C-H Functionalization of Heteroarenes Using Unactivated Alkyl Halides through Visible-Light Photoredox Catalysis under Basic Conditions

Article abstract of DOI:10.1021/acs.joc.8b01589

C-H functionalization of electron-deficient heteroarenes using commercial unactivated alkyl halides through reductive quenching photoredox catalysis was developed. Mainstream approaches rely on the use of an excess of strong acids that result in regioselectivities dictated by the innate effect of the protonated heteroarene, leaving the functionalization of other carbons unexplored. We report a mild method under basic conditions that allows access to previously underexplored regioselectivities by relying on a combination of conjugate and halogen ortho-directing effects. Overall, this methodology gives quick access to a variety of alkylated heteroarenes that will be of interest to medicinal chemistry programs.

Full text of DOI:10.1021/acs.joc.8b01589

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Article
C-H Functionalization of Heteroarenes Using Unactivated Alkyl Halides
through Visible-Light Photoredox Catalysis under Basic Conditions
Noah B. Bissonnette, Michael J. Boyd, Gregory D. May, Simon Giroux, and Philippe Nuhant
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01589 • Publication Date (Web): 09 Aug 2018
Downloaded from http://pubs.acs.org on August 9, 2018
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The Journal of Organic Chemistry
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C-H Functionalization of Heteroarenes Using Unactivated Alkyl Hal-
ides through Visible-Light Photoredox Catalysis under Basic Condi-
tions
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Noah B. Bissonnette, Michael J. Boyd, Gregory D. May, Simon Giroux, and Philippe Nuhant*
Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States
ABSTRACT: A CꢀH functionalization of electronꢀdeficient heteroarenes using commercial unactivated alkyl halides through reꢀ
ductive quenching photoredox catalysis has been developed. Mainstream approaches rely on the use of an excess of strong acids
that result in regioselectivities dictated by the innate effect of the protonated heteroarene, leaving functionalization of other carbons
unexplored. We report a mild method under basic conditions that allows access to previously underexplored regioselectivities by
relying on a combination of conjugate and halogen orthoꢀdirecting effects. Overall this methodology gives quick access to a variety
of alkylated heteroarenes that will be of interest to medicinal chemistry programs.
INTRODUCTION
activates the C2, C4 and/or C6 positions increasing its ability
to react with nucleophilic radicals. However, the regioselectivꢀ
ity of the functionalization is dictated by the innate effect of
the heteroarene and the necessity of using an excess of strong
acid, rendering the exploration of the remaining carbons unexꢀ
plored (e.g. C3 and C5).12,16,18,21
Metalꢀcatalyzed crossꢀcoupling reactions have emerged as
highly useful and widely applicable methods for accessing
structurally diverse heterocyclic compounds via carbonꢀcarbon
bond formation. As a result, these methods have profoundly
influenced both drug design and organic synthesis fields.1
However, typical synthetic strategies rely on the simultaneous
use of functional groups such as aryl halides and organometalꢀ
lic monomers (e.g. boronic acids or esters, Grignard reagents,
etc.) leading to lengthy and/or tedious synthetic optimizations
and may leave certain substitution patterns unexplored. There
is therefore, a need for new and robust approaches that allow
rapid access to a wider variety of functionalized heteroarenes
via simplification of the Csp2ꢀCsp3 and Csp2ꢀCsp2 couplings
strategies. Towards this end, CꢀH functionalization chemistry
has emerged as a powerful and efficient tool to perform transꢀ
formations that allow direct and convergent syntheses of highꢀ
ly substituted cores with successful application to singleton
synthesis, parallel array synthesis, and late stage modification
of lead molecules.2,3 The incorporation of small structural
modifications on heteroarene rings (e.g. small alkyl groups)
can provide medicinal chemists the ability to introduce new
vectors for structureꢀbased drug design as well as alter physiꢀ
cochemical properties for the purposes of enhancing potency,
and improving target selectivity, solubility, and metabolic
stability.4,5 Recently, academic and industrial laboratories have
increasingly reported multiple CꢀH functionalizations of hetꢀ
eroarenes which rely on the innate reactivity of the protonated
electronꢀdeficient heteroarenes.6,7,16–22,8–15 For instance, protoꢀ
nation of a heteroarene, such as pyridine, (Scheme 1, eq. 1)
Scheme 1: CꢀH Functionalization of Heteroarenes
In theory, innate reactivity and its resulting regioselectivity
induced from the preactivation of the core by protonation may
be bypassed by favoring and enhancing the conjugate reactiviꢀ
ty and the halogen orthoꢀdirecting effect under basic condiꢀ
tions. To date, few examples of alkylation of heteroarenes in
basic conditions have been reported in the literature (Scheme
1, eq. 2).6,23–26 These methods, though useful, however suffer
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from several limitations. For instance, alkylation reactions are
usually not compatible with primary alkyl groups and rely on
the use of strong bases at elevated temperature, sometimes in
nonpolar aprotic solvents (e.g. toluene, trifluorobenzene, etc.)
with occasionally high catalyst loads (up to 10 mol%), which
may lead to complications such as decomposition, and/or poor
solubility of common heteroarenes.
Page 2 of 9
catalytic cycle with the regeneration of the catalyst ground
state (M), d) addition of the alkyl radical to C2 of indole 1, e)
oxidation of the subsequent radical by another reductive
quenching cycle to deliver the desired C2 functionalized inꢀ
dole 2 via a carbocation intermediate. This proposed mechaꢀ
nism may be supported by previous report36 and the radical
formation was confirmed via radical clock (see supporting
information) and TEMPO control experiments (Table 1, entry
14). In addition, further experiments using trifluoroacetic acid,
or without added amine (Table 1, entry 13), led to no converꢀ
sion, highlighting the importance of the tertiary amine as a
reductant in the catalytic pathway.
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RESULTS AND DISCUSSION
Recently, our research lab has demonstrated27–29 an increasing
interested in photoredox technologies6,30–34 that led us to invesꢀ
tigate new methodologies around the CꢀH functionalization of
π electronꢀdeficient systems which would give access to unꢀ
charted chemical space. As a starting point, we elected alkyl
halides as suitable sources of alkyl radicals due to their broad
commercial availability and previous successful applicaꢀ
tions.8,9 Interestingly, radical generation from the reduction of
alkyl halides using iridium photoredox catalysis has been unꢀ
derstudied and is limited to few reports (halide reduction, amꢀ
ide formation, intramolecular cyclization and borylation).34–38
Furthermore, we reasoned that only a selection of iridium cataꢀ
lysts could be powerful enough to efficiently reduce alkyl
halides via either reductive or oxidative quenching cycles. In
general, the reductive quenching pathway allows access to
stronger reduction potential for the catalyst (e.g. E1/2 II/III= ꢀ2.19
V, ꢀ1.51 V versus saturated calomel electrode (SCE) for facꢀ
Ir(ppy)3 and Ir(ppy)2(dtbbpy) respectively)34 versus the oxidaꢀ
tive quenching cycle (e.g. E1/2 III*/IV= ꢀ1.73 V, ꢀ0.96 V versus
SCE for facꢀIr(ppy)3 and Ir(ppy)2(dtbbpy) respectively).35
Cognizant of the strengths and weaknesses of both catalytic
pathways, we initiated an unprecedented intermolecular CꢀH
functionalization of heteroarenes using unactivated alkyl halꢀ
ides through visibleꢀlight photoredox catalysis. As a test exꢀ
periment, we designed an alkylation of indole 1 with ethyl
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Table 1: Optimization of the reaction conditionsa
Conversionb
(yield)c
Entry
Base
Different from above
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2
Bu3N
Bu3N
FacꢀIr(ppy)3
42%
-
92% (59%)
86% (54%)
78% (49%)
76%
3
Et3N
ꢀ
4
DIPEA
Cy2NH
quinuclidine
2,6ꢀlutidine
HTMP
Et3N
ꢀ
5
ꢀ
6
ꢀ
8%
7
ꢀ
ꢀ
4%
8
92% (64%)
43%
9
MeCN
DMSO
DCE
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Et3N
14%
Et3N
30%
Et3N
DMF
22%
iodide and tributylamine using both catalytic scenarios: facꢀ
Ir(ppy)3
entry 2). Pleasingly, we found that Ir(ppy)2(dtbbpy) with a
sacrificial reductant (e.g. tributylamine) was a better candidate
for the CꢀH functionalization reaction.
