Substituted pyrroles via olefin cross-metathesis

Article abstract of DOI:10.1021/ol101681r

Olefin cross-metathesis (CM) provides a short and convenient entry to diverse trans-γ-aminoenones. When exposed to either acid or Heck arylation conditions, these intermediates are converted to mono-, di-, or trisubstituted pyrroles. The value of this che

Full text of DOI:10.1021/ol101681r

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4094-4097
Substituted Pyrroles via Olefin
Cross-Metathesis
Timothy J. Donohoe,* Nicholas J. Race, John F. Bower, and
Cedric K. A. Callens†
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, U.K.
timothy.donohoe@chem.ox.ac.uk
Received July 20, 2010
ABSTRACT
Olefin cross-metathesis (CM) provides a short and convenient entry to diverse trans-γ-aminoenones. When exposed to either acid or Heck
arylation conditions, these intermediates are converted to mono-, di-, or trisubstituted pyrroles. The value of this chemistry is demonstrated
by its application to the tetrasubstituted pyrrole subunit of Atorvastatin.
Recently, we have reported highly efficient and convergent
methods for the synthesis of di- and trisubstituted furans.1
Scheme 1. Olefin CM-Based Approach to Pyrroles
This chemistry is reliant upon the generation of trans-γ-
hydroxyenones via olefin cross-metathesis (CM) of an enone
and allylic alcohol. Trans- to cis-isomerization and subsequent
cycloaromatization to the furan target are then promoted by
either an acid cocatalyst or separate Heck arylation step. This
latter process also serves to introduce a substituent onto the
enone ꢀ-position to afford ultimately trisubstituted furans.
Herein, we report that an analogous strategy is applicable to
the synthesis of mono-, di-, and trisubstituted pyrrole derivatives
(4 and 5) (Scheme 1). In these cases, the key aspect is the
synthesis and manipulation of a trans-γ-aminoenone intermedi-
ate 3 which is accessible via the CM of readily available allylic
amine 1 and enone 2 components. These studies further add to
the notion that olefin CM can provide a general and enabling
basis for the regiocontrolled synthesis of diverse aromatic and
heteroaromatic targets.2,3
† Author to whom correspondence regarding X-ray crystallography should
be addressed.
(1) Donohoe, T. J.; Bower, J. F. Proc. Natl. Acad. Sci. U.S.A. 2010,
107, 3373–3376. These studies represent the first systematic investigations
into the use of olefin CM for aryl synthesis.
Our initial studies focused upon evaluating the CM of a
representative range of allylic amine derivatives 1a-h with
enone partners 2a-d (Scheme 2).4-6 Here, we found that,
10.1021/ol101681r  2010 American Chemical Society
Published on Web 08/16/2010

Scheme 2.
Mono- and Disubstituted Pyrroles via a CM-Isomerization Tandema
a The R1 and R2 substituent definitions for 3a-l are the same as for 4a-l.
using 10 mol % Grubbs-Hoveyda second-generation catalyst
(G-H-II)7 in combination with 500 mol % of the enone
partner,8 a series of trans-γ-aminoenone intermediates 3a-l
were accessible in good yields (55-73%). These species
were then converted smoothly to the mono- or 2,5-disubsti-
tuted pyrrole targets 4a-l upon exposure to catalytic p-TsOH
at 70 °C.9 This sequence tolerates a range of protecting
groups on nitrogen (e.g., Cbz, Ts, COCF3) although car-
Scheme 3. One-Pot Pyrrole Formation
(2) For reviews on the use of olefin metathesis in the synthesis of
aromatic compounds, see: (a) van Otterlo, W. A. L.; de Koning, C. B. Chem.
ReV. 2009, 109, 3743–3782. (b) Donohoe, T. J.; Fishlock, L. P.; Procopiou,
P. A. Chem.sEur. J. 2008, 14, 5716–5726. (c) Donohoe, T. J.; Orr, A. J.;
Bingham, M. Angew. Chem., Int. Ed. 2006, 45, 2664–2670.
(3) ꢀ-Alkyl enones prepared by CM have been employed previously
for pyrrole synthesis: Poulard, C.; Cornet, J.; Legoupy, S.; Dujardin, G.;
Dhal, R.; Huet, F. Lett. Org. Chem. 2009, 6, 359–361.
bamates were found to be the most effective. Exemplification
using a range of Cbz-protected allylic amines (1a,e-h) shows
(4) CM between N-protected allylic amines and enones has previously
been reported on limited substrate ranges. For examples, see: (a) Dewi-
Wu¨lfing, P.; Blechert, S. Eur. J. Org. Chem. 2006, 1852–1856. (b) Gebauer,
J.; Dewi, P.; Blechert, S. Tetrahedron Lett. 2005, 46, 43–46. For Lewis
acid enhancement, see: (c) Vedrenne, E.; Dupont, H.; Oualef, S.; Elka¨ım,
L.; Grimaud, L. Synlett 2005, 670–672. For microwave enhancement, see:
(d) Ettari, R.; Micale, N.; Schirmeister, T.; Gelhaus, C.; Leippe, M.; Nizi,
E.; Di Francesco, M. E.; Grasso, S.; Zappala`, M. J. Med. Chem. 2009, 52,
2157–2160.
Scheme 4. Dihydroindolizinone Synthesis
(5) The efficiency of this process may be enhanced by hydrogen bonding
between the allylic amine N-H and the chloride ligands associated with
G-H-II: Hoveyda, A. H.; Lombardi, P. J.; O’Brien, R. V.; Zhugralin, A. R.
J. Am. Chem. Soc. 2009, 131, 8378–8379.
(6) The Supporting Information gives details for the preparation of the
allylic amine derivatives employed here. In general, these were prepared
via the corresponding R-amido sulfone. See: Mecozzi, T.; Petrini, M. J.
Org. Chem. 1999, 64, 8970–8972.
(7) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168–8179.
(8) Lower catalyst or enone loadings result in diminished yields of the
CM product (e.g. 5 mol % of G-H-II affords 3a in ca. 55% yield).
Org. Lett., Vol. 12, No. 18, 2010
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Scheme 5.
Di- and Trisubstituted Pyrroles via a CM-Heck Tandema
a For the yields of 3a-c,e,h,i, see Scheme 2.
that the process is amenable to the introduction of diverse
alkyl or aryl substituents at either R1 or R2.
Access to trisubstituted pyrrole derivatives is potentially
achieved via either (i) CM employing 1,1-disubstituted allylic
amine or enone components or (ii) modifying the trans-γ-
aminoenone intermediates 3a-l. While CM of 1,1-disubsti-
tuted derivatives was not effective, Heck arylation of the
trans-γ-aminoenone intermediates does provide an efficient
entry to tri- or disubstituted pyrrole derivatives (Scheme 5).
For example, Heck arylation of aminoenone 3a with bro-
motoluene, under the conditions reported by Fu,13 resulted
in the isolation of pyrrole 5a in 89% yield. Extension to the
introduction of other aryl groups was readily achieved, and
pyrroles 5b and 5c were also formed in good yield. This
sequence is also able to generate efficiently a variety of
differentially protected pyrroles such as 5d and 5e. Ap-
propriate choice of aminoenone precursor enables the
As both the CM and acid-catalyzed cycloaromatization
steps are conducted efficiently in CH2Cl2, and by analogy
with our earlier work on furans,1 we considered whether a
one-pot pyrrole synthesis could be developed. However,
using 1a and 2a as test substrates, simultaneous employment
of both the acid catalyst and G-H-II was not efficient, and
only very low conversions (<15%) to pyrrole 4a were
observed. A sequential one-pot protocol, involving addition
of p-TsOH after completion of the metathesis step, was more
promising, and after extensive optimization, pyrrole 4a was
accessible in 46% yield (Scheme 3). Nevertheless, this
sequence is still less efficient than the two-step method
presented in Scheme 2 (68% yield for 4a) and so was not
exemplified further.
(9) Acid-catalyzed cycloaromatization of isolable trans-γ-aminoenals/
enones has been reported previously: (a) Haidounne, M.; Mornet, R.; Laloue,
M. Tetrahedron Lett. 1990, 31, 1419–1422. (b) Paulus, O.; Alcaraz, G.;
Vaultier, M. Eur. J. Org. Chem. 2002, 2565–2572, and references cited
therein.
Extension of this chemistry provides access to bicyclic
pyrrole derivatives. For example, CM of allylic amide 1i10
with methyl vinyl ketone 2a afforded trans-γ-aminoenone
3m in good yield (Scheme 4). Cyclization of this species
was slow,11 but reasonably efficient, and afforded dihydroin-
dolizinone 4m in 56% yield. Substructures of this type are
common motifs in a range of natural products such as
rhazinicine.12
(10) Neipp, C. E.; Martin, S. F. J. Org. Chem. 2003, 68, 8867–8878.
(11) Cycloaromatization, which requires trans- to cis-isomerisation of
the enone moiety, may proceed via an aziridine intermediate. For 3m, this
would invoke the intermediacy of a strained 6,3-fused ring system which
may account for the slow rate of cyclization observed in this case.
(12) Gerasimenko, I.; Sheludko, Y.; Sto¨ckigt, J. J. Nat. Prod. 2001, 64,
114–116.
(13) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989–7000.
4096
Org. Lett., Vol. 12, No. 18, 2010

Scheme 6. CM-Based Approach to the Pyrrole Subunit of Atorvastatin
synthesis of 2,4-disubstituted pyrroles (as in 5f). Finally, as
the regiochemistry of the final target is dictated by the nature
of the aminoenone precursor, programmable access to various
different substitution patterns is readily achieved (cf. alkyl/
aryl substitution in 5g and 5h).
Sc(OTf)3-promoted Friedel-Crafts type acylation with
phenylisocyanate to deliver the key tetrasubstituted pyrrole
subunit 11 in good yield; the structure of 11 was confirmed
by X-ray crystallography (see Supporting Informa-
tion).17,18
The direct formation of pyrroles from the Heck step is
most likely due to mechanistic requirements that were
delineated previously in our furan studies.1 Carbopalladation
(syn) of the enone moiety is followed by ꢀ-hydride elimina-
tion (syn), and these processes should enforce trans to cis
isomerization of the alkene. The resulting adduct is then
perfectly set up for in situ aminal formation and dehydration
to the target pyrrole (see Scheme 1, bottom).14
The relatively high reactivity of the pyrrole nucleus
detracts from applications of this substructure in medicinal
chemistry. However, this belies the value of highly substi-
tuted derivatives where reactivity is often attenuated. Indeed,
such polysubstituted pyrroles have potentially profound
medicinal impact, as evidenced by Atorvastatin 12 (Lipitor),
the world’s largest selling pharmaceutical (Scheme 6).15 This
compound provides a suitable testbed for our CM-based
synthetic methodology and also acts as a vehicle to demon-
strate that tetrasubstituted pyrroles are available via C-H
functionalization of the trisubstituted variants reported
here. Accordingly, conversion of aldehyde 6 to allylic
amine derivative 7 was readily achieved via the corre-
sponding sulfone.6 Next, CM of 7 with enone 816 delivered
aminoenone 9 in 50% yield. Heck reaction of this species
(with bromobenzene) was demanding (cf. pyrrole 5g), but
after optimization, pyrrole 10 was generated in 56% yield.
Hydrolytic Cbz deprotection (KOH) was followed by
In summary, olefin CM provides an efficient and general
entry to trans-γ-aminoenones which then function as versatile
precursors to mono-, di-, and trisubstituted pyrrole deriva-
tives. Tetrasubstituted variants are accessible via function-
alization of the remaining pyrrole C-H bond, as demon-
strated by a synthesis of the core of Atorvastatin. The
methodologies presented here combine readily available
precursors in a direct, convergent, and regiocontrolled manner
to provide a powerful entry to polysubstituted pyrroles.
Acknowledgment. We thank the EPSRC for financial
support and the Oxford Chemical Crystallography Service
for use of instrumentation.
Supporting Information Available: Copies of 1H and 13C
NMR spectra and experimental procedures are available. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101681R
(17) The synthesis of pyrrole 11 has been reported previously: Pandey,
P. S.; Rao, T. S. Bioorg. Med. Chem. Lett. 2004, 14, 129–131. However,
the 13C NMR data obtained for our material are not consistent with that
reported earlier. For this reason structural confirmation of 11 was undertaken
by X-ray crystallography. This, in conjunction with 2D NMR and nOe data,
also underpins the structural assignment of the other pyrroles presented in
this paper (see Supporting Information).
(18) Selective (but low yielding; < 20%) N-alkylation of 11 with 2-(2-
bromoethyl)-1,3-dioxolane (see Supporting Information) affords an inter-
mediate which has been converted previously to 12 in 4 steps: Roth, B. D.;
Blankley, C. J.; Chucholowski, A. W.; Ferguson, E.; Hoefle, M. L.; Ortwine,
D. F.; Newton, R. S.; Sekerke, C. S.; Sliskovic, D. R.; Stratton, C. D.;
Wilson, M. W. J. Med. Chem. 1991, 34, 357–366. We are currently
investigating strategies for the efficient and direct installation of a fully
functionalized side chain.
(14) For a related aminal dehydration to afford a pyrrole, see: Mori,
M.; Hashimoto, A.; Shibasaki, M. J. Org. Chem. 1993, 58, 6503–6504.
(15) Roth, B. D. US Patent 5,273,995.
(16) Fujieda, S.; Tomita, M.; Fuhshuku, K.-i.; Ohba, S.; Nishiyama, S.;
Sugai, T. AdV. Synth. Catal. 2005, 347, 1099–1109.
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