Continuous-flow synthesis of primary amines: Metal-free reduction of aliphatic and aromatic nitro derivatives with trichlorosilane

Article abstract of DOI:10.3762/bjoc.12.257

The metal-free reduction of nitro compounds to amines mediated by trichlorosilane was successfully performed for the first time under continuous-flow conditions. Aromatic as well as aliphatic nitro derivatives were converted to the corresponding primary amines in high yields and very short reaction times with no need for purification. The methodology was also extended to the synthesis of two synthetically relevant intermediates (precursors of baclofen and boscalid).

Full text of DOI:10.3762/bjoc.12.257

Continuous-flow synthesis of primary amines:
Metal-free reduction of aliphatic and aromatic nitro
derivatives with trichlorosilane
Riccardo Porta, Alessandra Puglisi*, Giacomo Colombo, Sergio Rossi
and Maurizio Benaglia*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 2614–2619.
Dipartimento di Chimica, Università di Milano, Via Golgi 19, 20133,
Milano, Italy
doi:10.3762/bjoc.12.257
Received: 29 September 2016
Accepted: 23 November 2016
Published: 05 December 2016
Email:
Alessandra Puglisi* - alessandra.puglisi@unimi.it; Maurizio Benaglia* -
maurizio.benaglia@unimi.it
This article is part of the Thematic Series "Green chemistry".
Guest Editor: L. Vaccaro
* Corresponding author
Keywords:
chemoselectivity; continuous processes; flow synthesis; nitro
reduction; trichlorosilane
© 2016 Porta et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The metal-free reduction of nitro compounds to amines mediated by trichlorosilane was successfully performed for the first time
under continuous-flow conditions. Aromatic as well as aliphatic nitro derivatives were converted to the corresponding primary
amines in high yields and very short reaction times with no need for purification. The methodology was also extended to the syn-
thesis of two synthetically relevant intermediates (precursors of baclofen and boscalid).
Introduction
The reduction of nitro compounds to amines is a fundamental Among the different available methodologies for the reduction
transformation in organic synthesis. The nitration of aromatic of nitro compounds [8], we have recently reported a very con-
rings followed by reduction is the most classical entry for the venient, mild, metal-free and inexpensive procedure, of wide
preparation of anilines [1,2]. Lately, also aliphatic nitro deriva- applicability [9,10]. The simple combination of trichlorosilane
tives have become more and more popular: a wide variety of (HSiCl3) and a tertiary amine generates in situ a dichlorosily-
highly functionalized and chiral aliphatic nitro compounds, pre- lene species which is the actual reducing species [11].
cursors of the corresponding chiral amines, are accessible via
several synthetic routes. In the last years nitro compounds have Even though nitro derivatives are fundamental building blocks
been the subject of numerous studies since they served as reac- in organic synthesis, their application on a large scale is still
tants in many, highly efficient, organocatalytic transformations quite limited because they are dangerous and potentially explo-
[3-7]. Furthermore, the introduction of an amino group offers a sive chemicals. Flow chemistry has recently emerged as a pow-
well-known plethora of further synthetic elaborations.
erful technology in synthetic chemistry [12] as it can reduce
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risks associated to the use of hazardous chemicals and favors Results and Discussion
reaction scale-up [13-17]. The possibility to efficiently perform In our methodology, a nitro derivative is reacted with commer-
nitro reduction in continuo would make the transformation safer cially available HSiCl3 in the presence of a tertiary base (typi-
and more appealing in view of an industrial application and a cally Hünig’s base) in an organic solvent (typically CH2Cl2, al-
possible scale-up of the process [18-20].
though CH3CN affords comparable results). The continuous-
flow reduction of 4-nitrobenzophenone (1a) was chosen as
Herein we report a very convenient, metal-free reduction of model reaction. A syringe pump equipped with two gas-tight
both aromatic and aliphatic nitro derivatives, including chiral 2.5 mL syringes was used to feed the reagents into a 0.5 mL
compounds, to amines with HSiCl3 under continuous-flow PTFE reactor (i.d. = 0.58 mm, l = 189 cm) through a T-junction
conditions.
