1,2-N-migration in a gold-catalysed synthesis of functionalised indenes by the 1,1-carboalkoxylation of ynamides

Article abstract of DOI:10.1002/chem.201403040

Unique α-hemiaminal ether gold carbene intermediates were accessed by a gold-catalysed 1,1-carboalkoxylation strategy and evolved through a highly selective 1,2-N-migration. This skeletal rearrangement gave functionalised indenes, and isotopic labelling c

Full text of DOI:10.1002/chem.201403040

DOI: 10.1002/chem.201403040
Communication
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Skeletal Rearrangements
1,2-N-Migration in a Gold-Catalysed Synthesis of Functionalised
Indenes by the 1,1-Carboalkoxylation of Ynamides
Holly V. Adcock,[a] Thomas Langer,[b] and Paul W. Davies*[a]
Abstract: Unique a-hemiaminal ether gold carbene inter-
mediates were accessed by a gold-catalysed 1,1-carbo-
alkoxylation strategy and evolved through a highly selec-
tive 1,2-N-migration. This skeletal rearrangement gave
functionalised indenes, and isotopic labelling confirmed
the rare CꢀN bond cleavage of the ynamide moiety. The
effect of substituents on the migration has been explored,
Scheme 1. 1,2- and 1,1-carboalkoxylation pathways. Oxygen may be teth-
ered to the alkyne through either R (resulting in external migration), or the
migrating group Y (resulting in internal migration).
and a model is proposed to rationalise the observed selec-
tivity.
p-Acid-mediated alkyne carboalkoxylations are
potent transformations for the rapid assembly of sub-
stituted carbo- and heterocyclic frameworks from
simple precursors under mild reaction conditions.[1–3]
Attack of an oxygen nucleophile onto a metal-acti-
vated p system is followed by cationic or sigmatropic
migration from oxygen to carbon. Carbon–carbon
bond formation can potentially occur a- or b- to the
metal, as 1,2- or 1,1-carboalkoxylations, respectively
(Scheme 1). The little-explored 1,1-pathway provides
a complexity increasing and synthetically enticing
non-diazo route to form a metal carbene (Scheme 1,
path b).[4–5] Nakamura et al.’s seminal platinum- or
palladium-catalysed cycloisomerisation of o-alkynyl
benzaldehyde acetals[1c,d] was the only report of such
processes, until very recent studies of Wang et al. on
exploring catalyst control with terminal alkynes.[6]
Our interest in accessing carbenoid reactivity from
ynamides led us to question whether the electronic
bias of an ynamide might enforce a 1,1-carboalkoxy-
lation pathway in systems in which the 1,2-pathway
Scheme 2. Gold-catalysed carboalkoxylation: proposed ynamide-dictated carboalkoxyla-
tion mode.
might be expected based on geometrical bias.[7] Al-
though the use of ynamides in gold catalysis has rap-
idly increased over recent years, their carboalkoxyl-
ation chemistry had not previously been investigated.[8–10]
During the final stages of this work, Hashmi and co-workers re-
ported the formation of functionalised benzofurans by 1,2-ex-
ternal carboalkoxylation of phenol-derived ynamides
(Scheme 1, path a).[8]
For this study, we selected ynamides F to contrast with the
1,2-carboalkoxylations reported by Toste and co-workers using
o-alkynylbenzylethers A (Scheme 2).[13] We envisaged that the
electronic influence of F would divert the process down a 1,1-
internal carboalkoxylation pathway by favouring a 6-endo cycli-
sation over the previously reported 5-exo pathway [Eq. (1) in
Scheme 2].[14] On fragmentation of G, vinyl gold H was predict-
ed to form a unique gold carbene I, adjacent to a hemiaminal
ether, through CꢀC bond formation b to the metal [Eq. (2) in
[a] H. V. Adcock, Dr. P. W. Davies
School of Chemistry, University of Birmingham (UK)
Fax: (+44)121-4144403
E-mail: p.w.davies@bham.ac.uk
[b] Dr. T. Langer
AstraZeneca, Pharmaceutical Development
Silk Road Business Park, Macclesfield, SK10 2NA (UK)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403040.
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vs. 6). AgNTf2 alone did not catalyse the reaction, and only
degradation was observed in the presence of s-Lewis or
Brønsted acids (Table 1, entries 11–14).
Table 1. Study of reaction conditions.[a]
Indene 2a was thought to result from a 1,2-N-migration
onto gold carbene I. Such processes are rare, and to the best
of our knowledge, unreported in gold catalysis.[18–19] Doyle and
co-workers recently reported N-migration of an endocyclic hy-
drazide on dediazotisation of b-methylene-b-silyloxy-b-amido-
a-diazoacetates with a variety of metal catalysts.[20] For com-
pound 2a, a selective 1,2-migration of an exocyclic sulfon-
amide would occur from a b-methine-b-alkoxy-b-sulfonamido
quaternary centre generated in unison with the gold carbene
(Scheme 1, Eq. (2)). The relative migratory aptitude of different
amide substituents was therefore probed further by using yna-
mides 1a–i (Table 2).
Sulfonylated aniline groups, including nosyl, generally
worked well (Table 1, entries 1–3). N-Benzyl-substituted yna-
mide 1d also underwent efficient cycloisomerisation affording
2d in 72% yield (entry 4). In contrast, N-methyl-substituted
ynamides were poorer substrates (entries 5 and 6): reactions of
both methane- and 4-nitrobenzene sulfonamides 1e/f were
slow; products 2e/f were only isolated in low yields, and simi-
lar quantities of the regioisomers 3e/f were observed. A small
amount of the isomer was also seen in the reaction of N-allyl
methane sulfonamide 1g, though a high yield of 2g was ob-
tained (entry 7). The use of other gold catalysts had relatively
little impact on the outcome of this reaction (entries 7-9), and
no products of cyclopropanation were observed.[21] A cyclic
carbamate 1h underwent the reaction cleanly with high selec-
tivity for N-migration (entry 10). The use of a more hindered
chiral benzyl substituted oxazolidinone derivative led to a com-
plex reaction mixture alongside unreacted 1i (entry 11). The
Entry[a] Catalyst
t [h] Yield 1a [%][b] Yield 2a [%][b]
1
AuCl
24
53
27
–
2
3
4
PtCl2
24 >95
[AuLCl2][c]
PPh3AuCl/AgNTf2
24
6
17
–
–
–
–
63
79
73
89
88
78
–
5
o-biphenyl(tBu)2PAuCl/AgNTf2 20
6
7
8
9
10
11
12
13
14
(p-CF3C6H4)3PAuCl/AgNTf2
(p-CF3C6H4)3PAuCl/AgBF4
(p-CF3C6H4)3PAuCl/AgOTs
(p-CF3C6H4)3PAuCl
(p-CF3C6H4)3PAuNTf2
AgNTf2
HNTf2
BF3·OEt2
SiO2
2
2
6
–
24 >95
2
–
88
–
24 >95
24
24
24
66
31
80
–
–
–
[a] Reaction conditions: 1a (0.1 mmol, 1 equiv), catalyst (5 mol%), CH2Cl2
(0.1m), time as indicated. [b] Yields calculated by 1H NMR spectroscopy
against a known quantity of internal standard (1,2,4,5-tetramethylben-
zene). [c] L=Picolinate. Ts=toluene-4-sulfonyl.
Scheme 2]. From I, several outcomes could be envisaged to
give functionalised indenes, of interest due to their function as
core structures in many natural products[15] and pharmaceuti-
cals,[16] as well as being useful ligands for transition metals.[17]
Our study commenced with ynamide 1a, which reacted in
the presence of AuCl to give N-indenyl sulfonamide 2a as the
sole product through
a new
skeletal rearrangement (Table 1,
entry 1). No reaction was ob-
served with PtCl2; however,
a AuIII complex gave a higher
yield of 2a (entries 2 and 3). Cat-
ionic gold(I)–phosphine com-
plexes proved to be more effec-
tive, with complete conversion
of 1a and higher yields of 2a
(entries 4–8). The use of an elec-
tron-poor phosphine ligand was
beneficial to both the reaction
rate and yield relative to an elec-
tron-rich phosphine (Table 1,
entry 6 vs. 4 and 5). The phos-
phine gold chloride alone was
ineffective (entry 9), and little
variation was observed on
changing the silver salt (Table 1,
entries 6–8). The study was con-
tinued with the preformed gold
triflimidate complex, because it
gave identical results to the
complex formed in situ (entry 10
Table 2. Study of the migrating group.[a]
Entry[a]
1: NR1R2
t [h]
Yield 2 [%][b]
Yield 3 [%][b]
1
1a NPhTs
2
1
78
–
–
–
–
20[e]
23
9
10
5
–
2
3
1b NPhSO2Ph
1c NPhNs
68[c,d]
76
0.75
3
48
24
1
24
24
2
4
1d NBnMs
72[d]
23
5
6
1e NMeMs
1 f NMeNs
29
74
58
64
7
1g N-allylMs
1g N-allylMs
1g N-allylMs
1h N(Ox)[h]
8[f]
9[g]
10
11
78
–
1i N(5-(s)Bn-Ox)[e]
24
–
[i]
[a] Reaction conditions: 1 (0.2 mmol, 1 equiv), catalyst (5 mol%), CH2Cl2 (0.1m), time as indicated. [b] Isolated
yields after flash column chromatography unless otherwise stated. [c] 3 mmol, 1.4 g scale. [d] Isolated yield
after recrystallisation without chromatography. [e] Yield calculated by 1H NMR spectroscopy: present as an in-
separable mixture with 1e. [f] Catalyst: (C5F5)3PAuCl/AgNTf2. [g] Catalyst: [AuLCl2] L=picolinate. [h] Ox=2-oxa-
zolidinone. [i] 37% of 1i remaining. Ms=methane sulfonyl, Ns=4-nitrobenzene sulfonyl.
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(Table 2, entry 7). Pleasingly, variation at the migrat-
ing alkoxy group was well tolerated with both O-
benzyl and O-allyl substitution despite the possibility
of direct external migration of an allylic or benzylic
cation following initial nucleophilic attack (2p–r).[22]
Increasing the steric bulk around the benzylic posi-
tion with naphthyl, o-tolyl and o-anisole substituents
(2s–u) saw a significant reduction in regioselectivity
with an N-phenyl-p-tosyl substituted ynamide. How-
ever, the analogous ynamide 1v, containing non-aro-
matic N-substituents gave a clean reaction, with 2v
formed as a single regioisomer in high yield.
The resulting functionalised indenes were found to
be sensitive to basic conditions: C-sulfonylated
indene-1-amine (4) was isolated in good yield when
chromatographic purification of 2c was attempted
using triethylamine-treated silica gel to improve sep-
aration (Scheme 4), and could be deliberately pre-
pared from 2c. The product of double-bond migra-
tion was instead observed when carbamate 2n was
exposed to triethylamine (see the Supporting Infor-
mation). Although 1a did not rearrange in the pres-
ence of triethylamine, a-alkoxy conjugated imine 5
was isolated on treatment with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU). Single-crystal X-ray diffrac-
tion analysis of 2a showed the indene and nitrogen
to be resonance decoupled with the NꢀS bond
aligned to the enol p system accounting for the
ready elimination of the sulfonyl group.[23]
An isotopic-labelling study was carried out to sup-
port the mechanistic hypothesis. Ynamide 1g was se-
lected to allow isolation of both isomeric indenes,
and a 13C-enriched sample was prepared from 13C-
labelled benzoic acid (see the Supporting Informa-
tion). Cleavage of the ynamide CꢀN bond was con-
firmed with the formation of 13C-2g, in which nitro-
gen is connected to the 13C-enriched carbon. Addi-
Scheme 3. Reaction scope. [a] Reaction conditions: 1 (0.2 mmol, 1 equiv), was reacted
with (p-CF3C6H4)3PAuNTf2 (5 mol%) in CH2Cl2 (0.1m) at RT, time as indicated. [b] Using
10 mol% catalyst. Regioisomer 3o also isolated in a 10% yield.
practicality of this method was demonstrated by the
gram-scale synthesis of 2b, obtained after filtration
to remove metal residues and then recrystallisation
(entry 2).
The impact of modification at other positions on
the skeletal rearrangement was then explored
(Scheme 3). Electron-donating and electron-with-
drawing aryl groups (2j and 2k) were well tolerated.
Although complex mixtures were observed with fur-
anyl or vinyl benzylic substituents, the ferrocene-sub-
stituted derivative 2l could be prepared as a single
regioisomer in moderate yield. Methoxy substitution
on the core benzene ring was well tolerated at both
the 3- and the 4- positions giving single products
(2m and 2n). The 4-fluoro-substituted variant re-
quired a longer reaction time (24 h) and an increased
Scheme 4. Base-mediated reactions of N-indenyl sulfonamides. DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene. Crystal structure of 2a with ellipsoids drawn at the 50% probability
catalyst loading to achieve a good yield of 2o along-
side expected small amounts of regioisomer 3o level.
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benzene units (2s–u) might be
explained by stabilising p and
through-space
interactions[27]
with the N-phenyl-p-toluene sul-
fonamide, so raising the barrier
to N-migration. The high selec-
tivity for N-migration with N-
allyl-methane sulfonamide 2v,
incapable of such interactions, is
in line with this hypothesis.
In conclusion, a cycloisomerisa-
tion of ynamides that features
a rare CꢀN bond cleavage is re-
ported. A 1,1-carboalkoxylation
pathway is enforced by the elec-
tronic properties of ynamides to
generate a unique a-hemiaminal
ether carbene environment. La-
belling studies confirmed a sub-
sequent 1,2-N-migration with
the high selectivity over 1,2-O-
migration rationalised based on
developing steric encumbrance.
Further studies to harness the
regiodetermining role of yna-
mides in cycloisomerisation reac-
tions are ongoing.
1
Scheme 5. Mechanistic studies. [a] Yields calculated by H NMR spectroscopy against a known quantity of internal
standard (1,2,4,5-tetramethylbenzene).
Acknowledgements
Scheme 6. Proposed rationale for the observed regioselectivity.
The authors thank EPSRC and
AstraZeneca plc for funding (stu-
tionally, the absence of cross-over products when ynamides 1c
and 1q were reacted together confirmed the intramolecular
nature of this reaction (Scheme 5).
dentship to H.V.A.). We thank Dr. Louise Male (University of Bir-
mingham) for X-ray crystallography analysis. The facilities used
in this research were partially supported through Birmingham
Science City AM2 by Advantage West Midlands and the Euro-
pean Regional Development Fund.
The formation of indenes 2 and 3 and the generally high se-
lectivity for N- versus O-migration can be rationalised from the
gold carbene I (Scheme 6). Fast, neighbouring-group-aided
1,2-migration must proceed with planarisation of both the a-C
and the non-migrating heteroatom (I!K or M). Therefore, N-
migration is favoured as iminium M would result in greater
steric congestion than oxonium K due to the enforced proxim-
ity of its larger substituents with the adjacent groups. Because
gold carbene I is expected to show considerable carbocationic
character, nitrogen’s greater ability to stabilise positive charge
would also favour 1,2-N migration (J vs. L).[3,24] As high selectiv-
ity for N-migration of N-sp2 carbamates and sulfonamides with
electron-withdrawing groups was also observed, the late tran-
sition-state assessment (K vs. M) appears more accurate. This
scenario can also explain why a loss in selectivity was observed
with substrates such as 1e, where the smaller substituents on
nitrogen allow a planar configuration to be accessed affording
isomer 3.[25] The relative spatial positioning of the amide and
alkoxy groups to the adjacent metal carbene may also have an
impact on the migration, though as the relative stereochemis-
try in I is unknown, little comment can be made at this
stage.[26] The reduced selectivity observed with o-substituted
Keywords: carbenes
regioselectivity · ynamides
·
cycloisomerisation
·
gold
·
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[21] Similarly, attempts to trap the gold carbene with a large excess of sty-
rene were unsuccessful.
[22] For examples of carboalkoxylations featuring external migrations of al-
lylic and benzylic cations, see Ref. [1a,b,f,k,l].
[23] CCDC-971399 (Compound 2a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
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[25] Isomers
3 could potentially result from exo-cyclisation [Scheme 2,
Eq. (1)], but it seems unlikely that this pathway would be favoured for
smaller substituents, such as NMeMs when it is not observed with
larger groups.
[26] a) A. Nickon, Acc. Chem. Res. 1993, 26, 84–89; b) B. M. Trost, T. Yasukata,
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Received: April 11, 2014
[14] Examples of 1,2-carboalkoxylation with internal migration: a) H. J. Bae,
B. Baskar, S. E. An, J. Y. Cheong, D. T. Thangadurai, I.-C. Hwang, Y. H.
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Skeletal Rearrangements
H. V. Adcock, T. Langer, P. W. Davies*
&& – &&
1,2-N-Migration in a Gold-Catalysed
Synthesis of Functionalised Indenes
by the 1,1-Carboalkoxylation of
Ynamides
Migrating nitrogen: A unique a-hemia-
minal ether gold carbene intermediate
is invoked in a new gold-catalysed cy-
cloisomerisation to access functionalised
indenes. The use of an ynamide to en-
force a 1,1-carboalkoxylation pathway is
followed by a highly selective 1,2-nitro-
gen migration for which a selectivity
model is proposed (see scheme).
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!