Palladium(II)-catalyzed intramolecular tandem aminoalkylation via divergent C(sp3)-H functionalization

Article abstract of DOI:10.1021/ja5102739

(Chemical Equation Presented) We have developed a Pd(II)-catalyzed oxidative tandem aminoalkylation via divergent C(sp³)-H functionalization, a ffording three- and five-membered-ring fused indolines in good yields under two optimized conditions, respectively. The mechanism studies have indicated that the benzylic C - H cleavage involved in the former transformation is the rate-determining step, while the cleavage of amide α-C - H in the latter is not. This is the first example of a Pd-catalyzed tandem reaction involving C(sp³)-H activation without the employment of prefunctionalized reagents (e.g., halogenated and boron reagents) and directing groups, representing a green and economic protocol for the construction of N-containing heterocycles.

Full text of DOI:10.1021/ja5102739

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Article
Palladium(II)-Catalyzed Intramolecular Tandem
Aminoalkylation via Divergent C(sp3)–H Functionalization
Dan Yang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Dec 2014
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Palladium(II)-Catalyzed Intramolecular Tandem
Aminoalkylation via Divergent C(sp3)–H Functionalization
Journal: Journal of the American Chemical Society
Manuscript ID: ja-2014-102739.R2
Manuscript Type: Article
Date Submitted by the Author: 19-Dec-2014
Complete List of Authors: Du, Wei; University of Hong Kong, Chemistry
Gu, Qiangshuai; The University of Hong Kong, Chemistry
Li, Zhongliang; The University of Hong Kong, Chemistry
Yang, Dan; The University of Hong Kong, Department of Chemistry
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Palladium(II)-Catalyzed Intramolecular Tandem Aminoalkylation via
Divergent C(sp3)–H Functionalization
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Wei Du, Qiangshuai Gu, Zhongliang Li, and Dan Yang*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. China
ABSTRACT: We have developed a Pd(II)ꢀcatalyzed oxidative tandem aminoalkylation via divergent C(sp3)–H functionalization,
affording threeꢀ and fiveꢀmemberedꢀring fused indolines in good yields under two optimized conditions, respectively. The mechaꢀ
nism studies have indicated that the benzylic C–H cleavage involved in the former transformation is the rateꢀdetermining step,
while the cleavage of amide αꢀC–H in the latter is not. This is the first example of Pdꢀcatalyzed tandem reaction involving C(sp3)–H
activation without the employment of prefunctionalized reagents (e.g. halogenated and boron reagents) and directing groups, repreꢀ
senting a green and economic protocol for construction of Nꢀcontaining heterocycles.
of π electrons that can readily interact with transitionꢀmetals.3ꢀ6
In particular, C(sp3)–C(sp3) bond formation through C(sp3)–H
INTRODUCTION
functionalization via a σ–alkylmetal intermediate is much less
developed, and current methods for this strategy inevitably
require the employment of prefunctionalized substrates (diꢀ
recting groups, boron or halogenated reagents) or stoichioꢀ
metric organic oxidants.7 Thus, more atomꢀeconomical proꢀ
cesses are highly desirable. With a continuing effort to our
previous interest in the construction of Nꢀheterocycles through
tandem reactions involving C–N/C(sp2)–C(sp3) formation
(Scheme 1, eq 1 and 2),8 here we describe a novel aminoalkylꢀ
ation [C–N/C(sp3)–C(sp3) formation] via C(sp3)–H functionalꢀ
ization of simple unsaturated anilides with molecular oxygen
as the sole oxidant (Scheme 1, eq 3). The σ–alkylPd(II) interꢀ
mediates formed in the aminopalladation step could activate
benzylic C–H or amide αꢀC–H divergently under different
conditions, and deliver the corresponding cyclopropaneꢀfusedꢀ
indolines or pyrolizidines respectively, which are structural
