Regioselectivities of (4 + 3) cycloadditions between furans and oxazolidinone-substituted oxyallyls

Article abstract of DOI:10.1021/ol1023745

The (4 + 3) cycloadditions of oxazolidinone-substituted oxyallyls and unsymmetrically substituted furans lead to syn regioselectivity when the furan has a 2-Me or 2-COOR substituent, while anti regioselectivity is obtained with a 3-Me or 3-COOR group. DFT calculations are performed to explain the selectivities. The reactivities and regioselectivities are consistent with the ambiphilic reactivity of amino-oxyallyls with furans.

Full text of DOI:10.1021/ol1023745

ORGANIC
LETTERS
2
010
Vol. 12, No. 23
506-5509
Regioselectivities of (4 + 3)
5
Cycloadditions between Furans and
Oxazolidinone-Substituted Oxyallyls
†
Andrew G. Lohse, Elizabeth H. Krenske,* Jennifer E. Antoline, K. N. Houk,*
,‡
†
,§
,†
and Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry, UniVersity of
Wisconsin, Madison, Wisconsin 53705, United States, School of Chemistry, UniVersity
of Melbourne, Victoria 3010, Australia, and Australian Research Council Centre of
Excellence for Free Radical Chemistry and Biotechnology, Department of Chemistry and
Biochemistry, UniVersity of California, Los Angeles, California 90095, United States
ekrenske@unimelb.edu.au; houk@chem.ucla.edu; rhsung@wisc.edu
Received October 1, 2010
ABSTRACT
The (4 + 3) cycloadditions of oxazolidinone-substituted oxyallyls and unsymmetrically substituted furans lead to syn regioselectivity when the furan
has a 2-Me or 2-COOR substituent, while anti regioselectivity is obtained with a 3-Me or 3-COOR group. DFT calculations are performed to explain
the selectivities. The reactivities and regioselectivities are consistent with the ambiphilic reactivity of amino-oxyallyls with furans.
The (4 + 3) cycloaddition of oxyallyls with dienes (Scheme
1
1
) is a useful route to seven-membered carbocycles. Theoretical
2
Scheme 1
.
Regioselectivities in (4 + 3) Cycloadditions of
Oxyallyls with Substituted Dienes
studies have examined the mechanisms of these cycloadditions,
which may be either stepwise or concerted depending on the
†
University of Wisconsin.
Australian Research Council Centre of Excellence for Free Radical
‡
Chemistry and Biotechnology.
§
University of California.
(
1) Reviews: (a) Harmata, M. Acc. Chem. Res. 2001, 34, 595–605. (b)
Harmata, M.; Rashatasakhon, P. Tetrahedron 2003, 59, 2371–2395. (c)
Hartung, I. V.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2004, 43, 1934–
1
949. (c) The designation (m + n) is used here in accordance with
groups X and M in 1. The use of a heteroatom-stabilized
oxyallyl, in particular an oxygen-, nitrogen-, or sulfur-derivative,
in conjunction with an unsymmetrical diene has often been
reported to provide high levels of regioselectivity (2-syn vs
Woodward-Hoffmann/IUPAC conventions for describing cycloadditions
based on the number of atoms, as opposed to the bracketed [m + n]
description that indicates numbers of electrons.
(
2) (a) Walters, M. A.; Arcand, H. R. J. Org. Chem. 1996, 61, 1478–
1486. (b) Cramer, C. J.; Barrows, S. E. J. Org. Chem. 1998, 63, 5523–
5532. (c) Cramer, C. J.; Barrows, S. E. J. Phys. Org. Chem. 2000, 13, 176–
186. (d) Cramer, C. J.; Harmata, M.; Rashatasakhon, P. J. Org. Chem. 2001,
66, 5641–5644. (e) Harmata, M.; Schreiner, P. R. Org. Lett. 2001, 3, 3663–
3665. (f) S a´ ez, J. A.; Arn o´ , M.; Domingo, L. R. Org. Lett. 2003, 5, 4117–
4120. (g) Arn o´ , M.; Picher, M. T.; Domingo, L. R.; Andr e´ s, J. Chem.sEur.
1,3
2-anti). However, there have to date been few systematic
studies of how the regioselectivity for a given class of
oxyallyl is influenced by the substituents on the diene.
J. 2004, 10, 4742–4749. (h) S a´ ez, J. A.; Arn o´ , M.; Domingo, L. R.
Tetrahedron 2005, 61, 7538–7545. (i) Krenske, E. H.; Houk, K. N.; Harmata,
M. Org. Lett. 2010, 12, 444–447.
We have previously reported a method for (4 + 3)
cycloadditions that commences with the oxazolidinone-
10.1021/ol1023745  2010 American Chemical Society
Published on Web 11/04/2010

