Organocatalyzed, Visible-Light Photoredox-Mediated, One-Pot Minisci Reaction Using Carboxylic Acids via N-(Acyloxy)phthalimides

Article abstract of DOI:10.1021/acs.joc.8b00205

An improved, one-pot Minisci reaction has been developed using visible light, an organic photocatalyst, and carboxylic acids as radical precursors via the intermediacy of in situ-generated N-(acyloxy)phthalimides. The conditions employed are mild, demonstrate a high degree of functional group tolerance, and do not require a large excess of the carboxylic acid reactant. As a result, this reaction can be applied to drug-like scaffolds and molecules with sensitive functional groups, enabling late-stage functionalization, which is of high interest to medicinal chemistry.

Full text of DOI:10.1021/acs.joc.8b00205

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Note
Organocatalyzed, Visible-Light Photoredox-Mediated, One-Pot
Minisci Reaction Using Carboxylic Acids via N-(Acyloxy)phthalimides
Trevor C. Sherwood, Ning Li, Aliza N. Yazdani, and T. G. Murali Dhar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00205 • Publication Date (Web): 08 Feb 2018
Downloaded from http://pubs.acs.org on February 9, 2018
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The Journal of Organic Chemistry
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Organocatalyzed, Visible-Light Photoredox-Mediated, One-Pot
Minisci Reaction Using Carboxylic Acids via N-
(Acyloxy)phthalimides
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Trevor C. Sherwood*, Ning Li, Aliza N. Yazdani, T. G. Murali Dhar
Research and Development, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, New Jersey 08543-4000 United
States
Supporting Information Placeholder
ABSTRACT: An improved, one-pot Minisci reaction has been developed using visible light, an organic photocatalyst and carbox-
ylic acids as radical precursors via the intermediacy of in situ-generated N-(acyloxy)phthalimides. The conditions employed are
mild, demonstrate a high degree of functional group tolerance, and do not require large excess of the carboxylic acid reactant. As a
result, this reaction can be applied to drug-like scaffolds and molecules with sensitive functional groups, enabling late-stage func-
tionalization
which
is
of
high
interest
to
medicinal
chemistry.
The Minisci reaction is well appreciated as a way to C–H
functionalize heteroarenes.1-3 This transformation classically
uses an excess of carboxylic acid in conjunction with an oxi-
dant, strong acid, and heat to functionalize at electron-
deficient positions of an arene substrate. These conditions are
harsh and, therefore, functional group tolerance is low. In the
ensuing decades since Minisci’s original disclosure,4 the reac-
tion has been explored by a number of groups. Several modern
versions of the Minisci reaction have been developed using
photoredox chemistry employing radical precursors such as
bromides,5 iodides,6 trifluoroborates,7 boronic acids,8 primary
alcohols,9-10 activated amines,11 ethers,12 and peresters.13 Re-
cently, carboxylic acids were also reported to be viable radical
precursors in a metal-mediated photoredox Minisci reaction
when used in ten-fold excess to the heteroarene in conjunction
with an added oxidant.14 Non-photoredox-mediated methods
have also been developed, most notably the use of alkyl sul-
finate salts as radical precursors.15
Scheme 1. Proposed photocatalytic cyclea
aPC = photocatalyst, SET = single-electron transfer
To satisfy these criteria, we focused on carboxylic acids and
visible-light photoredox chemistry.17-18 We were specifically
inspired by work from Okada19-20 and Overman21-24 in which
N-(acyloxy)phthalimides (NAPs) are exposed to light in the
presence of a photosensitizer19 or photocatalyst20-24 to generate
alkyl radicals after single-electron reductive fragmentation
(E1/2 = –1.26 to –1.39 V vs SCE).19,25 Reductive generation of
the radical was attractive as many Minisci variants involve
oxidation of the radical precursor and therefore require an
external oxidant to turn over the catalytic cycle. It was our
hope that the use of NAPs would obviate the need for an ex-
ternal oxidant. We also sought to identify an organic photo-
catalyst to avoid the use of an expensive, metal-based catalyst,
such as iridium-based complexes often used in photoredox
chemistry.18,26 Finally, it was our ultimate goal to develop a
Many of these recently reported methods still require a large
excess of the radical precursor, an added oxidant, or are lim-
ited in their scope. We sought to identify mild conditions that
employed near-stoichiometric levels of a radical precursor that
would be commercially available with a diverse array of in-
corporated functional groups. It was our aim to develop a reac-
tion with high functional group tolerance that could be used
either as an early step in a synthetic campaign or as a late-
stage functionalization (LSF) approach to diversify a complex
scaffold rapidly. LSF strategies are considered highly advan-
tageous in disciplines such as medicinal chemistry wherein the
ability to generate a diverse library of analogs to understand
structure-activity relationship (SAR) is essential.16
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one-pot Minisci protocol in which a starting carboxylic acid scribed in Table 1, entry 1, adding lepidine (8), TFA, and 10 to
1
2
3
4
5
6
7
8
would undergo NAP formation in situ followed by subsequent
addition of a heteroarene and photocatalyst. Such a process
would enable rapid analog generation using a class of reagents
that are abundantly available in a high level of structural di-
versity and avert the need for isolation of a prefunctionalized
alkyl partner.
a solution of the NAP of cyclohexanecarboxylic acid (7)
(formed in situ by mixing 7, N-hydroxyphthalimide, DMAP,
and N,N’-diisopropylcarbodiimide (DIC) in DMSO) and ex-
posing the solution to 34 W blue LEDs (see Experimental
Section) under a N2 atmosphere for 3 h without an external
cooling fan (internal reaction temperatures range from 40 to
48 °C) provided 83% yield of the desired Minisci product 9. It
may be somewhat surprising that 10 is a viable photocatalyst
for this reaction with such a weak reducing potential in the
photoexcited state relative to the NAP intermediate, but there
are some possible explanations. During the course of our
work, Fu, Shang, and coworkers28-29 disclosed a two-step
Minisci procedure using NAPs synthesized and chromato-
graphed in a first step followed by a second step of photore-
dox-mediated Minisci reaction employing DMA as solvent
From a mechanistic standpoint, we envisioned the photo-
catalytic cycle in Scheme 1 would be operative in our desired
Minisci reaction. The NAP (1) could oxidatively quench the
excited photocatalyst via single-electron transfer (SET) and
undergo reductive fragmentation to generate the alkyl radical 2
in addition to CO2 and phthalimide. Radical intermediate 2
could attack a protonated heteroarene 3 to generate adduct 4,
which could undergo deprotonation to generate α-amino radi-
cal 5. Intermediate 5 is well-poised to undergo SET with the
oxidized form of the photocatalyst to generate protonated
product 6, turning over the catalytic cycle.
9
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and the photocatalyst [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (11,
E1/2
IV/III*
= –0.89 vs SCE),18 which also has a weak reduction
potential in the excited state relative to the NAP substrates. Fu
and Shang invoked the possibility of in situ photocatalyst re-
Table 1. Optimization for coupling of cyclohexanecarbox-
ylic acid (7) and lepidine (8)
duction by DMA or another component of the reaction mix-
III/II
ture to iridium(II) (E1/2
= –1.37 vs SCE), which has an ap-
propriate potential for NAP reduction. In our reaction, in situ
reduction of 10 is also conceivable to form a stronger reducing
species (E1/2PC/PC– = –1.21 vs SCE)27 to reduce the NAP, possi-
bly formed by 10 oxidizing N,N’-diisopropylurea byproduct
from NAP formation, DMAP, or another component of the
reaction mixture.30 Alternatively, thermodynamically unfavor-
able SET processes have been documented, and when such a
process is coupled to a subsequent irreversible step, reactions
that would seem difficult can occur.31 In our proposed catalytic
cycle, irreversible decarboxylative fragmentation after SET
may enable our reaction to proceed even if the potentials for
photoexcited 10 and the NAP intermediate are not perfectly
matched. Following up on Fu’s and Shang’s results, we at-
tempted our one-pot procedure in DMA with 11 (entry 2) and
obtained a slightly diminished 71% yield, although using
DMSO as solvent with catalyst 11 (entry 3) provided equiva-
lent results to catalyst 10.
change to
esterification
none
change to
photochemistry
none
yield of
entry
9 (%)a
1
2
83b
1
mol
%
11,
DMA used as solvent
71
DMA
3
4
5
6
7
none
none
none
none
none
1 mol % 11
1 mol % 12
1 mol % 13
no catalyst
83
83
7
28
80
no catalyst, 24 h
Catalysts with higher reduction potentials in the photoexcit-
no catalyst, no
light, 48 °C
ed state were also screened, and replacing 10 in our standard
conditions with Ir(ppy)3 (12, E1/2
8
none
NDc
IV/III*
= –1.73 vs SCE)18 pro-
vided equivalent results to both catalysts 10 and 11 (entry 4).
Finally, the organic catalyst 10-phenylphenothiazine (13,
E1/2PC+/PC* = –2.1 vs SCE)32-33 was attempted, but poor conver-
sion was observed and only 7% yield of 9 was obtained (entry
5).
9
none
no light, rt
no light, 48 °C
none
ND
10
11
none
ND
traced
No DIC
No
DIC,
N-
12
13
hydroxyphthalimide,
or DMAP
none
traced
18e
Control reactions revealed that in the presence of light but
no photocatalyst, reaction could still occur, though more slow-
ly than with photocatalyst present (entries 6 and 7). Although
Fu and Shang reported that isolated NAPs did not react in the
absence of photocatalyst with visible light irradiation,28-29 our
findings are in line with those reported by Overman,23 who
observed slow NAP reactivity with exposure to visible light in
the absence of photocatalyst. Subsequent control reactions
demonstrated that reactions run in the dark (entries 8 – 10)
gave no product, and in the absence of NAP (entries 11 and
12), only trace product could be observed. Finally, attempts to
accelerate NAP formation with the use of 2-(1H-
benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluorobo-
rate (TBTU) instead of DIC resulted in only 18% yield of 9,
possibly due to the presence of byproducts from TBTU or
TBTU, Et3N, 15 min
none
aIsolated yields on 0.25 mmol scale; entry 1 standard conditions
run with lepidine (8, 1.0 equiv), cyclohexanecarboxylic acid (7,
1.5 equiv), N-hydroxyphthalimide (1.5 equiv), DIC (1.5 equiv),
DMAP (5 mol %), TFA (2.0 equiv), and 4-CzIPN (10, 1 mol %)
in DMSO (0.1 M); cND = not detected; dtrace observed by LCMS;
b
e0.5 mmol scale; 10
dicyanobenzene; 11
Ir(ppy)3; 13 = 10-phenylphenothiazine
=
1,2,3,5-tetrakis(carbazol-9-yl)-4,6-
[Ir(dF(CF3)ppy)2(dtbbpy)]PF6; 12
=
=
After extensive screening, we identified the organic photo-
catalyst 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4-
CzIPN, 10, E1/2PC+/PC* = –1.04 vs SCE)27 as the optimal species
for use in our photoredox-mediated Minisci reaction. As de-
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The Journal of Organic Chemistry
product (30) could also be obtained in 66% yield. Saturated,
interference from stoichiometric Et3N. Therefore, DIC with
1
2
3
4
5
6
7
8
catalytic DMAP was selected for NAP formation.
nitrogen-containing rings of various sizes proved to be viable
coupling partners in our reaction, affording moderate yields of
products 31 – 34. Products with tetrahydropyran (35) and tet-
rahydrothiopyran (36) were formed in 58% and 59% yield,
respectively. In general, the success of substrates with BOC
groups (28, 29, 31 – 33) or an oxidizable thioether functional
group (36) highlights the mildness of the reaction conditions.
Finally, 1-cyclohexenoic acid and benzoic acid proved unreac-
tive as substrates (37 and 38), which may be expected given
that these products would require the intermediacy of sp2-
centered radicals to form.
With our envisioned one-pot, organocatalyzed photoredox-
mediated Minisci reaction in hand, we embarked on substrate
scope exploration. As shown in Scheme 2, a wide variety of
carboxylic acids could alkylate C-2 of lepidine (8) under our
standard conditions employing TFA or camphor-10-sulfonic
acid (CSA) to protonate the heteroarene. For electron-deficient
radicals such as primary alkyl radicals and cyclopropane radi-
cal, CSA gave higher conversions than TFA. All reactions
were completed in 3 h as judged by consumption of NAP in-
termediate unless otherwise indicated (see Schemes 2 and 3).
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Scheme 3. Heteroarene scopea
A methyl group (14) as well as small, unfunctionalized pri-
mary and secondary alkyl groups (15 – 17) could be intro-
duced in modest to good yield. A cyclopropyl group (18)
could be appended in 17% yield with extended reaction time.
Introduction of a trifluoroethyl group (19) was not successful,
likely due to the electrophilic character of the generated radi-
cal. An allyl group (20) could not be introduced under our
developed conditions with either catalyst 10 or 11, and at-
tempts to introduce a propargyl group also proved fruitless
(21). While a benzyl group (22) could be introduced in only
15% yield, the more electron-rich, indole-containing substrate
23 was produced in a slightly more useful yield of 32%. Ter-
tiary alkyl groups worked quite well for the developed condi-
tions as a tert-butyl group (24) and a [2.2.2]bicyclooctane
group (25) were appended in 88% yield and 76% yield, re-
spectively. However, a tertiary benzylic group could not be
introduced (26).
