Ring expansion of sulfur substituted p-quinamines: Regiospecific synthesis of 4-aminotropones

Article abstract of DOI:10.1039/b414666b

Synthesis of 4-aminotropones through a cyclization-ring expansion process occurs in a single step and with excellent yields from 4-amino-2,5- cyclohexadienones (p-quinamines) bearing a 4-sulfinyl or sulfonyl methyl group. The Royal Society of Chemistry 20

Full text of DOI:10.1039/b414666b

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Ring expansion of sulfur substituted p-quinamines: regiospecific
synthesis of 4-aminotropones{
M. Carmen Carren˜o,* M. Jesu´s Sanz-Cuesta and Mar´ıa Ribagorda
Received (in Cambridge, UK) 23rd September 2004, Accepted 16th November 2004
First published as an Advance Article on the web 5th January 2005
DOI: 10.1039/b414666b
acetal group (Scheme 1). Sulfones 6a–c resulted from MCPBA
oxidation of the sulfoxides 5a–c. Removal of the N-Boc protecting
group afforded free NH2 derivatives 7a–c and 8a–c.
Synthesis of 4-aminotropones through
a cyclization–ring
expansion process occurs in a single step and with excellent
yields from 4-amino-2,5-cyclohexadienones (p-quinamines)
bearing a 4-sulfinyl or sulfonyl methyl group.
Having in mind the known synthesis of tropones based on a
radical cyclization and ring enlargement of 4-halomethyl-2,5-
cyclohexadienones,10c–e and the lack of efficient methods to amino
substituted tropones, we decided to explore whether sulfinyl
substituted p-quinamines {4-amino-4-[(p-tolylsulfinyl)]methyl-2,5-
cyclohexadienones} could be transformed into the cycloheptatrie-
none derivatives. To our delight, when we checked the behavior of
the N-Boc protected p-quinamine 5a in the presence of a base
(K2CO3, NaOH, LDA, KHMDS, LiHMDS) we observed the
exclusive formation of N-Boc-4-aminotropone 9a. After several
trials, we established that upon treatment of a THF solution of 5a
with NaH (4 equiv.), compound 9a was rapidly formed in excellent
yield (Table 1, entry 1).16
The tropone ring system is a recurring structural motif in a number
of natural products,1 ranging from structurally simple monocyclic
systems2 to more complex norditerpenoids3 and alkaloids.4 The
wide range of biological properties that embrace these compounds
have stimulated important synthetic efforts, with the regioselective
construction of a seven-membered ring being one of the more
prominent problems to be solved.1c,5,6 Moreover, tropone seven-
membered ring systems embody a variety of reactivities that
continue to challenge the synthetic chemist.7
Among the strategies applied to the synthesis of the tropone
ring,8 different cycloaddition reactions have been reported.9 Ring
expansion of six-membered rings is also a recurring key step to
synthesize the cycloheptatriene system.10 However, appropriately
substituted tropones are not easily synthesized, because the specific
introduction of substituents at desired positions is difficult to
achieve. In particular, an inspection of published work has
unveiled the synthesis of 4-aminotropone from 4-aminotropolone
sulfate11 and 4-hydroxytropone12 in stepwise sequences. Thus,
development of general and flexible routes to aminotropones are
welcome.
The formation of tropone 9a is assumed to proceed from an
initial a-sulfinyl carbanion resulting upon basic treatment of 5a,
which evolved to a norcaradiene-like intermediate I,10c,17 by a
favoured intramolecular 1,4-addition. Subsequent elimination of
the p-toluene sulfenate anion from I occurred with simultaneous
ring expansion leading to the tropone 9a (Scheme 2). With the aim
of trapping the intermediate enolate I and/or the sulfenate ion,18
reaction of 5a with NaH was run in the presence of MeI. Under
these conditions, a clean mixture of 9a and MeSOTol 3 (84%
isolated yield), resulting from reaction of the nucleophilic sulfenate
moiety, was formed. This result showed that the evolution of the
cycloheptatrienone is strongly favoured and therefore recovery of
the starting sulfoxide 3 for reutilization is possible.
As a part of an ongoing program devoted to synthetic
applications of sulfinyl substituted p-quinols13 and nitrogen
analogues,14 we discovered that these systems behave like natural
quinol metabolites giving rise to a trimerization process through a
domino sequence of four conjugate additions when treated with
NaH or LiCl.14c Herein, we report our findings on the ring
expansion of the p-quinamine core promoted by a base and
mediated by a pendant sulfinyl or sulfonyl methyl group. To our
knowledge, this represents the first efficient synthesis of 4-amino-
tropones. The overall process opens easy and regiospecific access
to C-3 or C-5 alkyl substituted 4-aminotropones.
The ring enlargement of sulfoxides was proved to occur also
with p-quinamines bearing other substitution at the nitrogen.
Thus, N,N-dimethyl 5d, N-methyl 5e and N-benzyl 5f derivatives
The starting materials, N-(tert-butoxycarbonyl)-4-amino-4-
[(p-tolyl or phenylsulfinyl)methyl]-2,5-cyclohexadienones14b 5a–c,
are accessible in three steps from N-Boc p-anisidine derivatives 1,
through anodic oxidation,15 addition of the a-lithiocarbanion
derived from methyl p-tolylsulfoxide 3 or ethyl phenyl sulfoxide 4
to the quinoneimine monoacetals 2, and acid hydrolysis of the
Scheme 1 Synthesis of 4-sulfinyl (or sulfonyl) methyl substituted p-quina-
mines 5–8. Conditions: (i) Anodic oxidation, Pt/Cu, MeOH, LiClO4, Py,
0 uC, (2a) 99%, (2b) 93%; (ii) MeSOTol (3) or EtSOPh (4), LDA, THF,
278 uC to rt; (iii) Oxalic acid, THF–H2O, rt, (5a) 80% and (5b) 82% from
3 (R2 5 H), (5c) 40% from 4 (R2 5 Me) (yield of two steps); (iv) MCPBA,
CH2Cl2, 0 uC, 99% (6a–c); (v) TFA, CH2Cl2, rt, (7a) 99%, (7b) 78%, (7c)
96%, (8a) 99%, (8b) 99%, (8c) 52%. See Table 1 for substrate details.
{ Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data of 9a–f, 10a–c, 11
(including NOESY experiments) and 12. See http://www.rsc.org/suppdata/
cc/b4/b414666b/
*carmen.carrenno@uam.es
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Chem. Commun., 2005, 1007–1009 | 1007

