Gold-catalyzed nitrene transfer to activated alkynes: Formation of α,β-unsaturated amidines

Article abstract of DOI:10.1021/ol2002607

A gold-catalyzed intermolecular nitrene transfer to alkynes was developed for the first time, revealing a new mode of nitrene transfer and providing a novel access to versatile α-imino metal carbenes. Various mild nitrene-transfer reagents were examined, and iminopyridium ylides especially those based on 3,5-dichloropyridine proved be highly effective. With activated alkynes such as N-alkynyloxazolidinones as substrates, α,β- unsaturated amidines were formed in mostly good yields.

Full text of DOI:10.1021/ol2002607

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1738–1741
Gold-Catalyzed Nitrene Transfer
to Activated Alkynes: Formation of
r,β-Unsaturated Amidines
Chaoqun Li and Liming Zhang*
Department of Chemistry and Biochemistry, University of California, Santa Barbara,
California 93106, United States
zhang@chem.ucsb.edu
Received January 26, 2011
ABSTRACT
A gold-catalyzed intermolecular nitrene transfer to alkynes was developed for the first time, revealing a new mode of nitrene transfer and providing
a novel access to versatile R-imino metal carbenes. Various mild nitrene-transfer reagents were examined, and iminopyridium ylides especially
those based on 3,5-dichloropyridine proved be highly effective. With activated alkynes such as N-alkynyloxazolidinones as substrates, R,β-
unsaturated amidines were formed in mostly good yields.
A rather unique and potent reactivity of gold catalysis is
the capability of the metal to form gold carbenes via γ-
eliminations. Although there are still some ambiguities
regarding discrete reaction mechanisms,1 this strategy
has been applied successfully in intramolecular transfor-
mations using tethered oxygen-delivering oxidants such as
sulfoxides,2 N-oxides,1b,3 nitrones,4 and epoxide5 where
their oxygenless parts (i.e., Y) behave as nucleofuges
(Scheme 1A). Attempts to realize intermolecular versions
of this strategy using external sulfoxides6 led to 3,3-re-
arrangements instead, and the intermediacy of R-oxo gold
carbenes was ruled out both by experiments and via
calculations. We discovered, however, that pyridine N-
oxides and quinoline N-oxides were suitable external
oxidants for the generation of these reactive gold inter-
mediates intermolecularly, thus offering valuable opportu-
nities to replace hazardous and potentially explosive diazo
ketones with benign alkynes in gold carbene chemistry
(Scheme 1B). We have applied this strategy successfully
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r
10.1021/ol2002607
Published on Web 02/25/2011
2011 American Chemical Society

Scheme 1. Gold-Catalyzed Oxygen/Nitrene Transfer to Alkyne:
Concept
Figure 1. Selected nitrene-transfer reagents (NTR).
include sulfilimines and derived from
1
2
dibenzothiophene,12 cyclic sulfilimine 3,13 iminoiodinane
4, which is soluble in organic solvents,14 and iminopyridi-
nium ylides 5-8,15 and iminoquinolinium ylide 9.15
Afterhaving little successwithaliphaticinternalalkynes,
we turned our attention to activated alkynes, specifically
N-alkynyloxazolidinones,7c,16 which are readily available
from terminal alkynes via several convenient methods.17
Table 1 shows some of the reaction optimization results.
To our delight, expected amidine 11 was indeed formed
when various nitrene-transfer reagents were used. While
sulfilimines 1 and 2 were mostly ineffective, cyclic sulfili-
mine 3 gave good yields with a range of different gold
catalysts including IPrAuNTf2 (entry 5) and
(F5C6)3PAuNTf2 (entry 6). While the result with
IPrAuNTf2 was excellent, the fact that the propylsulfanyl
group remained in the product prompted us to search
further for oxidants that deliver a simple tosyl group.
While soluble iminoiodinane 4 was less effective, imino-
pyridinium ylides offered mostly good to excellent yields
(entries 8-13). Iminopyridinium ylide 8 derived from 3,5-
dichloropyridine proved to be the most effective and led to
the formation of 11 in excellent yields regardless of the
electrophilic nature of the gold catalyst (comparing entries
11, 12, and 13). Notably, steric bulk on the oxidant was
detrimental, and the 2-Me group in ylide 7 decreased the
reaction yield from 65% to 25% (comparing entries 8 and
10). For the same reason, iminoquinolinium ylide 9 was a
poor oxidant (entry 14).
to rather expedient syntheses of several classes of func-
tional molecules.7
With all the studies so far focused on oxidation using
oxygen-delivering oxidants, there is surprisingly little at-
tention paid to nitrene-delivering oxidants. While a teth-
ered azido group8 and a tethered sulfilimine (one example
only)2a could be considered as intramolecular cases, no
gold-catalyzed intermolecular nitrene transfer to alkynes has
been reported (Scheme 1C). Several features of this mode of
nitrene transfer are notable: (1) the nitrene moiety is deliv-
ered via an outer sphere attack, and no gold nitrene complex9
is involved; this new mode of nitrene transfer is different
from many known nitrene transfer reactions;10 (2) it would
make alkynes equivalent to R-diazo imines, which are difficult
to access. It is known that R-diazo imines readily cyclize into
1,2,3-triazoles although in the presence of electron-with-
drawing substituents at N-1 the reversed process could be
utilized to generate R-imino rhodium carbenes.11 Herein, we
disclose our effort in synthesizing and evaluating various
external nitrene-transfer reagents in generating R-imino gold
carbenes directly from C-C triple bonds, which led to
efficient synthesis of R, β-unsaturated amidines.
At the outset, a range of nitrene-transfer reagents were
synthesized for screening. As shown in Figure 1, they
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Org. Lett., Vol. 13, No. 7, 2011
1739

Table 1. Reaction Optimization
Table 2. Scope Studiesa
reaction conver- yield
entrya NTR
gold catalyst
conditions sion (%) (%) E/Z
1
1
1
1
2
3
3
4
5
6
7
8
8
8
9
Ph3PAuNTf2
IPrAuNTf2
rt, 12 h
rt, 12 h
80
20
10 2/1
<5
2
-
3
(F5C6)3PAuNTf2 rt, 12 h
(F5C6)3PAuNTf2 rt, 12 h
100
100
100
90
35 1.5/1
30 1.5/1
90 3.2/1
70 1.5/1
46 3/1
4
5
IPrAuNTf2
rt, 3 h
6
(F5C6)3PAuNTf2 rt, 12 h
(F5C6)3PAuNTf2 rt, 3 h
(F5C6)3PAuNTf2 rt, 18 h
(F5C6)3PAuNTf2 rt, 48 h
(F5C6)3PAuNTf2 rt, 48 h
(F5C6)3PAuNTf2 rt, 12 h
7
100
80
8
65 2.5/1
60 1.5/1
25 1.5/1
90 1.5/1
95b 4/1
9
70
10
11
12
13
14
50
100
100
100
30
IPrAuNTf2
12c
rt, 3 h
rt, 3 h
rt, 48 h
95 4/1
IPrAuNTf2
10 3/1
a [10]=0.05 M. b 92% isolated yield. c 12=dichloro(2-picolinato)
gold(III).
The amidine product 11 was formed as an inseparable
mixture of two isomers. 1H NMR indicated that they were
isomeric at the C-C double bond2d and the E-isomer was
major but only to a small extent. Interestingly, this lack of
stereoselectivity was in stark contrast to our previousresult
with the same substrate, which was oxidized into an
R,β-unsaturated imide with a >50/1 E/Z ratio.7c The
geometries of the C-N double bonds in both isomers were
assigned as E and discussed later.
a [13] = 0.05 M. b (F5C6)3PAuNTf2 was the catalyst. c 15% of the
ring-expansion product was formed. d The oxidant used was analogous
to 8 with the only difference at the sulfonyl group. e Dichloro(2-
picolinato)gold(III).
Our attempts to improve the E/Z selectivities of the
C-C double bond were mostly unsuccessful. A notable
feature of the optimized reaction conditions is the absence
of an acid additive, which was required in our previous
studies using pyridine N-oxides.7a,b
The reaction scope was then studied, and the results are
shown in Table 2. Good to excellent yields were obtained
with substrates substituted at the alkyne terminus by a
primary alkyl group (entry 1) and several functionalized
ones (entries 2-6). Functional groups such as chloro
(entry 2), aryl (entry 3), ester (entry 4), MsO (entry 5),
and ether (entry 6) were readily tolerated; however, proxi-
mally positioned HO and azido groups appeared to inter-
fere with the desired reaction, and little or no desired
product was observed. The allowance of MsO is note-
worthy as it offers a reactive electrophilic site for further
transformation while highlighting the mild nature of this
nitrene transfer process. A cyclohexyl group was easily
accommodated, leading to 14g as the only isomer in 90%
yield (entry 7). Similarly, anefficient reaction was observed
with a cyclopentyl group (entry 8); however, besides the
expected 1,2-C-H insertion, a ring expansion occurred as
a minor event, leading to a cyclohexene product18 in 15%
yield. In addition to tosylnitrene, other arenesulfonylni-
trenes were readily transferred to alkynes using analogous
iminopyridium ylides regardless of the electronic proper-
ties of the arene (comparing entries 9 and 10) as well as
its steric bulk (entry 11, Mts=2,4,6-trimethylbenzene-
sulfonyl). While the oxazolidinone moiety appeared to be
ideal for this nitrene transfer reaction, an N-phenyltolue-
nesulfonamido moiety, as shown in entry 12, could also
play the role of activating the C-C triple bond toward this
intermolecular nitrene transfer.
(18) The product was formed likely via the following sequence:
The geometry of the C-N double bond was difficult to
assign even after rather extensive NOESY studies. Even-
tually we were able to secure a single crystal of the major
component of compound 14j (Figure 2), and its X-ray
diffraction studies revealed that the C-N double bond has
1740
Org. Lett., Vol. 13, No. 7, 2011

