New short access to pyrrolo[2,3-c]pyridazin-6-ones via β-spirolactams

Article abstract of DOI:10.1016/j.tetlet.2014.12.017

Treatment of 4-aminoalkyl-2,6-dichloropyridazines with acid chlorides in the presence of triethylamine leads to the formation of β-spirolactams (X-ray confirmed) which subsequently can be transformed into pyrrolo[2,3-c]pyridazin-6-ones. A putative mechani

Full text of DOI:10.1016/j.tetlet.2014.12.017

Tetrahedron Letters 56 (2015) 772–774
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New short access to pyrrolo[2,3-c]pyridazin-6-ones via
b-spirolactams
⇑
Theodor Stoll , André Alker, Sabine Kolczewski, Andrea Menzi, Vincent Revil-Baudard
Roche Pharma Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of 4-aminoalkyl-2,6-dichloropyridazines with acid chlorides in the presence of triethylamine
leads to the formation of b-spirolactams (X-ray confirmed) which subsequently can be transformed into
pyrrolo[2,3-c]pyridazin-6-ones. A putative mechanism based on the Staudinger Ketene–Imine Cycloaddi-
tion is proposed.
Received 24 November 2014
Revised 3 December 2014
Accepted 5 December 2014
Available online 16 December 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
b-Spirolactam
Rearrangement
Ketene
Staudinger Ketene–Imine Cycloaddition
Heterocyclic compounds are
a
common motif in organic
after an aqueous workup in the second step (Scheme 2), leading
to a slightly improved yield.
chemistry and their synthesis has always attracted attention.1
A
vast majority of marketed drugs contain heterocyclic entities
underlining their pivotal role in medicinal chemistry.2 In the
course of our work we became interested in pyrrolo-pyridazinones
as they are interesting and versatile building blocks which are
under-represented in the chemical literature.
Herein we wish to report the synthesis of pyrrolo[2,3-c]pyrida-
zin-6-ones from 3,6-dichloro-pyridazin-4-amines via b-spirolac-
tams through an interesting mechanism.
This work was triggered by the unexpected finding that
treatment of pyridazine 1a according to Scheme 1 did not result
in pyrrolo[3,2-c]pyridazin-6-one A, but its isomer pyrrolo[2,3-
c]pyridazin-6-one 3a in 29% yield. Further investigation of the
obtained material after using conditions (a) revealed that b-spiro-
lactam 2a was formed as an intermediate and its structure could be
confirmed by X-ray (Scheme 2 and Fig. 1).
In order to optimize the reaction conditions and to gain insight
into the reaction and its mechanism, a screening of conditions for
the reaction from 2a to 3a was performed (see Supporting informa-
tion for details) where the best conditions were found to be cesium
carbonate in DMF at 80 °C.
Using these conditions an array of differently substituted pyr-
rolo[2,3-c]pyridazin-6-ones was successfully synthesized (Table 1)
in moderate to good yields.
As shown, the conditions optimized for the reaction from 1a to
3a were used to prepare different pyrrolo[2,3-c]pyridazin-6-ones
(Table 1) which to the best of our knowledge have not been
reported before. These products serve as versatile building blocks
and may be derivatized further. Although 6-hydroxy-pyrrolo[2,3-
c]pyridazine-5-carboxylates are described,3 they do not allow
access to the products we report in this Letter.
N
N
O
N
N
Cl
Cl
N
Cl
A
X
N
a, b
Cl
NH
N
The procedure could be further simplified by not purifying the
b-lactam after the first step, but using the crude material directly
1a
N
O
3a
⇑
Corresponding author. Tel.: +41 61 688 8637.
E-mail address: theodor.stoll@roche.com (T. Stoll).
Scheme 1. Reagents and conditions: (a) i-PrCOCl, Et3N, DCM, rt; (b) NaOtBu,
Pd(OAc)2, di-1-adamantyl phosphine oxide, dioxane, 80 °C.
http://dx.doi.org/10.1016/j.tetlet.2014.12.017
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

T. Stoll et al. / Tetrahedron Letters 56 (2015) 772–774
773
O
N
Cl
N
Cl
N
a
b
N
N
N
N
O
Cl
NH
Cl
2a
99%
81%
Cl
N
O
3a
1a
82%
c
Scheme 2. Reagents and conditions: (a) i-PrCOCl (2.2 equiv), Et3N (2.7 equiv), DCM, rt; (b) solvent, reagent, 80 °C, 4 h, best conditions: Cs2CO3 (2 equiv), DMF; (c) best
conditions without purification of 2a.
intermediates was less of an issue. Although compound 2a was
chromatographed and crystallized for X-ray analysis, the material
decomposed within several days at room temperature.
O
N
Cl
N
Regarding the scope of the reaction, different R1 substituents
were tolerated (entries 1–4). Access to compound 3e through the
PMB-cleavage of 3d using TFA/TfOH at 110 °C may allow the intro-
duction of a variety of R1-substituents at a later stage, for example,
by alkylation or arylation. Unfortunately, when at least one of R2 or
R3 was hydrogen, the reaction failed (entry 10), chlorine was not
tolerated (entry 12), and two bulky substituents also prevented
product formation (entry 13).
Cl
2a
N
O
Figure 1. Structure of b-spirolactam 2a confirmed by X-ray.
In order to shed light on the reasons for this, an idea about a
putative mechanism of this reaction may be helpful. A mechanism
has been proposed for a similar reaction.4 The isolation and charac-
terization of b-spirolactam 2a is especially interesting and con-
firms one proposed intermediate.
The formation of b-lactams from imines under these conditions
is known as the Staudinger Ketene–Imine Cycloaddition reaction
for more than a century.5
Table 1
Scope of the reaction
O
R2
Cl
R1
N
N
Cl
R3
N
N
N
O
Cl
NH
R1
Cl
R2
Our own experiments provide some clues toward a possible
mechanism of the transformation (Table 2).
R3
Entry
Starting Material
3-Substituents
Product
Yield+ (%)
When only acid chloride was used without a base no reaction
occurred (no ketene formation, entry 1). The same was observed
when an acid chloride which is unable to form a ketene was
employed (entry 2). These results indicate that formation of a
ketene is needed to start the reaction.
Using a mixture of both acid chlorides gave only the known
b-lactam 2a (entries 3 and 4). This suggests that in all steps of
the reaction only the ketene reacts rather than the acid chloride.
It is also important to note that even when an enantiomerically
pure acid chloride was employed (Table 1, entry 11), the product
was obtained as racemate.
Based on these results we propose a putative mechanism
(Scheme 3) where the acid chloride serves only as the precursor
of the ketene and does not have any other role in the reaction.
The ketene on the other hand is involved both in first: Formation
of the amide on the pyridazine nitrogen creating the imine (inter-
mediate B) and second: The b-lactam formation.
No
R1
R2
R3
No
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1a
1a
1a
1a
1a
1a
1a
1a
c-Pr
Me
Ph
PMB
H
c-Pr
c-Pr
c-Pr
c-Pr
c-Pr
c-Pr
c-Pr
c-Pr
Me
Me
Me
Me
Me
Me
3a
3b
3c
3d
3e
82
68
Me
Me
Me
Me
41
62++
0*
c-Pr
0***
68
c-Bu
c-Pent
4-THP
4a
5a
6a
63
69
0
H
H, Me, Ph
Me
Cl
Ph
Ph
Me, Cl
Ph
7a
39+++
0***
0**
+
++
Isolated yields are reported.
PMB group can be cleaved using TFA/TfOH to give compound 3e in 77% yield.
(S)-(+) enantiomer of acid chloride used, 7a isolated as racemate.
N-acetylaction was observed.
+++
*
**
First step failed.
Second step failed.
The Staudinger Ketene–Imine Cycloaddition is believed to pro-
ceed by first the attack of the imine nitrogen on the ketene (inter-
mediate B to C) and a subsequent conrotatory electrocyclization
leading to the b-lactam.6
***
It is noteworthy that performing just an aqueous workup after
the first step led to major advantages. Besides circumventing
possible purification problems when having diastereomeric
b-spirolactams (e.g., entries 10 and 11), instability of the resulting
The formation of the pyrrolo[2,3-c]pyridazin-6-one (Scheme 4)
will likely happen by attack of the base at either the
a-hydrogen or
the carbonyl group of the amide, leading to re-aromatization and
Table 2
Experiments around b-lactam formation
Entry Conditions
Result
1
2
3
1a, i-PrCOCl 2.2 equiv, no base, DCM
1a, t-BuCOCl 2.2 equiv, Et3N 2.7 equiv, DCM
1a, i-PrCOCl 1 equiv, t-BuCOCl 1 equiv, Et3N 2.7 equiv, Exclusive formation of b-lactam 2a
No reaction
No reaction
DCM
4
1a, i-PrCOCl 2.2 equiv, t-BuCOCl 10 equiv, Et3N
13 equiv, DCM
Formation of b-lactam 2a, small amounts of byproducts which did not incorporate reaction with
pivaloyl chloride

774
T. Stoll et al. / Tetrahedron Letters 56 (2015) 772–774
reactive enough and/or too bulky (Table 1, entry 13) and prevent
formation of the b-lactam.
If the b-lactam or the open form (Scheme 4, intermediate D) is
enolizable, it is easily deprotonated leading to possible side
reactions.
O
N
Cl
O
N
R2
R2
C
Cl
H
Cl
N
R1
R3
R3
In summary we have demonstrated an easy way to form pyrrol-
o[2,3-c]pyridazin-6-ones which can serve as versatile building
blocks.
Treatment of 4-aminoalkyl-2,6-dichloropyridazines with acid
chlorides in the presence of triethylamine led to the formation of
b-spirolactams which subsequently were transformed into pyrrol-
o[2,3-c]pyridazin-6-ones in the presence of cesium carbonate.
A mechanism is proposed based on the Staudinger Ketene–
Imine Cycloaddition. In situ formation of ketene is likely responsi-
ble for the generation of the imine and also the b-spirolactam.
O
R2
R3
Cl
R2
R3
O
R2
N
N
C
O
R2
N
Cl
N
R3
Cl
N+ O–
R1
R3
Cl
N
R1
C
B
O
O
Cl
Cl
R2
N
Acknowledgments
R2
R3
R2
N
N
R2
R3
N
R3
Cl
R3
Cl
The authors thank Roche Pharma Research and Early Develop-
ment, especially Dr. A. Thomas, for providing the necessary
resources for this work.
N
R1
N+
R1
O–
O
The authors also thank the Analytical Department of the Roche
Innovation Center Basel for measurements and interpretation of
NMR and HR-MS. Thanks to the Separation Science Group for per-
forming preparative HPLC separations and analytical chiral HPLC.
The authors also thank Dr. H. Hilpert and Dr. T. Woltering for
helpful discussions.
Scheme 3. Proposed putative mechanism for the formation of b-lactam.
O
Cl
R2
H
N
R2
N
N
Cl
R1
R3
O
N
N
R3
Cl
Cl
O–
N
R1
Supplementary data
Base-
R2 R3
CCDC 1035350–1035352 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data (experimental data including analytics
may be found in the supporting information) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2014.12.017. These data include MOL files and
InChiKeys of the most important compounds described in this
article.
D
R1
N
N
N
O
Cl
R3
R2
Scheme 4. Proposed putative mechanism for the formation of pyrrolo[2,3-c]pyri-
dazin-6-ones.
subsequent cleavage of the C–N bond of the b-lactam giving an
intermediate similarly described (intermediate D),4 which then
subsequently forms the five membered ring by nucleophilic aro-
matic substitution. In most cases intermediate D after ring opening
could not be detected.
With these results in hand some possible explanations may be
found why certain products could not be formed. The first limita-
tion may be the formation of the ketene and its reactivity. While
some ketenes may be too reactive (Table 1, entry 10, ketene from
acetyl chloride) leading to side reactions, others may be not
References and notes
1. Brown, D. Cumulative Index of Heterocyclic Systems; John Wiley & Sons, 2008.
2. Gomtsyan, A. Chem. Heterocycl. Compd. 2012, 48, 7–10.
3. Uritskaya, M. Y.; Prokopov, A. A.; Yakhontov, L. N. Patent SU 520364 A1, 1976.
4. Getlik, M.; Wilson, B. J.; Morshed, M. M.; Watson, I. D. G.; Tang, D.; Subramanian,
P.; Al-awar, R. J. Org. Chem. 2013, 78, 5705–5710.
5. Staudinger, H. Justus Liebig’s Ann. Chem. 1907, 356, 51–123.
6. Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org. Chem. 1999,
3223–3235.