The selective reaction of primary amines with carbonyl imidazole containing compounds: Selective amide and carbamate synthesis

Article abstract of DOI:10.1021/ol006020n

matrix presented A new highly selective synthesis of amides and carbamates is described. In both cases the syntheses involve the formation of carbonyl imidazole intermediates which subsequently undergo previously unreported selective reactions with primary amines. Acid imidazolides with sufficient chain length will exclusively react with primary amines even in the presence of secondary and tertiary functionality. The imidazole carboxylic esters of secondary or tertiary alcohols also react selectively with primary amines, forming controlled carbamate structures.

Full text of DOI:10.1021/ol006020n

ORGANIC
LETTERS
2
000
Vol. 2, No. 14
117-2120
The Selective Reaction of Primary
Amines with Carbonyl Imidazole
Containing Compounds: Selective
Amide and Carbamate Synthesis
2
,†
‡
Steve P. Rannard* and Nicola J. Davis
UnileVer Research Port Sunlight, Quarry Road East,
Bebington, Wirral L63 3JW, England
steVen.rannard@unileVer.com
Received May 5, 2000
ABSTRACT
A new highly selective synthesis of amides and carbamates is described. In both cases the syntheses involve the formation of carbonyl
imidazole intermediates which subsequently undergo previously unreported selective reactions with primary amines. Acid imidazolides with
sufficient chain length will exclusively react with primary amines even in the presence of secondary and tertiary functionality. The imidazole
carboxylic esters of secondary or tertiary alcohols also react selectively with primary amines, forming controlled carbamate structures.
Highly selective chemistry, capable of selecting between
primary and secondary functional groups on the same
molecule, has applications in a number of different synthetic
strategies to form controlled structures without lengthy
protection/deprotection steps. Recently we reported the use
of imidazole carboxylic esters in the controlled and selective
formation of dialkyl carbonates of polyols containing mix-
tures of primary, secondary and tertiary hydroxyls. The
selectivity was also used to controllably form cyclic carbon-
ates.
tertiary, further reaction to form carbonates is exclusively
limited to primary alcohols with no detectable reaction at
secondary or tertiary hydroxyl groups.
1
During our previous study the reactivity of these imida-
zole carboxylic esters with amines was also described briefly;
they were noted not to react with the secondary amine
functional group present in an amino-triol during a cyclic
carbonate synthesis.
1
CDI has also been used for many years to form amides
3
and peptides by reaction with aliphatic acids to form acid
The imidazole carboxylic esters were formed via the
reaction of 1,1′-carbonyl diimidazole (CDI) with different
imidazolides, analogues of acid chlorides, and subsequent
reaction with amines. The advantages of this method include
the mild reaction conditions which minimize racemization
2
alcohols. Our studies have shown that if the parent alcohol
of the imidazole carboxylic ester is either secondary or
4
of the amino acid, the lack of formation of amine hydro-
†
chloride when using acid chlorides, and the removal of
lengthy purification stages.
Work carried out at Courtaulds Corporate Technology, Coatings and
Sealants, Coventry, CV6 5RS, U.K.
‡
Current address: Dextra Laboratories Limited, The Innovation Centre,
The University, Reading, RG6 6BX, England. Fax: 0118 986 1894.
(1) Rannard, S.; Davis, N. Org. Lett. 1999, 1(6), 933
(3) Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 1, 351
(2) Rannard, S.; Davis, N. WO97/23443.
(4) Paul, R.; Anderson, G. W. J. Am. Chem. Soc. 1960, 82, 4596.
1
0.1021/ol006020n CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

