Pd-catalyzed intramolecular C-N bond cleavage, 1,4-migration, sp3C-H activation, and Heck reaction: Four controllable diverse pathways depending on the judicious choice of the base and ligand

Article abstract of DOI:10.1021/ja512212x

Diverse and controllable pathways induced by palladium-catalyzed intramolecular Heck reaction of N-vinylacetamides for the synthesis of nitrogen-containing products in reasonable to high yields via tuning the phosphine ligands and bases are reported. Domi

Full text of DOI:10.1021/ja512212x

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Article
Pd-Catalyzed Intramolecular C–N Bond Cleavage, 1,4-Migration,
sp3 C–H Activation, and Heck Reaction: Four Controllable Di-verse
Pathways Depending on the Judicious Choice of the Base and Ligand
Teck-Peng Loh
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 29 Dec 2014
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Pd-Catalyzed Intramolecular C–N Bond Cleavage, 1,4-
Migration, sp3 C–H Activation, and Heck Reaction: Four
Controllable Di-verse Pathways Depending on the Judicious
Choice of the Base and Ligand
Journal: Journal of the American Chemical Society
Manuscript ID: ja-2014-12212x
Manuscript Type: Article
Date Submitted by the Author: 28-Nov-2014
Complete List of Authors: Wang, Min; University of Science and Technology of China, Hefei National
Laboratory for Physical Sciences at the Microscale and Department of
Chemistry
Zhang, Xiang; University of Science and Technology of China, Hefei
National Laboratory for Physical Sciences at the Microscale and Department
of Chemistry
Zhuang, Yu-Xuan; University of Science and Technology of China, Hefei
National Laboratory for Physical Sciences at the Microscale and Department
of Chemistry
Xu, Yun-He; University of Science and Technology of China, Hefei National
Laboratory for Physical Sciences at the Microscale
Loh, Teck-Peng; Nanyang Technological University, Division of Chemistry &
Biological Chemistry, School of Physical & Mathematical Sciences
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Pd-Catalyzed Intramolecular C N Bond Cleavage, 1,4-Migration, sp3
C H Activation, and Heck Reaction: Four Controllable Diverse Path-
ways Depending on the Judicious Choice of the Base and Ligand
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Min Wang,a Xiang Zhang,a Yu-Xuan Zhuang,a Yun-He Xua * and Teck-Peng Loha ,b*
aHefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei, 230026, China
bDivision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371
ABSTRACT: Diverse and controllable pathways induced by palladium-catalyzed intramolecular Heck reaction of N–
vinylacetamides for the synthesis of nitrogen-containing products in reasonable to high yields via tuning the phosphine ligands and
bases are reported. Domino reactions including unique β–N–Pd elimination, 1,4-Pd migration or direct acyl C–H bond functionali-
zation were found to be involved forming different products respectively. Given the ability of using the same starting material to
generate diverse products via completely different chemoselective processes, these current methodologies offer straightforward
access to valuable nitrogen-containing products under mild reaction conditions as well as inspire the discovery of novel reactions.
■ INTRODUCTION
and 5 respectively) did not yield any of the desired products.
Different bases were tested to adjust the chemoselectivity of
this reaction. To our delight, when triethylamine was applied,
product 2a was exclusively obtained (Table 1, entry 7).
Due to their diverse and efficient catalytic performance, palla-
dium catalysts have been used widely in various coupling re-
actions to forge new C–C or C–heteroatom bonds for rapid
access to complex and useful molecules.1 In recent years, there
has been a great interest in the use of transient palladium com-
plexes generated in a Heck reaction for domino reactions to
construct complex polycycles.2 This transient palladium com-
plex may be involved in β-elimination,3 sp3 or sp2 C–H bond
functionalization,4 1,4-migration,5 to yield complex structures.
In light of our interest in the use of transient palladium inter-
mediates for domino reactions and our previously reported
works on direct functionalization of N-vinylacetamides,6 we
studied the palladium-catalyzed transformation of vinyla-
cetamide derivative 1. To our surprise, we found that the reac-
tion can furnish either the 1,1'-disubstituted ethylene deriva-
tive 2, the 2-azabicyclo[3,3,0]octadiene derivative 3, isoquino-
line derivatives 4 or 5/5/6-membered pyrroloisoindolone de-
rivative 5 depending on the ligand and base used in the reac-
tion (Scheme 1). Therefore, the realization of a very rare β–N–
Pd elimination pathway and the divergent routes leading to
different products from the same starting material with high
selectivity is the subject of current work.