Scheme 2. Carboxylic acid scopea
aIsolated yields on 0.25 mmol scale following conditions from
b
c
Table 1, entry 1; TFA (1.0 equiv) used; also isolated 20% yield
of inseparable isomers with a second Cy group; d0.10 mmol scale;
eReactions run at listed scales with 4-chloro-2-methylpyridine and
4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid
aIsolated yields on 0.25 mmol scale following conditions from
b
c
Table 1, entry 1; (1R)-(–)-CSA (2.0 equiv) used; ND = not de-
tected; dproduct also not detected when reaction run with 1 mol %
e
of 11; 10:1 ratio of 24 to product with second t-Bu group, regio-
Regarding heteroarene scope, we explored simple 5- and 6-
membered rings (Scheme 3a) as well as more complex struc-
tures including nucleosides and marketed drug scaffolds
(Scheme 3b). In general, substrates containing 6-membered
heteroarenes reacted well, although mixtures of product iso-
mers and products with bis-alkylation were observed in some
cases. 4-Methylpyridine provided 39 in 50% yield and 40 in
19% yield, and 4-chloropyridine formed 41 in 36% yield and
42 in 30% yield. Quinoline underwent functionalization at the
C-2 and C-4 positions to give all three possible products 43 –
45, while quinaldine formed the mono-alkylated product 46 in
58% yield. Isoquinoline reacted smoothly to give 47 in 78%
yield, and phthalazine and quinoxaline, each possessing multi-
ple reactive sites, formed products 48 – 51 with modest yields.
chemistry unassigned; ( )-CSA (1.0 equiv) used; gTFA (1.0
f
equiv) used; h63% yield when run with (1R)-(–)-CSA (1.0 equiv)
Examining alkyl partners with heteroatom-containing
functional groups, a primary alkyl bromide was tolerant of the
reaction conditions, providing 27 in 38% yield from the corre-
sponding carboxylic acid. The decrease in yield of 27 relative
to unfunctionalized primary alkyl substrates like 15 and 16
may be due to the formation of small amounts of byproducts
from some reactivity of the primary alkyl bromide in 27. Pro-
tected, racemic glutamic acid with a free carboxylic acid side
chain formed protected non-natural amino acid derivative 28
in 28% yield, and BOC-protected glycine provided amino-
methylated 29 in 67% yield. Pleasingly, an alkoxymethylated
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4-Quinazolinone gave 55% yield of 52, and purine provided like medicinal chemistry wherein C-H functionalization is of
1
2
3
4
5
6
7
8
mono-alkylated 53 in 59% yield along with 20% yield of an
inseparable mixture of two bis-alkylated materials. 4-chloro-7-
azaindole proved relatively unreactive providing 54 in poor
yield. Moving on to 5-membered heterocycles, benzimidazole
formed the desired product 55 in 39% yield, and benzothiazole
provided desired product 56 in 31% yield. Unfortunately, ben-
zoxazole proved less reactive and gave product 57 in only 5%
yield. Indazole also proved recalcitrant with none of 58 isolat-
ed although trace was observed by LCMS, but caffeine did
afford desired product 59 in 20% yield.
high importance.
EXPERIMENTAL SECTION
General Information. Unless otherwise stated, reactions were
run in 2-dram vials purchased from Chemglass with caps con-
taining a teflon-lined septum. Reactions were monitored by
liquid chromatography/mass spectrometry (LCMS) on a Wa-
ters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 ꢀm);
solvent A: water with 0.05% TFA, solvent B: acetonitrile with
0.05% TFA; gradient from 2% B to 98% B over 1.0 min then
98% B for 0.5 min, flow rate 0.8 mL/min, detection at 220 nm
and low resolution mass spectrometry detection with either
Waters SQ Detector 2 with electrospray ionization (ESI) or
Waters 3100 Detector with ESI. Flash column chromatog-
raphy was performed on a Teledyne Isco instrument using
redisep Rf silica columns and 40-63 ꢀm silica gel from Fluka
Analytical. Hexanes, EtOAc, DCM and MeOH used for puri-
fication were purchased as UPLC grade from Sigma Aldrich.
Analytical HPLC purity and retention times, where noted,
were obtained using a Shimadzu Scientific Instruments SIL-
10AF HPLC with two columns: column 1: ACE Ucore Super
C18 (3.0 × 125 mm, 2.5 ꢀm) and column 2: ACE UCore Su-
perHexPh (3.0 × 125 mm, 2.5 ꢀm); solvent A: 95% water/5%
acetonitrile with 0.05% TFA, solvent B: 5% water/95% ace-
tonitrile with 0.05% TFA; gradient from 10% B to 100% B
over 12 minutes, held at 100% B from 12 to 15 minutes; flow
rate 1 mL/min; detection at 220 nm. Reaction solvents (DMSO
and DMA) were purchased from Sigma Aldrich in a Sure/Seal
bottle and used without further purification. All reagents and
organic building blocks were purchased from commercial
suppliers and used without further purification. All yields are
isolated yields for materials that are >95% pure as judged by
HPLC and NMR unless otherwise stated.
1H and 13C NMR spectra were obtained on Bruker Avance
III and Avance III HD instruments at fields of 400 MHz, 500
MHz and 700 MHz, equipped with 5mm BBFO Probe, Prodi-
gy BBO Probe and TCI Cryoprobe, respectively. All NMR
spectra were obtained at room temperature unless otherwise
stated. NMR spectra were internally referenced to the solvent
peak.38 Chemical shifts are reported in parts per million (ppm).
Data is reported in the following format: chemical shift (δ
ppm), descriptor if applicable (br = broad, app = apparent),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet, spt = septet), coupling constant (Hz), integration.
High resolution mass spectra (HRMS) were obtained on a
ThermoFinnigan LTQ Orbitrap XL (ESI) or a ThermoFinni-
gan Orbitrap Exactive (ESI).
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60
Lastly, nucleosides and marketed drug scaffolds were inves-
tigated as LSF substrates to demonstrate the functional group
tolerance of this method as well as its utility in library synthe-
sis for SAR development. Nebularine and peracetylated nebu-
larine both reacted smoothly to give 60 and 61 in 73% and
61% yield, respectively, demonstrating the robustness of this
method in the presence of primary and secondary hydroxyl
groups. Adenosine gave only 11% yield of 62, likely due to
the 6-amino group blocking the most reactive position. Never-
theless, 62 demonstrates that unprotected nucleosides with free
amines can provide functionalized analogs with this method.
The formation of 63 in 48% yield from quinine further demon-
strates the functional group tolerance of this method, with a
terminal alkene present in addition to a tertiary amine and free
alcohol. Analogs of camptothecin have been of high interest
due to its anticancer activity,34 and our method provides deriv-
ative 64 in 17% yield. The anticancer agent vemurafenib35
afforded the analog 65 in 31% yield, showing surprising pref-
erence for alkylation at C-2 of the 7-azaindole system, likely
owing to the electrophilicity induced by the C-3 difluoroaryl-
ketone and possible steric shielding of C-4 and C-6 by the C-5
4-chlorophenyl group.36 By contrast, in the reaction to form
54, alkylation was only observed at C-6. In addition, imatinib,
a marketed drug to treat cancer,37 underwent Minisci reaction
to give 66 – 71 in combined yield of 48%. While this may
seem an inefficient synthesis of any one analog, the ability to
generate multiple compounds from one reaction can be advan-
tageous from a LSF and library design perspective, providing
multiple derivatives to establish SAR.
To probe the scale-dependence of our reaction, the for-
mation of 72 was investigated on 0.25 mmol, 1.25 mmol, and
6.25 mmol scales, giving relatively consistent yields of 68%,
78%, and 73%, respectively (Scheme 3c). These reactions
were run in a 2-dram vial, a 20-mL vial, and a 200-mL flask,
and while the small-scale reaction was sealed, the mid- and
large-scale reactions were each affixed with a N2 balloon to
accommodate the pressure build-up from CO2 generation.
Furthermore, the large-scale reaction required extended time
to go to completion, perhaps limited by the penetration of light
due to the smaller surface area to volume ratio at this scale.
General Procedure for Minisci Reaction. Run in a 2-dram
vial with a cap containing a teflon-lined pressure-release sep-
tum. To a solution of the carboxylic acid substrate (0.375
mmol, 1.5 equiv), N-hydroxyphthalimide (61.2 mg, 0.375
mmol, 1.5 equiv), and DMAP (1.5 mg, 0.0125 mmol, 5 mol
%) in DMSO (1.25 mL) is added DIC (0.0587 mL, 0.375
mmol, 1.5 equiv). The reaction is stirred at room temperature
for 24 hours to form the NAP intermediate in situ. Then, a
solution of the heteroarene substrate (0.250 mmol, 1.0 equiv)
and the appropriate protic acid [TFA (57.0 mg, 0.0383 mL,
0.500 mmol, 2.0 equiv) if the carboxylic acid substrate gener-
ates a secondary or tertiary radical; 1R-(–)-CSA (116 mg,
0.500 mmol, 2.0 equiv) if the carboxylic acid substrate gener-
ates a primary, cyclopropyl, or methyl radical] in DMSO (0.75
In conclusion, we have developed a mild, one-pot, organo-
catalyzed photoredox-mediated Minisci reaction employing
carboxylic acids as radical precursors which displays a high
degree of functional group tolerance. The use of an organic
photocatalyst avoids elemental impurity toxicity concerns
presented by iridium-based catalysts, and the one-pot proce-
dure as well as the extensive substrate scope explored repre-
sent significant advantages over the existing photoredox
Minisci variant with isolated NAPs.28-29 We believe this exten-
sion of the Minisci reaction can be used as an early step in a
synthetic campaign or a tool for LSF by researchers in fields
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The Journal of Organic Chemistry
cyclohexyl-4-methylquinoline (9, 20 mg, 18% yield, 74%
mL for solution formation and initial transfer + 0.5 mL rinse
1
2
3
4
5
6
7
8
of vial containing transferred solution of heteroarene and pro-
tic acid) is transferred to the solution containing the NAP.
Then 4-CzIPN (10, 1.97 mg, 2.50 µmol, 1 mol %) is added to
the reaction mixture. The solution is bubbled vigorously for 60
– 90 seconds with nitrogen gas, sealed, and placed between
two blue Kessil brand KSH150B Grow Light LED 34 W
lamps (~400 – 520 nm, for more information see Kessil.com)
secured with gooseneck clamps. The center of the reaction
vessel is roughly 5 cm from one lamp and 7 cm from the other.
No cooling fan is used, and multiple measurements show that
the internal temperature rises to anywhere between 40 to 48
°C. The reaction is stirred and irradiated with blue light until
completion (3 to 25 h) as judged by full consumption of the
NAP intermediate and/or the heteroarene substrate. Upon
completion, the reaction is opened to air, diluted with CH2Cl2
(35 mL), poured into a separatory funnel containing water (35
mL) and either solid NaHCO3 or a 1.5 M aqueous solution of
K2HPO4 is added until the solution reaches roughly pH 8 as
judged by pH paper. The organic layer is separated and
washed with water (35 mL) made slightly basic by the addi-
tion of either solid NaHCO3 or a 1.5 M aqueous solution of
K2HPO4 (1.5 mL). The organic layer is dried (Na2SO4), fil-
tered, and concentrated to afford a crude solid. This crude
material is purified by silica gel chromatography on a Tele-
dyne Isco instrument unless otherwise noted. The fractions
containing the desired product are isolated and concentrated.
analytical HPLC purity).
2-cyclohexyl-4-methylquinoline (9). Compound prepared by
the general procedure using cyclohexanecarboxylic acid (7, 48
mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol,
1.0 equiv) as substrates with TFA (58 mg, 39 ꢀL, 0.51 mmol,
2.0 equiv) used in the photochemical portion. Irradiated with
blue light for 3 h in the photochemical portion. Purified by
flash column chromatography using silica gel on a Teledyne
Isco instrument to give 2-cyclohexyl-4-methylquinoline (9, 47
mg, 83% yield) as a clear oil. LCMS tr = 0.69 min; 1H NMR
(499 MHz, CHLOROFORM-d) δ 8.08 - 8.02 (m, 1H), 7.93
(dd, J=8.3, 0.9 Hz, 1H), 7.65 (ddd, J=8.4, 6.9, 1.4 Hz, 1H),
7.48 (ddd, J=8.3, 6.9, 1.3 Hz, 1H), 7.16 (app d, J=0.7 Hz, 1H),
2.88 (tt, J=12.1, 3.4 Hz, 1H), 2.67 (d, J=0.9 Hz, 3H), 2.05 -
1.96 (m, 2H), 1.92 - 1.85 (m, 2H), 1.82 - 1.75 (m, 1H), 1.62
(qd, J=12.6, 3.1 Hz, 2H), 1.47 (qt, J=12.9, 3.3 Hz, 2H), 1.39 -
1.28 (m, 1H); 13C NMR (126 MHz, CHLOROFORM-d) δ
166.6, 147.7, 144.3, 129.6, 129.0, 127.1, 125.4, 123.6, 120.3,
47.7, 32.9, 26.7, 26.2, 18.9; HRMS (ESI) m/z calcd for
C16H20N [M+H+] 226.1590, found 226.1581.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,4-dimethylquinoline (14). Compound prepared by the gen-
eral procedure using acetic acid (23 mg, 0.38 mmol, 1.5 equiv)
and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates
with 1R-(–)-CSA (116 mg, 0.50 mmol, 2.0 equiv) used in the
photochemical portion. Irradiated with blue light for 3 h in the
photochemical portion. Purified by flash column chromatog-
raphy using silica gel on a Teledyne Isco instrument to give
2,4-dimethylquinoline (14, 10 mg, 26% yield) as a clear oil.
LCMS tr = 0.50 min; 1H NMR (400 MHz, CHLOROFORM-d)
δ 8.01 (d, J=8.5 Hz, 1H), 7.95 (dd, J=8.3, 1.0 Hz, 1H), 7.67
(ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.50 (ddd, J=8.2, 6.9, 1.2 Hz,
1H), 7.14 (app d, J=0.8 Hz, 1H), 2.70 (s, 3H), 2.67 (d, J=0.9
Hz, 3H); 13C NMR (101 MHz, CHLOROFORM-d) δ 158.8,
147.8, 144.4, 129.3, 129.3, 126.7, 125.6, 123.7, 122.9, 25.3,
18.7; HRMS (ESI) m/z calcd for C11H12N [M+H+] 158.0964,
found 158.0966.
Table 1, entries 1 – 12: Entries 1 – 12 were run following the
general procedure for Minisci reaction using cyclohexanecar-
boxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and lepidine (8,
36 mg, 0.25 mmol, 1.0 equiv) as substrates, TFA (58 mg, 39
ꢀL, 0.51 mmol, 2.0 equiv), and irradiated with blue light for 3
h in the photochemical portion. Reactions in entries 2 – 13
were run with the noted modifications to either the in situ for-
mation of the NAP or the photochemical portion. Entries 8 –
10 were wrapped in foil and stirred without blue LED irradia-
tion. Additionally, entries 8 and 10 were heated in a metal
heating block. Entries 11 and 12 were run without 24 h of
stirring normally alloted for in situ formation of the NAP and
were immediately progressed to the photochemical portion of
the reaction following the listed modification for the esterifica-
tion.
