Formation of Aza-ortho-quinone Methides under Room Temperature Conditions: Cs2CO3 Effect

Article abstract of DOI:10.1021/acs.joc.7b00697

Since the first report of a facile, room temperature process to access aza-ortho-quinone methides (aoQMs) by Corey in 1999, this chemistry has remained dormant until our report of an enantioselective catalytic example in 2014. We report a theoretical and experimental study of the key to success behind these successful examples to enable broader exploitation of this useful intermediate. We have discovered that transformations involving the aoQM are remarkably facile with barriers <17 kcal/mol. The main difficulty of exploiting aoQM in synthesis is that they are unstable (ΔG > 30 kcal/mol), precluding their formation under mild conditions. The use of Cs₂CO₃ as base is critical. It provides a thermodynamically and kinetically favorable means to form aoQMs, independent of the salt solubility and base strength. The exothermic formation of salt byproducts provides a driving force (average ΔG = -30.8 kcal/mol) compensating for the majority of the inherent unfavorable thermodynamics of aoQM formation.

Full text of DOI:10.1021/acs.joc.7b00697

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Article
On the Formation of Aza-ortho-quinone Methides
Under Room Temperature Conditions: Cs2CO3 Effect
Daniel M. Walden, Ashley A. Jaworski, Ryne C. Johnston, M. Todd Hovey,
Hannah V. Baker, Matthew P. Meyer, Karl A. Scheidt, and Paul Ha-Yeon Cheong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00697 • Publication Date (Web): 26 Jun 2017
Downloaded from http://pubs.acs.org on June 26, 2017
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The Journal of Organic Chemistry
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On the Formation of Aza-ortho-quinone Methides Under Room
Temperature Conditions: Cs2CO3 Effect
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Daniel M. Walden,‡ Ashley A. Jaworski,§ Ryne C. Johnston,‡ M. Todd Hovey,§ Hannah V. Baker,‡
Matthew P. Meyer,ς Karl A Scheidt*,§, and Paul Ha-Yeon Cheong*,‡
‡Department of Chemistry, Oregon State University, 135 Gilbert Hall, Corvallis, OR 97331 (USA)
§Department of Chemistry, Northwestern University 2145 Sheridan Rd, Evanston, IL 60208 (USA)
ςDepartment of Chemistry and Biochemistry, University of California, Merced, CA 95453 (USA)
Cs2CO3
+ CsHCO3
+ CsCl
H
XR
H
in situ XR
Michael
Nuc
formation
Cl
XHR
Cl
Cl
XHR
∆G
–HCl
H
XHR
XR
H
SN2
X
∆GX=O < ∆GX=N
Nuc
ABSTRACT: Since the first report of a facile, room temperature process to access aza-ortho-quinone methides (aoQMs)
by Corey in 1999, this chemistry has remained dormant until our report of an enantioselective catalytic example in 2014.
We report a theoretical & experimental study of the key to success behind these successful examples to enable broader
exploitation of this useful intermediate. We have discovered that transformations involving the aoQM are remarkably
facile with barriers <17 kcal/mol. The main difficulty of exploiting aoQM in synthesis is that they are unstable (∆G = ~30
kcal/mol), precluding their formation under mild conditions. The use of Cs2CO3 as base is critical. It provides a thermo-
dynamically and kinetically favorable means to form aoQMs, independent of the salt solubility and base strength. The
exothermic formation of salt byproducts provides a driving force (average ∆G = –31.1 kcal/mol) compensating for the ma-
jority of the inherent unfavorable thermodynamics of aoQM formation.
