Novel solution phase strategy for the synthesis of chemical libraries containing small organic molecules

Article abstract of DOI:10.1021/ja9530681

A simple, versatile, and general approach to the solution phase, parallel synthesis of chemical libraries conducted on a generalized or universal template, which allows the preparation of multi-milligram quantities of each individual member, is described.

Full text of DOI:10.1021/ja9530681

J. Am. Chem. Soc. 1996, 118, 2567-2573
2567
Novel Solution Phase Strategy for the Synthesis of Chemical
Libraries Containing Small Organic Molecules
Soan Cheng, Daniel D. Comer, John P. Williams, Peter L. Myers, and
Dale L. Boger*
Contribution from CombiChem, Inc., 9850 Camino Santa Fe, San Diego, California 92121, and
Department of Chemistry, The Scripps Research Institute, 10666 North Torrey Pines Road,
La Jolla, California 92037
ReceiVed September 5, 1995X
Abstract: A simple, versatile, and general approach to the solution phase, parallel synthesis of chemical libraries
conducted on a generalized or universal template, which allows the preparation of multi-milligram quantities of each
individual member, is described. In each step of the sequence, the reactants, unreacted starting material, reagents
and their byproducts are removed by simple liquid/liquid or liquid/solid extractions providing the desired intermediates
and final compounds in high purities (95% average) irrespective of the reaction yields and without deliberate reaction
optimization.
The generation and use of combinatorial chemical libraries
for the identification of novel chemical leads or for the
optimization of a promising lead candidate has emerged as a
potentially powerful method for the acceleration of the drug
discovery process.1-4 Initially explored with peptide or oligo-
nucleotide libraries and related oligomeric structures,2,5-13 more
recent efforts have been directed at exploiting the greater
diversity and range of useful properties embodied in small
molecule libraries.11-17
X Abstract published in AdVance ACS Abstracts, March 1, 1996.
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0002-7863/96/1518-2567$12.00/0 © 1996 American Chemical Society

2568 J. Am. Chem. Soc., Vol. 118, No. 11, 1996
Cheng et al.
excesses to effect high yield conversions required for each of
the repetitive steps. However, its scale is generally restricted
by the amount of required solid support and its loading
capacity26 and the production of multi-milligram quantities of
each library member can be cumbersome and expensive.27 Its
use also requires functionalized substrates and solid supports,23
compatible spacer linkers, orthogonal attachment and detach-
ment chemistries often with the release of spectator functional
groups, specialized protocols for monitoring the individual steps
of a multistep synthesis28 including orthogonal capping strategies
for blocking unreacted substrate, and does not permit the
purification of resin-bound intermediates. This latter feature
necessarily produces the released product of a multistep
sequence in an impure state and requires that each reaction on
each substrate proceed with an unusually high efficiency. For
a modest criterion of final product purity of 85%, this would
require that each step of a two-step reaction sequence proceed
in 92% yield on each substrate or that each step of a three-step
reaction sequence proceed in 95% yield on each substrate. Our
experience has been that such generalized reaction efficiencies
are not routinely obtainable and require an extensive investment
Figure 1.
in reaction optimization and/or a purification of the released
solid phase product.29
An important complement to adapting solution phase chem-
istry to solid phase combinatorial synthesis is the development
of protocols for solution phase combinatorial synthesis. Given
that solution and solid-phase sample manipulation are both
convenient and easily automated, the limitation to the solution
phase parallel synthesis of chemical libraries is the isolation or
purification of the library members. If the advantages of sample
isolation characteristic of solid phase synthesis may be embodied
in a solution phase synthesis, its nonlimiting scale, expanded
repertoire of chemical reactions, direct production of soluble
intermediates and final products for assay or purification, and
the lack of required linking, attachment/detachment, or capping
strategies make solution phase combinatorial synthesis an
attractive complement. A number of potential techniques are
available for such purposes, and one of the most attractive is
liquid/liquid or solid/liquid extraction. Herein, we detail a high-
purity solution phase parallel synthesis of chemical libraries
employing a general template which implements one such
simple purification protocol at each step. The recently disclosed
but not yet detailed24 single-step parallel synthesis of individual
compounds using reliable solution chemistry as well as recent
reports of solution phase, single step amide, ester, or carbamate
condensations in the preparation of library mixtures20 have
provided the incentive for us to disclose our efforts.
The template 1, which is representative of a series of
anhydride-based templates that have been examined, consists
of a densely functionalized core which imposes little structural
or conformational bias which might limit its use.30 The added
pendant groups provide the molecular diversity and, as such,
libraries built upon 1 may prove applicable to many biological
targets. Its symmetrical structure contains three positions which
can be controllably functionalized with nucleophiles or an
acylating agent enabling the synthesis of libraries with up to
three variable regions (Figure 1). As an anhydride, the starting
template is activated for the first functionalization which upon
reaction liberates its second functionalization site (-CO2H).
Thus, no orthogonal protecting groups are required for the
template functionalization and only four chemical steps are
required for the N3 diversification (Scheme 1). At each step,
the same released functionality may be used for both the
isolation and purification of the intermediates and expected
products from the starting material, reactants, reagents, and their
reaction byproducts by simple liquid/liquid or solid/liquid
extraction providing highly pure materials (g90-95%) regard-
less of the reaction efficiencies.
(19) Brenner, S.; Lerner, R. A. Proc. Natl. Acad. Sci. U.S.A. 1992, 89,
5381. Nielsen, J.; Brenner, S.; Janda, K. D. J. Am. Chem. Soc. 1993, 115,
9812. Needels, M. C.; Jones, D. G.; Tate, E. H.; Heinkel, G. L.;
Kochersperger, L. M.; Dower, W. J.; Barrett, R. W.; Gallop, M. A. Proc.
Natl. Acad. Sci. U.S.A. 1993, 90, 10700. Nikolaiev, V.; Stierandova, A.;
Krchnak, V.; Seligmann, B.; Lam, K. S.; Salmon, S. E.; Lebl, M. Peptide
Res. 1993, 6, 161. Kerr, J. M.; Banville, S. C.; Zuckermann, R. N. J. Am.
Chem. Soc. 1993, 115, 2529. Ohlmeyer, M. H. J.; Swanson, R. N.; Dillard,
L. W.; Reader, J. C.; Asouline, G.; Kobayashi, R.; Wigler, M.; Still, W. C.
Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 10922. Nestler, H. P.; Bartlett, P.
A.; Still, W. C. J. Org. Chem. 1994, 59, 4723. Baldwin, J. J.; Burbaum, J.
J.; Henderson, I.; Ohlmeyer, M. H. J. J. Am. Chem. Soc. 1995, 117, 5588.
Moran, E. J.; Sarshar, S.; Cargill, J. F.; Shahbaz, M. M.; Lio, A.; Mjalli,
A. M. M.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 10787.
(20) Pirrung, M. C.; Chen, J. J. Am. Chem. Soc. 1995, 117, 1240. Smith,
P. W.; Lai, J. Y. Q.; Whittington, A. R.; Cox, B.; Houston, J. G.; Stylli, C.
H.; Banks, M. N.; Tiller, P. R. Bioorg. Med. Chem. Lett. 1994, 4, 2821.
Carell, T.; Wintner, E. A.; Bashir-Hashemi, A.; Rebek, J., Jr. Angew Chem.,
Int. Ed. Engl. 1994, 33, 2059.
(21) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
(22) Fodor, S. P. A.; Read, J. L.; Pirrung, M. C.; Stryer, L.; Lu, A. T.;
Solas, D. Science 1991, 251, 767.
(23) Atherton, E.; Sheppard, R. C. Solid Phase Peptide Synthesis: A
Practical Approach; IRL Press: Oxford, 1989. Grubler, G.; Stoeva, S.;
Echner, H.; Voelter, W. In Peptides: Chemistry, Structure, and Biology;
Proceedings of the Thirteenth American Peptide Symposium; Hodges, R.
A., Smith, J. A., Eds.; ESCOM-Leiden: The Netherlands, 1994; p 51.
Englebretsen, D. R.; Harding, D. R. K. Int. J. Pept. Protein Res. 1992, 40,
487. Frank, R. Bioorg. Med. Chem. Lett. 1993, 3, 425. Frank, R.; Doring,
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(24) Peterson, J. B. Exploiting Molecular Diversity: Small Molecule
Libraries for Drug Discovery, La Jolla, CA, January 23-25, 1995.
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Wolfe, M. M.; Brenner, S.; Janda, K. D. Proc. Natl. Acad. Sci. U.S.A. 1995,
92, 6419.
(26) Crowley, J. I.; Rapoport, H. Acc. Chem. Res. 1976, 9, 135.
(27) For a 10 000 member library (three-step synthesis at 95% yield/
step) to obtain 50 mg of each component (MW ) 500 g/mol) on Merrifield
resin with a typical loading of 1 mmol/g requires 1.166 kg of solid support,
which equals $2499/library; on Wang resin with loading of 0.7 mmol/g,
1.666 kg of solid support is required, or $8331/library.
(28) Egner, B. J.; Langley, G. J.; Bradley, M. J. Org. Chem. 1995, 60,
2652. Anderson, R. C.; Jarema, M. A.; Shapiro, M. J.; Stokes, J. P.; Ziliox,
M. J. Org. Chem. 1995, 60, 2650. Fitch, W. L.; Detre, G.; Holmes, C. P.;
Shoolery, J. N.; Kiefer, P. A. J. Org. Chem. 1994, 59, 7955. Look, G. C.;
Holmes, C. P.; Chinn, J. P.; Gallop, M. A. J. Org. Chem. 1994, 59, 7588.
Metzger, J. W.; Wiesmuller, K.-H.; Gnau, V.; Brunjes, J.; Jung, G. Angew.
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Lacey, M. P.; Keough, T. Rapid Commun. Mass Spectrom. 1994, 8, 77.
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To illustrate the library constructions with 1, herein we
provide full details of our initial efforts which were conducted
without prior optimization and that provided a fully characterized
27 member library constructed as a 3 × 3 × 3 matrix affording
39 unique components in individual vessels (Scheme 2, Figure
2). Including enantiomer and diastereomer mixtures, 51 unique
(29) For example, see: Wang, G. T.; Li, S.; Wideburg, N.; Krafft, G.
A.; Kempf, D. J. J. Med. Chem. 1995, 38, 2995.
(30) Related, conformationally restricted templates including a general
dipeptidomimetic template have been developed and serve as useful
secondary libraries for subsequent examination. Efforts with such templates
will be disclosed in due course.

Chemical Libraries Containing Small Organic Molecules
J. Am. Chem. Soc., Vol. 118, No. 11, 1996 2569
Scheme 1
Figure 2.
byproducts. Both primary and secondary aliphatic or aryl
amines were found to work well, and the first derivatization of
1 with an amine proved sufficiently effective that the deliberate
aqueous base dissolution of the desired product was not required
for isolation of pure product. In the instances of the use of a
neutral nucleophile (R1OH, R1SH, R1Met) in this first func-
tionalization, the purification may be effectively accomplished
by removal of the coupling reagent (EDCI) and its byproducts
by dissolution in 10% aqueous HCl, extraction of the product
carboxylic acid into 10% aqueous NaOH for the removal of
neutral reactants, and reacidification and extraction into EtOAc
or CH2Cl2 for product isolation. The three monoamides were
each partitioned into three portions with one smaller portion
being retained for archival purposes. Each of the equal three
portions were treated with three R2NH2 (1 equiv) and PyBOP
(1 equiv, 2 equiv of i-Pr2NEt, DMF, 20 °C, 25 h, 65-99%) to
afford nine diamides which were effectively purified by acid
and base extractions of the unreacted R2NH2, PyBOP, and its
reaction byproducts. Although this is illustrated in Scheme 2
with a primary amine, secondary amines as well as aryl amines
could also be employed without difficulty. In the instances of
the use of neutral nucleophiles (R2OH, R2SH, R2Met) in this
second functionalization, the further purification of the neutral
reactants from the desired products may be readily accomplished
upon N-BOC deprotection and aqueous acid extraction of the
resulting secondary amine. Following the second functional-
ization and N-BOC deprotection (4 N HCl, dioxane, 25 °C, 45
min), reaction of three equal portions of each amine with three
R3CO2H (1 equiv) in the presence of PyBOP (1 equiv, 3 equiv
of i-Pr2NEt, DMF, 25 °C, 20 h, 16-100%) provided 27 agents
which were purified by aqueous acid and base extractions to
remove unreacted starting materials, reagents, and their reaction
byproducts. Overall yields for the 27 components ranged from
9 to 84% with an average overall yield of 61% for the three
derivatizations. Importantly and irrespective of individual
yields, all intermediates and final products were g90% pure
and the average purity was 95.3% (Table 1, Experimental
Section).31 Without optimization and in these first efforts, most
of the final library products were obtained in 20-60 mg
quantities as individual identified samples at this exceptional
level of purity suitable for direct use in screening efforts without
further purification.
Scheme 2
entities were contained in the chemical library. Although this
has been subsequently expanded to much larger library genera-
tions and more carefully optimized, the disclosure of its initial
implementation serves to highlight a number of the advantages
of the approach and is representative of the more extensive
efforts. The most notable is that each of the expected library
members was obtained in a purified form (g90-100% pure)31
irrespective of the reaction efficiencies in amounts ranging from
5 to 60 mg without prior optimization. In situ closure of
N-BOC-iminodiacetic acid to the anhydride 1 (1 equiv of
3-ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydrochloride
(EDCI), DMF, 25 °C, 1 h) followed by treatment with one of
three R1NH2 (1 equiv, DMF, 25 °C, 20 h, 84-86%) cleanly
afforded the monoamides which were purified by simple acid
extraction to remove unreacted R1NH2, EDCI, and its reaction
Without further optimization, subsequent extensions of these
efforts to the preparation of a similarly characterized 125
member library constructed as a 5 × 5 × 5 matrix affording
155 unique compounds in individual vessels (Figure 3) provided
comparable observations. Each library member was obtained
(31) 1H NMR spectra of all intermediates and final library members of
the 3 × 3 × 3 matrix synthesis are provided in the supporting information,
and the HPLC purity of the final products is summarized in Table 1.

2570 J. Am. Chem. Soc., Vol. 118, No. 11, 1996
Cheng et al.
Figure 3.
as an individual entity in 30-100 mg quantities in pure form
(>90%, generally g95% pure) in overall yields ranging from
32 to 85% (64% average).
One of the largest libraries addressed to date by manual
manipulation of the reactions is a 960 member library con-
structed in a 6 × 8 × 20 matrix affording 1014 final components
in individual vessels including intermediates constituting a
library of 1158 compounds including diastereomers/enantiomers
(Figure 4). Each library member was obtained in final sample
sizes of 10-148 mg in overall yields ranging from 10 to 71%
(52% average).
Conclusions. Complementary to the emerging solid phase
synthesis of combinatorial libraries, a method for the rapid and
simple multistep, solution phase, parallel synthesis of chemical
libraries in which each component is produced as an individual
compound in unlimited quantities (typically 30-150 mg) for
extensive or broad screening purposes has been developed. In
each step of the sequence, intermediates and final products were
subjected to simple purification by liquid/liquid or liquid/solid
extraction to remove reactants, unreacted starting material,
reagents, and their byproducts providing the library members
in high purities (g90-98%) irrespective of the reaction yields
and without deliberate reaction optimization. The template 1
on which this technology was illustrated is unusually flexible
possessing one to three functionalization sites for diversification
and little inherent structural or conformational bias which might
limit its use. Although the initial examples described above
enlist conventional liquid/liquid extractions, similar results
employing solid-supported resins, columns, or pads have been
used to effect solid/liquid extractions by simple batch, column,
or filtration protocols. The one secondary amine protecting
group may be easily altered to accommodate its sensitivity to
selected liquid/liquid or liquid/solid extraction protocols used
to remove starting materials and reaction byproducts. Although
not illustrated herein, the strategy is not limited to the parallel
synthesis of individual compounds but is also applicable to split
or mixed synthesis employing limiting amounts of variable units
and excess template to construct combinatorial libraries of
compound mixtures subject to subsequent compound identifica-
tion by repeat parallel synthesis or recursive deconvolution.
Figure 4.
Studies employing larger targeted libraries with matrix char-
acterization of each reaction type, their adaptation to automation,
and the development of related library templates, as well as
additional approaches to the solution phase synthesis of chemical
libraries, will be disclosed in due time.31
Experimental Section
General Procedure for the Preparation of N-((tert-Butyloxy)-
carbonyl)iminodiacetic Acid Monoamides. A solution of N-((tert-
butyloxy)carbonyl)iminodiacetic acid (0.349 g, 1.50 mmol) in DMF
(15 mL) was treated with EDCI (0.294 g, 1.54 mmol) at 25 °C. The
mixture was stirred at 25 °C for 1 h before the amine (R1NH2, 1 equiv)
was added, and the solution was stirred for 20 h at 25 °C. The reaction
mixture was poured into 10% aqueous HCl (60 mL) and extracted with
EtOAc (100 mL). The organic phase was washed with 10% HCl (40
mL) and saturated aqueous NaCl (2 × 50 mL), dried (Na2SO4), filtered,
and concentrated in vacuo to yield the pure N-((tert-butyloxy)carbonyl)-
iminodiacetic acid monoamides.

Chemical Libraries Containing Small Organic Molecules
J. Am. Chem. Soc., Vol. 118, No. 11, 1996 2571
N-((tert-Butyloxy)carbonyl)-N′-benzyliminodiacetic Acid Monoa-
mide: 417 mg (86%); H NMR (CD3OD, 300 MHz) δ 7.28 (m, 5H),
4.40 (br s, 2H), 4.04, 4.01, 3.98 and 3.93 (four s, total 4H), 1.40 and
1.32 (two s, total 9H); FABHRMS (NBA) m/e 323.1615 (M + H+,
C16H23N2O5 requires 323.1607).
4H), 6.32 (br s, 1H), 4.02, 3.95, 3.91 and 3.86 (four s, total 4H), 3.32
(m, 2H), 2.56 (m, 1H), 1.81-1.48 (m, 6H), 1.43 and 1.40 (two s, total
9H), 1.22 (m, 3H), 0.93 (t, J ) 7.3 Hz, 3H), 0.81 (t, J ) 7.2 Hz, 3H);
FABHRMS (NBA-CsI) m/e 552.1823 (M + Cs+, C23H37N3O4Cs
requires 552.1838).
1
N-((tert-Butyloxy)carbonyl)-N′-(n-butyl)iminodiacetic Acid Mono-
amide: 362 mg (84%); 1H NMR (CD3OD, 300 MHz) δ 4.04 and 4.00
(two s, total 2H), 3.92 and 3.89 (two s, total 2H), 3.22 (m, 2H), 1.55-
1.31 (m, 4H), 1.42 (s, 9H), 0.95-0.89 (m, 3H); FABHRMS (NBA)
m/e 289.1769 (M + H+, C13H25N2O5 requires 289.1763).
N-((tert-Butyloxy)carbonyl)-N′-cyclohexyliminodiacetic Acid Mono-
amide: 402 mg (85%); 1H NMR (CD3OD, 300 MHz) δ 4.03 and 3.99
(two s, total 2H), 3.90 and 3.87 (two s, total 2H), 3.68 (m, 1H), 1.90-
1.20 (m, 10H), 1.42 (s, 9H); FABHRMS (NBA) m/e 315.1928 (M +
H+, C15H27N2O5 requires 315.1920).
General Procedure for the Second Derivatization. Each of the
N-((tert-butyloxy)carbonyl)iminodiacetic acid monoamides was dis-
solved in anhydrous DMF (20 mL/mmol) and was divided into three
equal portions in three separate vials. Each solution was treated with
one of three amines (R2NH2, 1 equiv), diisopropylethylamine (2 equiv),
and PyBOP (1 equiv). The solution (20 mL DMF/mmol) was stirred
at 25 °C for 20 h. The mixture was poured into 10% aqueous HCl
and extracted with EtOAc. The organic phase was washed with 10%
aqueous HCl, saturated aqueous NaCl, 5% aqueous NaHCO3, and
saturated aqueous NaCl. The organic layer was dried (Na2SO4), filtered,
and concentrated in vacuo to yield the diamides (65-99%).
N-((tert-Butyloxy)carbonyl)-N′′-(4-sec-butylphenyl)-N′-cyclo-
hexyliminodiacetic Acid Diamide: 198 mg (99%); 1H NMR (CDCl3,
300 MHz) δ 9.60 (m, 1H), 7.63 (d, J ) 8.0 Hz, 2H), 7.15 (d, J ) 8.0
Hz, 2H), 6.61 and 5.80 (two m, total 1H), 4.03 and 3.95 (two s, total
2H), 3.90 and 3.84 (two s, total 2H), 2.57 (m, 1H), 2.0-1.55 (m, 8H),
1.45 and 1.41 (two s, total 9H), 1.22 (d, J ) 6.9 Hz, 3H), 0.82 (t, J )
7.2 Hz, 3H); FABHRMS (NBA) m/e 446.3005 (M + H+, C25H40N3O4
requires 446.3019).
N-((tert-Butyloxy)carbonyl)-N′-(n-butyl)-N′′-(3-methoxypropyl)-
iminodiacetic Acid Diamide: 75 mg (65%); H NMR (CD3OD, 300
MHz) δ 3.90 and 3.88 (two s, total 4H), 3.43 (m, 2H), 3.31 and 3.29
(two s, total 3H), 3.22 (m, 2H), 1.86-1.74 (m, 4H), 1.41 (s, 9H), 0.93
(m, 3H); FABHRMS (NBA-CsI) m/e 492.1461 (M + Cs+, C17H33N3O5-
Cs requires 492.1475).
1
N-((tert-Butyloxy)carbonyl)-N′-(n-butyl)-N′′-(2,2-diphenylethyl)-
iminodiacetic Acid Diamide: 155 mg (99%); 1H NMR (CD3OD, 300
MHz) δ 7.27-7.15 (m, 10H), 4.30 (t, J ) 7.7 Hz, 1H), 3.86 and 3.83
(two s, total 2H), 3.81 and 3.77 (two s, total 2H), 3.30 (m, 2H), 3.21
(t, 6.8 Hz, 2H), 1.56-1.42 (m, 2H), 1.37 and 1.30 (two s, total 9H),
0.96 and 0.95 (two t, J ) 7.2 Hz, total 3H): FABHRMS (NBA-CsI)
m/e 600.1821 (M + Cs+, C27H37N3O4Cs requires 600.1838).
General Procedure for the Third Derivatization. Each of the N′-
((tert-butyloxy)carbonyl)-N,N-disubstituted iminodiacetic acid diamides
was dissolved in 4 N HCl-dioxane (32 mL/mmol), and the mixture
was stirred at 25 °C for 45 min. the solvent was removed in vacuo,
and the residue was dissolved in anhydrous DMF (28 mL/mmol) and
was divided into three equal portions and placed in three separate vials.
The solution was treated with one of three carboxylic acids (R3CO2H,
1 equiv) followed by diisopropylethylamine (3 equiv) and PyBOP (1
equiv). The solution was stirred for 20 h at 25 °C. The mixture was
poured into 10% aqueous HCl and extracted with EtOAc. The organic
phase was washed with 10% aqueous HCl and extracted with EtOAc.
The organic phase was washed with 10% aqueous HCl, saturated
aqueous NaCl, 5% aqueous NaHCO3, and saturated aqueous NaCl. The
organic phase was dried (Na2SO4), filtered, and concentrated in vacuo
to yield the final products (16-100%).
N-(Benzylcarbonyl)-N′-cyclohexyl-N′′-(2,2-diphenylethyl)imino-
diacetic Acid Diamide: 47 mg (86%); 1H NMR (CDCl3, 300 MHz) δ
9.10 and 8.75 (two m, total 1H), 7.50-7.05 (m, 15H), 6.10 and 5.95
(two m, total 1H), 4.40 and 4.18 (two t, J ) 8.4 Hz, total 1H), 3.91
(m, 2H), 3.82 and 3.73 (two s, total 2H), 3.61 and 3.58 (two s, total
2H), 3.21 (br s, 2H), 1.93-1.14 (m, 10H); FABHRMS (NBA) m/e
512.2907 (M + H+, C32H38N3O3 requires 512.2913).
N-((tert-Butyloxy)carbonyl)-N′-cyclohexyl-N′′-(3-methoxypropyl)-
1
iminodiacetic Acid Diamide: 135 mg (88%); H NMR (CDCl3, 300
MHz) δ 7.98 (m, 1H), 6.99 and 6.82 (two m, total 1H), 3.84 and 3.79
(two s, total 4H), 3.47 (t, J ) 5.9 Hz, 2H), 3.43-3.39 (m, 2H), 3.34
(s, 3H), 1.92-1.15 (m, 10H), 1.43 (s, 9H); FABHRMS (NBA-CsI)
m/e 518.1647 (M + Cs+, C19H35N3O5Cs requires 518.1631).
N-Benzoyl-N′-cyclohexyl-N′′-(2,2-diphenylethyl)iminodiacetic Acid
Diamide: 37 mg (69%); 1H NMR (CDCl3, 300 MHz) δ 9.18 and 6.40
(two br s, total 1H), 8.35 and 6.05 (two m, total 1H), 7.38-7.21 (m,
15H), 4.48 and 4.22 (two t, J ) 8.4 Hz, total 1H), 3.99 (m, 2H), 3.89-
3.84 (m, 2H), 3.13 (m, 2H), 2.04-1.20 (m, 10H); FABHRMS (NBA)
m/e 498.2759 (M + H+, C31H36N3O3 requires 498.2756).
N-((tert-Butyloxy)carbonyl)-N′-cyclohexyl-N′′-(2,2-diphenylethyl)-
iminodiacetic Acid Diamide: 197 mg (82%); H NMR (CDCl3, 300
1
MHz) δ 7.90 and 6.85 (two t, total 1H), 7.78 and 6.78 (two d, total
1H), 7.26 (m, 10H), 4.26 (m, 1H), 3.95, 3.94, 3.93 and 3.91 (four s,
total 4H), 3.72 and 3.70 (two s, total 2H), 3.15 (m, 1H), 1.92-1.61
(m, 4H), 1.40 and 1.33 (two s, total 9H), 1.29-1.21 (m, 6H);
FABHRMS (NBA-CsI) m/e 626.2023 (M + Cs+, C29H39N3O4Cs
requires 626.1995).
N-(Ethylcarbonyl)-N′-cyclohexyl-N′′-(2,2-diphenylethyl)iminodi-
1
acetic Acid Diamide: 39 mg (81%); H NMR (CDCl3, 400 MHz) δ
9.27 and 6.05 (two t, total 1H), 8.80 and 5.87 (two d, J ) 7.3 Hz, total
1H), 7.37-7.15 (m, 10H), 4.38 and 4.16 (two t, J ) 8.4 Hz, total 1H),
3.89 and 3.84 (two s, total 2H), 3.76 and 3.62 (two s, total 2H), 3.15
(m, 2H), 2.25 (q, J ) 7.3 Hz, 2H), 1.95-1.07 (m, 10H), 0.88 (t, J )
7.4 Hz, 3H); FABHRMS (NBA) m/e 450.2749 (M + H+, C27H36N3O3
requires 450.2756).
N-(Benzylcarbonyl)-N′-benzyl-N′′-(3-methoxypropyl)iminodiace-
tic Acid Diamide: 28 mg (76%); 1H NMR (CDCl3, 300 MHz) δ 9.61
and 8.71 (two t, total 1H), 7.12-7.37 (m, 10H), 6.89 and 6.85 (two t,
total 1H), 4.43-4.40 (m, total 2H), 4.04 and 4.00 (two s, total 2H),
3.89 and 3.84 (two s, total 2H), 3.64 and 3.58 (two s, total 2H), 3.42
(t, J ) 6.7 Hz, 2H), 3.30 (s, 3H), 3.13 (t, J ) 3.5 Hz, 2H), 1.82-1.72
(m, 2H); FABHRMS (NBA) m/e 412.2231 (M + H+, C23H30N3O4
requires 412.2236).
N-Benzoyl-N′-benzyl-N′′-(3-methoxypropyl)iminodiacetic Acid
Diamide: 24 mg (67%); 1H NMR (CDCl3, 300 MHz) δ 9.35 and 8.46
(two br s, total 1H), 7.42-7.20 (m, 10H), 6.98 (br s, 1H), 4.49 (d, J )
5.7 Hz, 2H), 4.00 (m, 4H), 3.47-3.31 (m, 5H), 3.13 (m, 2H), 1.80 (m,
2H); FABHRMS (NBA) m/e 398.2077 (M + H+, C22H28N3O4 requires
398.2079).
N-(Ethylcarbonyl)-N′-benzyl-N′′-(3-methoxypropyl)iminodiace-
tic Acid Diamide: 15 mg (48%); 1H NMR (CDCl3, 300 MHz) δ 9.75
and 8.90 (two t, total 1H), 7.30-7.26 (m, 5H), 6.85 and 6.65 (two t,
total 1H), 4.47 and 4.46 (two d, J ) 17.8 Hz, 2H), 4.03 and 4.00 (two
N-((tert-Butyloxy)carbonyl)-N′-benzyl-N′′-(4-sec-butylphenyl)imi-
nodiacetic Acid Diamide: 180 mg (99%); 1H NMR (CDCl3, 300 MHz)
δ 9.43 (br s, 1H), 7.61 (d, J ) 8.3 Hz, 1H), 7.52 (d, J ) 8.0 Hz, 1H),
7.30 (br s, 5H), 7.13 (d, J ) 8.2 Hz, 2H), 6.60 (t, 1H), 4.52 and 4.50
(two s, total 2H), 4.01, 3.95 and 3.89 (three s, total 4H), 2.56 (m, 1H),
1.57 (m, 2H), 1.40 and 1.36 (two s, total 9H), 1.21 (d, J ) 6.8 Hz,
3H), 0.81 (t, J ) 7.4 Hz, 3H); FABHRMS (NBA-CsI) m/e 586.1662
(M + Cs+, C26H35N3O4Cs requires 586.1682).
N-((tert-Butyloxy)carbonyl)-N′-benzyl-N′′-(3-methoxypropyl)imi-
nodiacetic Acid Diamide: 141 mg (90%); 1H NMR (CDCl3, 300 MHz)
δ 8.82, 7.85, 7.58 and 6.90 (four br s, total 2H), 7.30 (m, 5H), 4.49
and 4.47 (two s, total 2H), 3.90 and 3.86 (two s, total 2H), 3.84 and
3.81 (two s, total 2H), 3.46 (t, J ) 5.8 Hz, 2H), 3.32 (s, 3H), 3.14 (m,
2H), 1.80 (m, 2H), 1.42 and 1.35 (two s, total 9H); FABHRMS (NBA-
CsI) m/e 526.1335 (M + Cs+, C20H31N3O5Cs requires 526.1318).
N-((tert-Butyloxy)carbonyl)-N′-benzyl-N′′-(2,2-diphenylethyl)imi-
nodiacetic Acid Diamide: 212 mg (99%); 1H NMR (CDCl3, 300 MHz)
δ 8.50, 7.78 and 6.50 (three br s, total 2H), 7.33-7.21 (m, 15H), 4.47
and 4.45 (two s, total 2H), 3.93-3.89 (m, 2H), 3.72-3.67 (m, 2H),
3.15 (m, 1H), 1.32 (s, 9H); FABHRMS (NBA-CsI) m/e 634.1664 (M
+ Cs+, C30H35N3O4Cs requires 634.1682).
N-((tert-Butyloxy)carbonyl)-N′-(n-butyl)-N′′-(4-sec-butylphenyl)-
1
iminodiacetic Acid Diamide: 137 mg (99%); H NMR (CDCl3, 300
MHz) δ 9.60 (br s, 1H), 7.61, 7.52, 7.13 (three d, J ) 8.2 Hz, total

2572 J. Am. Chem. Soc., Vol. 118, No. 11, 1996
Cheng et al.
s, total 2H), 3.94 and 3.88 (two s, total 2H), 3.48-3.34 (m, 2H), 3.32
and 3.31 (two s, total 3H), 3.16 (m, 2H), 2.26 (m, 2H), 1.86-1.74 (m,
2H), 1.07 (m, 3H); FABHRMS (NBA) m/e 350.2054 (M + H+,
C18H28N3O4 requires 350.2079).
N-(Benzylcarbonyl)-N′-benzyl-N′′-(2,2-diphenylethyl)iminodiace-
tic Acid Diamide: 52 mg (88%); 1H NMR (CDCl3, 300 MHz) δ 9.38
and 9.00 (two t, total 1H), 7.32-7.18 (m, 20H), 6.42 and 5.98 (two t,
total 1H), 4.44-4.36 (m, 2H), 3.95-3.84 (m, 2H), 3.82 and 3.72 (two
s, total 2H), 3.62 and 3.55 (two s, total 2H), 3.20 (s, 2H), 3.16-3.11
(m, 2H); FABHRMS (NBA) m/e 520.2606 (M + H+, C33H34N3O3
requires 520.2600).
Table 1. HPLC Purity of 3 × 3 × 3 Library Intermediates and
Final Products
agent
purity (%)
agent
purity (%)
A1
A2
A3
A1B1
A1B2
A1B3
A2B1
A2B2
A2B3
A3B1
A3B2
A3B3
A1B1C1
A1B1C2
A1B1C3
A1B2C1
A1B2C2
A1B2C3
A1B3C1
A1B3C2
100
95.6
100
A1B3C3
A2B1C1
A2B1C2
A2B1C3
A2B2C1
A2B2C2
A2B2C3
A2B3C1
A2B3C2
A2B3C3
A3B1C1
A3B1C2
A3B1C3
A3B2C1
A3B2C2
A3B2C3
A3B3C1
A3B3C2
A3B3C3
95.6
100
90.1
95.2
93.6
nda
95.6
92.6
91.3
93.7
97.5
96.1
96.8
94.3
nda
96.7
90.7
96.1
91.4
100
95.6
94.8
96.5
97.5
100
N-Benzoyl-N′-benzyl-N′′-(2,2-diphenylethyl)iminodiacetic Acid
1
100
Diamide: 49 mg (86%); H NMR (CD3OD, 300 MHz) δ 9.00 (m,
nda
1H), 7.36-7.14 (m, 20H), 6.75 (m, 1H), 4.45 (br s, 2H), 4.05-3.83
(m, 4H), 3.30 (m, 2H); FABHRMS (NBA) m/e 506.2448 (M + H+,
C32H32N3O3 requires 506.2443).
97.5
94.0
91.3
96.2
93.5
95.3
90.6
91.2
92.9
N-(Ethylcarbonyl)-N′-benzyl-N′′-(2,2-diphenylethyl)iminodiace-
tic Acid Diamide: 45 mg (87%); 1H NMR (CDCl3, 300 MHz) δ 9.50
and 9.25 (two t, total 1H), 7.35-7.16 (m, 15H), 6.95 and 6.30 (two t,
total 1H), 4.46 (m, 2H), 4.36 and 4.15 (two t, J ) 8.4 Hz, total 1H),
3.94 and 3.82 (two s, total 2H), 3.75 and 3.68 (two s, total 2H), 3.15
(m, 2H), 2.20 (q, J ) 7.2 Hz, 2H), 1.02 and 0.87 (two t, J ) 7.2 Hz,
total 3H); FABHRMS (NBA) m/e 458.2439 (M + H+, C28H32N3O3
requires 458.2443).
a Not determined, no UV active chromophore.
N-(Benzylcarbonyl)-N′-(4-sec-butylphenyl)-N′′-cyclohexylimino-
diacetic Acid Diamide: 57 mg (99%); 1H NMR (CDCl3, 300 MHz) δ
9.38 and 8.50 (m, total 1H), 7.61 (d, J ) 8.5 Hz, 1H), 7.43 (d, J ) 8.5
Hz, 1H), 7.26-7.04 (m, 7H), 6.45 (m, 1H), 4.13 and 4.02 (two s, total
2H), 3.98 and 3.89 (two s, total 2H), 3.68 and 3.64 (two s, total 2H),
3.14 (m, 2H), 2.56 (m, 1H), 1.86-1.12 (m, 15H), 0.81 (t, J ) 7.2 Hz,
3H); FABHRMS (NBA) m/e 464.2893 (M + H+, C28H38N3O3 requires
464.2913).
N-Benzoyl-N′′-(4-sec-butylphenyl)-N′-cyclohexyliminodiacetic Acid
Diamide: 55 mg (98%); 1H NMR (CDCl3, 300 MHz) δ 9.78 and 8.00
(m, total 1H), 7.05-7.66 (m, 9H), 4.15 and 4.10 (two s, total 2H),
4.04 and 4.00 (two s, total 2H), 3.78 (m, 2H), 2.55 (m, 1H), 1.16-
1.81 (m, 14H), 0.81 (t, J ) 7.4 Hz, 3H); FABHRMS (NBA) m/e
450.2748 (M + H+, C27H36N3O3 requires 450.2756).
3.91 (two s, total 2H), 3.69 and 3.65 (two s, total 2H), 3.23 (m, 2H),
2.55 (m, 1H), 1.59-1.14 (m, 6H), 1.20 (t, J ) 6.9 Hz, 3H), 0.88 (d, J
) 7.2 Hz, 3H), 0.81 (t, J ) 7.2 Hz, 3H); FABHRMS (NBA) m/e
438.2762 (M + H+, C26H36N3O3 requires 438.2756).
N-Benzoyl-N′-(n-butyl)-N′′-(4-sec-butylphenyl)iminodiacetic Acid
Diamide: 30 mg (89%); 1H NMR (CDCl3, 300 MHz) δ 9.10 and 8.85
(two br s, total 1H), 7.70-7.12 (m, 9H),6.31 (m, 1H), 4.13-4.06 (m,
4H), 3.32 (m, 2H), 3.15-3.12 (m, 2H), 2.58 (m, 1H), 1.54 (m, 2H),
1.19 (m, 3H), 0.92 (t, J ) 7.0 Hz, 3H), 0.82 (t, J ) 7.2 Hz, 3H);
FABHRMS (NBA) m/e 424.2607 (M + H+, C25H34N3O3 requires
424.2600).
N-(Ethylcarbonyl)-N′-(n-butyl)-N′′-(4-sec-butylphenyl)iminodi-
1
acetic Acid Diamide: 30 mg (100%); H NMR (CDCl3, 300 MHz) δ
11.33 and 9.30 (two br s, total 1H), 8.78 and 6.63 (two br s, total 1H),
7.66, 7.46, 7.14, 7.07 (four d, J ) 8.2 Hz, total 4H), 4.15, 4.07 and
3.98 (three s, total 4H), 3.27 (m, 2H), 3.15 (m, 1H), 2.54 (m, 1H),
2.34 (m, 2H), 1.83 (m, 1H), 1.59-1.25 (m, 6H), 1.19 (t, J ) 7.2 Hz,
3H), 1.09 (t, J ) 7.7 Hz, 3H), 0.89 (m, 3H), 0.80 (m, 3H); FABHRMS
(NBA) m/e 376.2588 (M + H+, C21H34N3O3 requires 376.2600).
N-(Benzylcarbonyl)-N′-cyclohexyl-N′′-(3-methoxypropyl)imino-
diacetic Acid Diamide: 20 mg (60%); 1H NMR (CDCl3, 300 MHz) δ
8.93 and 6.12 (two d, total 1H), 8.82 and 6.60 (two t, total 1H), 7.30-
7.22 (m, 5H), 4.00 (s, 2H), 3.85 (s, 2H), 3.66 and 3.65 (two s, 2H),
3.48-3.38 (m, 2H), 3.32 (s, 3H), 3.16 (m, 1H), 1.86-1.10 (m, 10H);
FABHRMS (NBA) m/e 404.2550 (M + H+, C22H34N3O4 requires
404.2549).
N-Benzoyl-N′-cyclohexyl-N′′-(3-methoxypropyl)iminodiacetic Acid
Diamide: 14 mg (43%); 1H NMR (CDCl3, 300 MHz) δ 8.68 (m, 1H),
7.46-7.26 (m, 5H), 6.78 and 6.35 (two m, 1H), 3.98 (s, 2H), 3.95 (s,
2H), 3.52-3.34 (m, 2H), 3.33 (s, 3H), 3.14 (m, 1H), 1.90-1.10 (m,
12H); FABHRMS (NBA) m/e 390.2364 (M + H+, C21H32N3O4 requires
390.2392).
N-(Ethylcarbonyl)-N′′-(4-sec-butylphenyl)-N′-cyclohexyliminodi-
1
acetic Acid Diamide: 54 mg (99%); H NMR (CDCl3, 300 MHz) δ
11.30 and 9.56 (two br s, total 1H), 8.52 and 6.57 (two d, J ) 7.6 Hz,
total 1H), 7.65, 7.58, 7.13 and 7.07 (four d, J ) 8.5 Hz, total 4H),
4.15 and 4.07 (two s, total 2H), 4.06 and 3.96 (two s, total 2H), 2.55
(m, 1H), 2.33 (m, 1H), 1.90-1.14 (m, 17H), 1.09 (t, J ) 7.2 Hz, 3H),
0.80 (t, J ) 7.2 Hz, 3H); FABHRMS (NBA) m/e 402.2747 (M + H+,
C23H36N3O3 requires 402.2756).
N-(Benzylcarbonyl)-N′-benzyl-N′′-(4-sec-butylphenyl)iminodiace-
tic Acid Diamide: 50 mg (99%); 1H NMR (CDCl3, 300 MHz) δ 9.40
and 9.00 (two br s, total 1H), 7.58-7.04 (m, 14H), 4.38 and 4.36 (two
s, total 2H), 4.07 and 4.02 (two s, total 2H), 3.91 and 3.88 (two s, total
2H), 3.63 and 3.54 (two s, total 2H), 2.55 (m, 1H), 1.55 (m, 2H), 1.21
and 1.18 (two d, J ) 6.8 Hz, total 2H), 0.80 (t, J ) 7.1 Hz, 3H);
FABHRMS (NBA) m/e 472.2603 (M + H+, C29H34N3O3 requires
472.2600).
N-Benzoyl-N′-benzyl-N′′-(4-sec-butylphenyl)iminodiacetic Acid
Diamide: 47 mg (97%); 1H NMR (CDCl3, 300 MHz) δ 9.60 and 8.95
(two br s, total 1H), 8.70 (m, 1H), 7.44-7.12 (m, 14H), 4.48-4.10
(m, 4H), 3.59 (q, J ) 7.0 Hz, 2H), 1.58 (m, 2H), 1.19 (m, 3H), 0.80
(t, J ) 5.6 Hz, 3H); FABHRMS (NBA) m/e 458.2436 (M + H+,
C28H32N3O3 requires 458.2443).
N-(Ethylcarbonyl)-N′-benzyl-N′′-(4-sec-butylphenyl)iminodiace-
tic Acid Diamide: 41 mg (95%); 1H NMR (CDCl3, 300 MHz) δ 9.40
and 9.20 (two t, total 1H), 7.64, 7.42, 7.12, 7.05 (four d, J ) 8.5 Hz,
total 4H), 7.26 (br s, 5H), 4.46 (m, 2H), 4.09 and 4.05 (two s, total
2H), 4.03 and 3.98 (two s, total 2H), 1.20 (m, 3H), 1.07 and 1.01 (two
t, J ) 7.5 Hz, total 3H), 0.80 and 0.79 (two t, J ) 7.4 Hz, total 3H);
FABHRMS (NBA) m/e 410.2429 (M + H+, C24H32N3O3 requires
410.2443).
N-(Ethylcarbonyl)-N′-cyclohexyl-N′′-(3-methoxypropyl)iminodi-
1
acetic Acid Diamide: 6 mg (21%); H NMR (CDCl3, 300 MHz) δ
4.00 and 3.98 (two s, 2H), 3.87 (br s, 2H), 3.85-3.36 (m, 5H), 3.34
(s, 3H), 3.16 (m, 2H), 2.30 (q, J ) 7.2 Hz, 2H), 1.88-1.18 (m, 12H),
1.11 (t, J ) 7.2 Hz, 3H); FABHRMS (NBA) m/e 342.2407 (M + H+,
C17H32N3O4 requires 342.2392).
N-(Benzylcarbonyl)-N′-(n-butyl)-N′′-(2,2-diphenylethyl)iminodi-
1
acetic Acid Diamide: 38 mg (89%); H NMR (CDCl3, 300 MHz) δ
9.05 and 8.90 (two t, total 1H), 7.29-7.18 (m, 15H), 6.20 and 6.10
(two t, total 1H), 4.38 and 4.16 (two t, J ) 7.7 Hz, total 1H), 3.92 (br
s, 2H), 3.82 and 3.72 (two s, total 2H), 3.61 (s, 2H), 3.25-3.12 (m,
2H), 1.51-1.32 (m, 4H), 0.94 and 0.93 (two t, J ) 7.2 Hz, 3H);
FABHRMS (NBA) m/e 486.2765 (M + H+, C30H36N3O3 requires
486.2756).
N-(Benzylcarbonyl)-N′-(n-butyl)-N′′-(4-sec-butylphenyl)iminodi-
1
acetic Acid Diamide: 34 mg (98%); H NMR (CDCl3, 300 MHz) δ
9.14 and 8.57 (two t, total 1H), 7.61, 7.43, 7.10, 7.06 (four d, J ) 8.2
Hz, total 4H), 7.22 (m, 5H), 4.13 and 4.05 (two s, total 2H), 3.99 and
N-Benzoyl-N′-(n-butyl)-N′′-(2,2-diphenylethyl)iminodiacetic Acid
Diamide: 34 mg (80%); 1H NMR (CDCl3, 300 MHz) δ 9.05 and 8.50

Chemical Libraries Containing Small Organic Molecules
J. Am. Chem. Soc., Vol. 118, No. 11, 1996 2573
(two br s, total 1H), 7.37-7.14 (m, 15H), 6.50 and 6.30 (two br s,
total 1H), 4.44 and 4.22 (two t, J ) 7.7 Hz, total 1H), 3.97 (m, 2H),
3.87 and 3.83 (two s, total 2H), 3.30 (q, J ) 6.2 Hz, 2H), 1.53-1.35
(m, 4H), 0.94 (t, J ) 7.1 Hz, 3H): FABHRMS (NBA) m/e 472.2581
(M + H+, C29H34N3O3 requires 472.2600).
(two br s, total 1H), 7.46-7.38 (m, 5H), 6.72 and 6.52 (two br s, total
1H), 3.98 (s, 4H), 3.47-3.42 (m, 2H), 3.33 and 3.31 (two s, total 3H),
3.16 (m, 1H), 1.85-1.79 (m, 2H), 1.70 (br s, 2H), 1.60-1.25 (m, 6H),
0.94 (t, J ) 7.7 Hz, 3H); FABHRMS (NBA) m/e 364.2236 (M + H+,
C19H30N3O4 requires 364.2236).
N-(Ethylcarbonyl)-N′-(n-butyl)-N′′-(2,2-diphenylethyl)iminodi-
N-(Ethylcarbonyl)-N′-(n-butyl)-N′′-(3-methoxypropyl)iminodiace-
1
acetic Acid Diamide: 32 mg (86%); H NMR (CDCl3, 300 MHz) δ
1
tic Acid Diamide: 3 mg (16%); H NMR (CDCl3, 300 MHz) δ 4.00
9.21 and 9.00 (two t, total 1H), 7.33-7.16 (m, 10H), 6.18 and 6.12
(two t, total 1H), 4.38 and 4.19 (two t, J ) 7.7 Hz, total 1H), 3.91 and
3.84 (two s, total 2H), 3.76 and 3.65 (two s, total 2H), 3.27 (m, 2H),
3.15 (m, 1H), 2.26 (q, J ) 7.3 Hz, 2H), 1.87-1.81 (m, 4H), 1.56-
1.32 (m, 4H), 1.09 (t, J ) 7.3 Hz, 3H), 0.87 (t, J ) 7.3 Hz, 3H);
FABHRMS (NBA) m/e 424.2578 (M + H+, C25H34N3O3 requires
424.2600).
(br s, 2H), 3.87 (br s, 2H), 3.85-3.38 (m, 6H), 3.34 (s, 3H), 2.16 (q,
J ) 7.2 Hz, 2H), 1.70-1.23 (m, 6H), 1.12 (t, J ) 7.3 Hz, 1H), 0.91 (t,
J ) 6.6 Hz, 3H); FABHRMS (NBA) m/e 316.2245 (M + H+,
C15H30N3O4 requires 316.2236).
Supporting Information Available: 1H NMR spectra of
the 3 × 3 × 3 matrix library intermediates and final products
(38 pages). This material is contained in many libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, can be ordered from the ACS, can can
be downloaded from the Internet; see any current masthead page
for ordering information and Internet access instructions.
N-(Benzylcarbonyl)-N′-(n-butyl)-N′′-(3-methoxypropyl)iminodi-
1
acetic Acid Diamide: 15 mg (70%); H NMR (CDCl3, 300 MHz) δ
9.10 and 8.71 (two t, total 1H), 7.32-7.22 (m, 5H), 6.58 and 6.32
(two t, total 1H), 4.01 (s, 2H), 3.88 and 3.85 (two s, total 2H), 3.66 (s,
2H), 3.49-3.34 (m, 2H), 3.33 (s, 3H), 3.25-3.15 (m, 2H), 1.82-1.76
(m, 2H), 1.52-1.30 (m, 4H), 0.91 (t, J ) 7.0 Hz, 3H); FABHRMS
(NBA) m/e 378.2406 (M + H+, C20H31N3O4 requires 378.2392).
N-Benzoyl-N′-(n-butyl)-N′′-(3-methoxypropyl)iminodiacetic Acid
Diamide: 10 mg (49%); 1H NMR (CDCl3, 300 MHz) δ 8.95 and 8.50
JA9530681