Hydropyridylation of Olefins by Intramolecular Minisci Reaction

Article abstract of DOI:10.1021/acs.orglett.7b00833

An unprecedented cheap, mild and easy methodology for an intramolecular Minisci reaction based on a hydrogen atom transfer (HAT) initiated hydrofunctionalization of olefins was developed. The method is suitable for the construction of unusual dihydropyrano-pyridine and 1,2,3,4-tetrahydronaphthiridine structures and, unlike most similar reactions, does not require exclusion of air from the reaction medium.

Full text of DOI:10.1021/acs.orglett.7b00833

Letter
pubs.acs.org/OrgLett
Hydropyridylation of Olefins by Intramolecular Minisci Reaction
Samuele Bordi† and Jeremy T. Starr*
Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United States
†School of Science and Technology, Chemistry Division, University of Camerino, via S. Agostino 1, I-62032 Camerino (MC), Italy
S
* Supporting Information
ABSTRACT: An unprecedented cheap, mild and easy
methodology for an intramolecular Minisci reaction based on
a hydrogen atom transfer (HAT) initiated hydrofunctionaliza-
tion of olefins was developed. The method is suitable for the
construction of unusual dihydropyrano-pyridine and 1,2,3,4-
tetrahydronaphthiridine structures and, unlike most similar
reactions, does not require exclusion of air from the reaction medium.
Scheme 1. Minisci Reaction and Alkene Radical
Hydrofunctionalizations
he radical substitution of protonated heteroarenes, often
Tcalled the “Minisci” reaction, is enjoying a resurgence in
popularity for late stage functionalization of heteroaromatic
structures in the synthesis of natural and biologically active
products.1 The scope of the reaction has been widely expanded,
including many methods for radical generation and new radical
sources,2 but intramolecular variants are comparatively rare.
The main limitation faced by an intramolecular Minisci reaction
is often the necessity of an excess of the radical source, making
the reaction seem untenable when the radical nucleophile is in a
1:1 stoichiometry with the electrophile, as in an intramolecular
case. However, we believe the close proximity of nucleophile
and electrophile may overcome the kinetic limitations of some
Minisci reactions.
Among the methods for radical based carbon−carbon and
carbon−heteroatom bond formation, the hydrofunctionaliza-
tion of olefins has proved to be an effective approach and has
been used in total synthesis for the construction of structures
difficult to obtain in other ways.3 The main advantage of this
reaction over the Brønsted acid promoted hydrofunctionaliza-
tion of olefins is that it proceeds by way of a carbon centered
radical, which may be intercepted to form a new carbon−
carbon bond. Additional advantages include its relative
mildness and the tolerance for the presence of other functional
groups, making it useful in the late stage of a synthetic pathway,
where it may be necessary to deal with complex structures or
undesirable to use protecting groups.
In the last 30 years, many transition metal based catalytic
systems were developed for hydrofunctionalization of double
bonds, among them, Carreira’s Co/Salen complexes,4 Shigehi-
sa’s Co/fluoropyridinium system,5 and, lately, Baran’s Fe(III)/
hydrosilane system (Scheme 1).6 In particular, the latter has
proved to be a useful methodology for both inter- and
intramolecular reductive olefin coupling and has been used for
the synthesis of alkylated styrene derivatives,7 unnatural amino
acids,8 and substituted phenols.9 Moreover, Baran’s protocol
has been used as key step in the total synthesis of Hippolachnin
A10 and Emindol SB.11
We were attracted to the Baran method in particular as a
starting point for an intramolecular Minisci reaction because of
its mildness, versatility, and simplicity. Herein we describe the
extension of the Fe(acac)3/PhSiH3 system to a convenient
method for heteroannulation of pyridine to give semisaturated
heterobicycles.