In this report, we studied three reactions that can pro-
ceed through aoQM intermediacy using experiments and
theory.11 We have identified the enabling factor behind
INTRODUCTION
Quinone methides, particularly ortho-quinone methi-
des (oQMs), are highly reactive and useful intermediates1
successful cases of aoQM-mediated reactions under mild
with numerous examples in synthetic methodologies,2
conditions. Herein, we describe the thermodynamic and
total syntheses,3 and natural product chemistry.4 A multi-
kinetic effect Cs2CO3 has in accessing the reactive aoQM
tude of reports disclose oQM use under mild conditions.5
In contrast, reports of in situ generation of aza-ortho-
intermediate in synthesis and asymmetric catalysis. Our
results highlight and refine the cesium effect12 that has
quinone methides (aoQMs) as reactive intermediates un-
der mild conditions are demonstrably rare (Scheme 1,
Top).6 E. J. Corey first reported the use of aoQMs as useful
reactive intermediates in 1999,7 and for more than a dec-
ade, this chemistry remained underexplored until our
report in 2014.8 While there are examples of aoQMs being
formed as a result of pyrolysis, photolysis, with non-
removable stabilizing groups9 or from even more reactive
precursors,10 the difficulty of its generation under mild
conditions have limited aoQMs as general electrophiles in
catalysis and synthesis.
been at the forefront of many organic reactions that take
place under basic conditions. While this current study
focuses on the use of ortho substituted benzyl chloride
precursors as substrates, we will continue to leverage our
newfound understanding to develop novel substrates for
aoQM-mediated reactions.
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orthoꢀquinone methides [oQM]
prevalence of the former in literature. The stability differ-
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ences are attributed to the relative π-bond strengths be-
tween carbon and the heteroatoms. The stronger, more
polarized C=O π-bond in the oQM derivatives helps miti-
gate the energetic penalty of losing aromaticity. The C=O
π-bond is stronger than C=N π-bond by 10–15 kcal/mol,
matching the stability differences between oQM and
aoQM.21
X
Base
Common
>50 examples
< 40 °C
–HX
OH
O
oQM
azaꢀorthoꢀquinone methides [aoQM]
X
Base
Rare
<5 examples
< 40 °C
–HX
NHR
NR
aoQM
9
• more controlled conditions
• opportunities for asymmteric catalysis
Table 1. Computed ortho-quinone and aza-ortho-
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quinone methide equilibria.
Corey, Angewandte Chemie 1999
Cl
Cs2CO3,
CH2Cl2, 23 °C
OEt
via
NH
Y
N
Y
OEt
N
Y
Y = Mesyl, Tosyl, Boc
Up to 83%
X
∆G (DCM)
19.6
∆G (DEE)
19.9
∆G (THF)
19.7
Our work, J. Am. Chem. Soc. 2014
O
N
BF4
20 mol%
NH
NBoc
29.1
29.3
29.1
N
N
Me
O
Mes
O
Cl
Bn
32.9
33.4
33.0
CDI, Cs2CO3
imidazole, CPME, 23 °C
OH
NHBoc
N
Boc
82%, 92:8 er
Me
Cesium carbonate equilibrium facilitates aoQM
production. Any reaction which generates methides
must overcome the resonance energy of benzene.22 Under
harsh conditions, much of this energy will come from
light or heat. Under milder reaction conditions, the har-
nessing of chemical energy will play a much larger role.
We postulated that the basic conditions used to generate
these reactive intermediates may be responsible in miti-
gating the unfavorable thermodynamics. Specifically, we
considered the thermodynamic effect of converting
Cs2CO3 and HCl to CsHCO3 and CsCl. Computations
showed that this reaction is highly exergonic in three dif-
ferent polar aprotic solvents (∆Gavg = –30.8 kcal/mol, blue
arrows, Chart 1). By coupling this reaction with the aoQM
formation process, aoQMs were now shown to be in equi-
librium with the ortho amino benzyl chloride precursors
under ambient conditions (∆G aoQM 1.7–3.2 kcal/mol).
Scheme 1. Summary of oQM chemistry and recent aoQM
chemistry.
