Construction of α-amido-indanones via formal allenamide hydroacylation-Nazarov cyclization

Article abstract of DOI:10.1039/c2cc34644c

A two-step modular synthesis of an α-hydroxycyclopentenone and α-amido-indanones has been developed based on the Nazarov cyclization of 2-amido-1,4-pentadien-3-ones, readily accessed via formal hydroacylation of allenamides.

Full text of DOI:10.1039/c2cc34644c

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COMMUNICATION
Construction of a-amido-indanones via formal allenamide
hydroacylation–Nazarov cyclizationw
Yen-Ku Wu, Tianmin Niuz and F. G. West*
Received 28th June 2012, Accepted 20th July 2012
DOI: 10.1039/c2cc34644c
A two-step modular synthesis of an a-hydroxycyclopentenone
and a-amido-indanones has been developed based on the Nazarov
cyclization of 2-amido-1,4-pentadien-3-ones, readily accessed via
formal hydroacylation of allenamides.
The Nazarov reaction has become a well-established protocol
for constructing a diverse array of five-membered carbocycles,
notably since the disclosure of silicon-directed Nazarov reactions
by Denmark and co-workers.1 Recent efforts toward expanding its
synthetic versatility have been devoted to several aspects including
the development of catalytic and asymmetric variants,2a,b inter-
ception of intermediates derived from the cyclization,2c and the use
of unconventional substrates and activations.2d However, the
Scheme 1 A one-pot synthesis of Nazarov precursors from simple
efficiency in terms of step/atom economy for the preparation
of conventional Nazarov precursors, namely 1,4-dien-3-ones,
remains an underemphasized subject. Traditional approaches for
their syntheses from simple ketones involved aldol or Knoevenagel
condensations,3 which generally required harsh basic or acidic
conditions. Horner–Wadsworth–Emmons or related Wittig-type
olefinations have also been employed to install the alkenes
conjugated with the carbonyl, but the stoichiometric production
of phosphorus-containing side products is undesirable.4 A [3+2]
cycloaddition–oxidative rearrangement sequence has been
revealed to specifically target the syntheses of polarized divinyl
or aryl vinyl ketones.5 On the other hand, coupling reactions
between a variety of vinylmetallic donors and supplemental
fragments offered a flexible route to cross-conjugated dienones
with various substitution patterns, although the preparation of
necessary starting materials may be tedious in some cases.6 There-
fore, economical and operationally simple procedures for dienone
synthesis are still demanded in Nazarov chemistry.
aldehydes and allenamides.
allenyl alcohol 3a thus formed could be isomerized to cross-
conjugated ketone 4a under suitable conditions.8 Fortuitously, we
found that 4a was directly generated in lieu of the expected product
3a in a one-pot operation (Scheme 1). We set out to explore the
scope of this intriguing transformation, which constitutes a metal-
free formal hydroacylation of the allenamide,9 and attempted to
elucidate its mechanism. Herein, we describe our preliminary
studies on this novel route to a-amidodienones, and the applica-
tions of the products in the Nazarov cyclization.10
As shown in Table 1 (entries 1–7), aryl aldehydes with
distinct para-substituents reacted with lithiated allenamide 2
uniformly resulting in the formation of oxazolidinone-substituted
aryl vinyl ketones in moderate to low yields.11 The results
indicated that strong polarizing groups such as carboxylate or
methoxy group at the para position are detrimental to the
overall process. There is no obvious trend between yields and
substituent effects; it may simply reflect the fact that addition
of 2 to the carbonyl carbon and the presumed isomerization of
the allenylic hydrogen are favored by different electronic
factors.12 Furthermore, 2-furfural was employed to capture 2
providing an efficient synthesis of heteroaryl vinyl ketone
(entry 8). Analogously, the reaction between simple unsaturated
aldehyde 1i and a-deprotonated allenamide gave the corres-
ponding divinyl ketone 4i in moderate yield (entry 9). The
geometry of the conjugated alkene was assigned based on
observed TROESY correlations between vinyl and aryl protons.
While the substrate scope has been briefly examined, we
embarked on an investigation of the reaction mechanism.
Deuterated benzaldehyde d-1a was prepared and treated with
Recently, Hsung and co-workers’ described a regioselective
functionalization of allenamides with a range of electrophiles
such as stannyl or silyl chlorides and alkyl halides.7 Inspired by their
work, we envisioned that aldehyde (e.g. 1a) could be used as an
alternative electrophilic trap for a-lithiated allenamides, where the
Department of Chemistry, University of Alberta, E3-43 Gunning/
Lemieux Chemistry Centre, Edmonton, AB, Canada T6G 2G2.
