Ring-closing metathesis in methanol and water

Article abstract of DOI:10.1021/jo981678o

The ring-closing metathesis (RCM) of acyclic dienes in both methanol and water has been achieved through the use of water-soluble ruthenium alkylidenes. These alkylidenes react readily with acyclic olefins in protic solvents, but they do not cyclize α,ω-dienes because of the instability of the resulting methylidene. Successful cyclization has been achieved through simple substrate modification - incorporation of an olefin substituent allows cyclization to proceed in good yield. A methyl-substituted substrate was cyclized in 60% conversion in methanol, and the incorporation of a phenyl substituent resulted in nearly quantitative cyclization. Phenyl-substituted substrates are best suited for the reaction, as a more stable, active catalyst is regenerated upon each catalyst turnover. Using this methodology, 90% conversion of a water-soluble substrate to a substituted cyclopentene has been achieved in aqueous solution. This methodology has also been successfully applied to increase RCM yield in organic solvents.

Full text of DOI:10.1021/jo981678o

9904
J . Org. Chem. 1998, 63, 9904-9909
Rin g-Closin g Meta th esis in Meth a n ol a n d Wa ter
Thomas A. Kirkland, David M. Lynn, and Robert H. Grubbs*
Contribution from the Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of
Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received August 18, 1998
The ring-closing metathesis (RCM) of acyclic dienes in both methanol and water has been achieved
through the use of water-soluble ruthenium alkylidenes. These alkylidenes react readily with acyclic
olefins in protic solvents, but they do not cyclize R,ω-dienes because of the instability of the resulting
methylidene. Successful cyclization has been achieved through simple substrate modifications
incorporation of an olefin substituent allows cyclization to proceed in good yield. A methyl-
substituted substrate was cyclized in 60% conversion in methanol, and the incorporation of a phenyl
substituent resulted in nearly quantitative cyclization. Phenyl-substituted substrates are best suited
for the reaction, as a more stable, active catalyst is regenerated upon each catalyst turnover. Using
this methodology, 90% conversion of a water-soluble substrate to a substituted cyclopentene has
been achieved in aqueous solution. This methodology has also been successfully applied to increase
RCM yields in organic solvents.
In tr od u ction
Recently, several techniques have been developed for
the metathesis of water-soluble substrates. Aqueous
emulsions have allowed the ring-opening metathesis
polymerization (ROMP) of water-soluble monomers with
alkylidene 1.7 The use of MeOH/CH2Cl2 blends has also
allowed the ROMP of monomers that are insoluble in
CH2Cl2.7a However, the successful application of these
methods to RCM has not been reported. Current methods
of applying RCM to biologically relevant substrates focus
on rendering the substrate soluble in organic solvents,
either by extensive substrate protection5b,8 or binding of
the substrate to solid support.5b,9 However, the use of
organic solvents can alter or destroy important higher-
order structures that these substrates typically display
in water.10 The development of a methodology that
enables efficient carbon-carbon bond formation in aque-
ous media would allow the synthesis of a variety of
interesting compounds with biological applications. To
this end, the RCM of unprotected substrates in water has
remained an important goal.11
Ring-closing metathesis (RCM) has emerged as a
useful method for the synthesis of carbocycles and
heterocycles.1 Although several early transition metal
alkylidenes are highly active for RCM,2 their use in
organic synthesis is limited by their intolerance to protic
functional groups and impurities.1a,3 In contrast, ruthe-
nium alkylidene 1 is stable and active in the presence of
polar and protic moieties such as alcohols, aldehydes,
ketones, carboxylic acids, esters, amides, and water.3c,4
Although this increased functional group tolerance has
enabled the application of RCM to densely functionalized
substrates,5 many interesting substrates are derived from
biological systems and therefore are insoluble in organic
solvents. Although alkylidene 1 is active in the presence
of protic solvents such as water and methanol, it is
completely insoluble in these solvents.6
Metathesis in water was initially demonstrated with
ill-defined catalysts such as RuCl3 and Ru(H2O)6tos2 (tos
) p-toluenesulfonate), which were shown to ROMP
strained, cyclic olefins in aqueous media.7c,12 Although
these complexes do not contain a formal alkylidene, small
amounts of alkylidenes are generated in situ in the
(1) For recent reviews on RCM, see: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413-4450. (b) Schuster, M.; Blechert, S. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2037-2056. (c) Grubbs, R. H.; Miller,
S. J .; Fu, G. C. Acc. Chem. Res. 1995, 28, 446-452.
(2) For examples of RCM with tungsten and molybdenum alkyl-
idenes, see: (a) Leconte, M.; Salvatore, P.; Mutch, A.; Lefebvre, F.;
Basset, J . M. Bull. Soc. Chem. Fr. 1995, 132, 1069-1071. (b) Nugent,
W. A.; Feldman, J .; Calabrese, J . C. J . Am. Chem. Soc. 1995, 117,
8992-8998. (c) Fu, G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1992, 114,
5426-5427.
