N-Boc-O-tosyl hydroxylamine as a safe and efficient nitrogen source for the N-amination of aryl and alkyl amines: Electrophylic amination

Article abstract of DOI:10.1055/s-0030-1261170

β-Boc-protected aryl and alkyl hydrazines, useful intermediates for azapeptides and N-substituted pyrazoles, were synthesized by electrophylic amination methodology, using less energetic N-Boc-O-tosyl hydroxylamine as an efficient nitrogen source. Also we have demonstrated a two-step, chromatography-free synthesis of N-Boc-O-tosyl hydroxylamine. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261170

LETTER
1993
N-Boc-O-Tosyl Hydroxylamine as a Safe and Efficient Nitrogen Source for the
N-Amination of Aryl and Alkyl Amines: Electrophylic Amination
N
-Amination of
h
A
ryl and Al
a
kyl Amines
n
Using
N
-Bo
k
c-
O
-Tosyl
H
a
ydroxylam
p
ine pan Baburaj,a Sivalingam Thambidurai*b
a
Anthem Biosciences Pvt. Ltd., Bommasandra Industrial Area, Phase I, 49, Canara Bank Road, Bangalore 560 099, India
Department of Industrial Chemistry, Alagappa University, Karaikudi 630 003, India
Fax +91(4565)225202; E-mail: sthambi01@yahoo.co.in
b
Received 26 April 2011
amines gave good to excellent yields with 1 (Figure 1),
whereas in the case of primary amines, the reactive
byproduct 4-cyanobenzaldehyde generated from 1 in-
volved in competitive side reaction resulting the forma-
Abstract: b-Boc-protected aryl and alkyl hydrazines, useful inter-
mediates for azapeptides and N-substituted pyrazoles, were synthe-
sized by electrophylic amination methodology, using less energetic
N-Boc-O-tosyl hydroxylamine as an efficient nitrogen source. Also
we have demonstrated a two-step, chromatography-free synthesis tion of unwanted imines as side products, resulting in the
loss of isolated yields of required products.12 In the case
of N-Boc-O-tosyl hydroxylamine.
of other reagents 2 and 3, the synthesis of the reagents it-
self is a multistep synthesis and not efficient in a small
scale.
Key words: electrophylic amination, b-Boc-alkylhydrazines, b-
Boc-arylhydrazines, N-Boc-O-tosyl hydroxylamine, azapeptides
O
O
O
Terminal tert-butoxycarbonyl (Boc)-protected aryl and
alkyl hydrazines are useful intermediates for azapeptides,
by reacting it with isocyanates of amino acids or, by acti-
vating it as a suitable carbamate derivative, followed by
reacting it with amino acids.1–3 These intermediates are
also useful for the synthesis of 1-alkyl or arylpyrazoles by
reacting with 1,3-dicarbonyl compounds, after deprotect-
ing with standard reaction conditions4 (Scheme 1).
MeO2C
N
Cl
Cl
N
N
Boc
Boc
Boc
CO2Me
Cl
1
3
NC
2
Figure 1 Structures of 1, 2, and 3
In an effort to find a suitable aminating agent, we screened
the literature reports, and we could find that most of the
derivatives of aminating agent 4 (Figure 2) are not safe to
handle because of the unstable or explosive nature, and
even some of them can detonate.13 N-Boc-O-tosyl hydrox-
ylamine (5),14 has been used as an aminating agent after
lithiation (5a), as a source of NH-Boc, for the electro-
philic amination of Grignard reagents and carbonyl com-
pounds having highly acidic protons.15 As the synthesis
and handling of this protected aminating agent is relative-
ly easy and safe when compared to the hazard involved in
the other aminating agents, we felt using 5 for our study
towards N-amination.
R3
R4 NCO
or
O
H+
NHBoc
R1NHNHBoc
R2
R4NH
N
R1
N
R2
O
O
O
N
R1
R4HN
X
R3
azapeptide
X = leaving group
pyrazole
Scheme 1 Synthetic applications of b-Boc-hydrazines
To our knowledge direct amination of anilines by electro-
phylic amination is not well documented, probably be-
cause of the poor nucleophilicity of anilines or the
inefficiency of available electrophilic aminating agents.
Anilines are converted to corresponding N-aryl hydra-
zines mostly by diazotization followed by reducing the re-
sulting diazonium salt by suitable reducing agents5 such
as SnCl2.6 The tedious workup procedure and isolation of
highly polar, water-soluble hydrazines is the major disad-
vantage of this method. However, N-amination of hetero-
R3
O
O
O
H2N
O
N
R
Ts
R1
R2
4
5
5
R = H
5a R = Li
cycles
can
be
achieved
by
O-(diphenyl-
Figure 2 Structures of 4 and 5
phosphinyl)hydroxylamine,7 chloramine,8 or by O-
arylhydrroxylamines9 with isolated yields ranging from
45–97%. Oxaziridine derivatives 1,10 2,11 and 34 were
used as very good reagents for electrophilic amination of
alkyl amines and amino acid derivatives. Secondary
As the initial task towards our study, we have synthesized
N-Boc hydroxylamine by avoiding tert-butyl azidofor-
mate.14 This hazardous reagent was readily replaced with
(Boc)2O without any difficulty, by treating commercially
available cheap aqueous hydroxylamine and (Boc)2O in
the presence of a base.16 The crude N-Boc hydroxylamine
obtained was taken as such for tosylation using dichlo-
SYNLETT 2011, No. 14, pp 1993–1996
Advanced online publication: 10.08.2011
DOI: 10.1055/s-0030-1261170; Art ID: B08111ST
x
x
.x
x
.2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

