An atom-economic synthesis of nitrogen heterocycles from alkynes

Article abstract of DOI:10.1021/ja110117g

A robust route to 2,4-disubstituted pyrrole heterocycles relying upon a cascade reaction is reported. The reaction benefits from operational simplicity: it is air and moisture tolerant and is performed at ambient temperature. Control over the reaction conditions provides ready access to isopyrroles, 2,3,4-trisubstituted pyrroles, and 3-substituted pyrollidin-2-ones.

Full text of DOI:10.1021/ja110117g

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An Atom-Economic Synthesis of Nitrogen Heterocycles from Alkynes
Barry M. Trost,* Jean-Philip Lumb, and Joseph M. Azzarelli
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States
S Supporting Information
b
Scheme 1. Pyrroles from Alkynes
ABSTRACT: A robust route to 2,4-disubstituted pyrrole
heterocycles relying upon a cascade reaction is reported.
The reaction benefits from operational simplicity: it is air
and moisture tolerant and is performed at ambient tem-
perature. Control over the reaction conditions provides
ready access to isopyrroles, 2,3,4-trisubstituted pyrroles,
and 3-substituted pyrollidin-2-ones.
he finite nature of chemical feedstocks coupled with the
negative impacts of manufacturing waste streams necessi-
T
tates the continued development of increasingly efficient pro-
cesses for the preparation of valuable synthetic building blocks.1
In this regard, our group has demonstrated that simple addition
reactions between differentially substituted alkynes can be inter-
faced with subsequent isomerizations to generate functional
molecules while upholding high levels of atom-economy.2 These
one-pot reactions benefit from the ability to conduct multiple
chemical transformations in a single reaction vessel, providing
their intended target while minimizing waste associated with
traditional isolation and purification protocols.3
whereas decreasing the amount of TDMPP resulted in competi-
tive formation of isopyrrole 4a (entries 2 and 3). Importantly,
pyrrole formation was not observed under the reaction conditions,
and increasing either the reaction time or temperature resulted in
complex mixtures and poor mass recovery.
While both free and phosphine-ligated Pd(OAc)2 were ineffec-
tive at promoting isomerization to the pyrrole product, we quickly
found that Pd(OTFA)2 resulted in clean formation of pyrrole 5k
from ynenoate 3k (Table 2).2b In this case, both acetonitrile and
benzonitrile complexes of PdCl2 (entries 4 and 5) were not as
effective as Pd(OTFA)2, which promoted the desired cyclization
and tautomerization in near quantitative yield. Once again,
TDMPP was found to inhibit both of these transformations
(compare entries 1 and 3), suggesting that a nonphosphine-ligated
Pd species is responsible for catalysis.15
The results presented in Tables 1 and 2 led us to adopt a set of
optimized conditions for the one-pot synthesis of either pyrrole
or enyne products (Table 3). Thus, treatment of 1 with a variety
of aromatic alkynes in the presence of Pd(OAc)2 (0.75 mol %)
and TDMPP (0.75 mol %) in PhMe at room temperature
afforded the corresponding ynenoate 3 in 77-97% isolated
yields after 6 h. Nonaromatic donor alkynes generally required
slightly longer reaction times (12-24 h), and provided yneno-
ates 3 in 64-97% isolated yield.
We envisioned that such a strategy could be applied to the
efficient production of valuable pyrrole heterocycles from alkyne
starting materials (Scheme 1).4 The addition of terminal alkyne 2
to suitably activated propargyl amine 1 under alkyne cross-
coupling conditions5 would result in ynenoate 3, whose isomer-
ization via a 5-endo-dig cyclization and tautomerization would
then provide pyrrole 5 (Scheme 1).6
While this sequence represents an efficient, isohypsic7 entry
into 2,4-disubstituted pyrroles,8 we anticipated that intermediates
3 and 4 could serve as strategic points of product diversification if
suitable conditions could be found for their selective preparation.9
In this regard, we viewed the design of a flexible route to topo-
logically varied five-membered nitrogen heterocycles as an intri-
guing challenge for atom-economic reaction design.10
We anticipated that electron-deficient propargyl amine 111
would serve as a suitable acceptor in an alkyne cross-coupling
reaction. It should be noted that propargyl amides similar to 1 are
prone to 5-endo-dig cyclization, affording the corresponding
oxazole heterocycle.12 In this regard, the current method pro-
vides a novel avenue of reactivity for these versatile building
blocks, while avoiding such an isomerization process.
