Key words
benzothiazolines - phosphoric acids - isoquinolines - nitroarenes - anilines - reduction
Aniline is a fundamental motif, frequently found in pharmaceuticals, natural compounds,
and building blocks. It is also an important building block for organic synthesis.[1] A conventional method for the synthesis of aniline involves the reduction of aryl
nitroarenes by using metals.[2] The Béchamp reduction, which uses tin or zinc in the presence of a Brønsted acid
at high temperature, is extensively employed.[3] Alternatively, transition-metal-catalyzed reductions of nitroarenes with hydrogen
gas are used under relatively mild reaction conditions. Palladium on carbon is a widely
used catalyst in reductions performed in the laboratory and industry because it presents
benefits with regards to cost and handling.[4] However, the reduction using palladium is sometimes hampered by such issues as residuals,
flammability, and chemoselectivity. The reduction of nitroarenes by using such organic
reductants as trichlorosilane[5] or phenyl(2-pyridyl)methanol[6] has been developed. Recently, Uozumi and co-workers reported a reduction that used
diboronic acid and water.[7]
We have reported an enantioselective transfer hydrogenation of ketimines, in which
we used a benzothiazoline (2,3-dihydro-1,3-benzothiazole) as the hydrogen donor in
combination with a chiral phosphoric acid.[8]
[9] Benzothiazolines proved to be effective for the transfer hydrogenation of C=N bonds
in a range of ketimines. To expand the utility of benzothiazolines, we set our sights
on the reduction of nitroarenes. Here we describe a rapid metal-free reduction of
nitroarenes that uses a combination of a benzothiazoline and a Brønsted acid. Furthermore,
we applied this reaction to the enantioselective synthesis of 2-arylquinolines, starting
from 1-aryl-3-(2-nitrophenyl)propan-1-ones (Scheme [1]).
Scheme 1 Reduction of nitroarenes
At the outset, we examined the reduction of methyl 4-nitrobenzoate (1a) with 2-phenylbenzothiazoline (2a) in the presence of a catalytic amount of 10-camphorsulfonic acid (CSA) as a Brønsted
acid (Scheme [2]). Gratifyingly, aniline 3a was obtained in 44% yield, accompanied by the corresponding N-benzylamine 4aa in 19% yield. We already knew that the hydrolysis and condensation of benzothiazolines
and benzaldehydes occur under these reaction conditions. We therefore believed that
4aa was formed by the reduction of imine 5aa, derived from 3a and 4-cyanobenzaldehyde.
Scheme 2 Reduction of nitroarenes and the formation of N-benzylamine 4aa
Table 1 Effects of Molecular Sieves and Various Substituents on the Benzothiazolinea
|
|
Entry
|
H donor
|
MS
|
Time (h)
|
Yield (%) of 3a
|
Yield (%) of 4
|
|
1
|
2a
|
MS 3Å
|
24
|
43
|
0
|
|
2
|
2a
|
MS 4Å
|
24
|
86
|
5
|
|
3
|
2a
|
MS 5Å
|
24
|
52
|
27
|
|
4b
|
2a
|
MS 4Å
|
48
|
88
|
<8
|
|
5
|
2b
|
MS 4Å
|
19
|
84
|
15
|
|
6
|
2c
|
MS 4Å
|
24
|
87
|
10
|
|
7
|
2d
|
MS 4Å
|
10.5
|
75
|
<38
|
|
8b
|
2e
|
MS 4Å
|
0.5
|
98
|
-
|
|
9
|
2e
|
MS 4Å
|
0.5
|
97
|
-
|
|
10
|
7
|
MS 4Å
|
20
|
23
|
-
|
a Reaction conditions: 1a (0.080 mmol), H donor (0.32 mmol), CSA (0.008 mmol), MS (100 mg), toluene (0.80 mL).
b Without CSA.