The methodology in Scheme 2 has previously been applied
4,8
to a variety of asymmetric cycloadditions. Here we present
an experimental and theoretical study of the regioselectivity
of the achiral oxyallyl 5 toward unsymmetrical furans.
The cycloadditions of 5 with monosubstituted furans were
examined first. Methyl was chosen as a representative
electron-donating group, and COOMe or COOEt for the
electron-withdrawing group. Cycloadditions involving the
more electron-rich 2-methoxyfuran failed, due to competing
Scheme 2
.
(4 + 3) Cycloadditions of Allenamide-Derived
Oxyallyls
8
oxidation and decomposition. The measured regioselectivities
for cycloadditions of 5 with 7-12 are shown in Table 1.
a
Table 1. Cycloadditions of Oxyallyl 5 with Furans 7-12.
4
containing allenamide 3 (Scheme 2). Oxidation of 3 by
dimethyldioxirane (DMDO) in the presence of a furan
5
furnishes selectively the endo cycloadduct 4, and can be
performed successfully with either electron-rich (Me) or
electron-poor (COOR) groups on the furan. The cycloaddi-
tion is believed to involve the oxyallyl 5, and is promoted
2
by a Lewis acid (ZnCl ). We recently studied the electronic
structures of the oxyallyls by density functional theory
6
calculations on 6. They are zwitterions (unlike the parent
7
oxyallyl, which is a diradical ), and there is substantial
electron delocalization from the nitrogen onto the allyl group,
consistent with an iminium enolate structure. The (4 + 3)
cycloadditions of 5 and 6 with furan are calculated to be
concerted processes. Only the ECdN isomer of the oxyallyl
(
5-E, 6-E) is involved, because the ZCdN isomer (5-Z) is
destabilized by electrostatic repulsion between the oxygen
atoms, even when coordinated to ZnCl
2
.
a
4
.0 equiv of DMDO in acetone/CH
Cl
2 2
was added over 18 h via syringe
Cl
pump to a solution of the allenamide (concn 0.05 M) and furan in CH
2
2
(3) For (4 + 3) cycloadditions of donor-substituted oxyallyls, including
b
at -78 °C. Where applicable, 2.0 equiv of Lewis acid was used. 3.0 equiv
regioselective examples, see: (a) F o¨ hlisch, B.; Krimmer, D.; Gehrlach, E.;
Kaeshammer, D. Chem. Ber. 1988, 121, 1585–1594. (b) Murray, D. H.;
Albizati, K. F. Tetrahedron Lett. 1990, 31, 4109–4112. (c) Walters, M. A.;
Arcand, H. R.; Lawrie, D. J. Tetrahedron Lett. 1995, 36, 23–26. (d) Lee,
J. C.; Jin, S.; Cha, J. K. J. Org. Chem. 1998, 63, 2804–2805. (e) Harmata,
M.; Rashatasakhon, P. Synlett 2000, 1419–1422. (f) Beck, H.; Stark,
C. B. W.; Hoffmann, H. M. R. Org. Lett. 2000, 2, 883–886. (g) Myers,
A. G.; Barbay, J. K. Org. Lett. 2001, 3, 425–428. (h) Harmata, M.; Ghosh,
S. K.; Hong, X.; Wacharasindhu, S.; Kirchhoefer, P. J. Am. Chem. Soc.
c
of the furan was used, except for 7 and 9, where 6.0 equiv was used. Isomer
1
13
d
e
ratios were determined by H and/or C NMR. Isolated yield. NaClO
4
2
gave higher yields than ZnCl .
The cycloadditions were conducted either under thermal
conditions or in the presence of a Lewis acid (ZnCl or
NaClO ). Inclusion of the Lewis acid generally increased
2
2
003, 125, 2058–2059. (i) Harmata, M. AdV. Synth. Catal. 2006, 348, 2297–
4
2
306. (j) MaGee, D. I.; Godineau, E.; Thornton, P. D.; Walters, M. A.;
Sponholtz, D. J. Eur. J. Org. Chem. 2006, 3667–3680. (k) Chung, W. K.;
Lam, S. K.; Lo, B.; Liu, L. L.; Wong, W. T.; Chiu, P. J. Am. Chem. Soc.
the yield, but did not alter the regioselectivity. Surprisingly,
the regioselectivities for both the 2- and the 3-substituted
furans were found to be independent of the electronic
character of the substituent. Both 2-methylfuran (7) and
methyl 2-furoate (8) gave predominantly the syn cycload-
ducts, with syn:anti ratios of 86:14 and g95:5, respectively.
The 3-methylfuran (9) and ethyl 3-furoate (10) both gave
predominantly the anti cycloadducts, with syn:anti ratios of
22:78 and 9:91, respectively.
2
009, 131, 4556–4557.
(
4) For a review on allenamide chemistry, see: (a) Wei, L.-L.; Xiong,
H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773–782. For chemistry of
nitrogen-stabilized oxyallyls, see: (b) Xiong, H.; Hsung, R. P.; Berry, C. R.;
Rameshkumar, C. J. Am. Chem. Soc. 2001, 123, 7174–7175. (c) Xiong,
H.; Huang, J.; Ghosh, S. K.; Hsung, R. P. J. Am. Chem. Soc. 2003, 125,
1
2
1
2694–12695. (d) Rameshkumar, C.; Hsung, R. P. Angew. Chem., Int. Ed.
004, 43, 615–618. (e) Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005,
27, 50–51. (f) Antoline, J. E.; Hsung, R. P.; Huang, J.; Song, Z.; Li, G.
Org. Lett. 2007, 9, 1275–1278.
(5) We use the term “endo” to denote the relationship between the diene
The origins of these regioselectivities were investigated
with density functional theory calculations at the B3LYP/
unit and the oxyallyl oxygen in 4-syn/anti and the TSs leading to them.
Hoffmann has used the term “compact” to describe this geometry, see:
Hoffmann, H. M. R. Angew. Chem., Int. Ed. 1973, 12, 819-835.
9
10
6
-31G(d) level in Gaussian 03. Activation energies in
(
6) Krenske, E. H.; Houk, K. N.; Lohse, A. G.; Antoline, J. E.; Hsung,
R. P. Chem. Sci. 2010, 1, 387–392.
(
7) (a) Coolidge, M. B.; Yamashita, K.; Morokuma, K.; Borden, W. T.
(8) Antoline, J. E.; Hsung, R. P. Synlett 2008, 739–744
.
J. Am. Chem. Soc. 1990, 112, 1751–1754. (b) Ichino, T.; Villano, S. M.;
Gianola, A. J.; Goebbert, D. J.; Velarde, L.; Sanov, A.; Blanksby, S. J.;
Zhou, X.; Hrovat, D. A.; Borden, W. T.; Lineberger, W. C. Angew. Chem.,
Int. Ed. 2009, 48, 8509–8511.
(9) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Stephens,
P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994,
98, 11623–11627. (c) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988,
37, 785–789.
Org. Lett., Vol. 12, No. 23, 2010
5507

