Catalytic asymmetric intermolecular stetter reaction of heterocyclic aldehydes with nitroalkenes: Backbone fluorination improves selectivity

Article abstract of DOI:10.1021/ja904375q

(Chemical Equation Presented) The catalytic asymmetric intermolecular Stetter reaction of heterocyclic aldehydes and nitroalkenes has been developed. We have identified a strong stereoelectronic effect on catalyst structure when a fluorine substituent is

Full text of DOI:10.1021/ja904375q

Published on Web 07/16/2009
Catalytic Asymmetric Intermolecular Stetter Reaction of Heterocyclic
Aldehydes with Nitroalkenes: Backbone Fluorination Improves Selectivity
Daniel A. DiRocco, Kevin M. Oberg, Derek M. Dalton, and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received May 29, 2009; E-mail: rovis@lamar.colostate.edu
a b
,
The Stetter reaction utilizes the Umpolung1 reactivity of alde-
hydes, the inversion of their normal mode of reactivity, to give
rise to acyl-anion equivalents capable of participating in 1,4-
conjugate additions with a variety of Michael acceptors.2 Following
a seminal report by Enders3 on the asymmetric version, our group
has reported extensive investigation on the asymmetric intra-
molecular Stetter reaction.4 Although the intramolecular version
of this reaction has been rendered highly enantioselective, advances
in the asymmetric intermolecular reaction have only recently been
reported.5 Enders and co-workers described an asymmetric inter-
molecular Stetter using aryl aldehydes with chalcones as Michael
acceptors.6 Independently and concurrently, we reported the use
of glyoxamides in conjuction with alkylidene malonates to afford
Stetter products in high yields and high enantiomeric excess.7
Chart 1. Catalyst Screen
As part of our efforts to improve this method, we envisioned
that nitroalkenes may serve as viable Michael acceptors in the Stetter
reaction based on their high reactivity toward conjugate addition.8,9
The corresponding ꢀ-nitro ketones derived from this transformation
are also highly attractive intermediates, which can be derivatized
into many synthetically useful compounds due to the versatility of
the nitro group.10
a Reactions conducted with 1 equiv of 1a and 1.5 equiv of 2a at 0 °C.
b Enantiomeric excess determined by HPLC analysis on a chiral stationary
phase. BF4 counterions omitted for clarity.
triazolium salt 9 displays decreased reactivity with no apparent
change in enantioselectivity compared to the nonfluorinated ana-
logue 6.
We began our investigation by reacting the nucleophilic coupling
partner picolinaldehyde 1a with ꢀ-substituted nitroalkene 2a in the
presence of triazolium salt 4 and Hu¨nig’s base. A brief solvent
screen revealed methanol to be optimal, providing the desired
ꢀ-nitro ketone 3a in a promising 82% yield and 74% ee (Chart
1).11 Using a slight excess of nitroalkene at 0 °C provides better
yields while ensuring the integrity of the newly formed stereocenter.
Under these conditions, catalysts lacking the C6F5 N-aryl substituent
prove inactive while morpholinyl-based catalyst 5 is less effective
(Chart 1). These results prompted us to initiate a new exploration
of catalyst design in hopes of increasing the enantioselectivity of
this transformation.
To better understand these differences, we analyzed the triazolium
salts by X-ray crystallography. Triazolium salt 6 unambiguously
displays a Cγ-endo ring pucker (Figure 1), placing the isopropyl
group in a lower energy pseudoequatorial position thereby minimiz-
ing 1,3-diaxial interactions. In contrast, X-ray analysis of cis-
fluorinated triazolium salt 8 shows a Cγ-exo ring pucker that cannot
be rationalized by steric arguments (Figure 1). We suggest the
switch in conformational preference is due to multiple stereoelec-
tronic effects that overcome the inherent steric bias for the Cγ-
endo conformation.14
Since bicyclic triazolium salt 4 gives good yield and enantio-
selectivity, we hypothesized that increasing the steric environment
near the reactive center would improve enantioselectivity without
a substantial loss in reactivity. Triazolium salt 6, derived from
L-valine, generates the desired product in 90% yield and 88% ee
(Chart 1). Further modification of the steric environment to a larger
tert-butyl substituent produces only trace amounts of products.
