The rearrangement of cyclopropylketone arylhydrazones. Synthesis of tryptamines and tetrahydropyridazines

Article abstract of DOI:10.1016/j.tetlet.2014.09.017

The cyclopropyliminium rearrangement of cyclopropylketone arylhydrazones may result in two possible products. The first one forms via cyclopropane ring-opening and ring-closure to give six-membered tetrahydropyridazines. The second is formed via ring-closure resulting in a five-membered ring and subsequent Grandberg rearrangement into a tryptamine. The product ratio depends on the nature of the starting hydrazones.

Full text of DOI:10.1016/j.tetlet.2014.09.017

Tetrahedron Letters 55 (2014) 5936–5939
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The rearrangement of cyclopropylketone arylhydrazones. Synthesis
of tryptamines and tetrahydropyridazines
Rinat F. Salikov a, , Aleksandr Yu. Belyy b, Yury V. Tomilov a,
⇑
a N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospect, 119991 Moscow, Russian Federation
b Higher Chemical College, Russian Academy of Sciences, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 June 2014
Revised 22 August 2014
Accepted 3 September 2014
Available online 16 September 2014
The cyclopropyliminium rearrangement of cyclopropylketone arylhydrazones may result in two possible
products. The first one forms via cyclopropane ring-opening and ring-closure to give six-membered
tetrahydropyridazines. The second is formed via ring-closure resulting in a five-membered ring and
subsequent Grandberg rearrangement into a tryptamine. The product ratio depends on the nature of
the starting hydrazones.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Tryptamines
Tetrahydropyridazines
Cyclopropyliminium rearrangement
Grandberg rearrangement
Cyclopropane ring-opening
Tryptamine derivatives are psychoactive compounds and are
widely used as 5-HT agonists. For example, compound 1 (Suma-
triptan)1 is used for the treatment of migraine, while compound
22 has demonstrated high potential for the treatment of obesity.
with subsequent decarboxylation and cyclization. Recently, a
Pd-catalyzed reaction of 2-iodoanilines with protected
c-amino-
butanal to form tryptamines was reported.8 Nevertheless, in most
cases, the syntheses of tryptamine derivatives are based on the
Fischer indolization reaction. Since aminoaldehydes and ketones
can be unstable, synthetic methods often demand the use of their
precursors and latent forms.9a–d One of these methods reported
Me
NMe2
NH2
by Grandberg9d involves the cyclization of
c-chloroketone arylhyd-
EtO
MeHNO2S
razones into N-(arylamino)pyrrolines, which in turn rearrange into
tryptamines by analogy to the Fischer synthesis mechanism.
In contrast, methods for the synthesis of 1,4,5,6-tetrahydropyrid-
N
H
N
1
2
azines, are scarce. Thus, in some cases, the cyclization of c-chlorok-
etone arylhydrazones, besides tryptamine derivatives, leads to the
formation of tetrahydropyridazines.10 Several syntheses of various
alkaloids are based on this method.11,12 Tetrahydropyridazine deriv-
atives form in the reactions of 3-acylpropionic acids with hydra-
zines,13 in the rearrangement of bicyclic diaziridines,14 and in the
reaction of vinyl carbenes with aromatic aldehyde hydrazones.15
It should be noted that the Grandberg method is general for the
synthesis of both tryptamines and tetrahydropyridazines. In these
transformations, hydrazones were generated directly from chlorok-
etones and arylhydrazines. Subsequently, a few examples of their
generation from haloalkynes were reported in the literature.16,9c
Here we report that cyclopropylketone arylhydrazones, which can
undergo cyclopropane ring-opening as in the cyclopropyliminium
rearrangement,17,18 are used to form haloketone hydrazones and
subsequently tetrahydropyridazines and tryptamines. Thus we
Derivatives of 1,4,5,6-tetrahydropyridazine, in turn, have not
been screened in detail for their biological activity. They are
described as nonsteroidal progesterone receptor ligands3 and
antibacterial drugs.4
There are numerous methods available for the synthesis of tryp-
tamines, many of which5a–o consist of modifications of other indole
derivatives. Fleming et al.6 suggested a pathway to N,N-dialkyltryp-
tamines via the amination and aminomethylation of 2-bromophe-
nyl vinyl ketone followed by the formation of an indole ring.