1994
T. Baburaj, S. Thambidurai
LETTER
romethane as solvent and N-methylmorpholine (NMM) as
base at 0 °C, and the residue was purified by recrystalliza-
tion, to get the pure product 5 as white crystalline solid
(Scheme 2).17 As most of the reported electrophilic ami-
nating agents are potential explosives, we decided to
study the safety aspects of 5, before using it for trials.
Table 1 Electrophylic Amination of Aryl Amines by 5
BocHNOTs
ArNH2
ArNHNHBoc
DMF, K2CO3
3a–l
Entry
1
ArNH2
Product Time (h) Yield (%)
NH2
F
(ii) MeOH, NaHCO3
3a
3b
3c
2
2
2
84
88
82
(Boc)2O, 10 °C to r.t., 2 h
HN2OH
BocHNOTs
(ii) TsCl, NMM, CH2Cl2
0 °C to r.t., 2 h
5
NH2
2
3
Scheme 2 Synthesis of 5
I
Cl
NH2
The differential scanning calorimetry results of 5 showed
that the decomposition energy was 215 J/g with an onset
temperature of 95 °C, which is much lesser than the de-
composition energy of derivatives of 4 (>1200 J/g to ca.
2300 J/g).18,8a With this motivating information, we
screened the possibility of N-amination of anilines first,19
and of the various reaction conditions tried, the combina-
tion of p-anisidine, potassium carbonate and N,N-dimeth-
ylformamide was found to be more efficient (Scheme 3).
Cl
NH2
4
5
3d
3e
16
3
68
82
NH2
NH2
O
H
6
3f
2
90
N
NH2
N
O
BocNHOTs
H
DMF, K2CO3
F3C
NH2
NH2
MeO
MeO
7
8
3g
3h
3i
2
2
85
89
83
72
86
Scheme 3 Electrophylic amination of anilines by 5
The product was isolated just by adding water into the re-
action mixture and by collecting the solid product by fil-
tration.20 The reactivity of anilines are subject to steric and
electronic factors of anilines. In the case of 2,6-dimethyl-
aniline and p-nitro aniline the reaction took longer time to
complete, and the yields are also slightly lower than other
anilines. Heteroaryl amines also afforded the required
products with good yields. The presence of a Boc group in
5, not only facilitated the product formation, but also the
isolation of products. The reaction time and yields of var-
ious amines studied are reported in Table 1.
MeO
O2N
NH2
NH2
9
2
10
11
3j
16
2
O2N
NH2
NH2
3k
N
N
To study the reactivity of 5 with aliphatic amines, mor-
pholine was treated with these reaction conditions, and we
could observe that the isolated product was contaminated
with N,N-dimethylformamide. When we attempted to re-
move N,N-dimethylformamide completely by repeat wa-
ter wash, we lost sufficient quantity of product. To avoid
this, we changed the reaction medium to dichloromethane
and aliphatic tertiary amine based bases, of that 4-methyl-
morpholine was found to be more efficient. Various pri-
mary and secondary amines afforded product with
excellent yield under these reaction conditions.21 Benzyl-
amines and heteroarylmethylamines also reacted to give
the product in excellent yields (Table 2).
12
3l
2
78
N
In conclusion we demonstrated a very efficient procedure
for terminal protected aryl and alkyl hydrazines by elec-
trophilic amination strategy. These protected hydrazines
can be used as very good intermediates for aza peptides
and other heterocyclic analogues.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 14, 1993–1996 © Thieme Stuttgart · New York

