Excess substrate is a spectator ligand in a rhodium-catalyzed asymmetric [2 + 2 + 2] cycloaddition of alkenyl lsocyanates with tolanes

Article abstract of DOI:10.1021/ol9020805

Excess substrate has been identified as an unintended spectator ligand affecting enantioselectivity In the [2 + 2 + 2] cycloaddition of alkenyl isocyanates with tolanes. Replacement of excess substrate with an exogenous additive affords products with cons

Full text of DOI:10.1021/ol9020805

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4934-4937
Excess Substrate is a Spectator Ligand
in a Rhodium-Catalyzed Asymmetric
[2 + 2 + 2] Cycloaddition of Alkenyl
Isocyanates with Tolanes
Mark Emil Oinen, Robert T. Yu, and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
roVis@lamar.colostate.edu
Received September 8, 2009
ABSTRACT
Excess substrate has been identified as an unintended spectator ligand affecting enantioselectivity in the [2 + 2 + 2] cycloaddition of alkenyl
isocyanates with tolanes. Replacement of excess substrate with an exogenous additive affords products with consistent and higher ee’s. The
increase in enantioselectivity is the result of a change in composition of a proposed rhodium(III) intermediate on the catalytic cycle. The net
result is a rational probe of a short-lived rhodium(III) intermediate and gives insight that may have applications in many rhodium-catalyzed
reactions.
The efficacy of transition-metal-catalyzed transformations
relies ultimately on the ability to fine-tune the chemical
environment of a metal catalyst in different ways. One can
alter catalyst activity both electronically and sterically by
manipulating the ligand environment, which can lead to
changes in product-, chemo-, regio-, and enantioselectivity.
Understanding the mechanistic details of these observed
changes can lead to synthetically useful solutions resulting
from manipulation of unobserved reaction intermediates.
Additives have been recognized as indispensible tools in an
effort “towards perfect asymmetric catalysis”.1 A handful
of reports describe changes in selectivity with the introduc-
tion of spectator (chiral or achiral) ligands, but the source
of these effects remains unaddressed.2,3 Herein, we describe
an extraordinary example of substrate-dependent enantiose-
lectivity in the [2 + 2 + 2] cycloaddition of tolanes and
alkenyl isocyanates. Investigation of this substrate depen-
dence implicated participation of excess alkyne as a spectator
ligand, a possibility that has not been recognized. This insight
inspired us to introduce an exogenous spectator ligand to
standardize enantioselectivity across a range of substrates.
The role of rhodium(III) coordination chemistry in the
enantioselectivity of this reaction suggests that manipulation
of these intermediates may improve other rhodium catalyzed
reactions.4
(2) Additives have been previously implicated as affecting enantiose-
lectivity as well as product selectivity of Rh-catalyzed processes. (a)
Duursma, A.; Hoen, R.; Schuppan, J.; Hulst, R.; Minnaard, A. J.; Feringa,
B. L. Org. Lett. 2003, 5, 3111. (b) Hoen, R.; Boogers, J. A. F.; Bernsmann,
H.; Minnaard, A. J.; Meetsma, A.; Tiemersma-Wegman, T.; de Vries,
A. H. M.; de Vries, J. G.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44,
4209. (c) Selvakumar, K.; Valentini, M.; Pregosin, P. S.; Albinati, A.
Organometallics 1999, 18, 4591. (d) Evans, P. A.; Nelson, J. D. Tetrahedron
Lett. 1998, 39, 1725.
(3) For reviews on the use of the use of both chiral and achiral pairs of
ligands, see: (a) Reetz, M. T. Angew. Chem., Int. Ed. 2008, 47, 2556. For
a supramolecular approach, see: (b) Breit, B. Angew. Chem., Int. Ed. 2005,
44, 6816.
(1) Vogl, E. M.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999,
38, 1570.
(4) Evans, P. A. Modern Rhodium-Catalyzed Organic Reactions; Wiley-
VCH: Weinheim, 2005.
10.1021/ol9020805 CCC: $40.75
Published on Web 10/05/2009
 2009 American Chemical Society

