Regio- and stereospecific synthesis of C-3 functionalized proline derivatives by palladium catalyzed directed C(sp3)-H Arylation

Article abstract of DOI:10.1021/ol502511g

Functionalization of C(sp³)-H bonds at the unactivated 3-position of proline derivatives has been achieved using aryl iodides and palladium catalysis. This directly affords cis-2,3-disubstituted pyrrolidines as single stereoisomers. 3-Arylation

Full text of DOI:10.1021/ol502511g

Letter
pubs.acs.org/OrgLett
Regio- and Stereospecific Synthesis of C‑3 Functionalized Proline
Derivatives by Palladium Catalyzed Directed C(sp3)−H Arylation
Dominic P. Affron, Owen A. Davis, and James A. Bull*
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom
S
* Supporting Information
ABSTRACT: Functionalization of C(sp3)−H bonds at the
unactivated 3-position of proline derivatives has been achieved
using aryl iodides and palladium catalysis. This directly affords
cis-2,3-disubstituted pyrrolidines as single stereoisomers. 3-
Arylation occurs in high yield under solvent-free conditions
with aminoquinoline and methoxyaminoquinoline directing
groups. The latter was readily removed to give primary amide
derivatives with physicochemical properties appropriate for use
as fragments in drug discovery.
aturated heterocycles are central to life, biology, and
medicine. The pyrrolidine ring is of particular interest due
to its presence in cyclic amino acid proline, which has a pivotal
role in protein secondary structure.1 Pyrrolidines feature heavily
in alkaloid natural products that display a wide variety of
biological activity (Figure 1)2 and are prevalent in active
pyrrolidines at C-3.10 Moreover, there are no methods to
functionalize the unactivated pyrrolidine C(3)−H bond.
Recently in drug discovery there has been considerable interest
in incorporating more sp3-rich heterocycles,11 and in the
development of synthetic methods that can afford heterocyclic
derivatives with desirable physicochemical properties and
reliable stereocontrol.12 As part of our program of fragment-
oriented synthesis,13 we considered that iterative functionaliza-
tion at the pyrrolidine C-3 position would provide interesting
fragments14 in new and biologically relevant chemical space.15
Here we report the synthesis of 2,3-difunctionalized pyrrolidines
as single stereoisomers via directed C−H functionalization at the
3-position of proline derivatives (Figure 2B). Functionalized and
heterocyclic aryl iodides are employed with minimal excess, and
the resulting 3-(hetero)aryl pyrrolidines are transformed to
compounds that comply with desirable criteria for drug
discovery.
S
Figure 1. Pyrrolidine containing natural products.
pharmaceutical ingredients.3 Furthermore, proline derivatives
provide privileged catalysts for stereoselective synthesis.4
Consequently, tremendous effort has been expended to develop
synthetic routes to novel pyrrolidine derivatives.5−10
Functionalization of pyrrolidines at C-2 has received particular
attention.6−9 The activated C(2)−H bonds of N-Boc pyrroli-
dines allow enantioselective α-lithiation and trapping with
electrophiles7 or Negishi cross-coupling (Figure 2A).7d Catalytic
C−H functionalization of pyrrolidines at C-2 with both aryl and
alkyl groups has been achieved using Ru-catalysis, utilizing 1-
pyrroline8 or 2-pyridyl9 N-directing groups. On the other hand,
there are markedly fewer methods for the functionalization of
Catalytic direct functionalization of unactivated sp3 C−H
bonds has taken enormous strides in the past few years.16−22
Unactivated primary and secondary alkyl C−H bonds undergo
Pd-catalyzed arylation,17,18 facilitated by the incorporation of
removable directing groups to orient and stabilize palladacycle
intermediates.16 Daugulis’ seminal report on the arylation of alkyl
C−H bonds by a PdII/PdIV redox cycle used amide linked 8-
aminoquinoline (AQ) as a directing group, with Pd(OAc)2 and
excess aryl iodide.17a Directed C(sp3)−H arylations have been
extended to cyclopropanes,19 cyclobutanes,20 and acyclic amino
acids.21,22 However, to date there are only very limited
applications of Pd-catalyzed functionalization to the unactivated
C(sp3)−H bonds of heterocycles.23
Our study commenced from N-protected L-proline, from
which we prepared amides 1 to 5 using EDC (N-(3-
(dimethylamino)propyl)-N′-ethylcarbodiimide), to examine
Received: August 26, 2014
Figure 2. Pyrrolidine C−H functionalization approaches.
