Multicomponent Reactions
DOI: 10.1002/anie.201410751

Double Heteroatom Functionalization of Arenes Using Benzyne
Three-Component Coupling**
Jos¦-Antonio Garc�a-Lýpez, Meliha Çetin, and Michael F. Greaney*

Abstract: Arynes participate in three-component coupling
reactions with N, S, P, and Se functionalities to yield 1,2-
heteroatom-difunctionalized arenes. Using 2-iodophenyl aryl-
sulfonates as benzyne precursors, we could effectively add
magnesiated S-, Se-, and N-nucleophilic components to the
strained triple bond. In the same pot, addition of electrophilic
N, S, or P reagents and a copper(I) catalyst trapped the
intermediate aryl Grignard to produce a variety of 1,2-
difunctionalized arenes.

1,2-Heteroatom-functionalized arenes represent privi-
leged structures in pharmaceuticals and catalysis
(Scheme 1).[1] Covering a vast area of chemical structure
and function, their synthesis usually entails multistep sequen-
ces with attendant multiple purification steps. In the 2-
functionalized aniline series, for example, an ortho-halo-
nitrobenzene is commonly used for initial SNAr C¢X bond
formation, followed by nitro reduction and a second C¢N
bond forming reaction at the amine functional group.[2] More
recently, sequential metal-catalyzed C¢N and C¢S bond
formations have been developed on suitably differentiated
haloarene precursors.[3] Our interest in benzyne chemistry[4]

led us to speculate whether this compound class could be
made in a single operation through a three component
coupling of two heteroatom moieties and an aryne.[5]

Nucleophilic addition to benzyne to form a reactive aryl
anion intermediate 2, followed by trapping with an electro-
philic component, is a fundamental reaction mode in benzyne
chemistry that has seen extensive application in synthesis.[6,7]

Perhaps surprisingly, the three-component coupling of ben-
zyne and two heteroatom moieties has yet to be described as
a general method.[8, 9] The development of this reaction would

yield valuable heteroatom-functionalized arenes in a single
step, with broad application in synthesis.

We chose to study tandem S- and N-addition to benzyne in
the first instance. Important precedent from Knochel and co-
workers had shown that magnesium thiolates undergo
efficient addition to benzynes generated from 2-iodophenyl
arylsulfonates 4 with iPrMgCl, with the resulting adducts
being trapped with simple carbon electrophiles in good
yield.[10] Using this chemistry for the initial nucleophilic
addition, we then planned to try O-benzoyl N,N-dialkyl-
hydroxylamines as the nitrogen source. These electrophilic
aminating agents are simple to prepare as stable, crystalline
solids, and have recently been shown to have excellent
versatility in C¢N bond formation.[11]

Treatment of 2-iodophenyl-sulfonate 4 with two equiv-
alents of iPrMgCl in the presence of 4-tert-butyl-benzene-
thiolate 5 at ¢78 88C in THF, followed by warming of the
mixture to 0 88C, afforded the expected 2-magnesiated benzo-
thioether 6 (Scheme 2). Pleasingly, dropwise addition of this
intermediate Grignard to a mixture containing one equivalent

Scheme 1. 1,2-Heteroatom-functionalized arenes and proposed ben-
zyne three-component coupling approach.

[*] Dr. J.-A. Garc�a-Lüpez, Dr. M. Çetin,[+] Prof. M. F. Greaney
School of Chemistry, University of Manchester
Oxford Rd, Manchester, M13 9PL (UK)
E-mail: michael.greaney@manchester.ac.uk

[++] Visiting researcher from Uludaḡ University
Faculty of Arts and Science, Department of Chemistry
16059 Bursa (Turkey)

[**] We thank T�BİTAK-BİDEB (scholarship to M.Ç.), Fundaciün S¦neca
(CARM, Spain) (Fellowship to J.-A.G.-L.) and the EPSRC (Leader-
ship Fellowship to M.F.G.) for funding. Dr. James Raftery is thanked
for X-ray crystallography.

Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410751.

Ó 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.

