Late-Stage C-H Alkylation of Heterocycles and 1,4-Quinones via Oxidative Homolysis of 1,4-Dihydropyridines

Article abstract of DOI:10.1021/jacs.7b05899

Under oxidative conditions, 1,4-dihydropyridines (DHPs) undergo a homolytic cleavage, forming exclusively a C_sp³-centered radical that can engage in the C-H alkylation of heterocyclic bases and 1,4-quinones. DHPs are readily prepared from aldehydes, and considering that aldehydes normally require harsh reaction conditions to take part in such transformations, with mixtures of alkylated and acylated products often being obtained, this net decarbonylative alkylation approach becomes particularly useful. The present method takes place under mild reaction conditions and requires only persulfate as a stoichiometric oxidant, making the procedure suitable for the late-stage C-H alkylation of complex molecules. Notably, structurally complex pharmaceutical agents could be functionalized or prepared with this protocol, such as the antimalarial Atovaquone and antitheilerial Parvaquone, thus evidencing its applicability. Mechanistic studies revealed a likely radical chain process via the formation of a dearomatized intermediate, providing a deeper understanding of the factors governing the reactivity of these radical forebears.

Full text of DOI:10.1021/jacs.7b05899

Article
pubs.acs.org/JACS
Late-Stage C−H Alkylation of Heterocycles and 1,4-Quinones via
Oxidative Homolysis of 1,4-Dihydropyridines
†
†
́
́
Alvaro Gutierrez-Bonet, Camille Remeur, Jennifer K. Matsui, and Gary A. Molander*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
*
S Supporting Information
ABSTRACT: Under oxidative conditions, 1,4-dihydropyridines
DHPs) undergo a homolytic cleavage, forming exclusively a
(
3
sp
C -centered radical that can engage in the C−H alkylation of
heterocyclic bases and 1,4-quinones. DHPs are readily prepared
from aldehydes, and considering that aldehydes normally require
harsh reaction conditions to take part in such transformations,
with mixtures of alkylated and acylated products often being
obtained, this net decarbonylative alkylation approach becomes
particularly useful. The present method takes place under mild
reaction conditions and requires only persulfate as a
stoichiometric oxidant, making the procedure suitable for the
late-stage C−H alkylation of complex molecules. Notably,
structurally complex pharmaceutical agents could be function-
alized or prepared with this protocol, such as the antimalarial Atovaquone and antitheilerial Parvaquone, thus evidencing its
applicability. Mechanistic studies revealed a likely radical chain process via the formation of a dearomatized intermediate,
providing a deeper understanding of the factors governing the reactivity of these radical forebears.
7
8
9
10
INTRODUCTION
alcohols, boronic acids, sulfinate salts, alkenes, and
■
11
alkyltrifluoroborates. However, in most of the previous
contributions, high temperatures, (sub)stoichiometric amounts
of expensive metal salts, an excess of the radical precursor, and
strong oxidants or expensive photocatalysts
to achieve good yields.
Aldehydes, which are readily available, have been employed
as acyl radical precursors to access acylated products and, to a
lesser extent and with limited applicability, as a source of alkyl
Nitrogen-containing heterocycles and quinones are ubiquitous
chemical motifs present in pharmaceuticals, natural products,
and ligand scaffolds among other examples, thus highlighting
7
,11a,12
1
are required
the importance of such structures. Late-stage modification of
these entities within the context of complex molecules is not
trivial, and often, a simple modification of such compounds
requires a lengthy synthetic strategy where the new substituent
must be installed at an early stage. In an ideal scenario,
numerous derivatives should be accessible from a common and
complex molecule at any stage in a synthesis. Consequently,
rapid, late-stage, selective alkylation processes of complex
molecules under mild reaction conditions are of great value and
13
14
radicals as well, generated through decarbonylation of an acyl
15
radical (I) (Scheme 1). Unfortunately, this acyl radical can
react with the heterocycle or undergo further oxidation,
resulting in nonproductive pathways. It is known that the
acyl/alkyl radical equilibrium can be shifted by increasing the
reaction temperature, resulting in a more efficient CO extrusion
event. Consequently, such transformations usually employ
temperatures above 100 °C to improve the selectivity toward
the alkylation, whereas an excess of the aldehyde motif is
required to achieve competitive yields, thus highlighting the
2
significance.
