Direct Synthesis of Highly Substituted Pyrroles and Dihydropyrroles Using Linear Selective Hydroacylation Reactions

Article abstract of DOI:10.1002/chem.201600311

Rhodium(I) catalysts incorporating small bite-angle diphosphine ligands, such as (Cy₂P)₂NMe or bis(diphenylphosphino)methane (dppm), are effective at catalysing the union of aldehydes and propargylic amines to deliver the linear hydroacylation adducts in good yields and with high selectivities. In situ treatment of the hydroacylation adducts with p-TSA triggers a dehydrative cyclisation to provide the corresponding pyrroles. The use of allylic amines, in place of the propargylic substrates, delivers functionalised dihydropyrroles. The hydroacylation reactions can also be combined in a cascade process with a Rh^I-catalysed Suzuki-type coupling employing aryl boronic acids, providing a three-component assembly of highly substituted pyrroles. Down the line: Rhodium catalysts featuring small-bite-angle bisphosphine ligands allow the linear-selective combination of aldehydes and propargylic amines (see scheme). The resultant γ-amino-enone products are converted in situ to a diverse range of substituted pyrroles. Allylic amine substrates can also be employed, leading in these cases to dihydropyrrole products.

Full text of DOI:10.1002/chem.201600311

DOI: 10.1002/chem.201600311
Full Paper
&
Homogeneous Catalysis
Direct Synthesis of Highly Substituted Pyrroles and
Dihydropyrroles Using Linear Selective Hydroacylation Reactions
Manjeet K. Majhail, Paul M. Ylioja, and Michael C. Willis*[a]
Abstract: Rhodium(I) catalysts incorporating small bite-angle
diphosphine ligands, such as (Cy2P)2NMe or bis(diphenyl-
phosphino)methane (dppm), are effective at catalysing the
union of aldehydes and propargylic amines to deliver the
linear hydroacylation adducts in good yields and with high
selectivities. In situ treatment of the hydroacylation adducts
with p-TSA triggers a dehydrative cyclisation to provide the
corresponding pyrroles. The use of allylic amines, in place of
the propargylic substrates, delivers functionalised dihydro-
pyrroles. The hydroacylation reactions can also be combined
in a cascade process with a RhI-catalysed Suzuki-type cou-
pling employing aryl boronic acids, providing a three-com-
ponent assembly of highly substituted pyrroles.
termolecular hydroacylation reactions,[6] which combine alde-
hydes with alkenes and alkynes, are one such class of reaction.
These reactions are atom-economical CÀH activation processes
that deliver a variety of carbonyl-containing molecules through
the formation of new CÀC bonds. Such processes are emerg-
ing as useful tools in synthesis, and recent years have seen the
first applications of these reactions to heterocycle construction.
Our laboratory has reported the synthesis of highly substituted
furans through intermolecular alkyne hydroacylation,[7] while
the Dong group has reported the efficient preparation of ben-
zofuran rings using rhodium-catalysed coupling of aldehydes
and vinylphenols.[8] In addition, both ourselves[9] and the Stan-
ley group[10] have described intramolecular conjugate addition-
based processes to access dihydroquinolones and chroma-
nones, respectively, from hydroacylation adducts.
Introduction
The synthesis of aza-heterocycles has been the subject of
much investigation over recent years due to their abundance
in nature and their wide application. Of particular significance
is the pyrrole motif, as it is integral to many bioactive natural
products, successful pharmaceuticals, and has a growing pres-
ence in materials science (Scheme 1).[1] Many classical methods
for the preparation of pyrroles employ 1,4-dicarbonyl com-
pounds,[2] which are often limited by the availability of starting
materials, especially when structural complexity is required.
The surge in catalytic protocols for the construction of this
ubiquitous heterocycle indicates that there is a requirement to
deliver functionalised ring systems using mild reaction condi-
tions, from simple substrates, in an experimentally straightfor-
ward fashion.[3,4] One of the driving forces for the development
of these new methods is the desire to employ non-traditional
starting materials, potentially allowing access to new areas of
chemical space.[5]
Carbonyl-containing compounds are archetypal intermedi-
ates for heterocycle synthesis, and consequently catalytic reac-
tions that deliver these molecules, preferably from alternative
feedstocks, are ideal candidates to be employed in these ven-
tures, and to address many of the shortfalls associated with
classical heterocycle syntheses. Transition-metal-catalysed in-
[a] M. K. Majhail, Dr. P. M. Ylioja, Prof. M. C. Willis
Department of Chemistry, University of Oxford
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: michael.willis@chem.ox.ac.uk
Homepage: http://mcwillis.chem.ox.ac.uk/MCW/Home.html
Supporting information and ORCID from the author for this article are
available on the WWW under http://dx.doi.org/10.1002/chem.201600311.
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons At-
tribution License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited.
Scheme 1. Selected examples of pyrroles in bioactive molecules and materi-
als, and our proposed alkyne hydroacylation route to their synthesis.
Chem. Eur. J. 2016, 22, 7879 – 7884
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We wished to exploit the benefits of alkyne hydroacylation
in a route to complex pyrroles; our proposed retrosynthesis is
shown in Scheme 1, and involves the hydroacylative union of
aldehydes and propargylic amines to deliver g-amino enone
products.[11] Dehydrative cyclisation of these enones would de-
liver the targeted pyrroles. Employing appropriately substitut-
ed aldehydes and alkynes would allow the direct synthesis of
highly substituted ring systems. In this article we demonstrate
how recent advances in catalyst design have allowed us to de-
velop efficient syntheses of both pyrroles and dihydropyrroles
using highly selective intermolecular alkyne and alkene hydro-
acylation reactions.
(Table 1). Our concerns over regioselectivity were soon proved
correct, with reactions employing a catalyst incorporating the
ligand DPEphos[14c] delivering the hydroacylation adducts as
a 2:1 mixture of linear and branched enones, respectively
(entry 1). We have recently shown that small-bite-angle, meth-
ylene-bridged diphosphines generate efficient and selective
catalysts for a variety of hydroacylation reactions.[22] Unfortu-
nately, in the present study, both bis(diphenylphosphino)me-
thane (dppm) and bis(dicyclohexylphosphinomethane) (dcpm)
ligands offered only modest improvement (entries 2–4). How-
ever, it was the electronic parameters of the PNP ligand
system, specifically the ligand (Cy2)P2NMe, that offered a signifi-
cant increase in the level of regiocontrol (entry 5).[23] To achieve
higher conversions we turned our attention to evaluating the
effect of concentration and temperature on the reactions. In-
creasing the concentration to 1.0m with respect to the alde-
hyde, allowed complete conversion for both the PCP and PNP
systems (entry 4 and 6). When assessing the effect of tempera-
ture, the general trend indicated that decreased temperatures
accomplished greater linear selectivity, without any loss in con-
version under ambient conditions (entry 8). Reaction at 08C
provided a more selective transformation but required a slightly
longer reaction time (entry 9). We also evaluated Cbz- and Ts-
protected propargylic amines in order to determine whether
the nature of the amine-protecting group played a significant
role in the selectivity of the reactions. In both cases the PNP-
derived catalyst outperformed the corresponding dcpm
system, and for the Cbz substrate was able to provide the de-
sired linear adduct with reasonable, but diminished with re-
spect to Boc-derivative, selectivity (entries 10 and 11). The N-Ts-
substrate was poorly selective with either catalyst (entries 12
and 13). For convenience we decided to undertake subsequent
reactions using the room temperature conditions shown in
entry 8, and to employ N-Boc-protected amines.
Results and Discussion
One of the main limitations of intermolecular hydroacylation
reactions employing RhI-catalysts is a competing reductive de-
carbonylation pathway.[6] The majority of approaches to over-
come this issue invoke some form of substrate chelation, be it
from the aldehyde,[12–16] or alkene or alkyne.[17] Although there
are now a number of successful non-chelation intermolecular
hydroacylation methods,[18,19] the most general and selective
processes invariably rely on chelation control and have allowed
the development of reactions that operate under mild condi-
tions, employ low loadings of catalyst and achieve high levels
of selectivity.[20] Accordingly, we selected chelating aldehydes
as our preferred substrates. The presence of coordinating func-
tionality on the alkene or alkyne coupling partner has also
been shown to have a significant impact on the course of sev-
eral hydroacylation reactions, and has been employed to facili-
tate both reactivity and selectivity.[17] For example, both Dong
and Suemune employed alkenes bearing coordinating func-
tionality to achieve branched-selective reactions,[21] required to
develop enantioselective processes. We were therefore con-
scious that our proposed alkyne substrates—propargylic
amines—may well be involved in coordination to the metal
catalyst and that this could effect the regioselectivity of the
proposed reactions. Poor regiocontrol would have significant
consequences for our designed pyrrole synthesis, as only the
linear hydroacylation adducts are capable of undergoing a pyr-
role-forming cyclisation (Scheme 2).
