Mechanism of gold(I)-catalyzed rearrangements of acetylenic amine-N-oxides: Computational investigations lead to a new mechanism confirmed by experiment

Article abstract of DOI:10.1021/ja208860x

Figure Persented: Quantum mechanical studies of the mechanism of gold-catalyzed rearrangements of acetylenic amine-N-oxides to piperidinones or azepanones have revealed a new mechanism involving a concerted heteroretroene reaction, formally a 1,5 hydrogen shift from the N-alkyl groups to the vinyl position of a gold-coordinated methyleneisoxazolidinium or methyleneoxazinanium. Density functional calculations (B3LYP, B3LYP-D3) on the heteroretroene mechanism reproduce experimental regioselectivities and provide an explanation as to why the hydrogen is transferred from the smaller amine substituent. In support of the proposed mechanism, new experimental investigations show that the hydrogen shift is concerted and that gold carbenes are not involved as reaction intermediates.

Full text of DOI:10.1021/ja208860x

Article
pubs.acs.org/JACS
Mechanism of Gold(I)-Catalyzed Rearrangements of Acetylenic
Amine-N-Oxides: Computational Investigations Lead to a New
Mechanism Confirmed by Experiment
Elizabeth L. Noey,† Yingdong Luo,‡ Liming Zhang,*,‡ and K. N. Houk*,†
†Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
‡Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106-9510, United States
S
* Supporting Information
ABSTRACT: Quantum mechanical studies of the mechanism of gold-catalyzed rearrangements of acetylenic amine-N-oxides to
piperidinones or azepanones have revealed a new mechanism involving a concerted heteroretroene reaction, formally a 1,5
hydrogen shift from the N-alkyl groups to the vinyl position of a gold-coordinated methyleneisoxazolidinium or methyl-
eneoxazinanium. Density functional calculations (B3LYP, B3LYP-D3) on the heteroretroene mechanism reproduce experimental
regioselectivities and provide an explanation as to why the hydrogen is transferred from the smaller amine substituent. In support
of the proposed mechanism, new experimental investigations show that the hydrogen shift is concerted and that gold carbenes
are not involved as reaction intermediates.
arylsulfoxides9 argue against such intermediacy. Here we pre-
INTRODUCTION
■
sent computational and experimental studies to suggest that
gold carbene intermediates are not involved in two intramo-
lecular cases; moreover, we disclose the first example of a gold-
catalyzed reaction involving a heteroretroene reaction.
Cationic gold catalysts activate π bonds for reactions with a
range of nucleophiles, leading to sigmatropic rearrangements, migra-
tions, and cycloisomerizations.1 A particularly important class
of nucleophiles is an oxidant that possesses a nucleophilic
oxygen and can formally deliver the oxygen atom during the
reaction, and this type of gold-catalyzed alkyne oxidation has been
proposed to generate a reactive α-oxo gold carbene inter-
mediate, which would undergo an array of versatile transformations
One of our groups reported the gold-catalyzed annulation to
form piperidin-4-ones or azepan-4-ones (eq 2).7These reactions
were hypothesized to proceed via the mechanism in Scheme 1.
The amine oxides, 1, are prepared by reactions of amines with
butynyl or pentynyl tosylates followed by oxidation with mCPBA.
Coordination of 1 with gold(I) catalyst is proposed to form 3.
Nucleophilic attack on the gold-activated alkyne, 3, forms 4.
(eq 1).2 Early studies in this area use tethered oxidants such as
sulfoxide,3 nitrone,4 epoxide,5 nitro,6 and amine N-oxide,7 and
recently one of us has used pyridine/quinoline N-oxides as
external oxidants to achieve intermolecular alkyne oxidation.8
While α-oxo gold carbenes have been invoked as reactive
intermediates in many of these studies, studies using external
Received: September 20, 2011
Published: December 22, 2011
© 2011 American Chemical Society
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Scheme 1. Proposed Mechanism7 for the Rearrangements of
basis sets for gold and for all other atoms, respectively. Structures
were optimized with the CPCM model for dichloromethane (DCM)
solvent. The gold catalyst ligand, PPh3 or P(2-biphenyl)Cy2, was
modeled by PH3. The coordination of the gold to either the N-oxide
or alkyne as well as the syn addition to the alkyne were additionally
modeled with PPh3 and gave comparable results to that of the PH3
ligand. Modeling PPh3 with PH3 is very common12 because it gives
good structures and approximates reaction barriers.12c,13 B3LYP has
recently been shown to give reasonable energy and geometry
predictions for homogeneous gold catalysis.14
Acetylenic Amine-N-oxides to Piperidinones and
a
Azepanones
RESULTS AND DISCUSSION
■
Two different mechanisms for the conversion of 13 to 17 were
investigated; the original proposal is shown in black and the
lowest energy path described here is shown in blue in Scheme 2.