q
q
Figure 1
kcal/mol at 298.15 K and 1 mol/L.
. Transition states for the (4 + 3) cycloadditions of 5-E with substituted furans. Distances in Å, ∆H in kcal/mol at 0 K, ∆G in
1
4
CH Cl
2 2
were simulated by computing free energies of
and drops to -0.05e in the furoate ester TSs. The
solvation with the Conductorlike Polarizable Continuum
ambiphilicity of 5 distinguishes it from other synthetically
1
1
1-3
Model (CPCM). Transition states for the syn and anti
cycloadditions of 5-E with furans 7-10 were located (using
COOMe as a model for COOEt in 10). The TS geometries
useful oxyallyl derivatives such as 13 and 14
(Scheme
3), which are cationic, electrophilic species.
1
2
and activation energies are shown in Figure 1. The
cycloadditions are concerted but asynchronous processes.
Stepwise transition states were also located, but were at least
Scheme 3
.
Electrophilic Oxyallyl Cations
2
.6 kcal/mol higher in energy.
Three of the substituted furans are predicted to react more
easily than furan itself, which has an activation energy of
q
q
∆
H ) 6.4 kcal/mol (∆G ) 20.8 kcal/mol) (Supporting
Information). The oxyallyl is therefore ambiphilic toward
furans, although the Me substituent effect is quite small and
the ester substituent effect is relatively large. The energies
of the HOMO and LUMO of 5-E are calculated to lie
q
q
The calculated regioselectivities (∆∆H and ∆∆G ) in
Figure 1 predict the correct major product for each furan. In
spite of the ambiphilic character displayed in the reactivity
patterns, the transition states do all show more bonding at
the enolate terminus than the iminium terminus. The ester
group has a regiochemical preference consistent with elec-
tronic effects, while the regioselectivities observed for
methylfurans likely result from steric effects: for 2-methyl-
furan, the oxyallyl attacks the less substituted (5-) terminus,
while for 3-methylfuran, the favored anti TS avoids steric
hindrance involving the oxazolidinone (see TS-9-syn in
Figure 1). The regioselectivities are also the same as would
be expected for a diradical mechanism; however, all diradical
1
3
between those of furan. The presence of both an electron-
-
rich O atom and electron-withdrawing iminium group on
the central carbon confers both nucleophilic and electrophilic
character to the unsubstituted terminus (C ). There is,
ω
however, only a small degree of charge transfer in any of
the transition states. The oxyallyl is calculated to have a
charge of -0.14e in the transition state for reaction with
furan; this value increases to -0.17e for the methylfurans,
1
5
(
10) Frisch, M. J.; et al. Gaussian 03, Revision C.02, Gaussian, Inc.,
TSs that we have located lie at least 2.0 kcal/mol higher
than the closed-shell TSs.
Wallingford, CT, 2004. A complete citation is available in the Supporting
Information.
(
11) (a) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995–2001.
b) Barone, V.; Cossi, M.; Tomasi, J. J. Comput. Chem. 1998, 19, 404–
17.
12) Activation energies were calculated with respect to the oxazolidi-
From our investigation of cycloadditions of 5 with the 2,3-
disubstituted furans 11 and 12 (Table 1), both 11 and 12
(
4
(
none-substituted cyclopropanone isomer of 5-E, which is 5.2 kcal/mol more
stable than 5-E.
(14) Mulliken charges at the B3LYP/6-31G(d) level.
(15) Singlet diradicals were modeled with the guess)mix keyword in
Gaussian.
(
13) Orbitals were calculated at the HF/6-31G//B3LYP/6-31G(d) level.
5508
Org. Lett., Vol. 12, No. 23, 2010

