Highly ortho-Selective Chlorination of Anilines Using a Secondary Ammonium Salt Organocatalyst

Article abstract of DOI:10.1002/anie.201607388

An organocatalytic, highly facile, efficient, and regioselective ortho-chlorination of anilines is described. A secondary ammonium chloride salt has been employed as the catalyst and the reaction can be conducted at room temperature without protection from air and moisture. In addition, the reaction is readily scalable and the catalyst can be recycled and reused. This catalytic protocol has been applied to the efficient synthesis of a highly potent c-Met kinase inhibitor. Mechanistic studies revealed that unique structural features of the secondary ammonium chloride salt are important for both the catalysis and regioselectivity of the electrophilic ortho-chlorination.

Full text of DOI:10.1002/anie.201607388

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607388
German Edition: DOI: 10.1002/ange.201607388
Halogenation
Highly ortho-Selective Chlorination of Anilines Using a Secondary
Ammonium Salt Organocatalyst
Xiaodong Xiong and Ying-Yeung Yeung*
Abstract: An organocatalytic, highly facile, efficient, and
regioselective ortho-chlorination of anilines is described. A
secondary ammonium chloride salt has been employed as the
catalyst and the reaction can be conducted at room temperature
without protection from air and moisture. In addition, the
reaction is readily scalable and the catalyst can be recycled and
reused. This catalytic protocol has been applied to the efficient
synthesis of a highly potent c-Met kinase inhibitor. Mechanistic
studies revealed that unique structural features of the secondary
ammonium chloride salt are important for both the catalysis
and regioselectivity of the electrophilic ortho-chlorination.
years.[6] Thus, the development of a mild, selective, and
effective catalytic protocol for the synthesis of ortho-halo-
genated anilines is still highly desired. Herein, we are pleased
to report an organocatalytic and highly regioselective ortho-
chlorination of N-Boc and N-Ns anilines under mild reaction
conditions using a secondary ammonium chloride salt as the
catalyst (Scheme 1). The reaction is not air and moisture
sensitive and can be operated at room temperature. In
addition, the N-Boc and N-Ns substituents can be easily
removed and can enhance the flexibility in the derivation of
the ortho-chlorinated aniline products. Moreover, the sub-
strate scope is broad and the reaction is readily scalable.
ꢀ
A
romatic halogenation/C H functionalization is one of the
most important organic transformations. The resulting halo-
genated aromatic compounds are very useful and attractive
building blocks. In addition, there are many well-developed
methods for the derivatization of aryl halides.[1] Among the
halogenated aromatic compounds, halogenated anilines are
particularly attractive since aniline moieties frequently
appear as pharmaceutical building blocks, constitutional
components of novel functional materials, and cores of dyes
and pigments.[2]
Electrophilic halogenation has been frequently employed
in the preparation of halogenated anilines. However, a mix-
ture of ortho- and para-halogenated anilines can be obtained,
and halogenation at the less-hindered para-position is usually
predominant.[3] The introduction of a substituent/blocking
group at the para-position can lead to the halogenation at the
second favorable position, the ortho-position of an aniline
system.[4] However, highly selective ortho-halogenation of
aniline in the absence of a blocking group at the para-position
is a challenging task. Over the past decades, considerable
effort has been devoted to the development of ortho-
halogenation of anilines with the aim of high reaction
efficiency and functional-group tolerance. Typically, electro-
philic halogenations, halogenations of aryldiazoniums, and
directed ortho-metalation are the main ways to access to
halogenated aromatic compounds.[5] However, these methods
suffered from low regioselectivity, tedious and harsh reaction
procedures, and narrow substrate scope. The use of metals
including RhIII, PdII, MgII, and CuII in catalyzing the ortho-
halogenation of anilines, along with either an N-acetyl or N-
(2-pyridyl)sulfonyl directing group, has emerged in the recent
Scheme 1. Organocatalytic ortho-selective halogenation of anilines.
