Phenyl esters, preferred reagents for mono-acylation of polyamines in the presence of water

Article abstract of DOI:10.1016/j.tetlet.2009.07.142

In the presence of water, several diamines and one triamine were mono-acylated at ambient to moderate temperatures using phenyl esters and a phenyl carbonate as acylation agents in good to excellent isolated yields. Both linear and cyclic polyamines were suitable substrates, and the acylating agents can be aryl and alkyl carboxylic acid esters.

Full text of DOI:10.1016/j.tetlet.2009.07.142

Tetrahedron Letters 50 (2009) 5741–5743
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Phenyl esters, preferred reagents for mono-acylation of polyamines
in the presence of water
*
Kyrie Pappas, Xiang Zhang, Wei Tang, Shiyue Fang
Department of Chemistry, Michigan Technological University, 1400 Townsend Drive, Houghton, MI 49931, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of water, several diamines and one triamine were mono-acylated at ambient to moderate
temperatures using phenyl esters and a phenyl carbonate as acylation agents in good to excellent isolated
yields. Both linear and cyclic polyamines were suitable substrates, and the acylating agents can be aryl
and alkyl carboxylic acid esters.
Received 10 July 2009
Revised 18 July 2009
Accepted 28 July 2009
Available online 3 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Mono-acylation
Diamine
Water
Phenyl ester
Piperazine
The formation of an amide bond between an amine and a car-
boxylic acid derivative is one of the most studied reactions in or-
ganic chemistry. However, the selective acylation of one amino
group in the presence of others in a polyamine remains difficult.1
Statistically, with equal moles of diamine and acylating agent, it
is possible to obtain the desired mono-acylated product in 50%
yield, which is acceptable in most cases.2 Unfortunately, these
statistically predicted results are not easy to be achieved. For exam-
ple, when a polyamine such as 1,4-diaminobutane, 2,20-(ethylene-
dioxy)bis(ethylamine), piperazine, 1,2-cyclohexane diamine, or
diethylenetriamine is reacted in organic solvents with a carboxylic
acid anhydride or chloride, even with more than 1 equiv polyamine,
di-acylated product is formed predominantly or exclusively. Sayre
and co-workers attributed this phenomenon to the inefficient
mixing of reactants during the addition of acylating agent to the
diamine.2 More specifically, when a drop of acylating agent contacts
the solution of the diamine, the acylation reaction is so fast that
before additional diamines reach the reaction site, the mono-acyl-
ated products continue to react with the locally excess acylating
agent, and therefore di-acylated product predominates. This
hypothesis is supported by the fact that the yields of mono-acyla-
tion products can be increased by using the less reactive acid anhy-
drides as opposed to acid chlorides under high dilution conditions
at low temperature in the presence of excess diamine. Under these
conditions, mono-acylation of 1,2-ethanediamine and 1,4-butane-
diamine could be achieved in close to or slightly higher than statis-
tical yields.2 Later, many other research groups continued to
approach the problem with the goal of developing more practically
useful methods as well as to extend the scope of diamines to cyclic
ones and ones that have longer spacer between the two amino
groups.1 For example, Wang’s group treated diamines with 2 equiv
BuLi and reacted the resulting di-anions with 1 equiv acylating
agents to give mono-acylated products.3 The same group also
achieved mono-acylation using 9-BBN to protect one of the two
amino groups followed by acylation.4 Christensen’s group used al-
kyl phenyl carbonates for selective acylation of polyamines.5 Other
reported methods include performing the reaction under acidic
conditions,6 using metal cations to protect one of the two amino
groups and using special acylating agents.1 Simple mix and react
procedures were available for mono-acylation of diamines with
short spacer between the two amino groups such as piperazine
and ethylenediamine.7 Unfortunately, the methods were not appli-
cable to diamines with long spacers due to the similarity of the two
pKas of the diamines and limited reduction of the reactivity of the
second amino group upon acylation of the first amino group.2 The
protocol developed by Krapcho and Kuell for selective protection
of some diamines using Boc2O under high dilution and slow addi-
tion conditions in 1,4-dioxane is quite simple to follow and good
yields of desired product can be obtained.8 More recently, Pringle
reported a new mono-acylation method using ionic immobilization
of diamines to sulfonic acid-functionalized silica gel. The method
worked well for mono-acylation of piperazine and homopiperazine,
but failed to give useful yields for other polyamines.9
* Corresponding author. Tel.: +1 906 487 2023; fax: +1 906 487 2061.
