Transformations of Isonitriles with Bromoalkanes Using Photoredox Gold Catalysis

Article abstract of DOI:10.1021/acs.joc.8b01380

Isonitriles have excellent electronic compatibility to react with free radicals. Recently, photoredox catalysis has emerged as a powerful tool for the construction of C-C bonds with few protocols for alkylative heterocycle synthesis through isonitrile addition. Herein, we describe the photocatalytic generation of alkyl radicals from unactivated bromoalkanes as part of an efficient cross-coupling strategy for the diversification of isonitriles using a dimeric gold(I) photoredox catalyst, [Au₂(dppm)₂]Cl₂.

Full text of DOI:10.1021/acs.joc.8b01380

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Article
Transformations of Isonitriles with
Bromoalkanes using Photoredox Gold Catalysis
Samantha Rohe, Terry McCallum, Avery O. Morris, and Louis Barriault
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01380 • Publication Date (Web): 06 Jul 2018
Downloaded from http://pubs.acs.org on July 6, 2018
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The Journal of Organic Chemistry
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Transformations of Isonitriles with Bromoalkanes using
Photoredox Gold Catalysis
Samantha Rohe, Terry McCallum, Avery O. Morris, Louis Barriault*
Centre for Catalysis, Research and Innovation Department of Chemistry and Biomolecular Sciences,
University of Ottawa, 10 Marie Curie, Ottawa, ON, K1N 6N5 (Canada).
Supporting Information Placeholder
ABSTRACT: Isonitriles have excellent electronic compatibility to react with free radicals. Recently, photoredox
catalysis has emerged as a powerful tool for the construction of C-C bonds, with few protocols for alkylative
heterocycle synthesis through isonitrile addition. Herein, we describe the photocatalytic generation of alkyl
radicals from unactivated bromoalkanes as part of an efficient cross-coupling strategy for the diversification of
isonitriles using a dimeric gold(I) photoredox catalyst, [Au2(dppm)2]Cl2.
A
A
Path A
R1
R1
INTRODUCTION
R2
R1
N C
+
R2
N
R2
N
1
2
Inspired by the complexity found in the light-harvesting
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biomolecules in Nature, chemists have developed
photoexcitable complexes that serve well in energy storage,
water splitting, photovoltaic devices, and transformations of
organic molecules.1 Modern applications of photoredox
catalysis to classical radical chemistry have produced
unconventional reactivity in organic synthesis, unlocking mild
and efficient methodology for the construction of new C-C, C-
O, and C-N bonds. These processes are advantageous to
classical methods of radical generation by circumventing the
use of radical initiators, harsh reagents and conditions.2 The
Path B
R1
+
N
R2
3
Previous Studies with Activated Bromoalkanes
EWG Br
R4
R4
Y
Y
R3
Photoredox Catalyst
hv
R3
(1)
EWG
N+
N
C-
EWG = CO2Et, Y = alkyl, F
EWG = RF, Y = F
Y
Y
construction
of
heterocyclic
scaffolds
through
multicomponent radical coupling reactions and cascade
cyclizations has been instrumental in the expedient synthesis
of complex and medicinally relevant structures.3 The use of
isonitrile moieties in the fabrication of such structures has
allowed the synthesis of various heteroarene scaffolds.
This Study with Unactivated Bromoalkanes
Y
het
Br
R2
X
R1
R2
[Au2(dppm)2]Cl2 5 mol%
N+
N
and
(2)
C-
DABCO, hv
O
Original work from Shono and Saegusa showed that radical
intermediates can add to isonitriles to form an imidoyl radical
intermediate 1 (Figure 1).4 The latter can undergo two
competitive pathways, addition to an acceptor (path A) to
provide compound 2 or a β-fragmentation to give the
- operationally simple, broad scope
- unactivated 1o, 2o, 3o bromoalkanes
- 39 examples, up to 99% yield
R1
N
R2
H
Figure 1. Phenanthridine and amide synthesis as examples of
isonitrile functionalization using photoredox catalysis.
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Page 2 of 11
corresponding nitrile 3 (path B). The addition of carbon
centered radical types to isonitriles has been a rich medium
for methodological advancements.5
made available where haloalkanes may bind, leading to inner
1
2
3
4
5
6
7
8
sphere activation which can occur through photoinduced
electron transfer of the exciplex.11 This unique inner sphere
mechanism allows for activation of haloalkanes that have
reduction potentials greater than the dimeric gold(I) complex
and that are unavailable to Ru and Ir-based polypyridyl
complexes that operate through an outer sphere mechanism
of metal-to-ligand charge transfer (MLCT).
Particularly, unactivated alkyl radical genesis has been an
area where little mild and broadly applicable methodology
exists for isonitrile functionalization.6 These processes
typically employ stoichiometric initiators/oxidants or use the
parent alkane as solvent; reagent intensive methodology that
is limiting in scope. Recently, a variety of photoredox
catalyzed reaction modes have been developed to circumvent
the described limitations (Figure 1, eq. 1).7 Although the use
of common photocatalysts like Ru and Ir-based polypyridyl
complexes has given mild and high yielding protocols, these
complexes are limited by the redox potentials inherent to each
photocatalyst. With this in mind, we hypothesized that
several practical coupling strategies for path A (selective
isonitrile alkylation) of broader applicability could be
conceived using photoredox catalysis and simple
bromoalkanes (Figure 1, eq. 2). To that effect, a dimeric
gold(I) photocatalyst, [Au2(dppm)2]Cl2, for the mild
generation of a broad scope of alkyl radicals for the
functionalization of isonitriles is described.
RESULTS
9
To verify our hypothesis, we first examined the generation of
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phenanthridines
6 via UVA irradiation (365 nm) of
bromocyclohexane 4a and isonitrile 5a in the presence of
[Au2(dppm)2]Cl2 (5.0 mol %) and Na2CO3 (3 equivalents)
(Table 1). Further optimizations established that reactions
carried out at 0.1 M in degassed acetronitrile gave 6aa along
with 6a’ (R = H) in 74% and 7% yield, respectively (entry 1).
The addition of a sub-stoichiometric quantity of DABCO
proved to be beneficial to the reaction, yielding 6aa in 87%
yield (82% isolated yield, entry 2). As shown in a previous
study,12 this reagent may act as a resuscitator or repair agent
of the [AuI-AuII]3+ intermediate if the oxidation of
intermediate becomes unfavourable and leads to degradation
products. Alternatively, the amine base could promote a
Based on previous studies in our laboratory, we envisioned
that a redox-neutral isonitrile functionalization protocol
employing a photoredox dimeric gold catalyst as reductant
and oxidant would mitigate the need for stoichiometric
additives and harsh conditions.8 This strategy generates alkyl
radicals derived from readily available bromoalkanes 4 (> –
2.0 V vs. SCE)9 through an oxidative quenching mechanism
with photoexcited [Au2(dppm)2]Cl2 (–1.63 V vs. SCE) (Figure
2).
reductive quenching process of excited state photocatalyst
DABCO
(kq
= 1.97 x 108 M-1s-1), leading to a complex [AuI-Au0]1+
which can reduce bromoalkane
corresponding alkyl
4
to generate the
Interestingly, the
radical.11
phenanthridine by-product 6a’ (R = H) was not observed
when using DABCO. Decreasing the catalyst loading to 2.5 and
1.0 mol% gave similar results of 85% and 82% yields,
respectively, showing the efficiency of the transformation
(entries 3 and 4). Furthermore, the gram-scale reaction gave
the desired product in 66% yield (entry 5), demonstrating the
robustness of the process. Finally, light irradiation and
photocatalyst were shown to be vital to the success of the
reaction (entries 6, 7).
*
AuI
AuI
Br
R = 1°, 2°, 3° alkyl
R2
Br
R2
4
Oxidative
Quench
R2
Inner Sphere
Exciplex
Isonitrile
Addition
Table 1. Optimization of the reaction conditions.a
*
Photoredox
Catalysis
AuI
AuI
AuI
AuII
Br
R1
N
C
5
-H+, -e-
hv
(365 nm)
R1
or
N
R2
-e-
, + H2O
I
Au
AuI
2Cl-
Ph
Ph
Ph
Entry
[Au2(dppm)2]Cl2 (mol %)
DABCO (mol%)
Yield (%)
74
P
Au
P
P
Ph
O
Au
1
2
3
4
5
6
7
5.0
5.0
2.5
1.0
1.0
---
---
R1
N
or
Ph
Ph
Ph
P
R2
20
20
20
20
20
20
87 (82)
85
Ph
R2
H
N
7
6
82
66b
Figure 2. Proposed mechanism gold-catalyzed photoredox.
s.m.
s.m.c,d
The incumbent alkyl radicals would then react with isonitriles
5 allowing for the formation of a sp2 hybridized radical that
would then go through one of two pathways: 1) further cyclize
upon a pendant arene to form a cyclohexadienyl radical,
followed by oxidation by [Au2(dppm)2]3+ to complete the
catalytic cycle and produce the phenanthridine products 6; 2)
the imidoyl radical formed prior to addition to the isonitrile
could be directly oxidized by [Au2(dppm)2]3+ and be trapped
with water, hydrolyzing to amide products 7. Binuclear Au(I)
phosphine complexes such as [Au2(dppm)2]Cl2 have little
aurophilic interaction in the ground state but upon excitation,
an Au-Au interaction is forged.10 An open coordination site is
5.0
a Procedure: 5a (0.2 mmol), CyBr 4a, (3 equiv.), [Au (dppm) ]Cl (x mol%), Na CO (3
2
2
2
2
3
equiv.), DABCO (20 mol%), MeCN, Ar degas, irradiation with UVA LEDs for 16 hours. Yields
determined by 1H NMR analysis using an internal standard mesitylene (isolated yield). b 1.0
gram (5.2 mmol, c = 0.5 M) scale of 5a irradiated for 36 hours using 3 UVA LEDs. c In absence
of irradiation, 36 hours. d In absence of irradiation and heating to 80 °C, 36 hours.
Following the optimization, the addition of various
bromoalkanes to aryl isonitrile was explored (Table 2).
