Hydroxylamine catalyzed Nazarov cyclizations of divinyl ketones Dedicated to Professor Hilton Weiss on his 80th birthday

Article abstract of DOI:10.1016/j.tetlet.2015.10.039

The first examples of iminium catalyzed Nazarov cyclizations of divinyl ketones are presented. Experiments describing hydroxylamine catalysis of the cyclization of eight α-alkoxy divinyl ketones (60-79% yield) and one unactivated divinyl ketone (38% yield) are reported. Phenyl substitution at the β-position of the divinyl ketone inhibits cyclization, whereas β-alkyl substituted α-alkoxy divinyl ketones readily cyclize.

Full text of DOI:10.1016/j.tetlet.2015.10.039

Tetrahedron Letters 56 (2015) 6622–6624
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Hydroxylamine catalyzed Nazarov cyclizations of divinyl ketones
⇑
Joseph Z. Hamilton, Nathaniel T. Kadunce, Michael D. McDonald, Laura Rios, Albert R. Matlin
Department of Chemistry, Oberlin College, Oberlin, OH 44074, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The first examples of iminium catalyzed Nazarov cyclizations of divinyl ketones are presented.
Experiments describing hydroxylamine catalysis of the cyclization of eight -alkoxy divinyl ketones
(60–79% yield) and one unactivated divinyl ketone (38% yield) are reported. Phenyl substitution at the
b-position of the divinyl ketone inhibits cyclization, whereas b-alkyl substituted a-alkoxy divinyl ketones
readily cyclize.
Received 8 August 2015
Revised 7 October 2015
Accepted 9 October 2015
Available online 19 October 2015
a
Ó 2015 Elsevier Ltd. All rights reserved.
Dedicated to Professor Hilton Weiss on his
80th birthday
Keywords:
Nazarov cyclization
Hydroxylamine catalysis
Iminium ions
Divinyl ketones
Introduction
O
O
H
N
MeCN, H2O
Me
Ph
O
+
rt, 7.5 days
OH
Me
The Nazarov cyclization continues to be an area of active inter-
est due its utility in the synthesis of substituted cyclopentenones.1
Recent studies have focused on new catalysts,2 new substrates,3
enantioselective cyclizations,4 interrupted cyclizations/tandem
reactions,5 and applications to the synthesis of natural products.6
Despite the overwhelming success of pyrrolidine-based organocat-
alysts to promote a wide range of reactions involving both enals
and enones, there are no examples of iminium ion catalyzed
Nazarov cyclizations of divinyl ketones in the literature.7 There
have been a few examples of Nazarov cyclizations with other
substrates reported that involve imino/iminium ions, but these
reactions require stoichiometric amounts of the reactants.8 For
example, Tius and co-workers have reported a chiral bifunctional
primary/secondary amine catalyst that promotes the cyclization
60% yield
97% er
NH3
Ph
Scheme 1. Diamine catalysis of a-ketoenones Nazarov cyclizations.
H
H
H
H
H
H
N
N
N
1
2
3
Scheme 2. Iminium catalysis of a divinyl ketone.
of a-ketoenones with high enantiomeric ratios (er’s), but the reac-
as the activation barrier for the formation of iminium ion 1 was
not prohibitive, then an unfavorable equilibrium between
intermediates 1 and 2 could be drawn off in the next step
(formation of iminium ion 3), which should be energetically
favorable. Here we report our initial studies directed at developing
an amine-catalyzed Nazarov cyclization of divinyl ketones.
tion requires 1 equiv of the diamine (Scheme 1).8a They proposed
that the cyclization involves formation of an enamine–iminium
ion that does not readily hydrolyze under the reaction conditions.
The absence of reports of amine-catalyzed Nazarov cyclization
with divinyl ketones may be the result of a computational study
published by Smith.9 He concluded that the ammonia catalyzed
Nazarov cyclization would have an unfavorable equilibrium
between the divinyl iminium ion 1 and the cyclized product 2
(Scheme 2). Considering this issue we hypothesized that as long
Results and discussion
We began our investigation with a DFT computational study of
the iminium Nazarov cyclization reaction in Scheme 2. Using the
B3LYP functional with 6-31G(d) basis set we calculated the
⇑
Corresponding author. Tel.: +1 440 775 8308; fax: +1 440 775 6682.
