A divergent mechanistic course of Pd(0)-catalyzed aza-claisen rearrangement and aza-rautenstrauch-type cyclization of N -allyl ynamides

Article abstract of DOI:10.1021/ol100446p

A fascinating mechanistic study of ynamido-palladium-allyl complexes is described that features isolation of a unique silyl ketenimine via aza-Claisen rearrangement, which can be accompanied by an unusual thermal N-to-C 1,3-Ts shift in the formation of tertiary nitriles and a novel cyclopentenimine formation via a palladium-catalyzed aza-Rautenstrauch-type cyclization pathway.

Full text of DOI:10.1021/ol100446p

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1840-1843
A Divergent Mechanistic Course of
Pd(0)-Catalyzed Aza-Claisen Rearrangement
and Aza-Rautenstrauch-Type Cyclization of
N-Allyl Ynamides
Kyle A. DeKorver, Richard P. Hsung,* Andrew G. Lohse, and Yu Zhang
DiVision of Pharmaceutical Sciences and Department of Chemistry, UniVersity of
Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
Received February 22, 2010
ABSTRACT
A fascinating mechanistic study of ynamido-palladium-π-allyl complexes is described that features isolation of a unique silyl ketenimine via
aza-Claisen rearrangement, which can be accompanied by an unusual thermal N-to-C 1,3-Ts shift in the formation of tertiary nitriles and a
novel cyclopentenimine formation via a palladium-catalyzed aza-Rautenstrauch-type cyclization pathway.
We recently reported an account on the synthesis of
pharmacologically useful amidines1-4 from ynamides5,6 via
Scheme 1. Ynamido-Pd-π-Allyl Complexes
a Pd(0)-catalyzed N-to-C allyl transfer.7 As shown in Scheme
1, the formation of amidine 3 was proposed to proceed
(1) Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30, 203
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through ynamido-π-allyl complexes 2a or 2b after the initial
oxidative addition (O.A.) of N-allylynamides 1. Subse-
quently, after the addition of an amine, the reaction pathway
Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575
.
10.1021/ol100446p  2010 American Chemical Society
Published on Web 03/25/2010

would diverge from 4 or 5 depending upon the concentration
of the amine HNR2 and the nature of the palladium catalyst
and ligands. Excess amounts of amines or more nucleophilic
secondary amines8 tend to attack the ynamido-π-allyl
complexes 4 (or 5), leading to deallylated amidines 6,
whereas Pd(0) catalysts such as Pd2(dba)3 [instead of
starting from Pd(II) species] and more bulky ligands such
as X-phos9 and/or bidentate ligands with unique bite
angles such as xantphos10,11 that presumably promote
reductive elimination (R.E.) favored the formation of allyl-
transferred amidines 3. Given the novelty of these ynamido-
metal complexes and the potential of harvesting new
reactivities, we examined this reaction in greater detail
mechanistically and uncovered a unique ketenimine inter-
mediate, a rare 1,3-Ts shift, and an unusual and formally a
Nazarov-type pathway leading to cyclopentenimine forma-
tion. We report here these findings.
Scheme 2. Isolation of a Stable Silyl Ketenimine
Our initial experiments involved removing the amine
nucleophile to suppress amidine formation in an attempt to
isolate and/or observe key intermediates. As shown in
Scheme 2, in the presence of 1 mol % of Pd2(dba)3 and 2
mol % of xantphos, heating of N-allylynamide 7 at 70 °C
afforded two interesting products: cyclopentenimine 8 and
silyl ketenimine 9 in ∼5% and 88% yield, respectively.12
The yield of 9 was improved with the formation of 8
completely impeded when the reaction was run at lower
temperatures. While characterizations of 9 were unambiguous
given its stability, the formation of amidine 10 in 95% yield
via treatment of 9 with c-hex-NH2 solidifies the identification
of this novel intermediate.13
Despite the potential reactivity of N-sulfonylketenimines,
the surprising stability of ketenimine 9 is likely unique to
the silyl substitution.14,15 Under similar reaction conditions,
ynamide 11 containing a Ph substituent led to a very different
product, although in low yields. The product was initially
assigned on the basis of a literature report16 as cyclobutane
bis-imine 13, presumably attained through a facile dimer-
ization or [2 + 2] cycloaddition of the less stable ketenimine
12.
The formation of ketenimines from N-allyl ynamides
invokes an aza-Claisen rearrangement,17 specifically 3-aza-
Claisen, although those involving a C1-C2 acetylenic motif
are very rare if not unprecedented.17–19 However, the
involvement of the palladium metal in the formation of 9 is
distinctly clear, as a non-palladium-involved aza-Claisen
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NMR studies to be revealing of possible ynamido-π-allyl complexes even
at 25 °C. Only the starting ynamide 7 and silyl ketenimine 9 (and amidine
10 if the reaction was run in the presence of an amine) were clearly on
display spectroscopically.
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(12) See the Supporting Information.
Vol. 5, p 827.
Org. Lett., Vol. 12, No. 8, 2010
1841

