Friedel-Crafts hydroxyalkylation through activation of a carbonyl group using AlBr3: An easy access to pyridyl aryl/heteroaryl carbinols

Article abstract of DOI:10.1039/c2nj40871f

Aromatic electrophilic substitution of aromatic/electron rich heteroaromatic compounds with AlBr₃ activated aldehydes/ketone to afford pyridyl aryl/heteroaryl or diaryl carbinols is described. The strong electron donating group dictates the regiochemical outcome of the product.

Full text of DOI:10.1039/c2nj40871f

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Friedel–Crafts hydroxyalkylation through activation of
a carbonyl group using AlBr3: an easy access to pyridyl
aryl/heteroaryl carbinols†‡
Cite this: NewJ.Chem., 2013,
37, 563
Received (in Montpellier, France)
26th September 2012,
Adhikesavan Harikrishnan, Jayaraman Selvakumar, Elumalai Gnanamani,
Suman Bhattacharya and Chinnasamy Ramaraj Ramanathan*
Accepted 3rd December 2012
DOI: 10.1039/c2nj40871f
www.rsc.org/njc
Aromatic electrophilic substitution of aromatic/electron rich het- through the addition of Grignard reagent/lithium reagent to a
eroaromatic compounds with AlBr3 activated aldehydes/ketone to carbonyl group3 or [1,2]-anionic rearrangement reactions.4 These
afford pyridyl aryl/heteroaryl or diaryl carbinols is described. The methodologies, generally utilize preformed nucleophiles, such as
strong electron donating group dictates the regiochemical outcome Grignard reagents or lithium reagents, in more equivalents
of the product.
or involve multiple steps. Thus the development of simple
methodology will always be warranted for the synthesis of pyridyl
Heteroaryl aryl or diaryl carbinols and their derivatives are an aryl/heteroaryl or diaryl carbinols.
important class of molecules known to possess laxative,
The reaction of Lewis acid activated carbonyl compounds,
antihistamine, anticholinergic, antitussive, antiemetic, sedative such as aldehydes with p-nucleophiles, for example, silyl enol
and antiplasmodial activities.1 Pyridyl aryl carbinols and their ethers are well documented vide infra. There are reports in
derivatives have also been used as chiral ligands in asymmetric which the Lewis acid assisted hydroxyalkylation of an aromatic
catalysis2 (Fig. 1). This class of molecules are generally synthesized ring using aldehydes falls short with structural restriction, for
example, the nucleophile must possess a hydroxy group on the
benzene ring.5 Subsequently to this report, enantioselective
aromatic electrophilic substitution of N,N-dimethylaniline with
pyridine carboxaldehydes was reported.6 In addition, the reaction
of aromatic compounds with carboxaldehydes in the presence of a
Lewis acid catalyst usually leads to triarylmethanes.7 These
observations render an opportunity to find the Lewis acid that
may facilitate the aromatic electrophilic substitution of aromatic
compounds with carboxaldehydes and hence avoid the use of
Grignard reagent or lithium reagents.
Lewis acids, which are known to weaken the CQO bond of
aldehydes via interaction with the oxygen lone pair and make it
more susceptible for nucleophilic attack. Hence, we have
treated the anthracene 1a with pyridine-2-carboxaldehyde in
presence of various Lewis acids at 0 1C to room temperature as
model reaction to establish the reaction conditions
Fig. 1 Pyridyl-containing drug molecules and chiral molecules.
a
(Scheme 1). Usually the carbinol 2a was prepared through
Department of Chemistry, Pondicherry University, Puducherry – 605 014, India.
E-mail: crrnath.che@pondiuni.edu.in; Fax: +91 413-2656740; Tel: +91 413-2654416
† Dedicated to Professor Anil K. Bhatnagar on the occasion of his 70th birthday.
‡ Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, NMR spectra for new compounds. X-ray
crystallography details for compounds 2b, 2c, 2n and 6a. CCDC 847587,
847589, 847590, 847592. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2nj40871f
Scheme 1 Addition of 1a to pyridine-2-carboxaldehyde.
c
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Table 1 Lewis acid assisted addition of anthracene to pyridine-2-carboxaldehydea
Table 2 Reaction of p-nucleophiles with AlBr3 activated pyridine-2-carboxaldehydea
Entry
1
Ar–H
Product
Yieldb (%)
81
Entry
Lewis acid
Time (h)
Yieldb (%)
1
2
3
4
BF3ÁOEt2
FeCl3
TiCl4
48
48
48
36
24
24
24
24
24
7
3
21
27
AlCl3
5
AlBr3
49
2
3
89
77
6c
7c
8c
9c
TiCl(OiPr)3
Ti(OiPr)4
ZnCl2
N. R.
N. R.
N. R.
N. R.
SnCl4
a
Reaction conditions: 1a (1.2 mmol), pyridine-2-carboxaldehyde
b
c
(1.0 mmol) in dry dichloromethane, 0 1C-rt. Isolated yield. N.R. no
reaction.