Despite the method having been substantially optimized for
reductive olefin coupling, we found optimization was necessary
in order to adapt it for a net redox neutral process under the
Received: March 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00833
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Organic Letters
Letter
a
acidic conditions required for activation of the heteroarene. We
started our optimization with the pyridine 1a as substrate, using
2.5 equiv of PhSiH3 and 1 equiv of Fe(acac)3 and trifluoroacetic
acid in a series of solvents, heating at 60 °C for 18 h. Table 1
Table 2. Optimization of Additives
a
Table 1. Initial Solvent and Additive Screen
TFA
Fe(acac)3
b
entry
solvent
MeOH
(equiv)
(equiv)
additive
conv (%)
1
2
4
4
1
1
55
60
MeOH/H2O
(4:1)
b
b
3
4
EtOH
4
4
1
1
80
68
entry
conditions
conv (%)
chemosel
EtOH/H2O
(4:1)
1
2
3
4
5
6
7
MeOH, EtOH, or iPrOH as solvent
H2O as solvent
50−60
55
5:1
1:10
5
6
EtOH
EtOH
2
2
2
100
90
DMF or THF as solvent
TFA (7 equiv)
traces
45
0.5
DTBP
(1.5 equiv)
>20:1
1:10
1:1
c
no TFA added
65
7
8
9
EtOH
EtOH
EtOH
2
2
2
0.5
0.5
0.1
DTBP
(3 equiv)
100 (82)
PhSiH3 (5 equiv)
90
d
DTBP
(3 equiv)
0
entry 1, degassed solvents
30−40
5:1
a
General conditions: 1a (0.3 mmol), phenylsilane (2.5 equiv),
Fe(acac)3 (1 equiv), and trifluoroacetic acid (1 equiv) were mixed
in the chosen solvent (1.5 mL) and stirred at 60 °C for 18 h.
Conversions and chemoselectivity determined by GC−MS analysis
DTBP
(5 equiv)
95
a
b
General conditions: 1b (0.3 mmol), phenylsilane (2.5 equiv),
Fe(acac)3, and trifluoroacetic acid were mixed in the chosen solvent
(1.5 mL), then the additive was eventually added and the mixture
stirred at 60 °C for 18 h. Conversions determined by GC−MS
analysis. In brackets, isolated yield on 1 mmol scale. Reaction
performed without phenylsilane. Starting material was recovered.
(chemoselectivity calculated as (2 + 3)/4 ratio).
b
summarizes the early results in terms of conversion and
chemoselectivity. The reaction worked well in protic solvents,
with good selectivity for cyclization over alkene reduction,
except in water where reduction was strongly favored. It did not
proceed at all in aprotic solvents such as DMF or THF. An
excess of TFA was crucial for a good outcome of the reaction,
leading to nearly complete suppression of the reduced olefin
product. Generally, the conversions were observed between
50% and 60%, leaving a considerable amount of unreacted
substrate, we believe due to the known instability of
phenylsilane in acidic media.12 Unfortunately increasing the
amount of phenylsilane led only to a decrease in chemo-
selectivity (albeit with improved conversions). In these initial
experiments it was found that degassed reactions, excluding
oxygen, performed poorly compared with those run in the
presence of air. Typically, radical reactions exhibit the opposite
trend, often producing unwanted side reactions with adventi-
tious oxygen13 and often needing to be degassed in order to
work properly. In our case, oxygen seemed to play an important
role, perhaps in the reoxidation of Fe(II) to Fe(III) or in the
direct rearomatization of the radical addition product.
c
d
Scheme 2 shows that across a variety of substrates, good
yields of products, occurring where possible as a regioisomeric
a
Scheme 2. Substrate Scope
From these preliminary results, we switched to the pyridine
1b as substrate to further optimize conditions, reasoning that
the longer lived and more stable tertiary radical would undergo
the desired addition reaction at a faster rate than reduction to
the alkane (Table 2). Using ethanol as solvent and decreasing
the TFA to 2 equiv, we observed full conversion of starting
material to desired product as a mixture of regioisomers 2b and
3b (entry 5). The addition of 3 equiv of di-tert-butylperoxide
(DTBP) as a substitute for air as oxidant resulted in an 82%
isolated yield of the product, even after decreasing Fe(acac)3
from 2 to 0.5 equiv. Further decreasing the amount of
Fe(acac)3 to 0.1 equiv together with an increase of DTBP also
leads to excellent conversions, but with an increase in
deleterious side reactions leading to impurities in crude
product. Next, we investigated the scope of the reaction by
using a series of olefin chain-containing pyridines where the
method proved to be general.