RESULTS AND DISCUSSION
Computational details. Geometry optimizations were
performed with the M06-2X method13 with SDD+ECP for
Cs and 6-31G(d)14 basis sets for all other atoms. Solvation
was modelled implicitly15 using PCM16 with the solvent
employed in the experiments. Geometry optimizations,
vibrational frequency analysis, and PCM solvation was
completed using Gaussian 09.17 Energy refinements were
computed at M06-2X/def2-QZVPP18 using the ORCA
computational package19 with PCM solvation corrections
at M06-2X/6-311++G(2df,p)20 & SDD+ECP using Gaussian
09.
Reliable energetics involving partially heterogeneous,
strongly ionic acid/base reactions in which constituent
reactants, intermediates, or products can potentially di-
merize/oligomerize are theoretically challenging at pre-
sent, and these results should be taken as a model process
Chart 1. The affect of in situ salt formation on aoQM
thermodynamics with imidazole and cesium car-
bonate as base.
that
assumes
homogeneity,
precluding
nuclea-
tion/oligomerization and other experimental anomalies.
Regardless, the key discovery here is that the Cs2CO3 is
critical in effecting aoQM formation under mild condi-
tions.
Inherent stability of aoQM vs. oQM. The discrepan-
cy between the proliferation of oQM over aoQM mediat-
ed reactions was first investigated. We evaluated the ef-
fect of the heteroatom on the quinone equilibria. The
computed equilibria in dichloromethane, diethylether,
and tetrahydrofuran between the ortho substituted benzyl
chloride precursor and their corresponding methides are
shown in Table 1. The oQM is more stable than the aoQM
by ~10 kcal/mol, corresponding to ~107-fold ease of form-
ing the oQM at room temperature. This may explain the
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We wondered if other more moderate bases such as im-
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idazole behave similarly. Computations suggested that
the complexation of an imidazole to the in situ generated
HCl puts the NBoc-protected aoQM at ~25 kcal/mol
(∆Gavg = 25.9 kcal/mol, Chart 1, green arrows). The ther-
modynamic stabilization afforded by the formation of an
imidazole-HCl complex is ~8 kcal/mol, which would pre-
dict little aoQM formation at room temperature from
thermodynamics alone.23
9
Mechanistic analysis of aoQM formation. Three
pathways for aoQM formation can be envisioned (Figure
1), beginning with fast deprotonation of the labile amine
proton by cesium carbonate (TS-Deprotonation, ∆G‡ =
3.6 kcal/mol). All computed mechanisms originate from
the post-deprotonation cesium complex (∆G = 0.4
kcal/mol). Two modes of intramolecular SN2 attack24 fol-
lowed by electrocyclic ring opening were considered (ma-
genta and blue pathways). While the barrier of 6-exo-tet-
TS (∆G‡ = 24.6 kcal/mol) lies close to the estimated ex-
perimental barrier, the intermediate that follows presents
a significant thermodynamic sink (∆G = –18.1 kcal/mol).
The stability of this intermediate hinders Oxatine-
opening-TS from occurring, even if electrocyclic ring
opening gives a reasonable barrier from starting material
(∆G‡ = 21.4 kcal/mol). The computed barrier to Oxatine-
opening-TS of 39.5 kcal/mol (relative to the benzoxatine
intermediate) is consistent with computed and experi-
mental barriers of retro-Diels-Alder reactions of 1,2-
benzoxazines to form oQMs.25 A similar trend is observed
for 6-exo-tet-TS, although both the initial ring closure
(∆G‡ = 33.7 kcal/mol) and Azitidine-opening-TS (∆G‡ =
38.8 kcal/mol) are highly disfavored regardless of the
thermodynamics of the fused ring intermediate. Ultimate-
ly, simple elimination of the chloride leaving group is
computed as the favored pathway (Elimination-TS, ∆G‡
= 12.1 kcal/mol).
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Figure 1. Computed mechanisms of aoQM formation in THF
solvent. Stepwise deprotonation followed by chloride elimi-
nation is the favored mechanism (black) over intramolecular
SN2 and ring-opening (blue and magenta).
