Evidence for a Sigmatropic and an Ionic Pathway in the Winstein Rearrangement

Article abstract of DOI:10.1021/acs.joc.8b00961

The spontaneous rearrangement of allylic azides is thought to be a sigmatropic reaction. Presented herein is a detailed investigation into the rearrangement of several allylic azides. A combination of experiments including equilibrium studies, kinetic ana

Full text of DOI:10.1021/acs.joc.8b00961

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Article
Evidence for a Sigmatropic and an Ionic
Pathway in the Winstein Rearrangement
Amy A. Ott, Mary H. Packard, Manuel A. Ortuno, Alayna Johnson,
Victoria P. Suding, Christopher J. Cramer, and Joseph J. Topczewski
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00961 • Publication Date (Web): 05 Jun 2018
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The Journal of Organic Chemistry
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Evidence for a Sigmatropic and an Ionic Pathway in the Win-
stein Rearrangement
Amy A. Ottǂ, Mary H. Packardǂ, Manuel A. Ortuño, Alayna Johnson, Victoria P. Suding, Christopher J.
Cramer, Joseph J. Topczewski*
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Department of Chemistry, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, United States
ABSTRACT: The spontaneous rearrangement of allylic azides is thought to be a sigmatropic reaction. Presented herein is a
detailed investigation into the rearrangement of several allylic azides. A combination of experiments including equilibrium
studies, kinetic analysis, density functional theory calculations, and selective 15N-isotopic labeling are included. We conclude
that the Winstein rearrangement occurs by the assumed sigmatropic pathway under most conditions. However, racemization
was observed for some cyclic allylic azides. A kinetic analysis of this process is provided, which supports a previously un-
described ionic pathway.
Introduction
Sigmatropic rearrangements are central to organic
for stereoselectivity.19 A single diastereomer was isolated
from a tandem insertion rearrangement sequence (Scheme
1b). Spino observed stereoselectivity during a tandem
Mitsunobu reaction rearrangement sequence (Scheme
1c).20 A few reports describe an analysis of crotyl and prenyl
systems computationally and concluded that the process is
cyclic.21–23 These observations are all consistent with a con-
certed [3,3] sigmatropic mechanism for the allylic azide re-
arrangement and the [3,3] mechanism has been generally
accepted.
chemistry and their synthetic applications are numerous.
Famous examples include the Cope,1 Claisen,1 Wittig,2 Car-
roll3, Sommelet-Hauser4, Mislow-Evans5, Meisenheimer6,
and Overman7 rearrangements or modifications thereof.8–10
In principle, all of these reactions are reversible. However,
the most heavily utilized sigmatropic rearrangements have
a clear thermodynamic driving force. Most also require
heating to achieve efficient reactivity. When viewed in this
light, the Winstein rearrangement of allylic azides is an odd-
ity because i) it occurs at or near room-temperature and ii)
it results in an equilibrium mixture of allylic azides (Scheme
1a).11 This is because the azide functional group is dipolar
and symmetric. A C-N, N=N, and C=C bond is present in both
the starting material and product of the azide rearrange-
ment, making it near thermo-neutral. This parallels the
Cope rearrangement, where, in most cases, the starting ma-
terial and product are similar in energy, resulting in an equi-
librium distribution.12 This also parallels the rearrange-
ment of allylic acetates.13–15 These unusual properties make
the allylic azide rearrangement an interesting candidate for
further study.
Scheme 1. Winstein Rearrangement
The rearrangement of allylic azides was first described
by Winstein and co-workers (Scheme 1a).11 In hindsight,
this rearrangement was likely observed but not recognized
until later by VanderWerf and Heasley.16,17 Winstein’s initial
report describes the rate constant and equilibrium constant
for the rearrangement of prenyl azide and crotyl azide.
These parameters were minimally sensitive to solvent po-
larity, indicating a relatively neutral transition state and im-
plying a sigmatropic process. Le Noble found that at high
pressure the reaction’s activation volume was consistent
with a neutral pathway.18 Padwa provided the first evidence
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A unique aspect of the allylic azide rearrangement is the amine was subjected to diazo-transfer conditions, which
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abnormally low activation barrier, which allows this pro-
cess to occur at ambient temperature. The Winstein rear-
rangement has limited synthetic applications due to diffi-
culties controlling the rearrangement.24–30 We have an on-
going interest in using the Winstein rearrangement and be-
came interested in more precisely defining the parameters
of the rearrangement on a broader set of allylic azides.31–33
Presented herein is a summary of several experiments that
more fully define the energetics and mechanism of this re-
arrangement. We investigated the effect of competitive con-
jugation on the equilibrium constant. A rearrangement with
15N isotopically labeled allylic azide unambiguously con-
firms the [3,3] pathway. We describe a pathway for the E to
Z isomerization of trisubstituted alkenes. These results led
to us to probe whether racemization of chiral allylic azides
could occur. Under certain conditions, these allylic azides
racemize. A kinetic analysis supports an ionic pathway.
Each of these pathways is supported by DFT calculations.
These combined experiments indicate that more than one
pathway is operable for allylic azide isomerization.
formed azide 20. This azide spontaneously rearranged to
afford 15N-cinnamyl azide (21), which was isolated as a sin-
gle isomer due to conjugation. The label was again clearly
evident by NMR, IR, and HRMS. Reduction of the azide liber-
ated N2 and afforded phosphoramidate 22. Analysis of this
product by NMR and HRMS indicated the complete loss of
the 15N label. An authentic sample of 15N-22 was synthe-
sized by a separate route. This experiment provides direct
evidence for the [3,3] mechanism of the Winstein rear-
rangement.
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Scheme 2. Effects of Conjugation on Keq
Results and Discussion:
Effect of Conjugation on Keq. Scattered reports provide
insight into biasing the azide rearrangement. Hassner orig-
inally synthesized cinnamyl azide and reported only a single
isomer (Scheme 2a).34 In this example, conjugation to the
phenyl ring strongly influences the equilibrium and results
in a single observable isomer.35 Panek observed a similar ef-
fect with γ-azido-α,β-unsaturated esters (Scheme 2b) and
Evans made an analogous observation with 3-azido-vinyl
sulfones (Scheme 2c).36,37 In all cases, the conjugated com-
pound is favored. This is reminiscent of strategies to render
the Cope rearrangement effectively irreversible by forming
a conjugated product.38 We were interested in re-establish-
ing a detectible equilibrium with conjugated azides. To this
end, compounds 15 through 18 were synthesized (Figure
2d). Each allylic terminus is substituted with a different
group for conjugation. After isolation, samples were incu-
bated at 40 °C for 48h to allow equilibration and then ana-
lyzed. The observed equilibrium ratio ranges from 2.3:1 to
1.2:1 for azides 15 through 17, indicating that a detectible
equilibrium can be re-established if both termini stabilize
the system through conjugation. The effect seemed insensi-
tive to the nature of the aryl (16 vs 17). For nitriles 18a and
18b, the other isomer was not detected. The remainder of
this report describes allylic azides that are conjugated to an
aryl ring. These systems were intentionally designed to
minimize the number of isomers present in the mixture as a
means of simplifying analysis.
Scheme 3. Rearrangement of 15N-Labeled Allylic Azide
15N-Labelling Experiment. One means to unambigu-
ously discern between a [1,3], [3,3], and ionic mechanism is
to isotopically label one end of the azide group. Sodium az-
ide containing a 15N-label is commercially available; how-
ever, either end of the azide anion could attack an electro-
philic carbon center. This would likely generate a 1:1 mix-
ture of proximal and distal 15N-azides, which would be diffi-
cult to analyze. Instead, we turned our attention to an alter-
nate approach (Scheme 3). We synthesized 15N-amine 19 in
two steps from potassium 15N-phthalimide. The 15N-label
was evident by 15N NMR and by HRMS. Images of all mass
spectra are included in the supporting information. The
E to Z Isomerization. Many allylic azides are isolated as
a mixture of alkene isomers.11,24,27,39,40 Typically, the ob-
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served distribution of isomers is related to the relative ther- half chair (C-N-N-N-C in plane and C-C-C pucker). The rear-
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modynamic stability of the alkenes. Little is known regard-
ing the mechanism of alkene isomerization via the Winstein
rearrangement.22 Labadie et. al, investigated several iso-
prenyl azides.23 That report concluded that allylic azides
conjugated to an aryl ring do not rearrange. This is contrary
to a prior report that cis-cinnamyl azide isomerizes to trans-
cinnamyl azide.41 We observed that azide 23 forms a mix-
ture of E and Z isomers upon standing (Scheme 4a). The
naphthyl containing compound was studied because the
isomers were separable by column chromatography.42 We
conducted a kinetic analysis of the E to Z isomerization by
1H NMR at 75 °C in C6D6. The observed rate constant (k1+k-
1) was 7.2 x 10-4 s-1 and the observed ratio of 23:24 was
3.2:1 at equilibrium (equilibrium reached after 90 min). The
same approximate values were measured by monitoring the
reverse Z to E rearrangement (k1+k-1 = 6.9 x 10-4 s-1, average
reported in Scheme 4). The observed rate is slower than
that reported by Winstein for crotyl azide.
rangement is relatively synchronous (CN bond lengths of
2.036 and 2.069 Å). This study did not address if the transi-
tion state is pericyclic or pseudopericyclic.15,45,46 These re-
sults indicate that the Winstein rearrangement is kinetically
viable on conjugated systems, even though the isomeric
benzylic azide is present at too small a concentration to be
readily detected by 1H NMR.