pathway required higher temperatures and longer reaction
times (see 14 f 15 f 16 in Scheme 3). When the aza-
Having established the significance of the palladium metal
in this aza-Claisen rearrangement, we believe ynamido-π-
allyl complexes 2 derived from the oxidative addition of
ynamide 7 should be responsible for the formation of
ketenimines (Scheme 4). The question is whether it proceeds
Scheme 3. An Unusual N-to-C 1,3-Ts Shift
Scheme 4. Pd Model for the Ketenimine Formation
through a reductive elimination process via an intramolecular
pathway or a Tsuji-Trost pathway. To address this question,
we pursued two experiments.
Claisen rearrangement was carried out at 70 °C, the reaction
was sluggish as evident in the yield of the trapping of the
ketenimine 15 with pyrrolidine, and the usage of Ts or p-Ns
group was not critical to the reactivity.
The first experiment involved the use of ynamide 25
containing a crotyl group as shown in Scheme 4. While the
reaction temperature had to be higher, new ketenimine 27
was isolated in 90% yield with a regiochemical ratio of 5:1.
While this outcome concisely suggests that the crotyl group
is scrambled through the oxidative addition, the resulting
regiochemical ratio reflects that both pathways are possible
with the major isomer 27a being derived from either
reductive elimination of 2a (or 2a′: a ketenimine palladium
complex) or a favored addition of ynamido anion (N-) to
26 at the less hindered site (blue arrow).
When heating ynamide 17 at 110 °C led again to the dimer
19 and not the intended intramolecular cycloadduct 20
(Scheme 3), we sensed a possible mis-assignment because
an intermolecular process had just dominated over an
intramolecular one. We attained the X-ray structure of the
aza-Claisen product from 11 and were surprised that it was
not the dimer 13 but a tertiary nitrile 22. Aza-Claisen
rearrangements of ynamides in fact can occur in tandem with
a rare N-to-C 1,3-Ts shift at 110 °C,20 leading to nitriles
with a quaternary carbon formation.
The second study is a revealing crossover experiment as
shown in Scheme 5. With a 1:1 mixture of ynamides 25 and
It is noteworthy that these results further accentuate the
stability of silyl ketenimine 9. While thermal rearrangement
of 7 took place at 110 °C, 1,3-Ts shift to give TIPS-less
nitrile 23 only proceeded after desilylation (9 f 9′), thereby
suggesting sterics could also be at play. While this unusual
1,3-Ts shift in the formation of tertiary nitriles holds
significant merit in synthesis21 and our finding cautions the
assignment of possible homodimeric products from keten-
imines, details of this shift will be examined in another study.
Scheme 5. Crossover Experiment
(19) For some examples of aza-Claisen rearrangements, see: (a) Ma-
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E.; Wudl, F. Org. Lett. 2005, 7, 783. It is noteworthy that our work distinctly
indicates that the N-to-C 1,3-Ts shift took place after the aza-Claisen
rearrangement. Monitoring the thermal aza-Claisen rearrangement of 11
using NMR did not reveal any ketenimine 12, thereby suggesting the 1,3-
Ts shift was very fast at 110 °C.
28 containing a crotyl and allyl group, respectively, we were
able to concisely assign four sets of ketenimines: 27a/b, 9,
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Org. Lett., Vol. 12, No. 8, 2010