Secondary ammonium salts can easily be prepared by the
reaction between amines and acids, followed by recrystalliza-
tion. The salts are air-stable, nontoxic, inexpensive, and easy
to handle, and thus make them attractive organocatalysts for
green and environmental benign chemical transformations.
While secondary ammonium salts have been widely utilized
as the organocatalysts in various transformations through the
formation of iminium or aminal intermediates, their applica-
tion to site-selective aromatic halogenation remains
unknown.[7]
At the initial stage of investigation, the halogenation of
the nosyl aniline 2a was examined at room temperature using
toluene and 1,3-dichloro-5,5-dimethylhydantoin (DCDMH)
as the solvent and halogenation source, respectively (Table 1).
In the absence of catalyst, no reaction was observed after
14 hours (entry 1). On the other hand, 75% yield of the ortho-
chlorinated product 3aCl was obtained when using 10 mol%
of the dimethylammonium chloride salt 1a as the catalyst
(entry 2).[8] Next, a series of cyclic and acyclic secondary
ammonium chloride salt catalysts (1) were subjected to the
study. To our delight, it was realized that the bulky diisopro-
pylammonium salt catalyst 1g gave the desired product 3aCl
exclusively in 94% yield (entries 3–8).[8] More importantly, no
para-chloroaniline product was detected. While the reaction
[*] Dr. X. Xiong, Prof. Dr. Y.-Y. Yeung
Department of Chemistry, The Chinese University of Hong Kong
Shatin, N.T., Hong Kong (China)
E-mail: yyyeung@cuhk.edu.hk
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607388.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
Table 1: Optimization of the reaction conditions.[a]
Table 2: Substrate scope of the organocatalytic ortho-chlorination of
anilines.[a]
Entry
Halogen source
Substrate, R
Catalyst
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
DCDMH
DCDMH
DCDMH
DCDMH
DCDMH
DCDMH
DCDMH
DCDMH
NCS
2a, Ns
2a, Ns
2a, Ns
2a, Ns
2a, Ns
2a, Ns
2a, Ns
2a, Ns
2a, Ns
2a, Ns
4a, Ts
–
n.r.
75
87
90
26
91
90
94
trace
61
1a
1b
1c
1d
1e
1 f
1g
1g
1g
1g
1g
1g
1g
1g
NBS
DCDMH
DCDMH
DCDMH
DCDMH
DCDMH
90
68
82
60
6a, Ms
8a, Boc
10a, MeCO
12a, PhCO
71
[a] Reactions were carried out with aniline substrate (0.1 mmol), catalyst
1 (0.01 mmol), and halogen source (0.095 mmol) in toluene (2 mL) in
the absence of light at 258C. [b] Yield of the isolated product based on
the substrate. Boc=tert-butoxycarbonyl, DCDMH=1,3-dichloro-5,5-
dimethylhydantoin, Ms=methanesulfonyl, NBS=N-bromosuccin-
imide, NCS=N-chlorosuccinimide, Ns=4-nitrobenzenesulfonyl, Ts=
4-toluenesulfonyl.
[a] Reactions were carried out with aniline substrate (0.1 mmol), catalyst
1g (10 mol%, 0.01 mmol), and DCDMH (0.095 mmol) in toluene
(2 mL) in the absence of light at 258C. The yields are those of isolated
products based on the substrates. [b] Reactions were carried out at
ꢀ208C. [c] 0.19 mmol of DCDMH was used. [d] A minor portion of
isomer was observed. For details, see in the Supporting Information.
[e] CH2Cl2 was used as the solvent.
was sluggish when using N-chlorosuccinimide (NCS), 61% of
the ortho-brominated product 3aBr could be obtained when
employing N-bromosuccinimide (NBS) as the halogen source
(entries 9 and 10). A brief survey of the reaction media
revealed the superior performance of toluene as the solvent in
the secondary ammonium salt catalyzed electrophilic ortho-
chlorination of aniline.[9] With the optimized reaction con-
ditions in hand, we examined the compatibility of different N-
substituents. It was realized that the reaction still could
proceed smoothly when replacing the Ns group with Ts and
Ms. A range of carbonyl substituents including Boc, acetyl,
and benzoyl could also be tolerated (entries 11–15).
