Rhodium-catalyzed enantioselective 1,6-addition of arylboronic acids to enynamides: Asymmetric synthesis of axially chiral allenylsilanes

Article abstract of DOI:10.1021/ja1066509

Rhodium-catalyzed asymmetric 1,6-addition of arylboronic acids to β-alkynyl acrylamides substituted with a silyl group on the alkyne terminus took place to give high yields of axially chiral allenylsilanes with 94-99% enantioselectivity, which was realized by use of a rhodium/chiral diene complex.

Full text of DOI:10.1021/ja1066509

Published on Web 08/31/2010
Rhodium-Catalyzed Enantioselective 1,6-Addition of Arylboronic Acids to
Enynamides: Asymmetric Synthesis of Axially Chiral Allenylsilanes
Takahiro Nishimura,* Hiroki Makino, Makoto Nagaosa, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Kyoto 606-8502, Japan
Received July 27, 2010; E-mail: tnishi@kuchem.kyoto-u.ac.jp; thayashi@kuchem.kyoto-u.ac.jp
Table 1. Rhodium-Catalyzed Asymmetric 1,6-Addition of
Phenylboronic Acid (2m) to Enynamide 1aa
Abstract: Rhodium-catalyzed asymmetric 1,6-addition of arylbo-
ronic acids to ꢀ-alkynyl acrylamides substituted with a silyl group
on the alkyne terminus took place to give high yields of axially
chiral allenylsilanes with 94-99% enantioselectivity, which was
realized by use of a rhodium/chiral diene complex.
Axially chiral allenes (1,2-propadienes) are attractive compounds
as chiral building blocks in organic synthesis, and useful synthetic
approaches to this class of compounds starting from prochiral
compounds have recently been developed.1,2 The 1,6-addition of
carbon nucleophiles to conjugated enyne-carbonyl compounds is one
of the most efficient approaches for the preparation of functionalized
allenes.3 Copper reagents or catalysts have been used for the selective
1,6-addition of organometallic reagents to enynoates leading to allenes,4
but the asymmetric variant catalyzed by copper complexes has not
been reported to date. In this context, we recently reported the
enantioselective synthesis of axially chiral allenes by means of 1,6-
addition of aryltitanates to enynones in the presence of chlorotrim-
ethylsilane, which is catalyzed by a rhodium/chiral bisphosphine
complex.5 The 1,6-addition products were obtained as ꢀ-allenylidene
silyl enolates with high enantioselectivity, but the substrates were
limited to ꢀ-alkynylated cycloalkenones, which effectively shield the
competing 1,4-addition reaction. Here we report the asymmetric 1,6-
addition of arylboronic acids to linear enynamides to give axially chiral
allenylsilanes6 in high yields with high enantioselectivity.
We found that enynamide 1a substituted with a terminal silyl group
on the alkyne is a good substrate that gives allenylsilane derivatives
with high enantioselectivity in the addition of arylboronic acids. Thus,
treatment of 1a with phenylboronic acid (2m, 2 equiv) in the presence
of the rhodium/chiral diene7 catalyst [RhCl((S,S)-Fc-tfb*(L1))]2 (Fc
) ferrocenyl)8 (5 mol % Rh) and K3PO4 (20 mol %) in 1,4-dioxane
and H2O at 50 °C for 3 h gave allenylsilane 3am with 98% ee together
with a small amount of 4am (total yield 87%, 3am/4am ) 98/2),
whereas the formation of the corresponding 1,4-adduct was not
observed (Scheme 1). The characteristic 1,6-selectivity observed in
the addition to 1a arises from the amide functionality. For example,
the reaction of a tert-butyl ester of the same enyne moiety gave a
mixture of the corresponding 1,6- and 1,4-addition products (82% yield,
1,6-/1,4-adduct ) 1/1).
entry
Rh cat.
time (h)
conv. (%)b
yield (%)b
1
2
3
[RhCl((S,S)-L1)]2
3
3
3
9
3
3
3
3
100
24
27
40
26
0
85 (98% ee)
16
19
22 (89% ee)
18
0
[RhCl((R,R)-L2)]2
[RhCl((R,R)-L3)]2
[RhCl((R,R)-L3)]2
[RhCl(C2H4)2]2/(R)-L4
[RhCl((R)-L5)]2
[Rh(OH)((R)-L5)]2
[RhCl(C2H4)2]2/(S,S,S)-L6
4
5c
6
7
3
0
0
0
8d
a Reaction conditions: 1a (0.20 mmol), 2m (0.40 mmol), Rh catalyst
(5 mol % Rh), K3PO4 (0.040 mmol), 1,4-dioxane (1.0 mL), H2O (0.1
mL) at 50 °C for 3 h. b The conversion of 1a and the yield of 3am were
determined by 1H NMR spectroscopy. Values in parentheses are ee’s of
3am determined by HPLC analysis. c L4 (6 mol %). d L6 (12 mol %).
The choice of ligand is important for the catalytic activity in the
present reaction (Table 1). Complete consumption of starting 1a
was observed when diene ligand L1 substituted with ferrocenyl
groups was used (entry 1). In contrast, the use of diene ligands
substituted with benzyl (L2) and phenyl (L3) gave 3am in 16 and
19% yield, respectively, with recovery of a significant amount of
unreacted 1a (entries 2 and 3). The yield of 3am was low (22%)
in the reaction catalyzed by [RhCl(L3)]2, even with a prolonged
reaction time (9 h) (entry 4), indicating that the catalyst lost its
activity during the reaction (see below). Ligand L49 also displayed
low activity, giving 3am in 18% yield (entry 5). The formation of
the addition products was not observed with binap L510 or
phosphoramidite L611 (entries 6-8).
Scheme 1
The absolute configuration of 3am was determined to be (S)-
(+) by X-ray crystallographic analysis of compound 6, which was
derived from 3am in two steps (Scheme 2).12 Thus, reduction of
13
the Weinreb amide in 3am by treatment with NaBH4 followed
by Mitsunobu-type amination with phthalimide and (cyanometh-
ylene)tributylphosphorane14 gave 6 in good yield without loss of
its enantiomeric purity.
9
10.1021/ja1066509  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 12865–12867 12865

C O M M U N I C A T I O N S
Scheme 2
Scheme 3. Proposed Catalytic Cycle
Table 2. Rhodium-Catalyzed Asymmetric 1,6-Addition of
Arylboronic Acids to Enynamides 1a
Scheme 4
entry
1
Ar
time (h)
yield (%)b
ee (%)c
1
2
3
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Ph (2m)
3
3
3
87 (3am)
89 (3an)
86 (3ao)
86 (3ap)
87 (3aq)
80 (3ar)
74 (3as)
79 (3at)
80 (3bm)
75 (3cm)
70 (3dm)
82 (3em)
86 (3fm)
98 (S)
97 (S)
97 (S)
97 (S)
96 (S)
96 (S)
96 (S)
95 (S)
94 (S)
96 (S)
94 (S)
96 (S)
99 (S)
4-MeC6H4 (2n)
3-MeC6H4 (2o)
4-MeOC6H4 (2p)
3,4-(OCH2O)C6H3 (2q)
4-ClC6H4 (2r)
4-BrC6H4 (2s)
4-CF3C6H4 (2t)
Ph (2m)
Ph (2m)
Ph (2m)
Ph (2m)
Ph (2m)
4
3
5d
6
12
36
36
24
6
7
8
9
10
11
12
13
3
the formation of a stable alkenylrhodium species (Scheme 4). Thus,
in the reaction of 1a with 2m in the presence of a catalytic amount
of [RhCl(L3)]2 (Table 1, entry 4), alkenylrhodium complex 7 was
isolated by column chromatography on silica gel with hexane/ethyl
acetate under air. The structure of 7 was assigned by analogy with
8, which was separately prepared by a stoichiometric reaction of
[RhCl(L3)]2 with 1f and the neopentyl glycolate ester of 2m (Figure
1).19 The formation of 7 can be explained by alkyne insertion with
regioselectivity opposite to that leading to 3am (Scheme 4). Thus,
insertion of the alkyne into the phenyl-rhodium bond that places
the phenyl group away from the silyl group generates alkenyl-
rhodium F (route a). Subsequent geometrical isomerization produces
alkenylrhodium 7. Complex 7 is too stable to regenerate an active
catalytic species. Actually, the reaction of 1a with 2m in the
presence of a catalytic amount of 7 (5 mol %) in a separate
experiment did not give the addition products at all. The high
catalytic activity of the rhodium complex coordinated with L1 is
attributed to the regioselective alkyne insertion leading to alkenyl-
72
24
12
a Reaction conditions: 1 (0.20 mmol), ArB(OH)2 (2) (0.40 mmol),
[RhCl((S,S)-L1)]2 (5 mol % Rh), K3PO4 (0.040 mmol), 1,4-dioxane (1.0
mL), H2O (0.1 mL) at 50 °C. b Isolated yields. Inseparable isomers are
included in entries 1-10 (2-5%). c Determined by HPLC analysis. The
absolute configurations were assigned by analogy with entry 1.
d Performed with (ArBO)3 (0.13 mmol).
The results obtained for the rhodium-catalyzed 1,6-addition of
several arylboronic acids to enynamides are summarized in Table
2. Arylboronic acids with aryl groups bearing a variety of
substituents (2m-t) were successfully introduced into the reaction
of 1a, giving the corresponding addition products (3am-at) in good
yields with enantioselectivities ranging from 95 to 98% ee (entries
1-8).15 The addition of 2m to enynamides substituted with tert-
butyldimethylsilyl (1b) and triethylsilyl (1c) groups on the alkyne
proceeded well to give 3bm and 3cm, respectively, with high
enantioselectivity (entries 9 and 10).16 Diisopropyl- (1d), dibenzyl-
(1e), and diphenylamide (1f) were also good substrates, giving the
corresponding addition products (3dm-fm) in good yields with
94-99% ee (entries 11-13).
A proposed catalytic cycle for the present reaction is shown in
Scheme 3. Transmetalation of a phenyl group from the boron to
the rhodium center forms phenylrhodium species B. Insertion of
an alkyne into the phenyl-rhodium bond with regiochemistry in
which the phenyl is placed proximal to a silyl group on 1a generates
alkenylrhodium C, and isomerization by coordination of an alkene
moiety forms benzylidene-π-allylrhodium D.17 Hydrolysis of D
or oxa-π-allylrhodium E gives the allene 3am and hydroxorhodium
species A.18
Figure 1. (left) Synthesis of 8. (right) ORTEP illustration of 8 with thermal
ellipsoids drawn at the 30% probability level. Hydrogen atoms and a solvent
molecule have been omitted for clarity.
It was found that the catalyst deactivation observed in the reaction
with chiral diene ligand L3 (Table 1, entries 3 and 4) is caused by
9
12866 J. AM. CHEM. SOC. VOL. 132, NO. 37, 2010

C O M M U N I C A T I O N S
Scheme 5. Proposed Stereochemical Pathway
References
(1) For a review of catalytic asymmetric synthesis of axially chiral allenes,
see: (a) Ogasawara, M. Tetrahedron: Asymmetry 2009, 20, 259. For reviews
of the synthesis of allenes, see: (b) Brummond, K. M.; DeForrest, J. E.
Synthesis 2007, 795. (c) Krause, N.; Hoffmann-Ro¨der, A. Tetrahedron 2004,
60, 11671.
(2) For selected examples of catalytic enantioselective synthesis of allenes,
see: (a) de Graaf, W.; Boersma, J.; van Koten, G.; Elsevier, C. J. J.
Organomet. Chem. 1989, 378, 115. (b) Matsumoto, Y.; Naito, M.; Uozumi,
Y.; Hayashi, T. J. Chem. Soc., Chem. Commun. 1993, 1468. (c) Ogasawara,
M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 2089.
(d) Han, J. W.; Tokunaga, N.; Hayashi, T. J. Am. Chem. Soc. 2001, 123,
12915. (e) Tillack, A.; Michalik, D.; Koy, C.; Michalik, M. Tetrahedron
Lett. 1999, 40, 6567. (f) Tillack, A.; Koy, C.; Michalik, D.; Fischer, C. J.
Organomet. Chem. 2000, 603, 116. (g) Imada, Y.; Ueno, K.; Kutsuwa, K.;
Murahashi, S.-I. Chem. Lett. 2002, 140. (h) Trost, B. M.; Fandrick, D. R.;
Dinh, D. C. J. Am. Chem. Soc. 2005, 127, 14186. (i) Oku, M.; Arai, S.;
Katayama, K.; Shioiri, T. Synlett 2000, 493. (j) Liu, H.; Leow, D.; Huang,
K.-W.; Tan, C.-H. J. Am. Chem. Soc. 2009, 131, 7212.
rhodium C (route b). The selectivity may be caused by the bulkiness
of the ferrocenyl substituents on L1, which places the rhodium away
from the bulky silyl group.
(3) For reviews, see: (a) Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1986,
25, 947. (b) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997,
36, 186. (c) Krause, N.; Thorand, S. Inorg. Chim. Acta 1999, 296, 1.
The formation of addition products having the S configuration
is presumably explained by the stereochemical model shown in
Scheme 5. The rhodium complex coordinated with (S,S)-L1
constructs an effective C2-symmetric environment with the ferro-
cenyl substituents located at upper-left and lower-right positions.8
When isomerization of the alkenyl species C into the ben-
zylidene-π-allylrhodium D occurs in the catalytic cycle, the bottom
face of the double bond intramolecularly coordinates to the rhodium
center in a manner that avoids the steric repulsions between the
substituent on the diene ligand and the benzylidene moiety (and/or
the amide Z). Thus, the formation of the D-1 structure to give (S)-3
is favorable.
(4) (a) Hulce, M. Tetrahedron Lett. 1988, 29, 5851. (b) Cheng, M.; Hulce, M.
J. Org. Chem. 1990, 55, 964. (c) Krause, N. Chem. Ber. 1990, 123, 2173.
(d) Haubrich, A.; van Klaveren, M.; van Koten, G.; Handke, G.; Krause,
N. J. Org. Chem. 1993, 58, 5849. (e) Handke, G.; Krause, N. Tetrahedron
Lett. 1993, 34, 6037. (f) Canisius, J.; Gerold, A.; Krause, N. Angew. Chem.,
Int. Ed. 1999, 38, 1644.
(5) Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett. 2004, 6, 305.
(6) Curtis-Long, M. J.; Aye, Y. Chem.sEur. J. 2009, 15, 5402.
(7) For reviews, see: (a) Shintani, R.; Hayashi, T. Aldrichimica Acta 2009,
42, 31. (b) Defieber, C.; Gru¨tzmacher, H.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2008, 47, 4482.
(8) Nishimura, T.; Kumamoto, H.; Nagaosa, M.; Hayashi, T. Chem. Commun.
2009, 5713.
(9) Okamoto, K.; Hayashi, T.; Rawal, V. H. Chem. Commun. 2009, 4815.
(10) Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.;
Taketomi, T.; Akutagawa, S.; Noyori, R. J. Org. Chem. 1986, 51, 629.
(11) Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.;
In summary, we have developed a rhodium-catalyzed asymmetric
1,6-addition of arylboronic acids to enynamides that gives axially
chiral allenylsilanes with high enantioselectivity, which was realized
by use of a rhodium/chiral diene complex.
Feringa, B. L. Tetrahedron 2000, 56, 2865.
(12) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876.
(13) Mori, A.; Kato, T. Synlett 2002, 1167.
(14) Sakamoto, I.; Nishii, T.; Ozaki, F.; Kaku, H.; Tanaka, M.; Tsunoda, T.
Chem. Pharm. Bull. 2005, 53, 1508.
(15) The reaction of 1a with (E)-2-phenylethenylboronic acid did not give the
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research (S) (19105002) from the MEXT, Japan.
M.N. thanks the JSPS for a Research Fellowship for Young
Scientists.
corresponding allene, and 80% of the starting 1a was recovered.
(16) The reaction of an enynamide terminally substituted with phenyl on the
alkyne of 1a did not give the corresponding allene at all.
(17) Ogasawara, M.; Okada, A.; Watanabe, S.; Fan, L.; Uetake, K.; Nakajima,
K.; Takahashi, T. Organometallics 2007, 26, 5025.
(18) The addition to 1f with phenylboroxine in the presence of D2O instead of
H2O gave the 2-deuterated product [D]3fm (91% D) in 86% yield with
high diastereoselectivity (>95%).
Supporting Information Available: Experimental procedures,
spectroscopic and analytical data for the substrates and products, and
crystallographic data (CIF) for 6 and 8. This material is available free
of charge via the Internet at http://pubs.acs.org.
(19) Crystal data for 8 are reported in the Supporting Information.
JA1066509
9
J. AM. CHEM. SOC. VOL. 132, NO. 37, 2010 12867