Improved and expanded one-pot, two-component Boulton-Katritzky syntheses of N–N bond containing bicyclic heterocycles

Article abstract of DOI:10.1016/j.tetlet.2016.11.092

Improved and expanded one-pot, two-component syntheses of bicyclic heterocycles containing a 3-N-acyl-3-amino-1,2-pyrazole motif from N'-hydroxy-carboxyamidines and acylbenzotriazoles have been developed. Importantly, this sequence obviates the need for h

Full text of DOI:10.1016/j.tetlet.2016.11.092

Accepted Manuscript
Improved and expanded one-pot, two-component Boulton-Katritzky syntheses
of N-N bond containing bicyclic heterocycles
Kyle W. Knouse, Laura E. Ator, Lauren E. Beausoleil, Zachary J. Hauseman,
Rebecca L. Casaubon, Gregory R. Ott
PII:
S0040-4039(16)31573-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.092
TETL 48378
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
18 October 2016
21 November 2016
Please cite this article as: Knouse, K.W., Ator, L.E., Beausoleil, L.E., Hauseman, Z.J., Casaubon, R.L., Ott, G.R.,
Improved and expanded one-pot, two-component Boulton-Katritzky syntheses of N-N bond containing bicyclic
heterocycles, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.092
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Improved and expanded one-pot, two-
component Boulton-Katritzky syntheses of
N-N bond containing bicyclic heterocycles
Leave this area blank for abstract info.
Kyle W. Knouse, Laura E. Ator, Lauren E. Beausoleil, Zachary J. Hauseman, Rebecca L. Casaubon, and
Gregory R. Ott*
1) RT, DMSO
B
B
A
A
( )
or
or
2) NaOtBu
( )
n
n
150ºC
RT
12 Examples

1
Tetrahedron Letters
Improved and expanded one-pot, two-component Boulton-Katritzky syntheses of N-N
bond containing bicyclic heterocycles
Kyle W. Knouse, Laura E. Ator, Lauren E. Beausoleil, Zachary J. Hauseman, Rebecca L. Casaubon, and
Gregory R. Ott
Small Molecule Discovery, Discovery and Product Development, Teva Branded Pharmaceutical Products R&D, 145 Brandywine Parkway, West Chester, PA,
19380
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Improved and expanded one-pot, two-component syntheses of bicyclic heterocycles containing a
3-N-acyl-3-amino-1,2-pyrazole motif from N’-hydroxy-carboxyamidines and acylbenzotriazoles
have been developed. Importantly, this sequence obviates the need for hydrazine or N-aminating
reagents to synthesize the key nitrogen-nitrogen (N-N) bond of these heterocycles, which is
formed via Boulton-Katritzky rearrangement. A diverse array of pharmaceutically relevant N-N
containing heterocycles has been prepared with this methodology using readily available
reagents without the need for special equipment or conditions.
Available online
Keywords:
Boulton-Katritzky rearrangement
Acylbenzotriazole
2009 Elsevier Ltd. All rights reserved.
N’-hydroxy-carboxyamidine
N-N bond
3-N-acyl-3-amino-1,2-pyrazole
1. Introduction
Bicyclic heterocycles containing carbon and at least one
nitrogen are found throughout Nature, notably in the biological
macromolecules DNA/RNA (purine bases) and proteins/peptides
(indole amino acid tryptophan). In addition, physiologically
important biomolecules in this general class include
serotonin/melatonin (indole nucleus), kynurenic acid (quinoline),
and the natural products caffeine and theobromine (xanthines). In
contrast, bicyclic heterocycles containing a nitrogen-nitrogen (N-
N) bond are relatively rare in Nature1 but are pervasive in the
pharmaceutical industry. This is likely due to their novelty and
properties relative to the naturally occurring congeners, and
thusly, this motif is found in many approved drugs (cf.
ponatinib,2 olaparib,3 sildenafil4). Methods of installing the key
N-N bond of these heterocycles rely mainly on the use of
hydrazine5 or formation via N-amination,6-10 along with other
methods to a lesser extent.11,12 Limitations for all these
methodologies include functional group tolerance, non-
convergence, and multiple synthetic manipulations.
Figure 1. Pharmaceutically relevant heterocycles containing 3-N-acyl-3-
amino-1,2-pyrazole motif (blue)
2. Results and Discussion
Previous efforts from our laboratories directed toward the
synthesis of 3-N-acyl-aminoindazoles identified new electronic
factors in the mononuclear heterocyclic Boulton-Katritzky
rearrangement as well as a two-component, one-pot protocol to
deliver 3-N-acyl-indazoles from N’-hydroxy-carboxyamidines
and esters.18 Caveats for this one-pot method include the need for
microwave irradiation and melt conditions to effect the
transformation.
In particular, the bicyclic heterocycles shown in Figure 1, all
containing a 3-N-acyl-1,2-aminopyrazole motif (highlighted in
blue), have been reported for applications in oncology,
neurology, and metabolic pathologies (1-3),13-15 as adenosine
mimics (4),16 as well as for autoimmune/inflammatory diseases
(5).17 Methods to synthesize and prepare analogues rapidly
around these scaffolds are of specific interest to the medicinal
To expand the utility of our convergent, one-pot protocol, we
revisited the sequence with an eye toward more diverse
substrates. Herein, we report an improved protocol and expanded
scope
of
the
one-pot,
two-component
chemistry community.
———
 Corresponding author. Tel.: +1-610-738-6861; fax: +1-610-344-0065; e-mail: gregory.ott@tevapharm.com

