Rhodium(I)-Catalyzed Cycloisomerization of 1,6-Enynes

Article abstract of DOI:10.1055/s-0034-1380359

A new and unexpected rhodium(I)-catalyzed cycloisomerization of 1,6-enynes is reported. Several different alkyne substitution patterns were evaluated under the reaction conditions, including a deuterated derivative that provides some insight into the reaction mechanism.

Full text of DOI:10.1055/s-0034-1380359

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1533–1536
letter
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Y. Matsushima et al.
Letter
Synlett
Rhodium(I)-Catalyzed Cycloisomerization of 1,6-Enynes
Yuji Matsushimaa
Eric M. Phillipsa
Robert G. Bergmanb
Jonathan A. Ellman*a
R
R
Bn
Bn
R
H2O
cat. [Rh]
O
N
N
a Department of Chemistry, Yale University, New Haven, CT 06520, USA
jonathan.ellman@yale.edu
b Lawrence Berkeley National Laboratory and Department of Chemistry, University of
California, Berkeley, CA 94720, USA
This manuscript is dedicated to Peter Vollhardt, who launched SYNLETT 25 years ago and
since that time has continuously served in a number of important editorial capacities.
Received: 21.01.2015
Accepted after revision: 23.02.2015
Published online: 27.02.2015
α,β-unsaturated imine via the nitrogen substituent
(Scheme 2).8 Subsequent electrocylization provides 6 with
bridgehead double bonds.
DOI: 10.1055/s-0034-1380359; Art ID: st-2015-b0044-l
R1
Abstract A new and unexpected rhodium(I)-catalyzed cycloisomeriza-
tion of 1,6-enynes is reported. Several different alkyne substitution pat-
terns were evaluated under the reaction conditions, including a deuter-
ated derivative that provides some insight into the reaction
mechanism.
cat. [Rh]
N
R2
5
R1
R1
Key words rhodium, homogeneous catalysis, ring closure, isomeriza-
tion, enones
R2
R2
N
N
Previously we have published on rhodium(I)-catalyzed
C–H alkenylation and electrocyclization cascades for the
convergent assembly of 1,2-dihydropyridines 4 from α,β-un-
saturated imines 1 and alkynes 2 (Scheme 1).1,2 The 1,2-di-
hydropyridine products have further proven to be versatile
intermediates for the synthesis of a variety of heterocyclic
structures,1 including pyridines,1,3,4 piperidines,5 isoquinu-
clidines,6 and tropanes.7
6
Scheme 2 Intramolecular C–H alkenylation–electrocyclization cascade
of substrates 5 with alkynes tethered to the nitrogen
In the present study we explored cyclization of
1,6-enyne substrates 7 in which the alkynyl group is teth-
ered to the α,β-unsaturated imine functionality with a dif-
ferent connectivity than that used for 5 (Scheme 3). Howev-
er, to our surprise, the rhodium(I)-catalyzed reaction of
1,6-enynes 7 did not provide any of the expected bicyclic
products 8, but rather resulted in the cycloisomerization
products 9, which upon hydrolysis provided exocyclic enals
109 with good levels of Z-selectivity.
R6
R6
R6
R1
R2
R5
R4
R1
R2
R5
R4
R5
R1
R2
[Rh]
2
Δ
N
N
N
+
R4
R3
R3
R3
We began our investigations by exploring the rhodi-
um(I)-catalyzed transformation of α,β-unsaturated imine
7a (Scheme 4). Using conditions previously determined to
be optimal for α,β-unsaturated imine C–H bond functional-
ization, which employed Rh[Cl(coe)2]2 as the precatalyst
and the commercially available electron-rich phosphine
4-Me2NPhPEt2, exocyclic enal 10a was obtained in 48%
yield, predominantly as the less stable Z-isomer. The stereo-
4
1
3
Scheme 1 C–H alkenylation–electrocyclization cascade to provide
1,2-dihydropyridines
To access complex, multicyclic heterocycles 6 with high
levels of regiocontrol we have explored the intramolecular
alkenylation of substrates 5 with the alkyne tethered to the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1533–1536

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Y. Matsushima et al.