Chiral Acyclic Allylic Azide. These results led us to con-
sider whether azide 26 could racemize through the Win-
stein rearrangement (Scheme 5). Stereoselectivity is a key
feature to effectively utilizing allylic azides in synthetic con-
texts.20 Racemization can occur readily if one isomer is achi-
ral (see SI for the calculated profile for crotyl azide) or if the
product is the enantiomer of the starting material.32,47 It was
unclear whether a system such as azide 26 would racemize
via a sigmatropic process. The examples from Padwa and
Spino (Scheme 1b-c) document that racemization was not
observed in those instances. However, the example from
Padwa is cyclic, cannot form E/Z mixtures, and it is effec-
tively irreversible (kinetically mediated). The example from
Spino contains a trans alkene, which may not be able to
adopt multiple reactive conformations. Azide 26 rapidly
forms a mixture of E/Z isomers, with a rate constant (k1+k-
1) of 5.0 x 10-3 s-1 in C6D6 at 75 °C and a 2.5:1 equilibrium
ratio of 26:27. Equilibrium is reached considerably faster
for compounds 26 and 27 (after 20 min) relative to 23 and
24 (90 min). The observation that an additional methyl
group speeds the rearrangement is consistent with Win-
stein’s work where krel for prenyl/crotyl azides ranged from
2.6-3.6 in a variety of solvents.11 To determine if racemiza-
tion occurs, we used semi-preparative chiral HPLC to isolate
enantioenriched azide 26 (>99:1 er). The equilibration of
compound 26 was monitored by 1H NMR at 75 °C. Once
equilibrium was reached, the enantiopurity of the sample
was measured by chiral HPLC. Only a single enantiomer was
observed for both the E isomer (>99:1 er) and Z isomer
(>99:1 er). This indicates that racemization via a sigma-
tropic process is unlikely.
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Scheme 4. Equilibration of Azides 23 and 24
We investigated the [3,3] mechanism computationally
(Scheme 5b-c). The lowest energy pathway is similar to that
shown for compounds 23 and 24, where a three step pro-
cess is responsible for the alkene isomerization (Scheme
5b). The azide rearranges to trans-azide 28, undergoes a
bond rotation, and then rearranges for a second time to af-
ford (Z)-azide 27. For compounds 26 and 27, a second sig-
matropic pathway was identified, which is similar to the
first except in the order of events. In the second pathway
(Scheme 5c), (E)-azide 26 undergoes a sigma bond rotation
and then a rearrangement to afford cis-azide 28. This azide
undergoes a second bond rotation and subsequent rear-
rangement to afford (Z)-azide 27. In both pathways, the in-
itial azide was intentionally assigned as (S)-(E)-azide 26
and the product of both pathways was (R)-(Z)-azide 27. The
stereoselectivity in both pathways is consistent with the ex-
perimental findings.
a) Values determined by 1H NMR. b and c) Free energies
(kcal/mol, 1 M standard state, 75 °C) computed at the
SMD(CHCl3)/M06-2X/6-311+G(2df,p)//SMD(CHCl3)/
M06-2X/6-31G(d) level of theory. The vertical scale has
been compressed by 15.0 kcal/mol between the ground
states and transition states.
We turned to density functional theory (DFT) calcula-
tions to describe the pathway for the observed alkene isom-
erization (Scheme 4b). These calculations were conducted
at the M06-2 level of theory, both in the gas phase and ac-
counting for solvation effects implicitly with the SMD solva-
tion model (e.g., chloroform, as shown in Scheme 4, see
Computational Details).43,44 The analysis indicates a three
step process: (1) endothermic rearrangement to benzylic
azide 25, (2) sigma bond rotation, and (3) a second Win-
stein rearrangement to the conjugated isomer 24. The cal-
culated barriers and relative stationary point energetics are
in good agreement with the experimental data. In both re-
arrangements, the transition-state structure is a fairly flat
A third ionic pathway was identified which was signifi-
cantly higher in energy. The azide ionizes to form free azide
anion and a stabilized allylic cation (Scheme 6). In the gas
phase and in chloroform, this pathway was significantly
higher in energy relative to the sigmatropic pathway (134.3
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and 48.7 kcal/mol, respectively). However, in methanol, the level of theory for gas-phase and SMD-solvated reaction co-
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ionic pathway was calculated to be much closer in energy to
the sigmatropic pathway, at only 30.0 kcal/mol. This
prompted further exploration.
ordinates. The vertical scale has been compressed by 60.0
kcal/mol between chloroform and gas phase.
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Identifying a Racemization Pathway. To examine the
proposed ionic pathway, a new series of allylic azides was
investigated (Scheme 7). These allylic azides are readily
prepared from cyclohexenone. The cyclohexyl ring prevents
E to Z isomerization and simplifies analysis. These azides
could be easily separated by semi-preparative chiral HPLC.
Once characterized, azide 30e was subjected to prolonged
heating in a variety of solvents. After one week at 100 °C no
or negligible racemization was observed in hexanes, tolu-
ene, chloroform, and tetrahydrofuran. In these solvents,
even after prolonged heating, these allylic azides can be
thought of as static structures that are configurationally and
isomerically stable. However, rapid racemization was ob-
served in methanol at 100 °C. As an example, for azide 30b
(4-Me), the er decreased considerably after only 1h from
>99:1 er to 74:26 er and full racemization occurred within
8h. Solvent-dependent racemization is consistent with the
pathway identified by DFT.
Scheme 5. Equilibration of Chiral Allylic Azide
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Intrigued by the observed racemization, we conducted a
more detailed kinetic analysis. The rate of racemization was
determined by chiral HPLC. Using the method of initial
rates48, the rate was found to be first order in azide. Several
analogous substrates were synthesized and subjected to the
same analysis. A Hammett plot was generated for racemiza-
tion (Figure 1). Therate of racemization is highly correlated
with the Hammett parameter σ+ (R2 = 0.99, ρ = - 3.9). The
relative energies of the ions (31a-f) were calculated at the
SMD/M06-2X level. The ion stabilities ranged from 21.4 –
30.0 kcal/mol (SMD(MeOH)) and the stabilities were also
correlated to σ+ (see SI). This analysis is consistent with rate
determining formation of an ion pair.
A more detailed analysis revealed a byproduct of the rac-
emization process, identified as the corresponding methyl
ether. At all-time points, the methyl ether is racemic. The
appearance of this product is consistent with an ionic sol-
volysis reaction. Adding exogenous tetrabutylammonium
azide did not noticeably inhibit the formation of the methyl
ether. The rate of methyl ether formation is also correlated
with the Hammett parameter σ+ (Figure 2, R2 = 0.92, ρ = -
3.1). When heated in methanol, acyclic azide 26 also race-
mizes, indicating that other azides can participate in this
process.
a) Values determined by 1H NMR. b and c) Free energies
(kcal/mol, 1 M standard state, 75 °C) computed at the
SMD(CHCl3)/M06-2X/6-311+G(2df,p)//SMD(CHCl3)/
M06-2X/6-31G(d) level of theory. The vertical scale has
been compressed by 15.0 kcal/mol between the ground
states and transition states.
Scheme 6. Relative Ionization Energies of Azide 26
Conclusion: Presented herein is a description of two
competing pathways for the rearrangement of allylic azides.
A
15N-labeling experiment, supported by DFT calculations,
indicates that under most circumstances, the rearrange-
ment is sigmatropic. A pathway for the isomerization of a
chiral allylic azide, with a trisubstituted alkene, is reported
to occur without racemization. A second ionic pathway is
available in highly polar media and we observed it in meth-
anol. This reaction is Hammett constant (σ+) correlated and
is kinetically consistent with a solvolysis mechanism.
Free energies (kcal/mol, 1 M standard state, 75 °C) com-
puted at the M06-2X/6-311+G(2df,p)//M06-2X/6-31G(d)
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Scheme 7. Racemization and Solvolysis of Cyclic Azides
evaporation. All waste and aqueous solutions, which could
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be contaminated with azide were kept in individually la-
beled containers and were kept STRICTLY free of acid to
avoid the accidental production of HN3.
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General Methods. All reactions used magnetic stirring.
All reactions conducted at elevated temperatures used alu-
minum block heating. Temperatures reported are based on
an external thermocouple. All commercially available rea-
gents were used without further purification. Dry THF and
DCM were obtained from a commercial solvent system uti-
lizing activated alumina columns under an argon pressure.
