Employing arynes in transition-metal-free monoarylation of aromatic tertiary amines

Article abstract of DOI:10.1021/ol4029258

The highly monoselective N-arylation of aromatic tertiary amines using a transition-metal-free approach using arynes has been developed. The reaction afforded functionalized diaryl amines in moderate to excellent yield. High levels of functional group compatibility especially with halogen containing substrates, dyes and donor-acceptor systems, and high yields of products are the notable features of the present reaction.

Full text of DOI:10.1021/ol4029258

ORGANIC
LETTERS
2013
Vol. 15, No. 21
5452–5455
Employing Arynes in Transition-Metal-
Free Monoarylation of Aromatic Tertiary
Amines
Sachin Suresh Bhojgude, Trinadh Kaicharla, and Akkattu T. Biju*
Organic Chemistry Division, CSIR-National Chemical Laboratory (CSIR-NCL),
Dr. Homi Bhabha Road, Pune - 411008, India
at.biju@ncl.res.in
Received September 5, 2013
ABSTRACT
The highly monoselective N-arylation of aromatic tertiary amines using a transition-metal-free approach using arynes has been developed. The
reaction afforded functionalized diaryl amines in moderate to excellent yield. High levels of functional group compatibility especially with halogen
containing substrates, dyes and donorꢀacceptor systems, and high yields of products are the notable features of the present reaction.
Aromatic amines are ubiquitous in various natural
products, pharmaceuticals, agrochemicals, dyes, and ma-
terials and are useful synthetic building blocks.1 Tradition-
ally, methods such as substitution on an aromatic system
with nucleophilic amine functionality, installation of the
nitro group on an aromatic ring followed by reduction,
and arylation of the N-containing functional group using
copper following the UllmannꢀGoldberg protocol are
the different ways of constructing the aromatic carbonꢀ
nitrogen bonds.2 However, with the advent of transition-
metal catalysis, the N-arylation of amines can be easily
realized by the BuchwaldꢀHartwig coupling (coupling of
aryl halides with primary or secondary amines in presence
of Pd-catalyst), Ullmann-type coupling (reaction of aryl
halides with amines in presence of Cu), and the Chanꢀ
Lam coupling (coupling of an organoboron reagent with
NꢀH functionality) (Scheme 1).3 Moreover, the synthetic
utility of organometallic reagents derived from B, Mg,
Zn, etc. in a transition-metal-catalyzed amination reaction
with an electrophilic source of nitrogen, and CꢀH activa-
tion of (hetero)aromatic rings have been useful for the
construction of CarylꢀN bonds.4 Recently, transition-
metal-freeN-arylation reactions employing organoboronic
acid derivatives represent an alternative methodology for
the CarylꢀN bond-forming reactions.5 Interestingly, how-
ever, whereas the transition-metal-catalyzed arylation of
primary and secondary amines is well-established, the
analogous CꢀN bondconstruction using aromatictertiary
amines, to the best of our knowledge, has not been
reported. Herein, we report an efficient and facile transi-
tion-metal-free, monoselective N-arylation of aromatic
tertiary amines using arynes as the aryl source. Notably,
the present procedure is efficient for the selective mono-
arylation of the ꢀNMe2 group and the method is applic-
able to several donorꢀacceptor systems and dyes.
Arynes are extremely electron-poor reactive intermedi-
ates in organic chemistry, and they are widely used for the
(1) (a) Amines: Synthesis Properties and Applications; Lawrence,
S. A., Ed.; Cambridge University Press: Cambridge, 2004. (b) Rappoport,
Z., Ed. The Chemistry of Anilines; Wiley-VCH: Weinheim, 2007. (c) Amino
Group Chemistry: From Synthesis to the Life Sciences; Ricci, A., Ed.;
Wiley-VCH: Weinheim, 2008.
(2) For reviews, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003,
2428. (c) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48,
6954.
