Pd(II)-Catalyzed Alkylation of Tertiary Carbon via Directing-Group-Mediated C(sp3)-H Activation: Synthesis of Chiral 1,1,2-Trialkyl Substituted Cyclopropanes

Article abstract of DOI:10.1021/acs.orglett.5b03229

A Pd(OAc)₂-catalyzed alkylation reaction of the tertiary carbon of chiral cyclopropane substrates with alkyl iodides and bromides via C(sp³)-H activation has been developed. This is an elusive example of a C-H activation-mediated alkylation of tertiary carbon to effectively construct a quaternary carbon center. The alkylation proceeded with various alkyl halides, including those of functional groups, to provide a variety of chiral cis- and trans-1,1,2,-trialkyl substituted cyclopropanes of medicinal chemical importance.

Full text of DOI:10.1021/acs.orglett.5b03229

Letter
pubs.acs.org/OrgLett
Pd(II)-Catalyzed Alkylation of Tertiary Carbon via Directing-Group-
Mediated C(sp3)−H Activation: Synthesis of Chiral 1,1,2-Trialkyl
Substituted Cyclopropanes
Naoyuki Hoshiya,*,† Kei Takenaka,† Satoshi Shuto,*,‡,§ and Jun’ichi Uenishi†
†Department of Pharmaceutical Chemistry, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
‡Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo, 060-0812, Japan
§Center for Research and Education on Drug Discovery, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo, 060-0812, Japan
S
* Supporting Information
ABSTRACT: A Pd(OAc)2-catalyzed alkylation reaction of the
tertiary carbon of chiral cyclopropane substrates with alkyl
iodides and bromides via C(sp3)−H activation has been
developed. This is an elusive example of a C−H activation-
mediated alkylation of tertiary carbon to effectively construct a
quaternary carbon center. The alkylation proceeded with various alkyl halides, including those of functional groups, to provide a
variety of chiral cis- and trans-1,1,2,-trialkyl substituted cyclopropanes of medicinal chemical importance.
irecting-group-mediated C−H functionalization is one of
cyclopropane substrate cis-1 as well as trans-substrate trans-1
(Scheme 1).5
D
the most useful transformations in organic synthesis
because it allows regio- and stereoselective functionalizations
and alternative synthetic routes that are different from
conventional transformations via prefunctionalization of the
C−H bond, such as halogenation and/or metalation.1 Thus,
these C(sp3)−H functionalizations have been effectively used in
the synthesis of a variety of complex molecules.2 Considerable
effort has been devoted to the functionalizations of C(sp3)−H
as well as C(sp2)−H bonds, and many primary or secondary
C(sp3)−H bond activation examples are known. In contrast,
only a few examples of tertiary C(sp3)−H functionalization
have been reported, probably because sterically hindered
tertiary carbons are less reactive than primary and secondary
carbons.
Scheme 1. Functionalization of Tertiary C(sp3)−H Bond on
Cyclopropanes
In our continuing studies using cyclopropanes as key
conformational restriction units,3 we needed to prepare a
variety of chiral 1,1,2-trisubstituted cyclopropane structures
with a quaternary carbon (Figure 1). To construct such
Furthermore, we were required to obtain chiral 1,1,2-
trialkylsubstituted cyclopropanes. For their synthesis, we
considered that the directing-group-mediated alkylations of
C(sp3) would be very effective, which might allow us to
construct the quaternary carbon center while preparing a wide
variety of chiral 1,1,2-trialkyl-substituted cyclopropanes. Again,
cis-1 as well as trans-1 would be effective substrates (Scheme 1).
Although directing-group-mediated alkylations of C(sp3)
have recently been studied intensively by Dauglis,6 Shi,7
Chen,8 and Ge,9 alkylation of tertiary C(sp3) has not yet
been reported. However, we hypothesized that, when chiral
cyclopropane substrates cis-1 and trans-1 are employed, the
tertiary C(sp3) alkylation forming the quaternary carbon center
Figure 1. Target chiral 1,1,2-trisubstituted cyclopropanes.
structures,4 directing-group-mediated substitution via transi-
tion-metal-catalyzed direct C−H activation can be the most
attractive strategy because it regio- and stereoselectively
provides a wide range of compounds via a short synthetic
route.1 In fact, we successfully developed tertiary C(sp3)
arylation on chiral cyclopropanes with aryl iodides via Pd(II)-
catalyzed chelation-assisted C(sp3)−H activation, using cis-
Received: November 9, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03229
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might proceed owing to the following characteristic features of
cyclopropane: (i) the tertiary carbon of cyclopropanes is less
sterically hindered compared with the usual ones due to the
small and rigid ring structure, (ii) the ring carbons forming the
cyclopropane structure are unusually sp2-like-hybridized, and
(iii) the C(sp3)−H activation may be potentially promoted due
to conformational restriction of the directing group attached to
the rigid cyclopropane ring.10
and 9), the use of t-AmylOH or t-BuOH as the solvent clearly
improved the yield (50%, entry 10; 58%, entry 11). Next, we
screened the silver salts. The use of Ag2PO4 or AgOTf instead
of AgOAc significantly decreased the yield (entries 12 and 13);
however, the switch to Ag2CO3 provided the product 3a in 66%
yield (entry 14). Thus, we fine-tuned the reaction conditions
with Ag2CO3 as a base. The use of 1.3 equiv of (BnO)2P(O)-
OH increased the yield to 75% (entry 15). When we examined
the alkylation in the presence of Pd(OAc)2 (15 mol %), cis-1
was effectively consumed to produce 3a in 85% yield (entry
16). Even at a lower temperature (50 °C), the reaction
proceeded smoothly to give 3a in 95% yield (entry 17). When
the amount of Ag2CO3 or (BnO)2P(O)OH was reduced, the
reaction was not completed (entries 18−20). As described, we
found that the ethylation at the tertiary C(sp3) of chiral
cyclopropane cis-1 efficiently occurred and that the optimized
reaction conditions were those in entry 17.
To gain information about the effect of Ag2CO3 and
(BnO)2P(O)OH, we examined the alkylation using (BnO)2P-
(O)OAg instead of the combination of Ag2CO3/(BnO)2P(O)-
OH. As a result, we obtained 3a in 56% yield (entry 21).
Addition of K2CO3 to the reaction system did not improve the
yield (58%, entry 22). When KHCO3 was added to the reaction
system, however, the yield effectively increased to 80% (entry
23). These results suggest that (BnO)2P(O)OAg might be
formed in situ and that the bicarbonate ion (−HCO3) plays an
important role in promoting the alkylation.12−14
Here, we report Pd(II)-catalyzed tertiary C(sp3) alkylation
via a directing-group-mediated C−H activation by employing
chiral cyclopropane substrates.11 To the best of our knowledge,
this is the first example of tertiary C(sp3) alkylation via metal-
catalyzed C−H activation with a directing group, although the
arylations of tertiary C(sp3) have been reported.1
We first examined the tertiary C(sp3) alkylation of chiral
cyclopropane cis-1 with EtI (2a) as an electrophile. As a result,
we found that the reaction under our conditions previously
optimized for the arylation using 2a instead of an aryl iodide
i.e., 2a (3 equiv), Pd(OAc)2 (10 mol %), AgOAc (1.5 equiv), in
toluene at 100 °C, 12 hactually produced the desired
alkylated quaternary cyclopropane product 3a, although the
yield was very low (17%) (Table 1, entry 1). K2CO3, a
Table 1. Optimization of Reaction Conditions
With the optimized reaction conditions in hand, we
investigated the reactions of cis-1 with various alkyl iodides
and bromides. The results are summarized in Scheme 2.15 The
reaction with low molecular weight primary alkyl iodides, i.e.,
methyl iodide (2b) and butyl iodide (2c), afforded the
corresponding products in high yields. Fatty dodecyl iodide
(2d) and branched 3-methylbutyl iodide (2e) were also suitable
electrophiles, and they gave the corresponding alkylated
product in 82% yield and 62% yield, respectively. However,
a
Scheme 2. Substrate Scope of cis-1
a
b
Pd(OAc)2 (15 mol %), for 12 h. Yields were estimated by 1H NMR
c
using anthracene as an internal standard. Numbers in parentheses are
remaining cis-1. Isolated yield.
d
nonsilver salt, was also tested, but the reaction did not proceed
at all (entry 2). We then tested various additives together with
AgOAc. Addition of PivOH (0.3 equiv) or TsNH2 (0.3 equiv)
was not effective in improving the yield (entries 3 and 4).
Addition of (BnO)2P(O)OH (0.3 equiv), which was reported
to be effective for C(sp3)−H alkylation by the Chen group,8
somewhat improved the yield (31%, entry 5). We also
examined other phosphate additives; however, addition of
(PhO)2P(O)OH or BnOP(O)(OH)2 was ineffective (entries 6
and 7). Next, we examined the reaction solvent. Although
dioxane and CF3CF2OH were not suitable solvents (entries 8
a
All reactions were carried out using cis-1 (0.05 mmol) and R−I or R−
b
Br (3 equiv). Yield of 0.5 mmol (250 mg) scale reaction was 86%.
B
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the reaction with secondary isopropyl iodide (2f) did not
proceed at all. Next, we tested alkyl iodides with functional
groups, i.e., 3-iodopropanol (2g), iodoacetonitrile (2h), and 1-
chloro-6-iodohexane (2i).
Scheme 4. Transformation of the 8-Aminoquinoline Moiety
These functional groups tolerated the alkylation to provide
the corresponding coupling products, while the yields were
moderate. Alkyl iodides with thiophene (2j) and phthalimide
(2k) were also good coupling partners. The reactions with a
TIPS-protected terminal alkyne (2l) and cis-olefin (2m)
proceeded smoothly. We next examined the reaction with
alkyl bromides. When the reaction was carried out with EtBr,
only a trace of the desired coupling product was obtained.
However, the reactions with active alkyl bromides, such as ethyl
bromoacetate (2n) and allyl bromide (2o), proceeded to give
the corresponding alkylated products in 43% and 50% yield,
respectively. Benzyl bromide (2p) and 4-nitrobenzyl bromide
(2q) were also effective electrophiles for the alkylation.
We next investigated the alkylation of trans-1, which was a
more challenging substrate than cis-1 because its tertiary
C(sp3)−H bond to be activated was significantly sterically
hindered due to the adjacent cis-substituent. In fact, only a 21%
yield of the coupling product 4a was obtained under the
reaction conditions optimized for cis-1 and EtI (Supporting
Information Table S1, entry 1). We conducted the alkylation
under various conditions and found that the reaction at higher
temperature (75 °C) made the yield slightly higher, obtaining
4a in 31% yield (Supporting Information Table S1, entry
2).16,17
Scheme 5. C(sp3)−H Alkylation of Non-cyclopropane
Substrates 6 and 7
temperature at 100 °C. These results suggest that the
characteristic steric and hybridization property of cyclopropane
enables the tertiary C(sp3) alkylation of cyclopropane
substrates to proceed, as we hypothesized.
In conclusion, we successfully developed the directing-group-
mediated tertiary C(sp3) alkylation of chiral cyclopropanes with
alkyl iodides and activated alkyl bromides in the presence of
Pd(OAc)2. This is the elusive example of tertiary C(sp3)
alkylation via C(sp3)−H activation, and it allows us to prepare a
variety of chiral 1,1,2-trialkylcyclopropanes of medicinal
chemical importance. The results of the control experiments
with noncyclopropane substrates suggested that the tertiary
C(sp3) alkylation effectively occurs due to the characteristic
structural and hybridization feature of the cyclopropane ring.
The reaction results of trans-1 with various alkyl halides are
summarized in Scheme 3. The reaction with a simple alkyl
Scheme 3. Substrates Scope for trans-1
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03229.
Experimental data, characterization data for new
compounds, and chiral HPLC chart (PDF)
Reactions were carried out at 50 °C.
AUTHOR INFORMATION
Corresponding Authors
■
iodide 2a, branched alkyl iodide 2e, TIPS-protected terminal
alkyne 2l, and ester 2r provided the corresponding alkylated
product in 22%−48% yields. Activated alkyl bromides 2p and
2q also worked as coupling partners.
*E-mail: hoshiya@mb.kyoto-phu.ac.jp.
*E-mail: shu@pharm.hokudai.ac.jp.
Notes
We then examined the transformation of the 8-amino-
quinoline moiety. A two-step sequence was employed: (i) Boc
introduction at the amide and (ii) hydrolysis of the resulting
secondary amide with LiOH and H2O2. This gave the
carboxylic acid 5 in 72% yield from 3d (Scheme 4).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Sanyo Fine Co., Ltd. for the gift of the chiral
epichlorohydrins. This investigation was supported by Grant-
in-Aids for Scientific Research Grant Number 26860003 (N.H.)
and 15H02495 (S.S.) from the Japan Society for the Promotion
of Science, and also for Creation of Innovation Centers for
Advanced Interdisciplinary Research Areas Program from
We also examined the tertiary C(sp3) alkylation with
noncyclopropane substrates, i.e., cyclobutane substrate 6 and
acyclic substrate 7 (Scheme 5). When 6 or 7 was treated with
EtI under the optimized reaction conditions for cis-1, the
ethylation did not proceed at all, even under the higher
C
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(17) The reaction of cis-1 with Pd(TFA)2 instead of Pd(OAc)2 under
the optimized conditions (entry 17) provided the desired product 3a
in 56% yield and recovered cis-1 in 18% yield.
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