We next investigated whether this intermolecular hydroacy-
lation could maintain high levels of selectivity when varying
the propargylic amine substrates (Table 2). Pleasingly, introduc-
ing substituents a to the nitrogen atom displayed enhanced
selectivity for the linear product (3b–d), demonstrating that
further improvements in regiocontrol could be achieved by
substrate design. A range of aldehydes, including substituted
aryl (3 f), alkyl (3g), alkenyl (3h), heteroaromatic variants (3i),
and the use of a nitrogen-chelating atom (3j), were also intro-
duced without incident. We then expanded the process to in-
clude internal alkyne substrates, which following cyclisation
would allow the direct formation of tetra-substituted pyrroles.
The hydroacylation of an internal alkyne proceeded efficiently,
although an alternative ligand was required (3e); the PNP(Cy)-
based catalyst did not deliver the necessary regiocontrol (2:1,
linear: branched), however, when using dppm, a PCP-based
ligand system, acceptable levels of linear-selectivity were ach-
ieved (8:1). This brief study also established that it was possi-
ble to employ a catalyst loading of only 1 mol% (3d), although
for pragmatic reasons the majority of reactions were per-
formed using a 5 mol% loading.
We began our investigation by studying the coupling of o-
SMe-benzaldehyde 1a and N-Boc propargylic amine 2a
With a selective hydroacylation reaction in hand, we next
studied the cyclisation to generate the desired pyrroles. g-
Scheme 2. Linear versus branched selectivity in alkyne hydroacylation.
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Table 1. Ligand evaluation for the hydroacylation reaction between alde-
hyde 1a and propargylic amine 2a.[a]
Table 2. Substrate scope for linear selective preparation of g-amino eno-
nes.[a]
Entry
PG
Ligand
Time
T [8C]
Conv. [%][b]
3a/3a’[b]
1[c]
2[c]
3[c]
4
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Cbz
Cbz
Ts
DPEphos
dppm
dcpm
16 h
16 h
16 h
1 h
55
55
55
55
55
55
80[d]
22
0
22
22
22
22
41 (32)
76 (69)
85
100 (87)
78
2:1
5:1
3:1
5:1
9:1
10:1
7:1
17:1
20:1
4:1
12:1
1:1
dcpm
5[c]
6
PNP(Cy)
PNP(Cy)
PNP(Cy)
PNP(Cy)
PNP(Cy)
dcpm
PNP(Cy)
dcpm
PNP(Cy)
16 h
10 min
10 min
30 min
2 h
16 h
30 min
16 h
100
100
7
8[e]
9
100[f] (90)
100 (94)
100 (79)
100 (82)
100
10
11
12
13
Ts
10 min
100
4:1
[a] Reaction conditions: aldehyde (1.0 equiv, 0.15 mmol), alkyne
(1.3 equiv), [Rh(nbd)2]BF4 (5 mol%), PNP(Cy) (5 mol%), acetone (1m with
respect to aldehyde), RT. Yields are of isolated linear products; l/b ratios
were determined by 1H NMR analysis of the crude reaction mixture.
[b] Aldehyde (3.0 mmol, 1.0 equiv), [Rh(nbd)2]BF4 (1 mol%), PNP(Cy)
(1 mol%). [c] dppm (5 mol%) used in place of PNP(Cy).
[a] Reaction conditions: 1a (1.0 equiv, 0.15 mmol), 2a (1.3 equiv),
[Rh(nbd)2]BF4 (5 mol%), ligand (5 mol%), acetone, 1m with respect to alde-
hyde. [b] Determined by 1H NMR analysis of the crude reaction mixture.
