Mechanism of a No-Metal-Added Heterocycloisomerization of Alkynylcyclopropylhydrazones: Synthesis of Cycloheptane-Fused Aminopyrroles Facilitated by Copper Salts at Trace Loadings

Article abstract of DOI:10.1021/jacs.7b06007

A mechanistic study of a new heterocycloisomerization reaction that forms annulated aminopyrroles is presented. Density functional theory calculations and kinetic studies suggest the reaction is catalyzed by trace copper salts and that a Z- to E-hydrazone

Full text of DOI:10.1021/jacs.7b06007

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Article
On the Mechanism of a No-metal-added Heterocycloisomerization
of Alkynylcyclopropylhydrazones: A Synthesis of Cycloheptane-
fused Aminopyrroles Facilitated by Copper Salts at Trace Loadings.
Sidney M. Wilkerson-Hill, Diana Yu, Phillip P. Painter, Ethan L.
Fisher, Dean J Tantillo, Richmond Sarpong, and Jason E Hein
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b06007 • Publication Date (Web): 06 Jul 2017
Downloaded from http://pubs.acs.org on July 8, 2017
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On the Mechanism of a No-metal-added Heterocycloisomerization
of Alkynylcyclopropylhydrazones: A Synthesis of Cycloheptane-
fused Aminopyrroles Facilitated by Copper Salts at Trace Loadings
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Sidney M. WilkersonꢀHill,1 † Diana Yu,2 †† Phillip P. Painter,3 Ethan L. Fisher,1 ††† Dean J. Tantilꢀ
lo,3* Richmond Sarpong1*and Jason E. Hein2*††.
1 Department of Chemistry, University of California, Berkeley, CA 94720, United States.
2 Chemistry and Chemical Biology, University of California, Merced, CA 95343, United States.
3 Department of Chemistry, University of California, Davis, CA 95616, United States.
ABSTRACT: A mechanistic study of a new heterocycloisomerization reaction that forms annulated aminopyrroles is presented.
Density functional theory (DFT) calculations and kinetic studies suggest the reaction is catalyzed by trace copper salts and that a Z-
to Eꢀhydrazone isomerization occurs through an enehydrazine intermediate before the rateꢀdetermining cyclization of the hydrazone
onto the alkyne group. The aminopyrrole products are obtained in 36–93% isolated yield depending on the nature of the alkynyl
substituent.
A
new automated sampling technique was developed to obtain robust mechanistic data.
the choice of metal or ligands on the active catalyst complex.
The Sarpong laboratory12 and others13 have described the proꢀ
INTRODUCTION
High turnover catalysis (HTC), defined as catalysis using
transition metal complexes at 0.1 mol% or lower loading and
leading to quantitative conversion of starting materials, has
surfaced in recent years as an extremely powerful and enviꢀ
ronmentally benign form of transition metal catalysis.1–4 Howꢀ
ever, ‘accidental’ HTC has also beset researchers when trying
to develop mechanistic understanding of certain reactions, as
sometimes reaction milieu contain trace impurities that faciliꢀ
tate catalysis with very high turnover number (TON). Studies
by Leadbeater and Marco on “transition metalꢀfree” Suzuki
crossꢀcouplings in water, for example, were shown to be cataꢀ
lyzed by trace palladium impurities found in the sodium carꢀ
bonate used for the reaction.5a Likewise, amination reactions
studied by Bolm that were thought to be mediated by iron
salts, were in fact catalyzed by trace copper impurities at the
partsꢀperꢀmillion level (Figure 1, A).5b These studies attest to
the significant challenge of identifying the true active catalyst
in crossꢀcoupling reactions and serve as a starting point for
developing a mechanistic understanding of other metalꢀ
catalyzed, and “metalꢀfree” processes.
motion of heterocycloisomerization reactions that had been
previously conducted using πꢀphillic transition metal catalysts
by barrierꢀlowering hydrogen bonding networks.14 For examꢀ
ple, several transition metal salts and complexes based on Pt,
Cu or Ag had been reported to facilitate the heterocycloisomꢀ
erization reaction to form indolizine 8 (Figure 1, B) from 7.
The Sarpong group found that the transformation proceeds
simply by heating in water (or MeOH) and, importantly, proꢀ
ceeds in an appreciably higher yield (compared to the PtCl2ꢀ
catalyzed example) (Figure 1, B). However, detailed mechaꢀ
nistic studies of these metalꢀfree reactions have not been perꢀ
formed, and so the possibility of trace levels of transition metꢀ
als facilitating this class of reactions cannot be excluded.
Herein, we report our detailed mechanistic investigation of a
newly discovered “noꢀmetalꢀadded” variant of chemistry reꢀ
ported by Schmalz and Zhang15 (Figure 1, C) using density
functional theory (DFT) calculations and in situ monitoring of
the reaction using an automated sampling approach. We
demonstrate that the reaction is not metalꢀfree and is catalyzed
by trace copper salts at very low catalyst loadings. Importantꢀ
ly, our understanding of the chemical reactivity observed
hinged on the combination of a diverse array of tools and
techniques, ranging from analytical instrumentation to compuꢀ
tational and experimental evaluation of model systems.16
Over the last decade, transition metalꢀcatalyzed cycloisomꢀ
erization reactions involving alkyne substrates that rely on the
use of ‘soft’ πꢀLewis acid catalysts have emerged.6–9 These
reactions are attractive synthetically because, ideally, all of the
starting material is converted to the product without the forꢀ
mation of byproducts.10,11 The underlying tenet for successful
application of πꢀLewis acid metal salts as catalysts in these
reactions is that highly favorable interactions between the alꢀ
kyne group and metal center serve to initiate the cycloisomeriꢀ
zation process. For many of these reactions, substantial rate
accelerations are observed compared to the uncatalyzed proꢀ
cess, and the course of the reaction is heavily influenced by
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A. HTC precedent ꢀ cross couplings
Br B(OH)2
onset of cycloisomerization. Notably, productive cycloisomerꢀ
ization was only observed when a slight excess of PTSH was
used, again in line with the proposed mode of activation.2
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8
50 ppb ꢀ 2.5 ppm Pd
H2O ꢁW Na2CO3
R
R
R
R
We hypothesized that if this unique mode of alkyne activaꢀ
tion was in fact operational, the reaction rate should display a
significant kinetic isotope effect. Thus, we undertook a series
of deuterium labeling experiments.