29a/b, and 30. While the regiochemical ratio of 27a/b or
29a/b is the same at 5:1, the ratios of crossover of 10:1 even
when the reaction was run at 0.10 M suggest that the
ketenimine formation is likely an intramolecular process and
that these are likely tightly bound ynamido-π-allyl com-
plexes shown as 2a and 2b (or 2a′/2b′).
an aza-Nazarov-type cyclization)26,27 as shown in Scheme
7. While the Pd complex 2b could readily reductively
Scheme 7. Aza-Rautenstrauch-Type Cyclization Pathway
While literature precedents15 suggest that ketenimines
represent highly reactive entities for developing useful
synthetic methods, the observation of trace amounts of
cyclopentenimine 8 and its mechanistic course captured our
attention. Although it took much effort to optimize the
formation of 8,22 it was found that conditions which relatively
disfavored reductive elimination (5 mol % of Pd(PPh3)4) as
well as the use of a phenolic substrate as an additive led to
cyclopentenimine 8 in 70% yield. Preparation of 31 led to
an X-ray structure, allowing an unambiguous assignment.
The difference in conditions implied that cyclopentenimine
8 is likely derived from a different mechanistic course for
which silyl ketenimine 9 is not an intermediate.23 This
assertion is consistent with the fact that treatment of 9 with
either 5 mol % of Pd(PPh3)4, or by using thermal conditions,
did not provide any identifiable amount of 8, thereby ruling
out the possibility of a formal imino-Nazarov-type cycliza-
tion24,25 involving 32a-c (Scheme 6).
eliminate to give ketenimine 9, under conditions in which
the reductive elimination is slowed, a Pd-[3,3] sigmatropic
rearrangement could occur to give R-imino palladium
carbenoid 33a. While a number of possibilities could take
place from there on, one possibility that is consistent with
the use of PhOH would entail the formation of enamido-Pd
complex 33c, which could undergo migratory insertion (M.I.)
followed by ꢀ-elimination to afford cyclopentenimine 8 after
tautomerization of cyclopentadienamide 33e. An alternative
pathway would proceed through dienyl palladium carbenoid
34a derived from tautomerization of 33a.
Scheme 6. Effective Cyclopentenimine Formation
We have uncovered here a fascinating divergent mecha-
nistic pathway consisting of a Pd(0)-catalyzed aza-Claisen
rearrangement of N-allylynamides, which can also be ac-
companied with an N-to-C 1,3-Ts shift through the keten-
imine intermediate and an aza-Rautenstrauch cyclization.
These studies provide insight into the nature of ynamido-π-
allyl complexes as well as new reactivities with synthetic
potential. Efforts are underway in pursuing synthetic methods
involving ketenimines and the N-to-C 1,3-Ts shift as well
as applications using cyclopentenimines.
Acknowledgment. We thank the NIH [GM066055] for
funding. We thank Dr. Vic Young of the University of
Minnesota for providing X-ray structural analysis.
Instead, a likely mechanistic course would involve an aza-
variant of a Rautenstrauch-type cyclization (or also formally
Supporting Information Available: Experimental pro-
cedures as well as NMR spectra and characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Some of the conditions explored are as follows. Pd(0) source:
Pd2(dba)3, Pd(PPh3)4. Ligand: xantphos, X-Phos, (C6F5)3P. Solvent: THF,
dioxane. Concentration: 0.04-0.10 M. Lewis acid: Zn(OTf)2, Cu(OTf)2,
Sc(OTf)3, Ln(OTf)3. Base: K2CO3. Additive: t-BuOH, PhOH, 4-NO2C6H4OH,
2,6-dimethylphenol, 2,3-dimethylphenol.
(23) Sosa, J. R.; Tudjarian, A. A.; Minehan, T. G. Org. Lett. 2008, 10,
5091.
OL100446P
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