Value in parenthesis is the combined isolated yield of the two regioisomers.
[c] 0.3m with respect to aldehyde. [d] Performed in 1,2-dichloroethane.
[e] [Rh(nbd)2]BF4 (2 mol%), PNP(Cy) (2 mol%). [f] 86% isolated yield of linear
isomer. PG=protecting group.
ents, which have potential for further derivatisation (4l, 4n–p).
Heteroaryl groups, in the form of thiophene-derived aldehydes,
also proved to be good substrates (4u, v). Alkyl (4q–s) and al-
kenyl (4t) aldehydes displayed good reactivity, although lower
regioselectivity in the hydroacylation step was observed. We
were also successful in exchanging the chelating atom to nitro-
gen (4w, x).[9,15c] In addition, we were able to prepare a range
of tri-substituted N-Boc-pyrroles using internal propargylic
amines in conjunction with a dppm derived catalyst; alkyl
chains (4g–I, 4l and 4t) as well as a hydroxymethyl group
(4p) were successfully installed.
A limitation of the presented synthesis is the use of an
alkyne as one of the reaction components, as this necessarily
means that the C-3 position of the pyrrole products is unsub-
stituted. Accordingly, we chose to demonstrate the preparation
of fully substituted pyrroles from the functionalisation of repre-
sentative tetra-substituted examples (Scheme 3). Treatment of
pyrrole 4h with NBS delivered the 3-Br-derivative (5a) in excel-
lent yield. An acyl group could be installed employing In(OTf)3-
catalysed acylation (5b).[24] We also established that N-depro-
tection was straightforward, with TFA treatment of pyrrole 4g
delivering the parent NH-pyrrole (5c).
Amino enones are known to undergo Brønsted-acid-catalysed
cyclisation,[11] and pleasingly, addition of p-toluene sulfonic
acid and a small quantity of acetonitrile directly to the reaction
mixtures upon completion of the hydroacylation process al-
lowed rapid and clean conversions to the substituted pyrroles.
A series of N-Boc functionalised pyrroles was then prepared
using this one-pot cascade process (Table 3). Varied substitu-
ents at the propargylic position could be readily installed, with
alkyl (4b–c and 4u), functionalised aryl and heteroaryl (4k, 4n
and 4v) groups all tolerated. In particular, it is noteworthy that
the aryl substituents could possess steric bulk at the hindered
ortho-position (4r) and contain useful functionality such as hal-
ides (4m), esters (4s) and nitrile (4 f). In addition, owing to the
excellent functional group tolerance at the 2- and 5-position of
the pyrrole ring, we were able to directly synthesise several in-
teresting linked heterocycles in a concise manner (4k, n, u and
4v). Encouragingly, a larger scale preparation of pyrrole 4d
was also possible, achieving an 88% yield when using only
1 mol% of the catalyst, affording over 1 g of product. Variation
of the aldehyde component provided access to a variety of dif-
ferently functionalised pyrroles.
As the examples in Table 3 demonstrate, the use of chelating
aldehydes as substrates allowed the preparation of a broad
range of pyrroles, featuring diverse substituents, in good to ex-
cellent yields. However, the caveat to employing chelating al-
dehydes as substrates is that the pyrrole products also feature
the chelating substituent. In the majority of examples, this che-
lating substituent is a MeS group. We have recently shown
that for aryl methyl sulfides, the methyl sulfide group can func-
Substitution on every position of the aromatic-ring of aryl al-
dehydes was achieved in good-to-excellent yields, including
the sterically hindered ortho-position (4l), and halide substitu-
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Table 3. Substrate scope of the cascade pyrrole synthesis through g-
amino enones.[a]
Scheme 3. C-3 functionalisation and N-deprotection.
Table 4. Three-component couplings leading to pyrroles 6a–c.[a]
[a] Reaction conditions: aldehyde (1.0 equiv, 0.15 mmol), alkyne
(1.3 equiv), [Rh(nbd)2]BF4 (10 mol%), PNP(Cy) (5 mol%), dcpm (5 mol%),
acetone (1m with respect to aldehyde), 558C, 10 min; then Ag2CO3
(1.0 equiv), aryl boronic acid (1.5 equiv), acetone (0.3m with respect to al-
dehyde), 558C, 4 h; then filter through silica plug and add p-TSA
(1.0 equiv). Yields are of isolated products.
a common RhI salt. This approach allowed the preparation of
pyrroles 6a–c, resulting from the union of an aryl aldehyde,
a propargylic amine and an aryl boronic acid, and involving
the formation of two CÀC and one CÀN bonds.
[a] Reaction conditions: aldehyde (1.0 equiv, 0.15 mmol), alkyne
(1.3 equiv), [Rh(nbd)2]BF4 (5 mol%), PNP(Cy) (5 mol%), acetone (1m with
respect to aldehyde), RT. Yields are of isolated products. [b] Aldehyde
(1.0 equiv, 3.2 mmol), [Rh(nbd)2]BF4 (1 mol%), PNP(Cy) (1 mol%), 1.04 g of
isolated product. [c] dppm (5 mol%) used in place of PNP(Cy).
[d] [Rh(nbd)2]BF4 (7 mol%), PNP(Cy) (7 mol%).
To extend the general process to the synthesis of dihydro-
pyrroles required the hydroacylative coupling of aldehydes
with allylic amines (Table 5). Pleasingly, use of the PNP(Cy)-de-
rived catalyst allowed efficient reactions of allyl amines with S-
chelating aldehydes. A variety of alkyl (7b, d), aryl (7a, g, h)
and heteroaryl (7c) substituents were tolerated at the allylic
position of the alkenes. Substituted aryl (7c–e), as well as het-
eroaryl (7 f, 7g) aldehydes could also be employed without in-
tion as an activating group for a variety of rhodium-catalysed
processes.[25] When translated to the present study, we were
able to show that we can obtain “traceless” pyrrole products
by combining the key hydroacylation reactions with MeS-
Suzuki-type couplings using aryl boronic acids (Table 4). In
order to achieve efficient hydroacylation and Suzuki-type reac-
tions it was necessary to employ a mixed ligand system, in
which both PNP(Cy) and dcpm were used in combination with
cident. Unfortunately, aldehydes featuring
a coordinating
amino-substituent proved to be unreactive in this system,[9] as
did disubstituted alkenes. As in the pyrrole syntheses, the hy-
droacylation adducts were treated directly with p-TSA to
induce cyclisation. In the event, acid treatment also induced
cleavage of the Boc-group, resulting in the formation of dihy-
dropyrroles (7a–h) in good-to-excellent yields.
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pyrrolidine 8g was obtained in 68% yield from a crude 3:1
mixture of diastereomers. Finally, an allyl Grignard reagent
could also be employed as the nucleophile, delivering pyrroli-
dine 8h, featuring a quaternary centre, in excellent yield and
diastereoselectivity.[28]
Table 5. Dihydropyrrole synthesis from the combination of S-chelating al-
dehydes and allylic amines.[a]
Conclusions
We have developed a rhodium-based catalyst system that
allows the linear selective hydroacylation of propargylic
amines. We have further demonstrated the applicability of the
intermediates obtained from this novel hydroacylation in the
direct synthesis of tri- and tetra-substituted pyrroles, with the
ability to install a variety of functional groups in a one-pot cas-
cade. We have shown that access to fully substituted pyrroles
can be obtained by classical brominations and acylations. Fur-
thermore, we have demonstrated that the methyl sulfide
group, utilised as a chelating motif for the hydroacylation reac-
tion, can act as a pseudo-halide and be exploited in telescoped
cross-coupling reactions using the same catalytic species re-
quired for the initial CÀH activation. These cascade Suzuki-type
reactions allow access to considerable structural diversity from
simple starting materials in a three-component assembly, using
an experimentally straightforward method. In addition, we
have demonstrated that the methodology developed for the
coupling of alkynes and aldehydes is equally applicable to al-
kenes, allowing extension of the methodology to the synthesis
of dihydropyrroles, and by derivatisation, to pyrrolidines.
[a] Reaction conditions: aldehyde (1.0 equiv, 0.15 mmol), alkyne
(1.5 equiv), [Rh(nbd)2]BF4 (5 mol%), ligand (5 mol%), acetone (1m with re-
spect to aldehyde), 558C. Yields are of isolated products.
Dihydropyrroles are useful substrates to access the corre-
sponding saturated heterocycles. For example, reduction of di-
hydropyrroles to form the pyrrolidines through the syn-addi-
tion of hydride was achieved by the use of diisobutylalumini-
um hydride (DIBAL-H) (Table 6). Employing this bulky reducing
agent allowed the formation of a range of cis-pyrrolidines as
the only observed diastereoisomer.[26] However, formation of
the trans-pyrrolidines was not as straightforward, with the use
of sodium borohydride resulting in a mixture of diastereoiso-
mers in favour of the trans-isomer.[27] For example, pure trans-
Experimental Section
General procedure for the synthesis of N-Boc pyrroles as ex-
emplified by the synthesis of tert-butyl 2-[2-(methylthio)-
phenyl]-1H-pyrrole-1-carboxylate (4a)
Table 6. Reduction of dihydropyrroles to pyrrolidines.[a]
An oven-dried microwave vial was charged with [Rh(nbd)2BF4]
(2.8 mg, 5 mol%) [nbd=norbornadiene] and PNP(Cy) (3.2 mg,
5 mol%). Once under an inert atmosphere, they were dissolved in
acetone (1 mL). Hydrogen gas was bubbled through the solution
at room temperature for 1–2 min in order to generate the active
catalyst species. The hydrogen was purged using nitrogen gas, and
this was bubbled through the catalyst to dryness. The dry catalyst
was dissolved in acetone (75 mL) and this was transferred to a nitro-
gen-filled microwave vial containing 2-(methylthio)benzaldehyde
(1a; 19 mL, 0.15 mmol, 1.0 equiv) and N-Boc-propargylamine (2a;
30.2 mg, 0.195 mmol, 1.3 equiv). The reaction mixture, once homo-
genous (on occasion, sonication was required), was then stirred at
room temperature and monitored by TLC until complete. After
20 min, the reaction vessel was opened to air followed by the addi-
tion of acetonitrile (1.5 mL) and p-TSA (42.8 mg, 0.230 mmol,
1.5 equiv). The reaction mixture was further stirred until complete.
After 3 h the solution was diluted with acetonitrile (5 mL) and neu-
tralised by the addition of sat. NaHCO3(aq.) (10 mL) in a separatory
funnel. The aqueous mixture was extracted with EtOAc (3”5 mL)
and the combined organic extracts were washed with brine
(10 mL) and dried over MgSO4. The solvent was removed in vacuo
to obtain the crude product, and this was then purified by flash
column chromatography (5–10% Et2O in petrol) to afford title pyr-
role 4a as a colourless oil (34.8 mg, 81%).
[a] Reaction conditions: dihydropyrrole (1.0 equiv), DIBAL-H (3.0 equiv).
Yields are of isolated products, with >20:1 d.r. as determined by 1H NMR
analysis. [b] NaBH4 (2.5 equiv), AcOH, RT, in place of DIBAL-H in PhMe.
Crude product obtained as a 3:1, trans/cis mixture, as determined by
1H NMR analysis. [c] Allyl magnesium bromide (1.5 equiv), used in place of
DIBAL-H.
Chem. Eur. J. 2016, 22, 7879 – 7884
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2011, 13, 998; g) R. Pawley, M. Huertos, G. Lloyd-Jones, A. S. Weller,
M. C. Willis, Organometallics 2012, 31, 5650; h) S.-J. Poingdestre, J. D.
Goodacre, A. S. Weller, M. C. Willis, Chem. Commun. 2012, 48, 6354. For
an intramolecular example, see: H. D. Bendorf, C. M. Colella, E. C. Dixon,
M. Marchetti, A. N. Matukonis, J. D. Musselman, T. A. Tiley, Tetrahedron
Lett. 2002, 43, 7031.
Acknowledgements
We thank the EPSRC for the award of an Established Career
Fellowship (M.C.W.).
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Keywords: cascade process · heterocycles · hydroacylation ·
pyrrole · rhodium
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Received: January 22, 2016
Published online on April 23, 2016
Chem. Eur. J. 2016, 22, 7879 – 7884
www.chemeurj.org
7884 ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim