Rhodium-catalyzed 1,4-addition of terminal alkynes to vinyl ketones

Article abstract of DOI:10.1016/j.tetlet.2004.07.036

The metal complex Rh(acac)(CO)₂ in the presence of an eqimolar amount of tris(o-methoxyphenyl)phosphine provides a useful catalyst system for the 1,4-addition of alkynes to unsubstituted vinyl ketones. Best yields are obtained when the transfor

Full text of DOI:10.1016/j.tetlet.2004.07.036

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6591–6594
Rhodium-catalyzed 1,4-addition of terminal
alkynes to vinyl ketones
Ronald V. Lerum and John D. Chisholm*
Department of Chemistry, Syracuse University, Syracuse, NY 13244, USA
Received 16 June 2004; revised 3 July 2004; accepted 8 July 2004
Available online 24 July 2004
Abstract—The metal complex Rh(acac)(CO)2 in the presence of an eqimolar amount of tris(o-methoxyphenyl)phosphine provides a
useful catalyst system for the 1,4-addition of alkynes to unsubstituted vinyl ketones. Best yields are obtained when the transforma-
tion is performed in benzene at reflux with an excess of vinyl ketone. Both aryl and alkyl substituted alkynes participate in the reac-
tion. Primary alcohols and alkyl chlorides are well tolerated under these reaction conditions. The reaction also proceeds in aqueous
solvent mixtures, unlike most organometallic addition reactions.
Ó 2004 Elsevier Ltd. All rights reserved.
The 1,4-addition of alkynes to enones is known to be a
problematic reaction. The most common reaction condi-
tions for the 1,4-addition of carbon anions, cuprate
chemistry, fails when attempted with alkynes.1,2 This is
unfortunate because the products of the 1,4-addition
of alkynes, c, d-alkynyl ketones, are useful intermediates
for organic synthesis providing ready access to 1,4-di-
ketones,3 furans,4 and pyrroles.5
Scheme 1.
Because the reaction is performed in acetone as the sol-
vent, it is likely tolerant of at least small quantities of
water.
Numerous attempts have been made to bridge this gap
in synthetic methodology.6–13 In each of these cases,
acetylides must be generated by deprotonation, which
Intrigued by the potential of this process, a study was
requires stoichiometric quantities of at least one metal.
undertaken to improve upon the reaction. Despite its
Recently, several examples of the 1,4-addition of alkynes
promise, the original reaction conditions are marred
have emerged that are catalytic in transition met-
by some significant disadvantages. The addition is very
als.4,14,15 These methods take advantage of the facile
slow, requiring between two and five days to proceed
C–H insertion chemistry of alkynes to generate the
to useful levels of completion. Heating does not provide
acetylide, which then adds to the enone. Such reactions
a satisfactory solution, as it results in alkyne dimeriza-
are advantageous because they minimize waste with all
tion as the major reaction pathway. The catalyst for
of the atoms in the stoichiometric starting materials pre-
the 1,4-addition reaction, RhCl(PMe3)3, is not commer-
sent in the reaction product.
cially available. This limits the usefulness of the reaction
to laboratories, which are skilled in the synthesis of or-
In 1990, Kovalev published a rhodium catalyzed addi-
ganometallic compounds. Furthermore, synthesis of the
tion of alkynes to methyl vinyl ketone (Scheme 1).16 This
catalyst requires trimethylphosphine, a volatile, toxic,
and air-sensitive compound.
reaction possesses many promising features, such as not
needing to activate the alkyne with a stoichiometric
amount of another metal and low catalyst loading.
The first goal of this program was to find a catalyst that
did not require trimethylphosphine. The second was to
find a catalyst that increased the reaction rate. Pursuant
to these goals, a stable rhodium complex with ligands
that may be displaced easily with exogenous phosphines
Keywords: Alkyne; 1,4-Addition; Rhodium.
*
Corresponding author. Tel.: +1-315-443-6894; fax: +1-315-443-
4070; e-mail: jdchisho@syr.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.036

6592
R. V. Lerum, J. D. Chisholm / Tetrahedron Letters 45 (2004) 6591–6594
Table 2. Screen of reaction conditions
was desired. This stable rhodium complex would then be
the precatalyst, with the active catalyst formed in situ.