35,37
(Table 1, entry 1) or Ir(ppy)2(dtbbpy)36 (Table 1,
no base
Et3N
ꢀ
0%
3 eq. TEMPO
dark
0%
Et3N
0%
Et3N
no catalyst
12%
Scheme 2: Proposed mechanism for the CꢀH Functionalizaꢀ
tion of indole 1
[a] Reactions performed with 2x40W blue LEDs. [b] Conversions anaꢀ
lyzed by 1HNMR with 1,4ꢀdinitrobenzene as internal standard. [c] Isolated
yields.
After a quick screen of bases (Table 1, entries 3ꢀ8) and solꢀ
vents (Table 1, entries 9ꢀ12), we found that optimal conditions
were obtained when using 3.1 equivalents of 2,2,6,6ꢀ
tetramethylpiperidine (HTMP), 3 equivalents of alkyl iodide,
and 2.5 mol% of [Ir(ppy)2(dtbbpy)]PF6 at room temperature in
methanol under blue LED irradiation for 16 h (supporting
information). Overall, Et3N, Bu3N or HTMP showed similar
efficiency, however reactions using HTMP often gave a cleanꢀ
er profile and slightly improved yields. This may be explained
by the absence of acidic αꢀprotons adjacent to the Nꢀcentered
radical cation that could potentially create undesired side reacꢀ
tions.30 With our best conditions in hand, we screened the
scope of the reaction with primary, secondary and tertiary
alkyl halides and indole 1 (Scheme 3). We were delighted to
find that the reaction works with primary, secondary and terꢀ
tiary alkyl radicals, and is not limited to alkyl iodides but is
also compatible with alkyl bromides, albeit with slightly reꢀ
duced efficiency (~20% lower yields for primary 2a and secꢀ
ondary 2d radicals and 50% with tertiary radicals 2d). The
latter result greatly broadens the availability of commercial
We believe the reaction to proceed via the following proposed
mechanism (Scheme 2): a) excitation of the catalyst ground
state (M) to the excited state (*M), b) electron transfer from
the tertiary amine to (*M) resulting in the formation of a highꢀ
ly reductant iridium species (M–), c) formation of the alkyl
red
radical from the reduction of the carbon halogen bond (E1/2
= ꢀ1.67 V versus SCE for ethyl iodide)30 and completion of the
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alkyl radical precursors, particularly if the corresponding alkyl
cles are depicted and corresponding symbols in Scheme 4.
Interestingly we found that naturally electronꢀdeficient cores
(indole, benzothiazole, isoquinoline, pyrimidine) required
none or a minimum of electronic activation by either the presꢀ
ence of a halogen (Cl atom) or an electronꢀwithdrawing group
(EWG: aldehyde, nitrile, ester) in order to react. In addition,
we found that pyridines were more reluctant to convert and
usually required further activation (EWGs and/or Cl atom).
Furthermore, both halides and EWGs may play a dual role by
electronically activating the heteroarenes and may also serve
as functional handles for subsequent derivatizations. As preꢀ
dicted, when combining conjugate and innate effects, excellent
yields were observed (3 to 9, 59ꢀ81% yields). It is worth notꢀ
ing that higher yield and opposite regioselectivity were obꢀ
tained compared with previous report12 when pyrimidine 6 was
used with iꢀPr radical, emphasizing our hypothesis on attenuꢀ
ated innate reactivity under basic conditions. Remarkably,
pyrrolopyrimidine 7 could be functionalized at C2 and/or C6
with 72% yields overall. In theory, this would allow a mediciꢀ
nal chemist to vary three positions sequentially at C2, C4 and
C6 (coupling reactions) by controlling the reaction conditions.
In addition, combined conjugate and innate effects seem to
prevail against solely innate effects: 7ꢀazaindole 8 was selecꢀ
tively functionalized at C2 versus the electronꢀdeficient C4/C6
with 80% yield. We have also verified that steric hindrance
plays a role in regioselectivity: pyridine 9 was exclusively
functionalized at C6 against C4. Notably, we confirmed that
innate effect could be attenuated when competing with conjuꢀ
gate and halogen orthoꢀdirecting effects without loss of effiꢀ
ciency (10-18, 30ꢀ72% yields). This allowed access to vectors
that are difficult to obtain via classic CꢀH functionalization
reactions (e.g. acidic conditions that are mainly governed by
innate effect regioselectivity). Interestingly, pyridine 10 which
was reported to be unreactive under CꢀH functionalization12
performed well under our reaction conditions giving a mixture
(1:1.1) of C4 (combined innate/halogen orthoꢀdirecting efꢀ
fects) versus C5 (conjugate effect) in 45% yield. Concerning
naturally π electronꢀdeficient pyrimidine 11, innate effect
seems to be more prevalent than conjugate effect (2.7:1 ratio),
however it could be bypassed when competing with the comꢀ
bined conjugate/halogen orthoꢀdirecting effects with an excelꢀ
lent 12.3:1 ratio (12). Remarkably, unprecedented C4 funcꢀ
tionalization of isoquinolines 13 and 14 could be obtained
benefitting from the conjugate effect against innate effect. In
general, isoquinolines are exclusively alkylated at C1 (innate
effect) under acidic conditions.18 Another confirmation of how
steric hindrance plays a role in regioselectivity is observed
when comparing ester isoquinoline 13 (1.7:1, C4/C2 ratio)
versus nitrile isoquinoline 14, (2.9:1 C4/C2 ratio). Pleasingly,
C3 or C5 π electronꢀrich carbons of pyridines 15-17 and inꢀ
dole 18 could be successfully functionalized (30ꢀ72% yield).
This is exceptional because the synergy between the conjugate
and halogen orthoꢀdirecting effects could efficiently override
the innate effect allowing the exploration of a chemical space
which was difficult to access by other means. It is also imꢀ
portant to mention that for highly π electronꢀdeficient systems
(e.g. 15), partial reduction of the chloride atom could be obꢀ
served. This reduction was accentuated when pyridine 15 was
used with the Penn OC Photoreactor M1 (1:1.4, Cl/H ratio,
15a-b) compared to a 2x40W blue LED setup (2.8:1, Cl/H
ratio, 15a-b). We believe that greater light intensity and therꢀ
mal activation may be the major factors with this side reaction.
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iodide is not available. Another advantage of using basic conꢀ
ditions, compared to acidic conditions, allows the introduction
of acidꢀsensitive groups (e.g. oxetanes, Boc carbamates, spiroꢀ
cyclic systems, aldehydes) with great efficiency (2f, 49%; 2h,
64%; 2g, 55%). In addition, we confirmed that yields could be
increased (up to 20%, see 2a, 2d) when the reaction was perꢀ
formed with the Penn OC Photoreactor M139 compared to a
2x40W blue LED setup.
Scheme 3: CꢀH Functionalization of indole 1 using primary,
secondary and tertiary alkyl radicals
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[a] Reaction performed with Et3N using 2x40W blue LEDs. [b] Reaction
performed with HTMP using 2x40W blue LEDs. [c] Reaction performed
with Et3N using Penn OC Photoreactor M1 at maximum light intensity
and ventilation speed. [d] Reaction performed with HTMP using Penn OC
Photoreactor M1 at maximum light intensity and ventilation speed.