Calculations by Raines et al. suggest that the exo/endo conforma-
tions of 3-fluoroprolines can be stabilized by energies up to 2 kcal/
mol due to a gauche effect.15 The gauche effect arises from the
preference of electron-withdrawing substituents to orient themselves
gauche to one another. This orientation maximizes σ-σ* hyper-
conjugative interactions, leading to a lower energy conformer.16
A
Newman projection analysis of the C3-C4 bond of the triazolium
salt shows clear orbital alignment of the σ*C-F with an adjacent σ
Given the plateauing effects of increasing the steric bulk, we
turned our attention to manipulating the conformation by electronic
tuning of the backbone. Inspired by conformational effects induced
by fluorine substitution on pyrollidine ring systems,12 we sought
to investigate the role that fluorine substitution would have on our
bicyclic triazolium salts.13
bonding orbital (Figure 1). Likewise, a stabilizing gauche
C-H
conformation of the triazolium ring system with the C-F bond is
also present in the favored Cγ-exo pucker (Figure 1). A combination
of these interactions is likely the reason for a complete switch in
conformational preference.17
The use of fluorinated triazolium salt 8 under these conditions
shows increased reactivity and enantioselectivity as compared to
the nonfluorinated analogue, producing the desired ꢀ-nitro ketone
in 95% yield and 95% ee (Chart 1). Conversely, fluorinated
To gain further insight into this effect, the corresponding trans-
fluorinated triazolium salt 9 was also analyzed. If the proposed
stereoelectronic effects are dependent on the stereochemistry of the
fluorine substituent, then the trans-fluorinated analogue should favor
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10.1021/ja904375q CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Figure 1. Conformational analysis of fluorine-modified and nonmodified triazolium salts. Conformations determined by X-ray analysis; BF4 counterion
omitted for clarity. φ and ψ ) torsion angles (φ ) C5-N1-C2-C3; ψ ) N1-C5-C4-C3).
the Cγ-endo ring pucker, opposite its epimeric partner. Indeed,
X-ray analysis confirms a preference for the Cγ-endo conformer,
supporting our hypothesis (Figure 2).
The scope of this transformation was examined using the
fluorine-modified triazolium scaffold 8, which shows remarkable
a b
,
Chart 2. Reaction Scope
Figure 2. X-ray analysis of 9. Conformations determined by X-ray analysis;
BF4 counterion omitted for clarity. φ and ψ ) torsion angles (φ )
C5-N1-C2-C3; ψ ) N1-C5-C4-C3).
reactivity and enantioselectivity toward a variety of heterocyclic
aldehydes and alkyl-substituted nitroalkenes (Chart 2).18 Five- and
six-membered heterocyclic aldehydes participate with good to
excellent yield and ee. Secondary alkyl substitution of the nitro-
alkene provides high yield and excellent ee, while primary
substitution results in somewhat reduced selectivities. In all cases,
the fluorine-modified triazolium salt outperforms the nonfluorinated
analogue in terms of enantioselectivity.
It should be noted that the difference in energy between
diastereomeric transition states that corresponds to an increase from
86% ee to 96% ee amounts to 2.98 kJ/mol at 0 °C (Chart 2, 3d),
more than one-third of the energy required to go from 0% ee to
95% ee (8.03 kJ/mol).19 We propose the increase in enantioselec-
tivity in our system is due to the conformational change in the
bicyclic ring system, which we have fashioned through the use of
stereoelectronic effects. This further orients the incoming nitroalkene
electrophile to improve enantiofacial discrimination (Figure 3).
Figure 3. Proposed transition state model. Absolute stereochemistry
determined by X-ray analysis. See Supporting Information.
If the above hypothesis is true, it stands to reason that fluorination
alone is responsible for conformation in the five-membered ring
and may result in a measurable bias in enantiofacial preference as
the sole stereocontrol element. With this in mind, we synthesized
a Numbers in parentheses are ee’s obtained using precatalyst 6. b Enantiomeric
excess determined by HPLC analysis on a chiral stationary phase.
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C O M M U N I C A T I O N S
(c) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407–496. (d)
Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632–2634. (e) Enders,
D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606–5655. (f) Rovis,
T. Chem. Lett. 2008, 37, 2–7.
precatalyst 10. As the atomic radius of fluorine is 1.47 Å, only
∼20% larger than hydrogen (1.20 Å), and less than 75% of the
size of a methyl group (2.00 Å), it has been used extensively as a
hydrogen surrogate.20,21 Discounting the small steric influence of
the fluorine atom, chirality should arise from the conformation
dictated by stereoelectronic effects alone. Triazolium salt 10
provides moderate enantioselectivity (65% ee, 3.6 kJ/mol) of the
desired product when used in the Stetter reaction and further
supports our hypothesis (Figure 4). X-ray analysis of 10 confirms
that the Cγ-exo ring pucker found in 8 is also present.
(3) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. HelV. Chim. Acta 1996,
79, 1899–1902.
(4) Read de Alaniz, J.; Rovis, T. Synlett. 2009, 1189–1207. For the syntheses
of triazolium salts, see: Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org.
Chem. 2005, 70, 5725–5728. For other contributions, see: (a) Pesch, J.;
Harms, K.; Bach, T. Eur. J. Org. Chem. 2004, 2025–2035. (b) Mennen,
S. M.; Blank, J. T.; Tran-Dube, M. B.; Imbriglio, J. E.; Miller, S. J. Chem.
Commun. 2005, 195–197. (c) Matsumoto, Y.; Tomioka, K. Tetrahedron
Lett. 2006, 47, 5843–5846.
(5) (a) Enders, D.; Breuer, K. ComprehensiVe Asymmetric Catalysis; Springer:
Berlin, 1999; 1093-1104. (b) Enders, D.; Balensiefer, T. Acc. Chem. Res.