(syringe A: 0.8 M solution of HSiCl3 in CH2Cl2; syringe B:
0.2 M solution of 1a in CH2Cl2, Hünig’s base 6 equiv,
Typically, the transformation of nitro compounds to amines Scheme 1).
under continuous-flow conditions is performed through the
metal-catalyzed hydrogenation [21-23] with ThalesNano The outcome of the reactor was collected into a flask contain-
H-Cube®, which exploits H2 generated in situ by water electrol- ing 10% NaOH solution in order to quench the reaction. After
ysis [24]. The procedure involves relatively mild reaction phase separation the crude reaction mixture was analyzed by
conditions, but the presence of noble metal catalysts, packed 1H NMR to determine the conversion. When the reaction
into disposable cartridges, suffers from functional group reached a full conversion (>98%) no further purification step
compatibility and catalyst poisoning during time.
was required and the aniline was recovered as clean product
after simple concentration of the organic phase and extraction
In 2012 Kappe’s research group reported the microwave- with ethyl acetate. A screening of flow rates was initially per-
assisted continuous-flow synthesis of anilines from nitroarenes formed and the results are reported in Table 1.
using hydrazine as reducing agent and iron oxide nanocrystals
as the catalyst [25]. This methodology ensured fast transformat- As data show, the reaction is very fast and a complete conver-
ions (2 to 8 minutes) of a wide number of substrates and was sion of nitroarene 1a to aniline 2a was achieved with very short
extended to large scale preparation of pharmaceutically rele- residence times (10, 5 and 2.5 min, Table 1, entries 1–3). With a
vant anilines [26]. However, this procedure required harsh reac- 1.2 minutes residence time, 91% conversion was reached. The
tion conditions (T = 150 °C), is limited to aromatic substrates faster reaction in the flow process compared to the batch one
and could not be applied to compounds bearing ketones or alde- (5 minute vs 18 hours [8]) can be partially attributed to the
hydes as functional groups.
higher reaction temperature: the flow reaction can be per-
formed at 25 °C while the batch reaction required a cooling to
In the present work we provide an alternative continuous-flow 0 °C, at least at the beginning of the reaction (the first few
metal-free methodology for the synthesis of both aliphatic and hours).
aromatic amines, which requires inexpensive reagents, mild and
fast reaction conditions (25 °C, 5 minutes), and a very simple Having demonstrated that the flow transformation is very fast
and user-friendly reaction set-up.
we next explored reaction scale-up employing a bigger flow
Scheme 1: Continuous flow reduction of 4-nitrobenzophenone using a 0.5 mL PTFE flow reactor.
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Beilstein J. Org. Chem. 2016, 12, 2614–2619.
due to the bigger internal diameter of the reactor (2.54 mm vs
0.58 mm) which affects the mixing of the reagents [27,28].
Lowering the residence time resulted in minor conversions
(Table 1, entry 7, 25 min residence time, 82% conversion). A
cheaper base than Hünig’s base as TEA (triethylamine) could
also effectively promote the reduction with only marginally
lower conversion (Table 1, entry 6 vs entry 5) [9-11]. The pos-
sibility to use commercially available HSiCl3, in combination
with an inexpensive base as TEA, and the simple work-up make
this very mild reduction methodology appealing for several
future synthetic applications, also of industrial interest.
Table 1: Screening of reaction conditions.
Entrya
Flow rate
(mL/min)
Residence
time (min)
Conversion
(%)b
1
0.05
0.1
0.2
0.4
0.1
0.1
0.2
10
5
98 (96)
98 (96)
98 (93)
91 (85)
97
2
3
2.5
1.2
50
50
25
4
5c
6c,d
7c
87
82
aReaction performed using a 0.2 M solution of Ar-NO2 (0.6 mmol) in
CH2Cl2, HSiCl3 (4 equiv), Hünig’s base (6 equiv) at room temperature;
breaction conversion determined by NMR of the crude; isolated yields
in parentheses; creaction performed in a 5 mL PTFE reactor; dreaction
performed using TEA as a base.
We next focused on expanding the scope of the reaction and
proof the general applicability. Using both 0.5 mL and 5 mL
reactors, under the best reaction conditions, the continuous-flow
reduction of different nitroarenes was studied (Scheme 2).
reactor (5 mL PTFE reactor, i.d. = 2.54 mm, l = 100 cm), in
order to increase the productivity of the process.
As already demonstrated for the batch procedure [8], the reac-
tion in continuo tolerates a large variety of functional groups:
Using the same reaction set-up illustrated in Scheme 1, a resi- aromatic nitro groups are selectively reduced with quantitative
dence time of 50 minutes was necessary to reach a full conver- conversions in the presence of ketones (Table 2, entry 1), halo-
sion of the starting material (Table 1, entry 5). This is mainly gens (Table 2, entries 3–5) and esters (Table 2, entry 6).
Scheme 2: Continuous flow reduction of aromatic nitro compounds.
Table 2: Scope of the reaction (see Scheme 2).
Entrya
R
0.5 mL Reactorb
Conversion (%)c
5 mL Reactord
Conversion (%)e
1
2
3
4
5
6
4-nitrobenzoyl, 1a
4-Me, 1b
98 (96)
98 (96)
98 (92)
98 (92)
98 (90)
98 (95)
97
98
98
92
91
98
4-Br, 1c
2,4-Cl2, 1d
4-F, 1e
4-COOMe, 1f
aReaction performed using a 0.2 M solution of Ar-NO2 in CH2Cl2, HSiCl3 (4 equiv), Hünig’s base (6 equiv) at room temperature; bResidence time =
5 min; cReaction conversion determined by NMR of the crude; isolated yield in parenthesis; dResidence time = 50 min; eDetermined by NMR of the
crude.
