Palladium/norbornene-mediated tandem C-H amination/C-I alkenylation reaction of aryl iodides with secondary cyclic O-benzoyl hydroxylamines and activated terminal olefins

Article abstract of DOI:10.1002/chem.201400084

A novel palladium-catalyzed norbornene-mediated three-component reaction for the construction of ortho-alkenyl aromatic tertiary amines has been achieved, which represents a useful extension of the Catellani-type tandem ortho-selective C-H amination trans

Full text of DOI:10.1002/chem.201400084

DOI: 10.1002/chem.201400084
Communication
&
CÀH Activation
Palladium/Norbornene-Mediated Tandem CÀH Amination/CÀI
Alkenylation Reaction of Aryl Iodides with Secondary Cyclic
O-Benzoyl Hydroxylamines and Activated Terminal Olefins
Zhi-Yuan Chen,* Chang-Qing Ye, Hui Zhu, Xing-Ping Zeng, and Jian-Jun Yuan[a]
Abstract: A novel palladium-catalyzed norbornene-medi-
ated three-component reaction for the construction of
ortho-alkenyl aromatic tertiary amines has been achieved,
which represents a useful extension of the Catellani-type
tandem ortho-selective CÀH amination transformations.
By using aryl halides or pseudo halides as readily available
starting materials, great diversity of CÀC or CÀhetero bonds
Scheme 1. Pd-catalyzed cross-coupling reaction based on aryl iodide.
can be regioselectively generated through known palladium-
catalyzed cross-coupling reactions. For example, the alkenyla-
tion of aryl iodide, as represented by Mizoroki–Heck reaction,
is one of the most important CÀC bond formation processes
for the preparation of alkenyl aromatic derivatives.[1] Palladium-
catalyzed Buchwald–Hartwig amination reaction of aryl halides
with amines,[2] the current state of the art in nucleophilic ami-
nation, has been intensively studied as a prominent tactic for
the generation of functional arylamines (Scheme 1a). Recently,
electrophilic amination based on Umpolung strategy[3] of or-
ganometallic reagents with R2N+ synthons, such as chloro- and
hydroxylamines,[4] has attracted significant interest in the syn-
thetic organic community (Scheme 1b). Transition-metal-cata-
lyzed electrophilic amination reaction enables not only organo-
metallic reagents,[5] but also heteroaromatic CÀH bonds[6] to be
efficiently aminated, thus providing attractive alternatives to
the previously established CÀN bond formation protocols.
While Pd-catalyzed CÀC or CÀN bond formation reactions have
aroused significant interest even at industrial scale, the one-
step preparation of ortho-alkenyl aromatic anilines using aryl
halides as reliable substrates has been less developed, al-
though such type of aromatic amines may find important ap-
plications as synthetic building blocks in the laboratory or in-
dustry,[7a] as bioactive drugs in medicinal chemistry,[7b] and or-
ganic light-emitting materials.[7c]
tion vessel.[8] Domino reactions that involve sequential CÀH ac-
tivation processes are of particular value, since these types of
reactions do not require prefunctionalization of one or both of
the substrates, thus significantly shortening the number of syn-
thetic steps.[9,10] Inspired by the seminal work of Catellani,[11]
Lautens,[12] and others,[13] who demonstrated a fascinating
domino reaction of aryl iodides with alkyl bromides and al-
kenes by Pd/norbornene-mediated tandem CÀH alkylation/CÀI
alkenylation sequences (the Catellani reaction),[11–14] we envi-
sioned that a direct CÀH amination/CÀX alkenylation reaction
based on the electrophilic amination strategy could be applied
to the Catellani reaction process (Scheme 1c).[15]
In view of the widespread application of CÀC bond forma-
tion transformations based on Catellani reaction,[11–14] we hy-
pothesized that a similar mechanism might also operate in
a designed Pd-catalyzed cascade CÀN bond formation process
