Synthesis of diverse phenylglycine derivatives via transformation of Ugi four-component condensation primary adducts

Article abstract of DOI:10.1016/j.tetlet.2011.03.074

3-(N-Substituted)amino-4-arylamino-1H-isochromenones (isocoumarins) which can be regarded as the enediamine tautomers of the Ugi four-component condensation primary adducts between 2-formylbenzoic acids, arylamines, and isocyanides undergo a facile ring c

Full text of DOI:10.1016/j.tetlet.2011.03.074

Tetrahedron Letters 52 (2011) 2673–2675
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Tetrahedron Letters
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Synthesis of diverse phenylglycine derivatives via transformation of Ugi
four-component condensation primary adducts
⇑
Stefano Marcaccini, Gloria Menchi , Andrea Trabocchi
Dipartimento di Chimica ‘Ugo Schiff’, Università di Firenze, Via Della Lastruccia 13, I-50019 Sesto Fiorentino (FI), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
3-(N-Substituted)amino-4-arylamino-1H-isochromenones (isocoumarins) which can be regarded as the
enediamine tautomers of the Ugi four-component condensation primary adducts between 2-formylben-
zoic acids, arylamines, and isocyanides undergo a facile ring cleavage with amines to give a series of
phenylglycine derivatives. Thus, a synthetically useful post-condensation transformation of Ugi four-
component condensation primary adducts is described for the first time.
Received 29 December 2010
Revised 9 March 2011
Accepted 15 March 2011
Available online 22 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Amides
Amino acids
Cleavage reactions
Multicomponent reactions
Ugi four-component condensation
(Ugi-4CC)
The Ugi four-component condensation (Ugi-4CC) between car-
bonyl compounds, amines, carboxylic acids, and isocyanides af-
substituted)amino-4-arylamino-1H-isochromenones (isocouma-
rins) 1, by reacting 2-formylbenzoic acid (2), anilines 3, and
isocyanides 46 (Scheme 2).
fords
a-acylamino amides via rearrangement of the initially
formed primary adducts1,2 (Scheme 1).
The presence of a cyclic enol ester moiety in the isochromenon-
es 1 prompted us to attempt the ring cleavage of these compounds
with a series of amines 5. Because of the inherent instability of iso-
chromenones 1 in solution6 we performed the reactions in solvent-
less conditions by employing an excess of the amine. The reaction
took place smoothly at room temperature to afford the desired
pure phenylglycine derivatives 6 in almost quantitative yields after
removal of the unreacted amine. The low boiling point isobutyl-
amine was easily removed by evaporation under diminished pres-
sure, whereas high boiling point amines were removed upon
Because of elusive nature of the Ugi-4CC primary adducts, until
recently only two examples of the successful isolation of these
products were reported.3
An examination of the literature showed that the Ugi-4CC
accompanied by post-condensation transformations (spontaneous
or upon addition of suitable reagents) is a powerful synthetic tool
for the preparation of a plethora of very interesting compounds
which appear to be not easily obtainable by other synthetic
routes.4
The general unavailability of the Ugi-4CC primary adducts has
prevented their use as starting materials for further transforma-
tions.5 In a very recent Letter, we reported a general method that
allowed the preparation of Ugi primary adducts, namely 3-(N-
NHAr
CHO
CO2H
Ar NH2
NHR
2
O
MeOH, b. p.
45 min, ref. 6
40 °C
+
3a-e
4a,b
O
O
R3
N
H
N
+ R NC
R1
R2
1a-e
R4
R1
R2
R3
R3 NH2
R1
R2
1
a
b
c
d
e
Ar
R
3
Ar
4
a
R
O
O
O
N
R5
NH
4-ClC6H4
4-FC6H4
C6H5
c-C6H11
4-CH3C6H4
c-C6H11
c-C6H11
c-C6H11
a
b
c
d
e
4-ClC6H4
4-FC6H4
C6H5
c-C6H11
R4
R4 CO2H R5 NC
R5
O
b
4-CH3C6H4
Scheme 1. The Ugi four-component condensation (Ugi-4CC).