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Synlett
1. [Rh(coe)2Cl]2 (5 mol%)
Me2NPhPEt2 (10 mol%)
2. filtration through
R
R
D3C
cat. [Rh]
Bn
Bn
D3C
O
Bn
N
N
N
activity (III) alumina
R
8
7b
10b
48%, 6.7:1 Z/E
Bn
N
EXPECTED
Scheme 5 No deuterium exchange occurs upon rhodium-catalyzed
cyclisomerization of deuterated substrate 7b
7
R
O
Bn
R
H2O
cat. [Rh]
N
more sterically hindered products is due to reduced isomer-
ization during imine hydrolysis upon filtration through alu-
mina.11
9
10
OBSERVED
Scheme 3 Unexpected reaction pathway for substrate 7 with alkynes
tethered to the β-carbon of the α,β-unsaturated imine
1. [Rh(coe)2Cl]2 (5 mol%)
Me2NPhPEt2 (10 mol%)
2. filtration through
activity (III) alumina
R
R
Bn
O
N
chemistry of 10a was further rigorously confirmed by com-
plete isomerization to the more stable E-isomer 11a9 under
acidic conditions.
10c (R = Et)
45%, 20:1 Z/E
7c, R = Et
7d, R = Bn
10d (R = Bn)
51%, 15:1 Z/E
1. [Rh(coe)2Cl]2 (5 mol%)
Me2NPhPEt2 (10 mol%)
2. Filtration through
Me
Me
O
Bn
Scheme 6 C–H alkenylation–electrocyclization cascade to provide
N
activity (III) alumina
1,2-dihydropyridines
10a
48%, 6.7:1 Z/E
7a
Cycloisomerizations of 1,6-enynes to give cyclohexene-
based products have previously been reported using ruthe-
nium and molybdenum metathesis catalysts,12 cationic gold
catalysts,13 and even rhodium(I) catalysts.14,15 However,
almost all of the previous reports, including all of the rhodi-
um(I)-catalyzed transformations, employ 1,6-enyne sub-
strates that incorporate a terminal alkyne. Transformations
of 1,6-enynes with internal alkynes to give cyclohexenyl
products are limited to ruthenium and molybdenum cata-
lysts proceeding by endo-selective enyne ring-closing me-
tathesis pathways. In fact, the previously reported rhodi-
um(I)-catalyzed cycloisomerizations of 1,6-enynes all con-
tained terminal alkynes and monosubstituted alkenes, and
for this class of 1,6-enynes, mechanistic studies support a
reaction pathway that proceeds via a rhodium–vinylidene
intermediate. It is notable that rhodium–vinylidene inter-
mediates are not accessible for the 1,6-enynes 7 reported
here that incorporate internal alkynes.
Me
Me
O
1 M aq HCl, r.t.
O
10a (6.7:1 Z/E)
11a 89%
Scheme 4 Rhodium-catalyzed cycloisomerization of 7a and confirma-
tion of stereochemistry of hydrolysis product 10a by equilibration to
11a
An intriguing aspect of this cycloisomerization reaction
is the formal trans-C–H bond addition across the alkynyl
group.10 We hypothesized that 7a might first isomerize to a
terminal allene or alkyne prior to cyclization and therefore
evaluated methyl-deuterated substrate 7b (Scheme 5).
Product 10b was isolated in the same yield and stereoiso-
meric purity as 10a with the methyl group remaining fully
deuterated without any deuterium transfer to other sites in
the structure. This result argues against the cycloisomeriza-
tion first proceeding by π-bond isomerization.
Two additional substrates were evaluated to demon-
strate that the reaction is applicable to substitution pat-
terns beyond methyl alkyne derivatives. As shown in
Scheme 6, ethyl 1,6-enyne 7c and benzyl 1,6-enyne 7d pro-
vided cyclic products 10c and 10d, respectively, in compa-
rable yields and with very high selectivity for the Z-alkene
isomer. We believe that the higher selectivity for these
In conclusion, we have identified a novel rhodium(I)-
catalyzed cycloisomerization of 1,6-enynes incorporating
internal alkyne moieties that gives functionalized six-
membered carbocyclic systems. Further mechanistic inqui-
ry will be necessary to elucidate the reaction mechanism.
Acknowledgment
This work was supported by the NIH under Grant No. GM069559
(J.A.E.). R.G.B. was supported by the Director, Office of Science, Office
of Basic Energy Sciences, and by the Division of Chemical Sciences,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1533–1536

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Y. Matsushima et al.
