Predictable and regioselective insertion of internal unsymmetrical alkynes in rhodium-catalyzed cycloadditions with alkenyl isocyanates

Article abstract of DOI:10.1021/ja903899c

A regioselective, rhodium-catalyzed cycloaddition between a variety of internal, unsymmetrical alkynes is described. We document the impact of both steric and electronic properties of the alkyne on reaction course, efficiency, and enantioselectivity. The

Full text of DOI:10.1021/ja903899c

Published on Web 07/01/2009
Predictable and Regioselective Insertion of Internal
Unsymmetrical Alkynes in Rhodium-Catalyzed Cycloadditions
with Alkenyl Isocyanates
Rebecca Keller Friedman and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received May 13, 2009; E-mail: rovis@lamar.colostate.edu
Abstract: A regioselective, rhodium-catalyzed cycloaddition between a variety of internal, unsymmetrical
alkynes is described. We document the impact of both steric and electronic properties of the alkyne on
reaction course, efficiency, and enantioselectivity. The substituent that better stabilizes a positive charge
or the larger group, all else being equal, inserts distal to the carbonyl moiety in a predictable and controllable
fashion. The reaction scope is broad and the enantioselectivities are high, providing an “instruction manual”
for substrate choice when utilizing this reaction as a synthetic tool.
Introduction
bination with a phosphine, gives rise to the formation of lactam
and vinylogous amide products dependent on the nature of the
Transition-metal catalyzed cycloadditions provide an efficient
route to complex carbocyclic and heterocyclic compounds.1 In
particular, reactions involving three π-components, such as
[2+2+2] cycloadditions, allow for access to many complex
molecules. The use of isocyanates as one π-component allows
for introduction of nitrogen functionality into the cycloadducts.2
The pioneering work of Yamazaki,3 Hoberg4 and Vollhardt5
on alkyne/isocyanate cycloadditions to form pyridones has
recently been furthered by Itoh6 and Louie.7 Asymmetric
pyridone-forming cycloadditions have appeared from the labo-
ratories of Tanaka.8
Building on these key precedents, all of which report
cycloadditions involving two alkynes as π components, we have
recently described the asymmetric, rhodium-catalyzed cycload-
dition between an isocyanate, tethered alkene and an exogenous
alkyne.9 Initial studies9a revealed that a catalyst formed from
rhodium bis(ethylene) chloride dimer [Rh(C2H4)2Cl]2, in com-
symmetrical alkyne. Further development9b led to the discovery
of successful reaction conditions employing TADDOL-phos-
phoramidite ligands (L1-L3, Figure 1), which allow the
reaction to proceed asymmetrically with terminal alkynes. We
have also shown that 1,1-disubstitution on the alkene is tolerated
in the reaction.9c The nature of the terminal alkyne (aryl or alkyl)
controls the product selectivity. Aryl groups and larger substitu-
tions tend to favor vinylogous amide product (4), while alkyl
and smaller substituents produce the lactam (3) as the major
product with the TADDOL-based ligands (L1-L3). We have
shown that a carbodiimide may be used in place of the
isocyanate, leading to a profound influence on product selectivity
due to their inherent steric bulk.9d More recently,9e we have
reported an inversion in product selectivity with the use of a
BINOL- or biphenol-phosphoramidite ligand (L4, L5 in Figure
1) and aliphatic alkynes. The ability to predict product selectivity
through alteration of the ligand allows for greater control within
the reaction. Lastly, we have gained an insight into the
coordination geometry of the active catalyst in the reaction of
diarylalkynes and alkenyl isocyanates finding that excess alkyne
substrate acts as a sixth ligand on octahedral Rh(III).9f Exploiting
this sixth ligand effect has allowed us to manipulate enantiose-
lectivities with the use of a nonparticipating additive.