units in many natural products and pharmaceutics.9,10
Transitionꢀmetal catalyzed direct C–H functionalization repꢀ
resents a highly efficient, straightforward and powerful methꢀ
od for the construction of organic frameworks.1 Compared to
the wellꢀestablished C(sp2)–H functionalization,2 decorating
less reactive C(sp3)–H bonds is more challenging, as they lack
Scheme 1. Tandem Cyclization involving C–N/C–C Forꢀ
mation for Synthesis of Nꢀheterocycles
previous work:
aminopalladation/alkene insertion
amino-
palladation
-H
alkene
insertion
N
N
NH
elimination
HX
HX
PdX
Pd(0)
(eq 1)
(eq 2)
PdX2
aminopalladation/arylation
amino-
palladation
RESULTS AND DISCUSSION
arylation
N
N
H
N
Initially, the readily accessible unsaturated anilide 1a was
subjected to the conditions employed by Fagnou et al. for inꢀ
tramolecular C(sp3)–H activation,11 with oxygen as an enviꢀ
ronmentally benign oxidant. Surprisingly, both 2a and 3a were
obtained in 19% and 13% yields, respectively (Scheme 2). We
reasoned that after the first aminopalladation step, the σ–
alkylPd(II) intermediate underwent benzylic C–H and amide
HX
HX
Pd(0)
PdX
PdX2
this work:
aminopalladation/C(sp3) H bond functionalization
R1
O
NH
R2
Scheme 2. Preliminary Result of Pd(II)ꢀCatalyzed Aminoꢀ
alkylation
PdII
amino-
palladation
R1
R1
O
O
R1
O
PdII
N
N
N
R2
(eq 3)
R2
-alkylPd(II)
intermediate
amide -C
functionalization
H
benzylic
H activation
C
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αꢀC–H activation, thereby affording corresponding product 2a duct 2c was obtained in 45% yield without the formation of 3c
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2
3
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7
8
or 3a, respectively.
(entry 1). However, the phosphine ligand was not compatible
with the oxygen atmosphere.12,13 Therefore, nitrogen and Nꢀ
heterocyclic carbene (NHC) ligands were evaluated (entries 2–
4). IPr·HCl [1,3ꢀbis(2,6ꢀdiisopropylphenyl)imidazolium chloꢀ
ride] as an NHC precursor was proved to be the best, affording
2c in a moderate yield (41%; entry 4). Subsequent screening
of reaction conditions revealed that the yield of 2c could be
improved to 87% under the following reaction conditions:
(allylPdCl)2 (5 mol%), IPr·HCl (11 mol%), pivalic acid (30
mol%), K2CO3 (1.1 equiv) and 5 Å molecular sieves in xylene
under oxygen atmosphere at 130 °C (entries 5–9).14
With this encouraging result, further optimization for amiꢀ
noalkylation through benzylic C–H activation was then carried
out by employing isobutyranilide 1c as a substrate (Table 1),
as we expect that the other pathway, i.e., the amide αꢀC–H
functionalization, might be inhibited due to the steric hinꢀ
drance of the isopropyl group. To our delight, the desired proꢀ
Table 1. Condition Optimization for Pd(II)ꢀCatalyzed
Tandem Cyclization via Aminopalladation/Benzylic C–H
Activationa
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Notably, pivalic acid, which is considered to be helpful for
C(sp3)–H activation via a concerted metalationꢀdeprotonation
(CMD) pathway, did improve the yield significantly (entry 5
t
vs 6).15 It is interesting that a strong base, BuOK, resulted in
the formation of 3c in 35% yield without the formation of 2c
(entry 8). It was probably because strong base would prefer to
deprotonate the αꢀC–H of the amide rather than activate the
benzylic C–H. This provided very useful information for us to
optimize the tandem reaction for functionalization of the αꢀC–
H of amides (vide infra).
entry
1c
2c
Pd(II)
ligand
base
time (h)
yield (%)b
45
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
(allylPdCl)2
(allylPdCl)2
(allylPdCl)2
(allylPdCl)2
(allylPdCl)2
Cy3P·HBF4 Cs2CO3
8
pyridine
1,10ꢀphen
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
IPr·HCl
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KOtBu
K2CO3
20
20
40
40
40
40
40
20
8
N.R.
