A Rh(I)-catalyzed cycloisomerization reaction affording cyclic trienones

Article abstract of DOI:10.1055/s-2008-1032111

A Rh(I)-catalyzed carbocyclization reaction of alleneynones affords functionalized 2-alkylidene-3-vinylcyclohexenones and 2-alkylidene-3- vinylcyclopentenones. The scope, limitations, and utility of this triene-forming protocol have been examined and the results reported within. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032111

CLUSTER
759
A Rh(I)-Catalyzed Cycloisomerization Reaction Affording Cyclic Trienones
Rh(I)-Catalyzed
C
a
ycloisomer
y
izationReaction Af
M
fording Cyclic Trieno
.
Department of Chemistry and University of Pittsburgh Center for Chemical Methodologies and Library Development,
University of Pittsburgh, Pittsburgh, PA 15260, USA
Fax +1(412)6248611; E-mail: kbrummon@pitt.edu
Received 4 December 2007
O
O
Abstract: A Rh(I)-catalyzed carbocyclization reaction of allene-
ynones affords functionalized 2-alkylidene-3-vinylcyclohexenones
and 2-alkylidene-3-vinylcyclopentenones. The scope, limitations,
and utility of this triene-forming protocol have been examined and
the results reported within.
R1
R1
2a–j
N
, n-BuLi
•
•
BF3⋅OEt2, AcOH
51–98%
1
3a–k
Key words: allenes, alkynes, Rh(I), cycloisomerization, triene
3g R1 = Ph, 98%
3a R1 = Me, 93%
3h R1 = 4-MeOC6H4, 93%
3i R1 = 4-F3CC6H4, 90%
3j R1 = OEt, 83%
3b R1 = (CH2)3OTBS, 51%
3c R1 = (CH2)2OTBS, 99%
3d R1 = (CH2)2OTHP, 98%
3e R1 = TMS, 64%
Selective and concise entry into molecular complexity via
carbocyclization reactions of unsaturated carbon–carbon
bonds is an important area in organometallic chemistry.1
Recently, it was demonstrated that Rh(I)-catalyzed cy-
cloisomerization reactions of allenes lead to trienyl-con-
taining carbocycles,2 heterocycles,2 d- and e-lactams,3 and
d-lactones.4 Combining these functional motifs with a
cross-conjugated trienyl moiety provides functionally
dense substructures and if chemical reactivity can be con-
trolled, a means of gaining rapid access to molecular com-
plexity.
3k R1 = H, 90%
3f R1 = 1-cyclohexenyl, 97%
Scheme 1 Formation of allenyl alkynones 3a–k
Next, the scope and limitations of this reaction were ex-
amined by varying the substituents on the alkyne. These
variations had a significant impact on the rate and yields
of these cycloisomerization reactions. For example, if
R1 = Me (3a) or a TBS-protected propanol 3b, conversion
to 4a or 4b required 90 minutes (entries 1 and 2, Table 1).
Interestingly, shortening the tether between the protected
alcohol and the alkyne from three to two methylene units
dramatically reduces the reaction time to ca. 20 minutes
(entries 3 and 4, Table 1).9 Alternatively, placing an aro-
matic ring on the alkyne terminus slows the reaction, re-
quiring that substrate 3g be heated to 50 °C and 8 mol%
of Rh(I) catalyst to effect the formation of trienone 4g. An
electron-withdrawing or electron-donating group on the
para-position of the aryl ring had a negligible effect on
this reaction; since each of these reactions occurred within
five minutes and the corresponding products were ob-
tained in similar yields (entries 7–9). An ethoxy group on
the alkyne terminus furnished a product that quickly de-
composed before it could be characterized (entry 10,
Table 1). Terminal alkynes were not tolerated under the
reaction conditions since complete decomposition was
observed immediately upon addition of the Rh(I) catalyst
(entry 11).10,11
Using cross-conjugated trienes in complexity generating
reactions requires novel approaches to controlling double-
bond selectivity.5 It was this control element that led us to
consider the carbocyclization reactions of alkynones6 be-
cause the resulting trienones would possess double bonds
that are sterically biased and electronically differentiated
by the carbonyl group. In this Letter we report on the as-
sembly of the allene-ynones and their participation in
Rh(I)-catalyzed carbocylization reactions to produce
trienones. Selective reactions of the double bonds of the
trienones were briefly investigated and also reported on.
Allene-ynones 3a–j7 were conveniently prepared by addi-
tion of the corresponding lithium acetylides 2a–j to amide
1 (Scheme 1). Compound 3k, possessing a terminal
alkynone, was obtained by removal of the TMS group
from 3e.7c Subjecting allene-ynone 3e to the standard re-
action protocol developed in our group for the Rh(I)-cata-
lyzed
cycloisomerization
reaction
{10
mol%
[Rh(CO)2Cl]2, r.t.} afforded a 10% yield of 4e. Reasoning
that alkynone 3e was either more reactive and/or trienone
4e less stable, the reaction was performed at 0 °C using
only 3 mol% of catalyst.8 To our delight, trienone 4e was
obtained in 95% yield after only five minutes at 0 °C (en-
try 5, Table 1).
