A new entry for preparation of 2-substituted azaindoles

Article abstract of DOI:10.3987/COM-09-S(S)29

A series of 2-substituted 5-, 6- and 7-azaindoles were synthesized from iodo-N-(tert-butoxycarbonyl)aminopyridines via the corresponding allenyl derivatives.

Full text of DOI:10.3987/COM-09-S(S)29

HETEROCYCLES, Vol. 80, No. 1, 2010
133
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 133 - 139. © The Japan Institute of Heterocyclic Chemistry
Received, 20th May, 2009, Accepted, 15th June, 2009, Published online, 16th June, 2009
DOI: 10.3987/COM-09-S(S)29
A NEW ENTRY FOR PREPARATION OF 2-SUBSTITUTED
AZAINDOLES†
Montaser Shaykoon Ahmed Shaykoon, Fuyuhiko Inagaki, and Chisato
Mukai*
Division of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
cmukai@kenroku.kanazawa-u.ac.jp
Abstract – A series of 2-substituted 5-, 6- and 7-azaindoles were synthesized
from iodo-N-(tert-butoxycarbonyl)aminopyridines via the corresponding allenyl
derivatives.
Recently, we reported a novel method for the one-step synthesis of 2-methyl-3-substituted indoles 3
(R3=H) under the typical Stille conditions1 in the presence of tetrabutylammonium chloride (TBAC) that
effected the coupling reaction between N-acyl-2-iodoanilines 1 and the 1-(tributylstannyl)-1-substituted
allenes 2, followed by the formal endo-mode cyclization of the resulting allenyl species.2 An alternative
one-pot procedure including a successive Stille reaction (with or without TBAC) and a subsequent TBAF
treatment resulted in the efficient formation of the other types of 2-alkyl-3-substituted indoles (Scheme 1).
This method could successfully be applied to the synthesis of indomethacin.
R2
nBu3Sn
+
R2
R3
R1
R1
I
a,(b)
R3
•
N
Boc
NHBoc
1
2
3
a) Pd2(dba)3 (3 mol%), TFP (24 mol%). CuI (10 mol%),
TBAC (3 equiv.), DMF, rt; b) TBAF (3 eq.), THF, 0 °C.
Scheme 1. Palladium(0)-catalyzed Coupling Reaction of 1 with 2
The azaindole frameworks,3 a bioisostere of indole, are involved as a core framework in various natural
products and pharmaceuticals.4 We describe here a new synthetic protocol for the preparation of
† This paper is dedicated to Emeritus Professor Akira Suzuki on the occasion of his 80th birthday.

134
HETEROCYCLES, Vol. 80, No. 1, 2010
2-substituted azaindole derivatives based on the our own newly developed method for the construction of
the indole skeleton.
At the beginning of this program, synthesis of 2-substituted 7-azaindole was examined (Table 1).
According to the previously established conditions, which directly led N-acylanilines to the
corresponding indole derivatives, 2-aminopyridine derivative 4 was treated with 5a5 in DMF in the
presence of 3 mol % Pd2(dba)3, tri-2-furylphosphine (TFP, 24 mol %), CuI (10 mol %), and TBAC (3
equiv) at room temperature (condition A) for 60 h to afford unexpectedly a complex mixture (entry 1).
When the reaction was carried out in the absence of TBAC (condition B), the Stille coupling product 6a
was obtained in 86% yield (entry 2). Changing the solvent from DMF to THF decreased the chemical
yield of 6a (entry 3). Treatment of 6a with TBAF in THF gave 7-azaindole 7a in 58% yield as expected
(Scheme 2).
nBu3Sn
•
I
Pd(0)
+
N
N
•
Boc
N
NHBoc
N
NHBoc
7a
not observed
4
5a
6a
conditiona
time (h) 6a (%)
entry
1b
2
-
60
18
14
A
86
B
Bc
3
52
aCondition A: Pd2(dba)3 (3 mol%), TFP (24 mol%),
CuI (10 mol%), TBAC (3 equiv.), DMF, rt. Condition
B: Pd2(dba)3 (3 mol%), TFP (24 mol%), CuI (10
b
mol%), DMF, rt. Complex mixture was obtained.
cTHF was used under the same condition.
Table 1. Palladium(0)-Catalyzed Coupling Reaction of 4 with 5a
•
TBAF
THF, rt
N
N
Boc
N
NHBoc
58%
7a
6a
Scheme 2. Conversion of 6a into 7a
Compound 4 was exposed to other allenes 5b-f in the presence of a palladium catalyst providing the
corresponding Stille coupling products 6b-f in satisfactory yields as summarized in Table 2. As can be
seen in Table 2, the condition without TBAC (condition B) consistently produced the allenyl derivatives
6b-f (entries 1-5), whereas the condition with TBAC (condition A) was again found not to be effective for

HETEROCYCLES, Vol. 80, No. 1, 2010
135
our purpose (entries 6-10). This was not the case in the reaction of 1 with 2 where the condition with
TBAC generally afforded indole frameworks directly and the Stille coupling products were obtained
R
nBu3Sn
•
I
Pd(0)
R
+
•
N
N
Boc
N
NHBoc
N
NHBoc
7b-f
not observed
R
4
5b-f
6b-f
product and
entry
yield (%)
6b (91)
6c (67)
6d (88)
time (h)
allene
R
conditiona
B
B
1
2
3
3
4
5
5b
5c
5d
H
CH2OTBS
nC5H11
(CH2)2Ph
iPr
B
B
B
4
5
16
3
6e (81)
5e
5f
6f (85)
-
-
6
7
12
2
5b
H
A
A
5c CH2OTBS
nC5H11
7
12
4
6c (48)b
8
9
5d
A
A
A
(CH2)2Ph
-
5e
iPr
10
6f (42)
5f
aCondition A: Pd2(dba)3 (3 mol%), TFP (24 mol%), CuI (10 mol%),
TBAC (3 equiv.), DMF, rt. Condition B: Pd2(dba)3 (3 mol%), TFP
(24 mol%), CuI (10 mol%), DMF, rt. bAminopyridine 4 was
recovered in 36 % yield.
Table 2. Palladium(0)-Catalyzed Coupling Reaction of 4 with 5b-f
R
•
TBAF
R
N
N
N
N
Boc
THF, rt
N
NHBoc
Boc
7b-f
7c'
6b-f
entry
substrate
R
time (h) 7 (%)
1
2
3
4
5
1
3
4
4
4
6b
6c
6d
6e
6f
H
7b (69)
a
-
CH2OTBS
nC5H11
7d (74)
7e (37)b
7f (68)
(CH2)2Ph
iPr
a7c' was obtained in 67% yields. b6e was recovered in
50% yield.
Table 3. Conversion of 6 into 7

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HETEROCYCLES, Vol. 80, No. 1, 2010
under the condition without TBAC. Cyclization of allenylaminopyridine derivative 6b with TBAF gave
2-methyl-7-azaindole (7b) in 69% yield (Table 3, entry 1). In the reaction of 6c, 2-vinyl-7-azaindole (7c’)
(67%) was obtained instead of 7c (entry 2).6 2-Hexyl- and 2-isobutyl-7-azaindoles 7d,f were synthesized
from 6d,f in 74% and 68% yield, respectively (entries 3,5). In the case of 6e, the corresponding cyclized
product 7e was obtained in a rather low yield along with the recovery of the starting material (50%
yield)(entry 4). Thus, it was shown that the palladium-catalyzed coupling reaction of 2-aminopyridines
with 3-substituted allenylstannanes, followed by base treatment results in the production of the
corresponding 2-substituted-7-azaindoles.
Our efforts were then directed toward synthesis of 6-azaindoles. Treatment of 3-amino-4-iodopyridine
derivative 8 with 1,2-butadienyltributylstannane (5a) in the presence of Pd2(dba)3, TFP, and CuI in DMF
at room temperature (condition B), however, afforded neither allenylpyridine 9a nor 6-azaindole 10a
(Table 4, entry 1). In contrast to the conversion of 4 into 7, the condition with TBAC (condition A)
worked well in this case providing directly 2-ethyl-6-azaindole (10a) in 82% yield (entry 2). Other
6-azaindoles 10b-f possessing Me, (CH2)2OTBS, and hexyl substituents at the C2-position were easily
prepared in high yields under the condition A (entries 3-5). In the case of tributyl(5-phenyl-
1,2-pentadienyl)stannane (5e), 6-azaindole derivative 10e was isolated in a moderate yield (entry 6). The
condition with TBAC (condition A) was not useful for the preparation of 10f. In fact, a mixture of 10f
and the allenyl derivative 9f was obtained in 31% yield when exposed to condition A (entry 7).
R
nBu3Sn
I
•
Pd(0)
+
+
N
R
•
N
N
N
NHBoc
NHBoc
Boc
10a-f
R
8
9a-f
5a-f
product and
yield (%)
entry
time (h)
allene
5a
R
Me
Me
H
conditiona
B
-
1
2
3
4
18
2
5a
A
A
A
10a (82)
2
5b
10b (92)
10c (85)
10d (83)
10e (50)
9f/10f (31)b
8
5c
CH2OTBS
nC5H11
(CH2)2Ph
iPr
5
6
7
12
3.5
4
5d
5e
5f
A
A
A
aCondition A: Pd2(dba)3 (3 mol%), TFP (24 mol%), CuI (10 mol%),
TBAC (3 equiv.), DMF, rt. Condition B: Pd2(dba)3 (3 mol%), TFP
(24 mol%), CuI (10 mol%), DMF, rt. bProduct was a 1:1 mixture of
9f/10f.
Table 4. Palladium(0)-Catalyzed Coupling Reaction of 8 with 5a-f

HETEROCYCLES, Vol. 80, No. 1, 2010
137
nBu3Sn
1) Pd2(dba)3,TFP
CuI, DMF, rt
(condition B)
I
+
•
N
N
N
2) TBAF, THF, rt
NHBoc
Boc
10f
66% (2 steps)
5f
8
Scheme 3. Synthesis of 10f from 8 and 5f via 2 steps
An efficient synthesis of 2-isobutyl-6-azaindole (10f) (66%) was accomplished by using condition B,
followed by base treatment as shown in Scheme 3.
2-Substitued-5-azaindoles were our final target compounds in this investigation. By taking into account
the aforementioned two conditions A and B (condition with or without TBAC), we attempted the
conversion of 3-iodo-4-aminopyridine derivative 11 into the targeted compounds. Treatment of 11 with
allenylstannane 5a under condition A gave no desired products at all. Instead, the formation of
3-allenyl-4-aminopyridine derivative 12a was observed in 80% yield under condition B (Table 5, entry 1).
Condition A was found to be effective for the direct synthesis of 2-methyl-5-azaindole derivative 13b in a
satisfactory yield (entry 2). 2-Silyloxyethyl congener 13c was also directly formed under condition A, but
R
nBu3Sn
•
I
N
Pd(0)
N
N
+
+
•
R
N
Boc
NHBoc
NHBoc
11
R
5a-f
12a-f
13a-f
product and
yield (%)
conditiona time (h)
entry
allene
R
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
B
A
A
B
B
B
6
Me
H
12a (80)
13b (86)
13c (31)b
12d (80)
12e (62)c
12f (86)
2
CH2OTBS
nC5H11
19
12
24
16
(CH2)2Ph
iPr
aCondition A: Pd2(dba)3 (3 mol%), TFP (24 mol%), CuI (10 mol%),
TBAC (3 equiv.), DMF, rt. Condition B: Pd2(dba)3 (3 mol%), TFP (24
b
mol%), CuI (10 mol%), DMF, rt. Reaction was carried out at room
c
temperature for 16 h, then 80 °C for 3 h. 11 was recovered in 28%
yield.
Table 5. Palladium(0)-Catalyzed Coupling Reaction of 11 with 5a-f

138
HETEROCYCLES, Vol. 80, No. 1, 2010
R
•
N
TBAF
N
R
N
THF
0 °C
NHBoc
Boc
13a,d-f
12a,d-f
product and
time (h) yield (%)
substrate
12a
R
entry
1
2
3
1.5
5
Me
13a (78)
13d (66)a
13e (80)
nC5H11
(CH2)2Ph
12d
12e
2
iPr
4
3
13f (98)
12f
a12d was recovered in 18% yield.
Table 6. Conversion of 12 into 13
the chemical yield was rather low (entries 3). Allenylstannanes 5d-f having n-pentyl, phenethyl, and
i-propyl groups on the R position reacted with 11 under condition B to give the corresponding
3-allenyl-4-aminopyridine derivatives 12d-f in good yields (entry 4-6). Cyclization of 12a,d-f with TBAF
treatment proceeded without any difficulty to provide the 2-substituted-5-azaindoles 13a,d-f in
satisfactory yields. The results are summarized in Table 6.
In summary, we have developed a new procedure for the synthesis of 2-substituted-7-azaindoles on the
basis of successive Stille coupling of 2-amino-3-iodopyridines with the 1-(tributylstannyl)-3-substituted
allenes, followed by cyclization of the resulting allenyl derivatives with TBAF treatment.
2-Substituted-6-azaindoles could be directly synthesized in a one-pot process under the
palladium-catalyzed condition with TBAC. Synthesis of 2-substituted-5-azaindoles could be achieved by
a proper choice of reaction conditions (with or without TBAC/base treatment). These results (formation
of allene and/or azaindole) would reflect the electronic property of the amino functionality of the starting
pyridine derivatives. Thus, we could add an alternative method for the preparation of 2-substituted-5-, 6-,
and 7-azaindoles.
ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, for which we are grateful. M. S. A. S. thanks the
Ministry of Higher Education and Scientific Research, Egypt, for a fellowship.
REFERENCES
1. J. K. Stille, Angew. Chem., Int. Ed. Engl., 1986, 25, 508; V. Farina, V. Krishnamurphy, and W. J.
Scott, Org. React., 1997, 50, 1.

HETEROCYCLES, Vol. 80, No. 1, 2010
139
2. N. Kuroda, Y. Takahashi, K. Yoshinaga, and C. Mukai, Org. Lett., 2006, 8, 1843; C. Mukai and Y.
Takahashi, Org. Lett., 2005, 7, 5793.
3. For some references, see: F. Popowycz, J.-Y. Mérour, and B. Joseph, Tetrahedron, 2007, 63, 8689; F.
Popowycz, S. Routier, B. Joseph, and J.-Y. Mérour, Tetrahedron, 2007, 63, 1031; Z. Zhang, Z. Yang,
N. A. Meanwell, J. F. Kadow, and T. Wang, J. Org. Chem., 2002, 67, 2345; D. Hands, B. Bishop, M.
Cameron, J. S. Edwards, I. F. Cottrell, and S. H. B. Wright, Synthesis, 1996, 877; I. Mahadevan and
M. Rasmussen, J. Heterocycl. Chem., 1992, 29, 359; M. H. Fisher and A. R. Matzuk, J. Heterocycl.
Chem., 1969, 6, 775; R. H. Dodd, X. Doisy, and P. Potier, Heterocycles, 1989, 28, 1101.
4. A. Trejo, H. Arzeno, M. Browner, S. Chanda, S. Cheng, D. D. Comer, S. A. Dalrymple, P. Dunten, J.
Lafargue, B. Lovejoy, J. Freire-Moar, J. Lim, J. Mcintosh, J. Miller, E. Papp, D. Reuter, R. Roberts,
F. Sanpablo, J. Saunders, K. Song, A. Villasenor, S. D. Warren, M. Welch, P. Weller, P. E. Whiteley,
L. Zeng, and D. M. Goldstein, J. Med. Chem., 2003, 46, 4702; C. N. Hodge, P. E. Aldrich, Z. R.
Wasserman, C. H. Fernandez, G. A. Nemeth, A. Arvanitis, R. S. Cheeseman, R. J. Chorvat, E.
Ciganek, T. E. Christos, P. J. Gilligan, P. Krenitsky, E. Scholfield, and P. Strucely, J. Med. Chem.,
1999, 42, 819; C. Marot, P. Chavatte, L. Morin-Allory, M. C. Viaud, G. Guillaumet, P. Renard, D.
Lesieur, and A. Michel, J. Med. Chem., 1998, 41, 4453; J. R. Henry, K. C. Rupert, J. H. Dodd, I. J.
Turchi, S. A. Wadsworth, D. E. Cavender, B. Fahmy, G. C. Olini, J. E. Davis, J. L.
Pellegrino-Gensey, P. H. Schafer, and J. J. Siekierka, J. Med. Chem., 1998, 41, 4196; J. R. Henry
and J. H. Dodd, Tetrahednm Lett., 1998, 39, 8763ꢀ J. J. Kulagowski, H. B. Broughton, N. R. Curtis,
I. M. Mawer, M. P. Ridgill, R. Baker, F. Emms, S. B. Freedman, R. Marwood, S. Patel, S. Patel, C. I.
Ragan, and P. D. Leeson, J. Med. Chem., 1996, 39, 1941.
5. All allenes used in this study were prepared by the method of Marshall, see: D. R. Williams, L. Mi,
R. J. Mullins, and R. E. Stites, Tetrahedron Lett., 2002, 43, 4841; J. A. Marshall and C. M. Grant, J.
Org. Chem., 1999, 64, 8214; J. A. Marshall and X.-J. Wang, J. Org. Chem., 1992, 57, 1242.
6. Compound 7c (23%) was isolated after heating a solution of 6c in DMF at 80 °C for 3 h.