The synthesis of ethanolamine libraries from olefin scaffolds

Article abstract of DOI:10.1016/S0040-4039(00)01503-3

A solution-phase, multi-reaction sequence has been developed for the parallel synthesis of ethanolamine libraries. This approach uses 2,3-dibromopropene as a template for the synthesis of a small olefin sub-library, which is then further functionalized to

Full text of DOI:10.1016/S0040-4039(00)01503-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8407–8411
The synthesis of ethanolamine libraries from olefin
scaffolds†
Michael G. Organ,a,* Stephen W. Kaldor,b Craig E. Dixon,a Daniel J. Parks,a
Upinder Singh,b David J. Lavorato,c Paul K. Isbestera and Miles G. Siegel*b
aDepartment of Chemistry, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3
bEli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46260, USA
cMDS SCIEX, 71 Four Valley Drive, Concord, Ontario, Canada L4K 4V8
Received 10 August 2000; revised 2 September 2000; accepted 6 September 2000
Abstract
A solution-phase, multi-reaction sequence has been developed for the parallel synthesis of ethanolamine
libraries. This approach uses 2,3-dibromopropene as a template for the synthesis of a small olefin
sub-library, which is then further functionalized to form the final ethanolamine library. The methodology
is demonstrated by the synthesis of a 5×4 array of ethanolamines. © 2000 Elsevier Science Ltd. All rights
reserved.
We have been interested in the synthesis of olefinic libraries1 from olefin templates.2 These
libraries contain several desirable properties for biological probes: they are readily synthesized in
well defined relative geometries, the substituents can be varied systematically in space, and
molecules of this type have proven valuable as pharmaceutical agents.3 Another intriguing
feature of olefin libraries is that the olefin component itself is a versatile functional group for
further transformations in a ‘libraries from libraries’ type approach (Fig. 1).4 In this paper, we
report the synthesis of a small library of olefins and their transformation into a larger library of
ethanolamines.
Figure 1. Olefin and olefin-derived libraries from simple multi-functional olefin templates
* Corresponding authors.
†
This work was first communicated at the ACS Central Regional Meeting, Midland, MI, May, 1997.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01503-3

8408
Although olefins are known to undergo a wide variety of transformations, we chose to first
examine the construction of ethanolamines due to the ubiquitous presence of this functionality
in a variety of biologically relevant small molecules.5 The ethanolamines were envisioned to be
obtained synthetically via a simple two step epoxide formation/aminolysis sequence,6 with the
required olefin starting materials for the epoxides assembled from 2,3-dibromopropene2 by
means of a phenolate substitution and subsequent Suzuki cross-coupling reaction. This synthetic
strategy allows for the installation of diversity via the phenol, aryl boronic acid and amine
moieties.
To test the viability of this synthetic approach in a parallel format, we examined the reaction
sequence under conditions amenable to parallel synthesis (Scheme 1). In this case, the reactions
were performed as discrete transformations. Compound 2 did not require chromatography, and
when allowed to react with piperidine (0.9 equiv.) in methanol generated ethanolamine 1 in 90%
yield.
Scheme 1.
Ideally, any reaction work-up, product isolation and purification should be reduced or
eliminated for high throughput synthesis. Thus, the reaction of 3 (2 equiv.) with phenol (1
equiv.) in the presence of 2.2 equiv. of polystyrene-1,5,7-triazabicyclo[4.4.0]dec-5-ene (PTBD
resin) as base1,7 provided 4, which then reacted smoothly with phenyl boronic acid to produce
5, with no need to isolate the vinyl bromide prior to cross-coupling (Scheme 1). The crude
phenylpropenyl ether 5 was epoxidized readily with dimethyldioxirane, generated in situ from
Oxone® and NaHCO3. Epoxide 2 was isolated by partitioning the compound between CH2Cl2
and H2O. The aqueous layer was removed by means of solid supported liquid–liquid extraction8
and evaporation of the solvent yielded crude epoxide 2. Heating the crude epoxide with
piperidine in MeOH produced the desired ethanolamine 1, which was readily isolated by SCX
1
chromatography.9 The product was isolated in 45% overall yield and was >95% pure by H
NMR spectroscopic analysis. This sequence compressed three of the four synthetic transforma-
tions into a single multi-reaction sequence, thus eliminating the need for intermediate isolation.
We next explored the scope of the reaction sequence with respect to both the phenol and aryl
boronic acid moieties to determine generally what functionality could be tolerated in a high
throughput format. Some observed trends in this study are worthy of note. Phenols and boronic

8409
acids used in this scope study that were unsuccessful are summarized in Fig. 2. We found that
any oxidizable functionality present in either the phenol or the boronic acid components did not
survive the epoxidation conditions. Furthermore, if an electron deficient phenol was used, the
resulting phenolic ether (4) would undergo Pd-catalyzed ionization of the phenoxide competi-
tively with oxidative insertion by Pd into the vinyl bromide under our Suzuki conditions
(Scheme 2). We have made the observation previously that phenolate ions will attack the central
carbon of the Pd p-allyl complex 6, ultimately yielding the diphenoxy products 7.10 Additionally,
heteroaryl boronic acids performed poorly in the Suzuki couplings.
Figure 2. Unsuccessful phenol and boronic acid examples
Scheme 2.
The final test of our approach was to synthesize the desired ethanolamines in an array format.
To that end, the three-step tandem reaction sequence was employed to synthesize four epoxy
ethers (vide supra). The 1H NMR spectra of compounds 2 revealed that these intermediates were
very clean with no visible signals arising from starting materials or potential byproducts. These
compounds were then incubated with five amines in methoxyethanol in a Robbins 96-well
FlexChem® Reactor Block (Scheme 3). Following purification by SCX and analysis by mass
spectrometry, it was found that all wells contained the expected pseudo-molecular ion (M+H)+
for the ethanolamine products (Table 1).
Scheme 3.

8410
Table 1
Four by five array of epoxides and secondary aminesa and their percent purityb,c
94%; (M+H)+, 412
93%; (M+H)+, 404
97%; (M+H)+, 454
98%; (M+H)+, 446
89%; (M+H)+, 423
89%; M+1, 415
89%; (M+H)+, 426
92%; (M+H)+, 418
94%; (M+H)+, 405
94%; (M+H)+, 378
92%; (M+H)+, 447
95%; (M+H)+, 420
81%; (M+H)+, 416
89%; (M+H)+, 389
83%; (M+H)+, 419
90%; (M+H)+, 392
56%; (M+H)+, 451
76%; (M+H)+, 493
72%; (M+H)+, 462
64%; (M+H)+, 466
a Reactions were carried out in a Robbins FlexChem® Reactor Block (epoxide/amine, 1:0.9) in methoxyethanol
solvent at 80°C (see Experimental for full details).
b Purity is based on LC/MS data (u=254 and 280 nm) and analysis of the 1H NMR spectra of the products
following SCX chromatography. Mass spectra (250–700 amu) were obtained using a PE Sciex API 2000 triple
quadrupole mass spectrometer using turboionspray as the method of ionization.
c The first term in each table entry is the percent purity. The second term is the observed pseudo molecular ion from
the LC/MS spectra.
In summary, we have demonstrated a solution-phase, multi-reaction sequence for the genera-
tion of ethanolamine libraries from olefin templates. The use of this methodology for the
creation of larger libraries of ethanolamines for general screening will be reported in due course.
Experimental: The following general procedure is representative for the aminolysis reactions
performed in the Robbins FlexChem® Reactor Block. The four epoxide products from the
tandem sequence (Scheme 3, products 2) were weighed and each dissolved in 1.0 mL of
methoxyethanol. Two hundred mL of each stock solution were loaded into four wells of the
block (20 total). Five stock solutions of amines were prepared by dissolving 0.5 mmol of the
amine in 1.0 mL of methoxyethanol, and 0.9 equiv. of each amine were dispensed orthogonally
to the epoxides 2 to complete the array. After sealing the block, the mixtures were heated at
80°C for 16 h. Upon cooling to rt, the residues were concentrated and taken up in 10%
AcOH/MeOH. The resulting solutions were passed through a 96-well filter plate containing 500
mg of SCX resin per well and the products were eluted with 20% NH3/MeOH. In general, no
1
signals corresponding to reactants or byproducts were observed in the H NMR spectra. The
yield/recovery range for the 20 compounds was from 30 to 60%.

8411
Acknowledgements
This work was supported financially by NSERC (Canada). D.J.L. wishes to thank NSERC
for an Industrial Research Fellowship (IRF).
References
1. For the preparation of an allylic amine library from olefin templates, see: Organ, M. G.; Mayhew, D.; Cooper,
J. T.; Dixon, C. G.; Lavorato, D. J.; Kaldor, S. W.; Siegel, M. G. J. Comb. Chem. 2000, in press.
2. For discussion of the ‘olefin template strategy’, see: (a) Organ, M. G.; Cooper, J. T.; Rogers, L. R.;
Soleymanzadeh, F.; Paul, T. J. Org. Chem. 2000, in press. (b) Organ, M. G.; Bratovanov, S. Tetrahedron Lett.
2000, 41, 6945–6949.
3. (a) Slater, J. W.; Zechnich, A. D.; Haxby, D. G. Drugs 1999, 57, 31. (b) Gibson, J. L. R.; Manna, V. K.;
Salisbury, J. J. Int. Med. Res. 1989, 17, 28B. (c) Straub, H.; Koehling, R.; Speckmann, E. J. Brain Res. 1994, 658,
119. (d) Andersen, K. E.; Sorensen, J. L.; Huusfeldt, P. O.; Knutsen, L. J. S.; Lau, J.; Lundt, B. F.; Petersen, H.;
Suzdak, P. D.; Swedberg, M. D. B. J. Med. Chem. 1999, 42, 4281. (e) Ashton, D.; Reid, K.; Willems, R.;
Marrannes, R.; Wauguier, A. Drug. Dev. Res. 1986, 8, 397.
4. (a) Xiao, X. Y.; Ngu, K.; Chao, C.; Patel, D. V. J. Org. Chem. 1997, 62, 6968. (b) Houghten, R. A.; Blondelle,
S. E.; Dooley, C. T.; Do¨rner, B.; Eichler, J.; Ostresh, J. M. Mol. Diversity 1996, 2, 41.
5. (a) Siegel, M. G.; Shuker, A. J.; Droste, C. A.; Hahn, P. J.; Jesudason, C. D.; McDonald III, J. H.; Matthews,
D. P.; Rito, C. J.; Thorpe, A. J. Mol. Diversity 1998, 3, 113. (b) Wright, S. W.; Harris, R. R.; Collins, R. J.;
Corbett, R. L.; Green, A. M.; Wadman, E. A.; Batt, D. G. J. Med. Chem. 1992, 35, 3148. (c) Khan, J. K.;
Montaseri, H.; Poglod, M.; Bu, H. Z.; Zuo, Z.; Salama, S. M.; Daneshtalab, M.; Micetich, R. G. Can.
Antimicrob. Agents Chemother. 2000, 44, 910.
6. Bolli, M. H.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1 1998, 2243.
7. (a) Xu, W.; Mohan, R.; Morrissey, M. M. Tetrahedron Lett. 1997, 38, 7337. (b) The reaction of template 3 with
sodium phenolate also proceeded efficiently. However, the subsequent Suzuki chemistry could not be run
successfully in the presence of the sodium bromide generated in this step.
8. Johnson, C. R.; Zhang, B.; Fantauzzi, P.; Hocker, M.; Yager, K. M. Tetrahedron 1998, 54, 4097.
9. (a) Chucholowski, A.; Masquelin, T.; Obrecht, D.; Stadlwieser, J.; Villalgordo, J. M. Chimia 1996, 50, 525. (b)
Lawrence, R. M.; Biller, S. A.; Fryszman, O. M.; Poss, M. A. Synthesis 1997, 553. (c) Siegel, M. G.; Hahn, P.
J.; Dressman, B. A.; Fritz, J. E.; Grunwell, J. R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357. (d) Boger, D.
L.; Tarby, C. M.; Myers, P. L.; Caporale, L. H. J. Am. Chem. Soc. 1996, 118, 2109. (e) Cheng, S.; Comer, D.
D.; Williams, J. P.; Myers, P. L.; Boger, D. L. J. Am. Chem. Soc. 1996, 118, 2567.
10. (a) Organ, M. G.; Miller, M. Tetrahedron Lett. 1997, 38, 8181. (b) Organ, M. G.; Miller, M.; Konstantinou, Z.
J. Am. Chem. Soc. 1998, 120, 9283.
.