2-ethyl-4-methylquinoline (15). Compound prepared by the
general procedure using propionic acid (28 mg, 0.38 mmol,
1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as
substrates with 1R-(–)-CSA (116 mg, 0.50 mmol, 2.0 equiv)
used in the photochemical portion. Irradiated with blue light
for 3 h in the photochemical portion. Purified by flash column
chromatography using silica gel on a Teledyne Isco instrument
to give 2-ethyl-4-methylquinoline (15, 32 mg, 74% yield) as a
clear oil. LCMS tr = 0.54 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ 8.06 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.3
Hz, 1H), 7.72 - 7.64 (m, 1H), 7.55 - 7.47 (m, 1H), 7.17 (s,
1H), 2.97 (q, J=7.6 Hz, 2H), 2.69 (s, 3H), 1.39 (t, J=7.6 Hz,
3H); 13C NMR (101 MHz, CHLOROFORM-d) δ 163.8, 147.7,
144.7, 129.4, 129.3, 126.9, 125.6, 123.7, 121.7, 32.3, 18.9,
14.2; HRMS (ESI) m/z calcd for C12H14N [M+H+] 172.1121,
found 172.1121.
Table 1, entry 13: To a solution of cyclohexanecarboxylic
acid (7, 96 mg, 0.75 mmol, 1.5 equiv), N-hydroxyphthalimide
(122 mg, 0.75 mmol, 1.5 equiv), and triethylamine (76 mg,
0.75 mmol, 1.5 equiv) in DMSO (2.5 mL) was added TBTU
(241 mg, 0.75 mmol, 1.5 equiv). The reaction was stirred at
room temperature for 15 min to form the NAP intermediate in
situ. Then, a solution of lepidine (8, 72 mg, 0.50 mmol, 1.0
equiv) and TFA (114 mg, 0.077 mL, 1.0 mmol, 2.0 equiv) in
DMSO (2 mL for solution formation and initial transfer + 0.5
mL rinse of vial containing transferred solution of heteroarene
and protic acid) was transferred to the solution containing the
NAP. Then 4-CzIPN (10, 3.9 mg, 4.9 µmol, 1 mol %) was
added to the reaction mixture. The solution was bubbled vig-
orously for 60 seconds with nitrogen gas, sealed, and placed
between two blue Kessil brand KSH150B Grow Light LED 34
W lamps secured with gooseneck clamps. No cooling fan was
used. The reaction was stirred and irradiated with blue light
for 3 h. Upon completion, the workup from the general proce-
dure was used. The crude material was purified by silica gel
chromatography on a Teledyne Isco instrument to give 2-
4-methyl-2-propylquinoline (16). Compound prepared by the
general procedure using butyric acid (33 mg, 0.37 mmol, 1.5
equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as sub-
strates with 1R-(–)-CSA (116 mg, 0.50 mmol, 2.0 equiv) used
in the photochemical portion. Irradiated with blue light for 3 h
in the photochemical portion. Purified by flash column chro-
matography using silica gel on a Teledyne Isco instrument to
give 4-methyl-2-propylquinoline (16, 30 mg, 64% yield) as a
clear oil. LCMS tr = 0.59 min; 1H NMR (499 MHz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 14
CHLOROFORM-d) δ 8.07 - 8.02 (m, 1H), 7.95 (dd, J=8.3, 1.0 yl)acetic acid (66 mg, 0.38 mmol, 1.5 equiv) and lepidine (8,
1
2
3
4
5
6
7
8
Hz, 1H), 7.67 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.50 (ddd, J=8.3,
6.9, 1.3 Hz, 1H), 7.14 (app d, J=0.7 Hz, 1H), 2.93 - 2.87 (m,
2H), 2.68 (d, J=0.9 Hz, 3H), 1.88 - 1.79 (m, 2H), 1.02 (t, J=7.4
Hz, 3H); 13C NMR (126 MHz, CHLOROFORM-d) δ 162.7,
147.9, 144.3, 129.5, 129.1, 126.9, 125.5, 123.7, 122.2, 41.4,
23.4, 18.8, 14.2; HRMS (ESI) m/z calcd for C13H16N [M+H+]
186.1277, found 186.1269.
36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg,
38 ꢀL, 0.50 mmol, 2.0 equiv) used in the photochemical por-
tion. Irradiated with blue light for 24 h in the photochemical
portion. Purified by flash column chromatography using silica
gel on a Teledyne Isco instrument to obtain solid material
which was further purified by trituration with methanol to give
2-((1H-indol-3-yl)methyl)-4-methylquinoline (23, 22 mg, 32%
1
yield) as a pale brown solid. LCMS tr = 0.68 min; H NMR
2-isopropyl-4-methylquinoline (17). Compound prepared by
the general procedure using isobutyric acid (33 mg, 0.37
mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.250 mmol, 1.0
equiv) as substrates with TFA (58 mg, 39 ꢀL, 0.51 mmol, 2.0
equiv) used in the photochemical portion. Irradiated with blue
light for 3 h in the photochemical portion. Purified by flash
column chromatography using silica gel on a Teledyne Isco
instrument to give 2-isopropyl-4-methylquinoline (17, 27 mg,
(400 MHz, CHLOROFORM-d) δ 8.18 - 8.01 (m, 2H), 7.93
(dd, J=8.3, 0.9 Hz, 1H), 7.70 (ddd, J=8.4, 7.0, 1.4 Hz, 1H),
7.61 (d, J=7.9 Hz, 1H), 7.51 (ddd, J=8.2, 7.0, 1.2 Hz, 1H),
7.37 (d, J=8.1 Hz, 1H), 7.18 (td, J=7.6, 1.0 Hz, 1H), 7.14 (s,
1H), 7.12 - 7.04 (m, 2H), 4.44 (s, 2H), 2.57 (d, J=0.8 Hz, 3H);
13C NMR (101 MHz, CHLOROFORM-d) δ 161.4, 147.7,
144.6, 136.6, 129.6, 129.2, 127.8, 127.1, 125.7, 123.8, 122.9,
122.3, 122.1, 119.7, 119.5, 114.1, 111.2, 35.5, 18.9; HRMS
(ESI) m/z calcd for C19H17N2 [M+H+] 273.1386, found
273.1386.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
58% yield) as a clear oil. LCMS tr = 0.57 min; H NMR (499
MHz, CHLOROFORM-d) δ 8.05 (d, J=8.4 Hz, 1H), 7.95 (dd,
J=8.3, 1.0 Hz, 1H), 7.67 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.50
(ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.18 (app d, J=0.8 Hz, 1H), 3.21
(spt, J=6.9 Hz, 1H), 2.69 (d, J=0.9 Hz, 3H), 1.39 (d, J=7.1 Hz,
6H); 13C NMR (126 MHz, CHLOROFORM-d) δ 167.5, 147.7,
144.5, 129.7, 129.1, 127.2, 125.5, 123.7, 119.9, 37.4, 22.7,
19.0; HRMS (ESI) m/z calcd for C13H16N [M+H+] 186.1277,
found 186.1276.
2-(tert-butyl)-4-methylquinoline (24). Compound prepared
by the general procedure using pivalic acid (38 mg, 0.37
mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0
equiv) as substrates with TFA (58 mg, 39 ꢀL, 0.51 mmol, 2.0
equiv) used in the photochemical portion. Irradiated with blue
light for 3 h in the photochemical portion. Purified by flash
column chromatography using silica gel on a Teledyne Isco
instrument to give 2-(tert-butyl)-4-methylquinoline (24, 44
mg, 88% yield, 10:1 ratio with a minor inseparable material
containing a second tert-butyl group of unknown regiochemis-
2-cyclopropyl-4-methylquinoline (18). Compound prepared
by the general procedure using cyclopropanecarboxylic acid
(32 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25
mmol, 1.0 equiv) as substrates with 1R-(–)-CSA (116 mg, 0.50
mmol, 2.0 equiv) used in the photochemical portion. Irradiated
with blue light for 25 h in the photochemical portion. Purified
by flash column chromatography using silica gel on a Tele-
dyne Isco instrument to give 2-cyclopropyl-4-methylquinoline
(18, 7.7 mg, 17% yield) as a clear oil. LCMS tr = 0.55 min; 1H
NMR (499 MHz, CHLOROFORM-d) δ 7.96 (d, J=8.4 Hz,
1H), 7.91 (dd, J=8.3, 1.1 Hz, 1H), 7.63 (ddd, J=8.4, 6.9, 1.4
Hz, 1H), 7.45 (ddd, J=8.2, 6.9, 1.3 Hz, 1H), 6.99 (app d, J=0.7
Hz, 1H), 2.65 (d, J=0.9 Hz, 3H), 2.20 (tt, J=8.2, 4.9 Hz, 1H),
1.16 - 1.11 (m, 2H), 1.10 - 1.04 (m, 2H); 13C NMR (126 MHz,
CHLOROFORM-d) δ 163.1, 147.9, 143.9, 129.3, 129.1,
127.0, 125.1, 123.7, 120.0, 18.8, 18.1, 10.1; HRMS (ESI) m/z
calcd for C13H14N [M+H+] 184.1121, found 184.1127.
1
try) as a clear oil. LCMS tr = 0.62 min; H NMR (400 MHz,
CHLOROFORM-d) δ 8.06 (d, J=8.5 Hz, 1H), 7.94 (dd, J=8.3,
0.9 Hz, 1H), 7.66 (ddd, J=8.3, 6.9, 1.4 Hz, 1H), 7.49 (ddd,
J=8.2, 6.9, 1.2 Hz, 1H), 7.35 (app d, J=0.6 Hz, 1H), 2.69 (d,
J=0.9 Hz, 3H), 1.46 (s, 9H); 13C NMR (101 MHz,
CHLOROFORM-d) δ 169.1, 147.5, 143.7, 130.1, 128.8,
126.7, 125.5, 123.5, 119.0, 38.1, 30.3, 19.1; HRMS (ESI) m/z
calcd for C14H18N [M+H+] 200.1434, found 200.1425.
2-(bicyclo[2.2.2]octan-1-yl)-4-methylquinoline (25). Com-
pound prepared by the general procedure using bicy-
clo[2.2.2]octane-1-carboxylic acid (58 mg, 0.38 mmol, 1.5
equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as sub-
strates with TFA (57 mg, 38 ꢀL, 0.50 mmol, 2.0 equiv) used
in the photochemical portion. Irradiated with blue light for 3 h
in the photochemical portion. Purified by flash column chro-
matography using silica gel on a Teledyne Isco instrument to
give 2-(bicyclo[2.2.2]octan-1-yl)-4-methylquinoline (25, 48
2-benzyl-4-methylquinoline (22). Compound prepared by the
general procedure using 2-phenylacetic acid (51 mg, 0.37
mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0
equiv) as substrates with TFA (58 mg, 39 ꢀL, 0.51 mmol, 2.0
equiv) used in the photochemical portion. Irradiated with blue
light for 3 h in the photochemical portion. Purified by flash
column chromatography using silica gel on a Teledyne Isco
instrument to give 2-benzyl-4-methylquinoline (22, 9 mg, 15%
yield, 93% analytical HPLC purity) as an off-white solid.
LCMS tr = 0.66 min; 1H NMR (499 MHz, CHLOROFORM-d)
δ 8.11 (d, J=8.4 Hz, 1H), 7.94 (dd, J=8.4, 0.9 Hz, 1H), 7.70
(ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.53 (ddd, J=8.2, 6.9, 1.3 Hz,
1H), 7.35 - 7.27 (m, 4H), 7.25 - 7.21 (m, 1H), 7.07 (app d,
J=0.8 Hz, 1H), 4.31 (s, 2H), 2.62 (d, J=0.8 Hz, 3H); 13C NMR
(126 MHz, CHLOROFORM-d) δ 160.9, 147.5, 145.0, 139.4,
129.5, 129.4, 129.4, 128.8, 127.0, 126.6, 126.0, 123.8, 122.3,
45.5, 18.9. HRMS (ESI) m/z calcd for C17H16N [M+H+]
234.1277, found 234.1275.
1
mg, 76% yield) as a white solid. LCMS tr = 0.75 min; H
NMR (400 MHz, CHLOROFORM-d) δ 8.04 (d, J=8.4 Hz,
1H), 7.92 (d, J=8.1 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.52 - 7.43
(m, 1H), 7.28 (s, 1H), 2.67 (s, 3H), 2.04 - 1.94 (m, 6H), 1.79 -
1.69 (m, 7H); 13C NMR (101 MHz, CHLOROFORM-d) δ
168.7, 147.6, 143.5, 130.0, 128.8, 126.7, 125.4, 123.6, 119.4,
37.8, 31.0, 26.5, 24.9, 19.1; HRMS (ESI) m/z calcd for
C18H22N [M+H+] 252.1747, found 252.1748.
2-(5-bromopentyl)-4-methylquinoline (27). Compound pre-
pared by the general procedure using 6-bromohexanoic acid
(73 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25
mmol, 1.0 equiv) as substrates with 1R-(–)-CSA (116 mg, 0.50
mmol, 2.0 equiv) used in the photochemical portion. Irradiated
with blue light for 3 h in the photochemical portion. Purified
by flash column chromatography using silica gel on a Tele-
dyne Isco instrument to give 2-(5-bromopentyl)-4-
2-((1H-indol-3-yl)methyl)-4-methylquinoline (23). Com-
pound prepared by the general procedure using 2-(1H-indol-3-
ACS Paragon Plus Environment

Page 7 of 14
The Journal of Organic Chemistry
methylquinoline (27, 28 mg, 38% yield) as a clear oil. LCMS
120.6, 79.6, 46.2, 28.6, 18.9; HRMS (ESI) m/z calcd for
tr = 0.70 min; 1H NMR (499 MHz, CHLOROFORM-d) δ 8.03
(dd, J=8.4, 0.7 Hz, 1H), 7.95 (dd, J=8.3, 0.9 Hz, 1H), 7.67
(ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.50 (ddd, J=8.3, 6.9, 1.3 Hz,
1H), 7.13 (app d, J=0.7 Hz, 1H), 3.41 (t, J=6.8 Hz, 2H), 2.96 -
2.90 (m, 2H), 2.67 (d, J=0.9 Hz, 3H), 1.96 - 1.89 (m, 2H), 1.88
- 1.80 (m, 2H), 1.60 - 1.52 (m, 2H); 13C NMR (126 MHz,
CHLOROFORM-d) δ 162.2, 147.9, 144.4, 129.5, 129.2,
126.9, 125.6, 123.7, 122.1, 39.1, 33.9, 32.8, 29.2, 28.2, 18.8;
HRMS (ESI) m/z calcd for C15H19NBr [M+H+] 292.0695,
found 292.0696.
C16H21N2O2 [M+H+] 273.1598, found 273.1600.
1
2
3
4
5
6
7
8
2-((benzyloxy)methyl)-4-methylquinoline (30). Compound
prepared by the general procedure using 2-(benzyloxy)acetic
acid (62 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg,
0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 ꢀL,
0.51 mmol, 2.0 equiv) used in the photochemical portion. Irra-
diated with blue light for 3 h in the photochemical portion.
Purified by flash column chromatography using silica gel on a
Teledyne Isco instrument to give 2-((benzyloxy)methyl)-4-
methylquinoline (30, 44 mg, 66% yield) as a yellow oil.
LCMS tr = 0.73 min; 1H NMR (499 MHz, CHLOROFORM-d)
δ 8.07 (d, J=8.5 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.70 (ddd,
J=8.4, 6.9, 1.4 Hz, 1H), 7.55 (ddd, J=8.2, 7.0, 1.1 Hz, 1H),
7.50 (s, 1H), 7.45 - 7.40 (m, 2H), 7.40 - 7.35 (m, 2H), 7.34 -
7.28 (m, 1H), 4.83 (s, 2H), 4.69 (s, 2H), 2.72 (s, 3H); 13C
NMR (126 MHz, CHLOROFORM-d) δ 158.8, 147.5, 145.1,
138.1, 129.7, 129.4, 128.6, 128.0, 127.9, 127.7, 126.2, 123.8,
120.2, 74.0, 73.2, 19.0; HRMS (ESI) m/z calcd for C18H18NO
[M+H+] 264.1383, found 264.1381.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
methyl
methylquinolin-2-yl)butanoate (28). Compound prepared by
the general procedure using ( )-4-((tert-
2-((tert-butoxycarbonyl)amino)-4-(4-
butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid [98
mg, 0.38 mmol, 1.5 equiv, prepared by mixing (+)-4-((tert-
butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid (49
mg, 0.19
mmol, 0.75 equiv) and (–)-4-((tert-
butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid (49
mg, 0.19 mmol, 0.75 equiv)] and lepidine (8, 36 mg, 0.25
mmol, 1.0 equiv) as substrates with ( )-CSA (58 mg, 0.25
mmol, 1.0 equiv) used in the photochemical portion. Irradiated
with blue light for 4 h in the photochemical portion. Purified
by flash column chromatography using silica gel on a Tele-
dyne Isco instrument, repurified by reverse phase preparative
HPLC using ammonium acetate buffer and the fractions con-
taining the desired material were concentrated. The material
was further purified by trituration with deuterated chloroform
to remove salts, concentration of the organic solution, and
flash column chromatography using silica gel on a Teledyne
tert-butyl 3-(4-methylquinolin-2-yl)azetidine-1-carboxylate
(31). Compound prepared by the general procedure using 1-
(tert-butoxycarbonyl)azetidine-3-carboxylic acid (75 mg, 0.37
mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0
equiv) as substrates with TFA (28 mg, 19 ꢀL, 0.25 mmol, 1.0
equiv) used in the photochemical portion. Irradiated with blue
light for 3 h in the photochemical portion. Purified by flash
column chromatography using silica gel on a Teledyne Isco
instrument to give tert-butyl 3-(4-methylquinolin-2-
yl)azetidine-1-carboxylate (31, 29 mg, 39% yield) as a clear
oil. LCMS tr
=
0.71 min; 1H NMR (400 MHz,
Isco
instrument
to
give
methyl
2-((tert-
butoxycarbonyl)amino)-4-(4-methylquinolin-2-yl)butanoate
(28, 25 mg, 28% yield) as a clear oil. LCMS tr = 0.69 min; 1H
NMR (400 MHz, CHLOROFORM-d) δ 8.06 (d, J=8.4 Hz,
1H), 7.95 (dd, J=8.3, 0.8 Hz, 1H), 7.67 (ddd, J=8.3, 7.0, 1.4
Hz, 1H), 7.51 (ddd, J=8.2, 6.9, 1.2 Hz, 1H), 7.13 (s, 1H), 6.20
– 5.75 (m, 1H), 4.48 - 4.18 (m, 1H), 3.71 (s, 3H), 3.02 (t,
J=7.5 Hz, 2H), 2.67 (d, J=0.7 Hz, 3H), 2.41 - 2.30 (m, 1H),
2.30 – 2.17 (m, 1H), 1.44 (s, 9H); 13C NMR (101 MHz,
CHLOROFORM-d) δ 173.3, 160.8, 155.8, 147.6, 144.9,
129.4, 129.4, 127.0, 125.9, 123.7, 122.3, 79.8, 53.8, 52.4,
34.8, 31.5, 28.5, 18.8; HRMS (ESI) m/z calcd for C20H27N2O4
[M+H+] 359.1965, found 359.1959.
CHLOROFORM-d) δ 8.04 (d, J=8.4 Hz, 1H), 7.96 (dd, J=8.3,
0.8 Hz, 1H), 7.69 (ddd, J=8.3, 6.9, 1.4 Hz, 1H), 7.53 (ddd,
J=8.2, 7.0, 1.2 Hz, 1H), 7.26 (s, 1H), 4.43 - 4.34 (m, 2H), 4.27
(dd, J=8.6, 5.9 Hz, 2H), 4.00 (tt, J=8.8, 5.9 Hz, 1H), 2.70 (d,
J=0.7 Hz, 3H), 1.48 (s, 9H); 13C NMR (101 MHz,
CHLOROFORM-d) δ 161.0, 156.7, 147.6, 145.3, 129.8,
129.5, 127.3, 126.2, 123.8, 120.1, 79.6, 54.7 (br), 35.9, 28.6,
18.9; HRMS (ESI) m/z calcd for C18H23N2O2 [M+H+]
299.1754, found 299.1751.
tert-butyl
3-(4-methylquinolin-2-yl)pyrrolidine-1-
carboxylate (32). Compound prepared by the general proce-
dure using 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic
acid (81 mg, 0.38 mmol, 1.5 equiv) and lepidine (8, 36 mg,
0.25 mmol, 1.0 equiv) as substrates with TFA (28 mg, 19 ꢀL,
0.25 mmol, 1.0 equiv) used in the photochemical portion. Irra-
diated with blue light for 3 h in the photochemical portion.
Purified by flash column chromatography using silica gel on a
Teledyne Isco instrument to give tert-butyl 3-(4-
methylquinolin-2-yl)pyrrolidine-1-carboxylate (32, 33 mg,
tert-butyl ((4-methylquinolin-2-yl)methyl)carbamate (29).
Compound prepared by the general procedure using N-(tert-
butoxycarbonyl)glycine (66 mg, 0.38 mmol, 1.5 equiv) and
lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with
TFA (28 mg, 19 ꢀL, 0.25 mmol, 1.0 equiv) used in the photo-
chemical portion. Irradiated with blue light for 3 h in the pho-
tochemical portion. Purified by flash column chromatography
using silica gel on a Teledyne Isco instrument to give tert-
butyl ((4-methylquinolin-2-yl)methyl)carbamate (29, 46 mg,
67% yield) as a white solid. Following the general procedure
using 1R-(–)-CSA (58 mg, 0.25 mmol, 1.0 equiv) in the pho-
tochemical portion (3 h) and identical purification procedure
gave tert-butyl ((4-methylquinolin-2-yl)methyl)carbamate (29,
1
42% yield) as a clear oil. LCMS tr = 0.71 min; H NMR (499
MHz, CHLOROFORM-d) δ 8.04 (br d, J=8.3 Hz, 1H), 7.96
(d, J=8.3 Hz, 1H), 7.69 (br t, J=7.6 Hz, 1H), 7.52 (t, J=7.5 Hz,
1H), 7.16 (app d, J=0.5 Hz, 1H), 3.95 - 3.82 (m, 1H), 3.75 -
3.59 (m, 3H), 3.52 - 3.40 (m, 1H), 2.71 – 2.67 (m, 3H), 2.40 -
2.21 (m, 2H), 1.49 (br s, 4H), 1.48 (br s, 5H); 13C NMR (126
MHz, CHLOROFORM-d) δ 161.1, 161.0, 154.8, 147.7, 145.0,
129.7, 129.4, 127.3, 126.0, 123.8, 120.8, 79.4, 51.3, 51.0,
47.1, 46.3, 46.2, 45.9, 32.4, 31.7, 28.7, 19.0 (five extra carbon
signals attributed to tert-butyl carbamate rotamers); HRMS
(ESI) m/z calcd for C19H25N2O2 [M+H+] 313.1911, found
313.1915.
1
43 mg, 63% yield) as a white solid. LCMS tr = 0.67 min; H
NMR (499 MHz, CHLOROFORM-d) δ 8.05 (d, J=8.4 Hz,
1H), 7.97 (dd, J=8.3, 0.9 Hz, 1H), 7.70 (ddd, J=8.3, 6.9, 1.4
Hz, 1H), 7.54 (ddd, J=8.3, 7.0, 1.2 Hz, 1H), 7.19 (s, 1H), 6.06
– 5.56 (m, 1H), 4.64 – 4.48 (m, 2H), 2.69 (d, J=0.7 Hz, 3H),
1.50 (s, 9H); 13C NMR (126 MHz, CHLOROFORM-d) δ
156.9, 156.2, 147.4, 145.1, 129.6, 129.5, 127.5, 126.2, 123.9,
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The Journal of Organic Chemistry
Page 8 of 14
tert-butyl
4-(4-methylquinolin-2-yl)piperidine-1-
dro-2H-thiopyran-4-carboxylic acid (55 mg, 0.38 mmol, 1.5
1
2
3
4
5
6
7
8
carboxylate (33). Compound prepared by the general proce-
dure using 1-(tert-butoxycarbonyl)piperidine-4-carboxylic
acid (86 mg, 0.38 mmol, 1.5 equiv) and lepidine (8, 36 mg,
0.25 mmol, 1.0 equiv) as substrates with TFA (28 mg, 19 ꢀL,
0.25 mmol, 1.0 equiv) used in the photochemical portion. Irra-
diated with blue light for 3 h in the photochemical portion.
Purified by flash column chromatography using silica gel on a
Teledyne Isco instrument to give tert-butyl 4-(4-
methylquinolin-2-yl)piperidine-1-carboxylate (33, 51 mg, 62%
yield) as a clear oil. LCMS tr = 0.75 min; 1H NMR (499 MHz,
CHLOROFORM-d) δ 8.02 (d, J=8.5 Hz, 1H), 7.94 (d, J=8.4
Hz, 1H), 7.67 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.54 - 7.47 (m,
1H), 7.14 (s, 1H), 4.52 - 4.05 (br m, 2H), 3.00 (tt, J=12.0, 3.7
Hz, 1H), 2.97 - 2.79 (br m, 2H), 2.68 (s, 3H), 1.96 (br d,
J=12.5 Hz, 2H), 1.89 - 1.77 (m, 2H), 1.48 (s, 9H); 13C NMR
(126 MHz, CHLOROFORM-d) δ 164.4, 154.9, 147.7, 144.8,
129.6, 129.3, 127.2, 125.8, 123.7, 120.1, 79.5, 45.6, 44.2 (br),
31.7, 28.6, 19.0; HRMS (ESI) m/z calcd for C20H27N2O2
[M+H+] 327.2067, found 327.2068.
equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as sub-
strates with TFA (58 mg, 39 ꢀL, 0.51 mmol, 2.0 equiv) used
in the photochemical portion. Irradiated with blue light for 3 h
in the photochemical portion. Purified by flash column chro-
matography using silica gel on a Teledyne Isco instrument to
give 4-methyl-2-(tetrahydro-2H-thiopyran-4-yl)quinoline (36,
1
36 mg, 59% yield) as a white solid. LCMS tr = 0.63 min; H
NMR (499 MHz, CHLOROFORM-d) δ 8.02 (d, J=8.5 Hz,
1H), 7.93 (d, J=8.3 Hz, 1H), 7.66 (ddd, J=8.4, 7.0, 1.4 Hz,
1H), 7.49 (ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.14 (s, 1H), 2.96 -
2.85 (m, 3H), 2.77 - 2.70 (m, 2H), 2.67 (s, 3H), 2.32 - 2.23 (m,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2H), 2.10
-
1.98 (m, 2H); 13C NMR (126 MHz,
CHLOROFORM-d) δ 165.0, 147.7, 144.8, 129.6, 129.2,
127.2, 125.8, 123.7, 120.0, 47.2, 33.6, 29.0, 19.0; HRMS
(ESI) m/z calcd for C15H18NS [M+H+] 244.1154, found
244.1154.
2-cyclohexyl-4-methylpyridine (39) and 2,6-dicyclohexyl-4-
methylpyridine (40). Compounds prepared by the general
procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37
mmol, 1.5 equiv) and 4-methylpyridine (23 mg, 0.25 mmol,
1.0 equiv) as substrates with TFA (57 mg, 38 ꢀL, 0.50 mmol,
2.0 equiv) used in the photochemical portion. Irradiated with
blue light for 3 h in the photochemical portion. Purified by
flash column chromatography using silica gel on a Teledyne
Isco instrument to give 2-cyclohexyl-4-methylpyridine (39, 22
mg, 50% yield) as a colorless oil and 2,6-dicyclohexyl-4-
methylpyridine (40, 12 mg, 19% yield) as a white solid. Data
for 39: LCMS tr = 0.61 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ 8.38 (d, J=5.0 Hz, 1H), 6.96 (s, 1H),
6.91 (d, J=5.0 Hz, 1H), 2.65 (tt, J=11.7, 3.4 Hz, 1H), 2.32 (s,
3H), 1.99 – 1.89 (m, 2H), 1.89 – 1.81 (m, 2H), 1.78 - 1.70 (m,
1H), 1.57 - 1.46 (m, 2H), 1.46 - 1.34 (m, 2H), 1.34 - 1.20 (m,
1H); 13C NMR (101 MHz, CHLOROFORM-d) δ 166.4, 148.9,
147.5, 122.2, 122.0, 46.6, 33.1, 26.8, 26.3, 21.2; HRMS (ESI)
m/z calcd for C12H18N [M+H+] 176.1434, found 176.1435.
4-methyl-2-(1-phenylpiperidin-4-yl)quinoline (34). Com-
pound prepared by the general procedure using 1-
phenylpiperidine-4-carboxylic acid (77 mg, 0.38 mmol, 1.5
equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as sub-
strates with TFA (58 mg, 39 ꢀL, 0.51 mmol, 2.0 equiv) used
in the photochemical portion. Irradiated with blue light for 24
h in the photochemical portion. Purified by flash column
chromatography using silica gel on a Teledyne Isco instrument
to give 4-methyl-2-(1-phenylpiperidin-4-yl)quinoline (34, 21
mg, 28% yield) as a white solid that darkened on standing.
