In situ anionic shielding for regioselective metalation: Directed peri and iterative metalation routes to polyfunctionalized 7-azaindoles

Article abstract of DOI:10.1002/anie.201108016

Strolling the ring: A general regioselective directed peri(C4)-metalation route to 1 through an in situ N-anionic protection of C2 is reported. The azaindoles may be elaborated by directed ortho metalation (DoM) and Suzuki coupling to more complex heterocyclic systems. An iterative ring-walk DoM sequence furnishes the exhaustively substituted 2. DMG=directed metalation group, TMEDA=N,N,N′,N′-tetramethylethylenediamine, TMS=trimethylsilyl. Copyright

Full text of DOI:10.1002/anie.201108016

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Angewandte
Communications
DOI: 10.1002/anie.201108016
Synthetic Methods
In Situ Anionic Shielding for Regioselective Metalation: Directed peri
and Iterative Metalation Routes to Polyfunctionalized 7-Azaindoles**
Cꢀdric Schneider, Emilie David, Anton A. Toutov, and Victor Snieckus*
Dedicated to Professor F. Marsais and Professor G. Quꢀguiner
Herein we report on a) the unusual peri(C4)-metalation[1]
reactivity of N-unprotected 7-azaindole 3-tertiary amide and
3-sulfonamide dianion frameworks (1, Figure 1) using the new
concept of anionic shielding of C2 and its generalization for
the synthesis of 4-substituted derivatives, b) the use of the
Figure 2. 7-Azaindole-containing pharmaceuticals and natural prod-
ucts.
isomeric systems, the commercially available 7-azaindole[9]
systems have received the greatest synthetic attention
Figure 1. Metalation chemistry of 7-azaindoles.
because of their broad spectrum of biological activity.[7,10,11]
To date, the majority of synthetic methods for 7-azain-
thereby derived powerful directed metalation group (DMG)
CONEt2 on C4 for the directed ortho metalation (DoM) of
C5, thus leading, through the linked Suzuki[2] and directed
remote metalation (DreM)[3] chemistries, to new annulated
heterocyclic systems, and c) the use of a ring-walk metalation
platform (2) for the regioselective construction of polysub-
stituted 7-azaindoles. The reported results constitute, to the
best of our knowledge, the first observation of peri-metalation
of CONEt2 and SO2NEt2 DMG systems,[4,5] demonstrate the
advantages of multiple sequential DoM reactions, and offer
a rational and general regioselective route to polysubstituted
7-azaindoles and the thereby derived, previously unknown,
heterocycles of potential pharmaceutical significance.
doles have provided N1-, C2-, or C3-substituted systems, with
few procedures offering general solutions for pyridine ring
functionalization.[12,13] To place into perspective with our
work, the previous DoM synthetic chemistry of 7-azaindoles
is based on the corresponding indole results[14] leading to the
regioselective C2 functionalization (3; Figure 1)[15] with very
limited examples of selective pyridine ring metalation and the
requirement of circuitous, multistep sequences (4).[16]
To test the notion that the formation of the N anion of 7-
azaindole would constitute a protective measure against the
normally favored C2 deprotonation and thereby lead to
pyridine ring metalation, systematic experiments were carried
out using the CD3OD electrophile quench (Table 1). Metal-
ation of 5a in THF [0.07m], using 2.5 equivalents of sBuLi/
TMEDA at À788C and normal addition conditions, showed
a clean reaction at C4 to yield 6a in 95% yield (D1 = 80%;
entry 1). Attempts to drive the metalation to completion
(À408C, 1 h) resulted in higher D1 incorporation (90%;
entry 2) but also with the formation of by-products resulting
from sBuLi and, surprisingly, THF addition to the amide (see
the Supporting Information).[17] Through careful optimiza-
tion, we found that after 5 minutes and 15 minutes of
metalation time at À408C, clean but lower C4 deuterium
incorporation of 65% and 80%, respectively (Table 1,
entries 3 and 4) were achieved whereas longer reaction
times at À408C led to the formation of by-products with
a similar deuterium incorporation (entry 5). Consideration of
the metalation time and observed insolubility of intermediate
anionic species led to the establishment of optimized reaction
conditions[18] (higher dilution [0.03m] and inverse addition of
Although first synthesized in 1927,[6] the azaindole
(pyrrolopyridine) ring systems have attracted considerable
attention from the synthetic chemistry community over the
past decade because they represent promising building blocks
with evolving potential and demonstrated value in pharma-
ceuticals and agrochemicals (Figure 2).[7,8] Among the four
[*] Dr. C. Schneider, Dr. E. David, A. A. Toutov, Prof. V. Snieckus
Department of Chemistry, Queen’s University
Kingston, Ontario, K7L 3N6 (Canada)
E-mail: snieckus@chem.queensu.ca
[**] We thank Dr. R Wang for X-ray structure determination and Dr. F.