Polar approaches to such transformations are limited because
of their typically lower functional group tolerance. By contrast,
radical processes have the advantage of tolerating a wider array
of functional handles. Yet, the reaction conditions required to
generate radical intermediates are themselves often harsh, thus
16
13,14
3
narrow applicability of such a strategy.
Recently, 1,4-dihydropyridines (DHPs), which are readily
prepared from aldehydes in one step, have been demon-
limiting their applicability. Indeed, radical alkylation of
complex heterocycles has been well-developed in the Minisci
17
4
reaction, where a radical is coupled with a heterocycle under
strated to undergo homolysis under photoredox conditions to
acidic, oxidizing conditions, delivering the functionalized
product. Interestingly, the regioselectivity is orthogonal to
that observed for the Friedel−Crafts reaction, thus increasing
the appeal of such transformations. Traditionally, carboxylic
3
form C -centered alkyl radicals that can be engaged in
sp
18
different processes with prefunctionalized substrates. Notably,
5
6
acids and halides have been employed as radical precursors,
but more recently, the toolbox has been expanded to include
Received: June 16, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b05899
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
Scheme 1. Circumnavigating Acyl Radicals from Aldehydes
via Homolysis of DHPs
Table 1. Optimization of the Reaction Conditions
b
entry
deviation from standard conditions
3a (%)
c
1
2
3
4
5
6
7
8
9
none
98 (97)
no Na S O added
4
2
2
8
no TFA added
71
91
88
6
K S O instead of Na S O
8
2
2
8
2
2
(NH ) S O instead of Na S O
8
4
2
2
8
2
2
t-BuOOH instead of Na S O
8
2
2
TCA instead of TFA
CSA instead of TFA
72
83
95
13
0
BF ·OEt instead of TFA
3
2
1
1
1
1
0
1
2
3
CH Cl /H O as solvent
2 2 2
DHPs can be regarded as masked aldehydes that exclusively
deliver alkyl radicals by circumnavigating acyl radical
intermediates, thus avoiding the formation of acylated by-
products or the requirement for high temperatures, strong
oxidants, and an excess of the aldehydic partner given the
efficiency of oxidative fragmentation from DHPs. Based on this,
we envisioned exploration of the reactivity of DHPs in a
transformation beyond prefunctionalized substrates, targeting,
therefore, a much more appealing, yet challenging, C−H bond.
In this regard, we considered the C−H alkylation of nitrogen-
containing heterocycles and 1,4-quinones, so that the tradi-
tional drawbacks of Minisci chemistry with aldehydes could be
overcome, thus allowing a reintroduction of this attractive
feedstock into radical C−H alkylation processes.
CH CN as solvent
3
DMSO as solvent
59
c
,
cd
Na S O (20 mol %)
2
47 (25)
2
8
a
Conditions: 1a (0.10 mmol, 1.0 equiv), 2a (0.11 mmol, 1.1 equiv),
oxidant (0.12 mmol, 1.2 equiv), additive (0.15 mmol, 1.5 equiv),
solvent (1.0 mL, 0.1 M), 18 h, rt. HPLC yield using 4,4′-di-tert-
butylbiphenyl as internal standard. Isolated yield. Yield of 6a. TFA =
trifluoroacetic acid. TCA = trichloroacetic acid. CSA = camphorsul-
fonic acid.