Letter
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Geosciences, and Biosciences of the U.S. Department of Energy at
LBNL under Contract No. DE-AC02-05CH11231. E.M.P. also acknowl-
0.62 mmol) in toluene (2 mL), and the mixture was stirred at
75 °C for 1 h. After removal of the solvent, the residual oil was
purified by column chromatography on grade III Al2O3 (hex-
anes–EtOAc, 100:0 to 99:1,) to afford 10a (Z/E = 6.7:1) as color-
less oil (41 mg, 0.30 mmol, 48% yield). Rf = 0.70 (hexanes–EtOAc.
4:1). 1H NMR (400 MHz, CDCl3): δ = 10.23 (d, J = 8.4 Hz, 1 H),
6.11 (ddd, J = 5.4, 2.7, 1.3 Hz, 1 H), 5.81 (d, J = 8.4 Hz, 1 H), 2.44
(ddd, J = 6.5, 4.3, 1.2 Hz, 2 H), 2.30–2.20 (m, 2 H), 2.17 (dd,
J = 3.3, 1.8 Hz, 3 H), 1.84–1.74 (m, 2 H). 13C NMR (101 MHz,
CDCl3): δ = 192.28, 156.42, 138.87, 131.95, 127.42, 35.59, 26.55,
26.04, 22.34. IR (thin film): 2927, 2867, 2834, 1653, 1615, 1580,
1448, 1406, 1223, 1178, 1149, 1130, 1101, 1025, 948 cm–1. MS
(EI): m/z [M]+ calcd for C9H12O+: 136.09; found: 136.10.
edges
support
from
an
NRSA
postdoctoral
fellowship
(F32GM090661).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380359. Included are the synthe-
sis procedures and analytical data for the cycloisomerization sub-
strates and intermediates in their synthesis. In addition, spectra are
provided for intermediates and cycloisomerization substrates 7a–d
and products 10a–d and 11a.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
(Z)-2-[2-(Methyl-d3)cyclohex-2-en-1-ylidene]acetaldehyde
(10b)
Compound 10b was synthesized according to the procedure
used for compound 10a. From 80 mg (0.57 mmol) of 7b was
obtained 39 mg (0.28 mmol, 49% yield) of 10b (Z/E = 6.7:1) as
colorless oil after purification by column chromatography on
grade III Al2O3 eluting with hexanes–EtOAc (100:0 to 99:1). Rf =
0.70 (hexanes–EtOAc. 4:1). 1H NMR (400 MHz, CDCl3): δ = 10.21
(d, J = 8.5 Hz, 1 H), 6.11 (td, J = 4.2, 1.3 Hz, 1 H), 5.81 (d, J = 8.5
Hz, 1 H), 2.48–2.40 (m, 2 H), 2.29–2.21 (m, 2 H), 1.83–1.74 (m, 2
H). 13C NMR (126 MHz, CDCl3): δ = 192.28, 156.44, 138.87,
131.89, 127.46, 35.60, 26.57, 22.38. IR (thin film): 3009, 2926,
References and Notes
(1) (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2008, 130, 3645. (b) For a general review on the synthesis and
further elaboration of 1,2-dihydropyridines prepared by C–H
bond functionalization–electrocyclization cascades, see:
Mesganaw, T.; Ellman, J. A. Org. Process Res. Dev. 2014, 18, 1097.
(2) For reviews on the synthesis and applications of 1,2-dihydro-
pyridines, see: (a) Tanaka, K.; Fukase, K.; Katsumura, S. Synlett
2011, 2115. (b) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette,
A. B. Chem. Rev. 2012, 112, 2642. (c) Silva, E. M. P.; Varandas, P.
A. M. M.; Silva, A. M. S. Synthesis 2013, 45, 3053.
1651, 1611, 1580, 1406, 1230, 1156, 1137, 1096, 1051, 974 cm–1
MS (EI): m/z [M]+ calcd for C9H9D3O+: 139.11; found: 139.15.
(Z)-2-(2-Ethylcyclohex-2-en-1-ylidene)acetaldehyde (10c)
.
(3) Martin, R. M.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2012,
77, 2501.
