A Gold Carbene Manifold to Prepare Fused γ-Lactams by Oxidative Cyclisation of Ynamides

Article abstract of DOI:10.1002/chem.201804378

Gold-catalysed oxidative cyclisation reactions of ynamides offer great promise in γ-lactam synthesis but are limited by preferential over-oxidation to form α-keto imides. Evaluating the factors that might limit N-cyclisation pathways led to effective gold-catalysed conditions that allow access to different fused γ-lactams on changing the ynamide N-substituent and accommodate previously incompatible substitution patterns. New and efficient methods for the synthesis of functionalised 3-aryl indoles and cyclohepta[c]pyrrol-1-one derivatives are presented. These conditions illustrate the complementarity of gold catalysis to other metals.

Full text of DOI:10.1002/chem.201804378

A Journal of
Accepted Article
Title: A Gold Carbene Manifold to Prepare Fused γ-Lactams by
Oxidative Cyclisation of Ynamides
Authors: Fernando Sanchez-Cantalejo, Joshua D Priest, and Paul
William Davies
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201804378
Link to VoR: http://dx.doi.org/10.1002/chem.201804378
Supported by

10.1002/chem.201804378
Chemistry - A European Journal
COMMUNICATION
A Gold Carbene Manifold to Prepare Fused γ-Lactams by
Oxidative Cyclisation of Ynamides
Fernando Sánchez-Cantalejo, Joshua D. Priest and Paul W. Davies*
Abstract: Gold catalysed oxidative cyclisation reactions of ynamides
offer great promise in γ-lactam synthesis but are limited by preferential
over-oxidation to form α-keto imides. Evaluating the factors that might
limit N-cyclisation pathways led to effective gold-catalysed conditions
that allow access to different fused γ-lactams on changing the
ynamide N-substituent and accommodate previously incompatible
substitution patterns. New and efficient methods for the synthesis of
functionalised 3-aryl indoles and cyclohepta[c]pyrrol-1-one
derivatives are presented. These conditions illustrate the
complementarity of gold catalysis to other metals.
Metal-catalysed oxidation of ynamides H provides a diazo-free
access to α-imido carbenoids (Scheme 1b).[6,7] Ynamides are
readily prepared with diverse substitution patterns[8] while gold
catalysis displays excellent functional group tolerance.[9] Together
this offers great promise for lactam synthesis. However, gold-
catalysed oxidative cyclisation’s do not currently provide a
general alternative to the use of diazoacetamide precursors.[10]
Generating sub-stoichiometric quantities of electrophilic
organometallics from a (super)stoichiometric nucleophilic oxidant
presents an intrinsic challenge as over-oxidation of the ynamide
to α-keto imides can dominate.[6a] Furthermore, N-aryl and N-
benzyl substituents are used in gold-catalysed oxidative
processes without forming lactams indicating that N-cyclisation of
the organogold species is slow when compared to
diazoacetamide processes.[6a,11]
γ-Lactams are common motifs in bioactive natural products and
pharmaceuticals.[1] The cyclisation of acetamido metal carbenes
A by reaction at N-tethered C-H or C-C bonds provides a powerful
hydrocarbon-forming strategy allowing access to different types
of lactam (Scheme 1a).[2] Divergent pathways are often
accessible in such processes and controlled by modifying the
substrate structure, with α-proton, -methyl, or -electron-
withdrawing groups commonly encountered, and by tuning the
reaction conditions and choice of catalyst.[3-5] The wider
application of carbene-based γ-lactam formation is limited by the
most common precursors, diazoacetamides G (Scheme 1b). The
need to install sacrificial and highly reactive diazo groups is
deleterious for step and process economy, safe-handling, and
wider compatibility with desirable structural or functional features.
Scheme 2. Gold catalysed oxidative reactions: The impact of ynamide C-
substitution on α-ketoimide formation versus desirable inter- or intramolecular
pathways. DBTP = Tris(2,4-di-t-butylphenyl) phosphite.