Primary bromoalkane coupling partners 4b-g proceeded in
moderate to excellent yields (33-83%), with notable success
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when using the glucose derivative 4g highlighting the
ring-opened product 7ar (n = 1) in 53% yield (entry 1). The
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4
5
6
7
8
potential of this methodology for application in the synthesis
of structurally complex compounds. Light-enabling addition of
protected bromoalcohols 4e and 4f gave the desired
phenanthridines 6ae and 6af in 83% and 33% yields,
respectively. In the cases where full conversion was not
obtained, the balance of the product was starting material.
Compounds 4h-o containing 2° and 3° bromoalkanes fared
significantly better, affording 6ah-ao in good to excellent
yields (64-99%). Notably, five of the substrates exhibited
comparable yields when using a catalyst loading of 1.0 mol%.
use of (bromomethyl)cyclobutane 4s afforded a 50:50
mixture of ring-opened and -closed products 6as (n = 2) and
7as (n = 2) in 64% yield (entry 2). One can see it as an
expected result given the rate of ring-opening is known to be
slower for cyclobutylmethyl radicals than cyclopropylmethyl
radicals. Conversely, ring-closing radical cyclization reactions
were attempted in entries 3-6. These substrates allow
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Table 2. Bromoalkane scope in phenanthridine
synthesis.
Table 3. Isonitrile scope using bromocyclohexane.
comparison of the putative radical intermediate by evaluating
direct addition to the isonitrile substrate versus the exo-trig
cyclization subsequent to isonitrile addition. Bromoalkane 4t
resulted in exclusive formation of 7as in 33% yield as the 4-
exo-trig cyclization is not favourable whereas bromoalkane 4u
gave 6au (n = 3) as the sole product in 52% yield, favouring
the 5-exo-trig cyclization prior the addition to 5a (entry 4).
Interestingly, a 48:52 ratio of 6av (n = 4) and 7av (n = 4) was
observed with bromoalkene 4v, indicating that addition of the
primary radical and the 6-exo-trig cyclization take place at
similar rates (entry 5). Finally, reaction with substrate 4w
gave 7aw in 64% yield as the sole product (entry 6).
a Reaction performed with 1mol% catalyst loading
As outlined in Table 3, the generality of the isonitrile coupling
partner under the optimized reaction conditions was
examined. In general, the nature of the substituents on the
biphenyl isonitrile right-hand ring did not have much
influence on the outcome of the reaction with little correlation
between the yield and electronic properties. For instance, the
cyclizations of 5c (R” = CF3) and 5g (R” = OMe) provided the
corresponding compounds 6ca and 6ga in 67% and 65%
yields, respectively. Irradiation of the pyrrole-substituted
isonitrile 5e using the standard conditions gave the
heterocycle 6ea in 64% yield. However, photodegradation of
the materials was observed when substituents R’ ≠ H or Me, or
heterocycles on the left-hand ring, with the exception of
isonitrile 5b (R’ = Cl) giving the desired product 6ba in 63%
yield. Aside from the initial biphenyl isonitrile starting
Table 4. Ring-opening and forming reactions of known
radical clock bromoalkanes.
material,
a double cyclization was attempted on p-
Entry
RBr
n =
Yield (%)
Ratio
6:7
methoxyphenylisonitrile 5i. The resulting quinoline 6ip and
quinoxaline 6iq from 5-bromopentyne 4q and 4-
bromobutyronitrile 4n were obtained in moderate isolated
yields of 55% and 30%, respectively.
1
2
1, 4r
2, 4s
53
64
0:100
50:50
An additional tool for mechanistic elucidation for
methodology involving radical additions is the use of
bromoalkane substrates that may undergo known radical
ring-opening and closing reactions before subsequent
addition to the isocyanide moiety, as demonstrated in Table 4.
The use of bromomethylcyclopropane 4r afforded exclusively
3
4
2, 4t
33
52
0:100
100:0
3, 4u
5
6
4, 4v
5, 4w
53
64
48:52
0:100
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cycle, the role of DABCO remains elusive and will be subject of
further study.
DISCUSSION
1
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5
6
7
8
Next, the absolute rate of 1° radical addition to isonitrile 5a
could be determined using
Full conversion was also observed with aryl isonitrile 5k
leading to the corresponding amides 9ka-9kf in 57-64%
yields while isonitrile 5i and bromide 4a produced amide 10
in 31% yield. One can recognize that photodegradation of
products is likely and rearrangement of isonitrile to nitrile
was observed in several cases.16
a
kinetic study with
(bromomethyl)cyclobutane 4s as shown in Figure 3. In this
experiment, the ratio of ring-closed product 6as versus the
rearranged ring-opened product 7as was compared under
increasing concentration of 5a. It was found that the absolute
rate of addition of primary alkyl radicals to 5a was 2.17 ± 0.25
x 104 M-1s-1. The results show a linear correlation under
pseudo-first order conditions, indicative of a free radical
addition process.13 Using the binuclear gold(I) photocatalyst
and bromoalkanes with known rearrangement rates offer an
attractive alternative to standard photochemical radical
clocking experiments using the pyridine-2-thione-N-
oxycarbonyl (PTOC) thiol method.14
Table 5. Bromoalkane and isonitrile scope in amide
synthesis.
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[Au2(dppm)2]Cl2 5 mol%
Na2CO3 (3 equiv.)
DABCO (1 equiv.)
O
R1
R2 Br
N+
R1
C-
O
N
R2
+
H2O (21 equiv.)
MeCN (0.1 M), Ar degas
UVA LED, 16 h
H
5i-k
8a-f
(3 equiv.)
9jr-lw
Figure 3. Kinetic study of the absolute rate of 1o radical
addition to isocyanide 5a, ratio of products 6as / 7as vs. [5a]
(M).
A
O
O
CO2Et
CO2tBu
CN
N
N
H
N
H
H
9jc (22%)
9ja (99%)
9jb (41%)
O
O
O
O
CO2tBu
CO2Et
N
H
N
6as
[Au2(dppm)2]Cl2 (0.02 M)
Na2CO3
N
H
O
N
H
Br
4q (1.0 M)
+
N+
9kb (64%)
9ka (57%)
C-
9jd (96%)
MeCN, Ar degas
UVA LED, 16 h
5a
MeO
O
O
O
N
CO2Et
CO2Et
3
N
N
N
Cy
7as
H
H
H
CO2Et
Me
9kf (58%)
10 (31%)
9ke (58%)
5 x 103 M-1s-1
B
R1
R2
O
+ H2O
- e
R1
R1
R1
R2
R2
N
R2
N
N
N
H
CONCLUSION
In summary, we demonstrated that alkyl and aryl isonitriles
and bromoalkanes can be coupled through photoredox
catalysis to generate functionalized phenanthridine scaffolds
and amides. Binuclear Au(I) complex, [Au2(dppm)2]Cl2,
proved to be an efficient photocatalyst in this transformation.
The reaction was shown to be robust and broad in scope with
relation to the bromoalkanes and isonitriles that were
coupled in this facile process. Further studies in the
development of radical transformations using isonitriles and
their applications to late-stage functionalization of
medicinally important molecules are currently being
explored.
6as / 7as
[5a] (M)
Finally, the prospects of applying the developed methodology
for alkyl radical addition to isonitriles for the synthesis of
amides were evaluated (Table 5). There are few examples
using isonitriles for the synthesis of amides and, to the best of
our knowledge, this would be the first photochemical and
alkyl radical mediated amide synthesis using isonitriles 5i-k.15
Employing the standard conditions described above with 1
equivalent DABCO, the addition of electrophilic radicals 8a-d
to tert-butyl isonitrile 5k gave the desired amides 9ja-jd in
yields ranging from 22% to 99%. During the establishment of
the reaction scope, we noted that the reaction yields were
improved significantly with the addition of a small quantity of
water (21 equiv). Interestingly, fragmentation products (cf.
Figure 1, path B) such as alkyl nitriles 3 were not observed.
One can consider that the formation of the amides 9 proceeds
through oxidation of the imidoyl radical intermediate to the
corresponding carbocation (Table 5B). When considering that
the reaction may proceed through an oxidative quenching
EXPERIMENTAL SECTION
General information. All reactions were performed under
argon atmosphere Pyrex glassware equipped with a magnetic
stir bar, capped with a septum, unless otherwise indicated. All
commercial reagents were used without further purification,
unless otherwise noted. Reactions were monitored by thin
layer chromatography (TLC) analysis. TLC plates were viewed
under UV light and stained with potassium permanganate or
p-anisaldehyde staining solution. Yields refer to products
isolated after purification, unless otherwise stated. Proton
nuclear magnetic resonance spectra were recorded on a
Bruker AMX 400 MHz. NMR samples were dissolved in
chloroform-d (unless specified otherwise) and chemical shifts
are reported in ppm referenced to residual non-deuterated
solvent. Data are reported as follows: chemical shift,
multiplicity, coupling, integration. Carbon nuclear magnetic
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The Journal of Organic Chemistry
resonance spectra were recorded on the same Bruker
Synthesized according to GP1. Purification by silica gel
instrument at 101 MHz. Assignments of 13C signals were made
by DEPT-135 experiments. IR spectra were recorded with an
Agilent Technologies Cary 630 FTIR Spectrometer equipped
with a diamond ATR module. HRMS were obtained on a
Kratos Analytical Concept EI-Magnetic Sector instrument
(University of Ottawa Mass Spectrum Centre). Isocyanide
starting materials were synthesized according to Chatani’s
procedure.17
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 48.1 mg of yellow oil (83%), characterized
according to NMR comparison.17 1H NMR (400 MHz, CDCl3): δ
= 8.65 (d, J = 8.0 Hz, 1H), 8.37-8.26 (m, 2H), 8.02 (d, J = 8.3 Hz,
1H), 7.80 (t, J = 7.2 Hz, 1H), 7.68 (t, J = 7.1 Hz, 1H), 7.53 (dd, J =
8.2, 1.6 Hz, 1H), 3.73-3.46 (m, 1H), 2.62 (s, 3H), 2.14-1.75 (m,
7H), 1.60 (s, 2H), 1.50-1.39 (m, 1 H) ppm; 13C NMR (101 MHz,
CDCl3): = 164.2 (C), 142.1 (C), 135.8 (C), 132.8 (C), 130.0
(CH), 129.6 (CH), 126.8 (CH), 125.5 (CH), 124.7 (C), 123.1 (C),
122.5 (2 X CH), 121.4 (CH), 41.9 (CH), 32.3 (2 X CH2), 26.9 (2 X
CH2), 26.3 (CH2), 21.9 (CH3) ppm.
