Synthesis of 5-methoxy-4-benzyloxazoles from tyrosine and m-tyrosine under Bischler-Napieralski conditions

Article abstract of DOI:10.1515/znb-2006-0408

Various 2-substituted 5-methoxy-4-benzyloxazoles 6 and 9 were obtained from tyrosine and m-tyrosine derived amides 5 and 8 by treatment with phosphoryl chloride. A mechanism is proposed in order to explain the observed steric effects of the substituents i

Full text of DOI:10.1515/znb-2006-0408

Synthesis of 5-Methoxy-4-benzyloxazoles from Tyrosine and m-Tyrosine
under Bischler-Napieralski Conditions*
Stefan Tussetschla¨ger, Angelika Baro, and Sabine Laschat
Institut fu¨r Organische Chemie, Universita¨t Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart,
Germany
Reprint requests to Prof. Dr. S. Laschat. E-mail: sabine.laschat@oc.uni-stuttgart.de
Z. Naturforsch. 61b, 420 – 426 (2006); received January 9, 2006
Various 2-substituted 5-methoxy-4-benzyloxazoles 6 and 9 were obtained from tyrosine and
m-tyrosine derived amides 5 and 8 by treatment with phosphoryl chloride. A mechanism is proposed
in order to explain the observed steric effects of the substituents in 2-position.
Key words: Amides, Bischler-Napieralski Reaction, 3,4-Dihydroisoquinolines, Oxazoles, Tyrosine
Introduction
Oxazoles are interesting from both a pharmacolog-
ical and a chemical point of view. For example, they
are known to interact with various proteins such as
sodium-dependent excitatory amino acid transporters
[1] or DNA repair protein OG-alkylguanine DNA-
alkyl-transferase [2], and furthermore, they display
bacteriostatic [3] and antiinflammatory activity [4].
Additionally, oxazoles provide useful entries into the
synthesis of other heterocyclic compounds such as
pyridines [5], α-amido oximes [6], and azlactones [7].
Since the seminal finding by Reeve and Pare´ [8] that
acylamidophenylalanine esters 1 can undergo a cy-
clization to the oxazole 3 instead of the desired di-
hydroisoquinolines 2 under Bischler-Napieralski con-
ditions [9] (Scheme 1), this reaction was observed by
several groups [6, 10]. The electronic influence of sub-
stituents at the phenyl moiety has been explored to
some extent [10b,10c], however, substituent effects at
the amide function remained unclear. Herein we wish
to disclose our studies on this reaction in more detail.
Scheme 1. Possible products from acylamidophenylalanine
esters 1 under Bischler-Napieralski conditions. EDG = elec-
tron donating group.
Results and Discussion
As shown in Scheme 2, methyl L-O-methyl-tyrosin-
ate (4) was first N-acylated with 1.1 equivalents of the
◦
respective acid chloride in pyridine at 0 C. The mix-
ture was then kept at r. t. for 16 h and after workup,
the amides 5a – h were obtained in 65 – 93% yield
Scheme 2. Bischler-Napieralski reaction of methyl L-O-
methyl-tyrosinate (4) to oxazoles 6.
Presented in part at the 7th Conference on Iminium Salts
(ImSaT-7), Bartholoma¨/Ostalbkreis, September 6 – 8, 2005.
c
0932–0776 / 06 / 0400–0420 $ 06.00 ꢀ 2006 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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S. Tussetschla¨ger et al. · Synthesis of 5-Methoxy-4-benzyloxazoles from Tyrosine and m-Tyrosine
Table 1. Formation of amides 5 and oxazoles 6.
421
Entry
R
Amide Yield Time Oxazole Yield
[%]
82
86
91
75
93
65
74
76
[min]
25
10
150
90
10
5
20
6 h
[%]a
49
1
2
3
4
5
6
7
Et
n-C5H11
t-Bu
CH2OBn
(R)-CHCH3OBn 5e
C(CH3)2OBn
p-ClC6H4
CO2t-Bu
5a
5b
5c
5d
6a
6b
6c
6d
6e
6f
50
28
40
b
–
b
5f
5g
5h
b
–
6g
6h
76
b
8
–
a
Isolated yields are given; only decomposition was observed.
(Table 1). Subsequent treatment of 5 with an excess
of phosphoryl chloride at 95 C following the proce-
Scheme 3. Bischler-Napieralski reaction of m-tyrosine
derivative 7.
◦
dure by Saxena [11] yielded the 5-methoxy-4-benzyl-
oxazoles 6. The course of reaction was followed by
GC, and the reaction mixture was worked up imme-
diately after the starting material could not be detected
any more. In the cases of aliphatic acid chlorides, the
yields of the oxazoles 6a – c decreased with steric bulk-
iness of the alkyl substituent from 50% for 2-ethyl and
2-pentyl-substituted oxazoles 6a, b (entry 1, 2) to only
28% for 2-tert-butyloxazole 6c (entry 3).
Benzyloxymethyl-substituted oxazole 6d was also
isolated in 40% yield without any problems (entry 4).
We were therefore curious whether the cyclization
of chiral amide 5e derived from O-benzyl (R)-lactate
Scheme 4. Mechanistic proposal for the oxazole formation.
would retain its stereochemistry during oxazole for- to Fodor [13] nitrilium cations such as 10 are inter-
mation. As a further derivative with a quaternary car- mediates in Bischler-Napieralski reactions. Thus, via
bon atom the benzyloxymethyl-substituted amide 5f path A, amide 5 is converted to 10, which is intramole-
was tested in the Bischler-Napieralski reaction. How- cularly attacked by the carbonyl group of the ester
ever, not even a trace of the desired oxazoles 6e and moiety to give intermediate 11. The latter is deproto-
6f could be detected (entries 5, 6). In contrast, the p- nated to yield oxazole 6. In path B, initial formation of
chlorophenyl-substitutedamide 5g reacted smoothly to the chloroiminium ion 12 analogous to the Vilsmeier-
afford the oxazole 6g (entry 7), while the tert-butyl Haack reaction [14] is proposed. Intramolecular nu-
glyoxylate-derivedamide 5h did not give the target ox- cleophilic attack of the ester moiety should lead to
azole 6h (entry 8).
the tetrahedral intermediate 13. Further elimination of
HCl and deprotonation should give the oxazole 6. The
Under similar conditions rac methyl 3-methoxy-
phenylalaninate (7) was converted with benzoyl chlo- sensitivity of the oxazole formation towards steric ef-
fects may be taken as evidence for mechanism B rather
ride to the corresponding benzamide 8 in 92% yield
than A. The linear nitrilium cation 10 should be less
phosphoryl chloride in toluene at 100 C in analogy prone to steric hindrance by the substituent R as com-
(Scheme 3). Subsequent treatment with an excess of
◦
pared to the tetrahedral intermediate 13.
to conditions by Chakravorti [12] yielded the oxazole
9 in 63% yield. It should be noted that we did not
detect any trace of the corresponding 3,4-dihydroiso-
quinolinecarboxylate. This finding is in clear contrast
to observations by Saxena [11], who found exclusively
the 3,4-dihydroisoquinolinecarboxylate under similar
reaction conditions.
