Condensations of N-arylhydroxylamines for the preparation of 5,5′-di-tert-butyl-2,2′-dihydroxydiphenylamine

Article abstract of DOI:10.1016/S0040-4039(02)02699-0

Acid-promoted condensation of 4-tert-butyl-2-hydroxylaminoanisole with p-tert-butylphenol resulted in the formation of 5,5′-di-tert-butyl-2,2′-dihydroxydiphenylamine upon demethylation with BBr₃. Protection of the acidic phenol unit was require

Full text of DOI:10.1016/S0040-4039(02)02699-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 849–851
Condensations of N-arylhydroxylamines for the preparation of
5,5%-di-tert-butyl-2,2%-dihydroxydiphenylamine
John D. Spence,* Ashley E. Raymond and Dianne E. Norton
Department of Chemistry, Trinity University, 715 Stadium Dr., San Antonio, TX 78212, USA
Received 14 October 2002; accepted 19 November 2002
Abstract—Acid-promoted condensation of 4-tert-butyl-2-hydroxylaminoanisole with p-tert-butylphenol resulted in the formation
of 5,5%-di-tert-butyl-2,2%-dihydroxydiphenylamine upon demethylation with BBr3. Protection of the acidic phenol unit was required
to isolate the acid labile N-arylhydroxylamine intermediate. © 2003 Elsevier Science Ltd. All rights reserved.
Macrocyclic oligomers of p-tert-butylphenol and form-
aldehyde, commonly referred to as calixarenes, have
received widespread interest over the past 30 years.1 A
major factor contributing to the rapid growth in calix-
arene chemistry can be traced to the ready availability
of the major calixarenes via one-step syntheses2 and the
development of fragment syntheses for non-symmetrical
systems.3 Their appeal is further multiplied by the ease
of modification along the upper rim para-alkyl and
lower rim phenolic groups allowing the preparation of
a diverse array of macrocycles. Functionalization along
the bridge position, however, has received limited atten-
tion primarily focused on alkanediyl,4 thia5 and the
expanded6 calixarenes. While dihomoazacalixarenes are
known6c analogs with a direct nitrogen bridge between
the aryl units have not been reported due to synthetic
difficulties in preparing diarylamines. As part of a
building block approach towards the preparation of
nitrogen-bridged calixarenes we sought to prepare
diphenylamines derived from p-tert-butylphenol that
can be employed in a fragment approach towards the
synthesis of azacalixarenes.
condensation of N-arylhydroxylamines with aryl rings.
The parent version of this reaction, the condensation of
hydroxylaminobenzene with benzene, has been reported
to produce a mixture of N-substituted diphenylamine 1
and C-substituted biphenylamines 2 and 3 (Scheme 1).7
Employment of this strategy for the preparation of
diarylamines would parallel those used in the fragment
syntheses of calixarenes that employ 2-hydroxymethyl
or 2-bromomethyl-4-tert-butylphenols to incorporate
methylene bridges between aryl subunits. Herein we
report on the synthesis of an N-arylhydroxylamine
derived from p-tert-butylphenol and its acid-promoted
condensation
to
prepare
5,5%-di-tert-butyl-2,2%-
dihydroxydiphenylamine.
Initial attempts to prepare the desired N-arylhydroxyl-
amine by the partial reduction of 4-tert-butyl-2-nitro-
phenol under a variety of conditions resulted in the
isolation of 2-amino-4-tert-butylphenol due to over
reduction. It is well known that N-arylhydroxylamines
are acid-sensitive8 and we speculated that the ortho-
phenol moiety facilitated a dehydration of the hydroxyl-
amine, producing an o-benzoquinonimine, which was
rapidly reduced to the aminophenol. While reductions
of substituted nitrobenzenes to hydroxylamines have
Among the methods available for the synthesis of
diphenylamines we chose to re-visit the acid-promoted
Scheme 1.
Keywords: nitroaromatics; reductions; N-arylhydroxylamines; diphenylamines.
* Corresponding author. Tel.: (210) 999-7660; fax: (210) 999-7569; e-mail: john.spence@trinity.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02699-0

