Aminochlorination in water: First Bronsted acid-promoted synthesis of vicinal chloramines

Article abstract of DOI:10.1021/jo701957t

A practical and scaleable route for the regio- and diastereo-selective synthesis of vicinal chloramines from electron-deficient olefins and Chloramine-T promoted by Bronsted acids in water has been realized for the first time. This novel protocol is effic

Full text of DOI:10.1021/jo701957t

by the use of several different nitrogen/chlorine sources such
as 4-TsNCl2,3a,c,e-h,j 2-NsNNaCl,3d or the combination of
2-NsNCl2 and 2-NsNHNa3b,i in the presence of metal catalysts.5
However, most of these systems involve toxic solvents and
transition metal catalysts. The use of more readily available and
nontoxic catalysts instead of expensive and sensitive catalysts
as well as non-organic solvents is highly desirable.
A metal-free aminochlorination reaction of chalcones with
2-NsNCl2 in ionic liquid was reported very recently.6 But the
reaction was performed in a dried and heated system, and a
large quantity of ionic liquid and other additives was employed
to achieve high selectivity and yield. We7 also reported the
aminochlorination of electron-deficient olefins using com-
mercially available inexpensive Chloramine-T8 as a nitrogen
and chlorine source promoted by (diacetoxyiodo)benzene under
our mechanical milling conditions.9 This methodology was very
convenient and easy to handle; however, the relatively expensive
hypervalent iodine reagent was used in 50 mol %, and therefore
greatly restricted its application. Thus, we were triggered to
develop more economical and environmentally friendly systems
for this transformation.
Aminochlorination in Water: First Brønsted
Acid-Promoted Synthesis of Vicinal Chloramines
Xue-Liang Wu and Guan-Wu Wang*
Hefei National Laboratory for Physical Sciences at Microscale,
Joint Laboratory of Green Synthetic Chemistry, and Department
of Chemistry, UniVersity of Science and Technology of China,
Hefei, Anhui 230026, People’s Republic of China
gwang@ustc.edu.cn
ReceiVed September 5, 2007
On the other hand, performing organic reactions in more
environmentally benign ways is an important goal from an
ecological point of view.10 Utilizing water as the reaction media
has attracted many synthetic organic chemists because it is one
of the best ways to avoid many environmental problems that
can occur with industrial organic synthesis.11 In our previous
work, we disclosed that various Lewis acids could promote the
aminochlorination of electron-deficient olefins.7 We envisioned
that Brønsted acids, which are cheaper and more readily
available, may facilitate this transformation. In continuation of
A practical and scaleable route for the regio- and diastereo-
selective synthesis of vicinal chloramines from electron-
deficient olefins and Chloramine-T promoted by Brønsted
acids in water has been realized for the first time. This novel
protocol is efficient, mild, ecofriendly, and broadly applicable
for the aminochlorination of various electron-deficient olefins
including R,â-unsaturated ketones, cinnamate, and cinna-
mide. Water represents as a privileged solvent for the ami-
nochlorination reaction in our system.
(4) For selected examples, see: (a) Bach, T.; Schlummer, B.; Harms,
K. Chem. Commun. 2000, 287. (b) Minakata, S.; Kano, D.; Oderaotoshi,
Y.; Komatsu, M. Org. Lett. 2002, 4, 2097. (c) Thakur, V. V.; Talluri, S.
K.; Sudalai, A. Org. Lett. 2003, 5, 861. (d) Tsuritani, T.; Shinokubo, H.;
Oshima, K. J. Org. Chem. 2003, 68, 3246. (e) Qi, X.; Lee, S. H.; Kwon, J.
Y.; Kim, Y.; Kim, S. J.; Lee, Y. S.; Yoon, J. J. Org. Chem. 2003, 68,
9140. (f) Nadir, U. K.; Singh, A. Synth. Commun. 2004, 34, 1337.
(5) For a recent review on aminohalogenation of electron-deficient
olefins, see: Li, G.; Kotti, S. R. S. S.; Timmons, C. Eur. J. Org. Chem.
2007, 2745.
(6) Wang, Y.-N.; Ni, B.; Headley, A. D.; Li, G. AdV. Synth. Catal. 2007,
349, 319.
(7) Wang, G.-W.; Wu, X.-L. AdV. Synth. Catal. 2007, 349, 1977.
(8) For a review on Chloramines-T, see: Campbell, M. M.; Johnson, G.
Chem. ReV. 1978, 78, 65. For a recent report on aminochlorination of
styrenes with Chloramines-T, see: Minakata, S.; Yoneda, Y.; Oderaotoshi,
Y.; Komatsu, M. Org. Lett. 2006, 8, 967.
Vicinal haloamines obtained from the aminohalogenation of
unsaturated carbon-carbon bonds are an important class of
compounds that serve as useful intermediates of various
pharmacologically active compounds by replacement of the
halogen atom with multifarious nucleophiles.1 Although the
aminohalogenation reaction has been known for about 40 years,
the preparation of vicinal haloamine derivatives still confronts
significant limitations.2 Recently, various procedures for the
aminohalogenation of electron-deficient olefins have been
successfully established by Li3 and others.4 A series of R,â-
unsaturated ketones,3g esters,3a-e and nitriles3j have been ami-
nochlorinated with good yield and excellent diastereoselectivity
(9) For a review, see: Wang, G.-W. Fullerene Mechanochemistry. In
Encyclopedia of Nanoscience and Nanotechnology; Nalwa, H. S., Ed.;
American Scientific Publishers: Stevenson Ranch, 2004; Vol. 3, p 557.
For mechanochemical nonfullerene reactions, see: (a) Zhang, Z.; Miao,
C.-B.; Wang, G.-W.; Dong Y.-W.; Shen, Y.-B. Chem. Commun. 2004, 1832.
(b) Zhang, Z.; Dong, Y.-W.; Wang, G.-W.; Komatsu, K. Synlett 2004, 61.
(c) Zhang, Z.; Gao, J.; Xia, J.-J.; Wang, G.-W. Org. Biomol. Chem. 2005,
3, 1617.
(10) (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: New York, 1998. (b) Eissen, M.;
Metzger, J. O.; Schmidt, E.; Schneidewind, V. Angew. Chem., Int. Ed. 2002,
41, 414. (c) Special Topic Issue on Green Chemistry: Acc. Chem. Res.
2002, 35, 685.
(1) Kemp, J. E. G. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, p 469.
(2) (a) Kharasch, M. S.; Priestley, H. M. J. Am. Chem. Soc. 1939, 61,
3425. (b) Ueno, Y.; Takemura, S.; Ando, Y.; Terauchi, H. Chem. Pharm.
Bull. 1967, 15, 1193. (c) Daniher, F. A.; Butler, P. E. J. Org. Chem. 1968,
33, 2637.
(3) (a) Li, G.; Wei, H.-X.; Kim, S. H.; Neighbors, M. Org. Lett. 1999,
1, 395. (b) Li, G.; Wei, H.-X.; Kim, S. H. Org. Lett. 2000, 2, 2249. (c)
Wei, H.-X.; Kim, S. H.; Li, G. Tetrahedron 2001, 57, 3869. (d) Li, G.;
Wei, H.-X.; Kim, S. H. Tetrahedron 2001, 57, 8407. (e) Kotti, S. R. S. S.;
Xu, X.; Wang, Y.; Headley, A. D.; Li, G. Tetrahedron Lett. 2004, 45, 7209.
(f) Xu, X.; Kotti, S. R. S. S.; Liu, J.; Cannon, J. F.; Headley, A. D.; Li, G.
Org. Lett. 2004, 6, 4881. (g) Chen, D.; Timmons, C.; Chao, S.; Li. G. Eur.
J. Org. Chem. 2004, 3097. (h) Li, Q.; Shi, M.; Timmons, C.; Li, G. Org.
Lett. 2006, 8, 625. (i) Liu, J.; Wang, Y.; Li, G. Eur. J. Org. Chem. 2006,
3112. (j) Han, J.-L.; Zhi, S.-J.; Wang, L.-Y.; Pan, Y.; Li, G. Eur. J. Org.
Chem. 2007, 1332.
(11) For reviews, see: (a) Li, C.-J. Chem. ReV. 1993, 93, 2023. (b) Li,
C.-J.; Chang, T.-H. Organic Reactions in Aqueous Media; John Wiley &
Sons: New York, 1997. (c) Organic Synthesis in Water; Grieco, P. A.,
Eds.; Blackie Academic and Professional: London, 1998. (d) Lubineau,
A.; Auge, J. Top. Curr. Chem. 1999, 206, 1.
10.1021/jo701957t CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/31/2007
9398
J. Org. Chem. 2007, 72, 9398-9401

TABLE 1. Aminochlorination of Chalcone 1a Promoted by
Various Brønsted Acids in Watera
TABLE 2. H2SO4-Promoted Aminochlorination of Chalcone 1a
Assisted by Various Phase-Transfer Catalysts (PTC)a
entry
acid
HCl
H2SO4
H3PO4
TsOH
MsOH
L-proline
HOAc
PhCO2H
TFA
time (h)
yieldb (%)
drc (anti/syn)
entry
PTC
SDS
TMAB
TBAI
CTAB
TBAB
TEBAC
TEBAC
TEBAC
time (h)
yieldb (%)
drc (anti/syn)
1
2
3
4
5
10
7
5
10
5
8
10
10
6
6
6
0
67
80
70
79
69
0
69
64
66
60
78
61
58
75
/
1
2
3
4
5
6
8
10
10
10
10
5
5
5
7
63
54
45
57
47
61
80
79
71
89/11
89/11
92/8
91/9
89/11
91/9
91/9
91/9
92/8
91/9
91/9
91/9
92/8
90/10
/
90/10
90/10
92/8
93/7
90/10
91/9
92/8
91/9
6
7d
8d
9d
10
11
12e
13f
14g
15h
7
8d
9f
a Unless otherwise specified, all reactions were performed with chalcone
1a (0.2 mmol), Chloramine-T (0.3 mmol), H2SO4 (0.24 mmol), and PTC
(0.04 mmol) in water (2.0 mL) as solvent. b Isolated yields by flash column
chromatography. c Determined by the analysis of 1H NMR. d 0.06 mmol
of TEBAC was employed. f 0.02 mmol of TEBAC was employed. SDS )
sodium dodecyl sulfate, TMAB ) tetramethylammonium bromide, TBAI
) tetrabutylammonium iodide, TBAB ) tetrabutylammonium bromide,
CTAB ) cetyltriethylammonium bromide.
TfOH
H2SO4
H2SO4
H2SO4
H2SO4
5
8
10
3
a Unless otherwise specified, all reactions were performed with chalcone
1a (0.2 mmol), Chloramine-T (0.3 mmol), acid (0.24 mmol), and TEBAC
(0.04 mmol) in water (2.0 mL) as solvent. b Isolated yields by flash column
chromatography. c Determined by the analysis of H NMR. d 2.0 equiv of
1
the acid was used. e 0.2 mmol of H2SO4 was employed. f 0.1 mmol of H2SO4
was employed. g 0.2 mmol of Chloramine-T was employed. h Reaction was
performed at 50 °C. TEBAC ) triethylbenzylammonium chloride.
more readily available and cheaper than TsOH. When we
reduced the H2SO4 loading to 1.0 equiv, only a slightly
decreased yield was observed (entry 12). Further reducing the
H2SO4 loading to 0.5 equiv compromised the yield obviously
even though the reaction time was prolonged (entry 13). When
the loading of Chloramine-T was reduced to 1.0 equiv, the yield
was decreased rapidly with lots of unreacted chalcone 1a (entry
14). Elevated temperature was not necessary and resulted in a
slightly decreased yield (entry 15). This H2SO4-promoted
process exhibited as the most convenient and clean procedure
to realize the highly efficient aminochlorination of chalcone 1a.