In conclusion, we found some steric influence of the
amide substituent in the phosphoryl chloride-mediated
cyclization of tyrosine derivatives 5 and 8 to the oxa-
zoles 6 and 9. While linear substituents like ethyl, n-
pentyl or benzyloxymethyl (5a, b, d) react without dif-
ficulty, a branch at the α-C atom as in amides 5c, e, f
As shown in Scheme 4, two mechanistic proposals either clearly diminished the yield of the correspond-
may be drawn for the oxazole formation. According ing oxazole 6 or led to decomposition.
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422
S. Tussetschla¨ger et al. · Synthesis of 5-Methoxy-4-benzyloxazoles from Tyrosine and m-Tyrosine
Experimental Section
192 [M+ – H – NHC(O)C2H5] (37), 161 (14), 122 (9),
121 [H3COC6H4CH2+] (100), 91 [C7H7+] (4), 77 (5), 57
[C(O)C2H5+] (10), 29 (12). – C14H19NO4 (265.3): calcd.
C 63.38, H 7.22, N 5.28; found C 63.16, H 7.15, N 5.18.
General information
The following compounds were prepared according to
literature procedures: benzyloxyacetyl chloride [15], (R)-
2-D-benzyllactic acid chloride [16], 2-benzyloxy-2,2-di-
methylacetyl chloride [17, 18], and tert-butyl-chloroglyoxyl-
ate [19]. Commercial reagents were used without further
purification unless otherwise indicated. Phosphoryl chloride
was distilled, pyridine and toluene were distilled from CaH2
prior to use. Reactions were performed in oven-dried glass-
ware under N2 atmosphere. Flash chromatography was per-
formed on silica gel Fluka 60 (230 – 400 mesh) or Merck alu-
minium oxide 90 active neutral or aluminium oxide 90 ac-
tive basic (0.063 – 0.200 mm). The following spectroscopic
and analytical instruments were used. IR: Bruker Vector
22 FTIR. – NMR: Bruker AC 250 and Avance 500 (1H:
250.13 MHz, 500.15 MHz, 13C: 62.90 MHz, 125.76 MHz).
For 1H spectra, TMS was used as internal standard. Sig-
nal assignments are based on DEPT and COSY experi-
ments. – Melting points: Bu¨chi SMP 20, m. p. are uncor-
rected. – Mass spectrometry: Finnigan MAT 95 and Varian
MAT 711. – GC: Hewlett-Packard HP 6890, column HP 5TA
(30 m × 0.32 mm), temperature program: 16 ◦C min−1 gra-
dient from 80 ◦C to 300 ◦C.
Methyl (S)-N-hexanoyl-O-methyltyrosinate (5b): Yield:
479 mg, 1.56 mmol, 86%, colorless crystals. – M. p.
38 ◦C. – Rf = 0.34 (hexanes/EtOAc = 3 : 1). – [α]2D2
=
+72.0◦ (c = 1.0, CH2Cl2). – IR (ATR): ν = 3286 (C-H),
2936, 2191, 1970, 1735 (C=O), 1645 (C=O), 1541 (N-H),
1512, 1435, 1244 (C-O), 1175, 1039, 1015, 812 (C-H),
727, 688 cm−1. – 1H NMR (500.15 MHz, CDCl3): δ =
0.88 (t, J = 7.0 Hz, 3 H, (CH2)4CH3), 1.23 – 1.33 (m,
4 H, CH2CH2CH2CH2CH3), 1.59 (quint, J = 7.5 Hz,
2 H, CH2CH2CH2CH2CH3), 2.18 (t, J = 7.3 Hz, 2 H,
CH2CH2CH2CH2CH3), 3.03 (dd, 2J = 14.0 Hz, 3J =
5.7 Hz, 1 H, MeOC6H4CH2), 3.09 (dd, 2J = 14.0 Hz,
3J = 5.8 Hz, 1 H, MeOC6H4CH2), 3.73 (s, 3 H, OCH3),
3.78 (s, 3 H, OCH3), 4.86 (dt, 3J = 7.9 Hz, 3J = 5.8 Hz,
1 H, MeO2CCH), 5.89 (br. d, J = 7.6 Hz, 1 H, NH), 6.82
(d, J = 8.7 Hz, 2 H, o-C6H4OCH3), 7.00 (d, J = 8.6 Hz,
2 H, m-C6H4OCH3). – 13C NMR (125.76 MHz, CDCl3):
δ = 13.9 ((CH2)4CH3), 22.4 (CH2CH2CH2CH2CH3),
25.3 (CH2CH2CH2CH2CH3), 31.4 (CH2CH2CH2CH2CH3),
36.5 (CH2CH2CH2CH2CH3), 37.1 (MeOC6H4CH2), 52.3
(OCH3), 53.04 (MeO2CCH), 55.2 (OCH3), 114.0 (o-
C6H4OCH3), 127.8 (p-C6H4OCH3), 130.3 (m-C6H4OCH3),
158.7 (i-C6H4OCH3), 172.3, 172.7 (C(O)NH, C(O)OMe). –
General procedure for the preparation of amides 5,
8, as described for methyl O-methyl-N-propionyltyrosinate
(5a): In a Schlenk flask methyl (S)-O-methyltyrosinate (4)
(499 mg, 2.38 mmol) was dissolved in pyridine (7 ml). Af-
ter cooling with an ice bath, propionyl chloride (0.23 ml,
242 mg, 2.62 mmol) was added via syringe. The resulting
slurry was allowed to warm to r. t. (16 h) and concentrated to
give a colorless, waxy solid. The solid was purified by filtra-
tion through 25 g neutral aluminium oxide with ethyl acetate
(EtOAc) to give 5a as colorless crystals (515 mg, 1.94 mmol,
82%). Rf = 0.14 (hexanes/EtOAc = 3 : 1). – [α]2D2 = +84.3◦
MS (EI, 70 eV): m/z (%) 307 [M+] (5), 193 [M+
–
C(O)C5H11] (12), 192 [M+ – H – NHC(O)C5H11] (100),
161 (9), 122 (7), 121 [H3COC6H4CH2+] (64), 91 [C7H7
]
+
(3), 71 [C5H11+] (3), 43 (11), 28 (16), 18 (17). – C17H25NO4
(307.4): calcd. C 66.43, H 8.20, N 4.56; found C 66.29,
H 8.13, N 4.50.