(Scheme 2). The five-membered palladacycle B would be pro-
duced first through oxidative addition of aryl iodide 1 with
Pd0, syn-carbopalladation with norbornene, and intramolecular
CÀH activation/deprotonation reaction. Oxidative addition of
the electrophilic amination agent (R2NÀX) 2 to the PdII center
of B would generate a PdIV species C,[16] which undergoes re-
ductive elimination to give an amination complex D. Alterna-
tively, the direct electrophilic amination of R2NÀX with pallada-
cycle B facilitated by the concomitant NÀO cleavage to form
amination complex D is conceivable.[6] Next, expulsion of nor-
bornene moiety followed by Mizoroki–Heck coupling between
the aminated ArPdX species E and alkene 3 would give the de-
sired CÀH amination/CÀX alkenylation product 4. Although the
sequential ortho CÀC formation reactions using alkyl or aryl
electrophiles (RÀBr) in Catellani reaction have been extensively
studied,[11–14] however, to our surprise, using nitrogen electro-
Recently, domino/tandem reactions have emerged as an effi-
cacious synthetic tool because they could provide straightfor-
ward access to structurally diverse molecules in a one-pot reac-
[a] Prof. Dr. Z.-Y. Chen, C.-Q. Ye, H. Zhu, X.-P. Zeng, J.-J. Yuan
Key Laboratory of Functional Small Organic Molecules
Ministry of Education, College of Chemistry & Chemical Engineering
Jiangxi Normal University, Nanchang, Jiangxi 330022 (P. R. China)
E-mail: zchenjx@hotmail.com
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400084.
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Communication
performances (Table 1, entries 6–
12). The base effect showed mar-
ginal influence on the transfor-
mation, since K2CO3 gave only
trace yield of product 4a, and
none of the other bases was su-
perior to Cs2CO3 (Table 1, en-
tries 13–15). Among the solvents
examined, toluene gave a reason-
able yield of 71% of 4a, while
inferior conversion was obtained
in 1,4-dioxane, and polar sol-
vents such as DMF, DMSO, and
DMA usually led to faster con-
version but lower yields (Table 1,
entries 16–20). Attempts to im-
prove the yield of 4a by varying
the temperature and concentra-
tion of the reaction were unsuc-
cessful as well (Table 1, en-
tries 21–23).
Scheme 2. Possible mechanism.
philes (R2N+) as an alternative in the palladium catalyzed reac-
tion conditions has rarely been documented till now,[6a,17] The
use of nitrogen as an electrophile in the Catellani reaction was
recently reported by Dong and prompts us to report our stud-
ies which provide further support for the feasibility of this ap-
proach.[17b] Therefore, this Pd/norbornene-mediated domino re-
action should provide an opportunity of ortho-selective CÀN
bond and ipso CÀC bond formation processes in a one-pot
procedure, thus would represent a useful extension to the
known Catellani-type CÀH amination reactions.
Table 1. Optimization of the reaction conditions.[a]
Our study commenced with the Pd(OAc)2-catalyzed norbor-
nene-mediated reaction of 1-iodo-2-methylbenzene (1a) with
a secondary cyclic electrophilic amination agent (R2NX) 2 and
tert-butyl acrylate (3a). After a survey of the reaction condi-
tions by varying the R2NX agents (2), ligands, bases, as well as
the effect of different additives, we were pleased to find that
when morpholino benzoate (2a) was employed[18] as a sub-
strate, the corresponding product 4a could be isolated in 34%
yield with excellent E configuration double bond in the pres-
ence of Cs2CO3 (3.0 equiv) in CH3CN at 808C (Table 1, entry 1).
In the absence of Ph3P, a complex mixture of products was ob-
served (entry 2). A reduced yield of 4a was obtained (24%
yield) while with 1.0 equivalent of norbornene (entry 3).[19] The
product 4a could be isolated in 32% yield when Pd2(dba)3
(10 mol%) was used as a catalyst instead of Pd(OAc)2 (entry 4).