LETTER
N-Amination of Aryl and Alkyl Amines Using N-Boc-O-Tosyl Hydroxylamine
1995
(8) (a) Hynes, J. Jr.; Doubleday, W. W.; Dyckman, A. J.;
Table 2 Electrophylic Amination of Aliphatic Amines by 5
Godfrey, J. D. Jr.; Grosso, J. A.; Kiau, S.; Leftheris, K.
J. Org. Chem. 2004, 69, 1368. (b) Bhattacharya, A.; Patel,
N. C.; Plata, R. E.; Peddicord, M.; Ye, Q.; Parlanti, L.;
Palaniswamy, V. A.; Grosso, J. A. Tetrahedron Lett. 2006,
47, 5341.
BocHNOTs
R1NHR2
R1NR2NHBoc
CH2Cl2, NMM
4a–l
Entry
1
R1NHR2
Product Time (h) Yield (%)
(9) Parlanti, L.; Discordia, R. P.; Hynes, J. Jr.; Miller, M. M.;
O’Grady, H. R.; Shi, Z. Org. Lett. 2007, 9, 3821.
(10) (a) Vidal, J.; Damestoy, S.; Guy, L.; Hannachi, J. C.; Aubry,
A.; Collet, A. Chem. Eur. J. 1997, 3, 1691. (b) Vidal, J.;
Guy, L.; Sterins, S.; Collet, A. J. Org. Chem. 1993, 58, 4791.
(11) Vidal, J.; Hannachi, J. C.; Hourdin, G.; Mlatier, J. C.; Collet,
A. Tetrahedron Lett. 1998, 39, 8845.
(12) Vidal, J.; Guy, L.; Sterin, S.; Collet, A. J. Org. Chem. 1993,
58, 4791.
(13) Radhakrishna, A. S.; Loudon, G. M.; Miller, M. J. J. Org.
Chem. 1979, 44, 4836.
4a
4b
18
18
92
88
O
NH
2
NH
3
4
4c
18
18
82
87
NH2
NH2
NH2
4d
(14) Carpino, L. A.; Giza, C. A.; Carpino, B. A. J. Am. Chem.
5
6
7
4e
4f
18
18
18
85
88
71
Soc. 1959, 81, 955.
(15) Genet, J. P.; Mallart, S.; Greck, C.; Piveteau, E. Tetrahedron
Lett. 1991, 32, 2359.
(16) Andrews, D. M.; Foote, K. M.; Matusiak, Z. M.; Arnould,
J. C.; Boutron, P.; Delouvrie, B.; Delvare, C.; Hamon, A.;
Harris, C. S.; Lambert-van der Brempt, C.; Lamorlette, M.
Tetrahedron 2009, 65, 5805.
NH2
4g
NH2
8
9
4h
4i
18
18
86
89
(17) Typical Procedure for 5
NH2
To a stirred solution of hydroxylamine (25 mL, 40% w/v, 0.3
mol) in MeOH (100 mL) was added NaHCO3 (27.7 g, 0.33
mol) and then (Boc)2O (72.0 g, 0.33 mol) dropwise over a
period of 30 min, by maintaining the reaction temperature at
20–25 °C. After stirring the reaction mixture at 25 °C for 5
h, MeOH was removed under vacuum, and the residue was
diluted with H2O (200 mL) and extracted with EtOAc
(2 × 100 mL). The combined organic layer was dried over
Na2SO4 and concentrated. The crude Boc-hydroxylamine
obtained was diluted with CH2Cl2 (200 mL), cooled to 0 °C
and was added NMM (60.6 g, 0.6 mol) and then tosyl
chloride (63 g, 0.33 mol) in CH2Cl2 (200 mL), dropwise over
a period of 1 h. After stirring at r.t. for 3 h, the reaction
mixture was diluted with H2O (500 mL), and the organic
layer was separated, washed with H2O (250 mL), 5% citric
acid solution in H2O (2 × 100 mL), dried over Na2SO4 and
concentrated. The resulting residue was crystallized from
20% EtOAc in PE to afford the pure product as white solid.
