Intramolecular photoaddition of vinylogous amides with allenes: A novel approach to the synthesis of pyrroles

Article abstract of DOI:10.1021/ol061453x

Irradiation of vinylogous amide or imide 5 (R = H, alkyl, or Ac) leads to the selective formation of either crossed photoadduct 7 (R = Ac) or parallel photoadduct 8 (R = H or alkyl) as a function of the nature of the group R. The latter result leads to a

Full text of DOI:10.1021/ol061453x

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4031-4033
Intramolecular Photoaddition of
Vinylogous Amides with Allenes: A
Novel Approach to the Synthesis of
Pyrroles
Jeffrey D. Winkler* and Justin R. Ragains†
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
winkler@sas.upenn.edu
Received June 13, 2006
ABSTRACT
Irradiation of vinylogous amide or imide 5 (R
parallel photoadduct 8 (R H or alkyl) as a function of the nature of the group R. The latter result leads to a novel approach to the synthesis
of pyrroles, that is, 8
) H, alkyl, or Ac) leads to the selective formation of either crossed photoadduct 7 (R ) Ac) or
)
′
.
We have reported that the [2+2] photocycloaddition reaction
of 1 leads to an efficient synthesis of azabicyclo[3.2.1]octane
4, as outlined in Scheme 1. Retro-Mannich fragmentation
intramolecular photocycloaddition of vinylogous amides and
imides with allenes, that is, 5, in which the presence or
absence of an electron-withdrawing R group on nitrogen
directs the regiochemical outcome of the ring closure of
triplet 6/6′, leading to the selective formation of products
derived from either 7 or 8, respectively (Scheme 2). The
Scheme 1. Synthesis of Azabicyclooctanones via Crossed
Intramolecular Vinylogous Amide Photocycloaddition
Scheme 2. Intramolcular Photocycloaddition of Vinylogous
Amides with Allenes
of the crossed photoadduct 2 gives ketoiminium 3 that, upon
Mannich cyclization, affords 4.1 We describe herein the
† Recipient of the Eli Lilly Predoctoral Fellowship, 2002-2003.
10.1021/ol061453x CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/01/2006

Scheme 3. Preparation of Photosubstrates
Scheme 5. Synthesis of Pyrroles via Intramolecular
Photocycloaddition of Vinylogous Amides
preparation of the photosubstrates is outlined in Scheme 3.
Condensation of 3-butyn-2-one with propargylamine and
protection of the resulting vinylogous amide 9 with (Boc)2O
or acetyl chloride generated 10 (R ) Boc) and 11 (R ) Ac),
respectively. Homologation of 10 and 11 to the corresponding
allenes was achieved using the method of Crabbe2 to afford
photosubstrates 12 (R ) Boc) and 13 (R ) Ac). Secondary
vinylogous amide photosubstrate 14 could be prepared via
Boc deprotection of 12. N-Methylation of 14 afforded tertiary
vinylogous amide photosubstrate 15.
results establish the critical role of the nitrogen R group on
the regiochemical outcome of the photocycloaddition. When
R ) Boc or Ac, we observe products, that is, 18, derived
exclusively from the crossed photoproducts corresponding
to 16. However, when R ) H or Me, that is, 14 or 15, only
products derived from parallel cycloaddition to the terminal
olefin of the allene, via 19 or 22, respectively, are observed.
This is the first example of which we are aware of the parallel
intramolecular photocycloaddition to the terminal olefin of
an allene,3 which leads, among other things, to a direct
process for the synthesis of 3-substituted pyrroles.
Irradiation of 13 (1.0 mM, CH3CN, Pyrex) led to the
formation of bridged bicyclic 18 in 52% yield (Scheme 4).
We next examined the effect of a geminal dimethyl group
as shown in 27 (Scheme 6) on the pyrrole-forming reaction.
Scheme 4. Photocycloaddition of Vinylogous Imides
Scheme 6. Synthesis and Photoreaction of Dimethylated
Photosubstrate 27
The formation of 18 can be explained via crossed photo-
cycloaddition of 13 to generate intermediate 16, which
undergoes retro-Mannich fragmentation to afford zwitterionic
intermediate 17, cyclization of which provides the observed
product 18. The N-Boc photosubstrate 12 underwent the same
transformation, although the N-Boc product corresponding
to 18 proved unstable to purification.
In contrast, irradiation of either 14 or 15 (1.0 mM, CH3CN,
Pyrex) led to the formation of pyrroles 21 and 24 via
cyclobutane photoadducts 19 and 22 (Scheme 5). These
We reasoned that the presence of the geminal dimethyl group
in zwitterionic intermediate corresponding to 20/23 would
preclude pyrrole formation and result in the isolation of a
2H-pyrrole. In the event, irradiation of 27, which was readily
prepared from carbamate 254 via the Crabbe methodology,
led to the formation of the 2H-pyrrole product 28 in 74%
yield.
(1) Kwak, Y.-S.; Winkler, J. D. J. Am. Chem. Soc. 2001, 123, 7429-
7430.
(2) Searles, S.; Li, Y.; Nassim, B.; Lopes, M.-T. R.; Tran, P. T.; Crabbe
J. Chem. Soc., Perkin Trans. 1 1984, 747-751.
(3) Becker, D.; Harel, Z.; Nagler, M.; Gillon, A. J. Org. Chem. 1982,
47, 3297-3306.
(4) Vereshchagin, L. I.; Kirillova, L. P.; Luzgina, G. M.; Gareev, G. A.
Russ. J. Org. Chem. 1984, 20, 29-33.
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Org. Lett., Vol. 8, No. 18, 2006

We next examined the scope and limitations of this
reaction, the results of which are summarized in Table 1.
which was prepared by reaction of 3-butyn-2-one with
allenylmethanol,5 led to none of the furan product 36. Only
a mixture of cis- and trans-35 was observed, presumably a
consequence of rotational deactivation of the acyclic chro-
mophore. Constraining the vinylogous ester into a six-
membered ring, as shown in 37 (prepared via Mitsunobu
reaction of allenylmethanol with cyclohexan-1,3-dione), led
to the formation of the desired furan product 38, albeit in
modest yield.
Table 1. Synthesis of Pyrroles and Furans via Intramolecular
Photocycloaddition
The striking difference in reactivity between acyclic
vinylogous amides (and imides) and esters is a particularly
noteworthy feature of this study. While the photochemical
literature is replete with examples of the failure of acyclic
chromophores to undergo intramolecular photocycloaddi-
tion,6,7 we have shown that vinylogous amides are the
exception, a result that can be attributed to stabilization of
the vinylogous amide triplet by the nitrogen atom, an effect
that is clearly not as significant with oxygen. This rotational
deactivation is precluded with the cyclic vinylogous ester
37, which affords furan product, albeit in modest yield.
This novel approach to the synthesis of substituted pyrrole
products from readily available cyclic and acyclic precursors
underscores the utility of this photochemically mediated
process in organic synthesis. Further studies of the application
of this methodology are currently underway in our laboratory,
and our results will be reported in due course.
Acknowledgment. We warmly thank Ms. Esther Lee
(University of Pennsylvania) for her invaluable assistance
in the preparation of this manuscript. We are grateful to the
NIH, GlaxoSmithKline, Wyeth-Ayerst, Merck, Amgen,
Boehringer Ingelheim, and Novartis for their generous
support of this work.
Supporting Information Available: Experimental pro-
1
cedures and H NMR, 13C NMR, and FTIR are available
While irradiation of cyclohexane-1,3-dione-derived vinyl-
ogous amides 29 and 31 gave pyrrole products 30 and 32 in
excellent yield, we were surprised to find that irradiation of
the corresponding cyclopentenone 33 proceeded in only 31%
yield to give 34. The basis for this difference in efficiency
with five- and six-membered ring chromophores is not clear.
We next attempted to extend this methodology to the
irradiation of vinylogous esters, which should lead by
analogy to the synthesis of furan products. Irradiation of 35,
for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL061453X
(5) Kimura, M.; Tanaka, S.; Tamaru, Y. Bull. Chem. Soc. Jpn. 1995,
68, 1689-1706.
(6) Turro, N. J. Modern Molecular Photochemistry; Benjamin Cummings
Publishing Co.: Menlo Park, CA, 1978.
(7) For a review, see: Crimmins, M. Chem. ReV. 1988, 1453-1473.
Org. Lett., Vol. 8, No. 18, 2006
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