These investigations greatly aid our understanding of this
reaction, and have provided an arsenal of reaction conditions
with which to tune new applications of this strategy. However,
all the above studies focused on internal symmetrical alkynes
or terminal alkynes, the latter having a large inherent difference
in both steric bulk and electronic contributions across the π
system. The use of internal, unsymmetrical alkynes in this
chemistry has the potential to introduce additional substituents,
complicated by potential problems of poor regiocontrol. In this
respect, our prior work indicating that there are elements of both
sterics and electronics influencing efficiency and selectivity was
especially worrisome. We envisioned that there may be internal,
unsymmetrical alkynes bearing contrasting substituent effects:
small, electron-withdrawing groups or large, electron-releasing
(1) (a) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (b)
Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006, 2209.
(2) (a) Braunstein, P.; Nobel, D. Chem. ReV. 1989, 89, 1927. (b) Chopade,
P. R.; Louie, J. AdV. Synth. Cat. 2006, 348, 2307.
(3) (a) Hong, P.; Yamazaki, H. Tetrahedron Lett. 1977, 18, 1333. (b) Hong,
P.; Yamazaki, H. Synthesis 1977, 50.
(4) (a) Hoberg, H.; Oster, B. W. J. Organomet. Chem. 1982, 234, C35.
(b) Hoberg, H.; Oster, B. W. Synthesis 1982, 324. (c) Hoberg, H.;
Oster, B. W. J. Organomet. Chem. 1983, 252, 359.
(5) (a) Earl, R. A.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1983, 105,
6991. (b) Earl, R. A.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49,
4786.
(6) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett. 2001, 3, 2117.
(7) Duong, H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004, 126,
11438.
(8) (a) Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737. (b)
Tanaka, K.; Takahashi, Y.; Suda, T.; Hirano, M. Synlett 2008, 1724.
(9) (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) Oinen, M. E.;
Yu, R. T.; Rovis, T. Manuscript submitted. (g) Oberg, K. M.; Lee,
E. E.; Rovis, T. Tetrahedron 2009, 65, 5056.
9
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Friedman and Rovis
Figure 1. Reactions from previous work9 and the current work.
groups that could participate predictably in cycloadditions. We
embarked on the following study to elucidate the parameters
governing reactivity while also providing a guide from which
to apply unique, individual, hitherto under-developed internal
alkynes to [2+2+2] cycloadditions.
The use of unsymmetrical, internal alkynes during metal-
catalyzed cycloadditions is not without precedent. The obvious
hurdle is to achieve regioselective insertion. A greater achieve-
ment still would be to realize the selectivity in a predictable
and dependable fashion with a keen understanding of the forces
driving the insertion. Several authors have pursued the problem
in metal-catalyzed annulations onto alkynes10 only to obtain poor
selectivities. The use of internal unsymmetrical alkynes in metal-
catalyzed cycloadditions, from [4+2],11 [3+2],12 [2+2+2],13
and [2+2+1]14 has met with some success. Several reports have
achieved success in selectively inserting unsymmetrical, internal
alkynes. However, the examples tend to be limited to extreme
differences (either in sterics or electronics),15 limited scope,16
or the selective insertion remains unexplained17 thus making
general use difficult.
Utilization of unsymmetrical, internal alkynes in metal-
catalyzed [2+2+2] cycloadditions with a variety of substrates
has been explored. As early as 1983, Vollhardt and co-workers5a
showed that unsymmetrical, internal alkynes participate in
cobalt-catalyzed [2+2+2] cycloadditions, eq 3 (Scheme 1). A
single regioisomer was observed for trimethylsilyl-substituted
alkynes. On the other hand, uniformly poor selectivity was seen
(13) (a) Hilt, G.; Vogler, T.; Hess, W.; Galbiati, F. Chem. Commun. 2005,
1474. For reviews on [2+2+2] cycloadditions foming benzenoid
systems, see: (b) Agenet, N.; Buisine, O.; Slowinski, F.; Gandon, V.;
Aubert, C.; Malacria, M. Org. React. 2007, 68, 1. (c) Tanaka, K. Chem.
Asian J. 2009, 4, 508.
(14) Barluenga, J.; Barrio, P.; Riesgo, L.; Lo´pez, L. A.; Toma´s, M.
Tetrahedron 2006, 62, 7547.
(10) (a) Kajita, Y.; Matsubara, S.; Kurahashi, T. J. Am. Chem. Soc. 2008,
130, 6058. (b) Chang, K.-J.; Rayabarapu, D. K.; Cheng, C.-H. J. Org.
