Metal-Free Visible Light-Mediated Photocatalysis: Controlling Intramolecular [2 + 2] Photocycloaddition of Enones through Axial Chirality

Article abstract of DOI:10.1021/acs.joc.6b01066

Atropisomeric enone-imides and enone-amides featuring N-C_Aryl bond rotation were evaluated for intramolecular [2 + 2] photocycloaddition. Straight addition product was observed over cross-addition product with good control over reactivity. The atropselectivity was found to be dependent on the substituent on the aryl ring. Substitution-dependent atropselectivity was rationalized on the basis of a divergent mechanistic pathway.

Full text of DOI:10.1021/acs.joc.6b01066

Article
pubs.acs.org/joc
Metal-Free Visible Light-Mediated Photocatalysis: Controlling
Intramolecular [2 + 2] Photocycloaddition of Enones through Axial
Chirality
Anthony Clay, Nandini Vallavoju, Retheesh Krishnan, Angel Ugrinov, and Jayaraman Sivaguru*
Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota 58108, United States
S
* Supporting Information
ABSTRACT: Atropisomeric enone-imides and enone-amides
featuring N-CAryl bond rotation were evaluated for intra-
molecular [2 + 2] photocycloaddition. Straight addition
product was observed over cross-addition product with good
control over reactivity. The atropselectivity was found to be
dependent on the substituent on the aryl ring. Substitution-
dependent atropselectivity was rationalized on the basis of a
divergent mechanistic pathway.
approaches to control reactivity and achieve selectivity from the
excited state due to its short lifetimes. In this regard, we have
employed the use of atropisomeric chromophores24−32 to
control excited state reactivity.33 We have shown that our
strategy34−44 can be employed to achieve high enantio- and
diastereoselectivity in the photoproduct in solution at ambient
conditions. The utility of this methodology has been high-
lighted in various systems with differing photochemical
transformations, such as 6π-photocyclization,34−37 Norrish−
INTRODUCTION
■
Cyclobutane derivatives are found in numerous naturally
occurring compounds with biological activity, ranging from
antivirals to antibiotics.1−7 Consequently, developing new
methods for the synthesis of cyclobutanes is of great interest
to pharmaceutical, biological, medicinal, and natural product
scientists alike. Additionally, cyclobutane analogues have
proven to be useful scaffolds for various functional group
manipulations in synthetic organic chemistry1,2,8 and materials
chemistry.9 Photochemistry is unparalleled in its ability to
afford complex structural scaffolds from simple and easily
accessible reactants. In addition, compounds with multiple
stereocenters can be accessed via photochemical pro-
cesses.10−12 Often, the short lifetimes involved in photo-
chemical reactions lead to multiple photoproducts with
stereocenters limiting their appeal. Efforts to address this
complicated reactivity and selectivity in photochemical trans-
formations have met with differing success. Organized media
yield among the highest of selectivities due to the lack of
degrees of freedom during the photochemical transformation.
Supramolecular scaffolds such as crystals, zeolites, molecular
cages, and hydrogen bonding templates have been utilized to
control excited state reactivity.13−15 Throughout the past
decade, photochemical transformations in the absence of
organized media have seen progress with the advent of novel
photocatalytic methods. One of the strategies that has received
particular attention is photoredox chemistry,16−23 where a one
electron oxidation or reduction of the reactant by a light-
absorbing sensitizer generates a ground state radical anion/
cation. The increase in the potential of the reactive substrate by
electron transfer enhances its reactivity in photoredox
chemistry, thereby making it react effectively from the ground
state to form products. This necessitates evaluation of new
Yang cyclization,38,39 4π-ring closure,40 the Paterno−
̀
Buchi
̈
reaction,41 and various photocycloadditions.42−44 In efforts to
further increase the scope, display the breadth, and highlight
the excited state control of the methodology employed, we
focused our attention on [2 + 2] photocycloaddition of enones
1 leading to cyclobutane photoproducts 2/3 (Scheme 1).
Photochemical transformations involving enones have been
extensively utilized to synthesize various natural products.45,46
As enones often feature a mixture of nπ* and ππ* excited
states,47 their reactivities can differ from simple manipulation of
reaction conditions. Additionally, the implementation of
atropisomers can further alter the reactivity of enones. Various
distinguished groups have investigated the intricacies involved
in the photochemical cycloadditions of enones.1,47−50 Piva and
co-workers have evaluated the [2 + 2] photocycloaddition of
enone-amides with N-allyl substitution where they observed a
straight-to-cross addition ratio of 60:40.51 They also observed
that N-substitution impacted both reactivity and selectivity.
This allowed us a platform to highlight our methodology
involving atropisomers to control the reactivity of enones. In
Special Issue: Photocatalysis
Received: May 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b01066
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. Intramolecular Photocycloaddition of Atropisomeric Enones 1
Scheme 2. Synthesis of Atropisomeric Enones 1a−e
a
this regard, the two sets of enones, enone-amides 1a−c and
enone-imides 1d and 1e, were synthesized and their photo-
chemical properties evaluated for atropselective [2 + 2]
photocycloaddition.
Table 1. Racemization of Atropisomeric Enones
racemization parameters
krac
t1/2‑rac
(days)
ΔG‡ (kcal
entry compound solvent
(days−1
)
mroacl−1
)
b
1
2
3
4
5
6
1b
1d
1e
toluene
MeCN
toluene
MeCN
toluene
MeCN
1.0
0.7
1.8
1.4
1.1
1.1
0.7
1.0
0.4
0.5
0.6
0.6
28.3
28.6
25.5
25.6
25.8
25.8
RESULTS AND DISCUSSION
■
Atropisomeric enone-amides 1a−c and enone-imides 1d and
1e with varying substitutions were synthesized from the
corresponding aniline derivative (Scheme 2) and evaluated
for [2 + 2] photocycloaddition.52 Atropisomeric enones were
characterized by 1H and 13C NMR spectroscopy, high-
resolution mass spectrometry, and single-crystal XRD.52 To
employ them for controlling photoreactions, we evaluated the
activation barrier for racemization (N-CAryl bond rotation) of
enones.53 The individual atropisomers of enones were
separated on a chiral stationary phase using preparative
HPLC. As the atropisomers were stable at room temperature,
we evaluated the racemization barrier at 45 °C in toluene and
acetonitrile. Inspection of Table 1 reveals a high barrier for
N−CAryl bond rotation that was reflected in the high values for
t1/2‑rac in both toluene and acetonitrile. Depending on the
substitution of the nitrogen (amide vs imide), the racemization
a
Optically pure isomers were employed for racemization kinetic
measurements in a given solvent at a set temperature. Racemization
was monitored by HPLC analysis on a chiral stationary phase (error =
3%). All measurements were performed at 45 °C unless otherwise
b
indicated. Racemization performed at 75 °C.
barrier was either ∼28 kcal/mol (amides; Table 1, entries 1−2)
or ∼26 kcal/mol (imides; Table 1, entries 3−6).
For the reaction conditions (Tables 2 and 3) to be
optimized, photoirradiation of enones was carried out under
both direct and sensitized irradiations (using visible light with
thioxanthone as a triplet sensitizer/catalyst). After the photo-
reaction, the reaction mixture was concentrated under reduced
B
DOI: 10.1021/acs.joc.6b01066
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
amide 1b. Enone-imide 1d gave excellent yield and mass
balance in all of the investigated solvent systems. For the
efficiency of the reaction with enone-amide 1b in different
solvents to be compared, the irradiation time was kept constant
at 6 h with the conversion varying from 12 to 34% (Table 2).
Higher irradiation time gave higher conversions. Alternatively,
excellent yield was observed with enone-amides 1b and 1c
upon direct irradiation at ∼350 nm (Table 4, entries 2 and 5).
It can be inferred from examination of Tables 3 and 4 that the
type of functionality and the length of the N-alkenyl chain of
atropisomeric enones played a crucial role in determining the
product distribution. With respect to enone-imides 1d and 1e,
we observed exclusive formation of the corresponding cis,cis-2
as the product. As we had employed a racemic mixture of
atropisomeric reactant 1d and 1e, we observed two
diastereomeric rotamers of cis,cis-2d, which arise due to
rotation of the N−CAryl bond (Table 4, entries 8 and 9).
