Thiol additions to acrylates by fluorous mixture synthesis: Relative control of elution order in demixing by the fluorous tag and the thiol substituent

Article abstract of DOI:10.1016/S0040-4020(01)00369-6

All possible combinations of a series of three fluorous benzyl tags and three acrylates have been made. The resulting acrylate esters were combined in groups of three (one of each tag) and the resulting mixtures were reacted with a mixture of four thiols under standard conditions to effect conjugate addition. Analysis of the resulting libraries by fluorous hplc showed a primary separation based on the tag and revealed reliable secondary separations based on the thiol and the acrylate. The primary and secondary separations were used together in a preparative 'mixture of mixtures' experiment in which one of the tagged acrylate mixtures was reacted with a mixture of three thiols. The resulting nine component mixture was demixed by fluorous and reverse phase hplc and then detagged to give all nine final products in pure form.

Full text of DOI:10.1016/S0040-4020(01)00369-6

TETRAHEDRON
Pergamon
Tetrahedron 57 ,2001) 5243±5253
Thiol additions to acrylates by ¯uorous mixture synthesis: relative
control of elution order in demixing by the ¯uorous tag and the
thiol substituent
²
Dennis P. Curranp and Yoji Oderaotoshi
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Dedicated to Professor Barry M. Trost on the occasion of his 60th birthday
Received 16 March 2001; accepted 27 March 2001
AbstractÐAll possible combinations of a series of three ¯uorous benzyl tags and three acrylates have been made. The resulting acrylate
esters were combined in groups of three ,one of each tag) and the resulting mixtures were reacted with a mixture of four thiols under standard
conditions to effect conjugate addition. Analysis of the resulting libraries by ¯uorous hplc showed a primary separation based on the tag and
revealed reliable secondary separations based on the thiol and the acrylate. The primary and secondary separations were used together in a
preparative `mixture of mixtures' experiment in which one of the tagged acrylate mixtures was reacted with a mixture of three thiols. The
resulting nine component mixture was demixed by ¯uorous and reverse phase hplc and then detagged to give all nine ®nal products in pure
form. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Existing solution phase mixture techniques tend to sidestep
the separation and identi®cation problems by directly
subjecting organized mixtures to biological assays in a
process called deconvolution.2 No attempts are made to
isolate individual pure components in these techniques.
The purposeful synthesis of mixtures of organic compounds
is a recent development. The inherent ef®ciency of making
more than one compound in one reaction vessel is the
primary attraction of mixture synthesis, but this is offset
by dif®culties in analyzing, separating and identifying
mixture components. Split-mix synthesis on the solid
phase addresses the separation and identi®cation problems,1
but a price is paid at the reaction stage since standard solu-
tion phase reaction conditions are not directly applicable.
A conceptual solution to the separation and identi®cation
problems inherent in solution phase mixture synthesis
involves the use of a `separation tag' as shown in Fig. 1.
Separation tags ,T) are chosen such that they dominate over
tagged molecules in a complementary separation technique.
Figure 1.
Keywords: mixture synthesis; ¯uorous synthesis; solution phase combinatorial chemistry.
Corresponding author. Tel.: 11-412-624-8240; fax: 11-412-624-9861; e-mail: curran1@pitt.edu
Current address: Department of Applied Chemistry, Faculty of Engineering, Osaka, University, 2-1 Yamadaoka Suita, Osaka 565-0871, Japan
p
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,01)00369-6

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D. P. Curran, Y. Oderaotoshi / Tetrahedron 57 '2001) 5243±5253
In other words, the separation of a mixture of tagged
molecules is dictated by the tag, not the molecule that is
tagged. In tag-based mixture synthesis, a series of organic
substrates ,S1¼Sn) is attached to a series of incrementally
different tags ,T1¼Tn). The tagged substrates ,T1S1¼TnSn)
are then mixed and taken through a series of reaction steps
to produce a tagged product mixture ,T1P1¼TnPn). This
mixture is then subjected to the appropriate separation
technique that complements the tag to generate the
individual pure products in a process called demixing.
Identi®cation of the tagged products follows directly from
the original tag-substrate pairings. Finally, the tag is
removed to give individual ®nal products ,P1¼Pn).
esters 5 {tag 1±3, acrylate 1±3}. These were then mixed in
groups of threeÐone of each tagÐand reacted with four
thiols 6{1±4} under standard conditions to give mixtures of
12adducts 7 {tag 1±3, acrylate 1±3, thiol 1±4}, which
were then analyzed by ¯uorous hplc. Three libraries were
prepared with different combinations of tags and acrylates
and the resulting three mixtures of 12compounds each
provided signi®cant information about factors effecting
retention time on ¯uorous hplc.
2.2. Synthesis of starting materials and authentic
product samples
The preparation of the benzyl alcohol tags 4 and their
coupling to the acrylates are summarized in Eq. ,1).
Palladium-catalyzed coupling of the zinc reagents derived
from per¯uoroalkylethyl iodides 8{1±3} provided
coupled products 9{1} ,48%), 9{2} ,46%) and 9{3}
,40%) after puri®cation by silica gel chromatography.6
Metalation of these products with BuLi followed by
addition of DMF and workup provided an intermediate
aldehyde ,not shown) which was directly reduced with
sodium borohydride. Flash chromatographic puri®cation
provided 4{1} ,81%), 4{2} ,68%), and 4{3} ,75%) as
colorless solids.
To reduce this conceptual approach to practice, we recently
introduced `¯uorous mixture synthesis ,FMS)'.3 In FMS,
the tags are ¯uorinated ,¯uorous) groups with increasing
numbers of ¯uorines, and the complementary tag-based
separation method is ¯uorous reverse phase chromato-
graphy.4
An example of FMS in the context of a synthesis of a
combinatorial library of mappicine analogs is shown in
Fig. 2. Four different alcohols were tagged with ¯uorous
silyl tags of increasing ¯uorine content, and the resulting
tagged products 1 were mixed to give M-1 and carried
through four steps to provide a mixture of tagged
mappicines M-2. This mixture was then demixed by
chromatography over silica gel with a ¯uorocarbon bonded
phase to give the individual pure products. More than 25
mixtures were made, and in each case, the products eluted in
order of increasing ¯uorine content of the tag.
To further extend FMS as a useful tool, much more
information is needed about the relative effects of tags and
tagged components on retention time in ¯uorous chromato-
graphy. For example, tags and substrates were paired
arbitrarily in the experiment in Fig. 2, so we could not
analyze the effect of the tag vs the tagged substrate on
retention time. Indeed, while it seems improbable, we
could not rigorously rule out the possibility that it was the
substrate and not the tag that determined the order of
demixing.
This paper describes a series of experiments designed to
glean additional information about the effects of tags vs
tagged substrates on demixing. While the tag shows the
predominant effect, clear structural effects of tagged
substrates are identi®ed. These effects are leveraged to
allow the synthesis of a mixture with three times more
components than the number of tags. This `mixture of
mixtures' experiment is the ®rst example of tag-based
mixture synthesis where the number of pure products that
are isolated exceeds the number of tags that are used.
ꢀ1†
All possible combinations ,nine) of the three benzyl
alcohols 4{1±3} with the three acrylate esters 3{1±3}
were then prepared individually by heating a benzene
solution of the alcohol, the acrylate and sodium hydride
with azeotropic distillation to remove methanol. Yields of
puri®ed products ranged from 43±97%, as summarized in
Eq. ,1).
2. Results and discussion
2.1. Mixture plan
Fig. 3 shows the plan for the mixture syntheses described in
this paper.5 Three acrylates 3{1±3} were tagged with three
¯uorous tags 4{1±3} to give nine ¯uorous-tagged benzyl
An initial pairing of tags and esters 5{1,1}, 5{2,2}, 5{3,3}
was selected arbitrarily and studied in some detail. First, a

D. P. Curran, Y. Oderaotoshi / Tetrahedron 57 '2001) 5243±5253
5245
of how ¯uorous solid phase extraction can be used to purify
tag compounds in a parallel synthesis experiment.7b
ꢀ2†
Figure 2. Making mappicine analogs by ¯uorous mixture synthesis
The tags were then removed individually by treating the
products, again in parallel, with titanium isopropoxide in
isopropanol. Workup and solid phase extraction through
¯uorous silica gel ,4/1 methanol/water) provided the
isopropyl esters 10 in the indicated overall yields. Further
elution with ethyl acetate provided the starting benzyl
alcohol tags 4, which were reused for subsequent
experiments. The yields of the recovered tags were close
to quantitative.
library of authentic samples of all 12adducts was made in
individual, parallel experiments by reaction of thiols 6{1±4}
,5 equiv.), triethylamine ,1 equiv.) and tagged esters 5
,1 equiv.) in THF for 15 h ,Eq. ,2)). The crude products 7
were puri®ed by solid phase extraction over ¯uorous reverse
phase silica gel.7 An initial pass with 4/1 methanol/water
provided an organic fraction ,amine, thiols), which was
discarded. A second pass with ethyl acetate provided a
¯uorous fraction, which contained substantially pure
Michael products 7. Crude yields of these products are
shown in Eq. ,2). This experiment provides a nice example
Mixture Experiments: Three mixture libraries were then
made by adding 0.2mmol of each of the four thiols
Figure 3. Synthesis of three mixture libraries and separation by tag

5246
D. P. Curran, Y. Oderaotoshi / Tetrahedron 57 '2001) 5243±5253
Table 1. Retention times ,in min) of the adducts in Libraries 1±3
spectra. Since all the products were readily identi®ed and
eluted in an order primarily dictated by the tag, we
deemed it unnecessary to prepare authentic samples of the
products in Libraries 2and 3. These compounds were
unambiguously identi®ed by the LCMS analysis of the
mixtures.