2
Tetrahedron
acylation/condensation/Boulton-Katritzky rearrangement for
needed, one which could undergo direct acylation of the N’-
hydroxy-carboxyamidine in the absence of base or heat to
suppress over (or under) acylation. A survey of the literature
found a report from the Katritzky laboratory that described
acylbenzotriazoles as effective coupling components to deliver
1,2,4-oxadiazoles.20
the synthesis of bicyclic heterocycles. The scaffolds synthesized
in this manner include those exemplified in Figure 1, namely,
indazole, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-d]pyrimidine,
pyrazolo[3,4-c]pyrazole, and
pyrazolo[1,5-a]pyridine.
All
contain an embedded 3-N-acyl-3-amino-1,2-pyrazole motif. The
linchpins of this protocol were the use of acylbenzotriazoles
(both aryl and alkyl) as the coupling partners to the N’-hydroxy-
carboxyamidines and controlled temperature regulation/base
addition. With these reagents and conditions, we were able to
efficiently manipulate each phase of the three-step, one-pot
transformation which was critical to the success of the overall
sequence.
Acylation
HX
+ Base
(rapid)
+ Base
(rapid)
Condensation
Our initial attempts to expand our protocol to the more diverse
set of N’-hydroxy-carboxyamidines proved challenging. Using
the original protocol (Scheme 1) of combining all material in the
presence of base and microwaving at 150 ºC, the solvent-free
conditions proved inconsistent for the new set of substrates,
presumably due to solubility or reactivity limitations.
Furthermore, when evaluated using added solvent (DMF),
product formation was realized, though complex mixtures were
observed with unidentified products, potentially due to the
extended heating times and/or competing side reactions.
Boulton-Katritzky
HX
H2O