Chem. 2004, 69, 4781. (c) Rayabarapu, D. K.; Yang, C.-H.; Cheng,
C.-H. J. Org. Chem. 2003, 68, 6726. (d) Miura, T.; Yamauchi, M.;
Murakami, M. Org. Lett. 2008, 10, 3085. (e) Larock, R. C.; Han, X.;
Doty, M. J. Tetrahedron Lett. 1998, 39, 5713. (f) Park, S. S.; Choi,
J.-K.; Yum, E. K.; Ha, D.-C. Tetrahedron Lett. 1998, 39, 627. (g)
Heller, S. T.; Natarajan, S. R. Org. Lett. 2007, 9, 4947.
(11) Koyama, I.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc. 2009,
131, 1350.
(15) (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2008, 130, 3645. (b) Lu, G.; Malinakova, H. C. J. Org. Chem. 2004,
69, 4701. (c) Duong, H. A.; Louie, J. Tetrahedron 2006, 62, 7552.
(d) Chang, K.-J.; Rayabarapu, D. K.; Cheng, C.-H. Org. Lett. 2003,
5, 3963.
(16) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K.
J. Am. Chem. Soc. 2009, 130, 16474.
(17) (a) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. Tetrahedron Lett. 1999,
40, 4089. (b) Hong, P.; Yamazaki, H. Synthesis 1977, 50. (c) Shibata,
T.; Takagi, K. J. Am. Chem. Soc. 2000, 122, 9852. (d) Takahasi, T.;
Tsai, F.-Y.; Li, Y.; Wang, H.; Kondo, Y.; Yamanaka, M.; Nakajima,
K.; Kotora, M. J. Am. Chem. Soc. 2002, 124, 5059.
(12) Man, S.; Necˇas, M.; Bouillon, J.-P.; Bailla, H.; Harakat, D.; Potácˇek,
M. Tetrahedron 2005, 61, 2387.
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A R T I C L E S
Scheme 1
for any alkyne that did not possess the silyl group, including
an alkyl alkynoate. In 2007, Tanaka and co-workers18 performed
cyclotrimerizations utilizing unsymmetrical internal alkynes.
They generally observe a single regioisomer and explain the
selectivity due to the electronics of the alkyne, eq 4 (Scheme
1). In 2008, Hilt and co-workers19 used cobalt-based catalyst
to cyclize two equivalents of alkyne with an alkene. The authors
observe moderate selectivity and yields (∼4:1 and up to 48%)
with the alkyl propiolate and a variety of alkenes, while the
aryl propiolate shows excellent selectivity and better yield (>20:
1, 45-86%), eq 5 (Scheme 1). The authors propose that both
ligand and substrate control regioselectivity. Louie and co-
workers20 have developed Ni(0) catalyzed [2+2+2] cycload-
ditions with internal alkynes and isocyanates to form a variety
of pyridones, eq 6 (Scheme 1). The authors report a wide range
of selectivities (1:1 to >20:1) and good yields (63-94%), with
the degree of selectivity highly alkyne dependent. The steric
bulk of the ligand also appears to play a role. Also in 2005,
Evans and co-workers21a explored [2+2+2] cycloadditions with
alkynes and enynes, catalyzed by Rh(I) in combination with a
phosphine. Impressively, these workers illustrate highly enan-
tioselective synthesis of the cycloadducts using a variety of aryl
propiolates, eq 7 (Scheme 1). In 2008, the Evans group again
showed that a [3+2+2] cycloaddition could be performed in a
similar fashion, eq 8 (Scheme 1). However, the internal alkynes
were not used in the enantioselective reactions in this case.21b
Also in 2008, Tanaka demonstrated control of axial chirality in
(18) Yoshida, K.; Morimoto, I.; Mitsudo, K.; Tanaka, H. Chem. Lett. 2007,
36, 998.
(21) (a) Evans, P. A.; Lai, K. W.; Sawyer, J. R. J. Am. Chem. Soc. 2005,
127, 12466. (b) Evans, P. A.; Inglesby, P. A. J. Am. Chem. Soc. 2008,
130, 12838.
