Rhodium-Catalyzed Intermolecular C-H Functionalization as a Key Step in the Synthesis of Complex Stereodefined β-Arylpyrrolidines

Article abstract of DOI:10.1021/acs.orglett.8b01362

The synthesis of β-arylpyrrolidines via a catalytic enantioselective intermolecular allylic C(sp)³-H functionalization of trans-alkenes followed by immediate reduction, ozonolysis, and then in situ diversification of the resulting cyclic hemiaminal to furnish highly substituted, stereoenriched β-arylpyrrolidines is reported. This methodology utilizes 4-aryl-1-sulfonyl-1,2,3-triazoles as carbene precursors and the dirhodium tetracarboxylate catalyst Rh₂(S-NTTL)₄. A variety of β-arylpyrrolidines were prepared in good yields with high levels of diastereo- and enantioselectivity over four linear steps, requiring only a single purification procedure.

Full text of DOI:10.1021/acs.orglett.8b01362

Letter
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Cite This: Org. Lett. 2018, 20, 3771−3775
Rhodium-Catalyzed Intermolecular C−H Functionalization as a Key
Step in the Synthesis of Complex Stereodefined β‑Arylpyrrolidines
Robert W. Kubiak, II and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S
* Supporting Information
ABSTRACT: The synthesis of β-arylpyrrolidines via a catalytic enantioselective intermolecular allylic C(sp)3−H
functionalization of trans-alkenes followed by immediate reduction, ozonolysis, and then in situ diversification of the resulting
cyclic hemiaminal to furnish highly substituted, stereoenriched β-arylpyrrolidines is reported. This methodology utilizes 4-aryl-
1-sulfonyl-1,2,3-triazoles as carbene precursors and the dirhodium tetracarboxylate catalyst Rh2(S-NTTL)4. A variety of β-
arylpyrrolidines were prepared in good yields with high levels of diastereo- and enantioselectivity over four linear steps,
requiring only a single purification procedure.
Scheme 1. Previous Allylic C−H Functionalization
n the past two decades, the field of C−H functionalization
I
has grown extensively, ushering in a variety of enabling new
methodologies for organic synthesis.1−3 In particular, the
ability of organic chemists to utilize simple C−H bonds to
effect meaningful, enantioselective chemical transformations
has caused a shift in the logical approach toward synthesis.4
Donor/acceptor carbenes have been especially attractive
synthons for C−H insertion reactions because they are
sufficiently reactive to functionalize C−H bonds. The donor
group attenuates the reactivity of the adjacent carbene
affording an impressive range of site-selectivity,5 which can
be further controlled by the steric nature of the catalyst.6
Traditionally, donor/acceptor metallocarbenes are accessed via
the metal-catalyzed decomposition of diazo compounds
utilizing dirhodium tetracarboxylates as optimal chiral
catalysts,5,6 which can be sterically tuned, such that primary,
secondary, or tertiary C−H bonds are selectively function-
alized.7
In recent years, 4-aryl-N-sulfonyl-1,2,3-triazoles, which
undergo a retro-6π electrocyclization in solution to unveil
latent diazo compounds possessing an α-imino acceptor group
(Scheme 1a),8 have been shown to act as competent alternates
to aryldiazoacetates, demonstrating the ability to access a wide
variety of traditional Rh(II)-catalyzed transformations.9−13
However, to date, their application toward intermolecular
C−H functionalization has been relatively limited in
comparison to their aryldiazoacetate congeners. C−H
functionalization of alkanes and cycloalkanes was achieved
using naphthalimido-based Rh2(S-NTTL)4 as an optimal
catalyst to provide high yields and enantioselectivities.14a
Attempts to extend C−H functionalization to substrates
containing functional groups have been limited. Cyclic ethers
were shown to be ineffective because ylide formation followed
by ring-expansion preferentially occurred to C−H insertion.15
In 2016, our group demonstrated that benzylic and allylic C−
H functionalization is a viable process (Scheme 1b),14b and we
have recently shown that cyclic and acyclic silanes are prone to
C−H functionalization at the β position to silicon.14c A key
reason for choosing 4-aryl-N-sulfonyl-1,2,3-triazoles in favor of
aryldiazoacetates in the synthetic strategy is the ability to map
the nitrogen functionality of the α-imino acceptor group into
target-oriented synthesis. In this paper, we demonstrate that
allylic C−H functionalization with α-imino carbenes can be
employed to gain access to a wide variety of highly substituted
and stereodefined β-arylpyrrolidines.