Scheme 1. (a) Utility of acetamido metal carbenes to access lactam motifs; (b)
Ynamide versus diazo method to access metal carbene reactivity.
Reported gold-catalysed oxidative N-cyclisations are sensitive to
the choice of carbene α-substituent: Over-oxidation predominates
over cyclisation when an N-allyl ynamide has an electron-rich
substituent, or when an N-phenyl ynamide has a substituent other
than hydrogen (Scheme 2).[10a,b] A three-component coupling
(Scheme 2, bottom) further illustrates the challenge of controlling
competing pathways: Intermolecular coupling is favoured over N-
cyclisation, and over-oxidation again dominates when the
ynamide bears an α-electron donor-group.[11d,12]
[a]
Dr Fernando Sánchez-Cantalejo, Joshua D. Priest and Dr. Paul W.
Davies
School of Chemistry,
University of Birmingham, Birmingham, UK
E-mail: p.w.davies@bham.ac.uk
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804378
Chemistry - A European Journal
COMMUNICATION
This apparent proclivity for over-oxidation under gold catalysis
has seen Rh(I)[13] and Zn(II)[14] catalysed oxidative N-cyclisations
developed to access cyclopropanation, metathesis and Friedel-
dilute conditions at elevated temperature, a bulky electron-rich
ligand on gold, and a polar solvent such as nitromethane or
acetonitrile (Scheme 4, see ESI). Yields dropped off sharply with
Craft pathways. As the metal will strongly influence reaction mode, more electron-deficient and less bulky ligands. Methylpicolinate-
process efficiency and substrate generality, our interest in
accessing gold carbene reactivity from ynamides[15] prompted us
to explore the aspects that appear to limit wider use of gold-
catalysis in this area. We show here that gold-catalysed oxidative
N-cyclisation can be considered as a general and productive tool
for fused γ-lactam synthesis that complements and diverges from
current methods employing gold and other metal catalysts.
derived oxidant 2a proved effective at near stoichiometric levels
to the ynamide. 2-Bromopyridine N-oxide 2e[11c] was similarly
effective but degrades on standing at room temperature, leaving
2a as a more practical choice. Other N-oxides used in alkyne
oxidation, such as 8-ethylquinoline N-oxide 2b,[19] were inferior
here.
We investigated the formation of oxindoles over α-ketoimides
by gold-catalysed oxidation of an internal N-phenyl ynamide. We
hypothesised that, while competing over-oxidation exacerbates
the problem, oxidative N-cyclisations of ynamides are challenging
because the ynamide-derived carbenoids are geometrically- and
electronically-compromised against cyclisation.
Application of the ynamide approach must consider that the
vinyl gold carbenoid J that precedes the gold carbene K is also a
functional electrophile (Scheme 3).[10a,11d] 5-Endo-trig cyclisation
is required from J[16] for an N-phenyl ynamide I, indicating that
formation of gold carbene K/K’ might be needed prior to
cyclisation. In contrast, oxidation can occur from either J or K/K’.
Furthermore, the electron-withdrawing N-substituent that
stabilises the ynamide can reduce the relative rate of cyclisation
of the gold carbene relative to diazoacetamide-derived metal
carbenes:[17] The s-cis and s-trans amide rotamers K/K’ will have
significantly different localised dipole moments, and the required
s-cis rotamer K’ is predicted to be disfavoured;[18] A second
electron-withdrawing group on nitrogen also reduces the
nucleophilicity of the aromatic ring.
Scheme 4. Effect of ligand and oxidant on the gold-catalysed oxidative
cyclisation of an internal ynamide to form a 3-phenyl oxindole.
The selectivity for N–cyclisation appeared consistent with our
model: an electron-rich ligand on gold and heating will both aid
elimination of the pyridine nucleofuge to form gold carbene K from
the potentially unproductive J (Scheme 3).[20] The reactive
rotamer K’ is rendered more accessible due to the polar reaction
media, which ameliorates the impact from dipole discrepancy,
and heating, which aids interconversion between amide rotamers.
Over oxidation to L is slowed by use of a bulky and deactivated
N-oxide at higher dilution.
Exploring the transformation more widely (Scheme 5) showed
that inductively and mesomerically electron-donating and
electron-withdrawing groups were tolerated on both the N-aryl
(3b-f,h) and C-terminus positions (3g-m). The ready
incorporation of desirable and synthetically useful functionality,
including thioether 3d, aryl iodide 3h and esters 3e,i,j, highlights
the tolerance of the gold-catalysed method.
Formation of the oxindole 3l is noteworthy as electron-
donating ynamide substituents such as the p-methoxybenzene
group were either not tolerated or not assessed in diverse
ynamide oxidation processes (Scheme 2).[10a,c,11a,c,d] Steric bulk at
the ortho-positions of both substituents can also be
accommodated (3k). In both cases, over-oxidation does start to
compete, but simply adding the oxidant portion-wise over the
course of the reaction recovers the good yields of oxindoles (see
ESI for details). The 3-(indol-3-yl) oxindole motif (3m) common
within bioactive natural products can be accessed in good yield
as a result. Alkyl substituents on the ynamide were not tolerated;
Scheme 3. A proposed model to explain the challenge of oxidative N-cyclisation
from ynamides. While oxidation is viable from all organometallic species, the
desired cyclisation needs access to a disfavoured rotamer of the gold carbene.
With this model in mind, we found that oxindole 3a could
indeed be accessed in high yield from N-phenyl-N-
(phenylethynyl)methanesulfonamide 1a when using relatively
This article is protected by copyright. All rights reserved.

10.1002/chem.201804378
Chemistry - A European Journal
COMMUNICATION
1,2-CH insertion dominates even when leading to a strained
system (1n4).[6a] Deprotection of N-sulfonyl lactams is well
established and 3f underwent desulfonylation with sodium
naphthalenide[21] to give the NH oxindole in 69% yield (See ESI).
Ye’s group avoided over-oxidation in
a
synthesis of
dihydrooxyisoquinolinones from N-benzylated ynamides by using
Zn(OTf)2. A Friedel-Crafts pathway is enforced from the vinyl zinc
species by precluding access to a metal carbene, (analogous to
J and not K in Scheme 3).[14] Having invoked formation of a gold
carbene, we were intrigued to see whether this would translate
into different reactivity with N-benzylated substrates.[18,23]
Oxidative Büchner-type cyclopropanation and electrocyclic
ring-opening process was observed using p–methoxy benzyl
ynamides 7a-d to give [5.3.0]azabicycles 8a-d under our
conditions (Scheme 7). No β-lactam formation by CH insertion at
the benzylic position was seen, possibly due to the deactivating
effect of two electron-withdrawing groups on nitrogen.[3d] No
conversion to other products was seen when 8a was resubjected
to the catalysis conditions, or exposed to trifluoroacetic acid,
indicating an irreversible cyclopropanation.[24]
A
dynamic
cycloheptatriene to norcaradiene relationship was apparent from
NMR spectroscopy (see ESI). Norcaradiene 8a’ was trapped out
with PTAD at lower temperature to access polycycle 9 in good
yield. Reaction of 7e unveils the cationic character of gold
carbenes with the m-methoxy substituent stabilising the Wheland
intermediate en route to 3-oxy-1,4-dihydroisoquinoline 10.
Scheme 5. Substrate scope for the oxindole synthesis. Isolated yields after
column chromatography. [a] 2a added portion-wise (See ESI for details).
N-Allyl ynamide 5 reacted smoothly under our conditions to give
3-azabicyclo[3.1.0]hexane in high yield, contrasting the
6
exclusive over-oxidation previously observed with this electron-
rich substituent (Scheme 6 cf Scheme 2).[10a,13,22] Achieving this
outcome by adding the oxidant in a single portion highlights the
greater challenge in cyclizing onto N-aryl than N-allyl groups.
Scheme 7. (Top) Oxidative Büchner type reaction of ynamides and trapping the
norcaradiene valence tautomer. (Bottom) Use of electronic influence to direct a
Friedel-Crafts type pathway to form a 3-oxy-1,4-dihydroisoquinoline.
While an ynamide bearing an unsubstituted benzyl group
favoured the [5.3.0]azabicycle (29%) over 3-oxy-1,4-
dihydroisoquinoline (5%), substantial over-oxidation was
observed (see ESI). The addition of a methyl substituent was
sufficient to direct the reaction solely to the cycloheptatriene-
fused lactam 8f in preparatively useful yield (Scheme 8). The allyl
enol ether 8g was also formed despite the potential for
fragmenting spirocyclisation on elimination of an allyl cation from
a cationic Wheland intermediate.[10c] Use of ortho-substituted
Scheme 6. Formation of 3-azabicyclo[3.1.0]hexane derivative with an electron
donating α-substituent.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804378
Chemistry - A European Journal
COMMUNICATION
substrates affords the 7-substituted products 8h/i. Some
Büchner-type product 8j was even isolated from the mesityl
system that requires formation of a highly strained cyclopropane
made up of three contiguous quaternary centres. Introducing
structural constraints to disfavour ring-opening saw the fused
cyclopropane 8k formed in good yield.
Keywords: ynamide • gold • oxidation • cyclisation • γ-lactam
§
All compounds are prepared in the racemic series with relative
stereochemistry indicated.
[1]
[2]
[3]
J. Caruano, G. G. Muccioli, R. Robiette, Org. Biomol. Chem. 2016, 14,
10134-10156.
Review into transition metal catalysed synthesis of lactams: L.-W. Ye, C.
Shu, F. Gagosz, Org. Biomol. Chem. 2014, 12, 1833-1845.
For representative examples, see: a) H. Nakayama, S. Harada, M. Kono,
T. Nemoto, J. Am. Chem. Soc. 2017, 139, 10188-10191; b) D. Sole, F.
Perez-Janer, I. Fernandez, Chem. Commun. 2017; c) S. A. Bonderoff, A.
Padwa, J. Org. Chem. 2017, 82, 642-651; d) Y. Deng, C. Jing, H. Arman,
M. P. Doyle, Organometallics 2016, 35, 3413-3420; e) K. Yamamoto, Z.
Qureshi, J. Tsoung, G. Pisella, M. Lautens, Org. Lett. 2016, 18, 4954-
4957; f) V. N. G. Lindsay, D. Fiset, P. J. Gritsch, S. Azzi, A. B. Charette,
J. Am. Chem. Soc. 2013, 135, 1463-1470; g) V. K.-Y. Lo, Z. Guo, M. K.-
W. Choi, W.-Y. Yu, J.-S. Huang, C.-M. Che, J. Am. Chem. Soc. 2012,
134, 7588-7591; h) S. Miah, A. M. Z. Slawin, C. J. Moody, S. M. Sheehan,
J. P. Marino Jr, M. A. Semones, A. Padwa, I. C. Richards, Tetrahedron
1996, 52, 2489-2514; i) A. Padwa, D. J. Austin, A. T. Price, M. A.
Semones, M. P. Doyle, M. N. Protopopova, W. R. Winchester, A. Tran,
J. Am. Chem. Soc. 1993, 115, 8669-8680.
[4]
M. P. Doyle, R. Duffy, M. Ratnikov, L. Zhou, Chem. Rev. 2010, 110, 704-
724.
[5]
[6]
A. Ring, A. Ford, A. R. Maguire, Tetrahedron Lett. 2016, 57, 5399-5406.
a) P. W. Davies, A. Cremonesi, N. Martin, Chem. Commun. 2011, 47,
379-381; b) C.-W. Li, K. Pati, G.-Y. Lin, S. M. Abu Sohel, H.-H. Hung, R.-
S. Liu, Angew. Chem., Int. Ed. 2010, 49, 9891-9894.
[7]
[8]
For a review of wider alkyne oxidative cyclisation: Z. Zheng, Z. Wang, Y.
Wang, L. Zhang, Chem. Soc. Rev. 2016, 45, 4448-4458.
Scheme 8. Varying the benzylic substituent for oxidative Büchner type reaction.
a) Y. Tu, X. Zeng, H. Wang, J. Zhao, Org. Lett. 2017; b) S. J. Mansfield,
C. D. Campbell, M. W. Jones, E. A. Anderson, Chem. Commun. 2015,
51, 3316-3319; c) A. Coste, G. Karthikeyan, F. Couty, G. Evano, Angew.
Chem., Int. Ed. 2009, 48, 4381-4385; d) T. Hamada, X. Ye, S. S. Stahl,
J. Am. Chem. Soc. 2008, 130, 833-835; e) Y. S. Zhang, R. P. Hsung, M.
R. Tracey, K. C. M. Kurtz, E. L. Vera, Org. Lett. 2004, 6, 1151-1154.
a) A. Fürstner, Angew. Chem., Int. Ed. 2017, 57, 4215-4233; b) R. Dorel,
A. M. Echavarren, Chem. Rev. 2015, 115, 9028-9072; c) A. S. K. Hashmi,
Chem. Rev. 2007, 107, 3180-3211; d) A. Fürstner, P. W. Davies, Angew.
Chem., Int. Ed. 2007, 46, 3410-3449.
In conclusion, by considering factors that might limit N-cyclisation
pathways in gold-catalysed oxidative reactions of ynamides,
conditions have been developed that allow formation of fused γ-
lactams and tolerate a range of useful functional groups and steric
and electronic influences. Different N-heterocycles, including 3-
aryl oxindoles and cyclohepta[c]pyrrol-1-one derivatives, are
accessed by varying the nitrogen-substituent. The assembly of a
novel sp3-rich framework, 9, illustrates how this approach can be
used to construct molecular complexity in short order from
modular and readily-assembled precursors. The inherent
competing over-oxidation pathway that has limited gold-catalysed
N-cyclisation reactions of ynamides can be overcome, even
allowing use of α-substituents that favour oxidation in previous
reports. Selective formation of [5.3.0]azabicyclic Büchner type
products from a gold carbene manifold contrasts with the
oxyisoquinoline derivatives accessed from vinyl zinc carbenoids
and the ß-lactams accessed from diazo precursors, illustrating the
complementarity of gold-catalysed methods against other metals.
[9]
[10] a) K.-B. Wang, R.-Q. Ran, S.-D. Xiu, C.-Y. Li, Org. Lett. 2013, 15, 2374-
2377; b) L.-Q. Yang, K.-B. Wang, C.-Y. Li, Eur. J. Org. Chem. 2013,
2775-2779; Reports published during the preparation of this manuscript:
c) M. Ito, R. Kawasaki, S. Kanyiva Kyalo, T. Shibata, Chem. Eur. J. 2018,
24, 3721-3724; d) M. Lin, L. Zhu, J. Xia, Y. Yu, J. Chen, Z. Mao, X. Huang,
Adv. Synth. Catal. 2018, 360, 2280-2284.
[11] a) C.-H. Shen, L. Li, W. Zhang, S. Liu, C. Shu, Y.-E. Xie, Y.-F. Yu, L.-W.
Ye, J. Org. Chem. 2014, 79, 9313-9318; b) F. Pan, S. Liu, C. Shu, R.-K.
Lin, Y.-F. Yu, J.-M. Zhou, L.-W. Ye, Chem. Commun. 2014, 50, 10726-
10729; c) L. Li, C. Shu, B. Zhou, Y.-F. Yu, X.-Y. Xiao, L.-W. Ye, Chem.
Sci. 2014, 5, 4057-4064; d) M. Dos Santos, P. W. Davies, Chem.
Commun. 2014, 50, 6001-6004; e) C.-F. Xu, M. Xu, Y.-X. Jia, C.-Y. Li,
Org. Lett. 2011, 13, 1556-1559; f) R. B. Dateer, K. Pati, R.-S. Liu, Chem.
Commun. 2012, 48, 7200-7202.
[12]
A substantially reduced yield was also reported with a p-anisole
substituent on the ynamide in the oxidative N-cyclisation-fragmentation
sequence reported during the preparation of this work, see Ref 10c.
Acknowledgements
[13] R. Liu, G. N. Winston-McPherson, Z. Y. Yang, X. Zhou, W. Song, I. A.
Guzei, X. Xu, W. Tang, J. Am. Chem. Soc. 2013, 135, 8201-8204.
[14] L. Li, B. Zhou, Y.-H. Wang, C. Shu, Y.-F. Pan, X. Lu, L.-W. Ye, Angew.
Chem., Int. Ed. 2015, 54, 8245-8249.
The authors thank the EC for a Marie-Curie IEF DIAZOFREE
(FSC) and the EPSRC and University of Birmingham (UoB) for a
studentship (JDP). Jasper Sach (UoB, Undergraduate) is thanked
for the preparation of some ynamide precursors. The authors
acknowledge support from the Centre for Chemical and Materials
Analysis in the School of Chemistry at UoB.
[15] a) H. V. Adcock, E. Chatzopoulou, P. W. Davies, Angew. Chem., Int. Ed.
2015, 54, 15525-15529; b) H. V. Adcock, T. Langer, P. W. Davies,
Chem.-Eur. J. 2014, 20, 7262-7266; c) P. W. Davies, A. Cremonesi, L.
Dumitrescu, Angew. Chem., Int. Ed. 2011, 50, 8931-8935.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804378
Chemistry - A European Journal
COMMUNICATION
[16] G. Henrion, T. E. J. Chavas, X. Le Goff, F. Gagosz, Angew. Chem., Int.
Ed. 2013, 52, 6277-6282.
[21] C. P. Seath, J. W. B. Fyfe, J. J. Molloy, A. J. B. Watson, Synthesis, 2017,
49, 891-898.
[17] a) G. Evano, A. Coste, K. Jouvin, Angew. Chem., Int. Ed. 2010, 49, 2840-
2859; b) K. A. De Korver, H. Li, A. G. Lohse, R. Hayashi, Z. Lu, Y. Zhang,
R. P. Hsung, Chem. Rev. 2010, 110, 5064-5106.
[22] Strong electron donor substituents were not reported in the Rh(I)
catalysed oxidative cyclopropanation, see ref 13.
[23] a) M. P. Doyle, M. S. Shanklin, H. Q. Pho, Tetrahedron Lett. 1988, 29,
2639-2642; b) D. Qian, J. Zhang, Chem. Soc. Rev. 2015, 44, 677-698.
[24] (a) Y. Wang, P. R. McGonigal, B. Herlé, M. Besora, A. M. Echavarren, J.
Am. Chem. Soc. 2014, 136, 801-809; (b) M. P. Doyle, M. S. Shanklin and
H. Q. Pho, Tetrahedron Lett. 1988, 29, 2639-2642.
[18] For an analysis in the diazo series, see: R. R. Nani, S. E. Reisman, J.
Am. Chem. Soc. 2013, 135, 7304-7311.
[19] D. B. Huple, S. Ghorpade, R.-S. Liu, Chem.-Eur. J. 2013, 19, 12965-
12969.
[20] B. Lu, Y. Luo, L. Liu, L. Ye, Y. Wang, L. Zhang, Angew. Chem., Int. Ed.
2011, 50, 8358-8362.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804378
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Fernando Sánchez-Cantalejo, Joshua D.
Priest and Paul W. Davies*
Page No. – Page No.
A Gold Carbene Manifold to Prepare
Fused γ-Lactams by Oxidative
Cyclisation of Ynamides
Oxidative N-cyclisations of ynamides provide efficient access to a variety of fused γ-lactams including oxindoles and
cyclohepta[c]pyrrol-1-one derivatives. A model is proposed to rationalise the reactivity challenges and show how previously dominant
over-oxidation pathways can be overcome to access the desirable reactivity patterns of gold carbenes.
This article is protected by copyright. All rights reserved.