Palladium-Catalyzed N-Arylation of Iminodibenzyls and Iminostilbenes with Aryl- and Heteroaryl Halides

Article abstract of DOI:10.1002/chem.201603449

Compounds containing the iminodibenzyl and iminostilbene ring systems are prevalent in medicinal targets and functional materials. Herein, we report palladium-catalyzed conditions for the N-arylation of these ring systems. This protocol could be applied to a variety of (hetero)aryl chloride and bromide substrates, including ones, which are sterically hindered or those containing a variety of functional groups. Use of the fourth-generation palladacycle precatalyst gave good to excellent yields by using low palladium-catalyst loadings (0.1 to 1 mol %).

Full text of DOI:10.1002/chem.201603449

A Journal of
Accepted Article
Title: Palladium catalyzed N-Arylation of Iminodibenzyls and Iminostilbenes with Aryl
and Hetero-Aryl Halides
Authors: Wenliang Huang; Stephen L. Buchwald
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201603449
Link to VoR: http://dx.doi.org/10.1002/chem.201603449
Supported by

Chemistry - A European Journal
10.1002/chem.201603449
COMMUNICATION
Palladium catalyzed N-Arylation of Iminodibenzyls and
Iminostilbenes with Aryl and Hetero-Aryl Halides
Wenliang Huang,[a] and Stephen L. Buchwald*[a]
Abstract: Compounds containing the iminodibenzyl and
the palladium catalyzed N-arylation of iminodibenzyl and
iminostilbene have appeared sporadically in the literature,
generally with unfunctionalized aryl halide substrates, and high
catalyst loadings are frequently employed (2-5 mol% Pd).[3a, 3e, 3i,
Alternatively, Ullmann-type conditions for N-arylation requiring
a stoichiometric copper promoter and high temperatures have
also been utilized.[3a]
iminostilbene ring systems are prevalent in medicinal targets and
functional materials.
Herein we report palladium catalyzed
conditions for the N-arylation of these ring systems. This protocol
could be applied to a variety of (hetero)aryl chloride and bromide
substrates, including ones which are sterically hindered or those
containing a variety of functional groups. Use of the fourth
generation palladacycle precatalyst allowed good to excellent yields
to be obtained using low palladium catalyst loadings (0.1 to 1 mol%).
7]
In the course of investigating the photophysical properties of
iminodibenzyls and iminostilbenes as candidates for
electroluminescent materials, we required the preparation of a
series of N-arylated analogues that covered a range of steric
and electronic profiles. We therefore pursued the development
of a general palladium-catalyzed method for the N-arylation of
these heterocyclic compounds. Here, we present general
conditions for the N-arylation of iminodibenzyls and
iminostilbenes resulting from these studies. Notably, heteroaryl
halides and sterically hindered aryl halides, including ones that
are 2,6-disubstituted, are readily tolerated by this protocol, and
catalyst loadings of 0.1 mol% are sufficient in most cases.
Nitrogen-containing heterocyclic compounds are widespread
substructures in compounds of interest to the biological and
materials sciences.[1] As prevalent subclasses of these
compounds, iminodibenzyls and iminostilbenes (dibenzo fused
azepanes and azepines, respectively) occur in a variety of
pharmaceutical agents, including those with antihistamine,
analgesic, and antipsychotic properties.[2] Recently, their
derivatives have also emerged as promising alternatives to
diphenylamine, carbazole, and acridine-based compounds for
use as emissive or host materials for organic light emitting
diodes (OLEDs).[3] In some cases, the iminodibenzyl and
iminostilbene analogues showed enhanced thermostability or
photophysical properties relative to other diarylamino based
materials.[3a, 3b] Hence, general methods for the preparation of
these functionalized ring systems would be of considerable
value to investigators in these fields.