In order to suppress the hydrolysis of the benzothiazoline 2a and to increase the yield of 3a, we added molecular sieves (MS), which had a pronounced effect; the addition of MS
4Å suppressed the formation of the benzylamine 4aa and gave aniline 3a in high yield (Table [1], entries 1–3). Next, we explored the effects of the Brønsted acid and of various
2-substituents on the benzothiazoline. A long reaction time was required in the absence
of a Brønsted acid (entry 4). The 2-substituent on the benzothiazoline did not affect
the yield (entries 5–7). During the investigations, we had difficulties purifying
the aniline after the reaction, because an excess of benzothiazole 6 (Ar = Ph) was generated and the separation of the desired product 3a from 6 (Ar = Ph) was not a trivial issue. We surmised that the introduction of a carboxy
group onto the benzothiazoline 2 might increase its polarity and facilitate separation. In addition, we expected that
the benzothiazoline bearing a carboxy group 2e might function as a Brønsted acid instead of CSA. We therefore attempted to perform
the reaction with 2e in the absence of CSA (entries 8 and 9). As expected, benzothiazole 6e was readily removed from the crude mixture by filtration with dichloromethane. Gratifyingly,
the use of 2e accelerated the reaction remarkably and improved the yield of 3a to 98% in 0.5 hours. We also examined the utility of the Hantzsch ester (7) as a hydrogen donor in place of a benzothiazoline, but this gave 3a in low yield (entry 10).[10] Benzothiazoline 2e was therefore found to be the most suitable hydrogen donor for the present reduction.
Having clarified the optimal reaction conditions, we investigated the substrate scope.
Nitroarenes bearing electron-withdrawing groups, such as an ester, nitrile, or ketone
group, gave the desired anilines 3b–d in excellent yields (Scheme [3]). Bromo- and iodo(nitro)benzenes provided the corresponding anilines 3e–i in good yields, except for 2-bromo-1-nitrobenzene. 4-Methoxy and 4-(benzyloxy)-1-nitrobenzenes
gave the desired anilines 3m and 3n in moderate yields, because benzylamines 4ma and 4na were also formed. The reduction was completed in 0.5 hours for all substrates. Aliphatic
nitro compounds, nitrobenzenes bearing vinyl groups, and trans-β-nitrostyrene were not suitable substrates for this reduction, and the corresponding
anilines were not obtained.
Scheme 3 Substrate scope of nitroarenes
We hypothesized that the reduction proceeds by a radical pathway. 2,2,6,6-Tetramethylpiperidine
1-oxyl (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT) were added to the reaction mixture as radical scavengers.
The addition of TEMPO suppressed the reduction completely, and 96% of 1a was recovered. On the other hand, amine 3a was obtained in 85% yield when BHT was added (Scheme [4]). The latter result did not agree with our hypothesis, so we are exploring other
reaction pathways.
Scheme 4 Mechanistic study
The present reduction of nitroarenes was applied in a tandem reaction to synthesize
2-substituted chiral quinoline derivatives (Scheme [5]).[11] The tandem reaction consists of (I) reduction of a 1-aryl-3-(2-nitrophenyl)propan-1-one
9, (II) imine formation by intramolecular cyclization, and (III) asymmetric reduction
by a chiral phosphoric acid and a benzothiazoline.[12]
Scheme 5 Tandem reaction
We optimized the reaction conditions to furnish the desired 2-arylquinolines 10a–c in good yields and with excellent enantioselectivities by the combined use of benzothiazoline
2f and chiral phosphoric acid 8 (Scheme [6]).[13]
Scheme 6 Asymmetric synthesis of 2-substituted quinolines
In summary, we have developed a reduction of nitroarenes by using a benzothiazoline
in the presence of a Brønsted acid. The reduction with a benzothiazoline bearing a
carboxy group was completed in a short time. Selective reduction without use of metal
reagents was achieved. A tandem reaction with a chiral phosphoric acid and a benzothiazoline
gave 2-aryltetrahydroquinoline derivatives with excellent enantioselectivities.