1
2
3
FeCl3 (10 mol%)
DMEADA (20 mol%)
I
N
N
HN
K2PO4, PhMe
135 ºC, 24 h
N
MeO
MeO
4
5
6
Yield
FeCl3/Cu2O
9
> 98% (Merck)
> 99.99 (Aldrich)
DMEAD + 5 ppm Cu2O
87
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77
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B. Previously reported
OPiv
OPiv
H
N
N
7
8
Yield (%)
79
Conditions
PtCl2 (5 mol %), L (5 mol %)
70 °C, 3 h
catalyzed by
trace transition
metals?
H2O (solvent),
100 °C, 2 h
95
C. Newly discovered
CO2Et
CO2Et
H
MeO
TsNHNH2
(1.1 equiv)
MeOH, 90 °C, 3 h
88%
O
N
NHTs
9
10
Figure 1: A) Trace metal catalysis in crossꢀcoupling chemistry. B)
Previously reported metalꢀfree cycloisomerization reaction C)
Newly developed cycloisomerization reaction.
DEUTERIUM LABELING AND COMPUTATIONAL
STUDIES.
Scheme 1: Initially proposed heterocycloisomerization
mechanism under metal free conditions.
The
initial
discovery
of
the
ringꢀ
First, upon treatment of ketone 9 with TsNDND2 in CD3OD,
deuteration at C(3) (90% D) was observed along with the addiꢀ
tion of the CD3OD group (see Eq. 1, Figure 2) as anticipated.
Deuteration at C(2) (97% D) and, surprisingly, at C(8) (99%
D) was also observed. Next, examining the reaction at several
time points allowed us to explain the likely origins of each
expansion/cycloisomerization reaction (Figure 1, C) led to a
key question; why does this reaction proceed with high effiꢀ
ciency solely through thermal activation in methanol? To inꢀ
vestigate the origin of alkyne activation by the protic solvent,
we began to explore the reaction mechanism and initially proꢀ
posed the straightforward reaction pathway outlined in
1
H/D exchange event. At low conversion (ca. 20%), H NMR
Scheme 1. Condensation of ketone
9
with paraꢀ
analysis of the product revealed 88% deuterium incorporation
at C(3) and only 42% D at C(2), which increased to 97% over
2 h. At this early time point, the product also displays 99%
deuterium incorporation at C(8), suggesting that the preꢀ
equilibrium between the Eꢀ and Zꢀhydrazone 11 via enhydraꢀ
zine 12 is quite facile, resulting in C(8) deuteration. We indeꢀ
pendently confirmed that C(8) deuteration precedes cycloiꢀ
somerization by reacting ketone 9 with TsNDND2 at 45 ºC.
This treatment gave 11 as a mixture of Eꢀ and Zꢀisomers, both
displaying > 95% C(8) deuterium incorporation without giving
significant cycloisomerization product 10. Furthermore, heatꢀ
ing the isolated product at 90 ºC in CD3OD also led to > 95%
deuteration at C(2) and C(3), indicating that H/D exchange at
these positons was likely occurring via electrophilic aromatic
substitution (Eq. 2, Figure 2). In this experiment, no deuterium
incorporation was observed at C(8).
toluenesulfonyl hydrazide (PTSH) was expected to give a mixꢀ
ture of Eꢀ and Zꢀ hydrazones 11. While it is likely that only the
Eꢀhydrazone would possess the required geometry for producꢀ
tive cycloisomerization, the two isomers could readily equiliꢀ
brate through enehydrazine 12.17 Pyrrole ring formation would
then occur via intramolecular 5ꢀendoꢀdig cyclization, giving
tricyclic iminium ion intermediate 13. Nucleophilic addition of
methanol at this stage would proceed with rupture of the endoꢀ
cyclic cyclopropane C–C bond and concomitant aromatization
of the pyrrole, furnishing bicyclic Nꢀaminopyrrole 10.
This pathway requires appropriate activation of Eꢀ
hydrazone 11 to facilitate ring closure. Our initial hypothesis
was that a Brønsted acid would provide the necessary activaꢀ
tion of the alkyne, possibly benefiting from assistance from
the proximal ester group. The most likely source of the needed
acid activator would be sulfinic acid, generated in situ from
thermal decomposition of tosyl hydrazide to liberate the acid
and diimide (Scheme 1, Step 1). This proposal aligned well
with preliminary results, accounting for the required elevated
temperature that would generate the Brønsted acid prior to the
In addition to observations relating to the regioselectivity of
deuterium incorporation, these experiments revealed that the
overall rate of reaction was significantly affected by deuterium
incorporation. Specifically, performing the reaction with d2ꢀ9,
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which was prepared by H/D exchange from 9 in EtOD using The ringꢀexpansion/cycloisomerization reaction was also
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base, led to a dramatically reduced rate of cycloisomerization,
with only 17% conversion to product after 2 h under normal
reaction conditions (Eq. 3, Figure 2). This preliminary result
was striking, as the reaction appeared to display an abnormally
large KIE of 24 when C(8) of ketone 9 was fully deuterated.18
Furthermore, this result was notable considering the rate of the
reaction in Eq. 1 was not affected by deuteration, even though
we demonstrated that deuteration of hydrazone intermediates
occurs under the reaction conditions and precedes cyclization.