Interestingly, the reaction of 3f, possessing a cyclohexe-
nyl group on the alkyne terminus, affords the tricyclic
compound 7 in 29% yield.12 The proposed reaction path-
way to account for the formation of 7 involves a carbocy-
clization of allene 3f to give trienone 5, then an
electrocyclization leading to 6 and an oxidative aromati-
zation reaction to give 7 (Scheme 2).
SYNLETT 2008, No. 5, pp 0759–0764
x
x.
x
x.
2
0
0
8
Advanced online publication: 10.03.2008
DOI: 10.1055/s-2008-1032111; Art ID: Y02207ST
© Georg Thieme Verlag Stuttgart · New York

760
K. M. Brummond et al.
CLUSTER
O
Table 1 Formation of 2-Alkylidene-3-cyclohexenones
O
R2
BrMgC
C
R2
1)
R1
R1
R1
R1
H
•
O
R1
O
R1
(1)
3 mol%
2) CrO3, H2SO4
•
[Rh(CO)2Cl]2
•
9a R1 = Me, R2 = n-Bu 55%a
9b R1 = Me, R2 = Me 44%
9c R1 = Me, R2 = Ph 54%
9d R1 = Me, R2 = 2-Py 42%b
9e R1 = Et, R2 = Me 79%
9f R1 = Et, R2 = H 82%
toluene, r.t.
8a R1 = Me
8b R1 = Et
8c R1–R1 = (CH2)5
3a–k
4a–k
Entry
1
Reaction
R1
Time (min) Yield (%)
9g R1–R1 = (CH2)5, R2 = Me 65%
3a → 4a
Me
90
75
80
88
93
95
–
2
3b → 4b
3c → 4c
3d → 4d
3e → 4e
3f → 4f
3g → 4g
3h → 4h
3i → 4i
(CH2)3OTBS
(CH2)2OTBS
90
20
15
5
3
O
O
MeONHMe⋅HCl,
1)
2)
Ph
O
R2
R1
Me2AlCl, CH2Cl2
4
(CH2)2OTHP
TMS
N
(2)
HN
•
5a
R1
BrMg
R2
•
Bz
6b
7c
cyclohexenyl
Ph
–
11a R1 = Me, R2 = H 79%
11b R1 = Me, R2 = Me 97%
11c R1 = Me, R2 = Ph 80%
11d R1 = Me, R2 = CH2OMe 80%
11e R1 = Bn, R2 = Ph 23%
11f R1 = i-Bu, R2 = Me 76%
10a R1 = Me
10b R1 = Bn
10c R1 = i-Bu
5
81
77
79
–
8c
4-MeOAr
4-CF3Ar
OEt
5
9c
5
a 1-Hexynyl lithium was used instead of the
corresponding magnesium bromide salt
b MnO2, CH2Cl2 used instead of CrO3, H2SO4
10d
11e
3j → 4j
3k → 4k
45
–
H
–
a Reaction performed at 0 °C.
Scheme 3 Synthesis of allenic alkynones 9a–g and 11a–f
b See the discussion below and Scheme 2.
c Reaction performed at 50 °C using 8 mol% catalyst.
d Obtained an unstable compound that could not be characterized.
e Immediate decomposition of starting material.
vented isomerization of the 1,2-diene of the allene to a
1,3-diene during the preparation of these substrates.
The [Rh(CO)2Cl]2-catalyzed cycloisomerization reactions
of 9a–g and 11a–f proceed smoothly at room temperature
to afford the cyclopentenones 12a–m (Table 2). These
trienones were found to be stable on the bench top for sev-
eral months.17 Interestingly, the carbocyclization reaction
was tolerant of coordinating heteroatoms, evidenced by
obtaining 12d in 50% yield (entry 4, Table 2); and the
methoxymethyl ether 12k in 53% yield (entry 11,
Table 2). Terminal alkynes are compatible with the reac-
tion conditions evidenced by the isolation of 12f and 12i
in 61% and 83% yield, respectively.18 A control experi-
ment was performed where allene-ynones 11b and 11c
were simply heated (no catalyst) in toluene at 100 °C for
one hour; trienones 12b and 12c were afforded in 63% and
68% yield, respectively. However, the products were con-
taminated with trace quantities of inseparable impurities.
Heating 9a in toluene at 100 °C afforded an unidentified
isomerization product in 71% yield. Based upon these re-
sults, the Rh(I)-catalyzed conditions were deemed more
reliable.
O
O
O
Rh(I)
3f
50 °C
7
5
6
Scheme 2 A Rh(I)-catalyzed cascade reaction
Encouraged by the results in Table 1, the formation of
2-alkylidene-3-vinylcyclopentenones was investigated.
