Pd-Catalyzed Intramolecular Aminoalkylation of Unactivated Alkenes: Access to Diverse N-Heterocycles

Article abstract of DOI:10.1021/acs.orglett.6b03295

A highly efficient palladium-catalyzed intramolecular aminoalkylation of unactivated alkenes in the absence of an external ligand and oxidant is described. New C-N and C(sp³)-C(sp³) bonds are formed simultaneously. This general transformation allows for construction of diverse N-heterocycles. Mechanistic studies show that the process may involve a four-membered Pd(alkyl)amido intermediate.

Full text of DOI:10.1021/acs.orglett.6b03295

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Intramolecular Aminoalkylation of Unactivated
Alkenes: Access to Diverse N‑Heterocycles
Liu Ye, Kai-Yip Lo, Qiangshuai Gu, and Dan Yang*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. China
S
* Supporting Information
ABSTRACT: A highly efficient palladium-catalyzed intramolec-
ular aminoalkylation of unactivated alkenes in the absence of an
external ligand and oxidant is described. New C−N and C(sp3)−
C(sp3) bonds are formed simultaneously. This general trans-
formation allows for construction of diverse N-heterocycles.
Mechanistic studies show that the process may involve a four-
membered Pd(alkyl)amido intermediate.
Scheme 1. Palladium-Catalyzed Intramolecular
Aminovinylation and Aminoalkylation
he Pd-catalyzed C−N bond formation via aminopalladation
Tof alkene has emerged as a powerful tool to access diversely
functionalized N-heterocycles.1 The development of cascade
reactions involving the formation of other bonds besides the C−
N bond in one single operation is particularly appealing.
Palladium-catalyzed carboamination (simultaneous formation
of C−N and C−C bonds from an olefin) represents an effective
strategy for the introduction of vicinal substituents onto a
carbon−carbon double bond.2 Despite impressive progress
achieved in aminocarbonylation,3 aminoarylation,4 aminovinyla-
tion,5 andaminoalkynylation,6 theaminoalkylationofunactivated
alkenes remains very rare.7 Meanwhile, either an expensive and/
or sensitive ligand or an excess amount of external oxidant is
required in those reported transformations. Therefore, the
development of an efficient Pd-catalyzed aminoalkylation of
unactivated alkenes under mild conditions with a simple
operation is a great challenge and highly desirable.
Nitrogen-containing heterocycles are commonly found in a
diverse array of natural products and biologically active
molecules.8 Among them, pyrroloindole, pyrroloquinoline,
pyrrolizidine, and indolizidine are important scaffolds due to
their prevalence in pharmacologically active natural compounds
(Figure 1).9 Hence, the development of general protocols for the
synthesis of these skeletons is of great interest. Recently, our
group developed effective methods for accessing pyrroloindoline
derivatives via Pd-catalyzed aminovinylation of unactivated
alkenes (Scheme 1a).5c−f On the basis of our continued interest
in Pd-catalyzed carboamination, we envisioned that by replacing
the unsaturated amide with an α-halo acetamide, we might realize
an intramolecular aminoalkylation. It is expected that an initial
oxidative addition of the C−X bond with Pd(0) would afford
intermediate A,10 which might undergo subsequent intra-
molecular aminopalladation11 and the final reductive elimination
to generate the target product (Scheme 1b). Herein, we report
our efforts in achieving such an intramolecular aminoalkylation of
unactivated alkenes under palladium catalysis without the
requirement of an expensive and/or sensitive ligand or external
oxidant, allowing for the expedient construction of a wide array of
biologically important N-containing scaffolds.
To test the hypothesis outlined in Scheme 1b, compound 1.1a
was initially chosen as the model substrate to screen the reaction
conditions (Table 1). When 1.0 equiv of Na2CO3 was employed,
the desired product was obtained only in moderate yield, along
with a significant amount of olefin isomerization byproduct12
(entry 1). Increasing the amount of Na2CO3 to 3.0 equiv
remarkably improved the yield to 70% (entry 2). A further
increase in the amount of Na2CO3 to 5.0 equiv, however, led to a
Received: November 2, 2016
Figure 1. Representative N-containing heterocycles in natural products.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03295
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Organic Letters
Letter
a
a b
,
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of Aromatic α-Halo Acetamides
b
entry
substrate
base (equiv)
t (h)
yield (%)
1
1.1a
1.1a
1.1a
1.1a
1.1a
1.1a
1.1a
1.1a
1.2a
1.2a
1.2a
Na2CO3 (1.0)
Na2CO3 (3.0)
Na2CO3 (5.0)
K2CO3 (3.0)
Cs2CO3 (3.0)
K2CO3 (3.0)
Na2CO3 (1.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (3.0)
16
16
10
10
6
45
70
53
86
50
91
90
82
86
69
86
2
3
4
5
6
7
8
9
c
12
12
34
23
48
15
d
ce
,
cef
,
,
cfg
, ,
10
11
cfh
, ,
a
Reaction conditions: substrate (0.2 mmol), Pd(OAc)2 (10 mol %),
b
and 4 Å MS (1 g/mmol substrate) in MeCN (2.0 mL) at 40 °C. Yield
of the isolated product. Without 4 Å MS. 10 mol % PdCl2 and 0.63
equiv of Ag2O were employed instead. 5 mol % Pd(OAc)2. Reaction
temperature was 70 °C. 2.5 mol % Pd(OAc)2. 5 mol % Pd2(dba)3 in
c
d
e
f
g
h
place of Pd(OAc)2.
diminished yield of the desired product (53%), favoring the
formation of the alkene isomerization product (entry 3).