..Angewandte
Communications

2156 Ó 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2015, 54, 2156 –2159

http://dx.doi.org/10.1002/anie.201410751


of O-benzoyl N-hydroxylpiperidine and catalytic CuCl2

(5 mol%) in dry THF, yielded the desired 2-(2-piperidine
phenyl)benzenethioether 7a in 35% yield.

An optimization study (see the Supporting Information,
SI) focusing on reaction stoichiometry and catalyst choice
improved the yield to 76%, using a CuCl catalyst (10 mol%)
and phenanthroline ligand (10 mol%) system. Catalyst load-
ing was a key parameter, as larger amounts of CuCl led to
copious homocoupling of the intermediate Grignard 6. No
product 7a was detected in the absence of copper, as C-
arylation of the O-benzoylhydroxylamine reagent is preferred
to yield the ketone.[12] We were pleased to find that the
reaction was general for a range of aromatic, pyridine, and
thiophene thiols, with electron-donating (OMe, tBu) and
electron-withdrawing (F, Br) substituents being well accom-
modated (7a–i, 51–76 % yield, Figure 1). Phenyl selenide was
also productive in the coupling, affording the expected ortho-
seleno-aminated product 7j in 59% yield.

In terms of the electrophilic amine moiety, the reaction
worked well for introducing cyclic (morpholine, thiomorpho-
line, and piperidine) and acyclic secondary amines (N,N-
diethyl and N,N-methyl benzyl amines). Primary O-benzoyl
hydroxylamines, however, worked poorly in the reaction. To
address this shortcoming, we experimented with the trans-
metalation of intermediate 6 with zinc; pioneering work from
Johnson has shown that arylzinc compounds can react with
primary O-benzoyl hydroxylamines under copper catalysis to
give secondary anilines.[13] We were pleased to find that the
addition of ZnCl2 (0.5 equiv) to the reaction mixture was
successful, enabling iPrNHOBz and CyNHOBz to be used as
electrophiles in the reaction (7k, 7 l) in 44 and 46 % yield,
respectively.

Substituted arynes could be successfully employed, with 3-
methoxybenzyne reacting smoothly to give the expected
1,2,3-O,N,S-functionalized product 7 o as a single regioiso-
mer.[14] Using 1,2-naphthyne as the starting material, by
contrast, gave the thioaminated products 7m and 7m’’ in 56%
yield, but as a separable mixture of regioisomers (1:1).
Addition to 1,2-naphthyne often favors the 2-position (e.g.,
for neutral nitrogen nucleophiles),[4d,e,h] but selectivity can
vary according to the nature of the nucleophile.[15] Here, the
strong thiolate nucleophile shows little discrimination (cf.
magnesium amide addition). We were pleased to extend the
reaction to 5,6-quinolyne, a hetaryne that has scarcely been
exploited in the literature.[16] The three-component coupling
afforded the piperazinyl-mercaptoquinolines (7n, 7n’’) in
55% yield (using ZnCl2 as an additive for the amination
step), again giving a 1:1 mixture of regioisomers.[17] Starting
material 4-methylbenzyne afforded a 66% yield of 7p in the

expected 1:1 mixture of isomers, exhibiting the regiodiver-
gence typical of additions to meta-substituted benzynes.
Finally, we demonstrated that electrophilic P and S sources
were effective in the three-component coupling, synthesizing
the S,P adduct 8a using CuCl (2 mol%) and ClPPh2, and the
mixed S,S adduct 8b through quenching with tolyldisulfide in
the presence of CuCl (10 mol%).

Having established a working thio- and seleno-amination
system, we turned our attention to benzyne double amination.

Scheme 2. Tandem S,N-functionalization of benzyne. phen =phenan-
throline.