LCMS tr = 0.60 min; 1H NMR (499 MHz, CHLOROFORM-d)
δ 8.05 (d, J=8.4 Hz, 1H), 7.97 (dd, J=8.3, 0.9 Hz, 1H), 7.69
(ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.52 (ddd, J=8.3, 6.9, 1.3 Hz,
1H), 7.31 - 7.27 (m, 2H), 7.22 (app d, J=0.7 Hz, 1H), 7.04 –
6.99 (m, 2H), 6.86 (tt, J=7.3, 1.0 Hz, 1H), 3.91 - 3.83 (m, 2H),
3.08 - 3.00 (m, 1H), 2.96 - 2.87 (m, 2H), 2.70 (d, J=0.8 Hz,
1
3H), 2.16
-
2.04 (m, 4H); 13C NMR (126 MHz,
Data for 40: LCMS tr = 0.83 min; H NMR (400 MHz,
CHLOROFORM-d) δ 164.8, 152.0, 147.8, 144.8, 129.7,
129.3, 129.2, 127.3, 125.8, 123.8, 120.1, 119.6, 116.8, 50.4,
45.6, 31.9, 19.0; HRMS (ESI) m/z calcd for C21H23N2 [M+H+]
303.1856, found 303.1855.
CHLOROFORM-d) δ 6.77 (s, 2H), 2.72 - 2.57 (m, 2H), 2.29
(s, 3H), 2.01 – 1.89 (m, 4H), 1.88 – 1.78 (m, 4H), 1.78 – 1.69
(m, 2H), 1.53 - 1.34 (m, 8H), 1.34 - 1.18 (m, 2H); 13C NMR
(101 MHz, CHLOROFORM-d) δ 165.7, 147.3, 118.7, 46.7,
33.3, 26.8, 26.4, 21.3; HRMS (ESI) m/z calcd for C18H28N
[M+H+] 258.2216, found 258.2215.
4-methyl-2-(tetrahydro-2H-pyran-4-yl)quinoline
(35).
Compound prepared by the general procedure using tetrahy-
dro-2H-pyran-4-carboxylic acid (49 mg, 0.38 mmol, 1.5
equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as sub-
strates with TFA (58 mg, 39 ꢀL, 0.51 mmol, 2.0 equiv) used
in the photochemical portion. Irradiated with blue light for 3 h
in the photochemical portion. Purified by flash column chro-
matography using silica gel on a Teledyne Isco instrument to
give 4-methyl-2-(tetrahydro-2H-pyran-4-yl)quinoline (35, 33
4-chloro-2-cyclohexylpyridine (41) and 4-chloro-2,6-
dicyclohexylpyridine (42). Compounds prepared by the gen-
eral procedure using cyclohexanecarboxylic acid (7, 48 mg,
0.37 mmol, 1.5 equiv) and 4-chloropyridine, HCl (38 mg, 0.25
mmol, 1.0 equiv) as substrates with TFA (28 mg, 19 ꢀL, 0.25
mmol, 1.0 equiv) used in the photochemical portion. Irradiated
with blue light for 3 h in the photochemical portion. Purified
by flash column chromatography using silica gel on a Tele-
dyne Isco instrument to give 4-chloro-2-cyclohexylpyridine
(41, 18 mg, 36% yield) as a colorless oil and 4-chloro-2,6-
dicyclohexylpyridine (42, 21 mg, 30% yield) as a white solid.
1
mg, 58% yield) as a white solid. LCMS tr = 0.53 min; H
NMR (499 MHz, CHLOROFORM-d) δ 8.04 (d, J=8.5 Hz,
1H), 7.94 (d, J=8.4 Hz, 1H), 7.71 - 7.63 (m, 1H), 7.53 - 7.47
(m, 1H), 7.17 (s, 1H), 4.12 (dd, J=11.1, 3.9 Hz, 2H), 3.59 (td,
J=11.7, 1.9 Hz, 2H), 3.12 (tt, J=11.9, 3.9 Hz, 1H), 2.69 (s,
3H), 2.06 - 1.96 (m, 2H), 1.94 - 1.87 (m, 2H); 13C NMR (126
MHz, CHLOROFORM-d) δ 164.3, 147.7, 144.8, 129.6, 129.2,
127.2, 125.8, 123.7, 120.0, 68.2, 44.5, 32.4, 19.0; HRMS
(ESI) m/z calcd for C15H18NO [M+H+] 228.1383, found
228.1381.
1
Data for 41: LCMS tr = 0.72 min; H NMR (400 MHz,
CHLOROFORM-d) δ 8.42 (d, J=5.4 Hz, 1H), 7.17 (d, J=1.9
Hz, 1H), 7.11 (dd, J=5.4, 2.0 Hz, 1H), 2.69 (tt, J=11.7, 3.3 Hz,
1H), 1.99 - 1.91 (m, 2H), 1.90 – 1.82 (m, 2H), 1.79 - 1.72 (m,
1H), 1.56 - 1.34 (m, 4H), 1.33 - 1.21 (m, 1H); 13C NMR (101
MHz, CHLOROFORM-d) δ 168.4, 150.1, 144.5, 121.6, 121.6,
46.5, 32.9, 26.6, 26.1; HRMS (ESI) m/z calcd for C11H15NCl
[M+H+] 196.0888, found 196.0896. Data for 42: LCMS tr =
4-methyl-2-(tetrahydro-2H-thiopyran-4-yl)quinoline (36).
Compound prepared by the general procedure using tetrahy-
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The Journal of Organic Chemistry
1
0.97 min; H NMR (400 MHz, CHLOROFORM-d) δ 6.95 (s,
2H), 2.66 (tt, J=11.5, 3.4 Hz, 2H), 1.99 - 1.91 (m, 4H), 1.87 –
1.79 (m, 4H), 1.78 - 1.70 (m, 2H), 1.51 - 1.34 (m, 8H), 1.33 -
1.20 (m, 2H); 13C NMR (101 MHz, CHLOROFORM-d) δ
167.5, 144.3, 118.3, 46.6, 33.0, 26.6, 26.2; HRMS (ESI) m/z
calcd for C17H25NCl [M+H+] 278.1670, found 278.1675.
HRMS (ESI) m/z calcd for C16H20N [M+H+] 226.1590, found
226.1588.
1
2
3
4
5
6
7
8
1-cyclohexylisoquinoline (47). Compound prepared by the
general procedure using cyclohexanecarboxylic acid (7, 48
mg, 0.37 mmol, 1.5 equiv) and isoquinoline (32 mg, 0.25
mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 ꢀL, 0.51
mmol, 2.1 equiv) used in the photochemical portion. Irradiated
with blue light for 3 h in the photochemical portion. Purified
by flash column chromatography using silica gel on a Tele-
dyne Isco instrument to give 1-cyclohexylisoquinoline (47, 41
4-cyclohexylquinoline (43), 2-cyclohexylquinoline (44), and
2,4-dicyclohexylquinoline (45). Compounds prepared by the
general procedure using cyclohexanecarboxylic acid (7, 48
mg, 0.37 mmol, 1.5 equiv) and quinoline (32 mg, 0.25 mmol,
1.0 equiv) as substrates with TFA (58 mg, 39 ꢀL, 0.51 mmol,
2.1 equiv) used in the photochemical portion. Irradiated with
blue light for 3 h in the photochemical portion. Purified by
flash column chromatography using silica gel on a Teledyne
Isco instrument to give 4-cyclohexylquinoline (43, 6.3 mg,
12% yield) as a clear oil, 2-cyclohexylquinoline (44, 5.9 mg,
11% yield) as a clear oil, and 2,4-dicyclohexylquinoline (45,
19 mg, 26% yield) as a clear oil. Data for 43: LCMS tr = 0.70
min; 1H NMR (499 MHz, CHLOROFORM-d) δ 8.84 (d, J=4.6
Hz, 1H), 8.14 – 8.08 (m, 2H), 7.69 (ddd, J=8.4, 6.9, 1.4 Hz,
1H), 7.56 (ddd, J=8.4, 6.9, 1.3 Hz, 1H), 7.28 (d, J=4.7 Hz,
1H), 3.39 - 3.28 (m, 1H), 2.07 - 1.98 (m, 2H), 1.98 - 1.89 (m,
2H), 1.89 - 1.83 (m, 1H), 1.61 - 1.50 (m, 4H), 1.41 - 1.30 (m,
1H); 13C NMR (126 MHz, CHLOROFORM-d) δ 153.6, 150.5,
148.5, 130.5, 128.9, 127.1, 126.3, 123.2, 117.6, 39.0, 33.7,
27.1, 26.4; HRMS (ESI) m/z calcd for C15H18N [M+H+]
212.1434, found 212.1435. Data for 44: LCMS tr = 0.65 min;
1H NMR (499 MHz, CHLOROFORM-d) δ 8.08 (d, J=8.5 Hz,
1H), 8.05 (app d, J=8.5 Hz, 1H), 7.77 (dd, J=8.1, 1.2 Hz, 1H),
7.67 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.47 (ddd, J=8.1, 6.9, 1.1
Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 2.93 (tt, J=12.0, 3.4 Hz, 1H),
2.06 - 1.99 (m, 2H), 1.94 - 1.86 (m, 2H), 1.83 - 1.76 (m, 1H),
1.63 (qd, J=12.6, 3.1 Hz, 2H), 1.48 (qt, J=12.9, 3.3 Hz, 2H),
1.39 - 1.29 (m, 1H); 13C NMR (126 MHz, CHLOROFORM-d)
δ 167.0, 147.9, 136.5, 129.4, 129.1, 127.6, 127.1, 125.7, 119.7,
47.8, 33.0, 26.7, 26.3; HRMS (ESI) m/z calcd for C15H18N
[M+H+] 212.1434, found 212.1435. Data for 45: LCMS tr =
0.91 min; 1H NMR (499 MHz, CHLOROFORM-d) δ 8.06 (dd,
J=8.4, 0.8 Hz, 1H), 8.03 (app d, J=8.4 Hz, 1H), 7.64 (ddd,
J=8.4, 6.9, 1.4 Hz, 1H), 7.47 (ddd, J=8.3, 6.9, 1.3 Hz, 1H),
7.20 (s, 1H), 3.35 - 3.24 (m, 1H), 2.88 (tt, J=12.1, 3.4 Hz, 1H),
2.07 - 1.98 (m, 4H), 1.97 - 1.82 (m, 5H), 1.82 - 1.74 (m, 1H),
1.70 - 1.42 (m, 8H), 1.41 - 1.30 (m, 2H); 13C NMR (126 MHz,
CHLOROFORM-d) δ 166.7, 153.5, 148.2, 130.0, 128.7,
125.8, 125.3, 122.9, 115.9, 48.0, 39.1, 33.8, 33.0, 27.1, 26.7,
26.5, 26.3; HRMS (ESI) m/z calcd for C21H28N [M+H+]
294.2216, found 294.2217.
9
1
mg, 78% yield) as a clear oil. LCMS tr = 0.64 min; H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(499 MHz, CHLOROFORM-d) δ 8.48 (d, J=5.6 Hz, 1H), 8.22
(br d, J=8.4 Hz, 1H), 7.82 – 7.76 (m, 1H), 7.66 - 7.60 (m, 1H),
7.60 - 7.54 (m, 1H), 7.49 – 7.45 (m, 1H), 3.61 - 3.51 (m, 1H),
2.04 - 1.89 (m, 4H), 1.89 - 1.77 (m, 3H), 1.59 - 1.48 (m, 2H),
1.44 - 1.34 (m, 1H); 13C NMR (126 MHz, CHLOROFORM-d)
δ 165.8, 142.0, 136.5, 129.6, 127.6, 126.9, 126.4, 124.8, 119.0,
41.7, 32.7, 27.0, 26.4; HRMS (ESI) m/z calcd for C15H18N
[M+H+] 212.1434, found 212.1432.
1-cyclohexylphthalazine
(48)
and
1,4-
dicyclohexylphthalazine (49). Compounds prepared by the
general procedure using cyclohexanecarboxylic acid (7, 48
mg, 0.37 mmol, 1.5 equiv) and phthalazine (33 mg, 0.25
mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 ꢀL, 0.51
mmol, 2.0 equiv) used in the photochemical portion. Irradiated
with blue light for 3 h in the photochemical portion. Purified
by flash column chromatography using silica gel on a Tele-
dyne Isco instrument to give 1-cyclohexylphthalazine (48, 14
mg, 26% yield, 92% analytical HPLC purity) as a clear oil and
1,4-dicyclohexylphthalazine (49, 35 mg, 47% yield) as a yel-
1
low solid. Data for 48: LCMS tr = 0.64 min; H NMR (499
MHz, CHLOROFORM-d) δ 9.40 (s, 1H), 8.18 (d, J=8.2 Hz,
1H), 7.97 - 7.93 (m, 1H), 7.93 - 7.85 (m, 2H), 3.51 (tt, J=11.4,
3.5 Hz, 1H), 2.10 - 2.02 (m, 2H), 2.02 - 1.92 (m, 4H), 1.87 -
1.80 (m, 1H), 1.59 - 1.48 (m, 2H), 1.46 - 1.36 (m, 1H); 13C
NMR (126 MHz, CHLOROFORM-d) δ 163.7, 150.2, 132.4,
131.8, 127.3, 126.8, 125.2, 123.6, 40.9, 32.5, 27.0, 26.3;
HRMS (ESI) m/z calcd for C14H17N2 [M+H+] 213.1386, found
1
213.1384. Data for 49: LCMS tr = 0.81 min; H NMR (499
MHz, CHLOROFORM-d) δ 8.20 - 8.13 (m, 2H), 7.88 - 7.82
(m, 2H), 3.46 (tt, J=11.3, 3.5 Hz, 2H), 2.09 - 2.01 (m, 4H),
2.01 - 1.91 (m, 8H), 1.85 - 1.78 (m, 2H), 1.58 - 1.46 (m, 4H),
1.44 - 1.33 (m, 2H); 13C NMR (126 MHz, CHLOROFORM-d)
δ 162.0, 131.3, 125.1, 124.4, 40.6, 32.5, 27.1, 26.4; HRMS
(ESI) m/z calcd for C20H27N2 [M+H+] 295.2169, found
295.2166.
2-cyclohexylquinoxaline
(50)
and
2,3-
4-cyclohexyl-2-methylquinoline (46). Compound prepared
by the general procedure using cyclohexanecarboxylic acid (7,
48 mg, 0.37 mmol, 1.5 equiv) and 2-methylquinoline (36 mg,
0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 ꢀL,
0.51 mmol, 2.0 equiv) used in the photochemical portion. Irra-
diated with blue light for 3 h in the photochemical portion.