Library 1a
Library 2b
Library 3c
{1,1,3}
{1,1,2}
{1,1,1}
{1,1,4}
{2,2,3}
{2,2,2}
{2,2,1]
{2,2,4}
{3,3,3}
{3,3,2}
{3,3,1}
{3,3,4}
18.5
18.9
19.3
23.8
28.7
28.7
29.5
32.6
34.1
34.1
35.1
37.7
{1,2,3}
{1,2,2}
{1,2,1}
{1,2,4}
{2,3,3}
{2,3,2}
{2,3,1}
{2,3,4}
{3,1,3}
{3,1,2}
{3,1,1}
{3,1,4}
20.3
20.8
21.0
25.3
26.4
26.4
27.0
30.8
34.2{
34.2{
35.1
37.8
{1,3,3}
{1,3,2}
{1,3,1}
{1,3,4}
{2,1,3}
{2,1,2}
{2,1,1}
{2,1,4}
3,2,3}
18.1
18.5
18.7
23.2
27.0
27.0
27.6
31.2
35.6
35.6
36.5
38.8
The HPLC chromatogram of a mixture similar to Library 1
is shown in Fig. 4 and the retention times of all three
libraries are tabulated in Table 1. The compounds elute in
order of the tag; a ®rst group of peaks is all the products with
the C6F13 tag ,18±25 min); a second group of peaks is all the
products with the C8F17 tag ,26±33 min), and a third group
of peaks is all the products with the C10F21 tag ,34±39 min).
Within these groups, the separation of peaks was much
better than expected; indeed, up to 11 of the 12possible
peaks could be resolved with only two compounds partially
overlapping. The adducts 7 bearing the same Rf group
eluted reliably in order based on the appended thiol: 6{3}
before 6{2} before 6{1} before 6{4}. The t-butyl-bearing
compounds 7{tag, acrylate,4} always eluted well after the
other three, which were closely spaced.
3,2,2}
{3,2,1}
{3,2,4}
a
From 5{1,1}, 5{2,2}, 5{3,3}.
From 5{1,2}, 5{2,3}, 5{3,1}.
From 5{1,3}, 5{2,1}, 5{3,2}.
b
c
6{1±4} to three separate mixtures of the three tagged
acrylates 5 ,0.05 mol) and triethylamine ,0.15 mol) in
THF. After puri®cation by solid phase extraction as
above, the ¯uorous fraction of each of the three mixture
libraries containing 12products 7 was analyzed by injection
onto a Fluo®x column ,gradient of 80/20 MeOH/water to
100% methanol over 40 min) with analysis by mass spectro-
scopy. The retention times of the components of the three
libraries are listed in Table 1. No effort was made to
quantify the reactions at this point, although it is clear
from TLC and LC analysis that all the starting acrylates
were consumed.
Comparison of the results of Libraries 2and 3 with Library
1 again shows that the primary separation is by the ¯uorous
tag with a secondary separation by thiol. A close inspection
of the data also shows that there is a small effect of the ester
as well ,comparison of retention times across libraries is
needed for this); methacrylates eluted before crotonates
which in turn eluted before hexanoates.
The 12products of Library 1 were identi®ed against the
individual pure products from Eq. ,2) by LC retention
time and co-injection and by comparison of the mass
2.3. Preparative mixture experiment
In addition to showing that the primary separation is based
Figure 4. An HPLC trace of a mixture of compounds similar to Library 1. Retention times are listed in minutes; Fluo®x column eluting with a gradient of 80%
methanol/water increased to 100% methanol over 40 min. The order of peaks is 5{1,1,3 then 2 then 1 then 4}, 5{1,1,3 then 2 then 1 then 4}; 5{1,1,3 then 2 then
1 then 4}. Peaks 5{3,3,3/2} overlap at 36.5 min. The peak at 39 min is an unknown impurity. The mixture was made from individual pure components in ratios
roughly proportional to the UV extinction coef®cients at 254 nm to give similar peak heights.

D. P. Curran, Y. Oderaotoshi / Tetrahedron 57 '2001) 5243±5253
5247
Figure 5. Effects of tags and substituents on retention times.
on the tag, these experiments identi®ed a reliable separation
based on the thiol. This suggests a way to leverage mixture
library synthesis experiments in a combinatorial setting by
reacting each mixture with more than one reagent in a
diversity generating step. Inspection of the data Libraries
1±3 showed that the t-butylthiol adducts were well
separated from the other three thiols. However, even though
the other three thiols eluted in the same order, they were
very closely spaced, sometimes even overlapping. By
conducting a few experiments with pure tagged adducts 7
on regular silica gel, we learned that the p-methoxy adducts
7{tag,acrylate,3} emerged well before the naphthyl adducts
7{tag,acrylate,2}. In contrast, the phenyl adducts 7{tag,
acrylate,1} were not readily separated so thiol 6{1} was
dropped from the preparative experiment.
the Michael acceptors, but tags also differ ,largest tag
gives lowest yeld) so the relative effects cannot be
disentangled from this experiment. Among each group of
three thiol adducts, the ratio was close to statistical
,1/1/1).
These analytical experiments lead the synthesis and
puri®cation of a prototype nine compound mixture as
shown in Eq. ,3). The three thiols 6{2±4} ,0.075 mmol
each) were reacted with the acrylate mixture used to make
Library 3 ,0.05 mmol each) and DBU ,0.05 mmol). The
mixture was then preparatively separated over a Fluo®x
column to provide six fractions: a mixture of 7{1,3,2/3}
and pure 7{1,3,4}, a mixture of 7{2,1,2/3} pure 7{2,1,4},
a mixture of 7{3,2,2/3}, and ®nally pure 7{3,2,4}. As
presaged by the analytical experiments, the separation
occurred in order by tag with the t-butylthiol adducts {tag,
acrylate,4} following the p-methoxythiol and napthylthiol
adducts {tag,acrylate,2/3}. No effort was made to separate
the later pairs at this stage. The three remaining two-
component mixtures were separated on regular reverse
phase ,C18) silica gel to give the other six pure products.
ꢀ3†
3. Conclusions
The yields of each product based on 100% for each tagged
precursor 5 are listed in Eq. ,3). These re¯ect a reactivity
difference for the three precursors; the combined yield of
products from the methacrylate ,7{1,3,thiol}) was 93%
while the crotonate ,7{2,1,thiol}) gave 43% yield and the
hexanoate ,7{3,2,thiol}) gave only 20% combined yield.
These yields re¯ect the expected relative reactivities of
The effects of the tag, the thiol and the analysis of retention
times are summarized in Fig. 5. The systematic tagging of
the three different acrylates with three different tags and the
synthesis and demixing of the resulting libraries clearly
show the dominance of tag in this series of compounds.
Tagged products eluted in groups based on the ¯uorine
content of the tag, from lowest to highest. Secondary

5248
D. P. Curran, Y. Oderaotoshi / Tetrahedron 57 '2001) 5243±5253
separations based on both the thiol and ester components
were also observed and these effects also are reliable across
the series of tags. The t-butyl group has an especially strong
effect in retaining compounds on the ¯uorous silica gel. The
effect is probably stronger than the CF2 group but is clearly
less than two. Other groups had much smaller effects which
cannot yet be fully interpreted. Polarity may play a role8 ,for
example, hexanoates are better retained than methacrylates
and crotonates), but it is not the only effect since the orders
of elution of some of the thiol adducts differ on ¯uorous and
regular reverse phase columns.
mixture was heated at re¯ux for 5 min and then cooled to
room temperature. Chlorotrimethylsilane ,0.100 ml) was
added and the resulting mixture was stirred for 15 min at
room temperature. A THF solution ,20 ml) of 1-iodo-
1H,1H,2H,2H-per¯uorooctane ,10.0 g, 21.00 mmol) was
added to the reaction mixture at 308C. The reaction mixture
was stirred for 15 h at room temperature. The mixture was
added to a THF solution ,20 ml) of tetrakis,triphenyl-
phosphine)palladium ,0.850 g, 0.735 mmol) and 1-bromo-
4-iodobenzene ,6.09 g, 21.5 mmol). The mixture was
heated at 458C for 12h, cooled, and partitioned between
dichloromethane ,20 ml) and FC-72 ,40 ml). The organic
layer was washed twice with FC-72and evaporated.