41
Under the optimized conditions for aminopalladaꢀ
tion/benzylic C–H activation, the substrate scope was examꢀ
ined (Table 2). Acetamide 1a gave rise to threeꢀmemberedꢀ
ring product 2a and fiveꢀmemberedꢀring product 3a in 84%
3c
4
5d
6d,e
7d
8d
60
and 12% yield, respectively, after 20 h. The amide
functionalization was prevented when substrates 1b and 1c
with ꢀsubstituents were employed, and the desired products
α
ꢀC(sp3)–H
42
60
0 (35)g
α
2b and 2c were obtained, respectively, in very good yield.
9d,,f
87
However, the cyclopropanyl substituted substrate 1d led to
the formation of fiveꢀmemberedꢀring product 3d in 28% yield
in addition to desired product 2d in 66% yield, probably beꢀ
cause of the higher acidity of the αꢀC–H on the cyclopropane
ring. As expected, substrates 1e and 1g without αꢀC–H cyꢀ
a
Reaction conditions: substrate 1c (0.2 mmol), Pd(II) source (10 mol%),
ligand (11 mol%), PivOH (30 mol%) and base (1.1 equiv) in xylene (2.0
mL) at 130 °C under O2 atmosphere. b NMR yield of 2c with nitrobenzene
as an internal standard. c 20 mol% ligand was used. d 5 mol% (allylPdCl)2
e
f
was used. Without PivOH. 5 Å molecular sieves (1 g/mmol substrate)
was added. Yield of 3c determined by H NMR analysis with nitrobenꢀ
zene as an internal standard in the parentheses.
g
1
clized smoothly. Remarkably, the reaction was compatible
Table 2. Substrate Scope of Pd(II)ꢀCatalyzed Tandem Cyclization via Aminopalladation/Benzylic C–H Activationa,b
a Reaction conditions: substrate (0.3 mmol), (allylPdCl)2 (5 mol%), IPr·HCl (11 mol%), PivOH (30 mol%), K2CO3 (1.1 equiv) and 5 Å molecular sieves (1
g/mmol substrate) in xylene (3.0 mL) at 130 °C under O2 atmosphere. b Isolated yield. c Isolate yield of side product.
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with the carboxybenzyl (Cbz) group, which could be easily
Table 4. Substrate Scope of Pd(II)ꢀCatalyzed Tandem Cyꢀ
1
2
3
4
5
6
7
8
deprotected by hydrogenation. Substrate 1f that bears a pheꢀ
nylacetamide unit generated both 2f and 3f in 19% and 44%
yield, respectively (entry 6), with 3f as the major product,
probably because the αꢀC–H of 1f is more acidic than that of
other substrates. When diphenyl amine substrate 1h was subꢀ
jected to the standard conditions, 4h rather than 2h was obꢀ
tained, indicating that the C(sp2)–H activation is more facile
than the C(sp3)–H activation. Then the electronic effect on the
aryl ring was examined with a series of propionanilides. Subꢀ
strates 1i–n with an electronꢀdonating or electronꢀwithdrawing
group on the paraꢀ or metaꢀposition all afforded products 2i–n
in very good yield, and notably, those electronꢀdeficient aniꢀ
lides 1k and 1n cyclized faster than their electronꢀrich counꢀ
terparts (1i, 1j and 1m). An ethyl and even a phenyl angular
substituents were well tolerated and the desired products 2o
and 2p were obtained in good yield, respectively. Interestingꢀ
ly, usually difficult sixꢀexo cyclization was realized by emꢀ
ploying aliphatic amide substrate 1q albeit with a low yield
(20%). However, anilide 1r failed to undergo cyclization in a
similar manner, because the C–H bond to be functionalized is
not at the benzylic position.
clization via Aminopalladation/Amide αꢀC–H Functionaliꢀ
zationa,b
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Table 3. Condition Optimization for Pd(II)ꢀCatalyzed
Tandem Cyclization via Aminopalladation/Amide αꢀC–H
Functionalizationa
entry
1
2d
Pd(II)
solvent
xylene
yield (%)b
66 (11)c
a
(allylPdCl)2
(allylPdCl)2
(allylPdCl)2
(allylPdCl)2
IPr·Pd(allyl)Cl
IPr·Pd(allyl)Cl
Reaction conditions: substrate (0.3 mmol), IPr·Pd(allyl)Cl (10 mol%),
PivOH (30 mol%), KOtBu (1.1 equiv) and 4 Å molecular sieve (1 g/mmol
xylene
20
substrate) in tAmOH (3.0 mL) at 90 °C under O2. b Isolated yield. c The dr
3e
tAmOH
dioxane
tAmOH
tAmOH
71
d
ratio was calculated based on the isolated yields of the two isomers.
e
Isolated yield of side product (in parentheses). The dr ratio was deterꢀ
4
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mined by 1H NMR spectroscopy.