yielded predominantly the syn cycloadducts, with selectivities
of g95:5. The syn-directing influence of the 2-substituent,
arising from steric and (for COOMe) electronic components,
is stronger than the anti-directing effect of the 3-substituent.
The selectivities are summarized in Scheme 4.
stituted furans incur a smaller distortion penalty in their syn
TS. This is supplemented, in the 2-COOMe case, by a
stronger interaction energy in the syn TS. The analysis for
the 3-substituted furans is less clear-cut. For 3-methylfuran,
both regioisomers have similar distortion energies, and the
balance is tipped in favor of the anti isomer by the interaction
energy. For 3-COOMe, the distortion energies strongly favor
the anti isomer, but the overall selectivity is small, because
the early anti TS has only a weak interaction between the
reactants. The anti preference becomes more pronounced
Scheme 4. Summary of Preferred Regioisomers
when entropic effects and solvation are taken into consid-
q
eration (∆∆G ) 2.0 kcal/mol in CH
2 2
Cl ).
(4 + 3) cycloadditions of donor-substituted oxyallyl
cations have often been calculated to occur by stepwise
pathways, with the oxyallyl cation exhibiting clearly elec-
2
trophilic behavior. Amino-substituted oxyallyls such as 5
are a distinct class of oxyallyl with ambiphilic properties.
Even for the achiral 5, an instantaneous facial selectivity is
present at the TS, which leads to the high anti selectivity
observed with 3-methylfuran. This steric feature, and their
relatively electron-rich character, provide oxazolidinone-
substituted oxyallyls with well-defined and unique regio-
chemical properties, leading to a coherent and predictive
model.
We have also analyzed the regioselectivities by computing
the distortion of the reactants and interactions that occur in
the transition states. In Table 2 are listed the distortion
Table 2. Distortion and Interaction Energies of Transition States
a
for Cycloadditions of 5-E with Furans
Acknowledgment. We thank the NIH and Australian
Research Council for generous financial support (GM-36700
to K.N.H., GM-66055 to R.P.H., and DP0985623 to E.H.K.)
and the NCSA, UCLA ATS, and NCI NF (Australia) for
computer resources. E.H.K. thanks the ARC Centre of
Excellence for Free Radical Chemistry and Biotechnology
for generous financial support. We also thank Dr. Vic Young
and Dr. Ben Kucera of The University of Minnesota for
X-ray crystallography.
Supporting Information Available: Experimental pro-
cedures, NMR spectra and characterizations for all new
compounds, B3LYP geometries, and energies. This material
is available free of charge via the Internet at http://pubs.acs.org.
a
b
q
q
q
Electronic energies in kcal/mol. ∆E predicts syn, but ∆H and ∆G
favor anti.
OL1023745
q
energies (∆E dist) and the energies of interaction between the
(16) (a) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2008, 130, 10187–
10198. (b) Hayden, A. E.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 4084–
q
distorted reactants at the TS (∆E int); these two quantities
add up to the activation energy ∆E . Both of the 2-sub-
4
089. (c) Schoenebeck, F.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 2496–
q
16
2497.
Org. Lett., Vol. 12, No. 23, 2010
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