Selective 1:2 Coupling of aldehydes and allenes with control of regiochemistry

Article abstract of DOI:10.1002/anie.201105077

Counterions in control: The rhodium(I)-catalyzed coupling of one molecule of aldehyde and two molecules of allene gave β,γ-dialkylidene ketones (see scheme). Either of two constitutional isomers was selectively obtained depending on the counterion of the rhodium(I) complex. Copyright

Full text of DOI:10.1002/anie.201105077

Communications
DOI: 10.1002/anie.201105077
Coupling Reactions
Selective 1:2 Coupling of Aldehydes and Allenes with Control of
Regiochemistry**
Takeharu Toyoshima, Tomoya Miura, and Masahiro Murakami*
Dedicated to Professor Christian Bruneau on the occasion of his 60th birthday
Transition-metal-catalyzed coupling reactions of aldehydes
[{RhCl(cod)}2] (5 mol% of Rh) and dppe (5 mol%) in
toluene (Table 1, entry 1). After the reaction mixture was
heated at 808C for 11 h, 40% of the aldehyde 1a was
consumed and the other portion of 1a remained intact. While
the formation of a 1:1 coupling product of 1a with 2a was not
observed, an isomeric mixture of 1:2 coupling products of 1a
with 2a was formed. Chromatographic purification afforded a
93:7 mixture of the products 3aa and 4aa in 33% combined
yield along with a trace amount (ca. 2%) of the product 5aa.
When the ratio 2a/1a was increased to 3.5:1, the aldehyde 1a
was quantitatively transformed into the b,g-dialkylidene
ketones (3aa:4aa:5aa = 90:6:4; Table 1, entry 2). Analogous
rhodium bromide and rhodium iodide complexes gave results
inferior to the chloride complex in terms of both yield and
product selectivity (Table 1, entries 3 and 4).[11] A slightly
better result was obtained with the use of [{RhCl(nbd)}2]
(3aa:4aa:5aa = 91:6:3; Table 1, entry 5; conditions A).
To our surprise, completely different product selectivity
was observed when cationic rhodium(I) complexes were
with unsaturated compounds provide useful methods for the
[1]
À
synthesis of alcohols and ketones by C C bond formation.
Allenes are often employed as the reactive coupling partner.
Their two orthogonal p-systems possess comparable potential
to participate in the coupling reactions, and the regiochem-
istry associated with unsymmetrical allenes results in wide
structural variations in the products. A nickel(0)-catalyzed
reductive coupling reaction of aldehydes, allenes, and silanes
affords allylic alcohol derivatives.[2] In contrast, homoallylic
alcohols are produced by a nickel(0)-catalyzed alkylative
coupling reaction using organozinc compounds instead of
silanes.[3,4] A hydrogenative coupling reaction of aldehydes
with allenes is catalyzed by iridium(I) and ruthenium(II)
complexes and leads to the formation of homoallylic alco-
hols.[5] A rhodium(I)-catalyzed coupling reaction of thio-
substituted aldehydes with allenes proceeds through oxidative
À
addition of an aldehydic C H bond to furnish b,g-unsaturated
ketones.[6,7] We recently found a rhodium(I)-catalyzed dime-
rization reaction of allenes;[8] this discovery led us to study a
rhodium(I)-catalyzed coupling reaction of aldehydes with
allenes.[9] Herein is described a new coupling reaction of one
molecule of aldehyde and two molecules of allene to give b,g-
dialkylidene ketones.[10] Either one of two constitutional
isomers is selectively obtained depending on the counterion
of the employed rhodium(I) catalyst [Eq. (1)].
Table 1: Rhodium(I)-catalyzed coupling reaction of 1a and 2a: Screening
of rhodium(I) complexes.[a]
Initially, 2-naphthaldehyde (1a) was treated with
1.1 equiv of 5-phenylpenta-1,2-diene (2a) in the presence of
No.
