Metal-free C-H alkylation of heteroarenes with alkyltrifluoroborates: A general protocol for 1°, 2° and 3° alkylation

Article abstract of DOI:10.1039/c7sc00283a

A photoredox-catalyzed C-H functionalization of heteroarenes using a variety of primary, secondary, and tertiary alkyltrifluoroborates is reported. Using Fukuzumi's organophotocatalyst and a mild oxidant, conditions amenable for functionalizing complex heteroaromatics are described, providing a valuable tool for late-stage derivatization. The reported method addresses the three major limitations of previously reported photoredox-mediated Minisci reactions: (1) use of superstoichiometric amounts of a radical precursor, (2) capricious regioselectivity, and (3) incorporation of expensive photocatalysts. Additionally, a number of unprecedented, complex alkyl radicals are used, thereby increasing the chemical space accessible to Minisci chemistry. To showcase the application in late-stage functionalization, quinine and camptothecin analogues were synthesized. Finally, NMR studies were conducted to provide a rationalization for the heteroaryl activation that permits the use of a single equivalent of radical precursor and also leads to enhanced regioselectivity. Thus, by ¹H and ¹³C NMR a distinct heteroaryl species was observed in the presence of acid catalyst and BF₃.

Full text of DOI:10.1039/c7sc00283a

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Metal-free C–H alkylation of heteroarenes with
alkyltrifluoroborates: a general protocol for 1ꢀ, 2ꢀ
and 3ꢀ alkylation†
Cite this: DOI: 10.1039/c7sc00283a
*
Jennifer K. Matsui, David N. Primer and Gary A. Molander
A photoredox-catalyzed C–H functionalization of heteroarenes using a variety of primary, secondary, and
tertiary alkyltrifluoroborates is reported. Using Fukuzumi's organophotocatalyst and a mild oxidant,
conditions amenable for functionalizing complex heteroaromatics are described, providing a valuable
tool for late-stage derivatization. The reported method addresses the three major limitations of
previously reported photoredox-mediated Minisci reactions: (1) use of superstoichiometric amounts of
a radical precursor, (2) capricious regioselectivity, and (3) incorporation of expensive photocatalysts.
Additionally, a number of unprecedented, complex alkyl radicals are used, thereby increasing the
chemical space accessible to Minisci chemistry. To showcase the application in late-stage
functionalization, quinine and camptothecin analogues were synthesized. Finally, NMR studies were
conducted to provide a rationalization for the heteroaryl activation that permits the use of a single
equivalent of radical precursor and also leads to enhanced regioselectivity. Thus, by 1H and 13C NMR
a distinct heteroaryl species was observed in the presence of acid catalyst and BF3.
Received 19th January 2017
Accepted 24th February 2017
DOI: 10.1039/c7sc00283a
rsc.li/chemical-science
Most importantly, from an efficiency standpoint, these strate-
gies are sub-optimal as they rst require a functional handle to
Introduction
be installed, only to be immediately replaced in a subsequent
displacement reaction.
Heteroaryl subunits are among the most commonly employed,
privileged structures in medicinal chemistry.1 Unfortunately,
the synthesis of many of these structures is oen predicated on
cyclization reactions2 from simple starting materials (e.g.,
aldehydes, hydrazines, alkynes, etc.). Although these methods
oen prove advantageous when the precursors needed for
a particular molecular target are inexpensive and commercially
available, these sequences are untenable when attempting to
access a diverse library of structurally rich heteroarenes with
a common core (Fig. 1).
To overcome this challenge, two predominant anionic
strategies have emerged for diversifying common heteroaryl
motifs (Scheme 1): uorination to enable facile SNAr-based
chemistry3 and halogenation (bromination,4 chlorination5) to
provide a site for cross-coupling.6 These methods are highly
effective for many systems, but in numerous cases installation
of the halide at the desired site is unselective or impossible,
requiring re-evaluation of the synthetic strategy. Furthermore,
when successful incorporation of halides has occurred, heter-
oarenes are oen obstinate partners in cross-coupling chem-
istry,7 requiring careful screening to achieve fruitful union.
Radical alkylations of heteroarenes (Minisci reactions)8
represent a more direct functionalization of specic C–H bonds.
