A dearomatizing, thionium ion cyclization for the synthesis of functionalized, azaspirocyclic cyclohexadienones

Article abstract of DOI:10.1021/ol8002095

(Chemical Equation Presented) Thionium ions, generated by the addition of thiols to N-benzylglyoxamides, undergo a dearomatizing spirocyclization. The alkyl or arylsulfanyl group introduced during the thionium ion cyclization can act as a synthetic handle and a stereochemical control element during modifications of the azaspirocyclic frameworks (R^F = CH ₂CH₂C₈F₁₇).

Full text of DOI:10.1021/ol8002095

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1441-1444
A Dearomatizing, Thionium Ion
Cyclization for the Synthesis of
Functionalized, Azaspirocyclic
Cyclohexadienones
Caroline Ovens,† Nathaniel G. Martin,‡ and David J. Procter*,†
School of Chemistry, The UniVersity of Manchester, Oxford Road, Manchester, M13
9PL, United Kingdom, and AstraZeneca, Mereside, Alderley Park, Macclesfield,
Cheshire, SK10 4TG, United Kingdom
daVid.j.procter@manchester.ac.uk
Received January 29, 2008
ABSTRACT
Thionium ions, generated by the addition of thiols to N-benzylglyoxamides, undergo a dearomatizing spirocyclization. The alkyl or arylsulfanyl
group introduced during the thionium ion cyclization can act as a synthetic handle and a stereochemical control element during modifications
of the azaspirocyclic frameworks (RF
) CH2CH2C8F17).
Pummerer reactions,1 involving nucleophilic additions to
thionium ions, are a useful tool for the synthesis of
heterocyclic compounds.2 We have recently investigated the
utility of a Pummerer-type3 reaction in which thionium ions
are generated by the addition of thiols to aldehydes4 and have
exploited the connective nature of the process in a fluorous
approach to N-heterocycles where a fluorous tag is introduced
and a heterocyclic scaffold is constructed in a single step.5
We wished to exploit thionium ions generated in this way
in cyclization reactions to access unusual N-heterocyclic
† The University of Manchester.
‡ AstraZeneca.
(1) Pummerer, R. Chem. Ber. 1909, 42, 2282.
(2) (a) Akai, S.; Kita, Y. Top. Curr. Chem. 2007, 274, 35. (b) Feldman,
K. S. Tetrahedron 2006, 62, 5003. (c) Bur, S. K.; Padwa, A. Chem. ReV.
2004, 104, 2401. (d) Padwa, A.; Danca, D. M.; Ginn, J. D.; Lynch, S. M.
J. Braz. Chem. Soc. 2001, 12, 571. (e) Padwa, A.; Waterson, A. G. Curr.
Org. Chem. 2000, 4, 175. (f) Padwa, A.; Gunn, D. E., Jr.; Osterhout, M. H.
Synthesis 1997, 1353.
(3) We describe these reactions as “Pummerer-type” processes to show
their relationship to “Pummerer” reactions in which similar thionium ions
are generated from sulfoxides. See ref. 2.
(4) Miller, M.; Tsang, W.; Merritt, A.; Procter, D. J. Chem. Commun.
2007, 498.
(5) (a) McAllister, L. A.; McCormick, R. A.; Brand, S.; Procter, D. J.
Angew. Chem., Int. Ed. 2005, 44, 452. (b) McCormick, R. A.; James, K.
M.; Willetts, N.; Procter, D. J. QSAR Comb. Sci. 2006, 25, 709. (c)
McAllister, L. A.; McCormick, R. A.; James, K. M.; Brand, S.; Willetts,
N.; Procter, D. J. Chem. Eur. J. 2007, 13, 1032.
10.1021/ol8002095 CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/12/2008