E-mail address: shifang@mtu.edu (S. Fang).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.142

5742
K. Pappas et al. / Tetrahedron Letters 50 (2009) 5741–5743
We recently found that diamines could be mono-acylated with
taining the mono-acylated products were combined. Evaporating
of solvents under reduced pressure gave pure products. In some
cases, the products contained small amount of phenol. This was re-
moved by partition between methylene chloride and 10% NaOH
followed by drying with Na2SO4 and evaporating the solvent.
The procedure worked well on linear diamines, a triamine and
the cyclic diamine piperazine. The results are summarized in Table
1.12 The reaction was first tested on 1,4-butanediamine (1) using
phenyl acetate (2) as the acylating agent. Using the general proce-
dure described above, at 50 °C the desired mono-acylated product
3 was obtained in 56% isolate yield (entry 1). Although the yield
was only slightly higher than the statistically predicted 50%, the re-
sult was significant because the procedure was simple and no ex-
cess diamine was needed. The reaction could also be carried out at
room temperature but the rate was low. Because 4-nitrophenoxide
is a better leaving group than phenoxide, we also tested using
4-nitrophenyl acetate (4) as the acylating agent (entry 2). However,
lower yield was obtained (22%). One reason might be the hydroly-
sis of 4 before its reaction with the diamine, but we believe that the
solid nature of 4 (melting point 75 °C) and its low solubility in the
mixture might play a more important role. From this observation,
we used phenyl esters in our next studies. The reaction between 1
and phenyl benzoate (5) also proceeded smoothly at 50 °C. The
mono-acylated product 6 was obtained in 63% isolated yield (entry
3). It was reported that diamines with longer spacer between the
two amino groups are more difficult for mono-acylation.2
However, under our conditions, 1,8-octanediamine (7) was
mono-acylated with equal efficiency to give product 8 in 62% yield
(entry 4). Under similar conditions, the more hydrophilic 2,20-(eth-
ylenedioxy)bis(ethylamine) (9), which also contains a long spacer
between the two amino groups, was mono-acylated with 2 and 5
to give products 10 and 11, respectively, in acceptable yields (en-
tries 5 and 6). A triamine was also tested for the reaction. At room
temperature using the general procedure, 12 was acylated to give
13 in 56% isolated yield (entry 7). The cyclic diamine piperazine
(14), which was recently mono-acylated with the more expensive
ionic immobilization approach,9 was also shown to be a good
substrate for our simple and inexpensive procedure. By simply
mixing 14 with 2 and suitable amount of water, the mono-acylated
product 15 was obtained in 39% yield at room temperature and in
69% yield at 55 °C (entries 8 and 9). It should be pointed out that
there was an excellent procedure for mono-acylation of piperazine,
in which the substrate was treated with 2 equiv of BuLi and the
lactones, alkyl esters, and phenyl and allyl carbonates in good to
quantitative yields in the presence of suitable amount of water.10,11
We hypothesized that the disruption of the hydrogen bonds be-
tween diamines by water along with other factors might be
responsible for the good selectivity of mono-acylation.10 The meth-
od has the following advantages. (a) No organic solvent is used. (b)
The acylating agents are stable, inexpensive, and readily available.
(c) Only 1 equiv diamine is required. (d) There is no need to use
high dilution and slow addition techniques, which is particularly
significant for large-scale synthesis. However, the method has
one drawback. In some cases, to drive the reaction to completion,
the reaction mixture must be heated to high temperature (more
than 100 °C).10 In order to lower the temperature, we recently
tested using phenyl esters as the acylating agent for the reaction.
We found that the reaction could proceed with useful rates at
50 °C and give mono-acylated products in good to excellent yields.
In this Letter, we report our results on this study.
In
a typical experimental procedure, 20 mmol polyamine,
20 mmol acylating agent, and 1 mL water were combined in a
round-bottomed flask. The mixture was stirred under a moderate
nitrogen flow for about 30 min. After stopping the nitrogen flow,
the reaction was continued for 24 h either at room temperature
or at other temperatures as indicated in Table 1. A small portion
of the mixture was then taken out and dissolved in methanol for
TLC analysis. We found that the solvent system MeOH/MeCN/
Et3N/Et2O (2:2:1:5) was excellent for separation of the mono-acyl-
ated products from the remaining polyamines on silica gel, which
could be easily visualized by staining with a ninhydrin solution
(ninhydrin 4.5 g, BuOH 300 mL, AcOH 9 mL) followed by gentle
heating with a heat gun. Under these conditions, the desired
mono-acylated products have an Rf between 0.2 and 0.6 and the
polyamines remained at the origin. In some cases, the blue color
of the mono-acylated product was significantly lighter than that
of the unreacted polyamine; this did not mean that the yield was
low. The reaction mixture was dissolved in the same solvents
and loaded on a flash chromatography silica gel column, which
was packed with the same solvent system. Alternatively, the mix-
ture was first concentrated under reduced pressure and then
loaded onto column in the same manner. If the mixture did not dis-
solve well in the solvent system, it was dissolved in methanol and
applied on a small amount of silica gel in a Petri dish. After air dry-
ing, the silica gel was loaded onto the column. The fractions con-
Table 1
Mono-acylation of polyamines using phenyl esters and a phenyl carbonate in watera
Entry
Amine
Acylating agent
Product
Temperature
Yieldb (%)
Ref.
2
1
2
3
4
5
6
7
H2N(CH2)4NH2 (1)
1
1
H2N(CH2)8NH2 (7)
[H2N(CH2)2OCH2]2 (9)
9
PhOAc (2)
4-NO2-PhOAc (4)
PhCO2Ph (5)
2
2
5
2
H2N(CH2)4NHAc (3)
3
H2N(CH2)4NHBz (6)
H2N(CH2)8NHAc (8)
H2NCH2(CH2OCH2)2CH2NHAc (10)
H2NCH2(CH2OCH2)2CH2NHBz (11)
H2N(CH2)2NH(CH2)2NHAc (13)
50 °C
50 °C
50 °C
50 °C
rt
56
22
63
62
42
33
56
4
10
10
13
14
50 °C
rt
[H2N(CH2)2]2NH (12)
HN
15
NAc
8
9
2
rt
39
69
68
15
(14)
NH
HN
(15)
14
2
55 °C
rt
10
14
PhOBoc (16)
9
HN
NBoc (17)
11
12
14
14
16
16
17
17
55 °C
Reflux
87
71
a
Reaction conditions: amine (20 mmol), acylating agent (20 mmol), water (1 ml), 24 h.
Isolated yields.
b

K. Pappas et al. / Tetrahedron Letters 50 (2009) 5741–5743
5743
2. Jacobson, A. R.; Makris, A. N.; Sayre, L. M. J. Org. Chem. 1987, 52, 2592.
3. Wang, T.; Zhang, Z. X.; Meanwell, N. A. J. Org. Chem. 1999, 64, 7661.
4. Zhang, Z. X.; Yin, Z. W.; Meanwell, N. A.; Kadow, J. F.; Wang, T. Org. Lett. 2003, 5,
3399.
5. Pittelkow, M.; Lewinsky, R.; Christensen, J. B. Synthesis-Stuttgart 2002, 2195.
6. Lee, D. W.; Ha, H.-J.; Koo, L. W. Synth. Commun. 2007, 37, 737.
7. (a) Hall, H. K. J. Am. Chem. Soc. 1956, 78, 2570; (b) Hill, A. J.; Aspinall, S. R. J. Am.
Chem. Soc. 1939, 61, 822.
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Bergstrom, D. E. Tetrahedron Lett. 2004, 45, 8501.
resulting dianion was then acylated with 1 equiv acylating agent.
Excellent yields were obtained.3 However, this method was only
demonstrated for mono-benzoylation. Obviously, when acylating
agents that contain acidic protons such as acetic anhydride are
used, side reactions will occur. This problem does not exist while
using our method. Finally, we tested the mono-Boc protection of
14. Using 16 as the acylating agent, compound 17 was obtained
in 68% yield at room temperature, 87% yield at 55 °C, and 71% yield
at reflux temperature (entries 10–12).
9. Pringle, W. Tetrahedron Lett. 2008, 49, 5047.
10. Tang, W.; Fang, S. Tetrahedron Lett. 2008, 49, 6003.
11. In our previous work,10 only linear diamines were used as substrates. We
recently found that the method was also useful for mono-acylation of cyclic
diamines using the same procedure. For example, piperazine was mono-
acylated with diallyl carbonate at rt to give piperazine-1-carboxylic acid allyl
ester16 in 59% yield. The racemic trans-1,2-cyclohexanediamine was mono-
acylated with the same reagent at 55 °C to give trans-1-(N-allyloxycarbonyl)-
cyclohexane-1,2-diamine (18) in 63% yield. Compound 18 (racemic): 1H NMR
(400 MHz, CDCl3) d 5.83–5.73 (m, 1H), 5.40 (br d, 1H, J = 8.4 Hz), 5.15 (dt, 1H,
J = 17.2, 0.4 Hz), 5.05 (d, 1H, J = 10.4 Hz), 4.41 (d, 2H, J = 5.2 Hz), 3.10–2.98 (m,
1H), 2.31–2.25 (m, 1H), 1.86–1.79 (m, 2H), 1.68 (br s, 2H), 1.58–1.55 (m, 2H),
1.18–0.97 (m, 4H); 13C NMR (100 MHz, CDCl3) d 156.2, 132.8, 117.2, 65.1, 57.7,
54.9, 34.7, 32.4, 24.8, 24.7; HRMS (ESI) m/z [M+H]+ calcd for C10H19N2O2:
199.1447, found 199.1445.
In summary, using water as the reaction medium and phenyl
esters and carbonates as acylating agents, we were able to mono-
acylate linear and cyclic polyamines at room temperature or mod-
erate temperature in good to excellent isolated yields. The proce-
dure is simple and environmentally benign, the starting materials
are commercially available and inexpensive, and the substrate
scope is broader than that of reported methods.3,9 We expect that
the method will become a favorite choice for organic and medicinal
chemists and other scientists to prepare mono-acylated diamines.
12. All products are known, references are given in Table 1.
13. Min, J.; Kim, Y. K.; Cipriani, P. G.; Kang, M.; Khersonsky, S. M.; Walsh, D. P.; Lee,
J.-Y.; Niessen, S.; Yates, J. R.; Gunsalus, K.; Piano, F.; Chang, Y.-T. Nat. Chem. Biol.
2007, 3, 55.
14. Kuswikrabiega, G.; Bruenger, F. W.; Miller, S. C. Synth. Commun. 1992, 22, 1307.
15. Ferroud, C.; Godart, M.; Ung, S.; Borderies, H.; Guy, A. Tetrahedron Lett. 2008,
49, 3004.
16. Sutton, J. C.; Bolton, S. A.; Davis, M. E.; Hartl, K. S.; Jacobson, B.; Mathur, A.;
Ogletree, M. L.; Slusarchyk, W. A.; Zahler, R.; Seiler, S. M.; Bisacchi, G. S. Bioorg.
Med. Chem. Lett. 2004, 14, 2233.
Acknowledgments
Financial supports from US NSF (CHE-0647129), Michigan Uni-
versities Commercialization Initiative Challenge Fund, and MTU
SURF (K.P. and W.T.); the assistance from Mr. Jerry Lutz (NMR),
Mr. Shane Crist (computation), and Mr. Dean Seppala (electronics);
and an NSF equipment grant (CHE-9512445) are all gratefully
acknowledged.
References and notes
1. Bender, J. A.; Meanwell, N. A.; Wang, T. Tetrahedron 2002, 58, 3111.