Sauriol for assistance with NMR analysis and interpretation. We
thank the NSERC Discovery Grant Program for the support of our
synthetic programs.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108016.
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Table 1: Optimization of time and temperature in the metalation of
azaindole 5a.
Table 2: Scope of C4 peri-metalation reaction of 3-CONEt2 and 3-
SO2NEt2 7-azaindole 5a,b.
Entry
T [8C]
t [min]
D1 [%][a]
Product
1
2
3
4
5
6
À788C
À408C
À408C
À408C
À408C
À408C
60
60
5
15
30
10
80[b]
90[b]
65[b]
80[b]
85[b]
95[c]
6a
E+
Product (DMG, E)
Yield [%][a]
6a[d]
6a
Entry
1
CD3OD
6a (CONEt2, D)
95
85
94
87
95
6a
6b (SO2NEt2, D)
9a (CONEt2, Me)
9b (SO2NEt2, Me)
10a (CONEt2,
p-MeOC6H4CHOH)
10b (SO2NEt2,
6a[d]
6a
2
3
MeI
[a] D1 incorporation at C4 determined by 1H NMR spectroscopy.
[b] Normal addition, [0.07m]. [c] Inverse addition, [0.03m]. [d] A side
product was also obtained; see the Supporting Information.
p-MeOC6H4CHO
85
p-MeOC6H4CHOH)
11a (CONEt2, CHO)
11b (SO2NEt2, CHO)
12a (CONEt2, Bpin)
12b (SO2NEt2, Bpin)
13a (CONEt2, OH)
13b (SO2NEt2, OH)
14a (CONEt2, F)
14b (SO2NEt2, F)
15a (CONEt2, Cl)
15b (SO2NEt2, Cl)
4
5
6
7
8
DMF
94
50[b]
54
2.5 equiv of sBuLi/TMEDA, À788C for 30 min then À408C,
10 min) which afforded the C4-deuterated product 6a (D1 =
95%; entry 6).[19] For complete studies using CD3OD and MeI
quenches, see the Supporting Information.
To determine the effect of the N anion in the C4
deprotonation event, the N-MOM azaindole 7 was subjected
to the À78 to À408C, inverse addition protocol using either
1.2 equivalents or 2.5 equivalents of sBuLi/TMEDA. When
using 1.2 equivalents of sBuLi/TMEDA, the C2-deuterated
product 8a was obtained in 95% yield (D1 = 95%; Scheme 1).
iPrOBpin
iPrOBpin then H2O2
NFSI
73
74
64
–
72[b,c]
85[d]
45[d]
Cl3CCCl3
[a] Yield based on the isolated product after flash chromatography.
[b] Yield based on 1H NMR analysis of crude material after 2 steps. [c] To
facilitate purification, the PhSO2 derivative was prepared and purified by
preparative HPLC. [d] The Boc derivative was prepared to facilitate
purification. NFSI=N-fluorodibenzenesulfonimide, pin=pinacol.
11b is due to the difficulty in purification of the latter product
(entry 4). The borylated derivatives 12a,b, although formed
quantitatively (1H NMR), were isolated in modest yields
presumably because of their instability to silica gel chroma-
tography (entry 5). Nevertheless, their treatment with hydro-
gen peroxide[20] led to the interesting 4-hydroxy derivatives
13a,b (entry 6). These structures were confirmed by nOe
correlation, thus ruling out the possibility of the alternative
pyridone tautomeric forms.