More importantly, we were able to separate the diastereomeric
rotamers by chromatography and confirmed their relationship
by 1H NMR spectroscopy and by single crystal XRD analysis.52
Both the major and minor diastereomeric rotamers of cis,cis-2d
crystallized as racemic crystals (containing a mixture of
enantiomers; Table 4, entry 8). From single crystal XRD
analysis, the configuration of the minor diastereomeric rotamer
of cis,cis-2d was established as (1R,6R,10R,M)-2d and
(1S,6S,10S,P)-2d. Similarly, from single crystal XRD analysis,
the configuration of the major diastereomeric rotamer of cis,cis-
2d was established as (1R,6R,10R,P)-2d and (1S,6S,10S,M)-2d.
To our surprise, we were able to isolate the chiral crystal of the
major diastereomeric rotamer of cis,cis-2e (as it was a mixture of
conglomerate crystals of individual enantiomers) and estab-
lished its absolute configuration as (1R,6R,10R,P)-2e (Table 4,
entry 9). The major and minor rotamers in cis,cis-2d differed
only by rotation about the N-CAryl bond (the same is true for
cis,cis-2e).29,31,53−56 Heating of the minor diastereomeric
rotamer of cis,cis-2d in DMSO-d6 resulted in the major
diastereomeric rotamer cis,cis-2d (Scheme 3).52 The rate
constant (monitored by NMR spectroscopy) for N-CAryl
bond rotation was found to be 1.7 × 10−7 s−1 at 75 °C in
DMSO-d6.
To evaluate the role of axial chirality in determining the
stereochemistry of the product, we carried out the photo-
chemical reaction of optically pure atropisomers of amides 1b
and 1c. High enantioselectivity was observed in the photo-
product during the photochemical transformation of optically
pure atropisomers of enone-amide 1b.57 To our surprise, para-
methoxy derivative 1c gave near racemic photoproducts cis,cis-
2c and cis,trans-2c. This necessitated a mechanistic under-
standing to rationalize the behavior of enones (vide infra).
In an effort to understand the mechanistic details, photo-
physical measurements were obtained for 1d. At 77 K, there
was no observable phosphorescence, showing that there is
efficient deactivation of the excited state by another pathway.
As the reaction was efficient with thioxanthone (TX) acting as a
visible light photocatalyst/sensitizer, we investigated its role in
promoting the reaction using transient absorption studies. Laser
excitation (λex = 355 nm; 7 ns pulse width; 5 m J/pulse) of TX
in the presence of varying concentrations of 1d in N2-degassed
acetonitrile solution showed that the triplet of thioxanthone
was efficiently quenched (Figure 1) with a bimolecular
quenching rate constant (kq) 8.2 × 109 M−1 s−1.44,58 No new
transient species were observed, and the bleach at 380 nm
showed very fast recovery in the presence of 1d. The
Table 2. [2 + 2] Photocycloaddition of Enone-Imide 1d
under Direct and Sensitized Irradiations
a
entry
irradiation conditions
2d (% yield)
1
2
3
4
bb/Pyrex cutoff, 1 h
∼350 nm, 3 h
∼420 nm, 9 h
>98
>98
>98
84
b
420 nm, thioxanthone, 1 h
a
Irradiation of 1d (c ≈ 2.7 mM) in MeCN at room temperature under
a N2 atmosphere unless otherwise noted. Values are based on 1H
NMR spectroscopy (error = 5%). bb/Pyrex cutoff = broadband
irradiation performed using a medium pressure 450 W mercury lamp
with a Pyrex cutoff (<295 nm cutoff); ∼350 nm and ∼420 nm
b
irradiations were carried out in a Rayonet reactor. Utilized 10 mol %
of thioxanthone.
Table 3. Solvent Effects on [2 + 2] Photocycloaddition
Involving Enone-Amide 1b and Enone-Imide 1d with 10 mol
a
% of Thioxanthone
bc
,
bd
,
entry
solvent
MCH
2b (% yield
)
2d (% yield (dr)
)
1
2
3
4
5
6
7
8
>98 (4:1)
>98 (3:1)
>98 (2:1)
>98 (3:1)
>98 (2:1)
>98 (3:1)
84 (4:1)
toluene
DCM
15
24
12
18
chloroform
EtOAc
MeOH
MeCN
34
DMSO-d6
>98 (4:1)
a
All reactions were performed in a Rayonet reactor at λ ≈ 420 nm
using thioxanthone (10 mol %) as a sensitizer; 1b with 6 h of
irradiation), and 1d with 1 h of irradiation). Values are an average of
three runs. The % yield and ratios were determined by H NMR
b
1
spectroscopy using triphenylmethane as an internal standard (error =
c
5%). The ratio of cis,cis-2b:cis,trans-2b was found to be ∼1:1 in all
d
the solvents except EtOAc, where it was 3:2. The 2d diastereomeric
ratio from N-CAryl bond rotation.
pressure, and the photoproduct(s) was purified by column
chromatography and characterized by NMR spectroscopy,
HRMS, and single crystal XRD (Table 4). The conversion,
yield, and mass balance were calculated by 1H NMR
spectroscopy using triphenylmethane as internal standard.
Inspection of the crystal structure of the photoproducts
shows that, in the case of both enone-amides 1a−c and
enone-imides 1d−e, the straight addition product 2 was
exclusively observed. More importantly, in the case of amides,
we observed two stereoisomers, cis,cis-2 and cis,trans-2 in
approximately 1:1 ratio in the solvents investigated (except for
irradiation in EtOAc; Tables 2 and 3). In the cis,cis-2, there was
cis-fusion of both ring systems (e.g., cis,cis-1d features cis-fusion
of four-six and four-five ring systems). On the other hand, in
cis,trans-2, there was cis-fusion of the six-four ring and trans-
fusion of the second bicyclic-ring system (e.g., cis,trans-1d
features cis-fusion of four-six ring system and trans-fusion of
four-five ring system). To our surprise, in the case of enone-
imides 1d−e, we observed exclusive formation of cis,cis-2 as the
product.
Inspection of Table 2 shows that the reaction of 1d in
acetonitrile was efficient both under direct irradiation (Pyrex
cutoff) and visible light irradiation with 10 mol % loading of
thioxanthone (acting as a catalyst/sensitizer). Inspection of
Table 3 shows that the [2 + 2] photocycloaddition of enone-
imide 1d was clean and efficient when compared to the enone-
C
DOI: 10.1021/acs.joc.6b01066
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 4. Intramolecular [2 + 2] Photocycloaddition of Atropisomeric Enones
a
Irradiations were carried out with 10 mol % of thioxanthone in a Rayonet reactor equipped with ∼420 nm (16 bulbs ×14 W) unless otherwise
noted. Reaction carried out with the 1:1 mixture of atropisomers. For atropselective reaction in entries 3, 4, 6, and 7, optically pure atropisomers that
were separated from HPLC were employed. pkA and pkB refer to the first and second peak that elutes out of the HPLC on a chiral stationary phase.
b
Reported values carry an error of 5%. Isolated yields for 1b and 1c were determined from direct irradiation conditions in a Rayonet reactor at
c
∼350 nm (16 bulbs ×14 W). Visible light irradiation was also effective and gave similar selectivity. Stereochemistry was deduced from single crystal
d
XRD analysis using Flack parameters. Racemic crystals of 2d (major and minor rotamers of cis,cis-2d) had both of the enantiomeric forms within
e
the same unit cell. Optically pure crystals from 2e were picked from a mixture of conglomerate crystals.
D
DOI: 10.1021/acs.joc.6b01066
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3. N-CAryl Bond Rotation in cis,cis-2d
Figure 1. Quenching studies of thioxanthone (TX) in the presence of 1d. Laser flash photolysis performed using Nd:YAG laser (355 nm, 5 mJ/
pulse, 7 ns pulse width). The transient absorption spectra were plotted 4 μs after laser flash. (Inset) Stern−Volmer quenching plot of TX in the
presence of 1d.
photophysical data implicates an energy transfer pathway rather
than electron transfer from the excited thioxanthone to the
enone.
employing optically pure atropisomers in 1c (Table 4, entries
6 and 7).
CONCLUSIONS
On the basis of the above results, we postulate that the enone
reaches the triplet excited state upon energy transfer from
excited thioxanthone. On the basis of the triplet state reactivity
of enone with electron-deficient alkene (as in the case of imides
1d and 1e), the reaction is likely triggered by a π*→ π*
interaction47 between the excited enone and the electron
deficient alkene leading to biradical BR2 that cyclizes to form
cis,cis-2 products. Upon increasing the chain length of the N-
alkenyl substituent (as in amide 1a or 1b), the longer flexible
alkenyl chain likely orients itself by exposing one of the two
faces of the alkene double-bond to the excited enone leading to
BR2, which cyclizes to cis,cis-2 and cis,trans-2 products.44 In a
parallel scenario, our present mechanism cannot rule out the
formation of BR3 in the reaction pathway as it can lead to
cis,cis-2 and cis,trans-2 products. However, considering that the
reaction is likely originating from the π* of excited enone, this
intermediate is less likely. The last aspect we will address is the
loss of atropselectivity with enone-amide 1c that features a
para-methoxy substituent. The electron transfer pathway has
previously been implicated for hydrogen abstraction involving
amido-cycloalkenones.59 On the basis of this precedence, we
believe the electron-rich nature of the p-OMe substituent likely
triggers an electron transfer pathway leading to loss of axial
chirality. This results in the loss of atropselectivity (Scheme 4),
which is reflected in the near racemic product despite
■
Our study has showcased that intramolecular [2 + 2]
photocycloaddition of excited enone could be effectively
controlled by incorporating axial chirality into the system.
The selectivity is dependent on the type of substituent on the
nitrogen. For short chain imide substituents, exclusive
formation of straight addition was observed. Our results
showcase that one may achieve excellent control of excited-
state reactivity by employing restricted bond rotation(s) leading
to stereoenriched product(s). Controlling such transformations
under visible light-mediated photocatalytic conditions will open
avenues to devise strategies to perform light-initiated reactions
in a stereocontrolled fashion.60−62
EXPERIMENTAL SECTION
■
General Methods. All commercially obtained reagents/solvents
were used as received without further purification. Spectrophotometric
grade solvents (ethanol and methylcyclohexane) were purchased and
used without further purification for emission measurements. Unless
stated otherwise, reactions were conducted in oven-dried glassware
1
under nitrogen atmosphere. H and 13C NMR spectra were recorded
on 400 MHz (100 MHz for 13C) and on 500 MHz (125 MHz for 13C)
1
spectrometers. Data from the H NMR spectroscopy are reported as
chemical shifts (δ ppm) with the corresponding integration values.
Coupling constants (J) are reported in hertz (Hz). Standard
abbreviations indicating multiplicity were used as follows: s (singlet),
b (broad), d (doublet), t (triplet), q (quartet), m (multiplet), and virt
E
DOI: 10.1021/acs.joc.6b01066
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 4. Mechanistic Aspects of [2 + 2] Photocycloaddition in Atropisomeric Enones
(virtual). Data for 13C NMR spectra are reported in terms of chemical
shift (δ ppm). In many instances it was not possible to obtain the
signal for the carbonyl carbon, wherever possible we have reported all
of the signals. High-resolution mass spectrum data in electrospray
ionization mode were recorded in positive (ESI+) ion mode. HPLC
analyses were performed on analytical HPLC. Preparative HPLC was
used for automated sample injection and separation of atropisomers.
All HPLC injections were monitored using a dual wavelength
absorbance detector at 254 and 270 nm or using a diode array
detector. Analytical and semipreparative injections were performed on
the chiral stationary phase using various columns as indicated below.
(R,R) WHELK-01; 25 cm × 4.6 mm column for analytical injections;
25 cm × 10 mm column for semipreparative injections. CHIRAPAK
AD-H; 0.46 cm × 25 cm column for analytical injections; 10 mm × 25
cm column for semipreparative injections. UV−vis spectra were
recorded using UV quality fluorimeter cells (with range until 190 nm).
When necessary, the compounds were purified by column
chromatography using hexanes:ethyl acetate as the mobile phase silica
as stationary phase.
Photophysical Methods. Spectrophotometric solvents were used
when necessary unless otherwise mentioned. UV quality fluorimeter
cells (with range until 190 nm) were used for optical measurements.
Emission spectra were recorded on a spectrometer equipped with
double-grating monochromators, dual lamp housing containing a 450-
W CW xenon lamp and a xenon flash lamp, Fluorohub/MCA/MCS
electronics, and PMT detector. The nanosecond transient absorption
experiments were performed with a laser flash photolysis kinetic
spectrometer equipped with a 300 mm focal length monochromator in
Czerny Turner configuration and an analyzing photomultiplier
featuring a side window photomultiplier detector. The pulses for the
experiment were from a third harmonic ultra compact flash lamp
pumped Nd:YAG laser (355 nm, 5 mj/pulse, 7 ns pulse width).
X-Ray Crystal Structure Determination. Single crystal X-ray
diffraction data of the compounds 2a−e were collected on an XRD
diffractometer equipped with a CCD area detector at T = 100 K. Cu
radiation was used. A direct method was used to solve the structures
after multiscan absorption corrections. Details of data collection and
refinement are given in the Supporting Information. All thermal
ellipsoid plots were generated with 50% probability.
Synthesis of 4-Amino-3-tert-butylphenol 11. Following a reported
procedure,63 a solution of sulfanilic acid 10 (55.9 mmol, 1.2 equiv) and
Na2CO3 (28 mmol, 0.6 equiv) was prepared in 60 mL of deionized
H2O and set to reflux for 30 min. The solution became colorless yet
turbid until it began to reflux, where it turned pale yellow and turbid
and then became clear. After reflux, the clear pale yellow solution was
cooled to 0 °C. Then, NaNO2 (55.9 mmol, 1.2 equiv) was dissolved in
25 mL and added dropwise to the reaction mixture. The reaction
mixture became dark yellow. The yellow solution was added to a
mixture of 9 mL of concentrated HCl and 56 g of ice. The resulting
yellow solution was added to another solution containing 3-tert-
butylphenol 15 (46.6 mmol, 1 equiv) prepared in 20% NaOH (note,
both solutions were cooled to 0 °C.). The blood red solution was
allowed to stir at room temperature overnight. Approximately 16 h
later, the red mixture was allowed to stir at 60 °C, and Na2S2O4 (140
mmol, 3 equiv) was added portion-wise. Upon addition of Na2S2O4,
the solution became brownish yellow in color. After 30 min, the
reaction mixture was cooled to room temperature and filtered. The
filter cake was extracted with CHCl3 (3 × 30 mL) and refiltered after
every extraction. The organic portions were combined, washed with
5% Na2CO3 solution and then brine, dried, and concentrated. The
dark purple solid was confirmed to be the product by 1H NMR
spectroscopy. Compound 11 was used without further purification in
the subsequent step as a dark purple solid (68% yield, 1.5 g); 1H NMR
(400 MHz, CDCl3) δ 6.75 (t, J = 1.6 Hz, 1H), 6.52 (d, J = 1.6 Hz,
2H), 4.27 (bs, 1H), 3.54 (bs, 2H), 1.38 (s, 9H).
F
DOI: 10.1021/acs.joc.6b01066
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Synthesis of 4-Amino-3-tert-butylanisole 12. Following a reported
procedure,63 compound 11 (18.6 mmol, 1 equiv) and KOtBu (19
mmol, 1.02 equiv) were evacuated and purged with N2 and then
dissolved in DMSO (10 mL). The reaction mixture was allowed to stir
for 1 h before the addition of Me2SO4 (19.7 mmol, 1.06 equiv). After
15 min, the reaction was quenched with water, extracted with Et2O,
washed with brine, dried over Na2SO4, filtered, and concentrated. The
organic layer was dried over anhyd Na2SO4 and filtered, and the
solvent was removed under reduced pressure to obtain the crude
product. The crude reaction mixture was purified via Combiflash using
80:20 hexanes:EtOAc as the mobile phase. Aniline derivative 12 was a
117.0, 115.4, 111.8, 44.0, 34.4, 31.8, 30.2, 29.1; HRMS (ESI/TOF-Q)
m/z calcd for C15H23NH+ [M + H]+ 218.1909, found 218.1918.
1
Compound 6c: amber liquid (66% yield, 0.61 g); H NMR (400
MHz, CDCl3) δ 6.89−6.88 (m, 1H), 6.71−6.68 (m, 1H), 6.63−6.61
(m, 1H), 5.91−5.80 (m, 1H), 5.09−4.97 (m, 2H), 3.74 (s, 3H), 3.56
(bs, 1H), 3.13 (t, J = 7.0 Hz, 2H), 2.24−2.16 (m, 2H), 1.82−1.73 (m,
2H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 151.8, 141.1,
138.3, 135.8, 115.3, 114.5, 113.2, 110.8, 55.9, 45.0, 34.6, 31.8, 30.1,
29.2; HRMS (ESI/TOF-Q) m/z calcd for C16H25NOH+ [M + H]+
248.2014, found 248.2021.
Synthesis of Amides 9a and 9b. A literature procedure43 was
employed as reported for the synthesis of amides 9a and 9b. To a
solution of the aniline derivative 4 or 12 (1.0 g, 1.0 equiv), and
triethylamine (2.0 equiv) in dry DCM (15 mL) at 0 °C under a N2
atmosphere was added the corresponding acyl chloride 8 (1.1 equiv).
The resulting solution was slowly allowed to warm to room
temperature over 16 h. After the reaction, water was added and
stirred, and the layers were separated. The organic layer was washed
with DI water (2 × 15 mL), dried over anhyd Na2SO4 and filtered, and
the solvent was removed under reduced pressure to yield the crude
product. The crude product was purified by combiflash using
hexanes:ethyl acetate as the mobile phase.
1
brown oil (40% yield, 0.66 g); H NMR (400 MHz, CDCl3) δ 6.85
(m, 1H), 6.60 (m, 2H), 3.73 (s, 3H), 3.55 (bs, 2H), 1.40 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 152.9, 138.5, 136.1, 119.0, 111.3, 55.8,
34.7, 29.8.
Synthesis of Ethyl 2,2-Dimethyl-4-oxo-3,4-dihydro-2H-pyran-6-
carboxylate 13. Enone 13 derivative was synthesized according to a
procedure reported in the literature.64 A flask was evacuated and
purged with N2. Absolute ethanol (EtOH) was added to the empty
round-bottom flask under nitrogen. Then, mixtures of mesityl oxide 16
(10.2 mmol, 1 equiv) and diethyl oxalate 17 (10.2 mmol, 1 equiv) in
EtOH were added to the round-bottom flask at 0 °C. After the
reaction mixture was allowed to stir for 5 min, sodium ethoxide in
ethanol (21 wt%; ∼11.2 mmol, ∼1.1 equiv) was added dropwise over
20 min. The resulting reaction mixture was dark yellow in color. The
reaction mixture was allowed to stir at 0 °C for an additional 10 min
before slowly rising to room temperature. The reaction mixture was
allowed to stir overnight. After approximately 20 h, the reaction was
diluted with diethyl ether and then poured into a flask containing 2 N
H2SO4 (∼5 mL concd acid into 76 mL of H2O). The organic layer was
separated, and the aqueous layer was extracted with ethyl acetate. The
crude product was purified by Combiflash yielding a light yellow oil
(60% yield, 2.4 g); 1H NMR (400 MHz, CHCl3) δ 6.18 (s, 1H), 4.30
(q, J = 7.1 Hz, 2H), 2.52 (s, 2H), 1.47 (s, 6H), 1.33 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 193.8, 162.3, 157.4, 107.5, 82.7,
62.6, 47.8, 26.0, 14.2.
Synthesis of 3,4-Dihydro-2-,2-dimethyl-4-oxo-2H-pyran-6-car-
boxylic Acid 14. To a solution of 13 (2 g) in THF (45 mL) was
added 5 M HCl (30 mL), which was stirred for 24 h or until
precipitation occurred. After starting material was consumed, the
solvent was removed under vacuum, followed by washing with water
and removing solvent under vacuum. The crude product was purified
by recrystallization in a THF:hexanes mixture to yield an off white
solid (80% yield, 1.7 g); 1H NMR (400 MHz, CDCl3) δ 6.30, (s, 1H),
2.57 (s, 2H), 1.50 (s, 6H).
Compound 9a: colorless solid (80% yield, 2.91 g); mp 104−107
°C; 1H NMR (400 MHz, CDCl3) δ 7.66−7.64 (m, 1H), 7.59 (bs, 1H),
7.39−7.37 (m, 1H), 7.23−7.19 (m, 1H), 7.16−7.13 (m, 1H), 5.82 (s,
1H), 5.45 (d, J = 0.6 Hz, 1H), 2.07 (s, 3H), 1.40 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 166.6, 142.4, 141.2, 135.4, 127.7, 127.0, 126.7,
126.2, 120.0, 34.7, 30.9, 19.1; HRMS (ESI/TOF-Q) m/z calcd for
C14H19NOH+ [M + H]+ 218.1545, found 218.1545.
Compound 9b: pale yellow solid (50% yield, 0.520 g); mp 127−129
1
°C; H NMR (400 MHz, CDCl3) δ 7.43−7.36 (m, 1H), 6.94−6.93
(m, 1H), 6.76−6.73 (m, 1H), 5.81 (s, 1H), 5.43 (s, 1H), 3.78 (s, 3H),
2.05 (s, 3H), 1.37 (d, J = 2.2 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ
167.0, 157.9, 145.5, 141.0, 130.0, 128.1, 119.9, 113.9, 110.7, 55.6, 35.0,
30.7, 19.1; HRMS (ESI/TOF-Q) m/z calcd for C15H21NO2Na+ [M +
Na]+ 270.1470, found 270.1478.
Synthesis of Substituted Atropisomeric Enone-Amides 1a−c. To
a solution of N-alkenyl aniline derivative 6a, 6b, or 6c (1.0 g, 1.0
equiv), triethylamine (2.0 equiv) in dry DCM (15 mL) at 0 °C under
N2 atmosphere the corresponding acyl chloride 7 (1.1 equiv) was
added. The resulting solution was slowly allowed to warm to room
temperature and stir for 16 h. After the reaction, water was added,
stirred and the layers were separated. The organic layer was washed
with DM water (2 × 15 mL), dried over anhyd. Na2SO4, filtered and
the solvent was removed under reduced pressure to yield crude
product. The crude product was purified by combiflash using
hexanes:ethyl acetate mixture.
Synthesis Protocol for N-Substituted Anilines 6a−c. Following a
reported procedure,44 the appropriate aniline derivative (4 or 12) (6.7
mmol, 1.5 equiv) was added to activated K2CO3 (11.2 mmol, 2.5
equiv) in a round-bottom flask and combined with a stir bar, then
evacuated and purged with N2. The mixture was then dissolved in
DMF (22 mL) followed by the addition of bromoalkene 5a or 5b (4.5
mmol, 1 equiv). The reaction mixture was set to 90 °C and allowed to
stir overnight. After ∼16 h, the reaction mixture was removed from
heat, quenched with H2O, and then extracted with EtOAc followed by
washing with brine solution. The organic layers were combined, dried
over Na2SO4 (anhyd), filtered, concentrated, and purified by
combiflash hexanes:EtOAc (95:5) as the mobile phase.
1
Compound 1a: yellow liquid (70% yield, 1.82 g); H NMR (400
MHz, CDCl3) δ 7.48 (dd, J = 8.1, 1.3 Hz, 1H), 7.27−7.19 (m, 1H),
7.08−7.01 (m, 1H), 6.87 (dd, J = 7.8, 1.4 Hz, 1H), 5.75−5.60 (m,
2H), 5.04−4.92 (m, 2H), 4.33 (ddd, J = 12.9, 10.0, 6.1 Hz, 1H), 2.91−
2.75 (m, 1H), 2.48−2.36 (m, 1H), 2.27−2.07 (m, 3H), 1.32 (d, J = 1.2
Hz, 9H), 1.00 (s, 3H), 0.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
192.5, 164.1, 162.9, 146.8, 138.3, 134.93, 132.1, 130.6, 128.8, 126.3,
117.2, 105.9, 82.6, 51.6, 47.4, 36.5, 32.6, 30.9, 26.3, 24.3; HRMS (ESI/
TOF-Q) m/z calcd for C22H29NO3H+ [M + H]+ 356.2243, found
356.2226.
Compound 1b: opaque white solid (77% yield, 0.65 g); mp 55−59
1
1
Compound 6a: yellow liquid (44% yield, 1.5 g); H NMR (400
°C; H NMR (400 MHz, CDCl3) δ 7.55−7.52 (m, 1H), 7.31−7.27
MHz, CDCl3) δ 7.23−7.20 (m, 1H), 7.12−7.08 (m, 1H), 6.68−6.64
(m, 2H), 5.89−5.79 (m, 1H), 5.21−5.12 (m, 3H), 3.96 (bs, 1H), 3.22
(t, J = 6.4 Hz, 3H), 2.48−2.43 (m, J = 3H), 1.37 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 146.6, 136.6, 133.3, 127.3, 126.4, 117.6, 117.0,
111.7, 43.4, 34.0, 30.1; HRMS (ESI/TOF-Q) m/z calcd for
C14H21NH+ [M + H]+ 204.1752, found 204.1760.
(m, 1H), 6.91−6.89 (m, 1H), 5.77−5.70 (m, 2H), 4.99−4.94 (m, 2
H), 4.32−4.25 (m, 1H), 2.88−2.81 (m, 1H), 2.34−2.14 (m, 2H),
2.07−1.86 (m, 4H), 1.61−1.54 (m, 1H), 1.38 (s, 9H), 1.05 (s, 3H),
0.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.7, 164.2, 162.8,
146.7, 138.5, 137.6, 132.0, 130.6, 128.8, 126.3, 115.5, 105.9, 82.6, 52.2,
47.5, 36.6, 32.6, 31.3, 26.4, 25.4, 24.4; HRMS (ESI/TOF-Q) m/z calcd
for C23H31NO3H+ [M + H]+ 370.2385, found 370.2382.
1
Compound 6b: amber liquid (76% yield, 0.55 g); H NMR (400
Compound 1c: pale yellow solid (49% yield, 0.48 g); mp 84−86 °C;
1H NMR (400 MHz, CDCl3) δ 7.03−7.02 (m, 1H), 6.83−6.80 (m,
1H), 6.63−6.61 (m, 1H), 5.78−5.68 (m, 2H), 4.99−4.91 (m, 2H),
4.29−4.22 (m, 1H), 3.77 (s, 3H), 2.84−2.77 (m, 1H), 2.35−2.15
MHz, CDCl3) δ 7.23 (m, 1H), 7.16−7.12 (m, 1H), 6.69 (t, J = 7.4 Hz,
2H), 5.94−5.82 (m, 1H), 5.13−4.99 (m, 2H), 3.86 (s, 1H), 3.21 (t, J =
7.0 Hz, 2H), 2.27−2.19 (m, 2H), 1.85−1.77 (m, 2H), 1.43 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 146.7, 138.2, 133.2, 127.4, 126.4,
G
DOI: 10.1021/acs.joc.6b01066
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(ABq, J = 16.4 Hz, 2H), 2.10−2.05 (m), 1.99−1.88 (m, 1H), 1.83−
1.79 (m, 1H), 1.63−1.61 (m, 1H), 1.36 (s, 9H), 1.10 (s, 3H), 0.82 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 192.7, 164.6, 163.2, 159.6,
148.3, 137.6, 133.1, 131.4, 116.6, 115.4, 110.6, 105.7, 82.6, 55.6, 47.5,
36.7, 32.5, 31.3, 26.4, 25.5, 24.6; HRMS (ESI/TOF-Q) m/z calcd for
C24H33NO4Na+ [M + Na]+ 422.2292, found 422.2307.
Synthesis of Substituted Atropisomeric Enone-Imides 1d and 1e.
Following a reported procedure,65 aniline derivative 9 (1.65 mmol, 1
equiv) was placed in a dry round-bottom flask and purged with N2
followed by the addition of dry THF (20 mL). The solution was
cooled to −78 °C, and LiHMDS (0.9 equiv) was added dropwise. The
solution was stirred at −78 °C for an hour before the slow addition of
freshly prepared acid chloride (1.75 mmol, 1.05 equiv). The reaction
mixture was allowed to slowly rise to room temperature and stirred for
16 h. After 16 h, the reaction mixture was quenched with H2O, washed
with HCl, extracted with ethyl acetate, dried over Na2SO4,
concentrated, and purified using column chromatography.
Compound 1d: colorless solid (65% yield, 2.21 g); mp 90−94 °C;
1H NMR (400 MHz, CHCl3) δ 7.55−7.52 (m, 1H), 7.33−7.29 (m,
1H), 7.23−7.17 (m, 1H), 6.89−6.86 (m, 1H), 6.02 (s, 1H), 5.6 (d, J =
14.9 Hz, 2H), 2.4 (ABq, J = 16.6, 12.1 Hz, 2H), 2.0 (s, 3H), 1.4 (s,
3H), 1.3 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 192.6, 173.0, 167.5,
161.7, 147.8, 142.2, 136.0, 131.2, 129.7, 129.4, 127.4, 124.1, 106.8,
83.8, 47.9, 36.1, 32.0, 27.0, 24.9, 19.4; HRMS (ESI/TOF-Q) m/z calcd
for C22H27NO4Na+ [M + Na]+ 392.1830, found 392.1838.
0.0885; R indices (all data) R1 = 0.0394, wR2 = 0.0920, largest diff.
peak and hole = 0.26 and −0.22 e Å−3, respectively.
1
Compound cis,trans-2a: pale yellow solid (22% yield, by H NMR
spectroscopy using internal standard); 1H NMR (400 MHz, CDCl3) δ
7.54−7.51 (m), 7.28−7.25 (m), 6.94−6.91 (m), 4.22−4.16 (m), 3.40−
3.37 (m), 3.34−3.29 (m), 2.82−2.73 (m), 2.59−2.47 (m), 2.36−2.32
(m), 2.30−2.18, 1.96−1.88 (m), 1.45 (s), 1.44 (s), 1.33 (s); 13C NMR
(100 MHz, CDCl3) δ 206.5, 171.0, 147.6, 142.5, 130.2, 128.5, 127.8,
127.6, 78.5, 77.8, 77.2, 54.5, 49.6, 45.4, 39.4, 35.8, 31.8, 31.6, 30.5,
30.4, 27.0, 19.7.
Crystal data for cis,trans-2a: C22H29NO3 (355.46), monoclinic, C2/
c, a = 32.5617(9) Å, alpha = 90.00°; b = 12.2539(3) Å, beta =
98.588(2)°; c = 19.7547(5) Å, gamma = 90.00°. V = 7793.9(4) Å3, Z =
16, T = 100(2) K, absorption coefficient = 0.33 mm−1, reflections
collected = 24883, unique = 6620 [R(int) = 0.0436], refinement by
Full-matrix least-squares on F2, data/restraints/parameters = 6620/0/
479, goodness-of-fit on F2 = 1.030, final R indices [I > 2sigma(I)] R1 =
0.0472, wR2 = 0.1130; R indices (all data) R1 = 0.0601, wR2 = 0.1206,
largest diff. peak and hole = 0.55 and −0.32 e Å−3, respectively.
Compound cis,cis-2b: colorless solid (37% yield, 0.0292 g); 1H
NMR (400 MHz, CDCl3) δ 7.57−7.55 (m), 7.33−7.24 (m), 6.99−
6.97 (m), 4.49−4.41 (m), 3.88−3.83 (m), 3.19−3.14 (m), 2.55 (s),
2.48−2.42 (m), 2.40−2.33 (m), 2.04−1.85 (m), 1.76−1.64 (m), 1.51−
1.48 (m), 1.43 (s), 1.40 (s), 1.32 (s); 13C NMR (100 MHz, CDCl3) δ
210.1, 170.7, 146.8, 141.7, 130.4, 128.7, 127.9, 127.1, 82.5, 78.1, 51.5,
49.4, 42.6, 41.4, 35.9, 31.7, 29.9, 29.1, 27.7, 25.0, 22.9.
Compound 1e: colorless solid (47% yield, 0.837 g); mp 130−132
1
Crystal data for cis-cis-2b (1S,6R, 2R,P)-2b: C23H31NO3 (369.49),
orthorhombic, P2(1)2(1)2(1), a = 8.2306(2) Å, alpha = 90.00°; b =
15.6867(5) Å, beta = 90.00°; c = 41.3174(13) Å, gamma = 90.00°. V =
4038.3(2) Å3, Z = 8, T = 100(2) K, absorption coefficient = 0.629
mm−1, reflections collected = 16255, unique = 6440 [R(int) = 0.0199],
refinement by Full-matrix least-squares on F2, data/restraints/
parameters = 6440/0/497, goodness-of-fit on F2 = 1.045, final R
indices [I > 2sigma(I)] R1 = 0.0265, wR2 = 0.0656; R indices (all
data) R1 = 0.0276, wR2 = 0.0663, largest diff. peak and hole = 0.14 and
−0.18 e Å−3, respectively; Flack parameter = 0.04(5).
°C; H NMR (400 MHz, CDCl3) δ 7.07−7.06 (m, 1H), 6.83−6.81
(m, 1H), 6.76−6.73 (m, 1H), 6.02 (s, 1H), 5.57 (m, 2H), 3.79 (d, J =
0.6 Hz, 3H), 2.54−2.42 (m, 2H), 2.00 (s, 3H), 1.44 (s, 3H), 1.36 (s,
3H), 1.32 (d, J = 0.6 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 192.6,
173.2, 167.8, 161.9, 159.8, 149.3, 142.2, 132.2, 128.8,124.1,116.0,
111.7, 106.7, 83.8, 55.5, 47.9, 36.1, 31.8, 27.1, 25.0, 19.5; HRMS (ESI/
TOF-Q) m/z calcd for C23H29NO5Na+ [M + Na]+ 422.1925, found
422.1943.
General Irradiation Procedure of Atropisomeric Enones 1a−
e with Thioxanone as Photocatalyst/Sensitizer. In a Pyrex test
tube, enone 1 (10 mg in 10 mL) and thioxanthone (mol %) were
dissolved in a given solvent and then degassed with N2 for 10 min. The
solution was irradiated for a specified time interval in a Rayonet
reactor (∼420 nm). After the reaction, a stock solution of internal
standard (triphenylmethane) was added, and this solution was
concentrated under reduced pressure to obtain the crude reaction
Compound cis,trans-2b: colorless solid (36% yield, 0.0292 g); mp
1
98−102 °C; C23H31NO3 (369.49); H NMR (400 MHz, CDCl3) δ
7.09−7.08 (m), 6.92−6.90 (m, 1H), 6.79−6.77 (m), 4.47−4.39 (m),
3.88−3.85 (m), 3.83 (s), 3.17−3.12 (m), 2.55 (s), 2.49−2.33 (m),
2.04−1.84 (m), 1.73−1.46 (m), 1.42 (s), 1.40 (s), 1.32 (s); 13C NMR
(100 MHz, CDCl3) δ 210.2, 171.0, 158.6, 148.3, 134.8, 131.2, 115.2,
111.0, 82.5, 78.1, 55.3, 51.4, 49.6, 42.6, 41.5, 35.9, 31.6, 29.9, 29.1,
27.7, 25.0, 22.9.
1
mixture. H NMR spectroscopy of the crude reaction mixture was
recorded to determine the mass balance and percent yield. For
atropselective reactions, optically pure enones were employed.
Direct Irradiation Procedure of Atropisomeric Enones 1. In a
Pyrex test tube, enone 1 (10 mg in 10 mL) was dissolved in a given
solvent and degassed with N2 for 10 min. The solution was irradiated
for the specified time interval in either a Rayonet reactor at ∼350 nm/
∼420 nm or using a 450 W medium-pressure Hg lamp enclosed in a
quartz jacket that was cooled with running water. After the reaction, a
stock solution of internal standard (triphenylmethane) was added, and
this solution was concentrated under reduced pressure to obtain the
Compound cis,cis-2c: colorless solid (35% yield, 0.0264 g); mp
1
139−142 °C; H NMR (400 MHz, CDCl3) δ 7.09−7.08 (m), 6.92−
6.90 (m, 1H), 6.79−6.77 (m), 4.47−4.39 (m), 3.88−3.85 (m), 3.83
(s), 3.17−3.12 (m), 2.55 (s), 2.49−2.33 (m), 2.04−1.84 (m), 1.73−
1.46 (m), 1.42 (s), 1.40 (s), 1.32 (s); 13C NMR (100 MHz, CDCl3) δ
207.1, 174.0, 146.1, 143.7, 130.3, 128.6, 127.8, 127.2, 81.7, 77.6, 53.8,
49.2, 42.2, 41.2, 35.7, 31.7, 30.6, 28.4, 27.2, 26.4, 26.1.
Crystal data for cis,cis-2c: C24H33NO4 (399.51), monoclinic, P2(1)/
c, a = 20.7554(7) Å, alpha = 90.00°; b = 6.2296(2) Å, beta =
101.719(2)°; c = 17.0708(6) Å, gamma = 90.00°. V = 2161.21(13) Å3,
Z = 4, T = 100(2) K, absorption coefficient = 0.660 mm−1, reflections
collected = 21165, unique = 3832 [R(int) = 0.0471], refinement by
Full-matrix least-squares on F2, data/restraints/parameters = 3832/0/
268, goodness-of-fit on F2 = 1.050, final R indices [I > 2sigma(I)] R1 =
0.0432, wR2 = 0.1058; R indices (all data) R1 = 0.0558, wR2 = 0.1135,
largest diff. peak and hole = 0.19 and −0.22 e Å−3, respectively.
1
crude reaction mixture. H NMR spectroscopy of the crude reaction
mixture was recorded to determine the mass balance and percent yield.
Compound cis,cis-2a: colorless solid (66% yield, by 1H NMR
1
spectroscopy using internal standard); mp 143−146 °C; H NMR
(400 MHz, CDCl3) δ 7.50−7.48 (m), 7.27−7.23 (m), 7.02−7.00 (m),
3.87−3.81 (m), 3.49−3.39 (m), 2.88−2.82 (m), 2.46−2.39 (m), 2.25−
2.18 (m), 1.97−1.79 (m), 1.39 (s), 1.35 (s), 1.32 (s); 13C NMR (100
MHz, CDCl3) δ 170.9, 147.3, 142.6, 129.7, 128.6, 128.4, 127.9, 80.0,
78.8, 52.1, 51.5, 45.2, 42.8, 42.8, 35.8, 31.8, 30.6, 30.1, 29.9, 24.9.
Crystal data for cis,cis-2a: C22H29NO3 (355.46), orthorhombic, Pccn,
a = 16.2407(5) Å, alpha = 90.00°; b = 18.9857(6) Å, beta = 90.00°; c =
12.4646(4) Å, gamma = 90.00°. V = 3843.3(2) Å3, Z = 8, T = 100(2)
K, absorption coefficient = 0.641 mm−1, reflections collected = 18521,
unique = 3387 [R(int) = 0.0295], refinement by Full-matrix least-
squares on F2, data/restraints/parameters = 3387/0/240, goodness-of-
fit on F2 = 1.037, final R indices [I > 2sigma(I)] R1 = 0.0351, wR2 =
1
Compound cis,trans-2c: colorless solid (35% yield, 0.0264 g); H
NMR (400 MHz, CDCl3) δ 7.06−7.05 (m, 1H), 6.96−6.94 (m, 1H),
6.77−6.75 (m, 1H), 4.66−4.60 (m, 1H), 3.82 (s, 3H), 3.45−3.40 (t,
1H), 3.12−3.07 (dd, J = 15.2, 5.2 Hz, 1H), 2.75−2.72 (d, J = 15.2 Hz,
1H), 2.51−2.43 (m, 1H), 2.35−2.27 (m, 2H), 2.19−2.03 (m, 2H),
1.84−1.64 (m, 3H), 1.51 (s, 3H), 1.39 (s, 9H), 1.32 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 207.1, 174.2, 158.5, 147.6, 136.9, 131.1, 115.1,
111.1, 81.8, 77.6, 55.3, 54.0, 49.2, 42.3, 41.3, 35.8, 31.5, 30.6, 28.5,
27.2, 26.4, 26.1.
H
DOI: 10.1021/acs.joc.6b01066
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Crystal data for cis,trans-2c: C24H33NO4 (399.51), triclinic, P-1, a =
11.7956(4) Å, alpha = 101.858(2)°; b = 12.4371(4) Å, beta =
99.6140(10)°; c = 16.1837(5) Å, gamma = 105.039(1)°. V =
2182.12(12) Å3, Z = 4, T = 100(2) K, absorption coefficient = 0.654
mm−1, reflections collected = 27433, unique = 7541 [R(int) = 0.0238],
refinement by Full-matrix least-squares on F2, data/restraints/
parameters = 7541/0/586, goodness-of-fit on F2 = 1.045, final R
indices [I > 2sigma(I)] R1 = 0.0423, wR2 = 0.0984; R indices (all
data) R1 = 0.0498, wR2 = 0.1033, largest diff. peak and hole = 0.28 and
−0.32 e Å−3, respectively.
2H), 3.84 (s, 3H), 3.27−3.23 (m, 1H), 2.80 (dd, J = 13.6, 10.5 Hz,
1H), 2.73−2.60 (m, 3H), 2.26 (dd, J = 13.6, 6.8 Hz, 1H), 1.57 (s, 2H),
1.50 (s, 3H), 1.48 (s, 3H), 1.44 (s, 3H), 1.34 (s, 9H); 13C NMR (100
MHz, CDCl3; minor N−CAryl rotamer) δ 206.2, 179.1, 177.2, 160.2,
149.2, 132.3, 123.3, 115.2, 111.5, 100.0, 78.6, 78.5, 77.2, 55.4, 51.2,
46.6, 40.1, 35.4, 31.2, 31.0, 30.0, 29.1, 15.7.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01066.
■
S
Compound cis,cis-2d (mixture of N-CAryl rotamers): colorless solid
(67% yield, calculated from 1H NMR spectroscopy); mp 199−201; 1H
NMR (400 MHz, CDCl3) δ 7.58−7.56 (m, 1H), 7.40−7.36 (m, 1H),
7.30−7.26 (m, 1H), 6.81−6.78 (m, 1H), 3.17−3.15 (m, 1H), 2.67−
2.56 (m, 3H), 2.29−2.24 (m, 1H), 1.47 (s, 3H), 1.42 (s, 3H), 1.39 (s,
3H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3; mixture of N-CAryl
rotamers) δ 179.2, 176.9, 148.5, 131.5, 130.5, 130.1(d), 130.0, 129.2,
128.6, 127.8, 127.6, 79.4, 79.0, 51.4, 51.3, 47.2, 46.9, 41.1, 40.3, 36.0,
32.0, 31.9, 31.8, 31.4, 31.14, 30.3, 30.2, 29.9, 29.4, 29.2, 15.8, 15.3.
Crystal data for cis,cis-2d (major rotamer): C22H27NO4 (369.44),
monoclinic, P2(1)/c, a = 14.8270(14) Å, alpha = 90.00°; b =
10.2711(9) Å, beta = 115.034(4)°; c = 14.4324(13) Å, gamma =
90.00°. V = 1991.4(3) Å3, Z = 4, T = 100(2) K, absorption coefficient
= 0.680 mm−1, reflections collected = 8770, unique = 3321 [R(int) =
0.0406], refinement by Full-matrix least-squares on F2, data/restraints/
parameters = 3321/0/250, goodness-of-fit on F2 = 1.165, final R
indices [I > 2sigma(I)] R1 = 0.0513, wR2 = 0.1591; R indices (all
data) R1 = 0.0671, wR2 = 0.1827, largest diff. peak and hole = 0.29 and
−0.32 e Å−3, respectively.
Experimental procedures, structure of compounds 10−
17, XRD analysis, characterization data, and analysis
conditions (PDF)
Single crystal XRD (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: jayaraman.sivaguru@ndsu.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Science Foundation for
generous support for their research (CHE-1465075) and for
the purchase of HPLC (CHE-1213880). The authors thank
Ms. Akila Iyer and Ms. Ramya Raghunathan for their help in
preparing this manuscript.
Compound cis,cis-2d (minor N-CAryl rotamer): colorless solid (17%
1
1
yield, calculated from H NMR spectroscopy); mp 201−203 °C; H
NMR (400 MHz, CDCl3) δ 7.56−7.54 (m, 1H), 7.40−7.35 (m, 1H),
7.28−7.24 (m, 1H), 6.84−6.82 (m, 1H), 3.24−3.20 (m, 1H), 2.79−
2.73 (m, 1H), 2.63−2.56 (m, 2H), 2.25−2.20 (m, 1H), 1.46 (s, 3H),
1.44 (s, 3H), 1.40 (s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 177.1, 147.9, 131.5, 131.0, 131.1, 128.7, 127.8, 78.8, 78.7, 51.4, 46.9,
51.4, 46.9, 40.3, 35.6, 31.5, 31.2, 30.2, 29.2, 15.9.
REFERENCES
■
(1) Turro, N. J.; Schuster, G. Science 1975, 187, 303.
(2) Oppolzer, W. Acc. Chem. Res. 1982, 15, 135.
(3) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485.
(4) Iriondo-Alberdi, J.; Greaney, M. F. Eur. J. Org. Chem. 2007, 2007,
4801.
Crystal data for cis,cis-2d (minor rotamer): C22H27NO4 (369.44),
orthorhombic, P2(1)2(1)2(1), a = 7.9328(3) Å, alpha = 90.00°; b =
14.3352(5) Å, beta = 90.00°; c = 16.9365(7) Å, gamma = 90.00°. V =
1925.99(13) Å3, Z = 4, T = 100(2) K, absorption coefficient = 0.703
mm−1, reflections collected = 12198, unique = 3295 [R(int) = 0.0246],
refinement by Full-matrix least-squares on F2, data/restraints/
parameters = 3295/0/251, goodness-of-fit on F2 = 1.073, final R
indices [I > 2sigma(I)] R1 = 0.0261, wR2 = 0.0660; R indices (all
data) R1 = 0.0266, wR2 = 0.0663, largest diff. peak and hole = 0.13 and
−0.18 e Å−3, respectively; twin law (−1.0, 0.0, 0.0, 0.0, −1.0, 0.0, 0.0,
0.0, −1.0), BASF [0.40(19)]
(5) Dembitsky, V. M. J. Nat. Med. 2007, 62, 1.
(6) Bach, T.; Hehn, J. P. Angew. Chem., Int. Ed. 2011, 50, 1000.
(7) Wrobleski, M. L.; Reichard, G. A.; Paliwal, S.; Shah, S.; Tsui, H.-
C.; Duffy, R. A.; Lachowicz, J. E.; Morgan, C. A.; Varty, G. B.; Shih, N.-
Y. Bioorg. Med. Chem. Lett. 2006, 16, 3859.
(8) Bauslaugh, P. G. Synthesis 1970, 1970, 287.
(9) Tateyama, S.; Masuo, S.; Suvannasara, P.; Oka, Y.; Miyazato, A.;
Yasaki, K.; Teerawatananond, T.; Muangsin, N.; Zhou, S.; Kawasaki,
Y.; Zhu, L.; Zhou, Z.; Takaya, N.; Kaneko, T. Macromolecules 2016, 49,
3336.
(10) Li, Y.; Urbas, A.; Li, Q. J. Org. Chem. 2011, 76, 7148.
(11) Li, Y.; Wang, M.; Wang, H.; Urbas, A.; Li, Q. Chem. - Eur. J.
2014, 20, 16286.
Compound cis,cis-2e (major N-CAryl rotamer): colorless solid (56%
1
yield, 0.112 g); mp 172−185 °C; H NMR (400 MHz, CDCl3) δ
7.13−7.12 (m, 1H), 6.85−6.82 (m, 1H), 6.78−7.76 (m, 1H), 3.84 (s,
3H), 3.22−3.17 (m,1H), 2.69−2.63 (m, 3H), 2.29 (dd, J = 13.4, 6.7
Hz, 1H), 1.50 (s, 3H), 1.45 (s, 3H), 1.42 (s, 3H), 1.30 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 206.3, 179.4, 176.9, 160.2, 149.8, 130.9,
122.9, 115.5, 111.6, 79.2, 78.8, 55.4, 51.1, 46.9, 40.9, 35.8, 31.8, 31.5,
31.4, 30.1, 29.2.
(12) Sun, R.; Xue, C.; Ma, X.; Gao, M.; Tian, H.; Li, Q. J. Am. Chem.
Soc. 2013, 135, 5990.
(13) Ramamurthy, V. In Photochemistry in Organized and Constrained
Media; Ramamurthy, V., Ed.; Wiley-VCH: New York, 1991; p 429.
(14) Vallavoju, N.; Sivaguru, J. Chem. Soc. Rev. 2014, 43, 4084.
(15) Pemberton, B. C.; Raghunathan, R.; Volla, S.; Sivaguru, J. Chem.
- Eur. J. 2012, 18, 12178.
