Acid- And base-switched palladium-catalyzed γ-C(sp3)-H alkylation and alkenylation of neopentylamine

Article abstract of DOI:10.1021/acs.orglett.1c00903

The functionalization of remote unactivated C(sp3)-H and the reaction selectivity are among the core pursuits for transition-metal catalytic system development. Herein, we report Pd-catalyzed γ-C(sp3)-H-selective alkylation and alkenylation with removable 7-azaindole as a directing group. Acid and base were found to be the decisive regulators for the selective alkylation and alkenylation, respectively, on the same single substrate under otherwise the same reaction conditions. Various acrylates were compatible for the formation of C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds. The alkenylation protocol could be further extended to acrylates with natural product units and α,β-unsaturated ketones. The preliminary synthetic manipulation of the alkylation and alkenylation products demonstrates the potential of this strategy for structurally diverse aliphatic chain extension and functionalization. Mechanistic experimental studies showed that the acidic and basic catalytic transformations shared the same six-membered dimer palladacycle.

Full text of DOI:10.1021/acs.orglett.1c00903

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Letter
Acid- and Base-Switched Palladium-Catalyzed γ‑C(sp3)−H Alkylation
and Alkenylation of Neopentylamine
Jinquan Zhang,† Shuaizhong Zhang,† and Hongbin Zou*
Cite This: Org. Lett. 2021, 23, 3466−3471
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ABSTRACT: The functionalization of remote unactivated C-
(sp3)−H and the reaction selectivity are among the core pursuits
for transition-metal catalytic system development. Herein, we report
Pd-catalyzed γ-C(sp3)−H-selective alkylation and alkenylation with
removable 7-azaindole as a directing group. Acid and base were
found to be the decisive regulators for the selective alkylation and
alkenylation, respectively, on the same single substrate under
otherwise the same reaction conditions. Various acrylates were
compatible for the formation of C(sp3)−C(sp3) and C(sp3)−
C(sp2) bonds. The alkenylation protocol could be further extended
to acrylates with natural product units and α,β-unsaturated ketones.
The preliminary synthetic manipulation of the alkylation and alkenylation products demonstrates the potential of this strategy for
structurally diverse aliphatic chain extension and functionalization. Mechanistic experimental studies showed that the acidic and
basic catalytic transformations shared the same six-membered dimer palladacycle.
Scheme 1. γ-C(sp3)−H Alkylation and Alkenylation
aturated aliphatic carbon, the basic unit of organic
S
molecules, makes the environmentally benign C(sp3)−H
manipulation strategy conducive to enrich molecular diversity
and complexity.1 The transition-metal catalysis technique
developed in the past decade has rapidly become a promising
and powerful tool for C(sp3)−H functionalization.2 Hence, in
this study, transition-metal-catalyzed C−H activation was
investigated for C(sp3)−H alkenylation3 (Scheme 1a), and
the results demonstrate the potential of this approach for
realizing C(sp3)−C(sp3) bond formation, besides the metal-
locarbene- and photoassisted alkylation approaches. The
alkylation of relatively more active α-C(sp3)−H was realized
when olefin derivatives and other coupling partners were
used,4 and β-C(sp3)−H alkylation was also achieved.5
However, the remote alkylation of stable γ- and δ-C(sp3)−H
is more challenging and rarely reported due to the kinetically
less favored formation of transition-metal intermediate
complexes. Rovis and Knowles demonstrated the δ-C(sp3)−
H alkylation with the assistance of iridium complex and blue
light-emitting diode.6 Rovis applied the same strategy to realize
γ-C(sp3)−H alkylation (Scheme 1b).7 Recently, Shi reported
the γ-C(sp3)−H alkylation of aliphatic carboxamides using
strained bicyclic olefins as the coupling agent (Scheme 1b).8
Because of the inert property of aliphatic C−H bond, it
remains a challenge to develop selective transition-metal
catalytic systems for the remote functionalization of
unactivated C(sp3)−H bonds.