Elimination of the chloride leaving group results in loss
of aromaticity, typically seen as a formidable hurdle in
most room temperature reactions. Complexation of the
cesium cation with the departing leaving group and the
partially anionic nitrogen atom (Figure 2, Elimination-
TS) is hypothesized to offset this penalty to the point of
facile aoQM formation under ambient conditions. Con-
sidering that the equilibrium between the ortho substi-
tuted benzyl chloride precursor and cesium bicarbonate
slightly favors the starting material by 0.4 kcal/mol, it is
proposed that the main driving force is the formation of
the ionic Cs–Cl bond itself. This effect is apparent is the
highly exergonic formation of the fused azitidine (∆G = –
7.8 kcal/mol) and oxazine ring (∆G = –18.1 kcal/mol) in-
termediates (Figure 1, Bottom), where aromaticity is in-
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tact and ring formation is concomitant with CsCl salt by loss of HCl and cyclization to furnish the observed
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formation.
dihydroquinolone product (Corey-SN2-TS, Figure 3, Top
panel). The developing negative charge of the departing
chloride is stabilized by the vicinal N–H (2.41 Å). Even
with the anionic Cl leaving group stabilized through hy-
drogen bonding, the SN2 barrier is considerably high (37.3
kcal/mol). The most favorable pathway is formation of
the aoQM (∆G = 2.0 kcal/mol) followed by concerted
[4+2] (Corey-Diels-Alder-TS, ∆G‡ = 17.8 kcal/mol). In
the absence of cesium carbonate, no reaction is expected
to occur given the high energy of the SN2 (∆G‡ = 37.3
kcal/mol) and [4+2] (∆G‡ = 48.8 kcal/mol) pathways, both
which lie far below the estimated barrier of 24 kcal/mol.
aromaticity
broken
aromaticity
retained
π bonds
formed
σ bonds
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DeprotonationꢀTS
Csꢀcatalyzed
Cl release
EliminationꢀTS
∆G‡ = 12.1
∆G‡ = 3.6
Figure 2. Computed TSs26 of the stepwise deprotona-
tion/elimination mechanism for aoQM formation.
Analysis of the NHC-catalyzed asymmetric dihydro-
quinolone synthesis reveals similar energetic trends (Fig-
ure 3, Bottom panel). While the nucleophilic substitution
pathway is lower in energy than the Corey example (SN2-
TS, ∆G‡ = 29.2 kcal/mol), it still lies above the estimated
room temperature barrier, and significantly below the
Major-Michael-TS (∆G‡ = 13.5 kcal/mol) as mediated by
aoQM formation. Dihydroquinolone formation is step-
wise, beginning with Michael addition and followed by
cyclization (Cyclization-TS, ∆G‡ = –15.2 kcal/mol). Re-
lease of the NHC from the resultant tetrahedral interme-
diate leads to product and begins a new catalytic cycle.