1
2
3
4
5
6
7
8
General procedure for the preparation of alkylated
heteroarenes (GP1). To an 8 mL pyrex screw-top reaction
vessel was added isonitrile 5 (0.20 mmol, 1.00 equiv),
bromoalkane 4 (0.60 mmol, 3.00 equiv), sodium carbonate
(0.60 mmol, 3.00 equiv), DABCO (0.04 mmol, 0.20 equiv),
[Au2(dppm)2]Cl2 (0.01 mmol, 0.05 equiv), and MeCN (2.00 mL,
0.10 M). The reaction vessel was degassed by sparging under
argon for 10 minutes, sealed with parafilm and irradiated
under an UVA (365 nm) LED at a distance of 1 cm for 16
hours. *Bromoalkanes with boiling points below 100°C (e.g. 2-
bromobutane) were added after sparging the mixture. The
resulting mixture was filtered over a short cotton plug,
concentrated in vacuo, and purified by silica gel
chromatography, where relevant fractions were combined,
concentrated and characterized by proton and carbon NMR
(400 and 101 MHz, respectively), HRMS, and IR unless
previously characterized.
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2-Methyl-6-(3-phenylpropyl)phenanthridine (6ab)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 37.4 mg of yellow oil (60%). IR (neat
NaCl) 3025, 2920, 2856, 1584, 1497, 1453, 825 cm-1. 1H NMR
(400 MHz, CDCl3) δ = 8.60 (dd, J = 8.4, 1.2 Hz, 1H), 8.30 (t, J =
1.3 Hz, 1H), 8.09 (dd, J = 8.3, 1.2 Hz, 1H), 8.01 (d, J = 8.3 Hz,
1H), 7.77 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.61 (ddd, J = 8.3, 7.0,
1.2 Hz, 1H), 7.53 (dd, J = 8.3, 1.9 Hz, 1H), 7.36-7.20 (m, 4H),
7.24-7.14 (m, 1H), 3.47-3.33 (m, 2H), 2.85 (t, J = 7.7 Hz, 2H),
2.60 (s, 3H), 2.34-2.20 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
160.8 (C), 142.2 (C), 142.0 (C), 136.1 (C), 132.7 (C), 130.3
(CH), 130.1 (CH), 129.3 (CH), 128.6 (2 X CH), 128.4 (2 X CH),
127.1 (CH), 126.2 (CH), 125.9 (CH), 125.3 (C), 123.5 (C), 122.5
(CH), 121.6 (CH), 36.0 (CH2), 35.6 (CH2), 30.9 (CH2), 21.9
(CH3). HRMS (EI) m/z: [M+]calcd for C23H21N 311.1674, found
311.1648.
General Procedure for the kinetic study (GP2). Reactions
were prepared from stock solutions of aryl isonitrile 5a (1.0
M), [Au2(dppm)2]Cl2 (0.2 M) in MeCN, (bromomethyl)-
cyclobutane (neat) and solid Na2CO3. In a given run, 5 samples
were prepared using the stock solutions of 2a (100-500 μL,
0.1-0.5 M), [Au2(dppm)2]Cl2 (100 μL, 0.02 M each), Na2CO3
(10.6-53.0 mg, 0.1-0.5 M) and reactions were degassed lightly
6-Butyl-2-methylphenanthridine (6ac)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 20.0 mg of yellow oil (40%), characterized
according to NMR comparison.17 1H NMR (400 MHz, CDCl3): δ
= 8.61 (dt, J = 8.3, 0.8 Hz, 1H), 8.30 (s, 1H), 8.22 (dt, J = 8.1, 1.0
Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.78 (ddd, J = 8.3, 7.0, 1.3 Hz,
1H), 7.65 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.51 (dd, J = 8.3, 1.9 Hz,
1H), 3.38-3.29 (m, 2H), 2.59 (s, 3H), 1.95-1.82 (m, 2H), 1.53
(dt, J = 14.8, 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H) ppm; 13C NMR
(101 MHz, CDCl3): = 161.5 (C), 142.1 (C), 136.0 (C), 132.8
(C), 130.3 (CH), 130.0 (CH), 129.3 (CH), 127.0 (CH), 126.3
(CH), 125.3 (C), 123.5 (C), 122.5 (CH), 121.6 (CH), 36.2 (CH2),
31.8 (CH2), 23.2 (CH2), 21.9 (CH3), 14.1 (CH3) ppm.
with argon for
5 minutes. A degassed solution of
(bromomethyl)cyclobutane 4q (113 μL, 1.0 M each) was then
added and each solution was added the remaining MeCN to
make a 1 mL volume (687μL, 587 μL, 487 μL, 387 μL, 287 μL,
respectively). The reactions were then irradiated for 16 hours
with a UVA LED. The resulting mixtures were then subjected
1
to the work-up portion of GP1. After irradiation, the H NMR
1
of crude products showed the same ratios as the H NMR that
had been purified by flash chromatography. The crude
mixture could then be analyzed by 1H NMR reliably for
product ratios.
Ethyl
3-(2-methylphenanthridin-6-yl)propanoate
(6ad)
General Procedure for the preparation of amides (GP3).
To an 8 mL pyrex screw-top reaction vessel was added
isocyanide 5 (0.20 mmol, 1.00 equiv), bromoalkane 4a or 8
(0.60 mmol, 3.00 equiv), sodium carbonate (0.60 mmol, 3.00
equiv), DABCO (0.2 mmol, 1 equiv), [Au2(dppm)2]Cl2 (0.01
mmol, 0.05 equiv), water (80μL, 21 equiv), and MeCN (2.00
mL, 0.10 M). The reaction vessel was degassed by sparging
under argon for 10 minutes, sealed with parafilm and
irradiated under an UVA (365 nm) LED at a distance of 1 cm
for 16 hours. *Bromoalkanes with boiling points below 100°C
(e.g. 2-bromobutane) were added after sparging the mixture.
The resulting mixture was diluted with DCM and washed
sequentially with 1N HCl, saturated sodium bicarbonate, and
brine. The organic phase was dried with Na2SO4, filtered,
concentrated in vacuo, and purified by silica gel
chromatography on base-neutralized silica, where relevant
fractions were combined, concentrated and characterized by
proton and carbon NMR (400 and 101 MHz, respectively),
HRMS, and IR unless previously characterized.
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 20% EtOAc in hexanes
gave the product as 33.6 mg of yellow oil (57%). IR (neat
1
NaCl) 2983, 2916, 1732, 1498, 1174 cm-1. H NMR (400 MHz,
CDCl3) δ = 8.63-8.56 (m, 1H), 8.32-8.20 (m, 2H), 7.96 (d, J = 8.3
Hz, 1H), 7.79 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.66 (ddd, J = 8.2,
7.0, 1.2 Hz, 1H), 7.54-7.46 (m, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.68
(t, J = 7.4 Hz, 2H), 3.08-3.00 (m, 2H), 2.59 (s, 3H), 1.25 (t, J =
7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 173.6 (C), 158.1 (C),
136.3 (C), 132.5 (C), 130.2 (CH), 129.4 (CH), 129.3 (CH), 127.2
(CH), 125.7 (CH), 125.3 (C), 123.5 (2 X C), 122.4 (CH), 121.6
(CH), 60.4 (CH2), 32.0 (CH2), 29.9 (CH2), 21.9 (CH3), 14.3
(CH3). HRMS (EI) m/z: [M+] calcd for C19H19NO2 293.1416,
found 293.1411.
2-Methyl-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-
phenanthridine (6ae)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 53.4 mg of yellow oil (83%). IR (neat,):
6-Cyclohexyl-2-methylphenanthridine (6aa)
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2942, 2869, 1119, 1032 cm-1. H NMR (400 MHz, CDCl3): δ =
8.58 (dt, J = 8.3, 0.6 Hz, 1H), 8.34-8.26 (m, 2H), 7.99 (d, J = 8.3
Hz, 1H), 7.78 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.64 (ddd, J = 8.3,
7.0, 1.2 Hz, 1H), 7.50 (dd, J = 8.3, 1.8 Hz, 1H), 4.67 (dd, J = 4.4,
2.9 Hz, 1H), 4.34 (ddd, J = 9.8, 7.8, 6.8 Hz, 1H), 4.15-3.96 (m,
2H), 3.79 (ddd, J = 11.1, 8.2, 3.2 Hz, 1H), 3.67 (t, J = 7.1 Hz, 2H),
3.50-3.40 (m, 1H), 2.59 (s, 3H), 1.83-1.60 (m, 2H), 1.60-1.36
(m, 2H), 1.24 (t, J = 7.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
158.3 (C), 136.2 (2 X C), 132.6 (C), 130.3 (CH), 130.1 (CH),
129.4 (CH), 127.1 (CH), 126.5 (CH), 125.8 (C), 123.5 (C), 122.3
(CH), 121.6 (CH), 99.0 (CH), 66.7 (CH2), 62.3 (CH2), 36.1 (CH2),
30.7 (CH2), 25.5 (CH2), 21.9 (CH3), 19.5 (CH2). HRMS (EI) m/z:
[M+] calcd for C21H23NO2 321.1729, found 321.1731.
