Ligand-Controlled Regiodivergent Hydroalkylation of Pyrrolines

Article abstract of DOI:10.1002/anie.201912629

Nickel hydride (NiH) catalyzed hydrocarbonation has emerged as an efficient approach to construct new C?C bonds containing at least one C(sp³) center. However, the regioselectivity of this reaction is by far dictated by substrates. Described here is a strategy to achieve two different regioselectivites of hydroalkylation of the same substrates by using ligand control. This strategy enables the first regiodivergent hydroalkylation of 3-pyrrolines, yielding both 2- and 3-alkylated pyrrolidines, valuable synthetic intermediates and common motifs in many bioactive molecules. This method demonstrates broad scope and high functional-group tolerance, and can be applied in late-stage functionalizations.

Full text of DOI:10.1002/anie.201912629

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Accepted Article
Title: Ligand-Controlled Regiodivergent Hydroalkylation of Pyrrolines
Authors: Deyun Qian and Xile Hu
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Ligand-Controlled Regiodivergent Hydroalkylation of Pyrrolines
Deyun Qian and Xile Hu*
Abstract: Nickel hydride (NiH) catalyzed hydrocarbonation has
emerged as an efficient approach to construct new C-C bonds
containing at least one C(sp3) center. However, the regioselectivity of
this reaction is by far dictated by substrates. Here we describe a
strategy to achieve two different regioselectivites of hydroalkylation of
the same substrates using ligand control. This strategy enables the
first regiodivergent hydroalkylation of 3-pyrrolines, yielding both 2-
and 3-alkylated pyrrolidines, valuable synthetic intermediates and
common motifs in many bio-active molecules. We demonstrate broad
scope, high functional group tolerance, and application in late-stage
functionalization of this method.
Thanks to the wide availability of olefins, hydrocarbonation
of alkenes via metal hydride (MH) insertion followed by cross-
coupling of in-situ generated organometallic intermediates offers
an attractive alternative to traditional cross-coupling,[1,2] which
employed preformed, often reactive, and stoichiometric
organometallic reagents.[3,4] In recent years, NiH-catalyzed
hydrocarbonation[2,5-7] has been developed to complement the
well-established Ni-catalyzed cross-coupling reactions of alkyl
nucleophiles.[4] Addition of NiH to a terminal alkene may generate
two isomeric products: a primary and a secondary alkyl-Ni species.
The primary alky-Ni species is typically favoured.[5] Addition of NiH
to an internal alkene often leads to isomerization and chain
walking of the alkenyl moiety to the terminal position.[6] Thus, Ni-
Scheme 1. Selectivity of the NiH-catalyzed hydrocarbonation of alkenes. a)
Linear selective hydrocarbonation of terminal and internal alkenes. b) Branch
selective hydrocarbonation of alkenes using strong directing groups. c) Our
design: Regioselective hydrocarbonation of alkenes using weak directing
catalyzed hydrocarbonation of both terminal and internal alkenes
is linear selective (Scheme 1A). Only recently branch-selective
NiH-catalyzed hydrocarbonation has been achieved utilizing a
strong directing group (e.g., aryl, boryl) that stabilizes an alkyl-Ni
intermediate at the α position (Scheme 1B).[7] Consequently, C-C
bond formation occurs exclusively at the α site. We reasoned that
with a suitable weak directing group, the stability of α- and β-alkyl-
Ni intermediates might become comparable so that their relative
concentration might be controlled by ligands (Scheme 1C). Thus,
different optimized ligands can lead to regiodivergent
hydrocarbonation,[8] which remains hitherto elusive. Here we
demonstrate this strategy in Ni-catalyzed hydroalkylation of 3-
pyrrolines (Scheme 1D).
Pyrrolidines bearing an alkyl substituent at the 2- or 3-
position are present as subunits in many natural products and bio-
active molecules.[9] They are also versatile synthetic
intermediates.[10] Cross-coupling reactions have been used to
synthesize C-alkyl pyrrolidines.[11] However, alkylation occurred
only at specific and pre-functionalized sites using these methods.
groups. d) This work: Ligand-controlled regiodivergent hydroalkylation of 3-
pyrrolines.
Recently, Martin and co-workers reported a novel method for
hydroalkylation of 3-pyrolline with α-haloboranes. However, the
method was only C2 selective.[5f] To our knowledge, C3-selectivity
remained elusive prior to our work. Our regiodivergen method
allows modular alkylation at either C2- or C3-site of pyrrolidines
using a common pyrroline reagent and a non-actived alkyl iodide.
