A new palladium-mediated approach to 4-N-arylamino-1-butanols from peroxidic tetrahydrofuran and primary aromatic amines

Article abstract of DOI:10.1016/j.tetlet.2006.12.136

Reaction of primary aromatic amines with peroxidic tetrahydrofuran (THF) in the presence of hydrogen and 10% palladium on carbon catalyst results in THF ring opening to give 4-N-arylamino-1-butanols in a good yield. The reaction mechanism is believed to i

Full text of DOI:10.1016/j.tetlet.2006.12.136

Tetrahedron Letters 48 (2007) 1637–1639
A new palladium-mediated approach to
-N-arylamino-1-butanols from peroxidic tetrahydrofuran
and primary aromatic amines
4
a,
b
a
*
Henry F. Russell, John B. Bremner, Jennifer Bushelle-Edghill,
c
a
a
Melissa R. Lewis, Stacey R. Thomas and Floyd Bates, II
a
Department of Science and Mathematics, Johnson C. Smith University, Charlotte, NC 28216, USA
b
Department of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
c
4
03 70th St., Seat Pleasant, MD 20743, USA
Received 5 May 2006; revised 20 December 2006; accepted 22 December 2006
Available online 22 January 2007
Abstract—Reaction of primary aromatic amines with peroxidic tetrahydrofuran (THF) in the presence of hydrogen and 10%
palladium on carbon catalyst results in THF ring opening to give 4-N-arylamino-1-butanols in a good yield. The reaction mecha-
nism is believed to involve a free-radical sequence resulting in an imino alcohol subsequently reduced to product.
Ó 2007 Elsevier Ltd. All rights reserved.
N-Substituted 4-amino-1-butanols have been synthe-
bility of this relatively simple and mild preparation of
aminobutanols. To our knowledge this reaction has
not been described previously. A brief series of reac-
tions using various aromatic and aliphatic amines, in
THF under a hydrogen atmosphere with 10% Pd/C
was then investigated (Scheme 1) and the results are
reported in this Letter.
1
–3
sized by various two- and three-step methods
and,
6
somewhat pertinent to this report, by high pressure
hydrogenation with ring opening of dihydrooxazines
4
using Pd/C. They are useful as solvents, plasticizers,
and dye intermediates. Their preparation is also of bio-
medical interest since tests have shown that the p-amino-
benzoate of 4-diethylamino-1-butanol is a more effective
2
0
anesthetic than cocaine. An ether derivative of 4-[(4 -
In a typical reaction, a solution of amine 1e (2.22 g,
20 mmol) and 10% Pd/C catalyst (0.4 g, 0.02 g per mmol
of amine) in 100 mL of peroxidic THF (CAUTION:
5
methoxyphenyl)amino]butan-1-ol was recently shown
to have antagonist activity at calcium T-type channels;
the required aminobutanol precursor in this case was
obtained via a two-step sequence starting from the reac-
tion of succinic anhydride with the aromatic amine fol-
lowed by the hydride reduction of the intermediate
amide acid.
7
Handle peroxidic THF with care ) was stirred under a
hydrogen atmosphere (1 atm) for 24–36 h at room tem-
perature. When TLC showed the absence of starting
amine, the catalyst was filtered and the filtrate concen-
trated under vacuum to give crude product 2e as an
oil. (NOTE: Before this evaporation, the filtrate should
be checked for the presence of any residual peroxide
00
0
Therefore, the unanticipated isolation of 4-{1 -[(2 -
7
aminophenyl)methyl]benzimidazole}-1-butanol (2a) (Table
(starch–iodide test ) and evaporation should only pro-
1
) as well as the expected amine 1a from the reduction of
ceed if this is negative.) Crude 2e was purified as de-
scribed in Ref. 9. Other crude products were also oils
except for 2a, which was a crystalline solid. Crude com-
pounds 2b–e were vacuum distilled or chromatographed
on silica except 2a, which was isolated as a solid byprod-
the corresponding nitro compound in THF with Pd/C
and hydrogen, led us to investigate the general applica-
1
4
5
uct. Compounds 2b, 2c, and 2d had been previously
Keywords: Palladium catalyzed; Ring opening; 4-Amino-1-butanols;
Hydrogenation; Tetrahydrofuran hydroperoxide.
*
reported, but were accessed by different routes. New
8
9
Corresponding author. Tel.: +1 704 378 1054; fax: +1 704 378
213; e-mail: hrussell@jcsu.edu
compounds 2a and 2e were characterized by elemental
1
13
1
analyses and H and C NMR. The main repetitive
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.136

1638
H. F. Russell et al. / Tetrahedron Letters 48 (2007) 1637–1639
Table 1. Pd-Mediated synthesis of 4-N-arylamino-1-butanols from amines and THF
a
d
Entry
Amine (1)
THF (U or S)
Time (h)
Product (2)
Yield (%)
N
N
OH
NH2
NH2
HN
e
N
N
1
U
96
30
1
a
2a
H
N
2
3
1b
U
24
24
OH
95 (78)
95 (84)
2b
H
N
OH
U
2
c
Me
Me
NH2
4
5
6
U (air atm)
48
72
72
Multiple products
1
c
U (N
2
atm)
NR
NR
S
H
N
7
8
U
24
OH
95 (79)
MeO
NH2
MeO
2d
1
d
1
b
U
U
72
24
Partial
c
2d
9
S
96
24
NR
F
NH2
H
N
e
OH
10
U
95 (80)
2e
F
11
12
13
Ph
PhCH
Et
2
NH
U
U
U
96
72
96
NR
NR
NR
2
NH
2
2
H
a
b
c
U = Unstabilized (hydroperoxides present); S = stabilized; NR = no reaction.
Insufficient amount of hydroperoxide present based upon amount of THF used.
After removal of solvent and introduction of new unstabilized THF.
d
e
Crude (isolated).
0
Yield from reduction of 1-(2 -nitrophenyl)methylbenzimidazole in THF; 62% 1a also formed.
H ; Pd/C; 1 atm.
The initial results of this investigation are shown in
Table 1 and indicate that only primary aromatic amines
react. It was also found that THF solvent containing
THF hydroperoxide was essential for the reaction to
proceed. The solvent used was unstabilized THF which
had been exposed to air. When THF from a newly
opened bottle (or stabilized THF) was used, the reac-
tions did not proceed. An additional evidence for the
involvement of THF hydroperoxide is the fact that a lar-
ger scale reaction using p-anisidine ceased after 1 day
with only partial conversion to aminobutanol product
but, upon evaporation of the solvent and replacement
with air-exposed THF, the reaction continued to
completion.
2
Ar
OH
ArNH2
+
N
peroxidic THF
H
O
2
a-e
1a-e
Scheme 1. THF ring opening to form 4-N-arylamino-1-butanols.
NMR features of all compounds are those of the amino-
butanol portion of the molecules: a 4-proton multiplet
around 1.6 d was assigned to the C-2 and C-3 protons
and two 2-proton broadened triplets around 3.0 and
.6 d were ascribed to the methylene protons adjacent
to the nitrogen and the oxygen, respectively. The
NMR spectra show the chemical shifts of the signals
for the four carbons of the aminobutanol portion of
the molecule being relatively consistent thus making
them useful for quick identification.
3
13
C
A possible free-radical-based mechanism for this ring
opening process is shown in Scheme 2. The cleavage of

H. F. Russell et al. / Tetrahedron Letters 48 (2007) 1637–1639
1639
and hydrogen has been demonstrated. This reaction
should provide access to a range of new amino alcohols
of value in further synthesis.
OOH
O
+
OH
OH
O
O
O
A
O
+
+
O
O
O B
Acknowledgments
The authors acknowledge support of The National
Institutes of Health, NIGMS, MBRS-SCORE Grant
GM 065299 and MBRS-RISE Grant GM 58042, and
NSF Instrumentation Grant 0116393. The assistance
of Drs. Craig Ogle and Cliff Carlin of the University
of North Carolina, Charlotte, is also appreciated.
O
+
ArNH2
ArNH
+
OH
O
O
A
C
OR ?
ArNH2
ArNH
+
O B
O
C
References and notes
+
ArNH
NHAr
D
O
O
1. Wichterle, O. Collect. Czech. Chem. Commun. 1949, 14,
2
09–218.
2
. Lunsford, C. D.; Murphy, R. S.; Rose, E. K. J. Org.
Chem. 1957, 22, 1225–1228.
. Flanikin, J. M.; Collins, J. C.; Lanz, M.; Singaram, B.
Org. Lett. 1999, 1, 799–801.
H
N
N Ar
N Ar
3
O
Ar
O
Pd
OH
E
Pd
4. Winberg, H. E. U. S. Patent 2,628,978, 1953.
5
. McCalmont, W. F.; Patterson, J. R.; Lindenmuth, M. A.;
Heady, T. N.; Haverstick, D. M.; Gray, L. S.; Macdonald,
T. L. Bioorg. Med. Chem. 2005, 13, 3821–3839.
H2
Ar
OH
N Ar
N
H
Pd/C
6. While the ring opening of THF on attack by amines has
been reported previously this involves the complexing of
the THF with cationic metal compounds. See: Boisson, C.;
Berthet, J. C.; Lance, M.; Nierlich, M.; Ephritikhine, M.
Chem. Commun. 1996, 2129; Borkowski, S. L.; Jordan, R.
F.; Hinch, G. D. Organometallics 1991, 10, 1268.
7. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.;
Tatchell, A. R. Vogel’s Textbook of Practical Organic
Chemistry, 5th ed.; Longman: Harlow, England, 1989
p 406 and 552.
OH
2
Scheme 2. A plausible mechanism for the Pd-mediated THF ring
opening.
THF hydroperoxide results in the peroxide free radical
A. Radical A can then abstract hydrogen from the 2-
position of THF to form radical B. Either radical A or
B could then abstract hydrogen from the amine nitrogen
to form the resonance stabilized aminyl radical C, which
could in turn couple with radical B to form the 2-amino-
THF intermediate D. At this point the ring of the palla-
dium complex opens to form imine E, which then could
0
0
0
8
. 4-{1 -[(2 -Aminophenyl)methyl]benzimidazole}butan-1-ol
2a). This compound was recrystallized from methanol to
(
1
give pale orange crystals; mp: 135.5–137 °C. H NMR
(
DMSO-d ) d: 1.4–1.8 (m, 4H, CH -2 and CH -3), 3.0–
6 2 3
3
.25 (m, 2H, CH -4), 3.35–3.65 (m, 2H, CH -1), 4.5 (t,
2
2
1
0
be hydrogenated to the final product 2.
J = 5.0 Hz, 1H, NH), 5.3 (t, 5.4 Hz, 1H, OH), 5.4 (s, 2H,
benzylic CH ), 6.4–6.85 (m, 3H, ArH), 7.0–7.35 (multiplet
2
Several facts support this proposed mechanism. Firstly,
the THF solvent initially being used was unstabilized
and had been open for many months thus allowing a
buildup of THF hydroperoxide. This strongly implies
that the presence of THF hydroperoxide is necessary
for the reaction to occur. Secondly, the fact that only
aromatic amines react strengthens the free-radical
approach since they can stabilize the amino free radical
D by resonance. The formation of imine intermediate
E with subsequent reduction is supported by two obser-
vations. One, the presence of hydrogen is necessary for
the reaction to occur. The reaction did not proceed in
a nitrogen atmosphere and a reaction of 1c in air gave
multiple products. Two, the requirement for the forma-
tion of the imine explains the non-reactivity of second-
ary aromatic amines since imine formation is not
possible.
with prominent doublet, J = 9.3 Hz, 3H, ArH), 7.45–7.55
(m, 1H, ArH), 7.6–7.75 (m, 1H, ArH), 8.3 (s, 1H, H-2).
1
3
C NMR (DMSO-d
4.4 (benzyl CH ), 60.5 (C-1); 110.35, 110.75, 115.7, 119.4,
20.2, 121.5, 122.3, 128.1, 128.9, 134.0, 143.5, 144.3, 146.0
O: C, 73.19; H, 7.17;
6
) d: 25.2 (C-3), 30.1 (C-2), 43.0 (C-4),
4
1
2
(
all ArC). Anal. Calcd for C18
H
21
N
3
N, 14.23. Found: C, 72.98; H, 7.23; N, 14.10.
. 4-[(4-Fluorophenyl)amino]butan-1-ol (2e). This com-
pound was isolated from the crude reaction product
9
(
ꢀ90% yield) by flash chromatography on silica gel using
ethyl acetate/hexane (3/2) as the eluent; 2e was isolated as
an oil (80% yield); bp 148–150 °C/3 Torr. H NMR
3 2
(CDCl ) d: 1.65 (m, 4H, CH -2 and -3), 3.1 (m with
1
prominent br s, 4H, CH
2
-4, N–H and O–H), 3.65 (t,
0
J = 6 Hz, 2H, CH
ArH-3 ), C NMR (CDCl ) d: 26.0 (C-3), 31.5 (C-2), 44.8
2
-1), 6.55 (m, 2H, ArH-2 ), 6.9 (m, 2H,
0
13
3
0
(
1
C-4), 62.15 (C-1), 114.2 (ArC), 115 (ArC ), 145.1 (ArC-
), 161.5 (ArC-4 ). Anal. Calcd for C10
0
0
H14FNO: C, 65.55;
H, 7.70; F, 10.37; N, 7.65. Found: C, 65.34; H, 7.84; F,
0.48; N, 7.60.
1
In summary, a new mild procedure for the one-pot con-
version of aromatic primary amines to 4-N-arylamino-1-
butanols in the presence of peroxidic THF and Pd/C
1
0. Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029; Saaby,
S.; Knudsen, K. R.; Ladlow, M.; Ley, S. V. Chem.
Commun. 2005, 2909.