Acyl iodides in organic synthesis: VIII. Reactions with amino acids

Article abstract of DOI:10.1134/S1070428002120023

Reactions of acyl iodides RCOI (R=Me, Ph) with glycine, β-alanine, and γ-aminobutyric acid were investigated. The reaction proceeded easily at room temperature without solvent involving both functional groups H₂N and COOH. The prevalence of one of the reaction directions depends on the acidity of the amino acid. The more acidic glycine (pK_a, 2.4) reacts with RCOI affording mainly N-acylated product, whereas β-alanine (pK _a 3.60) and especially γ-aminobutyric acid (pK_a 4.06) are predominantly involved into exchange iodination furnishing the corresponding aminoacyl iodides. Pleiades Publishing, Inc. 2006.

Full text of DOI:10.1134/S1070428002120023

ISSN 1070-4280 Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 2, pp. 172-174. Ó Pleiades Publishing, Inc. 2006.
Original Russian Text Ó M.G. Voronkov, L.I. Belousova, A.A. Trukhina, N.L. Vlasova, 2006, published in Zhurnal Organicheskoi Khimii, 2006,
Vol. 42, no. 2, pp. 189-191.
Acyl Iodides in Organic Synthesis:
VIII. Reactions with Amino Acids
M.G. Voronkov, L.I. Belousova,A.A. Trukhina, and N.L. Vlasova
Favorskii Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences, Irkutsk, 664033 Russia
e-mail: voronkov@irioch.irk.ru
Received December 27, 2004
Abstract—Reactions of acyl iodides RCOI (R=Me, Ph) with glycine, b-alanine, and g-aminobutyric acid were investigated.
The reaction proceeded easily at room temperature without solvent involving both functional groups H2N and COOH.
The prevalence of one of the reaction directions depends on the acidity of the amino acid. The more acidic glycine
(pÊa 2.4) reacts with RCOI affording mainly N-acylated product, whereas b-alanine (pÊa 3.60) and especiallyg-aminobutyric
acid (pÊa 4.06) are predominantly involved into exchange iodination furnishing the corresponding aminoacyl iodides.
DOI: 10.1134/S1070428002120023
The formation of compoundsAand B occurred along the
equations:
We formerly established by examples of simple acyl
iodides reactions with alcohols [1, 2], acyclic and cyclic
ethers [3], esters [4] and vinyl alkyl ethers [5], and also
with carboxylic acids [6] that acyl iodides RCOI (R =
Me, Ph) are efficient iodinating, acylating, and deoxy-
genating agent. For instance, the reaction of acetyl iodide
with carboxylic acids occurred exclusively as an exchange
process resulting in the corresponding acyl iodides and
acetic acid [6]. Here we report on the study of acyl iodides
RCOI (R = Me, Ph) reactions with a-, b-, and g-amino
acids. The reaction of a-amino acids with acyl chlorides
C1CH2COC1, C13CCOC1, and PhCOCl at heating in
solution without bases proceeded with formation of the
corresponding N-acylated derivatives and with HCl
liberation. This process occurred easily only with a-amino
acids [7, 8]. The attempts to bring into this reaction, e.g.,
b-alanine and some other b-amino acids failed [8].
Unlike that the reactions we studied of acetyl iodide
with glycine (I), b-alanine (II), and g-aminobutyric acid
(III) occurred without solvent at room temperature
without HI liberation. The process with amino acids I
and II proceeded with heat evolution. In all cases the
products were crystalline compounds virtually insoluble
in organic solvents corresponding to an empirical formula
0H&2,ꢀꢀꢀ1+ ꢁ&+ ꢂ &22+
+ ꢁ&+ ꢂ &22+
0H&21
,
(1)
(2)
0H&2,ꢀꢀꢀ1+ ꢁ&+ ꢂ &22+
0H&22ꢀꢀꢀ1ꢀꢀ+ ꢁ&+ ꢂ &2,
%
At n = 1 prevailed reaction (1), at n = 2, reaction (2).
For instance, with glycine (I) the main component
of the product is aceturic acid hydroiodide
I - MeCON+ H 2C H2 COOH ( IVA ). Salt B,
MeCOO-N+H3CH2COI (IVB), formed in small amount.
In the IR spectrum of the crystalline compound IV
a strong absorption band at 1750 cm-1 is present cor-
responding to the CO group in the fragment C(=O)N+H2-
of salt IVA. The presence in the adduct IV of the salt
structure IVB is confirmed by the presence in the IR
spectrum of absorption bands at 1790 and 1640 cm-1,
characteristic of the stretching vibrations of a carbonyl
group in the acyl iodide moiety COI and carboxylate anion
COO- respectively. However these bands are very weak.
The product of b-alanine (II) reaction with acetyl
iodide V is also a mixture of two salts VA and VB with
the latter MeCOO- N+ H3 (CH2)2COI prevailing. In this
case dominated the exchange reaction between the amino
acid II and MeCOI (2).
C
3 + nH6 + 2nNO3I [ n = 1 (IV), 2 (V), 3 (VI)]. According
to the IR spectra the reaction products IV and V obtained
from amino acids I and II are mixtures of an N-acetyl
derivative hydroiodide I- MeCON+H2(CH2)nCOOH (A,
ï = 1, 2) and an acetate of the acyl iodide of the initial
amino acid MeCOO- N+ H3 (CH2)nCOI (B, n = 1, 2).
The only direction of reaction between the g-amino-
butyric acid (III) with acetyl iodid was the exchange
172

