Synthesis and functionalization of unsymmetrical arylsulfonyl bisindoles and bisbenzazoles

Article abstract of DOI:10.1002/adsc.201200632

A three-component coupling of two different benzazole compounds with p-toluenesulfinic acid allows the efficient preparation of unsymmetrical arylsulfonyl bisbenzazole derivatives. Substitution of the arylsulfonyl group from these adducts using sodium borohydride leads to the corresponding bisbenzazoles. Functional implementation of the bisbenzazole system can be achieved using Grignard and Reformatsky reagents.

Full text of DOI:10.1002/adsc.201200632

FULL PAPERS
DOI: 10.1002/adsc.201200632
Synthesis and Functionalization of Unsymmetrical Arylsulfonyl
Bisindoles and Bisbenzazoles
Stefano Lancianesi,a Alessandro Palmieri,a,* and Marino Petrinia,*
a
School of Science and Technology, Chemistry Division, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy
Fax : (+39)-0737-402-297; e-mail: alessandro.palmieri@unicam.it or marino.petrini@unicam.it
Received: July 18, 2012; Revised: August 30, 2012; Published online: December 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200632.
Abstract: A three-component coupling of two differ- benzazoles. Functional implementation of the bis-
ent benzazole compounds with p-toluenesulfinic acid benzazole system can be achieved using Grignard
allows the efficient preparation of unsymmetrical ar- and Reformatsky reagents.
ylsulfonyl bisbenzazole derivatives. Substitution of
the arylsulfonyl group from these adducts using Keywords: bisindoles; coupling reactions; Grignard
sodium borohydride leads to the corresponding bis- reagents; reductions; Reformatsky reagents
Introduction
Compounds containing the bisindole scaffold are of
paramount importance as pharmacologically active
substances and for their applications in materials
chemistry.[1] Symmetrical bisindoles are usually avail-
able by coupling reactions involving an aldehyde or
its derivative and two equivalents of indole in the
presence of acid catalysts or promoters.[2] Less com-
monly, aldehyde is replaced by other electrophilic
groups in metal-catalysed reactions.[3] Such proce-
dures are unfit for the preparation of unsymmetrical
bisindoles since it is not possible to realise any control
in the cross coupling of two different indole molecules
present in the same environment. An efficient entry
to unsymmetrical bisindole derivatives would be
highly desirable since it provides an enlargement of
compound libraries available for practical purposes.
In this context, even more interesting would be the
development of a synthetic procedure allowing the
preparation of bisbenzazole systems embedding cou-
ples of different benzofused nitrogen heterocycles
such as indoles, indazoles and azaindoles. A very gen-
eral procedure for the synthesis of unsymmetrical
bisindoles starts from a 3-substituted indole 1 bearing
a good leaving group at the benzylic position
(Scheme 1). Upon elimination of the leaving group,
a stabilized carbocation 2 is generated which is able
to react with indole 3 providing the bisindole com-
pound 4.[4] A crucial aspect of this approach lies in
the limited availability and structural complexity of
Scheme 1. General strategies for the synthesis of unsymmet-
substrates of type 1.[5] In this paper, a different strat- rical bisbenzazole derivatives.
