Au-catalyzed synthesis of 5,6-dihydro-8H-indolizin-7-ones from N-(pent-2-en-4-ynyl)-β-lactams

Article abstract of DOI:10.1021/ol802159v

(Chemical Equation Presented) Au-catalyzed synthesis of 5,6-dihydro-8H-indolizin-7-ones from readily available N-(pent-2-en-4-ynyl)- β-lactams is developed. In this reaction, a 5-exo-dig cyclization of the β-lactam nitrogen to the Au-activated C-C triple bond is followed by heterolytic fragmentation of the amide bond, forming a highly nucleophilic acyl cation. An expedient formal synthesis of indolizidine 167B was easily achieved using this new method.

Full text of DOI:10.1021/ol802159v

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5187-5190
Au-Catalyzed Synthesis of
5,6-Dihydro-8H-indolizin-7-ones from
N-(Pent-2-en-4-ynyl)-ꢀ-lactams
Yu Peng, Meng Yu, and Liming Zhang*
Department of Chemistry, UniVersity of NeVada, Reno, NeVada 89557
lzhang@chem.unr.edu
Received September 16, 2008
ABSTRACT
Au-catalyzed synthesis of 5,6-dihydro-8H-indolizin-7-ones from readily available N-(pent-2-en-4-ynyl)-ꢀ-lactams is developed. In this reaction,
a 5-exo-dig cyclization of the ꢀ-lactam nitrogen to the Au-activated C-C triple bond is followed by heterolytic fragmentation of the amide
bond, forming a highly nucleophilic acyl cation. An expedient formal synthesis of indolizidine 167B was easily achieved using this new
method.
In the past few years, Au catalysis1 has rapidly evolved
from a relatively unknown phenomenon into an established
area in organic synthesis. Various practical synthetic methods
have been developed.
Scheme 1. Pt-Catalyzed Formation of Tricyclic Indoles
We reported previously that N-(2-alkynylaryl)lactams
underwent two consecutive 1,2-migrations in the presence
of PtCl4 or PtCl2, yielding cyclic ketone-fused indoles
(Scheme 1).2 Au(I) also catalyzed this reaction albeit less
efficient. This reaction was proposed to undergo an initial
5-endo-dig cyclization of the lactam nitrogen to the metal-
activated alkyne followed by the fragmentation of the lactam
amide bond and the formation of an acyl cation.3 The
benzene ring in the substrate was critical for conformation
control and for the ease of substrate assembly, but its very
(1) For selected recent reviews on Au catalysis, see: (a) Arcadi, A. Chem.
ReV. 2008, 108, 3266–3325. (b) Patil, N. T.; Yamamoto, Y. Chem. ReV.
2008, 108, 3395–3442. (c) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem.
ReV. 2008, 108, 3351–3378. (d) Jimenez-Nunez, E.; Echavarren, A. M.
Chem. Commun. 2007, 333–346. (e) Li, Z.; Brouwer, C.; He, C. Chem.
ReV. 2008, 108, 3239–3265. (f) Fu¨rstner, A.; Davis, P. W. Angew. Chem.,
Int. Ed. 2007, 46, 3410–3449. (g) Hashmi, A. S. K. Chem. ReV. 2007, 107,
3180–3211. (h) Zhang, L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal. 2006,
348, 2271–2296.
existence limited this method to the synthesis of indole
derivatives. While indoles are highly useful compounds,
extending this chemistry to nonaromatic substrates would
provide a new approach to other N-heterocycles.
We surmised that a cis-alkene could substitute the benzene
ring (i.e., 1, Scheme 2). For the ease of substrate preparation
and to avoid the relatively electron-rich C-C double bond
of the enamide moiety in 1, enynyl lactam 2 with an allyl
amine moiety was chosen. We expected that upon Au/Pt
(2) Li, G.; Huang, X.; Zhang, L. Angew. Chem., Int. Ed. 2008, 47, 346–
349.
(3) Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004,
126, 10546–10547.
10.1021/ol802159v CCC: $40.75
Published on Web 10/28/2008
2008 American Chemical Society

Scheme 2
.
Extending the Lactam Chemistry: Design
Scheme 3. General Approach for Substrate Synthesis
double bond, ꢀ-bromoenals, readily available from the
corresponding alicyclic ketones via Vilsmeier reaction,4 are
used.
In our initial study, strained ꢀ-lactam 5 indeed underwent
cycloisomerization with PtCl2 as catalyst, affording dihy-
droindolizinone 7 (Table 1, entry 2) albeit in only 18% yield.
Notably, compound 7 was not too stable on silica gel column
and also prone to oxidation over extended exposure to air;
consequently, it was isolated via quick flash chromatography
and stored cold under nitrogen. PtCl4, the catalyst used in
our previous study,2 did not catalyze this reaction (entry 1),
nor did AuCl3 (entry 3). Cationic Au(I) catalysts in general
were better than PtCl2 (entries 4-9), and the most efficient
was IPrAuNTf25 (entries 8 and 9). The reaction solvent was
critical for the success of this reaction, and anhydrous THF
allowed complete conversion and up to 94% isolated yield
with 10 mol % of the catalyst (entry 9). As a control
experiment, HNTf2 (1 equiv, entry 10) did not promote this
reaction, and ꢀ-lactam 5 was completely decomposed in 15
min. In these studies, no dihydropyrrolizinone 3 was
observed, suggesting that the aromatization to form B is
relatively slow. Under the optimized reaction conditions,
activation compound 2 would undergo a 5-exo-dig cyclization
preferentially instead of the 5-endo-dig cyclization observed
in our previous study.2 Nevertheless, subsequent heterolytic
fragmentation of the amide bond would generate intermediate
A possessing a highly nucleophilic acyl cation, which might
undergo formal 1,5-hydride migration and thus form pyrrole
acyl cation B. Cyclization of B would lead to bicyclic pyrrole
3. Alternatively, cyclization of the acyl cation in A to the
enamine moiety directly would afford isomeric bicyclic
pyrrole 4 with a larger fused ring.
Lactam starting material 2 can be readily prepared ac-
cording to two general sequences outlined in Scheme 3: from
cis-3-iodoprop-2-en-1-ol, the C-C triple bond can be
installed via the Sonogashira reaction, and the lactam moiety
can be attached via an SN2 reaction with the corresponding
allylic bromide; or, for substrates with a ring-fused C-C
Table 1. Initial Study and Reaction Conditions Optimization
entry
substratea
catalyst
PtCl4
PtCl2
AuCl3
Ph3PAuSbF6
Ph3PAuNTf2
Ph3PAuNTf2
Ph3PAuNTf2
IPrAuNTf2
reaction conditions
time
6 h
8 h
5 mind
3 h
15 h
15 h
2 h
yield (%)b
convn (%)
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
5
5
6
DCE, reflux, O2 (1 atm)
toluene, 80 °C, CO (1 atm)
DCE, 80 °C
acetone, rt
acetone, 45 °C
DCM, reflux
THF, 45 °C
THF, 45 °C
THF, 45 °C
THF, 45 °C
0
18
0
c
70
c
35
100
30
100
100
100
h
7
31
16
73
78
98f
0
2 h
2 h
15 min
e
9
10
11
IPrAuNTf2
g
HNTf2
IPrAuNTf2
THF, 45 °C
2 h
0
c
b
a Substrate concentration is 0.05 M. Estimated by H NMR using diethyl phthalate as internal reference. c Mostly starting material. d Au precipitates
1
observed. e 10 mol % of the catalyst. f 94% isolated yield. g 1 equiv of HNTf2. h The starting material was completely decomposed.
5188
Org. Lett., Vol. 10, No. 22, 2008

however, γ-lactam 6 remained mostly unreacted, and bicyclic
pyrrole 8 was not formed, indicating the importance of the
lactam ring strain for the success of this reaction.
A scope study of this chemistry was performed, and the
results are shown in Table 2. While substrates with substit-
sterically demanding cyclohexyl (entry 2) germinal to the
ethynyl group and hexyl (entry 3) and phenyl (entry 4) groups
vicinal to the lactam, leading to dihydroindolizinones with
different substitutions at their 1- and 2-positions. Substrates
with the C-C double bond embedded in medium-sized rings
(entries 5 and 6) also reacted well, yielding interesting seven-/
eight-membered ring fused dihydroindolizinones (e.g., 10e
and 10f) in good yields. Surprisingly, the corresponding
cyclopentene or cyclohexene substrates did not afford the
corresponding five-/six-membered ring-fused dihydroindoliz-
inones, and the starting materials were mostly unreacted for
the former and partly decomposed for the later after 10 h.
Table 2. Reaction Scope for the Formation of
Dihydroindolizinonesa
The ꢀ-lactam moiety was also studied for its substitution
scope. Besides ꢀ-methyl, no substitution (entry 7), R-methyl
(entry 8), ꢀ-benzyl (entry 9), R,R-diethyl (entry 10), and R,ꢀ-
diethyl (entry 11) were all allowed, affording products with
various substituents at the dihydroindolizinone 5- and 6-posi-
tions in acceptable yields. Of note, no trans-isomer of 10k
was observed, indicating little or no epimerization at the
carbonyl R-position during the reaction.
When substrate 9l with a phenyl R to the lactam nitrogen
was studied, three compounds were isolated and character-
ized (eq 1). Besides the expected dihydroindolizinone 10l,
isomeric cyclic N-acylpyrrole 11 was isolated in 25% yield
along with benzene-fused tricyclic pyrrole 12 (15%). This
result offers support to the reaction mechanism envisioned
in the initial design (Scheme 2): upon the lactam cyclization,6
ammonium intermediate C could undergo amide bond
heterolytic fragmentation, generating an acyl cation and
eventually affording 10l; alternatively, the fragmentation of
(4) (a) Coates, R. M.; Muskopf, J. W.; Senter, P. A. J. Org. Chem. 1985,
50, 3541–3557. (b) Ruck-Braun, K.; Moller, C. Chem. Eur. J. 1999, 5,
1038–1044.
(5) 1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidenegold(I) bis(trifluo-
romethanesulfonyl)imide; for its first catalysis study, see: Li, G.; Zhang,
L. Angew. Chem., Int. Ed. 2007, 46, 5156–5159. For its synthesis, see:
Ricard, L.; Gagosz, F. Organometallics 2007, 26, 4704–4707.
(6) For related studies, see: (a) Hashmi, A. S. K.; Buehrle, M.; Salathe,
R.; Bats, J. W. AdV. Synth. Catal. 2008, 350, 2059–2064. (b) Istrate, F. M.;
Gagosz, F. Org. Lett. 2007, 9, 3181–3184. (c) Cariou, K.; Ronan, B.;
Mignani, S.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2007,
46, 1881–1884.
a Reaction conditions: IPrAuNTf2 (5 mol %), THF (0.05 M), 45 °C.
b The ꢀ-lactams were best used right after preparation as most of them
decomposed over time. c Most of the products were prone to decompose
under acidic conditions and over extended exposure to air. d Isolated yield.
e 10 mol % of IPrAuNTf2 was used. f 87% NMR yield was observed using
a higher substrate concentration (0.1 M). g Reaction temperature: 55 °C.
h The other diatereomer was not observed.
(7) For selected previous total synthesis, see: (a) Polniaszek, R. P.;
Belmont, S. E. J. Org. Chem. 1990, 55, 4688–4693. (b) Jefford, C. W.;
Tang, Q.; Zaslona, A. J. Am. Chem. Soc. 1991, 113, 3513–3518. (c) Pearson,
W. H.; Walavalkar, R.; Schkeryantz, J. M.; Fang, W. K.; Blickensdorf,
J. D. J. Am. Chem. Soc. 1993, 115, 10183–10194. (d) Lee, E.; Li, K. S.;
Lim, J. Tetrahedron Lett. 1996, 37, 1445–1446. (e) Guazzelli, G.; Lazzaroni,
R.; Settambolo, R. Synthesis 2005, 3119–3123. (f) Sun, Z.; Yu, S.; Ding,
Z.; Ma, D. J. Am. Chem. Soc. 2007, 129, 9300–9301. (g) Stead, D.; O’Brien,
P.; Sanderson, A. Org. Lett. 2008, 10, 1409–1412.
uents at the alkyne terminus (e.g., Bu or Ph) did not undergo
this catalytic reaction, various substituents at the C-C double
bond were tolerated, including benzoxyethyl (entry 1) and
Org. Lett., Vol. 10, No. 22, 2008
5189

60% yield. Subjection of 9m to the standard Au catalysis
conditions yielded dihydroindolizinone 10m in 78% yield,
which was previously converted to indolizidine 167B via
hydrogenation.7b
Scheme 4. Formal Total Synthesis of Indolizidine 167B
In summary, we have developed an efficient Au-catalyzed
method for the synthesis of 5,6-dihydro-8H-indolizin-7-ones
from readily available enynyl ꢀ-lactam. This method allows
an expedient formal synthesis of indolizidine 167B.
Acknowledgment. The authors thank NSF, Merck, and
ACS PRF (43905-G1) for generous financial support. The
acquisition of an NMR spectrometer and upgrade of an
existing NMR spectrometer is funded by NSF CHE-0521191.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
the C(sp3)-N bond is competitive as a result of the formation
of a stable benzylic cation in D. Cyclization of D would
eventually yield 11 via approach a and 12 via approach b.
This method offers an expedient and novel approach to
the synthesis of indolizidine alkaloids. For example, a three-
step formal synthesis7 of indolizidine 167B, an alkaloid of
scarce quantitiy isolated from neotropical poison dart frogs,8
can be readily achieved from 5-bromo-pent-3-en-1-yne (i.e.,
13,9 Scheme 4). Thus, a SN2 reaction between 13 and
commerically available ꢀ-lactam 14 afforded lactam 9m in
OL802159V
(8) (a) Daly, J. W. In Progress in the Chemistry of Organic Natural
Products; Springer-Verlag: Vienna, 1982; Vol. 41, pp 205-340. (b) Daly,
J. W.; Spande, T. F. In Alkaloids: Chemical and Biological Perspectiues;
Pelletier, S. W., Ed.; Wiley: New York, 1986; Vol. 4, pp 1-274.
(9) This bromide was prepared from the corresponding alcohol in 55%
yield using Ph3P/Br2.
5190
Org. Lett., Vol. 10, No. 22, 2008