New and convenient syntheses of 1-amino-1-phenylbutane from n-butylbenzene

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Organic Preparations and Procedures
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New and Convenient Syntheses of
1-Amino-1-phenylbutane from n-
Butylbenzene
Lingaiah Nagarapu a , Satyender Apuri a , Chandana Gaddam a &
Rajashakar Bantu a
a Organic Chemistry Division-II , Indian Institute of Chemical
Technology , Hyderabad, India
Published online: 01 Jun 2009.
To cite this article: Lingaiah Nagarapu , Satyender Apuri , Chandana Gaddam & Rajashakar Bantu
(2009) New and Convenient Syntheses of 1-Amino-1-phenylbutane from n-Butylbenzene, Organic
Preparations and Procedures International: The New Journal for Organic Synthesis, 41:3, 243-247,
DOI: 10.1080/00304940902958545
To link to this article: http://dx.doi.org/10.1080/00304940902958545
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Organic Preparations and Procedures International, 41:243–247, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940902958545
OPPI BRIEFS
New and Convenient Syntheses
of 1-Amino-1-phenylbutane from n-Butylbenzene
Lingaiah Nagarapu, Satyender Apuri, Chandana Gaddam,
and Rajashakar Bantu
Organic Chemistry Division-II, Indian Institute of Chemical Technology
Hyderabad, India
n-Butylbenzene (1), an unwanted by-product formed in 10% yield during the manufacture
of isobutylbenzene, has few industrial applications and is discarded by burning. In an
attempt to produce a value-added product from 1, we aimed at the synthesis of 1-amino-1-
phenylbutane (5). 1-Amino-1-phenylbutane (5) is used as an intermediate for the synthesis
of substituted triazoles,1 aminothiazoles,2 and a quinoline derivative which is a neurokinin-
3 antagonist.3 In its chiral form, 5 is useful as a resolving agent.4 Because of its utility in
biologically active molecules, we wanted to develop new synthetic routes to 1-amino-1-
phenylbutane (5) starting from n-butylbenzene.
Racemic amine (5) had previously been prepared by: a) reduction of the oxime of buty-
rophenone with Ni, Na, Pd\C,3 etc., b) the Leuckart reaction of butyrophenone,5 c) reaction
of propionitrile with phenylmagnesium bromide followed by reduction,6 d) hydrolysis of
the iminophosphorane of butyrophenone.7 The chiral form of amine 5 was synthesized by:
a) asymmetric reduction of ketimines using optically active alkoxylithium hydride8 and
ketoxime ethers with chiral oxazaborolidines,9 b) asymmetric allylation of imines followed
by reduction,10 c) enantioselective synthesis via addition of Grignard reagent to chiral
hydrazones,11 d) asymmetric recognition by (R)-phenylglycyl-(R)-phenylglycine.12 This
paper reports three useful synthetic routes to compound 5 from n-butylbenzene.
In the first two methods, the bromination of (1) with NBS in CCl4 under reflux
conditions, gives α-bromophenylbutane (2). Although the reaction of (2) with potassium
phthalimide in acetone at reflux failed, the use of DMF as solvent at 90◦C led to compound
3. The required amine 5 was obtained by the Ing-Manske13 procedure. This first novel
method proceeds in 50% overall yield from 1.
Submitted by May 22, 2008.
Address correspondence to Lingaiah Nagarapu, Organic Chemistry Division-II, Indian Institute of
Chemical Technology, Hyderabad 500 007, INDIA. E-mail: nagarapu2@yahoo.co.in or nagarapu@
iict.res.in
243

244
Nagarapu et al.
Scheme
The second method involves the transformation of 2 to α-azidophenylbutane (4), using
sodium azide. Reaction of 4 with triphenylphosphine in ether at RT for 3 h gave the
corresponding iminophosphorane, which was hydrolyzed with aqueous alkali to afford the
required amine 5. The 1H NMR data of (5) from both reactions was in complete agreement
with its structure. The overall yield of compound (5) is 46% starting from 1.
The third route involved the conversion of n-butylbenzene to 1-phenyl-1-butanone
(6) followed by the Leuckart reaction conditions. In 1987, Muzart14 reported chromium
catalyzed benzylic oxidations using t-butyl hydroperoxide (TBHP).15 Accordingly a process
for the preparation of 1-phenyl-1-butanone (6) from n-butylbenzene via benzylic oxidation
using catalytic CrO3 in combination with TBHP under homogenous conditions on 150 g
batchsizewasdeveloped. Treatmentof(6) withammoniumformateledtothecorresponding
formamide, which, without isolation, was hydrolyzed, with conc. HCl to give the desired
amine 5 in 50% yield. The reductive amination of 6 has been performed on 100 g scale and
yields were optimized. However, the overall yield of 5 is only 31% starting from compound
1. Of the three methods, the first method was found to be superior in terms of overall yield
and convenience.
Experimental Section
Melting points were measured with a Fischer-Johns melting point apparatus, and are not
corrected. The 1H NMR spectra were recorded at GEMINI 200 MHz, BRUKER Avance 300
MHz and UNITY 400 MHz spectrometers with tetramethylsilane as an internal reference.
Mass spectra (MS) were measured on 7070 H (Manchester, UK) mass spectrometers
using a direct inlet probe. IR spectra were obtained on Thermo Nicolet Nexus 670 FT-IR
spectrometer. For column chromatography, silica gel 60–120 mesh was used. For TLC,
silica gel 60F254 (Merck) was used.