The benzoate of 4-pentyn-1-ol and methyl vinyl ketone
(3equiv) were used as the initial coupling partners for
this investigation. After examining several rhodium (I)
sources,
Rh(acac)(CO)2
(acac = acetylacetonoate)
proved to be the most effective precatalyst. The carbon
monoxide ligand is readily and quantitatively displaced
by better ligands, such as phosphines.17 Other precata-
lysts (such as [Rh(cod)Cl]2 (cod = cyclooctadiene) and
[Rh(norbornadiene)Cl]2) also gave small amounts of
1,4-addition product, however this was always contam-
inated with products resulting from dimerization or
polymerization of the alkyne. These side reactions were
less prevalent when Rh(acac)(CO)2 was used as the pre-
catalyst. While use of Rh(acac)(CO)2 without any phos-
phine ligands provided only small amounts of product,
addition of a phosphine ligand significantly increased
the yield of the reaction in most cases (Table 1).
Entry Solvent
Temperature (°C) Yield (%)
1
2
3
4
5
6
Benzene
Benzene
Toluene
Dioxane
50
80
90
90
22
61
49
56
53
15
90% Dioxane/10% H2O 90
75% Dioxane/25% H2O 90
was performed in 10% water/dioxane. Greater amounts
of water were not as well tolerated, likely because the
rhodium–phosphine complex lacked solubility.
The stoichiometry of rhodium complex and phosphine
ligand was the next reaction parameter investigated.
Further examination showed that only one equivalent
of the phosphine ligand with respect to the rhodium
complex was required for catalytic activity (Table 3).
This implies that one of the carbon monoxide ligands
may still be attached to the reactive catalytic complex.
Lowering the catalyst loading to 3mol% or 1mol% re-
sulted in a significant reduction in the yield of the reac-
tion. In an attempt to recoup some of the loss in yield, a
greater excess of methyl vinyl ketone was used in these
experiments. Using five equivalents of methyl vinyl
ketone instead of three significantly improved the yield
of the reaction (Table 3, entry 4).
Changing the phosphine used in the reaction signifi-
cantly changed the isolated yield of the 1,4-addition
product. With the initial experiments showing some
promise, a brief screen of phosphine ligands was per-
formed in an effort to find one that gave a reasonable
yield of the 1,4-addition product on a faster timescale
than observed by Kovalev. From this initial screen, tris-
(o-methoxyphenyl)phosphine 10 emerged as the best lig-
and. No trend as to what type of ligand (electron rich or
electron poor, large cone-angle, or small cone-angle)
emerged from this ligand screen. A control experiment
using phosphine 10 with no rhodium complex present
provided no 1,4-addition product.
With a promising catalyst-phosphine combination, a
number of experimental factors were varied in an effort
to further increase the yield and rate of the 1,4-addition
reaction (Table 2). Varying the temperature of the reac-
tion showed that a relatively high temperature was re-
quired (above 50°C). Changing the solvent showed
little difference among toluene, benzene, and dioxane.
The reaction demonstrated a significant water tolerance,
with little decrease in yield observed when the reaction
An excess of enone 2 may be required because of evap-
oration, as the boiling point of methyl vinyl ketone 2 is
close to that of benzene. To investigate this postulate 1-
octen-3-one (13) was explored as a reaction partner.
Both methyl vinyl ketone 2 and 1-octen-3-one 13 were
used in varying amounts to determine if the requirement
for excess vinyl ketone applied to only to methyl vinyl
ketone or to all substrates (Table 4). Use of a lesser
amount of enone 13 also resulted in lowered yields. This
result rules out evaporation as the reason an excess of
enone is needed. Instead, the excess of ketone is likely
Table 1. Screen of phosphine ligands
Table 3. Effect of catalyst and phosphine loading
Entry Phosphine
Yield (%)
1
2
3
4
5
6
7
8
None
6
21
Entry
Mol% Rh
Equiv 2
Mol% 10
Yield (%)
Tris(pentafluorophenyl)phosphine (6)
Tris(p-trifluoromethylphenyl)phosphine (7)
Triphenylphosphine (8)
1
2
3
4
5
6
5
5
5
5
3
1
3
3
3
5
5
5
20
10
5
63
53
54
82
63
11
18
Trace
20
61
Tri-o-tolylphosphine (9)
5
Tris(o-methoxyphenyl)phosphine (10)
Tris(p-methoxyphenyl)phosphine (11)
Tris(2,4,6-trimethoxyphenyl)phosphine (12) 11
3
17
1

R. V. Lerum, J. D. Chisholm / Tetrahedron Letters 45 (2004) 6591–6594
Table 4. Effect of decreasing the amount of enone
6593
Entry
Enone
Equiv enone
Yield
1
2
3
4
5
6
2
2
5
3
1
5
3
1
82% (5)
54% (5)
16% (5)
71% (14)
48% (14)
28% (14)
2
13
13
13
Figure 1. Proposed mechanism of the rhodium-catalyzed 1,4-addition
of alkynes.
required because it is a less effective ligand for the tran-
sition metal catalyst than a second equivalent of alkyne.