(4) (a) Barker, T. J.; Jarvo, E. R. Synthesis 2011, 3954. (b) Cho, S. H.;
Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (c)
Zhang, M.; Zhang, A. Synthesis 2012, 1. (d) Kuhl, N.; Hopkinson,
M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51,
10236.
(5) For a highlight, see: (a) Coeffard, V.; Moreau, X.; Thomassigny,
C.; Greck, C. Angew. Chem., Int. Ed. 2013, 52, 5684. For recent reports,
see: (b) Mlynarski, S. N.; Karns, A. S.; Morken, J. P. J. Am. Chem. Soc.
€
(3) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Acc. Chem. Res. 2008, 41,
1534. See also for ChanꢀEvansꢀLam coupling: (c) Qiao, J. X.; Lam,
P. Y. S. Synthesis 2011, 829.
2012, 134, 16449. (c) Zhu, C.; Li, G.; Ess, D. H.; Falck, J. R.; Kurti, L.
J. Am. Chem. Soc. 2012, 134, 18253. (d) Xiao, Q.; Tian, L.; Tan, R.; Xia,
Y.; Qiu, D.; Zhang, Y.; Wang, J. Org. Lett. 2012, 14, 4230. (e) Ou, L.;
Shao, J.; Zhang, G.; Yu, Y. Tetrahedron Lett. 2011, 52, 1430.
r
10.1021/ol4029258
Published on Web 10/14/2013
2013 American Chemical Society

C-arylation was observed.12 The additive was found to be
essential for better yields, as the reaction without the
additive furnished the product in 33% yield.11
Scheme 1. Methods for Forming CarylꢀN Bonds
Scheme 2. Monoselective N-Arylation of N,N-Dimethylaniline
With the optimized reaction conditions in hand, we
then examined the substrate scope of this transition-
metal-free N-arylation reaction (Scheme 3). A variety of
N,N-dimethyl anilines having an electron-donating or
-withdrawing group at the 4-position of the aromatic ring
were well tolerated, furnishing the diarylamine derivatives
in good to excellent yields (3bꢀf). Electron-rich aldehydes
usually insert into arynes in a [2 þ 2] fashion.13 However,
4-dimethylamino benzaldehyde derivative 1g still afforded
the desired product in 30% yield. Moreover, substitution
at the 3- and 2-position of the aromatic ring of 1 and
the disubstitution resulted in smooth conversion to the
product (3hꢀk). It is noteworthy, that halides, which are
very unlikely to survive under transition-metal-catalyzed
reaction conditions,3 are well tolerated under the present
N-arylation protocol (3c, 3d, 3i). Gratifyingly, N,N-
dimethyl aniline derivatives bearing a phosphonate group,
double bond, and triple bond on the aromatic ring readily
underwent efficient N-arylation thereby further expanding
the scope of this reaction (3lꢀ3n). The naphthyl substi-
tuted amine furnished the corresponding product 3o in
98% yield, and even more interesting is that the dansyl
chloride afforded the product 3p in 61% yield. Interest-
ingly, challenging substrates such as Leucomalachite green
underwent efficient N-arylation leading to the formation
of desired product 3q in 78% yield. Delightfully, N,N-
dimethyl anilines derived from donorꢀacceptor systems
resulted in a smooth N-arylation reaction affording the
desired products signifying the versatility of the present
reaction (3rꢀt).14
synthesis of several 1,2-disubstituted benzene derivatives
of complex structure.6 Due to the high electrophilicity and
extremely strained carbonꢀcarbon triple bond, arynes
undergo facile insertion into elementꢀelement bonds lead-
ing to multisubstituted arenes of synthetic value.7 In 2003,
Larock et al. reported the insertion of arynes into the NꢀH
bond of primary and secondary amines leading to the
N-arylated products.8 However, this method was not
applicable for the arylation of tertiary amines. To address
this issue based on our experience in aryne chemistry,9 we
initiatedthepresentstudybytreatingN,N-dimethylaniline
1a with the aryne generated in situ from 2-(trimethylsilyl)-
aryl triflate 2a10 using KF and 18-crown-6 in the pre-
sence of ammonium bicarbonate as an additive. Interest-
ingly, the reaction afforded the N-methyl-N-phenylaniline
3a in 95% yield (Scheme 2).11 The present method is
highly monoselective, and no product derived from the
(6) For recent reviews on aryne chemistry, see: (a) Wu, C.; Shi, F.