Finally, we were interested in evaluating our optimized reacꢀ
tion conditions with a variety of heteroarenes and alkyl ioꢀ
dides. Only a few reports have fully explored the regioꢀ
selectivities of the CꢀH functionalization of heteroarenes under
acidic conditions.12,16,18,21 These reports generally heavily rely
on the innate effect, accentuated by the protonation of the
cores with strong acids. Surprisingly, the regioselectivities for
the CꢀH functionalization of heteroarenes under basic condiꢀ
tions have not been reported. Based on our results, we beꢀ
lieved that under basic conditions, divergent regioselectivities
would be favored by promoting conjugate and halogen orthoꢀ
directing effects and attenuating the innate effect. The alkylaꢀ
tion regioselectivity accounting for predicted innate, conjugate
and halogen orthoꢀdirecting effects for a variety of heterocyꢀ
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groups, including acid sensitive groups, on carbons that are
Page 4 of 9
Scheme 4: CꢀH Functionalization of heteroarenes
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3
4
5
6
7
8
usually not functionalized using existing acidic conditions. In
addition, we found that preꢀactivation of the heteroarenes with
EWGs or Cl atom was needed to increase reactivity and help
with the control of the regioselectivity. These groups also play
a dual role by providing useful functional handles for further
derivatizations. Finally, this highly convergent method utilizes
abundant and commercially available alkyl halides that allow
quick exploration of vector for drug design, rendering this
methodology highly complementary to other CꢀH functionalꢀ
izations that usually require the synthesis of the alkyl radical
precursors (NHP esters, alkyl boronic acids, sulfinates, etc.).
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Scheme 5: Predictive model for regioselectivity
EXPERIMENTAL SECTION
General Information: [Ir(ppy)2(dtbbpy)]PF6 was purchased
from Sigma Aldrich and stored at ꢀ20 °C. All other reactants
were obtained commercially from various suppliers and stored
accordingly. Reactions were done in either the lights setup (2
x 40W, 420 nm Kessil LED A160WE lights, intensity set to
max, color dial completely counterclockwise, Chemglass stir
plate and small desk fan) or the reactor setup (Penn OC reactor
M1, 420 nm). Separations were done using a CombiFlash Rf+
Lumen Automated Flash Chromatography System with 200
mL/min max flow, 200 psi, with integrated ELSD and 200ꢀ
400 nm UV variable wavelength detector and a 40g HP Silica
RediSep Rf gold column. Thin layer chromatography (TLC)
was performed using 250 ꢁm silica gel plates. TLC plates
were visualized using an ultraviolet lamp. Solvents were
evaporated by either Biotage V10 touch or rotary evaporator.
1H NMR and 13C NMR spectra were recorded on a Brunker
400 MHz, 101 MHz spectrometer. Spectra are internally referꢀ
enced to residual solvent signals (CDCl3 δ = 7.26 (1H) and
77.16 (13C) or DMSO δ = 2.50 (1H) and 39.52 (13C)). Data for
1H NMR are reported according to the following conventions:
chemical shift (ppm), multiplicity (s = singlet, d = doublet, t =
triplet, m = multiplet, q = quintet, br = broad, and combinaꢀ
tions thereof), coupling constant J (Hz), integration. Lowꢀ
Resolution Mass Spectrometry analyses were conducted on
Waters Acquity UPLC (Acquity Binary Solvent Manager,
2777CꢀAutosampler, Acquity PDA, Acquity ELS and Acꢀ
quity Column Manager) and Waters Acquity SQ systems
from Waters Corporation, Milford, MA. Signal acquisition
conditions included: Waters Acquity HSS T3, 2.1mmx50mm,
C18, 1.7ꢁm; Column Temperature 60 °C as the column; 0.1%
formic acid in water (v/v) as the mobile phase A; 0.1% formic
acid in acetonitrile (v/v) as the mobile phase B; 1.25mL/min
as the flow and ESCI (ESI+/ꢀ, APCI+/ꢀ), 100ꢀ2000m/z scan,
0.4sec scan time, Centroid as the MS method. High Resolution
[a] Reaction performed for 16 h with HTMP using 2x40W blue LEDs. [b]
Reaction performed for 16 h with HTMP using 2x40W blue LEDs and 2
equiv. of alkyl iodide. [c] Reaction performed for 16 h with HTMP using
Penn OC Photoreactor M1 at maximum light intensity and ventilation
speed. [d] Reaction performed for 72 h with HTMP using 2x40W blue
LEDs.
In order to build confidence on the outcome of the reactions, a
predicted model is depicted within scheme 5. First, it is imꢀ
portant to identify the most prevalent forces that drive regioseꢀ
lectivity such as the innate and conjugate effects. In general,
when both are combined, high selectivity and excellent yields
are obtained. However, when opposed to each other, a mixture
of compounds is often observed that may vary depending on
the nature of the heteroarene used for the reaction (more or
less π electronꢀdeficient). Then, you may consider halogen
orthoꢀdirecting effect that increases reactivity and selectivity
when it is combined with another effect. In addition, steric
effect may also play a role and may help discriminate multiple
possible sites of alkylation.
CONCLUSION
In conclusion, we have developed an unprecedented, mild
photoredox CꢀH functionalization of heteroarenes under basic
conditions. Our method allows the introduction of small alkyl
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Mass spec data was collected on a Thermo QExactive, with an 2-(3-methoxypropyl)-1-methyl-indole-3-carbaldehyde
(2b).
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Orbitrap mass analyzer and with a Waters Acquity UPLC on
the front end. Chromatography was done on a Waters CSH
C18 column, 1.7 um, 2.1x150 mm. Mobile phase A was water
with 0.2% Formic Acid. Mobile phase B was acetonitrile with
0.2% Formic Acid. The gradient began at 2% B, increased to
100% B over 3 min, held for 1 minute at 100% B, followed by
a 1 min reꢀequilibration at 2% B. The flow rate was 0.35
mL/min throughout. Mass spec full scan positive mode was
employed for all samples. The full scan mass resolution was
set to 140,000. UV spectral data was collected from 220 to
350 nm.
Synthesized using Procedure 2, 64% yield, (37.0 mg). 1H
NMR (400 MHz, Chloroformꢀd) δ 10.18 (s, 1H), 8.32 – 8.24
(m, 1H), 7.39 – 7.27 (m, 3H), 3.76 (s, 3H), 3.40 (t, J = 5.8 Hz,
2H), 3.36 (s, 3H), 3.26 – 3.18 (m, 2H), 1.96 (ddt, J= 8.3, 7.3,
5.8 Hz, 2H). 13C NMR (101 MHz, Chloroformꢀd) δ 184.5,
151.2, 137.2, 125.9, 123.3, 123.0, 121.1, 114.3, 109.5, 70.8,
58.8, 30.0, 29.8, 21.1. HRMS (ESI), m/z: calculated for
C14H18NO2 [M+H]+: 232.1338, found: 232.1338.
1-methyl-2-(tetrahydropyran-4-ylmethyl)indole-3-
9
carbaldehyde (2c). Synthesized using Procedure 2, 35% yield
(22.5 mg). H NMR (400 MHz, Chloroformꢀd) δ 10.16 (s,
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1
Procedure 1: 1 equiv. of heteroarene (if solid), 3 equiv. of
1H), 8.36 – 8.20 (m, 1H), 7.33 (m, 3H), 4.04 – 3.87 (m, 2H),
3.77 (s, 3H), 3.44 – 3.22 (m, 2H), 3.17 – 3.01 (m, 2H), 1.95 –
1.83 (m, 1H), 1.66 – 1.58 (m, 2H), 1.57 – 1.42 (m, 2H). 13C
NMR (101 MHz, Chloroformꢀd) δ 184.4, 149.3, 137.2, 125.9,
123.5, 123.2, 121.0, 115.0, 109.6, 67.9 (2C), 36.6, 33.1 (2C),
31.8, 30.3. HRMS (ESI), m/z: calculated for C16H20NO2
[M+H]+: 258.1494, found: 258.1491.
alkyl
halide
(if
solid)
and
2.5
mol%
of
[Ir(ppy)2(dtbbpy)]PF6 were added to a vial (1 dram, ~3.7 mL),
15x45mm, 13ꢀ425 thread with red pressure relief cap
Chemglass vial. The vial was purged for 5 minutes under vacꢀ
uum and was filled with nitrogen gas. Then MeOH (0.5 mL),
3.1 equiv. of Et3N and 1 equiv. of the heteroarene (if liquid)
were successively added under N2 atmosphere. The nitrogen
line was removed and 3 equiv. of alkyl halide (if liquid) was
added. The vial was irradiated under blue LED light and
stirred overnight at room temperature at 1,000 RPM with a
small cooling fan (approx. 16 hours). In addition, NMR yield
can be obtained after the completion of the reaction by adding
to the vial 0.25 equiv. of 1,4ꢀdinitrobenzene and by comparing
the reference peak integration at 8.44 ppm in CDCl3 and one
of the product(s) aromatic peaks. The volatiles were evapoꢀ
rated using a V10 Biotage system. If the resulting product
contains one or several basic nitrogens, a basic workup is reꢀ
quired using partition between a saturated solution of sodium
bicarbonate and DCM, otherwise, the crude mixture was loadꢀ
ed onto a 40g gold ISCO column using Hexane/Ethyl Acetate
(100:0 to 0:100) as eluents to yield desired product(s).
