Practical and efficient synthesis of N-halo compounds

Article abstract of DOI:10.1016/j.tetlet.2004.12.088

A practical and efficient synthesis of N-halo compounds is described. Treatment of primary and secondary amines or amides with sodium hypohalite in the presence of tert-butanol and acetic acid afforded N-halo compounds in 90-100% yield.

Full text of DOI:10.1016/j.tetlet.2004.12.088

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1099–1101
Practical and efficient synthesis of N-halo compounds
Yong-Li Zhong,* Hua Zhou, Donald R. Gauthier, Jr., Jaemoon Lee, David Askin,
Ulf H. Dolling and Ralph P. Volante
Department of Process Research, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
Received 6 December 2004; accepted 17 December 2004
Abstract—A practical and efficient synthesis of N-halo compounds is described. Treatment of primary and secondary amines or
amides with sodium hypohalite in the presence of tert-butanol and acetic acid afforded N-halo compounds in 90–100% yield.
Ó 2005 Published by Elsevier Ltd.
N-Halo compounds are versatile reagents and have been
employed as potentially reactive intermediates that are
widely used in organic synthesis.1 Numerous methods
utilizing an electrophilic halogen source have been stud-
ied to achieve the N-halogenation of amines and
amides.2 Sodium hypohalites (bleach and NaOBr),
tert-butyl hypochlorite, and N-halo succinimides (NCS
and NBS) are the most common reagents used to per-
form this N–H to N–X oxidation. However, these re-
agents have several limitations, which curtail their use.
NCS and NBS are widely used as N-halogenating re-
agents, but removal of the succinimide by-product is of-
ten difficult.3 Sodium hypochlorite is a safe, inexpensive
commodity chemical, although R2N–H oxidations typi-
cally suffer from prolonged reaction times with modest
yields. N-halogenation with tert-butyl hypochlorite
generally provides good to excellent yields; however,
tert-butyl hypochlorite is an expensive, hazardous
reagent2d,4 that is best suited for small scale research
applications.
with the dropwise addition of the oxidant. The amine
or amide in an organic solvent such as EtOAc, IPAc,
MTBE or toluene reacts with the organic soluble tert-
butyl hypohalite to give the desired N–X product
(Scheme 1). The N–H oxidation occurs rapidly with
amines, and the resulting exotherm is then controlled
by the slow addition of sodium hypohalite to avoid
the large buildup of tert-butyl hypohalite. This feature
makes the protocol particularly attractive for industrial
scale processing given the low concentration of tert-
butyl hypohalite at any given time.
NaOX/t-BuOH
R1
R2
R1
R2
N
X
N
H
AcOH, MTBE
0 oC, 15 min. to 2 h
90-100%
X = Br, Cl
Scheme 1.
The scope of this new protocol was investigated and all
substrates shown in Table 1 were converted to N-halo
compounds in high yield. The substrates were dissolved
in the organic solvent along with 0.25–1 equiv of tert-
butanol. Then, 1–1.5 equiv of sodium hypohalite
(0.75 M or 0.5 M) and 1–1.5 equiv of acetic acid were
added dropwise at 0 °C. Under these conditions, the
reaction was typically completed within 15 to 30 min
for amines and 1 to 2 h for amides.5 Secondary amides
including sulfomaide (entries 1–5, 17) were oxidized to
the corresponding N-halo compounds in very high yield.
Amine hydrochloride salts (entries 8 and 9, 15 and 16)
can be oxidized to the corresponding N-chloro and
N-bromo compounds in the absence of acetic acid. An
Herein, we present a new and efficient protocol for the
preparation of N-halo compounds via the in situ gener-
ation of tert-butyl hypohalite. Organic solutions of
amines and amides are treated with aqueous sodium
hypohalite (NaOCl or NaOBr) in the presence of tert-
butanol and acetic acid. Under these biphasic condi-
tions, tert-butyl hypohalite is slowly generated in situ
Keywords: Amine oxidation; Amide oxidation; N-halogenation; Sodi-
um hypohalite; tert-Butyl hypohalite.
*
Corresponding author. Tel.: +1 732 594 8372; fax: +1 732 594
5170; e-mail: yongli_zhong@merck.com
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.12.088

1100
Y.-L. Zhong et al. / Tetrahedron Letters 46 (2005) 1099–1101
Table 1. Synthesis of N-halo compound
Entry
1
Substrate
Product
NaOX
(equiv)a
t-BuOH
(equiv)
AcOH
(equiv)
Solventb
Toluene
reaction
time (h)
Yield (%)c
100
1
1
1
2
N
O
N
Cl
O
1
H
O
N
O
2
3
1
1
0.5
0.5
1
1
IPAc
IPAc
1
1
99
99
N
Cl
2
H
O
N
CO2Et
O
O
3
CO2Et
O
N
Cl
H
BnO2C
BnO2C
N
N
4
5
1.5
1.5
0.5
0.5
1.5
1.5
IPAc
MTBE
1
1
100
98
X
4: X = Cl
5: X = Br
H
6
7
1
1
0.5
0.5
1
1
MTBE
MTBE
0.5
0.5
100
100
N
H
N
Cl
6
N
H
N
7
Cl
CO2Bn
CO2Et
N
X
CO2Bn
H. HCl
N
8
9
1
1
1
1
—
—
MTBE
MTBE
0.25
0.5
100
90
8: X = Cl
9: X = Br
10
1
0.5
1
MTBE
0.5
100
N
H
CO2Et
N
Cl
10
N
X
11
12
1
1.2
0.25
1
1
1.2
MTBE
MTBE
0.5
0.5
100
94
CO2Et
N
H
H
CO2Et
11: X = Cl
12: X = Br
CONH2
CONH2
N
X
13
14
1
1
1
1
1
1
EtOAc
EtOAc
0.5
1
90
90
N
13: X = Cl
14: X = Br
MeO
MeO
MeO
N
15
16
17
1
0.25
0.5
1
—
—
1.5
IPAc
0.5
1
100
96
N
MeO
Cl
H. HCl
15
Cl
NH
NH2. HCl
CO2Et
1
MTBE
IPAc
Ph
16
Ph
CO2Et
O
O
O
O
S
S
1.5
0.5
92
N
H
N
17
Cl
a Sodium hypochlorite solution (0.75 M) and 0.5 M of sodium hypobromide was used.
b IPAc = isopropyl acetate; MTBE = tert-butyl methyl ether; EtOAc = ethyl acetate.
c Isolated yields were obtained via evaporation of solvents to give desired products which were determined to be >95% pure by 1H NMR.

Y.-L. Zhong et al. / Tetrahedron Letters 46 (2005) 1099–1101
1101
J. Heterocycl. 1982, 19, 653–656; (k) Claxton, G. P.; Allen,
L.; Grisar, J. M. Org. Synth. 1988, 67, 968; (l) Arakawa, Y.;
Yoshifuji, S. Chem. Pharm. Bull. 1991, 39, 2219–2224; (m)
Snider, B. B.; Liu, T. J. Org. Chem. 1997, 62, 5630–5633;
(n) Zhao, M. M.; McNamara, J. M.; Ho, G.-J.; Emerson,
K. M.; Song, Z. J.; Tschaen, D. M.; Brands, K. M. J.;
Dolling, U. H.; Grabowski, E. J. J.; Reider, P. J. J. Org.
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amino amide (entries 13 and 14) was selectively oxidized
at the amine N–H. Finally, a primary amine (entry 16)
was selectively monochlorinated in 96% yield. Dichlori-
nated product was not detected.
In summary, we have developed a practical, efficient and
scaleable synthesis for the preparation of a wide range
N-halo compounds.6 tert-Butyl hypohalite is generated
in situ by treatment of sodium hypohalite with tert-buta-
nol in the presence of acid. The reaction is carried out
under mild conditions and produces N-halo compounds
in excellent purity and high yield. This method offers an
alternative to hazardous tert-butyl hypochlorite and
should find wide use for the oxidation of amines and
amides.
3. Fieser, M. In Reagents for Organic Synthesis; John Wiley
and Sons: New York, 1982; Vol. 10, p 67.
4. Paquette, L. A. In Encyclopedia of Reagents for Organic
Synthesis; John Wiley and Sons: New York, 1995; Vol. 2, p
890.
5. Typical procedure for the preparation of N-halo com-
pounds: To a solution of amine or amide (5.0 mmol), tert-
butanol (0.25–1 equiv) in MTBE was slowly added acetic
acid (1–1.5 equiv) and sodium hypohalite (1–1.5 equiv) at
À5 to 0 °C at the same time. The resulting solution was
aged at 0 °C for 15 min to 2 h. The organic layer was
separated, washed with water, and then brine. The organic
solution was concentrated to give desired N-halo com-
pound in 90–100% yield.
References and notes
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6. All new compounds gave satisfactory analytical and spec-
tral data in accordance to their structures. Selected data for
compound 4: 1H NMR (400 MHz, CDCl3) d: 7.44–7.34 (m,
5H), 5.27 (s, 2H), 4.53 (dd, J = 5.9, 2.7 Hz, 1H), 3.40 (dd,
J = 13.6, 5.9 Hz, 1H), 3.21 (dd, J = 13.6, 2.7 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d: 168.1, 164.8, 134.7, 128.9 (2C),
1
128,8, 128.5 (2C), 68.0, 57.4, 43.4. Compound 5: H NMR
(400 MHz, CDCl3) d: 7.40–7.30 (m, 5H), 5.21 (s, 2H), 4.27
(dd, J = 5.9, 2.7 Hz, 1H), 3.46 (dd, J = 13.3, 5.9 Hz, 1H),
3.29 (dd, J = 13.3, 2.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d: 168.5, 166.0, 134.7, 128.7 (2C), 128.5, 127.0.
Compound 15: 1H NMR (400 MHz, CDCl3) d: 6.58 (s, 2H),
4.19 (q, J = 6.6 Hz, 1H), 3.85 (s, 6H), 3.63 (m, 1H), 3.38 (m,
1H), 3.00–2.89 (m, 2H), 1.56 (d, J = 6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d: 148.0, 147.7, 129.7, 124.5, 111.1,
1
109.7, 65.3, 56.1, 55.9, 55.3, 27.1, 21.6. Compound 16: H
NMR (400 MHz, CDCl3) d: 7.39–7.19 (m, 3H), 7.12 (br d,
J = 7.0 Hz, 2H), 4.62 (d, J = 9.2 Hz, 1H), 4.20 (q, J =
7.2 Hz, 2H), 3.89 (td, J = 9.2, 6.8 Hz, 1H), 3.04
(d, J = 6.8 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d: 171.9, 135.8, 129.2 (2C), 128.6 (2C),
127.1, 68.4, 61.5, 37.9, 14.1.