At the outset of our study, we selected 2,6-
dimethylbromobenzene and iminodibenzyl as model substrates
because of the potential challenges in forming a bond between
sterically hindered starting materials of this nature.[5,8] The
reaction optimization process is summarized in Table 1. We first
evaluated a series of dialkylbiarylphosphine ligands,[9] L1 to L5
using Pd2(dba)3 as the palladium source and NaOtBu as the
base (Entry 1-5). Out of the ligands explored, RuPhos (L5)
afforded the best result. This is consistent with our previous
finding that RuPhos is a suitable ligand for the arylation of
secondary anilines.[10] We then examined the effect of different
bases on the reaction outcome (see the Supporting Information
for the complete tabulation of results) and found that use of
Li(NSiMe3)2 resulted in improved reactivity (Entry 6). Finally, we
studied the impact of palladium sources. The use of the fourth
generation palladacycle precatalyst (Pd-L5-G4), which provides
efficient entry into LPd(0), was found to be most effective and
allowed a low catalyst loading of 0.1 mol% with no need for
additional ligand (Entry 9). In comparison, the third generation
precatalyst (Pd-L5-G3) provided significantly lower yield (Entry
Several palladium-catalyzed methods to construct the
iminodibenzyl or iminostilbene core have been reported,
including two-component cyclizations of amines[4] or anilines[5]
with 2,2'-dihalostilbene or dihalodibenzyl precursors, and one-
pot cascade reactions using single or dual-catalyst systems.[6]
However, two component cyclization approaches require starting
materials whose preparation are often nontrivial, while cascade
processes are generally narrower in scope and functional group
tolerance, or furnish the desired product in only moderate yield,
limiting the applicability of these methods. On the other hand,
only a handful of methods for the functionalization of the
preexisting ring system have been reported. A few examples of
8).
This finding could be rationalized by the generation of
carbazole as a byproduct in the activation of the Pd-L5-G3,[11]
which could competitively bind to palladium when a weakly
nucleophilic amine like iminodibenzyl is used as a coupling
partner. The fourth generation precatalyst that our lab has
developed avoids this problem, since N-methylcarbazole is
generated instead.[12]
Table 1. Optimization of N-arylation of iminodibenzyl (1) and iminostilbene
(2).[a]
[a]
Dr. W. Huang, Prof. S. L. Buchwald
Department of Chemistry
Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, MA 02139
E-mail: sbuchwal@mit.edu
FAX: (617) 253-3297
Supporting information for this article is given via a link at the end of
the document.

Chemistry - A European Journal
10.1002/chem.201603449
COMMUNICATION
emitted blue light under UV-light excitation and could be
potential luminescent materials.
Subsequently, we investigated the functional group tolerance
of this process. Although moderate to excellent yields could be
achieved for functionalized substrates, higher catalyst loadings
(up to 1 mol%) were sometimes required. In addition, a lower
temperature (80 ºC) was sometimes optimal for substrates
containing sensitive functional groups (1l-1n, 1q-1u). In some
cases, this protocol was found to be applicable to unprotected
substrates bearing acidic protons, such as those containing
phenol, alcohol, or amide functional groups, as long as an
additional equivalent of base was added (2.2 equiv. Li(NSiMe3)2
for 1l-1n). Several additional carbonyl functional groups,
including a diaryl ketone, a methyl ketone, an ester, and an
aldehyde, could also be handled, affording the coupled product
in moderate to excellent yield (63-94% yield). For aryl bromides
bearing an ester group, transformation of the ester to an amide
could compete with palladium catalyzed C-N cross coupling.
When iminodibenzyl is used as the amine coupling partner, the
reaction rate of C-N cross coupling is significant faster than
amide formation and thus an ethyl ester could be tolerated (1q).
For iminostilbene, it was necessary to use a t-butyl ester to
obtain a high yield of the desired C-N coupled product (2q).
When an aldehyde was present, additional base (2.2 equiv.
Li(NSiMe3)2) was likewise necessary to achieve good yield (1r).