Synthesized according to GP1. Purification by silica gel
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4
5
6
7
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chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 39.8 mg of yellow oil (80%), characterized
according to NMR comparison.17 1H NMR (400 MHz, CDCl3): δ
= 8.63 (dt, J = 8.2, 0.6 Hz, 1H), 8.32-8.30 (m, 1H), 8.29 (ddt, J =
8.3, 1.3, 0.5 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.78 (ddd, J = 8.3,
7.0, 1.3 Hz, 1H), 7.65 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.52 (ddd, J
= 8.3, 2.0, 0.5 Hz, 1H), 3.73 (sex, J = 6.8 Hz, 1H), 2.60 (s, 3H),
2.21-2.07 (m, 1H), 1.80 (dt, J = 13.5, 7.2 Hz, 1H), 1.47 (d, J = 6.8
Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H) ppm; 13C NMR (101 MHz,
CDCl3): δ = 164.4 (C), 142.2 (C), 135.8 (C), 132.8 (C), 130.1
(CH), 129.7 (2 X CH), 126.9 (CH), 125.6 (CH), 125.3 (C), 123.1
(C), 122.5 (CH), 121.5 (CH), 38.3 (CH), 29.2 (CH2), 21.9 (CH3),
19.8 (CH3), 12.5 (CH3) ppm.
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6-(4-((tert-Butyldimethylsilyl)oxy)butyl)-2-
methylphenanthridine (6af)
6-(Adamantan-2-yl)-2-methylphenanthridine
(6aj)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 60.8 mg of yellow oil (97%). IR (neat
NaCl) 2904, 2850 cm-1. 1H NMR (400 MHz, CDCl3) δ = 8.61 (dd,
J = 8.3, 1.2 Hz, 1H), 8.30 (dd, J = 1.8, 0.9 Hz, 1H), 8.17-8.09 (m,
1H), 8.05 (d, J = 8.2 Hz, 1H), 7.74 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H),
7.61 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 7.51 (dd, J = 8.3, 2.0 Hz, 1H),
3.96 (s, 1H), 2.70-2.61 (m, 2H), 2.61 (s, 3H), 2.53-2.46 (m, 2H),
2.20-1.99 (m, 4H), 1.93 (p, J = 3.1 Hz, 1H), 1.84 (d, J = 3.2 Hz,
2H), 1.63 (dt, J = 13.9, 2.0 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ
162.9 (C), 141.8 (C), 135.8 (C), 132.8 (C), 130.0 (CH), 129.9
(CH), 129.4 (CH), 126.7 (CH), 126.1 (CH), 125.0 (C), 123.0 (C),
122.6 (CH), 121.4 (CH), 47.6 (CH), 40.2 (2 X CH2), 38.2 (CH2),
32.8 (2 X CH), 32.7 (2 X CH2), 28.6 (CH), 28.1 (CH), 22.0 (CH3).
HRMS (EI) m/z: [M+ -H] calcd for C24H25N 326.1909, found
326.1910.
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 24.1 mg of yellow oil (33%). IR (neat
NaCl) 2955, 2930, 2856, 1102 cm-1. 1H NMR (400 MHz, CDCl3)
δ = 8.65-8.58 (m, 1H), 8.35-8.28 (m, 2H), 8.03 (d, J = 8.2 Hz,
1H), 7.85-7.76 (m, 1H), 7.66 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H),
7.56-7.48 (m, 1H), 3.81 (t, J = 6.1 Hz, 2H), 3.50-3.40 (m, 2H),
2.60 (s, 3H), 2.20-2.07 (m, 2H), 0.92 (s, 9H), 0.07 (s, 6H). 13C
NMR (101 MHz, CDCl3) δ 161.1 (C), 158.5 (C), 132.8 (C), 130.4
(CH), 127.2 (CH), 127.0 (CH), 126.6 (C), 125.3 (C), 123.6 (C),
122.4 (2 X CH), 121.6 (2 X CH), 62.9 (2 X CH2), 32.5 (CH2), 26.0
(3 X CH3), 21.9 (CH3), 18.4 (C), -5.3 (2 X CH3). HRMS (EI) m/z:
[M+] calcd for C24H33NOSi 379.2331, found 379.2320.
(2S,3R,4S,5R,6R)-6-((2-Methylphenanthridin-6-yl)methyl)-
tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (6ag)
Synthesized according to GP1. Purification by silica gel
chromatography with a 30% EtOAc, 5% AcOH in hexanes gave
the product as 86.9 mg of yellow oil (83%). IR (neat NaCl)
2-Methyl-6-(tetrahydro-2H-pyran-4-yl)phenanthridine (6ak)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 44.9 mg of yellow oil (81%). IR (neat
1
2922, 1754, 1367, 1214, 1076, 1036 cm-1. H NMR (400 MHz,
CDCl3) δ = 8.62 (d, J = 8.2 Hz, 1H), 8.32 (s, 1H), 8.17 (d, J = 8.0
Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.82 (ddd, J = 8.0, 7.1, 1.0 Hz,
1H), 7.67 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 7.55 (dd, J = 8.4, 1.6 Hz,
1H), 5.79 (d, J = 8.2 Hz, 1H), 5.33-5.13 (m, 3H), 4.63 (ddd, J =
9.6, 6.8, 4.6 Hz, 1H), 3.69 (dd, J = 15.1, 6.9 Hz, 1H), 3.53 (dd, J =
15.3, 4.7 Hz, 1H), 2.62 (s, 3H), 2.03 (s, 3H), 2.01 (s, 6H) 1.78 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 170.1 (C), 169.8 (C), 169.3
(C), 168.7 (C), 155.4 (C), 141.8 (C), 136.5 (C), 132.6 (C), 130.4
(CH), 130.1 (CH), 129.6 (CH), 127.1 (CH), 126.1 (CH), 125.6
(C), 123.5 (C), 122.3 (CH), 121.5 (CH), 91.8 (CH), 73.2 (CH),
73.1 (CH), 72.0 (CH), 70.7 (CH), 37.7 (CH2), 21.9 (CH3), 20.7
(CH3), 20.6 (CH3), 20.6 (CH3), 20.5 (CH3). HRMS (ESI-MS) m/z:
[M+ Na+] calcd for C28H29NO9Na 546.1740, found 546.1771.
1
NaCl,): 2951, 2837, 1132 cm-1. H NMR (400 MHz, CDCl3) δ =
8.64 (dd, J = 8.2, 1.1 Hz, 1H), 8.30 (t, J = 1.2 Hz, 1H), 8.26 (d, J =
8.2 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.79 (ddd, J = 8.2, 6.9, 1.2
Hz, 1H), 7.66 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.52 (dd, J = 8.3, 1.9
Hz, 1H), 4.18 (ddd, J = 11.4, 4.5, 1.9 Hz, 2H), 3.82 (tt, J = 11.4,
3.6 Hz, 1H), 3.71 (td, J = 11.9, 2.0 Hz, 2H), 2.60 (s, 3H), 2.32
(dtd, J = 13.6, 11.8, 4.3 Hz, 2H), 1.94 (ddt, J = 13.5, 3.8, 2.1 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 161.9 (C), 142.1 (C), 136.2
(C), 132.9 (C), 130.2 CH), 129.9 (CH), 129.8 (CH), 127.0 (CH),
125.2 (CH), 124.5 (C), 123.2 (C), 122.8 (CH), 121.5 (CH), 68.3
(2 X CH2), 39.1 (CH), 32.0 (2 X CH2), 22.0 (CH3). HRMS (EI)
m/z: [M+ -C3H6O] calcd for C16H13N 219.1048, found 219.1033.
6-Isopropyl-2-methylphenanthridine (6al)
6-Cyclobutyl-2-methylphenanthridine (6ah)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 34.7 mg of yellow oil (74%). IR (neat
NaCl,): 2965, 2926, 2869, 1582, 1497 cm-1. 1H NMR (400 MHz,
CDCl3) δ = 8.62 (ddt, J = 8.3, 1.3, 0.6 Hz, 1H), 8.33-8.25 (m, 2H),
8.03 (d, J = 8.3 Hz, 1H), 7.77 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.65
(ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.52 (ddd, J = 8.3, 1.9, 0.6 Hz,
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 38.3 mg of yellow (77%), characterized
according to NMR comparison.18 1H NMR (400 MHz, CDCl3): δ
= 8.59 (ddt, J = 8.2, 1.1, 0.5 Hz, 1H), 8.32-8.26 (m, 1H), 8.13-
8.03 (m, 2H), 7.76 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.62 (ddd, J =
8.2, 7.0, 1.2 Hz, 1H), 7.56-7.48 (m, 1H), 4.45-4.31 (m, 1H),
2.83-2.67 (m, 2H), 2.60 (s, 3H), 2.56-2.45 (m, 2H), 2.29-2.12
(m, 1H), 2.06-1.90 (m, 1H) ppm; 13C NMR (101 MHz, CDCl3): δ
= 162.1 (C), 142.0 (C), 136.0 (C), 132.7 (C), 130.1 (CH), 129.9
(CH), 129.6 (CH), 126.9 (CH), 126.1 (CH), 124.9 (C), 123.4 (C),
122.4 (CH), 121.6 (CH), 53.4 (CH2), 39.8 (CH), 27.3 (CH2), 21.9
(CH3), 18.5 (CH2) ppm.
1H), 4.05-3.89 (m, 1H), 2.60 (s, 3H), 1.51 (d, J = 6.8 Hz, 6H). 13
C
NMR (101 MHz, CDCl3) δ 164.8 (C), 142.1 (C), 135.9 (C), 132.8
(C), 130.1 (CH), 129.7 (2 X CH), 126.9 (CH), 125.7 (CH), 124.8
(C), 123.2 (C), 122.6 (CH), 121.5 (CH), 31.4 (CH), 22.0 (2 X
CH3), 21.9 (CH3). HRMS (EI) m/z: [M+] calcd for C17H17N
235.1361, found 235.1358.
6-(Adamantan-1-yl)-2-methylphenanthridine (6am)
6-(sec-Butyl)-2-methylphenanthridine (6ai)
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The Journal of Organic Chemistry
1
Synthesized according to GP1. Purification by silica gel
3070, 2931, 2861, 1583, 1498 cm-1. For 6as: H NMR (400
MHz, CDCl3) δ = 8.60 (ddd, J = 8.3, 4.7, 1.1 Hz, 1H), 8.29 (s, 1H),
8.21 (ddd, J = 7.9, 6.3, 1.2 Hz, 1H), 8.01 (dd, J = 8.3, 4.8 Hz, 1H),
7.78 (dddd, J = 8.3, 7.0, 2.7, 1.3 Hz, 1H), 7.64 (tdd, J = 7.0, 3.1,
1.2 Hz, 1H), 7.51 (dt, J = 8.3, 2.0 Hz, 1H), 3.10-2.88 (m, 2H),
2.59 (s, 3H), 2.20-1.78 (m, 7H). 13C NMR (101 MHz, CDCl3) δ
161.0 (C), 160.0 (C), 142.0 (C), 136.0 (C), 132.7 (CH), 130.2
(CH), 129.3 (CH), 127.0 (CH), 126.2 (CH), 125.6 (C), 123.4 (C),
122.4 (CH), 121.5 (CH), 42.6 (CH2), 36.1 (CH), 34.0 (3 X CH2),
18.6(CH3). For 7as: 1H NMR (400 MHz, CDCl3) δ = 8.60 (ddd, J
= 8.3, 4.7, 1.1 Hz, 1H), 8.29 (s, 1H), 8.21 (ddd, J = 7.9, 6.3, 1.2
Hz, 1H), 8.01 (dd, J = 8.3, 4.8 Hz, 1H), 7.78 (dddd, J = 8.3, 7.0,
2.7, 1.3 Hz, 1H), 7.64 (tdd, J = 7.0, 3.1, 1.2 Hz, 1H), 7.51 (dt, J =
8.3, 2.0 Hz, 1H), 5.91 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.08 (dq, J
= 17.1, 1.7 Hz, 1H), 5.01 (ddd, J = 10.2, 2.2, 1.1 Hz, 1H), 3.45 (d,
J = 7.4 Hz, 2H), 3.39-3.30 (m, 2H), 2.59 (d, J = 1.8 Hz, 3H), 2.28
(q, J = 7.3 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 161.0 (C),
142.0 (C), 138.4 (CH), 136.1 (C), 132.8 (C), 130.0 (CH),
129.36(C), 129.2 (C), 127.1 (CH), 126.5 (CH), 125.6 (C), 123.4
(C), 122.5 (CH), 121.6 (CH), 115.1 (CH2), 36.1 (CH3), 35.6
(CH2), 28.5 (CH2), 21.8 (CH3). HRMS (EI) m/z: [M+] calcd for
C19H19N 261.1517, found 261.1526.
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3
4
5
6
7
8
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 46.0 mg of yellow oil (70%), characterized
according to NMR comparison.18 1H NMR (400 MHz, CDCl3): δ
= 8.83 (dd, J = 8.5, 1.2 Hz, 1H), 8.66 (dd, J = 8.4, 1.3 Hz, 1H),
8.28 (t, J = 1.3 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.73 (ddd, J =
8.2, 6.9, 1.2 Hz, 1H), 7.60 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.54-
7.47 (m, 1H), 2.60 (s, 3H), 2.48 (d, J = 2.9 Hz, 6H), 2.22 (p, J =
3.1 Hz, 3H), 1.90 (qt, J = 12.1, 3.1 Hz, 6H). 13C NMR (101 MHz,
CDCl3) δ = 165.0 (C), 141.5 (C), 136.2 (C), 133.9 (C), 130.0
(CH), 130.0 (CH), 129.0 (CH), 127.9 (CH), 125.5 (CH), 124.5
(C), 123.1 (CH), 123.1 (C), 121.3 (CH), 42.1 (3 X CH2), 37.3 (3 X
CH2), 29.3 (3 X CH), 22.0 (CH3).
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2-Methyl-6-(tert-pentyl)phenanthridine (6an)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 52.1 mg of yellow oil (99%), characterized
according to NMR comparison.19 1H NMR (400 MHz, CDCl3): δ
= 8.63 (dddd, J = 21.8, 8.5, 1.4, 0.7 Hz, 2H), 8.30 (tt, J = 1.5, 0.7
Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.74 (ddd, J = 8.3, 6.9, 1.3 Hz,
1H), 7.60 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.51 (ddd, J = 8.3, 1.9,
0.6 Hz, 1H), 2.61 (s, 3H), 2.21 (q, J = 7.5 Hz, 2H), 1.69 (s, 6H),
0.74 (t, J = 7.5 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ =
164.7 (C), 141.3 (C), 136.1 (C), 133.6 (C), 130.1 (CH), 130.0
(CH), 129.0 (CH), 127.6 (CH), 125.8 (CH), 124.9 (C), 123.1 (C),
122.9 (CH), 121.2 (CH), 43.9 (C), 35.5 (CH2), 29.2 (2 X CH3),
22.0 (CH3), 9.5 (CH3) ppm.
2-Methyl-6-(pent-4-en-1-yl)phenanthridine (7at)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 17.5 mg of yellow oil (33%). IR (neat
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NaCl) 3075, 2923, 2856, 1591, 1501, 911 cm-1. H NMR (400
MHz, CDCl3) δ = 8.68 – 8.55 (m, 1H), 8.30 (t, J = 1.4 Hz, 1H),
8.20 (dt, J = 8.1, 1.0 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.79 (ddd,
J = 8.3, 7.0, 1.3 Hz, 1H), 7.65 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.52
(dd, J = 8.4, 1.9 Hz, 1H), 5.91 (ddt, J = 16.9, 10.1, 6.7 Hz, 1H),
5.07 (dq, J = 17.1, 1.7 Hz, 1H), 5.00 (ddt, J = 10.2, 2.2, 1.2 Hz,
1H), 3.41 – 3.30 (m, 2H), 2.60 (s, 3H), 2.33 – 2.20 (m, 3H), 2.02
(tt, J = 8.4, 6.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ = 160.9
(C), 141.9 (C), 138.3 (CH), 135.9 (C), 132.6 (C), 130.1 (CH),
129.9 (C), 129.2 (C), 127.0 (CH), 126.1 (CH), 125.2 (C), 123.3
(C), 122.3 (CH), 121.4 (CH), 114.9 (CH2), 35.5 (CH2), 33.8
(CH2), 28.5 (CH2), 21.8 (CH3) ppm. HRMS (EI) m/z: [M+] calcd
for C19H19N 261.1517, found 261.1521.
6-(tert-Butyl)-2-methylphenanthridine (6ao)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 46.4 mg of yellow oil (93%), characterized
according to NMR comparison.18 1H NMR (400 MHz, CDCl3): δ
= 8.63 (dddd, J = 21.2, 8.5, 1.3, 0.6 Hz, 2H), 8.29 (dq, J = 2.0, 0.7
Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.74 (ddd, J = 8.3, 7.0, 1.3 Hz,
1H), 7.61 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.51 (ddd, J = 8.4, 1.9,
0.6 Hz, 1H), 2.65-2.56 (m, 3H), 1.73 (s, 9H) ppm; 13C NMR (101
MHz, CDCl3) δ = 165.6 (C), 141.3 (C), 136.1 (C), 133.8 (C),
130.0 (CH), 130.0 (CH), 129.0 (CH), 128.2 (CH), 125.8 (CH),
124.4 (C), 123.2 (C), 122.9 (CH), 121.3 (CH), 40.1 (C), 31.2 (3 X
CH3), 22.0 (CH3) ppm.
6-(Cyclopentylmethyl)-2-methylphenanthridine (6au)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 28.6 mg of yellow oil (52%), characterized
according to NMR comparison.17 1H NMR (400 MHz, CDCl3): δ
= 8.64-8.57 (m, 1H), 8.33-8.21 (m, 2H), 8.00 (d, J = 8.3 Hz, 1H),
7.78 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.64 (ddd, J = 8.2, 7.0, 1.2
Hz, 1H), 7.51 (ddd, J = 8.2, 1.9, 0.6 Hz, 1H), 3.35 (d, J = 7.4 Hz,
2H), 2.59 (s, 3H), 2.51 (tt, J = 8.6, 7.2 Hz, 1H), 1.81-1.53 (m,
3H), 1.59-1.20 (m, 4H), 0.91-0.78 (m, 1H) ppm; 13C NMR (400
MHz, CDCl3): δ = 160.9 (C), 142.1 (C), 135.9 (C), 132.7 (C),
130.2 (CH), 130.0 (CH), 129.4 (CH), 126.9 (CH), 126.5 (CH),
125.6 (C), 123.4 (C), 122.4 (CH), 121.5 (CH), 41.8 (CH2), 40.4
(CH), 32.7 (CH2), 25.0 (CH2), 21.9 (CH3).
2-Methyl-6-(but-3-en-1-yl)phenanthridine (7ar)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 17.3 mg of yellow oil (44%). IR (neat
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NaCl) 3080, 2919, 2856, 1584, 1498, 911 cm-1. H NMR (400
MHz, CDCl3) δ = 8.61 (dd, J = 8.4, 1.2 Hz, 1H), 8.33-8.27 (m,
1H), 8.21 (dd, J = 8.3, 1.2 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.79
(ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.66 (ddd, J = 8.3, 7.0, 1.2 Hz,
1H), 7.52 (dd, J = 8.3, 1.9 Hz, 1H), 6.03 (ddt, J = 16.8, 10.2, 6.6
Hz, 1H), 5.14 (dq, J = 17.1, 1.7 Hz, 1H), 5.02 (dq, J = 10.2, 1.4
Hz, 1H), 3.48-3.39 (m, 2H), 2.69 (dtt, J = 7.9, 6.6, 1.4 Hz, 2H),
2.60 (s, 3H). 13C NMR (101 MHz, CDCl3) δ = 160.3 (C), 141.9
(C), 138.1 (CH), 136.2 (C), 132.7 (C), 130.3 (CH), 130.2 (CH),
129.3 (CH), 127.2 (CH), 126.2 (CH), 125.3 (C), 123.4(C), 122.5
(CH), 121.6 (CH), 115.1 (CH2), 35.3 (CH2), 33.2 (CH2), 21.9
(CH3). HRMS (EI) m/z: [M+ -C2H3] calcd for C16H14N 220.1126,
found 220.1124.
