An anomalous Dakin-West reaction of N-carbamate substituted prolines and trifluoroacetic anhydride

Article abstract of DOI:10.1039/a708294k

A novel transformation of N-alkoxycarbonylprolines 1 to 4-trifluoroacetyl-2,3-dihydropyrroles 2 was efficiently realized by utilizing trifluoroacetic anhydride, in which probable intermediates were mesoionic 1,3-oxazolium-5-olates B.

Full text of DOI:10.1039/a708294k

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An anomalous Dakin–West reaction of N-carbamate substituted prolines and
trifluoroacetic anhydride
Masami Kawase,*a Michitaka Hirabayashi,a Hiromi Koiwai,a Katsumi Yamamotoa and Hiroshi Miyamaeb
a Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0290, Japan
b Faculty of Science, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0290, Japan
Table 1 Reactions of N-alkoxycarbonylprolines with TFAAa
A novel transformation of N-alkoxycarbonylprolines 1 to
4-trifluoroacetyl-2,3-dihydropyrroles 2 was efficiently re-
Starting
material
Product
(% yield)b
alized by utilizing trifluoroacetic anhydride, in which
probable intermediates were mesoionic 1,3-oxazolium-
5-olates B.
Entry
Solvent
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1c
1c
1d
1d
1e
1f
MeCN
DMF
MeCN
DMF
MeCN
DMF
MeCN
DMF
MeCN
MeCN
MeCN
MeCN
2a (66)
2a (67)
2b (61)
2b (53)
2c (58)
The Dakin–West (D–W) reaction of a-amino acids usually
produces a-amino ketones.1 However, treatment of N-acyl-
N-alkyl-a-amino acids or N-acylprolines with trifluoroacetic
anhydride (TFAA) under the D–W reaction conditions can lead
to trifluoromethylated oxazoles,2 acyloins3 or morpholines,4
depending on the nature of the N-substituents of the amino acids
and/or reaction conditions. In the course of our studies on the
reactivities of mesoionic 1,3-oxazolium-5-olates,5 we have now
found that N-alkoxycarbonylprolines 1 led unexpectedly, by
way of a novel decarboxylative dehydration followed by
trifluoroacetylation, to 4-trifluoroacetyl-2,3-dihydropyrroles 2
under the D–W reaction conditions.
2c (68)
2d (32)
2d (27)
2e (34)
2f (30) + 9a (54)
9b (94)c
8 (86)
10
11
12
1g
7
a
The reactions were carried out according to the general procedure
described in the text. b Isolated yields of pure products. All new compounds
gave satisfactory spectroscopic data (IR, MS, 1H and 13C NMR) and
analytical (combustion and/or high resolution mass) data. Plus 54% of
c
COCF3
proline.
COCF3
N
CO2H
N
N
CO2R
urethane-protected prolines 1a–f were reacted in this way and
the results are presented in Table 1. Among the
N-alkoxycarbonyl groups examined, Me, Et and Bu proved to
give a good yield of the product 2. The low yields of 2d–f could
be attributable to the ease of cleavage of the alkoxy group in the
mesoionic oxazole intermediate B. In the reaction of 1f,
N-allylacetamide 9a was isolated in 58% yield as a side
product.
CO2R
CO2R
3
2a R = Me
b R = Et
c R = Bu
d R = Ph
e R = fluoren-9-yl
f R = Allyl
1a R = Me
b R = Et
c R = Bu
R2
R1
O–
N
+
d R = Ph
R3O
e R = fluoren-9-yl
f R = Allyl
g R = Bn
O
A
The structure of 2 was determined from analytical and
spectral data† and was subsequently secured by single-crystal
X-ray diffraction analysis of 2d (Fig. 1).‡
A plausible mechanism for the formation of 2 is suggested in
Scheme 1. The existence of the mesoionic oxazole B is
supported by the following facts. (i) The reaction of Z-proline
R1CHCO2H
BnCHCOCF3
Me
R2
R1
R2
N
N
N
CO2R3
CO2R
O
O
O
5a R = Me
b R = Bn
6a R1 = Bn, R2 = Me
4a R1 = Bn, R2 = Me, R3 = Me
b R1 = Bn, R2 = Me, R3 = Bn
c R1 = H, R2 = Ph, R3 = Et
b R1 = H, R2 = Ph
F(1)
C(17)
RNHAc
CO2H
N
F(2)
C(16)
C(15)
9a R = CH2=CHCH2
b R = Bn
N
F(3)
C(3)
CO2Me
CO2Me
7
8
C(2)
Thus, treatment of 1a (1 mmol) with TFAA (3 mmol) in
MeCN (5 ml) at 80 °C for 5 h gave rise to N-methoxycarbonyl-
4-trifluoroacetyl-2,3-dihydropyrrole 2a in 66% yield. In the
reaction, the D–W reaction product, N-methoxycarbonyl-
2-trifluoroacetylpyrrolidine 3 (R = Me), was not isolated.
Reaction variables were briefly examined. Addition of
pyridine (3 equiv.) to the reaction reduced the yield (2c; 22%).
High temperatures (80 °C) were needed to obtain a high yield of
2c, lower temperatures (60 °C) reducing the yield (2c; 46%).
Various solvents such as MeCN, DMF, ClCH2CH2Cl, benzene,
MeNO2 and acetone are usable, and among them MeCN and
DMF are the solvents of choice for this reaction, while little or
no reaction takes place in THF, DME or dioxane. Several
C(4)
N(1)
C(5)
C(6)
O(7)
O(8)
C(14)
C(9)
C(13)
C(10)
C(12)
C(11)
Fig. 1 X-Ray Crystal structure of 2d (the probability level of the ellipsoids
is 50%)
Chem. Commun., 1998
641