b
c
d
2
). Both acyclic (3b−f, 3l) and alicyclic radicals (3g−k) could
be coupled with the heterocyclic backbone in moderate to good
yields. Notably, alkene functional groups were well tolerated as
demonstrated by the melonal-derived and cyclohexenyl DHPs
RESULTS AND DISCUSSION
For the optimization of the reaction conditions,
a as a model substrate in combination with i-Pr-DHP (2a) and
■
1
19,20
we chose
a
Table 2. Scope of 1,4-Dihydropyridines
found that the reaction proceeded in almost quantitative yields
using a small excess of 2a, sodium persulfate as oxidant, and
trifluoroacetic acid (TFA) to activate the heterocycle. Cation
exchange of the persulfate oxidant had little effect on the
reaction outcome (Table 1, entries 4 and 5), whereas stronger
oxidants (entry 6) typically employed for aldehydes had a
deleterious effect on the reactivity. Interestingly, the addition of
TFA was not an absolute requirement for the reaction to
proceed (entry 3), albeit a diminished yield was obtained
without this additive. Trichloroacetic acid (TCA) showed no
effect (entry 3 vs entry 7), whereas BF ·OEt (entry 9) showed
3
2
19,20
activity similar to that of TFA.
Not surprisingly, the solvent
system played a crucial role, as in this type of process diffusion
between the aqueous phase hosting the oxidant and the organic
2
1
phase accommodating the organic partners is critical.
Therefore, immiscible solvents gave poor yields (entry 10),
whereas pure acetonitrile (entry 11) failed because of the poor
persulfate solubility. Notably, more solubilizing DMSO
rendered modest yields (entry 12). It should be noted that
the use of DHPs allowed a metal-free, room temperature set of
reaction conditions with an almost equimolar mixture of
reaction partners in the presence of an inexpensive oxidant, in
striking contrast with previous reports using aldehydes as
radical precursors that generally employed 3−20 equiv of the
1
4
aldehyde partner at 115−140 °C.
Next, we tested this new set of reaction conditions with
a
b
DHPs featuring different alkyl units at the C4-position (Table
As in Table 1 (entry 1), 0.50 mmol scale. >20:1 dr.
B
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3f and 3h, respectively). Sterically demanding systems were
Article
(
To highlight the applicability of the protocol, we attempted
the late-stage C−H alkylation of different natural products and
pharmaceuticals (Table 4). Notably, we observed a wide
well accommodated, as demonstrated with the norbornyl
system (3i). Oxygen-containing heterocyclic motifs did not
hamper the reaction (3j−k). Importantly, primary radicals
could be engaged with 1a in the presence of a stabilizing α-
oxygen atom (3l). Unfortunately, nonstabilized, primary alkyl
radicals did not deliver the expected product because the
corresponding DHP does not undergo homolytic C−C
cleavage but rather C−H homolysis, resulting in the formation
Table 4. Late-Stage Alkylation of Natural Products and
a
Drugs
22
of a 4-alkylated pyridine byproduct.
Combinations of different heteroarenes with distinct DHPs
were then explored in an effort to access unprecedented
structural motifs (Table 3). For example, C2-alkylated lepidine
a
Table 3. Scope of Heteroarenes and Dihydropyridines
a
b
c
d
As in Table 1 (entry 1), 0.50 mmol scale. 1:1 dr. >20:1 dr. 2g or 2l
e
f
(1.5 equiv), Na S O (1.5 equiv). No TFA added. 2l (2.0 equiv),
2 2 8
Na S O (2.0 equiv), TFA (2.0 equiv).
2
2
8
functional group tolerance (e.g., amines, alkenes, hydroxyls,
sulfonamides) in alkylating natural products such as nicotine
(
3y) and caffeine (3z). Cinchonine, a common ligand scaffold
25
for numerous organocatalytic processes, could be quickly
modified (3aa), allowing the formation of a new generation of
cinchonine-based ligands under mild reaction conditions.
Likewise, structurally related quinine, an antimalarial drug,
could be diversified in high yields (3bb, 3cc). Antivasospatic
fasudil hydrochloride and apoptosis inducer camptothecin
were effectively elaborated under the reaction conditions,
delivering the C−H alkylated product in good to high yields
and excellent regioselectivity (3dd−3ff). Notably, alkylated
camptothecin derivatives have shown activities even higher than
a
b
c
As in Table 1 (entry 1), 0.50 mmol scale. No TFA added. 2n (2.0
26
d
equiv), Na S O (3.0 equiv). 2b (1.5 equiv), Na S O (1.5 equiv).
