Understanding and Interrupting the Fischer Azaindolization Reaction

Article abstract of DOI:10.1021/jacs.7b07518

Experimental and computational studies pertaining to the Fischer azaindolization reaction are reported. These studies explain why pyridylhydrazines are poorly reactive in Fischer indolization reactions, in addition to the origin of hydrazine substituent effects. Additionally, an interrupted variant of Fischer azaindolization methodology is disclosed, which provides a synthetic entryway into fused azaindoline scaffolds.

Full text of DOI:10.1021/jacs.7b07518

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX-XXX
Understanding and Interrupting the Fischer Azaindolization Reaction
Bryan J. Simmons, Marie Hoffmann, Pier Alexandre Champagne, Elias Picazo, Katsuya Yamakawa,
Lucas A. Morrill, K. N. Houk,* and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S
* Supporting Information
ABSTRACT: Experimental and computational studies
pertaining to the Fischer azaindolization reaction are
reported. These studies explain why pyridylhydrazines are
poorly reactive in Fischer indolization reactions, in
addition to the origin of hydrazine substituent effects.
Additionally, an interrupted variant of Fischer azaindoliza-
tion methodology is disclosed, which provides a synthetic
entryway into fused azaindoline scaffolds.
he Fischer indolization reaction, first described in 1883,1
T
remains a powerful tool in modern chemical synthesis.2
The transformation, which typically involves the acid-mediated
reaction of aryl hydrazines with ketones or aldehydes to give
indoles, has many applications in medicinal chemistry.2 The
Fischer indolization has also been used extensively in natural
product synthesis, including several recent examples, to
generate remarkable structural complexity.3
One deficiency associated with the Fischer indolization
involves the variant in which pyridylhydrazines are employed to
furnish azaindole products (a.k.a., Fischer azaindolization).4
This transformation was first tested over 100 years ago.5 It is
now known, particularly via the studies of Parrick4a,b and
Robinson4c that the azaindolization can proceed under extreme
thermal conditions. For the corresponding acid-mediated
process to take place, certain substituents on the hydrazine
(e.g., methoxy, halides) can be used to improve reactivity, but
the origins of such beneficial effects have remained
unknown.4d−g
The present study answers two key questions. (A) What
factors govern the success or failure of the Fischer
azaindolization reaction? (B) Could a general “interrupted”
variant of the Fischer azaindolization6 be developed as a
method to access fused azaindoline scaffolds? Although fused
azaindoline frameworks are uncommon,7 the parent azaindole
heterocycle serves as a bioisostere for indoles8 and is present in
compounds of medicinal relevance. In fact, more than 74,000
bioactive azaindoles are known,9 including the currently
marketed drugs Zelboraf (1, Figure 1) and Venclexta.10
Fused indolines are present in more than 22,000 bioactive
molecules, more than 870 of which are natural products (e.g.,
2).6c,9,11 We now report mechanistic insights into the Fischer
azaindolization reaction, the scope of the interrupted variant (3
+ 4 → 5), and the use of this methodology to access aza-
analogues of bioactive compounds.
Figure 1. Azaindole drug Zelboraf (1), indoline-containing natural
product aspidophylline A (2), and interrupted Fischer azaindolization
methodology.
investigated if the activation barrier for [3,3]-sigmatropic
rearrangement varies significantly based on the aryl hydrazine
employed. Thus, as summarized in Figure 2, the ΔG‡ was
calculated for this step under four scenarios:13 (a) the neutral
phenylhydrazone, (b) protonation of the β-nitrogen of
phenylhydrazone,14 (c) protonation of the β-nitrogen of 3-
pyridylhydrazone, and (d) protonation of the β-nitrogen of
methoxy-substituted 3-pyridylhydrazone. In all cases, we used
Figure 2. Comparative calculations of the [3,3]-sigmatropic rearrange-
ment transition states as a function of the arylhydrazine component.
With the goal of understanding the factors that lead to
success or failure of the Fischer azaindolization reaction, we
performed a series of SCS-MP2 calculations.12 We first
Received: July 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b07518
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
propionaldehyde as the Fischer indolization reaction partner.
For three of the scenarios (transition states 6, 7, and 9), the
calculations were in good accord with experimental trends.