Thus, we ascertained that other factors were at play and hyꢀ
pothesized that the effect could possibly be explained by inꢀ
voking a rate limiting preꢀequilibrium of Zꢀhydrazone 11 to Eꢀ
hydrazone 11 (i.e., αꢀdeprotonation of the Zꢀhydrazone 11 is
required to access the Eꢀhydrazone which then undergoes the
5ꢀexoꢀdig cyclization).
examined using quantum chemical computations. Our initial
calculations were aimed at finding an energetically viable
mechanism that was consistent with the observed isotope efꢀ
fect data. We employed a model system in which the tosyl and
ethyl groups of the substrate were truncated to mesyl and meꢀ
thyl groups for computational efficiency, and explicit methaꢀ
nol and CH3SO2H molecules were included. The M06ꢀ2X/6ꢀ
31+G(d,p)
DFT
method,19
as
implemented
in
GAUSSIAN09,20 was used, along with the SMD continuum
solvation model21 for methanol at 365 K.22, 23
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Consistent with the experimental results described above,
our calculations indeed predict that the Zꢀhydrazone (Figure 3,
ZꢀA) is lower in energy than the Eꢀhydrazone (Figure 3, EꢀA)),
by almost 2 kcal/mol. Furthermore, direct interconversion of
the two hydrazones via a linear C=NꢀNR geometry is predictꢀ
ed to have a barrier of 27 kcal/mol. Ring closure from the Eꢀ
hydrazone via transition state structure TSAC (activation of the
alkyne with sulfinic acid) is associated with a barrier (versus
Zꢀhydrazone) of 29 kcal/mol. Subsequent capture by methanol
(via TSCD) is predicted to be facile. These calculations suggest
that the ring closure step is rateꢀdetermining, yet deuteration of
the αꢀposition in such a scenario would result in a secondary
inverse effect (supported by DFT predictions; see the Supportꢀ
ing Information),24 as opposed to the observed apparent primaꢀ
ry effect. Enamine formation was also considered (Figure 3,
left), but ringꢀclosure from an enamine intermediate is predictꢀ
ed to have a prohibitively high barrier (>40 kcal/mol), due in
part to the poor nucleophilicity of the enamine nitrogen assoꢀ
ciated with loss of conjugation upon attack. These results left
us at a loss for understanding the ‘kinetic isotope effect’ obꢀ
served for the reaction in Eq 3.
Figure 2: Deuterium labeling studies using ketone 9, aminopyrrole
10 and ketone d2-9.
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+43.0
1
2
TSB
1.50
3
1.54
1.49
4
5
6
7
1.51
1.50
1.54
1.73
1.29
1.48
1.82
1.54
1.82
1.27
1.46
1.42
1.48
1.47
8
9
+29.2
1.29
1.92
1.40
1.71
1.71
TSAC
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1.56
2.29
1.46
2.06
1.98
1.40
1.51
1.37
1.44
1.36
1.39
E-A
+1.7
Z-B
E-B
1.39
Z-A
[0.0]
-2.7
+1.0
+0.5
TSCD
C
-13.3
1.46
1.76
1.53
1.58
1.43
2.94
1.44
1.47
1.34
1.55
2.57
2.50
1.38
1.43
1.51
1.42
1.39
1.73
1.37
1.38
1.39
1.38
D
-46.9
Figure 3: Optimized structures (SMD(methanol)ꢀM06ꢀ2X/6ꢀ31+G(d,p)) for metalꢀfree cyclization pathways. Relative free energies are
shown in kcal/mol and selected distances are shown in Å.
heated MeOH at 90 ºC) and the lack of discrete diagnostic
spectroscopic signals complicated our ability to apply those
IN SITU MECHANISTIC STUDIES
With these computational results in hand, we then sought to
conclusively exclude the possibility that the large effect of αꢀ
deuteration on the rate of the reaction using ketone 9 was not
due to a rateꢀdetermining preꢀequilibrium of hydrazone Zꢀ11
to Eꢀ11 (Scheme 1). Furthermore, we sought to rule out the
possibility that the sulfinic acid, generated from the thermal
decomposition of pꢀTsNHNH2,25 was serving as the active
catalyst for this reaction. As such we turned to monitoring the
reaction by ReactꢀIR and LCMS. Monitoring this reaction,
which proceeds above the boiling point of methanol, was not
trivial and required the development of a new apparatus (see
Figure 4).
technologies.
Instead, we developed an automated reaction sampling apꢀ
paratus, consisting of a programmable syringe pump, a highꢀ
torque 2ꢀposition ꢀ 6 port Rheodyne® valve and a Gilson 215
liquid handling robot.28 An example of the workflow for capꢀ
turing each aliquot is illustrated in Figure 4. The reaction is
initiated by adding the reagents, stir bar, and solvent. The vesꢀ
sel is then sealed in a vial using a PTFEꢀlined septum with a
1/32'' micro capillary threaded through to act as a sampling
port. The reaction vial is then immersed in an aluminum block
fitted into a EasyMax reactor preheated to 90 ºC. At the start
of the sampling sequence, the Rheodyne® value rotates to
bring a sample loop in line with the microꢀcapillary, and the
syringe pump withdraws a fixed volume (~5ꢀ10 µL) from the
reactor. The combination of overpressure in the reaction flask
and a predetermined draw rate ensures an accurate volume is
transferred to the sample loop, without cavitation of the solꢀ
vent. The Rheodyne® valve then switches, and the liquid hanꢀ
dler actuates, flushing the contents of the sample loop into an
HPLC vial. This sampling protocol proved to be highly reproꢀ
While DFT and deuteration analysis of individual reaction
aliquots each provided some clues, monitoring the dynamic
reaction progress was necessary to elucidate the underlying
mechanism of this reaction. Delineation of a mechanism using
this approach requires timeꢀdependent concentration data for
all species, over the entire course of the reaction, ideally with
a very high data sampling rate. Techniques such as NMR26 and
ReactIR27 are excellent candidates for monitoring reactions in
real time, but the required temperature and pressure (superꢀ
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ducible, allowing reaction profiles to be easily generated from
complex reaction mixtures.