2-isopropyl-1-methyl-indole-3-carbaldehyde (2d). Synthesized
1
using Procedure 4, 91% yield (45.8 mg). H NMR (400 MHz,
Chloroformꢀd) δ 10.38 (s, 1H), 8.35 (dd, J = 6.2, 2.7 Hz, 1H),
7.33 – 7.27 (m, 3H), 3.81 (s, 3H), 3.73 (hept., J = 7.4 Hz, 1H),
1.55 (d, J = 7.2, 6H). 13C NMR (101 MHz, Chloroformꢀd) δ
184.7, 156.3, 137.2, 126.2, 123.3, 123.1, 121.7, 113.7, 109.4,
31.1, 26.2, 22.6 (2C). HRMS (ESI), m/z: calculated for
C13H16NO [M+H]+: 202.1232, found: 202.1231.
2-cyclopropyl-1-methyl-indole-3-carbaldehyde (2e). Syntheꢀ
1
sized using Procedure 2, 23% yield (11.4 mg). H NMR (400
MHz, Chloroformꢀd) δ 10.43 (s, 1H), 8.41 – 8.25 (m, 1H),
7.35 – 7.20 (m, 3H), 3.88 (s, 3H), 2.01 (tt, J = 8.4, 5.6 Hz,
1H), 1.36 – 1.16 (m, 2H), 1.07 – 0.84 (m, 2H). 13C NMR (101
MHz, Chloroformꢀd) δ 185.7, 151.6, 136.8, 125.2, 123.7,
123.2, 122.2, 115.6, 109.3, 30.7, 6.6 (2C), 6.1. HRMS (ESI),
m/z: calculated for C13H14NO [M+H]+: 200.1075, found:
200.1075.
Procedure 2: Same as Procedure 1, however HTMP (3.1
equiv.) was used instead of Et3N.
Procedure 3: Same as Procedure 1, however the Penn OC M1
photoreactor (setup 2) was used instead of irradiation by blue
LED lights (setup 1). The photoreactor was set to max LED
light (100%), max stir speed (2,000RPM), and max fan speed
(5,200RPM).
1-methyl-2-(oxetan-3-yl)indole-3-carbaldehyde (2f). Syntheꢀ
1
sized using Procedure 2, 49% yield (26.3 mg). H NMR (400
MHz, Chloroformꢀd) δ 10.19 (s, 1H), 8.33 – 8.23 (m, 1H),
7.37 – 7.27 (m, 3H), 5.25 – 5.17 (m, 2H), 5.04 – 4.93 (m, 3H),
3.83 (s, 3H). 13C NMR (101 MHz, Chloroformꢀd) δ 184.1,
147.7, 137.4, 126.1, 123.9, 123.3, 121.1, 114.8, 109.6, 76.5
(2C), 32.6, 30.9. HRMS (ESI), m/z: calculated for C13H14NO2
[M+H]+: 216.1025, found: 216.1027.
Procedure 4: Same as Procedure 1, however HTMP (3.1
equiv.) was used instead of Et3N and the photoreactor (setup
2) was used instead of the lights (setup 1). The photoreactor
was set to max LED light (100%), max stir speed
(2,000RPM), and max fan speed (5,200RPM).
Tert-butyl-3-(3-formyl-1-methyl-indol-2-yl)azetidine-1-
carboxylate (2g). Synthesized using Procedure 1, 55% yield
1
Procedure 5: Same as Procedure 1, however HTMP (3.1
equiv.) was used instead of Et3N and 2 equiv. of alkyl halide
was used instead of 3 equiv.
(43.2 mg). H NMR (400 MHz, Chloroformꢀd) δ 10.22 (s,
1H), 8.28 – 8.12 (m, 1H), 7.35 – 7.20 (m, 3H), 4.59 – 4.35 (m,
3H), 4.26 – 4.15 (m, 2H), 3.79 (s, 3H), 1.42 (s, 9H). 13C NMR
(101 MHz, Chloroformꢀd) δ 184.1, 156.2, 148.0, 137.3, 126.0,
123.9, 123.3, 121.1, 115.0, 109.6, 80.4, 30.9, 56.0ꢀ55.0 (broad,
2C) 28.4 (3C), 25.3. HRMS (ESI), m/z: calculated for
C18H23N2O3 [M+H]+: 315.1709, found: 315.1708.
Procedure 6: Same as Procedure 1, however HTMP (3.1
equiv.) was used instead of Et3N and the reaction was ran for 3
days instead of 16 hours.
Compound Characterizations
1-methyl-2-(2-oxaspiro[3.3]heptan-6-yl)indole-3-
2-ethyl-1-methyl-indole-3-carbaldehyde (2a). Synthesized
carbaldehyde (2h). Synthesized using Procedure 2, 64% yield
1
using procedure 4, 70% yield (32.8 mg). H NMR (400 MHz,
1
(40.8 mg). H NMR (400 MHz, Chloroformꢀd) δ 10.10 (s,
Chloroformꢀd) δ 10.14 (s, 1H), 8.24 – 8.22 (m, 1H), 7.28 –
7.22 (m, 3H), 3.70 (s, 3H), 3.09 (q, J = 7.6 Hz, 2H), 1.30 (t, J
= 7.6 Hz, 3H). 13C NMR (101 MHz, DMSOꢀd6) δ 184.0,
154.2, 136.9, 125.0, 122.7, 122.4, 120.1, 112.4, 110.4, 29.6,
17.0, 14.7.HRMS (ESI), m/z: calculated for C12H14NO
[M+H]+: 188.1075, found: 188.1073.
1H), 8.29 – 8.17 (m, 1H), 7.27 – 7.12 (m, 3H), 4.82 (s, 2H),
4.58 (s, 2H), 3.69 – 3.59 (m, 1H), 3.57 (s, 3H), 2.90 – 2.75 (m,
2H), 2.70 – 2.56 (m, 2H). 13C NMR (101 MHz, Chloroformꢀd)
δ 184.6, 152.3, 137.0, 126.1, 123.5, 123.0, 121.6, 114.8, 109.3,
84.3, 82.0, 40.9, 40.0 (2C), 30.9, 27.6. HRMS (ESI), m/z:
calculated for C16H18NO2 [M+H]+: 256.1338, found 256.1341.
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The Journal of Organic Chemistry
1-methyl-2-tetrahydropyran-4-yl-indole-3-carbaldehyde (2i).
Page 6 of 9
Methyl 2-isopropylpyrimidine-5-carboxylate and Methyl 4-
isopropylpyrimidine-5-carboxylate (6a-b). Synthesized using
Procedure 5, inseparable by column chromatography, 51%
yield (23.0 mg). Cꢀ2:Cꢀ4 (1.4:1). 1H NMR (400 MHz, Chloroꢀ
formꢀd) Major: δ 9.18 (s, 2H), 3.95 (s, 3H), 3.28 (hept, J = 6.9
Hz, 1H), 1.35 (d, J = 6.9 Hz, 6H). Minor: δ 9.20 (s, 1H), 9.04
(s, 1H), 3.94 (s, 3H), 3.88 (hept, J = 6.7 Hz, 1H), 1.28 (d, J =
6.8 Hz, 6H). 13C NMR (101 MHz, Chloroformꢀd) Major: δ
179.3, 164.6 (2C), 158.3, 121.4, 52.6, 38.1, 21.66 (2C). Minor:
δ 176.4, 165.6, 160.3, 158.5, 123.1, 52.8, 32.3, 21.71 (2C).
HRMS (ESI), m/z: calculated for C9H13N2O2 [M+H]+:
181.0977, found: 181.0975.