(19) Hilt, G.; Paul, A.; Harms, K. J. Org. Chem. 2008, 73, 5187.
(20) Duong, H. A.; Louie, J. J. Organomet. Chem. 2005, 690, 5098.
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A R T I C L E S
Friedman and Rovis
Table 1. Ligand Screen
Table 2. Isocyanate Screen
a Reactions conducted with 2.5 mol % [Rh(C2H4)2Cl]2, 5 mol %
GUIPHOS, 1 eq 2, 1.2 eq 1a in PhMe at 110 °C for 14 h, unless
otherwise stated. b Regioisomers not observed by 1H NMR (>20:1).
c Determined by HPLC using a chiral stationary phase. d 1b used in
place of 1a, due to ease of separation on HPLC.
choosing methyl phenylpropiolate (1a) as the test unsymmetrical
alkyne, a brief ligand screen was conducted in order to determine
amenable reaction conditions (Table 1). It should be noted that
while all ligands gave a single regioisomer of the product
(vinylogous amide 4), GUIPHOS (L4) proved to be the best
ligand for this substrate, both in terms of enantioselectivity and
yield. Thus, this ligand was used to explore the unsymmetrical
alkyne scope.
After the initial success with GUIPHOS (L4) and the
unsubstituted alkenyl isocyanate, we sought to explore the to-
lerance in the reaction to a variety of substitutions on the alkene
(Table 2). While all reactions proceed in excellent yield, there
is a marked increase in enantioselectivity when disubstituted
alkenes are utilized. The constitution of this substitution does
not appear to be important. In particular, entry 5 illustrates the
efficiency that appears upon combination of an internal alkynoate
and the catalyst based on GUIPHOS (L4). This result stands in
stark contrast with the behavior of isocyanate 2e with TADDOL-
PNMe2 (L1) and a terminal, aryl alkyne (19% yield).23
Due to the increased selectivity with substituted isocyanates
(2b-2e vs 2a, Table 2), the scope was broadened in two parallel
a All reactions conducted with 1a (2 equiv), 2a (1 equiv),
[Rh(C2H4)2Cl]2 (0.025 equiv), Ligand (0.05 equiv) in PhMe at 110 °C,
unless otherwise stated. b 1a (1.2 equiv) used.
the [2+2+2] cycloaddition of diynes and tertiary alkynamides,
eq 9 (Scheme 1).22
Our previous work9 on the rhodium catalyzed [2+2+2]
cycloaddition had introduced us to the potential challenges
associated with unsymmetrical alkynes, the most significant
being that the inherent steric and electronic difference present
in the terminal alkynes would not necessarily be prevalent in
internal alkynes. Extending the reaction to internal, unsym-
metrical alkynes represents an important advance due to a great
increase in reaction scope as well as a better understanding of
the reaction mechanism. With these challenges in mind, we set
out to determine the minimal steric and electronic difference
necessary for the regio- and enantioselective [2+2+2] cycload-
dition of internal alkynes with alkenyl isocyanates. Herein, we
disclose our results.
(23) From ref 9c:
Results and Discussion
With the hope that a large electronic difference between ester
and aryl functionalities would provide good selectivity, alkynoates
were selected as our first unsymmetrical, internal alkynes. After
(22) Suda, T.; Noguchi, K.; Hirano, M.; Tanaka, K. Chem.sEur. J. 2008,
14, 6593..
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Insertion of Internal Unsymmetrical Alkynes
A R T I C L E S
Table 3. Electron-Deficient Alkyne Scope
a See Table 2. b Single regioisomer detected by 1H NMR. Regioisomer structure determined by NOE for select examples, with the rest assigned by
analogy. See Supporting Information.
Scheme 2
when coupled with alkynoates compared to the unsubstituted
counterparts. It should be noted that the obvious expansion to
use carbodiimides9d as a π-component was attempted (∼25-30%
yield); however, the products were extremely prone to oxidation
that eliminated the stereocenter.