In our preliminary asymmetric investigation into allylic
C(sp3)−H functionalization, we described our initial findings
using three trans-alkenes and p-cymene as substrates with 4-
phenyl-N-methanesulfonyl-1,2,3-triazole as a donor/acceptor
carbene precursor in the presence of Rh2(S-NTTL)4 as an
optimal chiral catalyst (Scheme 1b).14b One of the resulting
products from this study was methanesulfonamide 6a,
Received: April 28, 2018
Published: June 21, 2018
© 2018 American Chemical Society
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Letter
generated in 83% yield and 84% ee by lithium aluminum
hydride reduction of the initial C−H functionalization product.
We recognized that these types of C−H functionalization
products could be useful precursors toward the formation of
highly diversified β-arylpyrrolidines. In order to evaluate this
possibility, initial studies were conducted to determine if 6a
could be readily converted to the desired pyrrolidine 8a
(Scheme 2). Ozonolysis of 6a followed by quenching with
Scheme 2. Preliminary Studies
dimethyl sulfide generated cyclic hemiaminal 7a in 90% yield.
Reduction of 7a with triethylsilane and boron trifluoride
diethyl etherate furnished the desired pyrrolidine 8a in 95%
yield with retention of the asymmetric induction achieved
during C−H functionalization. Next, we sought to streamline
the synthetic sequence to increase the practicality of this
strategy. The sequence of C−H functionalization, imine
reduction, ozonolysis, and reductive amination was conducted
without chromatographic purification until the last step. Using
these conditions, the pyrrolidine 8a was formed in analogous
yield and enantioselectivity to the stepwise procedure (66%
yield, 81% ee). Similar results were obtained in a multigram-
scale reaction.
With the optimized procedure for the synthesis of 3-
arylpyrrolidines in hand, we continued our investigation by
examining the scope of the reaction with a wide range of 4-
aryl-N-sulfonyl-1,2,3-triazoles, as summarized in Figure 1.
Varying the N-sulfonyl group had little influence on the
reaction outcome. The N-mesyl protecting group gave the
highest yield as illustrated for 8a (66% yield, 82% ee), but the
2-(trimethylsilyl)ethanesulfonyl protecting group provided the
highest levels of enantioinduction as illustrated for 8c (56%
yield, 86% ee). Moving forward with the N-mesyl protecting
group, we explored the influence of varying the arene
component on the triazole ring, as seen with 8d−n. A variety
of electronically and sterically diverse triazoles were amenable
to the insertion event allowing for downstream access to the 3-
arylpyrrolidine motif. Electron-withdrawing groups gave
slightly decreased product yields with moderate levels of
enantioinduction 8d−f. Electron-neutral and -donating groups
both gave excellent yields of 8i−l with moderate to good levels
of enantioinduction. Varying the meta-position of the arene
ring gave similar results, but the ortho-substituted arenes
demonstrated significant increases in enantioinduction with
lower overall yields, as illustrated for the o-bromo derivative 8h
(22% yield, 98% ee).
Figure 1. Scope of triazole component. (a) Insertion reactions run at
4.0 equiv of 4a; ozonolysis reactions run at 4.0 equiv of DMS;
reduction reactions run at 3.2 equiv of HSiEt3 and BF3·OEt2. (b)
Isolated yields. (c) ee determined by HPLC analysis after purification.