Synthesized using Procedure 2, 75% yield (45.6 mg). 1H NMR
(400 MHz, Chloroformꢀd) δ 10.34 (s, 1H), 8.34 – 8.23 (m,
1H), 7.28 – 7.18 (m, 3H), 4.24 – 4.02 (m, 2H), 3.76 (s, 3H),
3.59 – 3.43 (m, 3H), 2.38 – 2.16 (m, 2H).1.79 – 1.70 (m, 2H).
13C NMR (101 MHz, Chloroformꢀd) δ 184.5, 152.3, 137.1,
126.1, 123.5, 123.1, 121.4, 114.1, 109.6, 68.5 (2C), 34.3 (2C),
32.1, 31.3. HRMS (ESI), m/z: calculated for C15H18NO2
[M+H]+: 244.1338, found: 244.1336.
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2-cyclohexyl-1-methyl-indole-3-carbaldehyde (2j). Syntheꢀ
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sized using Procedure 1, 67% yield (40.4 mg). H NMR (400
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MHz, Chloroformꢀd) δ 10.40 (s, 1H), 8.52 – 8.25 (m, 1H),
7.29 – 7.09 (m, 3H), 3.76 (s, 3H), 3.24 – 3.13 (m, 1H), 2.02 –
1.88 (m, 4H), 1.84 (m, 2H), 1.50 – 1.28 (m, 4H). 13C NMR
(101 MHz, Chloroformꢀd) δ 184.9, 155.4, 137.0, 126.2, 123.3,
123.0, 121.8, 114.1, 109.5, 37.5, 33.0, 31.1, 27.1 (2C), 25.9
(2C). HRMS (ESI), m/z: calculated for C16H20NO [M+H]+:
242.1545, found: 242.1545.
Methyl 2,4-diisopropylpyrimidine-5-carboxylate (6c). Syntheꢀ
sized using Procedure 5, 24% yield (13.3 mg). H NMR (400
1
MHz, Chloroformꢀd) δ 8.98 (s, 1H), 3.92 (s, 3H), 3.87 (hept, J
= 6.8 Hz, 1H), 3.21 (hept, J = 6.9 Hz, 1H), 1.33 (d, J = 6.9 Hz,
6H), 1.27 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz, Chloroꢀ
formꢀd) δ 177.4, 176.2, 166.1, 151.2, 119.9, 52.5, 37.9, 32.4,
21.73 (2C), 21.65 (2C). HRMS (ESI), m/z: calculated for
C12H19N2O2 [M+H]+: 223.1441, found: 223.1444.
2-tert-butyl-1-methyl-indole-3-carbaldehyde (2k).
Syntheꢀ
1
sized using Procedure 3, 17% yield (9.1 mg). H NMR (400
MHz, Chloroformꢀd) δ 10.68 (s, 1H), 8.57 – 8.51 (m, 1H),
7.34 – 7.27 (m, 3H), 3.97 (s, 3H), 1.71 (s, 9H). 13C NMR (101
MHz, Chloroformꢀd) δ 188.4, 156.1, 138.0, 126.5, 123.6,
123.2, 123.0, 116.0, 109.0, 35.9, 34.1, 32.2 (3C). HRMS (ESI)
failed after multiple attempts, LCMS was used instead, m/z:
calculated for C14H18NO [M+H]+: 216.1, found: 216.5.
Methyl 2-tetrahydropyran-4-ylpyrimidine-5-carboxylate and
methyl 4-tetrahydropyran-4-ylpyrimidine-5-carboxylate (6d-
e). Synthesized using procedure 5, inseparable by column
1
chromatography, 44% yield (24.4 mg), Cꢀ4:Cꢀ2 (1.8:1). H
NMR (400 MHz, Chloroformꢀd) Major: δ 9.23 (s, 1H), 9.11
(s, 1H), 4.08 (m, 2H), 3.96 (s, 3H), 3.86 (tt, J = 11.7, 3.9 Hz,
1H), 3.62 – 3.49 (m, 2H), 2.14 – 1.91 (m, 3H), 1.75 – 1.66 (m,
1H). Minor: δ 9.21 (s, 2H), 4.08 (m, 2H), 3.96 (s, 3H), 3.62 –
3.49 (m, 2H), 3.20 (tt, J = 10.5, 4.7 Hz, 1H), 2.14 – 1.91 (m,
3H), 1.75 – 1.66 (m, 1H). 13C NMR (101 MHz, Chloroformꢀd)
Major: δ 173.7, 165.2, 160.4, 158.7, 123.0, 67.9 (2C), 52.9,
39.9, 31.25 (2C). Minor: δ 176.2, 164.5, 158.3, 121.4, 67.8
(2C), 52.7, 44.6 31.27 (2C). HRMS (ESI), m/z: calculated for
C11H15N2O3 [M+H]+: 223.1083, found: 223.1077.
2-(1-adamantyl)-1-methyl-indole-3-carbaldehyde (2l). Syntheꢀ
1
sized using Procedure 2, 85% yield (62.3 mg). H NMR (400
MHz, Chloroformꢀd) δ 10.73 (s, 1H), 8.57 – 8.50 (m, 1H),
7.32 – 7.27 (m, 3H), 4.05 (s, 3H), 2.41 – 2.35 (m, 6H), 2.25 –
2.17 (m, 3H), 1.89 – 1.83 (m, 6H). 13C NMR (101 MHz, Chloꢀ
roformꢀd) δ 188.9, 155.8, 138.0, 126.6, 123.4, 123.0, 122.8,
116.2, 109.0, 42.4 (3C), 39.4, 36.4 (3C), 34.7, 28.5 (3C).
HRMS (ESI), m/z: calculated for C20H24NO [M+H]+:
294.1858, found: 294.1859.
Methyl 2,4-di(tetrahydropyran-4-yl)pyrimidine-5-carboxylate
1
(6f). Synthesized using procedure 5, 21% yield (16.1 mg). H
Methyl 2-isopropyl-1-methyl-indole-3-carboxylate (3). Synꢀ
1
NMR (400 MHz, Chloroformꢀd) δ 9.11 (s, 1H), 4.16 – 4.05
(m, 4H), 3.95 (s, 3H), 3.93 – 3.85 (m, 1H), 3.59 (td, J = 11.3,
2.2 Hz, 4H), 3.20 (tt, J = 11.6, 4.3 Hz, 1H), 2.16 – 1.99 (m,
4H), 1.96 (t, J = 7.9 Hz, 2H), 1.76 – 1.67 (m, 2H). 13C NMR
(101 MHz, Chloroformꢀd) δ 174.8, 174.0, 165.0, 158.2, 120.5,
67.9 (2C), 67.7 (2C), 52.8, 43.8, 39.9, 31.2 (2C), 31.1 (2C).
HRMS (ESI), m/z: calculated for C16H23N2O4 [M+H]+:
307.1652 found: 307.1652.
thesized using procedure 4, 64% yield (37.0 mg). H NMR
(400 MHz, Chloroformꢀd) δ 8.14 – 8.06 (m, 1H), 7.34 – 7.28
(m, 1H), 7.26 – 7.19 (m, 2H), 4.44 (hept, J = 7.3 Hz, 1H), 3.93
(s, 3H), 3.84 (s, 3H), 1.47 (d, J = 7.3 Hz, 6H). 13C NMR (101
MHz, Chloroformꢀd) δ 166.6, 153.8, 137.0, 126.7, 122.3,
121.9, 121.8, 109.2, 103.1, 50.9, 31.7, 25.2, 20.3 (2C). HRMS
(ESI), m/z: calculated for C14H18NO2 [M+H]+: 232.1338,
found: 232.1335.
4-chloro-6-isopropyl-7-methyl-pyrrolo[2,3-d]pyrimidine (7a).