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8
Zꢀhydrazone
Zꢀ11
Eꢀhydrazone
Eꢀ11
9
Figure 6: Xꢀray crystal structures of E- and Z- hydrazone 11.29
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The ability to visualize the dynamic behavior of multiple inꢀ
termediates, products and byproducts allowed us to directly
test our mechanistic hypothesis. We surmised that if in situ
generated sulfinic acid was indeed the active catalyst the rate
of pyrrole formation should increase with higher initial loadꢀ
ings of TsNHNH2 (14), as we would expect higher concentraꢀ
tions of the putative Brønsted acid catalyst.25 Instead, increasꢀ
ing the initial concentration of TsNHNH2 resulted in slower
formation of pyrrole, with a concomitant increase in alkane
byproduct 15, which arises from diimide reduction of the alꢀ
kyne group in Zꢀhydrazone 11. While this result transitively
confirms elevated thermal decomposition of TsNHNH2, the
lack of more rapid pyrrole formation suggests that if sulfinic
acid is indeed a Brønsted acid catalyst, the reaction rate is not
sensitive to its concentration, implying that either the system
displays saturation kinetics relative to sulfinic acid or that it is
not participating in the cycloisomerization pathway (Figure 7).
Figure 4: Representation of work flow for automated sampling
with offline HPLCꢀMS analysis apparatus.
Applying our automated sampling apparatus permits rapid,
detailed analysis of the reaction components. In a preliminary
survey, we were able to immediately identify several reaction
trends, which support our proposed reaction pathway (Figure
5). Within the first 60 minutes we observed rapid formation of
two isomeric hydrazones (Zꢀ11 and Eꢀ11), with maximum
concentration achieved at ~50 minutes. Only after these interꢀ
mediates are generated is the desired amino pyrrole 10 obꢀ
served. The induction period most likely reflects the need for
sufficient Eꢀhydrazone prior to cycloisomerization, however, it
could also be due to slow in situ generation of the necessary
sulfinic acid catalyst.
The reaction progress information compelled us to prepare
authentic samples of each hydrazone, unambiguously estabꢀ
lishing the configuration of each isomer by Xꢀray crystallogꢀ
raphy from individual samples (Figure 6). These data allow us
to conclusively show that the system does indeed form both
Figure 7: Changes in chemoselectivity with varied initial loading
of TsNHNH2, Rxn 1 = [TsNHNH2] = 0.35 M, [ketone 9] = 0.25
M, Rxn 2 = [TsNHNH2] = 0.55 M, [ketone 9] = 0.25 M.
Following this observation, we discovered that the rate of
pyrrole formation varies with the manner in which ketone 9 is
purified. The rate of aminopyrrole 10 formation was signifiꢀ
cantly faster when using ketone 9 that was purified by column
chromatography compared to ketone 9 that was purified by
recrystallization from EtOH. Furthermore, a rapid rate of cyꢀ
clization could be restored if an aliquot of the filtrate was addꢀ
ed to the cycloisomerization reaction using recrystallized keꢀ
tone 9 (Figure 8). Finally, the rate of ketone consumption to
form Zꢀ and Eꢀhydrazones is identical regardless of how the
reaction is performed (green line in graph). These results sugꢀ
gest that a trace catalyst exists in the sample that is not effecꢀ
Figure 5: Reaction profile for ketone 9 heterocycloisomerization
obtained by automated sampling and analysis by HPLCꢀMS.
hydrazones, with a 3:1 ratio favoring the unreactive Zꢀisomer,
which is in good agreement with our DFT analysis.
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tively removed by column chromatography and specifically Initial experiments had flagged the apparent differences in
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accelerates the cyclization from the intermediate hydrazone
without impacting the condensation or hydrazone equilibration
steps.
rate between 9 and d2ꢀ9 as having key mechanistic implicaꢀ
tions, however, the realization that trace copper salts are key to
catalysis forced us to reexamine the role of αꢀdeuteration. Esꢀ
pecially because our detailed computational investigation
could provide no rationale for the observed differences in reꢀ
action rate depending on deuterium incorporation at the αꢀ
position of 9.
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Figure 8: Rate of cycloisomerization varies with purification
method utilized for ketone 9. General reaction conditions [ketone
9] = 0.1 M, [TsNHNH2] = 0.11 M in MeOH at 95 °C; Rxn 1 –
Ketone 9 purified by column chromatography; Rxn 2 – ketone 9
purified by recrystallization from EtOH; Rxn 3 – Recrystallized
ketone 9 was treated with 5 µL of concentrated filtrate from reꢀ
crystallization.
To identify the nature of the trace catalyst present in the
sample, ICPꢀMS analysis was conducted on both the columnꢀ
purified and recrystallized ketone, as well as the supernatant
from the crystallization. While many trace metals were preꢀ
sent, the key difference between the samples is a depletion of
copper upon recrystallization from EtOH. In addition, there is
a concomitant increase of copper in the supernatant (Table 1).
