Novel synthesis of cinnolines and 1-aminoindolines via Cu-catalyzed intramolecular N-arylation of hydrazines and hydrazones prepared from 3-haloaryl-3-hydroxy-2-diazopropanoates

Article abstract of DOI:10.1021/jo8010864

(Chemical Equation Presented) A new and facile access to cinnolines, dihydrocinnolines, and 1-aminoindolines was established by use of diazo functionalities. The hydrazines and hydrazones as cyclization precursors derived from 3-haloaryl-3-hydroxy-2-diazopropanoates, which are prepared by one-pot procedure utilizing phase-transfer catalysis, are successfully converted to the corresponding nitrogen heterocycle by Cu-catalyzed N-arylation. Furthermore, analysis of UV spectra proved that 4-oxo-3-carboxylates predominantly exist not as 4-hydroxycinnoline (enol form) but as cinnolone (keto form).

Full text of DOI:10.1021/jo8010864

Novel Synthesis of Cinnolines and 1-Aminoindolines via
Cu-Catalyzed Intramolecular N-Arylation of Hydrazines and
Hydrazones Prepared from
3-Haloaryl-3-hydroxy-2-diazopropanoates
Kazuya Hasegawa, Naoki Kimura, Shigeru Arai, and Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, 1-33 Yayoi-cho, Inage-ku, Chiba
263-8522, Japan
nishida@p.chiba-u.ac.jp
ReceiVed May 19, 2008
A new and facile access to cinnolines, dihydrocinnolines, and 1-aminoindolines was established by use
of diazo functionalities. The hydrazines and hydrazones as cyclization precursors derived from 3-haloaryl-
3-hydroxy-2-diazopropanoates, which are prepared by one-pot procedure utilizing phase-transfer catalysis,
are successfully converted to the corresponding nitrogen heterocycle by Cu-catalyzed N-arylation.
Furthermore, analysis of UV spectra proved that 4-oxo-3-carboxylates predominantly exist not as
4-hydroxycinnoline (enol form) but as cinnolone (keto form).
Introduction
heteroaromatic π-system.3 With respect to the synthesis of
cinnoline-3-carboxylic acid derivatives, although three repre-
sentative methods have been reported, they have been used in
only limited appications. For example, strongly acidic media is
necessary to generate a diazonium salt in a typical von Richter
synthesis,4 and regiocontrolled cyclization is still difficult in
Barber synthesis.5 Furthermore, intramolecular aromatic sub-
stitution sometimes requires the protection of hydrazones to
Cinnoline1a and 1-aminoindoline1b are important skeletons
that are found in natural products and pharmaceuticals (Figure
1) and thus are potential candidates for biologically important
molecules.1c The development of their facile synthesis has been
an important issue.
The cinnoline scaffold can be an attractive structural template
in agriculture, biology, and medicine. In fact, over the past few
years cinnoline derivatives have been patented as agrochemical
and pharmaceutical drugs.2 They can also be used in organic
nonlinear optics (NLO) materials by utilizing a polarized
(3) Chapoulaud, V. G.; Ple´, N.; Turck, A.; Que´guiner, G. Tetrahedron 2000,
56, 5499–5507.
(4) (a) von Richter, V. Chem. Ber. 1883, 16, 677–683. (b) Li, J.-J.; Cook,
J. M. Name Reactions in Heterocyclic Chemstry; Wiley-Interscience: Hoboken,
NJ, 2005; pp 540-543. (c) Vasilevsky, S. F.; Tretyakov, E. V. Liebigs Ann.
1995, 775–779. (d) Schofield, K.; Swain, T. J. Chem. Soc. 1949, 2393–2399.
Haley and co-workers reported thermal cyclization of 2-ethynylphenyltriazenes;
see: (e) Kimball., D. B.; Hayes, A. G.; Haley, M. M. Org. Lett. 2000, 2, 3825–
3827.
(1) (a) Wieslawa, L.; Andrzej, S. Arch. Pharm. 2007, 340, 65–80. (b)
Cignarella, G.; Sanna, P. J. Med. Chem. 1981, 24, 1003–1006, and references
thereinFor isolation of schizocommunin, see: (c) Hosoe, T.; Nozawa, K.;
Kawahara, N.; Fukushima, K.; Nishimura, K.; Miyaji, M.; Kawai, K. Myco-
pathologia 1999, 146, 9–12.
(5) (a) Barber, H. J.; Washbourn, K.; Wragg, W. R.; Lunt, E. J. Chem. Soc.
1961, 2828–2843. (b) Shoup, R. R.; Castle, R. N. J. Heterocycl. Chem. 1965, 2,
63–66. (c) Al-Awadi, N. A.; Elnagdi, M. H.; Ibrahim, Y. A.; Kaul, K.; Kumar,
A. Tetrahedron 2001, 57, 1609–1614. (d) Sereni, L.; Tato´, M.; Sola, F.; Brill,
W. K.-D. Tetrahedron 2004, 60, 8561–8577.
(2) Turck, A.; Ple´, N.; Tallon, V.; Que´guiner, G. Tetrahedron 1995, 51,
13045–13060, and references therein.
10.1021/jo8010864 CCC: $40.75
Published on Web 07/09/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6363–6368 6363