[Rh]
Total yield [%][b]
3aa/4aa/5aa[c]
1
2
3
4
5
6
7
8
9
[{RhCl(cod)}2][d]
[{RhCl(cod)}2]
[{RhBr(cod)}2]
[{RhI(cod)}2]
[{RhCl(nbd)}2]
[Rh(cod)2]BF4
[Rh(cod)2]PF6
[Rh(cod)2]OTf
[Rh(cod)2]OTf[f]
41 (33)[e]
99 (84)[e]
72
89:7:4
90:6:4
83:8:9
72:9:19
91:6:3
13:0:87
9:0:91
6:0:94
5:0:95
51
100 (87)[e]
35
59
75
100 (79)[g]
[*] Dr. T. Toyoshima, Dr. T. Miura, Prof. Dr. M. Murakami
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University, Katsura, Kyoto 615-8510 (Japan)
E-mail: murakami@sbchem.kyoto-u.ac.jp
[a] 1a (0.2 mmol) and 2a (0.7 mmol, 3.5 equiv) in toluene (1 mL) were
heated at 808C for 11 h in the presence of [Rh] (10 mmol) and dppe
(10 mmol) unless otherwise noted. [b] Total yield of 3aa, 4aa, and 5aa
1
determined by H NMR spectroscopy of the crude reaction mixture.
Homepage: http://www.sbchem.kyoto-u.ac.jp/murakami-lab/
1
[c] Product ratios determined by H NMR spectroscopy of the crude
[**] This work was supported in part by MEXT (Grant-in-Aid for
Scientific Research on Innovative Areas Nos. 22105005 and
22106520, Young Scientists (A) No. 23685019) and Asahi Glass
Foundation. T.T. is grateful for a Research Fellowship from the JSPS
for Young Scientists.
reaction mixture. [d] Using 1a (0.2 mmol) and 2a (0.22 mmol,
1.1 equiv). [e] The combined yield of 3aa and 4aa after chromatographic
purification is in parentheses. [f] Using dppe-4-CF3 (10 mmol) at 408C for
24 h. [g] Yield of isolated 5aa after chromatographic purification in
parenthesis. cod=cyclooctadiene, dppe=1,2-bis(diphenylphosphino)-
ethane, 2-Naph=2-naphthyl, nbd=norbornadiene, Tf=trifluorometha-
nesulfonyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105077.
10436
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 10436 –10439

examined. The isomer 5aa became the major product when
[Rh(cod)2]BF4 was used instead of [{RhCl(nbd)}2] (Table 1,
entry 6). The selectivity was affected by the counterion, and
the triflate complex [Rh(cod)2]OTf showed better yield and
selectivity (Table 1, entry 8). The highest yield and selectivity
of 5aa (79%, 3aa:4aa:5aa = 5:0:95) were attained when
dppe-4-CF3 (1,2-bis(di(4-trifluoromethylphenyl)phosphino)-
ethane) was used as the additional ligand (Table 1, entry 9;
conditions B). Thus, either of the two constitutional isomers 3
and 5 was selectively prepared from the same starting
materials by using a suitable rhodium catalyst.
The results obtained with different combinations of
aldehydes and allenes under conditions A ([{RhCl(nbd)}2]/
dppe) are shown in Table 2. A diverse array of aldehydes 1b–
h reacted well with 2a to afford the corresponding 1:2
coupling products 3ba–ha in moderate to good yield with
good product selectivity (Table 2, entries 1–7). The reaction
of 1a with monosubstituted allenes 2b–g having various
primary alkyl groups proceeded efficiently to demonstrate
good functional group compatibility (Table 2, entries 8–13).
On the other hand, the allenes possessing cyclohexyl and tert-
butyl groups failed to undergo the coupling reaction with 1a,
probably because of steric reasons.
(entries 1–7). Functional groups such as benzyloxy, siloxy,
hydroxy, and 1,3-dioxoisoindolin-2-yl were tolerated in the
alkyl chain, as was the case with conditions A (Table 2,
entries 10–13). Higher product selectivity was generally
observed with the reaction under conditions B than with the
reaction under conditions A. In particular, the formation of
the isomer 4 was not observed under conditions B.