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egy based on our previous work in the field of azole its indazole analogue 5e is particularly significant
functionalizations is presented.[6]
since, to the best of our knowledge, there are no ex-
Various 3-formylbenzazole derivatives 5 are eligible amples of unsymmetrical bisbenzazole compounds in-
for a three-component coupling involving p-toluene- cluding these heterocyclic systems (Table 1, entries 7–
sulfinic acid and a second indole molecule 6. The 11). The enhanced pharmacological profile evidenced
mixed bisbenzazole compound 7 thus obtained works in many compounds having the 7-azaindole and inda-
as an efficient pivotal, stable intermediate which upon zole units makes bisadducts 7g–k and their functional-
reaction with a suitable nucleophile or a base gener- ized derivatives (vide infra), of particular interest in
ates an indolenine intermediate 8, amenable of a nu- the realm of medicinal chemistry.[10] The preparation
cleophilic addition to the final functionalized bis- of compound 7 is operationally simple, does not re-
A
quires harsh reaction conditions and the crude prod-
ucts obtained after usual work-up are easily isolated
by crystallization. As previously stated, the p-toluene-
sulfonyl group in compounds 7 can be removed under
basic conditions leading to a reactive vinylogous
Results and Discussion
The procedure previously disclosed by us has proved imine intermediate 8 which promptly reacts with
to be particularly effective also for the preparation of a wide array of nucleophiles providing the corre-
sulfonyl bisbenzazoles 7 (Table 1).[8] 3-Carbaldehyde sponding substitution products 9. Nucleophilic re-
derivatives of indoles, indazole and 7-azaindole 5 agents with enough basic character are expected to
react with different indoles 6 and p-toluenesulfinic assist the elimination of the sulfinate anion from 7 so
acid in a three component coupling in the presence of that no added basic reagents are needed for the over-
p-toluenesulfonic acid.[9] For a proper conversion, the all process as demonstrated for the reduction of com-
benzazole-3-carbaldehyde nitrogen must be adequate- pounds 7 with NaBH4 which affords the expected de-
ly protected since reduced yields (40–50%) of adducts sulfonylated bisbenzazoles 10 in good yield
are experienced with free N H substrates. The reac- (Table 2).[11]
À
tivity displayed by 7-azaindole-3-carbaldehyde 5d and
Table 1. Synthesis of arylsulfonyl bisbenzazoles 7.[a]
Entry
5
6
7
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
5a
5b
5b
5b
5c
5c
5d
5d
5d
5e
5e
6c
6a
6b
6d
6a
6f
6c
6b
6e
6c
6e
7a
7b
7c
7d
7e
7f
7g
7h
7i
4
4
5
5.5
4.5
3
3.5
5
78
81
90
80
82
92
88
79
80
92
83
9
10
11
5
5
5
7j
7k
[a]
Reaction conditions: aldehyde (3 mmol), indole (3.2 mmol), p-TolSO2H (3.6 mmol), p-TolSO3H·H2O (1.5 mmol), in CHCl3
ACHTUNGTRENNUNG(10 mL) at room temperature.
Yield of pure, isolated products.
[b]
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Synthesis and Functionalization of Unsymmetrical Arylsulfonyl Bisindoles and Bisbenzazoles
Table 2. Synthesis of bisbenzazoles 10.[a]
reactivity of the azole nitrogen in 7-azaindoles com-
pared to indole itself. The yield of 10g is comparable
to that obtained by applying crude 10d directly to the
column which results in the recovery of N-protected
10d. This evidences that an almost quantitative depro-
tection of the N-Boc-7-azaindole system is achievable
by simple absorption on silica gel.
Substitution of the arylsulfinyl group in compounds
7 with a carbon nucleophile would certainly represent
a valid option to implement the bisbenzazole struc-
ture with the insertion of functionalized carbon
frameworks. In this context different Grignard re-
agents 11 can be employed in the reaction with sulfo-
nyl bisbenzazoles 7 allowing formation of the alkylat-
ed bisbenzazoles 12 (Table 3). From a synthetic stand-
point, the two-step process involving formation of
compounds 7 and sulfonyl substitution to derivatives
12 is equivalent to a three-component cross-coupling
leading to unsymmetrical bisbenzazoles not achieva-
ble by a straightforward procedure. Primary and vinyl
Grignard reagents are effective in the reaction with
different sulfonyl bisbenzazoles 7, while rather curi-
ously allylmagnesium bromide 11d gives a sluggish re-
action with compound 7b evidencing a double bond
migration from the terminal position (Table 3,
entry 4). Reaction of arylorganometallic reagents
(PhMgBr and PhLi) with 7a and 7j, although attempt-
ed, proved to be ineffective in giving the correspond-
ing triarylmethane derivatives. The starting arylsul-
fonyl bisbenzazole was totally unaffected under stan-
dard reaction conditions (À308C/08C), while upon
reflux extensive decomposition of the substrate was
observed after 6 h.[13] The level of functional imple-
mentation obtainable using Grignard reagents is usu-
ally quite limited because of their nucleophilic power
which prevents many electrophilic functions to be
present in the organometallic framework. Stabilized
carbanionic systems such as zinc enolates could be
profitably used for this purpose since they are pre-
pared in situ from the corresponding halides and do
not require carefully controlled reaction conditions.