Nicolaou et al.7 synthesized tryptamine by the reaction of Boc-
aniline with N-Boc-3-pyrrolidone in the presence of a strong base
⇑
Corresponding author. Tel./fax: +7 499 135 63 90.
E-mail address: tom@ioc.ac.ru (Y.V. Tomilov).
Tel./fax: +7 499 135 63 90.
http://dx.doi.org/10.1016/j.tetlet.2014.09.017
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

R. F. Salikov et al. / Tetrahedron Letters 55 (2014) 5936–5939
5937
Table 1
Rearrangement of cyclopropyl ketone arylhydrazones
R1
R1
R1
NH2
R2
conditions
N
R2
N
+
N
N
H
N
H
R2
3a–
h
4a–h
5a–c
Entry
Hydrazone
R1
R2
Conditions
Products (yields, %)
1a
2a
3
3a
3b
3c
3d
3e
3f
H
Br
NO2
H
Br
NO2
H
NO2
Me
Me
Me
Ph
Ph
Ph
NH4I, MeCN,
D
4a (34)
4b (5)
5a (49)
HCl, EtOH,
D
D
5b (80)b
NH4I, DCB,d
NH4I, MeCN,
4c (31)
4d (69)
4e (54)
4f (44)
4g (60)
4h (45)
5c (25)c
4a
5a
6
D
—
—
—
—
—
HCl, EtOH, D
NH4I, DCB,d
NH4I, MeCN, D
D
7a
8
3g
3h
cyclo-C3H5
cyclo-C3H5
NH4I, DCB,d
D
a
b
c
Hydrazones were generated in situ from ketones and either 4-bromophenylhydrazine hydrochloride or phenylhydrazine.
The product was obtained as the hydrochloride.
The product was obtained as the hydroiodide.
d
1,2-Dichlorobenzene.
can simplify the Grandberg method by using stable cyclopropylke-
tones instead of highly reactive haloketones.
and cyclopropane ring-opening to form halides 6, which undergo
ring-closure into tetrahydropyridazines 4a–h (Scheme 1). The for-
mation of tryptamines 5a–c from halides 6 can proceed via two
possible mechanisms, analogous to those described by Grandberg
et al.10 The first consists of the ring-closure to give a five-
membered pyrroline 7, followed by rearrangement into trypta-
mines 5a–c analogous to the Fischer indole synthesis (Scheme 1).
It is worth noting that despite the apparent spatial restriction of
the sigmatropic rearrangement of 7 due to the presence of the
pyrroline ring, there is an example of a Claisen rearrangement with
structures similar to these.22
We are aware of two previous publications on cyclopropylketone
hydrazone rearrangements. In one of these the authors19 stated that
tryptamines were the only reaction products, since they obtained
only water-soluble hydrochlorides. In the second,20 the reaction of
cyclopropyl phenyl ketone with phenylhydrazine in hydrochloric
acid in ethanol gave a mixture of 3-methyl-1-phenyl-1,3,5,6-
tetrahydropyridazine (26%) and 2-phenyl-3-(2-chloroethyl)indole
(17%). In this article we present an investigation of the rearrangement
of cyclopropylketone arylhydrazones as a method for the synthesis of
tryptamines and tetrahydropyridazines; nitro group containing
hydrazones were synthesized in a separate reaction step, the others
being generated in situ.
We have found that cyclopropyl methyl ketone hydrazones 3a–c
(Table 1, entries 1–3) rearrange into a mixture of tetrahydropyrida-
zines 4a–c and tryptamines 5a–c, the best yield of the tryptamine
being observed in the case of in situ generated bromophenylhydrazone
3b21 (entry 2). At the same time, cyclopropyl phenyl ketone hydra-
zones 3d–f, and dicyclopropyl ketone phenyl- and 4-nitrophenylhyd-
razones 3g and 3h rearrange to give tetrahydropyridazines 4d–h
exclusively. In contrast to phenyl- and 4-bromophenylhydrazones,
which rearrange under relatively mild conditions, 4-nitrophenylhyd-
razones require more stringent reaction conditions, that is, heating in
1,2-dichlorobenzene (DCB).
