Mar 24, 2016 - cyclization of orthoâalkylamides with alkoxy bases at high temperatures to ... potassium metal by substituting potassium acetate, because the ...
FS
8
D
PR
labeled indole and d iscussed the mechanism involving potassium formate [10]. Applications of the original Madelung method are tabulated in Table 1 [11–16, 18–25]. As was found earlier, Augustine observed that potassium tert‐butoxide is superior to sodium methoxide, sodamide, lithium amide, and n‐butyllithium (Entries 4–6) [13]. The key factor in using potassium tert‐butoxide is to avoid sublimation of this base before cyclization has occurred. The mild conditions reported by Fuhrer and Gschwend (Entry 8) [15] have also been pursued by Houlihan and colleagues [16] (Entry 9) and earlier by Piozzi and Langella [17], who synthesized a large number of 2‐alkylindoles. The two‐step procedure shown in Entry 12 was first described by Clark and colleagues as summarized in Scheme 2 [26, 27]. This procedure is a powerful alternative to the classic Madelung protocol. A major development in the Madelung indole synthesis is the introduction of electron‐withdrawing groups to facilitate formation of a benzylic anion. A Wittig‐type solution to this situation is presented in the next section. Bergman and colleagues found that 4‐nitroindoles can be prepared via a modified Madelung indole synthesis that employs an oxalate ester functionality to acidify the benzylic hydrogen (Scheme 3) [28–30]. It might be noted that a conventional Madelung reaction on 4‐nitro‐2‐methylacetanilide caused an explosion [31]. The acylation of ortho‐methylnitrobenzenes (1 and 3), base‐catalyzed cyclization, and loss of
U
N
C
O
R
R
EC TE
Twenty‐six years after the initial discovery by Mauthner and Suida [1], Madelung explored and developed the cyclization of ortho‐alkylamides with alkoxy bases at high temperatures to give indoles [2–4]. These initial reactions are shown in Scheme 1, in addition to subsequent applications by other workers. Tyson found that potassium salts such as potassium amide and potassium t‐butoxide were better bases than the original sodium alkoxides in preparing indole itself (equation 3) [5]. Slightly lower yields were obtained with potassium amide, potassium ethoxide, and potassium methoxide, and virtually no indole was obtained with the corresponding sodium alkoxides. It should be noted that Madelung was unable to produce indole from ortho‐ toluide and sodium alkoxide. Galat and Friedman modified the Tyson discovery by avoiding the hazardous potassium metal by substituting potassium acetate, because the potassium ion is the key factor in these Madelung reactions (equation 4) [6]. In both reactions, the alcohol used to prepare the alkoxides is removed by distillation prior to the high‐ temperature reactions. A further modification by Tyson involved the generation of sodium or potassium o rtho‐toluide in the presence of carbon monoxide at high t emperature and high pressure. Yields of indole under these conditions ranged from 56% to 82% based on uncovered ortho‐toluidine [7]. An Organic Synthesis is available. Pichat and colleagues made use of Tyson’s work [5, 7–9] to prepare 14C‐2
O
O
Madelung Indole Synthesis
Indole Ring Synthesis: From Natural Products to Drug Discovery, First Edition. Gordon Gribble. © 2016 John Wiley & Sons, Ltd. Published 2016 by John Wiley & Sons, Ltd.
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Indole Ring Synthesis NaOEt
N R H R = Me, Et Me
Me
[eqn. 2] [3]
320–360 °C 26%
N H
O O
H N
NaOn-C5H11
N H
KOt-Bu (1.5 equiv.)
NH–CHO
Me
[eqn. 3] [5]
350–360 °C
N H
79%
NaOMe, KOAc
NH–CHO
300–310 °C 38%
N H
O
N H
N H
O
Me
[eqn. 1] [2]
R
360–380 °C
FS
Me O
[eqn. 4] [6]
PR
148
Scheme 1 Madelung Indole Syntheses
in equation 2, where the 2‐R1 substitution is the result of the ester R1CO2Me. Wacker and Kasireddy described a solid‐phase synthesis of 2,3‐disubstituted indoles (Scheme 5) [37] via the modified Madelung synthesis reported by Reinhoudt [34, 35]. The basic approach is shown in equation 1, and several synthesized indoles are posted. A collection of Madelung indole syntheses using electron‐withdrawing activation of the benzylic methylene group and other variations is summarized in Table 2 [38–43]. That extreme mildness is possible is shown by the cyclization in Entry 1, and Entry 4 features the synthesis of a new class of D2 in vivo agonists.
U
N
C
O
R
R
EC TE
D
g lyoxylate all occur in the same pot to give the indoles 2 and 4 (equations 1 and 2). Imidates such as 5 also undergo this facile cyclization to afford nitroindoles (equation 3). Melhado and Brodsky employed the Bergman cyclization to prepare 4‐nitroindole and derived compounds. Reinhoudt and coworkers used other electron‐withdrawing groups to promote a facile Madelung indole ring synthesis [33, 34]. Two examples are shown in Scheme 3 (equations 4 and 5). Bartoli and colleagues employed ortho‐trimethylsilylmethyl anilides to effect a Madelung cyclization in an intramolecular Peterson olefination, as shown in Scheme 4 [35, 36]. Whereas a normal Madelung product is obtained in equation 1, a reverse Madelung compound is the result
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149
Madelung Indole Synthesis Table 1 Applications of the Classic Madelung Indole Synthesis Entry
Substrate
Conditions
KOt-Bu 340–360 °C CHO
Me
NaNH2 N,N-DiEt-aniline 190–200 °C
Me
Me O
3
N H
N,N-diEt-aniline 200 °C
Et
Me O
4
KOt-Bu 300–325 °C
N R H R = Me, Ph, cyclopropyl
N
N H R = Me, Bn Me O
6
Me
R
N
C
N U
Et N H
R
KOt-Bu 300–340 °C
12
60–86%
13
72–92%
13
66%
13
76%
14
>90%
15
20–90%
16
N
N H
N N H Me N
KOt-Bu 340 °C
H N H
n-BuLi (2 equiv.) THF, rt
N H
N H
CH2R3 O R2
67%
N H
H
Me O
R1
9
R
O
N H
Me
12
R
R
Me O
7
63%
Me N H
KOt-Bu 300 °C
N
N H
Me
EC TE
Me O
5
11
FS
N H
11%
O
Me O
PR
Me 2
Ref.
N H
D
N H
% Yield
O
1
8
Product
N H R1 = H, OMe, Cl R2 = Ph, t-Bu, 1-adamantanyl R3 = H, Me
n-BuLi (2-3 equiv.) THF, rt
R1
R3 R2 N H
(continued overleaf)
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150
Indole Ring Synthesis
Table 1 (continued) Conditions
Me O
NaNH2 250 °C
N H
Me O
N H
Ph
1. sec-BuLi, –78 °C to 0 °C 2. DMF
O
N H
n
Me
O Me
R1
N H Me O
15
Ph
Ph
N U
R2
Me
H N
20
30–94%
21
22
Ph
Ph
N H
R1 R2
75–88%
23
55%
24
30–85%
25
N H
Me O N H
n-BuLi THF, 50 °C
Ph N H
O
C R1
17
65%
R
R O
N H
O
19
R2
Me O
16
KOt-Bu 320–330 °C
n-BuLi THF, 0 °C
N H R1 = H, Cl R2 = H, Cl, Me
D
Me O
EC TE
14
20%
N H
n
n = 1, 2, 3
H N
Ph
N Boc
R
NaNH2, DMA reflux
R = H, 5-Cl, 4-Me, 5-Me (indole numbering) Ph
18
N H
MeO
Me O
R
13
81%
t-BuLi THF, rt
Me O
12
(CH2)8CH3
O
N H
MeO
Ref.
N H
(CH2)8CH3
11
% Yield
O
10
Product
FS
Substrate
PR
Entry
n-BuLi THF, –20 °C to rt R3
R1 R3 R2
N H
R1 = H, NO2, OMe, F, Cl R2 = H, Cl, Me R3 = H, F, CF3, NO2
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Madelung Indole Synthesis 3 X
Me O N H
1. sec-BuLi
X
2. DMF
O
OH
aq. HCl THF
N Boc
X
151
[eqn. 1] N Boc
60–86%
X = H, 3-F, 3-Cl, 4-F, 4-Cl, 4-OMe, 4-Me R
N Boc
1. sec-BuLi
R
OMe
O
2. R
N
N H
Me
O 3. CF3CO2H, CH2Cl2, rt
D
>80% R1
R1
N H
OMe
O
2.
R2
N
Me
R2
X
EC TE
1. sec-BuLi
O
X
[eqn. 3]
PR
N H
O
60–61%
Me O
FS [eqn. 2]
3. aq. HCl THF
O
O
O
N H
R
1. sec-BuLi 2. DMF
[eqn. 4]
N H
O
X = H, 5-OMe, 7-OMe R1 = H, Ph R2 = Me, Bn, Ph, Bu
3. CF3CO2H, CH2Cl2, rt >80%
U
N
C
O
R
R
Scheme 2 Clark Modification of the Madelung Indole Synthesis
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152
Indole Ring Synthesis NO2
NO2 Me
(CO2Et)2, KOEt
O
[eqn. 1] [30]
DMF, 100 °C
N
N
80% 1
2
N H
69%
3
[eqn. 2] [30]
Ph
2. KOEt (CO2Et)2
Ph
FS
Me O
NO2
4
N Me
O
2. HOAc, EtOH reflux
H
5
93%
R1
CH2X O
R2
N
NaH, toluene, reflux [or KOt-Bu, THF, rt]
X = CN, CO2Me R1 = OMe, H R2 = Me, OMe, H n = 3–5
CH2SO2Ph
KOt-Bu
R
O N
N
R2
73%
[eqn. 4] [33]
(CH2)n
SO2Ph Ph
N Bn
[eqn. 5] [34]
R
Bn
THF, rt
Ph
Cl
[eqn. 3] [30]
X
R1
EC TE
61–88%
(CH2)n
Cl
N H
O2N
PR
N
CO2Me
D
O2N
Me NMe2
1. (CO2Me)2 KOt-Bu, DMF
O
1. (MeO)2SO2 DMF
O
NO2
U
N
C
O
Scheme 3 Applications of the Madelung Indole Synthesis
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Madelung Indole Synthesis
153
TMS MeO
MeO
1. LDA
O N
Ph
Me
Ph [eqn. 1] [35]
THF –20 °C 2. aq. HCl
N Me
TMS
N
O
N H
2Me
Li
0 °C
THF –10 °C
R
O
X
R1CO
N O
R1
R
PR
O
X = OMe, Me, Ph R = Ph, 4-MePh R1 = Ph, Me, i-Bu, Ar
Li
O
TMS X
FS
78%
TMS
X
N
O—
1. –TMSOLi
R1
2. NH4Cl
R
N H
52–74%
R1 + RCO2Me
[eqn. 2] [36]
D
O
X
EC TE
Scheme 4 Bartoli Modification of the Madelung Indole Synthesis
CN
CN
KOt-Bu
O N
DMF
Ph
Ph
N
TFA, rt
R
88%
CN
CN
R O C
NO2
N H
87%
N H
75%
CO2H
[eqn. 1] [37]
N
N H
N
Ph
N H
CN
N Ac
U
CN
Et3SiH
O
NMe2
85% CN O
Ph
N H 81%
Ph
N H 78%
N H
N
86%
Scheme 5 Wacker Solid-Phase Madelung Indole Synthesis
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154
Indole Ring Synthesis
Table 2 Miscellaneous Applications of Modified Madelung Indole Syntheses Substrate
Conditions
K2CO3, DMF 80–90 °C
N
N H
SO2Ar1
R
NaOH, DMSO 80–90 °C
CN
Ar2 N H
N Ar2
R = H, Cl Ar2 = Ph, 4-tol R
SO2Ar
3
N C N Ph
NaOH, DMSO rt
Ar = Ph, 4-tol
O Me O N H
O
CO2i-Pr
1. s-BuLi 2. DMF 3. HCl, THF
O
CO2Me O
6
Ph
CO2Me
Ph
68–83%
39
90%
40
83%
41
63%
42, 43
O
N Boc CO2i-Pr Ph N H CO2Me
NaOMe benzene reflux
Ph N
CO2Me
U
N
C
N
39
OH
PhCHO MeCN reflux
R
NH2
R
SO2Ph
5
EC TE
OTBS
N H
N H
D
R = H, Cl
4
56–83%
SO2Ar
PR
R
38
O
Ar1 = Ph, 4-tol
89%
O
SO2Ar1
2
Ref.
CO2H
O
R
% Yield
CO2Me
CO2Me O
1
Product
FS
Entry
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Madelung Indole Synthesis
155
U
N
C
O
R
R
EC TE
D
PR
O
O
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FS
References
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