The reaction with 4-chloromorpholine as an electrophilic ami-
nation agent led to reduced yield, presumably due to the high
reactivity and instability of this reagent under the reaction con-
dition (entry 5).[20]
Ligand
Base
Solvent
T [oC]
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Ph3P
–
Ph3P
Ph3P
Ph3P
(2-furyl)3P
PtBu3·HBF4
(4-MeOC6H4)3P
(4-CF3C6H4)3P
(4-MeC6H4)3P
SPhos
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1,4-dioxane
toluene
DMF
80
80
100
100
80
100
100
100
100
100
80
34
27
24[b]
32[c]
complex[d]
34
12
83
18
37
33
4
5
20
20
38
71
42
45
51
52
XantPhos
80
(4-MeOC6H4)3P
(4-MeOC6H4)3P
(4-MeOC6H4)3P
(4-MeOC6H4)3P
(4-MeOC6H4)3P
(4-MeOC6H4)3P
(4-MeOC6H4)3P
(4-MeOC6H4)3P
(4-MeOC6H4)3P
(4-MeOC6H4)3P
(4-MeOC6H4)3P
100
100
100
100
100
100
100
100
80
KOtBu
DBU
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMA
DMSO
CH3CN
CH3CN
CH3CN
100
100
70[e]
69[f]
As the investigation proceeded, we became aware that the
choice of phosphine ligand is crucial for the success of the
reaction. While tri-2-furylphosphine, PtBu3·HBF4, and (4-
CF3C6H4)3P gave low yields, a good result was obtained when
an electronically rich but sterically neutral ligand, (4-
MeOC6H4)3P, was employed, affording 83% yield of 4a. Remark-
ably, the other electronically rich but sterically hindrance li-
gands, such as SPhos and XantPhos, resulted in rather sluggish
[a] Reaction conditions: 1a (0.30 mmol, 1.0 equiv), 2a (0.45 mmol,
1.5 equiv), 3a (0.36 mmol, 1.2 equiv), Pd(OAc)2 (0.03 mmol, 10 mol%),
Ph3P (0.06 mmol, 20 mol%), norbornene (0.6 mmol, 2.0 equiv), Cs2CO3
(0.9 mmol, 3.0 equiv), CH3CN (3.0 mL, 0.10m), 808C, N2; isolated yields
based on 1a; [b] with norbornene (1.0 equiv); [c] Pd2(dba)3 (10 mol%) in-
stead of Pd(OAc)2; [d] 4-chloromorpholine (1.5 equiv) instead of 2a;
[e] CH3CN (1.0 mL, 0.30m); [f] CH3CN (2.0 mL, 0.15m).
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With the optimized reaction conditions in hand [Pd(OAc)2
(10 mol%), (4-MeOC6H4)3P (20 mol%), norbornene (2.0 equiv),
Cs2CO3 (3.0 equiv), CH3CN (3.0 mL, 0.10m), 1008C, N2], the
scope and limitation of this transformation was next explored
by using various iodoarenes 1, N,N-dialkyl O-acyl hydroxyl-
amines 2, and terminal alkenes 3. A wide range of alkenyl aro-
matic tertiary amines 4 could be readily obtained by following
the established procedure (Scheme 3). The reaction can be
mined by 1H NMR analysis. The unusual low E/Z selectivities
herein (as compared to typical Mizoroki–Heck coupling reac-
tions) were still uncertain at the present stage, presumablely
the choice of ligand should take into account in the case of 4c
and d. Besides, the inherent steric and electronic nature of the
substrates might play importance to some extent, since com-
pounds 4k and o (vide infra) were obtained in a sharp contrast
of E/Z selectivities under the same catalytic conditions. When
compound 1-iodo-2-nitrobenzene was employed in the reac-
tion, trace amount of compound 4e can be detected, and the
Mizoroki–Heck type byproduct (E)-tert-butyl 3-(2-nitrophenyl)-
acrylate was isolated in 43% yield under the standard condi-
tions. Switching to the use of 1-bromo-2-nitrobenzene in this
reaction resulted in less than 10% yield of 4e as estimated by
1
crude H NMR spectroscopy.