Received: March 17, 2021
Published: April 21, 2021
The functionalization of remote unactivated γ-C(sp3)−H,
which is attractive in organic chemistry, has always been a
challenge. Though C(sp2)−H switchable alkylation and
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© 2021 American Chemical Society
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alkenylation has been reported,9 no substrate has been
demonstrated capable of concurrently initiating both γ-
C(sp3)−H alkylation and alkenylation via a palladium catalytic
system. Following our previous report on temperature-
switched arylation of C(sp3)−H and C(sp2)−H and catalytic
indole manipulation,10 herein we report an acid/base-
modulated selective alkylation and alkenylation of remote γ-
C(sp3)−H bond (Scheme 1c). Here, 7-azaindole was used as
the N,N′-bidentate DG under a palladium catalytic system.
Moreover, γ-C(sp3)−H alkylation was realized with the
assistance of benzoic acid, while γ-C(sp3)−H alkenylation
was realized with the assistance of the organic base 1,4-
diazabicyclo[2.2.2]octane (DABCO) under otherwise the
same reaction conditions. A wide range of acrylates with
various alkyl chains and substituted benzene rings were tested
for these transformations, as well as α,β-unsaturated ketones or
acrylates with natural product units as the olefin coupling
partner. The synthetic utility of this protocol was further
investigated for structurally diverse alkanes from the alkylated
and alkenylated products. Experimental studies were per-
formed to further elucidate the underlying selective reaction
mechanism.
a,b
Scheme 2. Scope of for γ-C(sp3)−H Alkylation
We began our reaction investigations with N-neopentyl-1H-
pyrrolo[2,3-b]pyridine-1-carboxamide (1a) and methyl acryl-
ate (2a) under the Pd(OAc)2 catalytic system with Ag2CO3 as
an additive in the presence of acids or bases (see the
Supporting Information for details). Different reaction temper-
ature, various acids and bases as well as their amount were
tested. The results showed that 100 °C with 3 equiv. of
benzoic acid and 30 °C with 3 equiv. of triethylenediamine
(DABCO) were proved to be the most favorable conditions for
alkylation and alkenylation reactions, respectively.
With the optimal acid and base reaction conditions
established, we evaluated the substrate scope of C(sp3)−H
alkylation products (Scheme 2). The results showed that this
reaction could tolerate a wide range of acrylates with different
lengths of alkyl chains (2a−2d), cyclohexyl derivatives (2e,
2f), phenyl-substituted alkyl chains (2g−2k), and substituted
benzenes (2l−2t). The linear or cyclo-alkane coupled acrylates
produced similarly moderate yields of the alkylation products
(3b−3f). A clear trend was observed for 3g−3k: the longer the
alkyl chain between the phenyl group and the oxygen atom, the
lower the yield of the alkylated product 3, ranging from 61 to
82%. The acrylates with the same substituents on the para-
position of benzenes (3m, 3o) showed higher conversion rates
than those with ortho- (3s, 3t) or meta-substituents (3q, 3r).
The electron-donating groups (3m, 3n) at the phenyl para-
position was preferred to the electron-withdrawing groups (3o,
3p). The relatively deficient behaviors of 3s and 3t with ortho-
methyl and chloro group might be due to their steric hindrance
against intermediate complex formation.
a
Conditions: 0.2 mmol of 1a, 0.5 mmol of 2a, 0.02 mmol of
Pd(OAc)2, 0.6 mmol of Ag2CO3, 0.6 mmol of acid, 1 mL of HFIP,
100 °C reaction temperature, and 36 h reaction time. Isolated yields.
b
produced relatively lower yields (4m−4o). However, acrylates
with a substituted benzene ring containing an electron-
withdrawing group failed to yield the product. Interestingly,
α,β-unsaturated ketones could also form corresponding
alkenylation products (4p−4r).