4
84
either Friedel–Crafts acylation followed by reduction of the
carbonyl group8 or the addition of 9-anthracenylmagnesium
bromide to pyridine-2-carboxaldehyde.9
5
6
80
87
The reactivity of anthracene with pyridine-2-carboxaldehyde
showed significant variation depending on the Lewis acid
employed. The expected reaction proceeded less efficiently with
Lewis acids such as BF3ÁOEt2 and FeCl3 (entries 1–2, Table 1).
Whereas, the Lewis acids such as TiCl(OiPr)3, Ti(OiPr)4, ZnCl2
and SnCl4 failed to give the required product 2a (entries 6–9,
Table 1). However, a better yield of 2a was realized when the
reaction was performed in presence of AlBr3 (entry 5, Table 1).
With further optimization of reaction conditions using AlBr3, it
was observed that submolar loading (0.5 equiv.) as well as
excess loading (2.0 equiv.) of AlBr3, generated the product 2a
in diminished yields, 33% and 18%, respectively. This may be
due to the insufficient complexation of AlBr3 with pyridine-2-
carboxaldehyde in the case of a sub-stoichiometric quantity of
AlBr3 or further reaction of product 2a with Lewis acid or HBr in
the case of 2.0 equivalents of AlBr3.
7
79
73
78
8
9
Hence, using one equivalent of AlBr3, a variety of aromatic
substrates were examined to determine the substrate scope of
this methodology (Table 1). Strong electron donating groups,
such as –NEt2 or –OMe, present in the benzene ring 1b–j did
generally afford the carbinols 2b–j in higher yields (entries 1–9,
Table 2, see Fig. 3).10 Electron rich aromatic heterocycles, such
as thiophene, furan, pyrrole and indole 1k–n, delivered the expected
substitution products 2k–n in good yields (entries 10–13, Table 2,
see Fig. 3). The substrates with better global nucleophilicity
produced the carbinol in moderate to good yields. The strong
nucleophiles, such as pyrrole and indole, generated the triaryl-
methanes 3m–n along with carbinols 2m–n (entries 12–13,
Table 2).
10
84
88
11
12c
2m = 67
3m = 14
13c
2n = 71
3n = 17
Pyridine-3-carboxaldehyde conveniently reacted with anisole
(1.2 equiv.) in the presence of AlBr3 at 0 1C to room tempera-
ture, which furnished the corresponding carbinol 2w in 31%
yield, whereas the pyridine-4-carboxaldehyde, upon reaction
with anisole, furnished triarylmethane 3x in 89% yield (Fig. 2).
a
Reaction conditions: 1b–n (1.2 mmol), pyridine-2-carboxaldehyde
b
(1.0 mmol) in dry dichloromethane, 0 1C-rt, 24 h. Isolated yields.
c
Reaction was performed at 0 1C. Ar1 = 2-pyrrolyl, Ar2 = 3-indolyl.
c
564 New J. Chem., 2013, 37, 563--567
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Table 3 Reaction of p-nucleophiles containing either no electron releasing
group or poorly electron releasing groups with AlBr3 activated pyridine-2-
carboxaldehydea
Entry
Ar–H
Product
Yieldb (%)
Fig. 2 Substitution products from 3- and 4-pyridine carboxaldehyde.
Reaction of p-nucleophiles without activating group or with
poorly activating group either generated the carbinol in poor
yield or failed to produce the carbinol. For example, nucleo-
philes such as benzene, toluene, 1,3,5-trimethylbenzene, chloro-
benzene and phenanthrene failed to generate the substitution
product while the reaction was performed at room temperature.
The conversion was realized when the reaction was carried out at
elevated temperature. The reaction in refluxing dichloromethane
produced the carbinols 2o–u in moderate yields (entries 1–8,
Table 3). For example, the carbinol 2q, an intermediate used to
prepare carbinoxamine, possessing antihistamine and anti-
cholinergic activity,1c was produced in 43% yield from chloro-
benzene (entry 3, Table 3).
1
2
52
62
3
4
43
37
Though the ketones are less reactive towards nucleophiles
compared to aldehydes, the substrate 2-acetyl pyridine
delivered the tertiary alcohol 2v in 47% yield on treatment
with anisole through carbonyl group activation using AlBr3
(Scheme 2).
5
6
51
61
Scheme 2 Reaction of anisole with 2-acetyl pyridine.
7
41
40
To illustrate the utility of this protocol, we have examined
the reaction of anisole with benzaldehyde 4a, as well as electron
deficient aromatic aldehydes 4b–d as electrophiles. Surpris-
ingly, these aldehydes produced the triarylmethanes as
products, similar to pyridine-4-carboxaldehyde. This is the
common reactivity reported with other reagent systems.11
Pyridine-2-carboxaldehyde on the other hand furnished only
carbinols, and that may be due to the involvement of the
coordination of the lone pair of electrons on pyridine nitrogen
with aluminium in such a way to reduce the leaving group
ability of the –OAlBr2 group to generate a carbocation. This
speculation prompted us to examine the effect of nitrogen
containing ligands, which may stop at the mono nucleophile
addition stage through coordination with aluminium in
ROAlBr2. Also it is established that aluminium halides are
capable of forming penta coordinate complexes in certain
reactions.12 So, pyridine was chosen as an additive to retard
the carbocation formation.
8
a
Reaction conditions: 1o–t (1.2 mmol), pyridine-2-carboxaldehyde
b
(1.0 mmol) in dry dichloromethane, 0 1C-rt-reflux. Isolated yields.
triarylmethanes 6a–d in trace quantities (entries 1–4, Table 4,
see Fig. 3). It is important to note that loading 0.2 equiv. of
pyridine delivered the higher yield of diaryl carbinol 58% along
with triarylmethane 14%. Further reduction of pyridine loading
(0.1 equiv.) resulted in a higher yield of triarylmethane 34%.
Instead of pyridine, the use of other Lewis bases, such as
DABCO, DBU, bipyridine, etc. as well as the higher equivalent
of pyridine, failed to produce beneficial effects.
The formation of the triarylmethane, in certain cases, supports
the involvement of an intermediate alkoxy aluminium bromide.
Indeed, while using pyridine as an additive the reaction
produced diarylcarbinols 5a–d in moderate yields along with
c
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Table 4 Reaction of anisole with benzaldehyde/electron deficient benzaldehydesa
Entry
1
Aldehydes
5a–d Yieldb (%)
6a–d Yieldb (%)
14
Scheme 3 Formation of ethers by quenching with alcohols/thiol.
2
3
13
17
21
quenching with thiophenol produced the antiplasmodial agent
7c in 43% yield.13c
In summary, this paper describes a simple methodology
through classical carbonyl group activation using Lewis acid
AlBr3 to synthesise the pyridyl aryl/heteroaryl or diaryl carbinols
in moderate to good yields, which otherwise require Grignard
reagent/lithium reagents. The formation of triarylmethanes
may be reduced to a greater extent by retarding the formation
of a carbocation through the coordination of the Lewis base,
pyridine, with the intermediate alkoxy aluminium bromide.
The reaction of two different nucleophiles possessing different
global nucleophilicity with aldehydes in the presence of AlBr3
to generate unsymmetrical triarylmethanes is progressing in
this laboratory.
4
a
Reaction conditions: 4a–d (1.0 mmol), anisole (1.2 mmol) in dry
b
dichloromethane, 0 1C-rt, 24 h. Additive: pyridine (0.2 mmol). Isolated
yield.
Experimental procedure
Under an inert atmosphere, the reaction flask was charged with
stirring bar, AlBr3 (266 mg, 1.0 mmol) and dry dichloromethane
(3 mL) and cooled down to 0 1C (using ice). Then pyridine-
2-carboxaldehyde (1 mmol) was added. The mixture was stirred
for 30 minutes at 0 1C under a nitrogen atmosphere. To this
mixture was added a dichloromethane (5 mL) solution of
nucleophile (1.2 mmol) dropwise. The resulting suspension
was stirred at room temperature for 24 h. The reaction mixture
was poured into aq. NaHCO3 and stirred for 5 min, organic
layer was separated and the aqueous layer was extracted with
dichloromethane (2 Â 15 mL).
Fig. 3 ORTEP diagram of 2c, 2b, 2n and 6a at 50% probability level.
Mechanistically, the expulsion of Br2AlOÀ may generate the reac-
tive carbocation, which on reaction with water generates the
carbinols. Reaction of carbinol with thiophenol in presence of
AlCl3 at elevated temperature produced the thioether.13 Hence, the
quenching of this carbocation intermediate in situ with other
nucleophiles, such as methanol, allyl alcohol or thiol produced
the corresponding ether derivatives 7a–c in one pot manner
(Scheme 3). Interestingly, the reaction of pyridine-2-carboxaldehyde
with anisole (1.2 mmol) in presence of AlBr3 followed by
Acknowledgements
We thank DST and CSIR, New Delhi for financial support. AH
thanks UGC, New Delhi for JRF. JS and EG thank CSIR for SRF.
We gratefully acknowledge the Department of Chemistry, IITM,
Chennai, India for HRMS analysis, Central Instrumentation
Facility, Pondicherry University for NMR/IR data and Department
of Chemistry, Pondicherry University for Single Crystal XRD
facility (DST-FIST Sponsored).
c
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c
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