850
J. D. Spence et al. / Tetrahedron Letters 44 (2003) 849–851
Scheme 2. Reagents and conditions: (a) H2NNH2, Pd/C, THF, 0°C. (b) H+, p-tert-butylphenol, CH2Cl2 (two-step yield 13–60%,
see Table 1). (c) BBr3, CH2Cl2, 0°C (81%).
Table 1. Condensation of hydroxylamine 5 with p-tert-butylphenola
Entry
Acid
Conditions
Diphenylamine 6b (%)
1
2
3
4
5
TFA
2.5 equiv. acid, 1.0 equiv. p-tert-butylphenol
2.5 equiv. acid, 1.0 equiv. p-tert-butylphenol
2.5 equiv. acid, 1.0 equiv. p-tert-butylphenol
10 equiv. acid, 1.0 equiv. p-tert-butylphenol
2.5 equiv. acid, 5.0 equiv. p-tert-butylphenol
44
40
13
41
60
TsOH
TFSA
TFA
TFA
a Reaction conditions 0.1 M 5 in CH2Cl2, room temperature, under N2.
b Isolated two-step yield from 4 after purification.
been reported9 there are no examples describing the
synthetic preparation of 2-hydroxylaminophenols.
Reduction of anisole 4, however, under catalytic hydro-
gen transfer conditions afforded the desired hydroxyl-
amine 5 (Scheme 2) along with a minor amount of
2-amino-4-tert-butylanisole (<10%). The hydroxyl-
The acid-promoted condensation was initially examined
with TFA which has been reported to give the highest
yields of diphenylamine 1 in the condensation of
hydroxylaminobenzene with benzene (Scheme 1).7
Upon treatment of 5 with 1 equiv. of p-tert-butylphe-
nol in the presence of 2.5 equiv. of TFA in CH2Cl2
diphenylamine 6 was obtained as the only condensation
product in 44% yield (entry 1). p-TsOH, commonly
used in calixarene syntheses, was found to behave simi-
larly to TFA (entry 2). Stronger acids such as TFSA,
on the other hand, have been reported to produce
biphenylamines as major products and resulted in the
lowest observed yield of diphenylamine 6 in the present
study (entry 3). The presence of the bulky tert-butyl
substituent directly adjacent to the available C-alkyla-
tion sites is apparently large enough to prevent C-sub-
stitution as no evidence of biphenylamine products was
observed under any conditions studied.10 The reaction
was found to be insensitive to a large excess of acid
(entry 4), however, a fivefold excess of p-tert-butylphe-
nol increased the overall yield to 60% (entry 5). In each
reaction a minor amount of 2-amino-4-tert-butylanisole
was isolated (6–10%) along with trace amounts of azo
and azoxy products. To simplify purification the
2-aminoanisole by-product was removed by extract-
ing with 5% HCl and excess p-tert-butylphenol
was removed by sublimation prior to column chro-
matography. In our hands diphenylamine 6 could rou-
1
amine was readily identified by GCMS and H NMR
spectroscopy which displayed a characteristic AMX
system in the aromatic region along with two exchange-
able signals for the NHOH. Integration of the well
1
resolved tert-butyl or methoxy signals in the crude H
NMR spectra indicated an 11:1 ratio favoring hydroxyl-
amine 5 over 2-amino-4-tert-butylanisole. Due to the
lability of hydroxylamine 5 this mixture could not be
separated and the crude reduction product was taken
directly into the condensation reaction.
To examine the condensation reaction anisole 4 was
reduced on a 5 mmol scale in THF (150 mL) with
H2NNH2 (4.0 mL) and Pd/C (4.0 g) at 0°C for 2 h.
After vacuum filtration and evaporation of the THF
the crude yellow oil was dissolved in 50 mL CH2Cl2 to
prepare a 0.1 M stock solution. 10 mL Aliquots of this
stock solution were then immediately subjected to acid-
promoted condensation with p-tert-butylphenol to
optimize formation of diphenylamine 6 (Scheme 2). The
reaction conditions examined and two-step yields for
the conversion of 4 into 6 are shown in Table 1.