Figure 9: Cycloisomerization reaction initiated using either C(8)ꢀ
H2 or C(8)ꢀd2 ketone (both recrystallized from EtOH). Initial conꢀ
ditions ꢀ Rxn 1: [ketone 9] = 0.1 M, [hydrazide 14] = 0.11 M in
MeOH at 95 °C; Rxn 2: [ketone d2ꢀ9] = 0.1 M, [hydrazide 14] =
0.11 M in MeOH at 95 °C.
The trace copper contamination likely results from the Soꢀ
nogashira crossꢀcoupling, used to install the alkyne functional
group in ketone 9.15 It is quite remarkable that a catalytically
sufficient quantity of copper remains in 9, even after three
synthetic steps, each using purification by standard techniques
(column chromatography or extraction). Furthermore, this
result also illustrates the extraordinary catalytic efficiency of
copper, which is able to promote the cycloisomerization reacꢀ
tion at a loading of nearly 2.0 x 10ꢀ5 mol equiv (TON ≈
50000).
After recrystallizing ketone 9 and d2ꢀ9 from EtOH, both
starting materials were independently subjected to the reaction
conditions. Now, both the αꢀprotio and αꢀdeutero ketones proꢀ
duced nearly identical reaction progress curves (Figure 9).
Thus, our initially observed reduction in cycloisomerization
rate upon αꢀdeuteration is simply due to the synthetic operaꢀ
tions used to make d2-9, not the deuterium isotope itself. To
obtain d2ꢀ9, ketone 9 was dissolved in EtOD under basic conꢀ
ditions. Reaction and isolation lowers the concentration of
copper sufficiently, such that the rate of cyclization was seriꢀ
ously hindered for d2ꢀ9; recrystallization of ketone 9 also
serves a similar purpose.
Table 1: Comparison of Cu levels in starting material after
purifications.
%Cu
(mg/mg)a
Entry
Sample
Equiv Cub
9
2.76 x 10ꢀ2
1
9.01 x 10ꢀ4
(chromatography)
9
2
3
6.40 x 10ꢀ4
1.17 x 10ꢀ1
2.09 x 10ꢀ5
3.79 x 10ꢀ3
(recrystallized)
supernatant
a
b
percent Cu by mass expressed in mg Cu per mg total sample;
calculated equivalents of Cu present in cycloisomerization reacꢀ
tion, relative to ketone 9.
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steric bulk by orthoꢀsubstitution on the aryl group (see 10i)
1
2
3
4
5
6
7
8
leads to a lower yield of the desired product. A cyclohexenyl
substituent yielded the corresponding vinyl aminopyrrole
product (10j) in 36% yield. Vinyl pyrroles are known to readiꢀ
ly decompose under acidic and aerobic conditions, which likeꢀ
ly accounts for the low isolated yield of 10j.31 Significantly,
none of the desired product was observed for substrates posꢀ
sessing nꢀalkyl substitution on the alkyne group. In these cases
(e.g., R = nꢀBu or hexyl), only nonꢀspecific decomposition
occurred upon prolonged heating. Thus, it appears that a balꢀ
ance of stereoelectronic effects is important for these transꢀ
formations.
9
10
11
12
Figure 10: Cycloisomerization initiated by Cu(MeCN)4PF6
MECHANISTIC PROPOSAL
addition. General reaction conditions [ketone 9] = 0.2 M,
[TsNHNH2] = 0.2 M in MeOH at 45 °C. [Cu(MeCN)4PF6] =
0.2 ꢁM added at indicated time.
13
14
15
16
17
18
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On the basis of the collection of observations described
above, along with insights from the analogous goldꢀcatalyzed
transformations described by Schmalz and Zhang,15 a plausible
mechanism for the heterocycloisomerization can be formulatꢀ
ed as illustrated in Scheme 2, A. Condensation of ketones 9a-k
with TsNHNH2 leads to the formation of hydrazones E/Zꢀ11a-
k. Concurrent thermal decomposition of TsNHNH2 results in
the formation of small, but significant, quantities of pꢀ
TolSO2H, which possibly facilitates the isomerization of Z-
hydrazones Zꢀ11a-k to Eꢀhydrazones 11a-k through an enehyꢀ
drazine intermediate that is undetected in our kinetic studies
but implied from our deuterium labeling experiments (see
Figure 2, Eq. 3). Activation of the alkyne group with trace
copper salts and attack of the hydrazone imine in a 5ꢀendoꢀdig
fashion affords iminium ions 13a-k. The addition of methanol
to 13a-k at this stage may proceed with attendant rupture of
the endocyclic cyclopropane C–C bond and aromatization to
afford bicyclic aminopyrroles 10a-k.
1.69
1.97
2.04
2.26
1.49
1.28
1.48
1.41
1.30
+21.4
1.69
2.11
2.05
2.31
1.50
1.46
1.29
1.38
+5.4
1.23
3.43
[0.0]
1.95
1.50
1.34
1.44
1.37 1.98
1.46
1.40
Figure 11: Optimized structures (M06ꢀ2X/LANL2DZ) for Cuꢀ
promoted cyclization. Relative free energies are shown in
kcal/mol and selected distances are shown in Å.
Copper salts were confirmed to be a very effective catalyst
by performing the reaction with Cu(MeCN)4PF6. In this experꢀ
iment, recrystallized 9 and 14 were incubated in MeOH at 40
°C until all ketone was converted to hydrazone 11 (Figure 10).
The Cu(MeCN)4PF6 (0.1 mol%) was then added, resulting in
rapid cycloisomerization. Additional calculations with copper
(modeled here as Cu(CH3SO2)) were performed using the
M06ꢀ2X/LANL2DZ model chemistry30 to confirm that Cu(I)
does lead to barrier lowering. Our results (Figure 11) indicate
that ringꢀclosure from the Eꢀhydrazone does indeed have a
reduced (by ~6 kcal/mol) barrier when the copper salt comꢀ
plexes to the alkyne πꢀbond, as expected.