Aiming to generate two new stereogenic centers in one
synthetic operation, we turned our attention toward the
secondary C−H functionalization of trans-alkenes to provide
stereodefined 3-aryl-4-alkylpyrrolidines (Figure 2). In our
previous study, we demonstrated that trans-3-hexene under-
goes secondary C−H functionalization providing a 70:30
mixture of diastereomers 9a/9b. Therefore, we conducted a
brief study to enhance the level of diastereoselectivity prior to
downstream pyrrolidine synthesis. Initially, we explored
substrates with increased steric bulk on the alkene (Figure
2a). Using trans-2,2-dimethyl-3-hexene as a substrate switched
the diastereoselectvity of 10 but still led to lower
diastereoselective ratios overall (38:62 dr, 10a/10b). Attempt-
ing the reaction using trisubstituted 2-methyl-2-pentene failed
to generate any of the desired C−H functionalization product.
This result is not too surprising given that previous studies
with aryldiazoacetates have also shown that allylic C−H
functionalization is sterically blocked by using cis-substituted
alkenes.16 Next, we examined the effect of decreasing steric
bulk on the alkene component by using trans-2-pentene as a
substrate, which also provides the possibility for two distinct
regiochemical outcomes, insertion at the primary methyl or
secondary ethyl group. Previous C−H functionalization studies
using 4-aryl-N-sulfonyl-1,2,3-triazoles have shown that Rh2(S-
NTTL)4 has a preference for insertion into more substituted
secondary and tertiary sites,14a,b and we were pleased to
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Letter
improved yields and diastereoselectivites with a moderate
decrease in enantioselectivity (84% yield, 92:8 dr, 85% ee).
Following optimization for the secondary C−H functional-
ization, initial attempts at accessing stereoenriched 3-aryl-4-
alkylpyrrolidines were hindered by enamine induced epimeri-
zation of the 4-alkyl stereocenter. Allylic insertion product 13
was chosen as an optimal substrate to study the effects of
epimerization due to its relatively low levels of diastereose-
lectivity along with the ease of isolating the diastereomers
(Table 1). Examining the reaction conditions, we discovered
that epimerization could be controlled using chloroform as a
solvent and reducing the temperature of the triethylsilane,
boron trifluoride diethyl etherate mediated reduction of the
cyclic hemiaminal. In addition, the reagents were added in two
portions at 0 and 30 min to minimize the potential for rapid
epimerization of iminium ion 17 due to the presence of
excessive Lewis acid. The results were confirmed using both
diastereomeric mixtures and diastereopure allylic insertion
products 13a and 13b leading to the desired pyrrolidines with
less than five percent epimerization under the optimized
conditions.
Having gained control of the enamine-induced epimeriza-
tion, we examined the scope of the reaction with a range of 4-
aryl-N-sulfonyl-1,2,3-triazoles and trans-2-alkenes. The overall
yields were generally good with all substrates (Figure 3).
Utilizing the p-methoxy-substituted arene ring with trans-2-
pentene gave pyrrolidine 25 with the highest diastereoselec-
tivity (25a/25b, 92:8) but increasing the alkene chain length
resulted in modest decreases in diastereoselectivity. The
unsubstituted phenyl ring gave relatively consistent diaster-
eoselectivity regardless of the alkene chain length. In all cases,
excellent levels of enantioselectivity were observed (>92% ee)
except for pyrrolidine 24 derived from trans-2-octene and 4-
phenyl-N-methanesulfonyl-1,2,3-triazole, which provided the
major and minor diastereomer in 82 and 80% ee, respectively.
Trapping the iminium ion with nucleophiles other than
hydride would generate β-aryl pyrrolidines with a stereogenic
center at the C2 position of the pyrrolidine ring.