Binding of two alkynes to the rhodium catalyst is unde-
sirable because this could lead to dimerization and
polymerization.
into the alkyne C–H bond is well precedented from
other published studies.21,22 After coordination of the
enone, formation of the new C–C bond occurs by migra-
tory insertion of the alkyne into the olefin. The resulting
oxy-p allyl complex is then protonated by reductive
elimination. This releases the 1,4-addition product and
regenerates the catalyst for further reaction.
With good conditions for the 1,4-addition in hand, the
substrate tolerance of the reaction with respect to func-
tionality on the alkyne and the enone was explored
(Table 5). Both aromatic and alkyl substituted alkynes
showed good reactivity in the 1,4-addition reaction. Po-
lar protic functionality, such as alcohols, were well toler-
ated. Good electrophiles, such as primary alkyl
chlorides, also gave useful yields of the 1,4-addition
product. No 1,2-addition of the alkyne to the carbonyl
was observed in any of these rhodium-catalyzed reac-
tions. While the rhodium catalyzed 1,4-addition of alky-
nes performed well with unsubstituted enones,
substituted systems still provide a challenge. Only 10–
20% yields of 1,4-addition product were obtained when
alkynes were added to 3-octen-2-one under these reac-
tion conditions.
The rhodium-catalyzed 1,4-addition of alkynes repre-
sents an entry to c,d-alkynyl ketones, products that
are not easily accessed through classical methods. Cur-
rently, the reaction functions on unsubstituted vinyl ke-
tones with yields in the 61–86% range. Studies to
elucidate the mechanistic features of the reaction and
expand the substrate scope are ongoing.
Acknowledgements
Acknowledgment is made to the Donors of the Ameri-
can Chemical Society Petroleum Research Fund and
to Syracuse University for partial support of this
research.
A proposed reaction mechanism for the reaction is
shown in Figure 1. Insertion of the rhodium catalyst
Table 5. Substrate generality of the rhodium-catalyzed 1,4-addition of
alkynes18–20
References and notes
1. Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94,
7210.
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4. Picquet, M.; Bruneau, C.; Dixneuf, P. H. Tetrahedron
1999, 55, 3937.
Entry
Alkyne
Enone
Yield
5. Reisch, J. Arch. Pharm. 1965, 298, 591.
6. Hooz, J.; Layton, R. B. J. Am. Chem. Soc. 1971, 93, 7320.
7. Pappo, R.; Collins, P. W. Tetrahedron Lett. 1972, 13,
2627.
8. Schwartz, J.; Carr, D. B.; Hansen, R. T.; Dayrit, F. M.
J. Org. Chem. 1980, 45, 3053.
9. Sinclair, J. A.; Molander, G. A.; Brown, H. C. J. Am.
Chem. Soc. 1977, 99, 954.
10. Fujishima, H.; Takada, E.; Hara, S.; Suzuki, A. Chem.
Lett. 1992, 695.
1
R1 = (CH2)5CH3 (15)
R1 = Ph (16)
2
63% (22)
61% (23)
66% (24)
82% (5)
2
2
3
R1 = (CH2)3Cl (17)
R1 = (CH2)3OBz (4)
2
4
2
5
R1 = (CH2)3OH (18)
R1 = TIPS (19)
2
74% (25)
76% (26)
63% (27)
71% (14)
86% (28)
72% (29)
67% (30)
6
2
7
R1 = (CH2)3CN (20)
4
2
13
8
9
18
18
19
13
R2 = Ph (21)
21
10
11
11. Chong, J. M.; Shen, L.; Taylor, N. J. J. Am. Chem. Soc.
2000, 122, 1822.