(3) (a) Ivin, K. J .; Mol, J . C. Olefin Metathesis and Metathesis Poly-
merization; Academic Press: London, 1997. (b) Kirkland, T. A.; Grubbs
R. H. J . Org. Chem. 1997, 62, 7310-7318. (c) Fu, G. C.; Nguyen, S. T.;
Grubbs, R. H.; J . Am. Chem. Soc. 1993, 115, 9856-9857.
(4) (a) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc.
1996, 118, 100-110. (b) Schwab, P.; France, M. B.; Grubbs, R. H.;
Ziller, J . W. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039-2041.
(5) For additional examples of the functional group tolerance of 1,
see (a) Meng, D.; Su, D.-S.; Balog, A.; Bertinato, P.; Sorenson, E. J .;
Danishefsky, S. J .; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. J .
Am. Chem. Soc. 1997, 119, 2733-2734. (b) Miller, S. J .; Blackwell, H.
E.; Grubbs, R. H. J . Am. Chem. Soc. 1996, 118, 9606-9614.
(6) Alkylidene 1 is inactive in polar, aprotic solvents such as DMSO
and DMF.
(7) (a) Kanai, M.; Mortell, K. H.; Kiessling, L. L. J . Am. Chem. Soc.
1997, 119, 9931-9932, and references therein. (b) Lynn, D. M.;
Kanaoka, S.; Grubbs, R. H. J . Am. Chem. Soc. 1996, 118, 784-790.
(c) Fraser, C.; Grubbs, R. H. Macromolecules 1995, 28, 7248-7255.
(8) (a) Blackwell, H. E.; Grubbs, R. H., 1998, unpublished work. (b)
Xu, Z.; J ohannes, C. W.; Salman, S. S.; Hoveyda, A. H. J . Am. Chem.
Soc. 1996, 118, 10926-10927. (c) Overkleeft, H. S.; Pandit, U. K.
Tetrahedron Lett. 1996, 37, 547-550. (d) Clark, T. D.; Ghadiri, M. R.
J . Am. Chem. Soc. 1995, 117, 12364-12365.
(9) For general references on solid supported RCM, see: (a) Peters,
J .-U.; Blechert, S. Synlett. 1997, 348-350. (b) Pernerstorfer, J .;
Schuster, M.; Blechert, S. J . Chem. Soc. Chem. Commun. 1997, 1949-
1950. (c) Piscopio, A. D.; Miller, J . F.; Koch, K. Tetrahedron Lett. 1997,
38, 7143-7146. (d) van Maarseveen, J . H.; den Hartog, J . A. J .;
Engelen, V.; Finner, E.; Visser, G.; Kruse, C. G. Tetrahedron Lett. 1996,
37, 8249-8252. (e) Schuster, M.; Pernerstorfer, J .; Blechert, S. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1979-1980.
(10) Blackwell, H. E.; Grubbs, R. H. Unpublished results.
(11) For general reviews of other carbon-carbon bond forming
processes in water, see: (a) Li, C. J . Tetrahedron 1996, 52, 5643-5668.
(b) Breslow, R. A. Acc. Chem. Res. 1991, 24, 159-164.
10.1021/jo981678o CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/01/1998

Ring-Closing Metathesis
J . Org. Chem., Vol. 63, No. 26, 1998 9905
Sch em e 1. Th e F ir st Tu r n over Step of RCM
presence of strained, cyclic olefins. Limited reaction with
acyclic olefins has been observed during ROMP,12d,13 but
no RCM in methanol or water has been observed.13 We
recently reported the synthesis of well-defined, water-
soluble alkylidenes 2 and 3,14 which are highly active in
the ROMP of strained, cyclic olefins in both methanol and
water.15 In this contribution, we report that these alkyl-
idenes are active for both acyclic olefin metathesis and
RCM in water and methanol.
During the first turnover in the successful RCM of R,ω-
dienes, a benzylidene (Scheme 1, 6c) reacts with the
diene to generate an equivalent of cyclized product,
styrene and a methylidene (Scheme 1, 6a ). This meth-
ylidene is the true catalytic species. Although the meth-
ylidene derived from 1 is stable under a variety of
conditions,4b the instability of other transition metal
methylidenes is often a limiting factor in RCM.18 When
alkylidene 2 or 3 is reacted with an R,ω-diene, styrene
is observed by 1H NMR spectroscopy but the methylidene
is not. This indicates that 2 and 3 react with the
substrate but the methylidene that is formed decomposes
before reentering the catalytic cycle.
Further evidence that methylidene instability was
preventing RCM was obtained through reaction of alkyl-
idenes 2 and 3 with simple acyclic olefins. Whereas
reaction of 1 with ethylene proceeds quantitatively to the
expected methylidene,4b the reaction of 2 with ethylene
results in rapid decomposition (eq 2). Alkylidene 2 does
react with either propene or trans-2-butene to yield a new
resonance at 19.3 ppm in the 1H NMR, which was
assigned as an ethylidene (eq 3).
Resu lts a n d Discu ssion
In itia l Stu d ies. Initial attempts to probe the activities
of 2 and 3 toward RCM centered upon the cyclization of
R,ω-dienes such as diethyl diallylmalonate (4). Alkylidene
1 cyclizes 4 rapidly and quantitatively to cyclopentene
diester 5 in organic solvents.16 However, the treatment
of diene 4 with a catalytic amount of alkylidenes 2 or 3
in methanol gives no product (eq 1).17
The increased stability of the ethylidene prompted us
to examine RCM substrates containing substituted ole-
fins. In the RCM of dienes containing one terminal olefin
and one internal olefin (Scheme 1, R * H), metathesis
occurs initially at the terminal olefin3b,19 and the olefin
substituent is transferred to the alkylidene upon cycliza-
tion. Therefore, we reasoned that the incorporation of a
methyl substituent into a model diene would result in
the generation of a more stable catalytic species. Our
initial studies focused on the diethyl diallylmalonate
system as a scaffold. In this case, the cyclopentene diester
(12) (a) Hillmyer, M. A.; Lepetit, C.; McGrath, D. V.; Novak, B. M.;
Grubbs, R. H. Macromolecules 1992, 25, 3345-3350. (b) Feast, W. J .;
Harrison, D. B. J . Mol. Catal. 1991, 65, 63-72. (c) Novak, B. M.;
Grubbs, R. H. J . Am. Chem. Soc. 1988, 110, 7542-7543. (d) Novak, B.
M.; Grubbs, R. H. J . Am. Chem. Soc. 1988, 110, 960-961.
(13) Novak, B. M. Ph.D. Thesis, California Institute of Technology,
1989.
(17) In certain cases, the use of 5 mol % 2 in the RCM of 4 gives up
(14) Mohr, B.; Lynn, D. M.; Grubbs, R. H. Organometallics 1996,
15, 4317-4325.
to 5% product. The use of alkylidene 3 or increased loading of
alkylidene 2 affords no increase in conversion.
(18) Fu, G. C.; Grubbs, R. H. J . Am. Chem. Soc. 1992, 114, 5426-
5427, and references therein.
(19) Kim, S. H.; Zuercher, W. J .; Bowden, N. B.; Grubbs, R. H. J .
Org. Chem. 1996, 61, 1073-1081.
(15) Lynn, D. M.; Mohr, B.; Grubbs, R. H. J . Am. Chem. Soc. 1998,
120, 1627-1628.
(16) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J . Am. Chem. Soc.
1997, 119, 3887-3897.

9906 J . Org. Chem., Vol. 63, No. 26, 1998
Ta ble 1. RCM of F u n ction a lized Dien es In itia ted by Alk ylid en es 2 a n d 3a
Kirkland et al.
a
b
The following conditions were used unless otherwise noted: 5 mol % catalyst (2 or 3), 0.37 M substrate, 45 °C. E ) CO2Et.
c Conversions were determined by 1H NMR. Number in parentheses indicates alkylidene used. e Substrate conc. ) 0.24 M. f Substrate
conc. ) 0.1 M. 10 mol % 3 used.
d
g
is kinetically favored by the Thorpe-Ingold effect,20
analogues are easily synthesized, and the conversion of
these substrates to cyclized product is easily monitored
catalyst stability is still a limiting factor because the
ethylidene is observed to completely decompose before
the starting material is consumed. This problem is
further amplified by the decreased rate of olefin meta-
thesis that accompanies increasing steric bulk around the
olefin, allowing the rate of catalyst decomposition to be
more competitive with the rate of RCM. After considering
the greater reactivity and stability of benzylidene 1
compared with analogous methylidenes and ethylidenes,4b
we examined a phenyl-substituted substrate.
Phenyl-substituted diene 8 was synthesized in an
analogous manner to 7 using cinnamyl bromide. Incor-
poration of a phenyl substituent proved to be highly
effective, as treatment of 8 with alkylidene 2 resulted in
80% conversion to cyclopentene 5. Furthermore, cycliza-
tion proceeded nearly quantitatively in the presence of
alkylidene 3. Although some alkylidene decomposition is
evident, alkylidene 3 is still observed after all of diene 8
is converted to cyclic product. Alkylidenes 2 and 3 are
regenerated in the RCM of phenyl-substituted substrates,
and are therefore true catalysts.
1
by H NMR.
RCM of Su bstitu ted Olefin s in Meth a n ol. Methyl-
substituted diene 7 was synthesized through the reaction
of crotyl bromide with the anion of diethyl allyl mal-
onate.21 Treatment of 7 with 5 mol % alkylidene 2 or 3
in methanol gives 60% conversion to cyclic diester 5
(Table 1). The catalytic ethylidene was clearly observed
by 1H NMR spectroscopy during these reactions. The
reactions were clean, consisting primarily of cyclic prod-
uct and unreacted starting material. It should be noted
that although replacement of a terminal olefin with an
internal olefin in a RCM substrate alters the structure
of the catalytically active alkylidene, the structure of the
desired cyclized products remains unaffected.
Although the increased stability of the generated
ethylidenes allows for RCM with alkylidenes 2 and 3,
(20) Forbes, M. D. E.; Patton, J . T.; Myers, T. L.; Maynard, H. D.;
Smith, D. W.; Schulz, G. R.; Wagener, K. B. J . Am. Chem. Soc. 1992,
114, 10978-10980 and references therein.
(21) For a general procedure for malonate alkylation, see: Gilman,
H.; Blatt, A. H. Organic Syntheses, Coll. Vol. I; J ohn Wiley and Sons:
New York, 2nd ed., 250-251.
The reason for the decomposition of benzylidenes 2 and
3 in the RCM of 8 is unclear, as they are stable for days
in either methanol or water at 45 °C. Styrene generated
in the RCM of a phenyl-substituted diene could react with

Ring-Closing Metathesis
J . Org. Chem., Vol. 63, No. 26, 1998 9907
Sch em e 2
a benzylidene to generate an unstable methylidene,
although control reactions of alkylidenes 2 and 3 with
styrene indicate that this is not a significant decomposi-
tion pathway. Another consideration is the decomposition
of transitional alkylidene 9, which is generated upon
initial reaction of the catalyst with substrate 8 (Scheme
2). The stability of such an alkylidene is unknown but is
expected to be similar to the analogous ethylidene.
Alkylidene 3 is a significantly more active catalyst than
alkylidene 2 in these cyclizations. This difference in
reactivity can be explained through an analysis of phos-
phine electronic parameters.16 For alkylidenes of the type
(PR3)2Cl2RudCHR, metathesis activities generally in-
crease as the phosphine ligands become larger and more
electron-rich.16 Although the phosphines coordinated to
2 and 3 are sterically similar, the phosphines in 3 are
more electron-rich.15 Whereas differences in the activities
of these alkylidenes have not been noted for ROMP, the
RCM of substrate 7 allows for a qualitative assessment
of their relative activities. The treatment of 7 with
alkylidene 2 results in 30% conversion after 1.5 h,
whereas the use of alkylidene 3 results in 85% conversion
over the same time period. This result is in accord with
theoretical predictions.15 A quantitative assessment of
catalyst activities was not attempted because of alkyl-
idene decomposition over the course of the reaction.
Formation of cyclohexene diester 16 was achieved via
cyclization of phenyl-substituted diene 10 with 2 and 3
in methanol (Table 1). The slower formation of a six-
membered ring relative to a five-membered ring is
believed to be responsible for the lower conversion.22 The
decreased cyclization rate allows decomposition of the
intermediate alkylidene that is analogous to 9 to be more
competitive with the rate of RCM (Scheme 2).23 Surpris-
ingly, the cyclization of methyl-substituted diene 11 does
not suffer from this rate decrease. Although ruthenium
alkylidenes typically react sluggishly with trisubstituted
olefins, the cyclization of 11 to cyclopentene 17 proceeds
quickly and quantitatively.24
olefins are able to coordinate to the metal center better
than trans-olefins.3a The dramatic rate increase provided
by the inclusion of cis-olefins can be an effective method
for improving the overall conversion by increasing the
rate of cyclization relative to the rate of alkylidene
decomposition.
RCM in Wa ter . Having demonstrated the RCM of
several substrates in methanol, we turned our attention
to homogeneous RCM in water. Model substrates exam-
ined initially were based on a diallylamine hydrochloride
framework25 because analogues are easily synthesized
1
and conversions are easily monitored by H NMR. Phen-
yl-substituted diene 14 was synthesized from allylamine
and cinnamyl bromide, and cyclized with alkylidene 3
in methanol to give pyrroline hydrochloride 19 in 75%
conversion (Table 1). Although the RCM of this substrate
in water only proceeds to 5-10% conversion with both
alkylidenes, these reactions represent the first observa-
tion of RCM in water. The cyclization of a cis-substituted
analogue yielded similar results, giving 15% conversion
in the presence of catalyst 3.
Catalysts 2 and 3 are active in the presence of acid15
and have been shown to polymerize monomers containing
amine hydrochlorides without loss of activity,26 suggest-
ing that the ammonium functionality was not degrading
the alkylidene. Failure of the N,N-dimethyl analogue of
14 to cyclize under the same conditions further suggested
that other factors were responsible for these low conver-
sions. Because alkylidene 1 reacts slowly with electron-
deficient olefins,27 we considered that the strongly electron-
withdrawing nature of the ammonium group was deacti-
vating these dienes for RCM.
To circumvent this possibility, a water-soluble sub-
strate was designed with the quaternary ammonium
functionality further removed from the olefins. Diene 15
was synthesized through functional group manipulation
of malonate 8. This new substrate showed a dramatic
increase in conversion in both water and methanol.
Treatment of ammonium salt 15 with alkylidene 3 gives
cyclopentene 20 in 60% conversion in water and 90% in
methanol (Table 1). Although conversions in water are
lower than in methanol, excellent conversions in either
solvent can be achieved through an increase of the
catalyst loading. The increase in conversion observed
with this increase in catalyst loading indicates that
catalyst decomposition is still a limiting factor in these
reactions. For example, in the presence of 10 mol % 3,
cyclization of 15 proceeds to 90% conversion in aqueous
solution (eq 4).
Olefin geometry also has a significant impact on
cyclization rates. For example, the cyclization of trans-
substituted substrate 12 with alkylidene 3 requires 30
h to reach 90% conversion, whereas cyclization of the cis-
substituted derivative 13 proceeds quantitatively in 2 h
(Table 1). This effect is not surprising, as cis-substituted
(22) For a discussion of the effects of substrate homologation on
intramolecular cyclizations, see: J ung, M. E.; Gervay, J . J . Am. Chem.
Soc. 1991, 113, 224-232 and references therein.
(23) Another factor that should be considered is substrate dimer-
ization, but this does not appear to be significant in the RCM of 10 as
conversion is not dependent on substrate concentration.
(24) In the synthesis of unsymmetrical olefins with this methodol-
ogy, it is critical that the phenyl substituent be placed on the more
substituted olefin as in substrate 11. If the phenyl substituent is placed
on the less substituted olefin, the ruthenium carbene will preferentially
react with the 1,2-disubstituted olefin, then react with the gem-
disubstituted olefin intramolecularly, giving one equivalent of cyclized
product and the unstable methylidene.
(25) Chlorides were used exclusively, as exposure of ruthenium
alkylidenes of the type (PR3)2Cl2RudCHR to other coordinating anions
such as Br- results in fast anion exchange, typically yielding a
significantly less active catalyst. This effect is not observed for very
weakly coordinating anions such as SO3-. See ref 16.
(26) Lynn, D. M.; Grubbs, R. H. Unpublished results.
(27) Ulman, M.; Grubbs, R. H. Organometallics 1998, 17, 7, in press.

9908 J . Org. Chem., Vol. 63, No. 26, 1998
Kirkland et al.
reported. Substrate 4 is commercially available and was
degassed before its use. Argon was purified by passage through
columns of BASF R3-11 catalyst (Chemalog) and 4 Å molec-
ular sieves (Linde). Analytical TLC was performed with silica
gel 60 F254 precoated plates (0.25 mm thickness) with a
fluorescent indicator. Flash column chromatography was
performed with silica gel 60 (230-400 mesh) from EM Sci-
ence.35
Gen er a l RCM P r oced u r e. In a typical reaction, substrate
8 (35 mg, 0.11 mmol) was placed in a vial and dissolved in
CD3OD (0.15 mL). In a separate vial, 2 (5.0 mg, 5.54 µmol)
was placed in a vial and dissolved in CD3OD (0.15 mL). The
catalyst and substrate solutions were combined, placed in an
NMR tube, and the tube was sealed with a rubber septum.
The reaction was heated to 45 °C, and monitored by 1H NMR.
Conversion to product (80%) was determined via integration
of the methylene protons R to the olefin in the cyclized product
(2.95 ppm, s) relative to the methylene protons of the uncyc-
lized substrate (2.68 ppm, dd).
Rea ction of Alk ylid en e 2 w ith Acyclic Olefin s (Gen -
er a l P r oced u r e). A solution of alkylidene 2 (10 mg, 0.11
mmol) in CD3OD (0.5 mL) was placed in a NMR tube that was
sealed with a rubber septum. This solution was heated to 45
°C and purged with propene, resulting in a rapid color change
from deep purple to orange. After 15 min, the reaction was
monitored by 1H NMR. An alkylidene resonance for 2 was
observed at 19.94 ppm, as well as a new alkylidene resonance
at 19.29 ppm. Styrene was also observed in the reaction
mixture. The generation of a new alkylidene species was also
confirmed by 31P NMR (33.3 ppm, s). Evaporation of solvent
yielded an orange powder, but rapid decomposition precluded
isolation.
Ap p lica tion s to Or ga n ic System s. The beneficial
effects of diene substitution are not limited to RCM with
alkylidenes 2 and 3. Even though the methylidene
derived from 1 is quite robust, under certain reaction
conditions its instability can limit conversion. For ex-
ample, RCM of diallylamine hydrochloride with 5 mol %
alkylidene 1 only proceeds to 60% conversion in meth-
ylene chloride (eq 5). RCM of the readily synthesized
phenyl-substituted analogue 14, however, gives pyrroline
hydrochloride (19) quantitatively under the same condi-
tions with minimal decomposition of the catalytic ben-
zylidene. This simple modification of the starting mate-
rial greatly improved the yield of the desired product,
and could be applied generally to increase RCM yields
with 1 in organic solvents.
4,4-Dica r boeth oxy-1-p h en yl-1,7-octa d ien e (10). Diester
10 was synthesized from 1,1-dicarboethoxy-4-pentene and
cinnamyl bromide according to a previously published proce-
dure.36 1,1-Dicarboethoxy-4-pentene was synthesized according
to the same method. Diester 10 was isolated as a clear,
colorless oil (33%, two steps): 1H NMR δ (CDCl3) 7.32-7.17
(m, 5H), 6.44 (d, J ) 7.8 Hz, 1H), 6.11-6.00 (m, 1H), 5.84-
5.73 (m, 1H), 5.04 (d, J ) 8.6 Hz, 1H), 4.96 (d, J ) 5.1 Hz,
1H), 4.19 (q, J ) 5.3 Hz, 4H), 2.06-2.03 (m, 4H), 1.24 (t, J )
4.8 Hz, 6H); 13C NMR δ (CDCl3) 170.8, 137.3, 136.8, 133.5,
128.2, 127.1, 125.9, 123.8, 114.8, 61.0, 57.3, 36.2, 31.6, 28.2,
13.9; HRMS calcd for C20H26O4 (M+) 330.1831, found 330.1825.
4,4-Dica r boet h oxy-1-p h en yl-2-m et h yl-1,6-h ep t a d ien e
(11). Diester 11 was synthesized from diethyl allylmalonate
and 3-bromo-1-phenyl-2-methyl-2-propene in an analogous
manner to substrate 10. 3-Bromo-1-phenyl-2-methyl-2-propene
was synthesized from the commercially available alcohol in
an analogous manner to cis-cinnamyl bromide. Diester 11 was
isolated as a clear, colorless oil (12%, two steps): 1H NMR δ
(CDCl3) 7.32-7.27 (m, 3H), 7.19 (d, J ) 4.0 Hz, 2H), 6.35 (s,
1H), 5.79-5.68 (m, 1H), 5.13 (d, J ) 5.0 Hz, 1H), 5.09 (s, 1H),
4.22-4.14 (m, 4H), 2.86 (s, 2H), 2.73 (d, J ) 3.4 Hz, 2H), 1.79
(s, 3H), 1.24 (t, J ) 7.0 Hz, 6H); 13C NMR δ (CDCl3) 171.2,
137.9, 133.7, 132.8, 130.4, 129.0, 128.1, 126.4, 119.1, 61.3, 57.7,
43.4, 37.2, 18.7, 14.2.
Con clu sion s
We have demonstrated the first examples of RCM in
water and methanol. Although alkylidenes 2 and 3 do
not promote the RCM of R,ω-dienes, simple olefin sub-
stitution allows for successful RCM to afford the desired
cyclic product. We have determined several factors that
influence the success of these reactions. In particular, the
choice of olefin substituent is important because it
directly affects the stability and reactivity of the resultant
catalytic alkylidenes. Phenyl substituents have proven
to be the most effective, allowing for quantitative conver-
sions to cyclized product in methanol. Additionally,
dienes containing cis-olefins cyclize considerably faster
than those containing trans-olefins. This methodology
describes an efficient, metal-catalyzed, carbon-carbon
bond-forming process that proceeds to high conversion
in aqueous media. It has also been extended to increase
conversions in RCM catalyzed by 1 in organic solvents.
The incorporation of substituted olefins in complex,
water-soluble dienes may allow for the construction of
biologically interesting architectures in aqueous media.
N-Boc-N-a llyl-tr a n s-cin n a m yla m in e (12). Allylamine
(10.9 g, 0.191 mol) and di-tert-butyl dicarbonate (13.9 g, 63.6
mmol) were dissolved in CH2Cl2 (250 mL) at 0 °C and allowed
to stir for 8 h. The solution was then washed with water (100
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All manipulations and reactions
involving ruthenium alkylidenes were performed in a nitrogen-
filled dry box or by use of standard Schlenk techniques under
an atmosphere of argon. Distilled deionized water and reagent-
grade methanol were used for these reactions, and were
rigorously degassed by purging with argon and stirring under
high vacuum before use. All other reagents were used without
further purification unless otherwise noted. Alkylidenes 1,4b
2,14 3,14 substrates 7,28 8,29 14,30 and products 5,2b 16,31 17,32
18,3c 19,33 and 2034 have been previously prepared and
(29) Hanessian, S.; Leger, R. J . Am. Chem. Soc. 1992, 114, 3115-
3117.
(30) Crozet, M. P.; Kaafaran, M.; Surzur, J . M. Bull. Soc. Chim. Fr.
1984, 390-398.
(31) Bachman, G. B.; Tanner, H. A. J . Org. Chem. 1939, 4, 493-
501.
(32) Schweizer, E. E.; O’Neill, G. J . J . Org. Chem. 1965, 30, 2082-
2083.
(33) Gajda, T.; Zwierzak, A. Liebigs Ann. Chem. 1986, 992-1002.
(34) Tropsha, A. E.; Nizhinni, S. V.; Yaguzhinskii, L. S. Bioorg.
Khim. 1985, 11, 1931-1941.
(35) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(36) Gilman, H.; Blatt, A. H. Org. Synth. 1935, Collect. Vol. 1, 250-
251.
(28) Grigg, R.; Malone, J . F.; Mitchell, T. R. B.; Ramasubbu, A.;
Scott, R. M. J . Chem. Soc., Perkin Trans. 1984, 1745-1754.

Ring-Closing Metathesis
J . Org. Chem., Vol. 63, No. 26, 1998 9909
mL), dried with MgSO4, and concentrated to give N-Boc-
allylamine as a pale yellow solid (9.7 g, 97%), which was used
without further purification.
solution had stirred for 2 h it was quenched with H2O (1 mL),
followed by 15% NaOH (5 mL). Removal of the resulting solids
by filtration, removal of solvent in vacuo, and purification of
the resultant oil on silica gel gave the known alcohol in good
accordance with literature values (0.93 g, 49%, two steps).39
1-(N,N,N-Tr im eth ylam m on iu m ch lor ide)-2-allyl-5-ph en -
yl-4-p en ten e (15). A solution of tosyl chloride (0.55 g, 2.89
mmol) in CH2Cl2 (25 mL) was cooled to 0 °C. 2-Allyl-5-phenyl-
4-penten-1-ol (0.50 g, 2.63 mmol) and NEt3 (0.40 g, 3.94 mmol)
were added and the solution was allowed to warm to room
temperature. After stirring for 12 h, the reaction mixture was
quenched with water (25 mL), extracted with CH2Cl2 (25 mL),
and dried over MgSO4. The resulting oil was carried on without
further purification.
This tosylate (1.26 g, 3.66 mmol) was added to a solution of
LiBr (0.95 g, 10.97 mmol in acetone) (20 mL) and the reaction
mixture was refluxed. After 12 h, the reaction was quenched
with water (25 mL), extracted with pentane (3 × 25 mL), and
dried over MgSO4. The resulting oil was added to a flask
containing MeOH (15 mL), which had been purged with NMe3
for 5 min. This reaction mixture was heated to 50 °C for 24 h,
and then all of the solvent was removed to give a brown solid.
This solid was eluted through a column packed with Amberlite
IRA-400 Cl- ion-exchange resin with MeOH, then triturated
with Et2O to yield 15 as a white crystalline solid (53%, three
steps): 1H NMR δ (CDCl3) 7.38-7.18 (m, 5H), 6.48 (d, J ) 7.9
Hz, 1H), 6.27-6.17 (m, 1H), 5.86-5.77 (m, 1H), 5.17 (d, J )
4.4 Hz, 1H), 5.13 (d, J ) 5 Hz, 1H), 4.14 (s, 2H), 3.45 (s, 9H),
2.44-2.16 (m, 5H); 13C NMR δ (CDCl3) 136.8, 134.6, 134.2,
128.9, 127.8, 126.4, 125.9, 119.5, 69.8, 53.9, 38.5, 37.7, 33.5;
HRMS calcd for C17H26ClN (M-Cl+) 244.2065, found 244.2060.
N-Boc-allylamine (2.88 g, 18.29 mmol) was allowed to react
with NaH (0.48 g, 20.12 mmol) in DMF (50 mL) for 15 min.
Then trans-cinnamyl bromide (3.97 g, 20.12 mmol) was added
and the solution was heated to 60 °C. After stirring for 16 h,
the reaction was quenched with water (50 mL) and extracted
with ether (3 × 50 mL). The combined extracts were dried over
MgSO4, concentrated, and purified on silica gel (5% EtOAc in
hexanes) to yield 12 as a clear, colorless oil (3.98 g, 80%): 1H
NMR δ (CDCl3) 7.42-7.21 (m, 5H), 6.46 (d, J ) 7.9 Hz, 1H),
6.20-6.11 (m, 1H), 5.85-5.76 (m, 1H), 5.18-5.12 (m, 2H), 3.96
(br s, 2H), 3.87 (br s, 2H), 1.49 (s, 9H). 13C NMR δ (CDCl3)
155.5, 136.9, 134.1, 131.8, 128.7, 127.7, 126.5, 125.7, 116.8,
79.8, 48.8, 48.4, 28.6; HRMS calcd for C17H23NO2 (M+) 273.1729,
found 273.1730.
N-Boc-N-a llyl-cis-cin n a m yla m in e (13). Cis-cinnamyl al-
cohol (2.07 g, 15.4 mmol), which was prepared as previously
reported,37 was dissolved in CH2Cl2 (50 mL) and cooled to 0
°C. To this solution was added PPh3 (6.07 g, 23.1 mmol) and
CBr4 (7.66 g, 23.1 mmol). After 1 h the solvent was removed
in vacuo, the solid residue was taken up in hexanes, and
filtered through a plug of silica. This afforded cis-cinnamyl
bromide (1.8 g, 60%), which was used without further purifica-
tion.38
Substrate 13 was then synthesized in a manner similar to
12 using cis-cinnamyl bromide. It was isolated as a clear,
colorless oil (74%): 1H NMR δ (CDCl3) 7.38-7.19 (m, 5H), 6.57
(d, J ) 5.9 Hz, 1H), 5.74-5.61 (m, 2H), 5.01 (d, J ) 4.9 Hz,
1H), 4.91 (d, J ) 8.6 Hz, 1H), 4.12 (br s, 2H), 3.75 (br s, 2H),
1.44 (s, 9H). 13C NMR δ (CDCl3) 155.5, 136.8, 133.9, 131.2,
129.4, 128.9, 128.3, 126.5, 116.7, 79.8, 49.1, 44.3, 28.6; HRMS
calcd for C17H23NO2 (M+) 273.1729, found 273.1729.
2-Allyl-5-p h en yl-4-p en ten -1-ol. To a solution of diester 8
(3.14 g, 9.92 mmol) in DMSO (20 mL) was added H2O (0.67 g,
37.22 mmol) and NaCl (0.70 g, 12.41 mmol). This was heated
at reflux for 90 h, quenched with H2O (75 mL), extracted with
ether (3 × 40 mL), and dried over MgSO4. After removal of
solvent and elution of the resulting black oil through a pad of
SiO2 (10% EtOAc in hexanes), a yellow, clear oil was obtained
(1.31 g), which was used without further purification.
Dropwise addition of this oil dissolved in THF (10 mL) to a
suspension of LiAlH4 (0.41 g, 10.7 mmol) in THF (20 mL),
which was at 0 °C, was completed over 30 min. After this
Ack n ow led gm en t. We thank Dr. Bernhard Mohr
and Art Vandelay for many insightful discussions and
the National Institutes of Health for financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra
and IR data for 11, 12, 13, 15 (5 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O981678O
(37) Davis, F. A.; Reddy, R. T. J . Org. Chem. 1992, 57, 2599-2606.
(38) The quick isomerization of this compound resulted in the
presence of <10% 11 in 10, as determined by 1H NMR. This did not
affect the behavior of 11 and was discounted.
(39) Atkinson, R. S.; Grimshire, M. J . J . Chem. Soc., Perkin Trans.
1 1987, 1135-1145.