scaffolds. Although cyclizations of thionium ions 1 have been
used for the synthesis of tetrahydroisoquinolines and tet-
rahydroisoquinolones,6 we envisaged that appropriate aro-
matic substitution in thionium ions 1 would allow access to
functionalized, azaspirocyclic cyclohexadienes via a dearo-
matizing spirocyclization.7 The spirocyclic products would
be useful intermediates for the synthesis of targets possessing
the 2-azaspiro[4.5]decane skeleton (Scheme 1).
acid-catalyzed cyclizations of electron-rich aromatic dia-
zoacetamides,9a intramolecular additions of nitrenes to
electron-rich benzenes,9b carbanion additions to arene ru-
thenium complexes,9c and more recently, oxidative radical
cyclizations of xanthates.9d
Here we report a thionium ion approach to azaspirocyclic
cyclohexadienones. In contrast to several of the existing
methods for constructing this motif,9a,d the thionium ion
cyclization is accompanied by an increase in functionality:
carbon-carbon and carbon-sulfur bonds and up to two new
stereocentres are formed during construction of the azaspi-
rocyclic framework. To our knowledge, this constitutes the
first example of the dearomatization of a benzene derivative
by intramolecular addition of a thionium ion.7
Scheme 1. Dearomatizing Spirocyclizations of Thionium Ions
N-Benzylglyoxamides 2-9 were prepared from readily-
available benzylamines using Bartlett’s convenient and
scalable route,10 and the cyclization of these substrates was
studied using a range of thiols. One-pot cyclizations were
carried out by stirring thiol with the crude glyoxamide
followed by addition of trifluoroacetic anhydride then BF3‚
OEt2 (Table 1). At least two electron-releasing groups on
The 2-azaspiro[4.5]decane skeleton is found in a wide
variety of natural and unnatural products. The motif is found
in synthetic compounds displaying activity as HIV-1 protease
inhibitors8a and compounds with antiarthritic8b and antigastrin8c
activity. The azaspirocyclic framework is also found in the
natural products spirostaphylotrichin A,8d annosqualine,8e
and alkaloids isolated from didymeles madagascariensis8f
(Figure 1).
Table 1. Dearomatizing Spirocyclizations of Thionium Ionsa
Figure 1. 2-Azaspiro[4.5]decane skeleton.
Few methods for the synthesis of azaspirocyclic cyclo-
hexadiene systems have been reported.9 Strategies include
a RSH, CH2Cl2, then TFAA, then BF3‚OEt2. b Isolated yields are for 2
steps as glyoxamides are not purified. c Approximately 2:1 to 3:1 mixture
of diastereoisomers. d Only one diastereoisomer was isolated (PSE )
2-phenylsulfonylethyl, RF) -CH2CH2C8F17)
(6) (a) Saitoh, T.; Shikiya, K.; Horiguchi, Y.; Sano, T. Chem. Pharm.
Bull. 2003, 51, 667. (b) Hanaoka, M.; Hirasawa, T.; Cho, W. J.; Yasuda,
S. Chem. Pharm. Bull. 2000, 48, 399.
1442
Org. Lett., Vol. 10, No. 7, 2008

the benzene ring are required for successful isolation of
spirocyclic products. The azaspirocyclic structure of 10 was
confirmed by X-ray crystallography.11 In all cases, reaction
mixtures develop a bright coloration that we attribute to
cationic intermediates and give the expected spirocycles in
good overall yield after two steps. Substrates 4-7 give
azaspirocycles 17-22 with moderate selectivity for the anti
product12 (approximately 2:1 to 3:1 dr). Interestingly, only
a single diastereoisomer was isolated from the cyclization
of substrates 8 and 9. The anti stereochemistry of 23 and 24
was confirmed by NOE studies. When the commercial
fluorous thiol, C8F17CH2CH2SH, was used, fluorous solid-
phase extraction (FSPE)13 provides an additional option for
purification. The cyclization of substrates 3 and 4 illustrates
that the 2-phenylsulfonylethyl (PSE) group14 is suitable for
the synthesis of azaspirocycles with a protecting group on
nitrogen. We have also found that Sc(OTf)3 can be employed
as the Lewis acid in the cyclization: the reaction of 4 using
Sc(OTf)3 (0.5 equiv) gave 17 in 55% yield (2 steps).
The high diastereoselectivity observed in the cyclization
of 8 and 9 appears to arise from steric interactions rather
than electronic effects: the meta substituent (R2) increases
the steric presence of the ortho-methoxy group through a
buttressing effect thus favoring the anti transition structure
(Scheme 2). With a hydrogen in the meta position (R2) H)
are accessible leading to a lower preference for the anti
diastereoisomers.
In some cases, the azaspirocyclic motif was not isolated
from the reaction, for example, exposure of 2-fluoro-4-
methoxybenzylglyoxamide 25 to the reaction conditions gave
amide 26 in which the aryl group has undergone migration
to the position R- to sulfur, in 61% yield (Scheme 3). This
Scheme 3. Spirocyclization-Aryl Migration
(RF ) -CH2CH2C8F17)
migration occurs via fragmentation of the expected spiro-
cyclic, cationic intermediate, and hydrolysis of the resultant
N-acyl iminium ion.15 2,6-Dimethoxybenzylglyoxamide 27
also underwent cyclization-aryl migration to give 28. This
intramolecular arylation of thionium ions provides a valuable
alternative to the intermolecular additions of electron-rich
benzenes to thionium ions.2
The azaspirocyclic frameworks resulting from the cycliza-
tion are rich in functionality and have significant synthetic
potential. For example, the alkylsulfanyl group introduced
during the spirocyclization is a valuable synthetic handle
particularly as the oxidation state of sulfur can easily be
adjusted: oxidation of 11 with mCPBA (1 eq) gave sulfoxide
29 whereas oxidation of 11 and 12 with mCPBA (2 eq) gave
sulfones 30 and 31 (Scheme 4). The structure of 31 was
confirmed by X-ray crystallographic analysis.11
Scheme 2. Origin of Diastereoselectivity
(RF ) -CH2CH2C8F17)
the methoxy group has a lower steric influence on the course
of the cyclization and both syn and anti transition structures
Scheme 4. Adjusting the Oxidation State of Sulfur in the
Azaspirocycles (RF ) -CH2CH2C8F17)
(7) Previously reported Pummerer spirocyclizations involve addition to
indole derivatives. For selected examples, see: (a) Magnus, P.; Sear, N.
L.; Kim, C. S.; Vicker, N. J. Org. Chem. 1992, 57, 70. (b) Amat, M.; Bosch,
J. J. Org. Chem. 1992, 57, 5792. (c) Catena, J.; Valls, N.; Bosch, J.; Bonjoch,
J. Tetrahedron Lett. 1994, 35, 4433. (d) Feldman, K. S.; Vidulova, D. B.;
Karatjas, A. G. J. Org. Chem. 2005, 70, 6429. (e) Feldman, K. S.; Karatjas,
A. G. Org. Lett. 2006, 8, 4137.
(8) (a) Kazmierski, W. M.; Furfine, E.; Spaltenstein, A.; Wright, L. L.
Biorg. Med. Chem. Lett. 2002, 12, 3431. (b) Badger, A. M.; Schwartz, D.
A.; Picker, D. H.; Dorman, J. W.; Bradley, F. C.; Cheeseman, E. N.;
DiMartino, M. J.; Hanna, N.; Mirabelli, C. K. J. Med. Chem. 1990, 33,
2963. (c) Makovec, F.; Peris, W.; Revel, L.; Giovanetti, R.; Mennuni, L.;
Rovati, L. C. J. Med. Chem. 1992, 35, 28. (d) Sandmeier, P.; Tamm, C.
HelV. Chim. Acta 1989, 72, 784. (e) Yang, Y.; Chang, F.; Wu, Y. HelV.
Chim. Acta 2004, 87, 1392. (f) Sa´nchez, V.; Ahond, A.; Guilhem, J.; Poupat,
C.; Potier, P. Bull. Soc. Chim. Fr. 1987, 877.
(9) (a) Rishton, G. M.; Schwartz, M. A. Tetrahedron Lett. 1988, 29,
2643. (b) Wardrop, D. J.; Burge, M. S.; Zhang, W.; Ort´ız, J. A. Tetrahedron
Lett. 2003, 44, 2587. (c) Pigge, F. C.; Coniglio, J. J.; Dalvi, R. J. Am. Chem.
Soc. 2006, 128, 3498. (d) Ibarra-Rivera, T. R.; Ga´mez-Montano, R.;
Miranda, L. D. Chem. Commun. 2007, 3485.
Conversion to the sulfone facilitates modification of
the azaspirocyclic framework, for example, hydrogenation
(12) The stereochemistry was determined by NOE studies on the major
diastereoisomers of 21 and 22 and inferred for the remainder.
(13) For recent reviews; see: (a) Curran, D. P. In Handbook of Fluorous
Chemistry; Gladysz, J. A., Curran, D. P., Horva´th, I. T., Eds.; Wiley-VCH:
Weinheim, 2004. (b) Zhang, W. Tetrahedron 2003, 59,
4475.
(10) Marx, M. A.; Grillot, A.-L.; Louer, C. T.; Beaver, K. A.; Bartlett,
P. A. J. Am. Chem. Soc. 1997, 119, 6153. See also refs 4 and 5.
(11) See supporting information for CCDC numbers.
(14) DiPietro, D.; Borzilleri, R. M.; Weinreb, S. M. J. Org. Chem. 1994,
59, 5856.
(15) Padwa, A.; Kuethe, J. T. J. Org. Chem. 1998, 63, 4256.
Org. Lett., Vol. 10, No. 7, 2008
1443