However, for transition state 8 involving the experimentally
problematic 3-pyridylhydrazine, the activation barrier was
calculated to be reasonable (i.e., 13.5 kcal/mol). Thus, we
sought an alternative explanation for the poor reactivity of 3-
pyridylhydrazones in Fischer indolization reactions.
Table 1. Scope of the Aldehyde Surrogate in the Interrupted
Fischer Azaindolization
a
We next considered if the pyridine nitrogen might be
protonated (Figure 3). Indeed, protonation of this nitrogen is
Figure 3. Calculations suggest that an unfavorable equilibrium
between 10 and 11 leads to challenging Fischer azaindolization of 3-
pyridylhydrazones.
much preferred over hydrazone protonation, and pyridinium
salt 10 is the global minimum of the pathway. To convert 10 to
11 requires 21.8 kcal/mol, leading to a high total barrier of 35.3
kcal/mol for the tautomerization and [3,3]-sigmatropic
rearrangement (10 → 8). As noted earlier, it is known that
introduction of a methoxy substituent on the pyridylhydrazine
(e.g., see 9, Figure 2) leads to improved yields in experimental
studies.4d−g This has previously been rationalized by a “push/
pull” effect4d which, in turn, makes the [3,3]-sigmatropic
rearrangement more favorable. Instead, we suggest that the
methoxy group reduces the basicity of the pyridine nitrogen,
thus rendering the proton transfer/tautomerization more
feasible. We calculate that the tautomerization between the 2-
methoxy analogues of 10 and 11 is only 14.9 kcal/mol (versus
21.8 kcal/mol for 10 to 11).12 Consequently, the better
performance in Fischer azaindolizations of methoxy-substituted
pyridylhydrazines compared to the parent pyridylhydrazines
can be attributed to the diminished basicity of the pyridine
nitrogen in the former case.
We also explored the interrupted variant of the Fischer
azaindolization to access fused azaindolines since only a single
example of this transformation is available in the literature6d
and no methodology studies have been reported. To initiate
our efforts in this area, we used methoxy-substituted
pyridylhydrazine salt 12 (Table 1), due to its previously
established favorable reactivity in Fischer azaindolization
reactions. Following an initial survey of reaction conditions,
mainly involving variation of solvent, acid sources, time, and
temperature, we found that 12 underwent interrupted Fischer
azaindolization with a variety of aldehyde surrogates to give
fused 4-azaindoline products 13. Of note, the transformation
introduces two stereocenters, one of which is quaternary.
Results are depicted based on optimization of individual
substrates. Upon treatment of 12 with lactol 14, furanoazaindo-
line 15 was obtained in 97% yield (entry 1). Alternate
substituents on the lactol were tolerated, as demonstrated by
the successful interrupted Fischer azaindolization of phenyl
lactol 16 and allyl lactol 18 to furnish adducts 17 and 19,
respectively (entries 2 and 3). The 6-membered lactol 20 was
also deemed a suitable reaction partner, as demonstrated by the
a
Conditions unless otherwise stated: hydrazine 12 (1.5 equiv),
aldehyde surrogate (1.0 equiv), solvent (0.05 M). Yields shown reflect
the average of two isolation experiments.
formation of 6,5,6-tricycle 21 (entry 4). In addition, we
evaluated several hemiaminal substrates for the synthesis of
azapyrrolidinoindolines. The use of methyl substituted N-Ts
hemiaminal 22 led to 23 (entry 5), whereas employment of
allyl derivative 24 gave azaindoline 25 (entry 6). Lastly, we
evaluated carbamate-containing hemiaminal substrate 26, which
furnished 27 in 82% yield (entry 7).