E-mail: frederick.west@ualberta.ca; Fax: +1 780-492-8231;
Tel: +1 780-492-8187
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc34644c
z Graduate intern from the Zhejiang University, China.
c
9186 Chem. Commun., 2012, 48, 9186–9188
This journal is The Royal Society of Chemistry 2012

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Table 1 The overall hydroacylation of allenamides 2a
Entry
Aldehyde
Product
Yieldb (%)
1
2
3
4
5
6
R = H, 1a
R = H, 4a
65
44
18
52
46
14
R = Me, 1b
R = OMe, 1c
R = SMe, 1d
R = Cl, 1e
R = Me, 4b
R = OMe, 4c
R = SMe, 4d
R = Cl, 4e
Scheme 2 A plausible mechanism for this overall hydroacylation of
allenamides supported by the deuterium labelling experiment.
R = CO2Me, 1f
R = CO2Me, 4f
thus lowering the electrocyclization barriers.10,16 In the event, a
catalyst screening with 4a showed that only indium(III) triflate
was an effective catalytic promoter (DCE, 80 1C) providing 5a
in 65% yield, a surprising contrast to the recent observation
that Sc(OTf)3 displays superior reactivity in catalyzing the Nazarov
cyclization of heteroaromatic substrates.17 Subsequently, we
turned our attention to use commercially available superacids
as catalysts.2a The cyclization of 4a using a substoichiometric
amount of triflic acid gave partial conversion of the starting
material, but the optimized reaction conditions (Table 2, entry 5)
entailed excess TfOH with mild heating (65 1C). For substi-
tuted aryl vinyl ketones, In(OTf)3 displayed little to no
reactivity, demonstrating that subtle electronic changes exert
a large effect on catalysis of the Nazarov reaction. Nevertheless,
4b–4f did undergo efficient cyclization in the presence of triflic
acid, with negligible effects of substitution (entries 6–10).
Naphthyl substrate 4g could potentially undergo competing
Friedel–Crafts type cyclization to furnish the phenalan
skeleton;18 however, exclusive reaction via the Nazarov pathway
was observed, using either TfOH or In(OTf)3 (entries 11 and 12).
2-Furyl vinyl ketones are generally considered to be unreactive
substrates for the Nazarov reaction.6c,17 Nonetheless, 4h
underwent cyclization with triflic acid, though not with
indium(III) triflate (entry 13 vs. 14). This result is analogous
to the report of Flynn and co-workers, wherein the authors
attributed cyclization of conventionally inert substrates to the
potent activation exerted from the oxazolidinone auxiliary.10
Given our observations that Nazarov reactions of aryl and
2-furyl ketones 4a–h are quite sensitive to acid strength,19 we
propose an equally important role to the superacid (TfOH),
perhaps through formation of highly reactive dicationic inter-
mediate 8 or protosolvated species 9 might be equally essential
(Fig. 1).20 Finally, it should be noted that Lewis acid-catalyzed
cyclization of non-aromatic substrate 4i deviated from the
typical eliminative termination, furnishing hydrolysis product
5i (entries 14 and 15), in contrast to the reactivity observed by
the Flynn group in related cases.10
7
8
52
33
35
9
a
Standard procedure: to a homogeneous solution of allenamide 2
(0.5 mmol) in anhydrous THF under an argon atmosphere, 1.2 equiv.
n-BuLi was added dropwise at ꢀ78 1C. After 45 min, freshly distilled
aldehyde 1 (1.1 equiv.) was added at ꢀ78 1C, then the reaction was
warmed to rt. The reaction was quenched with sat. aq. NH4Cl, followed
by extraction, drying (MgSO4), and chromatographic purification.
b
Isolated yields based on allenamides.
2 to furnish d-4a as the only identifiable product where the
deuterium was incorporated at the b-carbon and no 4a was
detected even in the crude H NMR spectrum. As depicted in
1
Scheme 2, this result supports the hypothesis that a concerted
1,3-deuteride shift is the operating pathway for the generation
of d-4 from allenyl alkoxide 6, rather than the alternative
proton transfer mechanism involving external acid or base.8d
As reported by Hsung, the isomerization of a-allylated alle-
namides generally required additional promoters (heat or acid)
to give triene products.8,13 In this case, the facile 1,3-D shift
furnishing intermediate aryl diene 7 was likely facilitated by
alkoxide substitution at the deuterium-labeled center.14 No-
tably, the allenylation of unsaturated aldehydes with termin-
ally substituted propargyl-metal species has ample precedent
in the literature.15 To the best of our knowledge, those
reactions resulted in aryl or vinyl allenyl alcohols with no
evidence of the corresponding isomerizations. From this, we
infer that the oxazolidinone group plays an important role in
mediating the 1,3-deuteride shift.8d
In summary, we have described a novel approach to amido-
substituted Nazarov precursors through 1-step coupling of
simple aldehydes and a lithiated allenamide. As supported by a
deuterium labelling study, the reaction mechanism appears to
entail sequential carbonyl addition–1,3-sigmatropic rearrange-
ment. In the context of the Nazarov reaction, triflic acid
Next, we commenced to identify optimal catalytic conditions2a
for triggering the Nazarov reaction of 4, where the a-amido group
was expected to advantageously polarize the pentadienyl system,
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9186–9188 9187

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Table 2 Nazarov cyclizations of oxazolidinone-substituted cross-
conjugated ketones 4a
Notes and references
1 K. L. Habermas, S. E. Denmark and T. K. Jones, Org. React.,
1994, 45, 1–158.
2 For recent reviews on the Nazarov reaction, see: (a) T. Vaidya,
R. Eisenberg and A. J. Frontier, ChemCatChem, 2011, 3,
1531–1548; (b) N. Shimada, C. Stewart and M. A. Tius, Tetra-
hedron, 2011, 67, 5851–5870; (c) T. N. Grant, C. J. Rieder and
F. G. West, Chem. Commun., 2009, 5676–5688; (d) W. Nakanishi
and F. G. West, Curr. Opin. Drug Discovery Dev., 2009, 12, 732–751.
3 For example, see: (a) S. Giese and F. G. West, Tetrahedron, 2000,
56, 10221–10228; (b) L. N. Pridgen, K. Huang, S. Shilcrat,
A. Tickner-Eldridge, C. DeBrosse and R. C. Haltiwanger, Synlett,
1999, 1612–1614; (c) P. Yates, N. Yoda, W. Brown and B. Mann,
J. Am. Chem. Soc., 1958, 80, 202–205.
Yieldb (%)
Entry Dienone Acid (equiv.)/T (1C) Nazarov products (ratio)c
4 For example, see: (a) P. Chiu and S. Li, Org. Lett., 2004, 6,
613–616; (b) P. Cao, X.-L. Sun, B.-H. Zhu, Q. Shen, Z. Xie and
Y. Tang, Org. Lett., 2009, 11, 3048–3051.
5 D. P. Canterbury, I. R. Herrick, J. Um, K. N. Houk and
A. J. Frontier, Tetrahedron, 2009, 65, 3165–3179.
6 For selected examples, see: (a) D. J. Kerr and B. L. Flynn, J. Org.
Chem., 2010, 75, 7073–7084; (b) R. D. Mazzola, Jr., S. Giese,
C. L. Benson and F. G. West, J. Org. Chem., 2004, 69, 220–223;
(c) S. E. Denmark, K. L. Habermas and G. A. Hite, Helv.
Chim. Acta, 1988, 71, 168–194.
7 (a) H. Xiong, R. P. Hsung, L.-L. Wei, C. R. Berry, J. A. Mulder
and B. Stockwell, Org. Lett., 2000, 2, 2869–2871. For an overview
on the allenamide chemistry, see: (b) L.-L. Wei, H. Xiong and
R. P. Hsung, Acc. Chem. Res., 2003, 36, 773–782.
1
2
3
4
5
6
7
8
9
10
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
FeCl3 (0.2)/80
R = H, 5a
R = H, 5a
R = H, 5a
R = H, 5a
R = H, 5a
R = Me, 5b
R = OMe, 5c
R = SMe, 5d
R = Cl, 5e
NR
Trace
NR
65 (20 : 1)
98 (20 : 1)
87 (20 : 1)
88 (4 : 1)
97 (20 : 1)
94 (20 : 1)
Sc(OTf)3 (0.2)/80
Eu(OTf)3 (0.2)/80
In(OTf)3 (0.2)/80
CF3SO3H (5)/65
CF3SO3H (5)/65
CF3SO3H (5)/65
CF3SO3H (5)/65
CF3SO3H (5)/65
CF3SO3H (5)/65
R = CO2Me, 5f 91 (20 : 1)
11
12
4g
4g
In(OTf)3 (0.2)/80
CF3SO3H (5)/65
76 (20 : 1)
97 (20 : 1)
8 For related isomerizations of a-allylated allenamides resulting in
3-amido-trienes at elevated temperature or in acidic media, see:
(a) R. Hayashi, R. P. Hsung, J. B. Feltenberger and A. G. Lohse,
Org. Lett., 2009, 11, 2125–2128; (b) R. Hayashi, J. B. Feltenberger
and R. P. Hsung, Org. Lett., 2010, 12, 1152–1155; (c) R. Hayashi,
Z.-X. Ma and R. P. Hsung, Org. Lett., 2012, 14, 252–255;
(d) R. Hayashi, J. B. Feltenberger, A. G. Lohse, M. C. Walton
and R. P. Hsung, Beilstein J. Org. Chem., 2011, 7, 410–420.
9 For a review on the transition metal-catalyzed hydroacylation, see:
M. C. Willis, Chem. Rev., 2010, 110, 725–748.
10 During the course of our studies, the Flynn group reported an
elegant work on diastereoselective Nazarov reaction using Evans’
oxazolidinone as a chiral auxiliary. For details, please refer to:
D. J. Kerr, M. Miletic, J. H. Chaplin, J. M. White and B. L. Flynn,
Org. Lett., 2012, 14, 1732–1735.
13
14
4h
4h
In(OTf)3 (0.2)/80
CF3SO3H (5)/65
NR
65 (3 : 1)
14
15
4i
4i
Sc(OTf)3 (0.2)/80
BF3ꢁOEt2 (1.1)/ꢀ78
96
81
a
To a stirred solution of 4 in DCE at the indicated temperature, acid
was added to the mixture. Once the starting material was consumed
(based on TLC), the reaction was quenched with sat. aq. NaHCO3,
followed by extraction, drying (MgSO4) and chromatographic purifi-
11 For those low-yielding reactions, side products were isolated
in inconsistent yields (0–8%), whose structures were tentatively
assigned and are given in the ESIw.
12 For a related mechanistic perspective, see: C. Liu, J. Wang,
L. Meng, Y. Deng, Y. Li and A. Lei, Angew. Chem., Int. Ed.,
2011, 50, 5144–5148.
b
c
cation. Isolated yields; NR = no reaction. cis/trans isomers were
1
inseparable and the ratios were determined by H NMR.
13 For an isolated example of domino allylation/isomerization of a
specific allenamide resulting in a triene product, see: ref. 8c.
14 S. R. Wilson, Org. React., 1993, 43, 93–250.
15 For examples, see: (a) Y. Masuyama, A. Watabe, A. Ito and
Y. Kurusu, Chem. Commun., 2000, 2009–2010; (b) M. Banerjee
and S. Roy, Org. Lett., 2004, 6, 2137–2140; (c) G. Xia and
H. Yamamoto, J. Am. Chem. Soc., 2007, 129, 496–497; (d) V. M.
Marx and D. J. Burnell, Org. Lett., 2009, 11, 1229–1231.
16 For Nazarov reactions of 2-amino-1,4-pentadien-3-ones, where
nitrogen atom is encased within a ring, see: (a) P. Larini,
A. Guarna and E. G. Occhiato, Org. Lett., 2006, 8, 781–784;
(b) E. G. Occhiato, C. Prandi, A. Ferrali and A. Guarna, J. Org.
Chem., 2005, 70, 4542–4545.
Fig. 1 Proposed superelectrophilic intermediates.
was found to be a superior promoter for the aromatic or
heteroaromatic substrates. Alternatively, the cyclization of
divinyl ketones proceeded smoothly under mild conditions
where the oxazolidinone served as a traceless activating group.
An extension of the aforementioned overall hydroacylation
process to other heteroatom-substituted allenes will be further
explored.
17 J. A. Malona, J. M. Colbourne and A. J. Frontier, Org. Lett., 2006,
8, 5661–5664.
18 (a) A. Orita, J. Yaruva and J. Otera, Angew. Chem., Int. Ed., 1999,
38, 2267–2270; (b) Y. Zhang, P. J. Kindelin, D. DeSchepper,
C. Zhang and D. A. Klumpp, Synthesis, 2006, 1775–1780.
19 For instance, triflimide failed to mediate the cyclization of 4e.
20 (a) T. Suzuki, T. Ohwada and K. Shudo, J. Am. Chem. Soc., 1997,
119, 6774–6780; (b) D. A. Klumpp, Y. Zhang, M. J. O’Connor,
P. M. Esteves and L. S. DeAlmeida, Org. Lett., 2007, 9, 3085–3088.
We thank NSERC for support of this work. Y. K. W.
thanks Alberta Innovates–Technology Futures for a PhD
graduate scholarship. T. N. thanks the University of Alberta
for a research internship scholarship.
c
9188 Chem. Commun., 2012, 48, 9186–9188
This journal is The Royal Society of Chemistry 2012