Enamine-lminium ion nazarov cyclization of α-ketoenones

Article abstract of DOI:10.1021/ol9025765

[Chemical equaction presented] The mono-triflate salts of some chiral nonracemic 1,2-diamines react with α-ketoenones in a stoichiometric reaction to form products of the Nazarov cyclization in high enantiomeric ratios. The mechanism appears to involve rearrangement of an enamine-iminium ion.

Full text of DOI:10.1021/ol9025765

ORGANIC
LETTERS
2010
Vol. 12, No. 3
440-443
Enamine-Iminium Ion Nazarov
Cyclization of r-Ketoenones
William F. Bow, Ashok K. Basak, Anais Jolit, David A. Vicic,† and Marcus A. Tius*
Department of Chemistry, 2545 The Mall, UniVersity of Hawaii,
Honolulu, Hawaii 96822, and The Cancer Research Center of Hawaii,
1236 Lauhala Street, Honolulu, Hawaii 96813
tius@hawaii.edu
Received November 5, 2009
ABSTRACT
The mono-triflate salts of some chiral nonracemic 1,2-diamines react with r-ketoenones in a stoichiometric reaction to form products of the
Nazarov cyclization in high enantiomeric ratios. The mechanism appears to involve rearrangement of an enamine-iminium ion.
Recent years have seen a resurgence of interest in the
Nazarov cyclization.1,2 An attractive approach to the
Scheme 1
asymmetric Nazarov cyclization is through iminium ion
catalysis.3 For example, treatment of divinyl ketone 1
(Scheme 1) with an asymmetric secondary amine 2 can be
expected to lead to equilibrium with iminium ion 3. Nazarov
cyclization of the pentadienyl carbocation (cf. 4) might lead
to cyclic species 5 through a conrotatory process. Through
appropriate choice of amine 2 and reaction conditions,
asymmetric induction might be observed during this process.
Although this general approach appears to be sound, in fact
the pentadienyl cation (cf. 4) is rendered more stable than
the cyclic allylic cation 5 by conjugation with the nonbonding
electron pair on the nitrogen atom.4 This generally results
in an equilibrium favoring the acyclic iminium ion. This
† Author to whom inquiries regarding the crystal structure of 51 should
be directed.
(1) For reviews of the Nazarov reaction see: (a) Harmata, M. Chemtracts
2004, 17, 416–435. (b) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61,
7577–7606. (c) Pellissier, H. Tetrahedron 2005, 61, 6479–6517. (d) Tius,
M. A. Eur. J. Org. Chem. 2005, 2193–2206. (e) Habermas, K. L.; Denmark,
S.; Jones, T. K. In Organic Reactions, Vol. 45; Paquette, L. A., Ed.; John
Wiley & Sons, Inc.: New York, 1994; pp 1-158.
(3) Examples of the catalytic asymmetric Nazarov cyclization: (a)
Rueping, M.; Ieawsuwan, W. AdV. Synth. Catal. 2009, 351, 78–84. (b)
Walz, I.; Togni, A. J. Chem. Comm. 2008, 4315–4317. (c) Rueping, M.;
Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J. Ang. Chem. Int.
Ed. 2007, 46, 2097–2100. (d) Liang, G.; Trauner, D. J. Am. Chem. Soc.
2004, 126, 9544–9545. (e) Aggarwal, V. K.; Belfield, A. J. Org. Lett.
2003, 5, 5075–5078. (f) Liang, G.; Gradl, S. N.; Trauner, D. Org. Lett.
2003, 5, 4931–4934. Examples of the use of chiral auxiliaries for the
Nazarov: (g) Banaag, A. R.; Tius, M. A. J. Org. Chem. 2008, 73, 8133–
8141. (h) Dhoro, F.; Kristensen, T. E.; Stockmann, V.; Yap, G. P. A.;
Tius, M. A. J. Am. Chem. Soc. 2007, 129, 7256–7257. (i) de los Santos,
D. B.; Banaag, A. R.; Tius, M. A. Org. Lett. 2006, 8, 2579–2582. (j) Pridgen,
L. N.; Huang, K.; Shilcrat, S.; Tickner-Eldridge, A.; DeBrosse, C.;
Haltiwanger, R. C. Synlett 1999, 1612–1614.
(2) Recent examples of the Nazarov cyclization: (a) Malona, J. A.;
Cariou, K.; Frontier, A. J. J. Am. Chem. Soc. 2009, 131, 7560–7561. (b)
Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009, 131,
7504–7505. (c) Marx, V. M.; Burnell, D. J. Org. Lett. 2009, 11, 1229–
1231. (d) Bitar, A. Y.; Frontier, A. J. Org. Lett. 2009, 11, 49–52. (e) Basak,
A. K.; Tius, M. A. Org. Lett. 2008, 10, 4073–4076. (f) He, W.; Huang, J.;
Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2008, 130, 300–308. (g) Song,
D.; Rostami, A.; West, F. G. J. Am. Chem. Soc. 2007, 129, 12019–12022.
(h) Grant, T. N.; West, F. G. Org. Lett. 2007, 9, 3789–3792. (i) Gao, S.;
Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410–1412. (j) Nie, J.;
Zhu, H.-W.; Cui, H.-F.; Hua, M.-Q.; Ma, J.-A. Org. Lett. 2007, 9, 3053–
(4) Smith, D. A.; Ulmer, C. W., II J. Org. Chem. 1997, 62, 5110–
5115.
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10.1021/ol9025765  2010 American Chemical Society
Published on Web 12/23/2009