Synthesized using Procedure 6, 27% yield (14.1 mg). 1H NMR
(400 MHz, Chloroformꢀd) δ 8.57 (s, 1H), 6.34 (s, 1H), 3.82 (s,
2-isopropyl-1H-indole-3-carbaldehyde (4). Synthesized using
procedure 4, 79% (from NꢀAc, 37.0 mg), 81% (from NꢀH,
37.9 mg). 1H NMR (400 MHz, Chloroformꢀd) δ 10.27 (s, 1H),
8.53 (s, 1H), 8.35 – 8.19 (m, 1H), 7.48 – 7.32 (m, 1H), 7.33 –
7.19 (m, 2H), 3.82 (hept, J = 7.0 Hz, 1H), 1.46 (d, J = 7.0 Hz,
6H). 13C NMR (101 MHz, Chloroformꢀd) δ 184.4, 156.1,
134.8, 126.3, 123.6, 123.0, 121.3, 113.2, 111.0, 26.0, 22.8
(2C). HRMS (ESI), m/z: calculated for C12H14NO [M+H]+:
188.1075, found: 188.1074.
3H), 3.12 (hept, J = 6.8 Hz, 1H), 1.38 (d, J = 6.8 Hz, 6H). 13
C
NMR (101 MHz, Chloroformꢀd) δ 152.3, 150.5, 150.2, 149.9,
117.5, 94.2, 28.8, 26.3, 22.2 (2C). HRMS (ESI), m/z: calculatꢀ
ed for C10H13ClN3 [M+H]+: 210.0793, found: 210.0794.
4-chloro-2-isopropyl-7-methyl-pyrrolo[2,3-d]pyrimidine (7b).
Synthesized using Procedure 6, 24% yield (12.5 mg). 1H NMR
(400 MHz, Chloroformꢀd) δ 7.11 (d, J = 3.5 Hz, 1H), 6.52 (d,
J = 3.5 Hz, 1H), 3.86 (s, 3H), 3.25 (hept, J = 6.9 Hz, 1H), 1.38
(d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, Chloroformꢀd) δ
168.7, 152.2, 151.9, 129.3, 115.1, 99.2, 37.5, 31.5, 22.2 (2C).
HRMS (ESI), m/z: calculated for C10H13ClN3 [M+H]+:
210.0793, found: 210.0795.
2-isopropyl-1,3-benzothiazole (5). Synthesized using Proceꢀ
1
dure 4, 72% yield (31.9 mg). H NMR (400 MHz, Chloroꢀ
formꢀd) δ 7.98 (dd, J = 8.2, 1.2 Hz, 1H), 7.85 (dd, J = 8.0, 1.3
Hz, 1H), 7.45 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.34 (ddd, J =
8.3, 7.3, 1.2 Hz, 1H), 3.43 (hept, J = 6.9 Hz, 1H), 1.48 (d, J =
6.9 Hz, 6H). 13C NMR (101 MHz, Chloroformꢀd) δ 178.7,
153.3, 134.8, 126.0, 124.7, 122.7, 121.7, 34.2, 23.1 (2C).
HRMS (ESI), m/z: calculated for C10H12NS [M+H]+:
178.0690, found: 178.0687.
4-chloro-2,6-diisopropyl-7-methyl-pyrrolo[2,3-d]pyrimidine
1
(7c). Synthesized using Procedure 6, 21% yield (13.2 mg). H
NMR (400 MHz, Chloroformꢀd) δ 6.26 (s, 1H), 3.80 (s, 3H),
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The Journal of Organic Chemistry
3.23 (hept, J = 6.9 Hz, 1H), 3.09 (hept, J = 6.8 Hz, 1H), 1.38
formꢀd) Major: δ 162.8, 161.5, 154.2, 142.1, 106.0, 53.8, 29.2,
21.7 (2C). Minor peaks are too similar to noise. HRMS (ESI),
m/z: calculated for C9H12ClN2O2 [M+H]+: 215.0587, found:
215.0582.
(d, J = 6.9 Hz, 6H), 1.37 (d, J = 6.7 Hz, 6H). 13C NMR (101
MHz, Chloroformꢀd) δ 167.7, 153.1, 150.3, 149.2, 115.0, 93.7,
37.5, 28.6, 26.2, 22.28 (2C), 22.27 (2C). HRMS (ESI), m/z:
calculated for C13H19ClN3 [M+H]+: 252.1262, found:
252.1261.
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Methyl 4-ethylisoquinoline-3-carboxylate (13a). Synthesized
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using Procedure 6, 19% yield (10.2 mg). H NMR (400 MHz,
2-isopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde
(8).
Chloroformꢀd) δ 9.17 (s, 1H), 8.25 – 8.14 (m, 1H), 8.12 – 7.96
(m, 1H), 7.87 – 7.76 (m, 1H), 7.76 – 7.65 (m, 1H), 4.04 (s,
3H), 3.38 (q, J = 7.5 Hz, 2H), 1.40 (t, J = 7.5 Hz, 3H). 13C
NMR (101 MHz, Chloroformꢀd) δ 167.6, 150.6, 140.5, 136.7,
135.2, 131.1, 129.5, 128.7, 128.5, 124.3, 52.9, 21.6, 15.5.
HRMS (ESI), m/z: calculated for C13H14NO2 [M+H]+:
216.1019, found: 216.1018.
Synthesized using Procedure 5, used DCM/EtOAc (100:0 to
0:100) as eluents rather than Hexane/EtOAc with the same
1
gradient, 80% yield (37.6 mg). H NMR (400 MHz, Chloroꢀ
9
formꢀd) δ 12.68 (s, 1H), 10.30 (s, 1H), 8.66 (dd, J = 7.8, 1.6
Hz, 1H), 8.45 (dd, J = 4.9, 1.3 Hz, 1H), 7.32 (dd, J = 7.8, 4.9
Hz, 1H), 3.91 (hept, J = 7.0 Hz, 1H), 1.62 (d, J = 7.0 Hz, 6H).
13C NMR (101 MHz, Chloroformꢀd) δ 184.3, 158.1, 148.8,
143.3, 130.7, 119.7, 118.8, 111.7, 26.2, 23.0 (2C). HRMS
(ESI), m/z: calculated for C11H13N2O [M+H]+: 189.1028,
found: 189.1021.
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Methyl 1-ethylisoquinoline-3-carboxylate (13b). Synthesized
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using Procedure 6, 11% yield (5.9 mg). H NMR (400 MHz,
Chloroformꢀd) δ 8.45 (s, 1H), 8.28 – 8.19 (m, 1H), 8.00 – 7.92
(m, 1H), 7.82 – 7.67 (m, 2H), 4.05 (s, 3H), 3.42 (q, J = 7.6 Hz,
2H), 1.46 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, Chloroꢀ
formꢀd) δ 166.8, 164.3, 140.7, 136.1, 130.6, 129.4, 129.1,
128.2, 125.7, 123.1, 53.01, 29.2, 14.4. HRMS (ESI), m/z: calꢀ
culated for C13H14NO2 [M+H]+: 216.1019, found: 216.1019.
Methyl 2-chloro-6-isopropyl-pyridine-3-carboxylate (9). Synꢀ
thesized using Procedure 2, 59% yield (31.4 mg). 1H NMR
(400 MHz, Chloroformꢀd) δ 8.09 (d, J = 7.9 Hz, 1H), 7.16 (d,
J = 7.9 Hz, 1H), 3.92 (s, 3H), 3.07 (hept, J = 6.9 Hz, 1H), 1.29
(d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, Chloroformꢀd) δ
171.5, 165.2, 149.5, 141.0, 123.8, 119.0, 52.8, 36.3, 22.2 (2C).
HRMS (ESI), m/z: calculated for C10H12ClNO2 [M+H]+:
214.0635, found: 214.0629.
4-ethylisoquinoline-3-carbonitrile (14a). Synthesized using
1
Procedure 2, 26% yield (23.7 mg). H NMR (400 MHz, Chloꢀ
roformꢀd) δ 9.14 (s, 1H), 8.18 – 8.10 (m, 1H), 8.08 – 8.03 (m,
1H), 7.92 – 7.85 (m, 1H), 7.82 – 7.72 (m, 1H), 3.34 (q, J = 7.6
Hz, 2H), 1.42 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, Chloꢀ
roformꢀd) δ 152.3, 141.6, 133.7, 131.9, 129.9, 129.5, 128.9,
126.3, 123.9, 117.6, 23.3, 15.3. HRMS (ESI), m/z: calculated
for C12H11N2 [M+H]+: 183.0917, found: 183.0917.
