Highly selective rhodium-catalyzed conjugate addition reactions of 4-oxobutenamides

Article abstract of DOI:10.1021/jo701682c

(Chemical Equation Presented) A variety of 4-oxobutenamides 1 were subjected to rhodium-catalyzed conjugate addition with arylboronic acids providing high regio- and enantioselectivity (97:3 to >99:1, >96% ee) and moderate to excellent yields (54-99%). Th

Full text of DOI:10.1021/jo701682c

Highly Selective Rhodium-Catalyzed Conjugate Addition Reactions
of 4-Oxobutenamides
Jamie L. Zigterman, Jacqueline C. S. Woo, Shawn D. Walker, Jason S. Tedrow,*
Christopher J. Borths, Emilio E. Bunel, and Margaret M. Faul
Chemical Process Research and DeVelopment, Amgen Inc., Thousand Oaks, California 91320-1799
jtedrow@amgen.com
ReceiVed August 3, 2007
A variety of 4-oxobutenamides 1 were subjected to rhodium-catalyzed conjugate addition with arylboronic
acids providing high regio- and enantioselectivity (97:3 to >99:1, >96% ee) and moderate to excellent
yields (54-99%). The key to high selectivity is the use of sterically demanding P-chiral diphosphines,
such as Tangphos or Duanphos. The product oxobutanamides 2 may be converted to alternate targets by
selective derivatization of either the amide or ketone functional group. A stereochemical model predicting
the absolute sense of induction was developed based on single-crystal X-ray structures of product and
precatalyst.
First described in 1997, the addition of arylboronic acids to
electron-deficient olefins catalyzed by rhodium(I) complexes
has received considerable attention from the synthetic com-
munity as a powerful carbon-carbon bond-forming tool.1
Shortly after their first report, Hayashi and Miyaura disclosed
that the use of a chiral BINAP Rh(I) complex delivered superb
enantioselectivities in the conjugate addition of arylboronic acids
to simple unsaturated ketones.2 The ligands3 capable of deliver-
ing good enantiocontrol have expanded beyond the traditional
chiral biaryl systems to chiral aminophosphites,4 chiral diole-
fins,5 and more recently phosphine-olefin based structures.6
Further disclosures describe alternative electron-deficient olefins
such as unsaturated esters,7 amides,8 nitroolefins,9 phospho-
nates,10 heteroaromatic alkenes,11 symmetrical fumarates, and
FIGURE 1. Regio- and enantiocontrol issues surrounding conjugate
addition to 4-oxobutenamides.
(1) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16 (20),
4229-4231.
(2) Takaya, Y.; Ogasawra, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J.
Am. Chem. Soc.1998, 120 (22), 5579-5580.
(3) (a) For an excellent review on the rhodium-catalyzed conjugate
addition reaction see: Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103
(8), 2829-2844. (b) For a review on rhodium-catalyzed C-C bond forming
reactions see: Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103 (1), 169-
196.
substituted and unsubstituted maleimides12 as suitable electro-
philes. Notably absent from the list are electronically differenti-
ated 1,4-unsaturated dicarbonyl compounds13 such as the
oxobutenamides of type 1.14
(4) (a) Boiteau, J.; Minnaard, A.; Feringa, B. J. Org. Chem. 2003, 68
(24), 9481-9489. (b) Duursma, A.; Hoen, R.; Schuppan, J.; Hulst, R.;
Minnaard, A.; Feringa, B. Org. Lett. 2003, 5 (17), 3111-3113.
(5) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem.
Soc. 2003, 125 (38), 11508-11509.
(9) Hayashi, T.; Senda, T.; Ogasawra, M. J. Am. Chem. Soc. 2000, 122
(43), 10716-10717.
(10) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawra, M. J. Am. Chem.
Soc. 1999, 121 (49), 11591-11512.
(11) Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martin-Matute, B.