Convenient Syntheses of 1-Amino-1-phenylbutane
α-Bromophenylbutane (2)
245
o a stirred solution of n-butylbenzene (1, 3.5 g, 26.1 mmol) in CCl4 (18 mL) was added
NBS (5.55 g) at r.t. The mixture was refluxed for 3 h and then was cooled to 0◦C. The
precipitated succinimide was filtered off and the filtrate was evaporated in vacuo to give
the title compound 2 (4.98 g, 90%) as a brown colored liquid. The crude compound 2,
bp. 67–72◦C/1mm (lit.16 bp. 67–75◦C/1mm), was used in the next step without further
1
purification. H NMR (CDCl3, 300 MHz): δ 1. 0 (t, 3H, CH3), 2.2 (m, 2H, CH2), 2.6 (q,
2H, CH2), 5.0 (t, 1H, CH), 7.4–7.6 (m, 5H, ArH).
Anal. Calcd. for C10H13Br : C, 56.36; H, 6.15. Found: C, 56.22; H, 6.13.
α-Phthalimidophenylbutane (3)
To a stirred solution of potassium phthalimide (3.14 g, 16.97 mmol) in DMF (10 mL) was
added dropwise α-bromophenylbutane (2), 3.0 g, 14.15 mmol). The mixture was heated
at 90◦C for 3.5 h. After completion of the reaction, the reaction mixture was poured into
water (25 mL) and extracted into ether (2 × 15 mL). The organic phase was separated,
dried and evaporated in vacuo to afford the crude product which was purified by column
chromatography on silica gel using hexane: ethylacetate (7:3) to give the title compound
(3) (4.01g, 82%) as a semi-solid. 1H NMR (CDCl3, 200 MHz): δ 1. 0 (t, 3H, CH3), 1.4 (m,
2H, CH2), 2.2, 2.4 (2 × q, 2H, CH2), 5.3 (t, 1H, CH), 7.1–7.7 (m, 9H, ArH); MS: m/z =
279 [M+, 20].
Anal. Calcd. for C18H17 NO2 : C, 77.40; H, 6.13. Found : C, 77.12; H, 6.10.
1-Amino-1-phenylbutane (5)
To a stirred solution of α-phthalimidophenylbutane (3, 12.0 g, 43 mmol) in MeOH (60 mL)
was added hydrazine hydrate (3.2 g, 64.5 mmol). The mixture was refluxed for 2.5 h and
the solvent was evaporated in vacuo and to the liquid residue hexane (2 × 25 mL) was
added at 0◦C. The separated solid was filtered off and the filtrate evaporated under reduced
pressure to give title compound 5 (4.35 g, 69%) as a colorless liquid, bp. 63◦C/10mm (lit.6
bp. 102◦C/14mm), mp. 248–250◦C (dec) [lit.7 mp. 250◦C (dec)] (hydrochloride). IR (KBr):
3370, 3310 cm−1; 1H NMR (CDCl3, 300 MHz): δ 0.9 (t, 3H, CH3), 1.2 (m, 2H, CH2), 1.6
(q, 2H, CH2), 3.9 (t, 1H, CH), 7.2 (m, 5H, ArH); MS: m/z = 149 [M+, 100].
Anal. Calcd. for C10H15N: C, 80.48; H, 10.13. Found: C, 80.23; H, 9.93.
α-Azidophenylbutane (4)
To a stirred solution of NaN3 (22.0 g, 0.34 mol) in water (50 mL) and MeOH (200 mL) was
added α-bromophenylbutane (2, 20.0 g, 0.09 mol). The solution was stirred at r.t for 8 h, then
methanol was evaporated in vacuo and the aqueous layer extracted into dichloromethane
(2 × 50 mL). The organic phase was separated, dried and concentrated to afford the crude
product, bp. 85–90◦C/4mm (lit.16 bp. 81–87◦C/3mm), which was distilled to give the pure
1
title compound 4 (13.18 g, 80%) as a colorless liquid. IR (KBr): 2097 cm−1; H NMR
(CDCl3, 300 MHz): δ 0.9 (t, 3H, CH3), 1.2–1.4 (m, 2H, CH2), 1.6–1.7 (m, 2H, CH2), 4.4
(t, 1H, CH), 7.2–7.4 (m, 5H, ArH).
Anal. Calcd. for C10H13N3 : C, 68.54; H, 7.48. Found : C, 68.42; H, 7.33.

