Multicomponent synthesis of pyrroles from cyclopropanes: A one-pot palladium(0)-catalyzed dehydrocarbonylation/dehydration

Article abstract of DOI:10.1002/anie.201206177

Ring the changes: The cycloaddition of nitrones with 1-carboallyloxy-1- carbomethoxycyclopropanes yields tetrahydro-1,2-oxazines, which in turn undergo a Tsuji dehydrocarbonylation to give dihydro-1,2-oxazines (see scheme; dba=dibenzylideneacetone). Addition of base to this reaction mixture results in clean conversion to pyrroles. The result is a flexible three-component strategy for the synthesis of tetrasubstituted pyrroles. Copyright

Full text of DOI:10.1002/anie.201206177

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Angewandte
Communications
DOI: 10.1002/anie.201206177
Pyrrole Synthesis
Multicomponent Synthesis of Pyrroles from Cyclopropanes: AOne-Pot
Palladium(0)-Catalyzed Dehydrocarbonylation/Dehydration**
William J. Humenny, Polydoros Kyriacou, Katarina Sapeta, Avedis Karadeolian, and
Michael A. Kerr*
Since 1834 when Runge described a substance that was found
in coal tar and bone oil and turned red upon application to
acid-moistened pine splinters,[1] chemists have been fasci-
nated with the pyrrole moiety, which is found in a wide range
of bioactive natural products.[2] In addition to its ubiquity in
nature, the tremendous therapeutic and commercial impact of
pyrrole-containing drugs, such as Lipitor (atorvastatin cal-
cium), has driven the development of vast numbers of new
synthetic methods for the synthesis and functionalization of
this heterocycle.[3] Herein, we report a new and powerful
synthetic method for the generation of tetrasubstituted
pyrroles from tetrahydro-1,2-oxazines, which are in turn
prepared in excellent yields from donor/acceptor cyclopro-
panes.[4]
During our recently reported synthesis of isatisine A,[7] we
converted one of the geminal diesters in an adduct (a furan in
that case) into an allyl ester and then used a Tsuji dehydro-
genative decarbonylation (dehydrocarbonylation)[8] to intro-
duce the required alkene moiety. It occurred to us that use of
a cyclopropane substituted with an allyl ester (5) would give,
upon dehydrocarbonylation of the tetrahydro-1,2-oxazine 6,
access to dihydro-1,2-oxazines 7. In essence, the cyclopropane
would have a preinstalled unit of unsaturation, thus behaving
as synthon 9 in the overall conversion of 3 into 7. The allyl
ester moiety would serve both as an activating group as well
as a group capable of undergoing elimination in the adduct.
This idea could be used to access unsaturated analogues of
a variety of donor/acceptor cyclopropane adducts. Moreover,
it also occurred to us that when treated with base 7 may
undergo conversion into highly functionalized pyrroles 8.
Herein, we report a convenient synthesis of 4,5-dyhydro-1,2-
oxazines and their facile conversion into a wide variety of
tetrasubstituted pyrroles.
Our study commenced with the synthesis of a variety of 1-
carboallyloxy-1-carbomethoxy cyclopropanes 5 and their
reaction with a variety of nitrones 3 by either a 2- or 3-
component protocol (Scheme 2). The requisite cyclopropanes
were prepared by monosaponification[9] of the appropriate
bis(methylester) followed by treatment of the hemimalonate
with base and allyl bromide.[10] The decision on whether to use
a preformed nitrone or to generate it in situ is sometimes
determined by the stability of the hydroxylamine or nitrone,
but is more-often determined by the preference of the
chemist. The tetrahydro-1,2-oxazines are, for the most part,
formed in excellent yields and as a near 1:1 mixture of
epimers at the geminal diester center. This lack of selectivity
is ultimately inconsequential since the chirality at this center
is lost in subsequent transformations. It should be noted that
the formation of adducts 6l and 6o (Scheme 2) required the
use of the slightly more Lewis acidic Sc(OTf)3 to effect
efficient reaction. This requirement can be explained by the
absence of a donor group vicinal to the diester moiety.
With the tetrahydro-1,2-oxazines in hand, we submitted
them to the dehydrocarbonylation conditions described by
Tsuji and co-workers.[8] Scheme 3 shows the results of the
dehydrocarbonylation of five selected allyl esters 6 from
Scheme 2. The yields are generally good and are typical of the
reported yields for this type of reaction. Notably, the reactions
are 100% regioselective (to our levels of detection) for the
D4 isomer (alkene in the 4,5-position). The reasons for this are
not clear at this time, however as the last step in the putative
mechanism is a b-hydride elimination of a carbon-bound
palladium enolate, perhaps the b hydrogen at the oxazine 3-
Previous work reported by our group has shown that the
reaction of a nitrone 3 with a 1,1-cyclopropanediester 4 results
in the smooth formation of tetrahydro-1,2-oxazines
6
(Scheme 1).[5] Although the use of an isolable nitrone is an
option, the reaction is often conveniently performed as
a three-component coupling of an aldehyde 1, a hydroxyl-
amine 2, and a cyclopropane 4.[5g] This cycloaddition has been
useful in our preparation of several natural products.[6]
Scheme 1. The formation of tetrahydro-1,2-oxazines, dihydro-1,2-oxa-
zines, and pyrroles. dba=dibenzylideneacetone, Tf=trifluoromethane-
sulfonyl.
[*] W. J. Humenny, P. Kyriacou, K. Sapeta, A. Karadeolian, Dr. M. A. Kerr
Department of Chemistry
The University of Western Ontario
London, ON, N6A 5B7 (Canada)
E-mail: makerr@uwo.ca
[**] We thank the Natural Sciences and Engineering Research Council
(NSERC) for funding. We are grateful to Doug Hairsine for
performing MS analyses. The term dehydrocarbonylation refers to
a dehydrogenative decarbonylation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206177.
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poisoning. This issue was not overcome by performing the
reaction on the ammonium salt of the oxazines.
During attempts to use the dihydro-1,2-oxazines 7 in
subsequent transformations (cross-coupling to the 5-position,
for example) we noted that the compounds had a propensity
to rearrange with loss of water to pyrroles; the ease of pyrrole
formation was surprising. Scheme 4 shows a mechanism by
Scheme 4. Mechanism of pyrrole formation.
which a general base may promote the formation of such
a pyrrole. Although the mechanism shown is illustrated as
proceeding by an E1cb process (I!II), a mechanism pro-
ceeding via an enol (rather than an enolate) is also a distinct
possibility. We also cannot rule out a direct E2-style
ꢀ
elimination across the C O bond. Ring closure of II to III
followed by dehydration of hemiaminal IV leads to pyrrole 8.
Although rarely seen synthetically,[11] this type of trans-
formation has been reported as a side reaction in other
processes.[12]
Scheme 5 shows the facile conversion of the dihydro-1,2-
oxazines 7 into pyrroles 8 by using an excess amount of DBU
at room temperature. Although the reaction proceeds with
catalytic base, the use of an excess of base allows for a more
expedient conversion.
Scheme 2. Synthesis of tetrahydro-1,2-oxazines. Yields are for the
isolated products. M.S.=molecular sieves.
Scheme 5. Conversion of dihydro-1,2-oxazines into pyrroles. Yields are
for the isolated products. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
Scheme 3. Dehydrocarbonylation to dihydro-1,2-oxazines. Yields are for
the isolated products.
position lacks the stereoelectronic requirements for the
process. Also worthy of note is that an alkyl N-substituent
was not tolerated, presumably as a result of the increased
Lewis basicity of the nitrogen atom and subsequent catalyst
As the transformation of 7 into 8 was so facile, it occurred
to us that the addition of a small amount of base to the
dehydrocarbonylation reaction mixture (the conversion of 6
into 7) might effect a one-pot synthesis of pyrroles from the
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tetrahydro-1,2-oxazines 6. This was indeed the case and
Scheme 6 shows the results of this modified reaction. In the
event, upon completion of the dehydrocarbonylation (3 h),
Scheme 7. Synthesis of the atorvastatin pyrrole. DMF=N,N’-dimethyl-
formamide, NBS=N-bromosuccinimide.
DBU under the usual reaction conditions gave pyrrole 12 in
70% overall yield. Bromination of the remaining vacant
pyrrole position proceeded in near quantitative yield to give,
after hydrolysis, bromoacid 13 (86% yield overall). Conver-
sion into anilide 14 took place in variably good yields (65–
86%) via the acid chloride. Suzuki coupling of the bromo-
pyrrole 14 with phenylboronic acid gave the target pyrrole 15
in 75% yield. Deprotection of the pyrrole would provide
a substrate suitable for conversion into atorvastatin and
a variety of related compounds. Although arguably compa-
rable with regards to the number of steps to the industrial
(Paal–Knorr) synthesis of the pyrrole unit, the value of the
route described herein lies in its modularity, allowing access
to a wide variety of substitutions on the pyrrole ring.
In summary, we have described a new pyrrole synthesis
which will allow the preparation of a plethora of heterocyclic
compounds. The starting materials are inexpensive and
readily available and the method is technically simple.
Further applications of this method will be reported in due
course.
Scheme 6. One-pot conversion of tetrahydro-1,2-oxazines into pyrroles.
Yields are for the isolated products.
the reaction mixture was cooled to room temperature and
DBU (3 equiv) was added. After a short time (usually 5 min)
the conversion to the pyrrole was complete and the reaction
was worked up. It is noteworthy to compare the yields of the
one-pot syntheses of 8c, 8 f, 8i, and 8m (Scheme 6) with the
corresponding overall yields for the two-pot conversion of 6
into 8 (in parentheses in Scheme 5). In all cases the one-pot
procedure is at least as efficient as the two-pot procedure,
thus obviating the need for isolation of the dihydro-1,2-
oxazine en route to the pyrrole. In the cases where R1 = H or
Et (8k, 8m, 8l, and 8o), the reaction mixture was kept at
either 408C (24 h) or 608C (0.5 h) to effect conversion into
the pyrrole. The need for different reaction conditions was
presumably due to the decreased acidity of the C6 hydrogen
(Scheme 4) in these instances.
To show the utility of this route to pyrroles we applied the
preceding two-pot strategy to the synthesis of the atorvastatin
(Lipitor) pyrrole unit. Scheme 7 shows our synthesis of this
compound. We were surprised to find that the desired
cycloaddition did not occur under the usual reaction con-
ditions. Gratifyingly however, condensation of nitrone 9 and
cyclopropane 10 occurred under the catalytic influence of
MgI2 to give tetrahydro-1,2-oxazine 11 in 60% yield.[13]
Treatment of 11 with [Pd2dba3] followed by addition of
Received: August 1, 2012
Published online: October 4, 2012
Keywords: cycloaddition · cyclopropane · nitrogen heterocycles ·
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nitrones · synthetic methods
[1] H. J. Anderson, J. Chem. Educ. 1995, 72, 875 – 878.
[2] I. S. Young, P. D. Thornton, A. Thompson, Nat. Prod. Rep. 2010,
27, 1801 – 1839.
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[3] V. Estꢀvez, M. Villacampa, J. C. Menꢀndez, Chem. Soc. Rev.
2010, 39, 4402 – 4421.
l) Q. Ding, Z. Wang, J. Wu, Tetrahedron Lett. 2009, 50, 198 – 200;
m) B. Hu, J. Zhu, S. Xing, J. Fang, D. Du, Z. Wang, Chem. Eur. J.
2009, 15, 324 – 327; n) Y. B. Kang, X. L. Sun, Y. Tang, Angew.
Chem. 2007, 119, 3992 – 3995; Angew. Chem. Int. Ed. 2007, 46,
3918 – 3921; o) M. P. Sibi, Z. H. Ma, C. P. Jasperse, J. Am. Chem.
Soc. 2005, 127, 5764 – 5765.
[4] For reviews on donor/acceptor cyclopropanes, see: a) C. A.
Carson, M. A. Kerr, Chem. Soc. Rev. 2009, 38, 3051 – 3060; b) M.
Rubin, M. Rubina, V. Gevorgyan, Chem. Rev. 2007, 107, 3117 –
3179; c) M. Yu, B. L. Pagenkopf, Tetrahedron 2005, 61, 321 – 347;
d) H.-U. Reissig, R. Zimmer, Chem. Rev. 2003, 103, 1151 – 1196;
e) H. N. C. Wong, M. Y. Hon, C. W. Tse, Y. C. Yip, J. Tanko, T.
Hudlicky, Chem. Rev. 1989, 89, 165 – 198; f) S. Danishefsky, Acc.
Chem. Res. 1979, 12, 66 – 72.
[6] a) Nakadomarin A: I. S. Young, M. A. Kerr, J. Am. Chem. Soc.
2007, 129, 1465 – 1469; b) Phyllantidine: C. A. Carson, M. A.
Kerr, Angew. Chem. 2006, 118, 6710 – 6713; Angew. Chem. Int.
Ed. 2006, 45, 6560 – 6563.
[5] Contributions from our group: a) D. A. Dias, M. A. Kerr, Org.
Lett. 2009, 11, 3694 – 3697; b) M. B. Johansen, M. A. Kerr, Org.
Lett. 2008, 10, 3497 – 3500; c) C. A. Carson, I. S. Young, M. A.
Kerr, Synthesis 2008, 485 – 489; d) A. Karadeolian, M. A. Kerr, J.
Org. Chem. 2007, 72, 10251 – 10253; e) K. Sapeta, M. A. Kerr, J.
Org. Chem. 2007, 72, 8597 – 8599; f) T. P. Lebold, C. A. Carson,
M. A. Kerr, Synlett 2006, 364 – 368; g) I. S. Young, J. L. Williams,
M. A. Kerr, Org. Lett. 2005, 7, 953 – 955; h) M. D. Ganton, M. A.
Kerr, J. Org. Chem. 2004, 69, 8554 – 8557; i) I. S. Young, M. A.
Kerr, Org. Lett. 2004, 6, 139 – 141; j) I. S. Young, M. A. Kerr,
Angew. Chem. 2003, 115, 3131 – 3134; Angew. Chem. Int. Ed.
2003, 42, 3023 – 3026; contributions by other groups: k) Y.
Zhang, F. Liu, J. Zhang, Chem. Eur. J. 2010, 16, 6146 – 6150;
[7] a) A. Karadeolian, M. A. Kerr, J. Org. Chem. 2010, 75, 6830 –
6841; b) A. Karadeolian, M. A. Kerr, Angew. Chem. 2010, 122,
1151 – 1153; Angew. Chem. Int. Ed. 2010, 49, 1133 – 1135.
[8] I. Shimizu, T. Tsuji, J. Am. Chem. Soc. 1982, 104, 5844 – 5846.
[9] C. Perreault, S. R. Goudreau, I. E. Zimmer, A. B. Charette, Org.
Lett. 2008, 10, 689 – 692.
[10] See the Supporting Information for full experimental details.
[11] G. Kresze, H. Braun, Tetrahedron Lett. 1969, 10, 1743 – 1746.
ˇ
[12] a) V. Krchnꢁk, K. R. Waring, B. C. Noll, U. Moellmann, H. M.
Dahse, M. J. Miller, J. Org. Chem. 2008, 73, 4559 – 4567; b) P.
Kefalas, D. S. Grierson, Tetrahedron Lett. 1993, 34, 3555 – 3558.
[13] We have shown that MgI2 is an effective Lewis acid for this type
of transformation. See Ref. [5h].
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