5e,f
6e,f,g
80
88
Interestingly, IPr·Pd(allyl)Cl provided a higher yield than that
of the combination of (allylPdCl)2 and IPr·HCl (entry 5 vs
3).Lowering down the temperature to 90 °C led to a slightly
increased yield (entry 6).
a
Reaction conditions: substrate 1a (0.2 mmol), Pd(II) source (5 mol%),
IPr·HCl (11 mol%), PivOH (30 mol%), KOtBu (1.1 equiv) and 4 Å moꢀ
lecular sieve (1 g/mmol substrate) in xylene (2.0 mL) at 100 °C under O2
atmosphere for 15.5 h. b Yield of 3a determined by 1H NMR analysis with
c
nitrobenzene as an internal standard. Yield of 2a shown in parentheses
With the optimized conditions in hand, more anilides were
investigated for the tandem cyclization involving amide αꢀ
C−H functionalization (Table 4). To our delight, most reacꢀ
tions were completed in 4 h. Acetamide 1a afforded 3a in 80%
yield. The substrates 1c and 1d with two αꢀsubstituents affordꢀ
ed low yields of desired products due to steric congestion, and
3ꢀmemberedꢀring products 2c and 2d from benzylic C−H actiꢀ
vation were formed, whereas substrate 1b with only one αꢀ
substituent gave rise to 3b in a good yield with a dr ratio of
6:1. The electronic effect on the aryl ring was also studied.
Substrates 1s−u with either electronꢀdonating or electronꢀ
withdrawing group on the paraꢀposition all gave satisfactory
yields of desired products 3s−u, respectively, while 1w bearꢀ
ing a metaꢀF substituent afforded a lower yield than that of the
metaꢀOMe substituted 1v. The substituent on the benzylic
position of 1x seemed not to affect the desired cyclization, and
products 3x and 3x′ were isolated in 64% combined yield with
a dr ratio of 1.3:1. While 3y with an angular ethyl group could
determined by 1H NMR analysis with nitrobenzene as an internal standard.
d
e
f
11 mol% KOtBu was added.
Reaction time 4 h.
IPr·Pd(allyl)Cl was used, without IPr·HCl. g 90 °C.
10 mol%
We then optimized the reaction conditions for amide αꢀC−H
functionalization by employing acetylanilide 1a as the subꢀ
strate owing to its least bulkiness at the αꢀposition (Table 3).
KOtBu was used as the base since it seemed to favor the amide
αꢀC−H functionalization (vide supra). Good regioselectivity
was achieved (entry 1) although a stoichiometric amount of
KOtBu was necessary for the transformation (entry 1 vs 2).
Addition of PivOH was found to give better results.16 Polar
solvents, especially tertꢀamyl alcohol (tAmOH), were superior
to the nonꢀpolar one (xylene), affording 3a in good yield withꢀ
out the formation of 2a (entries 3–4 vs entry 2). This was
probably because the solubility of KOtBu in polar solvents
was better, and thus the deprotonation of αꢀC–H was easier.
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Scheme 3. Intermolecular 1H/2H KIE study for the tandem
aminopalladation/αꢀC–H of amides functionalization reacꢀ
tion of 1a and dꢀ1a under the optimized conditions.
be obtained in good yield, 3z with a Ph group did not formed
1
2
3
4
unexpectedly. Remarkably, substrate 1ab with one more carꢀ
bon in the side chain afforded the indolizidine derivative 3ab
in 61% yield; on the contrary, aliphatic amide 1aa failed to
provide the desired product, probably because of the less acidꢀ
ic NH compared to other anilide substrates.
