 1964–1966