A safe and selective method for reduction of 2-nitrophenylacetic acid systems to N-aryl hydroxamic acids using continuous flow hydrogenation

Article abstract of DOI:10.1016/j.tetlet.2017.01.008

The cyclic hydroxamic acid functional group is critical to the biological activity of numerous natural products and drug candidates. Efficient, reliable, and green synthetic methods to produce cyclic hydroxamic acids are needed. Herein, flow hydrogenation has been explored as a novel approach toward achieving the selective partial reduction of 2-nitrophenylacetic acid to 1-hydroxyindolin-2-one. The bidentate ligand, 1,10-phenanthroline, has been identified as a unique inhibitor for modulating product selectivity in this Pt/C-catalyzed process. Under the newly optimized reaction conditions, the targeted hydroxamic acid is produced with high selectivity (49:1) over the lactam by-product. The scope of the reaction is demonstrated for a variety of 2-nitrophenylacetic acid derivatives.

Full text of DOI:10.1016/j.tetlet.2017.01.008

Accepted Manuscript
A Safe and Selective Method for Reduction of 2-Nitrophenylacetic Acid Sys-
tems to N-Aryl Hydroxamic Acids Using Continuous Flow Hydrogenation
Ogar Ichire, Petra Jans, Galina Parfenov, Amy B. Dounay
PII:
S0040-4039(17)30008-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.008
TETL 48511
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 October 2016
23 December 2016
2 January 2017
Please cite this article as: Ichire, O., Jans, P., Parfenov, G., Dounay, A.B., A Safe and Selective Method for Reduction
of 2-Nitrophenylacetic Acid Systems to N-Aryl Hydroxamic Acids Using Continuous Flow Hydrogenation,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.008
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A Safe and Selective Method for Reduction of 2-Nitrophenylacetic Acid Systems
to N-Aryl Hydroxamic Acids Using Continuous Flow Hydrogenation
Ogar Ichire, Petra Jans, Galina Parfenov, and Amy B. Dounay*
Department of Chemistry and Biochemistry, Colorado College,14 E. Cache La Poudre,
Colorado Springs, CO 80903
E-mail: amy.dounay@coloradocollege.edu
Abstract: The cyclic hydroxamic acid functional group is critical to the biological activity
of numerous natural products and drug candidates.
Efficient, reliable, and green
synthetic methods to produce cyclic hydroxamic acids are needed. Herein, flow
hydrogenation has been explored as a novel approach toward achieving the selective
partial reduction of 2-nitrophenylacetic acid to 1-hydroxyindolin-2-one. The bidentate
ligand, 1,10-phenanthroline, has been identified as a unique inhibitor for modulating
product selectivity in this Pt/C-catalyzed process. Under the newly optimized reaction
conditions, the targeted hydroxamic acid is produced with high selectivity (49:1) over
the lactam by-product. The scope of the reaction is demonstrated for a variety of 2-
nitrophenylacetic acid derivatives.
The hydroxamic acid functional group is found in numerous biologically active
natural products and drug candidates.1 Histone deacetylase (HDAC) inhibitors such as
panobinostat (3), approved by the FDA in 2015 for multiple myeloma, require the
hydroxamate functionality for key hydrogen bonding interactions with active site side
chains and for zinc chelation.2 The broader utility of hydroxamic acid functionality in
drug candidates is currently being investigated for numerous indications, including
malaria,3 human African trypanosomiasis,4 cancer,5 and schizophrenia.6,7 (Figure 1). To
enable rapid medicinal chemistry studies and large-scale clinical candidate synthesis,

efficient methods for incorporating the hydroxamic acid group are required. Whereas the
preparation of acyclic hydroxamic acids (e.g., 3) is typically straightforward, the
synthesis of cyclic, N-arylhydroxamic acids (e.g., 1, 2, and 4) in high yields remains a
challenge.
Figure 1. Example hydroxamic acid-containing natural products and pharmaceutical agents8,9
The reductive cyclization of a 2-nitrophenylacetic acid scaffold (6) to the
corresponding N-aryl hydroxamic acid 9 (Scheme 1) has been explored extensively.10
According to the postulated step-wise mechanism for the reduction of nitroaromatics
(Scheme 1), partial reduction of nitrobenzene 6 affords hydroxylamine intermediate 7,
which cyclizes to form hydroxamic acid 9. Alternatively, complete reduction of 6 to
aniline intermediate 8 leads to lactam 10. Direct reductive cyclization of 6 is often