of 32 under microwave irradiation gave 33 in excellent
yield whereas attempted hydrogenation of the corresponding
sulfide 19 was unsuccessful. Sulfones can also be elaborated
through alkylation reactions, for example, treatment of 30
with MeI and DBU under microwave irradiation gave 34
(Scheme 5).
Scheme 6. Diastereoselective, Sequential Reduction of
Azaspirocycles
Scheme 5. Modification of the Azaspirocyclic Framework
(RF ) CH2CH2C8F17)
releasing groups required for cyclization can be removed to
access less-oxygenated systems.
Oxidation of sulfur has an added benefit in that spirocyclic
products that are obtained as a mixture of diastereoisomers
with only modest preference for the anti diastereoisomer,
for example 19 (∼2:1, anti:syn), undergo equilibration upon
conversion to the sulfones, giving products, such as 32 (85%)
greatly enriched in the anti diastereoisomers (>12:1, anti:
In summary, the addition of thiols to N-benzylglyoxamides
triggers a diastereoselective, dearomatizing cyclization to
give functionalized azaspirocyclic cyclohexadienones. The
alkyl or arylsulfanyl group introduced during the thionium
ion cyclization can play multiple roles, acting as a diver-
sity element, a synthetic handle, and a stereochemical
control element in modifications of the azaspirocyclic
frameworks.
1
syn by H NMR).
Further preliminary studies on the modification of the
azaspirocyclic structures have been carried out. Treatment
of spirocycles 11 and 35 with LiBH4 results in a reductive
sequence that generates three stereocentres giving allylic
alcohols 36 and 37, respectively, as single diastereoisomers
(Scheme 6).
Acknowledgment. We thank AstraZeneca (CASE award,
C.O.) and The University of Manchester. We also thank Dr.
Rosemary A. McCormick (University of Glasgow) and
Madeleine Da Silva (University of Manchester) for prelimi-
nary studies.
This sequence illustrates how the alkylsulfanyl group
introduced in the thionium ion cyclization can function
Supporting Information Available: Full experimental
details and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
as
a
stereochemical control element, orchestrating
the generation of stereochemistry elsewhere in the system.
Allylic alcohols 36 and 37 are unstable; for example, 36
converted to enone 38 upon standing in CDCl3 (Scheme 6).
The conversion of 11 to 38 illustrates how the electron-
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