For this reason, radical alkylation strategies have recently risen
to prominence for the late-stage functionalization of heteroaryl
systems. Although Minisci and coworkers initially used silver
oxidants at elevated temperatures to generate alkyl radicals
from the corresponding carboxylic acids,9 advances in alkyl
radical generation have enabled much milder methods to be
developed (Scheme 1). These have included methods using
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, 231 S. 34th Street, Philadelphia, Pennsylvania 19104-6323, USA.
E-mail: gmolandr@sas.upenn.edu
† Electronic supplementary information (ESI) available: Experimental details and
spectral data. See DOI: 10.1039/c7sc00283a
Fig. 1 Complex heteroarenes poised for diversification.
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limited by parasitic reactivity (e.g., homocoupling, H-atom
abstraction, and chain processes) that appear to outcompete
the desired Minisci alkylation. As such, oen the only solution
has been to push reactions to completion with increased
reagent loadings or successive dosing (Scheme 1A).
To combat the disproportionate stoichiometry and typically
harsh conditions, other groups have turned to photoredox
catalysis for the efficient generation of radical.15 Contributions
by the MacMillan,16 DiRocco,17 Chen,18 and Barriault19 groups
have all highlighted the advantages afforded under this para-
digm. Although a variety of alkyl radicals precursors were pre-
sented in these photoredox contributions, each method exhibits
some inherent limitations. For example, the MacMillan group
targets weak C–H bonds, limited to a-heteroatom bonds. Bar-
riault and coworkers demonstrated that alkyl bromides could
be reduced to generate the corresponding alkyl radicals, but 3
equivalents of these precursors and a UVA LED light source
were required. Additionally, MacMillan and Barriault used
expensive iridium or gold photocatalysts, respectively. The
recent report by Chen addressed many of these issues with the
use of sustainable boronic acid partners and inexpensive
Ru(bpy)3, but their method employs the use of a stoichiometric
iodine oxidant that seems uniquely required for activation.
In light of these advances, we recognized the potential to
marry photoredox Minisci chemistry with our laboratory's
interest in alkyltriuoroborate reagents, especially given reports
by our laboratory and others20 on the favorable single electron
oxidation potentials of these salts to form alkyl radicals (Ered
¼
+1.10 V vs. SCE for 1ꢀ benzylic20a and +1.50 V vs. SCE for 2ꢀ
alkyltriuoroborates20b). Here, with appropriate organic photo-
catalyst selection (for 1: *Ered ¼ +2.06 V vs. SCE21), all repre-
sentative radical classes could be activated under identical
reaction conditions (Scheme 1B). In this scenario, one can
envision photocatalyst excitation serving as a chaperone for
steady, synchronized, catalytic radical generation. Such
a protocol ensures that an excess of radicals are not generated,
minimizing at least some of the byproducts formed through
stoichiometric processes. The photoredox catalyst-coordinated
generation of radicals in this manner leads to improvement
in reagent and oxidant loading, thus enhancing the efficiency
and sustainability of these methods. Serendipitously, these
aforementioned concepts, in conjunction with the generation of
Lewis acidic BF3 byproduct, also led to enhanced reactivity and
selectivity in these transformations.
Scheme 1 Approaches to heteroarene functionalization.
boronic acids,10 peresters,11 and other precursors12 under much
less forcing conditions. Most notably, the Baran laboratory has
pioneered the use of sulnate salts13 that have enabled the
extremely facile introduction of functionalized alkyl radicals
into an impressive array of heteroarenes. These methods allow
the formal C–H alkylation of heterocycles in a mild, metal-free
manner – drawing rapid adoption by medicinal chemists for
the late stage diversication of pharmaceutically relevant
compounds.14
Unfortunately, even with these advances, current methods
are not without their limitations, particularly with regard to the
continued requirement for high loadings of both the radical
partner and oxidant. Even the milder methods employing sul-
nate salts oen require a signicant excess of an expensive and
synthetically demanding precursor (3–6 equiv.) and oxidant (5–
10 equiv.) to achieve good yields.13 To date, methods grounded
on stoichiometric radical generation have been continually
Results and discussion
Mechanistically, we anticipated that visible light irradiation of
organic photocatalyst 1 would generate the excited complex 1*,
which is highly oxidizing and capable of oxidizing an alkyltri-
uoroborate to release the desired alkyl radical 3 and BF3
(Scheme 2). The generated radical 3 can then intercept the
protonated heteroarene to form the radical cation 5. Reduction
of persulfate (Ered ¼ >+0.35 V vs. SCE22) by the reduced form of
the photocatalyst 4 (Ered ¼ +0.49 V vs. SCE21) generates the
sulfate dianion and sulfate radical anion, regenerating photo-
catalyst 1.21 Finally, H-atom abstraction of 5 by the sulfate
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Table 1 Optimization for tertiary alkyl couplinga
Entry
Deviation from standard conditions
% yieldb
1
2
3
4
None
No persulfate
No light
No photocatalyst
57
<5
<5
0
5
6
7
8
No acid
30
53
8
16
86
96
45
84
Open to air (needle puncture)
Ru(bpy)3Cl2 (photocatalyst)
Ru(bpz)3Cl2 (photocatalyst)
lr[dFCF3ppy]2(bpy)PF6 (photocatalyst)
4CzIPN (photocatalyst)
2.0 equiv. triuoroborate
4.0 equiv. persulfate
9
10
11
12
Photocatalysts
Scheme 2 Proposed mechanism.