Although no acidic proton is present, it is possible that the first
equivalent of base is consumed through addition into the
aldehyde to form a hemiaminal. In addition to its versatility in
organic synthesis, the nitrile group has been incorporated in
many OLED materials[13] because of its electron withdrawing
character and ability to extend the -system of the molecule.[14]
Thus, aryl bromides bearing ortho-, meta-, and para-nitrile
substituents were explored and were all found to be competent
substrates, providing the respective product in moderate to
excellent yield (66-93%).
Entry
[Pd] (mol%)
L (mol%)
L1 (2%)
L2 (2%)
L3 (2%)
L4 (1%)
L5 (1%)
L5 (1%)
L5 (0.2%)
--
Base
GC Yield
56%
2%
1
2
Pd2(dba)3 (1%)
Pd2(dba)3 (1%)
Pd2(dba)3 (1%)
Pd2(dba)3 (0.5%)
Pd2(dba)3 (0.5%)
Pd2(dba)3 (0.5%)
Pd2(dba)3 (0.1%)
Pd-L5-G3 (0.1%)
Pd-L5-G4 (0.1%)
Pd-L5-G4 (0.1%)
NaOtBu
NaOtBu
3
NaOtBu
10%
52%
64%
96%
88%
82%
96%
92%
4
NaOtBu
5
NaOtBu
6
Li(NSiMe3)2
Li(NSiMe3)2
LiN(SiMe3)2
Li(NSiMe3)2
Li(NSiMe3)2
7
8
9
--
10[b]
--
[a] Reaction conditions: 2-bromo-m-xylene and iminodibenzyl (1 mmol each),
base (1.1 mmol), 1,4-dioxane (2 mL), 100 ºC, 16 h. [b] Using iminostilbene as
nucleophile.
The conditions shown in Entries 9 and 10 of Table 1 were
adopted as the standard reaction conditions for exploration of
the substrate scope of this process.
The scope of the
transformation with respect to aryl halide was found to be broad
(Table 2). In most cases, the reactivity of iminodibenzyl (1,
products labeled as 1a-u) and iminostilbene (2, products labeled
as 2a-u) were comparable. For the sake of brevity, we will only
mention the iminodibenzyl product in the following discussion
unless a substantial difference was observed. Both electron rich
(1h) and electron poor (1i) aryl bromides underwent cross
coupling in excellent yield. Aryl bromides containing a variety of
ortho substituents, including methyl (1a, 1c), phenyl (1d),
trifluoromethyl (1i) and cyano (1u), also represented excellent
substrates. Furthermore, high yields were maintained when aryl
chloride was used in place of the aryl bromide under otherwise
identical reaction conditions (1a, 1b). However, when 1-chloro-4-
bromobenzene was used as the substrate, N-arylation took
place exclusively at the aryl bromide substituent (1k). Polycyclic
aryl bromides also provided high yields under standard
conditions (1e-g). Compound 1f, prepared in excellent yield
(96%) employing the current method, has been shown to exhibit
interesting photoluminescent properties as a consequence of its
distorted framework.[3i] In comparison, its previous synthesis
from identical starting materials using PEPPSI-IPr as the Pd
precatalyst (5 mol%) provided the coupling product in only 47%
yield. Preliminary results showed that compounds 1e-f and 2e-f
Heteroaryl groups are common structures in both
15]
pharmaceutical drugs and organic luminescent materials.[1,
and were thus explored as coupling partners (Table 3).
Heteroaryl bromides, such as 2-bromopyridine and 5-
bromoquinoline, were both excellent substrates, affording the
desired products in high yield under low catalyst loading (1v,
1w). In addition, the coupling of 5-membered heteroaryl
bromides, including 2-bromobenzo[b]thiophene and 3-bromo-
1H-indazole, was also possible and afforded the arylation
products (1x, 1y) in high and moderate yields, respectively.