Puri®cation of the residue by distillation under high vacuum
,0.2mmHg, 120 8C) afforded 5.06 g ,48%) of desired
product as colorless solid: mp 33±348C; IR ,KBr) 2954,
1485, 1236, 1145, 1004, 974, 851, 697, 570, 535, and
The generality of tag dominance still requires further study.
The compounds described herein are closely related
analogs, and it is premature to conclude that the tag
dominance observed in this and the prior mappicine series3
will translate to mixtures whose components have vastly
different structural types of sizes. More information will
be needed before we can assess the broad bounds of tag
vs substrate dominance.
1
507 cm21; H NMR ,CDCl3) d 7.46 ,d, Jˆ8.3 Hz, 2H),
7.11 ,d, Jˆ8.3 Hz, 2H), 2.90±2.85 ,m, 2H), and 2.45±
2.20 ,m, 2H); 13C NMR ,CDCl3) d 138.15, 131.99,
130.15, 120.69, 120±110 ,m), 32.83 ,t), and 26.05; 19F
NMR ,CDCl3, relative to CCl3F) d 279.61 ,3F), 2113.45
,2F), 2120.73 ,2F), 2121.71 ,2F), 2122.34 ,2F), and
2124.99 ,2F); Mass ,EI) ,rel intensity, %) m/z 505 ,6),
504 ,33), 503 ,7), 502,32, M 1), 423 ,7), 172 ,7), 171
,base peak), 170 ,8), 169 ,99), 153 ,6), 133 ,5), 109 ,37),
104 ,10), 103 ,5), 90 ,20), and 89 ,7); HRMS Calcd for
C14H8F13Br: m/z 501.9602. Found: m/z 501.96134.
Given that the organic components do have some effect on
the retention of tagged products, the arbitrary pairing of tags
and substrates will not always be desirable. While each of
the three different libraries described herein provided
reasonable separations, the tag substrate pairing in Library
3 maximized the space between the components, so this
pairing would probably be preferred for broader library
experiments. Because the effects of the organic
components translate across the different tags, it will be
possible to plan favorable pairings by attaching a single
tag to a series of different substrates or products from a
planned library. The tagged adducts should then be
analyzed by ¯uorous hplc and products that elute faster
should be given shorter tags while those that elute
slower should be given longer tags. This will help to ensure
the tag-substrate pairing expands rather than contracts
available chromatographic space between mixture
components.
4.1.2. 1-Bromo-4-02-per¯uorooctyl)ethylbenzene 9{2}. The
compound was prepared according to the procedure for the
preparation of 1-bromo-4-,2-per¯uorooctyl)ethylbenzene. A
THF solution ,40 ml) of 1-iodo-1H,1H,2H,2H-per¯uorode-
cane ,12.1 g, 21.00 mmol) was added to the suspension of
zinc. After workup, removal of palladium residue from the
crude product by column chromatography on silica gel with
hexane/ethyl acetateˆ19/1 gave a mixture of product and
1-bromo-4-iodobenzene ,6.75 g, product/starting compound
ˆ75/25, 46% yield). This mixture was used for the following
transformation: Colorless solid; mp 45±488C; IR ,KBr) 2998,
1
Perhaps most importantly, the work suggests that reliable
secondary separations based on organic components can be
identi®ed by simple hplc experiments on representative
compounds. Once identi®ed, these separations can be used
to make mixtures of mixtures by reacting each mixture of
tagged compounds with a mixture of organic reactants.
Primary and secondary separations can be accomplished
either by the ¯uorous chromatography or a standard
chromatography, or a combination. This approach leverages
¯uorous mixture synthesis by providing additional products
without additional tags or a proportional increase in effort.
In the mixture of mixtures experiment in Eq. ,3), nine pure
products emanated from one reaction and four hplc
separations.
1723, 1370, 1224, 998, 804, 669, and 527 cm21; H NMR
,CDCl3) d 7.46 ,d, Jˆ8.3Hz, 2H), 7.11 ,d, Jˆ8.3Hz, 2H),
2.90±2.86 ,m, 2H), and 2.45±2.18 ,m, 2H); 13C NMR
,CDCl3) d 138.16, 132.00, 130.14, 120.70, 120.00±100.00
,m), 32.85 ,t), and 26.06; 19F NMR ,CDCl3, relative to
CCl3F) d 279.52,3F), 2113.39 ,2F), 2120.47 ,2F),
2120.69 ,4F), 2121.51 ,2F), 2122.25 ,2F), and 2124.89
,2F); Mass ,EI) ,rel intensity, %) m/z 606 ,6), 602,7, M 1),
523 ,7), 172 ,6), 171 ,98), 170 ,6), 169 ,base peak), 153 ,7),
133 ,5), 109 ,42), 104 ,9) 91 ,6), 90 ,14), 89 ,5), and 69 ,6);
HRMS Calcd for C16H8F17Br: m/z 601.9538. Found: m/z
601.951328.
4.1.3. 1-Bromo-4-02-per¯uorodecyl)ethylbenzene 9{3}.
This was prepared according to the procedure for the
preparation of 1-bromo-4-,2-per¯uorooctyl)ethylbenzene.
A THF solution ,40 ml) of 1-iodo-1H,1H,2H,2H-per¯uoro-
dodecane ,14.2g, 21.00 mmol) was added to a suspension
of zinc. After workup, removal of palladium residue from
the crude product by column chromatography on silica gel
with hexane/ethyl acetateˆ19/1 gave a mixture of product
and 1-bromo-4-iodobenzene ,8.09 g, product/starting
compoundˆ52/48, 40% yield). This mixture was used for
4. Experimental
4.1. General
4.1.1. 1-Bromo-4-02-per¯uorohexyl)ethylbenzene 9{1}.
To zinc powder ,1.63 g, 25.0 mmol) under argon was
added THF ,4 ml) and 1,2-dibromoethane ,0.100 ml). The

D. P. Curran, Y. Oderaotoshi / Tetrahedron 57 '2001) 5243±5253
5249
the following transformation: Colorless solid; mp 64±698C;
IR ,KBr) 2951, 1489, 1347, 1204, 1145, 1073, 1018, 883,
808, 756, 650, 562, and 523 cm21; 1H NMR ,CDCl3) d 7.45
,d, Jˆ8.4 Hz, 2H), 7.11 ,d, Jˆ8.4 Hz, 2H), 2.92±2.79
,m, 2H), and 2.45±2.26 ,m, 2H); 13C NMR ,CDCl3) d
138.16, 132.00, 130.16, 120.69, 120.00±100.00 ,m), 32.84
,t), and 26.05; 19F NMR ,CDCl3, relative to CCl3F) d
279.54 ,3F), 2113.41 ,2F), 2120.86 ,10F), 2121.52
,2F), 2122.27 ,2F), and 2124.92 ,2F); Mass ,EI) ,rel
intensity, %) m/z 705 ,15), 704 ,83), 703 ,20), 702 ,91,
M1), 682 ,8), 683 ,10), 623 ,13), 314 ,26), 169 ,43), 153
,17), 152 ,base peak), 151 ,29), 150 ,13), 126 ,13), 109 ,14),
76 ,7), and 75 ,5); HRMS Calcd for C18H8F21Br: m/z
701.9474. Found: m/z 701.9536.
,CDCl3, relative to CCl3F) d 279.55 ,3F), 2113.39 ,2F),
2120.53 ,2F), 2121.71 ,2F), 2122.29 ,2F), and 2124.91
,2F); Mass ,EI) ,rel intensity, %) m/z 555 ,24), 554 ,base
peak, M1), 553 ,23), 552 ,15), 551 ,30), 537 ,10), 536 ,8),
535 ,27), 525 ,5), 167 ,5), 121 ,16), 109 ,10), 108 ,8), 107
,94), 105 ,8), 91 ,29), 79 ,18), and 77 ,6); HRMS Calcd for
C17H11F17O: m/z 554.0538. Found: m/z 554.0527.
4.1.6. 4-02-Per¯uorodecyl)ethylbenzylalcohol 4{3}. This
was prepared according to the procedure for the preparation
of 4-,2-per¯uorohexyl)ethylbenzylalcohol. Use of 1.7 M of
n-butyllithium in hexane ,15.1 ml, 25.6 mmol),
N,N-dimethylformamide ,1.98 ml, 25.6 mmol), THF
,16 ml), and sodium borohydride ,0.968 g, 25.6 ml) for
treatment of the mixture ,6.00 g) of 1-bromo-4-,2-per-
¯uorodecyl)ethylbenzene/1-bromo-4-iodobenzeneˆ52:48)
afforded 3.04 g ,75%) of product: Colorless solid; mp 95±
978C; IR ,KBr) 3366, 2958, 1706, 1370, 1335, 1208, 1149,
1081, 1013, 828, 700, 653, and 558 cm21; 1H NMR ,CDCl3)
d 7.35 ,d, Jˆ8.0 Hz, 2H), 7.23 ,d, Jˆ8.0 Hz, 2H), 4.70 ,s,
2H), 3.00±2.90 ,m, 2H), 2.47±2.19 ,m, 2H), and 1.80±1.50
,br, 1H); 13C NMR ,CDCl3) d 139.47, 138.72, 128.63,
121.00±100.00 ,m), 65.17, 33.06 ,t), and 26.26; 19F NMR
,CDCl3, relative to CCl3F) d 279.51 ,3F), 2113.41 ,2F),
2120.54 ,2F), 2121.48 ,10F), 2122.25 ,2F), and 2124.91
,2F); Mass ,EI) ,rel intensity, %) m/z 655 ,6), 654 ,30, M1),
653 ,7), 652 ,20), 635 ,11), 121 ,18), 109 ,9), 108 ,7), 107
,base peak), 105 ,8), 91 ,28) and 79 ,18); HRMS Calcd for
C19H11F21O: m/z 654.0474. Found: m/z 654.0463.