E-mail address: amatlin@oberlin.edu (A.R. Matlin).
cyclization step of 1 to 2 to have a
DG° value of 5.3 kcal/mol, which
http://dx.doi.org/10.1016/j.tetlet.2015.10.039
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

J. Z. Hamilton et al. / Tetrahedron Letters 56 (2015) 6622–6624
6623
is similar to that reported by Smith. However, as we anticipated,
the overall transformation of 1 to 3 is calculated to be highly
favorable with a
Encouraged by these calculations we initiated an experimental
study to develop an amine-catalyzed Nazarov cyclization of divinyl
ketones by examining three pyrrolidine based secondary amines
O
O
D
G° of À23.2 kcal/mol.
5
9
H
H
OH
H
N
H2O
H2O
OH
catalysts (pyrrolidine hydroperchlorate, DL-proline, and
L-proline
benzyl ester hydrochloride) with the ‘activated’ -alkoxy substrate
a
H
H
N
OH
N
4 (Scheme 3). We screened these catalysts (20 mol %) under a
variety of reaction conditions (solvents: methanol, methanol with
5% water, ethanol, ethanol with 5% water, dichloromethane,
acetonitrile; reaction temperature: rt to 70 °C for up to 3 days).
We failed to observe cyclized products under any of these condi-
tions. Instead, these reactions led to either decomposition of the
divinyl ketone or returned the starting material largely intact.
We also found that the MacMillan catalyst, (5S)-2,3,3-trimethyl-
6
8
H
OH
N
7
5-benzyl-4-imidazolinone, was unsuccessful in cyclizing
(20 mol % catalyst, ethanol, 70 °C, 15 h).
4
Scheme 4. Proposed catalytic cycle for hydroxylamine-catalyzed Nazarov
cyclizations.
The failure of pyrrolidine catalysts is likely due to their inability
to form the initial iminium ions. While these catalysts work well
with reactions involving enals and enones, divinyl ketones such
as 4 should be less susceptible to nucleophilic attack due to the
Table 1
Cyclopentenones from hydroxylamine-catalyzed Nazarov cyclizationsa
Entry
Divinyl ketone
Cyclopentenone
Yieldb (%)
increased electron density in the
p-system with the addition of
the second C–C double bond. Tomkinson has reported that sec-
ondary hydroxylamines and substituted hydrazines are effective
catalysts for the Diels–Alder reaction.10 These catalysts should be
O
O
O
O
Me
Me
1
67
more nucleophilic than simple amines due to the ‘a
-effect’.11
4a
4
Inspired by these reports, we decided to investigate the efficacy
of hydroxylamine hydrochloride as a catalyst for the Nazarov
cyclization. We chose to examine hydroxylamine for three reasons:
hydroxylamine is known to reversibly form oximes under acidic
O
O
O
O
O
Et
Et
2
3
79
60
conditions and the combination of the
a-effect with the small
10a
O
O
10
steric profile of the primary amine should facilitate nucleophilic
reactions.12
O
Reaction of divinyl ketone 4 with 20 mol % of hydroxylamine
hydrochloride in ethanol for 16 h at 70 °C resulted in the formation
of the cyclized product 4a in 67% isolated yield. To the best of our
knowledge this represents the first use of hydroxylamine as a cat-
alyst and the first example of an iminium ion-catalyzed Nazarov
cyclization of a divinyl ketone. In order to rule out the possibility
that the BrØnsted acid properties of hydroxylamine hydrochloride
(pKa 5.94) were responsible for the catalysis, we ran two control
reactions using acetic acid (pKa 4.76) and N,N-diethylhydroxy-
lamine oxalate (pKa ꢀ5.7) with divinyl ketone 4.13 No reaction
was observed after heating 4 at 70 °C in ethanol for 15 h in the
presence of 20 mol % of acetic acid or 20 mol % diethylhydroxy-
lamine oxalate. These results are consistent with the interpretation
that the reaction occurs by way of iminium ion catalysis.
We propose that the reaction follows the catalytic cycle illus-
trated in Scheme 4. The reaction is initiated by condensation of
hydroxylamine with divinyl ketone 5 to give the iminium ion 6.
Conrotatory ring closure of 6 produces cyclopentyl allyl cation 7,
which isomerizes via elimination of a proton followed by protona-
Me
Me
11a
Me
O
11
O
O
O
4
5
6
7
8
61
65
0
Me
O
Me
12a
Me
12
O
H
H
O
O
13
13a
O
O
O
O
—
Ph
14
O
O
O
Ph
Ph
73
38
i-Bu
tion at the
a-carbon to yield 8. Hydrolysis produces the isolated
15a
i-Bu
O
15
16
cyclopentenone product 9 and regenerates the hydroxylamine
catalyst.