Methyl (S)-N-(2,2-dimethylpropanoyl)-O-methyltyrosin-
ate (5c): Yield: 446 mg, 1.52 mmol, 91%, colorless crys-
tals. – M. p. 63 ◦C. – Rf = 0.28 (hexanes/EtOAc =
(c = 1.0, CH2Cl2). – M. p. 53 ◦C. – IR (ATR): ν = 8:1). – [α]2D2 = +66.1◦ (c = 1.0, CH2Cl2). – IR (ATR):
3305 (C-H), 2946, 2189, 1969, 1730 (C=O), 1643 (C=O), ν = 3327 (C-H), 2958, 2192, 1968, 1752 (C=O), 1730,
1538 (N-H), 1512, 1434, 1282, 1238 (C-O), 1219, 1174, 1628 (C=O), 1513 (N-H), 1438, 1245 (C-O), 1200, 1180,
1031, 1012, 829 (C-H), 685 cm−1. – 1H NMR (500.15 MHz, 1120, 1034, 1003, 841 (C-H), 785, 633 cm−1. – 1H NMR
CDCl3): δ = 1.13 (t, J = 7.6 Hz, 3 H, CH2CH3), 2.21 (q, J = (250.13 MHz, CDCl3): δ = 1.16 (s, 9 H, C(CH3)3), 3.04 (dd,
7.7 Hz, 2 H, CH2CH3), 3.04 (dd, 2J = 14.0 Hz, 3J = 5.6 Hz, 2J = 13.9 Hz, 3J = 5.6 Hz, 1 H, MeOC6H4CH2), 3.11 (dd,
1 H, MeOC6H4CH2), 3.09 (dd, 2J = 13.8 Hz, 3J = 5.9 Hz, 2J = 13.9 Hz, 3J = 5.6 Hz, 1 H, MeOC6H4CH2), 3.74 (s,
1 H, MeOC6H4CH2), 3.73 (s, 3 H, OCH3), 3.78 (s, 3 H, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 4.82 (dt, 3J = 7.6 Hz,
OCH3), 4.82 (dt, 3J = 7.6 Hz, 3J = 5.6 Hz, 1 H, MeO2CCH), 3J = 5.6 Hz, 1 H, MeO2CCH), 6.05 (br. d, J = 7.4 Hz,
5.92 (br. d, J = 7.4 Hz, 1 H, NH), 6.82 (d, J = 8.6 Hz, 2 H, 1 H, NH), 6.82 (d, J = 8.7 Hz, 2 H, o-C6H4OCH3), 6.99 (d,
o-C6H4OCH3), 7.00 (d, J = 8.7 Hz, 2 H, m-C6H4OCH3). – J = 8.7 Hz, 2 H, m-C6H4OCH3). – 13C NMR (62.90 MHz,
13C NMR (125.76 MHz, CDCl3): δ = 9.7 (CH2CH3), CDCl3): δ = 27.4 (C(CH3)3), 36.9 (MeOC6H4CH2), 38.7
29.6 (CH2CH3), 37.0 (MeOC6H4CH2), 52.2 (OCH3), 53.1 (C(CH3)3), 52.3 (OCH3), 53.0 (MeO2CCH), 55.2 (OCH3),
(MeO2CCH), 55.2 (OCH3), 114.0 (o-C6H4OCH3), 127.8 (p- 113.9 (o-C6H4OCH3), 127.9 (p-C6H4OCH3), 130.3 (m-
C6H4OCH3), 130.3 (m-C6H4OCH3), 158.7 (i-C6H4OCH3), C6H4OCH3), 158.7 (i-C6H4OCH3), 172.4, 177.8 (C(O)NH,
172.3, 173.4 (C(O)NH, C(O)OMe). – MS (EI, 70 eV): C(O)OMe). – MS (EI, 70 eV): m/z (%) 293 [M+] (5), 193
m/z (%) 265 [M+] (7), 193 [M+ – NHC(O)C2H5] (11), [M+ – NHC(O)C4H9] (8), 192 [M+ – H – NHC(O)C4H9]
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S. Tussetschla¨ger et al. · Synthesis of 5-Methoxy-4-benzyloxazoles from Tyrosine and m-Tyrosine
423
(100), 161 (10), 122 (7), 121 (65), 57 [C4H9+] (20), 41 (7), [H3COC6H4CH2+] (55), 91 [C7H7+] (36), 43 (6), 28 (7). –
29 (4). – C16H23NO4 (293.4): calcd. C 65.51, H 7.90, N 4.77; C21H25NO5 (371.4): calcd. C 67.91, H 6.78, N 3.77; found
found C 65.34, H 7.90, N 4.69.
C 67.88, H 6.84, N 3.69.
Methyl (S)-N-[2-(benzyloxy)-2-methylpropanoyl]-
O-methyltyrosinate (5f): Yield: 769 mg, 2.00 mmol,
Methyl (S)-N-[(benzyloxy)acetyl]-O-methyltyrosinate
(5d): Yield: 349 mg, 0.98 mmol, 75%, colorless oil. –
Rf = 0.15 (hexanes/EtOAc = 2 : 1). – [α]2D2 +35.3◦ (c = 1.0,
65%, colorless oil.