Zinc powder in the presence of a catalytic amount of
iodine is able to effect the addition of different easily
enolizable a-bromo derivatives 13 to sulfonyl bisbenz-
Entry
1
7
10
Yield [%][b]
76
7a
10a
10b
10c
10d
2
3
4
5
7d
7c
7g
80
72
88
7h
7k
10e
72
93
6
10f[c]
[a]
Reaction conditions: sulfonyl bisazole (0.4 mmol) in
CHCl3/i-PrOH (4 mL:2 mL), NaBH4 (0.8 mmol) at 08C.
Yield of pure, isolated products.
[b]
[c]
Ar=4-MeOC6H4.
Scheme 2. Cleavage of N-Boc protection on the 7-azaindole
moiety by absorption on silica gel.
An intriguing aspect concerns the robustness of the
ACHTUNGTRENaNGNU zoles 7 via the corresponding organozinc reagents
N-Boc protection in the 7-azaindole moiety which (Table 4). Beside the utilization of classical a-bromo
seems resistant to the acidic conditions needed for the ketone and ester 13a and 13b it is worthy of note that
synthesis of sulfonyl bisbenzazoles 7g–i. However, also bromoacetonitrile 13c is able to provide the cor-
during the purification step of crude 10d we observed responding adducts in high yield (Table 4, entries 3
that upon absorption on silica gel and subsequent ap- and 7). The utilization of bromonitromethane 13d in
plication of the solid mixture to the head of the chro- addition reactions as a nitromethane equivalent is
matographic column, only deprotected bisbenzazole rather limited in scope. This reagent is often used in
10g was recovered after elution (Scheme 2). The cyclopropanation reactions[14] and only recently it has
effect of silica gel on the selective deprotection of N- been involved in samarium- and indium-promoted re-
Boc-pyrrole is known, but the reported procedure re- actions with aldehydes and imines.[15] The general re-
quires prolonged heating (7–8 h) at 508C under re- action conditions proved effective for other bromo
duced pressure (1 mmHg).[12] This evidences a superior derivatives also, allowing the addition of bromonitro-
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Table 3. Reaction of sulfonyl bisbenzazoles 7 with Grignard
reagents 11[a]
Table 4. Reaction of sulfonyl bisbenzazoles 7 with bromo
derivatives 13 in the presence of zinc.[a]
Entry
1
7
11
12
Yield [%][b]
97
Entry
1
7
13
14
Yield [%][b]
7a 11a 12a
7b 11b 12b
7b 11c 12c
7j 13a 14a
85
2
3
95
2
3
7b 13b 14b
81[c]
80[c]
7c 13c 14c
7g 13d 14d
87
4
7b 11d 12d
40
4
5
55[d]
5
6
7
7c 11c 12e
7c 11e 12f
78[c]
7i
13b 14e
83[c,d,e]
77[c]
6
7j 13b 14f
76[c]
7j 11f 12g
7j 11e 12h
82
85
7
7j 13c 14g
89
8
[a]
Reaction conditions: Zn (2 mmol), I2 (0.1 mmol) in THF
(6 mL), bromo derivative (0.8 mmol), sulfonyl bisbenza-
zole (0.4 mmol) at reflux for 5 h.