Figure 1. Scope of the (2-aminophenyl)benzothioether substrate. Reac-
tion conditions: thiol (1 mmol), iPrMgCl (2.2 mmol), and aryne pre-
cursor (1.2 mmol) were stirred at ¢78 88C for 45 min, then warmed to
0 88C. The resulting intermediate Grignard was quenched with 1.5 mol
of R1R2N¢OBz in the presence of CuCl (10 mol%) and phenanthroline
(10 mol%; see SI). [a] An additional zincation step was performed by
adding ZnCl2 (0.5 equiv) after the initial thiolate addition. The thermal
ellipsoids of the X-ray structure of 7d were set at 50%.[19]

Angewandte
Chemie

2157Angew. Chem. Int. Ed. 2015, 54, 2156 –2159 Ó 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org

 15213773, 2015, 7, D
ow

nloaded from
 https://onlinelibrary.w

iley.com
/doi/10.1002/anie.201410751 by B

ursa U
ludag U

niversity K
utuphane ve D

okum
antasyon, W

iley O
nline L

ibrary on [21/07/2025]. See the T
erm

s and C
onditions (https://onlinelibrary.w

iley.com
/term

s-and-conditions) on W
iley O

nline L
ibrary for rules of use; O

A
 articles are governed by the applicable C

reative C
om

m
ons L

icense

http://www.angewandte.org


Access to this motif through stepwise metal-catalyzed C¢N
bond forming chemistry is underdeveloped, making a pro-
spective aryne three-component coupling route particularly
interesting.[18] Using magnesiated secondary anilines as the
initial nucleophiles, we were pleased to find that our
established three-component coupling conditions translated
well to diamine synthesis (Scheme 3). Although yields were
slightly lower than the thio system, we could successfully
access a variety of 1,2-diamino benzenes (10 a–l) in 30–73%
yield. It is likely that the initial aniline addition adduct
presents additional steric hindrance to the second amination
step, relative to the thio analogues, leading to some attenu-
ation in yields. Zinc transmetalation was beneficial for the
cyclic morpholine, piperidine, and piperazine products 10g–i,
plus the primary isopropylamine adduct 10j. The effect was
not general, however, with acyclic secondary amines 10b,c,f
reacting markedly worse under zincation conditions. The use
of 1,2-naphthyne in the diamination contrasted with the
thioamination, giving a single regioisomeric product 10k. The
less reactive magnesium anilide is evidently able to discrim-
inate between the differences in steric demand at either aryne
position, adding to the more accessible aryne 2-position.

Starting with 3-methoxy benzyne gave the O,N,N product 10 l
as a single regioisomer, albeit in low yield. As with the
thiolate addition system, we could also use phosphorus and
sulfur electrophiles to access the N,P and N,S products 11 a
and 11 b, respectively. The polarity reversal in synthesizing
11b is complimentary to thiolate addition and trapping with
R1R2NOBz reagents, as the O-benzoyl hydroxylaniline
reagents are less readily synthesized.[20]

We applied our three component coupling protocol to the
synthesis of vortioxetine, 13, an antidepressant drug that has
recently received FDA and EMA approval (sold as brintellix;
Scheme 4). The molecule had previously been prepared
through double nucleophilic substitution of 1,2-dichloroben-
zene, mediated by ferrocene, in 17% overall yield.[21]

Following our optimized procedure, 2,4-dimethylthiophenol
reacted with benzyne precursor 4 to generate an intermediate
Grignard 11. Transmetalation with ZnCl2 enabled efficient
copper-catalyzed amination with the N-Boc protected O-
benzoyl hydroxylamine derived from piperazine, affording
a 78% yield of 12 in a single manipulation. Simple TFA
treatment removed the Boc group, affording the desired
pharmaceutical 13 in 73% overall yield in two steps from 4,
without recourse to noble-metal catalysis.

In conclusion, we have developed the aryne three-
component coupling reaction to encompass double hetero-
atom substitution, showcasing a new, one-pot approach to
S,N-, N,N-, Se,N-, S,P-, and N,P-functionalized arenes that
avoids the isolation of intermediates. The method encom-
passes a variety of thiols, arynes (including hetarynes), and
amines, and uses inexpensive metal reagents and catalysts.