6-(Cyclohexylmethyl)-2-methylphenanthridine (6av) and 2-
methyl-6-(hept-6-en-1-yl)phenanthridine (7av)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 30.7 mg of yellow oil (53%, 48:52 mix of
6av and 7av). IR (neat NaCl) 2924, 2852, 1584, 1498 cm-1. For
6-(Cyclobutylmethyl)-2-methylphenanthridine (6as) and
2-methyl-6-(pent-4-en-1-yl)phenanthridine (7as)
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6av: H NMR (400 MHz, CDCl3) δ = 8.61 (d, J = 8.3 Hz, 1H),
Synthesized according to GP1. Use bromomethyl cyclobutane
4s. Purification by silica gel chromatography with a gradient
of 0 – 10% EtOAc in hexanes gave the product as 42.1 mg of
yellow oil (64%, 50:50 mix of 6as and 7as). IR (neat NaCl)
8.30 (d, J = 1.7 Hz, 1H), 8.21 (ddd, J = 7.8, 6.1, 1.2 Hz, 1H), 8.01
(t, J = 8.2 Hz, 1H), 7.79 (ddt, J = 8.2, 6.9, 1.1 Hz, 1H), 7.65 (ddd,
J = 8.2, 7.0, 1.2 Hz, 1H), 7.52 (dd, J = 8.3, 1.9 Hz, 1H), 3.22 (d, J =
7.2 Hz, 2H), 2.59 (s, 3H), 2.07 (tdd, J = 6.8, 5.4, 1.4 Hz, 1H),
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1.97-1.85 (m, 2H), 1.72 (m, 2H), 1.59-1.43 (m, 2H), 1.22-1.11
CH), 121.8 (CH), 41.9 (CH), 32.4 (2 X CH2), 26.8 (2 X CH2), 26.3
(CH2), 21.9 (CH3) ppm.
(m, 4H). 13C NMR (101 MHz, CDCl3) δ = 160.5 (C), 136.1 (2 X
C), 132.8 (C), 130.3 (CH), 130.1 (CH), 129.3 (CH), 127.1 (CH),
126.6 (CH), 125.8 (C), 123.5 (C), 122.5 (CH), 121.6 (CH), 43.6
(CH2), 38.8 (CH), 33.7 (2 X CH2), 29.5 (3 X CH2), 21.9 (CH3). For
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6-Cyclohexyl-2-methyl-8-phenylphenanthridine (6da)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 40.1 mg of yellow oil (57%), characterized
according to NMR comparison.20 1H NMR (400 MHz, CDCl3): δ
= 8.67 (d, J = 8.6 Hz, 1H), 8.44 (d, J = 1.8 Hz, 1H), 8.31 (t, J = 1.3
Hz, 1H), 8.06-7.97 (m, 2H), 7.78-7.72 (m, 2H), 7.59-7.48 (m,
3H), 7.44 (tt, J = 7.3, 1.2 Hz, 1H), 3.66 (tt, J = 11.1, 3.4 Hz, 1H),
2.61 (s, 3H), 2.16-2.06 (m, 2H), 2.03-1.88 (m, 4H), 1.90-1.79
(m, 1H), 1.65-1.52 (m, 2H), 1.44 (qt, J = 12.9, 3.3 Hz, 1H) ppm;
13C NMR (101 MHz, CDCl3) δ = 164.4 (C), 142.2 (C), 140.9 (C),
139.8 (C), 136.0 (C), 131.9 (C), 130.1 (CH), 129.7 (CH), 129.1
(2 x CH), 129.0 (CH), 127.7 (CH), 127.5 (2 X CH), 125.1 (C),
123.7 (CH), 123.2 (CH), 123.0 (C), 121.5 (CH), 42.0 (CH), 32.4
(2 X CH2), 26.9 (2 X CH2), 26.4 (CH2), 21.9 (CH3) ppm.
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7av: H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.3 Hz, 1H), 8.30
(d, J = 1.7 Hz, 1H), 8.21 (ddd, J = 7.8, 6.1, 1.2 Hz, 1H), 8.01 (t, J =
8.2 Hz, 1H), 7.79 (ddt, J = 8.2, 6.9, 1.1 Hz, 1H), 7.65 (ddd, J =
8.2, 7.0, 1.2 Hz, 1H), 7.52 (dd, J = 8.3, 1.9 Hz, 1H), 5.81 (ddt, J =
16.9, 10.2, 6.7 Hz, 1H), 5.04-4.88 (m, 2H), 3.38-3.29 (m, 2H),
2.59 (s, 3H), 2.07 (tdd, J = 6.8, 5.4, 1.4 Hz, 2H), 1.70-1.58 (m,
2H), 1.22-1.11 (m, 4H). 13C NMR (101 MHz, CDCl3) δ = 161.3
(C), 139.1 (CH), 136.1 (2 X C), 132.7 (C), 130.1 (CH), 130.1
(CH), 129.3 (CH), 127.0 (CH), 126.3 (CH), 125.3 (C), 123.4 (C),
122.4 (CH), 121.5 (CH), 114.3 (CH2), 36.3 (CH2), 33.7 (CH2),
28.8 (CH2), 26.5 (CH2), 26.4 (CH2), 21.9 (CH3). HRMS (EI) m/z:
[M+] calcd for C21H23N 289.1830, found 289.1819.
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2-Methyl-6-(oct-7-en-1-yl)phenanthridine (7aw)
4-Cyclohexylpyrrolo[1,2-a]quinoxaline (6ea)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 38.8 mg of yellow oil (64%). IR (neat
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 32.0 mg of yellow oil (64%), characterized
according to NMR comparison.7g 1H NMR (400 MHz, CDCl3): δ
= 7.92 (dd, J = 7.7, 1.8 Hz, 1H), 7.87 (dd, J = 2.8, 1.3 Hz, 1H),
7.79 (dd, J = 7.8, 1.7 Hz, 1H), 7.41 (ddd, J = 15.1, 7.3, 1.7 Hz,
2H), 6.91 (dd, J = 4.0, 1.3 Hz, 1H), 6.81 (dd, J = 4.0, 2.7 Hz, 1H),
3.11 (tt, J = 11.8, 3.3 Hz, 1H), 2.07-1.73 (m, 7H), 1.55-1.35 (m,
3H) ppm; 13C NMR (101 MHz, CDCl3) δ = 161.1 (C), 136.2 (C),
129.7 (CH), 127.2 (C), 126.7 (CH), 125.6 (C), 124.9 (CH), 113.9
(CH), 113.5 (CH), 113.2 (CH), 105.7 (CH), 43.6 (CH), 31.3 (2 X
CH2), 26.6 (2 X CH2), 26.1 (CH2) ppm.
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NaCl) 3072, 2926, 2855, 1584, 1498 cm-1. H NMR (400 MHz,
CDCl3): δ = 8.60 (dd, J = 8.3, 1.1 Hz, 1H), 8.32-8.17 (m, 2H),
8.00 (d, J = 8.3 Hz, 1H), 7.78 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.65
(ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.51 (dd, J = 8.3, 1.9 Hz, 1H), 5.80
(ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 4.98 (dd, J = 17.1, 1.8 Hz, 1H),
4.91 (ddt, J = 10.2, 2.4, 1.3 Hz, 1H), 3.43-3.29 (m, 2H), 2.59 (s,
3H), 2.03 (dtt, J = 7.0, 3.3, 1.8 Hz, 2H), 1.96-1.84 (m, 2H), 1.58-
1.43 (m, 2H), 1.40 (p, J = 3.7 Hz, 4H) ppm; 13C NMR (101 MHz,
CDCl3) δ = 161.4 (C), 142.0 (C), 139.1 (CH), 136.1 (C), 132.8
(C), 130.3 (CH), 130.1 (CH), 129.3 (CH), 127.1 (CH), 126.3
(CH), 125.3 (CH), 123.5 (C), 122.5 (C), 121.6 (CH), 114.2 (CH2),
36.4 (CH2), 33.8 (CH2), 29.8 (CH2), 29.6 (CH2), 29.1 (CH2), 28.9
(CH2), 21.9 (CH3) ppm; HRMS (EI) m/z: [M+] calcd for C22H25N
303.1987, found 303.1974.
6-Cyclohexyl-2,8-dimethylphenanthridine (6fa)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 37.8 mg of yellow oil (65%), characterized
according to NMR comparison.20 1H NMR (400 MHz, CDCl3): δ
= 8.50 (d, J = 8.4 Hz, 1H), 8.26 (dd, J = 1.6, 1.0 Hz, 1H), 8.05-
8.02 (m, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.59 (dd, J = 8.3, 1.7 Hz,
1H), 7.47 (dd, J = 8.3, 1.9 Hz, 1H), 3.57 (tt, J = 11.2, 3.3 Hz, 1H),
2.59 (d, J = 6.7 Hz, 6H), 2.11-2.00 (m, 2H), 2.05-1.85 (m, 4H),
1.90-1.79 (m, 1H), 1.66-1.49 (m, 2H), 1.44 (ddt, J = 16.1, 12.7,
6.2 Hz, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ = 164.0 (C),
141.9 (C), 136.7 (C), 135.7 (C), 131.4 (CH), 130.7 (C), 129.6
(CH), 125.0 (CH), 124.9 (C), 123.2 (C), 122.5 (CH), 121.3 (2 X
CH), 41.8 (CH), 32.3 (2 X CH2), 26.9 (2 X CH2), 26.4 (CH2), 22.0
(CH3), 21.9 (CH3) ppm.