Thin-layer chromatography (TLC) was used to monitor re-
action progress. TLC was performed using pre-coated glass
or plastic plates with silica gel impregnated with a fluores-
cent indicator (254 nm). Visualization was achieved using
UV light, PMA, or KMnO4 stains. Organic solutions were con-
centrated by rotary evaporation under reduced pressure.
Flash chromatography was performed on an automated
system utilizing normal phase pre-column load cartridges
and gold high performance columns. All proton (1H) nuclear
magnetic resonance spectra (NMR) were recorded on a 400
MHz or 500 MHz spectrometer. All carbon (13C) nuclear
magnetic resonance spectra were recorded on a 100 MHz or
125 MHz NMR spectrometer. All phosphorous (31P) nuclear
magnetic resonance spectra were recorded on a 162 MHz
NMR spectrometer. All nitrogen (15N) nuclear magnetic res-
onance chemical shifts were measured using 1H-15N Hetero-
nuclear Multiple Bond Correlation (HMBC) on a 93 MHz
spectrometer. Data is presented as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet
and m = multiplet), integration, and coupling constant in
Hertz (Hz). Infrared (IR) spectra were taken with KBr
plates. IR spectra were reported in cm-1. Mass spectrometry
was conducted at the University of Minnesota Mass Spec-
tometry Laboratory. Details on HPLC analysis and purifica-
tion are included in the supporting information.
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Figure 1. Plot of log(k/k0) vs σ+ for substituent effects on
the racemization of azides 30a-f in MeOH. Rates were meas-
ured in duplicate, replicates shown.
ethyl (E)-4-azido-4-(4-methoxyphenyl)but-2-enoate (15a)
and ethyl (E)-2-azido-4-(4-methoxyphenyl)but-3-enoate
(15b). Azides 15a and 15b were synthesized via a multi-
step sequence that is outlined here. A procedure was
adapted from a known method for the addition of ethyl pro-
piolate to 4-methoxybenzaldehyde and the product was iso-
lated (700 mg, 73%).49 Characterization data for this com-
pound has been reported. The material obtained from this
1
method provided an identical H NMR spectrum. An image
1
of the H NMR spectrum is supplied in the accompanying
Figure 2. Plot of log(k/k0) vs σ+ for substituent effects on
the solvolysis of azides 30a-f in MeOH. Rates were meas-
ured in duplicate, replicates shown.
file.
This product was reduced using an adapted procedure.50
To an ice-cold suspension of LiAlH4 (33 mg, 0.9 mmol) in
THF (2.5 mL), a solution of ethyl 4-hydroxy-4-(4-methoxy-
phenyl)but-2-ynoate (200 mg, 0.9 mmol) in THF (2.5 mL)
was added dropwise. After 10 min, the ice bath was re-
moved. After 30 min, the reaction was quenched by addition
of 1M HCl. The resulting solution was extracted with DCM
(3 × 10 mL). The combined organic phase was washed with
brine, dried (MgSO4), filtered, and concentrated under re-
duced pressure. Purification by column chromatography
(30% EtOAc in hexanes) afforded ethyl (E)-4-hydroxy-4-(4-
methoxyphenyl)but-2-enoate (82 mg, 41%) as an oil. Char-
acterization data for this compound has been reported. The
Experimental Section:
Azide Safety. Azides are known to be high-energy mate-
rials, and explosions have been reported when working
with azides. In the course of this work, no issues were en-
countered. All of the azides synthesized in this report have
C/N ratios equal to or above the recommended guideline of
3 C/N. Precautionary blast shields were used for all reac-
tions using or producing more than 1 mmol of azide. Blast
shields were used both in the fume hood and during rotary
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material obtained from this method provided an identical
(ESI-TOF) m/z: [M + Na]+ calcd for C15H19N3O3Na+ 312.1319,
found 312.1320.
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1H NMR spectrum.51 An image of the H NMR spectrum is
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supplied in the accompanying file.
tert-butyl (E)-2-azido-4-phenylbut-3-enoate (17a) and
tert-butyl (E)-4-azido-4-phenylbut-2-enoate (17b). Azides
17a and 17b were synthesized via a multi-step sequence
that is outlined here. A procedure was adapted from a
known method52 for the addition of tert-butyl propiolate to
benzaldehyde and the product was isolated as an oil (755
mg, 75%): 1H NMR (500 MHz; CDCl3): δ 7.52 (d, J = 7.1 Hz,
2H), 7.42-7.36 (m, 3H), 5.54 (s, 1H), 1.52 (s, 9H); 13C NMR
(125 MHz; CDCl3): δ 152.6, 138.8, 128.79, 128.78, 126.7,
84.2, 84.0, 79.0, 64.2, 28.0; IR (KBr, thin film, cm-1) 3401,
2981, 2935, 2238, 1707, 1278, 1155; HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C14H16O3Na+ 255.0992, found 255.0991.
To
a
solution of ethyl 4-hydroxy-4-(4-methoxy-
phenyl)but-2-enoate (67 mg, 0.28 mmol) in CH2Cl2 (1 mL)
was added TMSN3 (0.8 mL, 0.6 mmol) and Zn(OTf)2 (23 mg,
0.063 mmol) at room temperature. The vessel was sealed.
After 20 min, the reaction mixture was filtered through sil-
ica and washed with CH2Cl2. The resulting solution was con-
centrated under reduced pressure. Purification by column
chromatography (gradient elution 0-15% EtOAc in hex-
anes) afforded a mixture of azide 15a and 15b (15a : 15b =
2.0 : 1) as an oil (52 mg, 70%): Major isomer (15a): 1H NMR
(500 MHz; CDCl3) δ 7.24 (d, J = 8.7 Hz, 2H), 6.98-6.89 (m,
3H), 6.14 (d, J = 15.4 Hz, 1H), 5.16 (d, J = 5.5 Hz, 1H), 4.23 (q,
J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); Minor
isomer (15b): 1H NMR (500 MHz; CDCl3) δ 7.38 (d, J = 8.8
Hz, 2H), 6.98-6.89 (m, 2H), 6.73 (d, J = 15.8 Hz, 1H), 6.17-
6.12 (m, 1H), 4.53 (d, J = 7.7 Hz, 1H), 4.33-4.27 (m, 2H), 3.84
(s, 3H), 1.34 (t, J = 7.1 Hz, 3H); Mixture: 13C NMR (125 MHz;
CDCl3) δ 169.1, 165.9, 160.1, 160.0, 144.1, 135.5, 128.9,
128.4, 128.2, 122.5, 118.3, 114.4, 114.1, 65.0, 63.9, 62.1,
60.7, 55.3, 14.2, 14.1; IR (KBr, thin film, cm-1) 2980, 2838,
2103, 1720, 1608, 1513, 1255, 1176; HRMS (ESI-TOF) m/z:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This product was reduced using an adapted procedure.50
To an ice-cold suspension of LiAlH4 (57 mg, 1.7 mmol) in
THF (4 mL), a solution of tert-butyl 4-hydroxy-4-phenylbut-
2-ynoate (350 mg, 1.7 mmol) in THF (4mL) was added
dropwise. After 15 min, the reaction was quenched by addi-
tion of 1M HCl. The resulting solution was extracted with
CH2Cl2 (3 × 15 mL). The combined organic phase was
washed with brine, dried (MgSO4), filtered, and concen-
trated under reduced pressure. Purification by column
chromatography (30% EtOAc in hexanes) afforded tert-bu-
tyl (E)-4-hydroxy-4-phenylbut-2-enoate (200 mg, 56%) as
an oil. Characterization data for this compound has been re-
ported. The material obtained from this method provided
[M
+
Na]+ calcd for C13H15N3O3Na+ 284.1006, found
284.0998.
tert-butyl (E)-4-azido-4-(4-methoxyphenyl)but-2-enoate
(16a) and tert-butyl (E)-2-azido-4-(4-methoxyphenyl)but-3-
enoate (16b). Azides 16a and 16b were synthesized via a
multi-step sequence following the procedures for com-
pounds 15a and 15b, tert-butyl 4-hydroxy-4-(4-methoxy-
phenyl)but-2-ynoate was isolated as an oil (840 mg, 87%):
1H-NMR (500 MHz; CDCl3) δ 7.42 (d, J = 7.8 Hz, 2H), 6.89 (d,
J = 8.0 Hz, 2H), 5.47 (s, 1H), 3.80 (s, 3H), 3.49 (s, 1H), 1.50 (s,
9H); 13C NMR (126 MHz; CDCl3) δ 159.8, 152.6, 131.2, 128.2,
114.1, 84.5, 83.9, 78.8, 63.7, 55.3, 28.0; IR (KBr, thin film, cm-
1) 3400, 2981, 2936, 2838, 2237,1707, 1612, 1513, 1255,
1156; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H18O4Na+
285.1097, found 285.1097.
1
1
an identical H NMR spectrum.53 An image of the H NMR
spectrum is supplied in the accompanying file.
This product was acetylated using an adapted proce-
dure.54 To a solution of tert-butyl (E)-4-hydroxy-4-phenyl-
but-2-enoate (100 mg, 0.4 mmol) in CH2Cl2 (0.8 mL) was
added acetic anhydride (80 µL, 0.8 mmol), followed by pyr-
idine (30 µL, 0.4 mmol). After 24 h, the reaction was
quenched by addition of 1M HCl. The resulting solution was
extracted with CH2Cl2 (3 × 5 mL). The combined organic
phase was washed with brine, dried (MgSO4), filtered, and
concentrated under reduced pressure. Purification by col-
umn chromatography (30% EtOAc in hexanes) afforded
tert-butyl (E)-4-acetoxy-4-phenylbut-2-enoate as an oil (75
mg, 64%): 1H NMR (500 MHz; CDCl3): δ 7.41-7.36 (m, 5H),
6.92 (dd, J = 15.6, 5.2 Hz, 1H), 6.40 (dd, J = 5.2, 1.6 Hz, 1H),
5.97 (dd, J = 15.6, 1.7 Hz, 1H), 2.15 (s, 3H), 1.50 (s, 9H); 13C
NMR (125 MHz; CDCl3): δ 169.7, 165.2, 143.4, 137.4, 128.8,
128.7, 127.4, 123.6, 80.9, 74.3, 28.1, 21.1; IR (KBr, thin film,
cm-1) 2979, 2934, 1744, 1716, 1659,1456, 1369, 1230,
1153; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H20O4Na+
299.1254, found 299.1253.
The azide was installed using a known procedure.55 Al-
lylic azides 17a and 17b were isolated as an oil (43 mg, 46%
yield): Major isomer (17a): 1H NMR (500 MHz; CDCl3): δ
7.45-7.32 (m, 5H), 6.86 (dd, J = 15.4, 5.9 Hz, 1H), 6.07 (dd, J
= 15.4, 1.6 Hz, 1H), 5.18 (dd, J = 5.9, 1.3 Hz, 1H), 1.51 (s, 9H);
Minor isomer (17b): 1H NMR (500 MHz; CDCl3): δ 7.45-7.32
(m, 5H), 6.77 (d, J = 15.8 Hz, 1H), 6.27 (dd, J = 15.8, 7.3 Hz,
1H), 4.42 (d, J = 7.3 Hz, 1H), 1.54 (s, 9H); Mixture: 13C NMR
(125 MHz; CDCl3): δ 168.2, 165.0, 142.7, 136.7, 135.6, 135.3,
129.1, 128.9, 128.7, 128.6, 127.5, 126.8, 124.7, 121.2, 83.3,
81.0, 65.5, 64.1, 28.1, 28.0; IR (KBr, thin film, cm-1) 2979,
2931, 2104, 1716, 1253, 1152; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C14H17N3O4Na+ 282.1213, found 282.1216.
Tert-butyl 4-hydroxy-4-(4-methoxyphenyl)but-2-enoate
was isolated as an oil (220 mg, 56%): H-NMR (400 MHz;
1
CDCl3) δ 7.29-7.26 (m, 2H), 6.94 (dd, J = 14.4, 4.7 Hz, 1H),
6.92-6.88 (m, 2H), 6.05 (dd, J = 15.6, 1.7 Hz, 1H), 5.29 (dd, J
= 4.9, 1.3 Hz, 1H), 3.82 (s, 3H), 2.36 (s, 1H), 1.49 (s, 9H); 13
C
NMR (125 MHz; CDCl3) δ 165.8, 159.6, 147.5, 133.3, 128.0,
122.0, 114.2, 80.6, 73.2, 55.3, 28.1; IR (KBr, thin film, cm-1):
3409, 2977, 2933, 1710, 1512, 1249, 1152; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C15H20O4Na+ 287.1254, found
287.1249.
Allylic azides 16a and 16b were isolated as an oil (1.3 : 1,
160 mg, 65%): Major isomer (16a): H NMR (500 MHz;
1
CDCl3) δ 7.25 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 7.8 Hz, 2H), 6.85
(dd, J = 15.4, 5.4 Hz, 1H), 6.06 (d, J = 15.4 Hz, 1H), 5.13 (d, J
= 5.2 Hz, 1H), 3.84 (s, 3H), 1.51 (s, 9H); Minor isomer (16b):
1H NMR (500 MHz; CDCl3) δ 7.38 (d, J = 8.0 Hz, 2H), 6.90 (d,
J = 8.0 Hz, 2H), 6.71 (d, J = 15.8 Hz, 1H), 6.14 (dd, J = 15.8,
7.5 Hz, 1H), 4.38 (d, J = 7.4 Hz, 1H), 3.84 (s, 3H), 1.54 (s, 9H);
Mixture: 13C NMR (126 MHz; CDCl3) δ 168.2, 165.1, 160.0,
143.0, 135.0, 128.9, 128.6, 128.3, 128.2, 124.3, 118.8, 114.4,
114.1, 83.2, 80.9, 65.0, 64.3, 55.3, 28.1, 28.0; IR (KBr, thin
film, cm-1) 2978, 2933, 2102, 1716, 1512, 1252, 1152; HRMS
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The Journal of Organic Chemistry
(E)-4-azido-4-(4-methoxyphenyl)but-2-enenitrile (18a)
10.2 Hz, 1H), 4.55 (d, J = 6.1 Hz, 1H), 1.63 (s, 2H); IR (KBr,
thin film, cm-1): 3368, 3271, 3062, 3027, 2856, 1639, 1601,
1492, 1452, 995, 919, 701; HRMS (EI-TOF) m/z: [M]+ calcd
for C9H11N+ 133.0886, found 133.0848, [M - H]+ calcd for
C9H10N+ 132.0803, found 132.0803.
1
2
3
4
and (Z)-4-azido-4-(4-methoxyphenyl)but-2-enenitrile (18b).
Azides 18a and 18b were synthesized via a two step se-
quence. Following a known procedure56, (E)-4-(4-methoxy-
phenyl)-2-((trimethylsilyl)oxy)but-3-enenitrile was iso-
1
lated crude as an orange oil (698 mg, 88%). H NMR (400
Using a known diazotransfer procedure,60 the product
was isolated (24 mg) in 44% yield. The material obtained
5
MHz, CDCl3) δ 7.37 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H),
6.77 (d, J = 15.7 Hz, 1H), 6.08 (dd, J = 15.7, 6.2 Hz, 1H), 5.12
(d, J = 6.2 Hz, 1H), 3.85 (s, 3H), 0.27 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 160.1, 133.6, 128.3, 127.7, 121.3, 118.6,
114.2, 62.5, 55.3, 0.0; IR (KBr, thin film, cm-1) 2959, 2838,
1607, 1513, 1255, 1176, 845; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C14H19NO2Na+ [M + Na]+: 284.1077, found
284.1067.
6
7
8
9
1
from this method provided an identical H NMR spectrum
to a previous report.34 An image of the 1H NMR spectrum is
supplied in the accompanying file. The data provided here
is for comparison to the 15N-labeled compound; 1H NMR
(500 MHz; CDCl3) δ 7.44-7.43 (m, 2H), 7.38-7.35 (m, 2H),
7.32-7.28 (m, 1H), 6.68 (d, J = 15.8 Hz, 1H), 6.27 (dt, J = 15.8,
6.6 Hz, 1H), 3.98 (d, J = 6.6 Hz, 2H); IR (KBr, thin film, cm-1)
3029, 2923, 2100, 1493, 1448, 1236, 968; HRMS (EI-TOF)
m/z: [M]+ calcd for C9H9N3+ 159.0791, found 159.0747, [M -
N3]+ calcd for C9H9+ 117.0699, found 117.0693.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Starting from (E)-4-(4-methoxyphenyl)-2-((trimethylsi-
lyl)oxy)but-3-enenitrile and following the procedure above
for the azide installation for compounds 15 and 16 , a mix-
ture of azides 18a and 18b (17 mg, 38%) was isolated as an
oil. Major isomer (18a) 1H NMR (400 MHz, CDCl3) δ 7.21 (d,
J = 8.7 Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.71 (dd, J = 16.0, 4.6
Hz, 1H), 5.76 (dd, J = 16.0, 2.0 Hz, 1H), 5.18 (dd, J = 4.6, 2.1
1-phenylprop-2-en-1-amine-15N (19). Using the procedure
above for compound 9 with phthalimide-15N potassium salt
(98 atom % 15N), 2-(1-phenylallyl)isoindoline-1,3-dione-
1
15N was isolated (340 mg) in 74% yield as an oil: H NMR
1
Hz, 1H), 3.85 (s, 3H); Minor isomer (18b): H NMR (400
(500 MHz; CDCl3) δ 7.86 (dd, J = 5.4, 3.1 Hz, 2H), 7.73 (dd, J
= 5.5, 3.0 Hz, 2H), 7.47 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.5 Hz,
2H), 7.31-7.28 (m, 1H), 6.68 (dddd, J = 17.8, 10.2, 7.6 Hz, JN-
H = 1.1 Hz, 1H), 5.99 (d, J = 7.6 Hz, 1H), 5.40 (d, J = 10.2 Hz,
1H), 5.37 (d, J = 17.6 Hz, 1H); 13C NMR (125 MHz; CDCl3) δ
MHz, CDCl3) δ 7.31 (d, J = 8.8 Hz, 2H), 6.99 – 6.92 (m, 2H),
6.55 (dd, J = 10.9, 9.2 Hz, 1H), 5.56 – 5.49 (m, 2H), 3.84 (s,
3H);13C NMR (125 MHz, CDCl3) δ 160.4, 160.2, 150.7, 150.3,
129.1, 128.2, 127.0, 116.6, 114.7, 114.7, 101.0, 100.8, 64.8,
64.2, 55.4, 55.4; IR (KBr, thin film, cm-1) 2839, 22640, 2103,
1608, 1512, 1252; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C11H10N2O+ [M – N2]+: 186.0788, found 186.0782.
167.6 (d, JC-N = 11.9 Hz), 138.6, 134.3, 134.0, 131.9 (d, JC-N
=
=
7.9 Hz), 128.6, 127.83, 127.77, 123.3, 119.1, 56.8 (d, JC-N
1
8.6 Hz); 15N NMR (93 MHz; CDCl3, using H-15N HMBC) δ
171; IR (KBr, thin film, cm-1) 3467, 3062, 3031, 1767, 1716,
1612, 1468, 1382, 1086; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C17H1315NO2Na+ 287.0809, found 287.0816.
(3-azidoprop-1-en-1-yl)benzene (9). A procedure was
adapted from a known method57 and the product was iso-
lated (32 mg, 60%) . The material obtained from this
1
method provided an identical H NMR spectrum. An image
Using the phthalimide deprotection procedure used for
the synthesis of 9, 15N-1-phenylprop-2-en-1-amine (19)
was isolated (110 mg, 61%) as an oil and used without fur-
ther purification: 1H NMR (500 MHz; CDCl3) δ 7.37-7.34 (m,
4H), 7.28-7.27 (m, 1H), 6.05 (ddd, J = 17.0, 9.1, 7.3 Hz, 1H),
5.27 (d, J = 17.1 Hz, 1H), 5.14 (d, J = 9.2 Hz, 1H), 4.55 (d, J =
7.1 Hz, 1H), 1.57 (s, 2H); 13C NMR (125 MHz; CDCl3) δ 144.5,
1
of the H NMR spectrum is supplied in the accompanying
file. The data provided here is for comparison to the 15N-la-
beled compound:1H NMR (500 MHz; CDCl3) δ 7.87-7.85 (m,
2H), 7.73 (m, 2H), 7.48-7.46 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.4
Hz, 2H), 7.31-7.28 (m, 1H), 6.67 (ddd, J = 17.3, 9.0, 7.6 Hz,
1H), 5.99 (d, J = 7.6 Hz, 1H), 5.40 (d, J = 9.3 Hz, 1H), 5.37 (d,
J = 16.8 Hz, 1H); IR (KBr, thin film, cm-1) 3031, 1769, 1715,
1468, 1382, 1352, 989, 718; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C17H13NO2Na+ 286.0838, found 286.0832.
142.3 (d, JC-N = 4.2 Hz), 128.6, 127.1, 126.6, 113.7 (d, JC-N
=
6.6 Hz), 58.4 (d, JC-N = 16.3 Hz); 15N NMR (93 MHz; CDCl3,
using 1H-15N HMBC) δ 38; IR (KBr, thin film, cm-1) 3362,
3284, 3081, 3062, 3027, 2852, 1639, 1601, 1492, 1452, 918,
701; HRMS (EI-TOF) m/z: [M]+ calcd for C9H1115N+
134.0856, found 134.0829, calcd for C9H1015N+ [M -H]+
133.0778, found 133.0774.
The procedure to deprotect the phthalimide is based off
of a known method.58 To a solution of 2-(1-phenylallyl)iso-
indoline-1,3-dione (0.10 g, 0.40 mmol) in EtOH (5 mL) was
added ethanolamine (0.24 mL, 3.8 mmol). The solution was
sealed and heated to 40 °C. After 18 h, the solution was
poured over 6 M HCl (10 mL) and extracted with CH2Cl2 (1
x 10 mL). The aqueous layer was then basified with NaOH
(pH > 10) and the resulting solution was extracted with
CH2Cl2 (3 x 15 mL). The combined organic phases were
washed with brine, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The resulting compound
was isolated as a yellow oil (23 mg, 44%) and was used
without further purification. The material obtained from
this method provided an identical 1H NMR spectrum to pre-
vious report.59 An image of the 1H NMR spectrum is supplied
in the accompanying file. The data provided here is for com-
15N-(3-azidoprop-1-en-1-yl)benzene (21). Using the diazo-
transfer procedure for the synthesis of 9, the product was
isolated as an oil (45 mg, 80%): 1H NMR (400 MHz; CDCl3) δ
7.44 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.30 (m, 1H),
6.68 (d, J = 15.8 Hz, 1H), 6.28 (dt, J = 15.7, 6.6 Hz, 1H), 3.98
(d, J = 6.5 Hz, 2H); 13C NMR (101 MHz; CDCl3) δ 136.0, 134.6,
128.7, 128.2, 126.6, 122.4, 53.0; 15N NMR (93 MHz; CDCl3,
1
using H-15N HMBC) δ 214; IR (KBr, thin film, cm-1) 3028,
2923, 2077, 1493, 1448, 968; HRMS (EI-TOF) m/z: [M]+
calcd for C9H9N3+ 160.0761, found 160.0767, [M - N3]+ calcd
for C9H9+ 117.0699, found 117.0694.
15N-Diethyl cinnamylphosphoramidate (22).To a solution
of 15N-(3-azidoprop-1-en-1-yl)benzene (21) (21 mg, 0.12
mmol) in THF (0.5 mL) was added triethyl phosphite (24 µL,
0.14 mmol). After 3 h, KOH (97 mg, 1.7 mmol) in water (0.25
1
parison to the 15N-labeled compound: H NMR (400 MHz;
CDCl3) δ 7.39-7.34 (m, 4H), 7.30-7.26 (m, 1H), 6.05 (ddd, J =
16.9, 10.4, 6.3 Hz, 1H), 5.27 (d, J = 16.9 Hz, 1H), 5.14 (d, J =
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The Journal of Organic Chemistry
Page 8 of 12
mL) was added, and the solution was heated to 40 °C. After
6.3 Hz, 1H), 3.51 (d, J = 5.8 Hz, 2H), 1.84 (s, 2H); 13C NMR
1
2
3
4
5
6
7
8
2 h, the solution was heated to 80 °C. After an additional 2
h, the solution was poured over water (5 mL) and extracted
with CH2Cl2 (3 x 8 mL). The combined organic phases were
washed with brine, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The resulting yellow oil (29
(125 MHz; CDCl3) δ 137.2, 131.1, 129.5, 128.5, 127.3, 126.2,
44.3 (d, JC-N = 3.8 Hz); 15N NMR (93 MHz; CDCl3, using 1H-15N
HMBC) δ 23; IR (KBr, thin film, cm-1) 3258, 3021, 2838,
1632, 1565, 1435, 1395,957, 738; HRMS (EI-TOF) m/z: [M]+
calcd for C9H1115N+ 134.0856, found 134.0845, [M – H]+
calcd for C9H1015N+ 133.0778, found 133.0779.
1
mg, 86%) was used without further purification: H-NMR
(400 MHz; CDCl3) δ 7.38-7.31 (m, 4H), 7.28-7.23 (m, 1H),
6.56 (d, J = 15.8 Hz, 1H), 6.24 (dt, J = 15.8, 6.0 Hz, 1H), 4.16-
4.06 (m, 4H), 3.74-3.68 (m, 2H), 2.88 (td, JH-P = 17.0, 7.1 Hz,
1H), 1.35 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz; CDCl3) δ
136.6, 131.0, 128.6, 127.64, 127.5 (d, JC-P = 7.3 Hz), 126.3,
62.4 (d, JC-P = 5.3 Hz), 43.5, 16.3 (d, JC-P = 7.1 Hz);31P NMR
(162 MHz; CDCl3) δ 8.7; IR (KBr, thin film, cm-1) 3246, 2983,
2932, 2906, 1702, 1450, 1238, 963; HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C13H20NO3PNa+ 292.1073, found
292.1067
Using the diazotransfer procedure for the synthesis of 9,
1
the product was isolated in (31 mg, 54%): H NMR (500
MHz; CDCl3) δ 7.44 (d, J = 7.4 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H),
7.31 (m, 1H), 6.69 (d, J = 15.8 Hz, 1H), 6.28 (dt, J = 15.1, 6.5
Hz, 1H), 3.98 (d, J = 6.5 Hz, 2H); 13C NMR (126 MHz; CDCl3)
δ 136.0, 134.6, 128.7, 128.2, 126.7, 122.4, 53.0 (d, JC-N = 4.1
Hz); 15N NMR (93 MHz; CDCl3, using 1H-15N HMBC) δ 73; IR
(KBr, thin film, cm-1) 3028, 2927, 2102, 1492, 1449, 1224,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
968, 747, 693; HRMS (EI-TOF) m/z: [M]+ calcd for C9H9N3
+
160.0761, found 160.0742, [M-N3]+ calcd for C9H9
3-phenylprop-2-en-1-amine. Using a known procedure,61
2-cinnamylisoindoline-1,3-dione was isolated (600 mg,
76%). The material obtained from this method provided an
117.0699, found 117.0694
Diethyl cinnamylphosphoramidate-15N. Using the proce-
dure for the synthesis of 22, the product was isolated (25
1
1
identical H NMR spectrum. An image of the H NMR spec-
trum is supplied in the accompanying file. The data pro-
vided here is for comparison to the 15N-labeled com-
pound:1H NMR (400 MHz; CDCl3) δ 7.89 (dd, J = 5.5, 3.0 Hz,
2H), 7.75 (dd, J = 5.4, 3.1 Hz, 2H), 7.39-7.37 (m, 2H), 7.33-
7.24 (m, 3H), 6.69 (d, J = 15.8 Hz, 1H), 6.28 (dt, J = 15.8, 6.5
Hz, 1H), 4.47 (d, J = 6.5 Hz, 2H); IR (KBr, thin film, cm-1)
3043, 3024, 1770, 1704, 1427, 1396, 1108, 727; HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C17H13NO2Na+ 286.0838,
found 286.0828.
1
mg, 95%) and used without further purification; H NMR
(500 MHz; CDCl3) δ 7.38-7.31 (m, 4H), 7.28-7.24 (m, 1H),
6.57 (d, J = 15.8 Hz, 1H), 6.24 (dt, J = 15.8 6.8 Hz, 1H), 4.11
(apparent q, J = 7.3 Hz, 4H), 3.71 (td, JH-P = 12.2, 7.0 Hz, 2H),
2.85 (apparent d, JN-H = 84 Hz, 1H ), 1.35 (t, J = 7.1 Hz, 6H);
13C NMR (125 MHz; CDCl3) δ 136.6, 131.0 (d, JC-N = 1.5 Hz),
128.6, 127.7, 127.6 (d, JC-P = 6.1 Hz), 126.3, 62.4 (d, JC-P = 5.4
Hz), 43.4 (d, JC-N = 8.3 Hz), 16.2 (d, JC-P = 7.1 Hz). (Note: JC-P vs
JC-N were assigned by comparison to 22); 15N NMR (93 MHz;
CDCl3, using 1H-15N HMBC) δ 43; 31P NMR (162 MHz, CDCl3)
δ 8.68 (d, JP-N = 40.9 Hz); IR (KBr, thin film, cm-1): 3211,
2981, 2904, 1444, 1237, 1031, 966; HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C13H2015NO3PNa+ 293.1043; found
293.1047, [2M+Na]+ calcd for C26H4015N2O6P2Na+ 563.2195,
found 563.2207.
Using the phthalimide deprotection procedure for the
synthesis of 9, the product was isolated (130 mg, 47%). The
material obtained from this method provided an identical
1H NMR spectrum to a previous report.62An image of the 1H
NMR spectrum is supplied in the accompanying file. The
data provided here is for comparison to the 15N-labeled
compound: 1H NMR (500 MHz; CDCl3) δ 7.39 (d, J = 7.4 Hz,
2H), 7.33 (t, J = 7.4 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 6.52 (d, J
= 15.9 Hz, 1H), 6.35 (dt, J = 15.7, 6.0 Hz, 1H), 3.50 (d, J = 5.8
Hz, 2H), 1.48 (s, 2H); IR (KBr, thin film, cm-1) 3263, 3078,
2848, 1636, 1565, 1453, 965, 684; HRMS (EI-TOF) m/z: [M]+
calcd for C9H11N+ 133.0886, found 133.0879, [M – H]+ calcd
for C9H10N+ 132.0808, found 132.0804.
2-(4-azidobut-2-en-2-yl)naphthalene. Using a known pro-
cedure42 the product was isolated (520 mg, 65%). Charac-
terization data for this compound has been reported. The
material obtained from this method provided an identical
1H NMR spectrum. An image of the 1H NMR spectrum is sup-
plied in the accompanying file.
5-azido-2,3,4,5-tetrahydro-1,1'-biphenyl (rac-30e). Az-
ides 30 were prepaired by a multi-step sequence that is out-
lined here. A procedure was adapted from a known method
for the formation of tertiary alcohols and 3,4-dihydro-[1,1'-
biphenyl]-1(2H)-ol was isolated as an oil (1.38 g, 75%).63
Characterization data for this compound has been reported.
The material obtained from this method provided an iden-
tical 1H NMR spectrum. An image of the 1H NMR spectrum is
supplied in the accompanying file.
(3-azidoprop-1-en-1-yl)benzene-15N. Using the procedure
for the synthesis of 2-cinnamylisoindoline-1,3-dione, with
potassium 15N-phthalimide, the product was isolated (510
1
mg, 89%): H NMR (500 MHz; CDCl3) δ 7.89 (t, J = 2.7 Hz,
2H), 7.74 (t, J = 2.7 Hz, 2H), 7.37 (d, J = 7.5 Hz, 2H), 7.32-7.29
(m, 2H), 7.24 (t, J = 7.3 Hz, 1H), 6.68 (d, J = 15.8 Hz, 1H), 6.28
(dt, J = 15.1, 6.5 Hz, 1H), 4.47 (d, J = 6.5 Hz, 2H); 13C NMR
(125 MHz; CDCl3) δ 168.0 (d, JC-N = 13.1 Hz), 136.2, 134.0,
133.8, 132.2 (d, JC-N = 7.5 Hz), 128.5, 127.9, 126.5, 123.3,
122.7, 39.7 (d, JC-N = 9.8 Hz); 15N NMR (93 MHz; CDCl3, using
1H-15N HMBC) δ 163; IR (KBr, thin film, cm-1) 3024, 1769,
1702, 1469, 1381, 1095, 726; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C17H1315NO2Na+ 287.0809, found 287.0801.
To a solution of 3,4-dihydro-[1,1'-biphenyl]-1(2H)-ol
(0.28 g, 1.6 mmol) in CH2Cl2 (7.0 mL) was added TMS-N3
(0.41 mL, 3.2 mmol) and Zn(OTf)2 (57 mg, 0.16 mmol) at
room temperature. The vessel was sealed. After 20 min, the
solution was quenched with triethylamine (0.5 mL) and
MeOH (0.5 mL). The reaction mixture was filtered through
basic alumina and washed with excess CH2Cl2. The resulting
solution was concentrated under reduced pressure. Purifi-
cation by column chromatography (gradient elution 0-15%
EtOAc in hexanes) afforded rac-30e as an oil (0.25 g, 1.3
mmol, 79%). Characterization data for this compound has
Using the phthalimide deprotection procedure for the
synthesis of 9, the product was isolated (42 mg, 56%) and
used without further purification: 1H NMR (500 MHz;
CDCl3) δ 7.39 (d, J = 7.5 Hz, 2H), 7.33 (t, J = 7.3 Hz, 2H), 7.24
(t, J = 7.2 Hz, 1H), 6.53 (d, J = 15.9 Hz, 1H), 6.35 (dt, J = 15.4,
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The Journal of Organic Chemistry
132.4, 130.4, 125.2, 125.0, 72.0, 39.4, 34.4, 31.4, 25.1, 19.3;
been reported.42 The material obtained from this method
provided an identical 1H NMR. An image of the 1H NMR spec-
trum is supplied in the accompanying file.
IR (KBr, thin film, cm-1) 3050, 2817, 1571, 1401, 1161;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H22ONa+
253.1563, found 253.1574. Using ice bath cooling, rac-30c
(0.26 g, 79%) was isolated as an oil: 1H NMR (400 MHz,
CD3CN) δ 7.42 (s, 4H), 6.12 (dt, J = 3.8, 1.8 Hz, 1H), 4.19 –
4.13 (m, 1H), 2.58 – 2.46 (m, 1H), 2.46 – 2.36 (m, 1H), 1.95
– 1.85 (m, 2H), 1.84 – 1.67 (m, 2H), 1.33 (s, 9H); 13C NMR
(126 MHz, CD3CN) δ 150.8, 142.1, 138.1, 125.3, 125.1, 120.6,
56.9, 34.1, 30.5, 28.0, 26.9, 19.5; IR (KBr, thin film, cm-1)
2960, 2866, 2093, 1162; HRMS (CI-TOF) m/z: [M - N3]+ calcd
for C16H21+ 213.1638, found 213.1631.