Received: November 4, 2014
Published online: January 7, 2015

.Keywords: arynes · benzyne · Grignard reaction · heterocycles ·
multicomponent reactions

[1] Synthesis of representative structures in Scheme 1: a) R. J.
Lundgren, B. D. Peters, P. G. Alsabeh, M. Stradiotto, Angew.
Chem. Int. Ed. 2010, 49, 4071 – 4074; Angew. Chem. 2010, 122,
4165 – 4168; b) D. C. H. Oakes, B. S. Kimberley, V. C. Gibson,
D. J. Jones, A. J. P. White, D. J. Williams, Chem. Commun. 2004,
2174 – 2175; c) E. J. Hennessy, S. L. Buchwald, J. Org. Chem.
2005, 70, 7371 – 7375; d) G. J. Atwell, B. C. Baguley, G. J. Finlay,
G. W. Rewcastle, W. A. Denny, J. Med. Chem. 1986, 29, 1769 –
1776; e) E. J. Warawa, B. M. Migler, U.S. Patent 4,879,288, 1988 ;
f) J. F. Gertser, et al., J. Med. Chem. 2005, 48, 3481 – 3491.

Scheme 3. Synthesis of 2-aminoaniline. Reaction conditions: amine
(1 mmol), iPrMgCl (2.2 mmol), and aryne precursor (1.2 mmol) were
stirred at ¢78 88C for 45 min, then warmed to 0 88C. The resulting
intermediate Grignard was quenched with R1R2N¢OBz (1.5 mol) in the
presence of CuCl (10 mol%) and phenanthroline (10 mol%; see SI).
[a] An additional zincation step was performed by adding ZnCl2
(0.5 equiv) after the initial anilide addition. Bz = benzoyl, Boc= tert-
butyloxycarbonyl.

Scheme 4. Vortioxetine synthesis. TFA = trifluoroacetic acid.

..Angewandte
Communications

2158 www.angewandte.org Ó 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2015, 54, 2156 –2159

 15213773, 2015, 7, D
ow

nloaded from
 https://onlinelibrary.w

iley.com
/doi/10.1002/anie.201410751 by B

ursa U
ludag U

niversity K
utuphane ve D

okum
antasyon, W

iley O
nline L

ibrary on [21/07/2025]. See the T
erm

s and C
onditions (https://onlinelibrary.w

iley.com
/term

s-and-conditions) on W
iley O

nline L
ibrary for rules of use; O

A
 articles are governed by the applicable C

reative C
om

m
ons L

icense

http://dx.doi.org/10.1002/anie.201000526
http://dx.doi.org/10.1002/anie.201000526
http://dx.doi.org/10.1002/ange.201000526
http://dx.doi.org/10.1002/ange.201000526
http://dx.doi.org/10.1039/b409870f
http://dx.doi.org/10.1039/b409870f
http://dx.doi.org/10.1021/jo051096o
http://dx.doi.org/10.1021/jo051096o
http://dx.doi.org/10.1021/jm00159a035
http://dx.doi.org/10.1021/jm00159a035
http://www.angewandte.org


[2] F. Terrier, Modern Nucleophilic Aromatic Substitution, Wiley-
VCH, Weinheim, 2013, ISBN 978 – 3527318612.

[3] a) D. Tsvelikhovsky, S. L. Buchwald, J. Am. Chem. Soc. 2011,
133, 14228 – 14231; b) T. Dahl, C. W. Tornøe, B. Bang-Andersen,
P. Nielsen, M. Jørgensen, Angew. Chem. Int. Ed. 2008, 47, 1726 –
1728; Angew. Chem. 2008, 120, 1750 – 1752.

[4] a) B. Michel, M. F. Greaney, Org. Lett. 2014, 16, 2684 – 2684;
b) J.-A. Garc�a-Lýpez, M. F. Greaney, Org. Lett. 2014, 16, 2338 –
2341; c) C. Hall, J. L. Henderson, G. Ernouf, M. F. Greaney,
Chem. Commun. 2013, 49, 7602 – 7604; d) T. Pirali, F. Zhang,
A. H. Miller, J. L. Head, D. McAusland, M. F. Greaney, Angew.
Chem. Int. Ed. 2012, 51, 1006 – 1009; Angew. Chem. 2012, 124,
1030 – 1033; e) D. McAusland, S. Seo, D. G. Pintori, J. Finlayson,
M. F. Greaney, Org. Lett. 2011, 13, 3667 – 3669; f) K. Biswas,
M. F. Greaney, Org. Lett. 2011, 13, 4946 – 4949; g) A. A. Cant, L.
Roberts, M. F. Greaney, Chem. Commun. 2010, 46, 8671 – 8673;
h) A. A. Cant, G. H. V. Bertrand, J. L. Henderson, L. Roberts,
M. F. Greaney, Angew. Chem. Int. Ed. 2009, 48, 5199 – 5202;
Angew. Chem. 2009, 121, 5301 – 5304.