1H NMR (300 MHz, CDCl3): d = 1.32 (s, 9 H), 2.48 (s, 3 H),
7.38 (d, J = 8.4 Hz, 2 H), 7.61 (s, 1 H), 7.90 (d, J = 8.4 Hz,
2 H). 13C NMR (75 MHz, CDCl3): d = 21.7, 27.7, 83.8,
129.6, 129.7, 130.7, 146.0, 154.3.
NH2
NH2
10
4j
18
82
11
12
4k
4l
18
18
87
84
N
NH2
NH2
S
Acknowledgment
One of the authors Thankappan Baburaj acknowledges his thanks to
Anthem Biosciences Pvt. Ltd., Bangalore, India, for infrastructure.
(18) Boyles, D. C.; Curran, T. T.; Parlett, R. V. IV Org. Process
Res. Dev. 2002, 6, 230.
References
(19) Even though 5 is less energetic compared to other aminating
reagents, keeping safety as priority we carried out all
reactions and workup at temperatures below 50 °C.
(20) Typical Procedure for Aryl Amines (Method A)
To a stirred solution of 4-methoxyaniline (1 g, 8.13 mmol)
in DMF (10 ml) was added K2CO3 (1.46 g, 10.57 mmol), and
the reaction mixture was cooled to ca. 10 °C. To this was
added BocNHOTs (2.8 g, 9.76 mmol) and stirred at r.t. for 2
h. Reaction mixture was diluted with H2O, and the resulting
solid was filtered and dried under suction. The dried solid
was crystallized from 3% EtOAc in PE to afford the pure
product as brown solid. 1H NMR (300 MHz, CDCl3): d =
1.34 (s, 9 H), 3.81 (s, 3 H), 6.68 (br s, 1 H), 6.89 (dd, J = 9.0,
2.1 Hz, 2 H), 7.38 (dd, J = 9.0, 2.1 Hz, 2 H), 7.44 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 26.4, 55.5, 81.4, 114.3,
121.8, 130.3, 156.3, 158.5. LC-MS: m/z = 239.3 [M + H+].
(1) (a) Melendez, R. E.; Lubell, W. D. J. Am. Chem. Soc. 2004,
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(7) Bodio, E. Synlett 2008, 1744; and references cited therein.
Synlett 2011, No. 14, 1993–1996 © Thieme Stuttgart · New York

1996
T. Baburaj, S. Thambidurai
LETTER
(21) Typical Procedure for Alkyl Amines (Method B)
To a stirred solution of morpholine (0.5 g, 5.74 mmol) in
CH2Cl2 (10 mL) was added NMM (0.75 g, 7.46 mmol), and
the reaction mixture was cooled to ca. 10 °C and then added
BocNHOTs (1.98 g, 6.90 mmol), and the reaction mixture
was stirred at r.t. for 18 h. Reaction mixture was diluted with
H2O and extracted with CH2Cl2 (2 × 10 mL). The combined
organic layer was dried over Na2SO4 and concentrated. The
crude obtained was purified by flash column chromatog-
raphy to get the pure product as yellow liquid. 1H NMR (300
MHz, CDCl3): d = 1.27 (s, 9 H), 3.42 (t, J = 4.8 Hz, 4 H),
3.70 (t, J = 4.8 Hz, 4 H), 6.86 (br s, 1 H). 13C NMR (75 MHz,
CDCl3): d = 26.3, 43.9, 66.4, 80.4, 159.9. LC-MS: 203.3
[M + H+].
Synlett 2011, No. 14, 1993–1996 © Thieme Stuttgart · New York

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