Unprotected 5-bromoindole and 3-bromocarbazole similarly
provided high yield of the N-arylated product (1z, 1aa) with
relatively low catalyst loading (0.25 to 0.5 mol% Pd) when
additional base (2.2 equiv. LiN(SiMe3)2) was used. The selective
N-arylation of iminodibenzyl and iminostilbene in the presence of
indole or carbazole suggests that the seven-membered N-
heterocycles are better nucleophiles compared to the five-
membered ones under current reaction conditions. The
amination at the 3-position of carbazole provides access to
another potentially useful scaffold for the synthesis of OLED
materials.[16]

Chemistry - A European Journal
10.1002/chem.201603449
COMMUNICATION
Table 2. Substrate scope of aryl halide for the N-arylation of iminodibenzyl (1) and iminostilbene (2).[a]
[a] Reaction conditions (unless specified in parenthesis): aryl halide (1 mmol) and iminodibenzyl (1) or iminostilbene (2) (1 mmol), Li(NSiMe3)2 (1.1 mmol), 0.1
mol% Pd-L5-G4, 1,4-dioxane (2.0 mL), 100 ºC, 16 h. Yields are isolated yields after column chromatography, average of two runs (same for Table 3 and 4).
Table 3. Substrate scope of hetero-aryl bromide.[a]
In addition, we briefly studied the reactivity of functionalized
iminodibenzyl and iminostilbene starting materials, which are
present in a number of pharmaceutical products (Table 4).[2f, 4a,
6c]
N-arylation of 3-chloroiminodibenzyl (3) with 2,6-
dimethylbromobenzene provided the C-N coupled product in
high yield (86%) at low palladium loading (0.25 mol%) without
competitive amination of the aryl chloride (3a). The coupling of
3-trifluoromethyliminostilbene required a higher catalyst loading
(1 mol%) to give moderate yield (62%) presumably due to its
reduced nucleophilicity (4a). Notably, 3-azaiminostilbene (5)
underwent coupling to deliver the N-arylation product in
quantitative yield (5a). These results suggest that this protocol
may be applicable to the N-arylation of other functionalized
benzo-fused ring systems of interest in organic luminescent
materials and pharmaceutical drugs.
Table 4. Substrate scope of nucleophiles.[a]
[a] Reaction conditions (unless specified in parenthesis):
hetero-aryl halide (1 mmol) and iminodibenzyl (1) or
iminostilbene (2) (1 mmol), Li(NSiMe3)2 (1.1 mmol), 0.1 mol%
Pd-L5-G4, 1,4-dioxane (2.0 mL), 80 ºC, 16 h.

Chemistry - A European Journal
10.1002/chem.201603449
COMMUNICATION
Hirschfeld, S. Kasper, Int. J. Neuropsychoph. 2004, 7, 507; e) N. M. Tsankova,
O. Berton, W. Renthal, A. Kumar, R. L. Neve, E. J. Nestler, Nat. Neurosci.
2006, 9, 519; f) P. K. Gillman, Br. J. Pharmacol. 2007, 151, 737; g) J. M.
Gomez-Arguelles, R. Dorado, J. M. Sepulveda, R. Huet, F. G. Arrojo, E.
Aragon, A. Herrera, C. Trron, B. Anciones, J. Clin. Neurosci. 2008, 15, 516; h)
V. Krishnan, E. J. Nestler, Nature 2008, 455, 894; i) D. Lednicer, Strategies for
Organic Drugs Synthesis and Design, 2nd ed., Wiley, Hoboken, NJ, 2009; j) H.
Singh, N. Gupta, P. Kumar, S. K. Dubey, P. K. Sharma, Org. Process Res.
Dev. 2009, 13, 870; k) M. Tian, A. Abdelrahman, S. Weinhausen, S. Hinz, S.
Weyer, S. Dosa, A. El-Tayeb, C. E. Müller, Bioorg. Med. Chem. 2014, 22,
1077.
[3] a) B. E. Koene, D. E. Loy, M. E. Thompson, Chem. Mater. 1998, 10, 2235;
b) D. F. O'Brien, P. E. Burrows, S. R. Forrest, B. E. Koene, D. E. Loy, M. E.
Thompson, Adv. Mater. 1998, 10, 1108; c) T.-Y. Wu, Y. Chen, J. Polym. Sci. A
Polym. Chem. 2002, 40, 3847; d) M.-X. Yu, J.-P. Duan, C.-H. Lin, C.-H. Cheng,
Y.-T. Tao, Chem. Mater. 2002, 14, 3958; e) C.-T. Chen, J.-S. Lin, M. V. R. K.
Moturu, Y.-W. Lin, W. Yi, Y.-T. Tao, C.-H. Chien, Chem. Commun. 2005,
3980; f) T.-Y. Wu, M.-H. Tsao, F.-L. Chen, S.-G. Su, C.-W. Chang, H.-P.
Wang, Y.-C. Lin, W.-C. Ou-Yang, I.-W. Sun, Int. J. Mol. Sci. 2010, 11, 329; g)
Y.-H. Yu, C.-H. Huang, J.-M. Yeh, P.-T. Huang, Org. Electron. 2011, 12, 694;
h) Y. Suzuki, N. Fukui, K. Murakami, H. Yorimitsu, A. Osuka, Asian J. Org.
Chem. 2013, 2, 1066; i) S. Sasaki, K. Hattori, K. Igawa, G.-i. Konishi, J. Phys.
Chem. A 2015, 119, 4898; j) S. Sasaki, G. P. C. Drummen, G.-i. Konishi, J.
Mater. Chem. C 2016, 4, 2731.
[4] a) N. Božinović, I. Opsenica, B. A. Šolaja, Synlett 2013, 24, 49; b) H.
Christensen, C. Schjøth-Eskesen, M. Jensen, S. Sinning, H. H. Jensen, Chem.
Eur. J. 2011, 17, 10618.
[5] X. Zhang, Y. Yang, Y. Liang, Tetrahedron Lett. 2012, 53, 6406.
[6] a) D. Tsvelikhovsky, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132, 14048;
b) N. Della Ca, G. Maestri, M. Malacria, E. Derat, M. Catellani, Angew. Chem.
2011, 123, 12465; Angew. Chem. Int. Ed. 2011, 50, 12257; c) J. Tsoung, J.
Panteleev, M. Tesch, M. Lautens, Org. Lett. 2014, 16, 110.
[a] Reaction conditions (unless specified in parenthesis): 2-bromo-m-xylene
and nucleophile (3, 4, or 5) (1 mmol each), Li(NSiMe3)2 (1.1 mmol), 0.1 mol%
Pd-L5-G4, 1,4-dioxane (2.0 mL), 100 ºC, 16 h.
In summary, we have developed an efficient N-arylation
method for iminodibenzyls and iminostilbenes by employing a
RuPhos-based fourth generation palladacycle precatalyst. Due
to the importance of these two heterocyclic systems to
researchers in medicinal chemistry and organic materials, this
new general protocol should serve as a versatile synthetic tool
that complements currently available methods. Furthermore, the
operational simplicity of the protocol, in addition to the
commercial availability of the precatalyst and low catalyst
loadings required, are features that render the method reported
here practical for researchers in academic and industrial settings.
[7] a) P. D. Thornton, N. Brown, D. Hill, B. Neuenswander, G. H. Lushington,
C. Santini, K. R. Buszek, ACS Combinatorial Science 2011, 13, 443; b) K. H.
Chung, C. M. So, S. M. Wong, C. H. Luk, Z. Zhou, C. P. Lau, F. Y. Kwong,
Synlett 2012, 2012, 1181.
[8] Y. Nakayama, N. Yokoyama, H. Nara, T. Kobayashi, M. Fujiwhara, Adv.
Synth. Catal. 2015, 357, 2322.
[9] D. S. Surry, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 6338.
[10] a) D. Maiti, B. P. Fors, J. L. Henderson, Y. Nakamura, S. L. Buchwald,
Chem. Sci. 2011, 2, 57; b) D. S. Surry, S. L. Buchwald, Chem. Sci. 2011, 2, 27.
[11] N. C. Bruno, M. T. Tudge, S. L. Buchwald, Chem. Sci. 2013, 4, 916.
[12] N. C. Bruno, N. Niljianskul, S. L. Buchwald, J. Org. Chem. 2014, 79, 4161.
[13] a) T. Nakagawa, S.-Y. Ku, K.-T. Wong, C. Adachi, Chem. Commun. 2012,
48, 9580; b) G. Méhes, H. Nomura, Q. Zhang, T. Nakagawa, C. Adachi,
Angew. Chem., 2011, 124, 11473; Angew. Chem. Int. Ed. 2012, 51, 11311; c)
H. Uoyama, K. Goushi, K. Shizu, H. Nomura, C. Adachi, Nature 2012, 492,
234; d) Y. Tao, K. Yuan, T. Chen, P. Xu, H. Li, R. Chen, C. Zheng, L. Zhang,
W. Huang, Adv. Mater. 2014, 26, 7931; e) A. Chihaya, Jpn. J. Appl. Phys.
2014, 53, 060101; f) T. Nishimoto, T. Yasuda, S. Y. Lee, R. Kondo, C. Adachi,
Mater. Horiz. 2014, 1, 264; g) B. Li, H. Nomura, H. Miyazaki, Q. Zhang, K.
Yoshida, Y. Suzuma, A. Orita, J. Otera, C. Adachi, Chem. Lett. 2014, 43, 319.
[14] a) N. Akai, S. Kudoh, M. Nakata, Chem. Phys. Lett. 2003, 371, 655; b) A.
Yassar, F. Demanze, A. Jaafari, M. El Idrissi, C. Coupry, Adv. Funct. Mater.
2002, 12, 699; c) K. R. JustinꢀThomas, M. Velusamy, J. T. Lin, Y. T. Tao, C. H.
Chuen, Adv. Funct. Mater. 2004, 14, 387.
Experimental Section
Experimental procedures and characterization data including NMR
spectra are included in supporting information.
Acknowledgements
Research reported in this publication was supported by
Samsung Electronics. We thank Drs. Michael Pirnot and Yiming
Wang for advice on the preparation of this manuscript.
[15] a) S. Hotta, in Handbook of Thiophene-Based Materials, John Wiley &
Sons, Ltd, 2009, pp. 477; b) I. F. Perepichka, D. F. Perepichka, H. Meng, in
Handbook of Thiophene-Based Materials, John Wiley & Sons, Ltd, 2009, pp.
695.
References
[16] S. Hirata, Y. Sakai, K. Masui, H. Tanaka, S. Y. Lee, H. Nomura, N.
Nakamura, M. Yasumatsu, H. Nakanotani, Q. Zhang, K. Shizu, H. Miyazaki, C.
Adachi, Nat. Mater. 2015, 14, 330.
[1] a) P. Thansandote, M. Lautens, Chem. Eur. J. 2009, 15, 5874; b) D. Chen,
S.-J. Su, Y. Cao, J. Mater. Chem. C 2014, 2, 9565.
[2] a) F. Albani, R. Riva, A. Baruzzi, Pharmacopsychiat. 1995, 28, 235; b) T.
Okuma, A. Kishimoto, Psychiatry Clin. Neurosci. 1998, 52, 3; c) A. F.
Ambrosio, P. Soares-da-Silva, Neurochem. Res. 2002, 27, 121; d) R. M. A.

Chemistry - A European Journal
10.1002/chem.201603449
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Wenliang Huang, Stephen L. Buchwald*
Page No. – Page No.
Palladium catalyzed N-Arylation of
Iminodibenzyls and Iminostilbenes
with Aryl and Hetero-Aryl Halides
Crowded but Coupled! A general protocol of N-arylation of iminodibenzyls and
iminostilbenes is reported for a variety of hindered and heterocyclic aryl halide
substrates at low loadings of palladacycle precatalyst. This methodology has wide
substrate scope and excellent functional group tolerance and allows access to
products of relevance to the medicinal and materials sciences.
Keywords: Buchwald-Hartwig Amination • Palladium Pre-catalyst • Steric-Hindered Aryl Halide • Iminodibenzyl and iminostilbene •
OLED