hampered by competitive over-reduction to the corresponding aniline (8), resulting in
low yield of the targeted hydroxamic acid (9).
Scheme 1. Reductive cyclization of 2-nitrophenylacetic acid (6) to hydroxamic acid (9) and
lactam (10)
Although a variety of reaction conditions have been reported for the reduction of
nitroarenes to hydroxamic acids, the existing methods have notable limitations. Early
reports of this transformation suffered from low yields due to poor selectivity of the
reduction.10a Over-reduction to the aniline or lactam, which is typically the major side
reaction, is minimized by the use of SnCl2/NaOAc as a mild reductant;10b however, this
method requires stoichiometric Sn, which is undesirable from a green chemistry
perspective. Catalytic hydrogenation methods using either sulfided or unmodified Pt/C
catalysts have also been utilized for partial reduction of nitroaromatics to
hydroxylamines or hydroxamic acids in good yield.10c-e However, the use of pyridine as
solvent in these catalytic hydrogenations to minimize over-reduction10e introduces a
toxicity and green chemistry liability. Moreover, traditional batch hydrogenation methods

present significant safety concerns due to the use of hydrogen gas, pyrophoric
catalysts, and flammable solvents.11,12,13
Flow hydrogenation has emerged in recent years as a safer alternative to batch
hydrogenation.13,14 Continuous flow hydrogenation systems are superior to batch
hydrogenations due to safer hydrogen and catalyst handling and pressure control.13 In
the H-Cube Mini continuous flow hydrogenation system (ThalesNano), hydrogen is
generated on-demand via electrolysis of water, and the catalyst is enclosed in a
cartridge, avoiding air contact and reducing flash fire hazard. Particularly in an
academic research or teaching laboratory lacking appropriate hydrogenation facilities
and reactors, these safety improvements of flow hydrogenation over batch
hydrogenation are critical. Furthermore, product selectivity can potentially be optimized
by controlling the residence time of reactive intermediates in the catalyst cartridge.
Numerous examples of flow hydrogenations of nitroaromatics to anilines and
their derivatives have been reported.14 However, a systematic investigation of the
selective, partial reduction of nitroarenes to the corresponding cyclic hydroxamic acids
using flow hydrogenation has not previously been reported. Thus, our investigation
represents a novel approach towards an efficient synthesis of this useful ring structure.
Our goal was to develop a safe, selective, and general flow-hydrogenation method for
partial reduction of the 2-nitrophenylacetic acid scaffold (6) to the hydroxamic acid (9)
with minimal formation of the by-product lactam (10). To this end, we have also
investigated the role of additives in enhancing selectivity for this transformation.
In our initial optimization of the flow hydrogenation reductive cyclizations, the
reaction of commercially available 2-nitrophenyl acetic acid (11) to the hydroxamic acid

12 was explored as the simplest model system for this scaffold (Scheme 2). A brief
screen of commercially available Pt hydrogenation catalysts cartridges, or “CatCarts”
(ThalesNano) was conducted. Our catalyst screening efforts focused on Pt catalysts
because previous reports had identified Pt as a preferred metal for this type of selective
reduction.10e-f Spontaneous cyclization to 12 and 13 only occurs to only a limited extent
upon reduction of 11. Therefore, the initial complex product mixtures resulting from the
flow hydrogenation were treated with acetic acid in ethanol to ensure complete
cyclization. The crude product mixtures were then analyzed by LC-MS to determine the
extent of reaction (% conversion based on amount of unreacted 11 remaining) and
selectivity, expressed as the ratio of 12:13 (See Supporting Information, Table S2). The
5% Pt/C catalyst afforded full conversion of starting material to products and moderate
selectivity for 12:13 (selectivity ratio 4:1). This result is consistent with previous reports
for batch hydrogenations of analogous systems, in which moderate yields of the
hydroxamic acid product were obtained using 5% Pt/C in an ethanol/DMSO solvent
system.10d Based on these results, the 5% Pt/C catalyst was selected for further
optimization studies of other reaction parameters.
Scheme 2. Model Reductive Cyclization Process
Several solvents were screened to assess the impact of solvent on reduction
selectivity using the 5% Pt/C catalyst (Table 2). All three of the protic, alcoholic solvents

(Entries 1-3) afforded complete conversion to products at the expense of low selectivity
for 12, with methanol giving the lowest selectivity toward 12. Conversely, THF provided
improved selectivity for 12 (Entry 4), but afforded only moderate conversion. These
observations are consistent with previous studies on the influence of solvent on batch
hydrogenation of nitrobenzene.15 16 Solvent polarity and metal-coordination likely both
,
play a role in reaction rate. The observed reactivity profile in THF may also be
attributed, in part, to its ability to coordinate to the Pt catalyst, reducing catalytic activity.
Thus, the sterically hindered 2-methyl-THF (Entry 5) had less impact on selectivity
because of less effective coordination to Pt. In an attempt to optimize conversion and
selectivity, mixtures of THF and ethanol were evaluated (Entries 6-10). Although the
extent of reaction improved with decreasing concentration of THF, the selectivity for
12:13 likewise eroded. An additional experiment using 20% acetic acid in ethanol gave
exclusively the lactam product 13, confirming that the acid-promoted cyclization step
cannot be combined with the reduction step.

Table 1. Solvent effects on flow hydrogenation
Conversion
(%)[a]
Ratio
Entry
Solvent
Ethanol
12:13[b,c]
1
2
100
100
100
67
1:3
1:3
1:9
4:1
1:1
3:2
1:1
2:3
1:3
1:3
2-Propanol
3
Methanol
4
THF
5
2-Me-THF
63
6
10%Ethanol/THF
50%Ethanol/THF
70%Ethanol/THF
80%Ethanol/THF
90%Ethanol/THF
64
7
75
8
84
9
89
10
89
[a]Percentage of 11 consumed in reaction, determined by LC-MS analysis of crude reaction mixture; [b]Ratio was
determined by LC-MS analysis of crude reaction mixture, as described in Supporting Information. [c]All reactions were
conducted in duplicate and at 0.5 mL/min flowrate; H2 inlet pressure of ≤10 bar; Values represent arithmetic mean
from two experiments.
Our initial solvent screening outcomes and the literature examples of batch
hydrogenations10 suggest that coordinating solvents or additives (e.g., THF, pyridine,
and DMSO) can be employed to significantly enhance selectivity in the reduction of 11
to 12. To further explore this approach, a screen of various potential inhibitors (0.05
molar equiv) was conducted (Table 2). Previous studies had reported the inhibitory
activity of DMSO and pyridine toward catalytic hydrogenations;10 however, in our study
of these additives, only DMSO favored formation of 12 over 13 (Table 2, Entry 1). We
hypothesized that selectivity would be further improved with the use of bidentate
ligands. Although DPPE, a bidentate phosphine ligand, provided only modest selectivity

(Entry 6), the bidentate pyridyl ligands, 2,2’-bipyridine and 1,10-phenanthroline, both
produced dramatic improvements in selectivity for 12 (Entries 7 and 8). The inhibitory
action of 1,10-phenanthroline and 2,2’-bipyridine may be explained by strong bidendate
coordination of aromatic nitrogen lone pairs to platinum and the steric environment of
these aromatic ligands at the active center.17,18 Although 1,10-phenanthroline is toxic,
its use in sub-stoichiometric quantities represents a significantly greener method
compared to previous protocols that utilized the more highly toxic pyridine as solvent.
Table 2. Inhibitor effects on flow hydrogenation selectivity
Ratio
Entry
Inhibitor[a]
12:13[b,c]
2:3
1
2
3
4
DMSO[d]
Pyridine
1:9
Trimethylamine
DMAP[d]
1:9
1:10
TMEDA[d]
5
6
1:4
3:1
DPPE[d]
7
8
2, 2’-Bipyridine
19:1
1, 10-
phenanthroline
49:1
[a] All reactions were conducted in duplicate using 0.05 molar equivalents inhibitor, flow rate 0.5 mL/min; H2 inlet
pressure of ≤10 bar [b] 100% conversion of 11 was achieved in all reactions, as determined by LC-MS analysis of
crude reaction mixture; [c]Ratio was determined by LC-MS analysis of crude reaction mixture, as described in
Supporting Information; Values represent arithmetic mean from two experiments. [d] Abbreviations: DMSO =
dimethylsulfoxide; DMAP = 4-dimethylaminopyridine; TMEDA = N, N, N’, N’-tetramethyltethylenediamine; DPPE = 1,
2-bis(diphenylphosphino)ethane

The remarkable selectivity achieved using 1,10-phenanthroline with 5% Pt/C for
catalytic flow hydrogenation prompted further experiments under these optimal reaction
conditions (Table 3).19,20 To confirm the synthetic practicality for this method, the
reaction conditions were applied to the reduction of 11 on 300 mg scale, producing 12
in 69% isolated yield after column chromatography (Entry 1).21 To further illustrate the
synthetic practicality of the flow method, the same reaction has been completed on 1 g
scale, providing 12 in up to 83% yield if H2 pressure is maintained below 10 bar.22 For
comparison, use of identical flow hydrogenation conditions on 300 mg scale but in the
absence of inhibitor (Entry 2) afforded 12 in much lower yield. Likewise, batch
hydrogenation of 11 under analogous conditions (1 atm H2, 20 °C) produces 12 in
significantly diminished yield (Entry 3).23 Together, these experiments demonstrate the
important role of both the 1,10-phenanthroline and the flow methodology for optimal
yield of 12 in this selective reduction process.
Table 3. Reaction condition effects on isolated yield of 12
Hydrogenation
Method
Yield[d]
(%)
Entry
Inhibitor [c]
1,10-
1
2
3
Flow[a]
Flow[a]
Batch[b]
69
33
35
phenanthroline
None
1,10-
phenanthroline
[a] Reactions were conducted at flow rate of 1.5 mL/min, at 20 °C, H2 inlet pressure of ≤10 bar; [b] Balloon
hydrogenation conducted under 1 atm H2 at 20 °C; [c] All reactions were conducted using 0.15 molar equivalents of
inhibitor [d] Isolated yield

The scope of the optimized flow hydrogenation conditions was evaluated using a
series of 2-nitrophenylacetic acid systems bearing either an electron donating (methyl)
or electron withdrawing (F, Br, Cl, CF3) group at various positions on the phenyl ring
(Table 4). With the exception of the 3-methyl-2-nitrophenyl acetic acid (Entry 1), all
reductions proceeded to completion. This outcome is consistent with previous reports
for the reductive cyclization of 2-nitrophenylalanine derivatives10e in which electron
donating substituents at the 3-position also gave low conversion under typical reduction
conditions, due to unfavorable steric and electronic effects. Moderate to high isolated
yields of hydroxamic acid products (15) were achieved in all cases in which the
substituent is at the 4- or 6- position (Entries 2, 4, and 7-10). However, selectivity
(15:16) and isolated yields of 15 were lower in the 3- and 5-substituted systems (Entries
1, 3 and 5), suggestive of an electronic effect on the selective reduction. Additional
studies are needed to maximize selectivity in these more challenging systems.

Table 4. Flow hydrogenation and cyclization of substituted 2-nitrophenylacetic acid derivatives
Conversion Ratio Yield
Entry
R
(%)[a]
39
15:16[b] (%)[c]
1
2
3
4
5
3-Me
4-Me
5-Me
6-Me
3-F
1:1
4:1
12
71
100
100
100
100
2:3
n.d.
78
19:1
4:1
32
6
7
5-F
6-F
100
100
100
100
100
1:1
19:1
19:1
4:1
n.d.
81
83[d]
54[d]
63[d]
8
6-Br
4-CF3
4-Cl
9
10
3:2
[a]Percentage of 14 consumed in reaction, determined by LC-MS analysis of crude reaction mixture; [b]Ratio
determined by LC-MS analysis of crude reaction mixture, as described in Supporting Information; All reactions were
conducted in duplicate using 0.15 molar equiv.1,10-phenanthroline for flow hydrogenation, 1.5 mL/min flowrate; H2
inlet pressure of ≤10 bar; Values represent arithmetic mean from two experiments. [c]Isolated yield, from 1.65 mmol
14. [d]Pure product was obtained by concentrating reaction mixture from General Procedure and recrystallizing crude
product from ethanol and water.
In summary, we have developed an efficient and selective flow hydrogenation
method for partial reduction of the 2-nitrophenylacetic acid scaffold to the hydroxamic
acid with minimal formation of the by-product lactam. This method provides significant
advances in the safety, efficiency, and green chemistry aspects of this reduction
compared to previously reported batch hydrogenation methods. The addition of 1,10-
phenanthroline as an inhibitor of the reduction is critical to the high selectivity achieved
in the reductive cyclization. This study represents the first application of flow

hydrogenation to the challenge of partial reduction of nitroaryl carboxylic acids to
hydroxamic acids. This method is currently best suited for the synthesis of analogs
bearing substituents meta to the nitro group, but ongoing studies are investigating
modified conditions to improve access to other substitution patterns. The application of
this methodology toward the synthesis of biologically active hydroxamic acids will be
reported in due course.
Acknowledgements This work was supported by the Research Corporation for
Scientific Advancement Cottrell College Award, the Boettcher Foundation Webb-Waring
Biomedical Research Award, and NSF-MRI CHE-1429567. We wish to thank Prof.
Nathan Bower for helpful analytical chemistry discussions and Tanya Cervantes for
assistance with LC-MS method development and instrument support.
Keywords: green chemistry; hydroxamic acid; continuous flow; hydrogenation; Aryl
hydroxylamine
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19 The 5% Pt/C Catcarts were reused up to five times (for a 300 mg reaction) without loss of activity. Cartridges
were washed with ethanol (at least 10 mL at 1.0 mLmin-1) between each run.
20 Experiments summarized in Tables S1, 1-2 were completed using 5% Pt/C CatCarts (Batch 03700) supplied by
ThalesNano. Tables 3-4 were completed using Batch 03702. Due to differences in catalyst support material
between these CatCart batches, the increase in flow rate from 0.5 mL/min to 1.5 mL/min and increase in amount
of 1,10-phenanthroline from 0.05 to 0.15 molar equivalents was required in order to achieve comparable
selectivity in this transformation. Preliminary experiments showed greater selectivity for the hydroxamic acid with
increased flowrate.
21 Representative continuous-flow hydrogenation procedure: Ethanol (30 mL) was added to 2-nitrophenylacetic
acid (300 mg, 1.66 mmol) and 1,10-phenanthroline (33 mg, 0.23 mmol) in a reaction flask. The resultant solution
was pumped through the H-Cube Mini (5% Pt/C, 20 °C, flowrate 1.5 mLmin-1, H2 inlet pressure ≤10 bar) to near
dryness. Then the reaction flask was rinsed with ethanol (3 x 5 mL). The product eluant from the H-Cube was
collected and concentrated in vacuo to ~1 mL, then diluted to 6 mL with ethanol. Glacial acetic acid (0.21 mL, 36.7
mmol) was added and the reaction mixture stirred overnight at room temperature. The reaction mixture was
concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3
(5 x 5 mL). The combined aqueous extracts were treated with conc. H2SO4 to pH ~1 to precipitate the hydroxamic
acid, which was filtered and washed with cold deionized water (10 mL).
22 The yield of the 1 g scale conversion of 11 to 12 dropped to 60% in a separate experiment in which the H2
pressure increased to 21 bar.
23 Due to the inability to precisely control H2 pressure in the H-Cube Mini, particularly at low pressures (e.g., ≤10
bar), we observed some intra- and inter-experiment pressure fluctuation. Therefore, we report H2 pressures in
Tables 1-4 as ≤10 bar. This limitation of the H-Cube Mini system precludes a detailed analysis of the impact of
pressure in comparing the flow and balloon hydrogenations.

Graphical abstract
Highlights




Flow hydrogenation enables the safe, selectiv e synthesis of aryl hydroxamic acids
1,10-phenanthroline improves product selectivity in this Pt/C-catalyzed process
The hydroxamic acid is produced selectively over the lactam by-product (49:1)
The flow hydrogenation method is useful for a variety of 2-nitrophenylacetic acids