2-Chloro-6-cyclohexylphenanthridine (6ba)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 37.3 mg of yellow oil (63%), characterized
according to NMR comparison.20 1H NMR (400 MHz, CDCl3): δ
= 8.51 (dt, J = 8.1, 0.7 Hz, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.28 (dt,
J = 8.3, 0.6 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.78 (ddd, J = 8.3,
7.0, 1.3 Hz, 1H), 7.68 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 7.60 (dd, J =
8.7, 2.3 Hz, 1H), 3.57 (tt, J = 11.4, 3.3 Hz, 1H), 2.11-1.78 (m,
8H), 1.55 (qt, J = 11.7, 3.0 Hz, 2H), 1.41 (qt, J = 12.9, 3.4 Hz,
1H) ppm; 13C NMR (101 MHz, CDCl3) δ = 165.6 (C), 142.3 (C),
132.0 (C), 131.9 (C), 131.4 (CH), 130.2 (CH), 128.8 (CH), 127.7
(CH), 125.7 (CH), 124.8 (C), 124.4 (C), 122.6 (CH), 121.5 (CH),
42.0 (CH), 32.3 (2 X CH2), 26.8 (2 X CH2), 26.3 (CH2) ppm.
6-Cyclohexyl-8-methoxy-2-methylphenanthridine (6ga)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 48.4 mg of yellow oil (79%) characterized
according to NMR comparison.20 1H NMR (400 MHz, CDCl3): δ
= 8.57-8.50 (m, 1H), 8.24-8.18 (m, 1H), 7.97 (d, J = 8.3 Hz, 1H),
7.60 (d, J = 2.6 Hz, 1H), 7.48-7.37 (m, 2H), 3.99 (s, 3H), 3.53-
3.42 (m, 1H), 2.60-2.55 (m, 3H), 2.10-2.00 (m, 3H), 2.00-1.76
(m, 5H), 1.62-1.33 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ
= 163.4 (C), 158.4 (C), 144.7 (C), 141.4 (C), 135.9 (C), 129.6
(CH), 129.1 (CH), 127.1 (C), 124.2 (CH), 123.2 (C), 121.0 (CH),
119.5 (CH), 106.6 (CH), 55.5 (CH3), 42.1 (CH), 32.2 (2 X CH2),
26.9 (2 X CH2), 26.3 (CH2), 21.9 (CH3) ppm.
6-Cyclohexyl-2-methyl-8-(trifluoromethyl)phenanthridine
(6ca)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 46.1 mg of yellow oil (67%), characterized
according to NMR comparison.21 1H NMR (400 MHz, CDCl3): δ
= 8.69 (d, J = 8.7 Hz, 1H), 8.51 (s, 1H), 8.28 (t, J = 1.2 Hz, 1H),
8.03 (d, J = 8.3 Hz, 1H), 7.95 (dd, J = 8.7, 1.8 Hz, 1H), 7.57 (dd, J
= 8.3, 1.8 Hz, 1H), 3.56 (tt, J = 11.2, 3.3 Hz, 1H), 2.60 (s, 3H),
2.08-1.79 (m, 7H), 1.58 (qt, J = 12.8, 3.3 Hz, 2H), 1.43 (ddt, J =
16.4, 12.8, 6.2 Hz, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ =
164.1 (C), 142.9 (C), 136.6 (2 X C), 135.0 (2 X C), 131.3 (CH),
129.9 (CH), 128.7 (q, J = 32.6 Hz, C), 125.5 (q, J = 3.7 Hz, CH),
123.6 (CH), 123.1 (q, J = 187.9 Hz, CF3) 122.9 (q, J = 4.1 Hz,
6-Cyclohexyl-8-fluoro-2-methylphenanthridine (6ha)
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 47.6 mg of yellow oil (81%), characterized
according to NMR comparison.21 1H NMR (400 MHz, CDCl3): δ
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= 8.58 (dd, J = 9.1, 5.5 Hz, 1H), 8.21 (t, J = 1.3 Hz, 1H), 8.01 (d, J
Hz, 1H), 3.32 (dd, J = 9.8, 8.6 Hz, 1H), 2.72 (dtd, J = 13.3, 8.6,
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= 8.4 Hz, 1H), 7.87 (dd, J = 10.4, 2.6 Hz, 1H), 7.55-7.45 (m, 2H),
3.42 (tt, J = 11.4, 3.3 Hz, 1H), 2.58 (s, 3H), 2.08-1.85 (m, 6H),
1.83 (dddd, J = 10.5, 5.1, 3.2, 1.6 Hz, 1H), 1.58 (dt, J = 13.2, 3.6
Hz, 1H), 1.52 (dt, J = 11.3, 2.8 Hz, 1H), 1.43 (tt, J = 12.8, 3.3 Hz,
1H) ppm; 13C NMR (101 MHz, CDCl3) δ = 164.0 (C), 141.9 (C),
136.7 (C), 135.7 (C), 131.4 (CH), 130.7 (C), 129.6 (CH), 125.0
(CH), 124.9 (C), 123.2 (C), 122.5 (CH), 121.3 (CH), 41.8 (CH),
32.3 (2 X CH2), 26.9 (2 X CH2), 26.4 (CH2), 22.0 (CH), 21.9
(CH3) ppm.
8.0 Hz, 1H), 2.45 (dddd, J = 13.3, 9.8, 7.7, 4.6 Hz, 1H), 1.35 (s,
9H) ppm; 13C NMR (101 MHz, CDCl3) δ = 175.9 (C), 163.7 (C),
67.4 (CH2), 51.6 (C), 45.5 (CH), 28.5 (3 X CH3), 24.4 (CH2).
ppm.
Ethyl 3-((2,6-dimethylphenyl)amino)-3-oxopropanoate (9ka)
Synthesized according to GP3. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 26.9 mg of clear oil (57%). IR (neat NaCl)
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7-Methoxy-2,3-dihydro-1H-cyclopenta[b]quinoline (6ip)
δ = 8.52 (s, 1H), 7.19 – 6.99 (m, 3H), 4.25 (q, J = 7.1 Hz, 2H),
3.50 (s, 2H), 2.22 (s, 6H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ = 169.8 (C), 163.2 (C), 135.1 (2 X C), 133.4 (C),
128.1 (2 X CH), 127.3 (CH), 61.7 (CH2), 41.0 (CH2), 18.3 (2 X
CH3), 14.0 (CH3). HRMS (ESI) m/z: [M+ Na+] calcd for
C13H17NO3Na 258.1106, found 258.1115.
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Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 21.8 mg of yellow oil (55%), characterized
according to NMR comparison.22 1H NMR (400 MHz, CDCl3): δ
= 7.89 (d, J = 9.1 Hz, 1H), 7.78 (s, 1H), 7.29-7.22 (m, 1H), 7.00
(d, J = 2.8 Hz, 1H), 3.90 (s, 3H), 3.08 (dt, J = 22.3, 7.5 Hz, 4H),
2.18 (p, J = 7.5 Hz, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ =
165.3 (C), 157.0 (C), 143.4 (C), 135.8 (C), 129.8 (CH), 129.2
(CH), 128.2 (C), 120.4 (CH), 105.5 (CH), 55.4 (CH3), 34.2 (CH2),
30.5 (CH2), 23.6 (CH2) ppm.
tert-Butyl 3-((2,6-dimethylphenyl)amino)-3-oxopropanoate
(9kb)
Synthesized according to GP3. Purification by silica gel
chromatography on with a gradient of 0 – 25% EtOAc in
hexanes (1% Et3N) gave the product as 33.5 mg of clear oil
(64%). IR (neat NaCl) 3241, 2977, 2931, 1733, 1651, 1143 cm-
6-Methoxy-2,3-dihydro-1H-cyclopenta[b]quinoxaline (6iq)
1
1. H NMR (400 MHz, CDCl3) δ = 8.52 (s, 1H), 7.13 – 7.00 (m,
Synthesized according to GP1. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 12.0 mg of yellow oil (30%), characterized
according to NMR comparison.5d 1H NMR (400 MHz, CDCl3): δ
= 7.86 (dd, J = 8.4, 1.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 3.92 (s,
3H), 3.15 (td, J = 7.7, 1.9 Hz, 4H), 2.27 (p, J = 7.6 Hz, 2H) ppm;
13C NMR (101 MHz, CDCl3) δ = 160.5 (C), 159.9 (C), 157.9 (C),
143.0 (C), 137.4 (C), 129.6 (CH), 121.3 (CH), 107.0 (CH), 55.7
(CH3), 32.4 (CH2), 32.1 (CH2), 21.3 (CH2) ppm.
3H), 3.41 (s, 2H), 2.22 (s, 6H), 1.50 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ = 169.1 (C), 163.6 (C), 135.1 (C), 133.6 (C), 128.1 (2 X
CH), 127.2 (CH), 82.8 (C), 42.4 (CH2), 27.9 (3 X CH3), 18.3 (2 X
CH3). HRMS (ESI) m/z: [M+] calcd for C15H21NO3 263.1521,
found 263.1506.
Ethyl
(S)-3-((2,6-dimethylphenyl)amino)-2-methyl-3-
oxopropanoate (9ke)
Synthesized according to GP3. Purification by silica gel
chromatography with a gradient of 0 – 25% EtOAc in hexanes
(1% Et3N) gave the product as 29.1 mg of clear oil (58%). IR
(neat NaCl) 3237, 2983, 1737, 1646, 1203, 1179 cm-1. 1H NMR
(400 MHz, CDCl3) δ = 7.91 (s, 1H), 7.06 (q, J = 5.3 Hz, 3H), 4.25
(q, J = 7.1 Hz, 2H), 3.48 (q, J = 7.3 Hz, 1H), 2.20 (s, 6H), 1.58 (d,
J = 7.3 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ = 172.8 (C), 167.2 (C), 133.3 (2 X CH), 127.2 (CH),
61.7 (CH2), 47.1 (CH), 18.2 (2 X CH3), 15.8 (CH3), 14.0 (CH3)
ppm. HRMS (ESI) m/z: [M+] calcd for C14H19NO3 249.1365,
found 249.1345.