© XXXX American Chemical Society
A
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Letter
potential amide directing groups (Scheme 1).24 We proposed
that with carbamate N-protecting groups, the desired regio- and
reaction yield (entries 1−3); increasing the concentration to 1.0
M raised the yield to 97%. The loading of iodotoluene and of
AgOAc could both be reduced to 1.8 equiv with little
compromise in yield (entry 4). However, on scaling up the
reaction to 0.9 mmol the yield dropped to 64% (entry 5).
Increasing the concentration further, to 2.0 and 4.0 M (entries
6−7), increased the yield to 83% and 86%, respectively. Finally,
running the reaction in the absence of solvent increased the
conversion to 99% (entry 8), which corresponded to a 91%
isolated yield. Importantly the product was isolated as a single
stereoisomer (>98% ee).24 The reaction was operative under an
air atmosphere (entry 9) and was also successful on a larger scale,
affording 1.6 g of 6a in 85% yield (entry 10). With tolyl bromide
as the coupling partner the reaction was also successful, affording
a 33% yield (entry 11).
Scheme 1. Initial Optimization Varying Amide Auxiliary and
N-Protecting Group
Using the optimized reaction conditions (Table 1, entry 8) we
next examined an extensive range of aryl iodides to access 2-
amido-3-aryl-pyrrolidines (Table 2). Phenyl and m- and p-alkyl
substituted phenyl derivatives were successful (entries 1−3). 2-
Methyliodobenzene was not compatible, presumably due to the
increased steric congestion around palladacyclic intermediates,
preventing oxidative addition or reductive elimination steps. An
unfavorable steric effect was also apparent in 3,5-disubstituted
examples though to a lesser extent. 4-Fluoroiodobenzene gave a
high yield (entry 4), whereas the 2-fluoro analogue gave a 21%
yield under standard conditions, which was increased to 44%
upon heating for 60 h (entry 5). The 4-chloro-, 4-bromo-, and 4-
iodo-aryl derivatives were successful, providing handles for
potential further functionalization (entries 7−9). With both 4-
bromoiodobenzene and 1,4-diiodobenzene, the bis-pyrrolidine
aryl derivative was also isolated (9% and 33%, respectively).24
The installation of highly electron-rich (entries 10−11) and
electron-withdrawing (entries 12−18) aromatic groups was
possible in similarly high yields; (4-MeO)C6H4 was installed in
85% yield, and (4-CO2Et)C6H4 was installed in 90% yield.
Trifluoromethyl, ethyl ester, nitrile, and nitro functional groups
were all tolerated (entries 14−18). An aromatic group bearing a
methyl ketone gave a good yield (entry 19). Aromatics with
pendant aldehyde and hydroxymethyl groups were also
compatible though in reduced yields (entries 20−21).
Following this, the nature of the aromatic ring was varied. 2-
Iodonaphthalene required the addition of solvent (toluene,
2.0 M) for the reaction to proceed, affording a 73% yield of 6v
(entry 22). 2-Iodothiophene afforded 6w in 87% yield (entry
23), and pyridine derivatives substituted at the 2-, 3-, and 5-
positions could also be successfully installed (entries 24−26).
Finally, E-β-styryl iodide gave a 51% yield of the vinylated
product 8 (entry 27).
Having accessed a wide range of 3-substituted derivatives, we
next examined removal of the protecting group and auxiliary to
access compounds of interest for screening in biological
programs. Deprotection of the Cbz group from a selection of
the 3-arylated compounds occurred readily in high yield
(Scheme 2), providing interesting drug-like structures.24
To access the targeted 3-aryl pyrrolidine fragments, removal of
the directing group was required to afford appropriate MW and
cLogP values. However, with both N-Cbz and N-H derivatives
(6a and 9a) the AQ group proved highly resistant to a wide
variety of reagents. Therefore, we examined the use of 5-
methoxy-8-aminoquinoline, recently reported by Chen as a
directing group for C−H activations, which can be cleaved under
mild oxidative conditions.22a We prepared amide 10 (Scheme 3)
and found C−H arylation to be similarly successful under our
stereochemical outcome of the reaction would be facilitated by
the amide adopting the pseudoaxial conformation to orient the
directing group toward the cis-C(3)−H.