J. Am. Chem. Soc. 2001, 123 (22), 5358-5359.
(12) (a) Shintani, R.; Ueyama, K.; Yamada, I.; Hayashi, T. Org. Lett.
2004, 6 (19), 3425-3427. (b) Shintani, R.; Duan, W.; Hayashi, T. J. Am.
Chem. Soc. 2006, 128 (17), 5628-5629. (c) Duan, W.; I, Y.; Shintani, R.;
Hayashi, T. Tetrahedron 2007, 63 (35), 8529-8536.
(6) Duan, W.; Iwamura, H.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc.
2007, 129 (7), 2130-2138.
(7) Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J. Org. Chem. 2000,
65 (19), 5951-5955.
(8) Sakuma, S.; Miyaura, N. J. Org. Chem. 2001, 66 (26), 8944-8946.
10.1021/jo701682c CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/10/2007
8870
J. Org. Chem. 2007, 72, 8870-8876

Rh-Catalyzed Addition Reactions of 4-Oxobutenamides
FIGURE 2. Ligand classes which were screened in the enantioselective conjugate addition reaction.
SCHEME 1. Proposed Route to 2-Aryl-4-oxobutanamides (eq 1)
Recently, we desired access to 2-aryl-4-oxobutanamides 2
in high enantiomeric purity. Routes to generate 2 with enanti-
oselective transformations are limited and generally do not
provide a direct approach to these structures.15-17 We reasoned
that a regio- and enantioselective conjugate addition to elec-
trophile 1 would allow direct and flexible access to 2. Oxobute-
namides of type 1 (R ) Ph, Me) are easily prepared from
commercially available acylacrylic acids (Scheme 1).18 The use
of oxobutenamides as electrophilic coupling partners, however,
presents a particularly daunting challenge; the transformation
needs to be highly enantio- and regioselective requiring a
catalyst system that distinguishes not only enantiotopic π-faces
but also the subtle electronic differences of each conjugate
acceptor (Figure 1).19
Initially studying 1a, we examined a variety of commercially
available phosphorus-based ligands L1-L5 (Figure 2).20 The
commonly utilized chiral biaryl ligands of type L1 and L2
provided good enantioselecitivities ranging from 85% to 92%,
but only moderate regioselectivities (∼9:1) favoring the desired
2-aryl-4-oxobutanamides 2. More electron donating ligands,
such as the chiral phospholanes L3, afforded almost exclusively
the desired regioisomer (>98:2; 2:3), although the enantiose-
lectivities were lower (0-61% ee) than those with the biaryl
ligand systems. Ligands of class L4 failed to show significant
reactivity (conversions <20%). Sterically demanding P-chiral
phosphines L5, e.g. Tangphos21 and Duanphos,22 afforded
excellent enantioselectivity while still maintaining high regi-
oselectivity, delivering the desired regioisomer in >99:1 (2:3)
and 95-98% ee. To our knowledge, this is the first instance
where these P-chiral phosphines have been utilized in an
enantioselective conjugate addition reaction.23 While the un-
bound phosphine is rapidly oxidized in air, the bench-stable
complex [((S,S,R,R)-Duanphos)Rh(nbd)]BF4 524 afforded identi-
cal results to those of the in situ prepared precatalyst and was
used in further studies.25
A screen of reaction conditions in the conjugate addition of
1a with 4 mediated by catalyst 5 established that the reaction
was tolerant of a number of ethereal solvents and mild bases.
Potassium carbonate, potassium bicarbonate, potassium hydrox-
ide, triethylamine, and diisopropylethylamine all afforded full
conversion to the desired product with no appreciable difference
in selectivity and with no specific advantage over triethylamine.
The use of potassium acetate, however, resulted in low conver-
sion (<50%). With a base selected, solvent effects were next
examined. Tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-
dioxane were preferred over 1,2-dimethoxyethane, which af-
forded lower enantioselectivity (90% ee). Alcoholic solvents
such as methanol, ethanol, and 2-propanol afforded 1,4-
conjugate reduction of the enone with little or no nucleophilic
addition taking place. The optimized conditions described in
eq 226 were used for further reaction characterization. While
catalyst loading was not fully explored, we found that a 2 mol
% catalyst loading was sufficient for the majority of substrates
studied. On a 12 mmol scale, the reaction was complete in 6 h
at 65 °C (100% conversion; >99:1 regioselectivity, 98% ee;
eq 3). HPLC analysis of the crude reaction mixture calibrated
with an external standard showed a 93% solution assay for the
(13) Recently, Hoveyda has reported a regio- and enantioselective copper-
catalyzed conjugate addition of organozinc reagents to cyclic γ-ketoesters:
Brown, M. K.; May, T. L.; Baxter, C. A.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2007, 46 (7), 1097-1100.
(14) For a recent report on the preparation of oxobutenamides: Sonye,
J. P.; Koide, K. J. Org. Chem. 2006, 71 (16), 6254-6257.
(15) Hoffman, R. V.; Kim, H. W. Tetrahedron Lett. 1993, 34 (13), 2051-
2054.
(22) (a) Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 4, 646-649. (b)
Liu, D.; Gao, W.; Wang, C.; Zhang, X. Angew. Chem., Int. Ed. 2005, 44
(11), 646-649.
(23) While specifically Tangphos and Duanphos have not to our
knowledge been used in the rhodium-catalyzed 1,4-conjugate addition
reaction, P-Chiral phosphines have demonstrated high enantioselectivity in
the conjugate addition reaction to cyclic and acyclic enones: Imamoto, T.;
Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005, 127 (34), 11934-11935.
(24) nbd ) bicyclo[2.2.1]hepta-2,5-diene.
(25) Both enantiomers of the Duanphos ligand as well as the corre-
sponding LRh(cod)BF4 complexes may be obtained from Chiralquest Inc.
or alternatively the R,R,S,S-antipode of both ligand and Rh(cod)BF4
complex is sold by Strem chemicals.
(26) Reagents and conditions: 2 mol % of 5, 1.5 equiv of 4, 1.5 equiv
of Et3N, 19:1 THF:H2O, 65 °C.
(16) Hayashi, T.; Yamamoto, A.; Ito, Y. Chem. Lett. 1987, 1, 177-180.
(17) For a complementary approach that provides R-aryl ketoamides of
type 3 with moderate to high enantioselectivity see: Nahm, M. R.; Xin,
L.; Potnick, J. R.; Yates, C. M.; White, P. S.; Johnson, J. S. Angew. Chem.,
Int. Ed. 2005, 44 (16), 2377-2379.
(18) Lawrence, D. S.; Zilfou, J. T.; Smith, C. D. J. Med. Chem. 1999,
42 (24), 4932-4941.
(19) (a) Captain, L. F.; Xia, X.; Liotta, D. C. Tetrahedron Lett. 1996,
37 (25), 4293-4296. (b) Stack, J. G.; Curran, D. P.; Rebek, J.; Ballaster,
P. J. Am. Chem. Soc. 1991, 113 (15), 5918-5920.
(20) For a complete table of ligands screened and the results, see the
Supporting Information
(21) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002, 41, 1612-1614.
J. Org. Chem, Vol. 72, No. 23, 2007 8871

Zigterman et al.
desired product 2a. A simple aqueous workup, followed by
recrystallization of the desired product from heptane:isopropanol
(4:1) afforded 2a in 84% isolated yield,27 >99% regioselectivity,
99% ee.
nucleophillic coupling partner was examined (Table 1). A wide
variety of commercially available meta- and para-substituted
boronic acids were found to be competent coupling partners
with 1a (Table 1). Both electron rich (4a,b) and electron poor
(4d,e) boronic acids afforded high enantio- and regioselectivity
mediated by complex 5. The indolyl boronic acid 4g afforded
the conjugate addition product 2g in excellent enantioselectivity,
albeit with slightly diminished regioselectivity (Table 1, entry
7). (E)-Styrylboronic acid is also an efficient nucleophile in this
reaction manifold, affording the conjugate addition product 2i
in 92% yield and essentially a single isomer (Table 1, entry 9).
The absolute configuration of 2e and 2f was determined to be
R by single-crystal X-ray structure analysis, and the configura-
tions of the remaining addition products were assigned by
analogy.
The conjugate addition reaction to 1a mediated by complex
5 was also tolerant of ortho substitution on the boronic acid
nucleophile, and excellent regioselectivities and enantioselec-
tivities were obtained in the majority of cases (Table 2). With
With an appropriate set of reaction conditions, the generality
of the regioselective conjugate addition with respect to the
TABLE 1. Effect of Boronic Acid Structure on Yield, Product Distribution, and Enantioselectivity in the Reaction of 1a (eq 4)a
a Reactions were conducted at 65 °C for 24 h, using 1.5 equiv of 4, 1.5 equiv of Et3N, 2 mol % of 5 in THF:H2O 19:1 (10 mL/g of 1a). b As measured
by HPLC: peak area percent 2:3. c Determined by chiral HPLC analysis of major regioisomer 2 (see the Supporting Information). d Isolated yield based
upon the average of two separate reactions. e Absolute configuration determined by single-crystal X-ray diffraction (see the Supporting Information). f Product
configuration assigned for 2e and 2f. All others assigned by analogy.
8872 J. Org. Chem., Vol. 72, No. 23, 2007

Rh-Catalyzed Addition Reactions of 4-Oxobutenamides
TABLE 2. Effect of Boronic Acid Structure on Yield, Product Distribution, and Enantioselectivity in the Reaction of 1 (eq 5)a
a Reactions were conducted at 65 °C for 24 h, using 1.5 equiv of 4, 1.5 equiv of Et3N, 2 mol % of 5 in THF:H2O 19:1 (10 mL/g of 1a). b As measured
by HPLC: peak area percent 2:3. c Determined by chiral HPLC analysis of major regioisomer 2 (see the Supporting Information). d Isolated yield based
upon the average of two separate reactions. Values in parentheses are conversions based upon HPLC peak area percent. e Product configuration assigned by
analogy to 2e,f. f Not determined.
SCHEME 2. Synthesis of Various 4-Alkyl-4-oxobutenamides 1d,e,f
o-halo-substituted boronic acids, an increase in halogen size was
accompanied by a decrease in product formation (Cl ) 68%
yield; Br ) <10% conversion; Table 2, entries 3 and 4). The
highly electron deficient 2-fluoro-5-(trifluoromethyl)phenylbo-
ronic acid 4k underwent conjugate addition to afford product
2k in 80% yield, >99:1 regioselectivity (2k:3k), and 98% ee.
The sterically congested 2,6-dimethylphenylboronic acid ef-
ficiently underwent conjugate addition to provide 2n in 94%
conversion, however with low enantioselectivity.
enol-cyclopropanation/ring-expansion method of Zercher28
(Scheme 2) and subjected to the preferred reaction conditions
with complex 5 and boronic acid 4a (Table 3). Aliphatic
oxobutenamides uniformly afforded high regio- and enantiose-
lectivities similar to their aryl counterparts (1c,d vs 1a,b). The
more sterically demanding isopropyl and tert-butyl acrylamides
(1e, 1f) exhibited lower reactivity compared to other substrates.
Increased catalyst loadings and/or switching to a stronger base
(potassium hydroxide) was required to achieve synthetically
useful yields with these particular substrates.
Variation of the amide structure revealed more profound
differences in reaction selectivity. Following the previous trend,
N,N-dialkylamides afforded uniformly high enantio- and regi-
oselectivities (Table 4, entries 1 and 2). While conjugate addition
to Weinreb amide 1i furnished products in high enantioselec-
tivity (97% ee), the regioselectivity was low (2:1) although the
desired sense of regiochemistry was still favored. Subjecting
monosubstituted amide 1j to the reaction conditions resulted in
a modest reversal of selectivity, now favoring the undesired
Reaction scope with respect to electrophile structure was
examined next. Oxobutenamides 1d-f were prepared via the
(27) Loss to recrystallization mother liquors was calculated to be 9% of
theoretical mass based upon HPLC as calibrated by an external standard
(93% assay yield; 100% mass balance).
(28) Ronsheim, M. D.; Zercher, C. K. J. Org. Chem. 2003, 68 (11),
4535-4538.
(29) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124 (18), 5052-5058.
(30) Zhao, P.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2007,
129 (7), 1876-1877.
J. Org. Chem, Vol. 72, No. 23, 2007 8873

Zigterman et al.
TABLE 3. Effect of Ketone Substituent on Conjugate Addition
Reaction of 1 with 4a (eq 6)a
TABLE 4. Effect of Amide Structure on Conjugate Addition
Reaction of 1 with 4a (eq 7)a
a Reactions were conducted isothermally at 65 °C for 24 h, using 1.5
equiv of 4a, 1.5 equiv of Et3N, 2 mol % of 5. b As measured by HPLC
peak area percent 6:7. c Determined by chiral HPLC analysis of the major
regioismer (see the Supporting Information). d Absolute configuration
assigned by analogy. e Isolated yield based upon the average of two
reactions. f 10 mol % of catalyst 5 used. g KOH (1.5 equiv) was used in
place of Et3N. h Ratio as determined by 1H NMR analysis (authentic standard
of regioisomer could not be isolated from the racemic control reaction).
a Reactions were conducted isothermally at 65 °C for 24 h, using 1.5
equiv of 4a, 1.5 equiv of Et3N, 2 mol % of 5. b As measured by HPLC
peak area percent 6:7. c Determined by chiral HPLC analysis of the major
regioismer (see the Supporting Information). d Absolute configuration
assigned by analogy. e Isolated yield based upon the average of two
reactions. f Regioisomers were not separable by silica gel chromatography.
Values in parentheses are combined yields of both regioisomers. g Not
determined.
conjugate addition product 7j (Table 4, entry 4), although the
enantioselectivity of the desired regioisomer 6j was still high
(97% ee). Primary amide 1k was unstable under the reaction
conditions and no desired product was isolated from the reaction.
Analysis of the product stereochemistry in conjunction with
the solid-state structure of precatalyst 5 supports a simple steric
model that predicts the stereochemical outcome. On the basis
of the generally accepted mechanism of the rhodium-catalyzed
conjugate addition,29 (Figure 3), an aryl rhodium(I) species 9,
generated from transmetallation of the boronic acid,30 coordi-
nates substrate enone 1 to form complex 10. Coordination of
the substrate is the stereochemical determining step and is
followed by irreversible migratory insertion to form a rhodium
enolate species 11 that is hydrolyzed to deliver the product and
regenerate the active catalytic species 9 (Figure 2). Docking of
the substrate to the ligand-arylrhodium complex in proper olefin
alignment for migratory insertion shows that coordination of
the si-face of the substrate places the ketone substiuent away
from the sterically bulky tert-butyl group on the ligand (Figure
3). Migratory insertion from this intermediate complex would
afford the observed R-enantiomer. Alternatively, coordination
of the olefin from the re-face, which results in the opposite
enantiomeric product series, forces the ketone substituent into
close-contact with the tert-butyl group of the phosphine and is
expected to be disfavored. While we believe that the high
FIGURE 3. Proposed catalytic cycle for rhodium-catalyzed conjugate
addition of aryl boronic acids
regioselectivity furnished by this reaction is largely based upon
an electronic bias inherent in the starting electrophile, the
8874 J. Org. Chem., Vol. 72, No. 23, 2007

Rh-Catalyzed Addition Reactions of 4-Oxobutenamides
FIGURE 4. Model for prediction of stereochemical outcome in the conjugate addition reaction.