Our studies of selective carbonate formation led us to
undertake a more detailed investigation of the possible
selectivity of imidazole carboxylic esters and acid imida-
zolides with primary and secondary amines during the
formation of carbamates and amides.
Table 1. Starting Materials and Carbonyl Imidazole
Intermediates
The amines chosen for the study are shown in Figure 1
Figure 1. Amines used in selective urethane and amide synthesis.
and include 1-hexylamine 1, dihexylamine 2, and diethylene
triamine 3.
The imidazole carboxylic esters 7a-9a which have been
shown to react selectively with primary alcohols were chosen
for investigation of carbamate synthesis. A series of aliphatic
and aromatic acids with varying structures, 10-14, were
chosen to investigate the selective synthesis of amides. The
alcohols, acids, and carbonyl imidazole intermediates are
shown in Table 1.
a
Synthesis details have been previously reported.1 Intermediates are
b
not isolated but synthesized and reacted in situ.
Each of the imidazole carboxylic esters 7a-9a was
synthesized as described previously1 and reacted with
5
primary amine 1 and secondary amine 2. Reaction with 1
intermediates with primary, secondary, and tertiary alcohols1
during carbonate formation.
successfully formed carbamate in all cases and in high yield.
Since 9a is the synthetic equivalent of tert-butyl chlorofor-
mate, the reaction of 1 with 9a forms the t-BOC protected
amine via a facile one-pot reaction avoiding the use of di-
To study the possible selectivity of carbamate formation,
a and 9a were reacted with the triamine 3, using an
equimolar ratio based on primary amine groups. Mass
spectrometry of the products after a simple aqueous wash
yielded molecular ions, confirming formation of only two
carbamate groups per triamine (MH [8a + 3] ) 444.69
and MH [9a + 3] ) 304.62), Scheme 1. No higher mass
8
6
tert-butyl dicarbonate (t-BOC anhydride). Reaction of 2 with
7
a-9a only formed carbamate when 7a was used. Unreacted
imidazole carboxylic ester was recovered when using 8a and
a with no detectable carbamate formation. The difference
+
9
+
between the reactions of 8a and 9a with primary and
secondary amines is identical to the reaction of these
(
5) Typical experimental procedure: The procedure for reacting
imidazole carboxylic esters with amines is exemplified by the reaction of
a with 3. Dry toluene (150 mL), 9 (40 mmol), KOH (1 mmol), and CDI
40 mmol) were added to a 250 mL round-bottom flask fitted with a dry
N2 inlet and magnetic stirrer and heated to 60 °C with stirring for 3 h. 3
20 mmol) was added dropwise. The solution was left to stir at 60 °C for
Scheme 1
9
(
(
a further 3 h. The clear mixture was left to cool. The reaction was
concentrated in vacuo, dissolved in CH2Cl2 (100 mL), and washed three
times with water (3 × 50 mL). The solution was dried with anhydrous
Na2SO4 and concentrated in vacuo to give a colorless gum. Yield ) 95.4%.
1
H NMR (CDCl3, 300 MHz) δ ) 1.45 ppm (s, (CH3)3), 2.75 (m, CH2-
13
NHCH2), 3.20 (m, O(CdO)NHCH2). C NMR (CDCl3, 75 MHz) δ ) 28.39
+
(
CH3)3, 48.60 (CH2NHCH2), 78.89 (CR4), 156.33 (NH(C ) O)O). m/z (Es )
+
3
04.60 (MH , 100%). 9a may also be synthesized and isolated in a separate
reaction if required.
6) Ponnusamy, E.; Fotador, U.; Spisni, A.; Fiat, D. Synthesis 1986, 48.
(
2118
Org. Lett., Vol. 2, No. 14, 2000