Although it is difficult to delineate a single mechanistic
pathway leading to b,g-dialkylidene ketones 3 and 5 from
aldehyde 1 and allene 2, a plausible mechanism is depicted in
Scheme 1.[12] Initially, intermolecular oxidative cyclization of
1 and 2 occurs on rhodium(I) to give five-membered ring
oxarhodacyclic intermediates A and B.[3] The counterion of
The coupling reaction was carried out also under con-
ditions B ([Rh(cod)2]OTf/dppe-4-CF3) and the results are
shown in Table 2. The reaction of various aldehydes 1b–h
with 2a under conditions B afforded the corresponding
isolated products 5ba–ha in yields ranging from 45% to 78%
Scheme 1. Proposed mechanism for the rhodium(I)-catalyzed synthesis
of 3 and 5 from 1 and 2.
Table 2: Rhodium(I)-catalyzed coupling reaction of 1 and 2.[a]
the employed rhodium complexes
dictates the regiochemistry of this
step. The neutral rhodium(I) chlo-
ride complex favors the coupling at
the terminal sp2 carbon of the allene
to form A. On the other hand, the
cationic rhodium(I) triflate com-
Conditions A
Conditions B
No.
1 (R1)
2 (R2)
yield [%]
3/4/5[c]
yield [%]
3/4/5[c]
plex favors the coupling at the
internal sp2 carbon to form B,
although the reason for this
change in reactivity is unclear. Sub-
sequent insertion of another mole-
3+4[b]
5[d]
1
2
3
4
5
6
7
8
1b (Ph)
1c (4-tol)
1d (2-tol)
1e (4-CF3C6H4)
1 f (4-MeOC6H4)
1g (2-furyl)
1h (Cy)
1a (2-naphthyl)
1a
1a
1a
1a
1a
2a ((CH2)2Ph)
2a
2a
2a
2a
2a
2a
2b (nHex)
2c (CH2Cy)
2d ((CH2)4OBn)
2e ((CH2)4OTBS)
2 f ((CH2)4OH)
2g ((CH2)4N(phth))
82
76
79
82
87:7:6
86:7:8
90:8:2
90:7:3
88:7:5
81:6:13
90:7:3
89:6:5
90:6:4
88:7:5
89:7:4
89:7:4
89:7:4
67[h]
62[h]
45[h]
78
1:0:99
1:0:99
1:0:99
6:0:94
1:0:99
1:0:99
5:0:95
3:0:97
7:0:93
3:0:97
4:0:96
3:0:97
3:0:97
À
cule of 2 into the Rh Csp2 bond at
68[e]
68[f]
63
47[h]
77
[13]
À
the internal C C double bond
expands the five-membered ring
oxarhodacycles A and B to seven-
membered ring oxarhodacycles C
and D, respectively. b-Hydride
elimination furnishes a carbonyl
group and reductive elimination
follows to give the products 3 and
5 together with the catalytically
active rhodium(I) complex.
61
82
79
82
75
79
82
9
10
11
12
13
77
80
57[g]
97
56[i]
85
[a] Conditions A: 1 (0.2 mmol) and 2 (0.7 mmol, 3.5 equiv) in toluene (1 mL) were heated at 808C for
11 h in the presence of [{RhCl(nbd)}2] (5 mmol) and dppe (10 mmol) unless otherwise noted. Conditions
B: 1 (0.2 mmol) and 2 (0.7 mmol, 3.5 equiv) in toluene (1 mL) were heated at 408C for 24 h in the
presence of [Rh(cod)2]OTf (10 mmol) and dppe-4-CF3 (10 mmol) unless otherwise noted. [b] Combined
yield of 3 and 4 after chromatographic purification. [c] Product ratios determined by 1H NMR analysis.
[d] Yield of isolated 5. [e] 24 h. [f] Using 2a (0.9 mmol, 4.5 equiv) in the presence of [{RhCl(nbd)}2]
(7.5 mmol) and dppe-4-CF3 (15 mmol). [g] Using 2 f (0.9 mmol, 4.5 equiv) in the presence of [{RhCl-
(nbd)}2] (7.5 mmol) and dppe (15 mmol). [h] Using dppe (10 mmol) at 608C for 11 h. [i] Using 2 f
(0.9 mmol, 4.5 equiv). Bn=benzyl, phth=phthaloyl, TBS=tert-butyldimethylsilyl.
We carried out the coupling
reaction using deuterated benzalde-
hyde (PhCDO; Scheme 2). Prod-
ucts [D1]-3ba and [D1]-5ba had a
deuterium atom incorporated at the
allylic position; this result is consis-
Angew. Chem. Int. Ed. 2011, 50, 10436 –10439
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www.angewandte.org 10437

Communications
mixture was passed through a pad of Florisil and eluted with ethyl
acetate (40–50 mL). The filtrate was concentrated under reduced
pressure. The residue was purified by preparative thin-layer chroma-
tography (silica gel; n-hexane/ether= 10:1) to give the products 3aa
and 4aa (77.1 mg, 0.17 mmol, 87% combined yield, 3aa/4aa = 94:6).
Typical procedure for the coupling reaction of aldehydes with
allenes using [Rh(cod)2]OTf/dppe-4-CF3 as the catalyst (Table 1,
entry 9; conditions B): To a side-arm tube equipped with a stirrer bar
was added 1a (31.2 mg, 0.2 mmol, 1.0 equiv), [Rh(cod)2]OTf (4.7 mg,
5.0 mmol; 5 mol% of Rh), and dppe-4-CF3 (6.7 mg, 10 mmol, 5
mol%). The tube was evacuated and refilled with argon three times.
Then, 2a (100.9 mg, 0.7 mmol, 3.5 equiv) and toluene (1.0 mL) were
added via a syringe and the tube was closed. After being heated at
408C for 24 h, the reaction mixture was cooled to room temperature.
The resulting mixture was passed through a pad of Florisil and eluted
with ethyl acetate (40–50 mL). The filtrate was concentrated under
reduced pressure. The residue was purified by preparative thin-layer
chromatography (silica gel; n-hexane/Et2O = 10:1) and gel perme-
ation chromatography (GPC; CHCl3) to give the product 5aa
(70.3 mg, 0.158 mmol, 79% yield).
Scheme 2. Deuterium-labeling studies.
tent with the b-hydride elimination/reductive elimination
path from C and D.
b,g-Dialkylidene ketones can act as a diene in the Diels–
Alder reaction [Eq. (2) and Eq. (3)]. Treatment of 3aa and
5aa with diethyl acetylenedicarboxylate (6) in the presence of
galvinoxyl afforded cyclic adducts 7aa and 8aa, respectively.
Received: July 20, 2011
Published online: September 14, 2011
Keywords: aldehydes · allenes · regioselectivity · rhodium ·
.
synthetic methods
[1] For recent reviews, see: a) J. Montgomery, G. J. Sormunen, Metal
Catalyzed Reductive C-C Bond Formation: A Departure from
Preformed Organometallic Reagents (Ed.: M. J. Krische),
Springer, Berlin, 2007; pp. 1 – 23; b) R. M. Moslin, K. Miller-
Moslin, T. F. Jamison, Chem. Commun. 2007, 4441; c) J. F.
Bower, I. S. Kim, R. L. Patman, M. J. Krische, Angew. Chem.
2009, 121, 36; Angew. Chem. Int. Ed. 2009, 48, 34; d) M. C. Willis,
Chem. Rev. 2010, 110, 725.
[2] a) S.-S. Ng, T. F. Jamison, J. Am. Chem. Soc. 2005, 127, 7320;
b) S.-S. Ng, T. F. Jamison, Tetrahedron 2006, 62, 11350.
[3] M. Song, J. Montgomery, Tetrahedron 2005, 61, 11440.
[4] For examples of the preparation of homoallylic alcohols by
reactions of aldehydes, allenes, and organoboron or organozinc
compounds catalyzed by palladium(II) and rhodium(I) com-
plexes, see: a) C. D. Hopkins, H. C. Malinakova, Org. Lett. 2004,
6, 2221; b) C. D. Hopkins, L. Guan, H. C. Malinakova, J. Org.
Chem. 2005, 70, 6848; c) T. Bai, S. Ma, G. Jia, Tetrahedron 2007,
63, 6210; d) Y. Yoshida, K. Murakami, H. Yorimitsu, K. Oshima,
J. Am. Chem. Soc. 2010, 132, 8878.
[5] a) E. Skucas, J. F. Bower, M. J. Krische, J. Am. Chem. Soc. 2007,
129, 12678; b) J. F. Bower, E. Skucas, R. L. Patman, M. J.
Krische, J. Am. Chem. Soc. 2007, 129, 15134; c) S. B. Han, I. S.
Kim, H. Han, M. J. Krische, J. Am. Chem. Soc. 2009, 131, 6916;
d) E. Skucas, J. R. Zbieg, M. J. Krische, J. Am. Chem. Soc. 2009,
131, 5054.
[6] a) J. D. Osborne, H. E. Randell-Sly, G. S. Currie, A. R. Cowley,
M. C. Willis, J. Am. Chem. Soc. 2008, 130, 17232; b) H. E.
Randell-Sly, J. D. Osborne, R. L. Woodward, G. S. Currie, M. C.
Willis, Tetrahedron 2009, 65, 5110.
[7] For a similar allene hydroacylation reaction using salicylalde-
hyde, see: K. Kokubo, K. Matsumasa, Y. Nishinaka, M. Miura,
M. Nomura, Bull. Chem. Soc. Jpn. 1999, 72, 303.
In summary, a new rhodium-catalyzed coupling reaction
of one molecule of aldehyde and two molecules of allene was
developed, and gives selectively either of two constitutional
isomers of b,g-dialkylidene ketones that are difficult to
synthesize by other methods. Interestingly, the regioselectiv-
ity of the reaction depends on the counterion of a rhodium(I)
complex. Further studies to elucidate the mechanism of this
reaction and to expand its utility are in progress.
Experimental Section
Typical procedure for the coupling reaction of aldehydes with allenes
using [{RhCl(nbd)}2]/dppe as the catalyst (Table 1, entry 5; conditions
A): To a side-arm tube equipped with a stirrer bar was added 1a
(31.2 mg, 0.2 mmol, 1.0 equiv), [{RhCl(nbd)}2] (2.3 mg, 5.0 mmol; 5
mol% of Rh), and dppe (4.0 mg, 10 mmol, 5 mol%). The tube was
evacuated and refilled with argon three times. Then, 2a (100.9 mg,
0.7 mmol, 3.5 equiv) and toluene (1.0 mL) were added via a syringe
and the tube was closed. After being heated at 808C for 11 h, the
reaction mixture was cooled to room temperature. The resulting
[8] T. Miura, T. Biyajima, T. Toyoshima, M. Murakami, Beilstein J.
Org. Chem. 2011, 7, 578.
[9] For palladium-catalyzed 1:2 coupling reactions of nucleophiles
(e.g. carboxylic acids, amines, and water) and allenes, see:
a) G. D. Shier, J. Organomet. Chem. 1967, 10, P15; b) D. R.
Coulson, J. Org. Chem. 1973, 38, 1483; c) Y. Inoue, Y. Ohtsuka,
10438 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 10436 –10439

H. Hashimoto, Bull. Chem. Soc. Jpn. 1984, 57, 3345; d) C. H. Oh,
H. S. Yoo, S. H. Jung, Chem. Lett. 2001, 1288.
[12] Another mechanism involving oxidative cyclization of a homo-
pair of allenes followed by the insertion of an aldehyde is also
conceivable. For examples of isolated rhodacyclopentanes
prepared from two molecules of an allene, see: a) G. Ingrosso,
L. Porri, G. Pantini, P. Racanelli, J. Organomet. Chem. 1975, 84,
75; b) J.-C. Choi, S. Sarai, T. Koizumi, K. Osakada, T. Yama-
moto, Organometallics 1998, 17, 2037.
[10] For rhodium-catalyzed reductive 1:2 coupling reactions of
aldehydes and acetylenes, see: a) J. R. Kong, M. J. Krische, J.
Am. Chem. Soc. 2006, 128, 16040; b) V. M. Williams, J. R. Kong,
B. J. Ko, Y. Mantri, J. S. Brodbelt, M.-H. Baik, M. J. Krische, J.
Am. Chem. Soc. 2009, 131, 16054.
[11] For the effect of halide ions on regioselectivity in a rhodium-
catalyzed allylic substitution reaction, see: P. A. Evans, D. K.
Leahy, L. M. Slieker, Tetrahedron: Asymmetry 2003, 14, 3613.
[13] The minor isomer 4 could be formed through the insertion of 2
À
À
into the Rh Csp2 bond of A at the terminal C C double bond and
subsequent b-hydride elimination/reductive elimination.
Angew. Chem. Int. Ed. 2011, 50, 10436 –10439
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