Functional group scope in the methylene-free, tandem enyne metathesis

Article abstract of DOI:10.1021/ol060727d

The methylene-free ring synthesis of 1,3-cyclohexadienes has been expanded to include a diverse set of functional group-rich terminal and internal alkynes.

Full text of DOI:10.1021/ol060727d

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2539-2542
Functional Group Scope in the
Methylene-Free, Tandem Enyne
Metathesis
Brian P. Peppers, Amol A. Kulkarni, and Steven T. Diver*
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
Amherst, New York 14260
diVer@buffalo.edu
Received March 24, 2006
ABSTRACT
The methylene-free ring synthesis of 1,3-cyclohexadienes has been expanded to include a diverse set of functional group-rich terminal and
internal alkynes.
Tandem enyne metathesis1 between alkynes and dienes
provides a useful and efficient ring synthesis.1d The tandem
reaction (enyne cross metathesis and ring-closing metathesis)
is catalyzed by the Grubbs ruthenium carbene complexes.
The functional group tolerance of the second generation
Grubbs carbene complex 1 and the phosphine-free Hoveyda
complex 2,2 has significantly emboldened synthetic chemists
efforts to utilize metathesis in complex molecule synthesis.3
We recently developed a tandem metathesis as a method for
1,3-cyclohexadiene synthesis using conditions devoid of CH2
sources.4 The ‘methylene-free metathesis’ is designed to be
slow to allow interconversion of isomeric intermediates. As
a result, we noted difficulties with certain terminal alkynes.
We were interested to discover whether slow turnover
conditions compromised functional group tolerance. In this
report, we demonstrate that the ring synthesis is successful
for functional group-rich alkynes and internal alkynes
(Scheme 1).
Despite the tremendous advances in metathesis research,1-3
there are still problematic cases, especially in molecules
where functional group interactions with the carbene are
(1) Recent enyne metathesis reviews: (a) Diver, S. T.; Giessert, A. J.
Chem. ReV. 2004, 104, 1317-1382. (b) Mori, M. Ene-yne Metathesis. In
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003;
Vol. 2, pp 176-204. (c) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1-18.
(d) Cross-metathesis between alkyne and diene: Smulik, J. A.; Diver, S.
T. Tetrahedron Lett. 2001, 42, 171-174.
Scheme 1. Ring Synthesis by Tandem Diene-Yne Metathesis
(2) Grubbs’ second-generation complex: (a) Scholl, M.; Ding, S.; Lee,
C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956. Hoveyda complex: (b)
Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem.
Soc. 2000, 122, 8168-8179; J. Am. Chem. Soc. 2001, 123, 3186 [erratum].
(c) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett. 2000, 41, 9973-
9976. (d) Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett 2001,
430-432.
(3) Metathesis in total synthesis: (a) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490-4527. Development of
Grubbs initiators: (b) Love, J. A.; Sanford, M. S.; Day, M. W.; Grubbs, R.
H. J. Am. Chem. Soc. 2003, 125, 10103-10109. (c) Trnka, T. M.; Grubbs,
R. H. Acc. Chem. Res. 2001, 34, 18-29. Alkene metathesis reviews: (d)
Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900-1923.
(e) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043.