Asian J. Org. Chem. 2013, 2, 116. (b) Dubrovskiy, A. V.; Markina, N. A.;
Larock, R. C. Org. Biomol. Chem. 2013, 11, 191. (c) Tadross, P. M.;
Stoltz, B. M. Chem. Rev. 2012, 112, 3550. (d) Gampe, C. M.; Carreira,
E. M. Angew. Chem., Int. Ed. 2012, 51, 3766. (e) Bhunia, A.; Yetra, S. R.;
Biju, A. T. Chem. Soc. Rev. 2012, 41, 3140. (f) Bhojgude, S. S.; Biju, A. T.
Angew. Chem., Int. Ed. 2012, 51, 1520. (g) Okuma, K. Heterocycles 2012,
85, 515. (h) Sanz, R. Org. Prep. Proced. Int. 2008, 40, 215. (i) Yoshida,
H.; Ohshita, J.; Kunai, A. Bull. Chem. Soc. Jpn. 2010, 83, 199.
(7) For a recent account on aryne insertions, see: (a) Yoshida, H.;
Takaki, K. Synlett 2012, 23, 1725. For selected recent reports, see:
(b) Stephens, D.; Zhang, Y.; Cormier, M.; Chavez, G.; Arman, H.;
Larionov, O. V. Chem. Commun. 2013, 49, 6558. (c) Kim, J.; Stoltz,
B. M. Tetrahedron Lett. 2012, 53, 4994. (d) Fang, Y.; Rogness, D. C.;
Larock, R. C.; Shi, F. J. Org. Chem. 2012, 77, 6262. (e) Okuma, K.;
Itoyama, R.; Sou, A.; Nagahora, N.; Shioj, K. Chem. Commun. 2012, 48,
Next, we evaluated the effect of varying the substituents
on the aryne precursor 2 (Table 1). Electronically different
4,5-disubstituted symmetrical aryne precursors2bꢀd read-
ily afforded the diphenylamine derivatives 3uꢀw in excel-
lent yields (entries 1ꢀ3). Moreover, the 3,6-dimethyl sub-
stituted symmetrical aryne precursor 2e worked well to
afford the product 3x in 64% yield (entry 4). Additionally,
3-methoxy benzyne generated from 2fand the naphthalyne
~
ꢀ
ꢀ
11145. (f) Rodrıguez-Lojo, D.; Cobas, A.; Pena, D.; Perez, D.; Guitian,
E. Org. Lett. 2012, 14, 1363. (g) Mohanan, K.; Coquerel, Y.; Rodriguez,
J. Org. Lett. 2012, 14, 4686. (h) Dhokale, R. A.; Mhaske, S. B. Org. Lett.
2013, 15, 2218. (i) Hendrick, C. E.; McDonald, S. L.; Wang, Q. Org.
Lett. 2013, 15, 3444. (j) Yoshida, H.; Yoshida, R.; Takaki, K. Angew.
~
ꢀ
Chem., Int. Ed. 2013, 52, 8629. For a highlight, see: (k) Pena, D.; Perez,
D.; Guitian, E. Angew. Chem., Int. Ed. 2006, 45, 3579.
ꢀ
(8) (a) Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673. (b) Liu, Z.;
Larock, R. C. J. Org. Chem. 2006, 71, 3198. It may be noted that Larock
et al. observed the arylation of in situ generated N,N-dimethyl aniline in
the reaction of ketone-derived hydrazones with arynes. For details, see:
(c) Dubrovskiy, A. V.; Larock, R. C. J. Org. Chem. 2012, 77, 11232.