However, the rearrangement accompanied by N–N bond cleavage
can proceed before elimination of hydrogen chloride, in other words,
via the formation of imine 8, which transforms into tryptamines via
several straightforward steps (Scheme 2).
It is worth mentioning that tetrahydropyridazine 4d was previ-
ously obtained by Grandberg et al.10 by the reaction of phenylhydr-
azine and 3-chloropropyl phenyl ketone in a similar yield (52%)
indicating that the two processes are similar in mechanism.
In the case of dicyclopropyl ketone 4-bromophenylhydrazone (9),
which is generated in situ from the corresponding hydrazine 10 and
ketone 11, instead of the expected 2-cyclopropyltryptamine 12, we
obtained tryptamine 13, which forms via ring-opening of both cyclo-
propyl rings, in a mixture with a smaller amount of tetrahydropyrid-
azine 14. It is thought that hydrazone 9 initially transforms into
di(chloropropyl) ketone hydrazone 15. Intramolecular alkylation of
the latter leads to the formation of 16, which in turn rearranges into
13 through the intermediate pyrroline 17 (Scheme 3).
The first stages of these transformations correspond to those of
the cyclopropyliminium rearrangement and include protonation
Specific reaction products were observed in the rearrangement
of cyclopropyl methyl ketone 2,4-dinitrophenylhydrazone (18)
under heating with NH4I in DCB. Apparently, hydrazone 18 primar-
ily transforms into a mixture of the corresponding pyrroline 19 and
tetrahydropyridazine 20, analogous to the aforementioned hydra-
zones. The latter further rearranges into benzotriazole oxide 21,
X
R2
R1
R1
HX
3a–h
H
N
N
–
HX
N
H
N
H
R2
6
7
-
HX
R1
X
NH
NH2
R2
R1
N
R2
R1
N
5a–c
6
R2
NH2
N
H
c
4a
–h
5a–
8
Scheme 1. Proposed mechanism for the formation of tetrahydropyridazines and
Scheme 2. Proposed mechanism for the formation of tryptamines via rearrange-
tryptamines via the generation of a pyrroline ring.
ment of haloketone arylhydrazones.

5938
R. F. Salikov et al. / Tetrahedron Letters 55 (2014) 5936–5939
Cl
Br
Br
Br
O
MeCN
N
+
N
H
NH3
Cl
N
N
H
N
H
Cl
10
11
9
15
NH2
Br
Br
Br
N
H
N
N
N
N
12
H
Cl
14 (10%)
+
NH2
N
Br
Br
16
N
H
NH2
Cl
Cl
17
13 (44%)
Scheme 3. Rearrangement of dicyclopropyl ketone 4-bromophenylhydrazone.
O2N
NO2
O2N
NO2
O2N
NO2
NH4I
N
N
Me
+
N
N
DCB, Δ
N
H
N
H
Me
Me
18
19
20
O
O2N
O2N
N
O2N
NO2
N
redox
N
N
+
O
N
N
O
N
N
H
Me
Me
Me
23 (30%)
22 (61%)
21
Scheme 4. Rearrangement of cyclopropyl methyl ketone 2,4-dinitrophenylhydrazone.
O
O2N
NO2
O2N
N
O2N
NO2
Br
H+
N
EtOH
HN
N
Me
O
+
N
(Shine)
N
(Matsoyan,
Nazarov)
N
Me
Me
24
25
26
27
Scheme 5. Rearrangement of 1-(2,4-dinitrophenyl)-3-methylpyrazoline (24) into 5-nitro-1-(3-oxobutyl)benzotriazole 3-oxide (27).
which in turn undergoes a redox reaction with pyrroline 19 to give a
mixture of benzotriazole 22 and pyrrole 23. Since the product ratio
is not equimolar, oxide 21 presumably eliminates atomic oxygen,
which is partially consumed in the oxidation of 19 (Scheme 4).