radical anion leads to rearomatization, affording the desired
alkylated heteroarene 6.16 Quantum yield studies indicate this is
not a radical chain process as evidenced by a f of 0.31 (see ESI†).
Furthermore, addition of excess allyl acetate (a known sulfate
radical anion trap23) did not interfere with reaction efficiency or
conversion.
a
Optimization reactions were run with heteroarene (1.0 equiv.), tert-
butyltriuoroborate (1.0 equiv.), photocatalyst (5 mol%), K2S2O8 (2.0
equiv.), triuoroacetic acid (1.0 equiv.) in MeCN/H2O (1 : 1) on
b
0.1 mmol scale. Yields were obtained by HPLC using a calibration
curve.
To begin this optimization, we keyed in on tertiary radical
partners for our initial studies. In particular, tert-butyltri-
uoroborate as the appropriate radical precursor and iso-
quinoline carboxylate as the heteroaryl partner. Before
screening various photocatalysts, controls probing the need for
oxidant (Table 1, entry 2), light (entry 3), and photocatalyst
(entry 4) were completed. Additionally, the absence of acid
(entry 5) afforded 30% conversion to product, although as alkyl
radical 3 is generated, BF3 (an electron-decient Lewis acid) is
concomitantly being formed. Performing the reaction in air
provided a comparable yield (entry 6) to a reaction carried out
under inert conditions (entry 1).
organophotocatalysts that have been shown to exhibit similar
reactivity to their metal-based counterparts. Surprisingly,
4CzIPN (entry 10) signicantly outperformed MesAcr over a 12 h
period. Neither excess alkyltriuoroborate (entry 11) nor excess
oxidant (entry 12) provided any perceived advantages.
In view of their low cost and ease of access, going forward we
focused on the two organophotocatalysts, MesAcr and 4CzIPN.
To determine the most suitable organic photocatalyst for our
purposes, we scaled up the reactions described in entries 1 and
10, and discovered that running the reaction for 16 h afforded
similar yields, consistent with the small scale reactions. It was
important for this protocol to be general for primary, secondary,
and tertiary alkyltriuoroborates. Because primary alkyltri-
uoroborates have a markedly higher oxidation potential (Ered
¼ +1.90 V vs. SCE20k) than secondary or tertiary alkyltri-
uoroborates, MesAcr and 4CzIPN were compared with
a primary alkyltriuoroborate (Scheme 3). In this assay, MesAcr
outperformed CzIPN with 76% versus <10% isolated yields,
respectively.
The mesityl acridinium photocatalyst was then compared to
other photocatalysts (entries 7–10). Noting the need for a rela-
tively high oxidizing potential of the photocatalyst, it was ex-
pected that ruthenium photocatalysts (with signicantly lower
oxidation potentials than the acridinium dyes) would experi-
ence diminished yields, which proved to be the case (entries 7
and 8). During the period that photoredox catalysis has gained
traction in the organic chemistry community, one major criti-
cism has been the high cost of the key metal-based photo-
catalysts (i.e., those based on iridium and ruthenium).
