Achieving functional group diversity in parallel synthesis: solution-phase synthesis of a library of ureas, carbamates, thiocarbamates, and amides using carbamoylimidazolium salts

Article abstract of DOI:10.1016/j.tetlet.2008.06.096

A convenient protocol for the parallel solution-phase synthesis of a library of thiocarbamates, ureas, carbamates, and amides from carbamoylimidazolium salts has been developed. The crystalline carbamoylimidazolium salts are readily synthesized from secon

Full text of DOI:10.1016/j.tetlet.2008.06.096

Tetrahedron Letters 49 (2008) 5279–5282
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Achieving functional group diversity in parallel synthesis: solution-phase
synthesis of a library of ureas, carbamates, thiocarbamates, and amides
using carbamoylimidazolium salts
*
Justyna A. Grzyb, Robert A. Batey
Department of Chemistry, University of Toronto, 80, St. George Street, Toronto, Ontario, Canada M5S 3H6
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient protocol for the parallel solution-phase synthesis of a library of thiocarbamates, ureas,
carbamates, and amides from carbamoylimidazolium salts has been developed. The crystalline carba-
moylimidazolium salts are readily synthesized from secondary amines, CDI and iodomethane, and act
as stable carbamoylation reagents. A common set of reaction conditions and a straightforward non-chro-
matographic liquid–liquid extraction purification protocol were developed for reactions with thiols,
amines, phenols, and carboxylic acids, giving the products with high purities and yields. The resultant
library incorporates diversity arising from the choice of reaction partners and the functional group
linkage generated in the couplings.
Received 30 April 2008
Revised 17 June 2008
Accepted 22 June 2008
Available online 25 June 2008
Ó 2008 Published by Elsevier Ltd.
Generating structural diversity is one of the major concerns in
the design of small-molecule libraries.1 Most libraries are synthe-
sized using stepwise approaches in which the synthetic steps em-
ployed are usually, by necessity, common to all library members.
For example, a library constructed through the coupling of a set
of carboxylic acids and amines achieves diversity through the
choice of coupling partners, rather than the amide functionality
linking the two fragments, which is common to every library mem-
ber. Most libraries are synthesized by one or more of such pair-
wise fragment couplings,2,3 using common reaction steps, with
molecular diversity arising through the choice of building blocks
employed rather than the functionality linking the fragments.4 This
limitation can, in principle, be overcome by incorporating func-
tional group diversity as a design element in the library synthesis.5
For example, acylation reactions of amines, alcohols, thiols, and
enolate derivatives would lead to a library composed of amides, es-
ters, thioesters, and 1,3-dicarbonyl compounds (Fig. 1a). The chal-
lenge with such an approach, particularly when using semi- or
fully automated syntheses, is that it is often not possible to estab-
lish a common set of reaction and purification conditions suitable
for each functional group linker, by virtue of the different types of
coupling chemistry employed.6 Our goal was to establish whether
such an approach could be developed in the context of carbamoyl-
ation reactions using carbamoylimidazolium salts 3. We now re-
port the realization of this strategy using a parallel solution-
phase library synthesis of ureas, carbamates, thiocarbamates, and
a
O
O
O
O
2
2
2
R
R
R
1
1
1
1
R
O
R
R
N
O
3
R
1
R
X
O
2
S
R
R
b
O
O
O
1
3
3
1
3
R
R
R
R
R
R
N
S
N
N
2
2
4
O
R
R
R
1
R
N
R
X
O
2
1
1
R
3
N
R
O
N
R
2
2
R
Figure 1. Libraries incorporating diversity in the linker group derived through (a)
acylation or (b) carbamoylation.
amides (Fig. 1b), using a common set of reaction and purification
conditions.
Previous studies have established carbamoylimidazolium salts
3 as versatile N,N0-disubstituted carbamoyl cation equivalents7–10
that overcome many of the drawbacks associated with carbamoyl
chlorides,11 which are the most commonly used carbamoylating
* Corresponding author. Tel./fax: +1 416 978 5059.