Although the reaction of dimetalated derivative 5a with
NFSI led only to the recovery of the starting material (95%),
the corresponding 5b afforded the 4-fluoro azaindole 14b
(Table 2, entry 7).[21] Chlorination with Cl3CCCl3 proceeded
well to afford the compounds 15a,b in 45–85% yields over
two steps (entry 8). The structure of 10a was confirmed by
single-crystal X-ray structure determination (see the Sup-
porting Information). Using TMSCl as an electrophile, both
mono- and bis(silylated) products (16a and 17a, respectively)
were obtained (Scheme 2). To preclude the formation of the
minor product 17a, previously precedented to occur as an N-
to C2 TMS migration in indoles,[22] the reaction mixture was
maintained at À788C for 1 hour after addition of TMSCl and
quenched with MeOH at the same temperature. In the case of
5b, the optimum 70% conversion (1H NMR) into 16b was
achieved by maintaining the reaction temperature at À788C
for 4 hours after the addition of TMSCl. Carrying out
Scheme 1. Deuteration studies on the 7-azaindole 7. The metalation
was run at À788C for 30 min, then À408C for 10 min, with a subse-
quent CD3OD quench at À788C.
In contrast, the use of 2.5 equivalents of sBuLi/TMEDA led
to a complex mixture from which the main product 8b was
isolated in 68% yield (C2 D1 = 95%, and MOM D2 = 25%).
Significantly, the N-MOM C4-deuterated azaindole deriva-
tive was not detected. As a result of this stark contrast in
selectivity between 5a and 7, we conclude that the C4
lithiation regioselectivity is driven by the N-anionic shielding
effect (Table 1 and Scheme 1).
With the optimized inverse addition conditions in hand,
the establishment of the scope of the peri(C4)-metalation
reaction was undertaken for the azaindole 5a and extended to
the corresponding 3-SO2NEt2 derivative 5b (Table 2). Thus,
aside from deuterated products (6a,b), methylated (9a,b),
carbinol (10a,b) and 4-formyl (11a) derivatives were
obtained in both series in good to excellent yields. Note-
worthy is the formation of the methylated derivatives 9a,b to
the complete exclusion of N-methylated products, most likely
a result of the insolubility of intermediate anionic species (for
details, see the Supporting Information). The difference in
terms of yield between the two formylated products 11a and
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cross-coupling of 24 gave the 5-aryl derivative 25, which was
converted by the DreM protocol[3] into the fused azafluor-
enone[25] 26 (54%), which represents an important skeleton in
medicinal chemistry (Scheme 4).[26]
Scheme 2. Reaction of metalated 5a,b with TMSCl and ClCONEt2.
[a] Metalation: sBuLi/TMEDA (2.5 equiv), inverse addition, THF
[0.03m], À788C, 30 min, then À408C, 10 min; and then E+, À788C;
[b] Boc Protection: Boc2O (1.5 equiv), DMAP (cat.), CH3CN, 12 h, RT.
[c] The reaction performed on a 3 g scale gave similar yields. Boc=
tert-butoxycarbonyl, DMAP=4-(dimethylamino)pyridine, THF=tetrahy-
drofuram, TMS=trimethylsilyl, TMEDA=N,N,N’,N’-tetramethylethy-
lendiamine.
Scheme 4. a) NaH, PhSO2Cl, DMF, 708C; b) [PdCl2(dppf)],·CH2Cl2
(8 mol%), K2CO3 (4 equiv), 3,4-diMeOC6H3B(OH)2, 1,4-dioxane/H2O
(2:1), 1008C; c) LDA (10 equiv), THF, 608C, 4 h. dppf=1,1’-bis(diphe-
nylphosphanyl)ferrocene, DMF=N,N’-dimethyfomamide, LDA=
lithium diisopropylamide.
a quench with the important DMG-generating electrophile
ClCONEt2 (3.0 equiv) afforded a mixture of mono- and
dicarbamoylated products (18a,b and 19a,b, respectively;
Scheme 2) in nearly quantitative yields. The difference in
product ratios 18a/19a and 18b/19b may be a consequence of
anion solubility (see the Supporting Information).