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pendently gave the trifluoroacetyl derivative 2a in 65% yield
under the same reaction conditions as described for 1a. Finally,
trifluoroacetylation of C leads to the product 2.
TFAA
CO2H
N
N
O–
+
(a)
O
In summary, this work describes the reaction of N-alkoxy-
carbonylprolines and TFAA, which has great practical potential
because of the ready availability of the starting materials and
reagents and the ease of manipulation. Our method makes novel
compounds 2 readily accessible for further study as building
blocks for the synthesis of fluorine-containing compounds, in
view of the versatility of aminoenones (N–CNC–CNO) in
synthetic as well as heterocyclic chemistry.11 Detailed mecha-
nistic studies and synthetic utilization of 2 as trifluoromethyl
building blocks are now in progress.
CO2R
–
CF3CO2
RO
1
B
path (a)
(R = Bn)
N
N
O + BnOCOCF3
CO2R
C
O
O
TFAA
COCF3
D
H2O
MeCN
Notes and References
† Selected data for 2d: mp 99–101 °C (hexane); m/z 285 (M+, 100%); nmax
cm21 1670, 1740; dH(500 MHz; CDCl3; Me4Si) 3.04 (br s, 2 H), 4.12 (br s,
2 H), 7.17 (d, 2 H, J 7.9), 7.25–7.30 (m, 1 H), 7.40–7.43 (m, 2 H), 7.93 (s,
1 H); dC(125 MHz; CDCl3; Me4Si) 26.15 (CH2), 46.77 (CH2), 116.92 (C),
116.54 (CF3, 1JCF 290.0), 121.16 (CH), 126.42 (CH), 129.61 (CH), 144.46
(CH), 145.85 (C), 150.15 (C), 176.49 (C, 2JCF 35.5).
N
/
+ BnNHAc
CO2H
CO2R
2
N
9b
H
Scheme 1
‡ Crystal data for 2d: (C13H10NO3F3), FW
= 285.2, orthorhombic,
1g with TFAA afforded proline (45%) and N-benzylacetamide
9b (94%). Formation of proline is presumably due to hydrolysis
of anhydride D,6 which was produced by the attack of
trifluoroacetate ion on the mesoionic oxazole intermediate B via
path (a). N-Benzylacetamide 9a was formed by the Ritter
reaction of intermediary benzyl trifluoroacetate and the solvent
P212121, a = 8.409(7), b = 22.604(6), c = 6.774(6) Å, V = 1288(2) Å3,
Z = 4, m(Mo-Ka) = 1.26 cm21 by Rigaku AFC-5 diffractometer. Final R
value was 0.074 for 1331 reflections (Rw = 0.044, S = 2.770). CCDC
182/754.
1 G. L. Buchanan, Chem. Soc. Rev., 1988, 17, 91.
2 M. Kawase, H. Miyamae, M. Narita and T. Kurihara, Tetrahedron Lett.,
1993, 34, 859; M. Kawase, Heterocycles, 1993, 36, 2441.