Applications to dihydroquinolone synthesis. Co-
rey’s dihydroquinolone reaction was hypothesized to oc-
cur via a concerted or stepwise Diels-Alder to an aoQM
generated in situ. From our previous computations, we
can already predict that the cesium carbonate in solution
will render the aoQM accessible under room temperature
conditions. What is unknown is whether an alternative
mechanism competes with the subsequent cycloaddition
step. One such possible mechanism is direct nucleophilic
substitution, in which the vinyl ether may directly add to
the aoQM precursor via SN2-like transition state followed
Cl
Cs2CO3,
OEt
1999 Corey Racemic
Dihydroquinolone Synthesis
NHBoc
N
OEt
CH2Cl2, 23 °C
∆G‡expt = 24
Boc
Reaction Coordinates
Cl
H
N
Boc
H
H
H
N
OMe
Boc
H
OMe
CoreyꢀDielsꢀAlderꢀTS
48.8
NBoc
aoQM
CoreyꢀSN2ꢀTS
37.3
33.0
CsCl + CsHCO3
∆Gsalt = –31.0
17.8
A
2.0
aoQM Mediated [4+2]
0.0
sans aoQM
Cl
=
A
OMe
CoreyꢀSN2ꢀTS
NHBoc
CoreyꢀDielsꢀAlderꢀTS
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Me
O
1
2
3
4
Cl
1 (20 mol%)
N
BF4
Mes
1 =
N
N
2014 Asymmetric
Dihydroquinolone
Synthesis
CDI, Cs2CO3
imidazole, CPME, 23 °C
∆G‡expt = 22
OH
NHBoc
N
O
Bn
Boc
Me
82%, 92:8 er
5
6
7
8
Reaction Coordinates
H
N Boc
Cl
H
H
Me
O
NHC
H
N
Boc
H
Me
Me
MajorꢀMichaelꢀTS
9
NHC
O
NBoc
aoQM
NHC
MajorꢀMichaelꢀTS
42.5
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12
13
14
15
16
17
18
19
N
SN2ꢀTS
O
32.2
CsCl + CsHCO3
∆Gsalt = –29.0
Boc
29.2
CyclizationꢀTS
13.8
13.5
B
7.7
3.2
SN2ꢀTS
0.0
aoQM Mediated formal [4+2]
sans aoQM
–15.2
O
–21.3
Cl
=
B
Me
NHC
NHBoc
CyclizationꢀTS
Figure 3. Corey’s dihydroquinolone synthesis from vinyl ethers (Top); NHC-1-catalyzed dihydroquinolone synthesis from pro-
panoic acid (Bottom). Bidirectional reaction coordinate diagrams shown. To the right, two energetics for the aoQM-mediated
reaction: parent reaction without formation of any salt by-products (black) and with Cs2CO3 salt by-products (CsCl + CsHCO3,
blue). To the left, energetics for the non-aoQM mediated SN2 process.
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Enantioselectivity as theoretical evidence for
aoQMs. Unlike the achiral Corey example, stereoselectiv-
ity is critical in the NHC-catalyzed reaction. Our goal is to
develop a stereocontrol model that assumes an aoQM
mediated stereodetermining C–C bond formations step.
Agreement of the computed enantioselectivity with ex-
periment provides additional evidence for aoQM inter-
mediacy.
Experimental selectivity
∆∆G‡ = 1.4
In both the major and minor stereodeterming Michael
TSs (Figure 4), the developing negative charge on the ni-
trogen of the aoQM in the transition state is mitigated by
the proximity to the positively charged heterocycle of the
NHC catalyst. Conjugative stabilization of the developing
negative charge on the nitrogen by the BOC group is not
realized in these transition states – the π/π* system of the
BOC group is orthogonal to the conjugated π system of
the aoQM (∠C=N/C=O = ~95°) responsible for charge
delocalization resulting from nucleophilic attack of the
aoQM in the transition state. Moreover, the nitrogen is
bent significantly (~120°), indicating that charge delocali-
zation of the in-plane lone pair is also not present.
MajorꢀMichaelꢀTSꢀ(S)
MinorꢀMichaelꢀTSꢀ(R)
∆∆G‡ = 0.0
∆∆G‡ = 1.7
Figure 4. Enantiodetermining transition structures of NHC 1
catalyzed dihydroquinolone synthesis from propanoic acid
(Figure 1, Top panel). Green lines represent stabilizing
+NCH⋯N– interactions.
Experimental evidence for aoQM formation. With
all computations thus far suggesting aoQM intermediacy,
a model experiment was devised to test these findings.