E-mail address: rbatey@chem.utoronto.ca (R. A. Batey).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.06.096

5280
J. A. Grzyb, R. A. Batey / Tetrahedron Letters 49 (2008) 5279–5282
reagents. The salts 3 are in most cases readily synthesized, air-sta-
O
O
I
1
1
1
ble crystalline solids that can be stored for extended periods of
time at room temperature.7 Their application toward library syn-
thesis has been limited to a parallel synthesis of a library of tet-
ra-substituted ureas.7c However, they are known to react with
several classes of nucleophiles, including amines, alcohols, phe-
R
R
MeI
CDI, THF
reflux, o/n
R
N
R
N
NH
N
R
N
N Me
N
2
2
2
MeCN,
rt, 24 h
R
3
2
1
Scheme 1. Synthesis of carbamoylimidazolium salts 3.
Table 1
Parallel synthesis of a library of thioureas, ureas, carbamates, and amides from the reaction of carbamoylimidazolium salts 3 with thiols, amines, alcohols, and carboxylic acidsa
O
O
I
X = RS Nu = 4A-C
1
1
Nu (4), Et N
R
R
X = R N Nu = 4D-F
3
2
N
R
N
N
R
X
N Me
X = RO Nu = 4G-I
2
2
CH Cl , rt, 16h
2
2
X = R
Nu = 4J-L
3
5
Nucleophile (4)
O
O
O
I
I
O
I
I
N
N
N
N
N
N
N
N
N Me
N Me
N Me
N Me
O
O
3a
3c
3d
3b
O
Yieldb
94%
Purityc
Yieldb
98%
Purityc
94
Yieldb
87%
Purityc
Yieldb
95%
Purityc
SH
P95d
94
96
98
94
4A
SH
4B
99%
93
P99
P95d
P99
P95d
98
94%
93
P99
P95d
P99
P95d
P99
99
98%
Quant
Quant
83%
98%
Quant
98%
Br
SH
4C
Quant
Quant
86%
99%
P99
P95d
96
95
99
Quant
91%
NH
4D
N
NH
4E
Quant
Quant
99%
P99
95
NH
Quant
92%
97%
88%
P95d
P99
98
4F
OH
4G
Quant
Quant
Quant
Quant
95%
P99
98
O N
2
OH
98%
97
97%
4H
OH
93%
P99
P99
Quant
P99
99%
97
4I
O
88%
99%
P95%d
P95d
98%
P95d
P95d
Quant
99%
P95d
P95d
87%
89%
94
4J
OH
O
4K
Quant
P99
OH
O
92%
P99
98%
P99
Quant
92
Quant
99
4L
OH
a
3 (1.25 equiv), 4 (1.0 equiv) and NEt3 (1.0 equiv) were stirred for 16 h at room temp.
Isolated yields following aqueous work-up.
b
c
Purity determined by HPLC analysis (UV254, Hewlett–Packard series 1100MSD electrospray ionization mass spectrometer).
d
Purity determined by 1H NMR analysis.

J. A. Grzyb, R. A. Batey / Tetrahedron Letters 49 (2008) 5279–5282
5281
nols, thiols, and carboxylic acids.7–10 To achieve the goal of the cur-
rent study, a single set of reaction and purification conditions were
required for the reaction of 3 with different classes of nucleophiles,
using a parallel solution-phase synthesis approach. We were par-
ticularly interested in establishing a protocol that would not re-
quire the use of any type of chromatographic purification, but
which would give the products in high yield and purity.
Carbamoylimidazolium salts 3a–d were chosen as representa-
tive examples for the purpose of library synthesis, and were syn-
thesized using the previously reported protocol (Scheme 1). Thus,
refluxing the secondary amines 1 with N,N0-carbonyldiimidazole
(CDI) (1.1 equiv) in THF afforded carbamoylimidazoles 2, which
were isolated in excellent yields and purity after only an aqueous
work-up. Reaction of 2 with iodomethane (4.0 equiv) in acetoni-
trile at room temperature for 24 h gave the corresponding carba-
moylimidazolium salts 3a–d, which were isolated by simple
evaporation in vacuo of the volatile reagents and solvents.12 Fur-
ther purification of the salts was not necessary, although salts
3a–d can be recrystallized if required.
with carbamoylimidazolium salts using a common set of reaction
conditions and a straightforward liquid–liquid extraction purifica-
tion protocol. The strategy allows for diversification of the linking
functional group to be incorporated as a key element in the design
of a single library, using identical coupling conditions. It is antici-
pated that this approach will find utility for the synthesis of
other directed libraries. Further studies on the use of carbamoylim-
idazolium salts and related chemistry will be reported in due
course.
Acknowledgments
We thank Chemtura, the Natural Sciences and Engineering Re-
search Council (NSERC) of Canada, and the Environmental Science
and Technology Alliance of Canada for financial support. We thank
Dr. A. B. Young for MS analyses.
References and notes
1. For reviews, see: (a) Fergus, S.; Bender, A.; Spring, D. R. Curr. Opin. Chem. Biol.
2005, 9, 304–309; (b) Fitzgerald, S. H.; Sabat, M.; Geysen, H. M. J. Comb. Chem.
2007, 9, 724–734; (c) Martin, E. J.; Critchlow, R. E. J. Comb. Chem. 1999, 1, 32–
45; (d) Lee, M.-L.; Schneider, G. J. Comb. Chem. 2001, 3, 284–289.
2. The key coupling steps in which diversification is achieved often involve the
formation of one bond, as in the case of amide bond formation or metal
catalyzed cross-coupling reactions, but may involve multiple bond formations,
as in cycloaddition reactions, such as triazole formation via Huisgen 1,3-dipolar
cycloadditions, see: (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2001, 40, 2004–2021; (b) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H.
Eur. J. Org. Chem. 2006, 51–68; (c) Angell, Y. L.; Burgess, K. Chem. Soc. Rev. 2007,
36, 1674–1689.
O
O
I
I
N
N
N
N
N
N
N Me
N Me
O
3a
O
3b
I
O
I
N Me
N
N
O
N Me
3c
3d
O
3. Greater complexity is also available through the use of domino reactions,
‘diversity oriented synthesis’ (DOS) approaches, and through the use of
sequenced diversification reactions, such as for Houghten’s ‘libraries from
libraries’ approach. For reviews, see: (a) Domino Reactions in Organic Synthesis;
Tietze, L. F., Brasche, G., Gericke, K. M., Eds.; Wiley-VCH: Weinheim, 2005; (b)
Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. Engl. 2004, 43, 46–58; (c)
Nefzi, A.; Ostresh, J. M.; Yu, J.; Houghten, R. A. J. Org. Chem. 2004, 69, 3603–
3609.
4. Multi-component coupling reactions are also widely employed as complexity
generating reactions, see: Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.;
Wiley-VCH: Weinheim, 2006.
5. For a discussion of functional group diversification achieved through different
cleavage strategies of linker units in solid-supported synthesis, see: Scott, P. J.
H.; Steel, P. G. Eur. J. Org. Chem. 2006, 2251–2268.
With the imidazolium salts 3a–d in hand, we next set about
developing a common set of reaction conditions suitable for urea,
amide, carbamate, and thiocarbamate formation.
screening studies were run to establish the effect of solvents, base
additives, reaction time, and stoichiometry.7 Dichloromethane was
found to be an optimal solvent, and the use of triethylamine as a
base resulted in complete reaction conversion within 16 h at room
temperature. A small excess of the imidazolium salts 3 was re-
quired to push reactions to completion.
A series of
With optimized conditions established, a solution-phase paral-
lel synthesis of a small 48-member demonstration library of com-
pounds was completed using the coupling of 3a–d with 3 different
thiols, 3 amines, 3 phenols, and 3 carboxylic acids (Table 1). The
4 ꢀ 12 library comprised four different types of functional group
linkers; thiocarbamates from reaction with thiols, ureas from reac-
tion with amines, carbamates from reaction with phenols, and
amides from reaction with carboxylic acids. The library was syn-
thesized using a 12-tube Radleys carousel on a 0.4 mmol scale,
using a slight excess of the salts 3 (1.25 equiv) with triethylamine
(1.0 equiv).13,14 Since the by-products from the reactions as well as
the unreacted starting materials are water soluble, or could be
made water-soluble by an acid–base reaction, a liquid–liquid
extraction procedure using a sequential acidic (1 N HCl) and basic
wash (1 N NaOH) was used for product purification. The extrac-
tions were carried out using a reservoir (syringe barrel) containing
6. For example, in a recent library synthesis using a consecutive alkylation/Pd
catalyzed functionalization approach using parallel Suzuki-Miyaura,
Sonogashira, Stille and Heck reactions, the reaction conditions had to be
tuned appropriately for each reaction. See: Coelho, A.; Sotelo, E. J. Comb. Chem.
2005, 7, 526–529.
7. (a) Batey, R. A.; Santhakumar, V.; Yoshina-Ishii, C.; Taylor, S. D. Tetrahedron Lett.
1998, 39, 6267–6270; (b) Batey, R. A.; Yoshina-Ishii, C.; Taylor, S. D.;
Santhakumar, V. Tetrahedron Lett. 1999, 40, 2669–2672; (c) Batey, R. A.; Shen,
M.; Santhakumar, V.; Yoshina-Ishii, C. Comb. Chem. High Throughput Screening
2002, 5, 219–232; (d) Grzyb, J. A.; Batey, R. A. Tetrahedron Lett. 2003, 44, 7485–
7488; (e) Grzyb, J. A.; Shen, M.; Yoshina-Ishii, C.; Chi, W.; Brown, R. S.; Batey, R.
A. Tetrahedron 2005, 61, 7153–7175.
8. For selected recent applications of the use of carbamoylimidazolium salts, see:
(a) Clayden, J.; Turner, H.; Pickworth, M.; Adler, T. Org. Lett. 2005, 7, 3147–
3150; (b) Bridgeman, E.; Cavill, J. L.; Schofield, D. J.; Wilkins, D. S.; Tomkinson,
N. C. O. Tetrahedron Lett. 2005, 46, 8521–8524; (c) Williams, P. D.; Wai, J. S.;
Embrey, M. W.; Staas, D. D.; Zhuang, L.; Langford, H. M. Preparation of 2H-
Pyrazino[1,2-c]Pyrimidines as HIV Integrase Inhibitors, PCT Int. Appl., 2005, WO
2005092099 A1 20051006.; (d) Coleman, P. J.; Cox, C. D.; Garbaccio, R. M.;
Hartman, G. D. Preparation of Dihydropyrrolecarboxamides as Mitotic Kinesin
Inhibitors for Treating Cancer, PCT Int. Appl., 2005, WO 2005019206 A1
20050303; (e) Cumming, J. N.; Huang, Y.; Li, G.; Iserloh, U.; Stamford, A.;
Strickland, C.; Voigt, J. H.; Wu, Y.; Pan, J.; Guo, T.; Hobbs, D. W.; Le, T. X. H.;
Lowrie, J. F. Preparation of Cyclic Amine BACE-1 Inhibitors Having a Heterocyclic
Substituent, PCT Int. Appl., 2005, WO 2005014540 A1 20050217.; (f) Lau, J. F.;
Jeppesen, C. B.; Rimvall, K.; Hohlweg, R. Bioorg. Med. Chem. Lett. 2006, 16, 5303–
5308; (g) Jenkins, T. J.; Guan, B.; Dai, M.; Li, G.; Lightburn, T. E.; Huang, S.;
Freeze, B. S.; Burdi, D. F.; Jacutin-Porte, S.; Bennett, R.; Chen, W.; Minor, C.;
Ghosh, S.; Blackburn, C.; Gigstad, K. M.; Jones, M.; Kolbeck, R.; Yin, W.; Smith,
S.; Cardillo, D.; Ocain, T. D.; Harriman, G. C. J. Med. Chem. 2007, 50, 566–584; (h)
Edlin, C. D.; Holman, S.; Jones, P. S.; Keeling, S. E.; Lindvall, M. K.; Mitchell, C. J.;
Trivedi, N. Preparation of 1H-Pyrazolo[3,4-b]Pyridines as Phosphodiesterase,
Especially PDE4B, Inhibitors for Treatment of Inflammatory and/or Allergic
Diseases, PCT Int. Appl., 2007, WO 2007036733 A1 20070405; (i) Ebdrup, S.;
Refsgaard, H. H. F.; Fledelius, C.; Jacobsen, C. J. Med. Chem. 2007, 50, 5449–5456.
a hydrophobic membrane (two 20 lm polyethylene frits) that al-
lows only the passage of the denser organic phase (i.e., the dichlo-
romethane layer).15,16 After concentration in vacuo the products 5
could be obtained in excellent yields and purities. Purities were
determined by 1H NMR, and for those compounds possessing a
good chromophore by HPLC using a UV254 detector. In all cases
the purity as determined by NMR was P95%, and by HPLC was
P92%.
In conclusion, a solution-phase parallel synthesis of a small fo-
cused library of thioureas, ureas, carbamates, and amides has been
achieved through the coupling of different classes of nucleophiles

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J. A. Grzyb, R. A. Batey / Tetrahedron Letters 49 (2008) 5279–5282
9. For a review of azolides, including the application of CDI, see: Staab, K. M.;
Bauer, H.; Schneider, K. M. Azolides in Organic Synthesis and Biochemistry;
Wiley-VCH: Weinheim, 1998.
10. The salts 3 have also been used for solid-phase organic syntheses, see: Zheng,
C.; Combs, A. P. J. Comb. Chem. 2002, 4, 38–43.
11. Carbamoyl chlorides are in most cases not commercially available or have to be
prepared from amines and phosgene. Moreover, they are highly reactive, prone
to hydrolysis, and unstable, making them unsuitable for long-term storage, and
unattractive as combinatorial building blocks.
12. The salts 3 are much more reactive than 2 as carbamoyl transfer reagents. See
Refs. 7e and 9.
13. The library synthesis was carried out in a 12-position Radleys carousel station.
The imidazolium salts 3 (0.50 mmol, 1.25 equiv) were suspended in CH2Cl2
(4.0 mL). Nucleophile 4 (0.40 mmol, 1.0 equiv) and Et3N (0.40 mmol, 1.0 equiv)
were then added, and the reactions stirred at room temperature for 24 h. The
crude reaction mixtures were diluted with CH2Cl2 (15 mL) and 1 N HCl (10 mL),
shaken and poured into a 70 mL Bond Elute ReservoirÒ (Varian). The organic
layer was collected in a test tube, while the aqueous layer was left in the
reservoir. The organic layer was mixed with 1 N NaOH (5 mL) and poured again
through the Bond Elute ReservoirÒ
The products were obtained after
.
5
concentration in vacuo and were analyzed without further purification.
14. The Radleys carousel is a 12-position reactor that is capable of running 12
reactions in parallel. The system uses glass tubes with magnetic stirring,
heating/reflux, and inert atmosphere capabilities. See: Radleys Discovery
Technologies, Shire Hill, Saffron Walden, Essex, CB11 3AZ, United Kingdom
(http://www.radleys.com/).
15. Bond Elute ReservoirÒ tubes (polypropylene syringe barrel packed with
hydrophobic frits) are available from Varian Sample Preparation Products,
24201 Frampton Ave., Harbor City, CA 90710, Part No.: 1213–1018.
16. The Bond Elute ReservoirsÒ can be used for aqueous extractions only if the
organic phase (i.e., in this case dichloromethane) is denser than the aqueous
phase. The frit achieves
a gravity ‘filtration’ by allowing passage of the
dichloromethane layer, but preventing passage of the less dense aqueous layer
as a result of the hydrophobic frit. The Bond Elute ReservoirsÒ could be reused
by washing using acetone/water, followed by drying.