Table 1 lists the divinyl ketones that we have subjected to
hydroxylamine catalysis. With the exception of the unactivated
divinyl ketone 11 and b-phenyl divinyl ketone 9, the reactions
Me
Me
16a
a
All reactions were performed in ethanol at ꢀ0.2 M with 20 mol % hydroxy-
O
O
lamine hydrochloride catalyst, at 70 °C for ꢀ16 h.
b
O
Me
O
catalyst
Isolated by column chromatography.
Me
produce cyclopentenones in good yields (60–79%).14 The lack of
reactivity of 9 probably arises from the b-phenyl substitution,
which should stabilize the uncyclized iminium ion (e.g., 6 in
4
4a
Scheme 3. Nazarov cyclization of activated divinyl ketones.

6624
J. Z. Hamilton et al. / Tetrahedron Letters 56 (2015) 6622–6624
O
O
Supplementary data
O
NH2OH•HCl
EtOD, 70˚ C
O
D
Ph
i-Bu
Ph
Supplementary data (experimental section with procedures and
spectroscopic characterization: 1H and 13C NMR, HRMS, of
compounds 4a, 10a, 11, 11a, 12a, 13a, 15, 15a, 15b, 16 and 16a;
computational methods, Cartesian coordinates and energies for
compounds 1–3) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.039.
D
D
i-Bu
15b
15a
Scheme 5. H–D exchange in cyclization products.
Scheme 4) raising the barrier to cyclization. Alternatively the
b-phenyl group in 9 may be inhibiting the formation of the initial
iminium ion (e.g., 6) in the catalytic cyclic due to the increased
electron density at the carbonyl carbon. In contrast, placing a
phenyl group at the
the cyclized allylic cation intermediate 7. This behavior of
-substitution promoting the reaction while b-substitution inhibits
References and notes
1. Recent Reviews: (a) West, F. G.; Scadeng, O.; Wu, Y.; Fradette, R. J. Joy, S. In
Comprehensive Organic Synthesis; Knochel, P., Molander, G., Eds., 2nd ed.;
Elsevier: Amsterdam, 2014; pp 827–866; (b) Wenz, D. R.; Read di Alaniz, J. Eur.
J. Org. Chem. 2015, 2015, 23–37; (c) Ausran, G.; Bremond, P.; Feuerstein, M.;
Marque, S. R. A.; Santelli, M. Tetrahedron 2013, 69, 8325–8348.
2. Review: Vaidya, T.; Eisenberg, R.; Frontier, A. J. ChemCatChem 2011, 3,
1531–1548.
3. Reviews: (a) Di Grandi, M. J. Org. Biomol. Chem. 2014, 12, 5331–5345; (b) Tius,
M. A. Chem. Soc. Rev. 2014, 43, 2979–3002.
4. Review: (a) Shimada, N.; Stewart, C.; Tius, M. A. Tetrahedron 2011, 67,
5851–5870; (b) Hutson, G. E.; Turkmen, Y. E.; Rawal, V. H. J. Am. Chem. Soc.
2013, 135, 4988–4991; (c) Xu, Z.; Ren, H.; Wang, L.; Tang, Y. Org. Chem. Front.
2015, 2, 811–814.
5. (a) Grant, T. N.; Rieder, C. J.; West, F. G. Chem. Commun. 2009, 5676–5688; (b)
Wu, Y.-K.; McDonald, R.; West, F. G. Org. Lett. 2011, 13, 3584–3587; (c) Leboeuf,
D.; Gandon, V.; Ciesielski, J.; Frontier, A. J. J. Am. Chem. Soc. 2012, 134,
6296–6308; (d) Petrovic, M.; Scarpi, D.; Fiser, B.; Gomez-Bengoa, E. Eur. J. Org.
Chem. 2015, 2015, 3943–3956; (e) Liu, M.-Q.; Zhou, A. H.; Jian, S.; Wang, J.-Q.;
Ye, L.-w. Synthesis 2014, 46, 2161–2167.
a-position (as in divinyl ketone 15) stabilizes
a
cyclization has been previously noted.15 The good yields observed
with methyl (11) and dimethyl (12) b-substituted divinyl ketones
(Table 1) are consistent with the notion that extended conjugation
of the phenyl group at the b-position in the uncyclized iminium ion
(e.g., 6, Scheme 4) raises the barrier to cyclization more than b-alkyl
substitution. The net effect is that hydroxylamine is an effective cat-
alyst for the cyclization of b-alkyl substituted
a-alkoxy divinyl
ketones but is not a strong enough catalyst to overcome the elec-
tronic effects of b-phenyl substitution. Lewis acid catalysts do not
have this limitation and give excellent yields of cyclization products
with b-phenyl substituted divinyl ketones.16
6. Applications of Nazarov cyclization in natural product synthesis: (a) Bitar, A. Y.;
Frontier, A. J. Org. Lett. 2009, 11, 49–52; (b) Zhou, Z.; Tius, M. A. Angew. Chem.,
Int. Ed. 2015, 54, 6037–6040; (c) Shavartbart, A.; Smith, A. B. J. Am. Chem. Soc.