Given the appealing results so far, we applied the C(sp3)−H
alkenylation system to natural products (Scheme 3). Acrylates
with cholesterol (4s), fenchyl alcohol (4t), citronellol (4u),
isopulegol (4v), perillyl alcohol (4w), and L-menthol (4w)
were all well tolerated. These results demonstrate the
successful application of this catalytic protocol to perform
late-stage C(sp3)−H alkenylation of hydroxyl-containing
natural products.
The scope of C(sp3)−H alkenylation was also investigated
(Scheme 3). Acrylates with different alkyl chains successfully
reacted with 1a to give alkenylation products in moderate to
good isolated yields (4a−4e). The results showed that the
longer chain length led to less yields of products (4b−4e), and
the transformation rate on the branched alkyl substrates (4c,
4e) was slightly lower than the corresponding unbranched
alkylsubstrates (4b, 4d). The cyclohexyl and adamantyl group
further reduced the reaction productivity (4f and 4g). The
phenyl alkyl substituents also successfully produced moderate
to good isolated yields of products (4h−4l), whereas the
substituted benzenes with an electron-donating group
The manipulation of aliphatic chains is a major pursuit in
organic chemistry. To showcase the synthetic utility of the
C(sp3)−H alkylation and alkenylation reactions, scale-up (2.0
mmol) reactions of 1a and 2a were conducted. Products 3a
and 4a were selectively obtained with 55 and 62% yields,
respectively, confirming the catalytic system efficiency
(Scheme 4a). Moreover, the DG deprotection of 3a and 4a
was accompanied by hydrolysis to obtain free acid. In the
presence of an acid group, the benzoyl protection of the free
amine was conducted for easy purification and analysis. Hence,
the removal of DG from 3a led to amine hexanoate derivative
6, with 63% yield, whereas the newly formed amine after 4a
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a,
b
a
Scheme 3. Scope for γ-C(sp3)−H Alkenylation
Scheme 4. Synthetic Applications
a
Legend: (1) Pd(OAc)2, Ag2CO3, PhCOOH, HFIP, 100 °C, 36 h,
55%; (2) Pd(OAc)2, Ag2CO3, DABCO, HFIP, 30 °C, 36 h, 62%; (3)
K2CO3, MeOH, H2O, BzCl, 63%; (4) K2CO3, MeOH, H2O, BzCl,
51%; (5) NaBH4, MeOH, 52%; (6) Zn, AcOH, 43%; (7) B(C6F5)3, n-
butylsilane, CH2Cl2, 71%; (8) Pd/C, MeOH, H2, 94%.
provided the hydroxyl alkene product 8 with 52% yield, while
the hydrogenation of double bond of 4r with Zn/AcOH
enabled the formation of 9 with 43% yield (Scheme 4b). The
further treatment of 8 with B(C6F5)3 and n-butylsilane
afforded the olefin derivative 10. The following Pd/C
reduction of 10 afforded the saturated long-chain undecyl-
amine 11 in almost quantity yield, along with the hydro-
genation of active double bond from DG (Scheme 4b). These
transformations from the alkylated or alkenylated products
demonstrate the great potential of this selective γ-C(sp3)−H
functionalization for the further efficient construction of
diversified alkanes.
To gain insights into the reaction mechanism, we conducted
mechanistic study experiments (Scheme 5). Initially, indole
derivative 1b, instead of 7-azaindole, was reacted with 2a under
C(sp3)−H alkylation condition. Only the C(sp2)−H alkeny-
lation product (5b) was formed, indicating that N7 on 7-
azaindole was vital to initiate these C(sp3)−H alkylation and
alkenylation reactions (Scheme 5a). To further delineate the
reaction process, we performed a stoichiometric reaction to
obtain the intermediate palladium complex 12. Through X-ray
crystallography, the structure of 12 was confirmed to be a six-
membered palladacycle dimer (CCDC: 2058757), showing
that the palladium chelated with N7 and the alkyl nitrogen
(Scheme 5b). This result also proves that the N7 of 7-
azaindole was involved in the catalytic system. A further
a
Conditions: 0.2 mmol of 1a, 0.5 mmol of 2, 0.02 mmol of Pd(OAc)2,
0.6 mmol of Ag2CO3, 0.6 mmol of DABCO, 1 mL of HFIP, 30 °C
b
c
reaction temperature, 36 h reaction time. Isolated yields. 0.6 mmol
of Et3N as base.