Initial investigations employing phenyl acetylene (2a) as the
donor alkyne with toluene as the solvent13 revealed that product
distributions depend on the ratio of Pd(OAc)2 to the tris-(2,6-
dimethoxyphenyl)phosphine (TDMPP) ligand (Table 1).14 Ac-
cordingly, an equimolar amount of ligand and metal cleanly
afforded ynenoate 3a as a single geometrical isomer (entry 1),
Alternatively, pyrroles can be obtained in yields ranging from
60 to 99% in a two-stage, one-pot process. For aromatic donors,
addition of Pd(OTFA)2 (1.5 mol %) following complete conversion
to the ynenoate resulted in the cyclized/isomerized product after
only 6 h. Once again, nonaromatic donors require slightly longer
reaction times and higher catalyst loadings (5.0 mol % Pd(OTFA)2)
but nevertheless returned good to excellent yields of the desired
Received: November 10, 2010
Published: December 22, 2010
r
2010 American Chemical Society
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Table 1. Optimization of Selective Ynenoate Formationa
Table 3. One-Pot Synthesis of Ynenoates or Pyrroles
Pd(OAc)2
(mol %)
TDMPP
(mol %)
ratio
(3a/4a)b
conversionb
(%)
entry
1
2
3
3.0
3.0
3.0
3.0
1.5
0.8
20/1
3/2
100
100
100
1/5
a All reactions were performed using 0.1 mmol of 1 and 2a. b Determined
by 1H NMR.
Table 2. Optimization of Pyrrole Formationa
entry Pd(II)source TDMPP (mol %) ratio (4k/5k)b conversionb (%)
1
2
3
4
5
Pd(OTFA)2
-
1/20
1/20
1/2
100
95
Pd(OTFA)2
0.4
0.8
Pd(OTFA)2
72
PdCl2(CH3CN)2
PdCl2(PhCN)2
-
1/1
47
-
1/20
52
a Conditions A: 1 (0.1 mmol, 1 equiv), Donor Alkyne 2 (0.1 mmol,
1 equiv), PhMe (1.0 M), Pd(OAc)2 (0.75 mol %), TDMPP (0.75 mol
%), 6 h, rt. Reaction times other than 6 h are included in parentheses.
b Conditions B: 1 (0.23 mmol, 1 equiv), Donor Alkyne 2 (0.23 mmol,
1 equiv), PhMe (1.0 M), (Entries 1-8, 10): Pd(OAc)2 (0.75 mol %),
TDMPP (0.75 mol %), 6 h, rt; then Pd(OTFA)2 (2.0 mol %), 6 h, rt.
(Entries 11-16): Pd(OAc)2 (1.5 mol %), TDMPP (1.5 mol %), 24 h, rt;
then Pd(OTFA)2 (5.0 mol %), 24 h, rt. c Isolated yields. d From 3i
(0.1 mmol, 1 equiv), Pd(OAc)2 (5.0 mol %), THF (0.25 M), 60 °C, 14 h.
e BDMS = Benzyldimethylsilane.
a All reactions performed with 0.1 mmol of 3k. b Determined by H
1
NMR.
products after 24 h. Importantly, these reactions are performed in
screw-cap vials under an ambient atmosphere, with commercial
grade alkynes and benchtop solvents. Furthermore, yields remain
consistent upon scale-up, as both entries 1 and 11 have been per-
formed on half-gram and gram scales, respectively.
As evidenced by the breadth of substrates in Table 3, this
method tolerates a wide range of substituted donor alkynes.
Ortho-, meta-, and para-substituted aromatic alkynes with
both electron-donating and -withdrawing groups participate
effectively (entries 7-9 and entries 3 and 6, respectively).
Given the involvement of Pd(II) species throughout both the
coupling and the isomerization steps, aryl bromides do not
interfere with the reaction (entries 4 and 5). The basic
nitrogen of an unprotected aniline is also tolerated in the
coupling portion of the cascade (entry 9); however, cycliza-
tion to the pyrrole requires more rigorous conditions, starting
from ynenoate 3i.
ynenoate 3k was cyclized to isopyrrole 4k in the presence
of Pd(OAc)2 (3 mol %) in THF in quantitative yield.18
Gratifyingly, 4k underwent addition to both Echenmoser's
salt (7) and diazene 8, affording products of C-C and C-N
bond formation respectively. In addition, oxygenation adja-
cent to the methyl ester could be effected by simply stirring 4k
overnight open to the atmosphere in the presence of SiO2.19
The ability to intercept isopyrrole 4k provides an attractive,
atom-economical avenue for direct derivatization of the pyrrole side
chain.20
In addition to aromatic donors, aliphatic alkynes undergo
efficient coupling and isomerization. Importantly, both free and
acetylated propargyl alcohols react smoothly under the standard
conditions (entries 13-15). We note the use of a 1,3-enyne as a
donor (entry 10) which provides an efficient synthesis of desirable
C-vinyl pyrroles.16
Having established a robust set of conditions for the formation
of 2,4-disubstituted pyrroles, we turned our attention to the
synthesis of additional derivatives by exploiting the reactivity of
intermediates 3 and 4. We were particularly intrigued by the
utility of isopyrroles, which we identified as suitable donors
for ene-type addition reactions (Scheme 2).17 To this end,
The use of Pd catalysis to effect the cyclization of 3k offers
additional avenues for substitution of the pyrrole nucleus. For
example, we reasoned that 2,3,4-trisubstituted heterocycles 9 could
be accessed by trapping vinyl-palladium intermediate 40, which is
generated during the 5-endo-dig cyclization (Scheme 3).21 Thus,
exposure of ynenoate 3k to Pd(OAc)2 in the presence of acrolein
and LiBr afforded 9a via a reductive Heck-type addition reaction.22
Alternatively, allylation in the 3-position could be effected with allyl
chloride in the presence of PdCl2(CH3CN)2 and propylene oxide as
a suitable acid scavenger.23 This method complements current
strategies for the functionalization of 2,4-disubstitued pyrroles,
which remains a challenging transformation.24
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Scheme 2. Reactivity of Isopyrrole Intermediates
were performed using benchtop solvents under an ambient atmo-
sphere at room temperature. Current efforts are directed toward the
further functionalization of these intermediates, and results will be
presented in due course.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
analytical data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
bmtrost@stanford.edu
’ ACKNOWLEDGMENT
We thank the National Science Foundation (CHE 0846427)
and the National Institutes of Health (GM33049) for their
generous support of our programs. J.-P.L. is grateful for a NIH
postdoctoral fellowship (GM083428). J.M.A. thanks the Amer-
ican Chemical Society and the Barry M. Goldwater Foundation
for predoctoral fellowships. We thank Jacob Stern for technical
assistance. We thank Johnson-Matthey for generously providing
us with palladium salts.
Scheme 3. Synthesis of 2,3,4-Trisubstituted Pyrroles
’ REFERENCES
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(eq 1). Thus, exposure of ynenoate 3a to TMS-OTf in CH2Cl2
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chemoselective cyclization that highlights the versatility of our
overall strategy in accessing structurally distinct five-membered
nitrogen heterocycles.
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Chem. Soc. 1997, 119, 698. A reviewer has suggested that coupling of
1 and 2 may involve allene tautomer 1a (see below). Our previous
success utilizing acceptors 1b and 1d, where competitive formation of
1c was not observed and where formation of an allene intermediate is
not possible, respectively, suggests that allene intermediates are not
involved. For the use of 1b see reference 2a, and for the use of 1d see:
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In summary, we have developed an atom-economic synthe-
sis of 2,4-disubstituted pyrroles. The method utilizes readily
available alkynes and employs a Pd(II)-mediated cascade
reaction. By exerting control over the conditions, we have
also shown that several intermediates along the pathway
can be intercepted for further functionalization. These include
an ene addition reaction with an isopyrrole, as well as access to
2,3,4-trisubstituted pyrroles and 3-substituted pyrollidin-2-ones.
This method benefits from operational simplicity as all reactions
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(15) Attempts to isomerize 3k or 4k to 5k under basic and acidic
conditions returned low isolated yields of the desired product. 3k could
be cyclized to 5k under thermal conditions but required unacceptably
high temperatures (>100 °C) and reaction times (>48 h).
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(18) Following complete conversion, the reaction mixture is filtered
through a short column of fluorosil to provide analytically pure samples
of the isopyrrole. See Supporting Information for details.
(19) Reduction of crude reaction mixtures with NaBH4 simplified
product mixtures which were typically composed of alcohol 6c and the
corresponding ketone.
(20) Functionalization of 5k would require stoichiometric amounts
of activating agents and would reduce the overall atom economy of this
process.
(21) We note that Pd(OAc)2 and PdCl2 alone are not as effective as
Pd(OTFA)2 in the conversion of 3k to 5k (Table 2). Nevertheless,
under the conditions described in Scheme 3, substituted isopyrrole
products were not detected. We speculate that the additional additives
present under these conditions promote the isomerization of ispoyrrole
intermediates into the corresponding pyrrole products.
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