Various solvent systems were explored for the aminochlori-
antion reaction of chalcone 1a mediated by H2SO4. Organic
solvents including hexane, toluene, THF, CH2Cl2, ethanol, and
dioxane failed to produce any product. In CH3CN, chloramine
3a was isolated in 6% yield at room temperature. Aqueous
media such as EtOH/H2O ) 1:1 and THF/H2O ) 1:1 were also
screened; however, only trace products were observed. It is none
but water could facilitate this acid-promoted aminochlorination
reaction. Water represented as a unique reaction medium here.
Phase-transfer catalyst (PTC) was supposed to accelerate the
reaction. We then screened the effects of various PTCs on the
H2SO4-promoted aminochlorination reaction of chalcone 1a
(Table 2). Chloramine 3a was obtained in 63% yield after 8 h
without any PTC (entry 1). SDS, TMAB, TBAI, and CTAB
were detrimental to the reaction (entries 2-6). It was only
TEBAC that could facilitate this aminochlorination process. The
exact reason for the unique accelerating property of TEBAC is
unknown right now. With 20 mol % of TEBAC, the reaction
afforded 3a in 80% yield and excellent diastereoselectivity (entry
7). When we increased its loading, the yield did not rise (entry
8). However, reducing the loading caused an obvious decrease
in both yield and reaction rate (entry 9).
our interest in organic reactions in water,12 herein we report
the first Brønsted acid-promoted aminochlorination of electron-
deficient olefins with Chloramine-T in water.
In our initial study, we examined the inherent property of
various Brønsted acids for the aminochlorination reaction of
electron-deficient olefins in water with chalcone 1a as model
substrate. Because the reaction would generate hydroxide ion,3,7
stoichiometric acid was necessary to achieve high conversion.
Phase-transfer catalyst (PTC) was believed to accelerate this
heterogeneous reaction because of the ionic character of
Chloramine-T. The results are listed in Table 1 with triethyl-
benzylammonium chloride as the PTC agent. It should be
emphasized that all of the reactions were performed in pure
water in open air without any additive. The reaction was totally
inert without an acid mediator (entry 1). However, we were
pleased to find that the reaction promoted by common inorganic
acids provided the desired chloramine 3a in good yields and
excellent diastereoselectivities at room temperature (entries
2-4). Among these examined acids, H2SO4 afforded the best
result. TsOH gave a similar result as H2SO4, while MsOH
provided a decreased yield (entries 5-6). Unfortunately, amino
acid failed to give any product (entry 7). To our surprise, weak
organic acids such as acetic acid and benzoic acid afforded
moderate yields by increasing the acid loading (entries 8-9).
However, fluorinated strong acids resulted in decreased yields
(entries 10-11).
Although TsOH and H2SO4 exhibited similar activities, we
chose the latter to promote this reaction because H2SO4 was
(12) For our representative work on water mediated reactions, see: (a)
Xia, J.-J.; Wang, G.-W. Synthesis 2005, 2379. (b) Wang, G.-W.; Miao,
C.-B.; Kang, H. Bull. Chem. Soc. Jpn. 2006, 79, 1426. (c) Wang, G.-W.;
Jia, C.-S.; Dong, Y.-W. Tetrahedron Lett. 2006, 47, 1059. (d) Wang, G.-
W.; Miao, C.-B. Green Chem. 2006, 8, 1080. (e) Wang, G.-W.; Xia, J.-J.;
Miao, C.-B.; Wu, X.-L. Bull. Chem. Soc. Jpn. 2006, 79, 454. (f) Xia, J.-J.;
Wang, G.-W. Molecules 2007, 12, 231.