DG cleavage simultaneously underwent nucleophilic cyclo-
addition to olefin, affording the tetrahydropyrrole derivative 7
with 51% yield (Scheme 4a). The reduction of 4r using NaBH4
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On the basis of our experiments and previous research
reports on C(sp3)−H functionalization,12 we propose a
plausible mechanism (Scheme 6). The initial coordination of
1a with Pd(OAc)2 forms a dimer of six-membered palladacycle
intermediate 12, which is further converted to [6,5]-fused
palladacycle A with the assistance of RCOOH (RCOOH =
AcOH or PhCOOH) or D under basic conditions after
C(sp3)−H activation. The following coordination of A and D
to olefin leads to the corresponding complexes B and E, and
the subsequent double-bond insertion leads to the inter-
mediates C and F, respectively. Finally, the C(sp3)−H
alkylation product 3a is obtained after protonation in the
presence of H+, whereas β-hydride elimination and reductive
elimination give the C(sp3)−H alkenylation product 4a.
In summary, we demonstrate the first example of γ-C(sp3)−
H selective alkylation and alkenylation reactions controlled by
acid and base, respectively, using 7-azaindole as the DG and
Pd(OAc)2 as a catalyst. Benzoic acid selectively initiated the
C(sp3)−H alkylation, while the organic base DABCO
exclusively provided the alkenylation products. The results of
the mechanistic study showed that the acidic and basic
catalytic cycle shared the same palladacycle dimer as the
originating intermediate. Acrylates with various alkyl chains
and substituted benzene rings were well tolerated in the
selective alkylation and alkenylation reactions and the gram-
scale reaction. Moreover, α,β-unsaturated ketones were also
compatible with the C(sp3)−H alkenylation. Furthermore, the
reaction demonstrated tolerance to acrylates derived from
natural alcohols, indicating the potential application of the
manipulation strategy to natural products. Preliminary simple
DG removal or one-step reaction could convert the alkylation
and alkenylation products into structurally diverse molecules.
This transition metal−catalyzed selective γ-C(sp3)−H activa-
tion can allow for further potential extension and derivatization
of certain alkyl chains. This study results might also encourage
researchers to discover more promising strategies enriching
C(sp3)−H functionalization.
Scheme 5. Mechanistic Studies
attempt to the C−H insertion palladacycle from 12 failed to
get the plausible intermediate D, possibly due to its instability.
PPh3 was then used to trap the unstable D to afford complex
13 for the basic C(sp3)−H alkenylation (Scheme 5c).11
However, a similar strategy failed to afford the acidic catalytic
intermediate. To confirm the role of 12 in these trans-
formations, we used a catalytic amount of 12 to replace
Pd(OAc)2, forming 3a (71%) from benzoic acid and 4a (87%)
from DABCO (Scheme 5d). These findings suggest that 12 is
a shared key originating intermediate for C(sp3)−H alkylation
and alkenylation.
Scheme 6. Proposed Catalytic Cycle
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00903.
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Experimental procedures, characterization data for all
products, crystal data, and NMR spectra (PDF)
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Accession Codes
CCDC 2058757 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Hongbin Zou − College of Pharmaceutical Sciences, Zhejiang
University, Hangzhou 310058, P. R. China; orcid.org/
0000-0001-6784-2737; Email: zouhb@zju.edu.cn
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Authors
Jinquan Zhang − College of Pharmaceutical Sciences, Zhejiang
University, Hangzhou 310058, P. R. China; orcid.org/
0000-0002-3848-5491
Shuaizhong Zhang − College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou 310058, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00903
Author Contributions
†J. Z. and S. Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Key R&D Program
of China (2017YFE0102200), the Key Projects of Natural
Science Foundation of Zhejiang Province (LZ21B020001),
and the National Natural Science Foundation of China
(21472170).
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