Catalyst-based control of [2,3]- and [3,3]-rearrangement in α-diazoketone-derived propargyloxy enols

Full text of DOI:10.1021/ja015727h

J. Am. Chem. Soc. 2001, 123, 5095-5097
5095
Communications to the Editor
Scheme 1
Catalyst-Based Control of [2,3]- and
[3,3]-Rearrangement in r-Diazoketone-Derived
Propargyloxy Enols
George A. Moniz and John L. Wood*
Sterling Chemistry Laboratory, Department of Chemistry
Yale UniVersity, New HaVen, Connecticut 06520-8107
ReceiVed February 27, 2001
ReVised Manuscript ReceiVed March 26, 2001
Recent studies in these laboratories have revealed that R-di-
azoketones (e.g., 1) undergo rhodium(II)-catalyzed coupling with
alcohols to selectively deliver (Z)-alkoxy enols (e.g., 3, Scheme
1).1,2 When generated under these neutral conditions, alkoxy enols
are sufficiently stable to enable their manipulation in a number
of synthetically useful ways. In particular, we have been interested
in the sigmatropic chemistry of enols derived from allylic alcohols,
which undergo exceptionally facile Claisen rearrangement to
furnish tertiary R-hydroxy carbonyl compounds.1-3 Recently, we
reported the extension of this tandem enol formation/Claisen
process to furnish tertiary R-hydroxy allenes.2,4 In that study, it
was found that the standard Claisen conditions, when applied to
propargylic alcohols, also gave rise to a byproduct derived from
an apparent [2,3]-rearrangement (e.g., 5, Scheme 1). Furthermore,
the amount of 5 coproduced was dependent both on catalyst load
and ligand. In this communication, we describe investigations that
establish the [2,3]-rearrangement as a versatile, Lewis acid-
catalyzed process that can be selectively promoted or suppressed.
In addition, enantioselective [2,3]-rearrangement can be realized
using a chiral Lewis acid promoter.
Scheme 2
Extensive catalyst screening further clarified the relationship
between catalyst structure and reaction course (i.e., 1f4 vs 1f5,
Scheme 1), revealing a substantial dependence on electronics (cf.,
Rh2(cap)4 vs Rh2(tfa)4).5,6 However, at the outset, it was unclear
if the observed catalyst dependence derived from perturbation of
the primary sigmatropic event or catalysis of a secondary [1,2]-
R-ketol rearrangement (i.e., 4f5, Scheme 1). Our studies with
allyloxy enols, which undergo [3,3]-rearrangement regardless of
the Rh(II) catalyst employed, first led us to speculate that the
latter process was more likely. In an effort to substantiate this
hypothesis, we devised the isotope-labeling study shown in
Scheme 2.
Scheme 3
Diazoketone 1 was combined with 3-butyn-2-ol (2) under both
[3,3]-selective (i.e., Rh2(cap)4) and [2,3]-selective (i.e., Rh2(tfa)4)
conditions. Incorporated in each reaction was the independently
prepared, deuterium-labeled analogue of the unanticipated re-
gioisomer. Use of Rh2(tfa)4 in the presence of D-4 gave rise to
the apparent [2,3]-product 5 free of deuterium incorporation.
Similarly, use of Rh2(cap)4 in the presence of D-5 gave exclusively
protic [3,3]-product 4, illustrating that the anticipated [1,2]-R-
ketol rearrangement process was not operative.
Having demonstrated that rearrangement products 4 and 5 arise
via independent pathways, we began to favor a mechanism
wherein the rhodium(II) catalyst adopts a dual role, promoting
both enol formation and [2,3]-rearrangement. In this scenario,
coordination of Rh(II) to the enol ether oxygen promotes an SNI′
process (Scheme 3). Attenuating the Lewis acidity of the Rh(II)
catalyst (i.e., Rh2(cap)4 vs Rh2(tfa)4) would therefore be expected
to slow this process, enabling thermal [3,3]-rearrangement to
predominate. Initial support for this hypothesis was found in the
reaction kinetics, which showed that [2,3]-rearrangement of 3 in
the presence of 0.1 mol % Rh2(tfa)4 (t1/2 ) 5.4 min, 25 °C) was
dramatically accelerated relative to that in the presence of 1 mol
% Rh2(OAc)4 (t1/2 ) 3.5 h, 40 °C). To demonstrate that this rate
enhancement derived from interaction of the enol with Rh(II),
we treated a solution of 1 and 2 (1.2 equiv) with 1 mol % Rh2-
(1) Wood, J. L.; Moniz, G. A.; Pflum, D. A.; Stoltz, B. M.; Holubec, A.
A.; Dietrich, H.-J. J. Am. Chem. Soc. 1999, 121, 1748.