We performed the NHC 2-catalyzed addition of benzal-
dehyde to ortho-amino benzyl chloride (Figure 5). This
model reaction was chosen so that the reaction could be
performed in a sufficiently large scale to provide details of
the rate-determining step by measuring the 13C isotope
effects (IEs) at natural abundance by observing fractiona-
tion in the recovered starting materials.29 The computed
energetics were consistent with the previous reactions
(Figure 5). There was a large preference for the rac-
Stetter-TS (Right, blue pathway) over the rac-SN2-TS
(Left, black pathway) by ~20 kcal/mol.
Enantiocontrol arises from differential stabilization of
the developing negative charge at the nitrogen of the
aoQM in the Michael step. Both transition structures ex-
perience proximity of the aoQM nitrogen to the cationic
nitrogen atoms of the NHC catalyst. The major transition
structure (Major-Michael-TS-(S)) experiences greater
stabilization of the anionic aoQM nitrogen via a +NCH⋯N–
interaction27 (Figure 4, green lines). In the minor transi-
tion structure (Minor-Michael-TS-(R)), the chiral benzyl
group replaces this interaction with a significantly weaker
+NCCH2⋯N– interaction.28 The computed enantioselectivi-
ty of 1.7 kcal/mol agrees well with the experimental value
of 1.4 kcal/mol.
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1
2
3
4
5
O
Me
Me
Ph
Cl
2 (20 mol%)
Et
Model Stetter Reaction
2 =
O
Ph
H
Cs2CO3, THF, 23 °C
NHBoc
S
N
NHBoc
∆G‡expt = 24
ClO4
Et
6
Reaction Coordinates
7
8
9
Cl
H
N
Boc
H
H
Ph
NHC
H
N
H
OH
Boc
OH
Ph
racꢀStetterꢀTS
NHC
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NBoc
aoQM
41.7
racꢀSN2ꢀTS
33.1
CsCl + CsHCO3
∆Gsalt = –31.1
30.4
10.6
C
2.0
0.0
sans aoQM
aoQM Mediated Stetter
racꢀSN2ꢀTS
OH
Cl
C
=
Ph
racꢀStetterꢀTS
NHC
NHBoc
Figure 5. NHC 2-catalyzed Stetter-type reaction of benzaldehyde. Bidirectional reaction coordinate diagrams shown. To the
right, two energetics for the aoQM-mediated reaction: parent reaction without formation of any salt byproducts (black) and
with Cs2CO3 salt byproducts (CsCl + CsHCO3, blue). To the left, energetics for the non-aoQM mediated SN2 process.
,
In comparing the experimental and computed30 31 iso-
tope effects, rac-SN2-TS and rac-Stetter-TS both showed
significant KIE deviations only at C1, but the latter was in
better agreement with experiments (7.3% vs. 2.7% error at
C1, Figure 6). Computed equilibrium isotope effects for
the formation of the aoQM intermediate were more con-
sistent with experimental values, and suggested this step
may be rate determining. While equilibrium isotope ef-
fects are not rigorous substitutes for comparison with
experimental KIE measurements, they offer a valid ap-
proximation, considering that the transition state imme-
diately prior to aoQM formation is product-like in geome-
try.
Furthermore, the N-methylated precursor, which can-
not form the aoQM, did not provide any α-aryl ketone
product after 48 hours, instead yielding exclusively the
benzoin adduct (Scheme 2). This suggested that the pre-
clusion of the aoQM dramatically slowed down the Stet-
ter process. We anticipated that methylation of the sub-
strate might also affect the barrier of the nucleophilic
addition step. The computed barrier of 30.3 kcal/mol
(Figure 7, Me-rac-SN2-TS) is essentially identical to rac-
SN2-TS (∆G‡ = 30.4 kcal/mol), indicating that methylation
likely shuts down aoQM formation deprotonation step
without targeting the SN2 pathway.