Tricoordinate organoboron compounds are isoelectronic
with carbocations, and thus would not be expected to be easily
Nicewicz24
and
Zhang25
have
explored
alternative
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excellent 72% yield with methyl isoquinoline carboxylate aer
16 h.
tert-Butyltriuoroborate was selected to examine the
amenability of various heteroarene partners (Table 3). Regio-
selectivity was probed using quinoline itself, leaving both the C2
and C4 positions available for alkylation. Currently there are
two methods for installing tertiary radicals regioselectively into
the quinoline core structure. Namgoong and coworkers re-
ported the use of excess TMP-zincate to deprotonate selectively
at the C2 position, followed by incorporation of the tert-butyl
substituent.27 This was a singular transformation, with no
demonstrated scope. Additionally, Minisci and coworkers have
reported selective C2 C–H substitution on quinolines using a 3-
fold excess of alkyl iodide radical precursors.8b Although effi-
cient, drawbacks of this approach included using peroxide as
the oxidant, thereby limiting functional group tolerance, and
the limited number of commercially available, complex alkyl
iodides. Therefore, we were pleased to observe regioselective
addition to the C2 position of the heteroarene in 72% yield (1a).
With substitution at the C4 position of quinoline, the reaction
reached full conversion to product within 16 h as determined by
GC-MS analysis (1b). When isolated, a 95% yield of the desired
product was achieved. Beyond alkyl substituents, halides and
triuoromethyl groups incorporated within the hetero-
aromatics allowed excellent conversion to product (1c, 1d).
Scheme 3 Comparing organophotocatalysts.
oxidized by single electron transfer (SET) processes. To conrm
that this chemistry was unique to alkyltriuoroborates, a variety
of organoboron reagents were synthesized and analyzed by
cyclic voltammetry to determine their relative oxidation poten-
tials (Table 2). As expected, the trivalent organoboron variants
exhibit very high oxidation potentials as compared to their
tetravalent, “ate” complex analogues. Consequently, under the
reaction conditions, no radical formation from the boronic
acids and/or esters was observed. For the tetravalent species,
triolborates exhibit comparatively low reduction potentials.
Unfortunately, the swi hydrolysis of triolborates under the
acidic, aqueous reaction conditions forms the redox inactive
boronic acid.26 By contrast, alkyltriuoroborates are both stable
to the reaction conditions and redox amenable, resulting in an
Table 2 Exploring various alkylboron compoundsa
Alkylboron
Reduction potential
Result
Drawbacks
ꢁ Air sensitive
>2.5 V vs. SCE
No conversion
ꢁ Poor redox properties
ꢁ Limited commercial availability
ꢁ Poor atom economy
>2.5 V vs. SCE
No conversion
ꢁ Poor redox properties
ꢁ Air sensitive
ꢁ Poor atom economy
ꢁ Poor redox properties
>2.5 V vs. SCE
+1.1 V vs. SCE
<5% conversion
No conversion
ꢁ Limited commercial availability
ꢁ Hydrolytically unstable
ꢁ Poor atom economy
a
Reactions were run with heteroarene (1.0 equiv.), alkylboron reagent (1.0 equiv.), MesAcr (5 mol%), K2S2O8 (2.0 equiv.), triuoroacetic acid (1.0
equiv.) in MeCN/H2O (1 : 1) on 0.2 mmol scale.
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In addition to quinoline cores, indazole (1e), isoquinoline
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(1g), and quinoxaline (1h, 1i) moieties were successful partners
under standard conditions. Indazole 1e is particularly notable
because of the prevalence in medicinal chemistry1 and, to the
best of our knowledge, the absence of Minisci examples in the
literature. As expected, the use of the benzimidazole core
resulted in no conversion (1f) because of the electron-rich
nature of the C2 site. Additionally, N-methyl benzimidazole
was similarly unreactive. Pyridines also exhibited selective
mono-addition (1j–1l, 1n). There has appeared only one report
of nicotinamide alkylation via Minisci chemistry, wherein three
equiv. of the corresponding carboxylic acid were necessary
under silver catalyzed conditions.28 A medicinally relevant core,
quinazolinone 1p, afforded product in 90% yield. Purine 1q
contains two sites of potential radical addition, but substitution
was observed only on the pyrimidine subunit. Overall, this
Scheme 4 Synthesis of tertiary alkyltrifluoroboratea. aReactions were
run with heteroarene (1.0 equiv.), tertiary alkyltrifluoroborate (1.0
equiv.), MesAcr (5 mol%), K2S2O8 (2.0 equiv.), trifluoroacetic acid (1.0
equiv.) in MeCN/H2O (1 : 1) on 0.3 mmol scale.
