Oxyanion steering and CH-π interactions as key elements in an N-heterocyclic carbene-catalyzed [4 + 2] cycloaddition

Article abstract of DOI:10.1021/ja302761d

The N-heterocyclic carbene catalyzed [4 + 2] cycloaddition has been shown to give γ,δ-unsaturated δ-lactones in excellent enantio- and diastereoselectivity. However, preliminary computational studies of the geometry of the intermediate enolate rendered am

Full text of DOI:10.1021/ja302761d

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Article
Oxyanion-steering and CH-# Interactions as Key Elements
in a N-Heterocyclic Carbene-Catalyzed [4+2] Cycloaddition
Scott E. Allen, Jessada Mahatthananchai, Jeffrey W. Bode, and Marisa C Kozlowski
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja302761d • Publication Date (Web): 04 Jul 2012
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Oxyanion-steering and CH-π Interactions as Key Elements in
an N-Heterocyclic Carbene-Catalyzed [4+2] Cycloaddition
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Scott E. Allen,§ Jessada Mahatthananchai,‡ Jeffrey W. Bode,‡,* and Marisa C. Kozlowski§,*
§Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania
‡
19104, United States. Laboratorium für Organische Chemie, ETH-Zürich, Zürich 8093, Switzerland.
Supporting Information Placeholder
enolate intermediate (Scheme 1).3,7 Alternatively, the
ABSTRACT: The N-heterocyclic carbene catalyzed [4+2]
cycloaddition has been shown to give γ,δ-unsaturated δ-
enolate intermediate can also be reached from NHC attack
on an α-chloroaldehyde7 to obtain adduct V, followed by
lactones in excellent enantio- and diastereoselectivity.
elimination of HCl. Unexpectedly, initial calculations
However, preliminary computational studies of the
showed that the enolate of III lies perpendicular to the
geometry of the intermediate enolate rendered ambiguous
triazolium and is not stabilized by conjugation with the
both the origins of selectivity and the reaction pathway. In
NHC.3b Since the enolate is blocked by the indane on one
this communication, we show that a concerted, but highly
side and mesitylene on the other, the origin of the high
asynchronous, Diels-Alder reaction occurs rather than the
stereochemical fidelity was ambiguous.
stepwise Michael-type or Claisen-type pathways. In
addition, two crucial interactions are identified that enable
high selectivity: an oxyanion-steering mechanism and a
CH-π interaction. The calculations accurately predict the
enantioselectivity of a number of N-heterocyclic carbene
catalysts in the hetero-Diels-Alder reaction.
Scheme 1. Proposed catalytic cycle for the NHC-catalyzed
hetero-Diels-Alder reaction (only the NHC core shown).
O
O
N
R1
R2
O
H
R1
N
N
R3
I
O
Introduction
H
R1
Cl
R3
N-Heterocyclic carbenes (NHCs) are effective in a large
organocatalytic1
and
organometallic2
OH
O
number
of
H
O
O
N
N
applications. Starting in 2006, Bode and coworkers
reported an NHC-catalyzed [4+2] cycloaddition between
an enolate derived from an α,β-unsaturated aldehydes or α-
functionalized aldehydes and an enone as the diene.3,4
These reactions displayed remarkable diastereo- and
enantioselectivity, producing γ,δ-unsaturated δ-lactones
in up to 99% ee and greater than 20:1 dr, as well as near
quantitative yields (eq 1).5 In this communication, we
establish by computation that a concerted, but highly
asynchronous Diels-Alder reaction occurs rather than the
stepwise Michael-type or Claisen-type pathways. Two
crucial interactions were discovered that enable the high
selectivity: an oxyanion-steering mechanism and a CH-π
interaction. The calculations described herein accurately
predicted the selectivity of a number of NHC catalysts in
the hetero-Diels-Alder reaction.
R1
R1
N
N
N
R2
N
N
Cl
N
N
R1
V
II
IV
NEt3
NEt3•HCl
O
H
proton
transfer
N
N
O
R1
R2
R3
N
III
Methods
All calculations were performed using Gaussian 09.8 All
transition states were optimized with HF/6-31G(d) in the
gas phase and were confirmed to have one imaginary
frequency; all local minima were optimized with HF/6-
31G(d) and were found to have no imaginary frequencies.