Crystal data for cis,cis-2e (major N-CAryl rotamer, C23H29NO5)
(1R,6R,10R,P)-2e: C23H29NO5 (399.47), orthorhombic, P2(1)2(1)-
2(1), a = 8.0354(6) Å, alpha = 90.00°; b = 13.7812(10) Å, beta =
90.00°; c = 18.9887(14) Å, gamma = 90.00°. V = 2102.8(3) Å3, Z = 4,
T = 100(2) K, absorption coefficient = 0.719 mm−1, reflections
collected = 12152, unique = 3521 [R(int) = 0.0252], refinement by
Full-matrix least-squares on F2, data/restraints/parameters = 3521/0/
269, goodness-of-fit on F2 = 1.071, final R indices [I > 2sigma(I)] R1 =
0.0282, wR2 = 0.0708; R indices (all data) R1 = 0.0287, wR2 = 0.0712,
largest diff. peak and hole = 0.17 and −0.16 e Å−3, respectively; Flack
parameter = 0.06(6).
(16) Kranz, D. P.; Griesbeck, A. G.; Alle, R.; Perez-Ruiz, R.;
Neudorfl, J. M.; Meerholz, K.; Schmalz, H.-G. Angew. Chem., Int. Ed.
̈
2012, 51, 6000.
(17) Bergonzini, G.; Schindler, C. S.; Wallentin, C.-J.; Jacobsen, E.
N.; Stephenson, C. R. J. Chem. Sci. 2014, 5, 112.
(18) Condie, A. G.; Gonzal
Am. Chem. Soc. 2010, 132, 1464.
́ ́
ez-Gomez, J. C.; Stephenson, C. R. J. J.
Photoproduct cis,cis-2e (minor N-CAryl rotamer): colorless solid
(14% yield, 0.028 g); cis,cis-2e (minor N-CAryl rotamer; C23H29NO5);
1H NMR (400 MHz, CDCl3) δ 7.11−7.10 (m, 1H), 6.84−6.79 (m,
(19) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224.
(20) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011,
40, 102.
I
DOI: 10.1021/acs.joc.6b01066
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(21) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77.
(22) Arceo, E.; Montroni, E.; Melchiorre, P. Angew. Chem. Int. Ed.
2014, 53, 12064.
(61) Vallavoju, N.; Selvakumar, S.; Jockusch, S.; Prabhakaran, M. T.;
Sibi, M. P.; Sivaguru, J. Adv. Synth. Catal. 2014, 356, 2763.
(62) Vallavoju, N.; Selvakumar, S.; Pemberton, B. C.; Jockusch, S.;
Sibi, M. P.; Sivaguru, J. Angew. Chem., Int. Ed. 2016, 55, 5446.
(23) Tucker, J. W.; Zhang, Y.; Jamison, T. F.; Stephenson, C. R. J.
(63) Neumann, J. J.; Rakshit, S.; Droge, T.; Glorius, F. Angew. Chem.,
Int. Ed. 2009, 48, 6892.
(64) Brecker, L.; Pogorevc, M.; Griengl, H.; Steiner, W.; Kappe, T.;
Ribbons, D. W. New J. Chem. 1999, 23, 437.
(65) Amougay, A.; Pete, J.-P.; Piva, O. Tetrahedron Lett. 1992, 33,
7347.
Angew. Chem., Int. Ed. 2012, 51, 4144.
(24) Curran, D. P.; DeMello, N. C. J. Chem. Soc., Chem. Commun.
1993, 1314.
(25) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem.
Soc. 1994, 116, 3131.
̈
(26) Thayumanavan, S.; Beak, P.; Curran, D. P. Tetrahedron Lett.
1996, 37, 2899.
(27) Curran, D. P.; Geib, S.; DeMello, N. Tetrahedron 1999, 55,
5681.
(28) Clayden, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 949.
(29) Clayden, J. Synlett 1998, 1998, 810.
(30) Clayden, J. In Organic Synthesis Highlights IV; Wiley-VCH
Verlag GmbH, 2000; p 48.
(31) Clayden, J. Chem. Commun. 2004, 127.
(32) Clayden, J.; Lai, L. W.; Helliwell, M. Tetrahedron 2004, 60,
4399.
(33) Kumarasamy, E.; Raghunathan, R.; Sibi, M. P.; Sivaguru, J.
Chem. Rev. 2015, 115, 11239.
(34) Ayitou, A. J.-L.; Sivaguru, J. J. Am. Chem. Soc. 2009, 131, 5036.
(35) Ayitou, A. J.-L.; Vallavoju, N.; Ugrinov, A.; Sivaguru, J.
Photochem. Photobiol. Sci. 2011, 2011, 1380.
(36) Ayitou, A. J.-L.; Sivaguru, J. Chem. Commun. 2011, 47, 2568.
(37) Ayitou, A. J.-L.; Clay, A.; Kumarasamy, E.; Jockusch, S.;
Sivaguru, J. Photochem. Photobiol. Sci. 2014, 13, 141.
(38) Ayitou, A. J.-L.; Jesuraj, J. L.; Barooah, N.; Ugrinov, A.; Sivaguru,
J. J. Am. Chem. Soc. 2009, 131, 11314.
(39) Jesuraj, J. L.; Sivaguru, J. Chem. Commun. 2010, 46, 4791.
(40) Kumarasamy, E.; Jesuraj, J. L.; Omlid, J. N.; Ugrinov, A.;
Sivaguru, J. J. Am. Chem. Soc. 2011, 133, 17106.
(41) Raghunathan, R.; Kumarasamy, E.; Iyer, A.; Ugrinov, A.;
Sivaguru, J. Chem. Commun. 2013, 49, 8713.
(42) Kumarasamy, E.; Sivaguru, J. Chem. Commun. 2013, 49, 4346.
(43) Iyer, A.; Jockusch, S.; Sivaguru, J. J. Phys. Chem. A 2014, 43,
1816.
(44) Kumarasamy, E.; Raghunathan, R.; Jockusch, S.; Ugrinov, A.;
Sivaguru, J. J. Am. Chem. Soc. 2014, 136, 8729.
(45) Karkas, M. D.; Porco, J. A.; Stephenson, C. R. J. Chem. Rev.
̈
̈
2016, ASAP DOI: 10.1021/acs.chemrev.5b00760.
(46) Crimmins, M. T. Chem. Rev. 1988, 88, 1453.
(47) Turro, N. J.; Ramamurthy, V.; Scaiano, J. C. Modern Molecular
Photochemistry of Organic Molecules; University Science Books:
Sausalito, CA, 2010.
(48) Schuster, D. I.; Lem, G.; Kaprinidis, N. A. Chem. Rev. 1993, 93,
3.
(49) De Mayo, P. Acc. Chem. Res. 1971, 4, 41.
(50) Fort, D. A.; Woltering, T. J.; Nettekoven, M.; Knust, H.; Bach,
T. Angew. Chem., Int. Ed. 2012, 51, 10169.
(51) Sylvie Le, B.; Jean-Pierre, P.; Olivier, P. Tetrahedron Lett. 1993,
34, 635.
(52) Refer to Supporting Information.
(53) Wolf, C. Dynamic Stereochemistry of Chiral Compounds. Principles
and Applications; RSC Publishing: Cambridge, UK, 2008.
(54) Trapp, O. Springer: Berlin Heidelberg, 2013; p 1.
(55) Betson, M. S.; Clayden, J.; Helliwell, M.; Johnson, P.; Lai, L. W.;
Pink, J. H.; Stimson, C. C.; Vassiliou, N.; Westlund, N.; Yasin, S. A.;
Youssef, L. H. Org. Biomol. Chem. 2006, 4, 424.
(56) Clayden, J.; Lai, L. W. Tetrahedron Lett. 2001, 42, 3163.
(57) Only cis,cis-2b was investigated for enantioselectivity due to
limitations in separating enantiomers of cis,trans-2b on a chiral
stationary phase.
(58) Satzger, H.; Schmidt, B.; Root, C.; Zinth, W.; Fierz, B.; Krieger,
F.; Kiefhaber, T.; Gilch, P. J. Phys. Chem. A 2004, 108, 10072.
(59) Meyer, C.; Piva, O.; Pete, J.-P. Tetrahedron 2000, 56, 4479.
(60) Vallavoju, N.; Selvakumar, S.; Jockusch, S.; Sibi, M. P.; Sivaguru,
J. Angew. Chem., Int. Ed. 2014, 53, 5604.
J
DOI: 10.1021/acs.joc.6b01066
J. Org. Chem. XXXX, XXX, XXX−XXX