+ Base
(rapid)
Scheme 2. General Cascade Sequence
The use of acylbenzotriazoles was particularly compelling
since these reagents were either commercially available or easily
prepared via the acid/benzotriazole/SOCl2 and tended to be
KOtBu
21
150ºC µW
Solvent Free
(48-71%)
white, shelf-stable solids. Our initial attempts with the
acylbenzotriazole in the one-pot protocol in DMF (150ºC, no
added base) were indeed successful with desired product
observed. However, multiple side products were evident and long
reaction times were needed to drive the reaction to completion.
Though DMF proved effective for the rearrangement as
demonstrated by our earlier work, we decided to examine a
variety of solvents. Katritzky and co-workers used
ethanol/triethylamine to obtain the oxadiazole from the
acylbenzotriazoles but this was not ideal for the temperatures
needed to induce the rearrangement (≥150ºC) and would require
a sealed vessel. Thus, we decided to examine other high boiling
polar protic/aprotic solvents in place of DMF. In short order, we
found that DMSO provided a much cleaner reaction profile.
Katritzky and co-workers also showed that the initial acylation
with N’-hydroxy-carboxyamidines can be completed at room
temperature then heated to reflux to induce cyclocondensation.
Likewise in our system, using DMSO as a solvent, we could
induce acylation cleanly at room temperature and importantly,
induce cyclocondensation using only an increase in temperature
(100ºC). A further temperature increase to 150ºC gave the
rearrangement to the desired product, though extended reaction
times were required. Based upon our earlier observations, to
accelerate the cyclocondensation we returned to base-promotion
and found addition of a non-nucleophilic base (t-butoxide,
sodium or potassium salt, one equivalent) to be effective
following the completion of the acylation. Furthermore, addition
of another equivalent of base for the final temperature increase
also provided a more rapid rearrangement. With addition of 2
equivalents of base at the initiation of the reaction, no
intermediate acylation product was observed by HPLC, only
rapid conversion to the oxadiazole. However, as observed in
earlier iterations, numerous low-level byproducts were observed
and incomplete conversion was noted. Timing for base addition
following complete acylation proved critical. Two equivalents of
base can be added following acylation in a single delivery or
stepwise (i.e. after acylation and again after cyclocondensation);
the reactions proceeded with similar yield and purity profiles.
Thus, the single addition of 2 equivalents of base became our
optimized protocol.22
R = Me, Ph, p-NO2-Ph, p-MeO-Ph
Scheme 1. Originally devised 1-pot protocol
At this juncture, we decided to revisit the protocol and
reconfigure to find a general solution for the diverse set of N’-
hydroxy-carboxyamidines. We reasoned that the above protocol
could result in unwanted side reactions if the initial
acylation/condensation did not proceed to completion. For
instance, the presence of unreacted ester or retro-addition of
hydroxylamine to produce the cyano derivative were of particular
concern since these were potentially electrophilic substrates.
Towards this end, we focused our attention on the ester
component as the point for further optimization. Mechanistically,
the ester must first acylate the N’-hydroxy-carboxyamidine to
initiate the cascade. Unactivated esters, in general, tend to be
poor acylating agents. To gain a full understanding of the
sequence of events we repeated the reaction at ambient
temperature (Scheme 1, R = Ph) in the presence of 0.3 eq of
KOtBu. Interestingly, we did not observe the acylation
intermediate (via LC/MS), but rather, rapid formation of the
oxadiazole, though the reaction stalled before complete
conversion with both unreacted N’-hydroxy-carboxyamidine and
ester present, even after 4h. Using the above conditions in the
absence of base, no acylation or condensation occurred even at
high temperature (>150 ºC) though minor degradation products
were evident.
Following the cascade sequence (Scheme 2), we reasoned
that improving the acylation-condensation sequence would be
paramount to creating a cleaner, higher yielding protocol.
Previously, we had examined both acid chlorides as well as acids
with coupling reagents, both of which are known for oxadiazole
formations.19 However, they were unsuccessful when used in the
one-pot sequence, potentially due to increased reactivity of the
acylating agent and of the pendant unsubstituted nitrogen. We
decided an acylating reagent with balanced reactivity was

