Synthesis of N-aryl substituted, five- and six-membered azacycles using aluminum-amide complexes

Article abstract of DOI:10.1039/c4cc04111a

Synthesis of N-aryl substituted, five- and six-membered azacycloalkanes, isoindolines and tetrahydroisoquinolines, has been described. In this synthesis, cyclic ethers (n = 1, 2) were treated with dimethylaluminum-amide reagents, derived from a range of aryl amines and trimethylaluminum, to afford the corresponding azacycles in good yields. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04111a

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Synthesis of N-aryl substituted, five- and
six-membered azacycles using aluminum-amide
complexes†
Cite this: Chem. Commun., 2014,
50, 8985
Received 29th May 2014,
Accepted 17th June 2014
Balaji L. Korbad and Sang-Hyeup Lee*
DOI: 10.1039/c4cc04111a
www.rsc.org/chemcomm
Synthesis of N-aryl substituted, five- and six-membered azacycloalkanes,
isoindolines and tetrahydroisoquinolines, has been described. In this
synthesis, cyclic ethers (n = 1, 2) were treated with dimethylaluminum-
amide reagents, derived from a range of aryl amines and trimethyl-
aluminum, to afford the corresponding azacycles in good yields.
N-Substituted azacycles, such as pyrrolidines, piperidines, piperazines,
isoindolines and tetrahydroisoquinolines, etc, are very important
motifs that have a wide range of applications in pharmaceutical,
agrochemical and material industries.1 In addition, their structural
subunits exist in many natural products such as vitamins, hormones,
antigens, alkaloids, herbicides, dyes and many more compounds.2 In
recognition of their widespread importance, many synthetic methods
have emerged over the years for the formation of C–N bonds and
are categorized in Scheme 1: (a) dialkylation of primary amines
with dihalides under different reaction conditions,3 such as KI
Scheme 1 Literature survey for the synthesis of N-substituted azacycles.
in ethanol,3a,b NaHCO3 in sodium dodecyl sulphate–water,3c work-up process. Therefore it is highly desirable to develop
(i-Pr)2NEt3d under microwave irradiation in water,3e and aqueous some alternatives which use cheap and commercially available,
K2CO3;3f–h (b) reductive amination of dicarbonyl compounds4 or easily accessible starting materials and reagents.
using KHFe(CO)4,4a,b n-Bu2SnClH-HMPA,4c and NaBH4;4d (c) the
So far, many organoaluminum reagents have proven to be
cross-coupling reaction of N-unsubstituted azacycles and aryl remarkable reagents in organic synthesis due to their inherent
halides5 with the use of a catalytic or a stoichiometric system reactivity, wide range of applicability, low cost and commercial
derived from iron,5a–c cobalt,5d nickel,5e copper5f and palladium;5g availability.8 Organoaluminum compounds can easily react
(d) N-heterocylization of primary amines with diols or cyclic ethers6 with various heteroatoms in organic molecules, particularly
under drastic, dehydrating conditions in the presence of an oxide with oxygen and nitrogen, to generate 1 : 1 complexes.9 One
6b
catalyst, such as Al2O3,6a TiO2 and AlCl3.6c Different kinds of widely used reagent of note is dimethylaluminum amide,
N-heterocylizations utilizing diols through a ‘‘borrowing hydrogen’’ derived from the reaction between trimethylaluminum and the
(BH) strategy7 using transition metal catalysts such as ruthenium,7a–d corresponding amine. This reagent has been utilized in the
iridium7e–g and Pt–Sn/g-Al2O3 have also been reported.7h
direct conversion of esters or acids to amides,10,11 carbamates
Yet, aforementioned reactions have disadvantages such to urea12 and nitriles to amidines.13
as the use of toxic and expensive metals, and often require
As a part of on-going research on solution- and solid-phase
longer reaction times, harsh reaction conditions and a tedious synthesis of small organic molecules, we have utilized a
dimethylaluminum-amide reagent extensively to introduce
further diversity in core scaffolds.12,14 In these studies, amides
and substituted ureas were prepared from resin-bound esters and
carbamates, respectively, which we dubbed as ‘‘smart cleavage
reaction’’. Recently, we found that a substrate having an oxygen-
containing ring undergoes an unwanted side reaction when treated
Department of Life Chemistry, Catholic University of Daegu, Gyeongsan-si,
Gyeongbuk 712-702, South Korea. E-mail: leeshh@cu.ac.kr; Fax: +82-53-850-3728;
Tel: +82-53-850-3781
† Electronic supplementary information (ESI) available: General information, the
experimental procedure, characterization data and copies of 1H and 13C NMR
spectra of all the products. See DOI: 10.1039/c4cc04111a
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a
Table 1 Optimization of reaction conditions for the AlMe3-mediated
N-heterocyclization of aniline (1a) with THF (2a)a
Table 2 Synthesis of azacycloalkanes 3 using AlMe3
Entry
1a : AlMe3 : 2a
Yieldb (%)
1
2
3
4
1 : 1.2 : 1
1 : 1.2 : 5
1 : 1.2 : 10
1 : 0 : 10
20
40
72
0
Entry
1 (Ar)
2
Product 3
Yieldsc (%)
1
2
Ph (1a)
2a
2a
72
70
a
b
4-CH3Ph (1b)
All reactions were carried out on a 1 mmol scale. Isolated yields
based on 1a.
3
4
2-CH3Ph (1c)
2a
2a
68
71
with a dimethylaluminum-amide reagent, and this observation
provoked us to investigate the reaction between oxacycloalkanes
and this reagent. Herein, we wish to report the AlMe3-mediated