10.1021/ol060727d CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/18/2006

possible.5 Functional group interactions can slow catalysis
through reversible chelation, or they can lead to decomposi-
tion. One of the aims of our research is to identify these
interactions to aid in planning total synthesis. In our previous
methylene-free (MF) ring synthesis, homopropargyl ethers,4
long known to be difficult substrates in enyne metathesis,5
gave poor results (Scheme 2, eq 2). Even high catalyst
Table 1. Optimization Studies Using CODa
entry Ru cat. 1,5-COD (equiv) % yieldb (NMR) % 5 (NMR)
1
2
3c
1 (10)
1 (7.5)
1 (7.5)
6
9
9
18d
6
9
6
6
9
79.5 (93)
80 (96)
(81)
76 (90)
(53)
59 (61)
67 (84)
(39)
64 (67)
(12)
0
0
(15)
0
(26)
0
0
(38)
0
(47)
(30)
Scheme 2. Problematic Ring Syntheses by Methylene-Free
Tandem Dienyne Metathesis (from ref 4)
4d 1 (7.5)
5
6
7
8
9
1 (5.0)
1 (5.0)
2 (10)
2 (7.5)
2 (7.5)
2 (10)
2 (10)
10
11
2 + 2
4
(23)
a Standard conditions: 0.25 mmol of alkyne was added to n equiv of
1,5-cyclooctadiene and the carbene complex in refluxing CH2Cl2. After the
addition, the reaction was heated for 1 h. b Isolated yield. NMR yield against
mesitylene internal standard is provided in parentheses. c 8 h addition time.
d all- cis-Polybutadiene was used in this run.
loading resulted in incomplete conversion, with 26% unre-
acted alkyne (entry 5); increased concentration of COD gave
complete conversion of alkyne but a moderate chemical yield
was obtained (entry 6). In the next series of experiments,
the Hoveyda complex 2 was evaluated. At high loading,
similar performance was noted as compared to 1 (entry 7 vs
entry 1). At lower loading and 6 equiv of COD, incomplete
conversion was found (entry 8). In this run, the balance of
the mass was recovered alkyne. Increased COD concentration
improved conversion, but a moderate yield was obtained
(entry 9). In the last two entries, the performance of complex
2 was evaluated under conditions used in our original paper,4
but with higher catalyst loading (10 mol %). When 2 equiv
of COD was added along with the alkyne to 2 equiv of COD
and the carbene complex, only 12% NMR yield was
obtained, with 47% unreacted alkyne (entry 10). Similar
results were obtained in the last entry when 4 equiv of COD
was employed, with incomplete conversion and recovered
alkyne. In these two cases, only 53-59% alkyne-derived
mass can be accounted for in the crude NMR, suggestive of
alkyne polymerization and possibly other decomposition
pathways that consume alkyne. These two entries also show
that increasing catalyst loading by itself is not sufficient to
address functional group scope.
loadings resulted in incomplete conversions and low chemical
yields. From these data, we anticipated that homopropargylic
heteroatoms in general would present difficulty. In terms of
the enyne metathesis mechanism, the vinyl carbene turnover
is typically the slow step,6 so substrate interactions occurring
before this stage could slow catalysis. Chelation by functional
groups can retard the reaction rate or possibly direct the
carbene toward decomposition.
Several reaction variables were evaluated to improve
reaction scope (Table 1). The “methylene-free” metathesis
is conducted under slow addition of alkyne to carbene
catalyst and excess 1,5-cyclooctadiene (COD).7 Higher
catalyst loading was examined and found to give high
conversion to dihydrophenylalanine 6. The loading could be
dropped to 7.5 mol % with increased concentration of COD
(entry 2). Fewer equivalents resulted in incomplete conver-
sions at loadings below 10 mol %. The selectivity was high
in these cases, as evidenced by the near-quantitative NMR
yields of 6 (vs mesitylene internal standard). Longer addition
times (8 h) resulted in incomplete conversions (entry 3),
possibly due to catalyst decomposition over this period. We
employed polybutadiene8 (PB, 18 equiv) in place of COD
using the same number of alkene equivalents as entry 2,
which resulted in complete conversion and high isolated yield
(entry 4). Polybutadiene and COD can be used interchange-
ably at similar concentrations. Further reduction in catalyst
In the best circumstances, the carbene 2 performs similarly
to carbene 1. However, the phosphine-free nature of reaction
conditions using 2 may explain why the reaction is sensitive
to COD concentration.9 Since there is no phosphine to
populate 16-electron carbene resting states, it remains
possible that the carbene intermediates decompose. This
could occur via chelates or through generic carbene decom-
(4) Kulkarni, A. A.; Diver, S. T. J. Am. Chem. Soc. 2004, 126, 8110-
8111.