(9) (a) Bhunia, A.; Porwal, D.; Gonnade, R. G.; Biju, A. T. Org. Lett.
2013, 15, 4620. (b) Bhunia, A.; Roy, T.; Pachfule, P.; Rajamohanan,
P. R.; Biju, A. T. Angew. Chem., Int. Ed. 2013, 52, 10040. (c) Kaicharla,
T.; Bhojgude, S. S.; Biju, A. T. Org. Lett. 2012, 14, 6238. (d) Bhojgude,
S. S.; Kaicharla, T.; Bhunia, A.; Biju, A. T. Org. Lett. 2012, 14, 4098.
(10) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211. For a modified procedure for the synthesis of the triflate, see: (b)
(12) (a) Pirali, T.; Zhang, F.; Miller, A. H.; Head, J. L.; McAusland,
D.; Greaney, M. F. Angew. Chem., Int. Ed. 2012, 51, 1006. See also: (b)
Cant, A. A.; Bertrand, G. H. V.; Henderson, J. L.; Roberts, L.; Greaney,
M. F. Angew. Chem., Int. Ed. 2009, 48, 5199.
(13) Yoshida, H.; Watanabe, M.; Fukushima, H.; Ohshita, J.; Kunai,
A. Org. Lett. 2004, 6, 4049.
(14) It may be noted that aliphatic tertiary amines such as N,N-
dimethyloctylamine and sterically hindered aromatic amines such as N,
N,2,4,6-pentamethylaniline did not afford the N-arylated product under
the optimized conditions.
~
ꢀ
ꢀ
Pena, D.; Cobas, A.; Perez, D.; Guitian, E. Synthesis 2002, 1454.
(11) For details, see the Supporting Information.
Org. Lett., Vol. 15, No. 21, 2013
5453

Table 1. Variation of the Aryne Moietya
Scheme 3. Substrate Scope of the N-Arylation Reaction:
Variation of the Tertiary Aminesa
a General conditions: 1a (0.50 mmol), 2 (0.60 mmol), KF (2.4 equiv),
18-crown-6 (2.4 equiv), THF (2.0 mL), 60 °C and 12 h. Yields of the
isolated products are given. b The regioisomer ratio was determined by
1H NMR analysis.
a General conditions: 1 (0.50 mmol), 2a (0.60 mmol), KF (2.4 equiv),
18-crown-6 (2.4 equiv), THF (2.0 mL), 60 °C and 12 h. Yields of the
isolated products are given. b Reaction was run on 0.25 mmol scale. c The
reaction was carried out using 2.0 equiv of 2a and 4.0 equiv each of KF
and 18-crown-6.
Scheme 4. Experiments to Illustrate Selective Monoarylation
derived from 2g furnished single regioisomers 3y and 3z in
excellent yield (entries 5, 6). Finally, the unsymmetrical
benzyne derived from 2h underwent efficient N-arylation
to deliver an inseparable mixture of regioisomers 3aa and
3aa0 in 93% overall yield (entry 7).
We carried out a series of experiments to probe the
mechanism of this unique N-arylation reaction. To gain
insight into the nature of the arylation reaction and
the stability of product 3a under the reaction conditions,
3a was treated with aryne precursor 2a under the opti-
mized reaction conditions (Scheme 4, eq 1). This reaction
returned 3a quantitatively without the formation of any
detectable amount of diarylated product 4. Moreover,
when 1a was treated with an excess of 2a, KF, and [18]
crown-6, the reaction delivered only 3a and 4 was not
detected (eq 2).11 These observations tend to indicate that
the present arylation reaction is highly monoselective
under the optimized conditions.15
The mechanistic rationale for this transition-metal-free
transformation is shown in Scheme 5. The reaction is likely
initiated by the generation of aryne by the fluoride induced
1,2-elimination of 2a. The nucleophilic addition of N,N-
dimethylaniline 1a to the aryne generates the zwitterionic
intermediate 5, which was protonated to form the dimethyl
diphenyl ammonium salt 6. Demethylation induced by the
fluoride ion or the basic reaction medium furnishes the
final product 3a.16,17
(15) Possibly, the lone pair of electrons on nitrogen in 1a is more
available for nucleophilic attack on aryne. However, in the case of 3a,
since the lone pair of electrons on nitrogen is delocalized between two
benzene rings, it may not be available for nucleophilic attack on aryne.
(16) For a related demethylation of quaternary ammonium salt in the
presence of nucleophilic fluoride media, see ref 8c.
(17) For experiments indicating the role of fluoride ion or base in the
demethylation step, see the Supporting Information.
5454
Org. Lett., Vol. 15, No. 21, 2013

Scheme 5. Plausible Reaction Mechanism
Scheme 7. Mechanistic Experiments
A strong indication for the presence of 6 comes from the
fact that the reaction of tertiary amine 1b with aryne pre-
cursor 2c in the presence of CsF resulted in smooth forma-
tion of the quaternary ammonium salt 6 HOTf18 in 92%
3
along with 6% of the arylated product 3bb(Scheme6, eq3).
Scheme 8. Arylation of N,N-Diethyl Aniline and Tetrahydroi-
soquinoline
Scheme 6. Experiments to Confirm 6 HOTf as the Intermediate
3
product 10in 61% yield presumably bythe elimination of a
molecule of ethylene (Scheme 8, eq 7). Moreover, tetra-
hydroisoquinoline 11 underwent efficient cascade aryla-
tion involving the initial NꢀH insertion of aryne followed
by the arylation of the resultant N-arylamine leading to the
styrene derivative 12 in 86% yield (eq 8).
In conclusion, we have developed a transition-metal-free
and highly monoselective N-arylation of aromatic tertiary
amines using arynes. A broad substrate scope, high levels
of functional group compatibility especially with halogen
containing substrates, dyes, and donorꢀacceptor systems,
and high yields of products are the notable features of the
present reaction.
Moreover, subjecting the salt 6 HOTf under the optimized
reaction conditions resulted in the formation of the desired
arylated product 3bb in 73% yield (eq 4).
3
To shed light on protonation of the zwitterionic inter-
mediate 5, an experiment using D2O as the additive was
performed. Treatment of 1a with 2e in the presence of a
fluoride source and D2O afforded the desired product 3x-d
in 69% yield with 68% deuterium incorporation at the
2-position (Scheme 7, eq 5). This indicates the role of
additive in protonating the zwitterionic intermediate 5.
Moreover, to test the possibility of the competing O-aryla-
tion under the reaction conditions, the amine 1u was
treated with 2a under the optimized conditions (eq 6).
The reaction afforded the N-arylated product 3cc in 30%
yield along with the O-methylated product 7 in 53% yield,
which is likely formed by the demethylation of intermedi-
ate 6 by the phenol 3cc. In addition, the product 8 derived
from the O-arylation of 3cc was observed in 14% yield.
Furthermore, this novel arylation reaction is not limited
to N,N-dimethyl aniline derivatives. Interestingly, N,N-
diethyl aniline 9 resulted in the formation of N-arylated
Acknowledgment. This work was supported by Science
and Engineering Research Board, DST, Govt. of India
(Grant No. SR/S1/OC/12/2012). S.S.B. and T.K. thank
CSIR-New Delhi for the award of a research fellowship.
We thank Dr. P. R. Rajamohanan (CSIR-NCL) for NMR
spectra, Dr. J. Nithyanandhan (CSIR-NCL) for kindly pro-
viding some aniline derivatives, and Ms. B. Santhakumari
(CSIR-NCL) for the HRMS data.
Supporting Information Available. Detailed experimen-
tal procedures, mechanistic experiments, and character-
ization data of all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) For a report on the synthesis of a similar adduct using arynes,
see: Okuma, K.; Nojima, A.; Nakamura, Y.; Matsunaga, N.; Nagahora,
N.; Shioji, K. Bull. Chem. Soc. Jpn. 2011, 84, 328.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 21, 2013
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