Construction of the corresponding allene-ynones was car-
ried out by the addition of alkynyl magnesium bromides
to allenic aldehydes 8a–c and subsequent oxidation of the
alcohols to afford 9a–g (equation 1, Scheme 3).13 Alter-
natively, allenic oxazolidiones14 10a–c were reacted with
methylmethoxylamine to afford the allenic Weinreb
amide intermediate, and without purification, the amide
was then transformed into the allene-ynones 11a–f by ad-
dition of the corresponding Grignard reagents15 to afford
cyclization precursors possessing an unsymmetrically
substituted quaternary carbon and a benzamide group
(equation 2, Scheme 3).16 For each of these substrates, the
quaternary carbon between the carbonyl and allene pre-
The highly functionalized cyclopentenones 12h–m serve
as ideal candidates for accessing compounds possessing
other interesting arrays of functionality. For example, re-
action of 12h with N-phenyl maleimide in toluene at
80 °C affords the Diels–Alder adduct 13 in 54% yield as
a single diastereomer (Scheme 4).19,20 The ketone func-
tionality prevents the newly formed 1,3-diene in 13 from
Synlett 2008, No. 5, 759–764 © Thieme Stuttgart · New York

CLUSTER
Rh(I)-Catalyzed Cycloisomerization Reaction Affording Cyclic Trienones
761
(Scheme 5).21
The
corresponding
cis-
Table 2 Formation of 2-Alkylidene-3-cyclopentenones
divinylcyclopropane22 undergoes a Cope rearrangement
to provide 14 which is subsequently reacted with maleic
anhydride in toluene at 80 °C to afford the Diels–Alder
adduct 15 as a single diastereomer in 60% yield. The ste-
reochemistry of 15 has been assigned by X-ray crystallo-
graphic analysis of a related compound and this
information will be published in its entirety in the future.
O
R2
O
R1
R1
R3
R2
5 mol%
[Rh(CO)2Cl]2
R3
•
toluene, r.t.
9 or 11
12
Entrya Reaction
R1
R2
R3
Yield (%)
73
In summary, a Rh(I)-catalyzed allenic cycloisomerization
reaction of alkynones affords 2-alkylidene-3-vinyl-3-cy-
clopentenones and 2-alkylidene-3-vinyl-3-cyclohex-
enones. This scope and limitations study demonstrate that
the reactions conditions are compatible with amides,
ethers, and terminal alkynes; and that the highly unsatur-
ated products are stable and undergo selective cycloaddi-
tion and cycloisomerization reactions. Further research on
these functionally rich trienones will be reported in due
course.
1
2
9a → 12a
9b → 12b
9c → 12c
9d → 12d
9e → 12e
9f → 12f
Me
Me
Me
Me
Et
n-Bu
Me
Me
Me
Me
Me
Et
66
3
Ph
80
4
2-pyridyl
Me
50
5
94b
61
6
Et
H
Et
7
9g → 12g
11a → 12h
11b → 12i
11c → 12j
11d → 12k
11e → 12l
11f → 12m
(CH2)5 Me
65
Acknowledgment
8
Me
Me
Me
Me
Bn
Me
BzNH
BzNH
BzNH
BzNH
BzNH
BzNH
78b
83
We gratefully acknowledge the generous financial support provided
by the National Institutes of Health (GM067982 and GM54161).
T.O.P. thanks the Bayer Corporation for a graduate student fel-
lowship.
9
H
10
11
12
13
Ph
68b
53
CH2OMe
Me
References and Notes
79
(1) Evans, P. A. Modern Rhodium-Catalyzed Organic
Reactions; Wiley-VCH: Weinheim, 2005.
(2) (a) Brummond, K. M.; Chen, H.; Sill, P. C.; You, L. J. Am.
Chem. Soc. 2002, 124, 15186. (b) Shibata, T.; Takesue, Y.;
Kadowaki, S.; Takagi, K. Synlett 2003, 268.
i-Bu
Me
88
a Reaction time 1–2 h.
b Designates reactions that were scaled up to multigram scale with no
loss of yield.
(c) Brummond, K. M.; Mitasev, B. Org. Lett. 2004, 6, 2245.
(d) Mukai, C.; Inagaki, F.; Yoshida, T.; Yoshitani, K.; Hara,
Y.; Kitagaki, S. J. Org. Chem. 2005, 70, 7159. (e) Mukai,
C.; Hara, Y.; Miyashita, Y.; Inagaki, F. J. Org. Chem. 2007,
72, 4454.
O
O
BzHN
N-phenyl-
maleimide
H
O
(3) Brummond, K. M.; Painter, T. O.; Mitasev, B.; Probst, D.
Org. Lett. 2007, 9, 347.
BzHN
toluene, 80 °C
54%
N
(4) Jiang, X.; Ma, S. J. Am. Chem. Soc. 2007, 129, 11600.
(5) (a) Tsuge, O.; Waa, E.; Kanemasa, S. Chem. Lett. 1983,
1525. (b) Spino, C.; Liu, G.; Tu, N.; Girard, S. J. Org. Chem.
1994, 59, 5596. (c) Bräse, S.; de Meijere, A. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2545. (d) Woo, N.; Legoupy, S.;
Parra, S.; Fallis, A. G. Org. Lett. 1999, 1, 1013. (e) Kwon,
O.; Park, S. B.; Schreiber, S. L. J. Am. Chem. Soc. 2002, 124,
13402. (f) Brummond, K. M.; You, L. Tetrahedron 2005,
61, 6180. (g) Payne, A. D.; Willis, A. C.; Sherburn, M. S.
J. Am. Chem. Soc. 2005, 127, 12188. (h) Park, S.; Lee, D.
Synthesis 2007, 2313.
Ph
13
12h
O
Scheme 4 Selective Diels–Alder reaction of trienone 12h
undergoing a second Diels–Alder reaction with the same
dienophile.
Furthermore, a selective cyclopropanation reaction of the
vinyl group of trienone 12e occurs when reacted with di-
ethyl 4-diazo-2-pentenedioate and rhodium acetate
O
O
Et
Et
H
O
E
E
Et
H
Et
H
E
maleic
anhydride
N2
O
E
12e
H
Rh(OAc)2
toluene
80 °C
60%
O
CH2Cl2, 50 °C
47%
E
E
14
15
E = CO2Et
Scheme 5 Selective cyclopropanation reaction of the trienone 12e
Synlett 2008, No. 5, 759–764 © Thieme Stuttgart · New York

762
K. M. Brummond et al.
CLUSTER
mol%} was then added and the reaction progress was
monitored by TLC. Upon completion of the reaction, the
mixture was diluted with a 10% EtOAc–hexanes solution
and filtered through a pad of silica gel, further eluting with
10% EtOAc–hexanes solution. The resultant yellow solution
was concentrated under vacuum to yield the products as
yellow oils without further purification.
(6) Metal-catalyzed carbocyclization reactions of enynones
have been previously reported, for leading references, see:
Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2002, 124,
5025.
(7) General Procedure for the Preparation of Allene-ynones
3
(a) In a manner entirely analogous to that reported by
Trost:7b A solution of the alkyne (1.08 mmol) in THF (2.4
mL) was cooled to –78 °C and a solution of n-BuLi (0.6 mL
of a 1.6 M solution in hexanes, 0.96 mmol) was added
rapidly via syringe. After 5 min BF3·OEt2 (128 mL, 1.02
mmol) was added. The resultant solution/mixture was stirred
for 15 min then a solution of the allenyl amide 1 (100 mg,
0.60 mmol) in THF (3 mL) was added via cannula. After 1.5
h, more BF3·OEt2 (128 mL, 1.02 mmol) and AcOH (58 mL,
1.02 mmol) were added. The reaction was allowed to warm
to –20 °C and quenched with sat. aq NH4Cl (2.1 mL). After
warming to r.t., the reaction mixture was diluted with Et2O
and H2O. The layers were separated and the aqueous layer
was extracted with Et2O (3×). The combined organic layers
were washed with H2O (2×) and dried over MgSO4. This
mixture was filtered through a pad of silica gel and
concentrated under vacuum. The crude residue was purified
by column chromatography on silica gel to give the product
as a faint yellow to clear oil.
Data for 4e: 1H NMR (300 MHz, CDCl3): d = 6.27 (dd,
J = 11.3, 17.7 Hz, 1 H), 6.01 (s, 1 H), 5.45 (dd, J = 2.1, 11.3
Hz, 1 H), 5.15 (dd, J = 2.1, 17.7 Hz, 1 H), 2.61–2.51 (m, 4
H), 1.95 (s, 3 H), 0.13 (s, 9 H). 13C NMR (75 MHz, CDCl3):
d = 200.6, 145.6, 139.1, 135.3, 134.0, 133.7, 119.8, 37.8,
30.8, 21.8, –0.2. IR (thin film): n = 2945, 1701, 1542, 1245,
856 cm–1. MS: m/z (%) = 220 (1) [M+], 205 (40), 75 (13).
HRMS (EI): m/z calcd for C13H20OSi [M+]: 220.1283;
found: 220.1281.
Data for 4h: 1H NMR (300 MHz, CDCl3): d = 7.44 (d,
J = 8.7 Hz, 2 H), 6.83 (d, J = 8.8 Hz, 2 H), 6.61(s, 1 H), 6.34
(dd, J = 11.2, 17.7, 1 H), 5.49 (dd, J = 2.1, 11.2 Hz, 1 H),
5.27 (dd, J = 2.1, 17.8 Hz, 1 H), 3.81 (s, 3 H), 2.71–2.59 (m,
4 H), 1.94 (s, 3 H). 13C NMR (75 MHz, CDCl3): d = 202.6,
159.5, 133.7, 133.6, 132.7, 132.5, 131.3, 128.4, 119.7,
113.3, 55.1, 39.6, 32.3, 21.1. IR (thin film): n = 3081, 2908,
2836, 1698, 1603, 1509, 1254, 1032, 829 cm–1. MS: m/z (%)
= 277 (32) [M + 23Na+], 255 (17). ES-HRMS: m/z calcd for
C17H18O2 [M + 23Na+]: 277.1204; found: 277.1215.
(12) Preparation of 6,7,8,10a-Tetrahydro-2-methyl-1-vinyl-
5H-xanthene (7)
Data for 3e: 1H NMR (300 MHz, CDCl3): d = 5.06–4.98 (m,
1 H), 2.62 (dd, J = 6.7, 7.5 Hz, 2 H), 2.28–2.21 (m, 2 H), 1.66
(d, J = 2.7 Hz, 3 H), 1.57 (d, J = 7.0 Hz, 3 H), 0.21 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 201.6, 187.1, 101.9, 97.5,
97.1, 87.0, 43.0, 27.8, 19.3, 14.6, –0.9. IR (thin film): n =
2962, 2900, 2151, 1967, 1679, 1252, 847 cm–1. MS: m/z
(%) = 220 (16) [M+], 219 (6), 205 (8), 178 (12), 163 (29), 73
(100), 61 (100). HRMS (EI): m/z calcd for C13H20OSi [M+]:
220.1283; found: 220.1289.
Following the general procedure for the preparation of
trienone 4: toluene (2.8 mL), allene-ynone 3f (32 mg, 0.140
mmol), [Rh(CO2)Cl]2 (1.6 mg, 0.004 mmol, 5 mol%),
purification by silica gel column chromatography eluting
with 2% EtOAc–hexanes (column pretreated with a 1%
solution of Et3N in hexanes) to afford 7 as a green solid (9
mg, 29%). 1H NMR (300 MHz, CDCl3): d = 6.85 (d, J = 8.1
Hz, 1 H), 6.63 (dd, J = 11.4, 17.8 Hz, 1 H), 6.56 (d, J = 8.1
Hz, 1 H), 6.39 (s, 1 H), 5.58 (dd, J = 2.0, 11.4 Hz, 1 H), 5.23
(dd, J = 2.0, 17.8 Hz, 1 H), 4.86 (dd, J = 5.7, 10.9 Hz, 1 H),
2.60–1.19 (m, 8 H), 2.18 (s, 3 H). 13C NMR (75 MHz,
CDCl3): d = 151.3, 137.5, 134.4, 133.7, 128.8, 127.8, 120.4,
119.1, 114.9, 113.5, 76.1, 34.7, 33.2, 26.5, 24.2, 19.8. IR
(thin film): n = 3078, 3058, 2932, 2857, 1582, 1468, 1235,
1041, 811 cm–1. MS: m/z (%) = 226 (100) [M+], 225 (90),
223 (82), 198 (61), 197 (60), 145 (43), 128 (44), 115 (60).
HRMS (EI): m/z calcd for C16H18O [M+]: 226.1358; found:
226.1353.
Data for 3h: 1H NMR (300 MHz, CDCl3): d = 7.54 (d,
J = 8.9 Hz, 2 H), 6.90 (d, J = 8.9 Hz, 2 H), 5.11–5.04 (m, 1
H), 3.85 (s, 3 H) 2.76 (dd, J = 6.8, 8.1 Hz, 2 H), 2.39–2.31
(m, 2 H), 1.73 (d, J = 2.8 Hz, 3 H), 1.62 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 201.7, 187.2, 161.5, 134.9,
114.2, 111.8, 97.6, 91.4, 87.6, 86.8, 55.2, 43.2, 28.1, 19.3,
14.6. IR (thin film): n = 2979, 2899, 2849, 2553, 2197, 1965,
1665, 1254, 1092 cm–1. MS: m/z (%) = 254 (27) [M+], 253
(16), 239 (40), 237 (53), 211 (54), 197 (54), 165 (47), 159
(100), 144 (44), 116 (47), 77 (47). HRMS (EI): m/z calcd for
C17H18O2 [M+]: 254.1307; found: 254.1282. (b) Trost, B.
M.; Li, Y. J. Am. Chem. Soc. 1996, 118, 6625. (c) Walton,
D. R. M.; Waugh, F. J. Organomet. Chem. 1972, 37, 45.
(8) We have seen similarly facile reactions when the
cycloisomerization substrate possesses an aminoester tether.
See ref. 2c.
(13) Preparation of Allenyl Alkynone 9e
A flame-dried 100 mL round-bottomed flask was charged
with 2,2-diethylhexa-3,4-dienal (8b, 1.52 g, 10.0 mmol) and
THF (40 mL). After cooling to 0 °C, 1-propynylmagnesium
bromide (24 mL, 0.5 M in THF, 12 mmol) was slowly added
via syringe and the mixture was stirred at 0 °C for 2 h. The
reaction mixture was quenched with sat. NH4Cl (20 mL).
The mixture was partitioned between Et2O (30 mL) and H2O
(30 mL). The layers were separated and the aqueous phase
was extracted with Et2O (2 × 30 mL). The combined organic
layers were washed with brine, dried over MgSO4, and
concentrated under reduced pressure to afford a light yellow
oil (1.65 g). A portion of the oil (452 mg) was transferred
into a 50 mL round-bottomed flask fitted with a Teflon-
coated stirring bar and dissolved in acetone (20 mL). After
cooling to 0 °C, freshly prepared Jones reagent was added
dropwise via a pipette until an orange color persisted. The
reaction mixture was then poured into Et2O (20 mL) and
H2O (10 mL). The layers were separated and the aqueous
phase was extracted with Et2O (2 × 20 mL). The combined
organic layers were washed with brine, dried over MgSO4,
(9) Chelation of the tethered oxygen of 3c or 3d to the Rh(I)
catalyst may be responsible for the rate enhancement by
facilitating the oxidative addition step of the
cycloisomerization process. Trost observed a similar effect
in a palladium-catalyzed enyne cycloisomerization reaction,
see: Trost, B. M.; Romero, D. L.; Rise, F. J. Am. Chem. Soc.
1994, 116, 4268.
(10) Terminal ynones have been reported to undergo
decomposition in palladium-catalyzed cycloisomerization
reactions, see: Trost, B. M.; Phan, L. T. Tetrahedron Lett.
1993, 34, 4735.
(11) General Procedure for the Preparation of Trienone 4
A 2-dram vial, equipped with a stir bar was charged with
allene-ynone 3 (0.1 mmol) and toluene (0.33 mL), sealed
with a septum, and degassed (degassing was accomplished
by bubbling argon through the stirred solution for 20 min).
Rhodium biscarbonyl chloride dimer {[Rh(CO)2Cl]2, 3
Synlett 2008, No. 5, 759–764 © Thieme Stuttgart · New York

CLUSTER
Rh(I)-Catalyzed Cycloisomerization Reaction Affording Cyclic Trienones
763
and concentrated under reduced pressure. Purification of the
48.3, 31.7, 27.2, 23.6, 22.5, 13.9. IR (thin film): n = 2959,
2932, 2871, 1708 cm–1. MS: m/z (%) = 204 (43) [M+], 189
(15), 175 (25), 119 (88), 91 (100). HRMS: m/z calcd for
C14H20O [M+]: 204.1514; found: 204.1514.
yellow oil by flash chromatography (10% EtOAc–hexanes)
afforded the title compound 9e (425 mg, 79%) as a light
yellow oil. 1H NMR (300 MHz, CDCl3): d = 5.28–5.19 (m,
2 H), 2.04 (s, 3 H), 1.78–1.70 (m, 4 H),1.68 (dd, J = 6.6, 3.6
Hz, 3 H), 0.83 (t, J = 7.4 Hz, 3 H), 0.82 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 205.1, 191.4, 92.4, 90.6,
88.2, 78.8, 56.5, 27.5, 14.1, 8.5, 4.1. IR (thin film): n = 2968,
2938, 2218, 1963, 1666 cm–1. MS: m/z (%) = 190 (15) [M+],
175 (28), 161 (95), 147 (65), 81 (100). HRMS: m/z calcd for
C13H18O [M+]: 190.1357; found: 190.1358.
Data for 12c: 1H NMR (300 MHz, CDCl3): d = 7.94 (dd,
J = 7.8, 2.1 Hz, 2 H), 7.43–7.32 (m, 3 H), 6.85 (s, 1 H), 6.56
(ddd, J = 17.4, 11.1, 1.2 Hz, 1 H), 6.29 (s, 1 H), 5.74 (dd,
J = 17.4, 1.5 Hz, 1 H), 5.38 (dd, J = 11.1, 1.5 Hz, 1 H), 1.20
(s, 6 H). 13C NMR (75 MHz, CDCl3): d = 208.6, 141.7,
137.8, 135.2, 134.8, 133.0, 131.1, 130.5, 130.0, 129.6,
128.2, 117.9, 48.6, 24.0. IR (thin film): n = 2942, 1708
cm–1. MS: m/z (%) = 224 (40) [M+], 196 (50), 181 (65), 129
(100). HRMS (EI): m/z calcd for C16H16O [M+]: 224.1201;
found: 224.1198.
(14) (a) Castelhano, A. L.; Pliura, D. H.; Taylor, G. J.; Hsieh, K.
C.; Krantz, A. J. Am. Chem. Soc. 1984, 106, 2734.
(b) Castelhano, A. L.; Horne, S.; Taylor, G. J.; Billedeaux,
R.; Krantz, A. Tetrahedron 1988, 44, 5451.
(15) Tice, C. M.; Hormann, R. E.; Thompson, C. S.; Friz, J. L.;
Cavanaugh, C. K.; Michelotti, E. L.; Garcia, J.; Nicolas, E.;
Albericio, F. Bioorg. Med. Chem. Lett. 2003, 13, 475.
(16) Preparation of Allenyl Alkynone 11b
Data for 12e: 1H NMR (300 MHz, CDCl3): d = 6.44 (ddd,
J = 17.6, 11.2, 0.9 Hz, 1 H), 6.19 (dq, J = 7.6, 0.7 Hz, 1 H),
6.04 (s, 1 H), 5.63 (dd, J = 17.6, 1.6 Hz, 1 H), 5.27 (dd,
J = 11.2, 1.6 Hz, 1 H), 2.25 (dd, J = 7.6, 0.7 Hz, 3 H), 1.66
(dq, J = 13.6, 7.5 Hz, 2 H), 1.50 (dq, J = 13.6, 7.5 Hz, 2 H),
0.74 (t, J = 7.5 Hz, 6 H). 13C NMR (75 MHz, CDCl3): d =
212.1, 142.4, 137.9, 133.2, 130.5, 129.9, 116.7, 57.3, 29.6,
14.1, 9.3. IR (thin film): n = 2963, 2929, 1720 cm–1. MS:
m/z (%) = 190 (54) [M+], 161 (80), 133 (86), 84 (100).
HRMS (EI): m/z calcd for C13H18O [M+]: 190.1357; found:
190.1355.
A flame-dried 25 mL round-bottomed flask was charged
with N-[2-(N-methoxy-N-methylcarbamoyl)hexa-3,4-dien-
2-yl]benzamide (268 mg, 0.93 mmol) and THF (15 mL).
After cooling to 0 °C, 1-propynylmagnesium bromide (4.4
mL, 0.5 M in THF, 2.2 mmol) was slowly added via syringe
and the mixture was stirred at 0 °C for 3 h. The reaction
mixture was quenched with sat. NH4Cl (10 mL). The
mixture was partitioned between Et2O (15 mL) and H2O (15
mL). The layers were separated and the aqueous phase was
extracted with Et2O (2 × 15 mL). The combined organic
layers were washed with brine, dried over MgSO4, and
concentrated under reduced pressure to afford a white solid.
The solid was purified via silica gel column chromatography
(50% EtOAc–hexanes) to give the title compound 11b (242
mg, 97%) as a white solid. 1H NMR (300 MHz, CDCl3): d =
7.81–7.78 (m, 2 H), 7.54–7.41 (m, 3 H), 7.21 (br s, 0.3 H),*
7.11 (br s, 0.7 H), 5.24 (p, J = 7.1 Hz, 1 H), 5.40–5.32 (m, 1
H), 2.02 (s, 1 H),* 1.99 (s, 2 H), 1.81 (s, 1 H),* 1.78 (s, 2 H),
1.74 (dd, J = 7.0, 3.2 Hz, 2 H), 1.72 (dd, J = 7.0, 3.2 Hz, 1
H)*. 13C NMR (75 MHz, CDCl3): d = 204.4, 204.2,* 185.9,
166.6, 165.3,* 134.7, 134.6,* 131.8, 131.7,* 128.8, 127.1,
93.8,* 93.6, 93.5,* 93.0, 91.9, 91.7,* 77.4,* 77.3, 63.7,*
63.5, 21.9, 14.1,* 14.0, 4.50,* 4.42. IR (thin film): n = 3280,
2211, 1966, 1688, 1627 cm–1. MS: m/z (%) = 267 (10) [M+],
253 (28), 105 (100), 77 (65). HRMS: m/z calcd for
(19) The stereochemistry has been assigned based upon X-ray
crystal data of a similar compound. This information will be
published in the near future.
(20) Preparation of N-{(1Z,3aS,8S,8aR,8bR)-6-Ethylidene-
1,2,3,3a,4,6,7,8,8a,8b-decahydro-8-methyl-1,3,7-trioxo-
2-phenylcyclopenta[e]isoindol-8-yl}benzamide (13)
A flame-dried test tube equipped with a Teflon-coated
stirring bar was charged with N-[(13Z)-4-ethylidene-1-
methyl-5-oxo-3-vinylcyclopent-2-enyl]benzamide (12h,
100 mg, 0.37 mmol) and 1-phenyl-1H-pyrrole-2,5-dione (68
mg, 0.39 mmol). After adding toluene (4 mL), the test tube
was placed into a preheated 80 °C oil bath until complete
consumption of starting materials (as observed by TLC). The
solution was directly purified via silica gel column
chromatography (50% EtOAc–hexanes) to afford the title
compound 13 (87.4 mg, 54%). 1H NMR (300 MHz, CDCl3):
d = 7.89–7.85 (m, 2 H), 7.54–7.30 (m, 7 H), 7.06–7.03 (m, 2
H), 6.70 (q, J = 7.6 Hz, 1 H), 6.19–6.11 (m, 1 H), 3.58 (dd,
J = 8.3, 4.3 Hz, 1 H), 3.40 (t, J = 8.3 Hz, 1 H), 3.26–3.22 (m,
1 H), 2.92 (dd, J = 7.5 and 1.0 Hz, 1 H), 2.57–2.47 (m, 1 H),
2.30 (d, J = 7.6 Hz, 3 H), 1.74 (s, 3 H). 13C NMR (75 MHz,
CD2Cl2): d = 204.1, 178.7, 177.5, 167.3, 140.5, 137.1, 135.1,
132.3, 131.9, 131.1, 129.3, 128.9, 128.6, 127.4, 126.9,
116.8, 63.3, 46.4, 43.6, 41.7, 27.0, 25.9, 15.1. IR (thin film):
n = 3425, 2975, 1773, 1708, 1654, 1522 cm–1. MS: m/z
(%) = 441 (100) [M+ + 1], 308 (38). HRMS (EI): m/z calcd
for C27H25N2O4 [M+]: 441.1814; found: 441.1812.