obstacle may be overcome by incorporating a structu-
ral feature into 1 that raises the energy of 3/4 compared
to 5.
To the best of our knowledge, the Nazarov cyclization
of an iminium ion has been reported only twice. The first
example is summarized in Scheme 2.5 Addition of
We conceived of an alternative approach to the ones
described above that would allow us to use iminium ion
catalysis for a Nazarov cyclization. Scheme 3 summarizes
the approach. Exposure of an R-ketoenone such as 11 to
a diamine salt 12 is expected to generate enamine-iminium
ion 13 under Brønsted acid catalysis. The carbonyl group
of the methyl ketone is likely to be the more reactive of
the two and will form an enamine. Subsequent reaction
of the free amino group with the enone carbonyl group
leads to enamine-iminium ion 13. Intermediate 13 should
be an excellent substrate for the Nazarov reaction since
the enamine is polarized so as to favor cyclization.7
Critically, this Nazarov cyclization converts enamine-
iminium ion 13 to enamine-iminium ion 14. Conse-
quently, both 13 and 14 are stabilized by a nonbonding
electron pair on a nitrogen atom therefore there is no
reason to expect the equilibrium to favor 13. Hydrolysis
of 14 would regenerate diamine salt 12, liberating the
R-hydroxyenone product 15. We thought that this approach
had some merit since we knew from our earlier work that
efficient cyclization of 11 to 15 can be accomplished under
a variety of reaction conditions.
Scheme 2
We subsequently screened the series of diamines that
are listed in Figure 1, all based on the (1R,2R)-(-)-1,2-
lithioallenyl ether 7 to E-R-methyl cinnamonitrile 6 leads
to N-lithio imine 8. Workup with mild aqueous acid
protonates the imine that then undergoes Nazarov cy-
clization to 9. N-Acetylation in a separate step gave
acetamide 10 in 73% overall yield from 6. The success
of this reaction is probably due to release of allene strain
(10.76 kcal/mol)3g as well as the irreversible loss of
methoxymethyl cation during the cyclization. In the second
example of an imino Nazarov cyclization, the stability of
the iminium ion was attenuated by N-tosylation.6
We first screened a small set of monoamines to determine
whether they would catalyze the asymmetric conversion of
11 to 15 (Scheme 3). Stoichiometric L-proline, (S)-R-
Scheme 3
Figure 1. Diamines screened.
diaminocyclohexane motif that has been widely used in
asymmetric catalysis.8 All diamines were evaluated as
their mono-triflate salts in the stoichiometric reaction with
11. We were surprised that neither primary-primary
diamine 16, nor secondary-secondary diamines 17 and
18 led to cyclic product 15 under a variety of conditions.
Primary-tertiary diamines 24-27 were also ineffective.
On the other hand, primary-secondary diamines 19-23
were all effective in converting 11 to 15 with varying
degrees of asymmetric induction in a 4 M solution in
methylbenzylamine or (1R,2S)-(-)-ephedrine in the presence
of a Brønsted acid led to small amounts (<10%) of racemic
15 in a very slow reaction. These negative results suggested
a solution to the problem through a cooperative mechanism
(vide infra).
(7) (a) Tius, M. A.; Kwok, C.-K.; Gu, X.-q.; Zhao, C. Synth. Commun.
1994, 24, 871–885. (b) He, W.; Herrick, I. R.; Atesin, T. A.; Caruana, P. A.;
Kellenberger, C. A.; Frontier, A. J. J. Am. Chem. Soc. 2008, 130, 1003–
1011.
(8) (a) Luo, S.; Xu, H.; Chen, L.; Cheng, J.-P. Org. Lett. 2008, 10, 1775–
1778. (b) Stead, D.; O’Brien, P.; Sanderson, A. Org. Lett. 2008, 10, 1409–
1412. (c) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228–
9229. (d) Singh, A.; Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 5866–
5867. (e) Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286–287.
(5) Tius, M. A.; Chu, C. C.; Nieves-Colberg, R. Tetrahedron Lett. 2001,
42, 2419–2422.
(6) Suarez-Pantiga, S.; Rubio, E.; Alvarez-Rua, C.; Gonzalez, J. M. Org.
Lett. 2009, 11, 13–16.
Org. Lett., Vol. 12, No. 3, 2010
441