ACYL IODIDES IN ORGANIC SYNTHESIS: VIII.
173
iodination process affording the acetate of g-butyryl iodide
MeCOO- N+ H3 (CH2)3COI (VIB) (3).
However we failed to isolate from this adduct an
individual substance by procedures used with the amino
acids derivatives obtained by treating them with acetyl
iodide apparently because of higher strength of formed
salts owing to higher acidity of the benzoic acid compared
to that of the acetic acid (pÊa 4.19 and 4.75 respectively).
0H&2,ꢀꢀꢀ1+ ꢁ&+ ꢂ &22+
(3)
0H&22 1 + ꢁ&+ ꢂ &2,
%
Thus the reaction of amino acids with acyl iodides
involves both functional groups, H2N and COOH. The
prevailing direction of the reaction depends on the acidity
of the amino acid. With decreasing acidity the exchange
iodination process becomes more pronounced than
N-acyla-tion. For instance, when glycine (pÊa 2.4) treated
with acyl iodides mainly underwent N-acylation, for
b-alanine (pÊa 3.60), and especially for g-aminobutyric
acid (pÊa 4.06) the principal process was exchange
iodination. These results are well consistent with our
findings concerning reactions of acyl iodides with
carboxylic acids where the exchange iodination process
is the easier the weaker the acid [6].
Treating of the salt adducts IV-VI with acetone and
acetonitrile or subjecting salt VI to pyrolysis in xylene
gave rise in the case of salt IV aceturic acid
MeCONHCH2COOH (VII), and from salts V and VI
formed in hydroiodides of b-propiolactam (VIII) and g-
butyrolactam (IX) respectively originating from the
intramolecular cyclization of the the primarily formed
aminoacyl iodides (4).
0H&22 1 + ꢀ&+ ꢁ &2,
ꢂ;\OHQHꢂꢀꢃꢄꢅ ꢁꢆ
DFHWRQHꢆꢂDFHWRQLWULOHꢂꢀꢇꢈ &ꢁ
>1+ ꢀ&+ ꢁ &2,@
0H&22+
EXPERIMENTAL
&
2
Initial acyl iodides were prepared from appropriate
acyl chlorides by reaction with an anhydrous sodium
iodide by the known procedure [9]. IR spectra were
recorded on a spectrometer UR-20 from thin film or
solutions in acetonitrile or pyridine.
ꢀ&+ ꢁ
(4)
1+ꢂꢂ+,
In the IR spectra of compounds VIII and IX the
characteristic absorption bands of CO group in acyl
iodides at 1790 cm-1 are lacking, but appear strong
bands in the region 1730-1700 cm-1, characteristic of
stretching vibrations of a cabonyl in lactams. Besides
we succeeded in separation of pure b-propiolactam
(XI) by treating compound IX with potassium
carbonate (5).
Reaction of acetyl iodide with glycine. To 1.0 g
(0.005 mol) of acetyl iodide was added an equivalent
amount of glycine (0.4 g, 0.005 mol). The reaction mixture
self-heated. The mixture was maintained without addi-
tional heating for 4-5 h. We obtained 1.2 g (86%) of
crystalline compound with mp 75-76°C. IR spectrum, n,
cm-1: 3011-2923, 2653, 1976 (NH); 1790 (CO in COI),
1750 [CO in C(=O)N+H2-], 1640 [nas (COO-)], 1512
. &2
&
&
2
2
ꢁ&+ ꢂ
ꢁ&+ ꢂ
(5)
1+ꢀꢀ+,
1+
;,
[d(NH in RNH3 )], 1424 [ns (COO-)]. Found, %: C 19.42;
+
H 3.54; I 50.55; N 5.40. C4H8INO3. Calculated, %:
C 19.61; Ç 3.29; I 51.79; N 5.71.
The benzyl iodide reacted with amino acids similarly
to the acetyl iodide. Its reaction with b-alanine also
afforded a product of salt character corresponding to an
empirical formula C10H12NO3I and containing a mixture
of salts originating from N-acylationAand from iodination
B with considerable predominance of the latter (6).
Reaction of acetyl iodide with b-alanine. Under
similar conditions from 3.3 g (0.02 mol) of b-alanine and
1.7 g (0.02 mol) of acetyl iodide we obtained 4.8 g (96%)
of crystalline substance with mp 53-54°C. IR spectrum,
cm-1: 3136-2925, 2652-2545 (NH); 1750 [CO in
C(=O)N+H-], 1640 [nas (COO-)], 1540 [d(NH in
RNH3+)], 1387 [ns (COO-)], 540 (I in COI). Found, %:
C 24.52; H 4.36; I 48.83; N 5.26. C5H10INO3. Calculated,
%: C 23.18; H 3.89; I 48.99; N 5.41.
3K&2,ꢀꢀꢀꢁ1+ ꢂ&+ ꢃ &22+
, ꢀ3K&21 + ꢂ&+ ꢃ &22+
$
(6)
Reaction of acetyl iodide with g-aminoacetic acid.
Under similar conditions from 1.5 g (0.02 mol) of g-amino-
acetic acid and 2.5 g (0.02 mol) of acetyliodide we
3K&22 1 ꢀ+ ꢂ&+ ꢃ &2,
%
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 2 2006

VORONKOV et al.
174
obtained 3.5 g (89%) of crystalline substance with mp
112-113°C. IR spectrum, n, cm-1: 3000, 2600, 2000-1900
(NH in RNH3+), 1620 [nas (COO-)], 1500 [d(NH in
of g-butyrolactam hydroiodide, mp 90°C. Found, %:
C 22.73; H 4.03; I 58.39; N 6.68. C4H8INO3. Calculated,
%: C 22.55; H 3.79; I 59.58; N6.57.
RNH3 )], 1400 [ns (COO-)]. Found, %: C 26.86; H 4.48;
+
b. With 10 ml of anhydrous acetonitrile was mixed 2 g
of the product obtained from g-aminobutyric acid and
acetyl iodide. The mixture was stirred for 1 h at room
temperature, the precipitate was filtered off and kept at
reduced pressure. We obtained 1.4 g (87%) of g-butyro-
lactam hydroiodide with mp 90°C. IR spectrum, n, cm-1:
3400 (NH), 1710 (CO), 1630 [d(NH)], 1210 (CN). Found,
%: I 61.03; N 6.86. C4H8INO3. Calculated, %: I 59.58;
N 6.57.
I 46.03; N 4.45. C6H12INO3. Calculated, %: C 26.39;
H 4.43; I 46.47; N 5.13.
Reaction of benzoyl iodide with b-alanine. To
2.5 g (0.007 mol) of benzoyl iodide was added 0.6 g
(0.007 mol) of b-alanine. The mixture self-heated and
then was maintained at room temperature for 4 h. We
obtained 2.0 g (93%) of crystalline compound with mp
126-128°C. IR spectrum, n, cm-1 : 3000, 2590, 1990 (NH
+
in RNH3 ), 1750 [CO in C(=O)N+H-], 1625 [nas
Preparation of b-propiolactam. To 0.5 g of b-pro-
piolactam hydroiodide was added 5 ml of 10% solution
of Ê2CO3. On completion of the gas liberation the solution
was extracted with ether. On evaporating the ether from
the extract we obtained 0.1 g of b-propiolactam with
a melting point consistent with the published data [10].
(COO-)], 1580 [d(NH in RNH3+)], 1390 [ns (COO-)].
Found, %: C 36.95; H 3.67; I 40.92; N 3.88. C10H12INO3.
Calculated, %: C 37.40; H 3.76; I 39.52; N 3.46.
Preparation of aceturic acid. With 10 ml of
anhydrous acetone was mixed 2 g of the crystalline
product obtained from glycine and acetyl iodide. The
mixture was stirred without heating for 1 h, the precipitate
was filtered off and kept at reduced pressure to remove
the residual acetone. We obtained 0.7 g (75%) of aceturic
acid with the melting point in agreement with the
published data [10]. IR spectrum, n, cm-1: 3350 (NH in
-CONH-), 3300-2500 (OH in -COOH), 1710 (CO in
-COOH), 1600 (I amide band), 1540 (II amide band).
Found, %: C 40.59; H 6.02; N 12.11. C4H7NO3.
Calculated, %: C 41.03; Ç 6.03; N 11.95.
The authors are grateful to Dr. Chem. Sci. G.I. Sara-
pulova for the help in the spectral studies.
The study was carried out under the financial support
of the Council on Grants of the President of the Russian
Federation (grant NSh-1129.2003.3).
REFERENCES
1. Voronkov, M.G., Trukhina, A.A., and Vlasova, N.N., Zh.
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Preparation ofbb-propiolactam hydroiodide. With
10 ml of anhydrous acetonitrile was mixed 2.5 g of the
crystalline product obtained from b-alanine and acetyl
iodide. The mixture was stirred for 1 h at room tempera-
ture, the precipitate was filtered off and kept at reduced
pressure. We obtained 1.3 g (73%) of b-propiolactam
hydroiodide, mp 70°C. IR spectrum, n, cm-1: 3200 (NH),
1720 (CO), 1650 [d(NH)], 1220 (CN). Found, %:
C 18.31; H 3.98; I 58.58; N 6.76. C3H6INO3. Calculated,
%: C 18.11; H 3.04; I 63.78; N 7.04.
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Org. Khim., 2004, vol. 40, p. 498.
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p. 1007.
Preparation of g-butyrolactam hydroiodide. a. In
anhydrous xylene was boiled for 4 h 2.9 g of the product
obtained from g-aminobutyric acid and acetyl iodide. Then
the precipitate was filtered off . We obtained 2.1 g (93%)
10. Spravochnik khimika (Handbook of Chemist), Nikol’skii, B.P.,
Ed., Moscow: Khimiya, 1963, vol. 2, p. 398.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 2 2006