Syntheses of 7-Azaindoles Starting from Pyridine Derivatives

The most convenient approach to azaindoles consists in the formation of the pyrrole ring starting from substituted pyridine derivatives.⁶⁷

Unfortunately, the Fischer cyclization⁸¹ as one of the classical indole formation strategies cannot directly be translated to the synthesis of azaindoles, since pyridyl derived hydrazines need harsher conditions limiting the substrate scope dramatically and often resulting in only modest yields.^66a,67,73a Yet, while the group of Suzenet easily managed the formation of 4- and 6-azaindoles via the Fischer pathway,⁸² the synthesis of 7-azaindoles proved to be more difficult.^73e Still, it could be realized by Kroth et al.

under microwave irradiation (MWI) in moderate to good yields (Scheme 21; A).⁸³

Scheme 21: Fischer cyclization (A), Hemetsberger reaction (B) and Hossain reaction (C) for the syntheses of 7-azaindoles.

81 a) E. Fischer, F. Jourdan, Ber. Dtsch. Chem. Ges. 1883, 16, 2241. b) For a review, see: M. Inman, C. J.

Moody, Chem. Sci. 2013, 4, 29.

82 M. Jeanty, J. Blu, F. Suzenet, G. Guillaumet, Org. Lett. 2009, 11, 5142.

83 H. Kroth (AC Immune S.A.), WO 2011/128455, 2011.

Furthermore, Fresneda and Molina were the first to successfully adapt the Hemetsberger reaction,⁸⁴ another straightfoward route to indoles, to the synthesis of 7-azaindole compounds (Scheme 21; B).⁸⁵ Similarly, Fournier and co-workers managed to prepare 7-azaindoles from 2-(N-benzylamino)-3-formylpyridine according to Hossain’s indole⁸⁶ synthesis (Scheme 21; C).⁸⁷

Analogously to the construction of indoles, for the assembly of azaindoles, organometallic strategies proved to be extremely useful. In this context, especially palladium catalysis plays a key role in the synthesis of 7-azaindoles, and besides Heck,^88,89 Suzuki^90,91 and Stille^92,93 reactions, cross-couplings of ortho-aminohalopyridines with terminal (two-step process; Castro-synthesis)⁹⁴ or internal alkynes (one-step process; Larock-annulation)⁹⁵ constitute one of the main approaches to these heterocycles (Scheme 22).⁶⁷

Scheme 22: Pd-catalyzed approaches to 7-azaindoles involving internal and terminal alkynes.

84 H. Hemetsberger, D. Knittel, Monatsh. Chem. 1972, 103, 194.

85 P. M. Fresneda, P. Molina, S. Delgado, J. A. Bleda, Tetrahedron Lett. 2000, 41, 4777.

86 M. E. Dudley, M. M. Morshed, C. L. Brennan, M. S. Islam, M. S. Ahmad, M.-R. Atuu, B. Branstetter, M. M. Hossain, J. Org. Chem. 2004, 69, 7599.

87 P. Levesque, P.-A. Fournier, J. Org. Chem. 2010, 75, 7033.

88 a) R. F. Heck, J. Am. Chem. Soc. 1968, 90, 5518. b) For an early review, see: R. F. Heck, Org. React.

1982, 27, 345.

89 For the use of Heck-type reactions in the synthesis of 7-azaindoles, see: N. Lachance, M. April, M. A.

Joly, Synthesis 2005, 2571.

90 a) N. Miyaura, A. Suzuki, J. Chem. Soc., Chem. Commun. 1979, 866. b) For an early review, see: A.

Suzuki, Pure Appl. Chem. 1985, 57, 1749.

91 For the use of Suzuki-type reactions in the synthesis of 7-azaindoles, see: V. Kumar, J. A. Dority, E. R.

Bacon, B. Singh, G. Y. Lesher, J. Org. Chem. 1992, 57, 6995.

92 a) D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 3636. b) For an early review, see: T. N.

Mitchell, J. Organomet. Chem. 1986, 304, 1.

93 For the use of Stille-type reactions in the synthesis of 7-azaindoles, see: T. Sakamoto, C. Satoh, Y.

Kondo, H. Yamanaka, Heterocycles 1992, 34, 2379.

94 C. E. Castro, E. J. Gaughan, D. C. Owsley, J. Org. Chem. 1966, 31, 4071.

95 a) R. C. Larock, E. K. Yum, J. Am. Chem. Soc. 1991, 113, 6689. b) R. C. Larock, E. K. Yum, M. D.

Refvik, J. Org. Chem. 1998, 63, 7652. c) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875.