6594
R. V. Lerum, J. D. Chisholm / Tetrahedron Letters 45 (2004) 6591–6594
12. Bergdahl, M.; Eriksson, M.; Nilsson, M.; Olsson, T. J.
Org. Chem. 1993, 58, 7238.
13. Kim, S.; Lee, J. M. Tetrahedron Lett. 1990, 31, 7627.
14. Chang, S.; Na, Y.; Choi, E.; Kim, S. Org. Lett. 2001, 3,
2089.
15. Knoepfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003,
125, 6054.
16. Kovalev, I. P.; Nikishin, G. I. Tetrahedron Lett. 1990, 31,
7063.
22.4, 15.6, 13.9, 13.4. Anal. Calcd for C20H26O3: C, 76.40;
H, 8.33. Found: C, 76.22; H, 8.22. 22: TLC Rf = 0.27 (10%
ethyl acetate/hexanes). IR (neat): 2956, 2930, 1720cmÀ1
.
1H NMR (300MHz, CDCl3) d 2.57 (t, J = 7.1, 2H), 2.35–
2.29 (m, 2H), 2.08 (s, 3H), 2.05–2.00 (m, 2H), 1.42–1.16
(m, 8H), 0.80 (t, J = 7.1, 3H). 13C NMR (75MHz, CDCl3)
d 207.0, 80.9, 78.5, 43.0, 31.4, 29.9, 29.0, 28.6, 22.6, 18.7,
14.1, 13.5. Anal. Calcd for C12H20O: C, 74.84; H, 9.96.
Found: C, 74.69; 10.25. 25: TLC Rf = 0.20 (50% ethyl
17. Serron, S.; Huang, J.; Nolan, S. P. Organometallics 1998,
17, 534.
acetate/hexanes). IR (neat): 3419, 2924, 1716cmÀ1 1H
.
NMR (300MHz, CDCl3) d 3.67 (t, J = 6.2, 2H), 2.59 (t,
J = 7.2, 2H) 2.39–2.32 (m, 2H), 2.24–2.18 (m, 2H) 2.13 (s,
3H), 1.67 (p, J = 6.2, 2H). 13C NMR (75MHz, CDCl3) d
207.4, 80.12, 79.3, 61.8, 43.0, 31.6, 30.0, 15.4, 13.5. HRMS
(EI): m/z calcd for C9H14O2Na (M+Na) 177.0885. Found:
177.0883. 28: TLC Rf = 0.42 (50% ethyl acetate/hexanes).
18. Representative experimental procedure: Benzene (0.5mL)
was added to Rh(acac)(CO)2 (9.0mg, 0.035mmol,
5mol%) and phosphine 10 (12.3mg, 0.035mmol,
5mol%). A solution of the alkyne 19 (157lL, 0.70mmol)
and methyl vinyl ketone 2 (286lL, 3.5mmol) in benzene
(3.0mL) was then added. The reaction vessel was then
placed in a pre-heated oil bath at 85°C and stirred for 24h
at this temperature. The reaction mixture was then pre-
absorbed on silica gel and purified by silica gel chroma-
tography (gradient elution using 6–10% ethyl acetate/
hexanes) to afford 176mg (76%) of pure 6-(triisopropyl-
silyl)-5-hexyn-2-one (26) as a clear yellow oil. TLC
Rf = 0.29 (10% ethyl acetate/hexanes). IR (neat): 2942,
2865, 2173, 1721cmÀ1. 1H NMR (300MHz, CDCl3) d 2.63
(t, J = 7.6, 2H), 2.46 (t, J = 7.4, 2H), 2.13 (s, 3H), 0.92–
1.04 (m, 21H). 13C NMR (75MHz, CDCl3) d 206.6, 107.4,
81.0, 42.9, 30.0, 18.7, 14.8, 11.3. Anal. Calcd for
C15H28OSi: C, 71.36; H, 11.18. Found: C, 71.19; H, 11.40.
19. Characterization data for new compounds: 5: TLC
Rf = 0.36 (20% ethyl acetate/hexanes). IR (neat): 2921,
IR (neat): 3326, 2920, 1684cmÀ1 1H NMR (300MHz,
.
CDCl3) d 3.73 (t, J = 6.1, 2H), 2.60 (t, J = 7.4, 2H), 2.44–
2.37 (m, 4H), 2.28–2.23 (m, 2H), 1.82 (s, 1H), 1.72 (p,
J = 6.1, 2H), 1.58 (p, J = 7.5, 2H), 1.33–1.24 (m, 4H), 0.89
(t, J = 6.8, 3H). 13C NMR (75MHz, CDCl3) d 209.8, 80.1,
79.7, 62.1, 43.0, 42.1, 31.7, 31.6, 23.7, 22.6, 15.6, 14.1, 13.6.
Anal. Calcd for C13H22O2: C, 74.24; H, 10.54. Found: C,
74.35; H, 10.56. 29: TLC Rf = 0.34 (50% ethyl acetate/
hexanes). IR (neat): 3220, 2925, 2868, 1701cmÀ1 1H
.
NMR (300MHz, CDCl3) d 7.96 (dd, J = 8.0, 1.4, 2H), 7.57
(tt, J = 8.2, 1.3, 1H), 7.46 (t, J = 8.0, 2H), 3.72 (t, J = 6.1,
2H), 3.19 (t, J = 7.0, 2H), 2.61–2.55 (m, 2H), 2.29–2.23 (m,
2H), 2.03 (s, 1H), 1.71 (p, J = 6.2, 2H). 13C NMR
(75MHz, CDCl3) d 198.5, 136.6, 133.3, 128.7, 128.1,
80.2, 79.5, 61.7, 38.2, 31.6, 15.4, 13.8. Anal. Calcd for
C14H16O2: C, 77.75; H, 7.46. Found: C, 77.61; H, 7.58. 30:
TLC Rf = 0.39 (6% ethyl acetate/hexanes). IR (neat): 2942,
2864, 2174, 1690cmÀ1. 1H NMR (300MHz, CDCl3) d 7.97
(d, J = 7.4, 2H), 7.57 (tt, J = 7.6, 1.4, 1H), 7.47 (tt, J = 7.7,
1.4, 2H), 3.24 (t, J = 7.6, 2H), 2.69 (t, J = 7.7, 2H), 1.06–
1.02 (m, 21H). 13C NMR (75MHz, CDCl3) d 198.3, 136.9,
133.4, 128.8, 128.3, 107.7, 81.2, 38.3, 18.8, 15.2, 11.4. Anal.
Calcd for C20H30OSi: C, 76.37; H, 9.61. Found: C, 76.37;
H, 9.45.
1
1717cmÀ1. H NMR (300MHz, CDCl3) d 8.06–8.01 (m,
2H), 7.55 (tt, J = 7.3, 1.4, 1H), 7.43 (tt, J = 7.2, 1.5, 2H),
4.39 (t, J = 6.3, 2H), 2.61 (t, J = 6.9, 2H), 2.42–2.29 (m,
4H), 2.15 (s, 3H), 1.93 (p, J = 6.4, 2H). 13C NMR
(75MHz, CDCl3) d 207.1, 166.7, 133.1, 130.5, 129.8,
128.5, 79.7, 79.4, 63.9, 43.0, 30.1, 28.3, 15.8, 13.5. HRMS
(EI): m/z calcd for C16H18O3Na (M+Na) 281.1148.
Found: 281.1151. 14: TLC Rf = 0.39 (10% ethyl acetate/
hexanes). IR (neat): 2956, 2930, 1719cmÀ1 1H NMR
.
(300MHz, CDCl3) d 8.04 (d, J = 7.5, 2H), 7.55 (t, J = 7.5,
1H), 7.43 (t, J = 7.6, 2H), 4.39 (t, J = 6.3, 2H), 2.58 (t,
J = 7.6, 2H), 2.41–2.32 (m, 6H), 1.93 (p, J = 6.6, 2H) 1.57
(p, J = 7.3, 2H), 1.33–1.21 (m, 4H), 0.88 (t, J = 7.2, 3H).
13C NMR (75MHz, CDCl3) d 209.2, 166.4, 132.9, 130.3,
129.5, 128.3, 79.7, 79.1, 63.7, 432.8, 41.8, 31.4, 28.1, 23.4,
20. Compound 23 (Ref. 4), compound 24 (Ref. 14) and
compound 27 (Ref. 14) have been previously reported.
21. Zargfarian, D.; Chow, P.; Taylor, N. J.; Marder, T. B. J.
Chem. Soc., Chem. Commun. 1989, 9, 540.
22. Werner, H.; Brekau, U. Z. Naturforsch. B: Chem. Sci.
1989, 44, 1438.