Directed carbonylative (3+1+2) cycloadditions of amino-substituted cyclopropanes and alkynes: Reaction development and increased efficiencies using a cationic rhodium system

Article abstract of DOI:10.1016/j.tet.2015.08.052

Urea-directed carbonylative insertion of Rh(I)-catalysts into one of the two proximal C-C bonds of aminocyclopropanes generates rhodacyclopentanone intermediates. These are trapped by N-tethered alkynes to provide a (3+1+2) cycloaddition protocol that acc

Full text of DOI:10.1016/j.tet.2015.08.052

Tetrahedron 72 (2016) 2731e2741
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Directed carbonylative (3þ1þ2) cycloadditions of amino-substituted
cyclopropanes and alkynes: reaction development and increased
efficiencies using a cationic rhodium system
,
Megan H. Shawa, William G. Whittingham b, John F. Bower a
*
a School of Chemistry, University of Bristol, Bristol, BS8 1TS, United Kingdom
b Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2015
Received in revised form 19 August 2015
Accepted 21 August 2015
Available online 22 August 2015
Urea-directed carbonylative insertion of Rh(I)-catalysts into one of the two proximal CeC bonds of
aminocyclopropanes generates rhodacyclopentanone intermediates. These are trapped by N-tethered
alkynes to provide a (3þ1þ2) cycloaddition protocol that accesses N-heterobicyclic enones. Stoichio-
metric studies on a series of model rhodacyclopentanone complexes outline key structural features and
provide a rationale for the efficacy of urea directing groups. A comprehensive evaluation of cycloaddition
scope and a ‘second generation’ cationic Rh(I)-system, which provides enhanced yields and reaction rates
for challenging substrates, are presented.
Keywords:
Rhodium
Rhodacyclopentanone
Cycloaddition
N-Heterocycle
Catalysis
Ó 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
1. Introduction
the amino-rhodacyclopentanones intermediates are outlined, and
a simple modification to our original (3þ1þ2) cycloaddition pro-
Synthetically flexible and modular entries to stereochemically
rich N-heterocyclic scaffolds are of topical interest to the pharma-
ceutical sector.1 Recently, we reported a strategy to access selec-
tocol is disclosed, which provides enhanced yields and reaction
rates for challenging substrates.
tively amino-rhodacyclopentanones
3 by the carbonylative
insertion of Rh(I)-catalysts into the more hindered CeC bond of
amino-substituted cyclopropanes 1 (Scheme 1).2 Specifically, we
established that carbonyl-based N-protecting groups can direct
oxidative addition (to 2) and CO-insertion to generate regioisomer
3 in a selective manner. Trapping of 3 with N-tethered alkynes
provided a (3þ1þ2) cycloaddition strategy to generate N-hetero-
bicyclic enones (4/5).3 These investigations provided proof-of-
principle for an approach that has the potential to enable a wide
range of carbonylative cycloadditions for accessing directly ‘sp3-
rich’ chiral scaffolds.1,4 Indeed, to date, the catalysis platform out-
lined in Scheme 1 has served as the basis for related (3þ1þ2) cy-
cloadditions involving alkenes,5 and
a
(7þ1) cycloaddition-
fragmentation approach to substituted azocanes.6 In this article
we disclose our full studies on the development of urea-directed
(3þ1þ2) cycloadditions involving alkynes. In addition to key
mechanistic considerations, detailed studies on the generation of
Scheme 1. Directed generation of amino-rhodacyclopentanones (catalysis platform).
* Corresponding author. E-mail address: john.bower@bris.ac.uk (J.F. Bower).
http://dx.doi.org/10.1016/j.tet.2015.08.052
0040-4020/Ó 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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M.H. Shaw et al. / Tetrahedron 72 (2016) 2731e2741
2. Results and discussion
observed as the sole product, whereas [Rh(cod)2]BF4 delivered
a mixture of branched adducts 9aec. 9bec presumably arise from
Rh-catalysed isomerisation of alkene 9a. The sole formation of
branched alkenes 9aec from alkyl-substituted cyclopropane 8
confirms the importance of the N-directing group for the conver-
sion of 6a to 7a in Scheme 2.
At the outset of our studies, catalytic protocols reliant on the
intermediacy of rhodacyclopentanones were scarce and processes
involving amino-substituted variants had not been developed.
Pioneering studies by Wilkinson demonstrated Rh/CO insertion
into cyclopropane to generate a dimeric rhodacyclopentanone.7a
Subsequent work by McQuillin examined the regioselectivity of
this process for substituted variants.7b An alternative approach was
reported by Murakami and Ito, where rhodacyclopentanones were
accessed by the insertion of Rh(I)-systems into the acyl-carbon
bond of cyclobutanones.8 This process has served as the basis for
a series of methodologies,9e11 however, carbonylative rhodacyclo-
pentanone formation has not been as widely exploited in synthe-
sis.3a,12 Notable processes that harness this approach include
carbonylative rearrangements of spiropentanes, as reported by
Murakami,12b and (3þ1þ2) cycloadditions involving alkynes to
generate carbocyclic systems, as reported by Narasaka.3a In this
latter process, the alkyne is invoked as a directing group. For the
strategy outlined in Scheme 1, the most pertinent work is that of
Chirik, who demonstrated efficient phosphinite-directed insertion
of neutral Rh(I)-systems into alkyl-substituted cyclopropanes, al-
beit under non-carbonylative conditions.13,14 With this report in
mind, our initial goal was to establish the viability of using N-
directing groups to control Rh/CO insertion.
Scheme 3. Non-directed insertions of neutral and cationic Rh(I)-systems into an alkyl-
substituted cyclopropane.
Further studies were conducted to assess the capability of other
N-protecting groups for directing Rh-insertion (Scheme 4). Ac-
cordingly, amide 6b and sulfonamide 6c were exposed to
[Rh(cod)2]BF4/PPh3 under non-carbonylative conditions. The ex-
clusive formation of linear products 7b/c was observed in both
cases, thereby supporting a directed oxidative addition pathway.
2.1. Regioselective generation and key structural features of
amino-rhodacyclopentanones
Preliminary studies examined the regioselectivity of Rh(I)-
insertion into carbamate-protected aminocyclopropane 6a
(Scheme 2). A neutral Rh(I)-system, derived from [Rh(cod)Cl]2 and
PPh3, delivered branched vinyl carbamate iso-7a via insertion into
the less hindered CeC bond. In contrast, employment of [Rh(cod)2]
BF4 as the pre-catalyst resulted in rapid and quantitative formation
of linear vinyl carbamate 7a via Rh-insertion into the more hindered
CeC bond. For [Rh(cod)2]BF4, significant conversion to 7a was ob-
served even at 60 ꢀC; this indicates that oxidative addition is rea-
sonably facile. The faster rate of vinyl carbamate formation versus
[Rh(cod)Cl]2 may be due to an additional vacant coordination site
Scheme 4. Amide and sulfonamide directed Rh-insertions.
The studies described above show that, under non-carbonylative
conditions, only Lewis acidic cationic Rh(I)-catalysts can be utilised
for protecting group directed oxidative addition. It was anticipated
that, under carbonylative conditions, CO-ligated neutral catalysts
facilitating b-hydride elimination. These results suggest that rela-
tively Lewis acidic metal complexes (i.e., cationic vs neutral) are
required to ensure coordination to the carbamate directing group
and contrast Chirik’s studies where neutral Rh(I)-systems were
effective with strongly directing phosphinites.13
may be sufficiently Lewis acidic because CO is a strong p-acceptor
ligand, and this, in turn, should increase the electron deficiency of
the Rh-centre. However, when carbamate-protected cyclopropane
6a was exposed to a neutral Rh-catalyst ([Rh(cod)Cl]2, PPh3) under
a CO atmosphere, formation of linear or branched vinyl carbamates
7a and iso-7a did not occur. The absence of 7a or iso-7a is suggestive
of fast migratory insertion of CO at the stage of the incipient rho-
dacyclobutane to generate small quantities of the corresponding
rhodacyclopentanone. Consequently, stoichiometric reactions were
conducted with the aim of isolating and characterising neutral
amino-substituted rhodacyclopentanones and thereby determining
the regioselectivity of Rh/CO insertion. Wilkinson reported the
synthesis of a dimeric rhodacyclopentanone from cyclopropane and
[Rh(CO)2Cl]2; addition of triphenylphosphine generated the corre-
sponding monomeric complex.7a Accordingly, exposure of
Scheme 2. Catalyst and directing group controlled regioselective vinyl carbamate
formation.