ions were detected. In both cases, formation of the carbamate
at the primary amine functional group only was confirmed
formation, 10-14 were converted to the corresponding acid
imidazolides 10a-14a and reacted further with the primary
amine 1 and secondary amine 2. The isolation of acid
imidazolides is not easy, as they are highly reactive and
moisture sensitive; therefore they are formed in situ and
reacted without purification. In all cases, the formation was
1
13
by H and C NMR due to the unchanged signals at δ )
.75 ppm (CH NHCH ) and δ ) 48.60 (CH NHCH ) and
2
2
2
2
2
the corresponding carbonyl at δ ) 156.50 ppm (NH(Cd
O)O).
As stated earlier, the reaction of amines with 9a yields a
t-BOC-protected amine. 9a, which therefore allows the
controlled introduction of amine protection at primary amine
groups in polyamines containing mixtures of differently
substituted amines.
monitored by CO
starting acid by TLC. It is also very important to purge the
system with dry N before addition of amine as the reaction
of amines with CO hampers the amide formation.
2
evolution and the dissappearance of the
2
2
In all cases, the acid imidazolides 10a-14a reacted with
to form amides in high yield. However, when the same
The versatility of the selective protection was studied
further by reacting 9a with 4 (three methylene groups
between amines) and 5 (containing primary, secondary, and
tertiary amines). In all cases the imidazole carboxylic ester
was added in a 1:1 ratio based on the primary amine
functionality. The introduction of the t-BOC group occurred
at the primary amine in each case without carbamate
formation at the secondary amine functional group (con-
7
1
reaction was attempted with 2, the formation of amide with
2a was not possible. Amide synthesis however with 2 was
1
successful with the other acid imidazolides, 10a, 11a, 13a,
and 14a.
In an attempt to favor amide formation between 12a and
2
, a series of different reaction conditions were applied
1
13
including changing solvents (CH Cl , THF, and toluene) and
firmed by H and C NMR). Mass spectrometry yielded the
expected molecular ions for selective and single carbamate
2
2
increasing temperature (rt to reflux). Amide formation was
not detected even when the reaction was conducted at reflux
temperature in toluene for 8 h.
+
+
formation (MH [9a + 4] ) 189.36 and MH [9a + 5] )
59.23). A summary of selective carbamate synthesis is
2
shown in Scheme 1.
Amide formation between 12a and 3 produced the selec-
tive amino diamide at room temperature via reaction at the
primary amine functionality only, Scheme 3. The successful
The success of the selective carbamate formation was
expected on the basis of a previous observation that 9a
formed carbonate only when reacted with an amino diol. The
reaction of acid imidazolides with amines was not investi-
gated previously, and there are no reports of selective amide
formation using this route.
Scheme 3
The formation of an acid imidazolide is a trivial process
and involves equimolar addition of CDI to a solution of acid
in an anhydrous solvent at room temperature or higher. The
addition of CDI is accompanied by instant effervescence as
3
CO
2
is liberated. The reaction is thought to proceed via an
intermediate imidazole anhydride which decomposes after
either an intra- or intermolecular nucleophilic attack by an
imidazole group, Scheme 2.
reaction was again analyzed using mass spectrometry, which
+
confirmed the addition of only two acids (MH 15 ) 300.66)
1
13
and H and C NMR which confirmed amide formation δ
177.05 ppm (NH(CdO)) and unchanged signals at δ )
.75 ppm (CH NHCH ) and δ ) 48.91 (CH NHCH ).
The selective amide synthesis was unexpected and ap-
)
2
2
2
2
2
Scheme 2
peared to be due to the increased steric hindrance of acid 12
and subsequently acid imidazolide 12a. To investigate the
amide synthesis further, amine 2 was reacted with succinic
(7) Typical experimental procedure: The synthesis of aliphatic and
aromatic amides is exemplified by the selective synthesis of 15. 12 (67.5
mmol) was added to a 100 mL round-bottom flask containing HPLC grade
toluene (50 mL) and fitted with a reflux condenser, a dry N2 inlet, and a
magnetic stirrer. The solution was heated to 60 °C and stirred. CDI (67.5
mmol) was added to the solution and stirred until the CO2 evolution had
ceased. The solution was heated for a further 30 min and purged with dry
nitrogen. 3 (33.5 mmol) was added to the solution and allowed to stir at 60
°
C for a further 2 h and then cooled to room temperature. The reaction
mixture was concentrated in vacuo, and the remaining clear liquid was
dissolved in CH2Cl2 and washed three times with water (3 × 10 mL). The
washed CH2Cl2 solution was dried with anhydrous Na2SO4, filtered, and
The synthesis of acid imidazolides proceeds smoothly for
both aromatic and aliphatic acids, and a number of differing
acid structures have been investigated in this study, 10-14.
In a study identical to that for the selective carbamate
1
concentrated to give the product as a clear liquid. Yield 92.7%. H NMR
(300 MHz; CDCl3) δ ) 0.85 (t, CH3CH2), 1.3-1.7 (m, CH2CH3), 1.95 (m,
CH), 2.75 (m, CH2NHCH2), 3.35 (m, CH2NHC(dO)). 13C NMR (75 MHz;
CDCl3) δ ) 12.23 (CH3CH2), 25.86 (CH2CH3), 48.91 (CH2NHCH2), 51.09
+
+
(CH), 177.05 (NH(CdO)). m/z (ES ) 300.66 (MH ).
Org. Lett., Vol. 2, No. 14, 2000
2119

acid with CDI and subsequently with 3 also gave selective
amide formation as shown by NMR and mass spectrometry
Scheme 4
+
(MH 16 ) 639.14), Scheme 4.
To ensure that the selectivity was not purely driven by
steric hindrance, a final reaction was conducted which
involved decreasing the size of the starting amine by
substituting dihexylamine, 2, with a much smaller amine,
dipropylamine. Succinic anhydride was replaced with dig-
lycolic anhydride in order to increase the distance between
the amide group and the acid functionality while introducing
a more flexible ether link, and diethylenetriamine, 3, was
replaced with bis-hexamethylene triamine, 6, to remove any
possible influence on reactivity due to the proximity of the
amines in the triamine.
The formation of amido acid 17 was confirmed by mass
-
spectrometry (MH 17 ) 216.40). Reaction of the acid with
CDI and subsequently with 6 yielded the selective diamide
+
as expected (MH 18 ) 614.67). The selectivity appears to
be derived from the presence of substituents γ to the
imidazolide carbonyl group. Selectivity also appears to be
limited to aliphatic acids although further work is required
to confirm this assumption. Although steric factors cannot
be ruled out, steric hindrance alone cannot explain the
selectivity of acid 12 and the subsequent selectivity of the
ring opened cyclic anhydrides, e.g., 17.
In summary, we have identified new selective chemistry
that allows the facile controlled formation of either carbam-
ates or amides selectively at the primary amine functionality
of polyamines containing mixtures of primary, secondary,
and tertiary amines. The selectivity of carbamate formation
appears to be determined by the structure of the parent
alcohol of the imidazole carboxylic ester used. Selective
amide formation is still somewhat confusing but may be
limited to the reaction of aliphatic acids containing substit-
uents γ to the acid imidazolide. Further work is required to
confirm the nature of the selectivity in this case.
Acknowledgment. The authors thank the members of the
Courtaulds Corporate Technology Analytical Group espe-
cially Tim Jenkins for mass spectrometry and Ian Herbert
and Christine Wallace for their help with NMR spectroscopy.
anhydride to form an amido acid which we believe to be
less sterically hindered than 12. The reaction of the amido
OL006020N
2120
Org. Lett., Vol. 2, No. 14, 2000