Diethyl
2-((2,6-dimethylphenyl)carbamoyl)malonate
Synthesized according to GP3. Purification by silica gel
chromatography with a gradient of 0 – 20% EtOAc in hexanes
gave the product as 37.2 mg of yellow oil (99%), characterized
according to NMR comparison.23 1H NMR (400 MHz, CDCl3): δ
= 6.87 (s, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.19 (s, 2H), 2.01 (d, J =
0.6 Hz, 1H), 1.33 (d, J = 0.6 Hz, 9H), 1.26 (td, J = 7.2, 0.6 Hz, 3H)
ppm; 13C NMR (101 MHz, CDCl3) δ = 169.8 (C), 163.8 (C), 61.3
(CH2), 51.2 (CH2), 42.1 (C), 28.5 (3 X CH3), 13.9 (CH3) ppm.
tert-Butyl 3-(tert-butylamino)-3-oxopropanoate (9jb)
Diethyl 2-((2,6-dimethylphenyl)carbamoyl)malonate (9kf)
Synthesized according to GP3. Purification by silica gel
chromatography with a gradient of 0 – 20% EtOAc in hexanes
gave the product as 17.7 mg of yellow oil (41%), characterized
according to NMR comparison.24 1H NMR (400 MHz, CDCl3): δ
= 6.87 (s, 1H), 3.10 (s, 2H), 1.44 (s, 9H), 1.33 (s, 9H) ppm; 13C
NMR (101 MHz, CDCl3) δ = 169.0 (C), 164.4 (C), 82.11 (C), 51.1
(C), 43.4 (CH2), 28.6 (3 X CH3), 27.9 (3 X CH3) ppm.
Synthesized according to GP3. Purification by silica gel
chromatography on with a gradient of 0 – 25% EtOAc in
hexanes (1% Et3N) gave the product as 35.8 mg of clear oil
(58%). IR (neat NaCl) 3231, 2980, 2923, 2209, 1721, 1620,
1
1239 cm-1. H NMR (400 MHz, CDCl3) δ = 9.70 (s, 1H), 7.18 –
7.10 (m, 3H), 4.30 (q, J = 7.2 Hz, 4H), 2.26 (s, 6H), 1.29 (td, J =
7.1, 1.1 Hz, 9H). 13C NMR (101 MHz, CDCl3) δ = 165.5 (C),
162.2 (2 X C), 161.5 (C), 154.2 (C), 136.8 (C), 134.6 (C), 129.1
(CH), 128.3 (2 X CH), 91.1 (CH), 62.4 (2 X CH2), 18.2 (CH3),
17.9 (CH3), 13.7 (2 X CH3). HRMS (ESI) m/z: [M+ –CO2Et] calcd
for C13H16NO3 234.1130, found 234.1099.
N-(tert-butyl)-2-cyanoacetamide (9jc)
Synthesized according to GP3. Purification by silica gel
chromatography with a gradient of 0 – 20% EtOAc in hexanes
gave the product as 6.2 mg of yellow oil (22%), characterized
according to NMR comparison.25 1H NMR (400 MHz, CDCl3): δ
= 5.83 (s, 1H), 3.27 (s, 2H), 1.36 (s, 9H) ppm; 13C NMR (101
MHz, CDCl3) δ = 159.7 (C), 115.1 (C), 52.6 (C), 28.5 (3 X CH3),
26.7 (CH2) ppm.
Ethyl 3-(tert-butylamino)-3-oxopropanoate (10).
Synthesized according to GP3. Purification by silica gel
chromatography with a gradient of 0 – 20% EtOAc in hexanes
gave the product as 14.5 mg of yellow oil (31%), characterized
according to NMR comparison.27 1H NMR (400 MHz, CDCl3): δ
= 7.44 – 7.35 (m, 2H), 7.11 – 7.06 (m, 1H), 6.87 – 6.78 (m, 2H),
3.76 (s, 3H), 2.18 (tt, J = 11.7, 3.5 Hz, 1H), 1.97 – 1.88 (m, 2H),
1.87 – 1.77 (m, 2H), 1.51 (qd, J = 12.1, 3.2 Hz, 2H), 1.36 – 1.15
(m, 4H) ppm; 13C NMR (101 MHz, CDCl3) δ = 174.0 (C), 156.1
(S)-N-(tert-butyl)-2-oxotetrahydrofuran-3-carboxamide (9jd)
Synthesized according to GP3. Purification by silica gel
chromatography with a gradient of 0 – 20% EtOAc in hexanes
gave the product as 35.6 mg of yellow oil (96%), characterized
according to NMR comparison.26 1H NMR (400 MHz, CDCl3): δ
= 6.74 (s, 1H), 4.40 (td, J = 8.8, 4.6 Hz, 1H), 4.28 (dt, J = 9.0, 7.8
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(3) Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M., A New
(C), 131.1 (C), 121.5 (2 X CH), 114.0 (2 X CH), 55.4 (CH3), 46.3
(CH), 29.6 (2 X CH2), 25.6 (2 X CH2) ppm.
Photochemical Reaction1. J. Am. Chem. Soc. 1961, 83, 4076-4083.
(4) (a) Shono, T.; Kimura, M.; Ito, Y.; Nishida, K.; Oda, R., Studies of
Isocyanide. II. The Reaction of Isocyanide with Some Radical
Sources. Bull. Chem. Soc. Jpn. 1964, 37, 635-637. (b) Ito, Y.;
1
2
3
4
5
6
7
8
6-cyclohexylphenanthridine (11)
Synthesized according to GP2. Purification by silica gel
chromatography with a gradient of 0 – 10% EtOAc in hexanes
gave the product as 17.3 mg of yellow oil (33%), characterized
according to NMR comparison.28 1H NMR (400 MHz, CDCl3): δ
= 8.63 (dd, J = 8.3, 1.2 Hz, 1H), 8.52 (dd, J = 8.2, 1.4 Hz, 1H),
8.30 (dd, J = 8.4, 1.2 Hz, 1H), 8.14 (dd, J = 8.1, 1.3 Hz, 1H), 7.79
(ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.68 (dddd, J = 10.0, 8.3, 7.0, 1.3
Hz, 2H), 7.59 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 3.61 (tt, J = 11.2, 3.3
Hz, 1H), 2.14 – 2.03 (m, 2H), 1.99 (d, J = 3.3 Hz, 1H), 2.00 –
1.87 (m, 3H), 1.84 (dddd, J = 12.6, 5.2, 3.1, 1.5 Hz, 1H), 1.57
(dtd, J = 16.9, 13.5, 12.8, 4.2 Hz, 2H), 1.43 (qt, J = 12.9, 3.3 Hz,
1H) ppm; 13C NMR (101 MHz, CDCl3) δ = 165.1 (C), 143.8 (C),
132.9 (C), 129.8 (CH), 129.8 (CH), 128.3 (CH), 126.9 (CH),
126.0(CH), 125.5 (CH), 124.6 (C), 123.2 (C), 122.5 (CH), 121.7
(CH), 41.9 (CH), 32.2 (2 X CH2), 26.8 (2 X CH2), 26.2 (CH2)
ppm.
Inubushi, Y.; Saegusa, T., 1-(N-alkyliminoformyl)azole —
a
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isonitriles. Tetrahedron 1998, 54, 5587-5598.
(6) For recent reviews, see: (a) Zhang, B.; Studer, A., Recent
advances in the synthesis of nitrogen heterocycles via radical
cascade reactions using isonitriles as radical acceptors. Chem. Soc.
Rev. 2015, 44, 3505-3521 and references therein. (b) Lei, J.;
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Tron, G. C.; Zhu, J., To each his own: isonitriles for all flavors.
Functionalized isocyanides as valuable tools in organic synthesis.
Chem. Soc. Rev. 2017, 46, 1295-1357.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Spectroscopic data and NMR spectra of all products can be
found in the Supporting Information.
(7) (a) Sun, X.; Yu, S., Visible-Light-Promoted and Photoredox-
Catalyzed Radical Addition to Triple Bonds. Synlett 2016, 27,
2659-2675. (b) Jiang, H.; Cheng, Y.; Wang, R.; Zheng, M.; Zhang, Y.;
Yu, S., Synthesis of 6-Alkylated Phenanthridine Derivatives Using
Photoredox Neutral Somophilic Isocyanide Insertion. Angew.
Chem. Int. Ed. 2013, 52, 13289-13292. (c) Xiao, T.; Li, L.; Lin, G.;
Wang, Q.; Zhang, P.; Mao, Z.-w.; Zhou, L., Synthesis of 6-substituted
phenanthridines by metal-free, visible-light induced aerobic
oxidative cyclization of 2-isocyanobiphenyls with hydrazines.
Green Chemistry 2014, 16, 2418-2421. (d) Zhang, Z.; Tang, X.;
AUTHOR INFORMATION
Corresponding Author
*E-mail: lbarriau@uottawa.ca
Author Contributions
The manuscript was written through contributions of all
authors. / All authors have given approval to the final version
of the manuscript.
Dolbier,
W.
R.,
Photoredox-Catalyzed
Tandem
Notes
Insertion/Cyclization Reactions of Difluoromethyl and 1,1-
Difluoroalkyl Radicals with Biphenyl Isocyanides. Org. Lett. 2015,
17, 4401-4403. (e) Jin, Y.; Yang, H.; Fu, H., Thiophenol-Catalyzed
Visible-Light Photoredox Decarboxylative Couplings of N-
(Acetoxy)phthalimides. Org. Lett. 2016, 18, 6400-6403. (f) Zhou,
H.; Deng, X. Z.; Zhang, A. H.; Tan, R. X., Visible-light-promoted
synthesis of phenanthridines via an intermolecular isocyanide
insertion reaction. Org. Biomol. Chem. 2016, 14, 10407-10414. (g)
He, Z.; Bae, M.; Wu, J.; Jamison, T. F., Synthesis of Highly
Functionalized Polycyclic Quinoxaline Derivatives Using Visible-
Light Photoredox Catalysis. Angew. Chem. Int. Ed. 2014, 53,
14451-14455. (h) Yuan, Y.-C.; Liu, H.-L.; Hu, X.-B.; Wei, Y.; Shi, M.,
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the Natural Sciences and Engineering Research
Council (NSERC) for the Discovery grant to L.B. T.M. thanks
NSERC for a Ph.D. scholarship Alexander Graham Bell CGS-D.
S. R. thanks the government of Ontario for an OGS scholarship.
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