2004, 37, 534–541.
(6) (a) Enders, D.; Han, J.; Henseler, A. Chem. Commun. 2008, 3989–3991.
(b) Enders, D.; Han, J. Synthesis 2008, 3864–3868.
(7) Liu, Q.; Perreault, S.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 14066–
14067.
(8) (a) For a review, see Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877–1894. (b) Barrett, A. G. M.; Graboski, G. G. Chem.
ReV. 1986, 86, 751–762.
(9) Scheidt has reported a single example of the asymmetric conjugate addition
of a stoichiometrically generated acyl anion equivalent to nitroalkenes
mediated by a thiourea; see: Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.;
Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4932–4933.
(10) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York,
2001.
(11) Other solvents: PhMe (trace), THF (trace), EtOH (59%, 70% ee).
(12) Eberhardt, E. S.; Panasik, N., Jr.; Raines, R. T. J. Am. Chem. Soc. 1996,
118, 12261–12266.
(13) Fluorine substitution on catalyst frameworks has occasionally resulted in
improved selectivities, with explanations rarely given. (a) A C2-symmetric
difluoro-pyrrolidine derivative has been shown to be a moderately effective
ligand in the asymmetric epoxidation of an allylic alcohol: Marson, C. M.;
Melling, R. C. J. Org. Chem. 2005, 70, 9771–9779. (b) 4-Fluoroproline
has been demonstrated to provide improved selectivities in transannular
aldols. Chandler, C. L.; List, B. J. Am. Chem. Soc. 2008, 130, 6737–6739.
(c) It has recently been argued that a fluorine substituent improves iminium
ion geometry in asymmetric epoxidation of unsaturated aldehydes. Sparr,
C.; Schweizer, W. B.; Senn, H. M.; Gilmour, R. Angew. Chem., Int. Ed.
2009, 48, 3065–3068.
(14) We are aware of the caveats associated with solid-state analysis of a
precatalyst; however, these arguments are self-consistent and rationalize
the observed results.
(15) Hodges, J. A.; Raines, R. T. J. Am. Chem. Soc. 2005, 127, 15923–15932.
(16) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry; Perga-
mon Press: New York, 1983.
(17) Another hyperconjugative effect that cannot be ruled out is a π to σ*C-F
interaction. Schaefer et al. reported that fluorine in benzyl fluorides adopts
a perpendicular arrangement with respect to the aromatic ring, due to π
donation of the aromatic ring into the low lying σ*C-F. A similar effect
can be rationalized for our system where hyperconjugation can only occur
from the observed Cγ-exo ring pucker. We believe this is unlikely due to
the developing positive charge in the azolium ring occurring in the transition
state of the C-C bond-forming event but may play a small role. See:
Schaefer, T.; Schurko, R. W.; Sebastian, R.; Hruska, F. E. Can. J. Chem.
1995, 73, 816–825.
(18) Benzaldehyde fails to participate under these conditions. The reasons for
this are the subject of investigation in our laboratory. Evidence suggests
that the role of the heteroatom is not simply that of a proximal Lewis base
given that both pyridazine carboxaldehyde and furfural participate with
equal facility in spite of their very low basicity.
(19) Numerical comparison of ee values is problematic. Comparison of er values
can be equally problematic. For example, 3d is formed in 98:2 er with 8
and 93:7 er with 6, an apparent difference of 5 er points. However, a more
instructive comparison here would be 13:1 vs 49:1 for 3d.
(20) Bo¨hm, H. J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Mu¨ller, K.;
Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637–643.
(21) Bondi, A. J. Phys. Chem. 1964, 68, 441–451.
Figure 4. Examination of fluorinated triazolium salt 10. Conformations
determined by X-ray analysis; BF4 counterion omitted for clarity. φ and ψ
) torsion angles (φ ) C5-N1-C2-C3; ψ ) N1-C5-C4-C3).
In conclusion, we have designed a new NHC catalyst that renders
the desired intermolecular Stetter reaction of nitroalkenes and
heteroarylaldehydes highly efficient and enantioselective through
manipulation of stereoelectronic as well as steric effects. We believe
the use of stereoelectronic effects, as demonstrated here, will
become yet another powerful tool for the development of the next
generation of catalysts for asymmetric synthesis. Investigations into
the role that the aldehyde heteroatom plays in reactivity and
enantioselectivity are currently underway in our laboratory.
Acknowledgment. We thank NIGMS (GM72586) for support.
D.M.D. thanks NSF-LSAMP Bridge to the Doctorate Program.
D.M.D. and K.M.O. thank Oren Anderson and Susie Miller for
support and guidance. We thank Laura L. Kiessling and Ronald T.
Raines (UW Madison) for helpful discussions.
Supporting Information Available: Experimental procedures,
1
characterization, H/13C NMR spectra; CIF files for 6, 8, 9, 10, and
3m. This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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(2) (a) Stetter, H.; Schreckenberg, M. Angew. Chem., Int. Ed. Engl. 1973,
12, 81. (b) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 639–647.
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