Electronic variation of the aryl alkynoates reveals a strong
influence on reaction efficiency, with the most electron deficient
alkyne (1d) proceeding in only 33% yield (entries 7, 8). This
parallels the reactivity trend previously seen with electron-
deficient terminal aryl alkynes.9b Steric hindrance appears to
have the same effect on yield (entries 9, 10), with a more modest
effect on enantioselectivity (entries 9 vs 11, 10 vs 12). The
cycloadditions proceed with excellent product selectivity favor-
ing the vinylogous amide product. A single regioisomer is
1
observed in all cases (>20:1 regioselectivity determined by H
NMR). We next varied the nature of the electron-withdrawing
group. The tertiary alkynamide 1g does not behave as expected;
2b reacts to provide product in moderate yield and excellent
enantioselectivity. In contrast, 2a fails to react with alkyne 1g.
Secondary amide 1h did not present the same problem with
reactivity. Both isocyanates (2a, 2b) participate in the reaction
with excellent yields. However, the enantioselectivities are
surprisingly poor. This may be due to the coordination of the
basic amide oxygen to the rhodium catalyst. The corresponding
cyclohexyl ketone (entries 17, 18) behaves in a similar fashion
directions. We performed the cycloaddition with each new
alkyne with the unsubstituted alkyne (2a) and a substituted
counterpart (2b)24 allowing for an investigation into whether
or not the trend of increasing enantioselectivity held true for a
variety of alkynoates. The results (entries 1-12, Table 3) show
that the pattern holds for all alkynoates: substituted alkenyl
isocyanates proceed with greater enantioselectivity (94-99%)
(24) 2b was chosen due to its availability in bulk quantities.
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A R T I C L E S
Friedman and Rovis
Table 4. Electron-Neutral Alkyne Scope
a single regioisomer with high product selectivity. The enan-
tioselectivities in these cases remain roughly the same (71-83%
ee), regardless of alkene substitution, in contrast with the
alkynoates. Entries 5 and 6 (20 and 91% ee) show dependence
of ee on the isocyanate. The chloro phenyl acetylene, which
had been previously used successfully in ruthenium catalyzed
[2+2] reactions,25 shows aberrant behavior; this alkyne gener-
ates vinylogous amide adduct as a single regioisomer but forms
the lactam adduct with 2a as a 2:1 mixture of regioisomers (entry
5, Table 4).26 This remains the only unselective alkyne insertion
we have observed, and given that it forms lactam adduct
selectively in the absence of phosphoramidite ligands, we
suggest it arises by a fundamentally distinct mechanism.27,28
Entries 7 and 8 show that a large steric difference is enough to
control the regioselectivity of alkyne insertion. The large group
is also sufficient to control product selectivity, favoring the
vinylogous amide. These results, along with the failure of 1g
to react with 2a, indicate that sterics, alongside electronics, play
a profound role in the reaction outcome.
From the above results, it is clear that internal alkynes
selectively form vinylogous amide products. That there is a large
steric component to this effect is evident on the basis of our
previous studies. Branched aliphatic terminal alkynes provide
increased amounts of vinylogous amide adduct using the
Rh•TADDOL system, as do aryl acetylenes.9b The use of both
GUIPHOS (L4) and L5 leads to selective formation of viny-
logous amides even with small aliphatic alkynes such as
1-octyne.9e Diaryl alkynes provide vinylogous amides exclu-
a See Table 2. b Reaction stirred over 4 Å molecular sieves to remove
residual water present in alkyne. c Five mol % [Rh(C2H4)2Cl]2, 10 mol
% GUIPHOS. d The lactam adduct is generated as an apparent 2:1 ratio
1
of inseparable regioisomers (determined by H NMR).
9a
sively under the mediation of both Rh•PAr3 and Rh•
to the alkynoates. The enantioselectivities are excellent, increas-
ing when isocyanate 2b is used. The yield is low, presumably
due to the steric bulk of the ketone. The use of alkynyl nitriles
(entries 19-22) shows a possible influence of size on product
selectivity. The nitrile is much smaller than any of the carbonyls
used in the study, which is likely the cause of the change in
product selectivity for entries 19 and 20. When the alkynyl-R1
group is exchanged from an aryl to an alkyl moiety, the product
selectivity switches completely to the lactam.