Scheme 2. Rationale for the Formation of the E-C-N Double
Bond
and realized a new nitrene transfer strategy that provides a
novel and facile access to versatile R-imino metal carbenes.
Various mild nitrene-transfer reagents were examined, and
iminopyridium ylides especially those based on 3,5-di-
chloropyridine turned out to be highly effective. With
activated alkynes such as N-alkynyloxazolidinones as
substrates, R-imino gold carbene intermediates were read-
ily generated and underwent facile 1,2-C-H insertions,
leading to R,β-unsaturated amidines in mostly good yields.
Further studies to expand the scope to normal alkynes will
be pursued in due course.
Figure 2. ORTEP drawing of E-14j.
anE-configuration. Although the corresponding geometry
of the minor isomer was not determined, we reasoned it
should be the same as that of the major isomer as it is
difficult to imagine that the geometries of both C-N and
C-C double bonds would be paired in an exclusive
manner (i.e., E,E and Z,Z only). The exclusive formation
of the E-C-N double bond was also consistent with the fact
that 14g and 14h did not have any observed geometric
isomer. The reason for the selectivity, although not appar-
ent, could be rationalized by conformational analysis. As
shown in Scheme 2, assuming that gold carbene intermedi-
ate B is formed via a concerted elimination, stereoelectronic
effects require bond alignments as outlined in conformation
A. The preference for such a conformation can be reasoned
by invoking the minimization of charge repulsion between
the heteroatoms on the oxazolidinone ring and the sulfonyl
oxygens. Accordingly, the geometries of the C-N double
bonds in other cases were all tentatively assigned as E.
In conclusion, we have developed the first examples of
gold-catalyzed intermolecular nitrene transfer to alkynes
Acknowledgment. The authors thank the NIH and
UCSB for general financial support and Dr. Guang Wu
for his kind help with X-ray crystallography. L.Z. is an
Alfred P. Sloan fellow.
Note Added after ASAP Publication. In the second line
under Figure 1, ‘‘cyclic sulfilimine 2’’ was changed to ‘‘cyclic
sulfilimine 3’’; the corrected version reposted March 1, 2011.
Supporting Information Available. Experimental pro-
cedures, compound characterization and spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 7, 2011
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