Experiments
Percent error
Cl
C2: 1.006±0.013
C1: 0.991±0.019
Reference
1
2
4
O
Me
<2
Me
Me
2<X<3
>7
C9: 0.984±0.011
9
7
8
N
O
C6: 1.001±0.019
6
H
C7: 1.006±0.015 C8: 1.005±0.028
Kinetic isotope effects
C2: 1.007
C1: 1.067 (–7.3%)
racꢀStetterꢀTS
C1: 1.019 (–2.7%)
racꢀSN2ꢀTS
C2: 1.000
Cl
Cl
2
1
4
2
1
4
O
Me
O
Me
Cl
Me
Me
Me
N
H
O
Me
7
8
9
N
H
O
Me
C6: 1.006
7
8
9
H
N
C6: 1.000
6
H
C9: 0.999
6
C9: 1.001
Boc
OH
Ph
C7: 1.002 C8: 1.009
Equilibrium isotope effect
C7: 0.997 C8: 0.998
NHC
Cl
C2: 0.997
C1: 1.004
Me-racꢀSN2ꢀTS
∆G‡ = 30.3
2
1
4
O
Me
Me
+ CsHCO3
+ CsCl
Cs2CO3
N
O
Me
C9: 1.000
7
8
9
NBoc
C6: 0.997
H
6
aoQM
C7: 1.002 C8: 0.997
Figure 7. Computed methylated Stetter SN2 TS showing a
similar barrier to the non-methylated parent rac-SN2-TS.
Figure 6. Natural abundance isotope effects (IE) results.
Experiments (Top, average of triplicate runs ±standard devia-
tions), computed kinetic IE for SN2 and Stetter (Middle) and
equilibrium IE (Bottom).
Analysis of the formation of imidazole-HCl indicated
that while exergonic, the ~8 kcal/mol stabilization pro-
vided was not enough to drive aoQM formation (Chart 1).
As an experimental test, the model Stetter reaction (Fig-
ure 5) was run with imidazole as base in place of Cs2CO3.
As predicted by theory, there was no reaction with imid-
Scheme 2. Effect of Substrate N-Methylation on the
NHC-Catalyzed Stetter Reaction.
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General Procedure for NHC-catalyzed addition of ben-
zaldehyde to aza-oQMs: tert-Butyl (2-
(chloromethyl)phenyl)carbamate (1.209 g, mmol), 3-(2,6-
azole base (Scheme 3). These computations and experi-
1
2
3
ments, in combination with the isotope effect data, pro-
vided evidence supporting aoQM intermediacy for low
temperature aoQM mediated processes (Figures 3 and 4).
5
diethylphenyl)-4,5-dimethylthiazol-3-ium perchlorate 2 (0.346 g,
1.00 mmol), 2-methoxynaphthalene (NMR internal standard,
0.395 g, 2.500 mmol), and freshly dried and powdered cesium
carbonate (1.955 g, 6.00 mmol) were combined in an oven-dried
250 mL round bottom flask fitted with a magnetic stirbar under
argon. The reaction flask was evacuated under reduced pressure
for 15 minutes, then back-filled with argon 3 times. THF (50 mL)
was added and the mixture was stirred for 30s, until all soluble
materials went into solution. A 100 μL aliquot was taken for
NMR analysis (T0). Benzaldehyde (0.612 ml, 6.00 mmol) was
added to the flask via syringe, and the reaction vessel was sealed
and stirred vigourously under static argon. 100 μL aliquots were
taken periodically to monitor consumption of the starting mate-
rial. When an NMR aliquot indicated high (~90%) conversion
(12–16h), the entire reaction mixture was filtered through a 1 cm
pad of Celite and a final aliquot of the filtrate was taken to de-
termine the percent conversion of benzyl chloride at the end
timepoint (Tf). The filtered reaction mixture was concentrated
under reduced pressure, and the residue was applied to a 2-inch
pad of silica gel. Elution with 4:1 hexanes:ethyl acetate (until all
remaining starting material had been collected, ~200 mL, TLC
monitoring) followed by concentration of the eluent provided
the crude recovered starting material. The recovered benzyl
chloride was further purified by elution on a 50 g SNAP biotage
column, (gradient 2–15% hexanes:ethyl acetate, 14 column vol-
umes). The pure fractions of recovered benzyl chloride were
collected, concentrated, dried under reduced pressure and then
analyzed by quantitative 13C NMR spectroscopy (see supporting
information for details).
4
5
6
7
8
9
Scheme 3. Effect of Imidazole Base on the NHC-
Catalyzed Stetter Reaction.
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11
12
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CONCLUSIONS
To summarize, we have combined theory and experi-
ments towards the understanding of the synthetic acces-
sibility of aza-ortho-quinone methides, an underutilized
reactive synthetic intermediate with significant potential.
Specifically, we have discovered what enables the for-
mation of aoQM as viable reaction intermediates in syn-
thesis under room temperature conditions. The loss of
aromaticity over the course of the methide formation is
balanced by the exergonic formation of metal chloride
and metal bicarbonate salts (>30 kcal/mol), an independ-
ent effect from salt solubility and strength of the base.
This energetic trade off is distinctly different from the
parent oQMs, where the relative strength of the C=O π
bond is enough to render this species accessible even in
the absence of this thermodynamic and kinetic Cs2CO3
effect. The impact of salt formation in organocatalysis,
especially in rendering high energy reactive intermediates
thermodynamically accessible, is currently not well un-
derstood. We illustrate a thorough and enabling under-
standing that allows the community to leverage the utility
and unique reactivity of aoQMs in asymmetric catalysis
and chemical synthesis. These discoveries will enable a
broader discovery and development platform integrating
mild aoQM generation and its use in catalytic reactions,
as oQM has for decades.
ASSOCIATED CONTENT
Supporting Information
Cartesian coordinates, energies, experimental and
computational KIE data, additional figures, and charac-
terization of new compounds. The Supporting Infor-
mation is available free of charge on the ACS Publica-
tions website.
AUTHOR INFORMATION
Corresponding Author
EXPERIMENTAL
KIE Experimental Parameters: Data was collected from a
total of three Stetter reactions taken to 90.0%, 88.8% and 89.7%
completion respectively.32 The unreacted benzyl chloride from
the model Stetter reaction with catalyst 2 and benzaldehyde was
recovered and analyzed by quantitative 13C NMR spectroscopy
(see supporting information). All samples were prepared identi-
cally as described: 60 mg of recovered starting material was dis-
solved in 0.5 mL of CDCl3 and then filtered through a 3 mm plug
of celite directly into a 5 mm high-precision NMR tube. Each
NMR tube was filled to a constant sample height of 5 cm. Spectra
were acquired on a Bruker Avance III 500 MHz spectrometer
using proton-decoupled pulses with 80 s delays between pulses.
65536 data points were collected, which were then zero-filled to
256k before Fourier transformation. A zeroth order baseline
correction was applied to all spectra, and integrations were
measured using a ±0.5 ppm region centered on each peak. The
starting benzyl chloride used in all reactions and reference
measurements came from the same synthetic batch. T1 values
were measured for each sample using the inversion-recovery
method to ensure the absence of any paramagnetic impurities.
paulc@science.oregonstate.edu;
scheidt@northwestern.edu
ACKNOWLEDGMENT
PHYC is the Bert and Emelyn Christensen professor of OSU,
and gratefully acknowledges financial support from the
Stone family and the National Science Foundation (NSF,
CHE-1352663). We thank Dr. Yuyang Wu (NU) for assistance
with KIE experiments. KAS gratefully acknowledges support
from the National Institutes of Health (NIGMS R01
GM073072). DMW, RCJ, and PHYC also acknowledge com-
puting infrastructure in part provided by the NSF Phase-2
CCI, Center for Sustainable Materials Chemistry (NSF CHE-
1102637). DMW also acknowledges support from the Johnson
Research Fellowship.
REFERENCES
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2
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Structure images generated using the CylView molecular
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