Dicyclopropyl ketone and cyclopropyl phenyl ketone dini-
trophenylhydrazones, under these conditions, slowly decompose
to form dinitrophenylhydrazine.
previously, in our case oxide 21 is not observed due to the
stringent reaction conditions.
In conclusion, the rearrangement of cyclopropyl methyl ketone
phenyl-, 4-bromophenyl-, and 4-nitrophenylhydrazones proceeds
to form a mixture of tetrahydropyridazines and tryptamines, the
formation of the latter being due to the Cloke–Stevens–Grandberg
domino rearrangement. Cyclopropyl phenyl ketone phenyl-,
4-bromophenyl- and 4-nitrophenylhydrazones and dicyclopropyl
ketone phenyl- and 4-nitrophenylhydrazones only rearrange into
tetrahydropyridazines, while in the case of dicyclopropyl ketone
4-bromophenylhydrazone the tryptamine derivative is formed via
ring-opening of both cyclopropyl rings. Cyclopropyl methyl ketone
2,4-dinitrophenylhydrazone rearranges into a mixture of benzotri-
azole and pyrrole derivatives. We have shown that the rearrange-
ment of electron-deficient hydrazones requires stringent reaction
conditions. As a result, we have studied in detail the rearrangement
of cyclopropyl ketone hydrazones.
Previously Shine et al.23 synthesized pyrazoline 24 via the reac-
tion of 25 and 26 (Scheme 5) and found that its characteristics did
not coincide with those reported earlier by Matsoyan and Varta-
nyan,24 which in turn agreed with those of the product of unknown
structure obtained by Nazarov et al.25 The authors investigated the
previous results and demonstrated that in acidic medium, pyrazo-
line 25 (homologous to 20) undergoes rearrangement into benzo-
triazole oxide 27 (homologous to the intermediate 21), which
was in fact the product obtained by Matsoyan and Nazarov. Thus,
the rearrangement analogous to that of 20 into 21 was described

R. F. Salikov et al. / Tetrahedron Letters 55 (2014) 5936–5939
5939
A.; Michalik, M.; Beller, M. Tetrahedron Lett. 2004, 45, 3123; (d) Grandberg, I. I.;
Bobrova, N. I. Chem. Heterocycl. Compd. 1974, 10, 943.
Acknowledgments
10. Grandberg, I. I.; Zuyanova, T. I.; Przheval’skii, N. M.; Minkin, V. I. Chem.
Heterocycl. Compd. 1970, 6, 693.
11. Li, Q.; Hurley, P.; Ding, H.; Roberts, A. G.; Akella, R.; Harran, P. G. J. Org. Chem.
2009, 74, 5909.
12. Ding, H.; Roberts, A. G.; Harran, P. G. Angew. Chem., Int. Ed. 2012, 51, 4340.
13. Wawzonek, S.; Gueldner, R. C. J. Org. Chem. 1965, 30, 3031.
14. Konovalikhin, S. V.; Zolotoi, A. B.; Atovmyan, L. O.; Shustov, G. V.; Denisenko, S.
N.; Kostyanovsky, R. G. Russ. Chem. Bull. 1995, 44, 483.
15. Xu, X.; Zavalij, P. Y.; Doyle, M. P. Angew. Chem., Int. Ed. 2012, 51, 9829.
16. Azab, A.; Al Quntar, A. A. A.; Srebnik, M. Tetrahedron Lett. 2007, 48, 3213.
17. (a) Cloke, J. B. J. Am. Chem. Soc. 1929, 51, 1174; (b) Stevens, R. V. Acc. Chem. Res.
1977, 10, 193; (c) Soldevilla, A.; Sampedro, D. Org. Prep. Proced. Int. 2007, 39,
563.
This project was supported financially by the Presidium of the
Russian Academy of Sciences (Program for the Development of
Methods for the Synthesis of Chemical Compounds and the Crea-
tion of New Materials) and the Division of Chemistry and Materials
Science of the Russian Academy of Sciences (Program for Basic
research ‘Biomolecular and Medical Chemistry’).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.