For the reaction of various alkenes with o-iodotoluene 1a
and morpholino benzoate 2a, terminal alkenes such as n-butyl
acrylate (4 f), ethyl acrylate (4g), methyl acrylate (4h) and
acrylonitrile (4i) efficiently participate to produce the corre-
sponding amination/alkenylation products in good yields rang-
ing from 55–75% (Scheme 3). However, the alkenylation temi-
nal-step was completely inhibited and a complex mixture of 4j
was observed when unactivated styrene was used as a sub-
strate, presumably due to low reactivity of the olefin, and the
formation of various byproducts aroused from the competitive
reactions. Finally, the scope of the O-benzoyl hydroxylamines 2
in the present reaction was evaluated. It was found that the re-
action proceeds smoothly for secondary cyclic O-benzoyl hy-
droxylamines, since the piperidin-1-yl (4k) and Boc-protected
piperazin-1-yl (4l) were isolated in good to excellent yields
under the standard conditions. For the reaction of acyclic O-
benzoyl-N,N-diisopropylhydroxylamine participated reactions,
the desired product 4m was not isolated, suggesting that the
reaction may inherently suffered from steric demand limitation.
The reaction worked well in the reaction of 1-iodonaphthalene
with secondary cyclic O-benzoyl hydroxylamines 2 and tert-
butyl acrylates 3a, as the corresponding products which bear-
ing a naphthalene substituent (4n–p) can be accessed in high
yields using this methodology.
Scheme 3. Synthesis of alkenyl aromatic tertiary amine 4 by domino reaction
of aryl iodide 1, secondary cyclic R2NÀOBz 2 and activated terminal alkene 3.
1
[a] Isolated yield based on 1. E/Z ratio was determined by H NMR spectros-
copy. [b] Reaction was carried out in 5 mmol scale (1.23 g of 4a was ob-
tained). [c] (2-Furyl)3P (0.06 mmol, 20 mol%) and toluene (2 mL) instead of
(4-MeOC6H4)3P and CH3CN.
In the case of aryl iodides 1 bearing no ortho-substituent re-
acted with morpholino benzoate 2a and tert-butyl acrylate 3a,
the 1,3-diaminated cinnamates 5 can be obtained. Reasonable
yields of products 5a–f could be produced when 3.0 equiva-
lents of norbornene was employed in the reaction in anhy-
drous toluene at 1008C (Scheme 4). It is noteworthy that the
common reactive functional groups, such as fluoro, chloro,
nitro, alkene, and ester group, were compatible in the present
catalytic reaction, implying that further incorporation of such
molecules into larger systems by employing the reactive func-
tionalities as synthetic handles can be easily manipulated.
In summary, we have disclosed a novel palladium-catalyzed
norbornene-mediated domino reaction of aryl halides, second-
ary cyclic electrophilic amination agent (R2NÀOBz) and activat-
ed terminal olefins, selectively affording a series of ortho-alken-
yl aromatic amines in moderate to excellent yields. The success
of the present reaction demonstrates a useful extension of
ortho-selective CÀH amination processes to existing PdII/nor-
scaled up without difficulty to preparative gram scale of
5 mmol, affording 1.23 g of product 4a (81% yield) with an
E/Z isomer ratio of 20:1. Iodoarenes 1 with electron-donating
substituents at the ortho position of CÀI bond participated in
the amination/alkenylation domino reaction smoothly (4a and
b).
However, the transformation of ortho-halogen (F and Cl)
substituted iodoarenes 1 with 2a and 3a were rather sluggish,
affording the desired products 4c and d in poor yields under
the standard conditions, due to the formation of undesired
Mizoroki–Heck-type cross-coupling byproducts as the main
outcomes. To our delight, good yields of products 4c and d
were obtained when (2-furyl)3P was employed as a ligand and
toluene as the reaction medium.[21] Notably, the E/Z isomers
were almost equal and inseparable in 4c and d, and the
Z isomer of 4d was likely to be the major product as deter-
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Communication
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Typical procedure for the preparation of compound 4a
To a 25 mL of Schlenk tube equipped with a Teflon-coated magnet-
ic stir bar was charged with 1-iodo-2-methylbenzene 1a (65.4 mg,
0.30 mmol), morpholino benzoate 2a (93.2 mg, 0.45 mmol), tert-
butyl acrylate 3a (48.6 mg, 0.36 mmol), Pd(OAc)2 (6.7 mg,
0.03 mmol), (4-MeOC6H4)3P (21.1 mg, 0.06 mmol), Cs2CO3 (293.4 mg,
0.9 mmol), norbornene (57.6 mg, 0.6 mmol), and CH3CN (3.0 mL).