Purified by flash column chromatography using silica gel on a
Teledyne Isco instrument to give 4-cyclohexyl-2-
methylquinoline (46, 33 mg, 58% yield) as a clear oil. LCMS
tr = 0.72 min; 1H NMR (499 MHz, CHLOROFORM-d) δ 8.05
– 7.99 (m, 2H), 7.63 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 7.47 (ddd,
J=8.4, 7.0, 1.2 Hz, 1H), 7.15 (s, 1H), 3.34 – 3.21 (m, 1H), 2.71
(s, 3H), 2.05 – 1.96 (m, 2H), 1.96 – 1.87 (m, 2H), 1.87 – 1.81
(m, 1H), 1.59 – 1.46 (m, 4H), 1.38 – 1.28 (m, 1H); 13C NMR
(126 MHz, CHLOROFORM-d) δ 158.9, 153.4, 148.2, 129.6,
128.9, 125.3, 125.2, 122.9, 118.4, 38.9, 33.7, 27.0, 26.4, 25.6;
dicyclohexylquinoxaline (51). Compounds prepared by the
general procedure using cyclohexanecarboxylic acid (7, 48
mg, 0.37 mmol, 1.5 equiv) and quinoxaline (33 mg, 0.25
mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 ꢀL, 0.51
mmol, 2.0 equiv) used in the photochemical portion. Irradiated
with blue light for 24 h in the photochemical portion. Purified
by flash column chromatography using silica gel on a Tele-
dyne Isco instrument to give 2-cyclohexylquinoxaline (50, 15
mg, 28% yield) as a tan oil and 2,3-dicyclohexylquinoxaline
(51, 8 mg, 11% yield) as a brown oil. Data for 50: LCMS tr =
1
1.07 min; H NMR (499 MHz, CHLOROFORM-d) δ 8.77 (s,
1H), 8.10 - 8.02 (m, 2H), 7.77 - 7.67 (m, 2H), 2.97 (tt, J=12.0,
3.5 Hz, 1H), 2.08 - 2.01 (m, 2H), 1.97 - 1.90 (m, 2H), 1.84 -
1.78 (m, 1H), 1.72 (qd, J=12.6, 3.2 Hz, 2H), 1.48 (qt, J=12.9,
3.3 Hz, 2H), 1.41 - 1.31 (m, 1H); 13C NMR (126 MHz,
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The Journal of Organic Chemistry
Page 10 of 14
CHLOROFORM-d) δ 161.3, 145.1, 142.3, 141.6, 129.9, (tt, J=12.0, 3.4 Hz, 1H), 2.05 - 1.98 (m, 2H), 1.93 - 1.86 (m,
1
2
3
4
5
6
7
8
129.2, 129.2, 129.0, 45.2, 32.5, 26.5, 26.0; HRMS (ESI) m/z
2H), 1.82 - 1.76 (m, 1H), 1.58 (qd, J=12.6, 3.1 Hz, 2H), 1.45
(qt, J=12.9, 3.3 Hz, 2H), 1.36 - 1.27 (m, 1H); 13C NMR (126
MHz, CHLOROFORM-d) δ 161.0, 148.3, 137.2, 124.9, 118.1,
114.2, 99.7, 46.5, 33.5, 26.8, 26.2; HRMS (ESI) m/z calcd for
C13H16N2Cl [M+H+] 235.0997, found 235.0994.
calcd for C14H17N2 [M+H+] 213.1386, found 213.1395. Data
1
for 51: Analytical HPLC column 2 tr = 12.62 min H NMR
(499 MHz, CHLOROFORM-d) δ 8.00 - 7.96 (m, 2H), 7.64 -
7.59 (m, 2H), 3.09 (tt, J=11.1, 3.8 Hz, 2H), 1.97 - 1.90 (m,
4H), 1.90 - 1.77 (m, 10H), 1.53 - 1.34 (m, 6H); 13C NMR (126
MHz, CHLOROFORM-d) δ 159.8, 141.0, 128.8, 128.5, 41.9,
32.6, 26.9, 26.1; HRMS (ESI) m/z calcd for C20H27N2 [M+H+]
295.2169, found 295.2166.
2-cyclohexylbenzimidazole (55). Compound prepared by the
general procedure using cyclohexanecarboxylic acid (7, 48
mg, 0.37 mmol, 1.5 equiv) and benzimidazole (30 mg, 0.25
mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 ꢀL, 0.51
mmol, 2.0 equiv) used in the photochemical portion. Irradiated
with blue light for 5 h in the photochemical portion. Purified
by flash column chromatography using silica gel on a Tele-
dyne Isco instrument to give 2-cyclohexylbenzimidazole (55,
20 mg, 39% yield) as an off-white solid. LCMS tr = 0.59 min;
1H NMR (499 MHz, METHANOL-d4) δ 7.51 - 7.45 (m, 2H),
7.19 - 7.14 (m, 2H), 2.89 (tt, J=12.0, 3.6 Hz, 1H), 2.11 - 2.03
(m, 2H), 1.91 - 1.84 (m, 2H), 1.81 - 1.74 (m, 1H), 1.66 (qd,
J=12.5, 3.2 Hz, 2H), 1.46 (qt, J=12.8, 3.3 Hz, 2H), 1.39 - 1.29
(m, 1H); 13C NMR (126 MHz, METHANOL-d4) δ 160.8,
139.2 (br), 123.1, 115.3 (br), 39.8, 32.8, 27.2, 27.0; HRMS
(ESI) m/z calcd for C13H17N2 [M+H+] 201.1386, found
201.1388.
9
2-cyclohexyl-4-quinazolinone (52). Compound prepared by
the general procedure using cyclohexanecarboxylic acid (7, 48
mg, 0.37 mmol, 1.5 equiv) and 4-quinazolinone (37 mg, 0.25
mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 ꢀL, 0.50
mmol, 2.0 equiv) used in the photochemical portion. Irradiated
with blue light for 3 h in the photochemical portion. Purified
by flash column chromatography using silica gel on a Tele-
dyne Isco instrument to give 2-cyclohexyl-4-quinazolinone
(52, 32 mg, 55% yield) as a white solid. LCMS tr = 0.70 min;
1H NMR (400 MHz, CHLOROFORM-d) δ 10.96 (br s, 1H),
8.28 (br d, J=7.2 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.73 - 7.64 (m,
1H), 7.46 (br t, J=7.0 Hz, 1H), 2.78 - 2.63 (m, 1H), 2.06 (br d,
J=11.5 Hz, 2H), 2.00 – 1.86 (m, 2H), 1.85 - 1.66 (m, 3H), 1.55
- 1.33 (m, 3H); 13C NMR (101 MHz, CHLOROFORM-d) δ
163.8, 160.0, 149.6, 134.8, 127.5, 126.5, 126.4, 121.0, 45.0,
30.7, 26.1, 25.9; HRMS (ESI) m/z calcd for C14H17N2O
[M+H+] 229.1335, found 229.1333.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-cyclohexylbenzothiazole (56). Compound prepared by the
general procedure using cyclohexanecarboxylic acid (7, 48
mg, 0.37 mmol, 1.5 equiv) and benzothiazole (34 mg, 0.25
mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 ꢀL, 0.50
mmol, 2.0 equiv) used in the photochemical portion. Irradiated
with blue light for 3 h in the photochemical portion. Purified
by flash column chromatography using silica gel on a Tele-
dyne Isco instrument to give 2-cyclohexylbenzothiazole (56,
17 mg, 31% yield) as a pale yellow solid. LCMS tr = 1.12 min;
1H NMR (400 MHz, CHLOROFORM-d) δ 7.97 (d, J=8.1 Hz,
1H), 7.85 (d, J=7.9 Hz, 1H), 7.47 - 7.41 (m, 1H), 7.37 - 7.30
(m, 1H), 3.11 (tt, J=11.6, 3.6 Hz, 1H), 2.26 - 2.15 (m, 2H),
1.94 - 1.84 (m, 2H), 1.81 - 1.73 (m, 1H), 1.65 (qd, J=12.3, 3.2
Hz, 2H), 1.45 (qt, J=12.6, 3.1 Hz, 2H), 1.38 - 1.26 (m, 1H);
13C NMR (101 MHz, CHLOROFORM-d) δ 177.7, 153.3,
134.7, 125.9, 124.6, 122.7, 121.7, 43.6, 33.6, 26.2, 25.9;
HRMS (ESI) m/z calcd for C13H16NS [M+H+] 218.0998, found
218.0995.
6-cyclohexylpurine (53). Compound prepared by the general
procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37
mmol, 1.5 equiv) and purine (30 mg, 0.25 mmol, 1.0 equiv) as
substrates with TFA (57 mg, 38 ꢀL, 0.51 mmol, 2.0 equiv)
used in the photochemical portion. Irradiated with blue light
for 3 h in the photochemical portion. Purified by flash column
chromatography using silica gel on a Teledyne Isco instrument
to give 6-cyclohexylpurine (53, 30 mg, 59% yield) as a white
solid. Also obtained two inseparable isomers each incorporat-
ing a second cyclohexyl group at two different positions in an
unequal ratio, regiochemistry not confirmed (14 mg, 20%
1
yield) as a white solid. LCMS tr = 0.56 min; H NMR (400
MHz, CHLOROFORM-d) δ 12.54 (br s, 1H), 8.98 (s, 1H),
8.27 (s, 1H), 3.61 - 3.44 (m, 1H), 2.08 – 1.98 (m, 2H), 1.97 -
1.86 (m, 4H), 1.86 - 1.77 (m, 1H), 1.59 - 1.32 (m, 3H); 13C
NMR (101 MHz, CHLOROFORM-d) δ 167.2 (br), 152.1,
151.8 (br), 141.9, 131.5 (br), 42.2, 31.5, 26.4, 26.1; HRMS
(ESI) m/z calcd for C11H15N4 [M+H+] 203.1291, found
203.1290.
2-cyclohexylbenzoxazole (57). Compound prepared by the
general procedure using cyclohexanecarboxylic acid (7, 48
mg, 0.37 mmol, 1.5 equiv) and benzoxazole (30 mg, 0.25
mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 ꢀL, 0.51
mmol, 2.0 equiv) used in the photochemical portion. Irradiated
with blue light for 3 h in the photochemical portion. Purified
by flash column chromatography using silica gel on a Tele-
dyne Isco instrument to give 2-cyclohexylbenzoxazole (57, 2.6
mg, 5% yield, 89% analytical HPLC purity) as a tan oil.
LCMS tr = 1.08 min; 1H NMR (499 MHz, CHLOROFORM-d)
δ 7.71 - 7.66 (m, 1H), 7.51 - 7.44 (m, 1H), 7.31 - 7.27 (m, 2H),
2.96 (tt, J=11.4, 3.6 Hz, 1H), 2.22 - 2.14 (m, 2H), 1.91 - 1.84
(m, 2H), 1.78 - 1.66 (m, 3H), 1.48 - 1.38 (m, 2H), 1.38 - 1.28
(m, 1H); 13C NMR (126 MHz, CHLOROFORM-d) δ 170.6,
150.7, 141.3, 124.5, 124.2, 119.7, 110.4, 38.1, 30.6, 25.9,
25.8; HRMS (ESI) m/z calcd for C13H16NO [M+H+] 202.1226,
found 202.1230.
4-chloro-6-cyclohexyl-7-azaindole (54). Compound prepared
by the general procedure using cyclohexanecarboxylic acid (7,
48 mg, 0.37 mmol, 1.5 equiv) and 4-chloro-7-azaindole (38
mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39
ꢀL, 0.51 mmol, 2.0 equiv) used in the photochemical portion.
Irradiated with blue light for 3 h in the photochemical portion.
Purified by flash column chromatography using silica gel on a
Teledyne Isco instrument, repurified by reverse phase prepara-
tive HPLC using ammonium acetate buffer and the fractions
containing the desired material were concentrated. The materi-
al was further purified by flash column chromatography using
silica gel on a Teledyne Isco instrument to give 4-chloro-6-
cyclohexyl-7-azaindole (54, 3 mg, 5% yield) as a white solid
8-cyclohexyl-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-
dione (59). Compound prepared by the general procedure
using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5
equiv) and caffeine (49 mg, 0.25 mmol, 1.0 equiv) as sub-
1
with a faint purple hue. LCMS tr = 0.94 min; H NMR (499
MHz, CHLOROFORM-d) δ 10.39 (br s, 1H), 7.30 (dd, J=3.3,
1.7 Hz, 1H), 7.03 (s, 1H), 6.57 (dd, J=3.4, 1.3 Hz, 1H), 2.78
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The Journal of Organic Chemistry
Irradiated with blue light for 3 h in the photochemical portion.
strates with TFA (58 mg, 39 ꢀL, 0.51 mmol, 2.0 equiv) and
1
2
3
4
5
6
7
8
Purified by reverse phase preparative HPLC using ammonium
acetate buffer and the desired fractions were concentrated to
give (2R,3R,4S,5R)-2-(6-amino-2-cyclohexyl-9H-purin-9-yl)-
5-(hydroxymethyl)tetrahydrofuran-3,4-diol (62, 10 mg, 11%
extra DMSO (1 mL) used in the photochemical portion. Irradi-
ated with blue light for 3 h in the photochemical portion. Puri-
fied by flash column chromatography using silica gel on a
Teledyne Isco instrument to give 8-cyclohexyl-1,3,7-
trimethyl-3,7-dihydro-1H-purine-2,6-dione (59, 14 mg, 20%
1
yield) as a white solid. LCMS tr = 0.53 min; H NMR (400
1
MHz, METHANOL-d4) δ 8.19 (s, 1H), 5.93 (d, J=6.5 Hz, 1H),
4.84 - 4.80 (m, 1H), 4.35 (dd, J=4.9, 2.2 Hz, 1H), 4.19 - 4.15
(m, 1H), 3.95 - 3.85 (m, 1H), 3.75 (dd, J=12.5, 2.4 Hz, 1H),
2.77 - 2.62 (m, 1H), 1.92 - 1.60 (m, 7H), 1.50 - 1.24 (m, 3H);
13C NMR (101 MHz, METHANOL-d4) δ 170.6, 157.4, 150.8,
141.9, 119.4, 91.4, 88.2, 75.0, 72.9, 63.7, 33.2, 33.1, 27.5,
27.4, 27.2; HRMS (ESI) m/z calcd for C16H24N5O4 [M+H+]
350.1823, found 350.1821; Key NOE correlation: singlet at
8.19 ppm correlates with doublet at 5.93 ppm.
yield) as a white solid. LCMS tr = 0.86 min; H NMR (400
MHz, CHLOROFORM-d) δ 3.92 (s, 3H), 3.57 (s, 3H), 3.39 (s,
3H), 2.70 (tt, J=11.7, 3.4 Hz, 1H), 1.95 - 1.81 (m, 4H), 1.80 -
1.63 (m, 3H), 1.46 - 1.28 (m, 3H); 13C NMR (101 MHz,
CHLOROFORM-d) δ 158.1, 155.6, 151.9, 148.3, 107.2, 36.0,
31.5, 31.1, 29.9, 28.0, 26.1, 25.7; HRMS (ESI) m/z calcd for
C14H21N4O2 [M+H+] 277.1659, found 277.1653.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2R,3R,4S,5R)-2-(6-cyclohexyl-9H-purin-9-yl)-5-
(hydroxymethyl)tetrahydrofuran-3,4-diol (60). Compound
prepared by the general procedure using cyclohexanecarbox-
ylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and nebularine (63
mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38
ꢀL, 0.50 mmol, 2.0 equiv) used in the photochemical portion.
