Vilsmeier methodology for the synthesis of 3-(2-N-phthaloylacyl)indole derivatives, and its application to the synthesis of the GCDEF rings of diazonamide

Article abstract of DOI:10.1016/S0040-4039(00)02023-2

The synthesis of the GCDEF fragment of diazonamide was achieved using a modified Vilsmeier procedure that allows ready access to 3-(2-N-phthaloylacyl)indole derivatives.

Full text of DOI:10.1016/S0040-4039(00)02023-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 627–629
Vilsmeier methodology for the synthesis of
3-(2-N-phthaloylacyl)indole derivatives, and its application to the
synthesis of the GCDEF rings of diazonamide
Jennifer D. Kreisberg, Philip Magnus* and Edward G. McIver
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
Received 25 October 2000; revised 6 November 2000; accepted 7 November 2000
Abstract—The synthesis of the GCDEF fragment of diazonamide was achieved using a modified Vilsmeier procedure that allows
ready access to 3-(2-N-phthaloylacyl)indole derivatives. © 2001 Elsevier Science Ltd. All rights reserved.
In 1991 Fenical and Clardy reported the structure of
diazonamide A, 1 and diazonamide B, 2, Scheme 1.1
The diazonamides have generated some consider-
able synthetic interest,2 and the synthesis of oxazoles
and bis-oxazoles has undergone renewed interest.3–5 In
this letter we report the synthesis of the GCDEF frag-
ment (right-hand side) 4 of diazonamide, and a
Vilsmeier-based method to introduce the oxoethylamine
side chain at the 3-position of an indole ring.6 The
synthesis of 4 is most readily accomplished from the
Robinson–Gabriel oxazole dehydration of 5.7 Conse-
quently, we required a method that would convert an
indole into its 3-aminoacyl derivative.8 Surprisingly,
there is little information describing this transforma-
tion.9
Treatment of 6 with ethyl magnesium chloride followed
by 810 gave a mixture of 9, 10 and 11 (14%) (Scheme 2).
Transmetallation of the magnesium bromide salt of 6
with zinc chloride11 and addition of 8 gave 11 (40–
46%), but upon scale-up (500 mg) substantial amounts
of 10 were formed.
The N,N-dimethylamide derivative 13,12 in dioxane,
was treated with POCl3 and heated at 100°C for 1 h.
The solution was cooled to room temperature, 6 was
added, and the mixture heated at 95°C for 3 h. The hot
solution was poured into water, the pH adjusted to 8
(2.5 M NaOH), and the mixture was boiled for 10 min,
cooled in ice and filtered to give 11 (80%). Extension of
the procedure to 7 gave 12 (95%).
Me
H
Me
Me
H
Me
Me
H
Me
H
N
Cl
C
N
N
N
N
N
HN
H2N
H2N
F
E
O
F
E
O
Cl
R3HN
O
O
O
B
O
O
I
O
A
G
G
D
D
NH
NH
NH
H
RO
RO
O
R1
OH
C
5
4
O
R2
1, Diazonamide A, R1 = OH, R2 = H, R3 =
2, Diazonamide B, R1 = OH, R2 = Br, R3 = H.
3, R1 = O2 (acetal), R2 = Br, R3 = COC6H4Br-p.
NH2
Scheme 1.
Keywords: diazonamide; Vilsmeier; acylamino indoles.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02023-2

628
J. D. Kreisberg et al. / Tetrahedron Letters 42 (2001) 627–629
NPhth
O
O
O
EtMgCl
NH
N
N
+
O
RO
MeO
MeO
(NPhth)
O
NPhth
NPhth
9
10
N
Cl
8
6 (R = Me)
O
NPhth
7 (R = Bn)
O
MeMgBr followed by ZnCl2/8
NH
RO
O
11 (R = Me)
12 (R = Bn)
NPhth
13
Me2N
POCl3/dioxane/95°C
Scheme 2.
Me
Me
O
Me
H
Me
O
NR
H
H
O
N
N
N
N
O
BocHN
R'HN
O
NH
DMF
EDCI/HBT
O
Burgess
BnO
NR
NCO2Me
reagent
Me
H
Me
BnO
RO
12 (R = Phth)
14 (R = H,H)
N
(H2N)2
BocHN
HCO2NH4
Pd/C
TFA
CO2H
16 (77%, R = H)
17 (91%, R = CO2Me)
18 (88%, R = Bn, R' = Boc)
19 (92%, R = R' = H)
O
15
Scheme 3.
Table 1.
.

J. D. Kreisberg et al. / Tetrahedron Letters 42 (2001) 627–629
629
Kohrt, J. Synlett 1995, 415. Bagley, M.; Buck, R.; Hind,
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2000, 41, 835. Magnus, P.; McIver, E. G. Tetrahedron
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Chem. Ber. 1907, 40, 2648. Gabriel, S. Chem. Ber. 1910,
43, 1283. For the use of the Burgess reagent for this
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Heterocycles 1979, 12, 1457. Bergman, J. J. Heterocycl.
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Hydrazinolysis of 12 (R=Phth), Scheme 3, gave 14,
which was coupled to 1513 to give 16 (77% from 12).
Protection of the indole 16 as the carbamate derivative
17 followed by dehydration with the Burgess reagent
gave 18 (71%). Hydrogenolysis of the benzyl ether
followed by treatment with trifluoroacetic acid resulted
in the aminophenol 19 (77% from 18).14 The overall
sequence provides a convenient route to the GCDEF
fragment (right-hand side) of diazonamide in multi-
gram quantities, and avoids the dehydrogenation
methodology used to introduce the 3-carbonyl group
that requires 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ).15
Further examples of the Vilsmeier procedure for the
synthesis of 3-(2-N-phthaloylacyl)indole derivatives are
listed in Table 1. Interestingly, 2-phenyl indole 24 gave
25 and the remarkably stable enamine derivative 26.
The enamine 26 was converted into 25 (87%) by treat-
ment with 2 M HCl in THF heated at reflux (2 h).
Acknowledgements
The National Institutes of Health (CA 50512), Robert
A. Welch Foundation, Merck Research Laboratories
and Novartis are thanked for their support of this
research.
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