Applying the Castro-sequence⁹⁴ for the construction of 7-azaindoles, the first step involves a Sonogashira cross-coupling⁹⁶ of an ortho-aminohalopyridine with a terminal alkyne. Thereby, the aminopyridine may either be unprotected or substituted with different groups such as tert-butyloxycarbonyl(Boc)-, tosylate(Ts)- or alkyl-moieties.

The thus-obtained alkynyl pyridine is then subjected to a cyclization reaction mainly performed under Cu(I)-catalysis or base-promotion. For example, the group of Kumar reported the Sonogashira coupling of a polyfunctional iodopyridine with TMS-acetylene followed by Cu-catalyzed cyclization of the thus-obtained alkyne to a 7-azaindole scaffold (Scheme 23).⁹⁷ The low yield is attributed to the loss of the TMS-goup either during the reaction or during the aqueous work-up.

Scheme 23: CuI-catalyzed synthesis of a 7-azaindole.

An improvement of this Cu(I)-catalyzed ring closing reaction was achieved by Pearson developing a route alternative to the Robison⁹⁸ approach for the synthesis of 5-amino-7-azaindole.⁹⁹ Thereby, ring closure was achieved under microwave irradiation (Scheme 24).

N O₂N

NH₂ I

N NH₂ SiMe₃

N N

H 93%

SiMe₃ (1.5 equiv) Pd(PPh₃)₂Cl₂(2 mol%)

CuI (2 mol%) Et₃N/THF/DMA

25 °C, 16 h

CuI (20 mol%) NMP, MWI 190 °C, 0.5 h O₂N

O₂N

N N

H H₂N

75% over 2 steps

H₂, Pt/C

Scheme 24: Cu(I)-catalyzed synthesis of a 7-azaindole under microwave irradiation.

96 a) K. Sonogashira, Y. Thoda, N. Hagihara, Tetrahedron Lett. 1975, 4467. b) F. Monnier, F. Turtaut, L.

Duroure, M. Taillefer, Org. Lett. 2008, 10, 3203. c) C. He, J. Ke, H. Xu, A. Lei, Angew. Chem. Int. Ed.

2013, 52, 1527.

97 V. Kumar, J. A. Dority, E. R. Bacon, B. Singh, G. Y. Lesher, J. Org. Chem. 1992, 57, 6995.

98 M. M. Robison, B. L. Robison, F. P. Butler, J. Am. Chem. Soc. 1959, 81, 743.

99 S. E. Pearson, S. Nandan, Synthesis, 2005, 2503.

However, the examples shown above clearly indicate that ring closing reactions achieved with Cu-catalysts usually require rather harsh conditions. Another, milder protocol for the cyclization would therefore be highly desirable. To this end, base-promotion displays a valuable alternative, which has recently been proven by Knochel and co-workers employing bases like potassium hydride and cesium tert-butoxide in N-methylpyrrolidin-2-one (NMP) to smoothly convert an alkyne-substituted aminopyridine to the appropriate 7-azaindole derivative 72% yield (Scheme 25).¹⁰⁰

N Me

NH₂ N

Me

NH 72%

KH (1.3-1.7 equiv) NMP, 25 °C

3-12 h

Scheme 25: Potassium hydride-promoted synthesis of a 7-azaindole.

More recently, Riether and co-workers described the mild cyclization of N-Boc-protected alkynylated pyridines mediated by 1,8-diazabicycloundec-7-ene (DBU) for the synthesis of unprotected 7-azaindoles (Scheme 26). Noteworthy, the Boc-protection was crucial in this reaction sequence, since unprotected aminopyridines did not yield the desired fused heterocycles under these conditions.

Scheme 26: Synthesis of a 7-azaindole via DBU-promotion.

Another modification of the method involving terminal alkynes was achieved by Knight describing the construction of a 2-substituted 3-iodo-7-azaindole via an iodocyclization process employing a tosylate-protected alkyne to furnish a 3-iodinated heterocycle (Scheme 27).¹⁰¹

Scheme 27: Synthesis of a 7-azaindole via iodocylization.

100 C. Koradin, W. Dohle, A. L. Rodriguez, B. Schmid, P. Knochel, Tetrahedron 2003, 59, 1571.

101 M. Amjad, D. W. Knight, Tetrahdron Lett. 2004, 45, 539.

The Larock indole⁹⁵ synthesis, involving the palladium-catalyzed annulation of terminal alkynes (see Scheme 22), is one of the most valuable pathways for the construction of indoles and has found applications in the synthesis of 7-azaindoles, as well. If the alkyne substitutents are adequately different, these reactions usually proceed with high regioselectivities having the bulkiest group ending up in the C2-position of the (aza)indole core.⁶⁷

Already in 1998, Yum et al. described the smooth construction of 2,3-substituted 7-azaindoles by reaction of N1-protected pyridines with internal alkynes (Scheme 28).¹⁰² In this context, they discovered that 1) the addition of LiCl dramatically increases the yields, and 2) the presence and the nature of the protecting group attached to the N1-atom is crucial for a successful conversion. Thus, the absence of substituents on N1 or protecting groups such as acetyl-, pivaloyl- and Boc-moieties led either to no reaction at all or to very low yields of cyclized product, while protective groups such as alkyl or benzyl substituents guaranteed good results.¹⁰²

Scheme 28: Syntheses of 7-azaindoles via Larock heteroannulation of N1-protected aminopyridines.

A progress in this field could be achieved by Ujjainwalla and co-workers managing to use unprotected ortho-aminoiodopyridines in the presence of Pd(dppf)Cl2 (dppf = (diphenylphosphino)ferrocene) to prepare 2,3,5-substituted 7-azaindoles by Larock-heteroannulation with internal alkynes (Scheme 29).¹⁰³

102 S. Park, J.-K. Choi, E. K. Yum, D.-C. Ha, Tetrahedron Lett. 1998, 39, 627.

103 F. Ujjainwalla, D. Warner, Tetrahedron Lett. 1998, 39, 5355.

Scheme 29: Syntheses of 7-azaindoles via Larock synthesis of N1-uprotected amino pyridines.

Organolithium-based strategies display another useful organometallic approach to 7-azaindoles. Thus, in 2008, Collum and co-workers reported the successful synthesis of a 7-azaindole via the Chichibabin cyclization starting from 2-fluoro-3-picoline (Scheme 30; A).¹⁰⁴ Similarly, when 3-picoline, bearing no fluorine substitutent in the 2-position, is treated with lithium N,N-diisopropylamide (LDA)¹⁰⁵ and reacted with a nitrile, the corresponding 2-substituted 7-azaindole was obtained after oxidation during work-up (Scheme 30; B).¹⁰⁶

Scheme 30: Organolithium-based strategies for the syntheses of 7-azaindoles starting from 3-picolines.

104 Y. Ma, S. Breslin, I. Keresztes, E. Lobkovsky, D. B. Collum, J. Org. Chem. 2008, 73, 9610.

105 a) M. Hammell, R. Levine, J. Org. Chem. 1950, 15, 162. b) For a recent review, see: D. B. Collum, A. J.

McNeil, A. Ramirez, Angew. Chem. Int. Ed. 2007, 46, 3002.

106 M. L. Davis, B. J. Wakefield, J. A. Wardell, Tetrahedron 1992, 48, 939.

Furthermore, these heterocycles are also available by lithiation of Boc-protected 2-aminopicoline and subsequent quenching with an aldehyde to afford a 2-arylated and N1-unprotected 7-azaindole after cyclization (Scheme 31; A).¹⁰⁷ When the 3-methyl group of such Boc-protected aminopyridines was modified with other substituents, treatment with nBuLi¹⁰⁸ and subsequent trapping with DMF or Weinreb amides furnished 2,3-substituted 7-azaindoles (Scheme 31; B).¹⁰⁹

A

B N

Me NH O OtBu

S CHO tBuLi

N NH

O OtBu HO

S

N N

H S

64%

82%

1) NaH, DMF 25 °C, 10 min 2) Tf₂O, 120 °C

3 h 3) NaOH

N NH

O OtBu N N

H Ph

70%

5.5 M HCl 50 °C, 40 min 1)nBuLi (2.0 equiv)

THF, 0 °C, 1 h 2)

Ph N(Me)OMe O

(1.2 equiv)

N N

Ph

82%

OH O OtBu

Scheme 31: Organolithium-based strategies for the syntheses of 7-azaindoles.

A lithiation-based approach to 7-azaindoles could as well be accomplished involving 2,6-dichloropyridine demonstrated by Schirok (Scheme 32).¹¹⁰

Scheme 32: Organolithium-based strategy for the synthesis of a 7-azaindole.

107 J. Parcerisa, M. Romero, M. D. Pujol, Tetrahedron 2008, 64, 500.

108 H. Gilman, R. L. Bebb, J. Am. Chem. Soc. 1939, 61, 109.

109 D. Hands, B. Bishop, M. Cameron, J. S. Edwards, I. F. Cottrell, S. H. B. Wright, Synthesis 1996, 877.

110 H. Schirok, Synlett 2005, 1255.

Im Dokument New Strategies for the functionalization of N-heterocycles using Li-, Mg- and Zn-organometallics (Seite 38-45)