Prompted by these results, other substrates with N-Ns and
N-Boc substituents were investigated since Ns and Boc
groups can easily be removed under mild reaction conditions,
and this advantage is of great importance for late-stage
manipulation and derivatization.
aniline substrates 2, substituents such as methyl, isopropyl,
phenyl, and chloride at the para-position were compatible
with the reaction, thus providing the desired products 3b–e in
good to excellent yields. For the meta-substituted substrates
2 f (methoxy) and 2g (3,5-dimethyl), the corresponding ortho-
chlorinated products 3 f and 3g were also obtained smoothly.
Interestingly, double ortho-chlorination of 2h proceeded
readily to give 3h. Again, the reaction was found to be
highly ortho selective. The substrate 2i, which has a thiophene
core, could also be converted into 3i in 90% yield. The
reactions worked equally smoothly when employing the N-
Boc substrates 8. Under the optimized reaction conditions,
the para-substituted substrates 8b–g were successfully chlori-
nated at the ortho-position of the aniline to give 9b–g in
excellent yields. For the meta-substituted N-Boc-anilines,
ortho-chlorination at C6 occurred readily when subjecting
substrates 8h and 8i to the catalytic protocol. 9k could be
furnished smoothly when using the naphthyl substrate 8k.
We next explored the generality of this organocatalytic
reaction (Table 2). In general, the chlorination proceeded
smoothly with excellent ortho selectivity. In addition, differ-
ent functional groups were well-tolerated. For the N-Ns
2
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
Surprisingly, the ortho-chlorination happened selectively at
the bulkier C2 position when changing the meta-substitutions
to fluorine, ester, ketone, and boronic ester (i.e., substrates
8l–r), thus giving the corresponding chlorinated products 9l–r
in good yields upon isolation.[10] The amide substrates 10b–d
and 12b, which have either ester or ketone substituents at the
meta-position, also gave rise to the C2 chlorinated products
11b–d and 13b. The structures of 3 f and 13b were confirmed
unambiguously by X-ray crystallographic studies.[11] It is
important to note that these compounds are expensive and
valuable building blocks for many bioactive compounds.[12]
They are difficult to achieve by using conventional synthetic
methods, but can easily be prepared using this mild and
efficient secondary ammonium salt catalytic protocol.[13]
Furthermore, the reaction was found to be readily
scalable. For instance, 10 mmol of the aniline 8 f was subjected
to the reaction and 2.84 grams (99% yield) of the desired
ortho-chlorinated product 9 f was obtained (Scheme 2). The
Scheme 3. Synthesis of the highly potent c-Met kinase inhibitor 17.
TFA=trifluoroacetic acid.
Scheme 2. Reaction scale-up and catalyst recycling.
secondary ammonium salt catalyst 1g could be recovered by
aqueous extraction followed by evaporation of the water. The
recycled catalyst 1g was found to be equally effective (both
reaction conversion and selectivity) in the catalytic chlorina-
tion. The chlorination/catalyst recycling process was repeated
twice and no deterioration of the catalytic performance was
observed. The catalyst loading could be reduced to 5 mol%
although a longer reaction time was required. These practical
and environmentally benign features are keys of sustainable
development which are of great importance to the modern
manufacturing sectors.[14]
This newly developed methodology can be applied to the
preparation of valuable biologically relevant advanced inter-
mediates. For example, the compound 17 (Scheme 3) is
a highly potent inhibitor of c-Met Kinase for cancer treatment
(c-Met IC50 = 19 nm), but the existing synthesis methods are
not efficient.[15] By using 1g as the catalyst, 14 was chlorinated
regioselectively to give 15 in 71% yield (with 10% recovery
of starting material) and the structure of 15 was confirmed
unambiguously by an X-ray crystallographic study.[11]
A
Scheme 4. Control experiments and mechanistic studies.
relatively higher catalyst loading was required to achieve
a reasonable reaction rate attributable to the electron-
deficient nature of the substrate. Subsequent coupling of 15
with the the pyrazole-boronic ester furnished 16. The Boc
group in 16 could be unmasked using TFA to give 17.
To obtain a clearer picture on the mechanism and probe
the sole origin of the catalytic activity of the secondary
ammonium salt 1, a series of control experiments were
conducted (Scheme 4). First, the tetra-n-butyl ammonium
chloride salt 1h, which has no NH proton, was examined. It
was found that the ortho-selectivity was very poor when
employing 10 mol% of 1h (Scheme 4a). Next, the Mioskow-
ski reagent[16] was used as the chlorinating agent in the
halogenation of 2a and poor regioselectivity was observed
(Scheme 4b). The substrate 4b, which contains a NHTs and
NMeTs group at the 1- and 4-positions, respectively, was also
examined. Although NMeTs is a stronger electron-donating
group as compared to NHTs, the chlorination exhibited
a strong preference for the ortho-position of the NHTs moiety
to give the product 5b (Scheme 4c). It was also found that
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
both the N-methyl nosylaniline 2j and 2-methyl-substituted
aniline 2k returned a sluggish reaction under the optimized
reaction conditions, thus suggesting that the NH hydrogen
bonding and the steric factor might play crucial roles in the
catalysis (Scheme 4d).
A proposed catalytic cycle is proposed based on the
results from the mechanistic studies (Scheme 5). We believe
that DCDMH could undergo halogen exchange with 1g to
trigger the electrophilic aromatic chlorination reaction
through the proposed mechanistic pathway B!C!D, and
give the product 3 together with the regeneration of 1g.
Although the reaction between 1 and DCDMH might
generate molecular chlorine,[20] the poor performance of the
Mioskowski reagent in the reaction (Scheme 4b) suggests
that molecular chlorine might not play a crucial role in the
ortho-chlorination of 2. The regioselectivity in the electro-
philic chlorination of 4b and the low reactivity of substrate 2j
ꢀ
could be explained by the lack of N H in the substrates
(Scheme 4c,d). We believe that the mechanistic pathway B!
C might be energetically less favorable with the bulkier 2-
methyl-substituted substrate 2k and hence inhibit the for-
mation of the desired product.[21]
In summary, we have developed the first organocatalytic
highly ortho-selective halogenation of anilines using the
secondary ammonium salt 1g under mild reaction conditions.
The catalyst could be easily prepared, recovered, and reused,
thus providing an excellent platform for the green and
scalable preparation of ortho-chloroanilines.
Acknowledgments
We thank The Chinese University of Hong Kong (Project
code 4053157) for financial support.
Keywords: arenes · halogenation · organocatalysis ·
regioselectivity · synthetic methods
[1] For selected reviews, see: a) R. Martin, S. L. Buchwald, Acc.
Chem. Res. 2008, 41, 1461; b) G. A. Molander, N. Ellis, Acc.
Chem. Res. 2007, 40, 275; c) J. Magano, J. R. Dunetz, Chem. Rev.
2011, 111, 2177; d) R. Jana, T. P. Pathak, M. S. Sigman, Chem.
Rev. 2011, 111, 1417; e) J. Hassan, M. Sꢀvignon, C. Gozzi, E.
Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359; f) A. Moyeux,
G. Cahiez, Chem. Rev. 2010, 110, 1435; g) C. L. Sun, Z. J. Shi,
Chem. Rev. 2014, 114, 9219.
[2] a) D. Tsvelikhovsky, S. L. Buchwald, J. Am. Chem. Soc. 2010,
132, 14048; b) M. Nazarꢀ, C. Schneider, A. Lindenschmidt, D. W.
Will, Angew. Chem. Int. Ed. 2004, 43, 4526; Angew. Chem. 2004,
116, 4626; c) A. L. Rodriguez, C. Koradin, W. Dohle, P. Knochel,
Angew. Chem. Int. Ed. 2000, 39, 2488; Angew. Chem. 2000, 112,
2607; d) Y. J. Jang, H. Yoon, M. Lautens, Org. Lett. 2015, 17,
3895; e) P. C. Fritch, G. M. Smith, G. S. Amato, J. F. Burns, C. W.
