Redox-Triggered α-C-H Functionalization of Pyrrolidines: Synthesis of Unsymmetrically 2,5-Disubstituted Pyrrolidines

Article abstract of DOI:10.1021/acs.orglett.5b02298

By using o-benzoquinone as an internal oxidant, the regio- and diastereoselective functionalization of the secondary over the tertiary α-C-H bond of 2-substituted pyrrolidines is first realized. Subsequent intermolecular addition of a nucleophile to the g

Full text of DOI:10.1021/acs.orglett.5b02298

Letter
pubs.acs.org/OrgLett
Redox-Triggered α‑C−H Functionalization of Pyrrolidines: Synthesis
of Unsymmetrically 2,5-Disubstituted Pyrrolidines
Yong-Feng Cheng, Hao-Jie Rong, Cheng-Bo Yi, Jun-Jun Yao, and Jin Qu*
State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai
University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: By using o-benzoquinone as an internal oxidant,
the regio- and diastereoselective functionalization of the
secondary over the tertiary α-C−H bond of 2-substituted
pyrrolidines is first realized. Subsequent intermolecular
addition of a nucleophile to the generated N,O-acetal and
cleavage of the aromatic substituent leads to 2,5-disubstituted
pyrrolidines.
nsymmetrically 2,5-disubstituted pyrrolidines (either in
of the challenges in this research field is the selective
functionalization of the secondary over the tertiary α-C−H
bond of 2-substituted pyrrolidines. The functionalization of the
secondary α-C−H gives 2,5-disubstituted pyrrolidines, while the
functionalization of the tertiary α-C−H gives 2,2-disubstituted
pyrrolidines. Generally, selective functionalization of the tertiary
α-C−H bond to afford 2,2-disubstituted pyrrolidines predom-
inates because this transformation proceeds via the more
thermodynamically stable intermediate.6,9 There have been few
reports in which secondary α-C−H functionalization were
favored.6d,7a
U
trans- or cis- form) are found in many natural products1 and
pharmaceuticals (Figure 1).2 For example, pyrrolidine 225C, the
Figure 1. Unsymmetrically 2,5-disubstituted pyrrolidines.
In 2012, Maulide and co-workers successfully combined
redox-neutral pyrrolidine α-C−H functionalization with sub-
sequent intermolecular addition of a nucleophile to the
generated intramolecularly α-oxygenated pyrrolidine. After
cleavage of the aromatic substituent on the nitrogen atom, 2-
substituted pyrrolidines with various functional groups (e.g.,
alkyl, vinyl, aryl, and alkynyl) were obtained in high yields
(Scheme 1, eq 1).9c We envisioned that using o-benzoquinone,
which has a higher oxidizing capability than benzaldehyde, as an
internal oxidant would enable intramolecular redox-neutral C−H
functionalization at ambient temperature in the absence of an
acid.10 Furthermore, steric effects on the formation of a five-
membered-ring N,O-acetal in the present work should be larger
than the effects on the formation of the six-membered-ring
counterpart6,9 in previous reports. Therefore, functionalization
of the less substituted secondary α-C−H bond of 2-substituted
pyrrolidines should be favored. Herein, we presented that based
on the high regio- and diastereoselectivities of the intramolecular
α-oxygenation of 2-substituted pyrrolidines, the redox-triggered
C−H functionalization strategy for the synthesis of unsymmetri-
trans isomer, was isolated from ant venom toxins of Solenopsis
punctaticeps,1a and the cis isomer is a trail pheromone of the
pharaoh ant, Monomorium pharaonis.1b Monomorine, which has
also been isolated from M. pharaonis, is believed to be involved in
defense against predators.1c Xenovenine, isolated from Solenopsis
xenoveneum, inhibits the nicotinic acetylcholine response,1d and
cocaine is a powerful analgesic and stimulant.1e,f The develop-
ment of efficient methods for synthesizing structurally diverse
unsymmetrically 2,5-disubstituted pyrrolidines is highly desir-
able.
Many efficient methods for direct functionalization of the α-
C−H of pyrrolidines have been reported.3−7 Among various
elegant transformations, redox-neutral C−H functionalization
reactions offer special redox and atom economy.8 Most of these
reactions proceed through a key 1,5-hydride transfer from the
α‑C of pyrrolidine to an intramolecular hydride acceptor
(originally called the “tert-amino effect”) to form an iminium
ion, which is attacked by the reduced hydride-acceptor moiety,
leading to a heterocyclic product in which the α-C−H bond
functionalization of pyrrolidine is therefore realized.4 Besides,
Seidel et al. recently established the azomethine ylide-mediated
α-C−H bond functionalization of pyrrolidines.5−7 However, one
Received: August 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02298
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Redox-Triggered α-C−H Functionalization of
Pyrrolidine for Synthesis of (a) 2-Substituted Pyrrolidines
and (b) Unsymmetrically 2,5-Disubstituted Pyrrolidines
Scheme 2. Nucleophilic Addition of N,O-Acetal 3
cally 2,5-disubstituted pyrrolidines was realized (Scheme 1, eq
2).