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Beilstein J. Org. Chem. 2016, 12, 2614–2619.
The methodology was also extended to aliphatic nitro com- reaction conditions in a 5 mL PTFE reactor (flow rate
pounds (Scheme 3). These substrates are less reactive than aro- 0.1 mL/min, 50 min residence time), the desired amine 4 was
matic ones and they typically require higher hydrogen pres- obtained in quantitative yield as a clean product with no need
sures or reaction temperatures to be completely reduced to the for purification.
corresponding aliphatic amines.
We also investigated the continuous-flow reduction of nitro
By employing our metal-free methodology, at 25 °C in a ester 5, which can be conveniently prepared in one step through
0.5 mL reactor, aliphatic amines 2g and 2h were obtained with the organocatalyzed addition of diethyl malonate to trans-β-
a full conversion of the starting material and isolated yields of nitrostyrene promoted by a chiral thiourea [29]. The corre-
91% and 93%, respectively, by using a residence time of sponding amide 6 is a direct precursor of the GABA receptor
10 minutes only (when a residence time of 5 minutes was used a agonist Baclofen (Scheme 5).
slightly lower yield was obtained – 81% for amine 2g).
Nitro compound 5 was continuously reduced in a 5 mL reactor
We then applied the trichlorosilane-mediated continuous-flow and, after work-up under neutral conditions, chiral lactam 6 was
nitro reduction to the synthesis of advanced precursors of mole- isolated in 48% yield.
cules of pharmaceutical interest. The reduction of nitro com-
pound 3 afforded 2-(4'-chlorophenyl)aniline (4), the direct pre- Finally we explored the possibility of performing a reaction
cursor of the fungicide boscalid (Scheme 4). Under the best scale-up, followed by an in-line extraction in order to obtain a
Scheme 3: Continuous-flow reduction of aliphatic nitro compounds.
Scheme 4: Synthesis of 2-(4’-chlrophenyl)aniline (4) with a 5 mL flow reactor.
Scheme 5: Synthesis of intermediate 6, a direct precursor of the drug baclofen.
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full continuous process with no need for intermediate opera- (mL/min) at room temperature. The outcome of the reactor was
tions (Scheme 6).
collected in a flask containing a 10% NaOH solution. Five
reactor volumes were collected. CH2Cl2 was removed in vacuo
A syringe pump equipped with two SGE gas tight 25 mL and the aqueous layer was extracted three times with ethyl
syringes was used to feed the reagents into a 5 mL PTFE reactor acetate. The combined organic layers were washed with brine,
through a T-junction (syringe A: HSiCl3 (24 mmol) in 15 mL dried with Na2SO4 and concentrated in vacuo. 1H NMR spec-
CH2Cl2.; syringe B: substrate 1a (6 mmol), Hünig’s base troscopy of the crude was used to calculate the reaction conver-
(36 mmol in 15 mL CH2Cl2)) with a flow rate of 0.1 mL/min sion; in case of a full conversion of the starting material no
(residence time 50 min). The outcome of the reactor was further purification was required.
collected into a separatory funnel containing NaOH 10% solu-
tion (10 mL) and CH2Cl2 (10 mL). The biphasic system was
Supporting Information
kept under stirring and the organic layer was continuously
collected into a flask. Removal of CH2Cl2 gave pure amino
Supporting Information File 1
compound 2a in 94% yield. This system allowed to easily ob-
taining almost 1 g of pure 2a in about 4 hours (see Supporting
Information File 1 for further details).
General procedure for continuous-flow reactions, products
characterization and NMR spectra of the compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-257-S1.pdf]
Conclusion
In conclusion, a very convenient, mild, metal-free reduction of
aliphatic and aromatic nitro derivatives under continuous flow-
conditions has been successfully developed. The general appli-
cability to differently substituted compounds and the possibility
to scale-up the process have been demonstrated. The use of
extremely inexpensive and non-hazardous chemicals, the very
high chemoselectivity and the possibility to realize a complete-
ly automated reduction/work-up/isolation process are distinc-
tive features that make the protocol suitable for the reduction of
a large variety of products and attractive also for future indus-
trial applications.
Acknowledgements
A.P. thanks the University of Milan for the grant “Piano di
Sostegno alla Ricerca 2015-17 - LINEA 2 Azione A (Giovani
Ricercatori)”. M.B. thanks the University of Milan for the Tran-
sition Grant 2015-17-Horizon 2020. R.P. thanks the University
of Milan for a Ph.D. fellowship. S.R. thanks the University of
Milan for a postdoctoral fellowship.
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