[a]
Reaction conditions: sulfonyl bisbenzazole (0.4 mmol) in
THF (6 mL) at À308C, Grignard reagent (1.2 mmol).
Yield of pure, isolated products.
2 h at À308C then slowly warming to 08C.
[b]
[c]
[b]
[c]
[d]
[e]
Yield of pure, isolated products.
Reaction carried out at room temperature for 5 h.
N-Boc protection is removed in the reaction.
Ar=4-MeOC6H4.
methane 13d to sulfonyl bisbenzazole 7g (Table 4,
entry 4). The lability of the N-Boc protection in the 7- the synthesis of compounds 14d and 14e which are de-
azaindole moiety previously observed in the purifica- carbonylated in these reaction conditions (Table 4, en-
tion step of bisbenzazole 10d is further evidenced in tries 4 and 5).
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Synthesis and Functionalization of Unsymmetrical Arylsulfonyl Bisindoles and Bisbenzazoles
combined organic extracts were dried over NaSO4. The
Conclusions
crude product obtained after removal of the solvent at re-
duced pressure was purified by column chromatography
(hexanes-ethyl acetate 8:2).
The new synthetic approach for the preparation of
unsymmetrical bisbenzazole derivatives starts with
a three-component coupling involving a heterocyclic
carbaldehyde, an indole derivative and p-toluenesul-
finic acid. This reaction generates an arylsulfonyl bis-
benzazole system which acts as a pivotal intermediate
for subsequent functional group implementations.
Elimination of the arylsulfonyl moiety under basic
conditions leaves a vinylogous imino derivative which
upon reduction or reaction with organometallic re-
agents affords functionalized bisbenzazole systems.
The described procedure is simple, viable and pro-
vides access to a class of heterocyclic derivatives hith-
erto unknown but with potential practical applications
in the field of medicinal and materials chemistry.
General Procedure for the Preparation of Bisbenz-
azoles 14 by Reaction of Compounds 7 with Bromo
Derivatives 13 in the Presence of Zinc
To a stirred suspension of Zn (2 mmol), I2 (0.1 mmol) and 2-
bromo derivative 13 (0.8 mmol) in THF (6 mL) at room
temperature was added the appropriate bisbenzazole 7
(0.4 mmol). The reaction mixture was stirred at reflux for
2 h (5 h at room temperature for the reactions with methyl
bromoacetate 13b). After cooling to room temperature the
mixture was treated with saturated NH4Cl (5 mL), the aque-
ous layer was extracted with CHCl3 (3ꢁ10 mL) and the
combined organic extracts were dried over NaSO4. The
crude product obtained after removal of the solvent at re-
duced pressure was purified by column chromatography
(hexanes-ethyl acetate 8:2; for compounds 14d and 14e:
hexanes-ethyl acetate 7:3).
Experimental Section
General Procedure for the Preparation of Sulfonyl
Bisbenzazoles 7
Acknowledgements
To a stirred solution of indole 6 (3.2 mmol), p-toluenesulfin-
ic acid (3.6 mmol) and p-toluenesulfonic acid monohydrate
(1.5 mmol) in CHCl3 (10 mL), the carbaldehyde 5 (3 mmol)
was added. The resulting reaction mixture was stirred at
room temperature for the appropriate time (see Table 1),
and was then treated with saturated NaHCO3 (7 mL). The
aqueous layer was extracted with CHCl3 (3ꢁ20 mL),[16] the
combined organic extracts were dried over Na2SO4. The
crude product 7 obtained after filtration through a short
celite pad and removal of the solvent at reduced pressure,
was purifed by crystallization form ethyl acetate/hexane.
We acknowledge financial support from University of Camer-
ino, and FIRB National Project ꢀMetodologie di nuova gener-
azione nella formazione di legami carbonio-carbonio e car-
bonio-eteroatomo in condizioni eco-sostenibiliꢁ.
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Adv. Synth. Catal. 2012, 354, 3539 – 3544