Phosphoramidites are efficient, green organocatalysts for the Michael reaction. Mechanistic insights into the phosphorus-catalyzed Michael reaction of alkynones and implications for asymmetric catalysis

Article abstract of DOI:10.1021/jo026425g

Hexamethylphosphorous triamide (HMPT) and other phosphoramidites and phosphites have been found to be efficient catalysts for the Michael reaction of alkenones and alkynones with malonates, α-cyano esters, β-keto esters, and nitro compounds. The relativel

Full text of DOI:10.1021/jo026425g

P h osp h or a m id ites Ar e Efficien t, Gr een Or ga n oca ta lysts for th e
Mich a el Rea ction . Mech a n istic In sigh ts in to th e
P h osp h or u s-Ca ta lyzed Mich a el Rea ction of Alk yn on es a n d
Im p lica tion s for Asym m etr ic Ca ta lysis
Robert B. Grossman,* S e´ bastien Comesse, Ravindra M. Rasne, Kazuyuki Hattori, and
Matthew N. Delong
Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506-0055
rbgros1@uky.edu
Received September 9, 2002
Hexamethylphosphorous triamide (HMPT) and other phosphoramidites and phosphites have been
found to be efficient catalysts for the Michael reaction of alkenones and alkynones with malonates,
R-cyano esters, â-keto esters, and nitro compounds. The relatively nontoxic, easily hydrolyzed HMPT
catalyzes the Michael reaction within seconds at room temperature in the absence of a solvent,
and the reaction is worked up simply by removing the catalyst in vacuo. The Michael reactions of
alkynones, unlike those of alkenones, are shown to be irreversible. The implications for asymmetric
catalysis are discussed.
1
Since its discovery in the 1880s, the Michael reaction
has become one of the premier methods for the synthesis
We have recently found that the double Michael
reactions of certain tethered diacids with 3-butyn-2-one
proceed far more cleanly when basic catalysts are re-
2
of densely functionalized quaternary centers. Its com-
6
plete atom economy, wide substrate scope, susceptibility
to many classes of catalysts, and easily accessible starting
materials render it one of the most modern of classical
reactions. Asymmetric Michael reactions of prochiral
nucleophiles, on the other hand, remain difficult to
placed with Ph
3
P. Although we are by no means the first
7
to find that phosphines catalyze the Michael reaction,
we may be the first to apply them to the Michael reaction
of alkynones. We have proposed two catalytic cycles for
the phosphine-catalyzed Michael reaction of carbon acids
with 3-butyn-2-one (Schemes 1 and 2). Both involve an
execute via either stoichiometric or catalytic approaches,
8
despite recent advances.3
enolate-â-phosphonio enone ion pair, but in catalytic
cycle 1, the “direct addition” mechanism (Scheme 1), the
enolate attacks 3-butyn-2-one, whereas in catalytic cycle
We have spent much time exploring the double Michael
reaction of tethered diacids (compounds consisting of two
carbon acids connected by a tether) with alkynones to
give a variety of highly functionalized and substituted
2
, the “addition-elimination” mechanism (Scheme 2), the
enolate attacks the â-phosphonio enone in an addition-
9
elimination process. (Catalytic cycle 1 is directly analo-
4
carbocyclic and azacyclic compounds. The stereochem-
gous to the one generally written for alkenones.) In
catalytic cycle 2, the C-P bond is intact during the C-C
bond-forming, stereochemistry-determining step (assum-
ing a prochiral enolate), and the phosphine resides near
the nascent stereocenter, raising the intriguing possibil-
ity that a chiral, enantiopure phosphine catalyst might
induce asymmetry in the Michael reaction.
istry-determining step for most of these double Michael
reactions is the intermolecular Michael reaction of an
R-cyano ester to an ethynyl ketone. An asymmetric
double Michael reaction, then, requires a catalyst for
rendering this step asymmetric. Unfortunately, the
Michael reactions of R-cyano esters are among the most
difficult to render asymmetric.5
(
1) Komnenos, T. Ann. Chem. 1883, 218, 145. Michael, A. J . Prakt.
Chem. (Leipzig) 1887, 35, 349.
2) Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959, 10,
79. Martin, S. F. Tetrahedron 1980, 36, 419. Perlmutter, P. Conjugate
(5) Wynberg, H.; Helder, R. Tetrahedron Lett. 1975, 4057. Sawa-
mura, M.; Hamashima, H.; Ito, Y. J . Am. Chem. Soc. 1992, 114, 8295.
Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron 1994, 50, 4439.
Inagaki, K.; Nozaki, K.; Takaya, H. Synlett 1997, 119. Stark, M. A.;
J ones, G.; Richards, C. J . Organometallics 2000, 19, 1282. Motoyama,
Y.; Koga, Y.; Kobayashi, K.; Aoki, K.; Nishiyama, H. Chem.sEur. J .
2002, 8, 2968.
(
1
Addition Reactions in Organic Synthesis; Pergamon Press: Oxford,
U.K., 1992. Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLough-
lin, J . I. Org. React. 1995, 47, 315.
(
3) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771.
(6) Grossman, R. B.; Pendharkar, D. S.; Patrick, B. O. J . Org. Chem.
1999, 64, 7178.
Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997,
3
6, 1236. Corey, E. J .; Guzman-Perez, A. Angew. Chem., Int. Ed. Engl.
998, 37, 388. Leonard, J .; D ´ı ez-Barra, E.; Merino, S. Eur. J . Org.
(7) White, D. A.; Baizer, M. M. Tetrahedron Lett. 1973, 3597.
(8) We note that any enolate-â-phosphonio enone ion pair may be
in equilibrium with a phosphorane containing a P-O bond.
(9) A mechanism similar to the latter was written for the phosphine-
catalyzed addition of an alcohol to an acetylenic ester. Wende, M.;
Meier, R.; Gladysz, J . A. J . Am. Chem. Soc. 2001, 123, 11490.
1
Chem. 1998, 2051, 1. Krause, N.; Hoffmann-R o¨ der, A. Synthesis 2001,
71.
4) Grossman, R. B. Synlett 2001, 13. Hughes, F., J r.; Grossman,
R. B. Org. Lett. 2001, 3, 2911.
1
(
1
0.1021/jo026425g CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/21/2002
J . Org. Chem. 2003, 68, 871-874
871

Grossman et al.
SCHEME 1. Ca ta lytic Cycle 1: Dir ect Ad d ition a
esters with electrophilic alkynes to give the corresponding
adducts with 63-86% isolated yields (Table 1). The best
catalyst by far is (Me
catalysts include (MeO)
is fastest in polar solvents such as DMF and CH
2
N)
3
P (HMPT), but other viable
. The reaction
CN and
3
P and PhP(OMe)
2
3
at higher concentrations, suggesting that the rate-limit-
ing step is the addition of the P nucleophile to the
electrophilic π bond to give a zwitterion.
Mixtures of E and Z Michael adducts are obtained from
electrophilic alkynes. When 3-butyn-2-one is the electro-
phile (entries 1-12), the Z isomer predominates in every
case but one (entry 11). In the one case where the E
isomer predominates, we have resubjected the Z isomer
to the reaction conditions and found that it isomerizes
smoothly to the E isomer, presumably by an addition-
rotation-elimination mechanism. We attribute the labil-
ity of this adduct to the small steric bulk and potent
electron-withdrawing ability of the γ-cyano groups. Other
adducts fail to isomerize under the reaction conditions.
When ethyl propiolate is the electrophile, the E isomer
always predominates (entries 13-16). We have resub-
jected the Z isomer of one of these adducts to the reaction
conditions; conversion to the E isomer is not observed.
The kinetic Z selectivity of the butynone reactions can
easily be understood. If catalytic cycle 1 is operative,
irreversible protonation of allenolate A from the less
hindered face provides a Z Michael adduct directly
a
X ) OEt or alkyl, Z ) electron-withdrawing group, R ) alkyl.
SCHEME 2. Ca ta lytic Cycle 2:
Ad d ition -Elim in a tion
a
(Scheme 3a). If catalytic cycle 2 is operative, on the other
hand, the irreversible protonation of â-phosphonio alle-
nolate B from the less hindered face provides â-phos-
phonio enone C with a predominantly Z configuration
(Scheme 3b). This compound combines with the enolate
of the nucleophile to give a â-phosphonio enolate D as
conformer D1; minimal bond rotation to conformer D2
and elimination of the P catalyst then provides the
Michael adduct, which will have the same configuration
as C if intermediate D is short-lived.12
a
X ) OEt or alkyl, Z ) electron-withdrawing group, R ) alkyl.
The E selectivity of the ethyl propiolate reaction is less
easily understood. If catalytic cycle 2 is operative, inter-
mediates D may be expected to have a shorter lifetime
Although chiral monophosphines are well-known,10
their syntheses are often difficult, multistep endeavors.
We felt that our chances of discovering a successful
asymmetric phosphorus-based catalyst for the Michael
reaction would be enhanced if we could search for it by
combinatorial methods, and it occurred to us that, for
several reasons, chiral phosphites, phosphoramidites,
phosphonites, and phosphonamidites would be excellent
2
2
when X ) OEt than when X ) Me, and this argument
would suggest that the reaction should again favor the
2
Z isomer. However, it is possible that when X ) OEt,
the reversible protonation of â-phosphonio enolate D to
â-phosphonio ester E may compete with elimination,
thereby allowing elimination to occur from the more
thermodynamically favorable conformer D3 after recon-
version to the â-phosphonio enolate (Scheme 3b). On the
other hand, if catalytic cycle 1 is operative, perhaps
allenolate A interacts more strongly with the phospho-
compounds among which to execute a combinatorial
search for a catalyst.11 Before we could execute this
search, however, we first needed to establish whether
these compounds catalyzed the Michael reactions of
alkynones at all.
2
2
nium counterion when X ) OEt than it does when X )
Me, leading to a later TS for proton transfer and hence
an enhanced selectivity for the E isomer.
Resu lts
HMPT is a particularly efficient catalyst for the
Michael reaction of both alkynyl electrophiles (Table 1,
entries 1, 5-8, 11, 13, 14, 16-18, and 20) and vinyl
electrophiles (Table 2). In many cases, the Michael
reaction of R-cyano esters, â-keto esters, malonates, or
nitro compounds proceeds within seconds at room tem-
perature or 0 °C in the absence of solvent and in the
presence of 5-10 mol % HMPT. The monoalkylation of
Non a sym m etr ic Ca ta lysis. We have found that
phosphites, phosphonites, and phosphoramidites catalyze
the Michael reaction of various R-cyano esters and â-keto
(
10) Zhang, X. Enantiomer 1999, 4, 541.
(11) Lagasse, F.; Kagan, H. B. Chem. Pharm. Bull. 2000, 48, 315.
Komarov, I. V.; B o¨ rner, A. Angew. Chem., Intl. Ed. 2001, 40, 1197.
Denney, D. Z.; Chen, G. Y.; Denney, D. B. J . Am. Chem. Soc. 1969, 91,
6
838. Nielsen, J .; Dahl, O. J . Chem. Soc., Perkin Trans. 2 1984, 553.
Delapierre, G.; Brunel, J . M.; Constantieux, T.; Buono, G. Tetrahe-
dron: Asymmetry 2001, 12, 1345.
(12) Patai, S.; Rappoport, Z. In The Chemistry of Alkenes; Patai, S.,
Ed.; Wiley: New York, 1964; Chapter 8, p 469.
8
72 J . Org. Chem., Vol. 68, No. 3, 2003

Phosphoramidites
TABLE 1. P h osp h or u s-Ca ta lyzed Mich a el Rea ction s of Alk yn yl Electr op h iles
SCHEME 3. Or igin of Selectivity for Z a n d E
Isom er s of Mich a el Ad d u cts
TABLE 2. P h osp h or u s-Ca ta lyzed Mich a el Rea ction s of
Vin yl Electr op h iles
a
possible to remove it from the solventless reaction
mixture simply by applying a vacuum. When an alkenone
is the electrophile, the product is obtained in >95% pure
form, but when an alkynone is the electrophile, filtration
through silica gel or distillation to remove polymerized
alkynone is required. If a solvent is desired, HMPT allows
a
1
2
X ) OEt or alkyl, X ) OEt or Me, Z ) electron-withdrawing
group, R ) alkyl.
CH
3 2
NO with methyl acrylate in 57% yield (Table 2, entry
7
) is an especially significant result, because under other
2 2 3
the use of more nonpolar solvents (CH Cl , CHCl ) than
Michael reaction conditions it is difficult to prevent the
initial adduct from undergoing a second Michael reac-
tion.13 The high vapor pressure of HMPT makes it
(
13) Kisanga, P. B.; Ilankumaran, P.; Fetterly, B. M.; Verkade, J .
G. J . Org. Chem. 2002, 67, 3555.
J . Org. Chem, Vol. 68, No. 3, 2003 873

Grossman et al.
(
MeO)
3
P does (CH
3
CN, DMF). HMPT is relatively non-
cycle 1 is operative. In fact, the similarity of the E/Z ratios
when tertiary amines and HMPT are used to catalyze
the nonasymmetric Michael reaction also suggests that
HMPT serves merely to generate a counterion. We
hypothesize that phosphoramidites are such powerful
nucleophiles that the elimination part of catalytic cycle
2 is simply too slow. Even assuming that catalytic cycle
1 is operative, it remains somewhat surprising that the
chiral â-phosphonio enone counterion exerts absolutely
no asymmetric influence in the C-C bond-forming step
by an ion-pairing effect.14
toxic, easily hydrolyzed, and inexpensive. It is slowly
oxidized by air to the much more toxic HMPA, but an
atmosphere of N prevents this eventuality. Moreover,
2
although HMPA is much less volatile than HMPT, there
has been no sign of it in the NMR spectra of the crude
products. As a result, the color of the HMPT-catalyzed
Michael reaction can be nonhyperbolically described as
a very deep green. Phosphite and phosphonite catalysts
are less efficient than HMPT (Table 2, entries 2-4). In
these cases, Arbuzov or elimination reactions may de-
stroy the catalyst before the Michael reaction is complete.
There are some limitations to the HMPT-catalyzed
Michael reactions. Polymerization of 3-butyn-2-one is
faster than its reaction with a substituted malonate
derivative (Table 1, entry 12), the reaction of diethyl
isopropylmalonate and methyl vinyl ketone fails to
proceed to completion, and ethyl trans-crotonate is un-
reactive toward an R-cyano ester. These limitations are
easily understood in terms of the absolute and relative
rates of the steps in catalytic cycle 1 and other competing
reactions.
Con clu sion
HMPT is a very effective organocatalyst for the Michael
reaction of good carbon acids. Its reactivity, low cost, lack
of toxicity, and volatility allow it to be favorably compared
with other phosphorus-based catalysts for the Michael
reaction.7 Even though chiral phosphoramidites do not
induce asymmetry in the Michael reactions of alkynones,
we believe that the irreversibility of these Michael
reactions provides new opportunities for the development
of asymmetric Michael reactions, for example, by a chiral
,13
Although many HMPT-catalyzed Michael reactions are
catalyzed equally well by tertiary amines (Table 1, cf.
entries 5-8 and 11 to 9, 10, and 15), HMPT catalyzes
1
4
auxiliary or phase-transfer catalysis approach. Experi-
ments in this regard are ongoing and will be reported in
due course.
some Michael reactions that are not catalyzed by Et
3
N
(Table 1, entries 18-21). For example, ethyl 2-cyano-5-
methylhexanoate undergoes Michael reactions with 3-hex-
yn-2-one and 4-phenyl-3-buten-2-one in the presence of
Typ ica l Exp er im en ta l P r oced u r e for th e
HMP T-Ca ta lyzed Mich a el Rea ction
3
3
0 mol % HMPT but not 30 mol % Et N. The powerfully
Eth yl 2-Cyan o-5-m eth yl-2-(3-oxobu tyl)h exan oate. Meth-
nucleophilic HMPT can add to the hindered electrophile
at a reasonable rate, and the resulting allenolate is an
excellent and irreversible base, providing a high equi-
librium concentration of enolate. By contrast, in the
amine-catalyzed reaction, the amine does not add to the
electrophile at a reasonable rate, so it acts solely as a
base, and the enolate is probably reprotonated by the
ammonium counterion faster than it adds to the electro-
phile.
yl vinyl ketone (2.0 mL, 24 mmol) was added dropwise to a
stirred solution of ethyl 2-cyano-5-methylhexanoate (3.67 g,
15
2
0 mmol) and HMPT (182 µL, 1 mmol). (Caution: HMPT is
slowly oxidized by air to HMPA, a known carcinogen. Precau-
tions should be taken to avoid protracted exposure of HMPT
to air.) After 10 min, the reaction mixture was directly
concentrated under reduced pressure to give the title com-
pound (96% yield, 100% pure by GC-MS).
Ack n ow led gm en t. We thank the NIH (GM1002-
Asym m etr ic Ca ta lysis. All attempts to induce asym-
metry in the Michael reaction of alkynyl electrophiles by
using chiral analogues of HMPT as catalysts met with
abject failure. The electrophile was 3-butyn-2-one or ethyl
propiolate, and the nucleophile was an R-cyano or â-keto
ester bearing a configurationally pure menthyl group in
the alcohol portion (see Supporting Information). The
menthyl groups exerted no facial bias on the Michael
reaction of the intermediate enolate, but they allowed the
diastereoselectivity of the reaction to be determined
easily. A variety of chiral phosphoramidites were exam-
ined; several catalyzed the reaction efficiently, but none
gave any diastereoselectivity in the reaction under a
variety of reaction conditions.
0
1A1) for its support of this work. The NMR instru-
ments used in this research were obtained with funds
from NSF’s CRIF program (CHE-997841) and the
University of Kentucky’s Research Challenge Trust
Fund. We thank Professor Xumu Zhang and Manisha
Srivastava for working with us on exploratory studies.
Su p p or tin g In for m a tion Ava ila ble: Substrates and
catalysts used in the asymmetric catalysis experiments,
analytical data for all new compounds, and some experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O026425G
The complete lack of asymmetric induction with chiral
phosphoramidites and phosphites suggests that catalytic
(
14) Zhang, F.-Y.; Corey, E. J . Org. Lett. 2000, 2, 1097.
(15) Hessler, J . C. J . Am. Chem. Soc. 1913, 35, 990.
8
74 J . Org. Chem., Vol. 68, No. 3, 2003