carbamate-protected
cyclopropane
11
to
stoichiometric
7b
[Rh(CO)2Cl]2 delivered dimeric rhodacyclopentanone 12 in 75%
yield (Scheme 5A). The solid state structure of 12 was confirmed by
single crystal X-ray diffraction, which revealed: (a) a heterochiral
dimeric complex, (b) the desired regioselectivity for oxidative ad-
dition, (c) the desired regioselectivity for migratory insertion of CO
and (d) axial coordination of the carbamate directing group to the
Rh-centre. This demonstrates that carbonyl-ligated neutral Rh(I)-
To confirm the role of the directing group in the conversion of 6a
to 7a, analogous regioselectivity studies on alkyl-substituted cy-
clopropane 8 were conducted (Scheme 3). Both neutral and cationic
Rh(I)-systems delivered only branched products, resulting from Rh-
insertion into the less hindered CeC bond; no detectable levels of
linear product 10 were observed. Using [Rh(cod)Cl]2, alkene 9a was

M.H. Shaw et al. / Tetrahedron 72 (2016) 2731e2741
2733
catalysts are effective for directed insertion into amino-
cyclopropanes. Cowie and co-workers have reported an X-ray
crystal structure of a bimetallic rhodacyclopentanone derived from
allene insertion into a methylene-bridging CO-ligated RheRu
complex.15 However, the structure shown in Scheme 5A is the first
X-ray crystal structure of a rhodacyclopentanone derived from
carbonylative cyclopropane ring expansion.
monomeric complexes with two phosphine ligands bound to the
Rh-centre.7a In the present case, both the directing group carbonyl
and a CO ligand remain bound to the Rh-centre, consequently only
one phosphine ligand can be accommodated. The 13C NMR spec-
trum of complex 14 (see the Supplementary data) confirmed the
presence of the CO and PPh3 ligands, and also showed that the
carbamate directing group remains bound to the Rh-centre because
(a) 3J-coupling of C3 to phosphorus was observed (J¼10 Hz) and (b)
there was little change in the chemical shift of C3 between the
dimeric and monomeric complexes (dimer 12: 164.6 ppm vs
monomer 14: 165.3 ppm vs starting material 11: 157.8 ppm).
13C NMR coupling constants were used to assign the geometry of
complex 14. An alkyl/acyl CeRh coupling constant ofw20 Hz was
observed for C5 and C8 and a carbonyl-Rh coupling of 77 Hz was
observed for C9; these coupling constants are consistent with re-
lated structures in the literature.16 The CeP coupling constants for
C5, C8 and C9 are 86.0, 3.0 and 11.5 Hz respectively, indicating that
C5 has a trans relationship to PPh3 (large coupling constants are
reported for trans CeRheP relationships).16 C8 and C9 have small
CeP coupling constants which suggests a cis relationship to PPh3.
The structure of 14 was supported further by the relatively small
JRh-P, indicative of a complex with a coordination number of five or
six and containing an alkyl group trans to the phosphine.17 We have
recently reported an X-ray crystal structure of a related phosphine-
bound rhodacyclopentanone complex, the NMR data of which are
consistent with those of 14.5
For the strategy outlined in Scheme 1, a key factor is the co-
ordinating strength of the N-directing group. Studies in the litera-
ture have compared the binding strength of various carbonyl
groups with Lewis or Brønsted acids,18 but these results are not
directly transferable to transition metal complexes. Consequently,
we synthesised
a series of rhodacyclopentanone complexes
(15aec), which were characterised by X-ray diffraction, and eval-
uated the relative donor strength of each directing group by com-
paring the stretching frequencies of the trans CO ligand in each case
(Scheme 6).19 From these studies the following ranking of directing
group strength emerges: urea>>carbamate>amide. Attempted
synthesis of an analogous complex containing a sulfonamide
directing group was not successful (cf. Scheme 4) and so, at the
present time, we have been unable to quantify the donor strength
of this class of directing group.
Scheme 5.
At 27 ꢀC, the 1H and 13C NMR spectra (CD2Cl2) of rhodacyclo-
pentanone 12 were broad and suggestive of the presence of two
different species (Scheme 5B). Low temperature NMR data (ꢁ13 ꢀC)
revealed a divergence and sharpening of the two sets of signals,
indicating the presence of two components in dynamic equilib-
rium. The precise structure of the two components has not been
determined, however, rhodacycle 12 may be in equilibrium with
a monomeric species or, alternatively, two diastereomeric com-
plexes, such as 12 and 13, may be interconverting. Addition of one
equivalent of PPh3 resulted in sharpening of the signals in the 1H
NMR spectrum to a single, new, rhodacyclopentanone complex 14
(Scheme 5A). The 31P NMR spectrum showed a doublet at 16.2 ppm
(JRh-P¼80 Hz) confirming coordination of PPh3 to the Rh-centre.
Addition of a second equivalent of PPh3 resulted in no change in
the aliphatic region of the 1H NMR spectrum, whereas the 31P NMR
spectrum showed a doublet at 16.2 ppm and an additional singlet at
ꢁ5.56 ppm (corresponding to unbound PPh3) in a 1:1 ratio, thereby
demonstrating that only one phosphine ligand is coordinated in the
new rhodacyclopentanone complex. Wilkinson and co-workers
reported that addition of excess PPh3 to dimeric rhodacyclo-
pentanone complexes (derived from cyclopropane) delivered
Scheme 6. Relative donor strengths of potential directing groups.
2.2. Development of a neutral Rh(I)-system for (3D1D2)
carbonylative cycloadditions of aminocyclopropanes and
alkynes
The regioselectivity studies outlined above demonstrate that
amino-substituted rhodacyclopentanones can be accessed in a se-
lective manner utilising the directing group strategy outlined in
Scheme 1. Our initial synthetic studies sought to incorporate this
activation mode into (3þ1þ2) cycloadditions involving N-tethered
alkynes (Table 1). Narasaka and Koga have reported (3þ1þ2) car-
bonylative cycloadditions of alkyl-substituted cyclopropanes, pos-
sessing tethered alkynes, to afford carbocyclic enones.3a In this
process, the alkyne was proposed to direct oxidative addition of the
Rh(I)-catalyst into the more hindered CeC bond and relatively
harsh reaction conditions were required (20 mol % [Rh], 160 ꢀC). It

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M.H. Shaw et al. / Tetrahedron 72 (2016) 2731e2741
Table 1
oxidative addition. Indeed, for related processes involving alkenes,
Development of a neutral Rh(I)-systema
we have established that carbamate directing groups are preferred
over ureas.5 In these cases, the less strongly coordinating alkene
component does not inhibit directed oxidative addition and so
a strongly coordinating urea directing group is not required. Ad-
ditionally, equilibration to the intermediate
p-complex (cf. 19) is
more challenging, such that a less strongly coordinating directing
group leads to faster rates.
The scope of the reaction with respect to the alkyne component
has been assessed by exposing aminocyclopropanes 16een to the
optimised neutral Rh(I)-system (Table 2). Both alkyl- and aryl-
substituted alkynes can be utilised, and a range of electron-rich
and -neutral derivatives (16eei) cyclised to the target enones
17eei in moderate to good yield. The structure of cyclohexenone
17h was confirmed by X-ray crystallography. However, electron-
deficient alkynes (e.g., 16j) and heteroaromatic variants (e.g., 16k
and 16l) cyclised less efficiently and the target enones were isolated
in low yield. The inefficiency observed for quinoline derivative 17k
may be due, in part, to competitive coordination of the Rh-catalyst
Entry
Rh-source
Ligand
Solvent T/ꢀC Yield (%)
1
2
3
4
16a [Rh(cod)Cl]2
16b [Rh(cod)Cl]2
16c [Rh(cod)Cl]2
16d [Rh(cod)Cl]2
BINAP
BINAP
BINAP
BINAP
DCB
DCB
DCB
DCB
160
160
160
160
130
130
130
130
26
33
42
<5
53
5d,e 16c [Rh(cod)Cl]2
6d,e 16c [Rh(cod)2]BF4
P(3,5-(CF3)2C6H3)3 DCB
P(3,5-(CF3)2C6H3)3 DCB
29
7d,e 16c [Rh(cod)2]BARF P(3,5-(CF3)2C6H3)3 DCB
<10
72
8d,e 16c [Rh(cod)Cl]2
P(3,5-(CF3)2C6H3)3 PhCN
Table 2
a
Scope of the alkyne component
Isolated yields are quoted; DCB¼1,2-dichlorobenzene.
b
c
2.5 mol % for dimeric complexes and 5 mol % for monomeric complexes.
7.5 mol % for bidentate ligands and 15 mol % for monodentate ligands.