We chose commercially available 3,5-di-tert-butyl-o-benzoqui-
none (1) and pyrrolidine 2 as substrates for a model reaction
(Table 1; see the Supporting Information for the screening of the
Table 1. Pyrrolidine α-C−H Functionalization with o-
a
Benzoquinone 1 in Various Solvents
a
Reaction conditions: N,O-acetal 3 (0.2 mmol) and R1 MgBr or R1Li
b
(0.5 mmol) in DCE (2 mL) at 0 °C. Carried out with R1Li (1.0
mmol) in THF (3 mL) at −78 °C.
Grignard reagent was well tolerated (5e). The reaction of 3
with phenyl Grignard reagent afforded 5m′ (96%), presumably
via air oxidation of 5m.
Importantly, the o-hydroxy substituent on 5 facilitated removal
of the aryl moiety. Among various oxidative cleavage conditions
we tested, iodine in basic aqueous acetonitrile solution turned
out to be efficient and also mild for the cleavage of the C−N
bond.14 Under these mild conditions, various 2-substituted
pyrrolidines 6 were obtained in high yields (Scheme 3).
b
yield (%)
entry
solvent
time (h)
3
4
1
2
3
4
5
PhMe
DCM
DCE
MeOH
TFE
4
88
38
70
84
89
98
0
9
8
4
0
0
2
2
0.2
0.5
0.5
c
6
TFE
a
a
Reactions were carried out with 1 (0.2 mmol) and 2 (0.24 mmol) in
Scheme 3. Removal of the Aryl Moiety from 5
b
c
1.0 mL of solvent at room temperature. Isolated yields. 1 (0.2 mmol,
0.5 M in TFE) was added to a solution of 2 (0.24 mmol) in TFE (0.6
mL) over the course of 5 min.
o-benzoquinones). In room-temperature toluene in the absence
of acid, the desired redox product N,O-acetal 3 was obtained in
88% yield after 4 h (Table 1, entry 1). Use of a chlorinated alkane
solvent decreased the yield of the desired product and resulted in
the formation of o-aminophenol 4 as a byproduct in low yield
(Table 1, entries 2 and 3).10c,11 Conducting the reaction in a
polar protic solvent (methanol) markedly shortened the reaction
time (Table 1, entry 4). 2,2,2-Trifluoroethanol (TFE) provided
the highest yield of all of the tested solvents (Table 1, entry 5),
and slow addition of 1 to the reaction mixture further increased
the yield (Table 1, entry 6). When the reaction was carried out on
a large scale (5.6 mmol of pyrrolidine), it was complete within 0.5
h and 3 was obtained in 98% yield. However, under these
reaction conditions, piperidine reacted with 1 to yield mainly o-
aminophenol.10c,12
We next investigated the nucleophilic addition of Grignard
reagents to 3 (Scheme 2).13 The C−C bond-forming reactions
proved general for a broad range of nucleophiles. Therefore,
alkyl, allyl, benzyl, vinyl, and alkynyl moieties could be
introduced to the α-position of the pyrrolidine ring in high to
excellent yields (5a−l). Even a bulky tert-butyl-substituted
a
Reaction conditions: 5 (0.2 mmol), I2 (0.22 mmol), NaOH (1 M, 7
b
mL), CH3CN (14 mL). The yield of free amine is reported only if it
has a high boiling point. 7.0 mL of CH3CN was used.
c
We then investigated the regio- and diastereoselectivity of α-
C−H functionalization of 2-substituted pyrrolidines using 3,5-di-
tert-butyl-o-benzoquinone (1) (Scheme 4). The secondary α-C−
H bond of 2-methyl pyrrolidine was functionalized highly
selectively to afford trans-substituted N,O-acetal 7a in 95%
isolated yield. The relative configuration of 7a was unambigu-
ously determined by X-ray crystallography.15 Similar regio- and
diastereoselectivities were observed for the reactions of 2-n-
B
DOI: 10.1021/acs.orglett.5b02298
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Regio- and Diastereoselectivity of α-C−H
Scheme 6. Removal of Aryl Moiety
a
Functionalization of 2-Substituted Pyrrolidines
a
Reaction conditions: 8 (0.2 mmol) and I2 (0.22 mmol), aq NaOH (1
b
M, 7.0 mL), CH3CN (14 mL). The yield of free amine is reported
only if it has a high boiling point. 7.0 mL of CH3CN was used.
c
Disubstituted pyrrolidines 9b and 9c were also obtained in high
yields, and their double bonds can be expected to enable the
preparation of more complicated pyrrolidine alkaloids.18
We propose the following mechanism for the redox trans-
formation (Scheme 7). First, 3,5-di-tert-butyl-o-benzoquinone
a
Reaction conditions: 1 (0.2 mmol), 6 (0.24 mmol), K2CO3 (0.3
b
mmol), TFE (1.0 mL), room temperature. Free 2-methylpyrrolidine
was used; no K2CO3 was added.
butylpyrrolidine hydrochloride (6b) and 2-allylpyrrolidine
hydrochloride (6d); 7b and 7c, respectively, were isolated as
single isomers. Note that excellent regioselectivity was also
observed for 2-vinyl-substituted pyrrolidine 6e, which bears an
allylic α-C−H bond; 7d was the only product isolated.
