Tandem dienyne cross-metathesis/ring-closing metathesis

Article abstract of DOI:10.1016/S0040-4039(00)01922-5

Tandem enyne cross-metathesis/ring-closing metathesis between terminal alkynes and 1,5-hexadiene has been demonstrated using the 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene-substituted ruthenium benzylidene complex. Synthesis of 2-substituted 1,3-cyclohex

Full text of DOI:10.1016/S0040-4039(00)01922-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 171–174
Tandem dienyne cross-metathesis/ring-closing metathesis
Jason A. Smulik and Steven T. Diver*
Department of Chemistry, University at Buffalo, the State University of New York, Buffalo, NY 14260-3000, USA
Received 12 October 2000; revised 25 October 2000; accepted 31 October 2000
Abstract—Tandem enyne cross-metathesis/ring-closing metathesis between terminal alkynes and 1,5-hexadiene has been demon-
strated using the 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene-substituted ruthenium benzylidene complex. Synthesis of 2-substi-
tuted 1,3-cyclohexadienes using this one step tandem reaction is reported. In addition, metathesis products were subjected to [4+2]
cycloaddition with N-methylmaleimide yielding the corresponding cycloadducts in one synthetic step. © 2000 Elsevier Science
Ltd. All rights reserved.
The emergence of N-heterocyclic carbene-containing
ruthenium complexes has increased the scope of alkene
metathesis with the Grubbs’ ruthenium carbenes
(derived from parent catalyst 1).1 Complex 2, which
features the electron-rich sigma-donating dihydroimida-
zolylidene carbene ligand, has been recently employed
in a variety of metathesis applications. Ring closing
metathesis (RCM) applications have been expanded in
part due to the increased activity of complex 2.1f Func-
tional group tolerance using catalyst 2 has been demon-
strated both in alkene metathesis1f and in
intermolecular reactions like enyne cross-metathesis.2
Here we report a tandem metathesis3 operation which
features cross metathesis of alkynes with 1,5-hexadiene
followed in situ by RCM using ruthenium complex 2
(eq. 1). This tandem reaction offers a simple method
for the generation of 2-substituted cyclohexadienes in
one synthetic step starting from alkynes and 1,5-
hexadiene.
Various catalysts and reaction conditions were surveyed
to find the optimum conversion to products and to
probe the stereoselection in the initial enyne cross
metathesis (Table 1). The reaction between propargyl
benzoate and 1,5-hexadiene was evaluated using differ-
ent catalysts and by varying the reaction conditions. In
the cross metathesis, a mixture of Z and E isomers is
produced; however, only the Z isomer can undergo ring
closing metathesis in situ. The parent catalyst 1 gave a
1.1 to 1.0 mixture of cyclohexadiene:triene, reflecting a
1.1 to 1.0 ratio of intermediate Z and E isomers, in 7%
yield. Based on literature precedent, it was surprising
that higher conversions were not realized with this
catalyst.4 The highest conversions and shortest reaction
times were found instead with catalyst 2 using 9 equiv.
of 1,5-hexadiene. Increased temperature resulted in
quantitative conversion to products in 1 h (entries 2
versus 3). Elevated temperature (100°C, sealed tube) did
not further improve the ratio of 1,3-cyclohexadiene to
triene (entry 4) and fewer equivalents of diene resulted
in incomplete reaction after 24 h (entry 5). High con-
version to products was also realized in benzene and
trifluoromethylbenzene,5 but there was little effect on
the product ratio (entries 6, 7).
Ph
Ph
N
N
PCy3
Mes
N
N
Mes
Ph
Cl
Cl
Cl
Ru
Ru
Ru
Cl
Ph
Cl
Cl
Ph
PCy3
PCy3
PCy3
3
1
2
The chiral benzimidazolylidene catalyst 36 displayed
activity comparable to that of the parent Grubbs’ cata-
lyst 1 when used in CH2Cl2 at reflux. From Table 1 it
can be seen that catalysts 1–3 have varied activities but
exert little influence on product ratios.
cat. 2
R1O
R2
R1O
R2
R1O
R2
(1)
Ring-Closing
Metathesis
Cross Metathesis
A
C
E and Z-B
The results of tandem enyne cross metathesis/RCM are
shown in Table 2. Typical reaction conditions of Table
2 employ 0.06 M alkyne with 9 equiv. 1,5-hexadiene in
* Corresponding author.
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01922-5

172
J. A. Smulik, S. T. Di6er / Tetrahedron Letters 42 (2001) 171–174
Table 1. Effect of catalyst and temperature on tandem metathesis
5 mol % cat. 1-3
OBz
OBz
temp, 24 h
OBz
+
(2)
4
5
6
7
Entry
Catalyst/solvent
7 (equiv.)
Temp. (°C)
5/6 (Z/E)
Conversion (%)a
1
2
3
4
5
6
7
8
9
1 (DCM)
2 (DCM)
2 (DCM)
2 (DCM)
2 (DCM)
2 (PhH)
2 (PhCF3)
3 (DCM)
3 (DCM)
9
9
9
9
3
9
9
9
9
25
25
45
100
25
25
25
25
45
1.1:1.0
1.0:1.6
1.0:1.2
1.0:1.3
1.0:1.0
1.1:1.0
1.0:1.5
n/d
7
87
99b
99b
23
91
70
0
1.3:1.0
15b
a Product conversions and E/Z ratios were determined by GC.
b Reaction time: 1 h.
but was found to perform well (entry 2). Steric bulk is
also well-tolerated (entry 4). Intermolecular metathesis
of substituted propargyl alcohol 20 with diene demon-
strates that 1-alkenes may be used with free and poten-
tially coordinating2b functional groups in demanding
alkyne substrates. Selectivity was uniformly low and the
data in Table 2 suggest that the alkyne reactant exerts
the presence of 5 mol% 2 in refluxing CH2Cl2. Reac-
tions were generally clean, producing the cyclized diene
and triene products along with minor but detectable
amounts of styrene and 1,5-hexadiene homodimer. Ter-
minal alkynes gave excellent conversions (entries 1–5).
Benzyl ether 8 contains a potentially coordinating
group and is a difficult substrate in enyne metathesis,
Table 2. Tandem enyne cross metathesis/ring closing metathesis
Substrate
Time (h)
1.0
Entry
1
Products
Conversion
99 % (1:1.2)
OBz
OBz
OBz
4
5
6
OBn
OBn
OBn
99 % (1:1.5)
99 % (1:1.3)
2.0
2.0
2
3
4
5
6
7
8
9
10
C4H9
C4H9
N
C4H9
N
N
Ts
Ts
Ts
13
16
11
12
CH2Ph
CH2Ph
CH2Ph
OAc
OAc
99 % (1:1.2)
99 % (1:1.4)
OAc
2.0
0.5
14
15
Ph
Ph
17
Ph
18
19
CH2Ph
OH
CH2Ph
CH2Ph
OH
OH
48 % (1:1)
6.0
3.0
21
20
22
AcO
AcO
OAc
OAc
OAc
AcO
68 % (1:1.9)
23
25
24
7
Conditions: 5 mol % 2, CH2Cl2, 45°C, 9 eq . ( ) = product ratio, determined by GC.

J. A. Smulik, S. T. Di6er / Tetrahedron Letters 42 (2001) 171–174
9 eq 7, 5 mol % 2,
173
OBz
OBz
45º C, DCM, 1 h;
H
OBz
O
(3)
(4)
O
O
H
+
N
PhH (reflux),
18 h
N
CH3
O
N
4
H3C
H
O
H3C
O
H
29 (41 %)
30 (42 %)
C4H9
9 eq 7, 5 mol % 2,
45º C, DCM, 2 h;
C4H9
N
N
H
Ts
N
Ts
O
O
Ts
O
H
+
N
PhH (reflux),
18 h
N
CH3
O
N
H3C
H3C
H
O
11
O
H
31 (42 %)
32 (28 %)
Scheme 1. Tandem metathesis-[4+2] cycloaddition sequence.
little influence on the diastereoselectivity. Internal alky-
nes produce the desired products albeit with lower
conversion; longer reaction time gave additional uniden-
tified products. Reactions conducted using complex 1
failed to give useful conversions in all alkyne substrates
explored. For instance, reaction of 4 with 9 equiv.
1,5-hexadiene using 5 mol% 1 at 45°C gave 10% conver-
sion after 1 h along with considerable amounts of
homodimer and other unidentified products.
Society (33298G1) and SUNY Buffalo for financial
support of this work. J.A.S. is the recipient of an NIH
predoctoral fellowship (GM20439) which is gratefully
acknowledged.
References
1. (a) Weskamp, T.; Schattenmann, W. C.; Spiegler, M.;
Herrmann, W. A. Angew. Chem., Int. Ed. Engl. 1998, 37,
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Org. Chem. 2000, 65, 2204. (j) Chatterjee, A. K.; Morgan,
J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 3783. Recent review: (k) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012.
To explore the utility of the diene products obtained from
tandem metathesis and to corroborate their structural
assignment,7 the crude mixtures were subjected to Diels–
Alder reaction with N-methylmaleimide (Scheme 1). The
consecutive cycloaddition gives bicyclic products of sub-
stantially greater molecular complexity than the alkyne
and alkene starting materials.8
The effectiveness of this approach is illustrated for two
representative terminal alkynes in Scheme 1. The ratios
of the intermediate dienes correspond to the isolated
yields of cycloadducts. For instance, 4 underwent tandem
metathesis (1 h, 45°C) to give a 1:1.2 mixture of 5 and
6 (above, eq. 2), which underwent thermal cycloaddition
to yield a 1:1 mixture of cycloadducts, separated by
column chromatography in 41 and 42% isolated yield for
29 and 30, respectively.9 Similar results were obtained for
propargyl amine derivative 11 (eq. 4).
2. (a) Smulik, J. A.; Diver, S. T. J. Org. Chem. 2000, 65,
1788. (b) Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2,
2271.
In summary, a novel tandem intermolecular alkyne-diene
cross metathesis/in situ ring closing metathesis sequence
has been documented. Substrate scope on the alkyne
partner suggests that this method will be useful to
prepare a variety of 2-substituted-1,3-cyclohexadienes. A
consecutive Diels–Alder cycloaddition efficiently pro-
vides structurally-complex products. Current investiga-
tions are aimed at improving the selectivity in the cross
metathesis step and exploring the reaction scope using
functionalized dienes.
3. Recent examples of tandem metathesis–metathesis appli-
cations: (a) Randall, M. L.; Tallarico, J. A.; Snapper, M.
L. J. Am. Chem. Soc. 1995, 117, 9610. (b) Zuercher, W. J.;
Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc. 1996,
118, 6634. (c) La, D. S.; Ford, J. G.; Sattely, E. S.;
Bonitatebus, P. J.; Schrock, R. R.; Hoveyda, A. H. J. Am.
Chem. Soc. 1999, 121, 11603. (d) Stragies, R.; Schuster,
M.; Blechert, S. Chem. Commun. 1999, 237. (e) Ovaa, H.;
van der Marel, G. A.; van Boom, J. H.; Stragies, R.;
Blechert, S. Chem. Commun. (Cambridge) 2000, 1501. (f)
Weatherhead, G. S.; Ford, J. G.; Alexanian, E. J.;
Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 1828.
Acknowledgements
4. (a) Stragies, R.; Schuster, M.; Blechert, S. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2518. (b) Schu¨rer, S.; Blechert, S.
Synlett 1999, 1879. (c) Stragies, R.; Voigtmann, U.;
Blechert, S. Tetrahedron Lett. 2000, 41, 5465.
The authors thank the donors of the Petroleum Research
Foundation, administered by the American Chemical

174
J. A. Smulik, S. T. Di6er / Tetrahedron Letters 42 (2001) 171–174
5. For a review of the use of benzotrifluoride solvent, see:
Maul, J. J.; Ostrowski, P. J.; Ublacker, G. A.; Linclau, B.;
Curran, D. P. In Modern Solvents in Organic Synthesis;
Knochel, P., Ed.; Springer-Verlag: Berlin, 1999; Vol. 206,
p. 79.
N-methylmaleimide was added. The solution was stirred at
reflux for 18 h. The solvent was removed in vacuo (rotary
evaporator) to afford a yellow oil that was purified by
column chromatography (elution 1:3 ethyl acetate (EA)–
hexane) to give 29 as a colorless oil (36.1 mg, 41% yield,
analytical TLC: Rf 0.13 (1:3 EA–hexane)) and 30 as a
colorless oil (34.3 mg, 42% yield, analytical TLC: Rf 0.08
(1:3 EA–hexane)). Data for 29: 1H NMR (500 MHz,
CDCl3, ppm) l 8.05 (d, J=7.0 Hz, 2H), 7.57 (t, J=7.0
Hz, 1H), 7.46 (t, J=7.5 Hz, 2H), 5.84 (m, 1H), 5.81 (m,
1H), 5.07 (dd, J=17.0, 1.5 Hz, 1H), 5.00 (dd, J=10.5, 1.5
Hz, 1H), 4.69 (AB q, J=7.0 Hz, 2H), 3.19 (dt, J=9.0,
2.0, 1H), 3.13 (dd, J=8.5, 6.0 Hz, 1H), 2.87 (s, 3H), 2.83
(dd, J=15.0, 1.0 Hz, 1H), 2.34 (m, 2H), 2.25 (m, 2H), 2.04
(m, 1H), 1.88 (m, 1H). 13C NMR (125 MHz, CDCl3, ppm)
l 179.3, 177.6, 166.2, 137.9, 134.8, 133.0, 130.9, 129.9,
129.7, 128.3, 115.2, 66.7, 42.7, 40.3, 35.7, 31.9, 30.1, 25.8,
24.7; high-resolution MS (EI+) molecular ion calcd for
C21H23NO4 353.1627, found 353.1643, error 4.5 ppm. Data
for 30: 1H NMR (500 MHz, CDCl3, ppm) l 8.05 (d,
J=7.5 Hz, 2H), 7.57 (t, J=7.5 Hz, 1H), 7.45 (t, J=7.5
Hz, 2H), 6.14 (d, J=5.5 Hz, 1H), 4.73 (AB q, J=8.5 Hz,
2H), 3.22 (m, 2H), 2.89 (m, 2H), 2.87 (s, 3H), 1.66 (m,
2H), 1.44 (m, 2H). 13C NMR (125 MHz, CDCl3, ppm) l
178.7, 178.3, 166.1, 139.7, 133.0, 129.9, 129.7, 128.3, 127.7,
64.9, 44.6, 43.9, 33.6, 32.0, 24.5, 24.1, 23.8; high-resolution
MS (EI+) molecular ion calcd for C19H19NO4 325.1314,
found 325.1307, error 2.1 ppm.
6. Rivas, F. M.; Riaz, U.; Smulik, J. A.; Diver, S. T.,
submitted for publication.
7. Diene 12 and triene 13 were separated by preparative TLC
(Table 2, entry 3). Proton NMR of the vinylic region for
12 and 13 is representative: 12 (300 MHz, CDCl3, ppm) l
5.91 (m, 2H), 5.61 (br s, 1H); 13 (400 MHz, CDCl3, ppm)
l 6.03 (d, J=16.0 Hz, 1H), 5.92 (m, 1H), 5.81 (m, 1H),
5.06 (br s, 2H), 4.99 (br s, 2H).
8. An enyne ring closing metathesis-Diels–Alder reaction has
been reported: Heerding, D. A.; Takata, D. T.; Kwon, C.;
Huffman, W. F.; Samanen, J. Tetrahedron Lett. 1998, 39,
6815.
9. Representative experimental procedure for tandem metathe-
sis/cycloaddition: To an oven dried 25 mL pressure tube
was added 40 mg (0.25 mmol, 1 equiv.) 4, 0.27 mL (2.25
mmol, 9 equiv.) 1,5-hexadiene, 10.6 mg (12.5 mmol, 5
mol%) 1,3-dimesityl-4,5-dihydroimidazol-2-ylidenetricyclo-
hexylphosphine benzylidene ruthenium dichloride 2 and
4.0 mL CH2Cl2. The solution was stirred for 1 h at 45°C.
The crude products were filtered through a 3 cm plug of
silica to remove spent catalyst using CH2Cl2 as eluent and
concentrated. The crude product mixture was dissolved in
1.0 mL benzene to which 28 mg (0.25 mmol, 1 equiv.)
.