Eargle, R. Roeloffs, W. Harrison, L. Jones, A. D. Wickenden, J.
Med. Chem. 2010, 53, 887; f) Y. Zou, J. E. Melvin, S. S. Gonzales,
M. J. Spafford, A. B. Smith, J. Am. Chem. Soc. 2015, 137, 7095;
g) M. Liang, J. Chen, Chem. Soc. Rev. 2013, 42, 3453.
[3] a) U. Bora, G. Bose, M. K. Chaudhuri, S. S. Dhar, R. Gopinath,
A. T. Khan, B. K. Patel, Org. Lett. 2000, 2, 247; b) M. B. Smith, L.
Guo, S. Okeyo, J. Stenzel, J. Yanella, E. Lachapelle, Org. Lett.
2002, 4, 2321; c) J. M. Chrꢀtien, F. Zammattio, E. L. Grognec, M.
Paris, B. Cahingt, G. Montavon, J. P. Quintard, J. Org. Chem.
2005, 70, 2870; d) F. Toda, J. Schmeyers, Green Chem. 2003, 5,
701; e) H. Firouzabadi, N. Iranpoor, A. Garzan, Adv. Synth.
Catal. 2005, 347, 1925; f) A. J. Chen, S. C. Wong, C. C. Hwang,
C. Y. Mou, ACS Catal. 2011, 1, 783; g) R. C. Samanta, H.
Yamamoto, Chem. Eur. J. 2015, 21, 11976; h) D. T. Racys, S. A. I.
Sharif, S. L. Pimlott, A. Sutherland, J. Org. Chem. 2016, 81, 772;
Scheme 5. Proposed catalytic cycle.
give the species 1gCl, which was evidenced by the detection of
species 1 fCl using ESI high-resolution mass spectrometry
(Scheme 5a; see Table 1, entries 7 and 8, the performance of
catalysts 1 f and 1g are comparable). An 1H NMR experiment
on a mixture of 1g and DCDMH also revealed the existence
1
of 1gCl.[9] In the H NMR experiment, it was realized that
some of 1gCl decomposed to give the species E (probably
through the elimination of a molecule of HCl), thus leading us
to suspect that E might act as the active chlorinating agent.
However, this possibility was ruled out since no reaction was
observed when reacting E (prepared according to the
literature method)[17] with 2a (Scheme 5b). The chloride
anion in 1gCl might then hydrogen bond to the weakly acidic
hydrogen in 2, and it could bring the electrophilic Cl in close
proximity to the ortho-position of 2 through Coulombic
interactions (i.e., intermediate B).[18] The poor regioselectiv-
ity when using 1h could be rationalized since there is no N-H
in 1h and the formation of B becomes impossible (Sche-
me 4a).[19] The chloride anion in B could then deprotonate the
NsNH in 2 to give the basic NsN nitrogen center, which could
4
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
i) T. Hering, B. Mꢁhldorf, R. Wolf, B. Kçnig, Angew. Chem. Int.
Kreis, C. F. Nising, M. Schroen, K. Knepper, S. Brꢆse, Org.
Ed. 2016, 55, 5342; Angew. Chem. 2016, 128, 5428.
[4] a) A. W. Francis, A. J. Hill, J. Am. Chem. Soc. 1924, 46, 2498;
b) A. R. Hajipour, M. Arbabian, A. E. Ruoho, J. Org. Chem.
2002, 67, 8622; c) N. C. Ganguly, K. S. Barik, S. Dutta, Synthesis
2010, 1467; d) N. Narender, K. S. K. Reddy, K. V. V. Mohan, S. J.
Kulkarni, Tetrahedron Lett. 2007, 48, 6124; e) M. Wang, Y.
Zhang, T. Wang, C. Wang, D. Xue, J. Xiao, Org. Lett. 2016, 18,
1976.