1
2
3
4
5
6
7
8
9
(4-azidopent-2-en-2-yl)benzene (26). Following the azide
formation procedure above for compound 30e, the product
(0.24 g, 57%) was isolated as an oil: 1H NMR (500 MHz,
CDCl3) (E-isomer)δ 7.47 – 7.42 (m, 2H), 7.40 – 7.35 (m, 2H),
7.33 – 7.30 (m, 1H), 5.73 (dq J = 9.0, 1.5 Hz, 1H), 4.49 (dq, J
= 9.0, 6.6 Hz, 1H), 2.17 (d, J = 1.4 Hz, 3H), 1.37 (d, J = 6.6 Hz,
3H); 1H NMR (500 MHz, CDCl3) (Z-isomer) δ 7.50 – 7.15 (m,
5H), 5.47 (dq, J = 9.9, 1.6 Hz, 1H), 4.04 (dq, J = 9.9, 6.6 Hz,
1H), 2.12 (d, J = 1.4 Hz, 4H), 1.24 (d, J = 6.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3) (E-isomer) δ 142.5, 139.3, 128.3, 127.6,
126.7, 126.0, 55.5, 20.7, 16.6; 13C NMR (125 MHz, CDCl3) (Z-
isomer) δ 141.5, 140.7, 128.4, 127.7, 127.3, 126.2, 56.0,
25.7, 20.8; IR (KBr, thin film, cm-1) 2979, 2096, 1444, 1231;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-azido-4'-fluoro-2,3,4,5-tetrahydro-1,1'-biphenyl (rac-
30d). Following the procedure above for compound 30e, 4'-
fluoro-3,4-dihydro-[1,1'-biphenyl]-1(2H)-ol (0.83 g, 68%)
1
was isolated as an oil. H NMR (400 MHz, CDCl3) δ 7.50 –
HRMS (CI-TOF) m/z: [M - N3]+ calcd for C11H13 145.1012,
7.42 (m, 2H), 7.02 (apparent triplet, J = 7.02, 2H), 6.04 (dt, J
= 10.1, 3.7 Hz, 1H), 5.76 (d, J = 10.0, 1H), 2.23 (s, 1H), 2.19 –
2.03 (m, 2H), 2.02 – 1.92 (m, 1H), 1.89 – 1.72 (m, 2H), 1.66
+
found 145.1005.
5-azido-4'-methoxy-2,3,4,5-tetrahydro-1,1'-biphenyl (rac-
30a). Following the procedure above for compound 30e, 4'-
methoxy-3,4-dihydro-[1,1'-biphenyl]-1(2H)-ol (3.0 g, 47%)
was isolated as a waxy solid. Characterization data for this
compound has been reported.63 The material obtained from
this method provided an identical 1H NMR spectrum. An im-
– 1.56 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 161.8 (d, JC-F
=
243.3 Hz), 143.6 (d, JC-F = 3.0 Hz), 132.1, 130.9, 127.2 (d, JC-F
= 7.9 Hz), 114.7 (d, JC-F = 21.1 Hz), 71.9, 39.7, 25.0, 19.2; 19
F
NMR (376 MHz, CDCl3) δ -116.5; IR (KBr, thin film, cm-1)
3378, 2938, 1601, 1508, 1221, 1175, 833; HRMS (EI-TOF)
m/z: [M]+ calcd for C12H13FO+ 192.0945, found 192.0951.
The product rac-30d (0.17 g, 79%) was isolated as an oil:
1H NMR (400 MHz, CDCl3) δ 7.46 – 7.36 (m, 2H), 7.11 – 7.00
(m, 2H), 6.05 (dt, J = 3.6, 1.8 Hz, 1H), 4.14 – 4.08 (m, 1H),
2.55 – 2.35 (m, 2H), 2.03 – 1.90 (m, 2H), 1.88 – 1.74 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 162.5 (d, JC-F = 245.3 Hz), 141.5,
1
age of the H NMR spectrum is supplied in the accompany-
ing file. With slight modifications, Cu(hfac)2 instead of
Zn(OTf)2 with ice bath cooling, the product rac-30a (0.58 g,
86%) was isolated as a waxy solid. 1H NMR (500 MHz,
CDCl3) δ 7.39 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 6.07
– 6.01 (m, 1H), 4.12 – 4.10 (m, 1H), 3.84 (s, 3H), 2.53 – 2.48
(m, 1H), 2.44 – 2.39 (m, 1H), 2.00 – 1.91 (m, 2H), 1.84 – 1.77
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 159.4, 141.8, 133.5,
126.6, 119.8, 113.7, 57.0, 55.3, 28.4, 27.4, 19.8; IR (KBr, thin
film, cm-1) 2935, 2836, 2089, 1607, 1513, 1251, 1037; HRMS
(CI-TOF) m/z: [M - N3]+ calcd for C13H15O+ 187.1117, found
187.1110.
137.1 (d, JC-F = 3.4 Hz), 127.1 (d, JC-F = 7.8 Hz), 121.4 (d, JC-F
=
1.5 Hz), 115.2 (d, JC-F = 21.2 Hz), 56.8, 28.2, 27.5, 19.7; 19F
NMR (471 MHz, CDCl3) δ -114.6; IR (KBr, thin film, cm-1)
2940, 2096, 1601, 1510, 1231, 1161, 826; HRMS (CI-TOF)
m/z: [M - N3]+ calcd for C12H12F+ 175.0918, found 175.0924.
5-azido-4'-(trifluoromethyl)-2,3,4,5-tetrahydro-1,1'-bi-
phenyl (rac-30f). Following the procedure above for com-
pound 30e, 4'-(trifluoromethyl)-3,4-dihydro-[1,1'-bi-
phenyl]-1(2H)-ol (1.4 g, 78%) was isolated as an oil. Char-
acterization data for this compound has been reported.63
The material obtained from this method provided an iden-
tical 1H NMR spectrum. An image of the 1H NMR spectrum is
supplied in the accompanying file. The product rac-30f
(0.42 g, 83%) was isolated as an oil: 1H NMR (500 MHz,
CD3CN) δ 7.69 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 6.24
(dt, J = 3.8, 1.8 Hz, 1H), 4.23 – 4.17 (m, 1H), 2.56 – 2.50 (m,
1H), 2.47 – 2.41 (m, 1H), 2.05 – 1.95 (m, 1H), 1.95 – 1.86 (m,
1H), 1.84 – 1.72 (m, 2H); 13C NMR (125 MHz, CD3CN) δ
144.9, 141.0, 128.8 (q, JC-F = 32.0 Hz), 126.0, 125.8, 125.3 (q,
JC-F = 3.7 Hz), 124.5 (q, JC-F = 269.4 Hz), 56.7, 27.8, 26.8, 19.4;
19F NMR (471 MHz, CD3CN) δ -63.0; IR (KBr, thin film, cm-1)
2934, 2836, 2091, 1606, 1513, 1250, 1181; HRMS (CI-TOF)
m/z: [M - N3]+ calcd for C13H12F3+ 225.0886, found 225.0875.
5-azido-4'-methyl-2,3,4,5-tetrahydro-1,1'-biphenyl (rac-
30b). Following the above procedure for compound 30e, 4'-
methyl-3,4-dihydro-[1,1'-biphenyl]-1(2H)-ol (3.9 g, 68%)
was isolated as an oil. Characterization data for this com-
pound has been reported.63 The material obtained from this
method provided and identical 1H NMR spectrum. An image
1
of the H NMR spectrum is supplied in the accompanying
file. The product rac-30b (0.53 g, 71%) was isolated as an
1
oil: H NMR (400 MHz, CD3CN) δ 7.41 – 7.34 (d, J = 8.3 Hz,
2H), 7.19 (d, J = 8.0 Hz, 2H), 6.10 (dt, J = 3.8, 1.8 Hz, 1H), 4.18
– 4.14 (m, 1H), 2.56 – 2.36 (m, 2H), 2.35 (s, 3H), 1.95 – 1.85
(m, 2H), 1.83 – 1.71 (m, 2H); 13C NMR (125 MHz, CD3CN) δ
142.1, 138.1, 137.7, 129.0, 125.2, 120.5, 56.9, 28.0, 26.9,
20.1, 19.5; IR (KBr, thin film, cm-1) 2939, 2864, 2093, 1235;
HRMS (CI-TOF) m/z: [M - N3]+ calcd for C13H15 171.1168,
found 171.1166.