Irradiated with blue light for 3 h in the photochemical portion.
Purified by reverse phase preparative HPLC using TFA buffer
and the desired fractions were concentrated. The obtained
material was free-based using ion exchange resin and concen-
trated to give (2R,3R,4S,5R)-2-(6-cyclohexyl-9H-purin-9-yl)-
5-(hydroxymethyl)tetrahydrofuran-3,4-diol (60, 61 mg, 73%
(R)-(2-cyclohexyl-6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-
vinylquinuclidin-2-yl)methanol (63). Compound prepared by
the general procedure using cyclohexanecarboxylic acid (7, 48
mg, 0.37 mmol, 1.5 equiv) and quinine (81 mg, 0.25 mmol,
1.0 equiv) as substrates with TFA (57 mg, 38 ꢀL, 0.50 mmol,
2.0 equiv) used in the photochemical portion. Irradiated with
blue light for 3 h in the photochemical portion. Purified by
flash column chromatography using silica gel on a Teledyne
Isco instrument to give (R)-(2-cyclohexyl-6-methoxyquinolin-
4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methanol (63, 49
mg, 48% yield) as a white solid. Proton and carbon NMR
spectra match spectroscopic data previously reported in the
literature.8,39 LCMS tr = 0.64 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ 7.95 (br d, J=9.1 Hz, 1H), 7.47 (s, 1H),
7.30 (br d, J=8.8 Hz, 1H), 7.20 (br s, 1H), 5.80 - 5.66 (m, 1H),
5.58 (br s, 1H), 5.03 - 4.85 (m, 2H), 3.88 (s, 3H), 3.49 (br s,
1H), 3.20 - 3.04 (m, 2H), 2.89 - 2.76 (m, 1H), 2.75 - 2.60 (m,
2H), 2.35 - 2.20 (m, 1H), 1.94 (br d, J=11.8 Hz, 2H), 1.89 -
1.65 (m, 6H), 1.64 - 1.18 (m, 8H) 13C NMR (101 MHz,
CHLOROFORM-d) δ 164.1, 157.3, 147.7, 144.0, 142.1,
131.4, 125.2, 121.1, 116.8, 114.5, 101.5, 72.6, 60.1, 57.4,
55.8, 47.5, 43.5, 40.2, 33.0, 33.0, 28.1, 27.8, 26.7, 26.2, 21.6;
HRMS (ESI) m/z calcd for C26H35N2O2 [M+H+] 407.2693,
found 407.2695.
1
yield) as a white solid. LCMS tr = 0.60 min; H NMR (400
MHz, METHANOL-d4) δ 8.81 (s, 1H), 8.69 (s, 1H), 6.12 (d,
J=5.8 Hz, 1H), 4.75 (t, J=5.4 Hz, 1H), 4.37 (dd, J=4.9, 3.6 Hz,
1H), 4.17 (q, J=3.0 Hz, 1H), 3.93 - 3.86 (m, 1H), 3.82 - 3.73
(m, 1H), 3.52 - 3.40 (m, 1H), 1.99 - 1.77 (m, 7H), 1.63 - 1.46
(m, 2H), 1.46 - 1.36 (m, 1H); 13C NMR (101 MHz,
METHANOL-d4) δ 167.7, 153.1, 151.7, 145.6, 133.3, 90.7,
87.7, 75.7, 72.3, 63.1, 42.9, 32.3, 27.3, 27.0; HRMS (ESI) m/z
calcd for C16H23N4O4 [M+H+] 335.1714, found 335.1712.
(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-cyclohexyl-9H-
purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (61). Com-
pound prepared by the general procedure using cyclohex-
anecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and
(2R,3R,4R,5R)-2-(acetoxymethyl)-5-(9H-purin-9-
(S)-11-cyclohexyl-4-ethyl-4-hydroxy-1,12-dihydro-14H-
pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione
(64). Compound prepared by the general procedure using cy-
clohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv)
and camptothecin (87 mg, 0.25 mmol, 1.0 equiv) as substrates
with TFA (57 mg, 38 ꢀL, 0.50 mmol, 2.0 equiv) used in the
photochemical portion. Irradiated with blue light for 20 h in
the photochemical portion. Purified by flash column chroma-
tography using silica gel on a Teledyne Isco instrument to give
solid material that was further purified via trituration with
methanol to give (S)-11-cyclohexyl-4-ethyl-4-hydroxy-1,12-
dihydro-14H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-
3,14(4H)-dione (64, 18 mg, 17% yield) as a yellow solid. Pro-
ton NMR spectrum matches spectroscopic data previously
reported in the literature.8 LCMS tr = 0.96 min; 1H NMR (400
MHz, CHLOROFORM-d) δ 8.34 - 8.17 (m, 2H), 7.79 (td,
J=7.6, 1.1 Hz, 1H), 7.69 - 7.62 (m, 2H), 5.76 (d, J=16.3 Hz,
1H), 5.42 (s, 2H), 5.34 - 5.26 (m, 1H), 3.88 - 3.50 (m, 2H),
2.01 (br d, J=10.5 Hz, 4H), 1.96 - 1.81 (m, 4H), 1.64 - 1.52
(m, 3H), 1.51 - 1.39 (m, 1H), 1.04 (t, J=7.4 Hz, 3H); HRMS
(ESI) m/z calcd for C26H27N2O4 [M+H+] 431.1965, found
431.1973.
yl)tetrahydrofuran-3,4-diyl diacetate (95 mg, 0.25 mmol, 1.0
equiv) as substrates with TFA (57 mg, 38 ꢀL, 0.50 mmol, 2.0
equiv) used in the photochemical portion. Irradiated with blue
light for 3 h in the photochemical portion. Purified by flash
column chromatography using silica gel on a Teledyne Isco
instrument to give (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-
cyclohexyl-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate
(61, 70 mg, 61% yield) as a colorless oil. LCMS tr = 0.87 min;
1H NMR (400 MHz, CHLOROFORM-d) δ 8.91 (s, 1H), 8.16
(s, 1H), 6.23 (d, J=5.2 Hz, 1H), 5.98 (t, J=5.4 Hz, 1H), 5.69 (t,
J=5.1 Hz, 1H), 4.50 - 4.43 (m, 2H), 4.41 - 4.34 (m, 1H), 3.45
(tt, J=11.7, 3.3 Hz, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 2.09 (s,
3H), 2.03 - 1.75 (m, 7H), 1.57 - 1.31 (m, 3H); 13C NMR (101
MHz, CHLOROFORM-d) δ 170.4, 169.7, 169.5, 167.2, 152.8,
150.6, 142.0, 132.5, 86.6, 80.5, 73.2, 70.7, 63.2, 42.0, 31.4,
31.4, 26.4, 26.0, 20.9, 20.7, 20.5; HRMS (ESI) m/z calcd for
C22H29N4O7 [M+H+] 461.2031, found 461.2032.
(2R,3R,4S,5R)-2-(6-amino-2-cyclohexyl-9H-purin-9-yl)-5-
(hydroxymethyl)tetrahydrofuran-3,4-diol (62). Compound
prepared by the general procedure using cyclohexanecarbox-
ylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and adenosine (67
mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38
ꢀL, 0.50 mmol, 2.0 equiv) used in the photochemical portion.
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The Journal of Organic Chemistry
Page 12 of 14
N-(3-(5-(4-chlorophenyl)-2-cyclohexyl-1H-pyrrolo[2,3-
7.75 (dd, J=7.8, 1.5 Hz, 1H), 7.49 - 7.39 (m, 3H), 7.24 - 7.17
1
2
3
4
5
6
7
8
b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-
sulfonamide (65). Compound prepared by the general proce-
dure on 0.10 mmol scale using cyclohexanecarboxylic acid (7,
19 mg, 0.15 mmol, 1.5 equiv) and vemurafenib (49 mg, 0.10
mmol, 1.0 equiv) as substrates with TFA (22 mg, 15 ꢀL, 0.20
mmol, 2.0 equiv) used in the photochemical portion. Irradiated
with blue light for 3 h in the photochemical portion. Purified
by flash column chromatography using silica gel on a Tele-
dyne Isco instrument to give N-(3-(5-(4-chlorophenyl)-2-
cyclohexyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-
(m, 2H), 7.01 (s, 1H), 6.82 (d, J=5.0 Hz, 1H), 3.58 (s, 2H),
3.08 - 2.97 (m, 1H), 2.77 - 2.42 (m, 8H), 2.38 (s, 3H), 2.33 (s,
3H), 1.86 - 1.63 (m, 5H), 1.39 - 1.15 (m, 5H); 13C NMR (101
MHz, CHLOROFORM-d) δ 167.2, 165.5, 163.7, 160.4, 158.3,
150.0, 142.4, 137.9, 137.4, 136.7, 134.2, 133.2, 131.0, 129.5,
127.1, 124.2, 120.9, 115.6, 113.0, 112.8, 62.5, 55.0, 52.7,
45.7, 42.4, 32.8, 26.5, 26.0, 17.8; HRMS (ESI) m/z calcd for
C35H43N7O [M+2H]2+ 288.6759, found 288.6757. Data for 67:
Analytical HPLC column 1 tr = 4.45 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ 8.60 - 8.55 (m, 1H), 8.58 (s, 1H) 8.52
(d, J=5.0 Hz, 1H), 8.30 (d, J=1.6 Hz, 1H), 7.84 (s, 1H), 7.80
(br d, J=8.1 Hz, 2H), 7.50 (dd, J=8.2, 1.5 Hz, 1H), 7.44 (br d,
J=8.1 Hz, 2H), 7.29 (d, J=5.3 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H),
7.01 (s, 1H), 6.82 (d, J=5.0 Hz, 1H), 3.56 (s, 2H), 3.03 - 2.91
(m, 1H), 2.72 - 2.36 (m, 8H), 2.33 (s, 3H), 2.31 (s, 3H), 1.88 -
1.66 (m, 5H), 1.49 - 1.35 (m, 2H), 1.34 - 1.13 (m, 3H); 13C
NMR (101 MHz, CHLOROFORM-d) δ 165.9, 165.6, 160.4,
158.5, 154.8, 150.5, 150.0, 142.7, 137.8, 136.7, 134.1, 133.7,
131.0, 129.5, 127.1, 124.5, 121.7, 115.9, 113.3, 113.0, 62.6,
55.2, 53.2, 46.1, 39.6, 33.9, 26.5, 26.0, 17.8; HRMS (ESI) m/z
calcd for C35H43N7O [M+2H]2+ 288.6759, found 288.6760;
Key NOE correlations: doublet at 6.82 ppm correlates with
multiplet at 3.03 – 2.91 ppm, doublet at 6.82 ppm correlates
with singlet at 8.58 ppm. Data for 68: Analytical HPLC col-
umn 1 tr = 4.75 min; 1H NMR (400 MHz, CHLOROFORM-d)
δ 9.14 (d, J=1.9 Hz, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.48 (d,
J=5.2 Hz, 1H), 8.39 (dd, J=8.2, 2.2 Hz, 1H), 7.86 (br s, 1H),
7.84 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.37 (dd,
J=8.2, 2.0 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.20 (d, J=8.2 Hz,
1H), 7.15 (d, J=5.3 Hz, 1H), 7.01 (s, 1H), 3.57 (s, 2H), 2.77
(tt, J=11.7, 3.2 Hz, 1H), 2.50 (br s, 8H), 2.34 (s, 3H), 2.31 (s,
3H), 1.97 (br d, J=11.3 Hz, 2H), 1.92 - 1.83 (m, 2H), 1.81 -
1.73 (m, 1H), 1.56 (qd, J=12.4, 2.2 Hz, 2H), 1.50 - 1.37 (m,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
difluorophenyl)propane-1-sulfonamide (65, 18 mg, 31% yield)
1
as a white solid. LCMS tr = 1.08 min; H NMR (499 MHz,
ACETONE-d6) δ 11.68 (br s, 1H), 8.73 (br s, 1H), 8.56 (d,
J=2.3 Hz, 1H), 7.90 (app br s, 1H), 7.79 (td, J=9.0, 5.8 Hz,
1H), 7.63 - 7.59 (m, 2H), 7.52 - 7.48 (m, 2H), 7.32 - 7.24 (m,
1H), 3.29 - 3.17 (m, 1H), 3.15 - 3.09 (m, 2H), 1.95 (br d,
J=12.3 Hz, 2H), 1.88 - 1.75 (m, 6H), 1.75 - 1.68 (m, 1H), 1.35
- 1.18 (m, 3H), 0.96 (t, J=7.5 Hz, 3H); 13C NMR (126 MHz,
ACETONE-d6) δ 181.5, 157.4, 157.1 (dd, J=246.3, 7.4 Hz),
152.9 (dd, J=248.6, 8.7 Hz), 148.9, 143.7, 138.6, 133.9, 131.4,
130.0, 129.6, 128.7 (d, J=8.3 Hz), 127.0, 123.6 (dd, J=12.9,
3.7 Hz), 121.7 (t, J=23.9 Hz), 120.2, 113.2 (dd, J=22.5, 4.1
Hz), 112.1, 54.9, 38.0, 32.6, 27.3, 26.4, 18.0, 13.0; HRMS
(ESI) m/z calcd for C29H29N3O3F2SCl [M+H+] 572.1581, found
572.1581; Key NOE correlations: doublet at 8.56 ppm corre-
lates with multiplet from 7.63 – 7.59 ppm, apparent broad
singlet at 7.90 ppm correlates with multiplet from 7.63 – 7.59
1
pp; Key HMBC correlations: H signal (8.56 ppm, d, J=2.3
1
Hz, 1H) correlates with 13C signal at 127.0 ppm, H signal
(1.95 ppm, br d, J=12.3 Hz, 2H) correlates with 13C signal at
157.4 ppm.
Products 66 – 71. Compounds prepared by the general proce-
dure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol,
1.5 equiv) and imatinib (123 mg, 0.25 mmol, 1.0 equiv) as
substrates with TFA (57 mg, 38 ꢀL, 0.50 mmol, 2.0 equiv)
used in the photochemical portion. Irradiated with blue light
for 3 h in the photochemical portion. Purified by reverse phase
HPLC using TFA buffer. Isolated fractions were neutralized
with saturated aqueous sodium bicarbonate solution and con-
2H), 1.36
-
1.28 (m, 1H); 13C NMR (101 MHz,
CHLOROFORM-d) δ 169.0, 165.5, 163.2, 160.7, 158.9,
148.0, 142.6, 138.0, 136.7, 135.4, 134.1, 131.0, 130.3, 129.5,
127.2, 124.4, 121.3, 115.4, 113.3, 108.3, 62.7, 55.2, 53.2,
46.7, 46.1, 32.9, 26.7, 26.2, 17.8; HRMS (ESI) m/z calcd for
C35H43N7O [M+2H]2+ 288.6759, found 288.6759; Key NOE
correlations: doublet at 7.15 ppm correlates with doublet of
doublets at 8.39 ppm, doublet at 7.15 ppm correlates with
doublet at 9.14. Data for 69: Analytical HPLC column 1 tr =
centrated
to give N-(3-((4-(2-cyclohexylpyridin-3-
yl)pyrimidin-2-yl)amino)-4-methylphenyl)-4-((4-
methylpiperazin-1-yl)methyl)benzamide (66, 18 mg, 13%
yield) as a pale yellow solid, N-(3-((4-(4-cyclohexylpyridin-3-
yl)pyrimidin-2-yl)amino)-4-methylphenyl)-4-((4-
methylpiperazin-1-yl)methyl)benzamide (67, 17 mg, 12%
yield) as a pale yellow solid, N-(3-((4-(6-cyclohexylpyridin-3-
yl)pyrimidin-2-yl)amino)-4-methylphenyl)-4-((4-
methylpiperazin-1-yl)methyl)benzamide (68, 12 mg, 8% yield,
92% analytical HPLC purity) as a pale yellow solid, N-(3-((4-
(2,4-dicyclohexylpyridin-3-yl)pyrimidin-2-yl)amino)-4-
methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide
(69, 4 mg, 2% yield) as a yellow oil, N-(3-((4-(2,6-
dicyclohexylpyridin-3-yl)pyrimidin-2-yl)amino)-4-
methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide
(70, 10 mg, 6% yield, 94% analytical HPLC purity) as a yel-
low solid, N-(3-((4-(4,6-dicyclohexylpyridin-3-yl)pyrimidin-2-
yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-
1
5.05 min; H NMR (400 MHz, CHLOROFORM-d) δ 8.55 (d,
J=5.3 Hz, 1H), 8.52 (d, J=4.9 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H),
7.82 (d, J=8.2 Hz, 2H), 7.78 (s, 1H), 7.49 (dd, J=8.2, 2.1 Hz,
1H), 7.45 (d, J=8.2 Hz, 2H), 7.21 (d, J=8.4 Hz, 1H), 7.10 (d,
J=5.2 Hz, 1H), 7.02 (s, 1H), 6.68 (d, J=5.0 Hz, 1H), 3.58 (s,
2H), 2.76 - 2.44 (m, 8H), 2.43 - 2.36 (m, 1H), 2.34 (s, 3H),
2.32 (s, 3H), 2.29 - 2.20 (m, 1H), 1.91 - 1.03 (m, 20H); 13C
NMR (101 MHz, CHLOROFORM-d) δ 167.5, 165.6, 162.8,
160.4, 158.0, 154.1, 149.5, 142.5, 137.9, 136.7, 134.1, 132.3,
131.1, 129.5, 127.2, 124.4, 118.8, 115.8, 113.8, 113.2, 62.5,
55.1, 53.6, 52.9, 45.8, 43.4, 41.0, 34.0, 33.7, 32.7, 32.5, 29.8,
26.6, 26.5, 26.0, 26.0, 17.8, 14.3; HRMS (ESI) m/z calcd for
C41H53N7O [M+2H]2+ 329.7150, found 329.7150. Data for 70:
Analytical HPLC column 1 tr = 6.12 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ 8.47 (d, J=5.1 Hz, 1H), 8.40 (d, J=2.0
Hz, 1H), 7.81 (d, J=8.2 Hz, 2H), 7.79 (br s, 1H), 7.64 (d, J=8.0
Hz, 1H), 7.48 (dd, J=8.2, 1.8 Hz, 1H), 7.44 (d, J=8.1 Hz, 2H),
7.20 (d, J=8.3 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.98 (s, 1H),
6.82 (d, J=5.1 Hz, 1H), 3.57 (s, 2H), 3.06 - 2.93 (m, 1H), 2.72
(tt, J=11.5, 3.3 Hz, 1H), 2.52 (br s, 8H), 2.33 (s, 6H), 2.11 -
yl)methyl)benzamide (71, 11 mg, 7% yield, 93% analytical
HPLC purity) as a yellow solid. Data for 66: Analytical HPLC
column
1
tr
=
4.22 min; 1H NMR (400 MHz,
CHLOROFORM-d) δ 8.65 (dd, J=4.7, 1.5 Hz, 1H), 8.51 (d,
J=5.0 Hz, 1H), 8.41 (d, J=1.8 Hz, 1H), 7.85 - 7.77 (m, 3H),
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
1.10 (m, 20H); 13C NMR (101 MHz, CHLOROFORM-d) δ
of a 1.5 M aqueous K2HPO4 solution (1.5 mL). The organic
1
2
3
4
5
6
7
8
167.8, 166.8, 165.5, 162.6, 160.3, 158.0, 142.6, 138.0, 137.3,
136.7, 134.2, 131.0, 130.0, 129.5, 127.1, 124.0, 117.9, 115.4,
112.9, 112.8, 62.6, 55.1, 53.0, 46.5, 45.9, 42.4, 32.9, 32.8,
26.7, 26.6, 26.4, 26.1, 17.8; HRMS (ESI) m/z calcd for
C41H53N7O [M+2H]2+ 329.7150, found 329.7151; Key NOE
correlation: doublet at 7.64 ppm correlates with doublet at
6.82 ppm. Data for 71: Analytical HPLC column 1 tr = 5.83
layer was dried (Na2SO4), filtered, and concentrated to afford a
crude yellow solid. This crude material was purified by flash
column chromatography using silica gel on a Teledyne Isco
instrument to give methyl 4-(4-chloro-6-methylpyridin-2-
yl)bicyclo[2.2.2]octane-1-carboxylate (72, 285 mg, 78% yield)
as an off-white solid.
6.25 mmol scale: Run in a 200-mL flask using a standard
1
min; H NMR (400 MHz, CHLOROFORM-d) δ 8.53 - 8.48
rubber
septum.
To
a
stirred
solution
of
4-
(m, 1H), 8.51 (s, 1H) 8.30 (d, J=2.0 Hz, 1H), 7.84 - 7.77 (m,
2H), 7.80 (s, 1H), 7.53 (dd, J=8.2, 2.0 Hz, 1H), 7.44 (d, J=8.2
Hz, 2H), 7.21 (d, J=8.3 Hz, 1H), 7.15 (s, 1H), 6.98 (s, 1H),
6.82 (d, J=5.1 Hz, 1H), 3.57 (s, 2H), 2.97 (tt, J=11.9, 3.0 Hz,
1H), 2.73 (tt, J=11.8, 3.3 Hz, 1H), 2.51 (br s, 8H), 2.32 (s,
(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic
acid
9
(1.99 g, 9.38 mmol, 1.5 equiv), N-hydroxyphthalimide (1.53 g,
9.38 mmol, 1.5 equiv), and DMAP (38.5 mg, 0.32 mmol, 5
mol %) in DMSO (31 mL) was added DIC (1.46 mL, 9.37
mmol, 1.5 equiv). The reaction was stirred at room tempera-
ture for 24 h for in situ NAP formation. Then, a solution of 4-
chloro-2-methylpyridine (797 mg, 6.25 mmol, 1.0 equiv) and
TFA (1.43 g, 0.96 mL, 12.5 mmol, 2.0 equiv) in DMSO (20
mL for solution formation and initial transfer + 11 mL rinse of
vial containing transferred solution) was transferred to the
solution containing the NAP. Then, 4-CzIPN (10, 49 mg,
0.062 mmol, 1 mol %) was added to the reaction mixture. The
solution was bubbled vigorously for 8 min with nitrogen gas,
sealed, and affixed with a balloon containing nitrogen gas. The
reaction vessel was placed above a stir plate between two blue
Kessil brand KSH150B Grow Light LED 34 W lamps secured
with gooseneck clamps. The center of the reaction vessel was
roughly 6 cm from each lamp. No cooling fan was used, and
the internal temperature was measured to be 45 °C at comple-
tion. The reaction was stirred and irradiated with blue light for
24 h. Upon completion, the reaction was opened to air, diluted
with CH2Cl2 (250 mL) and poured into a separatory funnel
containing water (250 mL) and 1.5 M aqueous K2HPO4 solu-
tion (50 mL). The solution reached roughly pH 8 as judged by
pH paper. The aqueous layer was extracted with DCM (3 × 50
mL). The combined organic extracts were washed with water
(3 × 250 mL) that had been made slightly basic by the addition
of a 1.5 M aqueous K2HPO4 solution (1.5 mL) added to each
wash. The organic layer was dried (Na2SO4), filtered, and con-
centrated to afford a crude yellow solid. This crude material
was purified by flash column chromatography using silica gel
on a Teledyne Isco instrument to give methyl 4-(4-chloro-6-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6H), 2.01
-
1.17 (m, 20H); 13C NMR (101 MHz,
CHLOROFORM-d) δ 167.5, 166.3, 165.6, 160.3, 158.3,
155.1, 149.4, 142.6, 137.9, 136.7, 134.1, 131.3, 131.0, 129.5,
127.2, 124.3, 118.9, 115.7, 113.1, 113.0, 62.6, 55.2, 53.1,
46.8, 46.0, 39.7, 34.0, 33.1, 26.7, 26.6, 26.2, 26.1, 17.8;
HRMS (ESI) m/z calcd for C41H53N7O [M+2H]2+ 329.7150,
found 329.7153; Key NOE correlation: singlet at 8.51 ppm
correlates with doublet at 6.82 ppm.
Procedure for Substrate Run on 0.25 mmol, 1.25 mmol and
6.25 mmol Scale: methyl 4-(4-chloro-6-methylpyridin-2-
yl)bicyclo[2.2.2]octane-1-carboxylate (72). 0.25 mmol scale:
Compound prepared by the general procedure using 4-
(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (80
mg, 0.38 mmol, 1.5 equiv) and 4-chloro-2-methylpyridine (32
mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39
ꢀL, 0.51 mmol, 2.0 equiv) used in the photochemical portion.
Irradiated with blue light for 3 h in the photochemical portion.
Purified by flash column chromatography using silica gel on a
Teledyne Isco instrument to give methyl 4-(4-chloro-6-
methylpyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate (72, 50
mg, 68% yield) as a white solid.
1.25 mmol scale: Run in a 20-mL vial with a cap containing a
teflon-lined pressure-release septum. To a stirred solution of
4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid
(398 mg, 1.88 mmol, 1.5 equiv), N-hydroxyphthalimide (306
mg, 1.88 mmol, 1.5 equiv), and DMAP (7.7 mg, 0.063 mmol,
5 mol %) in DMSO (6.25 mL) was added DIC (0.29 mL, 1.86
mmol, 1.5 equiv). The reaction was stirred at room tempera-
ture for 24 h for in situ NAP formation. Then, a solution of 4-
chloro-2-methylpyridine (159 mg, 1.25 mmol, 1.0 equiv) and
TFA (283 mg, 0.19 mL, 2.48 mmol, 2.0 equiv) in DMSO (4
mL for solution formation and initial transfer + 2.25 mL rinse
of vial containing transferred solution) was transferred to the
solution containing the NAP. Then, 4-CzIPN (10, 9.9 mg,
0.013 mmol, 1 mol %) was added to the reaction mixture. The
solution was bubbled vigorously for 180 seconds with nitrogen
gas, sealed, and affixed with a balloon containing nitrogen gas.
The reaction vessel was placed above a stir plate between two
blue Kessil brand KSH150B Grow Light LED 34 W lamps
secured with gooseneck clamps. The center of the reaction
vessel was roughly 5 cm from one lamp and 7 cm from the
other. No cooling fan was used. The reaction was stirred and
irradiated with blue light for 3 h. Upon completion, the reac-
tion was opened to air, diluted with CH2Cl2 (60 mL) and
poured into a separatory funnel containing water (50 mL). A
1.5 M aqueous K2HPO4 solution was added until the solution
reached roughly pH 8 as judged by pH paper. The organic
layer was separated, washed with water (50 mL) and washed
again with water (50 mL) made slightly basic by the addition
methylpyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate
(72,
1.33 g, 73% yield) as an off-white solid. LCMS tr = 0.78 min;
1H NMR (499 MHz, DMSO-d6) δ 7.21 (d, J=1.5 Hz, 1H), 7.19
(d, J=1.3 Hz, 1H), 3.59 (s, 3H), 2.43 (s, 3H), 1.87 - 1.82 (m,
6H), 1.82 - 1.77 (m, 6H); 13C NMR (126 MHz, DMSO-d6) δ
177.3, 168.5, 158.6, 143.1, 120.3, 116.8, 51.5, 38.7, 37.3,
29.9, 28.1, 24.0; HRMS (ESI) m/z calcd for C16H21NO2Cl
[M+H+] 294.1255, found 294.1257.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Spectral data for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
* Trevor.Sherwood@bms.com; Tel (609)-252-3341
Author Contributions
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script.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We would like to thank Linping Wang and Robert Langish for
assistance with HRMS and Janet Caceres Cortes, Purnima
Khandelwal, and Xiaohua Stella Huang for assistance with NMR
characterization. We also thank Yingru Zhang for assistance with
purification of select compounds. We are grateful to Christopher
Jamison in BMS Chemical and Synthetic Development for
providing us with 4-CzIPN photocatalyst. We would like to thank
Andrew Dilger for helpful discussions. We are grateful to William
(Rick) Ewing for serving as chair of the summer intern program at
Bristol-Myers Squibb supporting Aliza N. Yazdani.
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