– Rf = 0.50 (hexanes/EtOAc =
CH2Cl2). – IR (ATR): ν = 3401 (C-H), 2951, 1741 (C=O), 3 : 1). – [α]2D2 = +83.9◦ (c = 1.0, CH2Cl2). – IR (ATR):
1677 (C=O), 1611, 1510 (N-H), 1439, 1343, 1246 (C-O), ν = 3416 (C-H), 2951, 1741 (C=O), 1675 (C=O), 1612,
1205, 1176, 1099, 1029, 839 (C-H), 738, 698 cm−1. – 1510 (N-H), 1441, 1359, 1246 (C-O), 1175, 1029,
1H NMR (500.15 MHz, CDCl3): δ = 3.08 (dd, 3J = 2.8 Hz, 837 (C-H), 736, 697 cm−1. – 1H NMR (500.15 MHz,
2J = 5.9 Hz, 2 H, MeOC6H4CH2), 3.73 (s, 3 H, OCH3), CDCl3): δ = 1.41 (s, 3 H, CH3), 1.47 (s, 3 H, CH3), 3.02
3.77 (s, 3 H, OCH3), 3.98 (s, 2 H, HNC(O)CH2), 4.52 (dd, 2J = 14.1 Hz, 3J = 6.5 Hz, 1 H, MeOC6H4CH2),
(dd, 3J = 11.7 Hz, 2J = 28.5 Hz, 2 H, PhCH2O), 4.87 3.09 (dd, 2J = 14.1 Hz, 3J = 5.6 Hz, 1 H, MeOC6H4CH2),
(dt, 3J = 8.4 Hz, 3J = 6.0 Hz, 1 H, MeO2CCH), 6.79 (d, 3.71 (s, 3 H, OCH3), 3.74 (s, 3 H, OCH3), 4.42 (dd,
J = 8.6 Hz, 2 H, o-C6H4OCH3), 7.02 (d, J = 8.6 Hz, 2 H, 2J = 22.3 Hz, 3J = 11.0 Hz, 1 H, PhCH2O), 4.82 (dt,
m-C6H4OCH3, NH), 7.25 – 7.27 (m, 2 H, o-PhCH2O), 7.32 – J = 8.2 Hz, J = 6.1 Hz, 1 H, MeO2CCH), 6.72 (d,
7.38 (m, 3 H, m-, p-PhCH2O). – 13C NMR (125.76 MHz, J = 8.6 Hz, 2 H, o-MeOC6H4), 6.97 (d, J = 6.7 Hz, 2 H,
CDCl3): δ = 37.1 (MeOC6H4CH2), 52.4 (OCH3), 52.5 m-MeOC6H4), 7.09 (d, J = 8.2 Hz, 1 H, NH), 7.23 (d,
(MeO2CCH), 55.2 (OCH3), 69.3 (HNC(O)CH2), 73.4 J = 7.0 Hz, 2 H, o-PhCH2O), 7.27 – 7.36 (m, 3 H, m-,
(PhCH2O), 114.0 (o-C6H4OCH3), 127.6 (p-C6H4OCH3), p-PhCH2O). – 13C NMR (125.76 MHz, CDCl3): δ = 23.5
127.8 (o-PhCH2O), 128.1 (p-PhCH2O), 128.6 (m-PhCH2O), (CH3), 24.5 (CH3), 36.9 (MeOC6H4CH2), 52.3 (OCH3),
130.2 (m-C6H4OCH3), 136.8 (i-PhCH2O), 158.7 (i- 52.8 (MeO2CCH), 55.2 (OCH3), 65.7 ((CH3)2COCH2Ph),
C6H4OCH3), 169.3, 171.8 (C(O)NH, C(O)OMe). – MS (CI, 78.8 (PhCH2O), 114.0 (o-MeOC6H4), 127.4 (o-PhCH2O),
CH4): m/z (%) 386 [M+ + C2H4] (11), 358 [M+ + H], 326 127.6 (m-, p-PhCH2O), 127.7 (p-MeOC6H4), 128.4 (m-,
[M+ – OCH3] (7), 298 [M+ – CO2CH3] (34), 280 (3), p-PhCH2O), 130.2 (m-MeOC6H4), 138.2 (i-PhCH2O),
251 (5), 223 (3), 192 [M+ – H – NHC(O)CH2OCH2Ph] 158.7 (i-MeOC6H4), 172.0, 175.1 (CO2Me, C(O)NH). –
(100), 161 (5), 121 [H3COC6H4CH2+] (40), 107 [PhCH2O] MS (EI, 70 eV): m/z (%) 385 [M+] (3), 354 [M+ – OCH3]
(2), 91 [C7H7+] (24), 77 (1). – C20H23NO5 (357.4): calcd. (1), 326 [M+ – CO2CH3] (2), 279 [M+ + H – OCH2Ph]
C 67.21, H 6.49, N 3.92; found C 67.12, H 6.52, N 3.82.
(25), 262 (1), 236 [M+ – C(CH3)2OCH2Ph] (12), 208 (7),
192 [M+ – H – NHC(O)C(CH3)2OCH2Ph] (100), 176
Methyl (S)-N-[(2S)-2-(benzyloxy)propanoyl]-O-methyl-
tyrosinate (5e): Yield: 816 mg, 2.20 mmol, 93%, colorless
oil. – Rf = 0.32 (hexanes/EtOAc = 3 : 1). – [α]2D2 = +48.0◦
(c = 1.0, CH2Cl2). – IR (ATR): ν = 3413 (C-H), 2935,
2191, 1971, 1740 (C=O), 1672 (C=O), 1510 (N-H), 1442,
1337, 1246 (C-O), 1106, 1029, 839 (C-H), 738, 698 cm−1. –
1H NMR (250.13 MHz, CDCl3): δ = 1.40 (d, J = 6.8 Hz,
3 H, OCH3), 3.03 (dd, 2J = 14.1 Hz, 3J = 6.7 Hz, 1 H,
[M+ + H – C(O)C(CH3)2OCH2Ph] (10), 149 (8), 121
+
[H3COC6H4CH2+] (59), 91 [C7H7+] (76), 59 [CO2CH3
]
(2). – C22H27NO5 (385.5): calcd. C 68.55, H 7.06, N 3.63;
found C 68.59, H 7.16, N 3.51.