Biomol. Chem. 2005, 3, 1835; h) S. Zhao, Y. Shen, A. V. Oeveren,
K. B. Marschke, L. Zhi, Bioorg. Med. Chem. Lett. 2008, 18, 3431.
[13] For example, 9l is a useful building block for the preparation of
pharmaceutically relevant 4-functionalized-1H-indoles. It could
be prepared using the directed ortho-metalation approach but
the process is tedious and low yielding (see: V. Guilarte, M. P.
Castroviejo, P. Garcꢄa-Garcꢄa, M. A. Fernꢅndez-Rodrꢄguez, R.
Sanz, J. Org. Chem. 2011, 76, 3416).
[5] a) E. Kolvari, A. Amoozadeh, N. Koukabi, S. Otokesh, M. Isari,
Tetrahedron Lett. 2014, 55, 3648; b) S. K. Dubey, A. K. Singgh,
H. Singh, S. Sharma, R. N. Iyer, J. Med. Chem. 1978, 21, 1178;
c) V. Snieckus, Chem. Rev. 1990, 90, 879.
[14] D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. L.
Leazer, Jr., R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearl-
man, A. Wells, A. Zaks, T. Y. Zhang, Green Chem. 2007, 9, 411.
[15] J. D. Katz, J. P. Jewell, D. J. Gurein, J. Lim, C. J. Dinsmore, S. V.
Deshmukh, B. S. Pan, C. G. Marshall, W. Lu, M. D. Altman,
W. K. Dahlberg, L. Davis, D. Falcone, A. E. Gabarda, G. Hang,
H. Hatch, R. Holmes, K. Kunii, K. J. Lumb, B. Lutterbach, R.
Mathvink, N. Nazef, S. B. Patel, X. Qu, J. F. Reilly, K. W. Rickert,
C. Rosenstein, S. M. Soisson, K. B. Spencer, A. A. Szewczak, D.
Walker, W. Wang, J. Young, Q. Zeng, J. Med. Chem. 2011, 54,
4092.
[16] T. Schlama, K. Gabriel, V. Gouverneur, C. Mioskowski, Angew.
Chem. Int. Ed. Engl. 1997, 36, 2342; Angew. Chem. 1997, 109,
2440.
[17] a) O. I. Kolodiazhnyi, O. R. Golovatyi, Phosphorus Sulfur
Silicon Relat. Elem. 1995, 102, 133; b) L. D. Luca, G. Giacomelli,
Synlett 2004, 12, 2180.
[6] a) X. Wan, Z. Ma, B. Li, K. Zhang, S. Cao, S. Zhang, Z. Shi, J.
Am. Chem. Soc. 2006, 128, 7416; b) R. B. Bedford, J. U.
Engelhart, M. F. Haddow, C. J. Mitchell, R. L. Webster, Dalton
Trans. 2010, 39, 10464; c) R. B. Bedford, M. F. Haddow, C. J.
Mitchell, R. L. Webster, Angew. Chem. Int. Ed. 2011, 50, 5524;
Angew. Chem. 2011, 123, 5638; d) N. Schrçder, J. W. Delord, F.
Glorius, J. Am. Chem. Soc. 2012, 134, 8298; e) G. Monzꢂn, I.
Tirotta, P. Knochel, Angew. Chem. Int. Ed. 2012, 51, 10624;
Angew. Chem. 2012, 124, 10776; f) X. Sun, G. Shan, Y. Sun, Y.
Rao, Angew. Chem. Int. Ed. 2013, 52, 4440; Angew. Chem. 2013,
125, 4536; g) B. Urones, ꢃ. M. Martꢄnez, N. Rodrꢄguez, R. G.
Arrayꢅs, J. C. Carretero, Chem. Commun. 2013, 49, 11044;
h) F. M. Moghaddam, G. Tavakoli, B. Saeednia, P. Langer, B.
Jafari, J. Org. Chem. 2016, 81, 3868.