+
5-azido-4'-(tert-butyl)-2,3,4,5-tetrahydro-1,1'-biphenyl
(rac-30c). Following the procedure above for compound
30e, 4'-(tert-butyl)-3,4-dihydro-[1,1'-biphenyl]-1(2H)-ol
(1.3 g, 72%) was isolated as an oil: 1H NMR (400 MHz,
CDCl3) δ 7.45 (apparent d, J = 8.6 Hz, 2H), 7.39 (apparent d,
J = 8.6 Hz, 2H), 6.05 (dt, J = 10.0, 3.7 Hz, 1H), 5.82 (d, J = 10.1
Hz, 1H), 2.22 – 2.07 (m, 2H), 2.06 – 1.99 (m, 1H), 1.91 (td, J
= 10.0, 3.1 Hz, 1H), 1.87 – 1.77 (m, 1H), 1.69 – 1.61 (m, 1H),
1.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 149.7, 144.8,
5-methoxy-2,3,4,5-tetrahydro-1,1'-biphenyl (32e). This
procedure was adapted from a known method.64 To a solu-
tion of 3,4-dihydro-[1,1'-biphenyl]-1(2H)-ol (189 mg, 1.08
mmol) in MeCN (5 mL) and MeOH (1 mL) was added sali-
cylic acid (15 mg, 0.11 mmol). The resulting solution was
heated at 40 °C. After 18 h, the reaction was diluted with
ethyl acetate and quenched by the addition of saturated
aqueous NaHCO3. The resulting solution was extracted with
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Page 10 of 12
EtOAc (3 × 10 mL). The combined organic phase was
(dt, J = 3.5, 1.8 Hz, 1H), 4.01 – 3.94 (m, 1H), 3.46 (s, 3H), 2.54
– 2.33 (m, 2H), 2.03 – 1.88 (m, 2H), 1.81 – 1.67 (m, 2H); 13
1
2
3
4
5
6
7
8
washed with brine, dried (MgSO4), filtered, and concen-
trated under reduced pressure. Purification by column
chromatography (gradient elution 0-20% EtOAc in hex-
anes) afforded the product (150 mg, 0.797 mmol, 73%) as
an oil. Characterization data for this compound has been re-
ported.64 The material obtained from this method provided
an identical 1H NMR spectrum. An image of the 1H NMR
spectrum is supplied in the accompanying file.
C
NMR (125 MHz, CDCl3) δ 145.1, 139.3, 129.2 (q, 32.2 Hz),
126.5, 125.7 , 125.2 (q, 3.7 Hz), 124.3 (q, 270.1 Hz), 74.8,
56.0, 27.6, 27.3, 19.5; 19F NMR (471 MHz, CDCl3) δ -62.5; IR
(KBr, thin film, cm-1) 2936, 2820, 1615, 1326, 1122, 1070;
HRMS (EI-TOF) m/z: [M]+ calcd for C14H15F3O+ 256.1070,
found 256.1078.
Computational Details: All calculations were performed
at the DFT level using the M06-2X density functional44 as
implemented in Gaussian09.65 The 6-31G(d) basis set was
used for all atoms.66,67 The structure of reactants, interme-
diates, products, and transition states were fully optimized
with the grid=ultrafine option in gas phase and in CHCl3 (ε
= 4.71) and MeOH (ε = 32.61) using the SMD approach.43
Transition states were identified by having one imaginary
frequency in the Hessian matrix. It was confirmed that tran-
sition states connect with the corresponding intermediates.
All frequencies below 50 cm−1 were replaced by 50 cm−1
when accounting for thermal contributions to vibrational
partition functions.68 Single-point calculations were per-
formed using the 6-311+G(2df,p) basis set.69,70 Final values
are reported as free energies computed at the specified tem-
perature and 1 M standard state.
4',5-dimethoxy-2,3,4,5-tetrahydro-1,1'-biphenyl
(32a).
9
Following the above procedure for compound 32e at room
temperature, the product 32a (0.16 g, 81%) was isolated as
a waxy solid: 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.8 Hz,
2H), 6.88 (d, J = 8.9 Hz, 2H), 6.13 (dt, J = 3.6, 1.7 Hz, 1H), 3.99
– 3.92 (m, 1H), 3.81 (s, 3H), 3.45 (s, 3H), 2.52 – 2.42 (m, 1H),
2.42 – 2.32 (m, 1H), 2.00 – 1.82 (m, 2H), 1.81 – 1.67 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 159.0, 139.8, 134.1, 126.5,
122.7, 113.6, 75.0, 55.8, 55.2, 27.7, 27.6, 19.7; IR (KBr, thin
film, cm-1) 2935, 2834, 1607, 1513, 1462, 1250, 1181, 1097,
1037, 822; HRMS (ESI-TOF) m/z: [M + Na]+calcd for
C14H18O2Na+ 241.1199, found 241.1206.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-methoxy-4'-methyl-2,3,4,5-tetrahydro-1,1'-biphenyl
(32b). Following the above procedure for compound 32e,
1
the product 32b (0.16 g, 76%) was isolated as an oil: H
NMR (400 MHz, CDCl3) δ 7.34 (apparent d, J = 8.2 Hz, 2H),
7.15 (apparent d, J = 7.9 Hz, 2H), 6.16 (dt, J = 3.5, 1.8 Hz, 1H),
3.98 – 3.94 (m, 1H), 3.45 (s, 3H), 2.53 – 2.32 (m, 2H), 2.37 (s,
3H), 2.00 – 1.85 (m, 2H), 1.82 – 1.67 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 140.3, 138.7, 137.0, 128.9, 125.3, 123.5, 75.0,
55.8, 27.7, 27.5, 21.1, 19.6; IR (KBr, thin film, cm-1) 2935,
2861, 1513, 1348, 1098, 808; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C14H18ONa+ 225.1250, found 225.1253.
ASSOCIATED CONTENT
Supporting Information. Spectral images, kinetic data, HPLC
traces, and calculated coordinates. This material is available
free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
4'-(tert-butyl)-5-methoxy-2,3,4,5-tetrahydro-1,1'-biphenyl
*Email: jtopczew@umn.edu.
(32c). Following the above procedure for compound 32e,
Author Contributions
ǂA.A.O. and M.H.P. contributed equally.
1
the product 32c (0.18 g, 87%) was isolated as an oil: H
NMR (400 MHz, CD3CN): δ 7.40 (s, 4H), 6.19 – 6.13 (m, 1H),
3.96 – 3.89 (m, 1H), 3.38 (s, 3H), 2.51 – 2.41 (m, 1H), 2.41 –
2.32 (m, 1H), 1.98 – 1.86 (m, 2H), 1.73 – 1.60 (m, 2H), 1.33
(s, 9H); 13C NMR (125 MHz, CD3CN): δ 150.3, 139.4, 138.7,
125.2, 125.0, 124.0, 74.8, 55.0, 34.1, 30.6, 27.5, 27.3, 19.5; IR
(KBr, thin film, cm-1): 2947, 2866, 1159, 1104; HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C17H24ONa+ 267.1719, found
267.1721.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Prof. Steve Kass for his many helpful discussions. We
thank the Wayland E. Nolan Fellowship for support (A.A.O.).
The Minnesota Supercomputing Institute (MSI) at the Univer-
sity of Minnesota provided resources that contributed to the
results reported within this paper. Financial support was pro-
vided by the University of Minnesota and The American Chem-
ical Society’s Petroleum Research Fund (PRF # 56505-DNI1).
This research was supported by the National Institute of Gen-
eral Medical Sciences of the National Institutes of Health under
Award Number R35GM124718. We also acknowledge NIH
Shared Instrumentation Grant #S10OD011952. Funding for
this work was provided by the Center for Sustainable Polymers
at the University of Minnesota, a National Science Foundation
(NSF)-supported Center for Chemical Innovation (CHE-
1413862).
4'-fluoro-5-methoxy-2,3,4,5-tetrahydro-1,1'-biphenyl
(32d). Following the above procedure for compound 32e,
the product 32d (0.15 mg, 82%) was isolated as a waxy
solid: 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.37 (m, 2H), 7.02
(apparent t, J = 8.7 Hz, 2H), 6.13 (dt, J = 3.6, 1.8 Hz, 1H), 4.01
– 3.92 (m, 1H), 3.45 (s, 3H), 2.52 – 2.41 (m, 1H), 2.39 – 2.31
(m, 1H) 2.01 – 1.87 (m, 2H), 1.81 – 1.66 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 162.2 (d, JC-F = 244.6 Hz), 139.5, 137.7
(d, JC-F = 3.3 Hz), 127.0 (d, JC-F = 7.9 Hz), 124.3, 115.0 (d, JC-F
=
21.1 Hz), 74.9, 55.9, 27.8, 27.4, 19.6; 19F NMR (376 MHz,
CDCl3) δ -115.4; IR (KBr, thin film, cm-1) 2938, 2818, 1601,
1509, 1099, 825; HRMS (EI-TOF) m/z: [M]+ calcd for
C13H15FO+ 206.1101, found 206.1093.
5-methoxy-4'-(trifluoromethyl)-2,3,4,5-tetrahydro-1,1'-bi-
phenyl (32f). Following the above procedure for compound
32e using 0.5 equiv. salicylic acid, the product 32f (0.10 g,
52%) was isolated as a waxy solid. 1H NMR (400 MHz,
CDCl3) δ 7.59 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 6.25
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