Methyl (S)-N-(4-chlorobenzoyl)-O-methyltyrosinate (5g):
Yield: 526 mg, 1.51 mmol, 74%, colorless crystals. –
M. p. 111 ◦C. – Rf = 0.32 (hexanes/EtOAc = 3 : 1). –
MeOC6H4CH2), 3.11 (dd, 2J = 14.1 Hz, 3J = 5.6 Hz, 1 H, [α]2D2 = +14.9◦ (c = 1.0, CH2Cl2). – IR (ATR): ν =
MeOC6H4CH2), 3.73 (s, 6 H, OCH3), 3.90 (q, J = 6.8 Hz, 3288 (C-H), 2949, 1736 (C=O), 1635 (C=O), 1536 (N-H),
1 H, CHCH3), 4.41 (s, 2 H, PhCH2O), 4.83 (dt, 3J = 6.1 Hz, 1513, 1485, 1436, 1247 (C-O), 1224, 1174, 1089, 1028,
3J = 8.2 Hz, 1 H, MeO2CCH), 6.74 (d, J = 8.7 Hz, 2 H, 1013, 848 (C-H), 834 (C-H), 765, 658 cm−1. – 1H NMR
o-C6H4OCH3), 7.00 (d, J = 8.7 Hz, 2 H, m-C6H4OCH3), (500.15 MHz, CDCl3): δ = 3.16 (dd, 2J = 14.0 Hz, 3J =
7.18 – 7.24 (m, 2 H, o-, m-, p-PhCH2O), 7.27 – 7.39 (m, 5.3 Hz, 1 H, MeOC6H4CH2), 3.23 (dd, 2J = 14.0 Hz,
3 H, o-, m-, p-PhCH2O). – 13C NMR (62.90 MHz, CDCl3): 3J = 5.7 Hz, 1 H, MeOC6H4CH2), 3.78 (s, 6 H, OCH3),
3
3
δ = 18.4 (CH3), 36.9 (MeOC6H4CH2), 52.3 (OCH3), 52.6 5.03 (dt, J = 7.6 Hz, J = 5.5 Hz, 1 H, MeO2CCH) 6.56
(MeO2CCH), 55.2 (OCH3), 71.7 (PhCH2), 76.0 (CHCH3), (d, J = 7.5 Hz, 1 H, NH), 6.82 (d, J = 8.5 Hz, 2 H,
114.1 (o-C6H4OCH3), 127.6 (o-, m-, p-PhCH2O), 127.7 o-MeOC6H4), 7.03 (d, J = 8.7 Hz, 2 H, m-MeOC6H4),
(i-PhCH2O), 128.0, 128.5 (o-, m-, p-PhCH2O), 130.2 7.39 (d, J = 8.4 Hz, 2 H, o-ClC6H4), 7.66 (d, J =
(m-C6H4OCH3), 137.4 (i-PhCH2O), 158.7 (i-C6H4OCH3), 8.6 Hz, 2 H, m-ClC6H4). – 13C NMR (125.76 MHz,
171.8, 173.0 (C(O)NH, C(O)OMe). – MS (EI, 70 eV): CDCl3): δ = 36.9 (MeOC6H4CH2), 52.5 (OCH3), 53.7
m/z (%) 371 [M+] (3), 265 [M+ + H – PhCH2O] (5), (MeO2CCH), 55.2 (OCH3), 114.0 (o-MeOC6H4), 127.6
193 [M+ – NHC(O)CH(CH3)OCH2Ph] (12), 192 [M+
NHC(O)CH(CH3)OCH2Ph] (100), 122 (6), 121 (m-MeOC6H4), 132.3 (i-ClC6H4), 138.1 (p-ClC6H4), 158.8
–
(p-MeOC6H4), 128.5 (m-ClC6H4), 128.9 (o-ClC6H4), 130.3
H
–
Unauthenticated
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424
S. Tussetschla¨ger et al. · Synthesis of 5-Methoxy-4-benzyloxazoles from Tyrosine and m-Tyrosine
+
(i-MeOC6H4), 165.7 (C(O)NH), 172.1 (C(O)OMe). – GC- H – NHC(O)Ph] (100), 161 (9), 121 [H3COC6H4CH2
]
MS (EI, 70 eV): m/z (%) 347 [M+] (4), 288 (2), 192 [M+
–
(3), 105 (51), 91 [C7H7+] (2), 77 [C6H5+] (16), 51 (1). –
H – NHC(O)C6H4Cl] (100), 161 (9), 139 [C(O)C6H4Cl+] C18H19NO4 (313.3): calcd. C 68.99, H 6.11, N 4.47; found
(20), 121 [H3COC6H4CH2+] (73), 111 [C6H4Cl+] (9), C 69.15, H 6.21, N 4.24.
81 (2), 77 (3), 28 (1). – C18H18ClNO4 (347.8): calcd.
C 62.16, H 5.22, N 4.03 Cl 10.19; found C 62.19, H 5.35,
N 3.86, Cl 10.32.
General procedure for the preparation of oxazoles 6, as
described for 2-ethyl-5-methoxy-4-(4-methoxybenzyl)-1,3-
oxazole (6a): In a Schlenk flask 5a (100 mg, 0.38 mmol)
Methyl (S)-O-methyl-N-pyruvoyltyrosinate (5h): Yield:
74 mg, 0.22 mmol, 76%, colorless oil. – Rf = 0.44
(hexanes/EtOAc = 2 : 1). – [α]2D2 = +61.8◦ (c = 0.5,
CH2Cl2). – IR (ATR): ν = 3341 (C-H), 2954, 1744 (C=O),
1698 (C=O), 1612, 1511 (N-H), 1441, 1369, 1298,
1246 (C-O), 1152, 1032, 837 (C-H) cm−1. – 1H NMR
(500.15 MHz, CDCl3): δ = 1.55 (s, 9 H, C(CH3)3),
3.10 (d, J = 5.8 Hz, 2 H, MeOC6H4CH2), 3.73 (s,
3 H, OCH3), 3.79 (s, 3 H, OCH3), 4.80 (dt, J =
5.8 Hz, J = 8.2 Hz, 1 H, MeO2CCH), 6.83 (d, J =
8.7 Hz, 2 H, o-C6H4OCH3), 7.03 (d, J = 8.7 Hz, 2 H,
m-C6H4OCH3), 7.41 (d, J = 7.9 Hz, 1 H, NH). –
13C NMR (125.76 MHz, CDCl3): δ = 27.7 (C(CH3)3),
36.9 (MeOC6H4CH2), 52.5 (OCH3), 53.7 (MeO2CCH), 55.2
(OCH3), 84.8 (C(CH3)3), 114.2 (o-C6H4OCH3), 127.2 (p-
C6H4OCH3), 130.2 (m-C6H4OCH3), 157.0, 158.88, 158.92
(m-C6H4OCH3, NHC(O)C(O)Ot-Bu), 171.0 (CO2Me). –
GC-MS (CI, CH4): m/z (%) 338 [M+ + H] (45), 322 (2),
310 (9), 296 (3), 282 (100), 250 (7), 236 [M+ – CO2t-Bu]
(11), 222 (10), 208 [M+ – C(O)CO2t-Bu] (2), 192
[M+ – H – NHC(O)CO2t-Bu] (72), 176 (4), 161 (3), 121
[H3COC6H4CH2+] (44), 57 [C4H9+] (12). – C17H23NO6
(337.4): calcd. C 60.52, H 6.87, N 4.15; found C 60.77,
H 6.93, N 4.08.
was dissolved in phosphoryl chloride (2.5 ml, 27 mmol).