3-chloro-5-isopropyl-pyridine-2-carbonitrile (10a). Syntheꢀ
1
sized using Procedure 2, 24% yield (10.8 mg). H NMR (400
MHz, Chloroformꢀd) δ 8.47 (d, J = 2.0 Hz, 1H), 7.68 (d, J =
1.9 Hz, 1H), 3.03 (hept, J = 6.9 Hz, 1H), 1.31 (d, J = 6.9 Hz,
6H). 13C NMR (101 MHz, Chloroformꢀd) δ 149.5, 148.2,
135.9, 135.2, 130.7, 115.1, 32.0, 23.3 (2C). HRMS (ESI), m/z:
calculated for C9H10ClN2 [M+H]+: 181.0533, found: 181.0529.
1-ethylisoquinoline-3-carbonitrile (14b). Synthesized using
1
Procedure 2, 9% yield (4.1 mg). H NMR (400 MHz, Chloroꢀ
formꢀd) δ 8.29 – 8.19 (m, 1H), 8.01 (s, 1H), 7.96 – 7.86 (m,
1H), 7.84 – 7.73 (m, 2H), 3.35 (q, J = 7.6 Hz, 2H), 1.45 (t, J =
7.5 Hz, 3H). 13C NMR (101 MHz, Chloroformꢀd) δ 165.5,
135.1, 131.4, 130.3, 128.1, 127.9, 126.5, 126.2, 125.7, 118.6,
28.6, 13.3. HRMS (ESI), m/z: calculated for C12H11N2
[M+H]+: 183.0917, found: 183.0917.
3-chloro-4-isopropyl-pyridine-2-carbonitrile (10b). Syntheꢀ
1
sized using Procedure 2, 21% yield (9.5 mg). H NMR (400
MHz, Chloroformꢀd) δ 8.52 (d, J = 5.0 Hz, 1H), 7.43 (d, J =
5.0 Hz, 1H), 3.42 (hept, J = 6.9 Hz, 1H), 1.29 (d, J = 6.9 Hz,
6H). 13C NMR (101 MHz, Chloroformꢀd) δ 156.7, 148.9,
135.3, 133.8, 124.8, 115.4, 30.6, 21.8 (2C). HRMS (ESI), m/z:
calculated for C9H10ClN2 [M+H]+: 181.0533, found: 181.0529.
Methyl 4,6-dichloro-5-isopropyl-pyridine-2-carboxylate (15a).
Synthesized using Procedure 2, 37% yield (22.9 mg). 1H NMR
(400 MHz, Chloroformꢀd) δ 8.02 (s, 1H), 3.98 (s, 3H), 3.88
(hept, J = 7.2 Hz, 1H), 1.43 (d, J = 7.2 Hz, 6H). 13C NMR
(101 MHz, Chloroformꢀd) δ 163.9, 146.4, 145.4, 143.0, 127.8,
124.7, 53.4, 30.0ꢀ31.5 (broad), 19.0 (2C). HRMS (ESI), m/z:
calculated for C10H12Cl2NO2 [M+H]+: 248.0245, found:
248.0239.
Methyl 5-isopropylpyrimidine-2-carboxylate (11a). Syntheꢀ
1
sized using Procedure 2, 40% yield (18.0 mg). H NMR (400
MHz, Chloroformꢀd) δ 8.98 – 8.63 (m, 1H), 7.42 – 7.29 (m,
1H), 4.04 (s, 3H), 3.16 (hept, J = 6.9 Hz, 1H), 1.33 (d, J = 6.9
Hz, 6H). 13C NMR (101 MHz, Chloroformꢀd) δ 177.5, 164.4,
157.7, 156.3, 119.9, 53.6, 36.3, 21.9 (2C). HRMS (ESI), m/z:
calculated for C9H13N2O2 [M+H]+: 181.0977, found: 181.0974.
Methyl 6-chloro-5-isopropyl-pyridine-2-carboxylate (15b).
Synthesized using Procedure 4, 39% yield (20.8 mg). 1H NMR
(400 MHz, Chloroformꢀd) δ 8.04 (d, J = 7.9 Hz, 1H), 7.75 (d,
J = 7.9 Hz, 1H), 3.99 (s, 3H), 3.41 (hept., J = 6.9 Hz, 1H),
1.29 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, Chloroformꢀd)
δ 164.8, 151.0, 146.7, 145.5, 136.2, 124.4, 53.2, 30.6, 22.2
(2C). HRMS (ESI), m/z: calculated for C10H13ClNO2 [M+H]+:
214.0635, found: 214.0627.
Methyl 4-isopropylpyrimidine-2-carboxylate (11b). Syntheꢀ
1
sized using procedure 2, 15% yield (6.8 mg). H NMR (400
MHz, Chloroformꢀd) δ 8.78 (s, 2H), 4.06 (s, 3H), 3.04 (hept, J
= 7.0 Hz, 1H), 1.35 (d, J = 7.0 Hz, 6H). 13C NMR (101 MHz,
Chloroformꢀd) δ 163.6, 156.2 (2C), 154.1, 143.5, 53.6, 30.0,
23.5 (2C). HRMS (ESI), m/z: calculated for C9H13N2O2
[M+H]+: 181.0977, found: 181.0975.
Methyl 4-chloro-5-isopropyl-pyrimidine-2-carboxylate and
methyl 4-chloro-6-isopropyl-pyrimidine-2-carboxylate (12a-
b). Synthesized using procedure 2, Inseparable by column
6-chloro-5-isopropyl-3-methyl-pyridine-2-carbonitrile (16a).
Synthesized using procedure 2, 60% yield (29.2 mg). 1H NMR
(400 MHz, Chloroformꢀd) δ 7.55 (s, 1H), 3.35 (hept, J = 6.9
Hz, 1H), 2.53 (s, 3H), 1.27 (d, J = 6.9 Hz, 6H). 13C NMR (101
MHz, Chloroformꢀd) δ 149.3, 146.8, 138.1, 137.5, 130.4,
115.6, 30.5, 22.2 (2C), 18.3. HRMS (ESI), m/z: calculated for
C10H12ClN2 [M+H]+: 195.0689, found 195.0684.
1
chromatography, 32% yield (17.1 mg), Cꢀ5:Cꢀ6 (12.3:1). H
NMR (400 MHz, Chloroformꢀd) Major: δ 8.72 (s, 1H), 4.03
(s, 3H), 3.35 (hept, J = 6.9 Hz, 1H), 1.34 (d, J = 7.0 Hz, 6H).
Minor: δ 6.69 (s, 1H), 3.99 (s, 3H), 3.05 (hept, J = 6.9 Hz,
1H), 1.27 (d, J = 7.0 Hz, 6H). 13C NMR (101 MHz, Chloroꢀ
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Functionalization of Drugꢀlike Molecules. Chem. Soc. Rev.
2016, 45, 546–576.
6-chloro-5-ethyl-3-methylpicolinonitrile and 6-chloro-4-ethyl-
1
2
3
4
5
6
7
8
3-methylpicolinonitrile (16b-c). Synthesized using procedure
1
2, 42% yield (19.0 mg), Cꢀ5:Cꢀ4 (7:1). H NMR (400 MHz,
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Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. CꢀH Bond
Functionalization: Emerging Synthetic Tools for Natural
Products and Pharmaceuticals. Angew. Chem. Int. Ed. 2012, 51,
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Taylor, A. P.; Robinson, R. P.; Fobian, Y. M.; Blakemore, D.
C.; Jones, L. H.; Fadeyi, O. Modern Advances in Heterocyclic
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Schönherr, H.; Cernak, T. Profound Methyl Effects in Drug
Discovery and a Call for New C-H Methylation Reactions.
Angew. Chem. Int. Ed. 2013, 52, 12256–12267.
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of Heteroarenes via RedoxꢀNeutral Radical Process: A Facile
Route to C–C Bonds Formation. Synthesis 2017, 49, 3407–3421.
GutiérrezꢀBonet, Á.; Remeur, C.; Matsui, J. K.; Molander, G. A.
LateꢀStage C–H Alkylation of Heterocycles and 1,4ꢀQuinones
via Oxidative Homolysis of 1,4ꢀDihydropyridines. J. Am. Chem.
Soc. 2017, 139, 12251–12258.