The failure of tertiary amide 1g to participate in the reaction
with isocyanate 2a (entry 13, Table 3 and eq 10 in Scheme 2)
is worth an additional comment. Similar attempts with the
corresponding dimethyl amide also failed, eq 12 in Scheme 2.
This profound difference in behavior between the terminal and
1,1-disubstituted olefin isocyanate is puzzling. We speculated
that the presence of the tethered terminal olefin on isocyanate
2b plays a role in modifying the Rh coordination sphere
potentially by occupying a site and displacing a competitive
ligand. In support of this hypothesis, we note that subjection of
isocyanate 2d, bearing a 1,1-disubstituted alkene but lacking
the second olefin, and the dimethylamide of phenylpropiolic
acid to the reaction conditions fails to deliver cycloadduct, eq
13 in Scheme 2. The impact of the butenyl side chain must be
exerted in an intramolecular fashion on an intermediate in the
catalytic cycle. The electronic and steric similarities between
the terminal alkene in the butenyl group with the terminal alkene
in isocyanate 2a likely eliminates the possibility that these effects
occur by simple intermolecular coordination of the alkene to
Rh.
GUIPHOS.9f We note that the steric model also explains the
somewhat more modest selectivities seen for smaller alkynes.
Alkyne 1f provides the vinylogous amide in only 7:1 selectivity,
comparable to that observed with 1-octyne (4:1).9e Lastly, the
smallest alkyne investigated in this study, 1k, leads to exclusive
formation of lactam adduct.
To rationalize regioselectivity in these reactions, which we
have noted is extremely high for all vinylogous amide adducts
in this study, a simple steric model cannot be applied in most
cases. The regioselective insertion of alkyne 1o in the metala-
cycle leading to the selective formation of products 4oa and
4ob is best explained by sterics, but the preponderance of
evidence, vis a vis the successful insertion of many polarized
alkynes, suggests there is an electronic component to regiose-
lectivity. In all cases, the stronger electron-releasing group is
placed alpha to the nitrogen in the vinylogous amide adduct.
If this hypothesis is true, based on the data seen thus far and
utilizing electronics as the primary factor governing insertion
of the unsymmetrical alkynes, it stands to reason that any
substitution more electron-releasing than phenyl should dictate
regioselectivity and lead to inversion, placing the phenyl ring
proximal to the carbonyl. We examined several groups in this
light (ynol ethers, ynamides29 and enynes) in an effort to test
(25) Jordan, R. W.; Villeneuve, K.; Tam, W. J. Org. Chem. 2006, 71, 5830.
(26) The reaction generates an apparent ∼2:1 ratio (determined by 1H NMR)
of inseparable regioisomers of the lactam adducts, but a single
vinylogous amide adduct. The HPLC trace indicates the presence of
two pairs of enantiomers. The 13C NMR also indicates the presence
of two compounds. Thus, the lactam adducts were not fully
characterized.
(27) A control experiment run in the absence of phosphoramidite ligand
generated lactam selectively in 25-30% yield, also as a 2:1 ratio of
regioisomers.
In an effort to determine the minimal extent of the steric/
electronic difference necessary for selectivity, we investigated
simpler alkynes, again surveying both 2a and 2b as the
isocyanate component in the reaction (Table 4). Entries 1 and
2 illustrate that an electronic difference as small as aryl versus
alkyl is enough for the reaction to proceed efficiently, generating
(28) Although unprecedented, mechanisms involving oxidative addition of
Rh into the C-Cl bond cannot be discounted.
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A R T I C L E S
Table 5. Electron-Rich Alkynes
a Regiochemistry was determined by NOE; see Supporting Information. b Inseperable mixture of regioisomers (10:1 favoring phenyl proximal to the
carbonyl, L5 as ligand). c The use of L4 as ligand provides 4 with 5:1 regioselectivity. d The use of L4 as ligand provides 4 with 3:1 regioselectivity.
e Regioselectivity 1.2:1.
Scheme 3
the limits of this hypothesis. Ynol ethers and ynamides each
participate in the cycloaddition with a clean reversal of
regioselectivity, placing the phenyl group proximal to the
carbonyl moiety in the vinylogous amide (Table 5, entries 1-4).