2
2
8
2
2
8
e
f
3
6% yield of dialkylated product was obtained. Na S O (2.2 equiv).
2 2 8
23
27
derivatives have shown antituberculosis activity, and thus
several different lepidine derivatives (3m−o) were prepared.
Whereas simple alkyl motifs rendered high yields of the
corresponding product (3m), more complex motifs led to
lower yields (3n,o). Interestingly, primary α-amidomethyl
radicals could be employed, although with poor yields (3o).
Substituted quinolines were explored and satisfactorily yielded
the expected products in moderate to good yields (3p,r,s).
Likewise, isoquinolines were well accommodated (3t,u) as well
as pyridine (3v), pyrimidine (3w), and benzothiazole cores
those of the base molecule itself.
Spurred on by the possibility of introducing the decarbony-
lated aldehyde feedstock while overcoming its inherent
drawbacks in radical processes, we envisioned the introduction
of quinones as radical acceptors. Quinones are of extreme
importance because of their ability to partake in electron
transport processes in primary metabolic routes. Furthermore,
they display important pharmacological activities and are very
2
8
versatile intermediates for organic synthesis. Because
functionalization of quinones usually relies on the use of
29
(
3x). To test the regioselectivity of the protocol, heterocycles
transition metal catalysis, we sought to carry out the metal-
free C−H alkylation of quinones from DHPs under mild
conditions. Previously, these interesting scaffolds have been
functionalized using radicals generated with metal-based
catalysts to afford mostly arylated quinones from organoboron
with differentially reactive C−H bonds were tested. Unfortu-
nately, mixtures of mono- and dialkylation were observed
(
3q,v). However, in the presence of other leaving groups under
radical conditions (e.g., MeSO -, and Cl-, 3w), exclusive
addition at the C−H bond was observed.
2
24
30
31
32
compounds and carboxylic acids, among others. However,
C
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aldehydes have never been employed before as alkyl radical
Scheme 2. One-Pot C−H Alkylation of Heterocycles with in
Situ Generated DHP
33
precursors with this class of substrates, thus ignoring an
important feedstock that could help increase the chemical
space.
To demonstrate the versatility of our protocol, different 1,4-
34
quinones were tested (Table 5). Interestingly, in the presence
a
Table 5. C−H Alkylation of p-Quinones
added to the crude mixture. Although yields were lower than
those in the stepwise protocol, these results suggest particularly
unstable DHP intermediates could be used directly as latent
37
radicals without sequential purifications.
Mechanistic Studies. Once the versatility of DHPs as
alkylating agents was demonstrated in radical C−H alkylating
processes, we moved on to study the influence of the 1,4-
dihydropyridine backbone in the reaction outcome. Because of
3
sp
their dual role as H atom donors and C -alkyl radical
precursors, DHPs are becoming more prominent in organic
18
synthesis. Consequently, it was of interest to gain a deeper
understanding of the factors controlling their reactivity. To this
end, six different 1,4-dihydropyridine cores were tested under
the developed reaction conditions (Scheme 3). Interestingly,
a
4
(0.50 mmol, 1.0 equiv), 2 (1.00 mmol, 2.0 equiv), Na S O (1.5
2 2 8
mmol, 3.0 equiv), TFA (0.75 mmol, 1.5 equiv), CH CN/H O (1:1 v/
v) (5.0 mL, 0.1 M), 48 h, rt. 62:38 cis/trans ratio; >1:20 cis/trans ratio
3
2
Scheme 3. Influence of the DHP Backbone
b
after acidic treatment.
of two identical reactive sites, monoalkylation was observed in
good levels (5a). Apoptosis inducer Coenzyme Q , with only
0
one reactive site and two methoxy groups, was effectively
coupled with different DHPs in moderate to good yields (5b,c).