The reaction mixture was heated at 95 ◦C for 25 min, cooled
to r. t. and poured into an ice-cold saturated NaHCO3 solu-
tion (50 ml), and further NaHCO3 was carefully added to
adjust pH 8. After warming to r. t., the mixture was stirred
for 15 min and was then extracted with dichloromethane
(3×30 ml). The combined organic layers were washed with
brine (2 × 50 ml), dried (Na2SO4), and concentrated. The
pale yellow liquid was purified by chromatography on ba-
sic aluminium oxide (10 g) with hexanes/EtOAc (4 : 1, Rf =
0.58) to give 6a as a colorless liquid (46 mg, 0.19 mmol,
49%). – IR (ATR): ν = 2942, 1668 (N=C), 1612, 1579, 1511
(C=C), 1461, 1353, 1241 (C-O), 1175, 1141, 1108, 1063,
1034, 974, 795 cm−1. – 1H NMR (500.15 MHz, CDCl3):
δ = 1.26 (t, J = 7.6 Hz, 3 H, CH2CH3), 2.64 (q, J = 7.6 Hz,
2 H, CH2CH3), 3.66 (s, 2 H, MeOC6H4CH2), 3.77 (s, 3 H,
C6H4OCH3), 3.83 (s, 3 H, OCH3), 6.82 (d, J = 8.7 Hz, 2 H,
o-C6H4OCH3), 7.18 (d, J = 8.7 Hz, 2 H, m-C6H4OCH3). –
13C NMR (125.76 MHz, CDCl3): δ = 11.1 (CH2CH3),
22.0 (CH2CH3), 30.1 (MeOC6H4CH2), 55.3 (C6H4OCH3),
61.2 (OCH3), 113.9 (o-MeOC6H4), 114.9 (C-4), 129.5 (m-
MeOC6H4), 131.7 (p-MeOC6H4), 154.7, 156.5 (C-2, C-5),
158.05 (i-MeOC6H4). – MS (EI, 70 eV): m/z (%) 247 [M+]
(67), 219 (6), 218 [M+ – C2H5] (25), 204 [M+ – COCH3]
(11), 190 [M+ – C(O)C2H5] (9), 188 (20), 186 (9), 161 (5),
147 (8), 133 (26), 121 [H3COC6H4CH2+] (26), 89 (5),
77 (9), 57 (100), 29 [C2H5] (19), 28 (14). – HRMS (EI,
70 eV): calcd. for C14H17NO3 247.1208, found 247.1210
[M+]. – C14H17NO3 (247.3): calcd. C 68.00, H 6.93, N 5.66;
found C 67.62, H 6.88, N 5.62.
Methyl N-benzoyl-3-(methoxyphenyl)alaninate (8): Yield:
131 mg, 0.42 mmol, 92%, colorless oil. – Rf = 0.24
(hexanes/EtOAc = 3 : 1). – IR (ATR): ν = 3315 (C-H),
2950, 1975, 1739 (C=O), 1639 (C=O), 1601, 1526 (N-H),
1487, 1435, 1256 (C-O), 1213, 1152, 1039, 875 (C-H), 775,
691 cm−1. – 1H NMR (500.15 MHz, CDCl3): δ = 3.21
(dd, 2J = 13.8 Hz, 3J = 5.3 Hz, 1 H, MeOC6H4CH2),
5-Methoxy-4-(4-methoxybenzyl)-2-pentyl-1,3-oxazole
3.28 (dd, 2J = 13.8 Hz, 3J = 5.8 Hz, 1 H, MeOC6H4CH2), (6b): Yield: 47 mg, 0.16 mmol, 50%, pale yellow liquid. –
3.74 (s, 3 H, C6H4OCH3), 3.78 (s, 3 H, CO2CH3), 5.09 Rf = 0.37 (hexanes/EtOAc = 20 : 1). – IR (ATR): ν = 2932,
(dt, J = 7.5 Hz, J = 5.6 Hz, 1 H, MeO2CCH), 6.59 (d, 2860, 1668 (N=C), 1611, 1578, 1511 (C=C), 1463, 1354,
J = 7.3 Hz, 1 H, NH), 6.66 – 6.68 (m, 1 H, 5-H), 6.72 (d, 1242 (C-O), 1175, 1142, 1084, 1034, 990, 804 cm−1. –
J = 13.8 Hz, 1 H, 9-H), 6.80 (dd, J = 8.1 Hz, J = 2.4 Hz, 1H NMR (500.15 MHz, CDCl3): δ = 0.88 – 0.90 (m, 3 H,
1 H, 7-H), 7.20 (t, J = 7.9 Hz, 1 H, 8-H), 7.42 – 7.45 (m, (CH2)4CH3), 1.29 – 1.35 (m, 4 H, (CH2)2CH2CH2CH3),
2 H, m-C(O)Ph), 7.50 – 7.53 (m, 1 H, p-C(O)Ph), 7.72 – 7.74 1.67 – 1.73 (m,
2
H, CH2CH2(CH2)2CH3), 2.59 (t,
(m, 2H, o-C(O)Ph). – 13C NMR (125.76 MHz, CDCl3): δ = J = 8.7 Hz,
2
H, CH2(CH2)3CH3), 3.66 (s, H,
2
37.9 (MeOC6H4CH2), 52.5 (CO2CH3), 53.5 (MeO2CCH), MeOC6H4CH2), 3.77 (s, 3 H, C6H4OCH3), 3.83 (s,
55.1 (C6H4OCH3), 112.8 (C-7), 114.9 (C-5), 121.7 (C-9), 3 H, OCH3), 6.82 (d, J = 8.7 Hz, 2 H, o-MeOC6H4),
127.0 (o-C(O)Ph), 128.6 (m-C(O)Ph), 129.6 (C-6), 131.8 7.16 (d, J = 8.6 Hz, 2 H, m-MeOC6H4). – 13C NMR
(p-C(O)Ph), 133.9, 137.3 (C-4, i-C(O)Ph), 159.7 (C-6), (125.76 MHz, CDCl3): δ = 13.9 ((CH2)4CH3), 22.3
166.8 (C(O)Ph), 172.0 (CO2Me). – GC-MS (EI, 70 eV): m/z ((CH2)2CH2CH2CH3),
26.7
(CH2CH2(CH2)2CH3),
(%) 314 [M+ + H] (2), 313 [M+] (12), 282 (1), 254 [M+
CO2CH3] (3), 193 [M+ – NHC(O)Ph] (12), 192 [M+
–
–
28.6 (CH2(CH2)3CH3), 30.1 (MeOC6H4CH2), 31.3
((CH2)2CH2CH2CH3), 55.3 (C6H4OCH3), 61.2 (OCH3),
Unauthenticated
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S. Tussetschla¨ger et al. · Synthesis of 5-Methoxy-4-benzyloxazoles from Tyrosine and m-Tyrosine
425
113.8 (o-MeOC6H4), 114.8 (C-4), 129.5 (m-MeOC6H4), 339.1471, found 339.1454 [M+]. – C20H21NO4 (339.4):
131.7 (p-MeOC6H4), 154.7, 155.8 (C-2, C-5), 158.1 calcd. C 70.78, H 6.24, N 4.13; found C 71.33, H 6.48,
(i-MeOC6H4). – GC-MS (EI, 70 eV): m/z (%) 289 [M+] N 3.59.
(100), 274 (11), 260 (4), 246 [M+ – COCH3] (4), 230 (11),
2-(4-Chlorophenyl)-5-methoxy-4-(4-methoxybenzyl)-1,3-
218 (7), 201 (9), 186 (9), 173 (16), 159 (7), 147 [M+
–
oxazole (6g): Yield: 74 mg, 0.22 mmol, 76 %, yellow solid. –
◦
COCH3 – C(O)C5H11] (32), 140 (31), 133 (18), 121
[H3COC6H4CH2+] (61), 103 (10), 91 (15), 83 (33), 71
[C5H11+] (26), 63 (10), 55 (38). – C17H23NO3 (289.4):
calcd. C 70.56, H 8.01, N 4.84; found C 70.47, H 8.07,
N 4.87.
M. p. 78 – 79 C. – Rf = 0.36 (hexanes/EtOAc = 15 : 1). –
IR (ATR): ν = 2943, 2832, 1657 (N=C), 1612, 1510 (C=C),
1479, 1449, 1355, 1290, 1241 (C-O), 1178, 1087, 1037, 970,
822 (C-H), 768, 727 (C-Cl), 694, 620, 560 cm−1. – 1H NMR
(500.15 MHz, CDCl3): δ = 3.76 (s, 2 H, MeOC6H4CH2),
3.79 (s, 3 H, C6H4OCH3), 3.94 (s, 3 H, OCH3), 6.84 (d,
2-tert-Butyl-5-methoxy-4-(4-methoxybenzyl)-1,3-oxa-
zole (6c): Yield: 26 mg, 0.094 mmol, 28%, colorless J = 8.7 Hz, 2 H, o-MeOC6H4), 7.23 (d, J = 8.6 Hz, 2 H,
liquid. – Rf = 0.35 (hexanes/EtOAc = 20 : 1). – IR (ATR): m-MeOC6H4), 7.37 (d, J = 8.7 Hz, 2 H, o-ClC6H4), 7.84
ν = 2971, 1669 (N=C), 1612, 1566, 1511 (C=C), 1461, (d, J = 8.5 Hz, 2 H, m-ClC6H4). – 13C NMR (125.76 MHz,
1368, 1299, 1241 (C-O), 1174, 1136, 1078, 1035, 987, 819, CDCl3): δ = 30.2 (MeOC6H4CH2), 55.3 (C6H4OCH3),
782 cm−1. – 1H NMR (500.15 MHz, CDCl3): δ = 1.32 61.2 (CO2CH3), 113.9 (m-MeOC6H4), 117.1 (C-4), 126.2
(s, 9 H, C(CH3)3), 3.69 (s, 2 H, MeOC6H4CH2), 3.79 (s, (m-MeOC6H4), 126.7 (m-ClC6H4), 128.9 (o-ClC6H4),
3 H, OCH3), 3.79 (s, 3 H, OCH3), 6.82 (d, J = 8.7 Hz, 2 H, 129.5 (m-MeOC6H4), 131.3 (p-ClC6H4), 135.5 (i-ClC6H4),
o-MeOC6H4), 7.16 (d, J = 8.6 Hz, 2 H, m-MeOC6H4). – 151.3, 155.3 (C-2, C-5), 158.1 (i-MeOC6H4). – MS (EI,
13C NMR (125.76 MHz, CDCl3): δ = 28.4 (C(CH3)3), 70 eV): m/z (%) 329 [M+] (96), 314 (6), 287 (4), 270 [M+
–
30.2 (C(CH3)3), 33.7 (MeOC6H4CH2), 55.3 (C6H4OCH3), CO2CH3] (14), 254 (2), 209 (5), 191 (1), 164 (2), 147 (3),
61.0 (OCH3), 113.7 (o-MeOC6H4), 114.5 (C-4), 129.5 139 [C(O)C6H5Cl+] (100), 111 [C6H5Cl+] (13), 77 (4),
(m-MeOC6H4), 131.8 (p-MeOC6H4), 154.6, 158.0, 161.6 59 [CO2CH3+] (2), 43 [COCH3+] (1). – C18H16ClNO3
(C-2, C-5, i-MeOC6H4). – GC-MS (EI, 70 eV): m/z (%) 275 (329.8): calcd. C 65.56, H 4.89, N 4.25, Cl 10.75; found
[M+] (50), 260 (5), 232 [M+ – COCH3] (5), 218 (23), C 65.39, H 5.01, N 4.14, Cl 10.66.
204 (6), 190 [M+ – C(O)C4H9+] (7), 186 (6), 160 (7),
5-Methoxy-4-(3-methoxybenzyl)-2-phenyl-1,3-oxazole
+
158 (6), 146 (5), 133 (9), 126 (17), 121 [H3COC6H4CH2+
]
]
(9): In a Schlenk flask 8 (45 mg, 0.14 mmol) was dissolved
in toluene (2.5 ml). Then phosphoryl chloride (0.45 ml,
0.74 g, 4.83 mmol) was added via syringe and the reaction
mixture was heated at 100 ◦C for 2.5 h. After cooling
to r. t., the mixture was poured into an ice-cold saturated
(21), 108 (5), 91 (7), 89 (7), 77 (13), 63 (7), 57 [C4H9
(100). – C16H21NO3 (275.3): calcd. C 69.79, H 7.69, N 5.09;
found C 69.76, H 7.78, N 5.04.
2-[(Benzyloxy)methyl]-5-methoxy-4-(4-methoxybenzyl)-
1,3-oxazole (6d): Yield: 16 mg, 0.047 mmol, 40%, pale NaHCO3 solution (35 ml). The reaction mixture was
yellow liquid. – Rf = 0.48 (hexanes/EtOAc = 3 : 1). – IR warmed to r. t., stirred for a further 10 min and was then
(ATR): ν = 2938, 1964, 1661 (N=C), 1511 (C=C), 1454, extracted with toluene (1 × 15 ml) and dichloromethane
1360, 1244 (C-O), 1176, 1072, 1029, 983, 807 (C-H), 738, (3 × 30 ml). The combined organic layers were washed
698 cm−1. – 1H NMR (500.15 MHz, CDCl3): δ = 3.68 with brine (2 × 40 ml), dried (Na2SO4), and concentrated.
(s, 2 H, MeOC6H4CH2), 3.77 (s, 3 H, C6H4OCH3), The residual yellow oil was purified by chromatography on
3.85 (s, 3 H, OCH3), 4.44 (s, 2 H, CH2OCH2Ph), 4.58 silica gel with hexanes/EtOAc (3 : 1, Rf = 0.62) to give 9
(s, 2 H, CH2OCH2Ph), 6.82 (d, J = 8.7 Hz, 2 H, o- as a colorless oil (27 mg, 0.091 mmol, 63%). – IR (ATR):
MeOC6H4), 7.17 (d, J = 8.5 Hz, 2 H, m-MeOC6H4) ν = 2941, 1654 (N=C), 1599 (C=C), 1487, 1450, 1358,
7.28 – 7.30 (m, 1 H, p-PhCH2O), 7.33 (d, J = 8.1 Hz, 1260 (C-O), 1147, 1047, 982, 769, 689 cm−1. – 1H NMR
4 H, o-, m-PhCH2O). – 13C NMR (125.76 MHz, CDCl3): (500.15 MHz, CDCl3): δ = 3.79 (s, 3 H, C6H4OCH3), 3.81
δ = 30.0 (MeOC6H4CH2), 55.3 (C6H4OCH3), 60.9 (s, 2 H, MeOC6H4CH2), 3.95 (s, 3 H, OCH3), 6.75 (dd,
(OCH3), 64.4 (CH2OCH2Ph), 72.8 (CH2OCH2Ph), 113.9 J = 8.2 Hz, J = 2.5 Hz, 1 H, 3’-H), 6.89 – 6.91 (m, 2 H,
(o-MeOC6H4), 115.3 (C-4), 127.9 (p-PhCH2O), 128.0, 7’-H, 5’-H), 7.21 (t, J = 7.9 Hz, 1 H, 6’-H), 7.37 – 7.42 (m,
128.5 (o-PhCH2O, m-PhCH2O), 129.5 (o-MeOC6H4), 3 H, m-, p-Ph), 7.84 (d, J = 8.5 Hz, 2 H, o-Ph), 7.91 – 7.93
131.4 (p-MeOC6H4), 137.3 (i-PhCH2O), 151.2, 155.5 (dd, J = 7.9 Hz, J = 1.6 Hz, 2 H, o-Ph). – 13C NMR
(C-2, C-5), 158.1 (i-MeOC6H4). – MS (CI, CH4): m/z (125.76 MHz, CDCl3): δ = 31.0 (MeOC6H4CH2), 55.2
(%) 679 (5) [2M + H]+, 571 (3), 460 (9), 430 (13), 355 (C6H4OCH3), 61.1 (OCH3), 111.6 (C-3’), 114.3 (C-7’,
[M+ + CH4] (7), 340 [M+ + H] (100), 298 (6), 232 C-5’), 116.3 (C-4), 120.9 (C-7’, C-5’), 125.5 (o-Ph), 127.7
[M+ – OCH2Ph] (40), 218 [M+ – CH2OCH2Ph] (26), (i-Ph), 128.6 (m-, p-Ph), 129.4 (C-6’), 129.6 (m-, p-Ph),
201 (8), 148 (8), 132 (9), 121 [H3COC6H4CH2+] (21), 141.0 (C-2’), 152.2, 155.4, 159.7 (C-2, C-4, C-4’). – MS
91 [C7H7+] (42). – HRMS (DCI): calcd. for C20H21NO4 (EI, 70 eV): m/z (%) 295 [M+] (100), 294 (24), 252 [M+
–
Unauthenticated
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426
S. Tussetschla¨ger et al. · Synthesis of 5-Methoxy-4-benzyloxazoles from Tyrosine and m-Tyrosine
COCH3] (11), 236 [M+ – CO2CH3] (32), 234 (8), 209 (9), Acknowledgements
+
192 (3), 179 (5), 147 (5), 133 (5), 121 [H3COC6H4CH2
]
Generous financial support by the Deutsche Forschungs-
gemeinschaft, the Fonds der Chemischen Industrie and the
Ministerium fu¨r Wissenschaft, Forschung und Kunst des
Landes Baden-Wu¨rttemberg is gratefully acknowledged.
(4), 105 [C(O)Ph+] (95), 103 (8), 91 [C7H7+] (3), 77 (10),
51 (2). – HRMS (EI, 70 eV): calcd. for C18H17NO3
295.1208, found 295.1207 [M+]. – C18H17NO3 (295.3):
calcd. C 73.20, H 5.80, N 4.74; found C 73.00, H 5.96,
N 4.60.
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