017.
18. (a) Tomilov, Y. V.; Platonov, D. N.; Frumkin, A. E.; Lipilin, D. L.; Salikov, R. F.
Tetrahedron Lett. 2010, 51, 5120; (b) Tomilov, Y. V.; Salikov, R. F.; Platonov, D.
N.; Lipilin, D. L.; Frumkin, A. E. Mendeleev Commun. 2013, 23, 22; (c) Salikov, R.
F.; Platonov, D. N.; Frumkin, A. E.; Lipilin, D. L.; Tomilov, Y. V. Tetrahedron 2013,
69, 3495; (d) Salikov, R. F.; Platonov, D. N.; Lipilin, D. L.; Frumkin, A. E.; Tomilov,
Y. V. Russ. Chem. Bull. 2014, 765.
References and notes
19. Patent JP 84 73568, 1984; Chem. Abstr., 1984, 101, p 171091.
20. Robinson, B.; Khan, M. I.; Shaw, M. J. J. Chem. Soc., Perkin Trans. 1 1987, 2265.
21. Reaction of cyclopropylethanone with 4-bromophenylhydrazine and subsequent
rearrangement. A mixture of 4-bromophenylhydrazine hydrochloride (1.48 g,
6.6 mmol), and cyclopropyl methyl ketone (1.00 g, 12 mmol) in EtOH (20 mL) was
heated at reflux for 7 h. The hot mixture was diluted with H2O (14 mL) and cooled
to rt. Theresulting precipitate was filtered and purified by column chromatography
(cyclohexane–EtOAc, 2:1) to give 4b (0.084 g, 5%). The filtrate was evaporated and
recrystallized from MeOH–CHCl3 (1:4) to give 5b (1.38 g, 80%).
1. Brandes, J. L.; Kudrow, D.; Stark, S. R.; O’Carroll, C. P.; Adelman, J. U.; O’Donnell,
F. J.; Alexander, W. J.; Spuill, S. E.; Barrett, P. S.; Lener, S. E. J. Am. Med. Assoc.
2007, 297, 1443.
2. Adams, D.; Benardeau, A.; Bickerdike, M. J.; Bentley, J. M.; Bissantz, C.; Bourson,
A.; Cliffe, I. A.; Hebeisen, P.; Kennett, G. A.; Knight, A. R.; Malcolm, C. S.; Mizrahi, J.;
Plancher, J.-M.; Richter, H.; Rover, S.; Taylor, S.; Vickers, S. P. Chimia 2004, 58, 613.
3. Combs, D. W.; Reese, K.; Phillips, A. J. Med. Chem. 1995, 38, 4878.
4. Ziegler, C. B.; Kuck, N. A.; Harris, S. M.; Lin, Y.-I. J. Heterocycl. Chem. 1988, 25,
1543.
5. (a) Ganellin, C. R.; Hollyman, D. R.; Ridley, H. F. J. Chem. Soc. (C) 1967, 2220; (b)
Pfeil, E.; Harder, U. Angew. Chem. 1967, 6, 178; (c) Righi, M.; Topi, F.; Bartolucci,
S.; Bedini, A. J. Org. Chem. 2012, 77, 6351; (d) Hoshino, T.; Shimodaira, K. Justus
Liebigs Ann. Chem. 1935, 520, 19; (e) Bergman, J.; Bäckvall, J.-E.; Lindström, J.-O.
Tetrahedron 1973, 29, 971; (f) Brutcher, F. V.; Vanderwerff, W. D. J. Org. Chem.
1958, 23, 146; (g) Snyder, H. R.; Katz, L. J. Am. Chem. Soc. 1947, 69, 3140; (h)
Flaugh, M. E.; Crowell, T. A.; Clemens, J. A.; Sawyer, B. D. J. Med. Chem. 1979, 22,
63; (i) Noland, W. E.; Hartman, P. J. J. Am. Chem. Soc. 1954, 76, 3227; (j) Young,
E. H. P. J. Chem. Soc. 1958, 3493; (k) Snyder, H. R.; Eliel, E. L. J. Am. Chem. Soc.
1948, 70, 1703; (l) Nagarathnam, D. J. Heterocycl. Chem. 1992, 29, 953; (m)
Akabori, Sh.; Soito, K. Ber. Chem. 1930, 63, 2245; (n) Ahmad, A.; Eelnurme, I.;
Spenser, I. D. Can. J. Chem. 1960, 38, 2523; (o) Merour, J. Y.; Buzas, A. Synth.