Representative systems were examined to determine the
feasibility of such a process. Reaction of cyclic hemiaminal
7a and 7i with allyltrimethylsilane using boron trifluoride
diethyl etherate as a Lewis acid led to the formation of
pyrrolidines 29 and 30 with exceptional diastereocontrol
(Scheme 3). Nucleophilic addition into the C2 position was
Figure 2. Optimization of secondary C−H insertion reaction. (a)
Reactions run with 4.0 equiv of alkene. (b) Isolated yields. (c) dr
determined by 1H NMR of crude reaction mixture. (d) ee determined
by HPLC analysis after purification. (f) Rh2(S-NTTL)4 used unless
otherwise indicated. (g) Reaction run at 60 °C.
observe the reaction proceed cleanly for the secondary site,
furnishing the desired insertion product 12 in 84:16 dr, 73%
combined yield, and 97% ee for the major diastereomer. The
phthalimido-based rhodium tetracarboxylate catalysts Rh2(S-
PTAD)4 and Rh2(S-PTTL)4 were examined for comparison to
the naphthalimido-based Rh2(S-NTTL)4, but both resulted in
the formation of 12 with inferior yields, diastereoselectivities,
and enantioselectivities (Figure 2b). Finally, we examined the
effect of varying the electronic environment of the arene
component on the triazole ring (Figure 2c). Using electron-
withdrawing and slightly donating para-substituents furnished
the desired insertion products 13−15 but in decreased yields,
diastereoselectivities, and enantioselectivities. The strongly
donating p-methoxy substituent gave desired product 16 with
a,f
Table 1. Minimizing Enamine-Induced Epimerization
b
T
(°C)
[R]
c
d
e
e
entry dr (13a/ 13b)
solvent
[O]
BF3·OEt3 (equiv) Et3SiH (equiv) combined yield (%) dr (20a/20b) % ee 20a % ee 20b
1
2
3
4
5
6
68:32
68:32
>97:3
>97:3
3:>97
3:>97
CH2Cl2
CHCl3
CH2Cl2
CHCl3
CH2Cl2
CHCl3
−78
−65
−78
−65
−78
−65
−10
−65
−10
−65
−10
−65
3.2
2.2
3.2
2.2
3.2
2.2
3.2
2.0
3.2
2.0
3.2
2.0
52
48
61
68
66
64
60:40
66:34
92:8
>97:3
8:92
94
94
93
93
88
86
88
90
b
b
b
85
85
3:>97
a
b
c
d
Ozonolysis reactions run at 4.0 equiv of dimethyl sulfide. All reactions proceed to 23 °C. isolated yields. dr determined by 1H NMR of crude
e
f
reaction mixture. ee determined by HPLC analysis after purification. Reactions run by adding half the equiv of HSiEt3 and BF3·OEt2 at t0 and t30.
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Letter
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.8b01362.
Full experimental data for the compounds described in
the paper (PDF)
Accession Codes
CCDC 1837567−1837569 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hmdavie@emory.edu.
ORCID
Figure 3. Synthesis of 3,4-disubstituted pyrrolidines. (a) Insertion
reactions run at 4.0 equiv of alkene; ozonolysis reactions run at 4.0
equiv dimethyl sulfide; reduction reactions run at 2.2 equiv of HSiEt3
and 2.0 equiv of BF3·OEt2. (b) Isolated yields. (c) dr determined by
1H NMR of crude reaction mixture. (d) ee determined by HPLC
analysis after purification.
Huw M. L. Davies: 0000-0001-6254-9398
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Scheme 3. Synthesis of Tetrasubstituted Pyrrolidines
■
This work was supported by the National Institutes of Health
(GM099142). R.W.K. is grateful for an NSF GRFP Fellowship.
Instrumentation used in this work was supported by the
National Science Foundation (CHE 1531620 and CHE
1626172). We thank Dr. John Bacsa, Emory X-ray
Crystallography Center, for the X-ray structural analysis.
REFERENCES
■
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