SCHEME 3. Functionalization of Oxobutanamide 2a
observed increase in regioselectivity upon moving to more
electron rich phosphine ligands is not well understood and is
currently under investigation.
chemoselective palladium-catalyzed deoxygenation of the ketone
group32 under the conditions of Maleckza generated the
4-arylbutanamide 13 in 80% isolated yield with excellent chiral
purity. Together, these approaches allow ready access to chiral
R-arylamides, ketoamides, diketones, and lactones, many of
which are not conveniently prepared by alternative methods.
The product oxobutanamides generated from the conjugate
addition reaction are synthetically versatile intermediates, and
selective manipulation of either the keto or amide functionality
may be achieved with minimal erosion of enantiomeric ratio
(Scheme 3). For example, diastereoselective reduction of the
aryl ketone with lithium tert-butoxyaluminum hydride afforded
an 8:1 mixture of alcohols that were subjected to acid-mediated
cyclization to provide the 2,4-trans-disubstituted lactone 15 as
the major diastereomer in 68% yield and the minor 2,4-cis-
disubstituted lactone 16 in 9% yield. The remarkably high
optical purities (>99% ee) of both lactone diastereomers
confirms that the desired cyclization process is not accompanied
by lactone equilibration. Alternatively, in situ protection of the
aryl ketone as the corresponding enolate (lithium hexamethyl-
disilazide), followed by methyl cerium addition to the morpho-
line amide afforded diketone 12 in 52% yield.31 Finally,
We have demonstrated that a variety of N,N-disubstituted
4-oxobutenamides are effective coupling partners with arylbo-
ronic acids mediated by a chiral rhodium complex 5. The
reaction is tolerant of various substitution patterns on the boronic
acid components and delivers 2-aryl-4-oxobutanamides in high
regioselectivity and enantiomeric purity. Structural analysis of
product absolute configuration and precatalyst structure affords
a simple and predictive stereochemical model for the conjugate
addition reaction of these substrates. Investigations into the
(32) (a) Private correspondence (R. E. Maleczka, Jr.) (b) Rahaim, R. J.,
Jr.; Maleczka, R. E., Jr. Palladium Catalyzed Deoxygenations with a Curious
Chlorobenzene Effect; 38th National Organic Chemistry Symposium, June
8-12, Bloomington, IN; The Division of Organic Chemistry of the
American Chemical Society: Washington, DC, 2003; Abstract No. C41.
(31) Kurosu, M.; Kishi, Y. Tetrahedron Lett. 1998, 39 (27), 4793-4796.
J. Org. Chem, Vol. 72, No. 23, 2007 8875

Zigterman et al.
0.81 (d, J ) 14.56 Hz, 18 H), 1.89 (s, 2 H), 3.41 (dd, J ) 17.82,
10.79 Hz, 2 H),3.85 (d, J ) 17.57 Hz, 2 H), 4.19 (s, 1 H), 4.24-
4.32 (m, 3 H), 5.81 (d, J ) 25.60 Hz, 4 H), 7.29-7.42 (m, 6 H),
7.47 ppm (d, J ) 7.53 Hz, 2 H); 13C NMR (101 MHz, CDCl3) δ
26.9, 55.9, 126.5, 128.1, 128.4, 128.6, 137.9 ppm; 31P NMR (100
MHz, CDCl3) δ 102.9, 103.8 ppm; IR (neat) 2956, 1737, 1579,
origins of the regioselectivity as well as broadening the substrate
scope are underway and will be reported in due course.
Experimental Section
General Procedure for Generation of 4-Oxobutenamides:
(E)-1-Phenyl-4-morpholinobut-2-ene-1,4-dione (1a). A 500-mL
3-necked round-bottomed flask was charged with (E)-4-oxo-4-
phenylbut-2-enoic acid (10 g; 56.8 mmol) and 100 mL of anhydrous
tetrahydrofuran. The solution was cooled to an internal temperature
of -25 to -30 °C whereupon N-methylmorpholine (6.9 mL, 62.4
mmol, 1.1 equiv) was added. Isobutyl chloroformate (7.7 mL; 59.6
mmol; 1.05 equiv) was added dropwise maintaining the reaction
temperature below -20 °C to form a thick precipitate. The reaction
was warmed to 0 °C and stirred 1 h whereupon the reaction was
chilled to -20 °C. Morpholine (5.9 mL; 68.1 mmol; 1.2 equiv)
was added, and the reaction was warmed to 0 °C and stirred for 1
h. The reaction was quenched with 50 mL of 1 N hydrochloric
acid and partitioned into 50 mL of ethyl acetate. The aqueous layer
was extracted with 50 mL of methyl tert-butyl ether, and the
combined organic extracts were washed with 50 mL of 10%
aqueous sodium carbonate and then dried over anhydrous magne-
sium sulfate. The organics were filtered and concentrated to provide
a solid. The solid was then suspended in 100 mL of 2:1 methyl
tert-butyl ether and hexanes. The suspension was stirred for 16 h
at ambient temperature, filtered, and then dried to afford 11.1 g of
(E)-1-phenyl-4-morpholinobut-2-ene-1,4-dione as a yellow solid.
Mp 133-134 °C. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J ) 8.53
Hz, 2 H), 7.98 (d, J ) 15.06 Hz, 1 H), 7.45 (d, J ) 14.56 Hz, 1
H), 6.99 (d, J ) 9.03 Hz, 2 H), 3.90 (s, 3 H), 3.69-3.83 (m, 6 H),
3.59-3.69 ppm (m, 2 H); 13C NMR (101 MHz, CDCl3) δ 187.6,
164.2, 134.7, 131.3, 131.0, 129.9, 114.1, 66.8, 55.6, 46.4, 42.6 ppm;
HRMS calcd for C15H17NO4 [M + Na] 298.1055, found 298.1067;
IR (neat) 2968, 2866, 1667, 1628, 1603, 1448, 1263, 1167, 1032,
1462, 1403, 1368, 1311, 1183, 1033, 829, 789, 769, 754, 677 cm-1
.
General Method for the Rhodium-Catalyzed Conjugate
Addition Reaction to 4-Oxobutenamides: Preparation of (R)-
2-(4-Methoxyphenyl)-1-morpholino-4-phenylbutane-1,4-dione (2a).
A 20-mL scintillation vial was charged with (E)-1-morpholino-4-
phenylbut-2-ene-1,4-dione (1a) (0.5 g, 2.0 mmol), 4-methoxyphe-
nylboronic acid (456 mg, 3.0 mmol), rhodium catalyst 5 (27 mg,
0.04 mmol), triethylamine (0.42 mL, 3.0 mmol), and tetrahydro-
furan/water (19:1, 5 mL). The reaction mixture was warmed to
65 °C and stirred for 16 h. HPLC analysis indicated that the reaction
had reached full conversion (99:1 2a:3a; 98% ee). The crude
reaction mixture was poured into 20 mL of ethyl acetate and washed
with 10 mL of saturated sodium bicarbonate. The organics were
dried over anhydrous magnesium sulfate, filtered, and concentrated
in vacuo. The crude material was analyzed by HLPC33 (Method
A: Tret(2a) ) 4.3 min, Tret(3a) ) 4.1 min, >99:1; Method B: Tret-
(R-2a) ) 1.08 min, Tret(S-2a) ) 1.47 min, 98% ee) and then purified
by flash column chromatography (30% to 100% ethyl acetate in
hexanes) to afford the product as a colorless solid (701 mg, 96%).
Mp (133-135 °C). [R]25D -157.4 (c 1.2 in CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 7.99 (d, J ) 7.53 Hz, 2 H), 7.44 (t, J ) 7.53 Hz,
2 H), 7.55 (t, J ) 7.28 Hz, 2 H), 7.16-7.31 (m, 2 H), 6.89 (d, J )
8.53 Hz, 2 H), 4.49 (dd, J ) 9.79, 3.76 Hz, 1 H), 4.10 (dd, J )
17.82, 9.79 Hz, 1 H), 3.81 (s, 3 H), 3.76-3.33 (m, 7 H), 3.30-
3.12 (m, 1 H), 3.06 ppm (dd, J ) 17.57, 3.51 Hz, 1 H); 13C NMR
(101 MHz, CDCl3) δ 198.7, 171.1, 158.8, 136.6, 133.1, 131.2,
128.7, 128.5, 128.2, 114.5, 66.8, 66.4, 55.3, 46.2, 44.3, 43.2, 42.6;
HRMS calcd for C21H24NO4 [M]+ 354.1699, found 354.1748; IR
(neat) 2972, 2856, 1698, 1628, 1606, 1502, 1441, 1231, 1024,
831, 761 cm-1
.
829 cm-1
.
[(Bicyclo[2.2.1]hepta-2,5-diene)rhodium(I) ((1S,1′S,2R,2′R)-
2,2′-bis(1,1-dimethylethyl)-2,2′,3,3′-tetrahydro-1,1′-bi-1H-iso-
phosphindole)] Tetrafluoroborate (5). In an inert-atmosphere
glovebox, a 100-mL Schlenk flask was charged with [bis(bicyclo-
[2.2.1]hepta-2,5-dienyl)rhodium(I)] tetrafluoroborate (3.56 g, 9.52
mmol, 1.0 equiv) and 40 mL of dichloromethane. To this solution
was added (1S,1′S,2R,2′R)-2,2′-bis(1,1-dimethylethyl)-2,2′,3,3′-tet-
rahydro-1,1′-bi-1H-isophosphindole (3.92 g , 10 mmol, 1.05 equiv)
in 15 mL of dichloromethane portionwise. The orange solution was
stirred at ambient temperature, and the flask was sealed and removed
from the glovebox. The dichloromethane was removed in vacuo
and redissolved in 20 mL of fresh dichloromethane. This solution
was then layered with 40 mL of methyl tert-butyl ether and left to
crystallize for 12 h. The supernatant was decanted and the crystals
were rinsed with 2 × 5 mL of methyl tert-butyl ether. A suitable
crystal was selected for single-crystal X-ray diffraction analysis
(see the Supporting Information, Section VII). The remaining
crystals were dried in vacuo and 5.9 g of 5 was isolated as deep
Acknowledgment. The authors thank Troy S. Soukup, Jenny
Chen, and Dr. J. Preston for their help in chiral HPLC analysis
of the product mixtures. Dr. Richard Staples (Harvard Univer-
sity) is acknowledged for solving single-crystal X-ray structures
of 2e, 2f, and 5. Drs. Tiffany Correll and Kevin Turney are
acknowledged for help in obtaining HRMS, optical rotation,
and infrared spectra of the products. Professor R. Maleczka
(Michigan State University) is kindly thanked for providing the
ketone deoxygenation procedure.
Supporting Information Available: Catalyst screening table,
general methods, chromatographic methods, characterization data,
NMR spectra, and single-crystal diffraction data. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO701682C
red prisms. Analytical data for 5: mp >230 °C (decomposes);
1
[R]25 18.5 (c 0.10 in CH2Cl2); H NMR (400 MHz, CDCl3) δ
(33) See the Supporting Information for details.
D
8876 J. Org. Chem., Vol. 72, No. 23, 2007