5
6
7
8
9
To discern the rateꢀdetermining step of the tandem aminoꢀ
palladation/benzylic C–H activation reaction, we applied Sinꢀ
gleton’s NMR technique to determine the product 12C/13C kiꢀ
netic isotope effect (KIE) from cyclization of 1e under the
optimized condition.17 The most pronounced carbon isotope
effect on the benzylic position (C1) of 2e was observed, by
comparing the 13C composition of the product 2e at a low conꢀ
version (ca. 20%) to that of 2e at 100% conversion (Figure
1).18 This result indicated that the activation of the benzylic C–
H is likely the reteꢀdetermining step.
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eme 3). After 2 h, 3a was obtained in 56% yield but without
any deuterium atom at the amide αꢀposition, and 28% of 1a
was recovered without any observation of dꢀ1a. As protic solꢀ
vent tAmOH and acidic additive pivalic acid were employed in
the reaction, the amide αꢀC–H might be deprotonated in the
presence of strong base KOtBu. The fact that the D/H exꢀ
change readily occurred in the tandem cyclization reaction
implies that the amide αꢀC–H bond cleavage is unlikely to be
the rateꢀdetermining step.
For tandem aminopalladation/amide αꢀC–H functionalizaꢀ
1
tion, on the other hand, an intermolecular H/2H KIE experiꢀ
ment was carried out to test whether the amide αꢀC–H bond
cleavage is the rateꢀdetermining step. Both 1a and deuteratedꢀ
substrate dꢀ1a were subjected to the standard conditions (Schꢀ
Based on the above experimental results, we proposed a
possible mechanism for the divergent cyclizations at the benꢀ
zylic and amide αꢀpositions (Scheme 4). 1a proceeds through
the aminopalladation first to generate intermediate I, which
could not undergo β–hydride elimination due to the existence
of the angular methyl group.19 For the activation of benzylic
C–H pathway, a threeꢀcenter agostic intermediate III might be
involved (left side).20 Recently, innerꢀsphere pivalate assisted
CMD mechanism had been proposed for Pdꢀcatalyzed C(sp3)–
H activation reactions.11a,15 In our case, pivalate did improve
the yield of 2a; in addition, bidentate ligands poisoned the
reaction while electroꢀrich monodentate ligand (IPr) provided
the best result. All these observations are consistent with the
CMD mechanism. The reteꢀdetermining step, benzylic C–H
abstraction assisted by pivalate, generates a fourꢀmembered
palladacycle intermediate IV, which gives 2a via reductive
Figure 1. Experimental 13C KIEs (k12C/k13C) for the tandem amiꢀ
nopalladation/benzylic C–H activation reaction of 1e under the
optimized conditions from two independent experiments. The
numbers in parentheses represent the standard deviation on the
last digit.
Scheme 4. Proposed Mechanism for the Palladium(II)ꢀCatalyzed Intramolecular Tandem Aminoalkylation via Divergent
C(sp3)–H Functionalization
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elimination. On the other hand, the αꢀC–H of the amide is
AUTHOR INFORMATION
Corresponding Author
1
2
3
4
5
6
7
8
deprotonated to form an enolate V in the presence of a strong
base (KOtBu) (right side). The enolate formation pathway had
been reported in Pdꢀcatalyzed αꢀarylation reactions.4b,c,e Beꢀ
sides, the requirement of a stoichiometric amount of strong
base and the KIE study are both consistent with this proposed
pathway. Addition of the enolate amide would afford a sixꢀ
membered palladacycle intermediate VI, and 3a is then
formed through reductive elimination.
yangdan@hku.hk
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the University of Hong Kong and the
Hong Kong Research Grants Council (HKU 706109P and HKU
706112P). We thank Prof. Yingchun Chen at Sichuan University
for generously providing some chemicals and experimental faciliꢀ
ties.
9
CONCLUSION
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In summary, we have developed a Pd(II)ꢀcatalyzed oxidaꢀ
tive cascade aminoalkylation via C(sp3)–H functionalization
for divergent synthesis of threeꢀmemberedꢀring or fiveꢀ
memberedꢀring fused indolines. The benzylic C–H and amide
αꢀC–H can be selectively activated under different reaction
conditions. This is the first example of palladium catalyzed
tandem reaction involving C(sp3)–H activation without emꢀ
ployment of prefunctionalized reagents (halogenated or boron
reagents) and/or directing groups, representing a green and
economic protocol for the construction of Nꢀcontaining heterꢀ
ocycles.