3
Shown in Table 1 are the N’-hydroxy-carboxyamidines (6-
12)23 that were used in the synthesis of 15-29 using the optimized
procedure. For the acylbenzotriazoles, we employed both aryl
(13, R2 = Ph) and alkyl (14, R2 = CH3) derivatives. For the
unsubstituted (15-16) and the substituted (17-20) 2-amino-N'-
hydroxy-benzamidine derivatives, reasonable to good yields were
obtained (51-85%). The yields were similar for both the pyridine
(21-22) and the pyrimidine (23-24) variants. This protocol could
also access 5-5 hetero-bicycles (25-26) in reasonable yields. Of
particular note, bridgehead nitrogen heterocycle pyrazolo[1,5-
a]pyridines 27 and 28 were accessible in practical yields using
this methodology.18
the N’-hydroxy-carboxyamidines efficiently in polar aprotic
solvent and the ability to induce cyclocondensation to the
oxadiazole by base addition and then Boulton-Katritzky
rearrangement via temperature increase. This synthetic
methodology, forming a nitrogen-nitrogen bond in the rapid,
convergent assembly of complex systems from simple starting
materials is of utility to both the chemical and pharmaceutical
communities.
Acknowledgments
K.W.K., L.E.A., L.E.B., and Z.J.H. were supported by the
Teva Summer Internship program. The Authors gratefully
acknowledge the support of Dr. Kevin Wells-Knecht for
obtaining high-resolution mass spectra and Dr. Mark Ator for
helpful editorial suggestions.
Table 1.
One-pot Syntheses of Bicyclic Nitrogen Heterocycles
a) DMSO, RT
15-28
b) NaOtBu
Supplementary data
RT to 150ºC
Experimental procedures and characterization for compound
26. Supplementary data associated with this article can be found,
in the online version.
6-12
See table
13, R2 = Ph
14, R2 = CH3
R1-N’-hydroxy-
carboxyamidines
Example (%
Isolated Yield)
Product
References and notes
1.
2.
Blair, L.M.; Sperry, J. J. Nat. Prod. 2013, 76, 794−812.
Huang, W. S.; Metcalf, C. A.; Sundaramoorthi, R.; Wang, Y. H.;
Zou, D.; Thomas, R. M.; Zhu, X. T.; Cai, L. S.; Wen, D.; Liu, S.
Y.; Romero, J.; Qi, J. W.; Chen, I.; Banda, G.; Lentini, S. P.; Das,
S.; Xu, Q. H.; Keats, J.; Wang, F.; Wardwell, S.; Ning, Y. Y.;
Snodgrass, J. T.; Broudy, M. I.; Russian, K.; Zhou, T. J.;
Commodore, L.; Narasimhan, N. I.; Mohemmad, Q. K.; Iuliucci,
J.; Rivera, V. M.; Dalgarno, D. C.; Sawyer, T. K.; Clackson, T.;
Shakespeare, W. C. J. Med. Chem. 2010, 53, 4701−4719.
Menear, K. A.; Adcock, C.; Boulter, R.; Cockcroft, X.; Copsey,
L.; Cranston, A.; Dillon, K. J.; Drzewiecki, J.; Garman, S.;
Gomez, S.; Javaid, H.; Kerrigan, F.; Knights, C.; Lau, A.; Loh, V.
M.; Matthews, I. T. W.; Moore, S.; O’Connor, M. J.; Smith, G. C.
M.; Martin, N. M. B. J. Med. Chem. 2008, 51, 6581−6591.
Terrett, N.K.; Bell, A. S.; Brown, D.; Ellis, P. Bioorg. Med. Chem.
Lett. 1996, 6, 1819-1824.
Tšupova, S; Mäeorg, U. Heterocycles 2014, 88, 129-173.
Kuz'menko, T. A.; Morkovnik, A. S.; Divaeva, L. N.; Borodkin,
G. S.; Kuz'menko, V. V. Chem. Heterocycl. Compd. 2015, 50,
1575-1585.
Nishigaya, Y.; Umei, K.; Yamamoto, E.; Kohno, Y.; Seto, S.
Tetrahedron Lett. 2014, 55, 5963-5966.
Tekiner-Gulbas, B.; Filak, L.; Vasko, G. A.; Egyed, O.; Yalcin, I.;
Aki-Sener, E.; Riedl, Z.; Hajos, G. Heterocycles 2008, 75, 2005-
2012.
15, R2 = Ph (85%)
16, R2 = CH3 (77%)
6
7
17, R2 = Ph (57%)
18, R2 = CH3 (51%)
3.
4.
19, R2 = Ph (54%)
20, R2 = CH3 (55%)
8
9
5.
6.
21, R2 = Ph (80%)
22, R2 = CH3 (72%)
7.
8.
23, R2 = Ph (65%)
24, R2 = CH3 (85%)
9.
Heim-Riether, A.; Healy, J. J. Org. Chem. 2005, 70, 7331-7337.
10
10. Evans, L.E.; Cheeseman, M.D.; Jones, K. Org. Lett. 2012, 14,
3546–3549
11. Correa, A,; Tellitu, I.; Domínguez, E.; SanMartin R. J. Org.
Chem. 2006, 71, 3501-3505.
12. Greszler, S.; Stevens, K. L. Org. Synth. 2009, 86, 18-27.
13. Deng, X.; Zhou, W.; Weisberg, E.; Wang, J.; Zhang, J.; Sasaki, T.;
Nelson, E.; Griffin, J.D.; Janne, P. A.; Gray, N. S. Bioorg. Med.
Chem. Lett. 2012, 22. 4579–4584
14. Witherington, J. ; Bordas, V.; Garland, S. L.; Hickey, D. M. B.;
Ife, R. J.; Liddle, J.; Saunders, M.; Smith, D.G.; Ward, R. W.
Bioorg. Med. Chem. Lett. 2003, 13, 1577-1580.
15. Witherington, J. PCT Int. Appl., WO 2003080617, 2003.
16. Berry, D.A.; Wotring, L.L.; Drach, J.C.; Townsend, L.B.
Nucleosides Nucleotides, 1994, 13, 405-420.
25, R2 = Ph (53%)
26, R2 = CH3 (53%)
11
12
27, R2 = Ph (58%)
28, R2 = CH3 (56%)
17. Menet, C. J.M.; Hodges, A.J.; Vater, H. D. PCT Int. Appl. WO
2012146659, 2012.
3. Conclusions
18. Ott, G.R.; Anzalone, A.V. Synlett 2011, 20, 3018-3022
19. Hemming, K. Science of Synthesis 2004, 13, 127-184.
20. Katritzky, A.R.; Shestopalov, A.A.; Suzuki, K. ARKIVOC 2005, 7,
36-55.
21. Katritzky, A.R.; Suzuki, K.; Wang, Z. Synlett 2005, 11, 1656-
1665.
In summary, we have expanded the scope and improved the
one-flask protocol to deliver diverse N-N bond containing
heterocycles
from
N’-hydroxycarboxyamidines
and
acylbenzotriazoles. The key linchpins of this general strategy
were the balanced reactivity of the acylbenzotriazole to acylate

4
Tetrahedron
22. General Procedure: The N’-hydroxy-carboxyamidines (1 eq.)
and the N-acyl benzotriazole (1 eq.) were added to a scintillation
vial and dissolved in DMSO (2 mL/mmol substrate), the cap was
replaced, and the mixture stirred at room temperature for 1 hour or
until the acylation was complete by HPLC. Sodium t-butoxide (2
eq.) was added and the reaction stirred for 5 min or until
oxadiazole formation was complete. The reaction was then heated
to 150 ºC for 5 minutes or until the oxadiazole was consumed. The
reaction was quenched with aqueous HCl (2 eq). The reaction
mixture either worked-up and purified by flash chromatography,
directly purified by reverse phase HPLC, or isolated by filtration if
a solid precipitate.
23. 6-14 are available commercially or were synthesized using known
procedures, see Korbonits, D.; Kanzel-Szoboda, I.; Horvath, K. J.
Chem. Soc., Perkin Trans. 1 1982, 759, refs. 18 and 25.
24. 15-25, 27-28 were characterized by 1H-NMR and high resolution
mass spectra and were consistent with published data. For
experimental procedure and characterization of compound 26, see
supplementary data.
25. 2-N-acyl-pyrazolo[1,5-a]pyridine was reported by heating 12 in
acetic anhydride which resulted in a mixture of intermediate
oxadiazole, 28, and over-acylated product, see: Suzue, S.; Hirobe,
M.; Okamoto, T. Chem. Pharm. Bull. 1973, 21, 2146-2160.

5
Highlights
 Expanded scope of substrates for one-pot,
two-component Boulton-Katritzky
rearrangement.
 Simplified procedure to build both diversity
and complexity in pharmaceutically relevant
heterocycles.
 Sequence obviates the need for hydrazine or
N-aminating reagents to synthesize the key
nitrogen-nitrogen (N-N) bond of these
diverse heterocycles.