4.1.4. 4-02-Per¯uorohexyl)ethylbenzylalcohol 4{1}. A
1.7 M solution of n-butyllithium in hexane ,1.17 ml,
1.99 mmol) was added dropwise to THF solution ,2ml) of
1-bromo-4-,2-per¯uorohexyl)ethylbenzene ,0.500 g, 1.99
mmol) at 2408C under argon. The resulting mixture was
stirred for 20 min at 2408C. N,N-Dimethylformamide
,0.154 ml, 1.99 mmol) was added dropwise to the mixture.
After 30 min, diluted hydrochloric acid was added, and the
mixture was extracted with dichloromethane three times.
The organic layer was dried with anhydrous sodium sulfate,
and evaporated.
To the above residue was added ethanol ,2ml) and sodium
borohydride ,75.2mg, 1.99 mmol). This mixture was stirred
at 258C for 16 h. The mixture was diluted with hydrochloric
acid, and then extracted with dichloromethane three times.
The organic layer was dried over sodium sulfate and
evaporated. Puri®cation of the residue by column chromato-
graphy on silica gel with hexane/ethyl acetateˆ3/1 afforded
0.366 g ,81%) of product: Colorless solid; mp 33±358 C; IR
,neat) 3889, 2954, 2871, 1367, 1318, 1235, 1140, 1083,
4.1.7. 4-02-Per¯uorohexyl)ethylbenzyl crotonate 5{1,1}.
Sodium hydride ,about 1 mg) and ethyl crotonate ,27.4 ml,
1.10 mmol) were added to a benzene solution ,2ml) of 4-,2-
per¯uorohexyl)ethylbenzylalcohol ,0.100 g, 0.220 mmol),
and then the mixture was heated at re¯ux for 1 h. Benzene
was distilled out at atmospheric pressure to give a residue.
The residue was quenched with dilute hydrochloric acid,
and this mixture was extracted with dichloromethane. The
organic layer was dried over anhydrous sodium sulfate and
evaporated. Puri®cation of the residue by column chromato-
graphy on silica gel with hexane/ethyl acetateˆ19/1
afforded 84 mg ,73%) of product: Colorless oil; IR ,neat)
2953, 1724, 1654, 1448, 1320, 1243, 1177, 1142, 1022, 975,
1
1101, 837, and 697 cm21; H NMR ,CDCl3) d 7.34 ,d,
Jˆ8.0 Hz, 2H), 7.23 ,d, Jˆ8.0 Hz, 2H), 4.96 ,s, 2H),
2.96±2.90 ,m, 2H), 2.47±2.28 ,m, 2H), and 1.80±1.50
,br, 1H); 13C NMR ,CDCl3) d 139.47, 138.71, 128.63,
127.62, 120.00±103.00 ,m), 65.17, 33.07 ,t), and 26.27;
19F NMR ,CDCl3, relative to CCl3F) d 279.54 ,3F),
213.46 ,2F), 2120.73 ,2F), 2121.71 ,2F), 2122.34 ,2F),
and 2124.97 ,2F); Mass ,EI) ,rel intensity, %) m/z 454 ,21,
M1), 121 ,18), 109 ,7), 106 ,13), 107 ,base peak), 105 ,5), 93
,7), 91 ,31), 79 ,47), 78 ,7), 77 ,22), and 60 ,5); HRMS Calcd
for C15H11F13O: m/z 454.0602. Found: m/z 454.0589.
1
847, 808, and 711 cm21; H NMR ,CDCl3) d 7.34 ,d,
Jˆ8.0 Hz, 2H), 7.22 ,d, Jˆ8.0 Hz, 2H), 7.03 ,dq,
Jˆ15.3 Hz and Jˆ7.0 Hz, 1H), 5.90 ,dq, Jˆ15.3 Hz and
Jˆ1.6 Hz, 1H), 5.18 ,s, 2H), 2.96±2.85 ,m, 2H), 2.47±
2.28 ,m, 2H), and 1.89 ,dd, Jˆ7.0 Hz and Jˆ1.6 Hz, 3H);
13C NMR ,CDCl3) d 166.43, 145.38, 139.24, 134.85,
128.60, 128.60, 122.54, 120.00±103.00 ,m), 65.74, 33.02
,t), 26.28, and 18.10; 19F NMR ,CDCl3, relative to CCl3F) d
279.62,3F), 2113.51 ,2F), 2120.75 ,2F), 2121.73 ,2F),
2122.38 ,2F), and 2125.01 ,2F); Mass ,EI) ,rel intensity,
%) m/z 522 ,13, M1), 477 ,10), 439 ,26), 117 ,10), 104
,13), 91 ,12), and 69 ,base peak); HRMS Calcd for
C19H15F13O2: m/z 522.0864. Found: m/z 522.0873.
4.1.5. 4-02-Per¯uorooctyl)ethylbenzylalcohol 4{2}. This
was prepared according to the procedure for the preparation
of 4-,2-per¯uorohexyl)ethylbenzylalcohol. Use of 1.7 M of
n-butyllithium in hexane
,14.6 ml, 24.9 mmol),
N,N-dimethylformamide ,1.93 ml, 24.9 mmol), THF
,16 ml), and sodium borohydride ,0.941 g, 24.9 ml) for
treatment of the mixture ,5.00 g) of 1-bromo-4-,2-
per¯uorooctyl)ethylbenzene/1-bromo-4-iodobenzene
ˆ75:25) afforded 2.70 g ,68%) of product: Colorless solid;
mp 68±698C; IR ,KBr) 3394, 2996, 1612, 1343, 1152, 1081,
1006, 883, 646, and 554 cm21; 1H NMR ,CDCl3) d 7.36 ,d,
Jˆ8.0 Hz, 2H), 7.23 ,d, Jˆ8.0 Hz, 2H), 4.96 ,s, 2H), 2.96±
2.90 ,m, 2H), 2.47±2.28 ,m, 2H), and 1.90±1.70 ,br, 1H);
13C NMR ,CDCl3) d 139.47, 138.70, 128.63, 127.62,
120.00±103.00 ,m), 65.16, 33.06 ,t), and 26.25; 19F NMR
4.1.8. 4-02-Per¯uorohexyl)ethylbenzyl 2-hexenoate 5{1,2}.
This was prepared according to the procedure for the
preparation of 4-,2-per¯uorohexyl)ethylbenzyl crotonate:
Colorless oil; IR ,neat) 2960, 1724, 1654, 1464, 1375,
1
1239, 1173, 1014, 975, 812, 707, and 653 cm21; H NMR
,CDCl3) d 7.35 ,d, Jˆ8.0 Hz, 2H), 7.22 ,d, Jˆ8.0 Hz, 2H),

5250
D. P. Curran, Y. Oderaotoshi / Tetrahedron 57 '2001) 5243±5253
7.02,dt, Jˆ15.5 Hz and Jˆ7.0 Hz, 1H), 5.87 ,d, Jˆ15.5 Hz,
1H), 5.16 ,s, 2H), 2.96±2.86 ,m, 2H), 2.50±2.30 ,m, 2H),
2.29±2.05 ,m, 2H), 1.65±1.44 ,m, 2H), and 0.94 ,t, Jˆ7.4 Hz,
3H); 13C NMR ,CDCl3) d 166.66, 150.20, 139.25, 134.84,
128.88, 128.62, 121.10, 120.00±105.00 ,m), 65.79, 34.38,
33.01 ,t), 26.27, 21.33, and 13.78; 19F NMR ,CDCl3, relative
to CCl3F) d 279.60 ,3F), 2113.48 ,2F), 2120.72 ,2F),
2121.70 ,2F), 2122.35 ,2F), and 2124.97 ,2F); Mass ,EI)
,rel intensity, %) m/z 550 ,28, M1), 494 ,10), 438 ,19), 437
,base peak), 117,25), 104 ,29), 97 ,99), 91 ,32), 77 ,10), and
56 ,11); HRMS Calcd for C21H19F13O2: m/z 550.1177. Found:
m/z 550.1202.
128.59, 121.10, 120.00±103.00 ,m), 65.77, 34.36, 33.01 ,t),
26.26, 21.32, and 13.72; 19F NMR ,CDCl3, relative to
CCl3F) d 279.80 ,3F), 2113.60 ,2F), 2120.64 ,2F),
2120.87 ,4H), 2121.68 ,2F), 2122.41 ,2F), and 2125.10
,2F); Mass ,EI) ,rel intensity, %) m/z 650 ,3, M1), 594 ,5),
590 ,5), 551 ,9), 538 ,17), 537 ,base peak), 178 ,15), 177
,10), 176 ,13), 115 ,7), 102,5), and 98 ,5); HRMS Calcd for
C23H19F17O2: m/z 650.1113. Found: m/z 650.1125.
4.1.12. 4-02-Per¯uorooctyl)ethylbenzyl methacrylate
5{2,3}. This was prepared according to the procedure for
the preparation of 4-,2-per¯uorohexyl)ethylbenzyl croto-
nate: Colorless oil: IR ,neat) 2953, 1724, 1638, 1456,
4.1.9. 4-02-Per¯uorohexyl)ethylbenzyl methacrylate
5{1,3}. This was prepared according to the procedure for
the preparation of 4-,2-per¯uorohexyl)ethylbenzyl croto-
nate: Colorless oil; IR ,KBr) 2959, 1720, 1634, 1456,
1371, 1200, 1154, 944, 812, and 657 cm21 1H NMR
;
,CDCl3) d 7.36 ,d, Jˆ8.0 Hz, 2H), 7.23 ,d, Jˆ8.0 Hz,
2H), 6.17 ,s, 1H), 5.60 ,s 1H), 5.19 ,s, 2H), 2.96±2.80 ,m,
2H), 2.48±2.28 ,m, 2H), and 1.99 ,s, 3H); 13C NMR
,CDCl3) d 167.44, 139.34, 136.44, 134.90, 128.79,
128.69, 126.02, 124.00±106.00 ,m), 66.28, 33.11 ,t),
26.38, and 18.51; 19F NMR ,CDCl3, relative to CCl3F) d
279.74 ,3F), 2113.56 ,2F), 2120.60 ,2F), 2120.83 ,4H),
2121.64 ,2F), 2122.38 ,2F), and 2125.06 ,2F); Mass ,EI)
,rel intensity, %) m/z 622 ,8, M1), 577 ,33), 551 ,23), 538
,20), 537 ,base peak), 165 ,13), 129 ,17), 128 ,23), 116 ,12),
115 ,26), 103 ,34), 89 ,23), 84 ,12), and 83 ,17);
HRMS Calcd for C21H15F17O2: m/z 622.0800. Found: m/z
622.0804.
1
1320, 1243, 1014, 940, 816, 704, and 650 cm21; H NMR
,CDCl3) d 7.36 ,d, Jˆ8.0 Hz, 2H), 7.25 ,d, Jˆ8.0 Hz, 2H),
6.17 ,s, 1H), 5.60 ,s 1H), 5.19 ,s, 2H), 2.97±2.64 ,m, 2H),
2.47±2.29 ,m, 2H), and 1.98 ,s, 3H); 13C NMR ,CDCl3) d
167.44, 139.34, 136.44, 134.90, 128.79, 128.70, 126.03,
120.00±105.00 ,m), 66.28, 33.10 ,t), 26.37, and 18.52; 19F
NMR ,CDCl3, relative to CCl3F) d 279.73 ,3F), 2113.55
,2F), 2120.78 ,2F), 2121.77 ,2F), 2122.41 ,2F), and
2125.06 ,2F); Mass ,EI) ,rel intensity, %) m/z 523 ,15),
522 ,73, M1), 504 ,10), 478 ,13), 477 ,61), 453 ,18), 451
,13), 438 ,21), 437 ,base peak), 118 ,16), 104 ,18), 91 ,29),
and 69 ,80); HRMS Calcd for C19H15F13O2: m/z 522.0864.
Found: m/z 522.0852.
4.1.13. 4-02-Per¯uorodecyl)ethylbenzyl crotonate 5{3,1}.
This was prepared according to the procedure for the
preparation of 4-,2-per¯uorohexyl)ethylbenzyl crotonate:
Colorless solid; mp 46±488C; IR ,KBr) 2939, 1715, 1655,
4.1.10. 4-02-Per¯uorooctyl)ethylbenzyl crotonate 5{2,1}.
This was prepared according to the procedure for the
preparation of 4-,2-per¯uorohexyl)ethylbenzyl crotonate:
Colorless solid; mp 33±348C; IR ,KBr) 2934, 1710, 1651,
1450, 1378, 1200, 1145, 1105, 1022, 986, 804, 741, 665, and
554 cm21; 1H NMR ,CDCl3) d 7.34 ,d, Jˆ8.0 Hz, 2H), 7.22
,d, Jˆ8.0 Hz, 2H), 7.03 ,dq, Jˆ15.5 Hz and Jˆ6.9 Hz, 1H),
5.90 ,dq, Jˆ15.5 Hz and Jˆ1.4 Hz, 1H), 5.14 ,s, 2H), 2.96±
2.89 ,m, 2H), 2.46±2.28 ,m, 2H), and 1.89 ,dd, Jˆ6.9 Hz
and Jˆ1.4 Hz, 3H); 13C NMR ,CDCl3) d 166.45, 145.42,
139.24, 134.83, 128.84, 128.61, 122.53, 120.00±105.00
,m), 65.76, 33.03 ,t), 26.47, and 18.13; 19F NMR ,CDCl3,
1
1450, 1196, 1149, 986, 887, 646, 558, and 531 cm21; H
NMR ,CDCl3) d 7.35 ,d, Jˆ8.0 Hz, 2H), 7.22 ,d, Jˆ8.0 Hz,
2H), 6.98 ,dq, Jˆ15.7 Hz and Jˆ7.0 Hz, 1H), 5.90 ,dq,
Jˆ15.7 Hz and Jˆ1.5 Hz, 1H), 5.15 ,s, 2H), 2.96±2.90
,m, 2H), 2.60±2.44 ,m, 2H), and 1.88 ,dd, Jˆ7.0 Hz and
Jˆ1.5 Hz, 3H); 13C NMR ,CDCl3) d 166.45, 145.41,
139.25, 134.84, 128.84, 128.60, 122.53, 120.00±105.00
,m), 65.75, 33.01 ,t), 26.25, and 18.11; 19F NMR ,CDCl3,
relative to CCl3F) d 279.67 ,3F), 2113.52,2F), 2120.65
,10F), 2121.59 ,2F), 2122.35 ,2F), and 2125.02 ,2F);
Mass ,EI) ,rel intensity, %) m/z 722 ,11, M1), 704
,14), 678 ,13), 677 ,53), 676 ,14), 654 ,23), 651 ,25),
638 ,22), 637 ,base peak), 171 ,14), 167 ,18), 166 ,11),
165 ,28), 163 ,10), 154 ,10), 148 ,14), 147 ,15), 144
,15), 133 ,17), 130 ,14), 129 ,11), 128 ,26), 127 ,12),
126 ,16), 125 ,12), 105 ,11), 104 ,43), 103 ,19), 102
,13), and 89 ,22); HRMS Calcd for C23H15F21O2: m/z
722.0736. Found: m/z 722.0729.
relative to CCl3F)
d
279.55 ,3F), 213.46 ,2F),
2120.52 ,2F), 2120.73 ,4F), 2121.54 ,2F), 2122.30
,2F), and 2124.94 ,2F); Mass ,EI) ,rel intensity, %) m/z
627 ,14), 622 ,27, M1), 604 ,13), 577 ,23), 553 ,13), 551
,11), 538 ,16), 537 ,72), 309 ,20), 308 ,75), 265 ,43), 223
,44), 180 ,28), 179 ,21), 178 ,34), 165 ,19), 117 ,14), 104
,12), 91 ,16), 69 ,base peak), and 57 ,12); HRMS Calcd for
C21H15F17O2: m/z 622.0800. Found: m/z 622.0808.
4.1.14. 4-02-Per¯uorodecyl)ethylbenzyl 2-hexenoate
5{3,2}. This was prepared according to the procedure for
the preparation of 4-,2-per¯uorohexyl)ethylbenzyl croto-
nate: Colorless solid; mp 36±388C; IR ,neat) 2958, 1719,
4.1.11. 4-02-Per¯uorooctyl)ethylbenzyl 2-hexenoate
5{2,2}. This was prepared according to the procedure for
the preparation of 4-,2-per¯uorohexyl)ethylbenzyl croto-
nate: Colorless solid; mp 33±348C; IR ,neat) 2950, 2712,
1653, 1460, 1373, 1330, 1217, 1145, 978, 704, 656 and
1655, 1465, 1382, 1223, 1150, 978, 879, 645, and 554 cm21
;
1H NMR ,CDCl3) d 7.35 ,d, Jˆ8.0 Hz, 2H), 7.23 ,d,
Jˆ8.0 Hz, 2H), 7.03 ,dt, Jˆ15.5 Hz and Jˆ7.0 Hz, 1H),
5.88 ,dd, Jˆ15.6 Hz and Jˆ1.5 Hz, 1H), 5.16 ,s, 2H),
2.96±2.85 ,m, 2H), 2.50±2.33 ,m, 2H), 2.23±2.13 ,m,
2H), 1.56±1.40 ,m, 2H), and 0.95 ,t, Jˆ7.4 Hz, 3H); 13C
NMR ,CDCl3) d 166.58, 150.10, 139.19, 134.76, 128.80,
128.52, 121.02, 120.00±105.00 ,m), 65.71, 34.30, 32.94 ,t),
1
561 cm21; H NMR ,CDCl3) d 7.36 ,d, Jˆ8.0 Hz, 2H),
7.23 ,d, Jˆ8.0 Hz, 2H), 7.03 ,dt, Jˆ15.6 Hz and
Jˆ7.0 Hz, 1H), 5.97 ,d, Jˆ15.6 Hz, 1H), 5.17 ,s, 2H),
2.96±2.90 ,m, 2H), 2.47±2.28 ,m, 2H), 2.23±2.09 ,m,
2H), 1.57±1.44 ,m, 2H), and 0.95 ,t, Jˆ7.4 Hz, 3H); 13C
NMR ,CDCl3) d 166.64, 150.16, 139.25, 134.85, 128.86,

D. P. Curran, Y. Oderaotoshi / Tetrahedron 57 '2001) 5243±5253
5251
26.20, 21.25, and 13.66; 19F NMR ,CDCl3, relative to
CCl3F) d 279.58 ,3F), 2113.46 ,2F), 2120.58 ,10F),
2121.53 ,2F), 2122.30 ,2F), and 2124.95 ,2F); Mass
,EI) ,rel intensity, %) m/z 750 ,5, M1), 725 ,6), 653 ,10),
638 ,18), 637 ,91), 537 ,9), 223 ,6), 179 ,28), 178 ,base
peak), 164 ,43), 121 ,23), 117 ,18), 115 ,12), 104 ,14), 97
,59), 91 ,32), 68 ,15), and 56 ,14); HRMS Calcd for
C25H19F21O2: m/z 750.1049. Found: m/z 750.1054.
124 ,46), 120 ,12), 118 ,40), 110 ,16), 109 ,49), 107 ,12),
105 ,21), and 104 ,35); HRMS Calcd for C29H21F21O2S: m/z
832.0944. Found: m/z 832.0947.
4.3. Library 1. Representative procedure for Michael
addition of four thiols with three acceptors 0LC-mass
analysis)
Benzenethiol ,20.6 ml, 0.200 mmol), naphthalenethiol
,32.1 mg, 0.200 mmol), 4-methoxybenzenethiol ,24.6 ml,
0.200 mmol), 4-tert-butylbenzenethiol ,33.6 ml, 0.200
mmol), and triethylamine ,18.3 ml, 0.15 mmol) were
added to a THF solution ,150.0 ml) of the three acceptors
,5{1,1}, 5{2,2}, 5{3,3}, 0.05 mmol each). The mixture was
stirred for 15 h at room temperature. The reaction mixture
was then charged on to 5.00 g of ¯uorous reverse phase
silica gel in short column wetted with methanol/
waterˆ4/1. The column was eluted ®rst with 20 ml of
methanol/waterˆ4/1, and then with 20 ml of ethyl acetate.
Evaporation of the ethyl acetate fraction gave the mixture of
Michael adducts. The mixture was analyzed by LC-MS
,APCI, positive mode) with a Fluo®x 120E ,1E415, 150£
4.6 mm) column ,MeOH/H2Oˆ4/1 gradient to MeOH only
for 40 min, ¯ow rate 1.0 ml/min). All 12adducts were present
as evidenced by the presence of the molecular ions in the MS.
Retention times for the peaks are shown in Table 1.
4.1.15. 4-02-Per¯uorodecyl)ethylbenzyl methacrylate
5{3,3}. This was prepared according to the procedure of
the preparation of 4-,2-per¯uorohexyl)ethylbenzyl croto-
nate: Colorless solid; mp 55±568C; IR ,KBr) 2950, 1897,
1723, 1652, 1450, 1374, 1212, 1149, 1081, 880, 642, and
558 cm21; 1H NMR ,CDCl3) d 7.35 ,d, Jˆ8.0 Hz, 2H), 7.23
,d, Jˆ8.0 Hz, 2H), 6.17 ,s, 1H), 5.60 ,s, 1H), 5.19 ,s, 2H),
2.97±2.90 ,m, 2H), 2.45±2.28 ,m, 2H), and 1.98 ,s, 3H); 13C
NMR ,CDCl3) d 167.37, 139.24, 136.31, 134.77, 128.70,
128.61, 125.99, 122.00±100.00 ,m), 66.19, 33.01 ,t), 26.27,
and 18.45; 19F NMR ,CDCl3, relative to CCl3F) d 279.59
,3F), 2113.50 ,2F), 2120.59 ,10H), 2121.56 ,2F),
2122.31 ,2F), and 2124.96 ,2F); Mass ,EI) ,rel intensity,
%) m/z 722 ,19, M1), 677 ,15), 637 ,27), 537 ,10), 177 ,19),
178 ,68), 169 ,17), 167 ,16), 166 ,10), 165 ,44), 121 ,18),
199 ,13), 117 ,31), 104 ,31), and 69 ,base peak);
HRMS Calcd for C23H15F21O2: m/z 722.0736. Found: m/z
722.0719.
4.4. General procedure for Michael addition of three
thiols with three acceptors to form a mixture library
0separation by HPLC)
4.2. General procedure for the synthesis of individual
Michael adducts
Twelve separate acceptor solutions ,4 each of 5{1,1},
5{2,2}, 5{3,3}) were prepared by diluting an acceptor
,0.05 mmol) with THF ,50 ml). One of the four thiols
6{1±4} ,0.25 mmol, benzenethiol, 2-naphthalenethiol,
4-methoxybenzenethiol, and 4-tert-butylbenzenethiol) was
added to each of the 12acceptor solutions such that all
possible combinations of three acceptors and four thiols
were generated. Triethylamine ,6.1 ml, 0.05 mol) was
added to each mixture. The mixtures were stirred for 15 h
at room temperature. The reaction mixtures were charged on
to 3.00 g of ¯uorous reverse phase silica gel in 12short
columns with methanol/waterˆ4/1. The columns were
eluted with methanol/waterˆ4/1 ,12ml), and then they
were eluted with ethyl acetate ,12ml). Removal of solvent
of the ethyl acetate fractions gave the 12individual Michael
adducts. These were used as standards to characterize the
mixture library. The characterization data of 4-,2-per¯uoro-
decyl)ethylbenzyl 2-methyl-3-phenylthiopropanate 7{3,1,1}
are representative: Colorless solid; mp 51±528C; IR ,KBr)
Naphthalenethiol ,8.0 mg, 0.050 mmol), 4-methoxybenzene-
thiol ,6.2 ml, 0.050 mmol), 4-tert-butylbenzenethiol ,8.4 ml,
0.050 mmol), and DBU ,7.5 ml, 0.050 mmol) were added to
a THF solution ,150.0 ml) of three acceptors ,0.05 mmol of
5{2,1}, 5{3,2}, 5{1,3}). The mixture was stirred for 5 h at
room temperature. The reaction mixture was then charged
onto 5.00 g of ¯uorous reverse phase silica gel in short
column wetted with methanol/waterˆ4/1. The column was
eluted with 20 ml of methanol/waterˆ4/1, and then with
20 ml of ethyl acetate. Evaporation of the ethyl acetate
fraction gave the mixture of Michael adducts.
This mixture was separated into six fractions [,1) a mixture of
7{1,3,2/3}, ,2) 7{1,3,4}, ,3) a mixture of 7{2,1,2/3}, ,4)
7{2,1,4}, ,5) a mixture of 7{3,2,2/3}, ,6) 7{3,2,4}] by
HPLC ,Fluo®x 120E, 1EW125, 250£10.0 mm, NEOS Co.
Ltd.) ,MeOH/H2Oˆ9/1 gradient to MeOH only for 30 min,
¯ow rate 3.0 ml/min). The mixtures ,1), ,3), and ,5) were
further separated by HPLC ,Nova-pack 250£100 mm,
Waters Corp.) ,MeOH/H2Oˆ19/1 to MeOH only for
20 min, ¯ow rate 5.0 ml/min) into the individual components.
2954, 1731, 1592, 1236, 887, 816, 737, 650, and 554 cm21
;
1H NMR ,CDCl3) d 7.39±7.17 ,m, 9H), 5.10 ,s, 2H), 3.29
,dd, Jˆ13.2Hz and Jˆ7.3 Hz, 1H), 2.96 ,dd, Jˆ13.2Hz
and Jˆ7.0 Hz, 1H), 2.95±2.85 ,m, 2H), 2.80±2.70 ,s,
1H), 2.50±2.25 ,m, 2H), and 1.30 ,d, Jˆ7.1 Hz, 3H); 13C
NMR ,CDCl3) d 174.86, 139.33, 135.76, 134.52, 130.19,
129.10, 128.76, 128.62, 126.61, 120.00±105.00 ,m), 66.25,
39.92, 37.47, 32.98 ,t), 26.28, and 16.88; 19F NMR ,CDCl3,
relative to CCl3F) d 279.60 ,3F), 2113.46 ,2F), 2120.59
,10H), 2121.55 ,2F), 2122.31 ,2F), and 2124.96 ,2F);
Mass ,EI) ,rel intensity, %) m/z 833 ,10), 832,30, M 1),
638 ,16), 637 ,93), 205 ,14), 196 ,13), 195 ,base peak),
177 ,12), 152 ,31), 149 ,37), 139 ,16), 137 ,19), 131 ,21),
Two other libraries were prepared similarly using different
combinations of tags and esters, as shown in Fig. 1. Data for
the products follow:
7{1,1,1}: 1H NMR ,CDCl3) d 7.46±7.20 ,m, 9H), 5.10 ,s,2H),
3.66±3.60 ,m, 1H), 2.96±2.90 ,m, 2H), 2.69 ,dd, Jˆ15.7 Hz
and Jˆ6.1 Hz, 1H), 2.49 ,dd, Jˆ15.7 Hz and Jˆ8.5 Hz, 1H),
2.45±2.30 ,m, 2H), and 1.33 ,d, Jˆ6.9 Hz, 3H).
1
7{1,1,2}: H NMR ,CDCl3) d 8.00±7.19 ,m, 11H), 5.09

5252
D. P. Curran, Y. Oderaotoshi / Tetrahedron 57 '2001) 5243±5253
,s, 2H), 3.80±3.74 ,m, 1H), 2.95±2.89 ,m, 2H), 2.74 ,dd,
Jˆ15.6 Hz and Jˆ6.2Hz, 1H), 2.54 ,dd, Jˆ15.6 Hz and
Jˆ8.3 Hz, 1H), 2.49±2.30 ,m, 2H), and 1.38 ,d, Jˆ6.8 Hz,
3H).
Jˆ13.3 Hz and Jˆ7.5 Hz, 1H), 2.96±2.80 ,m, 3H), 2.72±
2.63 ,m, 1H), 2.51±2.30 ,m, 2H), and 1.26 ,d, Jˆ7.0 Hz,
3H).
1
7{3,3,4}: H NMR ,CDCl3) d 7.51±7.19 ,m, 8H), 5.09
1
7{1,1,3}: H NMR ,CDCl3) d 7.43±7.21 ,m, 6H), 6.87±
,s, 2H), 3.26 ,dd, Jˆ13.3 Hz and Jˆ7.3 Hz, 1H), 2.97±
2.90 ,m, 3H), 2.80±2.70 ,m, 1H), 2.60±2.34 ,m, 2H), 1.31
,s, 9H), and 1.27 ,d, Jˆ6.7 Hz, 3H).
6.79 ,m, 2H), 5.06 ,s, 2H), 3.81 ,s, 3H), 3.49±3.42 ,m,
1H), 2.96±2.88 ,m, 2H), 2.64 ,dd, Jˆ15.5 Hz and
Jˆ6.3 Hz, 1H), 2.44 ,dd, Jˆ15.5 Hz and Jˆ8.2Hz, 1H),
2.48±2.28 ,m, 2H), and 1.21 ,d, Jˆ6.9 Hz, 3H).
1
7{1,3,2}: H NMR ,CDCl3) d 7.82±7.15 ,m, 11H), 5.09
,s, 2H), 3.38 ,dd, Jˆ13.3 Hz and Jˆ7.2Hz, 1H), 3.05 ,dd,
Jˆ13.3 Hz and Jˆ6.8 Hz, 1H), 2.95±2.90 ,m, 2H), 2.90±
2.75 ,m, 1H), 2.50±2.30 ,m, 2H), and 1.32 ,d, Jˆ7.0 Hz,
3H).
1
7{1,1,4}: H NMR ,CDCl3) d 7.47±7.17 ,m, 8H), 5.10
,s, 2H), 3.63±3.58 ,m, 1H), 2.96±2.90 ,m, 2H), 2.70 ,dd,
Jˆ15.6 Hz and Jˆ6.1 Hz, 1H), 2.47 ,dd, Jˆ15.6 Hz and
Jˆ8.4 Hz, 1H), 2.52±2.34 ,m, 2H), 1.32 ,d, Jˆ6.8 Hz,
3H), and 1.31 ,s, 9H).
1
7{1,3,3}: H NMR ,CDCl3) d 7.38±7.21 ,m, 6H), 6.85±
6.80 ,m, 2H), 5.09 ,s, 2H), 3.80 ,s, 3H), 3.16 ,dd,
Jˆ13.4 Hz and Jˆ7.4 Hz, 1H), 2.96±2.90 ,m, 2H), 2.84
,dd, Jˆ13.4 Hz and Jˆ6.7 Hz, 1H), 2.72±2.63 ,m, 1H),
2.50±2.30 ,m, 2H), and 1.20 ,d, Jˆ7.1 Hz, 3H).
1
7{2,2,1}: H NMR ,CDCl3) d 7.52±7.10 ,m, 9H), 5.09
,s, 2H), 3.53±3.48 ,m, 1H), 2.95±2.89 ,m, 2H), 2.70±2.55
,m, 2H), 2.45±2.30 ,m, 2H), 1.70±1.40 ,m, 4H), and 0.90
,t, Jˆ6.9 Hz, 3H).
1
7{1,3,4}: H NMR ,CDCl3) d 7.38±7.20 ,m, 8H), 5.08
1
7{2,2,2}: H NMR ,CDCl3) d 7.90±7.17 ,m, 11H), 5.07
,s, 2H), 3.25 ,dd, Jˆ13.3 Hz and Jˆ7.2Hz, 1H), 2.95±
2.88 ,m, 3H), 2.80±2.70 ,m, 1H), 2.50±2.30 ,m, 2H), 1.30
,s, 9H), and 1.27 ,d, Jˆ7.0 Hz, 3H).
,s, 2H), 3.70±3.61 ,m, 1H), 2.95±2.88 ,m, 2H), 2.69±2.60
,m, 2H), 2.49±2.30 ,m, 2H), 1.70±1.27 ,m, 4H), and 0.92
,t, Jˆ7.0 Hz, 3H).
7{2,1,2} 1H NMR ,CDCl3) d 7.90±7.00 ,m, 11H), 5.08 ,s, 2H),
3.80±3.72 ,m, 1H), 2.95±2.88 ,m, 2H), 2.73 ,dd, Jˆ15.6 Hz
and Jˆ6.1 Hz, 1H), 2.53 ,dd, Jˆ15.6 Hz and Jˆ8.3 Hz, 1H),
2.39±2.20 ,m, 2H), and 1.37 ,d, Jˆ6.9 Hz, 3H).
7{2,2,3}: 1H NMR ,CDCl3) d 7.42±7.20 ,m, 6H), 6.85±6.78
,m, 2H), 5.10 ,s, 2H), 3.80 ,s, 3H), 3.33±3.29 ,m, 1H),
2.96±2.89 ,m, 2H), 2.60±2.49 ,m, 2H), 2.48±2.30 ,m,
2H), 1.70±1.40 ,m, 4H), and 0.89 ,t, Jˆ6.8 Hz, 3H).
1
7{2,1,3}: H NMR ,CDCl3) d 7.43±7.20 ,m, 6H), 6.88±
1
7{2,2,4}: H NMR ,CDCl3) d 7.47±7.20 ,m, 8H), 5.09
6.79 ,m, 2H), 5.09 ,s, 2H), 3.81 ,s, 3H), 3.50±3.40
,m, 1H), 2.96±2.89 ,m, 2H), 2.63 ,dd, Jˆ15.5 Hz and
Jˆ6.4 Hz, 1H), 2.44 ,dd, Jˆ15.5 Hz and Jˆ8.0 Hz, 1H),
2.55±2.37 ,m, 2H), and 1.27 ,d, Jˆ7.1 Hz, 3H).
,s, 2H), 3.50±3.43 ,m, 1H), 2.96±2.90 ,m, 2H), 2.70±2.55
,m, 2H), 2.50±2.30 ,m, 2H), 1.70±1.40 ,m, 4H), 1.31 ,s,
9H), and 0.90 ,t, Jˆ6.6 Hz, 3H).
1
7{3,3,1}: Colorless solid; mp 51±528C; IR ,KBr) 2954,
7{2,1,4}: H NMR ,CDCl3) d 7.39±7.20 ,m, 8H), 5.09
1
1731, 1592, 1236, 887, 816, 737, 650, and 554 cm21; H
,s, 2H), 3.62±3.53 ,m, 1H), 2.96±2.89 ,m, 2H), 2.47 ,dd,
Jˆ15.6 Hz and Jˆ8.1 Hz, 1H), 2.38 ,dd, Jˆ15.6 Hz and
Jˆ7.9 Hz, 1H), 2.37±2.20 ,m, 2H), 1.31 ,d, Jˆ7.0 Hz,
3H), and 1.31 ,s, 9H).
NMR ,CDCl3) d 7.39±7.17 ,m, 9H), 5.10 ,s, 2H), 3.29 ,dd,
Jˆ13.2Hz and Jˆ7.3 Hz, 1H), 2.96 ,dd, Jˆ13.2Hz and
Jˆ7.0 Hz, 1H), 2.95±2.85 ,m, 2H), 2.80±2.70 ,s, 1H),
2.50±2.25 ,m, 2H), and 1.30 ,d, Jˆ7.1 Hz, 3H); 13C NMR
,CDCl3) d 174.86, 139.33, 135.76, 134.52, 130.19, 129.10,
128.76, 128.62, 126.61, 120.00±105.00 ,m), 66.25, 39.92,
37.47, 32.98 ,t), 26.28, and 16.88; 19F NMR ,CDCl3,
relative to CCl3F) d 279.60 ,3F), 2113.46 ,2F), 2120.59
,10H), 2121.55 ,2F), 2122.31 ,2F), and 2124.96 ,2F);
Mass ,EI) ,rel intensity, %) m/z 833 ,10), 832,30, M 1),
638 ,16), 637 ,93), 205 ,14), 196 ,13), 195 ,base peak),
177 ,12), 152 ,31), 149 ,37), 139 ,16), 137 ,19), 131 ,21),
124 ,46), 120 ,12), 118 ,40), 110 ,16), 109 ,49), 107 ,12),
105 ,21), and 104 ,35). HRMS Calcd for C29H21F21O2S: m/z
832.0944. Found: m/z 832.0947.
1
7{3,2,2}: H NMR ,CDCl3) d 7.89±7.10 ,m, 11H), 5.07
,s, 2H), 3.66±3.60 ,m, 1H), 2.94±2.88 ,m, 2H), 2.70±2.59
,m, 2H), 2.50±2.30 ,m, 2H), 1.70±1.40 ,m, 4H), and 0.90
,t, Jˆ7.0 Hz, 3H).
7{3,2,3}: 1H NMR ,CDCl3) d 7.41±7.10 ,m, 6H), 6.85±6.80
,m, 2H), 5.09 ,s, 2H), 3.80 ,s, 3H), 3.33±3.28 ,m, 1H),
2.96±2.89 ,m, 2H), 2.57±2.50 ,m, 2H), 2.50±2.20 ,m,
2H), 1.70±1.40 ,m, 4H), and 0.89 ,t, Jˆ7.0 Hz, 3H).
1
7{3,2,4}: H NMR ,CDCl3) d 7.38±7.20 ,m, 8H), 5.09
,s, 2H), 3.50±3.40 ,m, 1H), 2.96±2.89 ,m, 2H), 2.70±2.50
,m, 2H), 2.50±2.30 ,m, 2H), 1.70±1.40 ,m, 4H), 1.31
,s, 9H), and 0.90 ,t, Jˆ6.8 Hz, 3H).
1
7{3,3,2}: H NMR ,CDCl3) d 8.00±7.05 ,m, 11H), 5.07
,s, 2H), 3.40 ,dd, Jˆ13.3 Hz and Jˆ7.2Hz, 1H), 3.07
,dd, Jˆ13.3 Hz and Jˆ6.8 Hz, 1H), 2.94±2.90 ,m, 2H),
2.90±2.75 ,m, 1H), 2.50±2.25 ,m, 2H), and 1.33 ,d,
Jˆ7.0 Hz, 3H).
LC-Mass ,M11) of 7
1,1,1ˆ633; 1,1,2ˆ683; 1,1,3ˆ663; 1,1,4ˆ689
2,2,1ˆ761; 2,2,2ˆ811; 2,2,3ˆ791; 2,2,4ˆ817
3,3,1ˆ833; 3,3,2ˆ883; 3,3,3ˆ863; 3,3,4ˆ889
1
7{3,3,3}: H NMR ,CDCl3) d 7.39±7.20 ,m, 6H), 6.86±
6.79 ,m, 2H), 5.08 ,s, 2H), 3.80 ,s, 3H), 3.16 ,dd,

D. P. Curran, Y. Oderaotoshi / Tetrahedron 57 '2001) 5243±5253
5253
1,2,1ˆ661; 1,2,2ˆ711; 1,2,3ˆ691; 1,2,4ˆ717
Acknowledgements
2,3,1ˆ733; 2,3,2ˆ783; 2,3,3ˆ763; 2,3,4ˆ789
3,1,1ˆ833; 3,1,2ˆ883; 3,1,3ˆ863; 3,1,4ˆ889
1,3,1ˆ633; 1,3,2ˆ683; 1,3,3ˆ663; 1,3,4ˆ689
2,1,1ˆ733; 2,1,2ˆ783; 2,1,3ˆ763; 2,1,4ˆ789
3,2,1ˆ861; 3,2,2ˆ911; 3,2,3ˆ891; 3,2,4ˆ917
We thank the National Institutes of Health for funding this
work.
References
4.5. General procedure for the deprotection of the
Michael adducts
1. Lam, K. S.; Lebl, M.; Krchnak, V. Chem. Rev. 1997, 97, 411.
2. ,a) Houghten, R. A.; Pinilla, C.; Appel, J. R.; Blondelle, S. E.;
Dollery, C. T.; Eicheler, J.; Nefzi, A.; Ostresh, J. M. J. Med.
Chem. 1999, 42, 3743. ,b) Carell, T.; Wintner, E. A.;
Sutherland, A. J.; Rebek, Jr., J.; Dunayevskiy, Y. M.; Vouros,
P. Chemistry andBiology 1995, 2, 171. ,c) Boger, D. L.; Chai,
W. Y.; Jin, Q. J. Am. Chem. Soc. 1998, 120, 7220.
Titanium tetraisopropoxide ,12.5 mg, 0.0439 mmol) was
suspension of each Michael adduct
added to
a
,0.0240 mmol) in anhydrous 2-propanol ,0.5 ml) under
argon. The mixture was heated at re¯ux temperature for
6 h, cooled to room temperature, and was quenched with
dilute hydrochloric acid. The resulting mixture was
extracted with ethyl ether three times. The organic layer
was dried over sodium sulfate and evaporated. The residue
in a minimum amount of acetonitrile was charged on to
2.00 g of ¯uorous reverse phase silica gel in a short column
wetted with methanol/waterˆ4/1. The column was eluted
with 8 ml of methanol/waterˆ4/1 and then it was eluted
with 8 ml of ethyl acetate to give ¯uorous tagged benzyl-
alcohols. Removal of solvent from the ®rst eluate and the
second eluate afforded deprotected product and ¯uorous
tagged benzylalcohol, respectively. 1-Methylethyl 2-meth-
yl-3-phenylthiopropanate is a representative deprotected
product.
3. Luo, Z.; Zhang, Q.; Oderaotoshi, Y.; Curran, D. P.; Science, .
291 2001, 1766.
4. Overview, Curran, D. P., Synlett, submitted for publication.
5. The number system is that recommended by the Journal of
Combinatorial Chemistry. The bracketed numbers are always
in the order: tag, acrylate, thiol.
6. ,a) Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62,
6714. ,b) Curran, D. P.; Hadida, S.; Studer, A.; He, M.; Kim,
S.-Y.; Luo, Z.; Larhed, M.; Hallberg, M.; Linclau, B.
Combinatorial Chemistry: A Practical Approach, Fenniri, H.,
Ed.; Oxford Univ. Press: Oxford, 2001; Vol. 2. ,c) Ryu, I.;
Kreimerman, S.; Niguma, T.; Minakata, S.; Komatsu, M.;
Luo, Z. Y.; Curran, D. P. Tetrahedron 2001, 42, 947.
7. ,a) Kainz, S.; Luo, Z. Y.; Curran, D. P.; Leitner, W. Synthesis
1998, 1425. ,b) Zhang, Q.; Luo, Z.; Curran, D. P. J. Org. Chem.
2000, 65, 8866.
4.5.1. 1-Methylethyl 2-methyl-3-phenylthiopropanoate.
Colorless oil; IR ,KBr) 2979, 2929, 1728, 1585, 1458,
1
1315, 1211, 1170, 739, and 691 cm21; H NMR ,CDCl3)
8. ,a) Berendsen, G. E.; Galan, L. D. J. LiquidChromatogr. 1978,
1, 403. ,b) Berendsen, G. E.; Pikaart, K. A.; de Galan, L.;
Olieman, C. Anal. Chem. 1980, 52, 1990. ,c) Billiet, H. A. H.;
Schoenmakers, P. J.; De Galan, L. J. Chromat. 1981, 218, 443.
,d) Sadek, P. C.; Carr, P. W. J. Chromat. 1984, 288, 2 5.
d 7.40±7.20 ,m, 5H), 5.08±5.00 ,m, 1H), 3.26 ,dd,
Jˆ13.2Hz and Jˆ7.3 Hz, 1H), 2.92 ,dd, Jˆ13.2Hz and
Jˆ6.9 Hz, 1H), 2.69±2.58 ,m, 1H), and 1.27±1.22 ,m,
6H); 13C NMR ,CDCl3) d 174.59, 136.02, 130.04, 129.07,
126.50, 68.11, 40.01, 37.46, 21.94, and 16.94; Mass ,EI) ,rel
intensity, %) m/z 238 ,7, M1), 123 ,8), 88 ,14), 86 ,71), and
84 ,base peak); HRMS Calcd for C13H18O2S: m/z 238.1044.
Found: m/z 238.1016.