Having established the tolerance of the interrupted Fischer
azaindolization methodology toward variation in the aldehyde
surrogate, we shifted our attention to assessing changes in the
hydrazine component (Table 2). Halohydrazines 29 and 31
underwent interrupted Fischer azaindolization with lactol 14 to
deliver 4-azaindoline products 30 and 32, respectively (entries
1 and 2). Interestingly, the use of methoxyhydrazine 33 led to
azaindoline product 34, albeit in a lower yield (entry 3).15
Efforts to further optimize this transformation were un-
successful. Isomeric hydrazines 35, 37, and 39 were also
evaluated with the hopes of accessing 5-, 6-, and 7-substituted
azaindolines. Whereas the interrupted Fischer azaindolization
reaction failed to produce 5-azaindoline 36 (entry 4), the
methodology furnished 6-azaindoline 38 (entry 5) and 7-
azaindoline 40 (entry 6), albeit with a modest yield in the latter
case. Finally, unsubstituted 3-pyridylhydrazine 41 was tested as
a point of comparison (entry 7). Consistent with expectations
based on the literature4 and our calculations (see Figure 3), the
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DOI: 10.1021/jacs.7b07518
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(Table 2, entries 1, 2, 5, and Table 1). Overall, hydrazines with
poorly basic pyridine nitrogens had the smallest ΔG[H+].
The interrupted Fischer azaindolization methodology can be
used to synthesize new aza-analogues of bioactive molecules
(Figure 4). Treatment of benzyloxyhydrazine 43 with lactol 14
Table 2. Scope of Hydrazine Component and Correlation to
Calculated Free Energies
a
Figure 4. Synthesis of aza-analogues.
under acidic conditions delivered furanoazaindoline 44 in 81%
yield. Using a straightforward 3-step sequence, 44 was
elaborated to carbamate 45, a new analogue of the potent
acetylcholinesterase inhibitor phensvenine.17 Switching to a
significantly more complex system, we performed the
interrupted Fischer azaindolization of hydrazine 12 and
a
Conditions unless otherwise stated: hydrazine (1.5 equiv), aldehyde
surrogate 14 (1.0 equiv), solvent (0.05 M). Yields shown reflect the
b
average of two isolation experiments. Free energies (kcal/mol) for
[3,3]-sigmatropic rearrangement (ΔG‡[3,3]) and enehydrazine
formation (ΔG[H+]) were obtained using SCS-MP2 calculations
with propionaldehyde as a surrogate aldehyde model under acidic
reaction conditions.
known3 ketolactone 46. Following the acid-mediated rear-
j
rangement and subsequent hydrolysis in the same pot, a
straightforward methylation gave pentacycle 47. In turn,
azaindoline 47 was converted in two steps to 48, an analogue
of the anticancer agent aspidophylline A.11
transformation proved problematic and gave 42 in a poor yield
of 11%.16
We have performed an experimental and computational
study of the Fischer azaindolization reaction, related to a
transformation first attempted more than 100 years ago.
Calculations were used to explain the difficulty in employing
pyridylhydrazines in Fischer indolizations, in addition to the
origin of hydrazine substituent effects. Rather than the [3,3]-
sigmatropic rearrangement step being the single determining
factor, we find that reactions suffer if the pyridine nitrogen is
too basic, making the tautomerization step prohibitively
challenging. We have also developed an interrupted Fischer
azaindolization methodology, which provides a synthetic
entryway into fused azaindoline scaffolds. The syntheses of
new aza-analogues of phensvenine and aspidophylline A
underscore the potential of this methodology to deliver new
aza-derivatives of medicinally privileged fused indoline-contain-
ing compounds.
To complement these experimental studies, calculations were
performed for the reaction of each hydrazine depicted in Table
2, with propionaldehyde as a model aldehyde under acidic
conditions.12 Earlier, we hypothesized that the success or failure
of the Fischer azaindolization methodology hinges on the
feasibility of enehydrazine formation, rather than [3,3]-
sigmatropic rearrangement. Consistent with this notion, we
found the computed activation barriers for [3,3]-sigmatropic
rearrangement (ΔG‡[3,3]) were uniformly accessible and
ranged from 13.4 to 16.6 kcal/mol. On the other hand, the
calculated tautomerization equilibria (ΔG[H+]) varied consid-
erably between 11.5 and 23.7 kcal/mol. In cases where the
calculated ΔG[H+] is high, the reaction is experimentally
problematic (entries 4 and 7). In the cases of entries 3 and 6,
the ΔG[H+] is slightly more favorable leading to modest yields
of product. However, if ΔG[H+] is sufficiently low (i.e., less
than 15 kcal/mol), the reaction proceeds more efficiently
C
DOI: 10.1021/jacs.7b07518
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Journal of the American Chemical Society
Communication
(6) In the interrupted Fischer azaindolization, rather than rear-
omatization occurring to give an azaindole heterocycle, the transient
iminium species generated is trapped by a pendant nucleophile (see
mechanism for 3 + 4 → 5 in Figure 1). For reviews on the parent
interrupted Fischer indolization reaction (nonaza version), see: (a) Li,
S.; Han, J.; Li, A. Huaxue Xuebao 2013, 71, 295−298. (b) Mo, Y.;
Zhao, J.; Chen, W.; Wang, Q. Res. Chem. Intermed. 2015, 41, 5869−
5877. (c) Susick, R. B.; Morrill, L. A.; Picazo, E.; Garg, N. K. Synlett
2017, 28, 1−11. One example of the Fischer azaindolization has been
reported for the synthesis of a tetracyclic pyrrolidino-4-azaindoline; see
(d) de Graaff, C.; Bensch, L.; Boersma, S. J.; Cioc, R. C.; van Lint, M.