The brown suspension was stirred at room temperature for 10 min
under N2, and then heated to 1008C for 5 h. The reaction was
monitored by TLC. After being cooled to room temperature, the re-
action mixture was diluted with ethyl acetate (5 mL), transferred to
a 50 mL of separation funnel and washed with water (15 mL), ex-
tracted with ethyl acetate (3ꢁ10 mL). The organic phase was col-
lected, washed with brine, dried over Na2SO4, and concentrated.
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give the corresponding pure product 4a.
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Acknowledgements
Financial support from National Natural Science Foundation of
China (21202065), the Specialized Research Fund for the Doc-
toral Program of Higher Education (20123604120003), and
a Sponsored Program for Cultivating Youths of Outstanding
Ability from Jiangxi Normal University are gratefully acknowl-
edged.
Keywords: alkenylation
palladium · tandem reaction
·
CÀH amination
· norbornene ·
[1] a) The Mizoroki–Heck Reaction (Ed.: M. Oestreich), Wiley, Chichester,
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Chem. Eur. J. 2014, 20, 4237 – 4241
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Communication
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[13] For recent examples, see: a) L. Jiao, T. Bach, Angew. Chem. 2013, 125,
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[14] For reviews on norbornene-mediated ortho-alkylation reactions of aryl
halides, see: a) R. Ferraccioli, Synthesis 2013, 45, 581–591; b) M. Catella-
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[16] The arylpalladium(II) intermediate could be oxidized to the PdIV species
by R2N+, see: a) J. A. Jordan-Hore, C. C. Johansson, M. Gulias, E. M. Beck,
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[17] For Pd-catalyzed CÀH amination with electrophilic amination agents,
see: a) E. J. Yoo, S. Ma, T.-S. Mei, K. S. Chan, J.-Q. Yu, J. Am. Chem. Soc.
2011, 133, 7652–7655; during the preparation of this manuscript,
Dong and co-workers reported a Pd/norbornene-catalyzed ortho-arene
amination reaction: b) Z. Dong, G. Dong, J. Am. Chem. Soc. 2013, 135,
18350–18353.
[18] The starting N,N-dialkyl O-acyl hydroxylamine electrophiles 2 can be
easily prepared by Ganem’s method: A. J. Biloski, B. Ganem, Synthesis
1983, 537–538.
[19] Trace amount of product 4a and 46% yield of Mozoroki–Heck-type
cross-coupling byproduct were obtained when 25 mol% of norbornene
was loaded. Norbornene can be regarded as both a directing group for
the functionalization of the ortho position(s), or as a temporary protect-
ing group for the ipso carbon of the arene as it is not incorporated in
the final product.
[20] N-chloroamines participate in Pd-catalyzed aza-Heck-like reactions that
are presumably initiated by oxidative addition of Pd0 to an NÀCl bond.
For an example, see: J. Helaja, R. Gçttlich, Chem. Commun. 2002, 720–
721.
[21] The tri-(2-furyl)phosphine (TFP) ligand was successfully employed for
the synthesis of benzannulated N-heterocycles by Pd-catalyzed CÀC/
CÀN coupling Catellani reactions, see refs. [11f] and [12h].
[15] For reviews on direct CÀH aminations, see: a) H. M. L. Davies, J. R. Man-
Received: January 8, 2014
Published online on March 12, 2014
ning, Nature 2008, 451, 417–424; b) H. M. L. Davies, M. S. Long, Angew.
Chem. Eur. J. 2014, 20, 4237 – 4241
www.chemeurj.org
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim