Intramolecular Baylis-Hillman and morita reactions using unsaturated thiol ester substrates containing enolizable aldehydes.

Article abstract of DOI:10.1021/ol026638s

[reaction: see text] Previously unknown intramolecular Baylis-Hillman and Morita reactions involving cyclization of an unsaturated thiol ester onto a pendant aldehyde function are reported. These can be used successfully for the preparation of both cyclop

Full text of DOI:10.1021/ol026638s

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3687-3690
Intramolecular Baylis−Hillman and
Morita Reactions Using Unsaturated
Thiol Ester Substrates Containing
Enolizable Aldehydes
Gary E. Keck* and Dennie S. Welch
Department of Chemistry, UniVersity of Utah, Salt Lake City, Utah 84112-0850
keck@chemistry.utah.edu
Received July 30, 2002
ABSTRACT
Previously unknown intramolecular Baylis−Hillman and Morita reactions involving cyclization of an unsaturated thiol ester onto a pendant
aldehyde function are reported. These can be used successfully for the preparation of both cyclopentenols and cyclohexenols, but the results
are very sensitive to substrate and precise reaction conditions.
Recently, in the context of a synthetic project underway in
our laboratories, we had need of a functionalized cyclopen-
tenol containing the general structural motif embodied in
structure 1 below. In considering potential approaches to the
synthesis of such an intermediate, an intramolecular version
of the Baylis-Hillman reaction1 appeared to be an especially
direct possibility (eq 1).
only aldehyde-containing substrates for which such a reaction
has been reported are for one nonenolizable case that led to
a coumarin derivative3 and two examples reported by Murphy
and co-workers4 using an enone-containing substrate bearing
an enolizable aldehyde. Even in this latter case where an
enone could be used successfully in a reaction promoted by
piperidine, the corresponding ethyl ester failed to give any
of the desired Baylis-Hillman product. Instead, either no
reaction or aldol condensation was observed. Subsequent
studies using tri-n-butylphosphine (Morita reaction) in CHCl3
with such enones were successful for six-ring formation but
gave poor yields (20%) for five-ring formation.5 A full report
details limited success for cyclizations of an enoate or
thioenoate onto an enolizable aldehyde.6 It has been previ-
ously reported that both DBU and tributylphosphine are
However, attempts to identify precedent for such a process
revealed that examples of the intramolecular Baylis-Hillman
reaction, although known, are exceedingly rare. The first such
report utilized an unsaturated ester tethered to a methyl
ketone and was successful using phosphine catalysis.2 The
(3) Drewes, S. E.; Njamela, O. L.; Emslie, N. D.; Ramesar, N.; Field, J.
S. Synth. Commun. 1993, 23, 2807.
(4) Black, G. P.; Dinon, F.; Fratucello, S.; Murphy, P. J.; Nielsen, M.;
Williams, H. L.; Walshe, N. D. A. Tetrahedron Lett. 1997, 38, 8561.
(5) Dinon, F.; Richards, E.; Murphy, P. J.; Hibbs, D. E.; Hursthouse,
M. B.; Malik, K. M. A. Tetrahedron Lett. 1999, 40, 3279.
(6) Richards, E. L.; Murphy, P. J.; Dinon, F.; Fratucello, S.; Brown, P.
M.; Gelbrich, T.; Hursthouse, M. B. Tetrahedron 2001, 57, 7771.
(1) For reviews, see: (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron
1988, 44, 4653. (b) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
1996, 52, 8001.
(2) Roth, F.; Gygax, P.; Frater, G. Tetrahedron Lett. 1992, 33, 1045.
10.1021/ol026638s CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/13/2002

ineffective in promoting Baylis-Hillman-type reactions of
S-ethylthioacrylate with aldehydes.7
by providing stabilization for the aldol portion of the
pathway. Conditions under which reaction via an enol rather
than enolate ion could reasonably be expected were also
examined; these likewise allow for a low energy pathway
to product. The results of a number of these experiments
are summarized in Table 1.
Attempts to force reaction by employing elevated tem-
peratures with DMAP alone were marginally successful; thus,
raising the temperature to 65 °C (reaction in CHCl3) gave a
50% yield of the desired Baylis-Hillman product 4 after
48 h. Addition of DMAP‚HCl to the CH2Cl2 room-temper-
ature reaction was without effect; however, with the addition
of DMAP‚HCl, reaction did occur more rapidly in CHCl3 at
65 °C, to afford 4 in 48% yield after 24 h (entry 4). Other
solvents were then explored in an attempt to improve upon
these results. No reaction was observed using DMAP and
DMAP‚HCl in THF at 65 °C or in DMF at 23 °C. Reaction
was observed in DMF at higher temperatures, but the yield
(43% after 5 h at 78 °C, entry 8) was still low.
It occurred to us that previous observations from these
laboratories could potentially afford a solution to these
problems and allow for the synthesis of such cyclopentenols
using the intramolecular Baylis-Hillman approach (Figure
1). Specifically, we had previously demonstrated that Z R,â-
Figure 1. Previous observation and hypothesis.
Much better results were obtained using protic solvents.11
Although no reaction was observed in EtOH using conditions
that mimicked those of the previously reported Z-E isomer-
ization (catalytic amounts of DMAP at room temperature)
use of a full equivalent of DMAP in EtOH at 78 °C afforded
the desired 4 in 72% yield after only 2.5 h. Inclusion of
DMAP‚HCl gave a much cleaner reaction (TLC analysis)
and improved the yields (entry 11). Optimal results in terms
of yield were observed with 1.0 equiv of DMAP and 0.25
equiv of DMAP‚HCl, in which case an 87% isolated yield
was obtained after 1 h at 78 °C (entry 12). Comparison with
entry 11 shows that although lesser quantities of reagent can
be employed, reaction times are correspondingly longer.
Moreover, this ratio of DMAP to DMAP‚HCl was empiri-
cally determined to be optimal for this reaction. For example,
as shown in entry 13, using a full equivalent of DMAP‚HCl
under otherwise identical conditions lowers the yield to 60%
at the same reaction time.
Having identified conditions under which the desired
reaction was high yielding, it was of considerable interest
to compare these results with those obtained using amines
more typically employed in the Baylis-Hillman process.12,13
Treatment of 3 with DBU in CH2Cl2 led to complete
consumption of starting material within 3 h; however, 4 could
be isolated in only 25% yield. Reactions were also conducted
in EtOH using both DABCO and DBU to allow for direct
comparison with the DMAP results in the same solvent. With
DABCO, although the starting material was completely
consumed within 1 h at 78 °C, the desired 4 was obtained
in only 18% yield. The major product obtained in this case
was the acetal 5. With DBU, this process was much more
unsaturated thiol esters could be easily isomerized to E by
exposure to catalytic amounts of DMAP in CH2Cl2 at room
temperature.8 Presumably this process proceeds by a con-
jugate addition-â elimination sequence. Normal oxo-esters
were unaffected by such treatment.
It thus appeared that DMAP should be competent to serve
as a Baylis-Hillman catalyst with appropriate thiol ester
substrates. We record herein the results of an investigation
into this reaction that provide efficient access to the desired
cyclopentenols and offer some further insight into the
Baylis-Hillman reaction as well.
Initial attempts to induce cyclization simply by exposure
of 3 to DMAP in CH2Cl2 at room temperature gave no
reaction. Since our previous work strongly suggested that
the required initial 1,4 addition occurs readily under these
conditions, it appeared that the ensuing intramolecular aldol
step was too slow to compete with â-elimination of the
pyridyl group. We suspected that some additional activation
for the aldehyde carbonyl might be required to allow this
step to proceed smoothly. Successful aldol reactions involv-
ing enolates generally require transfer of metal ion from
enolate oxygen to the developing alkoxide oxygen in the
product; otherwise, loss of delocalization energy in going
from enolate to alkoxide renders the aldol equilibrium
unfavorable. This principle is now well recognized in the
context of the bimolecular aldol reaction (Zimmerman-
Traxler transition state).9 Elegant work by Noyori has also
shown that “naked” enolates do not undergo simple aldol
condensation reactions.10
This reaction was therefore investigated in the presence
of additives that could potentially mediate the overall reaction
(11) For rate accelerations of bimolecular Baylis-Hillman reactions in
protic media, see: (a) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams,
R. J. Org. Chem. 2002, 67, 510. (b) Yu, C.; Liu, B.; Hu, L. J. Org. Chem.
2001, 66, 5413.
(12) DMAP has been used in the Baylis-Hillman reaction of cyclohex-
enone with aqueous formaldehyde: Rezgui, F.; El Gaied, M. M. Tetrahedron
Lett. 1998, 39, 5965.
(7) Kataoka, T.; Iwama, T.; Kinoshita, H.; Tsujiyama, S.; Tsurukami,
Y.; Iwamura, T.; Watanabe, S. Synlett 1999, 197.
(8) Keck, G. E.; Boden, E. P.; Mabury, S. A. J. Org. Chem. 1985, 50,
709.
(9) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920.
(10) Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem. Soc. 1983, 105,
1598.
(13) It has been suggested that DBU is the best amine promoter for the
Baylis-Hillman reaction: Aggarwal, V. K.; Mereu, A. Chem. Commun.
1999, 2311.
3688
Org. Lett., Vol. 4, No. 21, 2002

Table 1. Reaction Conditions and Isolated Yields for Baylis-Hillman Cyclization of 3 with Amine and Phosphine Promoters
entry
solvent
temp (°C)
time
additive
equiv
yield (%)a
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
CH2Cl2
CHCl3
CH2Cl2
THF
DMF
DMF
EtOH
EtOH
rt
65
rt
65
rt
65
rt
∼24 h
48 h
∼24 h
∼24 h
3 h
10 h
3 h
5 h
45 h
2.5 h
2 h
1 h
1 h
DMAP
DMAP
DMAP, DMAP‚HCl
DMAP, DMAP‚HCl
DBU
DMAP, DMAP‚HCl
DMAP, DMAP‚HCl
DMAP. DMAP‚HCl
DMAP
1.0
1.0
no reaction
50b
0.5, 0.3
1.0, 0.25
1.0
1.0, 0.25
1.0, 0.25
1.0, 0.25
0.1
no reaction
48c
25
no reaction
no reaction
43
78
rt
9
no reaction
10
11
12
13
14
15
16
17
18
19
20
78
78
78
78
78
rt
65
rt
rt
DMAP
1.0
72
84
87
60
18
0d
70
63
0
EtOH
EtOH
EtOH
EtOH
DMAP, DMAP‚HCl
DMAP , DMAP ‚HCl
DMAP, DMAP‚HCl
DABCO
0.5, 0.125
1.0, 0.25
1.0, 1.0
1.0
1 h
EtOH
5 min
0.5 h
4 h
3 h
0.5 h
15 h
DBU
1.0
THF/H2O (1:1)
THF/H2O (4:1)
tert-amyl alcohol
CH2Cl2
CH2Cl2
DMAP, DMAP‚HCl
DMAP, DMAP‚HCl
PMe3
PMe3
PMe3
1.0, 0.25
1.0, 0.25
1.0
1.0
0.1
rt
rt
56
82
a Unless otherwise indicated, complete consumption of starting material was observed and substrate concentration was 0.1 M. b 46% of starting material
was recovered. c 18% of starting material was recovered. d In this case, ethoxy tetrahydrofuran 5 was formed essentially quantitatively within 5 min.
facile, and 5 was obtained quantitatiVely within 5 min at 23
°C. Thus, these more basic amines cannot be used in the
protic media in which the Baylis-Hillman process is
intrinsically more faVorable, as a result of the intrusion of
this alternatiVe reaction pathway.
Cyclopentenol 7 was obtained in 41% yield from the
corresponding aldehyde substrate, along with 58% of the
ethoxy tetrahydrofuran product.
Attempts to use added lithium ion (LiCl or LiClO4) in
THF or ether to promote the DMAP-mediated reaction were
unsuccessful. However, the use of THF-water as solvent
with DMAP‚HCl present gave good results. In this case, a
63% yield could be obtained in a room-temperature reaction.
Conducting the same reaction at 65 °C afforded the desired
product in 70% isolated yield after 30 min. Although these
reactions in aqueous THF were quite fast, the isolated yields
were never quite as high as those obtained in the EtOH
reactions.
Figure 2. Isolated yields for Baylis-Hillman-Morita cyclizations
using DMAP/DMAP‚HCl/EtOH or PMe3/CH2Cl2.
Several other potential substrates for this reaction were
prepared to assess the impact of substitution patterns upon
the viability of this approach to constructing such cyclopen-
tenols. The results of these reactions are summarized in
Figure 2, as are the results obtained using PMe3 as catalyst
(vide infra). Gem dimethyl substitution adjacent to the
aldehyde carbonyl was very well tolerated; thus cyclopen-
tenol 6 could be prepared in 88% yield using the reaction
conditions optimized for 3. Steric hindrance adjacent to the
â-carbon of the unsaturated thiol ester was less well tolerated
and encouraged reaction via initial hemiacetal formation.
Curiously, attempts to extend this reaction to the prepara-
tion of a cyclohexenol gave much lower yields. Application
of the protocol that proved optimal with 3 to the otherwise
identical six-ring case afforded the desired product 8 in only
29% yield after 48 h at reflux. The oxo-ester corresponding
to 3 also proved, as expected, to be much less reactive,
affording only a 40% yield of cyclopentenol product 2 after
48 h at reflux.
After these studies had been completed, two independent
reports appeared on intramolecular versions of the very
Org. Lett., Vol. 4, No. 21, 2002
3689

closely related vinylogous Baylis-Hillman-Morita reaction,
both using phosphine catalysis. Krische14 reported a number
of enone-enone cyclization reactions, while Roush15 re-
ported enone-enal, enal-enal, and enal-enoate cyclizations,
as shown in Figure 3.16 Although the one previous report of
after 15 h when the reaction was conducted in CH2Cl2 at
room temperature, 0.02 M in substrate, with 0.1 equiv of
PMe3.
Given the success of this reaction, we were curious to
determine whether this protocol could be applied to the
problematic case of six-ring formation. Reaction of the thiol
ester substrate under these conditions led to the desired
cyclohexenol 8 in 56% yield. Further experimentation
showed that with this substrate the yield could be improved
by slightly higher catalyst loading relative to that of the
parent case. The best results for this case were obtained using
0.25 equiv of trimethylphosphine in CH2Cl2 at 0.02 M in
substrate, which afforded a 75% isolated yield of 8 after 2
h at room temperature. In view of the excellent results
obtained using this procedure, it was applied to the other
materials studied using the DMAP conditions. A comparison
of the results obtained using the DMAP and PMe3 protocols
is summarized in Figure 2. The results depicted are for the
conditions that proved optimal for each substrate.
Figure 3. Vinylogous cyclizations by Krische and Roush.
In summary, two protocols for the intramolecular Baylis-
Hillman-Morita reaction have been developed that allow
for the use of alkenes activated by substituents at the ester
oxidation state. Under the conditions reported, side reactions
that complicate the use of enolizable aldehydes, such as
bimolecular condensations, are minimized. The results point
out the extreme sensitivity of such reactions to small
variations in experimental conditions. The availability of an
alternative reaction pathway initiated by hemiacetal formation
with these aldehyde containing substrates provides another
complicating aspect. These observations suggest that negative
results in such reactions be viewed with some suspicion
unless it is clear that the relevant reaction variables have
been thoroughly examined.
the use of phosphine catalysis in an intramolecular Baylis-
Hillman reaction was not encouraging, it was clearly of
interest to examine the protocols developed by Roush and
by Krische with our thiol ester-aldehyde substrates.
The conditions that were generally optimal in the Roush
study were most thoroughly investigated. Reaction of the
substrate 3 with trimethylphosphine (0.2 equiv) in tert-amyl
alcohol (0.1 M in 3) at room temperature for 3 h afforded
none of the desired Baylis-Hillman adduct, although starting
material was consumed with the formation of numerous
unidentified materials. However, in CH2Cl2 at room tem-
perature, reaction with trimethylphosphine (1.0 equiv) was
complete in 0.5 h and gave 4 in 56% isolated yield. Further
experimentation showed that this reaction gave higher yields
at lower substrate concentration and lower catalyst loading.
Under optimal conditions, an 82% yield of 4 was obtained
Acknowledgment. Financial support from the National
Institutes of Health (through GM-28961) is gratefully
acknowledged.
(14) Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J.
J. Am. Chem. Soc. 2002, 124, 2402.
(15) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002,
124, 2404.
(16) Neither author reported cyclizations in which the initial nucleophilic
addition occurred to an enoate or thioenoate.
Supporting Information Available: Spectral and ana-
lytical data and experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL026638S
3690
Org. Lett., Vol. 4, No. 21, 2002