With the optimized conditions in hand, the scope of this
efficient reaction was explored with various electron-deficient
olefins. The results are summarized in Table 3. Our method
was successfully applied to a wide range of chalcones 3a-3i,
allowing preparation of aminochlorinated ketones in good yields
J. Org. Chem, Vol. 72, No. 24, 2007 9399

TABLE 3. H2SO4-Promoted Aminochlorination of
Electron-Deficient Olefins in Watera
SCHEME 1. Gram-Scale Synthesis of 3a
time yieldb
product (h) (%) (anti/syn)
drc
SCHEME 2. Possible Pathway of Brønsted Acid-Promoted
Aminochlorination with Chloramine-T
entry
R1
R2
1
2
3
4
Ph
4-Cl-C6H4
2-Cl-C6H4
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
6
6
8
83
77
71
69
40
73
75
74
70
41
0
91/9
94/6
96/4
>99/1
>99/1
93/7
92/8
95/5
>99/1
95/5
/
>99/1
>99/1
3,4-Cl2-C6H4 Ph
12
20
8
10
10
12
15
10
15
12
5d,e 4-NO2-C6H4 Ph
6d
7d
8
Ph
4-Cl-C6H4
Ph
4-MeO-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-Cl-C6H4
Me
Ph
OMe
NEt2
9d,e 4-Cl-C6H4
10
Ph
Et
Ph
Ph
3j
3k
3l
11
12d
13d
71
65
3m
observed under our conditions. Based on the results, we
proposed a possible pathway of our aminochlorination reaction
(Scheme 2). In acidic medium, Chloramine-T was transformed
into chloramine 4, which could react with olefin 1 to yield
aziridium 5 by elimination of Cl-.3,7 Intermediate 5 was
immediately attacked by the nearby Cl- to afford the final
product 3. The highly regio- and stereoselectivity of the reaction
perfectly supported this SN2 process.
In summary, we have demonstrated a Brønsted acid-promoted
regio- and diastereoselective aminochlorination of electron-
deficient olefins in water with Chloramines-T as nitrogen as
well as chlorine source. The use of water as a green reaction
medium proved critical to achieve high yield and selectivity.
This unprecedented method has several synthetically attractive
features: environmental benign reaction medium, operational
simplicity, totally metal free, minimal byproducts, and suitable
for large-scale synthesis. To the best of our knowledge, this is
the most convenient and practical methodology so far.
a Unless otherwise specified, all reactions were performed with chalcone
(0.5 mmol), Chloramine-T (0.75 mmol), H2SO4 (0.6 mmol), and TEBAC
(0.1 mmol) in water (3 mL) as solvent. b Isolated yields by flash column
chromatography. c Determined by the analysis of 1H NMR. d 1.0 mmol of
Chloramine-T was employed. e Reaction was performed at 50 °C.
and diastereoselectivities except for 3e (entries 1-9). The
substrate with a strong electron-withdrawing NO2 group only
afforded the product in moderate yield (entry 5).
The superiority of our methodology could be successfully
extended to an enone with R2 as an alkyl group, which led to
a moderate yield that was comparable with the (diacetoxyiodo)-
benzene system7 (entry 10). However the reaction failed when
R1 was an alkyl group probably due to its electronic factors
(entry 11). The enones where R1 ) H or Me could be
successfully aminochlorinated by using TsNCl2 and CuOTf.3g
Our unsuccess in aminochlorination of enones with R1 as an
alkyl group might ascribe to the different activities of TsNCl2
and Chloramine-T.
Representative cinnamate 3l and cinnamide 3m were also
examined to show the scope. Much to our delight, both
cinnamate and cinnamide could be aminochlorinated smoothly
with good yields and excellent diastereoselectivities (entries 12
and 13).
To further demonstrate the advantage of our methodology, a
gram-scale synthesis of chloramine 3a was performed (Scheme
1). Again, the product was obtained in fairly good yield (75%)
and high diastereoselectivity (94/6 anti/syn) after simple work-
ups. It offered a robust access to gram quantities of aminochlo-
rinated carbonyl compounds that exhibited a possibility for
industrial application of our methodology.
Chloramine-T has recently been used for the aziridination of
olefins catalyzed by metal salts13 or halogenated compounds.14
Some of these reactions were even performed in aqueous
media.13e,14e,f However, the aziridinated products were not
Experimental Section
General Procedure for the Aminochlorination of Chalcone
1a Promoted by Various Brønsted Acids in Water. To a mixture
of chalcone 1a (41.6 mg, 0.2 mmol), Chloramine-T trihydrate (84.3
mg, 0.3 mmol), and TEBAC (9.1 mg, 0.04 mmol) in a 25 mL round-
bottom flask was added a chosen Brønsted acid (0.24 mmol) in
H2O (2.0 mL). This mixture was allowed to stir vigorously at room
temperature for the indicated time. The reaction was stopped, and
ethyl acetate (2 mL × 2) was added to extract the product. The
organic layer was dried with MgSO4 and then evaporated to dryness
in vacuo. The residual was separated on a silica gel column with
petroleum ether/ethyl acetate 7:1 as the eluent to get the desired
product 3a:3g 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J ) 7.8 Hz,
2H), 7.58 (t, J ) 7.3 Hz, 1H), 7.52 (d, J ) 8.1 Hz, 2H), 7.40 (t, J
) 7.3 Hz, 2H), 7.27-7.19 (m, 5H), 7.03 (d, J ) 8.1 Hz, 2H), 5.54
(d, J ) 9.6 Hz, 1H), 5.40 (dd, J) 9.6, 6.3 Hz, 1H), 5.11 (d, J )
6.3 Hz, 1H), 2.27 (s, 3H).
(13) (a) Albone, D. P.; Aujla, P. S.; Taylor, P. C. J. Org. Chem. 1998,
63, 9569. (b) Ando, T.; Minakata, S.; Ryu, I.; Komatsu, M. Tetrahedron
Lett. 1998, 39, 309. (c) Simkhovich, L.; Gross, Z. Tetrahedron Lett. 2001,
42, 8089. (d) Kumar, G. D. K.; Baskaran, S. Chem. Commun. 2004, 1026.
(e) Wu, H.; Xu. L.-W.; Xia, C.-G.; Ge, J.; Zhou, W.; Yang, L. Catal.
Commun. 2005, 6, 221. (f) Gao, G.-Y.; Harden, J. D.; Zhang, X. P. Org.
Lett. 2005, 7, 3191.
(14) (a) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K.
B. J. Am. Chem. Soc. 1998, 120, 6844. (b) Ando, T.; Kano, D.; Minakata,
S.; Ryu, I.; Komatsu, M. Tetrahedron 1998, 54, 13485. (c) Ali, S. I.; Nikalje,
M. D.; Sudalai, A. Org. Lett. 1999, 1, 705. (d) Thakur, V. V.; Sudalai, A.
Tetrahedron Lett. 2003, 44, 989. (e) Jain, S. L.; Sharma, V. B.; Sain. B.
Tetrahedron Lett. 2004, 45, 8731. (f) Minakata, S.; Kano, D.; Oderaotoshi,
Y.; Komatsu, M. Angew. Chem., Int. Ed. 2004, 43, 79.
9400 J. Org. Chem., Vol. 72, No. 24, 2007

General Procedure for the Aminochlorination of Electron-
Deficient Olefins 1a-m in Water. To a mixture of electron-
deficient olefins 1a (1b-m, 0.50 mmol), Chloramine-T trihydrate
(211.0 mg, 0.75 mmol), and TEBAC (22.8 mg, 0.10 mmol) was
added H2SO4 (58.8 mg, 0.60 mmol) in H2O (3.0 mL). This mixture
was allowed to stir vigorously at room temperature for the indicated
time. The same workup procedure afforded product 3a (3b-m).
Gram-Scale Synthesis of Chloramine 3a. To a mixture of
chalcone 1a (10.40 g, 50 mmol), Chloramine-T trihydrate (21.10
g, 75 mmol), and TEBAC (0.91 g, 4 mmol) in a 250 mL round-
bottom flask was added H2SO4 (4.90 g, 50 mmol) in H2O (100
mL). This mixture was allowed to stir vigorously at room
temperature for 12 h. The reaction was stopped, and ethyl acetate
(50 mL × 2) was added to extract the product. The organic layer
was dried with MgSO4 and then evaporated to dryness in vacuo.
The resulting pale yellow solid was washed with petroleum ether
(50 mL) and was then recrystallized from petroleum ether/EtOAc
5/1 to afford 15.51 g (75%) of product 3a.
Acknowledgment. We are grateful for the financial support
from National Natural Science Foundation of China (Nos.
20621061 and 20772117).
Supporting Information Available: Detailed experimental
1
procedures, H NMR spectral data and spectra of 3a-j,l,m. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO701957T
J. Org. Chem, Vol. 72, No. 24, 2007 9401