J. D. Spence et al. / Tetrahedron Letters 44 (2003) 849–851
851
tinely be isolated as a tan oil in a 50–60% two-step
6; The Royal Society of Chemistry: Cambridge, 1998; (b)
Gutsche, C. D. In Calixarenes; Stoddart, J. F., Ed.;
Monographs in Supramolecular Chemistry No. 1; The
Royal Society of Chemistry: Cambridge, 1989.
2. Gutsche, C. D.; Dhawan, B.; No, K. H.; Muthukrishnan,
R. J. Am. Chem. Soc. 1981, 103, 3782.
yield.†
The methyl protecting group in 6 was removed by
treatment with BBr3 at 0°C to afford 5,5%-di-tert-butyl-
2,2%-dihydroxydiphenylamine 7‡ in 81% yield after chro-
matography (Scheme 2). Care must be taken in the
demethylation step to avoid removal of the tert-butyl
substituent which occurred upon warming to room
temperature. While diphenylamine 6 is air stable, 7
required storage under nitrogen and rapidly decom-
posed to a complex mixture of products upon exposure
3. Bo¨hmer, V.; Merkel, L.; Kunz, U. J. Chem. Soc., Chem.
Commun. 1987, 896.
4. (a) Scully, P. A.; Hamilton, T. M.; Bennett, J. L. Org.
Lett. 2001, 3, 2741; (b) Bergamaschi, M.; Bigi, F.; Lan-
franchi, M.; Maggi, R.; Pastorio, A.; Pellinghelli, M. A.;
Peri, F.; Porta, C.; Sartori, G. Tetrahedron 1997, 53,
13037; (c) Biali, S. E.; Bo¨hmer, V.; Cohen, S.; Ferguson,
G.; Gru¨ttner, C.; Grynszpan, F.; Paulus, E. F.; Thon-
dorf, I.; Vogt, W. J. Am. Chem. Soc. 1996, 118, 12938.
5. For a review, see: Iki, N.; Miyano, S. J. Inclusion Phe-
nom. Macrocycl. Chem. 2001, 41, 99.
6. (a) For homocalixarenes, see: Ibach, S.; Prautzsch, V.;
Vo¨gtle, F.; Chartroux, C.; Gloe, K. Acc. Chem. Res.
1999, 32, 729; (b) For dihomooxacalixarene, see:
Dhawan, B.; Gutsche, C. D. J. Org. Chem. 1983, 48,
1536; (c) For dihomoazacalixarenes, see: Khan, I. U.;
Takemura, H.; Suenaga, M.; Shinmyozu, T.; Inazu, T. J.
Org. Chem. 1993, 58, 3158.
1
to acid. The H NMR spectrum of 7 indicated that the
diphenylamine adopts a non-planar conformation (7a)
in solution whereby the two aryl rings are non-equiva-
lent.11 The room temperature spectra showed
anisochronous signals for the 6,6%-hydrogens at l 6.61
and 6.15 in DMSO-d6 along with two singlets for the
tert-butyl substituents at l 1.24 and 1.23.
The procedure described here allows the incorporation
of nitrogen-bridges between aryl units derived from
para-substituted phenols and utilization of this conden-
sation strategy for the preparation of aza-bridged calix-
arenes will be reported elsewhere.
7. Shudo, K.; Ohta, T.; Okamoto, T. J. Am. Chem. Soc.
1981, 103, 645.
8. For a discussion of the Bamberger rearrangement, see:
Shine, H. J. In Aromatic Rearrangements; Eaborn, C.;
Chapman, N. B., Eds.; Reaction Mechanisms in Organic
Chemistry Monograph 6; Elsevier: New York, 1967, pp.
182–190.
9. Hudlicky´, M. In Reductions in Organic Chemistry; ACS
Monograph 188; American Chemical Society: Washing-
ton, DC, 1996, pp. 94.
Acknowledgements
This work was funded by grants from the Welch Foun-
dation (W-0031) and the NSF-REU program (CHE-
9820176). Mass spectra were obtained at the MSU
Mass Spectrometry Facility.
10. For a theoretical discussion on C-/N-substitution, see:
Moran, R. J.; Cramer, C.; Falvey, D. E. J. Org. Chem.
1997, 62, 2742.
References
1. (a) Gutsche, C. D. In Calixarenes Revisited; Stoddart, J.
11. Boyle, A. Theochem 1999, 469, 15.
F., Ed.; Monographs in Supramolecular Chemistry No.
† General experimental procedure: To a stirred solution of 4-tert-
butyl-2-nitroanisole (0.210 g, 1.0 mmol) in THF (30 mL) at 0°C was
added 5% Pd/C (0.8 g) and hydrazine (0.8 mL). After stirring 2 h
the solution was filtered, dried and evaporated to a yellow oil. The
crude oil was dissolved in CH2Cl2 (10 mL) and p-tert-butylphenol
(0.750 g, 5.0 mmol) was added followed by trifluoroacetic acid (0.2
mL, 2.5 mmol) and the solution was stirred overnight. The solution
was then diluted with ether, transferred to a separatory funnel and
washed sequentially with 5% HCl, water, saturated aqueous
NaHCO3, saturated aqueous NaCl, dried and evaporated. Excess
p-tert-butylphenol was removed by sublimation and column chro-
matography (5% EtOAc/hexane) on the residual oil afforded
diphenylamine 6 (0.197 g, 60%) as a tan oil: 1H NMR (300 MHz,
CDCl3) l 7.28 (d, 2H, J=8.9 Hz), 6.84 (d, 2H, J=8.9 Hz), 6.77 (s,
1H), 6.40 (s, 1H), 3.69 (s, 3H), 3.1 (br s, 2H), 1.32, (s, 9H), 1.31 (s,
9H); 13C NMR (75 MHz, CDCl3) l 156.5, 146.5, 145.9, 144.2,
133.9, 131.4, 126.2, 116.5, 113.7, 105.3, 55.7, 34.1, 34.0, 31.5, 30.5;
IR (neat) 3464, 3376, 1603, 1503, 1223, 1073, 877, 831 cm−1; HRMS
C21H29NO2 (FAB) calcd 327.2198, found 327.2191.
‡ Data for compound 7: 1H NMR (300 MHz, DMSO-d6) l 8.91 (s,
1H), 7.30 (d, 2H, J=8.7 Hz), 6.78 (d, 2H, J=8.7 Hz), 6.61 (s, 1H),
6.15 (s, 1H), 4.29 (s, 2H), 1.24 (s, 9H), 1.23 (s, 9H); 13C NMR (75
MHz, DMSO-d6) l 156.4, 144.9, 143.9, 142.7, 131.9, 131.2, 126.4,
116.7, 113.0, 108.0, 34.0, 33.7, 31.4, 30.6; IR (neat) 3373, 3311,
1602, 1502, 1226, 876, 834 cm−1; HRMS C20H27NO2 (FAB) calcd
313.2042, found 313.2046.