Moreover, the method enables facile provides a new route to the
formation of
a secondary-secondary C(sp3)–C(sp3) bond
formation, which has is challenging due to steric congestion in the
product as well as the general difficulty in cross-coupling of
secondary alkyl halides.[4,12]
We started our study using commercially available N-Cbz-
pyrroline 1a and iodocyclohexane 2a as model substrates, and
the influence of all reaction components was systematically
examined (Table S1-S5, SI). These explorations led to a set of
standard conditions for the evaluation of ligand dependence
(Table 1), which involved NiI•xH2O (10 mol%) as Ni precursor, a
ligand (15 mol%), (EtO)2MeSiH (2.0 equiv.) as hydride source, KF
(2.0 equiv.) as base, and DMA as solvent. The reactions were
conducted at room temperature for 36-48 h. We found that
bipyridine ligands (L1-L3) gave C2- (3a) and C3-alkylated (4a)
products in similar yields (Table 1, entries 1-3). Pyridine-oxazoline
ligands (L4-L7, L9), however, favoured the C3-alkylated product
(Table 1, entries 4-9). This selectivity had not been previously
achieved. The substituents of these ligands affected the yields.
With the best C3-selective ligand L10, a high yield (78%) and
[*]
Dr. D. Qian, Prof. Dr. X. L. Hu
Laboratory of Inorganic Synthesis and Catalysis
Institute of Chemical Sciences and Engineering,
Ecole Polytechnique Federale de Lausanne (EPFL),
ISIC-LSCI, BCH 3305, Lausanne 1015 (Switzerland)
E-mail: xile.hu@epfl.ch
Homepage: http://lsci.epfl.ch
Supporting information for this article is given via a link at the end of
the document.
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regioselectivity (20:1) could be achieved (Table 1, entry 9).
Strikingly, replacing a hydrogen by a methyl group at the C6
position of the pyridine moiety reversed the regioselectivity.
Probably the increased steric hindrance in the methyl-substituted
ligands facilitates -H elimination and the ensuing isomerization
(see below). Thus, the use of L8 and L11 led to C2-selectivity
(Table 1, entries 10-11). The best result was obtained with L8,
yielding 4a in about 80% yield and 30:1 regioselectivity (Table 1,
entry 11).
selective under C3-selective conditions, but gave both C3 and C2-
alkylated products under C2-selective conditions. The coupling
with tert-Bu-I was unsucessful.
The hydroalkylation method exihibited high functional group
tolerance. Ketals (3c and 4d), esters (3p, 3t, 4y, and 4ab), amides
(3s, and 4v), nitriles (3q, 4z and 4aa), various heterocyclic groups
such as and indole (3r and 4u), furans (3t and 4ab), thiophene
(4q), and olefin (4o) were all compatible with the reaction
conditions. The reactions were chemoselective so that alkyl
chlorides (3o and 4x) and aryl chloride (4t), which are potential
leaving groups in cross-coupling reactions, remained intact.
During the course of the study, we noted that under ligand-
free conditions C2-alkylation also occurred to a substantial
degree for some substrates (Table S6, SI). We thus explored the
scope of ligand-free C2-alkyaltion. These reactions typically gave
yields that are 10-15% lower than reactions catalyzed by L8. The
real ligand under these conditions is likely DMA (other amide
solvents performed similar results, see Table S7, SI), which
proves to be C2-selective.
Table 1. Influence of ligands.[a]
To further demonstrate the synthetic utility of this
hydroalkylation method,[14] we successfully applied it for the late-
stage modification of bio-active molecules, such as cholestanol
and ibuprofen derivative (Fig. 1).
A preliminary set of experiments were conducted to probe
the mechanism of the transformation. When a 2-pyrroline
analogue (5) was used as substrate, only C2-alkylated product
(4a) was obtained, using either L10 or L8 (Scheme 2, Eq. 1). In a
competition reaction of 3- and 2-pyrroline substrates (1a and 5,
respectively), C3-selective L10 gave C3- and C2-alkylation in
similar yields whereas C2-selective L8 gave nearly exclusive C2-
alkylation (Scheme 2, Eq. 2). These results suggest L10 disfavors
isomerization of 3-pyrroline to 2-pyrroline,
a
presumed
intermediate to C2-hydroalkylation. Otherwise with L10 C2-
alkylated product would be formed under standard catalytic
conditions, and an enrichment of C2-alkylated product is
expected in eq. 2. When a deuterated silane was used as the
hydride source, D-incorporation was found at the C4 position for
C3-selective hydroalkylation (Scheme 2, Eq.3) and both C3 and
C4 positions for C2-selective hydroalkylation (Scheme 2, Eq. 4).
This result supports the isomerization of 3-pyrroline to 2-pyrroline
in C2-selective hydroalkylation via reversible NiH insertion.
Coupling of a radical-probe substrate containing a cyclopropyl
ring (6) led to ring-opened products (SI, 6.2). The coupling was
inhibited by the presence of a significant amount of TEMPO (SI,
6.3). These results are consistent with the involvement of alkyl
radicals in the hydroalkylation, which agrees with literature
reports.[4,5d-f,6e-g]
A mechanism for our regiodivergent hydroalkylation is
proposed in Figure 2. A NiH species is generated from a [LNi-I]
precatalyst with the silane in the presence of KF. The Ni could be
in oxidation state of +1 or +2,[15] which is subjected to future study.