[5] Recent reviews on aryne chemistry: a) P. M. Tadross, B. M.
Stoltz, Chem. Rev. 2012, 112, 3550 – 3577; b) C. M. Gampe, E. M.
Carreira, Angew. Chem. Int. Ed. 2012, 51, 3766 – 3778; Angew.
Chem. 2012, 124, 3829 – 3842; c) A. V. Dubrovskiy, N. A. Mar-
kina, R. C. Larock, Org. Biomol. Chem. 2013, 11, 191 – 218;
d) R. W. Hoffmann, K. Suzuki, Angew. Chem. Int. Ed. 2013, 52,
2655 – 2656; Angew. Chem. 2013, 125, 2717 – 2718; e) C. Hol-
den (n¦e Hall), M. F. Greaney, Angew. Chem. Int. Ed. 2014, 53,
5746 – 5749; Angew. Chem. 2014, 126, 5854 – 5857; f) A. Bhunia,
A. T. Biju, Synlett 2014, 25, 608 – 614; g) E. Goetz, T. K. Shah,
N. K. Garg, Chem. Commun. 2015, 51, 34 – 45.

[6] Seminal work: R. Huisgen, H. Rist, Justus Liebigs Ann. Chem.
1955, 594, 137.

[7] Selected examples: a) P. D. Pansegrau, W. F. Rieker, A. I.
Meyers, J. Am. Chem. Soc. 1988, 110, 7178 – 7184; b) H.
Tomori, J. M. Fox, S. L. Buchwald, J. Org. Chem. 2000, 65,
5334 – 5341; c) H. Yoshida, H. Fukushima, J. Ohshita, A. Kunai,
Angew. Chem. Int. Ed. 2004, 43, 3935 – 3938; Angew. Chem.
2004, 116, 4025 – 4028; d) T. T. Jayanth, M. Jeganmohan, C.-H.
Cheng, Org. Lett. 2005, 7, 2921 – 2924; e) I. Larrosa, M. I.
Da Silva, P. M. Gýmez, P. Hannen, E. Ko, S. R. Lenger, S. R.
Linke, A. J. P. White, D. Wilton, A. G. M. Barrett, J. Am. Chem.
Soc. 2006, 128, 14042 – 14043; f) J. L. Henderson, A. S. Edwards,
M. F. Greaney, J. Am. Chem. Soc. 2006, 128, 7426 – 7427; g) F.
Berti, P. Crotti, G. Cassano, M. Pineschi, Synlett 2012, 2463 –
2468; h) T. Truong, M. Mesgar, K. K. A. Le, O. Daugulis, J. Am.
Chem. Soc. 2014, 136, 8568 – 8576; i) A. Nagaki, D. Ichinari, J.-i.
Yoshida, J. Am. Chem. Soc. 2014, 136, 12245 – 12248.

[8] The two-component coupling of benzyne and X¢Y components
through s-bond insertion is well described. Reviews: a) D. PeÇa,
D. PÀrez, E. Guiti�n, Angew. Chem. Int. Ed. 2006, 45, 3579 –
3581; Angew. Chem. 2006, 118, 3659 – 3661; b) H. Yoshida, K.
Takaki, Synlett 2012, 1725 – 1732; recent examples: c) M. Ala-
jarin, C. Lopez-Leonardo, R. Raja, R.-A. Orenes, Org. Lett.
2011, 13, 5668 – 5671; d) C. E. Hendrick, S. L. McDonald, Q.
Wang, Org. Lett. 2013, 15, 3444 – 3447; e) J. R. Hwu, Y. C. Hsu,
Chem. Eur. J. 2011, 17, 4727 – 4731; f) J. Chen, T. Murafuji, R.
Tsunashima, Organometallics 2011, 30, 4532 – 4538; g) C. Shen,
G. Yang, W. Zhang, Org. Lett. 2013, 15, 5722 – 5725; h) D.
Rodr�guez-Lojo, A. Cobas, D. PeÇa, D. P¦rez, E. Guiti�n, Org.
Lett. 2012, 14, 1363 – 1365; i) H. Yoshida, S. Kawashima, Y.
Takemoto, K. Okada, J. Ohshita, K. Takaki, Angew. Chem. Int.
Ed. 2012, 51, 235 – 238; Angew. Chem. 2012, 124, 239 – 242; j) H.