Scheme 1. Palladium-catalyzed Diverse Synthetic Path-
ways from N-(2-bromobenzyl)-N-(1-phenylvinyl)acetamide
1.
Next, we sought for appropriate reaction conditions to im-
prove the yield of product 3a. It was found that organic bases
do not favor the latter transformation even though different
phosphine ligands were tested. In the presence of the inorganic
base K2CO3 and bulky phosphine ligands, the formation of 3a
was facilitated (Table 1, entries 11-16). When Na2CO3 was
used as base, the yield of 3a was increased to 55% along with
the formation of 2a and 4a as the side products (Table 1, entry
18). After much screening, product 3a could be isolated in
75% yield when tetra-butyl-ammonium chloride (TBAC) was
introduced as additive (Table 1, entry 20). Other additives
such as tetra-butyl-ammonium bromide (TBAB) or PivOH did
not improve the efficiency of this transformation (Table 1,
entries 19 and 21). Finally, it was found that the combination
of PPh3 and Cs2CO3 would greatly favor the formation of
product 4a (Table 1, entry 22).
■ RESULTS AND DISCUSSION
Optimization of Palladium-Catalyzed Controllable Di-
verse N-Containing Copmpounds. Initially, we examined the
reaction of N-(2-bromobenzyl)-substituted vinylacetamide 1a
under Heck reaction conditions by using Pd(OAc)2 and tri-
phenylphosphine catalytic system with K2CO3. It was found
1
that products 2a and 3a were obtained (determined by H
NMR spectrum) along with the formation of 6-endo product
4a (Table 1, entry 3).7 However, the direct use of Pd(PPh3)4 or
the combination of Pd(PhCN)2Cl2 with PPh3 (Table 1, entry 4
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withdrawing group at meta- or para-position could all afford
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the desired products in good yields (Table 2, entries 2a-2j).
Especially, halogen substituents on the benzene ring do not
affect the Heck reaction’s selectivity which permits further
functionalization of products (Table 2, entries 2f-2h). Howev-
er, only a 40% yield was obtained when a methyl group was
installed at the ortho-position (Table 2, entry 2b). Heteroaryl
such as furyl or thioenyl substituted N-vinylacetamides both
performed well in this reaction, giving the products in 61 and
67% yields, respectively (Table 2, entries 2k and 2l). While,
the product was obtained in 49% yield when benzofuran-
substituted N-vinylacetamide was used in the reaction (Table 2,
entry 2m). When the para-toluenesulfonyl protected
Table 1. Optimization of Catalytic Conditions.
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Table 2. Synthesis of 1,1'-Disubstituted Ethylene Deriva-
tives from N-vinylacetamides Catalyzed by Palladium.a
a
Reaction conditions: To a mixture of 0.2 mmol 1a, catalyst,
ligand, base and additive was added anhydrous DMF (2 mL) and
allowed to stir for 24 h at 120 °C under argon atmosphere. b Yield
was determined by H NMR using phenyltrimethylsilane as inter-
nal standard; isolated yields are shown in parentheses. Reaction
conditions: To a mixture of 0.3 mmol 1a, catalyst, ligand, base
1
c
and additive, anhydrous DMF (5 mL) was added.
β-N-Pd Elimination for the Synthesis of 1,1’-
Disubstituted Ethylene Derivatives. The difficulty of con-
trolling the regioselectivity of traditional Mizoroki-Heck reac-
tions between common alkenes and organic (pseudo)halides
for the synthesis of 1,1'-disbstituted ethylenes has been known
to be a challenging task.8 Only few examples for highly regi-
oselective intermolecular Mizoroki-Heck reactions have been
successfully achieved.9 However, to the best of our knowledge
there has been no example reported on the intramolecular
Heck coupling pathway to access 1,1'-disubstituted alkenes via
a vinyl C–N bond cleavage. With the optimal reaction condi-
tions in hand (Table 1, entry 7), the scope of the palladium-
catalyzed intramolecular Heck reaction-induced domino reac-
tion for the synthesis of 1,1'-disubstituted ethylenes was inves-
tigated. Various 1,1'-disubstituted alkenes products are sum-
marized in Table 2. As shown, the tolerance scope of R1 group
was first examined. The reaction of phenyl-substituted N-
vinylacetamides with an electron-donating or electron-
a
Unless noted the reaction was conducted with 1 (0.3 mmol),
Pd(OAc)2 (0.03 mmol), PPh3 (0.06 mmol), Et3N (0.6 mmol) in
anhydrous DMF (5 mL) for 24 h at 120 °C under argon atmos-
phere. b Reaction time was extended to 48 h.