The low product selectivity observed with ynol ether 1p and
isocyanate 2a is surprising but a control experiment run in the
absence of phosphoramidite confirms the presence of a compet-
ing naked Rh-mediated cycloaddition forming the lactam.30
Even a difference as small as cyclohexenyl versus phenyl
(entries 5, 6) shows a distinct preference between regioisomers
(10:1 with L5), which suggests that the electronic control is
very sensitive.
Our proposed mechanism for the rhodium-catalyzed cycload-
dition of alkenyl isocyanates and alkynes is shown in Scheme
3. Product selectivity is determined in the initial oxidative
cycloaddition event generating intermediates I and II, entering
the lactam and vinylogous amide catalytic cycles from a
presumed common precursor. The high regioselectivities ob-
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A R T I C L E S
Friedman and Rovis
served in the alkyne insertion event may be explained using
Mayr’s scale of nucleophilicity.31 To predict relative ability to
stabilize an adjacent positive charge, we compared the Mayr
nucleophilicities of several alkenes, (Scheme 3). The greater
nucleophilicity (higher positive number) of a similar alkene
corresponds to preference for insertion distal to the carbonyl
group. However, one cannot exclude sterics entirely, as the large
group also prefers to insert away from the carbonyl. To
determine which property dominates, an alkyne was synthesized
that possesses both an electronically donating group in addition
to a sterically bulky group (entry 7, Table 5). Unfortunately,
both sterics and electronics appear to exert similar control when
placed in direct competition. Importantly, application of Mayr’s
nucleophilicity scale to alkyne substituents thus provides a
polarization model that rationalizes observed selectivities. For
example, the phenyl group better stabilizes a positive charge
relative to both a carbomethoxy as well as an alkyl leading to
alkyne polarizations for 1a and 1m (Scheme 3). On the other
hand, the increased nucleophilicity of isoprene (N ) 1.10) and
ethyl vinyl ether (N ) 3.92) relative to styrene (N ) 0.78) results
in an inversion of polarity of alkynes 1r and 1p, leading to the
regioselective dichotomy between intermediates of type IIa and
IIb (Scheme 3).
cycloaddition exclusively provides vinylogous amide products
with inversion of regioselectivity, eq 14. The intermediate γ-silyl
enones (4ta and 4tb) undergo a rapid protiodesilylation upon
workup, affording a final product that is regioisomeric to the
cycloadduct of phenylpropyne (contrast eq 14 with entries 3
and 4 in Table 4).
Conclusion
In summary, we have shown that unsymmetrical internal
alkynes participate successfully in the rhodium-catalyzed [2+2+2]
cycloaddition with alkenylisocyanates. We note nearly exclusive
formation of vinylogous amide adducts in these reactions. We
further observe very high regioselectivities with the vast majority
of alkynes screened, and have delineated the factors responsible
for controlling this sense of insertion. The successful develop-
ment of this chemistry increases the synthetic utility of the
rhodium-catalyzed [2+2+2] cycloaddition, thus allowing for
predictable incorporation of internal unsymmetrical alkynes into
indolizidine frameworks.
A closer examination of the Mayr scale suggests that
propargyl silanes should participate with high regioselectivity,
given the greater nucleophilicity of allylsilane relative to styrene
(Scheme 3). The use of 3-phenyl propargyl silane 1t in the
Acknowledgment. We thank NIGMS (GM80442) for support
of this research. T.R. thanks the Monfort Family Foundation for a
Monfort Professorship.
(29) Oppenheimer, J.; Hsung, R. P.; Figueroa, R.; Johnson, W. L. Org.
Lett. 2007, 9, 3969.
Supporting Information Available: Experimental procedures
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(30) A reaction using 5 mol % [Rh(C2H4)Cl]2, 1p and 2a in PhMe at 110
°C for 16 h provides lactam 3pa in 34% yield with >20:1 product
selectivity.
(31) (a) Mayr, H.; Ofial, A. R. J. Phys. Org. Chem. 2008, 21, 584. (b)
Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
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