Hasegawa et al.
FIGURE 1
SCHEME 1. Synthesis of Hydrazones
TABLE 1. Cu-Mediated N-Arylation of 4
avoid a Wolff-Kishner-type process.6 To overcome these
disadvantages, we planned to develop a general synthetic method
to produce a cinnoline skeleton using 3-haloaryl-3-hydroxy-2-
diazopropanoates,7 which have been shown to be useful building
blocks for the synthesis of nitrogen-containing molecules.8
Furthermore, we describe a facile synthesis of 1-aminoindolines
by a similar strategy.
Initially, we prepared some hydrazones 5 and 6 as cyclization
precursors for the synthesis of cinnolines and dihydrocinnolines
(Scheme 1). An aldol-type reaction of 2-bromo or 2-iodoben-
zaldehydes 1 with tosyl chloride in a one-pot synthesis gave 2
in respective yields of 81% and 88% using our procedure that
has been reported previously.8 After conversion to silyl ethers
3, stereoselective reduction of diazo group by LiEt3BH gave
(E)-4. The stereochemistry of (E)-hydrazone was previously
determined by X-ray analysis of phenylderivatives.8b Subsequent
acylation of terminal nitrogens with acid chlorides gave the
substrates 5 and 6 for cyclization in reasonable yields.
With the substrates in hand, we first attempted a palladium-
catalyzed N-arylation using 4a by Buchwald’s procedure;9
yield of
7a (%)
entry
4
Cul (mol %)
base (equiv)
time
1
2
3
4
4a
4c
4c
4c
200
200
10
CsOAc (5)
CsOAc (5)
CsOAc (5)
NaOAc (1.1)
15 h
10 min
9 h
30
quant
86
200
2 h
quant
however, the reaction resulted in the formation of a complex
mixture. Next we studied Cu-mediated cyclization,10 as shown
in Table 1. The reaction of 4a in the presence of an excess
amount of CuI with CsOAc in DMSO10b at room temperature
gave cinnoline 7a in 30% yield (entry 1). Iodide 4c was more
reactive and converted to 7a within 10 min in quantitative yield
(entry 2). This cyclization proceeded under catalytic conditions
with a longer reaction time in 86% yield (entry 3). This
(6) (a) Miyamoto, T.; Matsumoto, J. Chem. Pharm. Bull. 1988, 36, 1321–
1327. (b) Sandison, A. A.; Tennant, G. J. Chem. Soc., Chem. Commun. 1974,
752–753. (c) Ames, D. E.; Leung, O. T.; Singh, A. G. Synthesis 1983, 52–53.
(7) For reviews of R-diazocarbonyl compounds, see: (a) Doyle, M. P.;
McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with
Diazo Compounds; Wiley Interscience: New York, 1998. (b) Ye, T.; McKervey,
M. A. Chem. ReV. 1994, 94, 1091–1160. (c) Zhao, Y.; Wang, J. Synlett 2005,
2886–2892. For recent application of indole synthesis from N-arylhydrazone
prepared from R-diazoesters, see: (d) Yasui, E.; Wada, M.; Takamura, N.
Tetrahedron Lett. 2006, 47, 743–746.
(8) (a) Arai, S.; Hasegawa, K.; Nishida, A. Tetrahedron Lett. 2004, 45, 1023–
1026; 2005, 46, 6171. (b) Hasegawa, K.; Arai, S.; Nishida, A. Tetrahedron 2006,
62, 1390–1401.
(10) (a) Ley., S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–
5449. (b) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002,
231–234. (c) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421–7428.
(9) (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 10251–10263. (b) Prim, D.; Campagne, J.; Joseph, D.; Andrioletti, B.
Tetrahedron 2002, 58, 2041–2075.
6364 J. Org. Chem. Vol. 73, No. 16, 2008