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Scheme 2. One-pot Reaction between N-vinylacetamide 6
and 1-Bromo-2-(bromomethyl)benzene 7.
1
2
indole-substituted substrate was employed, the desired product
was generated in a 31% yield (Table 2, 2n). Notably, R1 group
could be extended to aliphatic substituents, the more bulky
cyclohexyl- and tert-butyl- substituted N-vinylacetamides also
worked well in this reaction to give the corresponding prod-
ucts in moderate yields (Table 2, entries 2o and 2p). Subse-
quently, we turned our attention to test the scope of bromo-
substituted groups. It was observed that the substrate with
electron-donating group favors a higher yield of the product
than that with Cl-substituent (Table 2, entries 2q-2s). In addi-
tion, substitution on the benzylic position had a dramatic effect
on the product yield; only 39% 2t was obtained (Table 2, entry
2t). Bromo-substituted naphthyl and heteroaryl groups were
also tolerated in this reaction, and the substrates were smooth-
ly transformed to the corresponding products in good yields
(Table 2, entries 2u-2w). To our delight, when cyclic alkenyl
bromides were applied as the coupling initiator, the conjugated
diene products could also be obtained in acceptable yields
(Table 2, entries 2x and 2y). It is to be noted that, we have
successfully achieved the synthesis of 1,1'-disubstitued eth-
ylene derivatives via the intramolecular pathway which ex-
clude the formation of 1,2-disubstitued ethylene products
commonly observed in the Heck coupling reaction. Moreover,
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a
one-pot reaction between vinylacetamide 6 and 2-
bromobenzyl bromide 7 was also carried out. The desired
product 2a could be isolated in 82% yield (Scheme 2).
a
Unless noted otherwise, the reaction was conducted with 1 (0.2
mmol), Pd(OAc)2 (0.02 mmol), JohnPhos (0.02 mmol), Na2CO3
(0.24 mmol), TBAC (0.2 mmol) in anhydrous DMF (2 mL) for 24
h at 120 °C under argon atmosphere. b Isolated yield.
Palladium-Catalyzed 5-exo-Heck, 1,4-Palladium Migra-
tion and aryl-aryl Coupling Domino Reactions. On the oth-
er hand, the reaction leading to 3a can be rationalized by in-
voking a 1,4-palladium shift as previously proposed by
Larock,10 Catellani,11 Lautens,12 Gallagher,13 Cάmpora,14
Buchwald,15 Dyker,16 Pan,17 Jia,18 Kim19 et al. for the synthesis
of 6/5-, 6/6- or 5/6-membered3i polycyclic compounds, while
examples for the formation of 5/5-membered heterocyclic
compounds has been rarely reported. In the presence of TBAC
Palladium-Catalyzed 6-endo-Heck Coupling Reaction
for the Synthesis of Isoquinoline Derivatives. Highly selec-
tive 6-endo Heck cyclization reaction for the synthesis of di-
hydroisoquinoline derivatives is always challenging due to
competitive 5-exo pathway. In our reaction system, we found
that when the base used in the coupling reaction was changed
into Cs2CO3, then various 3-(hetero)aryl-substituted 1,2-
dihydroisoquinoline derivatives could be smoothly generated
via a 6-endo Heck cyclization process (Table 4). It is im-
portant to note that different functional groups such as nitro-,
halides etc could be tolerated at the (hetero)aryl rings which
will permit the products to be further functionalized in se-
quence steps (Table 4, 4c, 4d, 4f, 4g and 4h). Moreover, the
N-acetyl-7-phenyl-5,6-dihydro-1,6-naphthyridine 4p and N-
acetyl-5-phenyl-6,7-dihydrothieno[2,3-c]pyridine 4q also
could be prepared in reasonable yields under the optimized
reaction conditions.
and
Na2CO3,
various
bisannelated
2-
azabicyclo[3,3,0]octadiene derivatives were obtained in mod-
erate to good yields (Table 3). The influence of the electronic
property of the phenyl ring A was first investigated. Both elec-
tron-donating groups (such as methoxyl and methyl groups)
and strong electron-withdrawing group (such as nitro group)
on the phenyl ring A could all drive the reaction to form the
desired products in good yields (Table 3, 3b, 3c and 3f respec-
tively). It was found that a Cl-substituent was well tolerated in
this reaction to afford the product in an excellent yield (Table
3, 3d). In addition, the naphthyl-group substituted N-
vinylacetamide also gave the product in a high yield (Table 3,
3h). However, the yield of 3e decreased sharply when bromine
was installed on the benzene ring due to side reactions. Sur-
prisingly, the steric hindrance of a methyl group at the ben-
zylic position could be completely ignored; 3i could be ob-
tained in 74% yield (dr = 90:10, determined from the crude 1H
NMR spectrum of the crude product). With regards to ring B,
methyl- or Cl-substituted N-vinylacetamides both provided the
products in good yields (Table 3, 3j, 3k and 3l).
Table 4. Palladium-Catalyzed Domino Coupling Reactions
for the Synthesis of Isoquinoline Compounds. a
Table 3. Palladium-Catalyzed Domino Coupling Reactions
for the Synthesis of 2-Azabicyclo[3,3,0]octadiene Deriva-
tives. a,b
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Table 5. Palladium-Catalyzed Domino Coupling Reactions
for the Synthesis of Pyrroloisoindolone Derivatives. a,b
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a
Unless noted otherwise, the reaction was conducted with 1 (0.2
mmol), Pd(OAc)2 (0.02 mmol), JohnPhos (0.02 mmol), Na3PO4
(0.4 mmol), TBAC (0.2 mmol) and AdCOOH (0.06 mmol) in
anhydrous DMF (2 mL) for 24 h at 110 °C under argon atmos-
phere. b Isolated yield.
a
Reaction conditions: The mixture of 0.3 mmol 1a, 10 mol%
Pd(OAc)2, 20 mol% PPh3 and 1.2 equiv Cs2CO3 in the dry DMF
(3 mL) under argon atmosphere was heated at 120 °C for 24 h.
Reaction conditions: The mixture 0.3 mmol 1a, 10 mol%
Pd(OAc)2, 10 mol% Johnphos, 1.2 equiv Na2CO3 and 1 equiv
TBAC in the dry DMF (3 mL) under argon atmosphere was heat-
ed at 120 °C for 24 h. c The ligand used in reaction was PCy3.
b
Proposed Mechanistic Pathways for the Synthesis of Di-
verse N-Containing Products. Similar to the synthesis of
products 2, 3 and 5 where a 5-exo-trig Heck reaction gave the
transient palladium complex B (Scheme 3), which undergoes a
β–N–Pd elimination to afford 1,1'-disubstituted ethylene de-
rivatives 2a.21 Pd(0) was regenerated with the aid of triethyla-
mine which serves as a reductant.20 Though β–hydride,22 oxy-
gen,23 halide24 or carbon25 elimination are common in palladi-
um chemistry, the β–N–Pd elimination has rarely been report-
ed.26 On the other hand, the reaction leading to 3a can be ra-
tionalized using the 1,4-palladium shift and C(aryl, sp2)–
C(aryl, sp2) coupling. The formation of 5/5/6-membered pyr-
roloisoindolone derivative 5a could be achieved by cross-
coupling between acyl sp3 carbon with neopentyl-type σ-
alkylpalladium(II) species generated via 5-exo-trig Heck reac-
tion. The formation of 3-aryl-substituted dihydroisoquinoline
4a was caused by the highly selective 6-endo Heck cyclization
reaction.
Neopentylpalladium Species Catalyzed Amide’s α C–H
Bond Direct Functionalization for the Synthesis of pyr-
roloisoindolone Derivatives. Finally, inspired by the good
reactivity of neopentyl-type σ-alkylpalladium(II) species in
reaction (as proposed in Scheme 1) and limited previously
reported examples on C(sp3)–C(sp3) formation through σ-
alkylpalladium induced C(sp3)–H activation,4g we embarked
on the development on the synthesis of pyrroloisoindolone
derivatives via α direct C–H functionalization of amide. With
careful optimization of the reaction conditions (see the details
in supporting information section), we found that the combina-
tion of Na3PO4, TBAC (tributylammonium chloride), adaman-
tane acid (AdCOOH) with the JohnPhos ligand would facili-
tate the desired product’s formation in good yields (Table 5).