a
General conditions: 1 (1 mmol), phenylsilane (2.5 mmol), Fe(acac)3
(0.5 mmol), and trifluoroacetic acid (2 mmol) were mixed in ethanol
(5 mL), then DTBP (3 mmol) was added and the mixture stirred at 60
°C for 18 h. 30% of 3b was isolated. Starting material was fully
recovered. No trace of the other regioisomer was detected.
b
c
d
B
DOI: 10.1021/acs.orglett.7b00833
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Letter
mixture of the 2- and 4-position adducts, were observed. One
exception was compound 2j, where only the 2-position adduct
formed, presumably due to a preference of the pyridyl C−N
bond to orient with the 2-position proximal to the amide in the
precursor. When a bromine atom is present at the 2-position
(example 2d) it directs the addition to occur exclusively at the
4-position; however, the bromine itself was partially reduced
from the product during the reaction, resulting in a mixture of
2d (46%) and 3b (30%). Interestingly, the rate of bromine
reduction is sufficiently slow to permit exclusive formation of a
single regioisomer suggesting Br is a convenient control
element in cases where an unsubstituted position may be
vulnerable to nucleophilic attack. Unfortunately, we could not
get the complete reduction of the bromine to occur in situ even
using additional equivalents of silane and longer reaction times.
The reaction tolerates benzyl radicals (2g), aminopyridine
derivatives (2h and 2j), and an amide in the cyclizing tether
(2j). When the reaction had a choice between positions on a 6-
aza-indole electrophile, addition to the pyridine nucleus was the
exclusive product (albeit in low yield, 2i). An ester in the
cyclizing tether proved problematic, however, and the
attempted product 2f was not formed after 18 h.
The reaction performs better in the case of external double
bonds as compared with internal ones. Comparing the results
on the cyclization of compound 1c with compound 1k (both
leading to the pyranopyridine 2c) we observed a substantial
decrease in yield in the case of the compound 1k with an
internal double bond, where the reaction does not go to
completion even after 48 h or using a greater amount of
phenylsilane (Scheme 3). Nevertheless, the yields are
preparatively useful even with internal double bonds, making
access to unusual spirocycles, such as 21, straightforward.
Scheme 4. Proposed Mechanism
of an internal oxidant may be due to the depletion of the
Fe(III) species, probably by single electron transfer (SET) from
intermediate C in the rearomatization step. Supporting this
hypothesis is our observation that full conversion of starting
material can be obtained with excess Fe(acac)3 (Table 2, entry
5). In conclusion, we have described a methodology for the
cyclization of olefin chains on pyridines, based on a HAT
initiated mechanism promoted by an Fe(III)/silane system.
The method does not require exclusion of air or moisture and
has proved useful for the construction of unusual dihydropyr-
ano-pyridine and 1,2,3,4-tetrahydronaphtiridine rings, which
would be difficult to obtain in other ways.
Scheme 3. Internal Double Bonds
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.7b00833.
Experimental procedures and characterization and
spectral data for new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jeremy.starr@pfizer.com.
ORCID
Jeremy T. Starr: 0000-0001-8651-507X
Notes
The proposed mechanism (Scheme 4) envisions a redox
neutral process, catalytic in Fe, as a fusion of Baran’s iron-
mediated olefin coupling6a and a Minisci reaction. The
mechanism starts with a hydrogen atom transfer (HAT) from
the Fe-hydride complex II, formed in situ from phenylsilane
and the iron catalyst I, to the olefin A, followed by addition of
the carbon radical B to the protonated pyridine residue. The
intermediate radical cation C is subsequently oxidatively
rearomatized to give the observed product(s).
The roles of di-tert-butylperoxide (or oxygen from air) may
be to generate product by rearomatization of the intermediate
C and to regenerate the active Fe(III) species I that delivers
hydride to the olefin. Low conversions obtained in the absence
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is in memory of Pfizer scientist Robert Oliver who
worked in the next hood over and who passed far too young.
The authors wish to acknowledge Jotham Coe, Mike Chen,
Dan Uccello of Pfizer and Susanna Sampaolesi of University of
Camerino for helpful discussions, and Jennifer Young of Pfizer
for final editing of the manuscript and Supporting Information.
Finally, we wish to thank Prof. Enrico Marcantoni of University
of Camerino for providing S.B. the opportunity to do this work
at Pfizer.
C
DOI: 10.1021/acs.orglett.7b00833
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Letter
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