Gratifyingly, the use of K2CO3 further enhanced the yield to
86% (entry 4). In contrast, a much stronger base, Cs2CO3, has
given rise to the formation of a dimer as the major side product
(see the Supporting Information (SI) for details) (entry 5). Thus,
the reaction efficiency seems to be greatly dependent on the
nature of the base employed, and the moderately basic K2CO3
proved to be the best. The optimal yield (91%) was obtained
when the reaction was performed without the addition of 4 Å
molecular sieves (MS) (entry 6). An alternative catalyst system
composed of PdCl2 and Ag2O, which presumably acts as an
efficient scavenger for the generated bromide anion, was also
developed at the same time to afford the desired product in 90%
yield (entry 7). Given the relative high expense of a silver salt, we
preferred the silver-free conditions whenever comparable
efficiency was observed for these two conditions (entries 6 and
7). Reducing the catalyst loading from 10 to 5 mol % caused a
slightly decreased efficiency after an extended reaction time
(entry8).Notably,thepresumablylessreactivesubstrate1.2awas
alsosuitableforthecyclization, producing 2ain86%isolated yield
atanelevatedtemperature(entry9).Inthiscase,acatalystloading
as low as 2.5 mol % was sufficient to deliver a moderate yield of 2a
(entry 10). Replacing Pd(OAc)2 with Pd2(dba)3 gave a
comparable yield of 2a (entry 11), which implies that a Pd(0)/
(II) catalytic cycle is likely involved in this transformation.
With the optimized conditions in hand, we next investigated
the scope of this reaction for the synthesis of pyrroloindolines
from aromatic α-halo acetamides (Scheme 2). A variety of
substrates, tethered by monocyclic aromatic rings with either
a
Reactions were run on 0.2 mmol scale; method A was employed for
α-bromo substrates, and method B was employed for α-chloro
substrates. Yield of the isolated product. Reaction was run on 9.0
mmol scale with 8 mol % Pd(OAc)2. Reaction was run on 2.0 mmol
scale with Pd(OAc)2 (4 mol %). Pd(OAc)2 (5 mol %). PdCl2 (10
b
c
d
e
f
g
mol %) and Ag2O (0.63 equiv) were used instead. PdCl2 (10 mol %)
h
and Ag2O (0.63 equiv) were used instead. Ratio was determined by
i
1H NMR analysis, and the major diastereomer is depicted. PdCl2 (10
j
k
mol %). Pd(OAc)2 (6.5 mol %). 16% OAc-substitution product was
detected by crude H NMR.
1
further access to more complex compounds by well-established
cross-coupling reactions, thus rendering this cyclization method-
ology more attractive. Besides, both 2,2-disubstituted alkene
substrate 1.1b and substrate 1.1g bearing an ethyl substituent at
the benzylic position reacted smoothly to give the expected
products in 82% and 67% yields, respectively. In addition,
complex tetracyclic product 2l was obtained as a single
diastereomer from substrate 1l possessing an exocyclic alkene
moiety in 89% yield. More significantly, the present catalytic
system could be applied to the construction of indolizidine
derivative 2m and tricyclic heterocycle 2n, albeit with lower
efficiency. In fact, only a few successful methods have been
reported for the synthesis of six-membered nitrogen heterocycles
via aminocyclization reactions.13
i
electron-donating (Me, Pr and OMe) or electron-withdrawing
substituents (Br and CN) or a bicyclic naphthalene ring (1.1k),
were all effectively converted into the desired products, whereas a
relatively low yield was observed with 4,6-dimethoxy-substituted
substrate 1.1i. Notably, the reaction yield was good (78%) when
performed on gram scale with an 8 mol % catalyst loading. Of
particular note is the tolerance of aryl bromide, which enables
B
DOI: 10.1021/acs.orglett.6b03295
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Organic Letters
Letter
In addition, less reactive α-chloro-substituted substrates are
amenable for this cyclization (Scheme 2). Substrates 1.2a−c and
1.2m provided roughly comparable yields of the same products
with those from corresponding α-bromo-substituted substrates.
Substituents, such as OMe, F, and Cl, para to the amide moiety
were all well tolerated. In some cases, ester side products resulting
fromreactionofthenucleophilicacetateligandwithalkylchloride
were detected. In contrast to the unreactive secondary α-bromo
acetamide substrate,14 the analogous secondary α-chloro ones
successfully cyclized to give corresponding products as single
diastereomers.15 Compared to α-phenyl and α-methoxymethyl
substituted products 2s and 2t, a better yield was obtained for α-
methyl substituted product 2r, which might be attributed to less
steric hindrance of the methyl group. It is also interesting to note
that no β-H elimination side products were detected from
substrates 1.2r and 1.2t given the facile nature of such a common
competitive pathway in palladium-catalyzed transformations.