Regardless of its bulky or electron-deficient character, various
aliphatic substituents could be tolerated at the 9-position of the
final products. However, a significant decrease of product
yield with good stereoselectivity was observed when the acet-
amide group was replaced by propionamide group (Table 2,
5l).
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We have successfully developed a new and efficient strategy
1
using a simple starting material for selective syntheses of four
types of products by tuning the ligands and bases used in the
reactions. i) Under basic condition, an unprecedented β–N–Pd
elimination occurred after an intramolecular Heck 5-exo-trig
cyclization reaction leading to the formation of 1,1'-
disubstituted ethylene derivatives; ii) 1,4-Palladium shift and
intramolecular oxidative diaryl cross-coupling reactions fol-
lowing intramolecular Heck cyclization can furnish unusual
bisbenzo-annelated 2-azabicyclo[3,3,0]octa-4,7-diene prod-
ucts. iii) Another pathway via highly selective direct 6-endo
Heck cyclization reaction can give isoquinoline products. iv)
Finally, via an intramolecular Heck 5-exo-trig cyclization re-
action followed by C(sp3)–C(sp3) coupling reaction can pro-
vide 5/5/6-membered pyrroloisoindolone compounds. Moreo-
ver, these methods provide simple and diverse ways for the
synthesis of nitrogen-containing molecules. Given the
knowledge of these results, the discovery of interesting and
novel reactions and their applications are in progress in our
laboratory.
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■ ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectral data for all new compounds
(1H NMR, 13C NMR, IR, HRMS), and crystallographic data (CIF)
of compounds 2j and 3a in CCDC numbers: 988450 and 988325.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 3. Proposed Mechanistic Pathways for the Synthe-
sis of Diverse and Controllable Products Using N–
vinylacetamides.
The possible effect of the used bases and ligands in control
of the diverse selectivities. As proposed in Scheme 3, the
synthesis of the four different products could be achieved via a
5-exo-trig or a 6-endo-trig pathway respectively. Firstly the
use of Cs2CO3 as base in the presence of Pd(OAc)2 and PPh3, a
rare 6-endo Heck cyclization product could be observed.27
While changing the base to triethylamine (Et3N), a 5-exo cy-
clization product was obtained. Although the real reason for
the diverse pathways (6-endo vs 5-exo) is not clear, the differ-
ence in regioselectivity caused by these two bases was possi-
bly attributed to their difference in coordination abilities. The
difference in the coordination sphere as well as the steric ef-
fect of the palladium complex may be the reasons for this re-
sult. Further investigation into this is still in progress. As for
the 5-exo selective process which results in the formation of
neopentyl σ-alkylpalladium species B, the ring strain of this
intermediate promotes β-C-N bond cleavage which after pro-
tonation by Et3N results in the formation of the desired prod-
uct 2.
AUTHOR INFORMATION
Corresponding Author
*E-Mail for T.P. L.: teckpeng@ntu.edu.sg;
*E-Mail for Y.H. X.: xyh0709@ustc.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
We gratefully acknowledge the funding support of National Sci-
ence Foundation for Young Scientists of China (21202156), the
National Natural Science Foundation of China (21372210), the
Fundamental Research Funds for the Central Universities
(WK2060190023) and Natural Science Foundation of Anhui
Province (1308085QB37). The authors also thank Nanyang Tech-
nological University for the funding of this research. Professor
Zhou J.-R (Steve) is acknowledged for valuable discussions.
Previous studies by Lautens,28 Larock,10e Hartwig,29 Zhu30 et
al. have demonstrated that the electron-rich and bulky phos-
phine ligands could stabilize the neopentyl-type σ-
alkylpalladium intermediate (resulted from the 5-exo pathway)
and suppress the direct elimination reaction. For substrates
containing two aryl groups, the 1,4-palladium migration from
σ-alkylpalladium to aryl group takes place to form an arylpal-
ladium species C or C′ which could further react with another
aryl group to give the product 3 in the presence of strong or-
ganic ionic bases generated in situ.31 On the other hand, re-
placing the aryl substituent with an alkyl group to prevent the
1,4-palladium migration reaction and the use of stronger ionic
base resulted in the sp3 C–H bond direct functionalization
which then undergoes the sp3-sp3 coupling reaction (Scheme 3,
F→5a).
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■ CONCLUSION
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