For initial investigation we selected conditions using 4-
iodotoluene (4 equiv), Pd(OAc)2 (5 or 10 mol %), and AgOAc as
base. The reaction of amide 1 (R = Cbz) bearing the AQ auxiliary
afforded an encouraging 55% conversion with a 5 mol % Pd
loading. The reaction was stereospecific, affording 2,3-disub-
stituted pyrrolidine 6a as the cis-diastereoisomer (J = 8.5 Hz,
TolCH−CHN). Other directing groups examined gave <5%
conversion even at 10 mol % Pd loading, and no conversion was
observed with the N-Cbz acid. Reduced conversion (18%) was
obtained for the N-Boc amide 5.
Optimization of this transformation continued with N-Cbz
AQ amide 1. We aimed to maximize the yield of 6a, but minimize
loadings of aryl iodide and other reagents employed. Initial
screening examined various Pd and Ni sources, with Pd(OAc)2
giving the best yield.24 The most suitable base was AgOAc from
the range of bases investigated, with or without added pivalic
acid, and toluene was the optimal solvent (Table 1, entry 1).24
The concentration of the reaction had a major effect on the
Table 1. Selected Optimization: Arylation of N-Cbz Proline
AQ Amide 1
a
mmol equiv of equiv of
solvent
(concn, M)
time
(h)
yield
(%)
entry
of 1
AgOAc
Tol-I
1
2
3
4
5
6
7
8
0.2
0.2
0.2
0.2
0.9
0.9
0.9
0.9
0.9
4.0
0.2
2.2
2.2
2.2
1.8
1.8
1.8
1.8
1.8
1.8
1.8
2.2
4.0
4.0
4.0
1.8
1.8
1.8
1.8
1.8
1.8
1.8
4.0
toluene (0.125)
toluene (0.5)
toluene (1.0)
toluene (1.0)
toluene (1.0)
toluene (2.0)
toluene (4.0)
15
15
15
15
20
20
20
20
20
36
20
55
86
97
91
64
83
86
b
c
−
−
−
99 (91)
94
d
b
9
b
c
10
(85)
e
b
11
−
33
a
1
Yields calculated by H NMR spectroscopy with respect to 1,3,5-
b
trimethoxybenzene as an internal standard. Reaction performed
without solvent. Isolated yield. Reaction performed under air rather
than argon. Reaction performed with Tol-Br in place of Tol-I.
c
d
e
B
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Letter
optimal reaction conditions to afford compounds 11a,b,d.
Pleasingly, oxidative deprotection with ceric(IV) ammonium
nitrate (CAN) now proceeded readily to give the corresponding
primary amides in high yields. Finally, removal of the Cbz group
by hydrogenolysis was facile, affording N-H 2-amido-3-aryl
pyrrolidines 13a,b,d exclusively as the cis-isomers, with attractive
physicochemical properties, and functional groups, for fragment
screening.
Table 2. Scope of the Aryl Iodides in the C−H Arylation of of
N-Cbz Proline AQ Amide 1
Scheme 3. Removal of Auxiliary and Cbz Groups To Afford
Enantiopure Primary Amide “Fragments”
In conclusion, Pd-catalyzed C−H functionalization stereo-
specifically installs (hetero)aryl and vinyl substituents at the
unactivated 3-position of proline derivatives that would
otherwise require lengthy synthetic sequences and/or resolution.
This enables the efficient preparation of small yet complex
enantiopure cis-2,3-disubstituted pyrrolidines in fragment and
drug-like chemical space. Efforts to extend this approach to other
heterocyclic systems are currently underway in our lab.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and copies of 1H
and 13C NMR spectra; details of reaction optimization; proposed
catalytic cycle and calculated molecular properties for
pyrrolidines 9 and 13. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: j.bull@imperial.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
a
b
c
For financial support we gratefully acknowledge the EPSRC
(Career Acceleration Fellowship to J.A.B.; EP/J001538/1) and
Imperial College London. Thanks are extended to Prof. Alan
Armstrong (Imperial College London) for generous support and
to Mr. Peter Haycock (Imperial College London) for NMR
services. We thank the EPSRC National Mass Spectrometry
Facility, Swansea.
ent-1 Afforded ent-6a in 80% yield. 60 h reaction time. Bis-
d
e
pyrrolidine: 9% yield. Bis-pyrrolidine: 33% yield. Modification to
conditions: ArI (3 equiv), AgOAc (2.2 equiv), toluene (2.0 M). E/Z =
f
95:5.
Scheme 2. Cbz Deprotection Affording Compounds with
Drug-like Characteristics
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