Evaluation of the substrate scope was then focused on the
synthesis of more challenging pyrrolizidine derivatives. However,
the catalytic system described above was not productive. After
rescreening a variety of reaction parameters (base, solvent,
temperature, additive, etc.), the modified conditions were
established as follows: Pd2(dba)3 (5 mol %), LiOtBu (1.0
equiv), and Ag2O (0.65 equiv) in tBuOH (0.1 M) under reflux
(Scheme 3). Gem-disubstituted substrates either with the same
Scheme 4. Control Experiments
cyclization is not likely (eq 1; for details see Scheme S1).16 The
enantiopure substrate 1.2r was converted to 2r with an almost
complete chirality transfer,17 which further rules out the radical
pathway (eq 2;fordetails see FigureS1). Furthermore, it provides
an alternative method to prepare chiral pyrroloindole derivatives
starting from readily available enantioenriched α-chloro acet-
amides. The presence of an additional chloride anion has a
deleterious effect on the efficacy, which reveals that the
dissociation of the Cl ligand from a putative intermediate
complex may be of importance in the transformation (eq 3).18
Although no pure intermediate was isolated, the ESI-MS analysis
of the reaction mixture of substrate 1.4a with a bipyridine ligand
strongly supports the formation of a four-membered Pd(alkyl)-
amido intermediate (eq 4).19
ab
,
Scheme 3. Substrate Scope of Aliphatic Chloro-acetamides
Based on the aforementioned observations, we propose a
catalytic cycle for this intramolecular aminoalkylation reaction
(Scheme 5). Pd(0), either from Pd2(dba)3 or in situ generated
Scheme 5. Plausible Mechanism
a
Reaction conditions: substrate 1.3 (0.3 mmol), Pd2(dba)3 (5 mol %),
Ag2O (0.65 equiv), and LiOtBu (0.3 mmol) in tBuOH (3.0 mL) under
reflux temperature. Yield of the isolated product. Ratio determined
by crude H NMR analysis. Pd(cod)2Cl2 (10 mol %) was used.
b
c
d
1
phenyl groups or a phenyl and a methyl one afforded the desired
products 3a and 3b in 87% and 78% yield, respectively. Substrates
bearing one phenyl substituent at either a homoallylic or an allylic
position proceeded smoothly to produce cyclized products in
good yields (3c and 3d). Notably, for geminally disubstituted
alkene 1.3e, the use of Pd(cod)2Cl2 instead of Pd2(dba)3 gave a
betteryield of 3e. Thespiro-tricyclic product 3fcould beobtained
from cyclohexylidene-substituted substrate 1.3f, albeit with low
effectiveness. Importantly, tetrahydroisoquinoline derivative 3g
with a newly generated 6/5 fused ring skeleton was also delivered
in 65% yield. It is worthy to note that a OtBu-substituted
byproductresultingfromnucleophilicsubstitutionbyLiOtBuwas
occasionally observed.
from Pd(OAc)2, was first oxidized by α-halo acetamide to Pd(II)
species I.10 Subsequent amide deprotonation and coordination to
the Pd(II) center produced four-membered palladacycle
intermediate II.19,20 The following alkene coordination afforded
four-coordinated Pd intermediate III.21 The conversion of III to
the desired product presumably proceeded through sequential
syn-aminopalladation11 and reductive elimination.22
To gain more insight into the reaction mechanism, some
controlexperimentswereperformed(Scheme4). Theadditionof
a stoichiometric amount of TEMPO did not affect the reaction
efficiency, which indicates that a radical pathway for this
C
DOI: 10.1021/acs.orglett.6b03295
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(5) For selected examples of PdII-catalyzed aminovinylation, see:
(a) Rogers, M. M.; Stahl, S. S. Org. Lett. 2006, 8, 2257. (b) Scarborough,
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In summary, we have developed an efficient intramolecular
aminoalkylation reaction involvingthesimultaneous formation of
C−N and C(sp3)−C(sp3) bonds. This reaction represents a
rather rare example of Pd-catalyzed carboamination. It shows
good functional group tolerance and provides a step-economical
synthetic approach toward diverse N-heterocycles, such as
pyrroloindole, pyrroloquinoline, pyrrolizidine, and indolizidine,
from simple and readily available α-halo acetamides under mild
conditions. The asymmetric variant of this transformation is
ongoing. This intramolecular aminoalkylation may find broad
application in the chemical synthesis of alkaloids.
ASSOCIATED CONTENT
* Supporting Information
■
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White, P. B.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 18594.
(19) The formation of four-membered azapalladacycles was previously
Experimental procedures, characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yangdan@hku.hk.
ORCID
Qiangshuai Gu: 0000-0002-3840-425X
Dan Yang: 0000-0002-1726-9335
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Jun-Feng Zhao (Jiangxi Normal University) for
help in preparation of this manuscript. This work was supported
by the University of Hong Kong and the Hong Kong Research
Grants Council (HKU 706109P and HKU 706112P).
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D
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