Table 3 Heteroarene scopea
method is broadly tolerant of a wide range of functional groups
as demonstrated with quinine 1r (possessing alkene, alcohol,
tertiary amine groups). Notably, the tertiary amine embedded
within quinine did not interfere with the photocatalytic cycle
despite its propensity for competitive oxidation.
Currently, there are a limited number of tertiary alkylbor-
anes commercially available and no alkyltriuoroborates.
Presumably, this is a result of narrow synthetic utility compared
to their primary and secondary counterparts. Although we
demonstrated that tert-butyltriuoroborate was viable, more
highly elaborated systems could also be incorporated. Cook and
coworkers recently reported a manganese-catalyzed borylation
of alkyl bromides. Using Cook's procedure,29 >1 g of pina-
colborane intermediate 1t was synthesized from the corre-
sponding alkyl bromide 1s. This borylation was followed by
treatment with saturated KHF2 to afford the corresponding
alkyltriuoroborate 1u (Scheme 4).
With tertiary alkyltriuoroborate 1u in hand, radical addi-
tion to caffeine 1v and benzothiophene 1w was carried out. The
development of the Cook approach to 3ꢀ alkyltriuoroborates
thus allows access to an even greater array of coupling partners.
In further studies, a wide range of alkyltriuoroborates were
found to be suitable partners in the developed photoredox
Minisci conditions (Table 4). First, a benzyl protected a-alkox-
yalkyltriuoroborate afforded 2a in 58% yield. Additional
examples of unactivated, secondary alkyl radical precursors
could be appended as in 2b–2j. For 2b, the successful addition
of uorinated isosteres is encouraging, given the well-
documented propensity these subunits have for modulating
solubility and binding affinity in medicinal chemistry.30 For 2c–
2e, the tetrahydropyranyl and piperidinyl moieties are
commonly introduced ring structures that serve as useful
probes for H-bond donors/acceptors in SAR efforts.31
To the best of our knowledge, primary alcohols appended to
the radical coupling partner have not been reported in Minisci-
type reactions, perhaps owing to their propensity to undergo H-
atom abstraction alpha to the hydroxyl group. Therefore, we
were pleased to obtain 2f, albeit in low yield. Of note, this
a
Reactions were run with heteroarene (1.0 equiv.), tert-
butyltriuoroborate (1.0 equiv.), MesAcr (5 mol%), K2S2O8 (2.0 equiv.),
triuoroacetic acid (1.0 equiv.) in MeCN/H2O (1 : 1) on 0.3 mmol
scale. Yield determined by uorine NMR using uorobenzene as
b
internal standard.
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Table 4 Secondary and tertiary alkyltrifluoroborate scopea
Table 5 Primary alkyltrifluoroborate scopea
a
Reactions were run with methyl isoquinoline-3-carboxylate (1.0
equiv.), alkyltriuoroborate (1.0 equiv.), MesAcr (5 mol%), K2S2O8 (2.0
equiv.), triuoroacetic acid (1.0 equiv.) in MeCN/H2O (1 : 1) on
0.3 mmol scale. b Reaction run in DCE/H2O (1 : 1).
a
Reactions were run with 1-methyl isoquinolinecarboxylate (1.0 equiv.),
primary alkyltriuoroborate (1.0 equiv.), MesAcr (5 mol%), K2S2O8 (2.0
equiv.), triuoroacetic acid (1.0 equiv.) in MeCN/H2O (1 : 1) on
0.3 mmol scale.
selectivity is complementary to the MacMillan group's work on
alcohols as radical precursors in photoredox-Minisci cou-
plings.16a A further exploration of 5- and 4-membered hetero-
cycles (2g–2i) was conducted with promising results, where
tetrahydrofuran 2g was afforded in 34% yield, but access to
pyrrolidine 2h was not successful. For azetidine 2i, standard
solvent conditions provided only trace amounts of product, but
switching to DCE/H2O (1 : 1) proved to be benecial. Cyclo-
propyltriuoroborate, although unproductive in previously re-
ported photoredox/Ni dual cross-coupling methods,20b afforded
2j, albeit in 20% yield. 1-Adamantyltriuoroborate has never
been used in Minisci-type alkylations. Using the standard
conditions, 2k was isolated in 45% yield. Lastly, chemoselective
radical addition to the isoquinoline was observed for 2l despite
containing an alternate site for alkylation within the alkyltri-
uoroborate partner.
Moving forward, this Minisci process was anticipated to be
broadly applicable even to primary alkyltriuoroborates, which
possess relatively high oxidation potentials (Table 5). As an
initial foray, we rst investigated whether stabilized primary a-
alkoxymethyltriuoroborates could be competent partners in
this process (3a–3d). Non-stabilized alkyl radicals were also
demonstrated in examples 3e–3l. Notably, 3j contains an ortho
bromide functional handle for further elaboration. Unfortu-
nately, electron decient 3,3,3-triuoropropyltriuoroborate
afforded 3l in diminished yield, likely because of its high
oxidation potential and resultant destabilization of the gener-
ated radical. These trends track with other recent reports
specically targeting more electrophilic radicals.13e,16b
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Table 6 Demonstration of diversitya
Scheme 5 Mild alternative for ligand synthesis. aReactions were run
with heteroarene (1.0 equiv.), alkyltrifluoroborate (1.0 or 2.0 equiv.),
MesAcr (5 mol%), K2S2O8 (2.0 equiv.), trifluoroacetic acid (1.0 equiv.) in
MeCN/H2O (1 : 1) on 0.3 mmol scale.
a
Reactions were run with heteroarene (1.0 equiv.), alkyltriuoroborate
(1.0 equiv.), MesAcr (5 mol%), K2S2O8 (2.0 equiv.), triuoroacetic acid
(1.0 equiv.) in MeCN/H2O (1 : 1) on 0.3 mmol scale.
As would be anticipated for the radical-based mechanism of
the transformation, cyclopropylcarbinyltriuoroborate 3m
formed the corresponding radical 3o aer SET oxidation and
subsequent rearrangement. Following radical addition to the
activated heteroaromatic, 3p was isolated in 55% yield.
was selected for further investigation. Commonly these ligands
are synthesized through the SNAr reaction of strong nucleo-
philes (e.g., tert-butyllithium) to a uorinated bipyridine
precursor, which is unfortunate given the popularity of these
ligands in Cu and Ni catalysis.33 In contrast to the use of such
pyrophoric alkylating agents, bench-stable alkyltriuoroborates
represent an attractive alternative. Gratifyingly, unfunctional-
ized substructures 5a and 5c were converted to the desired
products in 84% and 68% yields, respectively. Pyridine ligands
are also valuable for the synthesis of iridium photocatalysts.
Under the same reaction conditions, heteroarene 5e afforded
mono-alkylated product 5f in 82% yield. When tridentate ligand
terpyridine 5g was subjected to the standard conditions with
two equivalents of tert-butyltriuoroborate, mono-alkylated 5h
was formed exclusively.34
Although medicinal chemists have principally capitalized on
late-stage Minisci heteroarene alkylation,9 it can be advanta-
geous to introduce alkyl substitution earlier in a synthetic
sequence.35 Using the present protocol, the installation of alkyl
subunits on brominated heteroarenes provides an excellent
opportunity to highlight divergency in molecular synthesis.
Furthermore, the halides installed within a variety of hetero-
arenes can serve a dual purpose: they may serve as an electronic
The diversity of the process was expanded to underline the
potential for widespread utility (Table 6). Lepidine was coupled
with a variety of stabilized a-alkoxy (4a–4c) and unstabilized
(4d–4f) radicals. With quinoline, C2 regiospecicity was again
observed (4d, 4e), albeit in diminished yields. This is particu-
larly noteworthy given the challenges associated with avoiding
complex mixtures of isomers in prior Minisci-type reaction
reports.32 With heteroarene cores such as pyridine (4f), benzo-
thiazole (4g), indazole (4h), and quinazolinone (4i, 4j), excep-
tional yields were observed. When exploring reactivity with
caffeine, methylcyclopentyltriuoroborate afforded 4k in 37%
yield. Additionally, a secondary alkyl radical was successfully
appended to functionally rich quinine as demonstrated in 4l.
Practical applications
Given the success of this method, the use of this technology for
selective ligand modications was envisioned (Scheme 5). As
a case study, difunctionalization of a bipyridine-based ligand
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Table 7 Utilizing heteroarenes with functional handles
introduced, resulting in a more highly-active clinical candi-
date.37 Although SAR studies were conducted to conrm the
promising properties of alkyl decoration, the alkyl substituents
were primarily limited to simple alkyl groups (e.g., methyl,
ethyl) using the corresponding alkyl bromides, peroxide, and
acid under thermal conditions.38 To demonstrate the advan-
tages of using the currently developed, mild photoredox
conditions, secondary and primary alkyltriuoroborates were
selected as reagents for generation of analogues. As displayed in
Scheme 6, primary a-alkoxyalkyl subunits could be incorpo-
rated, along with secondary alkyl moieties (7a, 7b).
Mechanistic investigations
From our previous reports on Minisci chemistry12 and the
results provided herein, it became clear that the use of alkyl-
triuoroborates provided clear advantages in terms of both
reactivity (permitting a single equivalent of radical precursor to
be employed) and regioselectivity in heteroarene alkylation.
Given these observations, it seemed that there might be some
inherent advantage to the generation of BF3 byproduct during
the course of the reaction. Two distinct possibilities were
considered: (1) the BF3 produced was intimately involved with
the generated radical, providing a shepherding effect in deliv-
ering the radical with enhanced selectivity, or (2) the BF3 was
coordinating to the heteroarene prior to the radical addition,
activating the heteroaryl substrate and enhancing preference
for one site beyond the activation provided by the added protic
acid.
To assess the rst hypothesis, DFT calculations were per-
formed to determine the effective “bond order” for radical
association with BF3 in solution. This potential interaction was
of particular interest as this escorting effect has little precedent
in the chemical literature; currently, there are only examples of
nitrogen- and oxygen-centered radicals interacting with BF3 in
solution.39 Indeed, preliminary calculations suggest that
a strong preference exists for the free radical over a BF3-bound
complex in solution (see ESI†). Noting this lack of association,
we were quick to investigate an alternative hypothesis.
To probe each of the possible heteroarene complexes, we
prepared stoichiometric solutions of one of our successful,
selective substrates, quinoline, with no additive, triuoroacetic
acid (TFA) alone, BF3 alone, and nally TFA with added BF3,
hoping to probe the effect of coordination on the proton and
carbon shis of heteroarene and provide some rationale for the
differences between our chemistry and previously established
protocols.
bias for regioselective alkylations ortho to the halide,13d and they
provide a functional handle for cross-coupling reactions, etc.6
To initiate studies to explore these concepts, a number of
brominated heteroarenes were selected (Table 7). First, pyrim-
idine 6a was paired with an a-alkoxyalkyltriuoroborate to yield
exclusively the C4-substituted product. When moving to pyri-
dines, a mixture of C2 and C6 alkylation occurred with tosyl-
protected piperidinyltriuoroborate (6b). Conversely, with
primary alkyltriuoroborates, only the C2-substituted products
were observed in examples 6c and 6d. Chloride substitution was
also well tolerated as demonstrated in 6d. When 4-bromoiso-
quinoline was utilized as a substrate, a mixture of regioisomers
6e and 6f was generated. Based on these studies, 6a and 6c
contrast favorably with previous ndings in the Baran labora-
tory wherein regiomeric isomers were observed for heteroaryl
bromides and chlorides.13d
As a nal highlight of the potential for late-stage function-
alization, camptothecin (CPT) was selected as an appropriate,
complex heteroarene. In medicinal chemistry, CPT was identi-
ed as an anti-cancer drug candidate because of its cytotoxic
activity in a number of cancer cell lines. Unfortunately, poor
solubility was a systemic issue and prevented moving it forward
as a drug candidate.36 To tackle this challenge, various alkyl
substitutions on the C7 position of the natural alkaloid were
For triuoroacetic acid, a clear downeld shi was observed
in the C2 and C4 protons of quinoline (Fig. 2). Likewise, for the
addition of BF3, a slightly less pronounced, but clear, downeld
shi was also observed for the same protons. However, the
combination of both additives together produced a wholly
different shi in resonances to a unique heteroarene species.
Most importantly, the carbon shis of C2 relative to C4 (the
best indicator of relative radicophilicity) possess enhanced
differentiation in relative downeld shi (ꢂ3 ppm) in compar-
ison to the BF3 and triuoroacetic acid complexes alone (ꢂ1
Scheme
functionalization.