In the context of our recent studies on asymmetric
rhodium-catalyzed [2 + 2 + 2] cycloadditions involving
alkenyl isocyanates,5,6 we had occasion to study diarylacety-
lenes (tolanes). The advent of GUIPHOS (L1) proved crucial
for obtaining high enantioselectivities with product selectivity
favoring vinylogous amide adduct 3 (Figure 1).7
As a test of this hypothesis, we designed a competition
experiment between two different alkynes, which alone give
products of different ee (Figure 3). In this experiment, the
Figure 3. Alkyne competition experiment.
ee of 3a was affected by the presence of 2f in the reaction
mixture. This result is consistent with the presence of a second
alkyne during the enantiodetermining step (Figure 2).
During the course of these studies, we noted that electroni-
cally similar substrates 2e and 2f gave disparate enantiose-
lectivities presumably due to the Lewis basicity of the nitrile
and its ability to coordinate to rhodium. In an effort to
identify an exogenous additive that would not participate in
the cycloaddition, we hypothesized that weak Lewis bases
might be appropriate surrogates for alkynes in this reaction.
Indeed, both nitriles and pyridines affect enantioselectivity
(Figure 4). The more Lewis basic pyridine-type additives
Figure 1. Substrate-dependent enantioselectivity.
An initial substrate screen revealed extreme variation in
enantioselectivity (Figure 1). No linear trend was reconcilable
on the basis of either sterics or electronics. Sterically, the
para-substituent is much too distant to undergo through-space
interactions with either the ligand or the olefin-metal bond,
while electronic communication through π bonds is restricted
since the arene rings are likely bent out of coplanarity due
to strong A1,3 strain (I in Figure 2). Alternately, this variation
Figure 2. Potential diastereomeric olefin insertion precursors.
Figure 4. Additive enhancement of enantioselectivity.
may be explained by coordination of a second alkyne on an
octahedral rhodium(III) intermediate (II or III) rather than
a 5-coordinate intermediate (I) (Figure 2).8
Olefin insertion into the rhodacycle thus occurs through
several possible diastereomers via transition states whose
relative energy is affected by the close electronic and steric
communication with the spectator alkyne, leading to product
with variant ee’s.9
provide a larger increase in ee than nitriles, presumably a
reflection of their ability to out-compete alkynes for coor-
dination, with nicotinate 4d proving optimal. Furthermore,
(6) For reviews on [2 + 2 + 2] cycloadditions of alkynes, see: (a) Saito,
S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901–2915. (b) Agenet, N.;
Busine, O.; Slowinski, F.; Gandon, V.; Aubert, C.; Malacria, M. Org. React.
2007, 68, 1–302. (c) Tanaka, K. Synlett 2007, 1977–1993. (d) Galan, B. R.;
Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2830–2834. For reviews on
[2 + 2 + 2] cycloadditions of alkynes and nitrogen moieties, see: (e) Varela,
J. A.; Saa´, C. Chem. ReV. 2003, 103, 3787–3801. (f) Heller, B.; Hapke, M.
Chem. Soc. ReV. 2007, 36, 1085–1094. (g) Chopade, P. R.; Louie, J. AdV.
Synth. Catal. 2006, 348, 2307–2327.
(5) (a) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782. (b) Yu,
R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370. (c) Lee, E. E.; Rovis,
T. Org. Lett. 2008, 10, 1231. (d) Yu, R. T.; Rovis, T. J. Am. Chem. Soc.
2008, 130, 3262. (e) Yu, R. T.; Lee, E. E.; Malik, G.; Rovis, T. Angew.
Chem., Int. Ed. 2009, 48, 2379. (f) Friedman, R. K.; Rovis, T. J. Am. Chem.
Soc. 2009, 131, 10775. (g) Dalton, D. M.; Oberg, K. M.; Yu, R. T.; Lee,
E. E.; Perreault, S.; Oinen, M. E.; Pease, M. L.; Malik, G.; Rovis, T. J. Am.
Chem. Soc. 2009, 131, in press (DOI: 10.1021/ja905065j).
(7) TADDOL-PNMe2: 57%, 9% ee. MONOPHOS: 74%, 39% ee.
(8) A search of the Cambridge Crystallographic Database revealed 738
six-coordinate monomeric rhodium(III) complexes but only 106 five-
coordinate and three four-coordinate complexes.
Org. Lett., Vol. 11, No. 21, 2009
4935

this competition between additive vs alkyne as spectator
ligand is illustrated by the effect of the amount of additive
on enantioselectivity. At stoichiometric levels of additive high
ee’s are obtained at the expense of yield. At substoichiometric
levels of additive, changes in ee are noticeable but are not
optimal.10 Pyridine inhibits the reaction completely. At this
point, methyl nicotinate 4d was chosen as the additive to
optimize in the reaction, as it gave the highest levels of
enantioselectivity. To combat the decrease in yields using
methyl nicotinate, excess isocyanate was used. Although
nicotinate 4d is not consumed,11 it may lead to unwanted
side products (dialkyl ureas, carbamates, etc.) either by
slowing the reaction (vide infra), bringing in excess water
(due to its hygroscopic nature), or catalyzing potentially
unwanted side reactions.
additive acting as the sixth ligand on rhodium during the
olefin insertion event.
A competition experiment between two different alkenyl
isocyanates yields the respective products in a 1:1 ratio
(eq 1). This result suggests that the first irreversible step
does not involve the alkene and is consistent with our
proposed mechanism wherein the isocyanate, alkyne, and
rhodium initially engage in an oxidative cycloaddition
(Figure 3).14
Products from a series of tolanes were obtained in excellent
yields12 and enantioselectivities using these optimized reac-
tion conditions (Figure 5). The decrease in efficiency of some
Elucidation of this first irreversible step allowed us to
probe the composition of the complex undergoing oxidative
cyclization. By monitoring the disappearance of substrate,
we were able to determine that the reaction is first order in
alkyne, Figure 6.15 This data is consistent with an oxidative
Figure 6.
Consumption of 1n in cycloaddition as followed by 19F
NMR (presence and absence of 4d).
cyclization step occurring from a four-coordinate intermedi-
ate A rather than a five-coordinate intermediate B (Figure
7). The order of alkyne does not change in the presence of
additive.16
Figure 5. Tolane substrate scope in presence of additive.
(10) In the reaction of 1 and 2a with 3 mol % of Rh dimer and 6 mol
% of L1, the following results were obtained: 0 equiv of 4d ) 55%, 84%
ee; 0.05 equiv of 4d ) 53%, 86% ee; 0.4 equiv of 4d ) 52%, 91% ee; 0.8
equiv of 4d ) 45%, 93% ee; 1.6 equiv of 4d ) 32%, 93% ee.
(11) 1H NMR analysis of unpurified reaction mixtures shows good mass
balance of nicotinate remaining at the end of the reaction (92%).
(12) Excess isocyanate was used due to the increased formation of
dialkylureas in the presence of methyl nicotinate.
electron-deficient substrates with a given additive can be
attenuated by altering the basicity of the additive (see 3c,
Figure 5).13 With the exception of alkynes 2e and 2l, all
tolanes now produce adduct within a narrow window of
selectivity, suggesting that we have leveled the factors that
led to spurious results. This is most consistent with the
(13) Tolanes bearing pyridines or unprotected aldehydes are not
tolerated.
(14) For a discussion of the current proposed mechanism, see refs 5b
and 5g.
(15) The disappearance of alkyne 2n over time was followed by 19F
NMR. The linear shape of the graph indicates a first-order dependence on
alkyne (see the Supporting Information).
(9) A number of different diastereomeric intermediates may be envi-
sioned; those in Figure 1 are presented as reasonable suggestions.
4936
Org. Lett., Vol. 11, No. 21, 2009

the coordination environment of a metal and altering its
reactivity in the kinetically invisible regime after the first
irreversible step.
We have shown that excess substrate may act as an
unintended ligand on a Rh-catalyzed cycloaddition leading
to variant selectivities. In the presence of methyl nicotinate,
the influence of substrate electronics is attenuated. We
attribute this effect to a change in the ligand environment of
a presumably short-lived rhodium(III) intermediate. We
suggest these findings may have broad impact in other metal-
catalyzed transformations.
Acknowledgment. We thank the NIGMS (GM080442)
for support. T.R. thanks the Monfort Family Foundation for
a Monfort Professorship. We thank Johnson Matthey for a
generous loan of Rh salts. We thank Prof. Matthew Shores
(CSU) for helpful discussions.
Note Added after ASAP Publication. Footnotes for
Figures 1, 3, 4, 5 and equation 1 were missing in the version
published ASAP October 5, 2009; the correct version
published ASAP October 13, 2009.
Figure 7. Proposed mechanism and role of the additive.
Supporting Information Available: Experimental pro-
cedures, characterization, and 1H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In light of these observations, it is clear that the spectator
ligand is affecting the enantioselectivity after the oxidative
cyclization by modifying a Rh(III) intermediate, C or D, prior
to or during olefin insertion.17 Importantly, we are probing
OL9020805
(16) The slowing of the rate is also consistent with inhibition of the
oxidative cyclization by methyl nicotinate.
(17) No other intermediates were observed in the 31P or 19F spectra in
the course of the reaction.
Org. Lett., Vol. 11, No. 21, 2009
4937