Unveiling latent α-iminocarbene reactivity for intermolecular cascade reactions through alkyne oxidative amination

Article abstract of DOI:10.1002/anie.201301087

Setting a trap: Described is the development of a metallonitrene-initiated alkyne oxidation cascade with intermolecular trapping of the reactive intermediate with a variety of allyl ethers to provide α-oxyimine products in which new Ci￡N, C-O, and C-C bonds have all been generated (see Scheme; tfacam=trifluoroacetamide). Copyright

Full text of DOI:10.1002/anie.201301087

Angewandte
Chemie
DOI: 10.1002/anie.201301087
Heterocycles
Unveiling Latent a-Iminocarbene Reactivity for Intermolecular
Cascade Reactions through Alkyne Oxidative Amination**
Nina Mace, Aaron R. Thornton, and Simon B. Blakey*
The chemistry of reactive (electrophilic) metallocarbenes,
primarily obtained by metal-catalyzed decomposition of a-
diazocarbonyl compounds, has been extensively developed
intermediates, participating predictably in a range of tradi-
tional metallocarbene reactions to generate a-functionalized
imine products.[4] Implicit in this strategy is the recognition
that alkynes can serve as precursors to both a-oxy- and a-
iminocarbenes and that oxidation of an alkyne under
appropriate reaction conditions could serve to reveal the
desired reactive intermediate.[5] The approach of Raushel and
Fokin separates the alkyne oxidation, which is achieved
through copper-catalyzed azide–alkyne cycloaddition,[6] from
the rhodium-catalyzed metallocarbene generation.
Studies in our laboratory have focused on the direct
unveiling of an intermediate with an a-iminometallocarbene
reactivity profile by a metallonitrene-initiated oxidative
cascade process. In intramolecular settings we have demon-
strated the feasibility of this direct approach, terminating the
cascade in an array of predictable carbene reactions (oxygen-
ylide formation/[2,3] Wittig rearrangement,[7] electrophilic
aromatic substitution, and cyclopropanation).[8] Despite the
inherent attractiveness of this single-step approach, reaction
conditions that facilitate efficient intermolecular cascade
termination are required for broad applicability and synthetic
utility. Herein we describe the development of a metalloni-
trene-initiated alkyne oxidation cascade with intermolecular
trapping of the reactive intermediate by a variety of allyl
À
À
and offers significant opportunity for strategic C C, C O, and
À
C N bond formation through a variety of well-defined
reaction mechanisms.[1] Given the prevalence of nitrogen
atoms in biologically and pharmaceutically relevant mole-
cules and the intrinsic electronic similarities between carbon-
yl and imine functional groups, the development of analogous
metallocarbene chemistry with an a imine providing the
necessary electrophilic activation represents both an obvious
and synthetically important extension of this chemistry.
However, the requisite a-diazoimine precursors readily
isomerize to 1,2,3-triazoles, and these heterocycles were
long believed to represent a thermodynamic sink, thus
significantly delaying the development of metallocarbene
chemistry associated with such systems.[2] Nonetheless, the
perception that reliable methods to access a-iminocarbene
chemistry would offer the potential to build structurally
complex nitrogen-containing molecules in a remarkably effi-
cient manner has recently resulted in the development of
several complementary solutions to the a-diazoimine isomer-
ization problem (Scheme 1).
=
ethers to provide a-oxyimine products in which new C N,
À
À
C O, and C C bonds have all been generated.
The challenge associated with the development of an
intermolecular reaction cascade is one of chemoselectivity.
Under the conditions that were previously developed for
intramolecular metallonitrene/alkyne cascades (treatment of
the substrate with 2 mol% [Rh2(esp)2] and 1.1 equivalents of
PhI(OAc)2), we recognized the possibility of a multitude of
[9]
side reactions, including C H amination, aziridination,[5a]
À
Scheme 1. Alternative routes for a-iminometallocarbene synthons.
cyclopropanation, and carboxylate trapping (Scheme 2).[8]
Indeed, when a mixture of sulfamate ester 1 and methyl
allyl ether (2) were subjected to these established conditions
for intramolecular reactions, a complex mixture of products
was observed, and only a minor amount (< 5%) of the desired
cascade product 3 was isolated.