[18] An 1H NMR experiment on a mixture of 1gCl (in situ generated
from 1g and DCDMH in CDCl3) and 8q was performed and an
appreciable up-field shift of the aromatic signal was observed,
and could be attributed to the hydrogen-bond interaction. The
detail appears in Figure S3 in the Supporting Information.
[19] We have also examined a tertiary ammonium chloride salt. The
reaction was relatively sluggish but the ortho-selectivity was
found to be comparable to that of the secondary ammonium salt.
However, the tertiary ammonium chloride salt is hydroscopic
and hard to handle. For details, see Scheme S2 in the Supporting
Information.
[20] L. Eberson, M. Finkelstein, B. Folkesson, G. A. Hutchins, L.
Jçnsson, R. Larsson, W. M. Moore, S. D. Ross, J. Org. Chem.
1986, 51, 4400.
[21] The formation of the intermediate C with substrate 2k might be
inhibited because of the 1,3-syn steric stress between the Ns and
the ortho-methyl group. Indeed, this 1,3-syn steric stress appears
to be important to avoid over chlorination of the substrate. For
detail, see Scheme S3 in the Supporting Information.
[7] M. T. Gaunt, C. C. C. Johansson, A. McNally, N. T. Vo, Drug
Discovery Today 2007, 12, 8.
[8] The cut-off time was set at 14 h in order to have a parallel
comparison. However, the less bulky catalyst 1a could promote
the reaction faster, but with a lower regioselectivity, as compared
to that of the bulkier catalyst 1g. For detail, see Scheme S1 in the
Supporting Information.
[9] The details appear in the Supporting Information.
[10] We speculated that the substitutions at C1 and C3 of the
substrates might coordinate to the electrophilic Cl, potentially
through a mechanism similar to the ortho-lithiation of 1,3-
disubstituted aryl compounds (D. W. Slocum, C. A. Jennings, J.
Org. Chem. 1976, 41, 3653), and direct the chlorination at the
more hindered C2. However, a more detailed study is underway
to elucidate this result.
[11] CCDC 1496929 (3 f), 1496930 (13b) and 1496931 (15) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
[12] a) P. Wang, G. J. Zheng, Y. P. Wang, X. J. Wang, Y. Li, W. S.
Xiang, Tetrahedron 2010, 66, 5402; b) H. G. Menzella, T. T. Tran,
J. R. Carney, W. J. Lau, J. Galazzo, C. D. Reeves, C. Carreras, S.
Mukadam, S. Eng, Z. Zhong, P. B. M. W. M. Timmermans, S.
Murli, G. W. Ashley, J. Med. Chem. 2009, 52, 1518; c) M. Kim,
J. A. Boissonnault, P. V. Dau, S. M. Cohen, Angew. Chem. Int.
Ed. 2011, 50, 12193; Angew. Chem. 2011, 123, 12401; d) Z. Xu,
W. Hu, F. Zhang, Q. Li, Z. Lꢁ, L. Zhang, Y. Jia, Synthesis 2008,
3981; e) R. Morgentin, G. Pasquet, P. Boutron, F. Jung, M.
Lamorlette, M. Maudet, P. Plꢀ, Tetrahedron 2008, 64, 2772; f) J.
Hong, Z. Zhang, H. Lei, H. Cheng, Y. Hu, W. Yang, Y. Liang, D.
Das, S. H. Chen, G. Li, Tetrahedron Lett. 2009, 50, 2525; g) M.
Manuscript received: July 30, 2016
Revised: October 11, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Halogenation
Worth its salt: An efficient regioselective
ortho-chlorination of anilines is de-
scribed. A secondary ammonium chloride
salt is employed as the organocatalyst
and the reaction can be conducted at
room temperature without protection
from air and moisture. This catalytic
protocol has broad substrate scope, is
scalable, and was applied to the efficient
synthesis of a potent c-Met kinase inhib-
itor. DCDMH=1,3-dichloro-5,5-dime-
thylhydantoin.
X. Xiong, Y.-Y. Yeung*
&&&& — &&&&
Highly ortho-Selective Chlorination of
Anilines Using a Secondary Ammonium
Salt Organocatalyst
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!