Synthesis of Cinnolines and 1-Aminoindolines
SCHEME 2. One-Pot Synthesis of 7a
TABLE 2. Cu-Mediated N-Arylation of 5a-c
DMEN (%)
entry
5
Cul (mol %)
base (equiv)
conditions
9 (%)
yield of 7a (%)
10a (%)
1
2
3
4
5
6
5a
5b
5b
5b
5c
5c
200
200
200
200
10
CsOAc (5)
CsOAc (5)
NaOAc (5)
NaOAc (1.1)
Cs2CO3 (2)
Cs2CO3 (2)
rt, 3 h
9a: 15
9b: 28
9b: 53
9b: 65
9a: quant
9a: 93
0
38
40
25
0
70
0
0
0
0
50 °C, 8 h
50 °C, 19 h
50 °C, 19 h
rt, 1 h
10
10
rt, 10 min
0
0
SCHEME 3. Preparation and Reaction of (E)-10c
SCHEME 4. Reduction of 9b
aromatization seemed to be caused by the elimination of a silanol
from dihydrocinnoline under basic conditions. When a weaker
base (NaOAc) was used, only a trace amount of dihydrocin-
noline was observed and 7a was obtained in almost quantitative
yield (entry 4).
Dihydrooxadiazaborine 8, which is readily available by the
reduction of 2b, was also applicable for cyclization. Thus,
treatment of 2b with LiEt3BH followed by cyclization success-
fully gave 7a in 58% yield in two steps (Scheme 2).
Because the lower electron density on the terminal nitrogen
might prevent the elimination of silanol, we next investigated
N-acylated substrates 5a-c to obtain dihydrocinnolines. The
Cu-mediated cyclization of 5a with CsOAc at room temperature
gave 9a in 15% yield without any significant aromatization,
although deprotection of the TBS group proceeded to give 10a
in 70% yield (Table 2, entry 1). To minimize this desilylation,
a TBDPS ether 5b was chosen for further studies at 50 °C. The
reaction of 5b gave cyclized products 9b and 7a in respective
yields of 28% and 38% without formation of 10a (entry 2).
Because 9b did not give 7a at 50 °C in DMSO under neutral
conditions, a weaker base such as sodium acetate (5 equiv) was
used next. As expected, 9b was obtained as a major product in
53% yield, and using a reduced amount of base (1.1 equiv) was
more effective to give 9b in 65% yield together with 7a in 25%
yield (entries 3 and 4). The reaction using 5c with Cs2CO3 at
room temperature was quite efficient to give 9a in quantitative
yield even in a catalytic system without any aromatization or
deprotection (entry 5). This reaction was accelerated by diamine
ligand:10c the addition of N,N′-dimethylethylenediamine (DMEN,
10 mol %) gave 9a as a sole product in 93% yield within 10
min (entry 6).
The (E)-stereochemistry of 5 is found to be quite important
because the (Z)-isomer of 5c, easily prepared from (E)-4c, gave
a complex mixture under optimized conditions.11 We also found
that silyl protection is not necessary for this Cu-catalyzed
J. Org. Chem. Vol. 73, No. 16, 2008 6365

Hasegawa et al.
SCHEME 5. Transformation of 9a to 4-Oxo Derivatives
cyclization. For example, OH-free substrate 10c, prepared from
(E)-5c with TBAF, was smoothly converted to 11 in 89% yield
(Scheme 3).
72% yield, and its structure was determined by the comparison
to the reported analytical data,5d which suggests a keto form
(cinnolone) does exist predominantly.
After succeeding in Cu-catalyzed cyclization to cinnolines,
we next investigated the further transformation of 9b with
various reducing agents to expand its synthetic utility (Scheme
4). The reaction using NaBH4 proceeded with deacetylation and
deoxygenation to give 12 in 91% yield. Hydrogenation promoted
not only reduction of the CdN bond but also deoxygenation to
give 13 in 55% yield. Treatment with SmI2 resulted in
aromatization via deacetylative deoxygenation (7b: 65%).
Because 4-oxo derivatives such as cinoxacin, which shows
good antibacterial against Gram-negative bacteria,6a seem to be
useful, we next attempted the transformation of 9a to 16
(Scheme 5). Treatment of 8a with TBAF gave the three products
11, 7a, and 14. Compound 11 was then converted to 14 via
oxidation using MnO2 and aromatization under thermal condi-
tions (85%, 2 steps). The following acid treatment gave 16 in
To confirm the structure of the other related compounds, we
next analyzed the UV spectra of cinnoline 7a,b and 14-16 in
DMSO. As expected, a different UV pattern was observed: the
former shows one strong λmax around 260 nm and the latter has
two strong signals in both 260 and 340 nm, respectively (Figure
2). These results strongly suggest not cinnnoline but the
cinnnolone form is favored in 14-16. Caliculation (HF/3-21G
level with Spartan 06) also suggest that both 4-keto-cinnolone
calboxylic acid and calboxylate are more stable than the
corresponding enol form, due to the hydrogen bonding between
carboxylic proton and keto carbonyl group. The NMR analysis
also indicates the latter does exist as a keto form12 (see
Supporting Information).
We next studied the synthesis of 1-aminoindolines, which
are also important pharmacophores in medicinal chemistry.1b
FIGURE 2. UV spectra in DMSO for 7a,b and 14-16.
6366 J. Org. Chem. Vol. 73, No. 16, 2008