Notably, π-extended naphthoquinones such as vitamin K (5d)
3
smoothly reacted, as well as 2-hydroxynaphthoquinone (Law-
sone reagent) (5e,f), which, when combined with Cy-DHP,
yielded Parvaquone (marketed as Clexon, 5e) in 54% yield.
The latter is employed for the treatment of theileriosis, a cattle
disease that represents an important threat to livestock
production in Africa, generating losses above $200 million
3
5
annually. Alternatively, Atovaquone (5f, an antimalarial drug
that acts by inhibiting the mitochondrial electron transport
system and marketed as Malarone when combined with
a
b
In kcal/mol. Versus SCE.
36
proguanil hydrochloride) could be synthesized in a 54%
yield as a kinetic mixture of diastereomers that could be easily
converted to the more active trans-Atovaquone under acidic
conditions. Importantly, previous syntheses of Atovaquone
based on a radical alkylation approach relied on the use of silver
salts, significantly increasing the total cost of such a synthetic
cyano substitution at C3 and C5 (2a-CN) led to only traces of
product, whereas acridine derivative 2a-Acr led to no
conversion at all, and only 6-isopropylacridine could be
observed. Not surprisingly, no relationship between the
oxidation potential and the reactivity was observed because
3
1a
38
ox
2−
2−
persulfate [E (S O /SO4 ) = 2.01 V vs SCE] and
2
8
3
1a
ox
•−
2−
route.
[E (SO4 /SO4 ) = 2.6 V vs SCE] is strong enough to
39
Encouraged by the robust reactivity of DHPs, we tested the
possibility of achieving a one-pot procedure where the crude
reaction mixture from the DHP synthesis was used in the C−H
alkylative event without further manipulation (Scheme 2).
Indeed, formation of product 3a was observed in moderate
yields when the reaction was run in diethylene glycol, whereas
improved yields were observed when acetonitrile/water was
oxidize the different DHP backbones rapidly. However, a
40
1
trend between the steric bulk of the R group at C3 and C5
and the reactivity was detected. It appears that greater steric
hindrance at the C4-position of the pyridine byproduct formed
upon oxidation decreases the tendency of the isopropyl radical
to undergo competitive rebound with it, thus favoring the
alkylation of lepidine and providing higher yields of the desired
D
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product 3m. Notably, modification of the ester residue led to
comparable yields for isopropyl substitution (2a-i-Pr), whereas
the tert-butyl analogue 2a-t-Bu behaved poorly because of its
low solubility in the solvent system.
Scheme 5. Kinetic Isotope Effect Studies
Once the influence of the DHP backbone was studied, we
then explored the subtleties of this transformation. Upon
monitoring the reaction progress, an intermediate was observed
via HPLC that was later consumed to form product (Figure 1).
Later, we determined this observed intermediate to be the
dearomatized compound 6a.
SCE), which could be the reason for a slower homolysis of the
former. It should be noted that regardless of the deuteration of
the solvent, similar yields were obtained upon reacting
overnight. To study further the role of the N−H bond during
the oxidative cleavage, a test reaction with the N-methylated
DHP 2g-N-Me was conducted (Scheme 6). Whereas no
Figure 1. Monitoring the reaction between 1a and 2a.
To confirm its role as an intermediate, a reaction with 6a
under the developed reaction conditions was conducted,
showing quantitative conversion to 3a, thus demonstrating its
competency as an intermediate (Scheme 4).
Scheme 6. Influence of N-Substitution on the DHP
Backbone
Scheme 4. Testing the Intermediacy of Dearomatized
Intermediate 6a
product was formed, 2g-N-Me partially decomposed to several
To gain further insight into the reaction mechanism, we
performed two different deuterium-labeling experiments. First
Scheme 5A), an equimolar mixture of C2-deuterated and
byproducts as judged by GC-MS. Based on precedented
43
literature, we believe that this result might be indicative of a
+
•
(
deprotonation of the DHP prior to the homolytic cleavage.
The fact that no TFA was required for the reaction to proceed
(Table 1, entry 3) serves as additional, indirect evidence
supporting the generation of a proton upon oxidative cleavage
of the DHP. The in situ generated proton would be responsible
for selectively activating the heterocyclic substrate, which is
more basic than the formed pyridine 7, allowing the C−H
alkylation event to occur even in the absence of an external
proton source (2a, 3m, and 3cc), a behavior not observed in
previously reported protocols.
nondeuterated heterocycle 1a was treated under reaction
conditions. NMR analysis of the isolated compounds during
various time points showed proton enrichment of 1a, indicating
a secondary inverse kinetic isotope effect (KIE) (0.69 and 0.79
at 20 and 70 min, respectively), which can be rationalized on
2
3
the basis of a C −C rehybridization upon addition of
sp
sp
41
isopropyl radical II to the C2-position of the heterocycle.
Next, two similar reactions were performed, with the only
modification being the use of a deuterated solvent system and
TFA-d for one of them (Scheme 5B). Notably, a solvent KIE of
On the basis of the previous observations, we envision a
44
8
.5 was measured based on pyridine 7 formation, which
mechanistic scenario that is initiated by SET oxidation of the
probably arises from a fast scrambling of the DHP N−H proton
with the deuterated protic solvent. Afterward, such a scrambling
was confirmed to occur in less than 3 min by NMR analysis in
DHP 2a by Na S O , resulting in the formation of pyridine 7
2
2
8
and alkyl radical II (Scheme 7). The nature of such a homolysis
3
sp
has been discussed above. Subsequently, the C -radical adds to
42
+
1
:1 mixtures of CD CN/D O.
the protonated heterocycle (1aH ), resulting in the rehybrid-
3
2
The observed solvent isotope effect would be indicative of a
ization of the C2-carbon to form radical cation intermediate
slower homolysis for the N-deuterated DHP. Cyclic voltam-
IIIa, which is made evident by the observed inverse KIE. Next,
ox
ox
metric studies demonstrated the oxidation of 2a-d (E = +1.23
based on the oxidation potential of 6a (E = +1.19 V vs SCE),
ox
ox
V vs SCE) to be more demanding than for 2a (E = +1.05 V vs
we believe that IIIa is reduced by the DHP [E (2a) = +1.05 V
E
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Scheme 7. Putative Reaction Mechanism
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b05899.
■
*
S
Experimental details and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
gmolandr@sas.upenn.edu
■
*
ORCID
Jennifer K. Matsui: 0000-0003-0693-0404
Gary A. Molander: 0000-0002-9114-5584
Author Contributions
†
́
A.G.-B. and C.R. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Institutes of Health (No. NIGMS 1 R01
GM113878) for support. We acknowledge Dr. C.W. Ross, III
University of Pennsylvania) for HRMS analysis and Dr. N.R.
Patel (University of Pennsylvania) for useful experimental
vs SCE] via SET, thus resulting in formation of 6a and alkyl
radical II. Such a succession of events would be indicative of a
chain-radical mechanism. To confirm this hypothesis, a test
reaction with 20 mol % of Na S O was performed (Table 1,
■
(
2
2
8
entry 13) resulting in the isolation of product 3a in 47% yield
and intermediate 6a in 25% yield, indicating that at least 3.6
equiv of DHP is consumed per equivalent of oxidant and
supporting the initial hypothesis of a radical chain propagation
́
suggestions. We thank Dr. A. Correa (Universidad del Pais
Vasco), Dr. F. Julia-Hernandez (ICIQ), D. A. Lopez-Moure
GSK), and Dr. C. B. Kelly and D. N. Primer (University of
́
́
́
(
4
5,46
Pennsylvania) for helpful input.
mechanism.
Eventually, 6a will be oxidized by persulfate to
deliver the final product 3a (Scheme 4). Notably, the nature of
this step remains unknown, with several available options such
as SET oxidation to form IIIa, which will then undergo H atom
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