Nucleophilic addition of Grignard reagents to N,O-acetal 7
yielded 2,5-difunctionalized products 8 in excellent yields, but
the diastereoselectivity varied (Scheme 5). Trans-disubstituted
Scheme 7. Proposed Mechanism for Regio- and
Diastereoselective α-Functionalization of 2-Substituted
Pyrrolidines 6
Scheme 5. Nucleophilic Addition Reactions of N,O-acetal 7
(1) reacts with 2-pyrrolidines (6) to give iminium ion A. Owing
to the steric bulk of the R1 group, A preferentially undergoes 1,5-
proton abstraction to form iminium ion C. Subsequent
cyclization of C occurs from the less hindered face, leading to
trans-substituted N,O-acetal 7.
In summary, we developed an efficient, practical method for
the synthesis of structurally diverse 2-substituted and 2,5-
disubstituted pyrrolidines from pyrrolidine. The intramolecular
redox-neutral α-functionalization of 2-substituted pyrrolidine
was highly regio- and diastereoselective. The two substituents at
the α-position of the pyrrolidines could be varied easily by the
choice of appropriate Grignard reagents.
products were favored in most of the addition reactions13c−e
However, it was mysterious that 7b reacted with n-
heptylmagnesium bromide to give more cis product, while it
gave more trans product in its reaction with n-propylmagnesium
bromide and tert-butylmagnesium bromide. Fortunately, the
trans and cis diastereomers could be readily separated by column
chromatography. When R1 ≠ R2, the 1H NMR spectra of trans-
8b−8g were ambiguous because of the restricted rotation of the
disubstituted pyrrolidine moiety. Variable-temperature 1H NMR
studies of trans-8b in DMSO-d6 revealed that the two set of
signals broadened and began to coalesce at 333 K.16
ASSOCIATED CONTENT
■
S
* Supporting Information
To synthesize 2,5-disubstituted pyrrolidines, we removed the
aryl moieties of 8 under oxidative cleavage conditions similar to
those used for N-dearylation of 5 (Scheme 6). The racemic trans-
and cis- pyrrolidine alkaloid 225C (9a) were obtained in high
yields.17 This represents the first synthesis of these pyrrolidine
alkaloids by means of sequential C−H functionalization. 2,5-
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02298.
Experimental details, characterization data for new
compounds, NMR spectra, and HRMS data (PDF)
X-ray crystallographic data for 7a (CIF)
C
DOI: 10.1021/acs.orglett.5b02298
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
6123−6135. (f) Kang, Y.-K.; Richers, M. T.; Sawicki, C. H.; Seidel, D.
Chem. Commun. 2015, 51, 10648−10651.
AUTHOR INFORMATION
■
Corresponding Author
(7) For selected recent reports of intermolecular redox-neutral α-
functionalization of pyrrolidines involving azomethine ylide intermedi-
ates, see: (a) Ma, L.; Chen, W.; Seidel, D. J. Am. Chem. Soc. 2012, 134,
15305−15308. (b) Das, D.; Seidel, D. Org. Lett. 2013, 15, 4358−4361.
(c) Des, D.; Sun, A. X.; Seidel, D. Angew. Chem., Int. Ed. 2013, 52, 3765−
3769. (d) Chen, W.; Wilde, R. G.; Seidel, D. Org. Lett. 2014, 16, 730−
732. (e) Chen, W.; Seidel, D. Org. Lett. 2014, 16, 3158−3161.
(f) Haldar, S.; Mahato, S.; Jana, C. K. Asian J. Org. Chem. 2014, 3, 44−47.
(8) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int. Ed.
2009, 48, 2854−2867.
*E-mail: qujin@nankai.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the NSFC (21072098,
21372119, and 21121002) and Tianjin Natural Science
Foundation (14JCYBJC20200).
(9) For selected recent reports of redox-neutral α-functionalization of
unsymmetrically substituted pyrrolidines through intramolecular
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Chem. 2009, 74, 419−422. (b) Murarka, S.; Zhang, C.; Konieczynska,
M. D.; Seidel, D. Org. Lett. 2009, 11, 129−132. (c) Jurberg, I. D.; Peng,
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