Scheme 2. B3LYP/6-31G(d)/CPCM(DCM) (B3LYP-D3)
Energetics for the Conversion of the Gold-Coordinated
N-Oxide, 13, to Cyclic Ketones 17 and 19
a
When n = 1, piperidinones are formed, and when n = 2, azepanones
a
are formed.
Intermediate 4 was thought to ring-open to form a gold carbenoid
intermediate, 5. This intermediate undergoes a 1,6-hydride shift or
1,7-hydride shift to form the iminium intermediate 6, which leads
to the product, 2. While the proposed mechanism accounts for the
formation of the major product, it fails to explain the selective
hydride migration from one of the N-alkyl substituents.
That is, when the amine oxide has two different substituents,
the hydrogen shift occurs selectively from the smaller group.
The transformation shown in eq 37a yielded a 5:1 ratio of pro-
ducts (8:9). The longer chain substrate, 10, in eq 4,7b yielded a
single product, 11. Acidic hydrogens α to an ester group appear
a
Compound 19 is not observed experimentally. (t) indicates the
species is a ground-state triplet. *gas phase optimization with a single
point solvation correction.
The cationic gold catalyst preferentially coordinates to the N-
oxide to give 13. The alkynyl-gold complex, 20, is 15.6 kcal/mol
higher in energy than 13 (Scheme 3). Calculations with PPh3
as the gold ligand predict that coordination of gold to the
N-oxide is favored by 15.4 kcal/mol over coordination to the
alkyne. The syn addition to the alkyne from 13 has a barrier of
24.7 kcal/mol (TS13−14). The reaction is exothermic by
24.9 kcal/mol and gives intermediate 14. Anti addition has been
established for a variety of nucleophilic additions to alkynes;15
however, here the N-oxide strongly coordinates to the cationic
gold, and no transition structure for the anti addition could be
located (Scheme 3).16
If the N-oxide were protonated by m-chlorobenzoic acid
(m-CBA), the gold cation would be less likely to coordinate to
the OH group. However, calculations indicate that proton transfer
from m-CBA to the N-oxide, 1, is endothermic by 7.3 kcal/mol
in DCM.
Along the proposed mechanistic path, the ring opening of 14
has a barrier of 25.6 kcal/mol and leads to a triplet carbenoid,
15. This triplet acyl carbenoid is stabilized by conjugation with
the carbonyl, while the singlet (5.9 kcal/mol higher in energy)
is less stabilized.17 α-Carbonyl carbenes are ground state triplets
and adopt a planar geometry.18 Alkyl gold carbenoids have
been involved in other gold(I)-catalyzed reactions and are
predicted to be singlets.12c,19
to migrate either less effectively (n = 2) or not at all (n = 1)
(eq 5).7 We now present computational evidence for a different
mechanism that accounts for the selection observed in these
reactions. A novel heteroretroene reaction is identified.
COMPUTATIONAL METHODS
■
Calculations were performed with Gaussian0910 with a hybrid density
functional (B3LYP and B3LYP-D311) with LANL2DZ and 6-31G(d)
Intermediate 15 can undergo a 1,6-hydride shift with a
barrier of 29.6 kcal/mol (TS15−16) to form 16. The barrier
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Scheme 3. Anti Addition Pathway to 16
a
Scheme 4. B3LYP-D3 Free Energy Diagram for the Lowest Energy Path from 13 to 17
a
Carbon is grey; nitrogen is blue; oxygen is red; gold is gold; and phosphorus is orange.
for the 1,4-hydride shift (TS15−18) is 4.6 kcal/mol higher in
energy than that for the 1,6-hydride shift.
gold-coordinated N-oxide, 13, to form 14. Intermediate 14 under-
goes the heteroretroene reaction and forms 16. The final step is
the cyclization of 16 to yield the piperidine product, 17, and
regenerate the catalyst. This cyclization is calculated to be the rate-
determining step. The overall transformation is exothermic by
96.7 kcal/mol.
The role of the gold catalyst in the heteroretroene reaction
was probed by comparing the gold-catalyzed reaction to one
without the AuPH3 group. Figure 1 shows the transition struc-
tures for the reaction of 14 and of 22. In 22 AuPH3 is replaced
by H. While the reactions are equally exothermic, the barrier is
9.5 kcal/mol lower in energy with the gold catalyst than
without. In 14 the cationic gold-phosphine makes the adjacent
carbon more negative compared to 22. Because the carbon in
14 is more nucleophilic, the hydrogen transfer is favored, result-
ing in a lower energy transition structure.
An alternative to the mechanism involving the sequential ring
opening and 1,6-hydride shift was found to be energetically
much more favorable. This new mechanism involves a hetero-
retroene reaction and leads directly from 14 to 16, thus
avoiding the gold-carbenoid intermediate, 15, altogether. This
step is favored over ring opening by 18.6 kcal/mol. Cyclization
of 16 forms the product, 17, and regenerates the catalyst. This
final step was calculated to have a barrier of 35.8 kcal/mol. This
−
barrier should be lowered by the presence of an NTf2
counterion or the coordination to a molecule of the N-oxide
starting material, 1.20 Also, the actual aryl phosphine ligands
used experimentally are more electron-rich than our model
phosphine, which should facilitate the dissociation of the gold
catalyst. This step is exothermic by 23.9 kcal/mol.
Scheme 4 summarizes the lowest energy path from 13 to
17. In this path, the first step is the syn addition of the
As indicated earlier, experiments showed that the hydro-
gen is transferred from the smaller amine substituent.7 This
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Figure 3. Heteroretroene reaction transition structures dictating the
product distribution of 8 and 9. Highlighted hydrogens in TS7−9 are
2.28 Å apart. Free energies are determined by B3LYP-D3.
From the gold coordinated N-oxide intermediate, 23, the syn
addition to the alkyne forms 24. Intermediate 24 can either
ring-open or undergo a heteroretroene reaction. Analogous to
the annulation to piperidinones, the heteroretroene transition
structure, TS24−26, is favored, but only by 1.7 kcal/mol over
the ring opening. This indicates that a small amount of the gold
carbenoid, 25, could be formed, although the necessity for
intersystem crossing will disfavor this pathway. Intermediate 25
undergoes a 1,7-hydride shift, rather than a 1,5-hydride shift
(ΔΔG‡ = 17.8 kcal/mol). An iminium intermediate, 26, leads
to the product 27. Again, the barrier for the cyclization is
overestimated by our calculations. The transformation from 23
to 27 is exothermic by 85.9 kcal/mol. The free energy diagram
for the lowest energy pathway is shown in Scheme 7.
Figure 1. Comparison of the heteroretroene reaction with and without
gold including bond distances and Mulliken charges. The ΔGrxn is
−46.9 and −48.4 kcal/mol with and without gold, respectively. Free
energies determined by B3LYP-D3.
observation is consistent with the newly proposed mechanism.
Figure 2 shows the heteroretroene transition structure, TS14−
Calculations are in good agreement with the experimental
regioselectivity observed in this transformation as well. The
heteroretroene transition structure, TS24−26, is in a chair
conformation with the substituent involved in the rearrangement
in an axial position (Figure 4). This is consistent with the
experimental observation that smaller groups are involved in the
hydrogen shift. The acetylenic amine-N-oxide, 10, under experi-
mental conditions afforded only 11 (eq 4). As shown in Figure 5,
the activation energy of the heteroretroene reaction involving
the methyl group is 2.2 kcal/mol lower in energy than that
involving the ethyl substituent. The prediction is that a 43:1 ratio
of products should occur.
The annulation to azapanones is more regioselective than
the annulation to piperidinones (eqs 3 and 4), because the
axial/equatorial difference is larger in the chairlike transition
structure (TS10−12, Figure 5) than in the envelope transition
structure (TS9−11, Figures 3). The distances between the
ethyl substituent and the nearest hydrogen (both highlighted
in green) in TS10−12 and in TS9−11 are 2.10 and 2.28 Å,
respectively.
Figure 2. The heteroretroene transition structure, TS14−16. The
highlighted (green) hydrogen is at the least sterically hindered position
on the N substituents.
16. The least sterically hindered position on the amine sub-
stituent (highlighted in green) is not involved in the hetero-
retroene reaction. A quantitative study of this phenomenon was
undertaken as well. The acetylenic amine-N-oxide, 7, under
experimental conditions afforded 8 and 9 in a 5:1 ratio (eq 3).
This product distribution corresponds to the heteroretroene
reaction preferentially involving hydrogen shift from the methyl
group rather than the octyl substituent. Calculations on the
N-methyl, N-ethyl substrate gave a 1.0 kcal/mol preference for
TS7−8, corresponding to a 5.4:1 product ratio (Figure 3).
Similar mechanistic and regioselectivity studies were carried
out for the annulation to azepanones. The mechanism for the
conversion of 23 to 27, including competing pathways, is
shown in Scheme 5. Again, the gold preferentially coordinates
to the N-oxide rather than the alkyne, and no transition struc-
ture corresponding to the anti addition could be located
(Scheme 6). When PPh3 is used, calculations predict that
coordination of gold to the N-oxide is favored by 10.0 kcal/mol
and the barrier for the syn addition is 11.1 kcal/mol. The
heteroretroene mechanism is favored over the mechanism
involving stepwise ring opening followed by a hydride shift.
EXPERIMENTAL STUDIES
■
These computational studies indicate that the hydrogen migration is
intramolecular and the intermediacy of gold carbene intermediates
of type 5 (Scheme 1) is unlikely. Experiments were performed to
provide further support for these conclusions and thereby the
calculated heteroretroene mechanism.
To examine the hydrogen migration, the α-methylene group
in the tertiary amine 30-d2 was fully labeled by deuterium.
When compound 30-d2 was subjected to the oxidation and
gold catalysis sequence, little deuterium loss was detected in
the N-benzylazepanone product 31-d2 (eq 6), suggesting that
the hydrogen/deuterium migration is intramolecular.21 As
more than 1 equiv of m-CBA was present in the reaction
mixture during the gold catalysis, an intermolecular ionic
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Scheme 5. B3LYP/6-31G(d)/CPCM(DCM) (B3LYP-D3) Energetics for the Conversion of the Gold-Coordinated N-Oxide, 23,
a
to Piperidinone 27 and Cyclopentanone 29
a
Compound 29 is not observed experimentally. (t) indicates the species is a ground-state triplet.
Scheme 6. Anti Addition Pathway to 26
Scheme 7. B3LYP-D3 Free Energy Diagram for the Lowest Energy Path from 23 to 27
process would most likely lead to substantial loss of
deuterium. This result is consistent with the heteroretroene
mechanism.
To offer evidence against the intermediacy of gold carbene 5
or related carbenoid intermediates, the diazo ketone 33 was
prepared22 and treated with Ph3PAuNTf2 in 1,2-dichloroethane.
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Figure 4. The heteroretroene transition structure, TS24−26, for the
transformation from 24 to 26. The highlighted hydrogen is at the least
sterically hindered position on the N substituents.
highly electrophilic (vide infra), this unexpected preference
for the Wolff rearrangement suggests that concerted 1,2-alkyl
migration and nitrogen expulsion from carbenoid 38 are more
likely.
An alternative approach to access a gold carbene of type 39 was
then pursued. One of us has recently developed a facile access to
putative α-oxo gold carbenes via gold-catalyzed intermolecular
oxidations of alkynes using pyridine/quinoline N-oxides as
oxidants.8 By using this strategy, intermediate 41, with its gold
carbene moiety similar to that of 39, was most likely formed from
the substrate 40 in the presence of MsOH (2 equiv, eq 9). The
reaction, however, did not afford azepan-4-one 44 but instead
α-chloro ketone 42 and α-methanesulfonyloxy ketone 43. The
formation of 42 is a strong indication of the formation of a highly
electrophilic intermediate such as gold carbene 41 as it abstracts
a chloride from the solvent, dichloroethane.25 This chloride abstrac-
tion is supported by the observation of 2-chloroethyl mesylate,
which accounts for the remaining part of the solvent molecule.
When m-CBA (1.2 equiv) replaced MsOH, no oxidation of the
C−C triple bond occurred.
Figure 5. The heteroretroene reaction transition structures for the
formation of 11 and 12. The highlighted hydrogens in TS10−12 are
2.10 Å apart. Free energies are determined by B3LYP-D3.
The expected azepan-4-one product 35 was not formed (eq 7);
instead, the Wolff rearrangement23 product, amino acid 36, was
formed in 96% NMR yield. The addition of a stoichiometric
amount of m-CBA did not alter the reaction outcome. With 34,
similar results were observed; amino acid 36, but not the
piperidine-4-one product, was observed. When MeOH was
used as solvent, the corresponding methyl ether was isolated in
70% yield (eq 8). While there is no previous report on gold-
catalyzed Wolff rearrangements, the related Ag catalysis24 is
known, but the mechanistic role of the metal is not well
understood. It is commonly assumed, though, a carbene or
carbenoid intermediate might be involved. In these clean Wolff
rearrangements, either gold carbenoid 38 or gold carbene 39
is the mostly likely intermediate, and the 1,2-alkyl migration
could either be in concert with or follow the expulsion of N2.
This migration was seemingly highly facile as the tethered
tertiary amine moiety did not cyclize to the electrophilic
carbene/carbenoid center. Since the gold carbene 39 would be
These studies argue against the intermediacy of gold carbene
5 (Scheme 1) and are fully consistent with the concerted
heteroretroene reaction predicted computationally.
CONCLUSION
■
A heteroretroene mechanism for the rearrangements of acetylenic
amine-N-oxides to piperidinones and azapanones has been iden-
tified. The experimental regioselectivities are reproduced by the
computations of activation barriers for the heteroretroene reaction.
Experimental studies support the proposed mechanism. This is
the first case in which a retroene reaction of a gold-coordinated
intermediate has been identified. This type of mechanism may be
important in other gold-catalyzed alkyne oxidations.
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(12) (a) Cheong, P. H.-Y.; Morganelli, P.; Luzung, M. R.; Houk,
K. N.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 4517. (b) Xia, Y.;
Dudnik, A S.; Gevorgyan, V.; Li, Y. J. Am. Chem. Soc. 2008, 130, 6940.
(c) Benitez, D.; Tkatchouk, E.; Gonzales, A. Z.; Goddard, W. A.;
Toste, F. D. Org. Lett. 2009, 11, 4798. (c) M.; Hashmi, A. S. K.;
Pernpointner, M. ChemCatChem 2010, 2, 1226. (e) Touil, M.;
Bechem, B.; Hashmi, A. S. K.; Engels, B.; Omary, M. A.; Rabaa, H.
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THEOCHEM 2010, 957, 21. (f) Noey, E. N.; Wang, X.; Houk, K. N.
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ASSOCIATED CONTENT
* Supporting Information
Full ref 10, molecular orbitals for carbenoids 15 and 25, C−O
bond distance scan for the trans addition to the alkyne,
Cartesian coordinates, and experimental methods and com-
pound characterizations. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
(13) Haeberlen, O. D.; Roesch, N. J. Phys. Chem. 1993, 97, 4970.
AUTHOR INFORMATION
Corresponding Author
houk@chem.ucla.edu; zhang@chem.ucsb.edu
■
́
́
(14) Faza, O. N.; Rodríguez, R. A.; Lopez, S. C. Theor. Chem. Acc.
2011, 128, 647. For the comparison of fully relativistic DHF-SCF,
DFT/B3LYP, and GF, see: Pernpointner, M.; Hashmi, A. S. K.
J. Chem. Theory Computation 2009, 5, 2717.
ACKNOWLEDGMENTS
(15) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232.
(16) Several optimizations were run with the forming C−O bond
distances locked at distances between 1.9 and 2.9 Å. The negative
force constant in these outputs was appropriate for the desired
transition structure. However, full optimizations from these outputs
did not give the desired transition structure. A scan of the C−O bond
distance from 1.66 to 3.34 Å showed a gradual increase in energy with
the maximum at 3.22 Å. A TS optimization of this point did not yield a
transition structure. The energy of this structure is 19.0 kcal/mol
relative to 23. See Supporting Information for the output of the scan.
(17) See Supporting Information for MOs of the carbenoid species.
(18) (a) Bertrand, G. Singlet Carbenes. In Reactive Intermediate
Chemistry; Moss, R. A., Platz, M. S., Jones, M., Jr., Eds.; Wiley: NJ,
2004; p 278. (b) Termath, V.; Tozer, D. J.; Handy, N. C. Chem. Phys.
Lett. 1994, 228, 239. (c) Maier, G.; Reisenauer, H. P.; Cibulka, M.
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(19) Benitez, D.; Shaprio, N. D.; Tkatchouk, E.; Wang, Y.; Goddard,
W. A.; Toste, F. D. Nat. Chem 2009, 1, 482.
■
E.L.N. is grateful to the National Institute of Health Chemistry-
Biology Interface Training Program Grant (T32GM008496),
and K.N.H. is grateful to the National Science Foundation
(CHE-0548209) for financial support of this research and for
TeraGrid resources provided by NCSA (CHE-0400414) and
the UCLA Academic Technology Services (ATS) Hoffman2
and IDRE clusters for computational resources, and to Peng Liu
for helpful discussions. L.Z. is grateful for financial support from
the National Institute of General Medical Sciences, National
Institutes of Health (R01 GM084254) and to Dr. Li Cui for the
deuterium labeling studies.
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