2014, 136, 870–873; (d) Sudhakar, G.; Satish, K. Chem. Eur. J. 2015, 21,
6475–6480.
7. Reviews of iminium-ion catalysis: (a) MacMillan, D. W. C. Nature 2008, 455,
304–308; (b) Lelais, G.; MacMillan, D. W. C. Aldrichchim. Acta 2006, 39, 79–87;
(c) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, L.; JØrgensen, K. A. Acc. Chem.
Res. 2011, 45, 248–264.
8. (a) Bow, F. W.; Basak, A. K.; Jolit, A.; Vicic, D. A.; Tius, M. A. Org. Lett. 2010, 12,
440–443; (b) Tius, M. A.; Chu, C. C.; Nieves-Colbert, R. Tetrahedron Lett. 2001,
42, 2419–2422; (c) Suarez-Pantiga, S.; Rubio, E.; Alvarez-Rua, C.; Gonzalez, J. M.
Org. Lett. 2009, 11, 13–16; (d) Bonderoff, S. A.; Grant, T. N.; West, F. G.;
Tremblay, M. Org. Lett. 2013, 15, 2888–2891.
9. Smith, D. A.; Ulmer, C. W. J. Org. Chem 1997, 62, 5110–5115.
10. Cavill, J. L.; Elliot, R. L.; Evans, G.; Jones, I. L.; Platts, J. A.; Ruda, A. M.;
Tomkinson, N. C. O. Tetrahedron 2006, 62, 410–421.
11. Edwards, J. O.; Pearson, R. G. J. Am. Chem. Soc. 1962, 84, 16–24.
12. Shriner, R. L.; Fuson, R. C.; Curtin, D. Y. In The Systematic Identification of Organic
Compounds, 5th ed.; Wiley: New York, 1956; p 250.
13. (a)pKa Hydroxylamine hydrochloride and acetic acid: CRC Handbook of
Chemistry and Physics; Haynes, W. M., Ed., 95th ed.; CRC Press LLC: Boca
Raton: FL, 2014; pp 5–92. pp 5–94; Estimated pKa of diethylhydroxylamine:
(b) Hilal, S. H. In Quantitative Treatment of Solute/Solvent Interactions; Politzer,
Ed.; Elsevier: Amsterdam, 1994; pp 291–353.
In order to determine if the Nazarov cyclization of divinyl
ketone 15 was diastereoselective we heated the cyclized product
15a at 70 °C with hydroxylamine hydrochloride (20 mol %) in
ethan(ol-d) for 16 h. Analysis by 1H NMR showed the incorporation
of three deuterium atoms (15b, Scheme 5) indicating that any cis
product formed in the cyclization would have epimerized to the
more stable trans-isomer under the reaction conditions.
Conclusion
We have discovered a new catalyst for the Nazarov cyclization
of divinyl ketones. The ability of hydroxylamine to catalyze the
cyclization is likely due to the a-effect, which increases the nucle-
ophilicity of the amine allowing the transient formation of the req-
uisite iminium ion. Our current efforts are being directed at
exploring this new catalytic mode for the Nazarov cyclization in
order to find iminium ion catalysts that are effective under milder
reaction conditions.
14. The reaction appears to form ꢀ10% of the double isomer 2-methyl-2,3,3a,4,5,
Acknowledgements
6-hexahydro-1H-inden-1-one in addition to 11a.
15. Habermas, K. L.; Denmark, S. E. Org. React. 1994, 45, 1–154.
16. For examples of Lewis acid catalyzed Nazarov cyclizations of b-phenyl
dienones see: (a) Liang, G.; Gradl, S. N.; Trauner, D. Org. Lett. 2003, 5,
4931–4934; (b) Aggarwal, V. K.; Belfield, A. J. Org. Lett. 2003, 5, 5075–5078; (c)
He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125, 14278–14279.
A.R.M. gratefully acknowledges financial support of this work
from Oberlin College and the NSF (0420717) for funding of a
Beowulf computer cluster. We also thank the Mass Spectrometry
Center at the University of Akron for the HRMS measurements.