Insertion of NiH into 1 gives an alkyl-Ni intermediate I-A, which
can cross-couple an alkyl iodide to give the C3-alkylation. Species
I-A can also undergo first β-H elimination (I-B) and then alkene
re-insertion to give a second alkyl-Ni intermediate I-C, where the
Ni fragment is at a position α-to the N-R group. Cross-coupling of
I-C with an alkyl iodide then gives C2-alkylation. The
regioselectivity might be attributed to the relatively stability of
intermediates I-A and I-C. The N group is expected to stabilize
[a] Conditions: 1a (0.10 mmol, 1.0 equiv), 2a (0.15 mmol, 1.5 equiv), NiI2•xH2O
(10 mol%), L (15 mol%), (EtO)2MeSiH (0.20 mmol, 2.0 equiv), KF (0.20 mmol,
2.0 equiv), DMA (0.5 mL), rt, 36-48 h. [b] Yields were determined by GC-FID,
using 1-dodecane as an internal standard. [c] Isolated yield. DMA
dimethylacetamide.
=
With optimized reaction conditions in hand, we probed the
scope of the regiodivergent hydroalkylation (Table 2) using Cbz-,
Boc- and PhCO2-protected 3-pyrrolines as alkenes. A variety of
non-activated alkyl halides could be employed as alkylating
reagents. The regioselectivity was firmly controlled by ligands:
L10 was always C3-selective whereas L8 was C2-selective.
Notably, our method enabled alkyl-alkyl coupling of two
secondary alkyl fragments (3a-3k; 4a-4o), which is a long-
standing challenge in cross-coupling.[4,12] No isomerization of alkyl
fragments was observed, a non-trivial task given NiH’s tendency
to catalyze isomerization of secondary alkyl fragments.[13] This
result highlights the ligand control in the current system. The
method provides a facile access to C-alkyl pyrrolidines containing
small ring systems such as oxetane (3f and 4g), which are
privileged in medicinal chemistry. Acyclic secondary alkyl iodides
were also suitable coupling partners (3j-3k and 4m-4o).
Furthermore, a wide range of primary alkyl iodides could be used
as alkylating agents (3l-3t and 4p-4ab). As the reactions were
conducted at room temperature, alkyl bromides were unreactive.
However, using 50 mol% KI as additive, an alkyl bromide was
coupled in a modest yield (3p). Coupling of benzyl-Br was
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Table 2. Scope of the regiodivergent hydroalkylation.[a]
[a] All reactions were performed with NiI2•xH2O (10 mol%), L8 or L10 (15 mol%), 1 (0.20 mmol), alkyl halides 2 (0.30 mmol), (EtO)2MeSiH (0.40 mmol), KF (0.40
mmol) and DMA (0.5 mL) at rt for 36-48 hours. [b] Alkyl bromide with 50 mol% KI was used.
and C3-positions, which is ligand-dependent. In this case of
intermediates I-A and I-C are in rapid equilibrium. The results from
deuterium labelling experiments, however, suggest this possibility
is less likely, at least for L10.
Figure 1. Late-stage functionalization of natural product and drug.
I-C to some degree so that C2-alkytion is predominant under most
cases. However, a ligand such as L10 might reverse the relatively
stability of intermediates I-A and I-C, leading to C3-alkytion. It
might kinetically stabilize I-A by having a high barrier for β-H
elimination as well. Hence with proper ligand control
regiodivergent alkylation can be achieved. Alternatively, the
regioselectivity might reflect the kinetics of cross-coupling at C2-
Scheme 2. Results of preliminary mechanistic study.
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Figure 2. A proposed mechanism.
In summary, we conceived a strategy for regiodivergent
hydroalkylation employing ligand control and a weak directing
group as key design elements. We demonstrated this strategy for
hydroalkylation of 3-pyrrolines, yielding an efficient and diversity-
oriented method for the synthesis of C-alkylated pyrrolidines,
which are important molecules in medicinal chemistry. Further
applications of this strategy, including the development of
enantioselective catalysis, are currently ongoing in our
laboratories.
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We thank Dr. Srikrishna Bera and Dr. Renyi Shi (EPFL) for the
generous donation of some alkyl halides.
Keywords: alkenes • nickel hydride • hydroalkylation •
pyrrolidines • regiodivergent
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D. Qian, X. L. Hu*
Page No. – Page No.
Ligand-Controlled Regiodivergent
Hydroalkylation of Pyrrolines
Employing ligand control and a weak directing group as key design elements, we
developed an efficient and diversity-oriented method for the synthesis of C-
alkylated pyrrolidines.
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