J.; Janssen, E.; Turner, N. J.; Orru, R. V. A.; Ruijter, E. Angew. Chem.,
Int. Ed. 2015, 54, 14133−14136.
(7) Only four azaindoline compounds of the type 5 are known in the
literature. For two furano-4-azaindolines prepared by a Pd-catalyzed
intermolecular carboamination approach, see: (a) Bizet, V.; Borrajo-
Calleja, G. M.; Besnard, C.; Mazet, C. ACS Catal. 2016, 6, 7183−7187.
For a pyrrolidino-7-azaindoline derived from a [3+2] alkene/
isocyanate cycloaddition, see: (b) Huang, L.; Cheng, H.; Zhang, R.;
Wang, M.; Xie, C. Adv. Synth. Catal. 2014, 356, 2477−2484.
(c) Cheng, H.; Zhang, R.; Yang, S.; Wang, M.; Zeng, X.; Xie, L.;
Xie, C.; Wu, J.; Zhong, G. Adv. Synth. Catal. 2016, 358, 970−976. See
also reference 6d.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b07518.
■
S
Experimental details and computations (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*houk@chem.ucla.edu
*neilgarg@chem.ucla.edu
ORCID
Pier Alexandre Champagne: 0000-0002-0546-7537
K. N. Houk: 0000-0002-8387-5261
Neil K. Garg: 0000-0002-7793-2629
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the NSF (CHE-1464898 to N.K.G.,
CHE-1361104 to K.N.H. and DGE-1144087 for B.J.S.), the
Fulbright Research Fellowship (M.H.), the Fonds de recherche
(8) Mer
2014, 19, 19935−19979.
(9) A structural search using Reaxys was used to obtain these
statistics (accessed June, 2017).
́ ́
our, J.-Y.; Buron, F.; Ple, K.; Bonnet, P.; Routier, S. Molecules
́
du Quebec, Nature et Technologies (postdoctoral fellowship
for P A.C.), the NIH-NIGMS (F31-GM117945 to E.P. and
F31-GM121016 to L.A.M), the Foote Family (E.P. and
L.A.M.), and UCLA for financial support. These studies were
supported by shared instrumentation grants from the NSF
(CHE-1048804) and the NIH NCRR (S10RR025631).
Computations were performed on the Hoffman2 cluster at
UCLA.
(10) Bollag, G.; Tsai, J.; Zhang, J.; Zhang, C.; Ibrahim, P.; Nolop, K.;
Hirth, P. Nat. Rev. Drug Discovery 2012, 11, 873−886.
(11) Subramaniam, G.; Hiraku, O.; Hayashi, M.; Koyano, T.;
Komiyama, K.; Kam, T.-S. J. Nat. Prod. 2007, 70, 1783−1789.
(12) See the SI for details.
(13) ΔG‡[3,3] is the difference between the transition state energy of
the sigmatropic rearrangement step and the energy of the
enehydrazine precursor.
(14) [3,3]-Sigmatropic rearrangement in the Fischer indolization is
thought to proceed more favorably via protonation of the β-nitrogen.
For prior computational studies, see: Çelebi-Olcum, N.; Boal, B. W.;
̈
Huters, A. D.; Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2011, 133,
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DOI: 10.1021/jacs.7b07518
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX