Formation of 4-N-arylamino-1-butanol derivatives from aromatic nitro compounds via a novel palladium-catalyzed tetrahydrofuran ring-opening reaction

Article abstract of DOI:10.1080/00397911.2011.582978

4-N-Arylamino-1-butanol derivatives are produced via a palladium-catalyzed tetrahydrofuran ring-opening reaction. This reaction occurs during the reduction of aromatic nitro groups with polymethylhydrosiloxane (PMHS) and potassium fluoride in the presence of hydrogen peroxide. This represents a novel route for the synthesis of 4-N-arylamino-1-butanols.

Full text of DOI:10.1080/00397911.2011.582978

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Formation of 4-N-Arylamino-1-butanol
Derivatives from Aromatic Nitro
Compounds via a Novel Palladium-
Catalyzed Tetrahydrofuran Ring-Opening
Reaction
Brian W. Moran a & Peter T. M. Kenny a
a School of Chemical Sciences , National Institute for Cellular
Biotechnology, Dublin City University , Glasnevin , Dublin , Ireland
Accepted author version posted online: 11 Nov 2011.Published
online: 02 Aug 2012.
To cite this article: Brian W. Moran & Peter T. M. Kenny (2012) Formation of 4-N-Arylamino-1-butanol
Derivatives from Aromatic Nitro Compounds via a Novel Palladium-Catalyzed Tetrahydrofuran Ring-
Opening Reaction, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 42:23, 3413-3418, DOI: 10.1080/00397911.2011.582978
To link to this article: http://dx.doi.org/10.1080/00397911.2011.582978
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Synthetic Communications1, 42: 3413–3418, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.582978
FORMATION OF 4-N-ARYLAMINO-1-BUTANOL
DERIVATIVES FROM AROMATIC NITRO COMPOUNDS
VIA A NOVEL PALLADIUM-CATALYZED
TETRAHYDROFURAN RING-OPENING REACTION
Brian W. Moran and Peter T. M. Kenny
School of Chemical Sciences, National Institute for Cellular Biotechnology,
Dublin City University, Glasnevin, Dublin, Ireland
GRAPHICAL ABSTRACT
Abstract 4-N-Arylamino-1-butanol derivatives are produced via a palladium-catalyzed
tetrahydrofuran ring-opening reaction. This reaction occurs during the reduction of
aromatic nitro groups with polymethylhydrosiloxane (PMHS) and potassium fluoride in
the presence of hydrogen peroxide. This represents a novel route for the synthesis of
4-N-arylamino-1-butanols.
Keywords 4-Amino-1-butanol; nitro; palladium-catalyzed; reduction; ring opening;
siloxane; tetrahydrofuran
INTRODUCTION
The synthesis of N-substituted 4-amino-1-butanols has been reported by
various methods.[1–4] Many procedures require a two- or three-step synthesis; how-
ever, a one-step method has recently been reported by high-pressure hydrogenation
of primary aromatic amines. This procedure employs palladium on carbon, requires
24–36 h, and has been demonstrated on a series of amines as starting material.[5] In
this laboratory, fluorinated amino analogs of the natural phytoalexin resveratrol
were prepared generate stilbenes with improved biological activity.[6] Reduction of
the nitro group of (E)-3,5-difluoro-40-nitrostilbene (1a) via a palladium-catalyzed
Received March 30, 2011.
Address correspondence to Peter Kenny, School of Chemical Sciences, National Institute for
Celluar Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland. E-mail: peter.kenny@dcu.ie
3413

3414
B. W. MORAN AND P. T. M. KENNY
Figure 1. Synthesis of 4-f40-(3,5-difluorophenylethyl)phenylaminogbutan-1-ol (1c). Pd(OAc)2, anhydrous
THF, KF, PMHS, 0 ꢀC to rt (4 h).
siloxane (PMHS) aqueous potassium fluoride procedure,[7] yielded the
amino compound 1b and an unexpected by-product. The by-product was identified
by spectroscopic analysis as 4-f40-(3,5-difluorophenylethyl)phenylaminogbutan-1-ol
1c (Fig. 1). The scope of this palladium-catalyzed siloxane reduction reaction is
now reported using various aromatic and aliphatic nitro and amino compounds
(1–8).
RESULTS AND DISCUSSION
This palladium-catalyzed siloxane reduction reaction was initially investigated
on a series of nitro compounds (1a–4a), which were reduced to form both the amine
(b) and the amino-butanol species (c) respectively. All the reactions went to com-
pletion with quantitative yields, and the ratio of amine to amino-butanol is presented
in Table 1. The preparations of compounds 2c,[8] 3c,[9] and 4c[10] have been reported
previously, but by different methods than those employed here. This novel one-step
approach for the synthesis of amino-butanols requires approximately 4 h as opposed
to the previously reported reaction, which requires 24–36 h and appears to be selec-
tive for nitro compounds. Potassium fluoride may be used as a reagent because of the
ability of fluoride to activate the PMHS, and it has been reported that PMHS and
Pd(OAc)2 form highly active palladium nanoparticles.[7] Although the ring opening
of tetrahydrofuran (THF) by amines has been reported, it normally involves the
complexing of the THF with cationic metal compounds such as uranium amide
compounds[11] and zirconium complexes.[12]
A free-radical-based mechanism for the palladium-mediated tetrahydrofuran
ring opening has been reported.[5] This mechanism was based on the use of unstabi-
lized THF, allowing for a potential build up of THF hydroperoxide. With the addition
of hydrogen peroxide as a reagent, the formation of hydroperoxides is enhanced. This
can result in cleavage of the hydrogen-oxygen bond of the hydroperoxide forming a

4-N-ARYLAMINO-1-BUTANOL DERIVATIVES
3415
Table 1. Synthesis of 4-N-arylamino-1-butanols from nitro compounds and THF
Entry
Nitro (a)
Amino-butanol product (c)
b=c
1
1:1
2
3
3:5
3:5
4
1:2
peroxide free radical I, which can then abstract a hydrogen from the 2-position of
THF forming radical II (Scheme 1). Either radical (I or II) can then remove a hydro-
gen from the amine to form the aminyl radical III which is resonance stabilized. This
in turn could couple to radical II to form the intermediate 2-amino–THF IV. Com-
plexing of the palladium to the intermediate IV may occur at this point, which in turn
forces ring opening via an imino alcohol. Reduction of the imine double bond can
then take place to yield the final amino-butanol product V. This reaction mechanism
is plausible for the synthesis of the 4-amino-butan-1-ol compound 1c. The THF used
in this initial reaction was of anhydrous grade and free of inhibitor=stabilizer. It was
Scheme 1. Proposed free-radical-based mechanism for the palladium-mediated tetrahydrofuran ring
opening.

3416
B. W. MORAN AND P. T. M. KENNY
also a relatively old bottle of solvent (ꢁ1 year old), which makes the likelihood of
hydroperoxide formation a real possibility. A test for peroxide was carried out on
the THF solvent used in these reactions, using Quantofix peroxide test sticks (Sigma
Aldrich). The result of this starch=iodide test proved positive for the presence of per-
oxides in the solvent. Only the amino compound was formed when a fresh bottle of
anhydrous THF was used. However, the formation of the amino-butanol compounds
in addition to their respective amines was observed using fresh anhydrous THF as
solvent with the addition of hydrogen peroxide. Therefore, the addition of a few drops
of hydrogen peroxide to the reaction was employed for all subsequent experiments.
A series of compounds were reduced to investigate this palladium–siloxane
reaction in more detail. The initial results of this preliminary study employed nitro
compounds and is presented in Table 1. Following this, a second series of reductions
investigating the possible reaction between the respective amines and THF was
carried out. These results are presented in Table 2. In all cases the amino compounds
failed to be converted to the amino-butanol compounds. In an attempt to drive these
amino reactions to the desired product, the quantities of reagents and reaction times
were doubled. It has been noted that 0.75 molar equivalences of Pd(OAc)2 represents
a relatively high catalyst loading. However, it has been shown that quantities can
reduced significantly without affecting the reducing potential of this reaction.[7]
Further work will aim to reduce this capacity without affecting the reducing
capability and more importantly the ring-opening catalyzed reaction. Also attempts
to recover the catalyst on completion will be addressed.
Amino-butanols can display biological properties such as the p-aminobenzoate
analog of 4-diethylamino-1-butanol, which has in vivo anaesthetic properties greater
than those of cocaine.[13] A 4-amino-1-butanol derivative of 2-methylquinoline-5,8-
dione was recently shown to be a potent antitumor agent both in vitro and in vivo.
The amino-butanol analog in this case was obtained via a two-step sequence involving
Table 2. Attempted synthesis of 4-N-arylamino-1-butanols from amines and THF
Entry
Amine (a)
Product (b)
5
6
7
NRa
NRa
8
NRa
aNo reaction.

4-N-ARYLAMINO-1-BUTANOL DERIVATIVES
3417
the hydrolysis of an aminoacetyldione to the aminodione, followed by the addition of
a tetrahydrofuran molecule in the presence of concentrated sulfuric acid.[14]
EXPERIMENTAL
All chemicals were purchased from Sigma-Aldrich, Lennox Chemicals, or
Fluorochem Limited and used as received. Commercial-grade reagents were used
without further purification. Riedel-Hae¨n silica gel was used for thin-layer and
column chromatography. Melting-point determinations were carried out using a
Stuart melting-point (SMP3) apparatus and are uncorrected. Infrared (IR) spectra
were obtained on a Perkin-Elmer Spectrum GX Fourier transform (FT)–IR system.
Ultraviolet (UV) spectra were obtained on a UV-vis-NIR Perkin-Elmer Lambda 900
spectrometer. NMR spectra were obtained on a Bruker AC 400 NMR spectrometer
1
operating at 400 MHz for H NMR, 376 MHz for 19F NMR, and 100 MHz for 13C
1
NMR. The H and 13C NMR chemical shifts (d) are relative to tetramethylsilane,
and the 19F NMR, chemical shifts (d) are relative to trifluoroacetic acid. All coupling
constants (J) are in hertz (Hz).
Synthesis of 4-f4’-(3,5-Difluorophenylethyl)phenylaminogbutan-1-
ol (1c)
3,5-Difluoro-40-nitrostilbene 1a (0.5 g, 1.92 mmol) and palladium(II) acetate
(0.33 g, 1.44 mmol) were dissolved in anhydrous THF (20 ml) under an atmosphere
of nitrogen. Aqueous potassium fluoride (0.33 g, 5.76 mmol) was added dropwise,
and the solution was cooled on an ice bath prior to very slow addition of PMHS
(0.69 ml, 11.52 mmol). The reaction was stirred for a further 4 h. After all stilbene
starting material had been consumed, the black reaction mixture was diluted with
diethyl ether and washed repeatedly with water. The organic layers were combined
and stirred in celite. This mixture was passed through an alumina=celite plug to yield
an orange solution. Purification by column chromatography with hexane=ethyl
acetate as eluant yielded compound 1b (0.20 g, 45%) and the title compound 1c as
a beige powder (0.29 g, 50%).
Data for 1c
Mp 68–70 ꢀC. IR (KBr): t 3272, 2920, 2850, 1783, 1616, 1595, 1516, 1495, 1310,
1252, 1116, 1075, 968, 853, 825, 803, 747, 680 cmꢂ1. UV (ACN): kmax 254; 303 nm.
1H NMR (400 MHz, DMSO-d6): d 6.90–6.99 (5H, m, -ArH 2, 4, 6, 20 & 60, 6.46
(2H, d, J ¼ 8.4, Hz-ArH 30 & 50), 5.33 (1H, t, J ¼ 5.4 Hz, -NH-), 4.40 (1H, t,
J ¼ 5.2 Hz, -OH), 3.42 (2H, q, J ¼ 6.2, -CH2 1), 2.95 (2H, q, J ¼ 6.6, -CH2 4),
2.80–2.84 (2H, m, -CH2), 2.69–2.72 (2H, m, -CH2), 1.45–1.58 (4H, m, -CH2 2 & 3).
13C NMR (100 MHz, DMSO-d6): d 162.3 (d, J ¼ 244.0 Hz, -ArCF), 162.1 (d,
J ¼ 243.0 Hz, -ArCF), 147.3 (-ArC 40), 146.2 (t, J ¼ 9.4 Hz, -ArC 1), 128.7 (-ArC 20
& 60), 127.4 (-ArC 1’), 111.8 (-ArC 30 & 50), 111.5 (d, J ¼ 24.0 Hz, -ArC 2 & 6),
101.1 (t, J ¼ 25.8 Hz, -ArC 4), 60.5 (-CH2 1, -VE DEPT), 42.9 (-CH2 4, -VE DEPT),
37.0 (-CH2, -VE DEPT), 35.5 (-CH2, -VE DEPT), 30.2 & 25.4 (-CH2 2 & 3, -VE
DEPT). 19F NMR (376 MHz, DMSO-d6): d ꢂ110.84 (2 F, t, J ¼ 8.0 Hz).

3418
B. W. MORAN AND P. T. M. KENNY
CONCLUSION
In summary, a novel procedure for the one-pot conversion of aromatic nitro
compounds to 4-N-arylamino-1-butanols in the presence of palladium and the silox-
ane PMHS, has been demonstrated. It has been shown that the initial nitro reduction
step is essential for conversion to the amino-butanol product. A previously proposed
free-radical-based mechanism for a palladium-catalysed tetrahydrofuran ring open-
ing is highly plausible with the addition of hydrogen peroxide as a reagent. Further
studies are in progress to examine the scope of this reaction. This reaction should
prove useful in the synthesis of new amino alcohols.
ACKNOWLEDGMENT
This research was supported by the National Institute for Cellular Biotechnol-
ogy under the Programme for Research in Third Level Institutions (PRTLI, round 3,
2001-2006).
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