Commun. 1988, 18, 2331.
Compound 4b:, brownish crystals, mp 85–86 °C; IR (KBr) 3090, 3040, 2970, 2927,
2864, 1588, 1491 cm–1. EIMS (m/z, %) 252, 254 (both 100, M+), 237, 239 (9,
M+ÀCH3), 183, 185 (20), 182, 184 (30), 155, 157 (38, BrC6H4). 1H NMR (300 MHz,
CDCl3) d 7.38–7.30 (m, 2H), 7.10–7.02 (m, 2H), 3.47–3.38 (m, 2H), 2.12–2.18 (m,
2H), 2.07–1.94 (m, 5H). 13C NMR (75 MHz, CDCl3) d 147.4, 144.5, 131.7, 115.1,
111.3, 42.2, 25.6, 24.4, 19.0. Anal. Calcd for C11H13BrN2: C, 52.19; H, 5.18; N, 11.07.
Found: C, 50.79; H, 5.18; N, 11.04.
Compound 5bÁHCl:, brownish crystals, mp 254–255 °C; IR (KBr) 3355, 3312, 2963,
2935, 2909, 2888, 2844, 2741, 2020, 1493, 1468, 1453, 1433 cm–1. EIMS (m/z,%)
252, 254 (both 7, M+ÀHCl), 223, 225 (26), 183, 185 (46), 143 (20), 30 (100, CH2NH+2).
1H NMR (300 MHz, DMSO-d6) d 11.18 (s, 1H, NH), 8.12 (s, 3H, NH3), 7.66 (d,
J = 1.9 Hz, 1H, H(4)), 7.22 (d, J = 8.5 Hz, 1H, H(7)), 7.09 (dd, J = 8.5, 1.9 Hz, 1H, H(6)),
3.04–2.77 (m, 4H, CH2CH2), 2.34 (s, 3H, Me). 13C NMR (75 MHz, DMSO-d6) d 134.8,
133.9, 129.8, 122.5 (C(6)), 119.4 (C(4)), 112.5 (C(7)), 111.0, 105.4, 39.4 (CH2), 21.7
(CH2), 11.2 (CH3). Anal. Calcd for C11H14BrClN2: C, 45.62; H, 4.87; N, 9.67. Found: C,
45.43; H, 4.89; N, 9.64.
6. Fleming, I.; Woolias, M. J. Chem. Soc., Perkin Trans. 1 1979, 829.
7. Nicolaou, K. C.; Krasovsky, A.; Trépanier, V. É.; Chen, D. Y.-K. Angew. Chem., Int.
Ed. 2008, 47, 4217.
8. Hu, Ch.; Qin, H.; Cui, Yu.; Jia, Ya. Tetrahedron 2009, 65, 9075.
9. (a) Bidylo, T. I.; Yurovskaya, M. A. Chem. Heterocycl. Compd. 2008, 44, 379. and
references cited therein; (b) Kost, A. N.; Zabrodnyaya, V. G.; Portnov, Yu. N.;
Voronin, V. G. Chem. Heterocycl. Compd. 1980, 16, 368; (c) Khedkar, V.; Tillack,
22. Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 2000, 122, 3785.
23. Shine, H. J.; Fang, L.-T.; Mallory, H. E.; Chamberlain, N. F.; Stehling, F. J. Org.
Chem. 1963, 28, 2326.
24. Matsoyan, S. G.; Vartanyan, S. A. Izv. Akad. Nauk Arm. SSR 1955, 8, 31.
25. Nazarov, N. N.; Kasitsyna, L. A.; Zaretskaya, I. I. J. Gen. Chem. USSR 1957, 27, 606.