4-CH3C6H4
3-ClC6H4
4-CH3C6H4
3-ClC6H4
⇑
Corresponding author. Tel.: +39 055 4573506; fax: +39 055 4573531.
E-mail address: gloria.menchi@unifi.it (G. Menchi).
Scheme 2. Synthesis of isochromenones 1a–e.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.074

2674
S. Marcaccini et al. / Tetrahedron Letters 52 (2011) 2673–2675
NHAr
O
sponding primary adduct 9b which was reacted, without previous
NHAr
CONHR
NHR
isolation, with 4-chlorobenzylamine (5h) and 4-methylbenzyl-
amine (5b) to give the expected phenylglycine derivatives 10c
and 10d in 42% and 37% yield, respectively (Scheme 4).
+
R1 NH2
r. t., 1 d
100%
CONHR1
5a-h
O
The isolation of the Ugi primary adducts appeared to be crucial
for obtaining the desired amino acid derivatives in high yields and
purities. When the Ugi primary adducts were reacted without pre-
vious isolation the yields were substantially lowered (derivatives
10a–d). However, the method again was convenient because of
the simple experimental procedure. It is noteworthy that only in
two cases (derivatives 10a,b), column chromatography was neces-
sary to obtain pure products.
Evidence for the assigned structures 6a–k and 10a–d was pro-
vided by spectral and analytical data. In the 13C NMR spectra of
compounds 6a–e,g–k and 10a–d two well-separated signals were
found at 170.6–168.6 and 169.6–167.3 ppm in agreement with
the presence of two amide carbonyl groups.
6a-k
1a-e
6
a
b
c
d
e
f
Ar
R
R1
4-ClC6H4
4-FC6H4
C6H5
c-C6H11
4-CH3C6H4
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
i-Bu
i-Bu
4-CH3C6H4CH2
4-CH3OC6H4CH2
2-thienylmethyl
4-CH3OC6H4CH2
C6H5CH2CH2
C6H5
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-FC6H4
4-FC6H4
4-ClC6H4
g
h
i
3,4-(OCH2O)C6H3CH2
C6H5CH2
In the 13C NMR spectrum of 6f a unique signal at 169.6 ppm was
detected; its very high intensity accounted for the overlapping of
two signals. In all of the 1H NMR spectra of compounds 6a,c–k
and 10a,b a doublet signal at 8.56–8.20 ppm was detected, due
to the acetamide NH proton coupled with the H-1 of the cyclohexyl
group.
j
C6H5CH2CH2
k
4-CH3C6H4CH2
Scheme 3. Ring cleavage of isochromenones 1a–e with amines 5a–h to give
phenylglycine derivatives 6a–k.
In the 1H NMR spectrum of 6b the singlet signal of the acetam-
ide NH proton was found at about 11 ppm because of the deshiel-
ding effect of the aromatic ring. The 1H NMR spectra of 10c,d
showed a NH doublet signal at about 6.5 ppm; probably, this value
can be ascribed to the absence of hydrogen bonds involving the
amino group. In most of the 1H NMR spectra of phenylglycine
amides 6 and 10 the multiplet signal due to the NH proton of the
benzamide group was not detected because of the overlapping
with the aromatic proton signals. When the substituent at the
benzamide nitrogen is t-butyl (compounds 6a and 6b) and 2-phen-
ylethyl (compounds 6g,j and 10b) the NH proton signal was found
at the expected chemical shift (5.38–6.77 ppm).
The mass spectra of compounds 6 and 10a,b showed a common
fragmentation pathways. Besides the molecular ion although in a
low intensity,8 the ion [M–RNHCO–H–R1NH]+ was only detected
as the mother peak. The fragmentation pathway of compounds
10c,d was totally different. Thus, the absence of a hydrogen atom
linked to the amino nitrogen in position 4 plays a crucial role in
the fragmentation. Besides the molecular ion, again in low inten-
sity, the ions [R1]+ and [M–c-C6H11NHCO]+ were found in high
intensity.