DMSO at room temperature. Diamines 19 and 20 led to
15 in 85/15 and 86/14 er’s, respectively, whereas diamines
21 and 22 gave enantiomeric ratios of 79/21 and 77.5/
22.5, respectively. Diamine 23 led to nearly racemic
product (er 53/47). Under optimized conditions of solvent
and concentration (0.1 M in MeCN containing 25 mol %
water), the mono-triflate salt of 19 led to 15 in 60% yield
and 97/3 er after 7.5 d at room temperature (Figure 2).
from the reaction of 11 with some secondary amines,
suggesting that aldehyde 30 was the primary product and
that air oxidation to 29 had taken place during the reaction.
The ꢀ-vinylic methyl group in 29 must have its origin as
the acetyl methyl group in 11. It is difficult to imagine a
means of forming the carbon-carbon bond between the
ꢀ-vinyl carbon atom and the acetyl methyl group of 11
unless the two are first joined in a ring. Scheme 5
Scheme 5
Figure 2. ORTEP diagram of 51, the ester derivative of 15 with
(-)-camphanic acid chloride. Ellipsoids are shown at the 50% level.
Selected bond lengths (Å): C(1)-C(2) 1.472(2), C(2)-C(3) 1.329(2),
O(1)-C(1) 1.2139(19). Selected bond angles (deg): C(3)-C(2)-C(1)
113.11(14),C(2)-C(3)-C(4)110.42(14),C(3)-C(4)-C(5)104.28(12),
C(1)-C(5)-C(4) 105.46(13).
summarizes our postulated mechanism. Alternative mech-
anisms involving the initial formation of an enamine-
iminium species similar to 13 that rationalize the formation
of 30 can also be imagined. Protonated keto enamine 31
can undergo Nazarov cyclization to 32. A series of proton
transfer steps converts 32 to 34. The cleavage step that
converts 34 to 35 can be thought of as a retro-Nazarov
reaction.10 Enol-keto conversion leads from 35 to 36.
Hydrolysis of 36 gives 30 and regenerates the catalyst
28. The origins of the differences in reactivity between
28 and 19 are difficult to rationalize.
Table 1 summarizes the results of the stoichiometric
reaction between the mono-triflate salt of 19 and a series
of diketones. The reactions are in all cases slow, requiring
approximately one week for completion. In the case of
products bearing R gem-dimethyl substitution (38, 40, 42,
and 44) the minor enantiomer was undetectable by chiral
HPLC. The cyclization is, however, delicately balanced
as indicated by the results with substrates 45, 47, and 49
that led to cyclic products of lower er in poor yield. These
reactions also led to the generation of numerous byprod-
ucts, rendering the purification of the cyclopentenones
difficult.
We were unable to find conditions that would allow 19
to function catalytically, either through inclusion of
additives9 or by varying the reaction conditions. Acid-
catalyzed liberation of the diamine from its bound form
is required, suggesting that product inhibition takes
place.
A catalytic process was observed with diamine 28;
however, this led to an unexpected product (Scheme 4).
Scheme 4
Exposure of 11 to 20 mol % of the mono-triflate salt of
28 in MeCN at room temperature overnight led to
R-ketoacid 29 in ca. 45% yield (unoptimized) along with
another unidentified dimeric product. R-Ketoacid 29 was
formed in variable yields along with R-ketoaldehyde 30
The absolute stereochemistry of 15 was determined
crystallographically from the (1S)-(-)-camphanic acid
chloride derivative 51 (Figure 2). Ester 51 crystallizes in
(10) (a) Harmata, M.; Lee, D. R.; Barnes, C. L. Org. Lett. 2005, 7, 1881–
1883. (b) Harmata, M.; Schreiner, P. R.; Lee, D. R.; Kirchhoefer, P. L.
J. Am. Chem. Soc. 2004, 126, 10954–10957. (c) Harmata, M.; Lee, D. R.
J. Am. Chem. Soc. 2002, 124, 14328–14329.
(9) The following additives were evaluated: silica gel, alumina (neutral,
basic, acidic), CuCl2, LiCl, LiClO4, aq NH4OH.
442
Org. Lett., Vol. 12, No. 3, 2010