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EXPERIMENTAL PROCEDURES
General procedure for oxidative cascade cyclization
via aminopalladation/benzylic C–H activation. In a 5ꢀmL
round bottom flask equipped with a magnetic stir bar, dry
xylene (3 mL) was added to a mixture of (allylPdCl)2 (5.5 mg,
0.015 mmol), IPr·HCl(14.0 mg, 0.033 mmol), pivalic acid (9.2
mg, 0.09 mmol), 1 (0.3 mmol), K2CO3 (45.6 mg, 0.33 mmol)
and activated 5 Å molecular sieves (300 mg). The reaction
flask was then connected to oxygen atmosphere and heated to
130 °C until TLC monitoring indicated the complete
conversion of the starting material. The reaction mixture was
cooled, filtered through a short pad of silica gel (EtOAc as
eluent) and concentrated in vacuo. The residue was purified by
flash column chromatography to give cyclopropaneꢀfusedꢀ
indoline 2.
(3) For recent reviews on C(sp3)–H functionalization: (a) Godula, K.;
Sames, D., Science 2006, 312, 67–72; (b) Collet, F.; Dodd, R. H.; Dauban,
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2011, 40, 4902; also see Ref. 2f–g and 2l–m.
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coumpounds: (a) LloydꢀJones, G. C., Angew. Chem., In. Ed. 2002, 41,
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Cosner, C. C.; Helquist, P., Chem. Eur. J. 2013, 19, 1858–1871.
General procedure for oxidative cascade cyclization
via aminopalladation/amide α-C–H functionalization. In
a 5ꢀmL round bottom flask equipped with a magnetic stir bar,
distilled tAmOH (3 mL) was added to a mixture of
IPrPd(allyl)Cl (17.2 mg, 0.03 mmol), pivalic acid (9.2 mg,
0.09 mmol), 1 (0.3 mmol), KOtBu (37.0 mg, 0.33 mmol) and
activated 4 Å molecular sieves (300 mg). The reaction flask
was then connected to oxygen atmosphere and heated to 90 °C
until TLC monitoring indicated the complete conversion of the
starting material. The reaction mixture was cooled, filtered
through a short pad of silica gel (EtOAc as eluent) and
concentrated in vacuo. The residue was purified by flash
column chromatography to give pyrrolizidine 3.
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C.ꢀG.; Hu, Q.ꢀS., Angew. Chem., In. Ed. 2006, 45, 2289–2292; (b) Ren, H.;
Knochel, P., Angew. Chem., In. Ed. 2006, 45, 3462–3465; (c) Niwa, T.;
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Takemoto, Y., Angew. Chem., In. Ed. 2012, 51, 2763–2766; (l) Piou, T.;
Bunescu, A.; Wang, Q.; Neuville, L.; Zhu, J., Angew. Chem., In. Ed. 2013,
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ASSOCIATED CONTENT
Supporting Information
Information regarding materials and methods, and all charꢀ
acterization data of compounds from this study. This material
is available free of charge via the Internet at
http://pubs.acs.org
(6) Selected examples on functionalization of unactivated C(sp3)–H bond:
(a) Baudoin, O.; Herrbach, A.; Guéritte, F., Angew. Chem., In. Ed. 2003,
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(13) We observed phosphine oxide by LCꢀMS analysis.
(14) K2CO3 and Cs2CO3 provided indentical yields, but we chose the
former due to its lower price.
(15) Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K., J. Am.
Chem. Soc. 2010, 132, 10692–10705.
(16) See Table S9 in the Supporting Information.
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9357–9358; (b) Frantz, D. E.; Singleton, D. A.; Snyder, J. P., J. Am. Chem.
Soc. 1997, 119, 3383–3384.
(18) The determination of 12C/13C KIE is dispicted in the Supporting
Information.
(19) Substrates without angular substitutions were found to give monoꢀ
cyclized products. See the Supporting Information for detail.
(20) The involvement of radical intermeidate can be excluded, as
addition of a stoichiometic amount of TEMPO had little effect on the
cyclization.
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