Compound 10c was synthesized according to the procedure
used for compound 10a. From 40 mg (0.27 mmol) of 7c was
obtained 18 mg (0.12 mmol, 45% yield) of 10c (Z/E = 20:1) as
colorless oil after purification by column chromatography on
grade III Al2O3 eluting with hexanes–EtOAc (100:0 to 99:1). Rf =
0.70 (hexanes–EtOAc. 4:1). 1H NMR (400 MHz, CDCl3): δ = 10.11
(d, J = 8.5 Hz, 1 H), 6.08 (ddd, J = 5.4, 2.8, 1.3 Hz, 1 H), 5.76 (d,
J = 8.5 Hz, 1 H), 2.53–2.44 (m, 2 H), 2.44–2.37 (m, 2 H), 2.30–
2.22 (m, 2 H), 1.84–1.75 (m, 2 H), 1.11 (t, J = 7.4 Hz, 3 H). 13C
NMR (126 MHz, CDCl3): δ = 192.40, 156.54, 138.12, 135.90,
126.41, 36.28, 30.99, 26.52, 22.88, 13.16. IR (thin film): 2966,
2928, 2876, 1660, 1617, 1583, 1453, 1409, 1222, 1174, 1150,
1127, 1107, 1081cm–1. MS (EI): m/z [M]+ calcd for C10H14O+:
150.10; found: 150.10.
(4) For leading references on alternative syntheses of pyridines via
C–H activation, see: (a) Parthasarathy, K.; Jeganmohan, M.;
Cheng, C.-H. Org. Lett. 2008, 10, 325. (b) Hyster, T. K.; Rovis, T.
Chem. Commun. 2011, 47, 11846. (c) Too, P. C.; Noji, T.; Lim, Y. J.;
Li, X.; Chiba, S. Synlett 2011, 2789. (d) Neely, J. M.; Rovis, T. J. Am.
Chem. Soc. 2013, 135, 66. (e) Zhang, Q.-R.; Huang, J.-R.; Zhang,
W.; Dong, L. Org. Lett. 2014, 16, 1684.
(5) (a) Duttwyler, S.; Lu, C.; Rheingold, A. L.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 4064. (b) Duttwyler, S.;
Chen, S.; Takase, M. K.; Wiberg, K. B.; Bergman, R. G.; Ellman, J.
A. Science 2013, 339, 678. (c) Ischay, M. A.; Takase, M. K.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2013, 135, 2478.
(d) Duttwyler, S.; Chen, S.; Lu, C.; Mercado, B. Q.; Bergman, R.
G.; Ellman, J. A. Angew. Chem. Int. Ed. 2014, 53, 3877.
(e) Mesganaw, T.; Ellman, J. A. Org. Process Res. Dev. 2014, 18,
1105.
(6) Martin, R. M.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2013, 15,
444.
(7) Ischay, M. A.; Takase, M. K.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2013, 135, 2478.
(8) Yotphan, S.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008,
130, 2452.
(9) Experimental Procedures for the Generation of Imines and
Rhodium-Catalyzed Cycloisomerization
(Z)-2-(2-Benzylcyclohex-2-en-1-ylidene)acetaldehyde (10d)
Compound 10d was synthesized according to the procedure
used for compound 10a. From 63 mg (0.30 mmol) of 7d was
obtained 32 mg (0.15 mmol, 51% yield) of 10d (Z/E = 15.5:1) as
colorless oil after purification by column chromatography on
grade III Al2O3 eluting with hexanes–EtOAc (100:0 to 99:1). Rf =
0.70 (hexanes–EtOAc. 4:1). 1H NMR (500 MHz, CDCl3): δ = 10.04
(d, J = 8.4 Hz, 1 H), 7.29 (t, J = 7.5 Hz, 2 H), 7.21 (t, J = 7.4 Hz, 1
H), 7.13 (d, J = 7.3 Hz, 2 H), 6.01 (td, J = 4.0, 1.0 Hz, 1 H), 5.73 (d,
J = 8.4 Hz, 1 H), 3.83 (s, 2 H), 2.50–2.43 (m, 2 H), 2.32 (ddd,
J = 6.0, 5.1, 2.0 Hz, 2 H), 1.90–1.82 (m, 2 H). 13C NMR (126 MHz,
CDCl3): δ = 192.10, 155.61, 140.14, 138.71, 135.05, 128.58,
128.55, 126.66, 126.41, 44.05, 36.22, 26.72, 22.65. IR (thin film):
3025, 2925, 2862, 1688, 1653, 1616, 1582, 1495, 1453, 1405,
1223, 1147, 1124, 978 cm–1. MS (EI): m/z [M]+ calcd for
(Z)-2-(2-Methylcyclohex-2-en-1-ylidene)acetaldehyde (10a)
In an inert atmosphere box, to the solution of 7a (86 mg, 0.63
mmol) in toluene (3 mL) was added benzylamine (68 mg, 0.63
mmol) and 3 Å MS (800 mg). The flask was removed from the
box, and the mixture was stirred at r.t. for 3 h. The 3 Å MS were
removed via filtration over Celite, which was washed with
toluene (8 mL). The filtrate was degassed and brought into an
inert atmosphere box. To the solution was added a solution of
[RhCl(coe)2]2 (23 mg, 0.031 mmol) and Me2NPhPEt2 (13 mg,
C
15H16O+: 212.12; found: 212.10.
(E)-2-(2-Methylcyclohex-2-en-1-ylidene)acetaldehyde (11a)
To a solution of 10a (40 mg, 0.29 mmol) in THF (2 mL) was
added a 1 M aqueous solution of HCl (1 mL, 1 mmol), and the
mixture was stirred at r.t. for 18 h. After being neutralized with
aq Na2CO3, the aqueous layer was extracted with EtOAc (3 × 5
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1533–1536

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Y. Matsushima et al.
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mL). The combined organic layers were washed with H2O and
brine and dried over with MgSO4. After filtration, the solvent
was removed under reduced pressure. The residual oil was puri-
fied by column chromatography on silica gel (33:1, pentane–
Et2O) to afford 11a as a colorless oil (36 mg, 0.26 mmol, 89%
yield). Rf = 0.70 (hexanes–EtOAc. 4:1). 1H NMR (400 MHz,
CDCl3): δ = 10.15 (d, J = 8.1 Hz, 1 H), 6.18 (t, J = 4.3 Hz, 1 H), 5.93
(d, J = 8.1 Hz, 1 H), 2.95–2.86 (m, 2 H), 2.26 (dtd, J = 7.8, 4.1, 1.9
Hz, 2 H), 1.85 (dd, J = 3.1, 1.7 Hz, 3 H), 1.80 (dt, J = 12.5, 6.2 Hz, 2
H). 13C NMR (126 MHz, CDCl3): δ = 191.49, 157.28, 138.03,
132.99, 122.62, 26.32, 25.82, 22.26, 19.65. IR (thin film): 2924,
2860, 1663, 1622, 1591, 1455, 1435, 1401, 1386, 1370, 1177,
1145, 1087, 1048 cm–1. MS (EI): m/z [M]+ calcd for C9H12O+:
136.09; found: 136.00.
hydrolysis. This loss in stereochemical purity was dependent
upon the structure of the imine. Colby, D. A.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 5604.
(12) (a) Trillo, B.; Gulias, M.; Lopez, F.; Castedo, L.; Mascarenas, J. L.
J. Organomet. Chem. 2005, 690, 5609. (b) Sashuk, V.; Grela, K.
J. Mol. Catal. A: Chem. 2006, 257, 59. (c) Singh, R.; Schrock, R. R.;
Müller, P.; Hoveyda, A. H. J. Am. Chem. Soc. 2007, 129, 12654.
(d) Lee, Y.-J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 10652.
(13) Nieto-Oberhuber, C.; Munoz, M. P.; Lopez, S.; Jiminez-Nunez, E.;
Nevado, C.; Herrero-Gomez, E.; Raducan, M.; Echavarren, A. M.
Chem. Eur. J. 2006, 12, 1677.
(14) (a) Grigg, R.; Stevenson, P.; Worakun, T. Tetrahedron 1988, 44,
4967. (b) Kim, H.; Lee, C. J. Am. Chem. Soc. 2005, 127, 10180.
(c) Joo, J. M.; Yuan, Y.; Lee, C. J. Am. Chem. Soc. 2006, 128, 14818.
(d) Joo, J. M.; Ramoncito, A. D.; Lee, C. Org. Lett. 2010, 12, 5704.
(15) For leading references on rhodium-catalyzed cycloisomeriza-
tions that proceed by ene-type pathways, see: (a) Okazaki, E.;
Okamoto, R.; Shibata, Y.; Noguchi, K.; Tanaka, K. Angew. Chem.
Int. Ed. 2012, 51, 6722. (b) Okamoto, R.; Okazaki, E.; Noguchi, K.;
Tanaka, K. Org. Lett. 2011, 13, 4894.
(10) For an unusual rhodium-catalyzed intramolecular trans
hydroacylation of an alkyne, see: Tanaka, K.; Fu, G. C. J. Am.
Chem. Soc. 2001, 123, 11492.
(11) In previous studies on rhodium-catalyzed β-alkylation of α,β-
unsaturated imines with alkenes, we observed >95:5 Z/E selec-
tivity for rhodium-catalyzed alkylation, but this Z/E ratio
degraded by as much as 5–15% during alumina-mediated imine
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1533–1536