(2) Wood, J. L.; Moniz, G. A. Org. Lett. 1999, 1, 371.
(3) Wood, J. L.; Holubec, A, A.; Stoltz, B. M.; Weiss, M. M.; Dixon, J.
A.; Doan. B. D.; Shamji, M. F.; Chen, J. M.; Heffron, T. P. J. Am. Chem.
Soc. 1999, 121, 6326.
(4) For recent synthetic applications of allenes, see: (a) Wan, Z.; Nelson,
S. G. J. Am. Chem. Soc. 2000, 122, 10470. (b) Jonasson, C.; Horvath, A.;
Backvall, J.-E. J. Am. Chem. Soc. 2000, 122, 9600. (c) Wender, P. A.; Zhang,
L. Org. Lett. 2000, 2, 2323.
(5) For a discussion of the electron-rich nature of the Rh2(cap)4 catalyst,
see: Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.; Boone,
W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958.
(6) For discussions of the electron-deficient nature of the Rh2(tfa)4 catalyst,
see: (a) Doyle, M. P.; Colsman, M. R.; Chinn, M. S. Inorg. Chem. 1984, 23,
3684. (b) Davies, H. M. L. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol 4, p 1031. (c)
Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1797.
1
(OAc)4, cleanly generating enol 3 (Scheme 4, observed by H
10.1021/ja015727h CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/08/2001

5096 J. Am. Chem. Soc., Vol. 123, No. 21, 2001
Communications to the Editor
Table 2. Examples with Monostabilized R-Diazoketones11
Scheme 4
Table 1. Examples with Doubly Stabilized R-Diazoketones11
a Conditions A: 0.25 mol % Rh2(cap)4, PhH, reflux, 10 min.
b Conditions B: 5 mol % Rh2(oct)4, PhH, reflux, 10 min. c 20 mol %
Rh2(oct)4 was employed. d An 11% yield of enone i (ref 10) was also
isolated. e A 5% yield of enone ii (ref 10) was also isolated. f Only
enone ii (ref 10) was isolated in 25% yield.
Table 3. Effect of Lewis Acid Additives on Rearrangement of
Enol 3a
Lewis acid additive/conditions
no additive, PhH, ∆, 10 min
1 equiv CuSO4, PhH, ∆, 10 min
5 mol % AgBF4, PhH, rt, 2 min
15 mol % [Sn-((S,S)-Ph-pybox)](OTf)2 (9),
CH2Cl2, rt, 35 min
5:4b
yield, %
1:2.3
2.5:1
60:1
78
70
80
76
a Conditions A: 0.5 mol % Rh2(cap)4, PhH, reflux, 10 min.
b Conditions B: 0.25 mol % Rh2(tfa)4, PhH, 10 min rt (1) or reflux
(6). c A 44% yield of tautomerized product was also isolated. d An 83%
yield of tautomerized product was isolated exclusively.
>100:1
2.5 mol % [Cu-((S,S)-Ph-pybox)](OTf)2 (10), >100:1
PhH, rt, 5 min
67
a Generated in all cases by treatment of 1 and 2 with 1 mol %
NMR).7 Treatment of the enol solution with 0.5 mol % Rh2(tfa)4
resulted in rapid [2,3]-rearrangement at room temperature, a
process that could be completely suppressed by prior addition of
dimethyl sulfide (2 equiv) to yield only [3,3]-rearrangement
product 4 upon heating.8
1
Rh2(OAc)4, rt, 5 min. b Ratios determined by integration of H NMR
resonances.
substrates due to a substituent-controlled reduction in [3,3] rate.2
However, this competition is not observed with [2,3]-rearrange-
ment. Reduced yields are observed for both processes with
2-methyl-3-butyn-2-ol (cf., entries 4a,b) due to inefficient car-
benoid capture.10
The determination that Rh2(tfa)4 was functioning in a Lewis
acidic capacity to facilitate [2,3]-rearrangement led to an inves-
tigation of other Lewis acid additives for similar activity. As can
be seen in Table 3, enol 3 is successfully intercepted by several
Lewis acids, including (pybox)-Sn(II) (9) and (pybox)-Cu(II) (10)
catalysts which afford, at room temperature and with low catalyst
loadings, the [2,3]-product (5) via a three-step, two metal-
catalyzed process.12
The success of Lewis acids 9 and 10 prompted us to explore
the possibility of asymmetric induction in the [2,3]-rearrangement
(Scheme 5). We were delighted to find that treatment of
R-diazoketone 1 and propargyl alcohol (1.2 equiv) with 1 mol %
Rh2(OAc)4 affords enol 11, which, upon treatment with [Cu(S,S)-
Ph-pybox(H2O)2](OTf)2 (12), affords (R)-13 in 61% yield13 and
Having established the basis for the divergent reactivity of enol
3, we explored our ability to manipulate reaction outcome in
related substrates. As shown in Tables 1 and 2, similar control
can be achieved with a number of R-diazoketones and propargylic
alcohols affording a variety of substituted allenes in good to
excellent yield. With doubly stabilized R-diazoketones (i.e., 1 and
6), use of Rh2(tfa)4 affords exclusively the product of [2,3]-
rearrangement. Use of Rh2(cap)4 generates the [3,3]-product with
1; however, this catalyst does not efficiently dediazotize 6. The
identical conditions (Rh2(cap)4, benzene, reflux) are employed
to effect exclusive [3,3]-rearrangement with monostabilized
R-diazoketones (i.e., 7 and 8, Table 2), while the harsher Rh2-
(tfa)4 catalyst is replaced by a higher catalyst loading of the more
mild Rh2(oct)4 to furnish the [2,3]-product.9 In accord with our
studies of allyloxy enols, tautomerization of propargyloxy enols
is observed to compete with [3,3]-rearrangement in certain
(7) <10% [2,3]-rearrangement of enol 3 is observed after 1 h in the presence
of 1 mol % Rh2(OAc)4 at 25 °C.