Yoshida, R. Yoshida, K. Takaki, Angew. Chem. Int. Ed. 2013, 52,
8629 – 8632; Angew. Chem. 2013, 125, 8791 – 8794.

[9] For heteroatom addition to benzyne followed by trapping with
molecular iodine or oxygen, see: a) Z. He, T. F. Jamison, Angew.
Chem. Int. Ed. 2014, 53, 3353 – 3357; Angew. Chem. 2014, 126,
3421 – 3425; b) Y. Nagashima, R. Takita, K. Yoshida, K. Hirano,
M. Uchiyama, J. Am. Chem. Soc. 2013, 135, 18730 – 18733.

[10] a) W. Lin, I. Sapountzis, P. Knochel, Angew. Chem. Int. Ed. 2005,
44, 4258 – 4261; Angew. Chem. 2005, 117, 4330 – 4333; b) I.
Sapountzis, W. Lin, M. Fischer, P. Knochel, Angew. Chem. Int.
Ed. 2004, 43, 4364 – 4366; Angew. Chem. 2004, 116, 4464 – 4466;
c) W. Lin, F. Ilgen, P. Knochel, Tetrahedron Lett. 2006, 47, 1941 –
1944; d) W. Lin, L. Chen, P. Knochel, Tetrahedron 2007, 63,
2787 – 2797.

[11] Reviews: a) X. Yan, X. Yang, C. Xi, Catal. Sci. Technol. 2014, 4,
4169 – 4177; b) M.-L. Louillat, F. W. Patureau, Chem. Soc. Rev.
2014, 43, 901 – 910.

[12] M. J. Campbell, J. S. Johnson, Org. Lett. 2007, 9, 1521 – 1524.
[13] A. M. Berman, J. S. Johnson, J. Am. Chem. Soc. 2004, 126, 5680 –

5681.
[14] For a recent discussion on aryne selectivity, see: J. M. Medina,

J. L. Mackey, N. K. Garg, K. N. Houk, J. Am. Chem. Soc. 2014,
136, 15798 – 15805.

[15] For examples of nonselective addition to 1,2-naphthyne, see:
a) B. Rao, X. Zeng, Org. Lett. 2014, 16, 314 – 317; b) T. Jin, Y.
Yamamoto, Angew. Chem. Int. Ed. 2007, 46, 3323 – 3325; Angew.
Chem. 2007, 119, 3387 – 3389; c) A. T. Biju, F. Glorius, Angew.
Chem. Int. Ed. 2010, 49, 9761 – 9764; Angew. Chem. 2010, 122,
9955 – 9958; d) E. R¦mond, A. Tessier, F. R. Leroux, J. Bayar-
don, S. Juge, Org. Lett. 2010, 12, 1568 – 1571; e) K. Z. Łaczkow-
ski, D. Garc�a, D. PeÇa, A. Cobas, D. P¦rez, E. Guiti�n, Org.
Lett. 2011, 13, 960 – 963; f) E. Yoshioka, H. Miyabe, Tetrahedron
2012, 68, 179 – 189; g) B. V. Lakshmi, U. K. Wefelscheid, U.
Kazmaier, Synlett 2011, 345 – 348.