c-C6H11NC 4a
Y
Ar
O
N
O
+
CHO
NHc-C6H11
2 X = H
7 X = OCH3
MeOH,
b. p. 40 °C
1 h
X
CO2H
X
X
X
3e
+ ArNHY
9a,b (not isolated)
8 Ar = Ph,Y = Me
Y
Ar
N
R1 NH2 (5)
CONHc-C6H11
CONHR1
r. t., 1 d
37-52%
X
X
10a-d
10
a
X
Y
H
H
Ar
R1
OCH3
OCH3
H
3-ClC6H4 4-CH3C6H4CH2
3-ClC6H4 C6H5CH2CH2
b
c
CH3 C6H5
CH3 C6H5
4-ClC6H4CH2
In summary, we have described for the first time a synthetically
useful post-condensation transformation of Ugi-4CC primary ad-
ducts. The present method allows the preparation of a hitherto un-
known class of diverse phenylglycine derivatives in high yields by
means of an experimentally simple two-step procedure.9 Although
nearly quantitative yields are obtained starting from the isolated
Ugi primary adducts, this procedure appears to be attractive even
if the isolation of the Ugi primary adducts is not possible.
d
H
4-CH3C6H4CH2
Scheme 4. Introduction of further diversity points into phenylglycine derivatives
10a–d.
treatment of the reaction mixture with H2PO4À/HPO42À buffer (pH
4.5). In this manner a series of eleven hitherto unknown phenylgly-
cine amides 6 with three diversity points were prepared by
employing a set of five isochromenones 1 and eight amines 5
(Scheme 3).
Supplementary data
In order to achieve the introduction of a fourth diversity point
we attempted the Ugi-4CC between the commercially available
opianic acid (7), cyclohexyl isocyanide (4a), and 3-chloroaniline
(3e). Unfortunately, the Ugi primary adduct (9a) did not precipitate
in the reaction medium. Thus, we reacted phenylethylamine (5e)
and 4-methylbenzylamine (5b) with the crude reaction mixture.7
The desired products 10a and 10b were isolated after column chro-
matography in 47% and 52% yield, respectively (Scheme 4).
A further structural change at the amino group proved to be
possible. Thus, the reaction between 2-formylbenzoic acid (2),
N-methylaniline (8), and cyclohexyl isocyanide (4a) gave the corre-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.074.
References and notes
1. Reviews: (a) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210; (b)
Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321–3329;
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2675
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Procedure B (derivatives 6c–k): The starting isochromenone 1 (1.2 mmol) and the
appropriate amine 5 (4.8 mmol) were reacted as described above. The reaction
mixture was taken up in chloroform (10 mL) and the resulting solution stirred
for 15 min with satd aqueous buffer NaH2PO4/Na2HPO4, pH 4.5 (7.5 mL). If a
precipitation occurred, water was gradually added until all the salts dissolved.
The organic layer was separated, washed with water (5 mL), and dried (MgSO4).
Removal of the solvent under diminished pressure left almost pure 6c–k in
nearly quantitative yields. Analytical samples were obtained from EtOH/i-Pr2O.
Procedure C (derivatives 10a,b): A small flask containing a solution of opianic acid
(7) (364 mg, 1.73 mmol) in MeOH (4 mL) was poured into an oil bath (bath
temperature 80 °C). When the solution began to boil a solution of cyclohexyl
isocyanide (4a) (197 mg, 1.8 mmol) and 3-chloroaniline (3a) (243 mg,
1.9 mmol) in MeOH (1 mL) was added and the flask lifted and maintained at
such a distance from the oil surface that the temperature dropped to 40 °C
during 15 min. The flask was then transferred to another bath and maintained at
40 °C (reaction mixture temperature) for 45 min. The flask was removed from
the bath and allowed to cool at room temperature. A small magnetic bar was
poured into the flask and stirring was started. After 15 min stirring at room
temperature the reaction mixture was cooled with an ice–salt bath and freed
2. The rearrangement consists of an O?N(a) acyl migration. In many publications
on the Ugi reaction such a rearrangement is erroneously referred as Mumm
rearrangement. The true Mumm rearrangement consists of the transformation
of an O-acyl isoamide into an imide. Professor Helmut Quast, University of
Würzburg, Germany, private communication.
3. Gokel, G.; Lüdke, G.; Ugi, I. In Isonitrile Chemistry; Ugi, I., Ed.; Academic Press:
New York, 1971; pp 158–159.
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López-García, L.; Marcaccini, S.; Marcos, C. F. Green Chem. 2006, 8, 787–789; (c)
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Rodríguez, T.; Rojo, J.; Torroba, T. Synlett 2007, 33–36; (e) Marcos, C. F.;
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Neo, A. G.; Marcaccini, S.; Menchi, G.; Revuelta, J. Tetrahedron Lett. 2008, 49,
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from
a small amount of insoluble matter by filtration. The filtrate was
evaporated to dryness under diminished pressure to give a glass-like residue,
which was stirred with the appropriate amine 5 (5.2 mmol) under a nitrogen
atmosphere for 24 h at room temperature. The reaction mixture was taken up in
chloroform (10 mL) and the resulting solution stirred for 15 min. with satd
aqueous buffer NaH2PO4/Na2HPO4, pH 4.5 (7.5 mL). The organic layer was
separated, washed with water (5 mL), and dried (MgSO4). Removal of the
solvent under diminished pressure left
a glass-like residue which was
chromatographed on a silica gel column (petroleum ether bp 40–70 °C/ethyl
acetate 60:40 v/v) to give 10a,b. Analytical samples were obtained by triturating
the crude products with i-Pr2O/i-PrOH 9:1.
Procedure
D (derivatives 10c,d): A small flask containing a solution of
phthalaldehydic acid (2) (226 mg, 1.5 mmol) in MeOH (3 mL) was poured into
an oil bath (bath temperature 80 °C). When the solution began to boil a solution
of cyclohexyl isocyanide (4a) (186 mg, 1.7 mmol) and N-methylaniline (8)
(193 mg, 1.8 mmol) in MeOH (1 mL) was added and the flask lifted and
maintained at such a distance from the oil surface that the temperature dropped
to 40 °C during 15 min. The flask was then transferred to another bath and
maintained at 40 °C (reaction mixture temperature) for 1 h. The flask was
removed from the bath and allowed to cool at room temperature. A small
magnetic bar was poured into the flask and stirring was started. After 15 min
stirring the reaction mixture was evaporated to dryness under diminished
pressure to give a glass-like residue which was stirred with the appropriate
amine 5 (4.5 mmol) under a nitrogen atmosphere for 24 h at room temperature.
The reaction mixture was taken up in chloroform (10 mL) and the resulting
solution stirred for 15 min. with satd. aqueous buffer NaH2PO4/Na2HPO4, pH 4.5
(7.5 mL). The organic layer was separated, washed with water (5 mL), and dried
(MgSO4). Removal of the solvent under diminished pressure left a semisolid
residue which was stirred overnight with a little i-Pr2O/i-PrOH 9:1 and filtered
to give 10c,d. Analytical samples were obtained from EtOH/i-Pr2O.
5. Quast, H.; Aldenkortt, S. Chem.-Eur. J. 1996, 2, 462–469.
6. Faggi, C.; García-Valverde, M.; Marcaccini, S.; Menchi, G. Org. Lett. 2010, 12, 788–
791.
7. Previous experiments performed in our laboratory showed that attempts to
isolate the Ugi-4CC primary adducts by column chromatography were
unsatisfactory because the rearrangement of the Ugi primary adducts to
secondary adducts took place to a large extent.
8. The molecular ion was not detected in the mass spectra of compounds 6c,f.
9. General procedures for the cleavage of isochromenones 1 and 9: Procedure A
(derivatives 6a,b): Isobutylamine (5a) (351 mg, 0.48 ml, 4.8 mmol) was added
under nitrogen to the starting isochromenone 1 (1.2 mmol) and the resulting
mixture stirred for 24 h at room temperature. Longer reaction periods (48–72 h)
had no detrimental effect. The resulting clear oil was taken up in chloroform and
the resulting solution evaporated to dryness under diminished pressure. The last
traces of solvent and unreacted amine were removed at 0.1 mm/Hg to give
almost pure 6a,b in nearly quantitative yields.