SUBSTRATE SCOPE
As illustrated in Figure 12, this HTC hydrazone variant of
the SchmalzꢀZhang transformation works for a range of interꢀ
nal alkyneꢀbearing substrates. The key difference between the
terminal alkyne case and the internal alkyne cases is that in the
latter, mixtures of diastereomeric products are observed. Aryl
substitution on the alkyne unit is readily tolerated as evidenced
by the formation of 10a–10f. A cyclopropyl substituent on the
alkyne led to the formation of 10g in 73% yield. Importantly,
this reaction proceeded at 75 °C as compared to the 90 °C
required for terminal alkyne substrate 9. Of note, increasing
Figure 12: Scope of the HTCꢀaminopyrrole formation. Unless
indicated, the stereochemistry of the major diastereomer was not
determined.
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Finally, changes in the electronic and steric properties of the thermal decomposition of tosylhydrazide generates diimide
1
2
3
4
5
6
7
8
alkyne substituent impact both the reactivity and diastereoseꢀ
lectivity of the resulting products. This may be explained by
the influence of substituents on Step 3 (see Scheme 2) of our
proposed mechanism. As illustrated in Scheme 2, B, groups
that are electronꢀreleasing are likely to stabilize cumulene
intermediates such as 16, which would in turn be reflected in a
lower associated barrier for the metal coordination step. Furꢀ
thermore, intramolecular cyclization by the hydrazone group
would be hampered by increased steric interaction with the R
group, which is reflected in our observations with, for examꢀ
ple, orthoꢀsubstituted phenyl groups (see 10i and 10k, Figure
12). Following attack, iminium intermediate 13a-k is formed.
The R group (in the cases where it is electron releasing) could
enhance stabilization of cationic intermediate 17 by the amiꢀ
nopyrrole moiety. As a result, the methanol addition step
would lead to a cationic intermediate (e.g., 18; the degree of
delocalization has not been determined) as opposed to a reacꢀ
tion via a diastereoselective SN2’ꢀlike scenario where methaꢀ
nol addition occurs from the βꢀface of 13a-k. These observaꢀ
tions are fully consistent with the alkyne substituent effects on
the stereoselectivity of these heterocycloisomerizations that
were observed and rationalized by Schmalz and coworkers
using an elegant enantioenriched substrate study.32
and sulfinic acid in situ, and these components are critical for
the success of the reaction, though we have conclusively
shown that the rateꢀdetermining step in the reaction has no
concentration dependence on the amount of tosylhydrazide
added. Computational and kinetic results suggest that enehyꢀ
drazine 12 is a plausible intermediate in this reaction; howevꢀ
er, it is not the species that undergoes cyclization onto the
alkyne group and is responsible for isomerization of the hyꢀ
drazone geometry. With this mechanistic model in hand, we
are actively investigating the nature of other “metalꢀfree” cyꢀ
cloisomerization reactions, such as those shown in Figure 1, B,
to establish whether trace metal catalysis is involved.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and spectroscopic data (PDF)
Xꢀray Crystallographic Data for compound Eꢀ11 (cif)
Xꢀray Crystallographic Data for compound Zꢀ11 (cif)
AUTHOR INFORMATION
Corresponding Authors
* rsarpong@berkeley.edu., djtantillo@ucdavis.edu,
jhein@chem.ubc.ca
Present Addresses
†1515 Dickey Dr. Atlanta, GA 30323
††2036 Main Mall, Vancouver, BC V6T 1Z1
†††Internal Medicine, Medicinal Chemistry, Pfizer Worldwide
Research & Development, Eastern Point Road, Groton, CT,
06340.
ACKNOWLEDGMENT
The work was supported by the NSF (CAREER 0643264 to RS)
NSERC (2016ꢀRGPINꢀ04613 to JEH) and a Research Scholar
Grant from the American Cancer Society (RSGꢀ09ꢀ017ꢀ01ꢀCDD
to RS). In addition, we thank Mettler Toledo Autochem for the
donation of a ReactIRꢀ15 (to JEH). We are grateful to the NSF for
a graduate fellowship to SMWH and Eli Lilly and Roche for fiꢀ
nancial support. Computations were supported by the NSF
XSEDE program.
REFERENCES
Scheme 2: Mechanistic proposal and rationalization of
diastereoselectivity.
1. For an overview of highꢀturnover catalyst (HTC), see: Farina,
V.; Adv. Synth. Catal. 2004, 346, 1553 – 1582. For the twelve
tenets of green chemistry, see: Anastas, P. T.; Kirchhoff, M. M.;
Acc. Chem. Res. 2002, 35, 686 – 694. For microreview on trace
metal catalysis, see: Hierso, J.ꢀC.; Beaupérin, M.; Meunier, P.
Eur. J. Inorg. Chem. 2007, 24, 3767 – 3780. For seminal work
on HTC initially using palladacycles, see: Herrmann, W. A.;
Brossmer, C.; Öefele, K.; Reisinger, C.ꢀP.; Priermeier, T.; Belꢀ
ler, M.; Fischer, H.; Angew. Chem. Int. Ed. Engl. 1995, 34, 1844
– 1848. Using adamantlyphosphine based ligands, see: Zapf, A.;
Ehrentraut, A.; Beller, M.; Angew. Chem. 2000, 112, 4315 –
4317; Angew. Chem. Int. Ed. 2000, 39, 4153 – 4155. For seminal
examples of trace palladium catalyst using dialkylbiarꢀ
ylphosphine ligands, see: Wolfe, J. P.; Buchwald, S. L.; Angew.
Chem. Int. Ed. 1999, 38, 2413 ꢀ 2416. Wolfe, J. P.; Singer, R.
A.; Yang, B. H.; Buchwald, S. L.; J. Am. Chem. Soc. 1999, 121,
9550ꢀ 9561.
CONCLUSION
We report a heterocycloisomerization to form cycloheptaneꢀ
annulated aminopyrroles facilitated by copper at remarkably
low catalyst loadings. These reactions are a ‘noꢀmetal added’
variant of a related gold(I)ꢀcatalyzed cycloisomerization deꢀ
veloped by Schmaltz and Zhang for the corresponding furans.
Through computational studies, reaction progress monitoring
and elemental analysis, we have established that the active
catalyst for these reactions is a copper complex present at trace
levels. Furthermore, we have demonstrated that both the E-
and Z- hydrazones are formed during this reaction and that,
counterintuitively, the Zꢀhydrazone 11 is the more thermodyꢀ
namically stable hydrazone isomer. We also believe that the
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Journal of the American Chemical Society
2. Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 4176 –
J.; Shaprio, B. L.; Vane, F. M.; Fleming, J. S.; Ratka, J. S. J. Am.
Chem. Soc. 1963, 85, 2784 ꢀ 2788.; Wilson, R. Marshall; Rekers,
J. W.; Packard, A. B.; Elder, R. C.; J. Am. Chem. Soc. 1980, 102,
1633 – 1641.; Adam, W.; Sahin, C.; Schneider, M.; J. Am.
Chem. Soc. 1995, 117, 1695 – 1702. For studies on azomethine
imines, see: Gergely, J.; Morgan, J. B.; Overman, L. E.; Béꢀ
langer, G.; Hong, F.ꢀT.; Overman, L. E.; Rogers, B. N.; Tellew,
J. T.; Trenkle, W. C. J. Org. Chem. 2002, 67, 7880 ꢀ 7883.;
Overman, L. E.; Tellew, J. T. J. Org. Chem. 1996, 61, 8338 –
8340.
4211. Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
122, 4020 – 4028.
1
2
3
4
5
6
7
8
3. Suzuki coupling using QꢀPhos Pd catalyst at 0.0005 mol%, see
Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F.; J. Org.
Chem. 2002, 67, 5554 – 5566. HTC Heck couplings, see
Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc.,
1999, 121, 2123 – 2132.
4. For work on HTC using multidentate phosphines on very elecꢀ
tron poor arene, see: Feuerstein, M.; Doucet, H.; Santelli, M.;
Synlett 2001, 1458 – 1460.
5. (a) For trace metal catalyzed Suzuki couplings, see: Leadbeater,
N. E.; Marco, M. Angew. Chem. Int. Ed. 2003, 42, 1407 ꢀ 1409.;
Leadbeater, N. E.; Marco, M. Org. Lett., 2002, 4, 2973 ꢀ 2976.;
Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 5660 ꢀ
5667.; Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.; Williams,
V. A.; Grandados, P.; Singer, R. D.; J. Org. Chem. 2005, 70, 161
ꢀ 168. (b) For a review of trace metal contaminants with FeCl3,
see Buchwald, S. L.; Bolm, C. Angew. Chem. Int. Ed. 2009, 48,
5586 – 5587.; Thomé, I; Nijs, A.; Bolm, C.; Chem. Soc. Rev.
2012, 41, 979 ꢀ 987.; Larsson, P.ꢀF.; Correa, A.; Carril, M.;
Norrby, P.ꢀO.; Bolm, C. Angew. Chem. Int. Ed., 2009, 48, 5691 ꢀ
5693.
18. This value is above the theoretical limit for KIE’s that do not
involve tunneling for proton transfers, see: Kiefer, P. M.; Hynes,
J. T. J. Phys. Org. Chem. 2010, 23, 632 – 646.
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
19. Zhao, Y.; Truhlar, D. Theor. Chem. Acct. 2008, 120, 215 ꢀ 241.
20. Gaussian 09, Revision B.01 Frisch, M. J.; Trucks, G. W.; Schleꢀ
gel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;
Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Naꢀ
katsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A.
F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara,
M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J.
A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothꢀ
ers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Norꢀ
mand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar,
S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.;
Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas; Forꢀ
esman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Wallingford
CT, 2009.
6. Kirsch, S. Synthesis 2008, 3183–3204.
7. Michelet, V.; Toullec, P. Y.; Genêt, J.ꢀP. Angew. Chem. Int. Ed.
2008, 47, 4268–4315.
8. Chianese, A. R.; Lee, S. J.; Gagné, M. R. Angew. Chem. Int. Ed.
2007, 46, 4042–4059.
9. Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102,
813–834.
10. Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705.
11. Li, C.ꢀJ.; Trost, B. M. Proc. Natl. Acad. Sci. U. S. A. 2008, 105,
13197–13202.
12. a) Bhanu Prasad, B. A.; Yoshimoto, F. K.; Sarpong, R. J. Am.
Chem. Soc. 2005, 127, 12468–12469.; Smith, C. R.; Bunnelle, E.
M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169–1171.;
Fisher, E. L.; WilkersonꢀHill, S. M.; Sarpong, R. J. Am. Chem.
Soc. 2012, 134, 9946–9949.
13. Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev. 2011, 111,
2937–2980.; Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Geꢀ
vorgyan, V. Chem. Rev. 2013, 113, 3084 ꢀ 3213.; Seregin, I. V.;
Schammel, A. W.; Gevorgyan, V. Org. Lett. 2007, 9, 3433–
3436.; Li, Z.; Chernyak, D.; Gevorgyan, V. Org. Lett. 2012, 14,
6056–6059.; Chernyak, D.; Gevorgyan, V. Org. Lett. 2010, 12,
5558–5560.; Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc.
2006, 128, 12050–12051.; Chernyak, D.; Gadamsetty, S. B.;
Gevorgyan, V. Org. Lett. 2008, 10, 2307–2310.; Li, Z.;
Chernyak, D.; Gevorgyan, V. Org. Lett. 2012, 14, 6056–6059.
14. (a) Narayan, A. R. H.; Sarpong, R. Green Chem. 2010, 12, 1556
ꢀ 1559. (b) Heller, S. T.; Kiho, T.; Narayan, A. R. H.; sarpong,
R. Angew. Chem. Int. Ed. 2013, 52, 11120 – 11133.
21. Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2009, 113, 6378 ꢀ 6396.