R-hydroxycyclopentenones shown in Table 1 has been
assigned by analogy with 15. The inversion in chromato-
graphic mobility that was observed for the enantiomers
of 44 and 50 may indicate an inversion of the stereo-
chemical preference in these cases, or it may be due to a
unique interaction of these two cyclopentenones with the
chiral stationary phase.12
Table 1. R-Hydroxycyclopentenones from the Nazarov Reaction
(All Reactions Were Performed in Acetonitrile at 0.1 M with 25
mol % Water and 1.05 equiv of the Mono-triflate Salt of 19)
In summary, we have described an iminium ion mediated
asymmetric Nazarov cyclization of R-diketones through a
mechanism requiring the formation of an enamine-iminium
ion.13 To the best of our knowledge this represents only the
third example of an imino Nazarov cyclization. Although
the process is not catalytic at its present level of development,
the results suggest a number of ways to overcome the
problem of product inhibition. The excellent enantioselec-
tivities provide an impetus to do so.
Acknowledgment. We thank the National Institutes of
Health (GM57873) for generous support. We thank Mr.
Paolo Larini (Universita` degli Studi di Torino) for his
contribution to this work.
Supporting Information Available: Experimental pro-
1
cedures for 15 and 19; H and 13C NMR, HRMS, and IR
data for 19, 40, 42, 48, and 50; HPLC and optical rotations
1
for 15, 19, 38, 42, 44, 46, 48, 50; reproductions of H and
13C NMR spectra for 15, 19, 38, 40, 42, 44, 46, 48, and 50.
Crystallographic data for 51 and for the (-)-camphanic acid
derivative of 38. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL9025765
(11) Flack, H. D. HelV. Chim. Acta 2003, 86, 905–921.
(12) Crystallographic data for the (-)-camphanic acid derivative of 38
show that the absolute stereochemistry of 38 is the same as 15. See
Supporting Information.
(13) A referee has suggested that the mechanism that we have
proposed may in fact be better described as an “intramolecular enamine-
Michael addition to enone”. We think that this is unlikely for two reasons.
First, such a process would correspond to a 5-endo-trig reaction that is
disfavored by Baldwin’s Rules. Second, if the reasonable assumption is
made that the rate-limiting step is the ring-forming step, then one would
have expected a very large difference in rate for the cyclizations leading
to 15 and to 38. Since the enamine derived from 37 is ꢀ,ꢀ-disubstituted
it is a much poorer Michael donor than the unsubstituted enamine derived
from 11 and would be expected to react at a significantly slower rate.
No difference in reaction rate was evident for the cyclizations of 11
and 37.
a Enantiomer ratios were determined by chiral HPLC with a Chiralcel AD-H
column. b Yields in parentheses are based on recovered diketone. c Volatile
solid. d Sequence of elution of major and minor enantiomers was inverted.
space group P21, which is compatible with chiral crystal
structures.11 The absolute stereochemistry of the other
Org. Lett., Vol. 12, No. 3, 2010
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