In the quest of iterative DoMs on the azaindole scaffold,
we selected the derivative 18b (also obtained by N-decar-
bamoylation of 19b[23]), bearing the potent DMG CONEt2 on
C4, to determine if C5 over C2 metalation would continue to
prevail and thereby provide new routes to pyridine ring
substituted 7-azaindoles. Following optimization conditions,
selective C5 lithiation (2.3 equiv of sBuLi/TMEDA, À788C)
of 18b was achieved and quenching with several electrophiles
at À788C afforded the 5-substituted azaindoles 20–23 in
modest to very good yields (Scheme 3).
In continuation of the iterative DoM path, we sought to
functionalize the remaining C6 position, thus completing the
exhaustive functionalization of 7-azaindole through a ring-
walk metalation strategy (Scheme 5). In this quest, treatment
of the 4-hydroxy azaindole 13b with ClCONEt2 in the
presence of Hꢀnigꢁs base afforded the intermediate O,N-
dicarbamoylated product 27 which, upon metalation with
LiTMP (1.2 equiv) under Barbier in situ conditions,[27]
afforded the TMS derivative 28 in quantitative yield, the
structure of which was confirmed by X-ray crystallographic
analysis (see the Supporting Information). Thus, the DoM
reaction occurs synergistically between two DMGs as
opposed to directed by the powerful OCONEt2 DMG and
Interestingly, compound 23 was obtained as two separable
diastereoisomeric atropoisomers in approximately a 1:1 ratio.
The structure of the syn diastereoisomer was established by
X-ray analysis (see the Supporting Information).[24] Further-
more, unambiguous confirmation of the atropoisomeric
nature of the products was established through thermal
interconversion which afforded approximately a 1:1 mixture
of atropoisomers regardless of the diastereoisomer employed
(for details, see the Supporting Information). Suzuki–Miyaura
Scheme 5. Ring-walk metalation sequence to 31. a) DIPEA (2.4 equiv),
ClCONEt2 (3.0 equiv), py, RT; b) LiTMP (1.2 equiv), TMSCl (1.2 equiv),
THF, À788C, 1 h; c) sBuLi/TMEDA (1.3 equiv), THF, À788C to RT, 3 h;
d) NaH (2.0 equiv), MeI (1.5 equiv), DMF, RT, 12 h; e) LiTMP
(2.5 equiv), TMSCl (3.0 equiv), THF, À788C, 1 h. DIPEA=diisopropyle-
thylamine, LiTMP=lithium 2,2,6,6-tetramethylpiperidide. 29=3-(N,N-
Diethylsulfamoyl)-N1,N1,N5,N5-tetraethyl-4-hydroxy-2-(trimethylsilyl)-1H-
pyrrolo[2,3-b]pyridine-1,5-dicarboxamide (see the Supporting Informa-
tion for the structure of 29).
Scheme 3. DoM reaction at C5 of 18b.
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[7] Reviews: a) J. J. Song, J. T. Reeves, F. Gallou, Z. Tan, N. K. Yee,
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the N-MOM azaindole 7.
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In the next step, the anionic ortho-Fries rearrangement[28]
of 28 proceeded in quantitative yield to the amide 29 which,
upon methylation, gave 30, which was poised for the final
DoM event. A second LiTMP/TMSCl in situ quench process
afforded the richly functionalized 31 (for X-ray structure, see
the Supporting Information), and completed the regioselec-
tive exhaustive elaboration of the azaindole core by a ring-
walk metalation sequence.
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In summary, we have demonstrated the regioselective
peri(C4)-metalation of N-unprotected, powerful, and versa-
tile[29] azaindoles 5a,b, bearing a DMG on C3, through a new
anionic C2 shielding concept, thus resulting in the first
observation of peri-metalation of CONEt2 and SO2NEt2
DMG systems. The reaction has been shown to be both
robust and scalable.[30] The anionic shielding concept was
extended to preferred C5 over C2 metalation to provide
a general regioselective route to new azaindoles and fused
derivatives. Importantly, we demonstrated by comparison of
substrates 5a and 7 that the N-anionic shielding effect is
crucial to regioselectively lithiate the C4 position over the
intrinsically favored C2 lithiation, thus allowing the first
reported synthesis of the fully dressed azaindole 31 through
a ring-walk metalation. The broader application of the
derived synthetic chemistry may be anticipated.
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Received: November 14, 2011
Published online: February 1, 2012
Keywords: heterocycles · metalation · regioselectivity ·
.
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