synthesis of N-aryl substituted azacycles from oxacycles and aromatic
amines.
Our investigation began by treating tetrahydrofuran (2a, 1 equiv.)
with a dimethylaluminum-amide reagent prepared from AlMe3‡
(1.2 equiv.) and aniline (1a, 1 equiv.) in toluene at 110 1C for 16 h.
However, to our disappointment the yield of N-phenylpyrrolidine
(3a) was not satisfactory (20%, Table 1, entry 1). Since 2a is quite
volatile considering the reaction temperature, we used the
aluminum-amide reagent as a limiting reagent. When 2a was used
in five- and ten-fold excess, the yield was increased to 40% and 72%,
respectively (Table 1, entries 2 and 3). In the absence of AlMe3,
product formation was not observed (Table 1, entry 4).
Then the scope of this reaction was examined using a
combination of aryl amines 1 and cyclic ethers 2 under optimized
reaction conditions (Table 2). In brief, the reaction was tolerant for a
variety of aryl amines and cyclic ethers (n = 1, 2) to afford the
corresponding products in moderate to high yields. As shown in
Table 2, the reactivity of the aryl amine is found to be relevant to the
electronic effect of the substituent on the aryl ring. Compared to
unsubstituted aniline 1a (Table 2, entry 1) and anilines with an
electron-donating substituent 1b–d (Table 2, entries 2–4), those with
electron-withdrawing substituent(s) 1e–h reacted with 2a faster, as
monitored by TLC, and gave the corresponding products in higher
yields (Table 2, entries 5–8). This reactivity trend was similar when
other cyclic ethers were employed as substrates (vide infra). Naphthyl-
amine (1i) and 9-ethyl-9H-carbazol-3-amine (1j) also reacted with 2a
and gave the corresponding products in 60 and 40% yields, respec-
tively (Table 2, entries 9 and 10). Steric hindrances on the cyclic ether
can also be tolerated. For example, 2-methyltetrahydrofuran (2b)
reacted well with anilines to afford the corresponding products in
moderate to high yields (Table 2, entries 11–13). When tetrahydro-
pyrane (2c) was employed, the reactions were somewhat sluggish,
3-CH3OPh (1d)
5
6
4-ClPh (1e)
4-FPh (1f)
2a
2a
85
80
7
8
2,4-F2Ph (1g)
2a
2a
82
79
2-Br-4-FPh (1h)
9
1-Naphthyl (1i)
2a
2a
60
40
9-Ethyl-9H-
carbazol-3-yl (1j)
10
11
12
1a
1b
1f
2b
2b
2b
78
63
90
13
14b
1a
1f
2c
2c
58
60
15b
a
Reaction conditions: aromatic amine 1 : AlMe3 : cyclic ether
2
(1 : 1.2 : 10 mmol); for THF (2a)/2-methylTHF (2b), in toluene, 110 1C,
16 h. For tetrahydropyrane (2c), in xylene, 150 1C, 24 h. Isolated
yields based on aromatic amines.
b
c
and thus elevated reaction temperature (150 1C) and prolonged of aromatic amines towards the synthesis of a nitrogen-containing
reaction time (24 h) were required to get the desired products in fused heterocyclic ring system (Table 3). The structure containing
moderate yields (Table 2, entries 14 and 15). When aliphatic amines tetrahydroisoquinoline and isoindoline fragments is found in
(benzylamine and phenethylamine) and hexamethylene oxide were many biologically active compounds, both synthetic and natural,
employed, no appreciable reaction occurred at all (data not such as alkaloids and pharmaceutical agents.15 Since the boiling
shown here).
point of isochroman (4a, 228 1C) and o-xylene oxide (4b, 192 1C) is
Encouraged by the above results, we then set out to further sufficiently higher than the reaction temperature, these oxacycles
expand the application of this AlMe3-mediated N-heterocyclization were employed as limiting reagents. Aluminum-amide reagents
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Table 3 Synthesis of tetrahydroisoquinolines and isoindolines 5 using
a
AlMe3
Entry
1
1 (Ar)
4
Product 5
Yieldsb (%)
65
1a
4a
Scheme 2 Plausible mechanism for AlMe3-mediated N-heterocyclization.
2
3
1d
1e
4a
4a
62
78
a-position of activated oxacycle 7 via a four-membered transition
state to afford the cyclic intermediate 8, followed by the evolution of
methane. Then the amide migrates again to the carbon connected
to oxygen to afford the desired azacycle 3a. In a separate experi-
ment, 4-(phenylamino)butan-1-ol 9 was prepared16 and treated with
AlMe3 in toluene at 140 1C for 16 h to afford 3a in 30% yield.
And we believe that this conversion may support the proposed
mechanism depicted in Scheme 2.
In conclusion, we have developed an efficient synthetic route
for the preparation of N-aryl substituted azacycles directly from
its oxacycles and dimethylaluminum-amide reagents derived
from aromatic amines and AlMe3. Since this procedure is simple
and utilizes cheap and commercially available starting materials,
it would be one of the alternative methods for the synthesis of
N-aryl substituted five- and six-membered azacycles.
4
5
6
1f
4a
4a
4a
85
80
83
2-FPh (1k)
1g
7
F5Ph (1l)
4a
83
Financial support of this research by the Basic Science
Research Program through the National Research Foundation
of Korea (2011-0007322) is gratefully acknowledged.
8
9
1a
1e
1f
4b
4b
4b
66
75
77
Notes and references
10
‡ Caution: Trimethylaluminum is moisture sensitive and pyrophoric,
and should be handled with great care. See ESI† for more details.
a
Reaction conditions: aromatic amine 1 : AlMe3 : cyclic ether
4
b
(2 : 1.5 : 1 mmol); in xylene, 150 1C, 16 h. Isolated yields based on
4a/4b.
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