22. Intrinsic Reaction Coordinate (IRC) calculations were used to
connect transition state structures to their local minima, as deꢀ
scribed in: (a) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys.
1991, 95, 5853 ꢀ 5860. (b) Gonzalez, C.; Schlegel, H. B. J Chem.
Phys. 1989, 90, 2154 ꢀ 2161. (c) C. Lee, C.; Yang, W.; Parr, R.
G. Phys Rev. B 1988, 37, 785 ꢀ 789. (d) Fukui, K. Acc. Chem.
Res. 1981, 14, 363 – 368.
23. Structural images were created with Ball & Stick, see: Ball &
Stick 4.0a12, Muller, N.; Faulk, A. Johannes Kepler University
Linz 2004.
24. Predicted KIE values were computed using the Bigeleisen and
Mayer method, as implemented in Quiver. (a) Bigeleisen, J.;
Mayer, M. G. J. Chem. Phys. 1947, 15, 261ꢀ267. (b) Saunders,
W.; Laidig, K. E.; Wolfsberg, M. J. Am. Chem. Soc. 1999, 111,
8989ꢀ8994. (c) A modified version of Quiver provided by Prof.
Daniel Singleton (Texas A&M) was utilized.
25. Phinyocheep, P.; Pasiri, S.; Tavichai, O. J. Appl. Polym. Sci.
2003, 87, 76–82.; Podešva, J.; Holler, P. J. Appl. Polym. Sci.
1999, 74, 3203–3213.; Samran, J.; Phinyocheep, P.; Daniel, P.;
Kittipoom, S. J. Appl. Polym. Sci. 2005, 95, 16–27.
26. (a) Dunn, A. L.; Landis, C. R. Magn. Reson. Chem. 2017, 55,
329–336. (b) Foley, D. A.; Bez, E.; Codina, A.; Colson, K. L.;
Fey, M.; Krull, R.; Piroli, D.; Zell, M. T.; Marquez, B. L. Anal.
Chem. 2014, 86, 12008–12013.
27. (a) Chung, R.; Hein, J. E. Top. Catal. 2017, 137, 1–15. (b) Theꢀ
ron, R.; Wu, Y.; Yunker, L. P. E.; Hesketh, A. V.; Pernik, I.;
Weller, A. S.; McIndoe, J. S. ACS Catal. 2016, 6, 6911–6917.
(c) Foley, D. A.; Doecke, C. W.; Buser, J. Y.; Merritt, J. M.;
Murphy, L.; Kissane, M.; Collins, S. G.; Maguire, A. R.;
Kaerner, A. J. Org. Chem. 2011, 76, 9630–9640.
28. (a) Rougeot, C.; Situ, H.; Cao, B. H.; Vlachos, V.; Hein, J. E.
React. Chem. Eng. 2017, 2 (2), 226–231. (b) Malig, T. C.;
Koenig, J. D. B.; Situ, H.; Chehal, N. K.; Hultin, P. G.; Hein, J.
E. React. Chem. Eng. 2017, 2 (3), 309–314.
29. XꢀRay structures were visualized with: Legault, CYL view 1.0b;
Universitè de Sherbrooke: Quebec, Canada, 2009;
http://www.cylview.org.
15. Zhang, J.; Schmalz, H.ꢀG. Angew. Chem. Int. Ed. 2006, 45,
6704–6707.
16. For the merits of merging synthesis, computation and kinetics,
see: (a) Lineberger, W. C.; Borden, W. C. Phys. Chem. Chem.
Phys. 2011, 13, 11792 – 11813. (b) For recent applications to
understanding KOtBu mediated reactions, see: Liu, W.ꢀB.;
Schuman, D. P.; Yang, Y.ꢀF.; Toutov, A. A.; Liang, Y.; Klare,
H. F. T.; Nesnas, N.; Oestreich, M.; Blackmond, D. G.; Virgil, S.
C.; Banerjee, S.; Zare, R. N.; Grubbs, R. H.; Houk, K. N.; Stoltz,
B. M. J. Am. Chem. Soc. 2017, 139, 6867 – 6879. (c) Banerjee,
S.; Yang, Y.ꢀF.; Jenkins, I. D.; Liang, Y.; Toutov, A. A.; Liu,
W.ꢀB.; Schuman, D. P.; Grubbs, R. H.; Stoltz, B. M.; Krenske,
E. H.; Houk, K. N.; Zare, R. N. J. Am. Chem. Soc. 2017, 139,
6880 – 6887.
17. For studies on E- and Z- hydrazone isomerism, see Hegarty, A.
F.; Scott, F. L.; J. Org. Chem. 1968, 753 ꢀ 762.; Karabatsos, G.
J.; Vane, F. M.; Taller, R. A.; Hsi, N. J. Am. Chem. Soc. 1964,
86, 3351 – 3357.; Karabatsos, G. J.; Taller, R. A.; Vane, F. M.;
Tetrahedron Lett. 1964, 1081 ꢀ 1085.; Karabatsos, G. J.; Taller,
R. A.; J. Am. Chem. Soc. 1963, 85, 3624 ꢀ 3629.; Karabatsos, G.
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30. Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270ꢀ283.
32. Labsch, S.; Ye, S.; Adler, A.; Neudörfl, J.ꢀM.; Schmalz, H.ꢀG.
Tetrahedron Asymm. 2010, 21, 1745–1751.
31. Jones, R. A.; Marriott, M. T. P.; Rosenthal, W. P.; Sepulveda
Arques, J. J. Org. Chem. 1980, 45, 4515–4519; Hosmane, R. S.;
Hiremath, S. P.; Schneller, S. W.; J. Chem. Soc. Perkin Trans. 1
1973, 2450 – 2453.
1
2
3
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ACS Paragon Plus Environment

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ACS Paragon Plus Environment