(5) Kinoshita, A.; Sakakibara, N.; Mori, M. Tetrahedron 1999, 55, 8155-
8167.
(6) Galan, B. R.; Giessert, A. J.; Keister, J. B.; Diver, S. T. J. Am. Chem.
Soc. 2005, 127, 5762-5763.
(7) Direct mixing of reactants as in entry 2, Table 1, gave only 25%
conversion to cyclohexadiene 6.
(8) Polybutadiene is immediately converted by carbenes 1 or 2 into
smaller oligobutadienes. High MW all-cis-PB is not soluble in CH2Cl2 but
quickly “dissolves” when carbene catalyst is added.
(9) A control experiment was performed using 7.5 mol % of Cy3P adduct
of complex 2 (preparation as ref 2c) under the conditions of entry 9, Table
1. In this case, a higher yield of cyclohexadiene 6 was obtained (89% vs
67% with 2, determined by NMR; 78% isolated).
2540
Org. Lett., Vol. 8, No. 12, 2006

position pathways.10 If this is true, then the role of COD
would be protective.11 With terminal alkynes, higher COD
may also help prevent competing pathways such as alkyne
polymerization, which is more apparent in the phosphine-
free system.
These results compare favorably with the nonstereoselec-
tive cross-metathesis/acrylic acid cross-metathesis cleanup
procedure.12 This procedure was developed previously as a
temporary solution to the problem of functional group scope.
The improved procedure here surpasses the efficiency of the
cleanup method. For instance, in entry 2 of Table 1 (above),
use of 7.5 mol % of Grubbs’ complex 1 gave 80% isolated
yield (0.25 mmol scale), whereas the cleanup procedure
yielded 36% using the same amount of catalyst 2 (0.5 mmol
scale). The doubled chemical yield of 6 is realized because
96% of the alkyne 5 was converted to the 1,3-cyclohexadiene
6. The advantage of the methylene-free metathesis is a result
of improved stereoselectivity.
loading and 6 equiv of COD (entry 3). The benzyl ether
required optimized conditions to give complete conversion
and good chemical yield of 8D (70%, entry 4). The
homopropargyl tosylate 7E underwent ring synthesis ef-
ficiently (entry 5); however, the product 8E was sensitive
to elimination and required special care in its handling.
Unprotected nitrogen functionality (with a free N-H bond)
is rarely employed in cross-metathesis. To circumvent
anticipated difficulties with free N-H functionality, Rodriguez
introduced nitrogen functionality (as carbamates) after the
cross-metathesis step.13 Under optimized methylene-free
conditions, both the homopropargylic sulfonamide 7F and
its higher homologue 7G underwent ring synthesis in high
yield (entries 6,7). The glycolate ester 7H in entry 8 gave
good isolated yield of diene 8H under high catalyst loading
and at higher reaction temperatures.
The synthesis of 2,3-disubstituted 1,3-cyclohexadienes
from internal alkynes was accomplished using the optimized
procedure (Table 3). The literature has focused on terminal
With optimized conditions employing the four-carbon
donor 1,5-COD, we examined terminal alkynes with a variety
of functional groups known to perform poorly in cross-
metathesis. The results are summarized in Table 2.
Table 3. Scope of Ring Synthesis for Internal Alkynesa
Table 2. Functional Group Tolerance in Terminal Alkynes
entry
R1
R2
1 (%) solvent yieldb (%)
1
2
3
4
5
6
7
8
CH2CH3 CH2OBz
5
5
5
10
10
10
5
CH2Cl2 10A, 65
CH2Cl2 10B, 59c
CH2Cl2 10C, 63
CH2Cl2 10D, 68
1,5-COD
1 (%) (equiv)
% yielda
(NMR)
CH3
CH2CH2OBz
entry
R
CH2OAc CH2OAc
CH3
CH3
CH(OAc)Bn
CH2CH2OTBS
1
2b
3
4
5
6
7
8b
7A, CH(CO2Me)2
7B, CH(SO2Ph)2
7C, CH2OTBS
7D, CH2OBn
7E, CH2OTs
7F, CH2NHTs
7G, (CH2)2NHTs
5.0
10
6
9
6
9
6
9
9
9
8A, 82 (100)
8B, 75 (93)
8C, 72 (87)
8D, 70 (85)
8E, 72 (79)
8F, 73 (94)
8G, 74 (92)
8H, 60 (74)
PhH
PhH
PhH
PhH
10E, 53
10F, 49
10G, 72
10H, 61
CH2CH3 CH2OBn
7.5
7.5
5.0
5.0
5.0
CH3
CH3
CH2CH2N(Ts)Boc
CO2Et
10
a Standard conditions: 0.25 mmol of alkyne was added to 9 equiv of
1,5-cyclooctadiene and the carbene complex in either refluxing CH2Cl2 or
in benzene at 65 °C. b Isolated yield. c 62% yield when 18 equiv of
polybutadiene and 5 mol % of 1 were used.
7H, CH(OTBS)(CO2Me) 10
a Isolated yield. b Benzene was used as solvent; reaction temperature was
65 °C.
alkynes in enyne metathesis. Unsymmetrical internal alkynes
have not been well-studied due to formation of mixtures of
unsymmetrical dienes on reaction with 1-alkenes.14 From the
optimization table, it was expected that high loadings of
carbene (7.5-10 mol %) would give complete conversion
of the internal alkyne reactants, but we examined each alkyne
at lower loading (5 mol %). Loading was increased to 10%
only if incomplete conversion was observed. Propargylic and
homopropargylic ester functionality was well tolerated on
the internal alkyne, giving the 2,3-disubstituted diene 10A,B
in good yields (entries 1 and 2). The symmetrical ester also
The optimized conditions established in Table 1 were used
as the starting point; however, most of the entries were
evaluated independently. This procedure helped identify
lower loading and when fewer equivalents of COD could
be used. A high yield of diene 8A from dimethyl propargyl
malonate was obtained (entry 1). The sulfone proved more
difficult, giving incomplete conversion under the same
conditions (5 mol % of 1; CH2Cl2, reflux). Higher catalyst
loading and higher temperatures were needed to obtain 8B
(entry 2). The homopropargyl silyl ether, a problematic
substrate as identified previously, gave high yield at modest
(13) Rodriguez-Conesa, S.; Candal, P.; Jimenez, C.; Rodriguez, J.
Tetrahedron Lett. 2001, 42, 6699-6702.
(14) Internal alkynes in cross-enyne metathesis: (a) Giessert, A. J.;
Snyder, L.; Markham, J.; Diver, S. T. Org. Lett. 2003, 5, 1793-1796. (b)
Giessert, A. J.; Diver, S. T. Org. Lett. 2005, 7, 351-354. Recently, Lee et
al. demonstrated that silyl alkynes perform well in cross metathesis: (c)
Kim, M.; Park, S.; Maifeld, S. V.; Lee, D. J. Am. Chem. Soc. 2004, 126,
10242-10243.
(10) Ulman, M.; Grubbs, R. H. J. Org. Chem. 1999, 64, 7202-7207.
(11) Similar to the original rationale of ethylene effect: Mori, M.;
Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 6082-6083.
(12) Middleton, M. D.; Diver, S. T. Tetrahedron Lett. 2005, 46, 4039-
4043.
Org. Lett., Vol. 8, No. 12, 2006
2541

underwent an efficient ring synthesis at low catalyst loading
(entry 3). The effectiveness of polybutadiene was established
for internal alkynes by repetition of entry 2 with 18 equiv
of PB to give 10B in 62% yield (footnote c in Table 3). The
propargyl-substituted ester proved to be a reactive substrate
but required a higher catalyst loading to obtain complete
conversion of the alkyne (entry 4). The potentially coordinat-
ing homopropargyl silyl ether was evaluated under the
optimized conditions, and a good yield of 10E was obtained
(entry 5). Similarly, the propargyl benzyl ether has the
potential to chelate to the vinyl carbenes (entry 6). Higher
catalyst loading was needed for complete conversion of
alkyne, with an isolated yield of 49%. Nitrogen functionality
could be introduced onto the disubstituted cyclohexadiene
without difficulty (entry 7). Electron-poor alkynes are not
commonly used in enyne cross-metathesis.1a However, we
found that ethyl 2-butynoate gave diene 10H in good yield
at elevated temperature (entry 8).
with certain functional groups, especially homopropargylic
ethers. COD may be playing additional kinetic roles protect-
ing the catalyst through degenerate alkene coordination
complexes. In ring syntheses that gave modest chemical
yields (50-60%), the remainder of the alkyne mass is
presumably incorporated into COD oligomers, which are
removed in the isolation step by a trituration procedure.
Higher alkene concentration may keep carbenes in the enyne
metathesis manifold and help to overcome chelation, but slow
oligomerization of E-A may significantly compete at even
higher alkene concentrations. This would reduce the ef-
ficiency of the stereoselective ring synthesis by converting
alkyne into oligomers. These proposals need to be further
evaluated by synthesis and reactivity studies of isomeric vinyl
carbene complexes.
The cyclohexadienes underwent cycloaddition with di-
enophiles and heterodienophiles in high yields. In situ
generation of an acyl nitroso species under oxidative condi-
tions yielded the N-O cycloadduct in 75% yield (Scheme
4, eq 7). Significantly, the oxidative conditions did not cause
The mechanism must explain both the isomerization of
vinyl carbenes and the effect of COD. First, it is likely that
the isomeric vinyl carbene intermediates A interconvert under
the methylene-free conditions (Scheme 3, eq 6). We suggest
Scheme 4. Cycloaddition of Functionalized Cyclohexadienes
Scheme 3. Proposed Mechanism
aromatization of the cyclohexadiene to any appreciable
extent, and no ene reaction products were observed. Simi-
larly, the thermal Diels-Alder cycloaddition of 8A pro-
ceeded in high yield to give cycloadduct 12 (Scheme 4, eq
8).
In conclusion, we have demonstrated functional group
tolerance in terminal and internal alkynes under the condi-
tions of stereoselective methylene-free metathesis. This
significantly extends the cyclohexadiene synthesis to dienes
featuring a wide array of organic functionality. Internal
alkynes have sufficient reactivity in the ring synthesis.
Further studies are directed toward kinetically evaluating the
chelative interactions and identifying the putative vinyl
carbene decomposition pathways.
that vinyl carbene Z-A undergoes an intramolecular RCM
to give the 1,3-cyclohexadiene and that E-A slowly isomer-
izes to Z-A. We previously suggested this equilibration
mechanism4 to account for the high chemical yields of 1,3-
cyclohexadienes in the ring synthesis. This rationale similarly
applies to the data presented here since the NMR yields of
Table 2 average 90%. Second, the role of COD helps to
improve catalyst efficiency and functional group scope.
Higher COD concentration would not directly affect the
conversion of Z-A into cyclohexadiene, and its role in the
equilibration of eq 6 is not required. We hypothesize that
the high COD concentration increases the proportion of
active alkylidenes, inhibits chelate formation (and possible
decomposition through chelate formation), and inhibits
catalyst decomposition. Chelate formation is more prevalent
Acknowledgment. The authors thank SUNY Buffalo and
the NSF (CHE-092434) for financial support of this work.
We also thank Materia (Pasadena, CA) for catalyst support.
Supporting Information Available: Experimental pro-
cedures and full characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL060727D
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Org. Lett., Vol. 8, No. 12, 2006