3 M. Kawase, Tetrahedron Lett., 1994, 35, 149.
4 M. Kawase, S. Saito, H. Kikuchi and H. Miyamae, Heterocycles, 1997,
45, 2185.
5 M. Kawase, Chem. Pharm. Bull., 1997, 45, 1248.
6 T. S. Kaufman, V. L. Ponzo and J. Zinczuk, Org. Prep. Proced. Int.,
1996, 28, 487 and references cited therein.
MeCN.
(ii)
Treatment
of
N-methoxycarbonyl-
N-methylphenylalanine 4a with TFAA in the presence of
pyridine gave the D–W reaction product, trifluoroacetyl
derivative 5a, in 93% yield.7 In the case of N-benzyloxycar-
bonyl-N-methylphenylalanine 4b, trifluoroacetyl derivative 5b
and the anhydride8 of 6a N-carboxyphenylalanine were ob-
tained in 39 and 43% yields, respectively. (iii) In attempts to
form the mesoionic oxazole A by treatment of N-ethoxycar-
bonyl-N-phenylglycine 4c with SOCl2, Potts et al. isolated the
anhydride 6b of N-carboxyglycine and ethyl chloride.9 This
suggests that ring closure to the mesoionic oxazole A actually
occurred and that it underwent rapid deethylation. However, it
is difficult to obtain a definitive explanation for the transforma-
tion of B to 2. The existence of intermediary C is supported by
the reaction of N-methoxycarbonyl-2,3-dihydroindole-1-car-
boxylic acid 7 with TFAA. Thus, the reaction yielded
N-methoxycarbonylindole 8 in 86% yield and disclosed the
probable intermediacy of C. Indeed, N-methoxycarbonylindole
7 Full details of the D–W reaction of N-alkoxycarbonyl-N-alkyl-a-amino
acids will be reported elsewhere.
8 R. Wilder and S. Mobashery, J. Org. Chem., 1992, 57, 2755; H. Collet,
C. Bied, L. Mion, J. Tailades and A. Commeyras, Tetrahedron Lett.,
1996, 37, 9043 and references cited therein.
9 K. T. Potts, D. Bhattacharjee and S. Kanemasa, J. Org. Chem., 1980, 45,
4985.
10 G. A. Kraus and K. Neuenschwander, J. Org. Chem., 1981, 46, 4791; Y.
Nomura, K. Ogawa, Y. Takeuchi and S. Tomoda, Chem. Lett., 1977,
693.
11 T. Nishio, C. Kashima and Y. Omote, J. Synth. Org. Chem. Jpn., 1976,
34, 526; J. V. Greenhill, Chem. Soc. Rev., 1977, 6, 277.
8
cannot
undergo
trifluoroacetylation,
whereas
N-methoxycarbonyl-2-pyrroline C (R = Me)10 prepared inde-
Received in Cambridge, UK, 18th November 1997; 7/08294K
642
Chem. Commun., 1998