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Table 1 Regioselective synthesis of 4-amino substituted tropones
Scheme 3 Diels–Alder reaction and 4p-electrocyclization of 9a.
Entry 5,6,8 NR3R4 R1 R2 Ar
n
Time/h 9–10 (Yield)a
1
2
3
4
5
6
7
8
5a
5d
5e
5f
5b
5c
6b
6c
6a
8a
8b
8c
NHBoc
NMe2
NHMe
NHBn
NHBoc Me
NHBoc
NHBoc Me
NHBoc
NHBoc
NH2
H
H
H
H
H
H
H
H
H
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
1
1
1
1
1
1
2
2
2
2
2
2
3
2
2
2
24
24
1
4
2
9a (99)
9d (99)
9e (70)
9f (99)
the Diels–Alder reaction with maleimide, yielding the single
adduct 11, resulting from the endo-approach, in 74% yield. The
structure of 11 was secured by NOESY experiments, where
interaction between the enone protons H-9 and H-10 with H-6 and
H-2 respectively, was observed (Scheme 3). The photochemical
behavior of 9a was also studied.19 Irradiating a MeCN solution of
9a, a 4p-electrocyclization led to the cis-bicyclo[3.2.0]hepta-3,6-
dien-2-one derivative 12 (60% yield). This bicyclic structure bears
a protected bridged nitrogen function. Heating compound 12
(40 uC) promoted the cyclobutene opening to regenerate 9a in
99% yield.
b
—
—
b
H
Me p-Tol
p-Tol
Me Ph
H
9b (77)
9c (94)
9a (97)
10a (99)c
10b (97)c
10c (99)c
b
H
H
H
Me
H
9
H
H
H
p-Tol
p-Tol
p-Tol
10
11
12
a
6
24
2
NH2
NH2
Me Ph
Yield after purification by column chromatography. Unaltered
starting material was recovered despite the addition of 8 equiv. of
c
NaH and heating at 50 uC. Purified on a BondElut LRC-SCX,
500 mg column chromatography.
In summary, we have reported regioselective access to
4-aminotropones starting from p-sulfinylmethyl substituted
p-quinamines, in turn accessible from N-Boc anilides in three
steps. The position of alkyl substituents at C-3 or C-5 of the
cycloheptatrienone can be directed by choosing the adequate
substitution at both starting materials. The sulfonyl analogues
behave similarly. To our knowledge, this is the first example of
a ring expansion mediated by a simple alkyl aryl sulfoxide or
sulfone.
This work was supported by the MCYT (Grant BQU2002-
00371). M. J. S. C thanks MCYT for a fellowship. M. R. thanks
the MEC for a Ramo´n y Cajal contract.
M. Carmen Carren˜o,* M. Jesu´s Sanz-Cuesta and Mar´ıa Ribagorda
Dpto. de Qu´ımica Orga´nica (C-I), Universidad Auto´noma,
Cantoblanco, 28049-Madrid, Spain. E-mail: carmen.carrenno@uam.es;
Fax: +34 914973966; Tel: +34 914973924
Scheme 2 Possible mechanism of 4-aminotropone formation and
trapping of the sulfenate leaving group.
Notes and references
afforded the N-substituted 4-aminotropones 9d–f in excellent yields
(Table 1, entries 2–4). 3-Methyl N-Boc p-quinamine 5b and the
a-methyl sulfinyl N-Boc derivative 5c remained unchanged upon
treatment with NaH (Table 1, entries 5 and 6). Nevertheless,
3-methyl-N-Boc-4-aminotropone 9b and the 5-methyl isomer 9c
were regioselectively obtained from the sulfonyl p-quinamines 6b
and 6c (Table 1, entries 7 and 8). According to the proposed
mechanism, the regioselective formation of 9b must be a
consequence of the initial conjugate addition of an intermediate
a-sulfonyl anion derived from 6b to the more electrophilic
unsubstituted double bond of the cyclohexadienone moiety.
The ring expansion from the sulfone bearing p-quinamines was
shown to be general. Tropone 9a was also obtained from 6a
(Table 1, entry 9). The free amino sulfinyl derivatives 7a–c under
the basic conditions were inert to ring expansion, but fortunately
the sulfone bearing analogues 8a–c gave tropones 10a–c in
excellent yields (Table 1, entries 10–12).
{ Crystal data for 9a: C12H15NO3,
M 5 221.25, monoclinic,
a 5 8.88460(10), b = 12.7624(2), c 5 10.1950(2) s, b 5 100.7030(10)u,
U 5 1135.89(3) s3, T 5 100(2) K, space group P21/c (no. 14), Z 5 4,
m(Mo–Ka) 5 0.765 mm21, 4550 reflections measured, 2015 unique (Rint
=
0.0247) which were used in all calculations. The final R1 and wR2 were
0.0348 and 0.0914 (I . 2sI). CCDC 247411. See http://www.rsc.org/
suppdata/cc/b4/b414666b/ for crystallographic data in .cif or other
electronic format.
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