Intrinsic reaction coordinate calculations were performed
regularly to confirm that the calculated transition states
reflected the correct reaction. Gibbs Free Energies were
calculated at 1 atm and 298.15 K and are uncorrected.9
O
N
N
N
Mes
O
Cl–
O
O
10 mol%
R1
R2
>20:1 dr
49–99% yield
94–99% ee
O
+
(1)
R2
1.0 equiv
R3
R1
H
20 mol% DMAP
or i-Pr2NEt
CH2Cl2, 40 °C
24 h
R3
1.5–2.0 equiv
Solvation with toluene was examined for the mesitylene,
para-trifluoromethyl, and pentafluoromethyl catalysts in
The transformation in equation 1 is intriguing because
the homoenolate equivalent (conjugated Breslow
intermediate, II) undergoes proton transfer6 to form an
the
IEFPCM(toluene)-HF/6-31G(d)//HF/6-31G(d).
A solution of 2-chloro-3-phenylpropanal (26.0 mg, 0.4
deprotonated
Diels-Alder
reaction
using
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‡
mmol, 1.0 equiv), triethylamine (20.0 µL, 0.6 mmol, 1.5
Diels-Alder
R2
1
2
3
4
5
equiv), and (E)-methyl 4-oxo-4-phenylbut-2-enoate (20.0
mg, 0.4 mmol, 1.0 equiv) was prepared using 0.5 mL PhCH3.
This solution was transferred to a vial containing a chiral
triazolium salt (Table 1). The reactions were carried out at
room temperature and the products were isolated by
preparative TLC using 7:1 hexanes: EtOAc. The identity of
6
4
3
O
O
N
R3
1
N
2
N
R1
Michael-type
5
6
‡
‡
R2
R2
R2
1
the product was confirmed by H NMR, 13C NMR, GC/MS
O
O
O
O
7
8
O
and LC/MS.10 Percent conversion was determined by the
integration of the product at 5.82–5.79 ppm against the
enone starting material at 6.91–6.86 ppm. Percent
enantiomeric excess was determined by SFC (AD-H,
gradient 5-50% CO2: iPrOH), tr = 8.31 min and 9.61 min.
The absolute configuration was assigned based on the previous
literature report.
O
N
N
N
R3
R3
R3
N
N
N
N
9
N
N
R1
R2
R1
R2
R1
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Claisen-type
‡
‡
R2
O
O
O
O
O
O
N
N
N
N
R3
R3
R3
N
N
N
N
N
Results & Discussion
R1
R1
R1
To understand the stereochemical factors in this system,
we examined a model system with acetaldehyde enolate as
the dienophile and acrolein as the diene (R1 = R2 = R3 = H,
eq 1 and Scheme 1) using HF/6-31G(d) in the gas phase.
The entire NHC catalyst from equation 1 was employed to
Figure 1. Possible reaction pathways.
,
accurately determine its role.11 12
View from the front
Line Style
Protonated Claisen
Analysis of the enantioselectivity determining step
revealed three distinct plausible reaction pathways (Figure
1): 1) a concerted Diels-Alder reaction, 2) a Michael type
addition of the NHC-enolate to the enone followed by
addition/elimination of the enolate intermediate to cyclize
the ring and expel the NHC catalyst, or 3) an initial
addition of the NHC-enolate to the enone carbonyl
followed by Claisen rearrangement and collapse of the
intermediate following the same pathway as the Michael-
type reaction. Examination of options 1 and 2 rapidly
revealed that the charge separation induced in the initial
Michael-type reaction gave rise to much higher energy
transition states relative to the Diels-Alder reaction.
H
O
N
N
O
H
N
O
Mes
Protonated Diels-Alder
For the Diels-Alder pathway, three constraints were
identified: 1) the acrolein adopts a cisoid geometry to
avoid undesirable charge separation in the transition state,
2) the acrolein does not approach endo to the triazolium,
which creates prohibitive steric interactions between the
diene and the mesitylene ring and gives rise to the incorrect
diastereomer, and 3) the enolate substituent (R1, Figure 1)
is cis to the enolate oxygen to avoid steric interactions
with the catalyst and to give rise to the correct
diastereomer. Upon examination of conformations and
optimization, transition states were located for the Diels-
Alder pathway in which the enolates adopt a planar
H
O
O
N
N
N
Mes
O
H
Deprotonated Diels-Alder
H
O
O
conformation with respect to the triazolium ring,
a
significant departure compared to the ground state
enolates,3b which are perpendicular to the plane of the
triazolium. This planarization of the enolate increases the
positive charge on the enolate C1-carbon (Figure 1, top,
and Figure 2, bottom) thereby optimizing the developing
interaction with the negative charge on the diene oxygen.
N
N
N
C2
C1
Mes
O
Figure 2. Sample Diels-Alder and Claisen transition states
(one Claisen protonated, one DA protonated, and one
zwitterionic DA) leading to the dihydropyranone products.
The transition state geometries indicate
a
very
asynchronous Diels-Alder reaction. In the lowest energy
model system transition state, the forming carbon-carbon
bond is 2.109 Å while the forming carbon-oxygen bond is
3.049 Å. The atom-atom net linear natural localized
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population analysis
molecular
orbital
natural
except that the integral equation formalism variant of the
polarization continuum model (IEFPCM) solvation method
was employed instead of the COSMO model.18 Each of the
four enolate conformations was calculated and the overall
pKa was generated from a weighted average of the four
resultant values using a Boltzmann distribution at 25 °C.
The resulting theoretical pKa of the enolate in water is 5.5,9
much less than that of the bases in water. Since the
reactions under discussion here are conducted in toluene or
dichloromethane, this estimate needs to be used with
caution. However, analysis of the conjugate acids of other
zwitterions, such as pyridine N-oxide, is informative. Here,
the acid is a resonance-stabilized cation and the conjugate base
is a zwitterion in which the negative charge is not stabilized by
resonance. The pKa of pyridine N-oxide is 0.79 in water and
1.63 in DMSO. On this basis we expect the pKa of the
triazolium enolate to be ~6.5 in DMSO (vs 9.00 for Et3NH+ in
DMSO). Therefore, the main species in solution is most
likely the enolate for which the Claisen-type pathway does
not occur.
(NLMO/NPA)13 bond orders14 are 0.435 and 0.0550
respectively. Similar values were seen for all the Diels-
Alder transition states.9
1
2
3
4
5
6
7
8
9
Intrinsic reaction coordinate (IRC) calculations show
that the enolate commences nearly perpendicular to the
triazolium ring and flattens as the enone approaches.
Notably, the starting geometry with the enolate oxygen up
always leads to enone approach from the top face; the
starting geometry with the enolate oxygen down always
leads to enone approach from the bottom face (seen in IRCs
of all the 7 transition states located, see Figure 4). This
trend suggests a secondary orbital interaction between the
enone carbonyl π* and an enolate lone pair (Figure 3),
which guides the enone in its approach and ultimately
leads to the Diels-Alder reaction.
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In the Diels-Alder pathway there are the eight possible
transition states differing by the ring conformation of the
morpholine, the orientation of the enolate, and the facial
approach of the enone. Upon examination of all the
combinations, only seven of the eight transition states
could be located (Figure 4); TS5, in which the morpholine
oxygen orients cis to the indane, the enolate oxygen points
toward the indane, and the acrolein approaches from the
bottom, converged instead to TS6.
Figure 3. The oxyanion guiding interaction as seen in the
intrinsic reaction coordinate calculation (NHC indane and
mesitylene rings removed for clarity).
The presence of this interaction also suggests an
alternative reaction pathway (Claisen-type, Figure 1) in
which the enolate oxygen first adds to the enone carbonyl.
Subsequent Claisen rearrangement of this intermediate
would lead to the product.15 When a protonated enolate
was used in the calculation, this Claisen transition state
was 7.0 kcal/mol lower in energy than the Diels-Alder
reaction, but when the deprotonated enolate was used the
model converged to the asynchronous Diels-Alder
transition state. This suggests two possibilities: 1) if the
reaction proceeds through the enolate, it possesses both
Diels-Alder and Claisen character, and 2) if the complex
reacts as the enol, it undergoes the Claisen
rearrangement.15a The reaction is performed with catalytic
For the morpholine ring, interconversion between two
different half-chair conformations causes a large distortion
of the catalyst. When the morpholine oxygen orients down
(cis to the indane), the indane ring extends in front of the
triazolium alleviating steric interactions with the mesityl
and resulting in the lowest energy conformation in the
absence of enone. In this conformation, the indane more
effectively blocks the approach of the substrate from the
bottom face as seen in the energy difference of 6.65 kcal/mol
between TS3 and TS7, which vary only in the enone facial
approach. In addition, this steric hindrance blocks enone
approach in the counterpart of TS1 (i.e. TS5) so effectively
that it could not be located. In all cases where the enone
approaches from the top, the lower energy conformation has
the indane extended forward (TS1 vs TS2 and TS3 vs TS4).
DMAP or i-Pr2NEt (water pKa
respectively), so the enol will dominate if its pKa is above
12.
= 9.2 and 10.8,
To calculate the pKa values16 of the relevant enolates, the
method that Pulay17 used with phenols was implemented
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enolate oxgyen toward indane
enolate oxgyen toward mesityl
1
2
3
4
5
morpholine
oxygen
cis to indane
6
7
8
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top facial
approach
of enone
(opposite
indane)
TS1Mes
0.00
TS3Mes
4.83
morpholine
oxygen
trans to indane
TS2Mes
1.11
TS4Mes
5.26
morpholine
oxygen
cis to indane
bottom
facial
approach
of enone
(same face
as indane)
TS5Mes
TS7Mes
11.48
morpholine
oxygen
trans to indane
TS6Mes
4.50
TS8Mes
8.79
Figure 4. The eight possible transition states and relative free energies for the NHC-catalyzed Diels-Alder reaction (relative ΔG
values in kcal/mol). Labels in red indicate transition states that lead to the major enantiomer; blue labels lead to the minor
enantiomer.
When the morpholine oxygen points up (trans to the
indane), the indane ring tucks under the triazolium (e.g.
TS2) incurring greater steric interactions with the mesityl
as compared to the other half-chair conformation (cf. TS1).
On the other hand, this conformation does open up
approach from the bottom face of the enolate such that TS6
is lower than TS5 and TS8 is lower than TS7. Even so,
considerable steric blocking remains on the bottom face and
all the transitions states are higher in energy (TS5-TS8).
when it is pointing toward the indane due to a CH–π
interaction between the terminal CH2 of the enolate and the
,
,
aromatic ring (5).19 20 21 Specifically, the inner hydrogen on
the enolate carbon is just 2.9 Å from C1 of the mesitylene,
well within the combined van der Waals distance of 3.4 Å.
Similar CH–π interactions have been observed in the
transition states of Diels Alder reactions,22 sulfide
oxidations,23 and hydride reductions.24 This effect can be
increased with electron donating groups and diminished
with withdrawing groups (see below).
On the whole, the transition states with C2 of the enolate
pointing toward the mesitylene are lower in energy than
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concurrently with the reaction in equation 2. In principle,
1
2
3
4
5
6
7
the stereoselectivity predictions provided are for both the
α-haloaldehydes or the enals since the both yield the same
enolate that precedes the stereoselectivity determining step
calculated here (Scheme 1). In practice, the enals are
unreactive with catalysts lacking ortho substitution on the
N-aryl ring due to reversibility in the formation of the
initial adduct between the aldehyde and the NHC.7
Overall, the calculations were highly effective in
anticipating the experimental selectivity, with the
exception of entry 5. Further calculations revealed that
M06-2X/6-311+G(d,p)27 single point calculations of the
full system were necessary to reproduce the experimental
results in this case, which is attributed to the combination
of five halogen substituents. Note that Table 1 contains all
the catalysts that were examined computationally; none
were excluded. Solvation with toluene was examined for
8
9
10
11
12
13
14
15
16
17
18
the
mesitylene,
para-trifluoromethyl,
and
pentafluoromethyl systems using IEFPCM(toluene)-HF/6-
31G(d)//HF/6-31G(d) of all the tranisition states; the
computed selectivities did not change significantly,
indicating that the gas phase calculations are sufficient for
this reaction in this nonpolar solvent.28
Figure 5. The CH-π interaction from the front (top) and from
overhead (bottom) for TS1. Enone and indane ring removed for
clarity.
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22
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53
54
55
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57
58
59
60
A significant drop in selectivity was expected with
electron-poor catalysts, which was confirmed in the
experiments (entries 6–8). Analysis of the computational
data shows that when Ar = mesitylene, the relative energy
between TS1 and TS3, which differ only in orientation of
the enolate, is 4.83 kcal/mol. When Ar = C6F5, that energy
difference drops to 1.35 kcal/mol. The electron-poor arene
cannot support the CH–π interaction, destabilizing TS1,
TS2, TS5, and TS6 relative to TS3, TS4, TS6, and TS7, and
eroding the theoretical selectivity.
Table 1. Prediction of reaction selectivities using the
computational model.
O
Cl–
N
N
N
Ar
O
O
O
10 mol% NHC
MeO
Ph
O
(2)
Ph
+
Ph
H
Ph
1.5 equiv NEt3
toluene
rt, 14 h
Cl
1.5 equiv
O
MeO2C
1.0 equiv
A Hammett analysis of the experimental results for aryls
without ortho-substitution shows a strong correlation
between enantiomeric ratio and the electron density of the
aryl ring (ρ = –0.63, R2 = 0.96).9 Electron-withdrawing
groups attenuate the CH-π interaction, decreasing the
enantiomeric ratio. On the other hand, ortho-substitution
rescues even highly electron deficient catalysts (entries 4-
5). Apparently, decreased rotational freedom of the N-aryl
bond is a key factor in these transformations and a further
analysis of this contribution is underway.
Entr
y
Calculate Conversio Experimen
Aryl
d ee (%)a
n (%)
tal ee (%)b
99
1
2,4,6-(CH3)-
C6H2
99.8
100
(100)
2
2-Me-4-OMe-
C6H3
96.4
100
99
3
4
5
2-Me-C6H4
97.7
97.3
100
95
98
99
97
2,4,6-Cl-C6H2
2,4,6-Cl-C6F2
86.2
93
(99.6)
Conclusions
6
C6F5
81.5
47
76
In summary, a computational model has been developed
that successfully estimates the enantioselectivity of various
catalysts in the NHC-catalyzed hetero-Diels-Alder
reaction. Two effects account for the selectivity in these
reactions: an oxyanion guiding interaction which delivers
the substrate and a CH-π interaction. This study provides a
basis for using these two elements in future development of
catalyst systems.
(83.2)
7
8
3,5-(CF3)-C6H3
4-CF3-C6H4
C6H5
84.1
87.5
93.0
95.0
34
15
50
75
89
95
97
98
9
10
4-OMe-C6H4
aCalculated ee values for R1 = R2 = R3 = H, eq 1 using HF/6-
31G(d). Parenthetical amounts are for the full system (eq 2) at
M06-2X/6-311+G(d,p)//HF/6-31G(d).25
values for the reaction in eq 2.
bExperimental
ee
ASSOCIATED CONTEN T
Supporting
Information.
Full
computational
and
To test the importance of the CH–π interaction, the eight
transition states of the model system were optimized for a
series of catalysts with varied aryl substitution and
enantioselectivities were calculated using Boltzmann
experimental details and full citation of reference 9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
,9
distributions (Table 1).26 The calculations were performed
AUTHOR INFORMATION
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(13) a) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988,
Corresponding Authors
1
2
3
4
5
6
7
8
88, 899-926. b) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J.
Chem. Phys. 1985, 83, 735-746. c) Reed, A. E.; Weinhold, F. J.
Chem. Phys. 1985, 83, 1736-1740
(14) Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F.
NBO Version 3.1.
(15) (a) Kaeobamrung, J.; Mahatthananchai, J.; Zheng, P.; Bode, J.
W. J. Am. Chem. Soc. 2010, 132, 8810–8812. (b) Wanner, B.;
Mahatthananchai, J.; Bode, J. W. Org. Lett. 2011, 13, 5378–5381.
(16) For a review: Alongi, K. S.; Shields, G. C. In Annual Reports
in Computational Chemistry; Wheeler, R. A., Ed.; Elsevier; Vol. 6, p
113–138.
marisa@sas.upenn.edu, bode@org.chem.ethz.ch
ACKNOWLEDGMENT
We are grateful to the National Institutes of Health (GM–
079339 and GM-087605) and the National Science
Foundation (CHE-0449587) for financial support of this
research. Computing resources were provided by the National
Science Foundation (CRIF CHE-0131132) and XSEDE (TG-
CHE110080). We thank Bill Dailey for helpful discussions.
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(6) The mechanism of this proton transfer is explored in: (a) (b)
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(9) See Supporting Information for computational details.
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(21) After this manuscript was submitted, a report (ref 6b) appeared
on calculations of NHC enolates reaching some similar conclusions.
(22) (a) Gordillo, R.; Houk, K. N. J. Am. Chem. Soc. 2006, 128,
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(26) For a review on the electronics of NHC catalysts, see: Dröge,
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(27) This functional reduces inflated relative energies seen in HF:
Simón, L.; Goodman, J. M. Org. Biomol. Chem. 2011, 9, 689–700.
(28) Enantioselectivies calculated using toluene solvation
(IEFPCM(toluene)-HF/6-31G(d)//HF/6-31G(d)): 2,4,6-(CH3)-C6H2,
99.8% ee; 4-CF3-C6H4, 90.7% ee; C6F5, 86.9% ee.
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