[16] For quinolynes in synthesis, see: a) T. Kauffmann, F.-P.
Boettcher, J. Hansen, Justus Liebigs Ann. Chem. 1962, 659,
102 – 109; b) I.-C. Grig-Alexa, E. Garnier, A.-L. Finaru, L. Ivan,
C. Jarry, J.-M. L¦ger, P. CaubÀre, G. Guillaumet, Synlett 2004,
2000 – 2004; c) G. E. Collis, A. K. Burrell, Tetrahedron Lett.
2005, 46, 3653 – 3656; d) N. Saito, K. Nakamura, S. Shibano, S.
Ide, M. Minami, Y. Sato, Org. Lett. 2013, 15, 386 – 389; e) Y.
Fang, R. C. Larock, Tetrahedron 2012, 68, 2819 – 2826.

[17] Aryne distortion in 5,6-quinolyne is known to be low, correlating
with low regioselectivities in nucleophilic addition: A. E. Goetz,
S. M. Bronner, J. D. Cisneros, J. M. Melamed, R. S. Paton, K. N.
Houk, N. K. Garg, Angew. Chem. Int. Ed. 2012, 51, 2758 – 2762;
Angew. Chem. 2012, 124, 2812 – 2816.

[18] For an elegant rearrangement approach to the 1,2-aminoaniline
motif, see: A. Porzelle, M. D. Woodrow, N. C. O. Tomkinson,
Org. Lett. 2010, 12, 1492.

[19] CCDC 1028839 (7d) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.

[20] The synthesis of O-benzoyl N-hydroxylanilines requires the
preparation of N-alkylated N-hydroxyl anilines (either by N-
alkylation from N-hydroxyl aniline or by treatment of a nitro-
soalkane with PhMgBr), followed by an O-benzoylation step.
See for example: a) A. Porzelle, M. D. Woodrow, N. C. O.
Tomkinson, Eur. J. Org. Chem. 2008, 5135 – 5143; b) Y. Endo,
S. Hizatate, K. Shudo, Tetrahedron Lett. 1991, 32, 2803 – 2806.

[21] T. Ruhland, G. P. Smith, B. Bang-Andersen, A. Pueschl, E. K.
Moltzen, K. Andersen, Int. Patent WO 2003029232A1, 2003.

Angewandte
Chemie

2159Angew. Chem. Int. Ed. 2015, 54, 2156 –2159 Ó 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org

 15213773, 2015, 7, D
ow

nloaded from
 https://onlinelibrary.w

iley.com
/doi/10.1002/anie.201410751 by B

ursa U
ludag U

niversity K
utuphane ve D

okum
antasyon, W

iley O
nline L

ibrary on [21/07/2025]. See the T
erm

s and C
onditions (https://onlinelibrary.w

iley.com
/term

s-and-conditions) on W
iley O

nline L
ibrary for rules of use; O

A
 articles are governed by the applicable C

reative C
om

m
ons L

icense

http://dx.doi.org/10.1021/ja206229y
http://dx.doi.org/10.1021/ja206229y
http://dx.doi.org/10.1002/anie.200705209
http://dx.doi.org/10.1002/anie.200705209
http://dx.doi.org/10.1002/ange.200705209
http://dx.doi.org/10.1021/ol500959e
http://dx.doi.org/10.1021/ol5006246
http://dx.doi.org/10.1021/ol5006246
http://dx.doi.org/10.1039/c3cc44529a
http://dx.doi.org/10.1002/anie.201106150
http://dx.doi.org/10.1002/anie.201106150
http://dx.doi.org/10.1002/ange.201106150
http://dx.doi.org/10.1002/ange.201106150
http://dx.doi.org/10.1021/ol201413r
http://dx.doi.org/10.1021/ol202049v
http://dx.doi.org/10.1039/c0cc02547j
http://dx.doi.org/10.1002/anie.200901410
http://dx.doi.org/10.1002/ange.200901410
http://dx.doi.org/10.1021/cr200478h
http://dx.doi.org/10.1002/anie.201107485
http://dx.doi.org/10.1002/ange.201107485
http://dx.doi.org/10.1002/ange.201107485
http://dx.doi.org/10.1039/c2ob26673c
http://dx.doi.org/10.1002/anie.201209041
http://dx.doi.org/10.1002/anie.201209041
http://dx.doi.org/10.1002/ange.201209041
http://dx.doi.org/10.1002/jlac.19555940204
http://dx.doi.org/10.1002/jlac.19555940204
http://dx.doi.org/10.1021/ja00229a037
http://dx.doi.org/10.1021/jo000691h
http://dx.doi.org/10.1021/jo000691h
http://dx.doi.org/10.1002/anie.200460009
http://dx.doi.org/10.1002/ange.200460009
http://dx.doi.org/10.1002/ange.200460009
http://dx.doi.org/10.1021/ol050859r
http://dx.doi.org/10.1021/ja0662671
http://dx.doi.org/10.1021/ja0662671
http://dx.doi.org/10.1021/ja0615526
http://dx.doi.org/10.1021/ja504886x
http://dx.doi.org/10.1021/ja504886x
http://dx.doi.org/10.1021/ja5071762
http://dx.doi.org/10.1055/s-0031-1290401
http://dx.doi.org/10.1021/ol202395s
http://dx.doi.org/10.1021/ol202395s
http://dx.doi.org/10.1021/ol401518c
http://dx.doi.org/10.1002/chem.201001735
http://dx.doi.org/10.1021/om200228x
http://dx.doi.org/10.1021/ol402748u
http://dx.doi.org/10.1021/ol300439r
http://dx.doi.org/10.1021/ol300439r
http://dx.doi.org/10.1002/anie.201106706
http://dx.doi.org/10.1002/anie.201106706
http://dx.doi.org/10.1002/ange.201106706
http://dx.doi.org/10.1002/anie.201302783
http://dx.doi.org/10.1002/anie.201302783
http://dx.doi.org/10.1002/ange.201302783
http://dx.doi.org/10.1002/anie.201310572
http://dx.doi.org/10.1002/anie.201310572
http://dx.doi.org/10.1002/ange.201310572
http://dx.doi.org/10.1002/ange.201310572
http://dx.doi.org/10.1021/ja409748m
http://dx.doi.org/10.1002/anie.200500443
http://dx.doi.org/10.1002/anie.200500443
http://dx.doi.org/10.1002/ange.200500443
http://dx.doi.org/10.1002/anie.200460417
http://dx.doi.org/10.1002/anie.200460417
http://dx.doi.org/10.1002/ange.200460417
http://dx.doi.org/10.1016/j.tetlet.2006.01.071
http://dx.doi.org/10.1016/j.tetlet.2006.01.071
http://dx.doi.org/10.1016/j.tet.2007.01.027
http://dx.doi.org/10.1016/j.tet.2007.01.027
http://dx.doi.org/10.1039/c3cs60318k
http://dx.doi.org/10.1039/c3cs60318k
http://dx.doi.org/10.1021/ol0702829
http://dx.doi.org/10.1021/ja049474e
http://dx.doi.org/10.1021/ja049474e
http://dx.doi.org/10.1021/ol403346x
http://dx.doi.org/10.1002/anie.200700101
http://dx.doi.org/10.1002/ange.200700101
http://dx.doi.org/10.1002/ange.200700101
http://dx.doi.org/10.1002/anie.201005490
http://dx.doi.org/10.1002/anie.201005490
http://dx.doi.org/10.1002/ange.201005490
http://dx.doi.org/10.1002/ange.201005490
http://dx.doi.org/10.1016/j.tet.2011.10.072
http://dx.doi.org/10.1016/j.tet.2011.10.072
http://dx.doi.org/10.1002/jlac.19626590111
http://dx.doi.org/10.1002/jlac.19626590111
http://dx.doi.org/10.1016/j.tetlet.2005.03.164
http://dx.doi.org/10.1016/j.tetlet.2005.03.164
http://dx.doi.org/10.1021/ol303352q
http://dx.doi.org/10.1016/j.tet.2012.02.002
http://dx.doi.org/10.1002/anie.201108863
http://dx.doi.org/10.1002/ange.201108863
http://dx.doi.org/10.1021/ol100196a
http://dx.doi.org/10.1002/ejoc.200800672
http://dx.doi.org/10.1002/ejoc.200800672
http://dx.doi.org/10.1016/0040-4039(91)85091-I
http://www.angewandte.org