Highly chemo-, regio-, and enantioselective rhodium-catalyzed cross-cyclotrimerization of two different alkynes with alkenes

Article abstract of DOI:10.1002/anie.201310336

It has been established that a cationic rhodium(I)/(R)-tol-binap complex catalyzes the cross-cyclotrimerization of silylacetylenes, di-tert-butyl acetylenedicarboxylates, and acrylamides with excellent chemo-, regio-, and enantioselectivities. Unsymmetrical alkynoates can also be employed in place of di-tert-butyl acetylenedicarboxylate for this process, but with reduced chemoselectivity. Cross-training: It has been established that a cationic rhodium(I)/(R)-tol-binap complex catalyzes the cross-cyclotrimerization of silylacetylenes, di-tert-butyl acetylenedicarboxylates, and acrylamides with excellent chemo-, regio-, and enantioselectivities. Unsymmetrical alkynoates can also be employed in place of di-tert-butyl acetylenedicarboxylate for this process, but with a reduced chemoselectivity.

Full text of DOI:10.1002/anie.201310336

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DOI: 10.1002/anie.201310336
Asymmetric Catalysis
Highly Chemo-, Regio-, and Enantioselective Rhodium-Catalyzed
Cross-Cyclotrimerization of Two Different Alkynes with Alkenes**
Jun Hara, Mana Ishida, Masayuki Kobayashi, Keiichi Noguchi, and Ken Tanaka*
Abstract: It has been established that a cationic rhodium(I)/
(R)-tol-binap complex catalyzes the cross-cyclotrimerization
of silylacetylenes, di-tert-butyl acetylenedicarboxylates, and
acrylamides with excellent chemo-, regio-, and enantioselectiv-
ities. Unsymmetrical alkynoates can also be employed in place
of di-tert-butyl acetylenedicarboxylate for this process, but with
reduced chemoselectivity.
acceptable yields. In addition, regioselectivities are insuffi-
cient in some cases. Recently, our research group accom-
plished the rhodium-catalyzed enantioselective cross-cyclo-
trimerization of electron-rich terminal alkynes, acetylenedi-
carboxylates, and enamides, however the product yields were
low to moderate.[7,8] Herein, we disclose the unprecedented
highly chemo-, regio-, and enantioselective catalytic cross-
cyclotrimerization of two different alkynes with an alkene.
Recently, our research group reported the chemo- and
regioselective synthesis of substituted trienes by the rhodium-
catalyzed intermolecular linear cross-trimerization of termi-
nal alkynes, acetylenedicarboxylates, and acrylamides.[11,12]
For example, a CH2Cl2 solution of N-methyl-N-phenylacryl-
amide (3a), di-tert-butyl acetylenedicarboxylate (2a), and n-
hexylacetylene (1a) or cyclohexylacetylene (1b) were
sequentially added to a CH2Cl2 solution of the cationic
rhodium(I)/H8-binap catalyst at room temperature to give
either the linear trimerization product 4aaa or 4baa in good
yield (Scheme 1).[11] However, tert-butyl acetylene (1c) failed
T
ransition-metal-catalyzed cross-[2+2+2] cyclotrimerization
reactions of three different unsaturated compounds are
efficient and atom-economical methods for the synthesis of
substituted six-membered compounds.[1] However, such trans-
formations have been accomplished in only a few examples
because of the difficulty in achieving high chemo- and
regioselectivities. For examples of the cross-cyclotrimeriza-
tion of three different alkynes,[2] Ikeda and co-workers
reported a nickel-catalyzed reaction[2a] and Kondoh and co-
workers reported a ruthenium-catalyzed reaction.[2b] For
examples of the cross-cyclotrimerization of two different
alkynes with alkenes,[3–10] Ikeda and co-workers reported the
nickel-catalyzed reaction[3] and Obora and co-workers
reported the niobium-catalyzed reaction.[4] Saito and co-
workers reported the nickel-catalyzed [3+2+2] cyclotrimeri-
zation of two different alkynes and ethyl cyclopropylidene-
acetate.[5] Our research group also reported the rhodium-
catalyzed cross-cyclotrimerization of terminal alkynes, acety-
lenedicarboxylates, and alkenyl acetates.[6] However, in these
reports, at least one component is in large excess so as to
obtain the three-component cyclotrimerization products in
Scheme 1. Rhodium-catalyzed linear trimerization versus cyclotrimeri-
zation. cod=cyclo-1,5-octadiene.
[*] J. Hara, M. Ishida, M. Kobayashi, Prof. Dr. K. Tanaka
Department of Applied Chemistry, Graduate School of Engineering
Tokyo University of Agriculture and Technology, Koganei
Tokyo 184-8588 (Japan)
to react with 2a and 3a (Scheme 1). Surprisingly, trimethyl-
silylacetylene (1d) reacted with 2a and 3a to give cyclo-
trimerization product 5daa in a good yield with an excellent
ee value, along with the linear trimerization product 4daa
(Scheme 1).
Thus, various axially chiral biaryl bisphosphine ligands
(Figure 1) were screened (Table 1, entries 1–5), and the use of
(R)-tol-binap afforded 5daa in the highest yield with an
excellent ee value (entry 4). Pleasingly, the simple addition of
a CH2Cl2 solution of 1d, 2a, and 3a to a CH2Cl2 solution of
a reduced amount of the catalyst (5 mol%) afforded 5daa
without erosion of the product yield and ee value (entry 6).
The substrate scope is shown in Scheme 2. With respect to
acrylamides, not only N-methyl-N-phenylacrylamide (3a) but
also N,N-dimethyl (3b), N,N-dibutyl (3c), N,N-tetramethy-
lene (3d), and Weinreb (3e) acrylamides could be employed.
With respect to alkynoates, not only 2a, but also the
E-mail: tanaka-k@cc.tuat.ac.jp
Homepage: http://www.tuat.ac.jp/~tanaka-k/
Prof. Dr. K. Noguchi
Instrumentation Analysis Center, Tokyo University of Agriculture
and Technology, Koganei, Tokyo 184-8588 (Japan)
Prof. Dr. K. Tanaka
Japan Science and Technology Agency (JST), ACT-C, 4-1-8 Honcho
Kawaguchi, Saitama, 332-0012 (Japan)
[**] This work was supported partly by a Grant-in-Aid for Scientific
Research (No. 20675002) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) and ACT-C from the Japan
Science and Technology Agency (JST) (Japan). We are grateful to
Umicore for generous support in supplying the rhodium complex,
and Takasago International Corporation for the gift of H8-binap,
segphos, and binap derivatives.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310336.
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Figure 1. Structures of axially chiral biaryl bisphosphine ligands.
Table 1: Optimization of reaction conditions for rhodium-catalyzed
enantioselective cross-cyclotrimerization of 1d, 2a, and 3a.[a]
Entry
Ligand
Catalyst
(mol%)
4daa
5daa
Yield [%][b]
Yield [%][b]
(ee [%])
1
2
3
4
(R)-H8-binap
(R)-binap
(R)-segphos
(R)-tol-binap
(R)-xyl-binap
(R)-tol-binap
10
10
10
10
10
5
16
<5
6
<5
56
74 (>99, +)
71 (95, +)
42 (>99, +)
91 (99, +)
20 (95, +)
92 (99, +)
5
6[c]
<5
[a] [Rh(cod)2]BF4/ligand (0.010 mmol), 1d (0.11 mmol), 2a
Scheme 2. Rhodium-catalyzed asymmetric cross-cyclotrimerization of
(0.10 mmol), 3a (0.11 mmol), and CH2Cl2 (2.0 mL) were used. Solutions
of 3a, 2a, and 1d in were added in this order to a solution of the Rh
catalyst in CH2Cl2. [b] Yield of isolated product. [c] A solution of 1d
(0.22 mmol), 2a (0.20 mmol), and 3a (0.22 mmol) in CH2Cl2 was added
to a solution of the Rh catalyst in CH2Cl2.
1d–g, 2a–d, and 3a–e. [Rh(cod)2]BF4 (0.010–0.040 mmol), (R)-tol-
binap (0.010–0.040 mmol), 1 (0.22–1.00 mmol), 2 (0.20 mmol), 3
(0.22 mmol), and CH2Cl2 (2.0 mL) were used. Cited yields are of
isolated products. [a] Conv. of 3a: ca. 60%. [b] [Rh(cod)2]BF4
(0.030 mmol), (R)-tol-binap (0.030 mmol), 1d (0.165 mmol), 2d
(0.225 mmol), 3a (0.150 mmol), and CH2Cl2 (2.0 mL) were used.
unsymmetrical alkynoates 2b,c reacted with 1d and 3a to give
cyclohexadienes 5 dba and 5dca in moderate yields, however
an increased amount of 1d and the catalyst were necessary. A
slight excess of the trifluoromethyl-substituted alkynoate 2d
also reacted with 1d and 3a to give the cyclohexadiene 5dda
with an excellent ee value, however the reaction was sluggish.
With respect to silylacetylenes, not only trimethylsilylacety-
lene (1d) but also triethylsilyl (1e) and benzyldimethylsilyl
(1 f) acetylenes could be employed, while tert-butyldimethyl-
silylacetylene (1g) failed to react with 2a and 3a. Importantly,
the present three-component cyclotrimerizations proceeded
with excellent regio- and enantioselectivities. The absolute
configuration of (+)-5dab was unambiguously determined to
be R by the anomalous dispersion methods.[13]
Next, the use of crotonamides in place of acrylamides was
attempted (Scheme 3).[14,15] We were pleased to find that the
reaction of 1d, 2a, and the N,N-dimethylcrotonamide 3 f in
the presence of the cationic rhodium(I)/(R)-tol-binap catalyst
(5 mol%) at room temperature affords the cyclotrimerization
product 5daf as a single diastereomer in a high yield with an
excellent ee value. With respect to crotonamides, N-methyl-
N-phenyl (3g) and N,N-tetramethylene (3h) crotonamides
could also be employed. However, N,N-dibutyl (3i) and
Weinreb (3j) crotonamides showed low reactivities and
required high catalyst loadings. Importantly, sterically more
demanding ethyl-, n-propyl-, and isopropyl-substituted acryl-
amides (3k–m) reacted with 1d and 2a to give the cyclo-
hexadienes 5dak–m, the yields of which were comparable to
that of 5daf. Unfortunately, the reaction of the phenyl-
substituted acrylamide 3n, 1d, and 2a afforded the cyclo-
hexadiene 5dan in low yield despite employing high catalyst
loading. With respect to alkynoates, not only the symmetrical
acetylenedicarboxylate 2a but also the unsymmetrical alky-
noates 2b,c reacted with 1d and 3 f to give cyclohexadienes
5 dbf and 5dcf in moderate yields, although increasing
amounts of 1d and the rhodium catalyst were necessary.
Unfortunately, the trifluoromethyl-substituted alkynoate 2d
showed poor reactivity. With respect to silylacetylenes, not
only trimethylsilylacetylene (1d) but also triethylsilyl (1e)
and benzyldimethylsilyl (1 f) acetylenes could be employed.
tert-Butyldimethylsilylacetylene (1g) could also react with 2a
and 3 f by using an increasing amount of the catalyst, although
the yield of 5gaf was low. Importantly, the present three-
component cyclotrimerization reactions proceeded with
excellent regio-, diastereo-, and enantioselectivities. The
absolute configuration of (+)-5daf was unambiguously deter-
mined to be (5R,6R) by the anomalous dispersion methods.[13]
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temperature. Cross-cyclotrimerization of 1d and 2a pro-
ceeded smoothly to give the substituted benzenes 10 and 11
(Scheme 5),[17] while 3a failed to react with both 1d and 2a
(Scheme 6).
Scheme 5. Treatment of 1d and 2a with the rhodium catalyst.
Scheme 6. Treatment of 3a and 1d or 3a and 2a with the rhodium
catalyst.
Scheme 3. Rhodium-catalyzed asymmetric cross-cyclotrimerization of
1d–g, 2a–d, and 3 f–n. [Rh(cod)2]BF4 (0.010–0.040 mmol), (R)-tol-
binap (0.010–0.040 mmol), 1 (0.22–1.00 mmol), 2 (0.20 mmol), 3
(0.22 mmol), and CH2Cl2 (2.0 mL) were used. Cited yields are of
isolated products. [a] Conv. of 3 f: ca. 30%. [b] [Rh(cod)2]BF4
(0.030 mmol), (R)-tol-binap (0.030 mmol), 1d (0.165 mmol), 2d
(0.225 mmol), 3 f (0.150 mmol), and CH2Cl2 (2.0 mL) were used.
THF=tetrahydrofuran.
Scheme 7. Possible reaction pathways.
Transformations of the reaction product were briefly
examined (Scheme 4). Desilylation and diene isomerization
of (+)-5daf proceeded by treatment with TBAF (tetra-n-
butylammonium fluoride) to give te cyclohexadiene (À)-6.
Hydrogenation of (À)-6 with Pd/C afforded (À)-7.[16] Dehy-
drogenation of (+)-5daf with MnO2 afforded the pentasub-
stituted benzene 8. Desilylation of 8 with TBAF afforded
tetrasubstituted benzene 9.
Possible reaction pathways for the formation of 5daa from
1d, 2a, and 3a are shown in Scheme 7. The reaction of 1d and
2a with rhodium generates the rhodacyclopentadiene A.
Insertion of 3a into A generates the intermediate B.
Reductive elimination would furnish 5daa and b-hydride
elimination with subsequent reductive elimination would
furnish 4daa. In contrast, the reaction of A with 1d or 2a
would furnish the either of the major by-products 10 or 11,
respectively. Alternatively, the formation of 5daa can be
explained by the formation of C through insertion of 3a into
Reactivities of 1d, 2a, and 3a were examined in the
presence of [Rh(cod)2]BF4/(R)-tol-binap catalyst at room
À
the sterically less demanding Rh C bond of A. Chelation of
the amide carbonyl to rhodium would suppress b-hydride
elimination.[18] However, given that 1) no linear trimerization
from b-hydride elimination of C was observed, 2) C has
a strained [4.2.1] bicyclic system, and 3) the insertion of the
À
Rh C bond across 3a would have to occur at the less
electrophilic site of the alkene, make this pathway unlikely.
Therefore, the formation of B is more likely, although the
precise mechanism cannot be identified at the present stage.
The bulky silyl groups would accelerate the reductive
Scheme 4. Transformations of (+)-5daf. TBAF=tetra-n-butylammo-
nium fluoride.
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Koma-gawa, I. Azumaya, H. Masu, S. Saito, Tetrahedron Lett.
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silyl and tert-butylcarbonyl groups.
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The experimental support of the former possibility is that
the reaction of sterically demanding tert-butylacetylene (1c)
with 2a and 3a afforded the cyclotrimerization product 5caa
without formation of the linear trimerization product 4caa,
however, the yield of 5caa was low (Scheme 8).
[6] a) H. Hara, M. Hirano, K. Tanaka, Org. Lett. 2008, 10, 2537;
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[8] The transition-metal-catalyzed enantioselective intermolecular
cross-cyclotrimerizations of two identical alkynes with alkenes
have been reported. See: a) S. Ikeda, H. Kondo, T. Arii, K.
Odashima, Chem. Commun. 2002, 2422; b) Y. Shibata, K.
Noguchi, M. Hirano, K. Tanaka, Org. Lett. 2008, 10, 2825.
[9] The transition-metal-catalyzed intermolecular cross-cyclotrime-
rizations of two different alkenes with alkynes have been
reported. See: a) S. Ogoshi, A. Nishimura, M. Ohashi, Org.
Lett. 2010, 12, 3450; For those of two identical alkenes with
alkynes, see: b) A. Nishimura, M. Ohashi, S. Ogoshi, J. Am.
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[10] For the use of temporary tethers to achieve the chemo- and
regioselective cyclotrimerization of three different unsaturated
compounds, see: a) Y. Yamamoto, J. Ishii, H. Nishiyama, K. Itoh,
J. Am. Chem. Soc. 2004, 126, 3712; b) Y. Yamamoto, J. Ishii, H.
Nishiyama, K. Itoh, J. Am. Chem. Soc. 2005, 127, 9625; c) G.
Chouraqui, M. Petit, C. Aubert, M. Malacria, Org. Lett. 2004, 6,
1519; d) B. L. Gray, X. Wang, W. C. Brown, L. Kuai, S. L.
Schreiber, Org. Lett. 2008, 10, 2621; e) T. J. Martin, T. Rovis,
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Scheme 8. Rhodium-catalyzed reaction of 1c, 2a, and 3a.
In conclusion, we have achieved the unprecedented highly
chemo-, regio-, and enantioselective catalytic cross-cyclo-
trimerization of two different alkynes with alkenes. When di-
tert-butyl acetylenedicarboxylate was employed, excess
amounts of cycloaddition partners are not required to
obtain three-component cyclotrimerization products in high
yields. Future work will focus on further exploration of the
rhodium-catalyzed intermolecular multicomponent reactions.
Received: November 28, 2013
Published online: February 6, 2014
[11] M. Kobayashi, K. Tanaka, Chem. Eur. J. 2012, 18, 9225.
[12] For examples of the transition-metal-catalyzed intermolecular
linear cross-trimerization reactions of two identical alkynes with
alkenes and two identical alkenes with alkynes, see: a) T.
Sambaiah, L.-P. Li, D.-J. Huang, C.-H. Lin, D. K. Rayabarapu,
C.-H. Cheng, J. Org. Chem. 1999, 64, 3663; b) Y. Nakao, H. Idei,
K. S. Kanyiva, T. Hiyama, J. Am. Chem. Soc. 2009, 131, 15996;
c) H. Horie, T. Kurahashi, S. Matsubara, Chem. Commun. 2010,
46, 7229; d) see Ref. [9a].
[13] CCDC 972328 [(+)-5dab] and CCDC 972329 [(+)-5daf] contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[14] The use of methacrylamide, acrylate, and vinyl ketone did not
afford three-component cyclotrimerization products.
[15] See the Supporting Information for optimization of reaction
conditions of 1d, 2a, and 3 f.
[16] Hydrogenation of another double bond and that of two double
bonds also proceeded in about 15% and 10% yield (NMR),
respectively. Cyclohexadiene (À)-7 (74% NMR yield) was
isolated as a mixture of these by-products and pure (À)-7 was
isolated in 60% yield by GPC.
[17] a) K. Tanaka, K. Shirasaka, Org. Lett. 2003, 5, 4697; b) K.
Tanaka, K. Toyoda, A. Wada, K. Shirasaka, M. Hirano, Chem.
Eur. J. 2005, 11, 1145.
Keywords: alkenes · alkynes · asymmetric catalysis ·
cyclotrimerization · multicomponent reactions · rhodium
.
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