Specifically, Park and co-workers showed that b oximino-
esters can be diazotized with minimal rearrangement to the
isomeric triazoles, thus providing an entry into a-oximino
acceptor–acceptor carbenoid chemistry.[3] More generally,
Fokin and co-workers demonstrated that 1,2,3-triazoles can
themselves act as precursors to a-iminometallocarbene
The report from Guthikonda and Du Bois indicating
[Rh2(tfacam)4] (tfacam = trifluoroacetamide) promoted met-
À
allonitrene interactions with p systems in preference to C H
bonds led us to explore its activity as a catalyst in the
intermolecular cascade reaction.[5a] As anticipated, in all the
experiments we conducted, [Rh2(tfacam)4] proved to be the
most effective catalyst for this cascade sequence, offering
both an improvement in yield and reduction in the formation
of side products.[10]
[*] N. Mace, A. R. Thornton, Prof. Dr. S. B. Blakey
Department of Chemistry, Emory University
Altanta, GA 30322 (USA)
E-mail: sblakey@emory.edu
Homepage: http://www.chemistry.emory.edu/faculty/blakey
[**] We are grateful for financial support from the NSF (CHE 0847258).
PhI(O2CtBu)2 was found to be a more efficient oxidant
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301087.
than PhI(OAc)2,[11] and, after examining solvents, we estab-
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Table 1: Allyl ether scope for intermolecular cascade termination.[a]
Scheme 2. Proposed intermolecular cascade mechanism with potential
undesired side products.
lished that the best conditions were 5 mol% [Rh2(tfacam)4] in
trifluorotoluene with 1.6 equivalents of PhI(O2CtBu)2. Under
these reaction conditions, the product of the alkyne amina-
tion/intermolecular ylide formation/[2,3] Wittig rearrange-
ment cascade (imine 3) was isolated in 75% yield (Table 1,
entry 1). This novel intermolecular cascade reaction is
generalizable to a variety of simple allyl ethers, providing
the corresponding products in good yields (entries 2–6).
Although the yield for cascade termination with cylohexyl
allyl ether (entry 5) was somewhat attenuated (46%), we note
that the product of this reaction contains a tertiary-secondary
dialkyl ether which would be particularly difficult to access by
other methods. Benzyl allyl ether showed almost total
selectivity for [2,3] Wittig migration of the allyl group
(entry 6), providing the product with a benzyl-protected
alcohol suitable for further manipulation, if required. E-
Crotyl methyl ether was efficiently incorporated, predictably
undergoing [2,3] Wittig rearrangement to provide the corre-
sponding imine (entry 7) in excellent yield (85%). However,
only limited diastereoselectivity was observed in this process,
and a 1.5:1 mixture of diastereomeric products was iso-
lated.[12]
Although both E and Z vinylsilanes could also participate
in the reaction (Table 1, entries 8 and 9), providing useful
allylsilane products, the yields were reduced in both cases
(39% and 43%, respectively), and poor diastereoselectivity
was observed. A secondary allyl ether underwent the cascade
reaction to provide the disubstituted olefin product in 47%
yield with a 3.5:1 E/Z ratio (entry 10).
A study on the impact of alkyne substitution pattern is
presented in Table 2. Alkynes bearing extended alkyl chains
capped with a primary tosylate (entry 1) and a silyl ether
(entry 2) were well tolerated. Likewise, a sulfamate ester
derived from a secondary homopropargylic alcohol was
successfully cyclized under the standard reaction conditions,
giving the N-sulfonyl imine in 55% yield (entry 3). However,
the chiral center present in this substrate did not induce any
[a] Reaction conditions: 5 mol% [Rh2(tfacam)4], 1.6 equiv PhI(O2CtBu)2,
6 equiv allyl ether, trifluorotoluene (TFT), 408C. Yield is of isolated
product. [b] 10 mol% [Rh2(tfacam)4], 12 equiv allyl ether.
diastereoselectivity in the cascade process, thus resulting in
a 1:1 mixture of diastereomeric products. Surprisingly, both
phenyl and vinyl substitution of the alkyne suppressed the
reaction under these conditions (entries 4 and 5). This
phenomenon is exclusive to the intermolecular cascade and
was not observed under the conditions previously established
for intramolecular reactions.[7,8]
We note that it is possible to efficiently transfer stereo-
chemical information from enantiomerically enriched allyl
ethers to the cascade product.[13] Reaction of benzyl allyl
ether (R)-4 with alkyne 1 generated the quaternary-stereo-
center-bearing imine 5 in good yield (67%) with excellent
enantiocontrol [93%, Eq. (1)].
The rich functionality present in the cascade products is
easily manipulated to provide an array of cyclic and acyclic
building blocks. Stereoselective reduction of the oxathiaze-
pine 6 (directed by the benzyl ether) with lithium aluminum
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Table 2: Intermolecular metallonitrene/alkyne cascade sulfamate ester
substrate scope.[a]
Scheme 3. Strategies for oxathiazepane opening to provide syntheti-
cally useful building blocks. DMAP=4-(dimethylamino)pyridine.