Nuhant, P.; Oderinde, M. S.; Genovino, J.; Juneau, A.; Gagné,
Y.; Allais, C.; Chinigo, G. M.; Choi, C.; Sach, N. W.; Bernier,
L.; Fobian, Y. M.; Bundesmann, M. W.; Khunte, B.; Frenette,
M.; Fadeyi, O. O. VisibleꢀLightꢀInitiated Manganese Catalysis
for C−H Alkylation of Heteroarenes: Applications and
Mechanistic Studies. Angew. Chem. Int. Ed. 2017, 56, 15309–
15313.
McCallum, T.; Barriault, L. Direct Alkylation of Heteroarenes
with Unactivated Bromoalkanes Using Photoredox Gold
Catalysis. Chem. Sci. 2016, 7, 4754–4758.
Jin, J.; MacMillan, D. W. C. Alcohols as Alkylating Agents in
Heteroarene C–H Functionalization. Nature 2015, 525, 87–90.
Sherwood, T. C.; Li, N.; Yazdani, A. N.; Dhar, T. G. M.
Organocatalyzed, VisibleꢀLight PhotoredoxꢀMediated, OneꢀPot
Minisci Reaction Using Carboxylic Acids via Nꢀ
(Acyloxy)Phthalimides. J. Org. Chem. 2018, 83, 3000–3012.
O’Hara, F.; Blackmond, D. G.; Baran, P. S.; O’Hara, F.;
Blackmond, D. G.; Baran, P. S. RadicalꢀBased Regioselective
CꢀH Functionalization of ElectronꢀDeficient Heteroarenes:
Scope, Tunability, and Predictability. J. Am. Chem. Soc. 2013,
135, 12122–12134.
Chloroformꢀd) Major: δ 7.52 (s, 1H), 2.78 (q, J = 7.5, 2H),
2.52 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H). Minor: δ 7.33 (s, 1H),
2.68 (q, J = 7.5 Hz, 2H), 2.49 (s, 3H), 1.27 (t, J = 7.5 Hz,
3H).13C NMR (101 MHz, Chloroformꢀd) Major: δ 149.7,
142.6, 139.7, 138.0, 130.5, 115.6, 26.5, 18.1, 13.1. Minor: δ
156.6, 150.1, 136.4, 133.3 (peak is not visible in 13C however
it was seen by 2D NMR (COESY, HMBC, HMQC)), 126.8,
115.9, 26.1, 15.3, 12.8. HRMS (ESI), m/z: calculated for
C9H10ClN2 [M+H]+: 181.0533, found: 181.0529.
(5)
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10
11
12
13
14
15
16
17
18
19
20
21
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23
24
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28
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30
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Methyl 2-cyano-5-isopropyl-pyridine-4-carboxylate (17). Synꢀ
1
thesized using Procedure 2, 30% yield (15.3 mg). H NMR
(400 MHz, Chloroformꢀd) δ 8.81 (s, 1H), 7.93 (s, 1H), 3.96 (s,
3H), 3.74 (hept, J = 7.0 Hz, 1H), 1.33 (d, J = 6.9 Hz, 6H). 13
C
NMR (101 MHz, Chloroformꢀd) δ 165.3, 151.2, 147.4, 137.6,
131.6, 127.8, 116.9, 53.2, 28.8, 23.3 (2C). HRMS (ESI), m/z:
calculated for C11H13N2O2 [M+H]+: 205.0977, found
205.0970.
(8)
3-isopropyl-1-methyl-indole-2-carbaldehyde (18a). Syntheꢀ
1
sized using procedure 4, 72% yield (36.2 mg). H NMR (400
MHz, Chloroformꢀd) δ 10.23 (s, 1H), 7.95 – 7.84 (m, 1H),
7.48 – 7.31 (m, 2H), 7.18 – 7.04 (m, 1H), 4.05 (s, 3H), 3.75
(hept, J = 7.0 Hz, 1H), 1.54 (d, J = 7.1 Hz, 6H). 13C NMR
(101 MHz, Chloroformꢀd) δ 181.9, 140.3, 137.2, 130.2, 127.0,
124.8, 123.3, 120.0, 110.6, 31.8, 25.7, 24.3 (2C). HRMS
(ESI), m/z: calculated for C13H16NO [M+H]+: 202.1232,
found: 202.1229.
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3-tetrahydropyran-4-yl-1-methyl-indole-2-carbaldehyde
(18b). Synthesized using procedure 4, 50% yield (30.4 mg).
1H NMR (400 MHz, Chloroformꢀd) δ 10.27 (s, 1H), 8.00 –
7.83 (m, 1H), 7.50 – 7.32 (m, 2H), 7.20 – 7.07 (m, 1H), 4.23 –
4.10 (m, 2H), 4.06 (s, 3H), 3.70 – 3.49 (m, 3H), 2.53 – 2.26
(m, 2H), 1.86 – 1.74 (m, 2H). 13C NMR (101 MHz, Chloroꢀ
formꢀd) δ 181.5, 140.1, 133.6, 130.4, 127.0, 124.9, 123.1,
120.3, 110.7, 68.7 (2C), 33.7 (2C), 33.4, 31.7. HRMS (ESI),
m/z: calculated for C15H18NO2 [M+H]+: 244.1334, found:
244.1334.
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Galloway, J. D.; Mai, D. N.; Baxter, R. D. SilverꢀCatalyzed
Minisci Reactions Using Selectfluor as a Mild Oxidant. Org.
Lett. 2017, 19, 5772–5775.
GarzaꢀSanchez, R. A.; TlahuextꢀAca, A.; Tavakoli, G.; Glorius,
F. Visible LightꢀMediated Direct Decarboxylative C–H
Functionalization of Heteroarenes. ACS Catal. 2017, 7, 4057–
4061.
Di Rocco, D. A.; Dykstra, K.; Krska, S.; Vachal, P.; Conway, D.
V.; Tudge, M. LateꢀStage Functionalization of Biologically
Active Heterocycles through Photoredox Catalysis. Angew.
Chem. Int. Ed. 2014, 53, 4802–4806.
Duncton, M. A. J. Minisci Reactions. Versatile CHꢀ
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ASSOCIATED CONTENT
Supporting Information
(15)
The Supporting Information is available free of charge on the
ACS Publications website.
(16)
(17)
(18)
Additional experiments (reaction optimizations), pictures of the
light setꢀup, kinetic study, 1H and 13C spectra (PDF)
Zhang, L.; Liu, Z.ꢀQ. Molecular OxygenꢀMediated Minisciꢀ
Type Radical Alkylation of Heteroarenes with Boronic Acids.
Org. Lett. 2017, 19, 6594–6597.
AUTHOR INFORMATION
Matsui, J. K.; Primer, D. N.; Molander, G. A. MetalꢀFree CꢀH
Alkylation of Heteroarenes with Alkyltrifluoroborates:
General Protocol for 1°, 2° and 3° Alkylation. Chem. Sci. 2017,
8, 3512–3522.
A
Corresponding Author
* Eꢀmail: philippe_nuhant@vrtx.com
(19)
(20)
(21)
Li, G.ꢀX.; MoralesꢀRivera, C. A.; Wang, Y.; Gao, F.; He, G.;
Liu, P.; Chen, G. PhotoredoxꢀMediated Minisci CꢀH Alkylation
of NꢀHeteroarenes Using Boronic Acids and Hypervalent
Iodine. Chem. Sci. 2016, 7, 6407–6412.
Shore, D. G. M.; Wasik, K. A.; Lyssikatos, J. P.; Estrada, A. A.
Minisci Alkylations of ElectronꢀDeficient Pyrimidines with
Alkyl Carboxylic Acids. Tetrahedron Lett. 2015, 56, 4063–
4066.
Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon, D.
D.; Rodriguez, R. A.; Baxter, R. D.; Herlé, B.; Sach, N.; Collins,
M. R.; Ishihara, Y.; Baran, P. S. Practical and Innate Carbon–
Hydrogen Functionalization of Heterocycles. Nature 2012, 492,
ACKNOWLEDGMENT
We would like to thank Vertex Pharmaceuticals Inc. for funding
Noah Bissonnette internship, Barry Davis for collecting HRMS
data and Jeremy Green for proofreading the manuscript.
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