Synthesis of Cinnolines and 1-Aminoindolines
conformationally fixed phenylalanine equivalents.14 The syn-
thesis is shown in Scheme 6; stereoselective reduction of (E)-
6a,b gave 17a,b as anti-isomers, exclusively.15 Although the
cyclization using 17a with CuI under the optimized conditions
(CuI, DMEN, Cs2CO3, DMSO, rt) was unsuccessful, 17b was
quite reactive to give 18a within 1 h in 88% yield. Cleavage of
SCHEME 6. Stereocontrolled Synthesis of 18a
16
the N-N bond by SmI2 followed by deprotection of a TBS
group with TBAF gave 19 in 86% yield.
To confirm the generality of these methods, four types of
hydrazones 5d-g and hydrazines 17c-f were prepared from
the corresponding aldol adducts. First, we applied the intramo-
lecular N-arylation of 5 under the optimized conditions (Table
3). Change in the electronic nature of the substituents on benzene
ring did not affect the efficiency in this cyclization (entries 1-3).
Even in the case of sterically hindered substrate such as 5g, the
reaction gave 9g in 58% yield (entry 4).
TABLE 3. Intramolecular N-Arylation of 5d-g
Similar investigation using 17c-e revealed that 1-aminoin-
dolines were obtained in good yield (entries 1-3). However,
17f, which has a substituent at the 3-position, prevented
cyclization to give 18f in low yield (entry 4). These results are
summarized in Table 4.
In summary, we have demonstrated that both hydrazones and
hydrazines are useful precursors for the facile synthesis of
cinnoline, dihydrocinnoline, and 1-aminoindoline derivatives by
Cu-catalyzed intramolecular N-arylation. Further application of
this protocol to natural product synthesis is currently under
investigation.
entry
5
yield (%)
1
2
3
4
5d
5e
5f
9d: 61a
9e: quant
9f: quant
9g: 58
5g
Experimental Section
a 9d is partially aromatized upon silica gel column chromatography to
give 7d (38%).
Typical Procedure for Cu-Catalyzed N-Arylation. Synthesis
of 9a (Table 2, entry 6). A test tube was charged with 5c (53.2
mg, 0.10 mmol), CuI (1.9 mg, 0.01 mmol), and Cs2CO3 (65.2 mg,
0.20 mmol). The tube was evacuated and backfilled with argon.
To the mixture were added dried DMSO (0.5 mL) and N,N′-
dimethylethylenediamine (DMEN, 1.1 µL, 0.01 mmol). The reaction
mixture was stirred at room temperature for 10 min. The resulting
mixture was filtered through a pad of silica gel, eluting with Et2O.
The filtrate was concentrated, and the residue was purified by flash
column chromatography (n-hexane/AcOEt ) 20:1) to give 9a (37.4
mg, 93%) as a colorless oil. IR (neat) ν: 2931, 1718 cm-1. 1H NMR
(CDCl3, 400 MHz) δ: 0.03 (s, 3H), 0.09 (s, 3H), 0.73 (s, 9H), 1.59
(s, 9H), 2.66 (s, 3H), 5.68 (s, 1H), 7.27-7.43 (m, 3H), 8.55 (d,
1H, J ) 8.4 Hz). 13C NMR (CDCl3, 100 MHz) δ: 173.3, 162.3,
140.7, 134.5, 129.0, 128.9, 126.2, 123.8, 119.5, 82.4, 58.6, 28.0,
25.5, 23.9, 18.0, -4.4. LRMS (FAB) m/z: 443 (M + K). HRMS
(FAB) calcd for C21H32N2O4SiK 443.1768, found 443.1735.
Synthesis of 18a (Scheme 6). A test tube was charged with 17b
(49.0 mg, 0.08 mmol), CuI (1.6 mg, 0.008 mmol), and Cs2CO3
(53.5 mg, 0.16 mmol). The tube was evacuated and backfilled with
argon. To the mixture were added dried DMSO (0.4 mL) and N,N′-
dimethylethylenediamine (0.9 µL, 0.008 mmol). The reaction
mixture was stirred at room temperature for 1 h. To the resulting
mixture were added AcOEt (5 mL) and ammoniacal solution of
NaCl (10 mL). The mixture was stirred vigorously to dissolve the
precipitate and then extracted with AcOEt (10 mL × 3). The
combined organic extracts were washed with brine, dried over
Na2SO4, and concentrated in vacuo. Flash column chromatography
(n-hexane/AcOEt ) 15:1) gave 18a (34.0 mg, 88%) as a colorless
amorphous solid. IR (neat) ν: 3285, 2929, 2857, 1725, 1660, 834
TABLE 4. Intramolecular N-Arylation of 17c-f
entry
17
yield (%)
1
2
3
4
17c
17d
17e
17f
18c: 70
18d: 71
18e: 71
18f: 29
The most widely used method for synthesizing 1-aminoindolines
is a multistep synthesis via N-amination of the corresponding
indolines or indoles.13 Indoline formation by nucleophilic attack
of the internal nitrogens of hydrazines should be achieved by
Cu-catalyzed N-arylation. Particularly, 3-hydroxyindoline-2-
carboxylates are expected to be attractive building blocks as
(11) Sakamoto reported that both E- and Z-isomer hydrazones successfully
cyclized to give indazole via intramolecular N-arylation under Pd catalysis; see:
Inamoto, K.; Katsuno, M.; Yoshino, T.; Suzuki, I.; Hiroya, K.; Sakamoto, T.
Chem. Lett. 2004, 33, 1026–1027. Our result using the Z-isomer is described in
Supporting Information.
(14) Collot, V.; Schmitt, M.; Marwah, P.; Bourguignon, J. Heterocycles 1999,
51, 2823–2847.
(15) The stereochemistry of 17a,b was determined by conversion to tert-
butyl 2-(N-benzoylhydrazino)-3-phenyl-3-(tert-butyldimethylsilyloxy)propionate
by dehalogenation (s-BuLi/THF,-78 °C, 1 h); see ref 8b.
(16) Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266–6267.
86.(12) Holzer, W.; Eller, G. A.; Scho¨nberger, S. Heterocycles 2008, 75, 77–
(13) Stanton, J. L.; Ackerman, M. H. J. Med. Chem. 1983, 26, 986–989.
J. Org. Chem. Vol. 73, No. 16, 2008 6367

Hasegawa et al.
1
cm-1. H NMR (CDCl3, 600 MHz) δ: 0.17 (s, 3H), 0.22 (s, 3H),
vanced Molecular Transformation of Carbon Resources” from
the Ministry of Education, Culture, Sports, Science and Tech-
nology, Japan.
0.94 (s, 9H), 1.48 (s, 9H), 4.41 (d, 1H, J ) 4.0 Hz), 5.48 (d, 1H,
J ) 4.0 Hz), 6.74 (d, 1H, J ) 8.4 Hz), 6.92 (dd, 1H, J ) 7.6, 7.6
Hz), 7.23-7.56 (m, 5H), 7.83 (d, 2H, J ) 7.8 Hz), 8.04 (s, 1H).
13C NMR (CDCl3, 150 MHz) δ: 169.9, 166.6, 149.4, 132.7, 132.0,
129.6, 128.7, 127.9, 127.1, 124.9, 121.3, 109.5, 82.6, 76.6, 74.6,
28.0, 25.8, 18.0, -4.3. LRMS (FAB) m/z: 507 (M + K). HRMS
(FAB) calcd for C26H36N2O4SiK 507.2081, found 507.2078.
Supporting Information Available: General experimental
1
procedures, H and 13C NMR spectra, charactrization data for
new compounds of 2-14 and 16-19. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research on Priority Areas “Ad-
JO8010864
6368 J. Org. Chem. Vol. 73, No. 16, 2008