[a] Yield is of isolated product. TBDPS=tert-butyldiphenylsilyl.
Scheme 4. Addition of Grignard reagent to cascade product and
subsequent generation of disubstituted cyclohexene 14.
Grubbs II catalyst formed bicyclic cyclohexene 13 in 85%
yield. In this particularly hindered system, we note that
common acylation agents, including (EtOCO)2O, could not
be used to activate oxathiazepane 13 for nucleophilic SO3
displacement.[16] However, a mixture of neat TFAA and
pyridine allowed dual oxathiazepane activation and subse-
quent nucleophilic attack, thus forming the substituted cyclo-
hexene 14 (45%).
With an understanding of the parameters controlling this
intermolecular cascade reaction, as well as the conditions
required to manipulate the products, we highlight its synthetic
potential with an efficient synthesis of the core AB ring
system of the Securinega alkaloids, in which the cascade
process generates the vicinal amino alcohol stereocenters
central to this class of biologically active molecules
(Scheme 5).[17,18] The cascade reaction of simple alkyne 15
and enantioenriched allyl ether (R)-4 allowed access to
protected tertiary alcohol 16. After a diastereoselective
reduction, SN2 ring closure of the primary tosylate closed
the A ring to provide piperidine 17. Subsequent SO3 extrusion
with NaI/NaH generated octahydroindolizine 18 found at the
core of viroallosecurinine.
hydride at 258C provided the vicinal amino alcohol derivative
in 96% yield (10:1 d.r.; Scheme 3). To subsequently open the
sulfamate ester with an external nucleophile, activation by N-
acylation was necessary.[14] Acylation with CbzCl, the usual
reagent of choice for such transformations,[15] was unsuccess-
ful, likely a result of the hindered nature of the nitrogen
nucleophile. However, N-acylation proceeded efficiently with
(EtOCO)2O, allowing reaction with NaI, followed by NaH, in
a ring-opening/ring-closing reaction for pyrrolidine formation
(8, 57%).[7] This activated sulfamate ester 7 can be used for
other transformations as well, such as opening with NaN3 to
provide azide 9 in 74%, or with water to provide alcohol 10 in
86%.[15a] The ethyl carbamate, although not commonly
utilized as a protecting group, can be cleaved with aqueous
potassium hydroxide, generating free amine 11 in 80% yield.
Alternatively, addition of allylmagnesium bromide to
cascade product 6 provided oxathiazepane 12 (80%, 3.7:1
d.r.; Scheme 4), which contains vicinal tertiary amine/tertiary
alcohol stereocenters. Ring-closing metathesis with the
In conclusion, we have developed reaction conditions for
a metallonitrene/alkyne cascade with termination of the
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[10] For a systematic optimization table, see the Supporting Infor-
mation.
Scheme 5. Synthesis of viroallosecurinine core using intermolecular
metallonitrene/alkyne cascade. DIBAL=diisobutylaluminum hydride,
DMF=N,N-dimethylaminopyridine, THF=tetrahydrofuran.
cascade process by intermolecular ylide formation/[2,3] Wit-
tig rearrangement. A variety of substrates were explored, and
enantioenriched products were generated by efficient transfer
of stereochemical information from simple enantioenriched
allyl ethers. The congested nature of the products required
development of specialized conditions for their manipulation,
and ultimately the utility of the cascade process was
demonstrated through a streamlined synthesis of the bicyclic
viroallosecurinine core.
Received: February 6, 2013
Revised: March 6, 2013
Published online: && &&, &&&&
[11] D. N. Zalatan, J. Du Bois, J. Am. Chem. Soc. 2009, 131, 7558.
[12] A discussion of diastereoselectivity is included in the Supporting
Information.
[13] For examples of transfer of stereochemistry by [2,3] Wittig
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18, 1; c) J. F. Bower, P. Szeto, T. Gallagher, Org. Lett. 2007, 9,
4909.
Keywords: alkynes · carbenoids · heterocycles · rhodium ·
synthetic methods
.
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4
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Heterocycles
N. Mace, A. R. Thornton,
S. B. Blakey*
&&&& — &&&&
Unveiling Latent a-Iminocarbene
Reactivity for Intermolecular Cascade
Reactions through Alkyne Oxidative
Amination
=
À
Setting a trap: Described is the develop-
ment of a metallonitrene-initiated alkyne
oxidation cascade with intermolecular
trapping of the reactive intermediate with
a variety of allyl ethers to provide a-
oxyimine products in which new C N, C
À
O, and C C bonds have all been gener-
ated (see Scheme; tfacam=trifluoro-
acetamide).
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!