Na2SO4 (20 mol %) was employed as desiccant.
d
e
[Rh] (7.5 mol %) and P(3,5-(CF3)2C6H3)3 (15 mol %) were used.
was anticipated that our carbonyl directed approach may allow
related ring expansions of substituted aminocyclopropanes to
proceed under milder reaction conditions. It is important to note
that, for processes described here, a key aspect is the requirement
that the directing group dissociates from the metal centre after
rhodacyclopentanone formation to allow CeN rotation and co-
ordination of the alkyne. Consequently, a range of directing groups
were evaluated in the hope of fine-tuning the equilibrium between
18 and 19 (Table 1).
Early studies identified that, at 160 ꢀC in DCB, a BINAP-ligated
neutral Rh(I)-system effected cycloaddition of amide 16a to 17a
in 26% yield under an atmospheric pressure of CO (Entry 1). At this
stage, the influence of the directing group was investigated, and it
was found that cycloaddition efficiency increased progressively as
the donor strength was increased to carbamate 16b and then urea
16c (Entries 2 and 3; cf. Scheme 6). Notably, complete consumption
of 16c was observed within 24 h, whereas cycloaddition of 16b to
17b took 72 h. The structure of N-heterobicyclic enone 17b was
confirmed by single crystal X-ray diffraction. To enhance reaction
efficiency further, methoxy-urea 16d was prepared, however, cyc-
lisation of this substrate was not effective and only trace quantities
of target 17d were observed (Entry 4). N-Boc and N-tosyl directing
groups were also completely ineffective. The urea directing group
of 16c allowed the reaction temperature to be lowered to 130 ꢀC
and further optimisation led to the conditions outlined in Entry 5,
which use 7.5 mol % [Rh] and P(3,5-(CF3)2C6H3)3 as ligand to deliver
17c in 53% yield. Under these conditions, cationic Rh-sources were
considerably less effective (Entries 6 and 7, vide infra). Final opti-
misation involved switching the solvent from DCB to PhCN and,
under these conditions, 17c was generated in 72% yield after 72 h
(Entry 8).
The results of the cycloadditions of 16aec (Entries 1e3) merit
further comment because they suggest that equilibration to 19 is
not a key issue (because stronger directing groups are more effec-
tive). It is likely that the dimethylurea directing group is especially
efficient because it is able to outcompete the alkyne moiety for
coordination of the Rh(I)-catalyst, and thereby enhance the rate of

M.H. Shaw et al. / Tetrahedron 72 (2016) 2731e2741
2735
to the Lewis basic nitrogen. Terminal alkynes (16m) are not toler-
ated and this limitation is tentatively attributed to competitive
formation of Rh-alkylidene complexes.20 In all cases, reaction times
are long and, ultimately, this stimulated the development of
a ‘second generation’ protocol, which is discussed later.
Heterocyclic products of greater stereochemical complexity can
be accessed by employing substrates with substitution on the al-
kyne tether (Table 3). Carbonylative cycloadditions of substrates
16oeq delivered cyclohexenones 17oeq in good yields and with
moderate diastereoselectivity; the relative stereochemistry of the
major diastereomers was determined by NOE experiments. Sub-
stitution on the alkyne tether resulted in increased rates of cyclo-
addition relative to unsubstituted substrate 16c, and, in certain
cases, this enabled the employment of marginally lower tempera-
tures (120 ꢀC for 16o vs 130 ꢀC for 16c). The increased rate of re-
action for 16oeq may reflect a greater propensity for the incipient
rhodacycle to adopt a conformation that allows alkyne insertion.
The observed levels of diastereoselectivity for 16oeq are constant
over the timeframe of the reaction. Additionally, no equilibration
was observed when the diastereomers of 17q were separated and
resubmitted to the reaction conditions. These observations suggest
that diastereoselection occurs during cycloaddition rather than by
equilibration (via epimerisation) of the products. The modest dia-
stereoselectivities are unsurprising given that high diaster-
eoselection likely requires the R1 group to bias Rh-insertion into
one of the two diastereotopic cyclopropane CeC bonds of 16oeq. In
related (3þ1þ2) cycloadditions involving alkenes, a solution to this
issue was developed which relies upon reversible rhodacyclo-
pentanone formation.5 Unfortunately, this strategy is not applicable
to the current scenario, perhaps due to more rapid insertion of the
alkyne (vs the alkene), which diminishes reversibility.
Fig. 1. Reaction profiles for Table 1, Entries 5 and 6.
stages of the reaction, but after this only gradual degradation of the
starting material occurs. These data establish that cationic Rh(I)-
sources provide higher initial turnover frequencies but less stable
catalysts (i.e., lower turnover numbers) than neutral systems.
To improve the performance of cationic Rh(I)-derived systems
we assayed a range of ligands and coordinating solvents that
might stabilise the catalyst further (Table 4). In the event, simply
changing the reaction solvent from DCB to PhCN provided con-
ditions that generated 17c in 72% yield after 9.5 h (Entry 1). Other
coordinating solvents (e.g., valeronitrile and DMF) were less ef-
fective (Entries 2 and 3).21 The difference in performance between
PhCN and the more strongly coordinating valeronitrile is particu-
larly striking and indicates that reversible binding of the solvent to
the metal centre is a key factor.22 Using PhCN as solvent, a range of
cationic Rh(I)-sources were efficient and no strong dependency on
the counterion was observed (Entries 4e6). The key benefits of the
conditions outlined in Entries 1 and 4e6 are the significantly
shorter reaction times (7.5e9.5 h vs 72 h for Table 1, Entry 8) and
better substrate scope (vide infra) compared to the neutral Rh(I)-
system. These ‘second generation’ conditions also tolerate de-
creased catalyst loading, but this comes at the expense of longer
reaction times (Entry 7).23 The reaction scope has been explored
using the conditions outlined in Table 4, Entry 6. We have focussed
on substrates that were problematic using the ‘first generation’
protocol and a comparison of the original and improved catalysis
conditions is presented in Table 5 ([Rh(cod)2]OTf versus [Rh(cod)
Cl]2). In all cases, reaction times are reduced significantly by
replacing [Rh(cod)Cl]2 with [Rh(cod)2]OTf. For example, cyclisa-
tion of 16f was complete after 16 h to give a 73% isolated yield of
Table 3
Substitution on the alkyne tether
17f, compared to
a 58% yield in 84 h using [Rh(cod)Cl]2.
Table 4
Optimisation of a cationic Rh(I)-system
2.3. Development of a cationic Rh(I)-system for (3D1D2)
carbonylative cycloadditions of aminocyclopropanes and
alkynes
Preliminary mechanistic studies indicated that cationic Rh(I)-
systems are especially effective for directed oxidative addition
(see Section 2.1), presumably because the more Lewis acidic Rh(I)-
centre (vs neutral Rh(I)-systems) enhances coordination to the
Lewis basic directing group. Accordingly, we decided to re-examine
cationic Rh(I)-systems in more detail and 1H NMR profiling of the
reactions outlined in Entries 5 and 6 in Table 1 was undertaken
(Fig. 1). This revealed that the use of [Rh(cod)Cl]2 effects slow but
steady formation of product 17c. On the other hand, employment of
[Rh(cod)2]BF4 promotes faster product formation over the initial
Entry
Rh-source
Solvent
Time/h
Yield (%)a
1
2
3
4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]SbF6
[Rh(cod)2]BARF
[Rh(cod)2]OTf
[Rh(cod)2]OTf
(7.5 mol %)
(7.5 mol %)
(7.5 mol %)
(7.5 mol %)
(7.5 mol %)
(7.5 mol %)
(5 mol %)
PhCN
BuCN
DMF
PhCN
PhCN
PhCN
PhCN
9.5
72
72
7.5
8
72
42
22
73
77
76
67
5
6
9
14
7b
a
Isolated yield.
P(3,5-(CF3)2C6H3)3 (10 mol %) was used.
b

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M.H. Shaw et al. / Tetrahedron 72 (2016) 2731e2741
Table 5
17r, which is derived from oxidative addition of the Rh(I)-catalyst
into less hindered proximal cyclopropane CeC bond a, complete
transfer of the cyclopropane stereochemistry of the major di-
astereomer of 16r was observed. The regiochemistry of 17r was
determined by HMBC analysis, and the relative stereochemistry
was corroborated by NOE experiments. Minor regioisomer iso-17r
was obtained as a 1:1 mixture of diastereomers, perhaps due to
epimerisation of the C6 stereocentre of the product under the re-
action conditions. Using [Rh(cod)2]OTf, a 76% yield of 17r/iso-17r
was achieved, and because the reaction temperature could be
lowered to 120 ꢀC (from 140 ꢀC), selectivity for 17r also increased
(4:1 17r:iso-17r vs 5:2 17r:iso-17r at 140 ꢀC using [Rh(cod)Cl]2).25
Notably, the cationic conditions resulted in a decrease in the re-
action time from 108 to 38 h. For 16s, where the steric bulk of the
cyclopropane substituent is increased, selectivity for oxidative ad-
dition of the Rh(I)-catalyst into the less hindered proximal CeC
bond a was increased and a 5:1 ratio of 17s:iso-17s was obtained
using the neutral system. Again, complete transfer of the cyclo-
propane stereochemistry to the major regioisomer 17s was ach-
ieved. In this case, the cationic Rh-system increased both the
reaction rate and regioselectivity, but only provided a modest im-
provement to the yield.
Comparison of neutral and cationic Rh(I)-systems for (3þ1þ2) cycloadditions in-
volving functionalised alkynes
Substrate
R
Neutral Systema
Cationic system
Time/h
Yield (%)
Time/h
Yield (%)
16f
16i
84
58
52
16
32
73
88
108
16j
132
192
30
15
32
48
82
16k
63b
16l
144
84
29
10
18
3
87
23
16m
16n
72
d
24
d
a
Na2SO4 (20 mol %) was used as an additive.
[Rh(cod)2]OTf (10 mol %) and P(3,5-(CF3)2C6H3)3 (20 mol %) were used.
b
Pronounced improvements were also seen with substrates 16iel
and higher yields (63e88%) of the targets 17iel could be achieved
in considerably shorter reaction times (18e48 h vs 108e192 h
using [Rh(cod)Cl]2). Quinoline 16k required a higher catalyst
loading (10 mol % [Rh(cod)2]OTf) for efficient conversion, pre-
sumably due to the aforementioned issues associated with the
Lewis basic quinoline nitrogen.24 Terminal alkyne 16m, which
provided only a 10% yield of 17m under the ‘first generation’
conditions, cyclised in 23% yield using the cationic Rh(I)-system.
Evidently, in this case, further optimisation is still required and
this will be a focus of future studies. However, even under these
modified conditions, electron deficient alkyne 16n does not par-
ticipate and target 17n was not observed. Intriguingly, for 16o and
16q (see Table 3), where additional substitution is present on the
alkyne tether, reaction rates were improved using [Rh(cod)2]OTf,
but the isolated yields and diastereoselectivities associated with
17o and 17q were lower than when [Rh(cod)Cl]2 was employed
(using [Rh(cod)2]OTf, 17o: 57% yield, 4:3 d.r., 39 h; 17q: 45% yield,
1:1 d.r., 24 h). In these particular cases, the neutral Rh(I)-system is
therefore preferred.
Scheme 7. Cycloadditions involving trans-1,2-disubstituted aminocyclopropanes.
2.5. Derivatisations of the cycloaddition products
The utility of the N-heterobicyclic enone products described
here is outlined in Scheme 8. Addition of the Gilman-cuprate de-
rived from n-BuLi to enone 17c proceeded with excellent facial
selectivity, in favour of the cis-ring junction, to deliver 18 in 56%
yield.26 The C2 stereocentre of 18 was not readily controlled and
attempted epimerisation of this position under a variety of basic or
acidic conditions did not enhance diastereopurity. Hydrogenation
of 17c (Pd/C, H2) proceeded smoothly under mildly basic conditions
(Et3N) to deliver 19 in 80% yield. Again, the stereochemistry of the
ring junction was readily controlled, presumably due to syn-addi-
tion of hydrogen to the less hindered face of 17c, which delivers
initially the depicted diastereomer of 19. The C2 stereocentre of 19
was labile under the reaction conditions, such that prolonged re-
action times (48 h vs 2 h) afforded predominantly the alternate
(and presumably thermodynamically favoured) diastereomer (not
depicted). Oxidative transformations are also feasible. For example,
under transfer hydrogenative conditions (Pd/C, cyclohexene),27 the
2.4. (3D1D2) cycloadditions of substituted
aminocyclopropanes
Carbonylative (3þ1þ2) cycloadditions involving trans-1,2-
disubstituted aminocyclopropanes can potentially deliver two dif-
ferent regioisomeric products depending on the selectivity of oxi-
dative addition. Carbonylative cycloaddition of methyl-substituted
cyclopropane 16r using the neutral Rh(I)-system, yielded a 5:2
mixture of regioisomers 17r and iso-17r, resulting from competing
oxidative addition of the Rh(I)-catalyst into either of the proximal
cyclopropane CeC bonds (Scheme 7). For the major regioisomer

M.H. Shaw et al. / Tetrahedron 72 (2016) 2731e2741
2737
cyclohexenone moiety of 17h underwent oxidation to provide
phenol 20, albeit in moderate yield.
recorded using either a Varian 400 MHz or JOEL ECS 400 MHz
spectrometer. Chemical shifts are quoted in parts per million
(ppm), coupling constants (J) are given in Hz to the nearest
0.5 Hz. Other abbreviations used are s (singlet), d (doublet), t
(triplet), m (multiplet) and br (broad). 1H and 13C NMR spectra
were referenced to the appropriate residual solvent peak. Mass
spectra were determined by the University of Bristol mass spec-
trometry service by either electron impact (EIþ) or chemical
ionization (CIþ) using a Fisons VG Analyticþal Autospec spec-
€
trometer, or by electrospray ionization (ESI ) using a Bruker
Daltonics Apex IV spectrometer. Experimental procedures and
data for compounds that were reported in our earlier work are
not included here.2 X-ray crystallographic data for compounds 12,
15b, 15c, 17b and 17h have been reported previously.2,5
4.2. General procedure for (3D1D2) carbonylative cycload-
ditions of aminocyclopropanes and alkynes using a neutral
Rh(I)-catalyst system
An oven-dried reaction tube, fitted with a magnetic stirrer, was
charged with [Rh(cod)Cl]2 (3.75 mol %), P(3,5-(CF3)2C6H3)3 (15 mol
%) and Na2SO4 (20 mol %). The tube was fitted with a rubber septum
and purged with argon. Aminocyclopropane substrate (100 mol %)
in argon sparged anhydrous PhCN (0.07 M) was added via syringe.
The reaction mixture was sparged with CO for ca. 2 min, then
heated at the specified temperature (120e140 ꢀC as noted) under
a CO atmosphere (1 atm) until complete consumption of starting
material was observed by thin layer chromatography (36e192 h as
noted). The mixture was cooled to rt and purified directly by flash
column chromatography, under the conditions noted, to afford the
target cyclohexenone.
Scheme 8. Synthetic manipulations of 17c and 17h.
3. Conclusions
In summary, we outline studies on the selective generation and
trapping of amino-substituted rhodacyclopentanones. A range of
N-directing groups are effective at directing oxidative addition of
Lewis acidic Rh(I)-systems. This underpins an efficient and con-
trolled approach to the key metallacyclic intermediates. For pro-
totypical cycloaddition processes involving N-tethered alkynes,
efficient oxidative addition requires a strongly donating urea
directing group to outcompete the alkyne for coordination of the
Rh(I)-catalyst. Subsequent dissociation of the urea at the stage of
the rhodacyclopentanone is relatively facile and allows alkyne in-
sertion to provide the heterocyclic target. A ‘first generation’ neu-
tral Rh(I)-system is effective at promoting (3þ1þ2) cycloadditions,
but suffers from low yields and long reaction times in cases where
the alkyne component is electron deficient or bears a heterocyclic
substituent. A ‘second generation’ cationic Rh(I)-system provides
increased efficiencies in these cases and the success of this protocol
is strongly dependent upon the use of PhCN as solvent. Current
studies are focussed on the development of catalyst systems that
tolerate synthetically versatile directing groups (e.g., carbamates)
and allow expansion of the approach to asymmetric processes and
6-ring cyclisations.
4.3. General procedure for (3D1D2) carbonylative cycload-
ditions of aminocyclopropanes and alkynes using a cationic
Rh(I)-catalyst system
An oven-dried reaction tube, fitted with a magnetic stirrer, was
charged with [Rh(cod)2]OTf (7.5 mol %) and P(3,5-(CF3)2C6H3)3
(15 mol %). The tube was fitted with a rubber septum and purged
with argon. Aminocyclopropane substrate (100 mol %) in argon
sparged anhydrous PhCN (0.07 M) was added via syringe. The re-
action mixture was sparged with CO for ca. 2 min, then heated at
the specified temperature (120e130 ꢀC as noted) under a CO at-
mosphere (1 atm) until complete consumption of starting material
was observed by thin layer chromatography (3e48 h as noted). The
mixture was cooled to rt, concentrated in vacuo and purified by
flash column chromatography, under the conditions noted, to af-
ford the target cyclohexenone.
4.4. Experimental procedures and data for new compounds
4.4.1. N-Benzyl-N-cyclopropylbenzamide (6b). To a solution of N-
cyclopropylbenzamide29 (1.00 g, 6.20 mmol) in anhydrous THF
(12.4 mL) was added NaH (1.24 g, 31.0 mmol). The suspension was
stirred at rt for 1 h and then benzyl bromide (3.7 mL, 31.0 mmol)
was added dropwise over 5 min. The reaction mixture was stirred
at rt for 16 h. The solution was cooled to 0 ꢀC and then water
(20 mL) and Et2O (20 mL) were added. The layers were separated
and the aqueous portion was further extracted with Et2O
(3ꢂ20 mL). The organic extracts were combined, washed with
brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash column chromatography (20%
EtOAc/hexane) to afford the title compound 6b (1.31 g, 84%) as
4. Experimental section
4.1. General experimental
Starting materials sourced from commercial suppliers were
used as received unless otherwise stated. Dry solvents, where
necessary, were obtained by distillation using standard pro-
cedures or by passage through a column of anhydrous alumina
using equipment from Anhydrous Engineering based on the
Grubbs’ design.28 Melting points were determined using a Reich-
ert melting point table and temperature controller and are un-
corrected. Infrared spectra were recorded in the range
4000e600 cmꢁ1 on a Perkin Elmer Spectrum either as neat films
or solids compressed onto a diamond window. NMR spectra were
a colourless oil; IR (neat): 1630, 1400 cmꢁ1
400 MHz):
7.60e7.18 (m, 10H), 4.75 (s, 2H), 2.59 (tt, J¼7.0,
4.0 Hz, 1H), 0.75e0.30 (m, 4H); 13C NMR (CDCl3, 100 MHz):
;
1H NMR (CDCl3,
d

2738
M.H. Shaw et al. / Tetrahedron 72 (2016) 2731e2741
d
172.5, 137.9, 137.3, 129.6, 128.6, 128.0, 127.3, 127.2, 50.7, 31.6, 9.9;
yellow crystals for characterisation by single crystal X-ray
HRMS: (ESIþ) calcd for C17H17NONa: 274.1208. Found [MþNa]þ:
crystallography.19
274.1205.
4.4.6. 1-Cyclopropyl-3,3-dimethyl-1-(4-(quinolin-3-yl)but-3-yn-1-
yl)urea (16k). An oven-dried reaction tube, fitted with a magnetic
stirrer, was charged with Pd(PPh3)4 (38.6 mg, 0.0334 mmol) and
CuI (12.7 mg, 0.0668 mmol). The tube was fitted with a rubber
septum and purged with argon. A solution of 16m2 (300 mg,
1.67 mmol), 3-bromoquinoline (0.34 mL, 2.51 mmol) and Et3N
(0.70 mL, 5.01 mmol) in anhydrous DMF (3.3 mL) was sparged with
argon and added to the reaction tube. The reaction was stirred at
60 ꢀC for 16 h and then the mixture was cooled to rt and concen-
trated in vacuo. The residue was purified by flash column chro-
matography (5% MeOH/EtOAc) to afford the title compound 16k
(427 mg, 83%) as a pale yellow solid; mp 95e98 ꢀC (CH2Cl2-hex-
4.4.2. (E)-N-Benzyl-N-(prop-1-en-1-yl)benzamide (7b). An oven-
dried reaction tube, fitted with a magnetic stirrer, was charged
with [Rh(cod)2]BF4 (11.0 mg, 0.0271 mmol) and PPh3 (21.3 mg,
0.0811 mmol). The tube was fitted with a rubber septum and
purged with argon. Amide 6b (136 mg, 0.541 mmol) in argon
sparged anhydrous toluene (5.4 mL) was added via syringe. The
tube was sealed and the reaction mixture was heated at 140 ꢀC for
4 h. The mixture was cooled to rt and concentrated in vacuo. The
residue was purified by flash column chromatography (20% Et2O/
hexane) to afford the title compound 7b (98 mg, 72%) as a colour-
less oil; IR (neat): 1636, 1397, 1372, 1318, 1284, 1148 cmꢁ1; 1H NMR
(CD3CN, 400 MHz):
d
7.49e7.27 (m, 10H), 6.45 (br m, 1H), 5.06e4.98
170.9,
ane); IR (neat): 1619, 1488, 1441, 1400, 1361, 1339, 1249, 1028 cmꢁ1
1H NMR (CDCl3, 400 MHz):
;
(m, 3H), 1.66e1.35 (br m, 3H); 13C NMR (CD3CN, 100 MHz):
d
d
8.86 (d, J¼2.0 Hz,1H), 8.17 (d, J¼2.0 Hz,
137.0, 131.0, 130.7, 129.6, 129.4, 128.7, 127.9, 127.6, 108.1, 47.6, 15.4;
1H), 8.08 (br d, J¼8.5 Hz, 1H), 7.77 (dd, J¼8.5, 1.0 Hz, 1H), 7.71 (ddd,
J¼8.5, 7.0, 1.0 Hz, 1H), 7.56 (ddd, J¼8.5, 7.0, 1.0 Hz, 1H), 3.56 (t,
J¼7.0 Hz, 2H), 2.93 (s, 6H), 2.81e2.76 (m, 3H), 0.83e0.78 (m, 2H),
m/z (CIþ) 105 (100%), 252 ([MþH]þ, 80%); HRMS: (CIþ) calcd for
C
17H18NO: 252.1388. Found [MþH]þ: 252.1380.
0.68e0.64 (m, 2H); 13C NMR (CDCl3, 100 MHz):
d 163.5, 152.3, 146.6,
4.4.3. (E)-N-Benzyl-4-methyl-N-(prop-1-en-1-yl)benzenesulfona-
mide (7c). An oven-dried reaction tube, fitted with a magnetic
stirrer, was charged with [Rh(cod)2]BF4 (11.0 mg, 0.0271 mmol)
and PPh3 (21.3 mg, 0.0811 mmol). The tube was fitted with
a rubber septum and purged with argon. Sulfonamide 6c30
(163 mg, 0.541 mmol) in argon sparged anhydrous toluene
(5.4 mL) was added via syringe. The tube was sealed and the re-
action mixture was heated at 140 ꢀC for 4 h. The reaction was
cooled to rt and concentrated in vacuo. The residue was purified
by flash column chromatography (10% Et2O/hexane) to afford the
title compound 7c (104 mg, 64%) as a colourless oil; 1H NMR
138.1,129.8,129.3,127.5,127.3,127.2,117.8, 91.6, 79.0, 47.9, 37.9, 31.1,
19.4, 8.9; m/z (CIþ) 308 ([MþH]þ, 90%); HRMS: (CIþ) calcd for
C
19H22N3O: 308.1763. Found [MþH]þ: 308.1760.
4.4.7. 1-Cyclopropyl-3,3-dimethyl-1-(4-(thiophen-3-yl)but-3-yn-1-
yl)urea (16l). An oven-dried reaction tube, fitted with a magnetic
stirrer, was charged with Pd(PPh3)4 (38.6 mg, 0.0334 mmol) and
CuI (12.7 mg, 0.0668 mmol). The tube was fitted with a rubber
septum and purged with argon. A solution of 16m2 (300 mg,
1.67 mmol), 3-bromothiophene (0.23 mL, 2.51 mmol) and Et3N
(0.70 mL, 5.01 mmol) in anhydrous DMF (3.3 mL) was sparged with
argon and added to the reaction tube. The reaction was stirred at
60 ꢀC for 18 h and then the mixture was cooled to rt and concen-
trated in vacuo. The residue was purified by flash column chro-
matography (50% EtOAc/hexane) to afford the title compound 16l
(310 mg, 71%) as a pale yellow oil; IR (neat): 2927, 1626, 1490, 1452,
(CD3CN, 400 MHz):
d 7.71e7.67 (m, 2H), 7.37e7.35 (m, 2H),
7.32e7.21 (m, 5H), 6.55 (dq, J¼13.5, 1.5 Hz, 1H), 4.75 (dq, J¼13.5,
6.5 Hz, 1H), 4.45 (s, 2H), 2.39 (s, 3H), 1.48 (dd, J¼6.5, 1.5 Hz, 3H);
13C NMR (CD3CN, 100 MHz):
d 145.3, 137.5, 136.9, 130.9, 129.5,
128.3, 128.0, 127.8, 127.3, 109.4, 50.2, 21.6, 15.3. The spectroscopic
properties of this compound were consistent with the data
available in the literature.31
1398,1355,1253,1171,1063 cmꢁ1; 1H NMR (CDCl3, 400 MHz):
d 7.35
(dd, J¼3.0, 1.0 Hz, 1H), 7.24 (dd, J¼5.0, 3.0 Hz, 1H), 7.06 (dd, J¼5.0,
1.0 Hz, 1H), 3.49 (t, J¼7.0 Hz, 2H), 2.90 (s, 6H), 2.74 (tt, J¼6.5, 4.0 Hz,
1H), 2.67 (t, J¼7.0 Hz, 2H), 0.80e0.75 (m, 2H), 0.65e0.61 (m, 2H);
4.4.4. Monomeric rhodacyclopentanone complex (14). To a solution
of dimer 12 (11.0 mg, 0.0163 mmol) in CD2Cl2 (1 mL) in an NMR
tube was added PPh3 (8.5 mg, 0.0326 mmol). NMR analysis showed
formation of the PPh3 bound monomer 14; 1H NMR (CD2Cl2,
13C NMR (CDCl3, 100 MHz):
d 163.6, 129.9, 127.8, 125.1, 122.6, 87.4,
77.2, 48.0, 37.9, 30.9,19.1, 8.9; m/z (CIþ) 263 ([MþH]þ,100%); HRMS:
(CIþ) calcd for C14H19N2OS: 263.1218. Found [MþH]þ: 263.1212.
400 MHz):
d 7.69e7.64 (m, 6H), 7.44e7.35 (m, 9H), 5.28 (m, 1H),
3.96e3.86 (m, 2H), 2.96 (d, J¼1.0 Hz, 3H), 2.46 (ddd, J¼16.0, 14.0,
4.4.8. Ethyl 5-(1-cyclopropyl-3,3-dimethylureido)pent-2-ynoate
(16n). To a solution of 16m2 (300 mg, 1.67 mmol) in THF (17 mL)
at ꢁ78 ꢀC was added n-BuLi (1.09 mL,1.67 mmol,1.54 M in hexanes)
and the solution was stirred for 1 h under nitrogen. Ethyl chlor-
oformate (0.32 mL, 3.34 mmol) was added and the reaction was
slowly warmed to rt and stirred for 16 h. Satd aq NH4Cl (30 mL) was
added and the solution was extracted with EtOAc (3ꢂ30 mL). The
organic extracts were combined, washed with brine (30 mL), dried
over Na2SO4 and concentrated in vacuo. The residue was purified by
flash column chromatography (5% acetone/Et2O) to afford the title
compound 16n (327 mg, 78%) as a yellow oil; IR (neat): 2235, 1706,
1630,1492,1399,1364, 1247,1067 cmꢁ1; 1H NMR (CDCl3, 400 MHz):
6.5 Hz, 1H), 2.38 (m, 1H), 2.12 (m, 1H), 1.86 (m, 1H), 1.08 (t, J¼7.0 Hz,
3H); 13C NMR (CD2Cl2, 100 MHz):
d
231.9 (dd, J¼27.5, 3.0 Hz, C8),
187.5 (dd, J¼77.0, 11.5 Hz, C9), 165.3 (d, J¼10.0 Hz, C3), 74.6 (dd,
J¼86.0, 20.0 Hz, C5), 65.4 (C2), 52.0 (d, J¼6.0 Hz, C7), 35.1 (d,
J¼4.5 Hz, C4), 33.5 (C6), 14.9 (C1). Aromatic signals are excluded as
characterisation by 13C NMR was conducted after the addition of
a second equivalent of PPh3.
4.4.5. Amide rhodacyclopentanone complex (15a). Di-m-chloro-tet-
racarbonyldirhodium (20.0 mg, 0.0514 mmol) and N-cyclopropyl-
N-methylbenzamide32 (0.4 mL) were stirred at 60 ꢀC for 24 h under
an atmosphere of N2 and then cooled to rt. Hexane (1 mL) was
added to complete precipitation of the metal complex and then the
solvent was removed upon sedimentation of the metallacycle. The
precipitate was washed with Et2O (5ꢂ1 mL) and then dried in vacuo
to afford metallacycle 15a (28.4 mg, 75%) as a pale yellow solid; IR
d
4.21 (q, J¼7.0 Hz, 2H), 3.47 (t, J¼7.0 Hz, 2H), 2.91 (s, 6H), 2.73 (m,
1H), 2.61 (t, J¼7.0 Hz, 2H), 1.30 (t, J¼7.0 Hz, 3H), 0.80e0.75 (m, 2H),
0.64e0.60 (m, 2H); 13C NMR (CDCl3, 100 MHz):
163.1, 153.6, 87.1,
d
74.1, 61.8, 47.0, 37.8, 31.5, 18.6, 14.0, 9.0; HRMS: (ESIþ) calcd for
C
13H20N2O3Na: 275.1363. Found [MþNa]þ: 275.1366.
(neat): 2046, 2029, 1701, 1589, 1567, 1502, 1452, 1443, 1411 cmꢁ1
;
Metallacycle 15a was poorly soluble in CD2Cl2, attempts to char-
acterise the metallacycle by NMR produced extremely weak spec-
tra. The metallacycle was recrystallised from CH2Cl2 to afford
4.4.9. 4-(Methoxymethyl)-N,N-dimethyl-5-oxo-2,3,5,6,7,7a-hexahy-
dro-1H-indole-1-carboxamide (17f). General procedure A: Amino-
cyclopropane 16f2 (40 mg, 0.18 mmol) was employed and the

M.H. Shaw et al. / Tetrahedron 72 (2016) 2731e2741
2739
reaction was stirred for 84 h at 130 ꢀC. Flash column chromatog-
3.54e3.50 (m, 2H), 2.89 (s, 6H), 2.85e2.52 (m, 5H), 1.76 (m, 1H); 13
C
raphy (100% EtOAc) afforded the title compound 17f (26 mg, 58%) as
an off white solid. General procedure B: Aminocyclopropane 16f
(40 mg, 0.18 mmol) was employed and the reaction was stirred for
16 h at 130 ꢀC. Flash column chromatography (100% EtOAc) affor-
ded the title compound 17f (33 mg, 73%) as an off white solid. The
spectroscopic data for 17f was consistent with that reported in our
previous publication.2
NMR (CDCl3, 100 MHz):
d
196.6, 162.9, 161.0, 134.0, 129.0, 125.2,
124.5, 58.6, 48.6, 38.0, 36.3, 31.4, 29.7; m/z (CIþ) 291 ([MþH]þ,
100%), 319 (10%); HRMS: (CIþ) calcd for C15H19N2O2S: 291.1167.
Found [MþH]þ: 291.1170.
4.4.14. N,N-Dimethyl-5-oxo-2,3,5,6,7,7a-hexahydro-1H-indole-1-
carboxamide (17m). General procedure A: Aminocyclopropane
16m2 (32 mg, 0.18 mmol) was employed and the reaction was
stirred for 84 h at 130 ꢀC. Flash column chromatography (100%
EtOAc) afforded the title compound 17m (4 mg, 10%) as a yellow oil.
General procedure B: Aminocyclopropane 16m (32 mg, 0.18 mmol)
was employed and the reaction was stirred for 3 h at 130 ꢀC. Flash
column chromatography (100% EtOAc) afforded the title compound
17m (8.5 mg, 23%) as a yellow oil; IR (neat): 1667, 1630, 1496, 1390,
4.4.10. 4-(4-Chlorophenyl)-N,N-dimethyl-5-oxo-2,3,5,6,7,7a-hexahy-
dro-1H-indole-1-carboxamide (17i). General procedure A: Amino-
cyclopropane 16i2 (52 mg, 0.18 mmol) was employed and the
reaction was stirred for 108 h at 130 ꢀC. Flash column chromatog-
raphy (100% EtOAc) afforded the title compound 17i (29 mg, 52%) as
a pale yellow oil. General procedure B: Aminocyclopropane 16i
(52 mg, 0.18 mmol) was employed and the reaction was stirred for
32 h at 130 ꢀC. Flash column chromatography (100% EtOAc) affor-
ded the title compound 17i (50 mg, 88%) as a pale yellow oil. The
spectroscopic data for 17i was consistent with that reported in our
previous publication.2
1265, 1188 cmꢁ1
;
1H NMR (CDCl3, 400 MHz):
d
5.95 (br dd, J¼2.5,
2.5 Hz, 1H), 4.70 (m, 1H), 3.59 (ddd, J¼10.0, 10.0, 6.5 Hz, 1H), 3.51
(ddd, J¼10.0, 10.0, 2.5 Hz, 1H), 2.89 (s, 6H), 2.81 (m, 1H), 2.64 (m,
1H), 2.56e2.38 (m, 3H), 1.64 (m, 1H); 13C NMR (CDCl3, 100 MHz):
d
198.8, 166.1, 163.0, 122.5, 57.8, 48.5, 37.9, 35.8, 31.7, 30.3; m/z (CIþ)
209 ([MþH]þ, 100%), 237 (10%); HRMS: (CIþ) calcd for C11H17N2O2:
4.4.11. N,N-Dimethyl-5-oxo-4-(4-(trifluoromethyl)phenyl)-
209.1290. Found [MþH]þ: 209.1294.
2,3,5,6,7,7a-hexahydro-1H-indole-1-carboxamide
(17j). General
procedure A: Aminocyclopropane 16j2 (58 mg, 0.18 mmol) was
employed and the reaction was stirred for 132 h at 130 ꢀC. Flash
column chromatography (100% EtOAc) afforded the title compound
17j (19 mg, 30%) as a yellow oil. General procedure B: Amino-
cyclopropane 16j (58 mg, 0.18 mmol) was employed and the re-
action was stirred for 32 h at 130 ꢀC. Flash column chromatography
(100% EtOAc) afforded the title compound 17j (52 mg, 82%) as
a yellow oil. The spectroscopic data for 17j was consistent with that
reported in our previous publication.2
4.4.15. (2S*,7aS*)-
2,3,5,6,7,7a-hexahydro-1H-indole-1-carboxamide
and
(2R*,7aS*)-N,N,2,4-Tetramethyl-5-oxo-
(17o). General
procedure A: Aminocyclopropane 16o2 (37 mg, 0.18 mmol) was
employed and the reaction was stirred for 156 h at 120 ꢀC. Flash
column chromatography (100% EtOAc) afforded the title compound
17o (30 mg, 71%) as a yellow oil. Cyclohexanone 17o was obtained
as a mixture of diastereomers (3:1 d.r.). Under standard reaction
conditions at 130 ꢀC, no starting material remained after 60 h (55%
yield). General procedure B: Aminocyclopropane 16o (37 mg,
0.18 mmol) was employed and the reaction was stirred for 39 h at
130 ꢀC. Flash column chromatography (100% EtOAc) afforded the
title compound 17o (24 mg, 57%) as a yellow oil. Cyclohexanone 17o
was obtained as a mixture of diastereomers (4:3 d.r.). The spec-
troscopic data for 17o was consistent with that reported in our
previous publication.2
4.4.12. N,N-Dimethyl-5-oxo-4-(quinolin-3-yl)-2,3,5,6,7,7a-hexahy-
dro-1H-indole-1-carboxamide (17k). General procedure A: Amino-
cyclopropane 16k (55 mg, 0.18 mmol) was employed and the
reaction was stirred for 192 h at 130 ꢀC. Flash column chromatog-
raphy (5% MeOH/EtOAc) afforded the title compound 17k (9 mg,
15%) as a yellow oil. General procedure B: In a modification to the
general procedure, 10 mol % [Rh(cod)2]OTf and 20 mol % P(3,5-
(CF3)2C6H3)3 were used. Aminocyclopropane 16k (55 mg,
0.18 mmol) was employed and the reaction was stirred for 48 h at
130 ꢀC. Flash column chromatography (5% MeOH/EtOAc) afforded
the title compound 17k (38 mg, 63%) as a yellow oil; IR (neat): 2943,
4.4.16. (2R*,7aS*)- and (2S*,7aS*)-N,N,4-Trimethyl-5-oxo-2-phenyl-
2,3,5,6,7,7a-hexahydro-1H-indole-1-carboxamide
(17q). General
procedure A: Aminocyclopropane 16q2 (48 mg, 0.18 mmol) was
employed and the reaction was stirred for 36 h at 125 ꢀC. Flash
column chromatography (100% EtOAc) afforded the title com-
pound 17q (33 mg, 61%) as a yellow oil. Cyclohexanone 17q was
obtained as a mixture of diastereomers (5:2 d.r.). General pro-
cedure B: Aminocyclopropane 16q (48 mg, 0.18 mmol) was
employed and the reaction was stirred for 24 h at 130 ꢀC. Flash
column chromatography (100% EtOAc) afforded the title com-
pound 17q (24 mg, 45%) as a yellow oil. Cyclohexanone 17q was
obtained as a mixture of diastereomers (1:1 d.r.). The spectro-
scopic data for 17q was consistent with that reported in our pre-
vious publication.2
1670, 1620, 1493, 1456, 1392, 1360, 1265 cmꢁ1
400 MHz):
;
1H NMR (CDCl3,
8.69 (d, J¼2.0 Hz, 1H), 8.09 (br d, J¼8.5 Hz, 1H), 7.98 (d,
d
J¼2.0 Hz, 1H), 7.81 (m, 1H), 7.71 (ddd, J¼8.5, 7.0, 1.5 Hz, 1H), 7.55
(ddd, J¼8.5, 7.0, 1.5 Hz, 1H), 4.95 (m, 1H), 3.54e3.50 (m, 2H),
2.97e2.88 (m, 7H), 2.78e2.57 (m, 4H), 1.83 (dddd, J¼14.0, 12.5, 11.5,
5.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz):
d 196.7, 163.5, 163.0, 151.3,
147.2, 137.2, 131.0, 130.0, 129.2, 128.1, 127.6, 127.4, 127.0, 58.8, 48.7,
38.1, 36.3, 31.3, 30.0; m/z (CIþ) 336 ([MþH]þ, 60%); HRMS: (CIþ)
calcd for C20H22N3O2: 336.1712. Found [MþH]þ: 336.1701.
4.4.13. N,N-Dimethyl-5-oxo-4-(thiophen-3-yl)-2,3,5,6,7,7a-hexahy-
dro-1H-indole-1-carboxamide (17l). General procedure A: Amino-
cyclopropane 16l (47 mg, 0.18 mmol) was employed and the
reaction was stirred for 144 h at 130 ꢀC. Flash column chromatog-
raphy (100% EtOAc) afforded the title compound 17l (15 mg, 29%) as
a pale yellow oil. General procedure B: Aminocyclopropane 16l
(47 mg, 0.18 mmol) was employed and the reaction was stirred for
18 h at 130 ꢀC. Flash column chromatography (100% EtOAc) affor-
ded the title compound 17l (45 mg, 87%) as a pale yellow oil; IR
4.4.17. (7R*,7aS*)-N,N,4,7-Tetramethyl-5-oxo-2,3,5,6,7,7a-hexahy-
dro-1H-indole-1-carboxamide (17r) and N,N,4,6-tetramethyl-5-oxo-
2,3,5,6,7,7a-hexahydro-1H-indole-1-carboxamide (iso-17r). General
procedure A: Aminocyclopropane 16r (37 mg, 0.18 mmol, 6:1 d.r.)
was employed and the reaction was stirred for 108 h at 140 ꢀC. Flash
column chromatography (100% EtOAc) afforded a mixture of
regioisomers 17r and iso-17r (17r:iso-17r, 5:2) (21 mg, 50%) as
a yellow oil. Cyclohexenones 17r and iso-17r were obtained as
a mixture of diastereomers (17r: 20:1 d.r., iso-17r: 1:1 d.r.). General
procedure B: Aminocyclopropane 16r (37 mg, 0.18 mmol, 6:1 d.r.)
was employed and the reaction was stirred for 38 h at 120 ꢀC. Flash
column chromatography (100% EtOAc) afforded a mixture of
(neat): 2932, 2880, 1668, 1624, 1496, 1388, 1356, 1173 cmꢁ1
NMR (CDCl3, 400 MHz):
7.32 (dd, J¼5.0, 3.0 Hz, 1H), 7.22 (dd,
J¼3.0, 1.0 Hz, 1H), 7.05 (dd, J¼5.0, 1.0 Hz, 1H), 4.87 (m, 1H),
;
1H
d

2740
M.H. Shaw et al. / Tetrahedron 72 (2016) 2731e2741
regioisomers 17r and iso-17r (17r:iso-17r, 4:1) (32 mg, 76%) as
a yellow oil. Cyclohexenone 17r was obtained as a single di-
astereomer (>20:1 d.r.), iso-17r was obtained as a mixture of di-
astereomers (3:1 d.r.). The spectroscopic data for 17r and iso-17r
was consistent with that reported in our previous publication.2
carbon (20.0 mg, 0.0188 mmol, 10% w/w) under N2 was added EtOH
(2 mL) and the solution was bubbled with H2 for 10 min. 17c2
(30.0 mg, 0.135 mmol) in EtOH (0.7 mL) and Et3N (0.3 mL) was
added and the reaction was stirred under an atmosphere of H2 for
2 h. The solution was filtered through CeliteÒ and concentrated in
vacuo. The residue was purified by flash column chromatography
(100% EtOAc) to afford the title compound 19 (24 mg, 80%) as
a colourless oil. Cyclohexanone 19 was obtained as a mixture of
4.4.18. (7R*,7aS*)-7-Butyl-N,N,4-trimethyl-5-oxo-2,3,5,6,7,7a-hex-
ahydro-1H-indole-1-carboxamide (17s) and 6-butyl-N,N,4-trimethyl-
5-oxo-2,3,5,6,7,7a-hexahydro-1H-indole-1-carboxamide
(iso-
diastereomers A and B (5:2, A:B); 1H NMR (CDCl3, 400 MHz):
d 4.50
17s). General procedure A: Aminocyclopropane 16s (45 mg,
0.18 mmol, >20:1 d.r.) was employed and the reaction was stirred
for 168 h at 140 ꢀC. Flash column chromatography (50% Et2O/tol-
uene) afforded a mixture of regioisomers 17s and iso-17s (17s:iso-
17s, 5:1) (20 mg, 41%) as a yellow oil. Cyclohexenones 17s and iso-
17s were obtained as a mixture of diastereomers (17s: 20:1 d.r., iso-
17s: 1:1 d.r.). General procedure B: Aminocyclopropane 16s (45 mg,
0.18 mmol, >20:1 d.r.) was employed and the reaction was stirred
for 40 h at 130 ꢀC. Flash column chromatography (50% Et2O/tolu-
ene) afforded a mixture of regioisomers 17s and iso-17s (17s:iso-
17s, 8:1) (22 mg, 45%) as a yellow oil. Cyclohexenone 17s was ob-
tained as a single diastereomer (>20:1 d.r.), iso-17s was obtained as
a mixture of diastereomers (2:1 d.r.). The spectroscopic data for 17s
and iso-17s was consistent with that reported in our previous
publication.2
(m, 1H, B), 4.12 (ddd, J¼5.5, 5.5, 5.5 Hz, 1H, A), 3.62 (ddd, J¼10.0,
10.0, 6.5 Hz, 1H, A), 3.40e3.28 (m, 1H (A) and 1H (B)), 3.13 (ddd,
J¼10.0, 7.5, 7.5 Hz, 1H, B), 2.87 (s, 6H, A), 2.81e2.69 (m, 8H, B), 2.43
(m,1H, A), 2.36e1.85 (m, 6H (A) and 5H (B)),1.81 (m, 1H, A), 1.51 (m,
1H, B), 1.07 (d, J¼6.5 Hz, 3H, A), 1.01 (d, J¼6.5 Hz, 3H, B); 13C NMR
(CDCl3, 100 MHz): d 214.0 (B), 213.7 (A), 163.8 (A),163.4 (B), 57.0 (A),
56.0 (B), 48.9 (A), 48.2 (B), 46.5 (A), 44.1 (A), 43.5 (2 signals, B), 38.4
(B), 38.1 (A), 36.5 (B), 35.9 (A), 30.5 (A), 27.5 (A), 27.1 (B), 26.3 (B),
13.2 (A), 11.8 (B); m/z (CIþ) 72 (100%), 224 ([MþH]þ, 30%); HRMS:
(CIþ) calcd for C12H20N2O2: 224.1525. Found [MþH]þ: 224.1530.
4.4.21. 5-Hydroxy-N,N-dimethyl-4-phenylindoline-1-carboxamide
(20). To a solution of Pd on carbon (17.0 mg, 0.016 mmol, 10% w/w)
and cyclohexene (0.11 mL, 1.06 mmol) in toluene (2 mL) under N2
was added a solution of 17h2 (30.0 mg, 0.106 mmol) in toluene
(2 mL). The reaction mixture was heated to 100 ꢀC for 72 h and then
cooled to rt and filtered through CeliteÒ. The solution was con-
centrated in vacuo and purified by flash column chromatography
(50% EtOAc/hexane) to afford the title compound 20 (13 mg, 43%) as
a white solid; IR (neat): 3204, 2395, 1619, 1472, 1455, 1429, 1389,
4.4.19. 3a-Butyl-N,N,4-trimethyl-5-oxooctahydro-1H-indole-1-
carboxamide (18). To a solution of CuI (257 mg, 1.35 mmol) in THF
(1.5 mL) at 0 ꢀC was added n-BuLi (1.70 mL, 2.70 mmol, 1.59 M in
hexanes) and the solution was stirred for 10 min. The reaction
mixture was cooled to ꢁ78 ꢀC and chlorotrimethylsilane (85
mL,
1255 cmꢁ1; 1H NMR (CD3OD, 400 MHz):
d 7.43e7.29 (m, 5H), 6.84
0.675 mmol) and hexamethylphosphoramide (0.16 mL, 0.90 mmol)
were added sequentially. The reaction mixture was stirred for 5 min
and then 17c2 (100 mg, 0.45 mmol) in THF (2 mL) was added. The
solution was warmed to rt and stirred for 90 min. Satd aq NH4Cl
solution (20 mL) and Et2O (30 mL) were added. The organic portion
was separated and washed with satd aq NH4Cl solution (10 mL) and
water (2ꢂ10 mL). The organic portion was dried over Na2SO4 and
concentrated in vacuo. The residue was dissolved in THF (2 mL),
tetra-n-butylammonium fluoride (0.9 mL, 0.90 mmol, 1 M in THF)
was added and the solution was stirred for 20 h. Water (20 mL) was
added and the solution was extracted with Et2O (3ꢂ10 mL). The
organic portions were combined, dried over Na2SO4 and concen-
trated in vacuo. The residue was purified by flash column chro-
matography (70% EtOAc/hexane) to afford the title compound 18
(70 mg, 56%) as a colourless oil. Cyclohexanone 18 was obtained as
a mixture of diastereomers A and B (2:1, A:B); IR (neat): 2932, 1710,
(d, J¼8.5 Hz, 1H), 6.73 (d, J¼8.5 Hz, 1H), 3.82 (t, J¼8.0 Hz, 2H), 2.95
(s, 6H), 2.84 (t, J¼8.0 Hz, 2H); 13C NMR (CD3OD, 100 MHz):
d 162.7,
150.7, 137.9 (2 signals), 133.1, 130.9, 129.1, 128.0, 127.9, 114.9 (2
signals), 52.1, 38.4, 29.5; m/z (CIþ) 72 (30%), 283 ([MþH]þ, 100%);
HRMS: (CIþ) calcd for C17H19N2O2: 283.1447. Found [MþH]þ:
283.1443.
Acknowledgements
M.H.S. thanks the Bristol Chemical Synthesis Doctoral Training
Centre, funded by the EPSRC (EP/G036764/1), and Syngenta for the
provision of a Ph.D. studentship. J.F.B. is indebted to the Royal So-
ciety for a University Research Fellowship. We thank the X-ray
Crystallography Service at the School of Chemistry, University of
Bristol for analysis of 15a. Ms. Ekaterina Melikhova, Mr. Antony
Burton and Mr. Jason Hui (all University of Bristol) are thanked for
contributions during preliminary studies.
1633, 1455, 1385, 1353, 1201 cmꢁ1
;
1H NMR (CDCl3, 500 MHz):
d
4.13 (dd, J¼4.5, 3.0 Hz, 1H, A), 3.89 (dd, J¼4.0, 4.0 Hz, 1H, B), 3.63
(ddd, J¼10.0, 10.0, 7.0 Hz, 1H, B), 3.27 (ddd, J¼10.0, 9.0, 2.5 Hz, 1H,
B), 3.20e3.09 (m, 2H, A), 2.89 (s, 6H, B), 2.79 (s, 6H, A), 2.60 (q,
J¼7.0 Hz, 1H, B), 2.55 (q, J¼6.5 Hz, 1H, A), 2.46 (ddd, J¼14.0, 12.0,
6.0 Hz, 1H, B), 2.37 (m, 1H, B), 2.27e2.24 (m, 2H, A), 2.17e2.10 (m,
1H (A) and 1H (B)) 2.05 (m, 1H, A), 1.94 (m, 1H, B), 1.83 (m, 1H, B),
1.74 (m, 1H, B), 1.68 (ddd, J¼13.0, 7.0, 6.0 Hz, 1H, A), 1.53e1.46 (m,
3H, A), 1.41e1.15 (m, 4H (A) and 6H (B)), 1.00 (d, J¼7.0 Hz, 3H, B),
0.98 (d, J¼6.5 Hz, 3H, A), 0.91 (t, J¼7.0 Hz, 3H, A), 0.85 (t, J¼7.0 Hz,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.08.052.
References and notes
3H, B); 13C NMR (CDCl3, 100 MHz):
d 215.3 (A), 213.8 (B), 164.2 (B),
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163.2 (A), 60.3 (A), 60.1 (B), 51.3 (B), 49.5 (A), 48.2 (B), 47.9 (A), 47.2
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Found [MþH]þ: 281.2223.
4.4.20. N,N,4-Trimethyl-5-oxooctahydro-1H-indole-1-carboxamide
(19). To a three-necked round-bottom flask containing Pd on

M.H. Shaw et al. / Tetrahedron 72 (2016) 2731e2741
2741
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