6 Camptothecin analogues: examples of late-stage
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ppm) (Fig. 3). Based on these chemical shis, it is reasonable to
suggest the C2 position is preferentially activated over the C4
position40 under the reaction conditions, resulting in the
enhanced regioselective mono-alkylation observed for the
quinoline system and, by analogy, many of the other systems in
which alkyltriuoroborates appear uniquely reactive and selec-
tive (vida infra).
To probe these ndings further, we hoped that the use of
alternative radical precursors (e.g., sulnate salts or carboxylic
acids) could be used in the presence and/or absence of BF3 to
achieve the same desired regioselectivity. Unfortunately, under
our standard conditions, sulnate salts were universally inef-
fective, and carboxylic acids gave the same regiomixture, even
with added BF3. Given this current ambiguity, this enhanced
reactivity and regioselectivity appears to remain unique to the
triuoroborate precursors (see ESI†).
At this time, although it is impossible to propose a structure
for this distinct, activated species, we speculate that BF3 acti-
vation of either the heteroarene p-cloud41 or polarization of the
triuoroacetic acid42 to increase its effective pKa may be
responsible. Intriguingly, this type of dual activation could
perhaps be more broadly operative in the selective alkylation of
other heteroaryl cores.
Conclusions
Fig. 2 1H NMR of A with trifluoroacetic acid and/or BF3 additive in
In summary, a mild, room temperature method for the intro-
duction of a diverse palette of alkyl groups has been developed.
Under a set of unied reaction conditions, primary, secondary,
and tertiary alkyltriuoroborates can be employed in photo-
redox Minisci chemistry for the rst time. This chemistry makes
use of an inexpensive, mild oxidant, organic photocatalyst, and
requires only one equivalent of alkyl radical partner, providing
one of the most cost efficient and sustainable approaches to
date. Additionally, enhanced regioselectivity was observed
compared to current “state of the art” Minisci-type alkylations.
Both of these phenomena may be related to the synchronized,
catalytic generation of radicals in conjunction with the in situ
generation of BF3 during the course of the reaction. The resul-
tant method has been demonstrated broadly with respect to the
heteroarene and alkyltriuoroborate partners. Furthermore,
access to bipyridine-type ligands as well as the late stage
diversication of medicinally relevant substructures has been
showcased. Finally, NMR studies provided support for a unique,
highly activated species caused by the formation of BF3 upon
the single-electron oxidation of alkyltriuoroborates. Currently,
further mechanistic studies are underway to elucidate the
nature of this complex.
CD3CN/H2O (1 : 1). TMS was used as a reference.
Given the wide array of commercially available alkyltri-
uoroborates, in addition to those synthesized by our labora-
tory and emerging from other groups, this approach provides
a valuable contribution to the Minisci-type alkylation literature
that is both highly competitive with, and complementary to,
existing protocols. As alkyltriuoroborates are well behaved,
bench stable salts, these reagents will continue to serve as
useful “radicals in a bottle” for synthetic chemists.
Fig. 3 13C NMR of A with trifluoroacetic acid and/or BF3 additive in
CD3CN/H2O (1 : 1). CD3CN solvent peak was used as a reference.
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D. Oehlrich, F. Rombouts and G. A. Molander, J. Org.
Chem., 2013, 78, 4615.
Acknowledgements
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Y. Fujiwara, J. A. Dixon, F. O'Hara, E. D. Funder,
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We thank the National Institutes of Health (NIGMS 1 R01
GM113878) for support. Dr Mirna El Khatib and Professor Ser-
gei Vinogradov (University of Pennsylvania) are thanked for
assisting in the quantum yield studies and providing the
necessary equipment. Dr Niki Patel (University of Pennsylvania)
is recognized for suggesting the use of allyl acetate as a sulfate
radical anion trap. Ms Shorouk Badir (University of Pennsylva-
nia) is acknowledged for the preparation of tertiary alkyltri-
uoroborate 1u. Frontier Scientic is thanked for the generous
donation of alkyltriuoroborates. Pzer graciously donated
organophotocatalyst MesAcr. Lastly, Mr Sergei Tcyrulnikov
(University of Pennsylvania) is thanked for performing DFT
calculations.
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