246
Nagarapu et al.
1-Amino-1-phenylbutane (5) from α-Azidophenylbutane
To a stirred solution of α-azidophenylbutane (4, 1.0 g, 5.7 mmol) in diethyl ether (10 mL)
was added dropwise a solution of Ph3P (1.5 g, 5.7 mmol) in diethyl ether (20 mL). The
contents were stirred at r.t. for 3 h and the solvent was evaporated in vacuo to afford the
crude iminophosphorane to which was added boiling EtOH (20 mL) and 2M aq. KOH
(20 mL). The reaction mixture was stirred at r.t for 1 h, and then was made acidic by
addition of 18% aq. HCl (40 mL) followed by reflux for 2 h. The solvent was evaporated
and the aqueous layer was extracted into ethyl acetate (2 × 10 mL). The aqueous phase
was separated and made alkaline with aq. NaOH, then extracted into dichloromethane (2 ×
15 mL). The separated organic phase was dried and concentrated to afford the title com-
pound 4 (0.54 g, 63%) as a colorless liquid, identical to the previously prepared compound.
1-Phenyl-1-butanone (6)
To a stirred solution of ethylene dichloride (200 mL) and CrO3 (5 g, 0.05 mol) was slowly
added a first portion of TBHP (190 mL) at 10–20◦C (addition time 30 min). Then a solution
of n-butylbenzene (1, 150 g, 1.2 mol) in ethylene dichloride (100 mL) was added. The
mixture was heated to an internal temperature of 70–75◦C for 2 h. Then a second portion
of TBHP (190 mL) was slowly added (30 min) under reflux conditions. Similarly after
every 1.5 h, third and fourth portions of TBHP (2 × 190 mL) were added, and reflux was
continued for additional 12 h. Then a solution of FeSO4 (1 g) in 250 mL of water was
added, the mixture was stirred for 15 min and allowed to separate into an upper organic
and a lower aqueous phase. The organic phase was washed with aqueous ammonia solution
(120 mL ammonium hydroxide in 300 mL water). The separated lower aqueous ammonia
phase was neutralized with 50% aq. HCl (135 mL) to give a filterable solid which was
identified as benzoic acid.
The organic phase was dried, concentrated and fractionated under vacuum (20 mm)
to afford 3 fractions. The first fraction (34 g) at 90◦C consisted of unreacted 1, the second
fraction (20 g) at 95–120◦C consisted of a mixture of n-butylbenzene and product 6 in the
ratio of 2:3. The third fraction at 120–135◦C contained pure compound 6 (79.5 g, 62%
based on the recovery of butylbenzene) as a yellowish liquid, bp. 100–102◦C/10mm (lit.17
bp. 110◦C/10mm); IR (KBr): 1698 cm−1; 1H NMR (CDCl3, 300 MHz): δ 1.0 (t, 3H, CH3),
1.7 (m, 2H, CH2), 3.0 (t, 2H, CH2), 7.4–7.5 (m, 5H, ArH); MS: m/z = 148 [M+, 100].
Anal. Calcd. for C10H12O : C, 81.04; H, 8.16. Found : C, 81.12; H, 8.18.
1-Amino-1-phenylbutane (5) from 1-Phenyl-1-butanone (6)
A mixture of 1-phenyl-1-butanone (6, 100 g, 0.67 mol) and ammonium formate (136 g,
0.46 mol) was heated. At 120◦C, the reaction mixture became homogenous and at 150◦C
1-phenyl-1-butanone and water distilled out. The organic phase was separated, poured
back into the reaction flask and the mixture maintained at 180◦C for 6 h. After completion
of the reaction, the mixture was poured into water (500 mL) and extracted into benzene
(600 mL). The organic phase was separated, dried and concentrated to give the crude
formamide (110 g). Conc. HCl (97 g) was added to the crude formamide and the reaction
was heated at 110◦C for 2 h. Then the mixture was poured into water (400 mL) and washed

Convenient Syntheses of 1-Amino-1-phenylbutane
247
with benzene (2 × 250 mL). The aqueous phase was separated and made alkaline with
aq. NaOH, extracted into DCM (2 × 100 mL). The separated organic phase was dried
and concentrated to afford the crude product, which was distilled under vacuum to afford
the title compound 5 (53 g, 50%) as a colorless liquid, bp. 63◦C/10mm, identical to the
previously prepared compound.
Acknowledgement
SA thanks CSIR-New Delhi for financial support and Director, IICT for his support.
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