(21) Davies, H. M. L.; Walji, A. M. Rhodium(II)-Stabilized
Carbenoids Containing Both Donor and Acceptor
Substituents, In Modern Rhodium Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005,
301.
C17H17NO2 [M+]: 267.1259; found: 267.1263. *Denotes the
minor diastereomer.
(17) With the exception of 12b, which had to be stored in benzene
at –20 °C, the only literature report on the formation of five-
membered cross-conjugated triene stressed product
instability. For details, see: Yamazaki, T.; Urabe, H.; Sato, F.
Tetrahedron Lett. 1998, 39, 7333.
(18) General Procedure for the Preparation of Trienones 12
A flame-dried test tube equipped with a Teflon-coated stir
bar was charged with allene-ynone 9 or 11 (1.0 mmol, 1
equiv) and toluene (10 mL) under an atmosphere of N2. After
adding [Rh(CO)2Cl]2 (0.05 mmol, 0.05 equiv), the reaction
mixture was stirred at r.t. until complete consumption of
starting material (as observed by TLC). The solution was
concentrated under reduced pressure and the residue was
purified via silica gel column chromatography (10%
EtOAc–hexanes) to afford trienone 12.
(22) Preparation of Adduct 15
To a refluxing solution of (5Z)-2,2-diethyl-5-ethylidene-4-
vinylcyclopent-3-enone (12e, 28 mg, 0.15 mmol) and
Rh(OAc)2 (3.3 mg, 0.0075 mmol) in CH2Cl2 (1.5 mL) was
added a CH2Cl2 (1 mL) solution of diethyl 4-diazo-2-
pentenedioate (48 mg, 0.23 mmol) over 10 min under argon.
After 30 min, TLC showed complete consumption of 12e.
The solvent was removed and the crude mixture was purified
via silica gel flash chromatography (10% EtOAc–hexanes)
to give 14 (26 mg, 47%) together with the trans-
Data for 12a: 1H NMR (300 MHz, CDCl3): d = 6.44 (dd,
J = 17.6, 11.1 Hz, 1 H), 6.16 (t, J = 7.4 Hz, 1 H), 6.12 (s, 1
H), 5.62 (dd, J = 17.6, 1.6 Hz, 1 H), 5.28 (dd, J = 11.1 1.6
Hz, 1 H), 2.78 (q, J = 7.5 Hz, 2 H), 1.45–1.36 (m, 4 H), 1.12
(s, 6 H), 0.92 (t, J = 6.9 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): d = 210.8, 139.5, 137.5, 136.2, 134.9, 129.8, 116.8,
Synlett 2008, No. 5, 759–764 © Thieme Stuttgart · New York

764
K. M. Brummond et al.
CLUSTER
divinylcyclopropane (cis/trans = 7:1). A test tube was
charged with 14 (19 mg, 0.051 mmol) and maleic anhydride
(7.5 mg, 0.077 mmol) and purged with N2 for 5 min. Toluene
(0.8 mL) was added and the test tube was placed into a
preheated oil bath (80 °C). After 3 h, the reaction mixture
was cooled to r.t. and directly applied to silica gel flash
chromatography (35% EtOAc–hexanes) to give 15 (14 mg,
60%) as a single diastereomer. 1H NMR (300 MHz, CDCl3):
d = 7.04 (dd, J = 7.2, 2.1 Hz, 1 H), 4.30–4.22 (m, 2 H), 4.12–
4.00 (m, 2 H), 3.81 (dd, J = 7.1, 2.8 Hz, 1 H), 3.60–3.57 (m,
1 H), 3.51 (q, J = 7.3 Hz, 1 H), 3.29–3.25 (m, 2 H), 3.12 (t,
J = 2.7 Hz, 1 H), 2.94–2.88 (m, 1 H), 1.69–1.62 (m, 2 H),
1.54–1.52 (m, 1 H), 1.48 (q, J = 7.4 Hz, 4 H), 1.39–1.27 (m,
2 H), 1.34 (t, J = 7.1 Hz, 3 H), 1.01 (t, J = 7.4 Hz, 3 H), 0.91–
0.84 (m, 2 H), 0.73 (t, J = 7.4 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): d = 208.1, 171.0, 170.8, 170.6, 170.2, 167.4, 137.5,
136.6, 134.9, 61.9, 53.3, 49.8, 46.9, 46.3, 45.2, 36.7, 31.8,
29.6, 27.7, 27.4, 22.9, 21.8, 14.7, 14.5, 14.1, 8.8, 8.6. IR (thin
film): n = 2969, 2937, 1781, 1699, 1461 cm–1. MS: m/z
(%) = 472 (100) [M+], 426 (71), 398 (84). HRMS (EI): m/z
calcd for C26H32O8 [M+]: 472.2097; found: 472.2101.
Synlett 2008, No. 5, 759–764 © Thieme Stuttgart · New York

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