(11) The structure assigned to each compound is in accord with its infrared
and high-field 1H (500 MHz) and 13C (125 MHz) NMR spectra as well as
with appropriate parent ion identification by high-resolution mass spectrometry.
(12) For the preparation of bis(oxazolinyl)pyridine catalysts 9 and 10, see:
(a) Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J. Am. Chem. Soc.
1997, 119, 10859. (b) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey,
C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999,
121, 669.
(13) (S)-(-)-15 is isolated as a byproduct of this reaction (30% yield);
however, isotope-labeling studies prove that 15 is not derived from 13 (see
Supporting Information). Rather, it is believed to arise from the same complex
14 via a proton-transfer event.
(8) This catalyst inhibition experiment illustrates the Rh(II)-dependent
nature of the [2,3]-rearrangement and the catalyst independence of the [3,3]-
rearrangement. The selection of dimethyl sulfide was based on the large Keq
reported for binding of tetrahydrothiophene to Rh2(but)4, see: Drago, R. S.;
Bilgrien, C. J. Polyhedron 1988, 7, 1453.
(9) Use of Rh2(tfa)4 with monostabilized R-diazoketones leads, in general,
to intractable mixtures of products. The Rh2(oct)4 catalyst is electronically
similar to Rh2(OAc)4 with solubility equivalent to Rh2(tfa)4.
(10) The principal byproduct in reactions with 2-methyl-3-butyn-2-ol is
the corresponding (Z)-enone (e.g., i, ii) which arises via â-hydride elimination
of the uncaptured carbenoid, see: Taber, D. F.; Herr, R. J.; Pack, S. K.;
Geremia, J. M. J. Org. Chem. 1996, 61, 2908.

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 21, 2001 5097
Scheme 5
In summary, we have shown that (Z)-propargyloxy enols are
capable of undergoing rearrangement to allenyl R-hydroxyketones
via thermal [3,3]-rearrangement and Lewis acid-catalyzed [2,3]-
rearrangement pathways. The latter has proven amenable to
asymmetric catalysis, affording [2,3]-rearrangement product in
good yield and high % ee. Further studies into asymmetric
catalysis of the [2,3]-rearrangement and the chemistry of alkoxy
enols are in progress.
Acknowledgment. We are pleased to acknowledge the support of
this investigation by Bristol-Myers Squibb, Eli Lilly, Glaxo-Wellcome,
Yamanouchi, Merck, Pfizer, and Zeneca through their Faculty Awards
Programs and the Camille and Henry Dreyfus Foundation through a
Teacher-Scholar Award. G.A.M. thanks Bristol-Myers Squibb for a
graduate fellowship. J.L.W. is a fellow of the Alfred P. Sloan Foundation.
The authors are grateful to Professor David A. Evans for helpful
discussions.
Supporting Information Available: Spectral data, experimental data,
and stereochemical proofs pertaining to all products illustrated in Schemes
2, 4, and 5 and Tables 1 and 2 as well as details regarding the computation
of complex 14 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 1. Computational structure of enol complex 14.
90% ee. The sense of stereochemical induction is predicted by
enol complex 14 (Figure 1), which represents the calculated global
minimum conformation of this complex by Monte Carlo methods,
further minimized by PM3 level calculations.14,15
JA015727H
(14) This stereochemical model is based upon those of Evans and
co-workers, see: Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S.
W. J. Am. Chem. Soc. 1999, 121, 686.
(15) The opposite enantiomer, (S)-(-)-13, can be prepared using the [Cu-
(R, R)-Ph-pybox(H2O)2](OTf)2 catalyst in equivalent yield and enantiomeric
excess.