Rhodium-catalyzed oxidative annulation of sulfonylhydrazones with alkenes

Article abstract of DOI:10.1021/ol302522n

An efficient rhodium-catalyzed tandem C-H bond olefination and annulation approach was developed to afford 1,2-dihydrophthalazines in good to excellent yields from easily accessible sulfonylhydrazones and alkenes.

Full text of DOI:10.1021/ol302522n

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium-Catalyzed Oxidative Annulation
of Sulfonylhydrazones with Alkenes
Guifei Li,† Zhengwei Ding,† and Bin Xu*,‡,§
Department of Chemistry, Shanghai University, Shanghai 200444, China, and State Key
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China, and Shanghai Key Laboratory
of Green Chemistry and Chemical Processes, Department of Chemistry,
East China Normal University, Shanghai 200062, China
xubin@shu.edu.cn
Received September 12, 2012
ABSTRACT
An efficient rhodium-catalyzed tandem CꢀH bond olefination and annulation approach was developed to afford 1,2-dihydrophthalazines in good
to excellent yields from easily accessible sulfonylhydrazones and alkenes.
Dihydrophthalazine derivatives represent a major class
of nitrogen-containing heterocycles with a wide range of
biological and pharmacological activities and play an
increasingly important role in drug discovery.1 1,2-Dihy-
drophthalazine antifolates are a novel family of antibac-
terial drugs; for example, BAL30544 and BAL30545
are new dihydrophthalazine inhibitors of dihydrofolate
reductase (DHFR) with activity against a broad range of
Gram-positive bacteria,2 and the 1,2-dihydrophthalazine
based trimethoprim derivative RAB1 is an effective inhi-
bitor for Bacillus anthracis and Staphylococcus aureus.3
On the other hand, the use of 1,2-dihydrophthalazines as
synthetic intermediates has also added to their impor-
tance.3a,4 Despite this promising precedence, synthetic
methods for the construction of dihydrophthalazine scaf-
folds have only scarcely been studied. The early synthetic
efforts for 1,2-dihydrophthalazines dated back to the
1890s when Gabriel and Muller reported that a mixture
of 2-methyl-l,2-dihydrophthalazine and 2-methyl-l(2H)-
phthalazinone could be converted from 2-methylphthalazi-
nium iodide.5 Other improved synthetic methods to build
this useful scaffold include the addition reaction of phtha-
lazine and Grignard reagent,3a reduction reaction of
phthalazines3a,6 or phthalazinones,4 and microwave irra-
diated cyclocondensation of hydrazines with dihalides.7
However, most of the existing methods suffer from a limited
scope of starting materials, use a stoichiometric catalyst, or
require multistep procedures. In this context, the develop-
ment of efficient syntheses of dihydrophthalazines from
† Shanghai University.
‡ Chinese Academy of Sciences.
§ East China Normal University.
(1) (a) Noga, E. J.; Barthalmus, G. T.; Mitchell, M. K. Cell Biol. Int.
Rep. 1986, 10, 239. (b) Craig, P. N. In Comprehensive Medicinal
Chemistry; Drayton, C. J., Ed.; Pergamon Press: New York, 1991; Vol. 8.
(c) Kodama, T.; Tamura, M.; Oda, T.; Yamazaki, Y.; Nishikawa, M.;
Takemura, S.; Doi, T.; Yoshinori, Y.; Ohkuchi, M. U.S. Patent 983928,
2003.
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K.; McGhee, P.; Dewasse, B.; Beachel, L.; Caspers, P.; Gaucher, B.;
Mert, G.; Shapiro, S.; Appelbaum, P. C. Antimicrob. Agents Chemother.
2009, 53, 1353. (b) Caspers, P.; Bury, L.; Gaucher, B.; Heim, J.; Shapiro,
S.; Siegrist, S.; Schmitt-Hoffmann., A.; Thenoz, L.; Urwyler, H. Anti-
microb. Agents Chemother. 2009, 53, 3620.
(3) (a) Bourne, C. R.; Bunce, R. A.; Bourne, P. C.; Berlin, K. D.;
Barrow, E. W.; Barrow, E. W. Antimicrob. Agents Chemother. 2009, 53,
3065. (b) Bourne, C. R.; Barrow, E. W.; Bunce, R. A.; Bourne, P. C.;
Berlin, K. D.; Barrow, W. W. Antimicrob. Agents Chemother. 2010, 54,
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(4) Johnson, R. E.; Hane, J. T.; Schlegel, D. C.; Perni, R. B.;
Herrmann, J. L., Jr.; Opalka, C. J.; Carabateas, P. M.; Ackerman,
J. H.; Swestock, J.; Birsner, N. C.; Tatlock, J. H. J. Org. Chem. 1991, 56,
5218.
(5) Gabriel, S.; Muller, F. Ber. 1895, 28, 1830.
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Clarke, L. F.; Hegarty, A. F. J. Org. Chem. 1990, 55, 6177.
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(b) Ju, Y. H.; Varma, R. S. J. Org. Chem. 2006, 71, 135.
r
10.1021/ol302522n
XXXX American Chemical Society

readily available starting materials continues to be an active
and rewarding research area.
Scheme 1. Tandem CꢀH Olefination/Annulation Strategy to
Owing to the prevalence of heterocycles in medicinal
chemistry, many methods have been developed recently
through a metal-catalyzed CꢀH bond functionalization
strategy,8 which provides an efficient and environmentally
benign process compared to traditional procedures. Among
all these methods, a vast majority of tandem CꢀH olefina-
tion and annulation reactions are devoted to the synthesis
of nitrogen-containing heterocycles via metal-catalyzed
reactions.9 Recently, N-tosylhydrazones, which are readily
prepared from carbonyl compounds with tunable reactivity
and potential usage in various transformations, have ra-
pidly become versatile cross-coupling partners in transition-
metal-catalyzed reactions.10 However, N-substituted
hydrazones are rarely utilized in the CꢀH bond activation
reactions to construct nitrogen-containing heterocycles.11
As a part of our continuing efforts to assemble hetero-
cycles through a tandem reaction strategy,12 we herein
report a rhodium-catalyzed tandem process consisting of
a sequential CꢀC/CꢀN bond formation to give 1,2-dihy-
drophthalazines as a privileged structural motif for many
pharmaceuticals from readily available sulfonylhydrazones
and alkenes (Scheme 1).
1,2-Dihydrophthalazines from Hydrazones and Alkenes
(2a) in the presence of [RhCp*Cl2]2 (2 mol %) in DMF
using Cu(OAc)2 H2O as an oxidant. Intriguingly, the
3
dihydrophthalazine product 3aa was produced in 75%
yield after reacting for 6 h at 120 °C under nitrogen
(Table 1, entry 1). A diminished yield was afforded when
the reaction was conducted under air or atmospheric oxygen
(entries 2ꢀ3). By lowering the reaction temperature, a clean
reaction was achieved at 80 °C in DMF, and the yield of 3aa
was increased to 86% (entries 4ꢀ6). When the solvent was
switched from DMF to DMA or NMP, the yield was slightly
decreased (entries 7ꢀ8); other solvents provided limited
reaction and gave trace amounts of product (entries 9ꢀ14).
The copper acetate monohydrate is essential to the success of
At the outset of this investigation, we started our study
by exploring the reaction of N0-(diphenylmethylene)-4-
methylbenzenesulfonohydrazide (1a) with n-butyl acrylate
Table 1. Condition Optimizations of 1,2-Dihydrophthalazinesa
(8) For reviews on CꢀH functionalization for the synthesis of
heterocycles, see: (a) Zhang, M. Adv. Synth. Catal. 2009, 351, 2243.
(b) Thansandote, P.; Lautens, M. Chem.;Eur. J. 2009, 15, 5874.
(c) Stokes, B. J.; Driver, T. G. Eur. J. Org. Chem. 2011, 4071. (d) Song,
G. Y.; Wang, F.; Li, X. W. Chem. Soc. Rev. 2012, 41, 3651.
(9) For some examples using Pd: (a) Ji, X. C.; Huang, H. W.; Li,
Y. B.; Chen, H. J.; Jiang, H. F. Angew. Chem., Int. Ed. 2012, 51, 7292. (b)
Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50,
temp
yield
(%)b
ꢀ
1064. (c) Garcıa-Rubia, A.; Urones, B.; Arrayas, R. G.; Carretero, J. C.
´
entry
Cu source
solvent
DMF
(°C)
atmos
Angew. Chem., Int. Ed. 2011, 50, 10927. (d) Zhu, C.; Falck, J. R. Org.
Lett. 2011, 13, 1214. (e) Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones,
G. C.; Booker-Milburn, K. I. Org. Lett. 2011, 13, 5326. (f) Kim, B. S.;
Lee, S. Y.; Youn, S. W. Chem.;Asian J. 2011, 6, 1952. (g) Wasa, M.;
Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680. (h) Houlden,
1
Cu(OAc)2 H2O
120
120
120
90
80
75
80
80
80
80
80
80
80
80
80
80
80
80
80
80
N2
air
O2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
N2
75
69
45
83
86
80
79
84
0
3
2
Cu(OAc)2 H2O
DMF
3
3
Cu(OAc)2 H2O
DMF
3
4
Cu(OAc)2 H2O
DMF
ꢀ
C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.;
3
Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066. (i) Li, J.-J.;
Mei, T.- S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452. (j) Miura,
M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org. Chem. 1998,
63, 5211. For some examples using Rh: (k) Wang, F.; Song, G. Y.; Du,
Z. Y.; Li, X. W. J. Org. Chem. 2011, 76, 2926. (l) Rakshit, S.; Grohmann,
C.; Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (m)
Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2011, 133,
6449. (n) Zhao, M.; Li, X. W. J. Org. Chem. 2011, 76, 8530. (o) Li, X. T.;
Gong, X.; Zhao, M.; Song, G. Y.; Deng, J.; Li, X. W. Org. Lett. 2011, 13,
5808. (p) Willwacher, J.; Rakshit, S.; Glorius, F. Org. Biomol. Chem.
2011, 9, 4736. (q) Wang, F.; Song, G. Y.; Li, X. W. Org. Lett. 2010, 12,
5430. For example using Ru: (r) Li, B.; Ma, J. F.; Wang, N. C.; Feng,
H. L.; Xu, S. S.; Wang, B. Q. Org. Lett. 2012, 14, 736.
5
Cu(OAc)2 H2O
DMF
3
6
Cu(OAc)2 H2O
DMF
3
7
Cu(OAc)2 H2O
DMA
3
8
Cu(OAc)2 H2O
NMP
3
9
Cu(OAc)2 H2O
DMSO
t-AmylOH
Toluene
ClCH2CH2Cl
THF
3
10
11
12
13
14
15
16
17
18
19
20
Cu(OAc)2 H2O
0
3
Cu(OAc)2 H2O
0
3
Cu(OAc)2 H2O
0
3
Cu(OAc)2 H2O
0
3
Cu(OAc)2 H2O
PhCN
DMF
0
3
Cu(TFA)2
Cu(acac)2
CuCl2
0
ꢀ
(10) For recent reviews, see: (a) Barluenga, J.; Valdes, C. Angew.
DMF
0
Chem., Int. Ed. 2011, 50, 7486. (b) Zhang, Y.; Wang, J. B. Eur. J. Org.
Chem. 2011, 1015. (c) Zhang, H. B.; Shao, Z. H. Chem. Soc. Rev. 2012,
41, 560.
(11) (a) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya,
K. Org. Lett. 2007, 9, 2931. (b) Zhang, G. W.; Miao, J. M.; Zhao, Y.; Ge,
H. B. Angew. Chem., Int. Ed. 2012, 51, 8318.
DMF
0
Cu(OAc)2
Cu(OAc)2.H2O
DMF
85
87c
92c,d
DMF
Cu(OAc)2 H2O DMF
3
(12) (a) Song, B. R.; Wang, S. Y.; Sun, C. Y.; Deng, H. M.; Xu, B.
Tetrahedron Lett. 2007, 48, 8982. (b) Sun, C. Y.; Xu, B. J. Org. Chem.
2008, 73, 7361. (c) Ye, W. C.; Mo, J.; Zhao, T. K.; Xu, B. Chem. Commun.
2009, 3246. (d) Zhao, T. K.; Xu, B. Org. Lett. 2010, 12, 212. (e) Wang,
C. M.; Sun, C. Y.; Weng, F.; Gao, M. C.; Liu, B. X.; Xu, B. Tetrahedron
Lett. 2011, 52, 2984. (f) Shao, J.; Huang, X. M.; Hong, X. H.; Liu, B. X.;
Xu, B. Synthesis 2012, 44, 1798. (g) Liu, B. X.; Hong, X. H.; Yan, D.; Xu,
S. G.; Huang, X. M.; Xu, B. Org. Lett. 2012, 14, 4398.
a Reaction conditions: 1a (0.30 mmol), n-butyl acrylate 2a (3.0 equiv),
[Cu] (2.0 equiv), [RhCp*Cl2]2 (2.0 mol %), and solvent (1.5 mL)
were allowed to react in a tube. Cu(acac)2 = Cupric acetylacetonate,
Cu(TFA)2 = Cupric trifluoroacetate, NMP = N-Methyl pyrrolidone.
[RhCp*Cl2]2
= Pentamethylcyclopentadienylrhodium(III) chloride
dimer. b Isolated yield. c [RhCp*Cl2]2 (2.5 mol %). d In DMF (1.0 mL).
B
Org. Lett., Vol. XX, No. XX, XXXX

this transformation, while other copper sources such as
Cu(TFA)2, Cu(acac)2, and CuCl2 gave only a trace amount
of product (entries 15ꢀ17) or led to a similar result when
using Cu(OAc)2 (entry 18). An improved yield could be
achieved using 2.5 mol % of rhodium catalyst with an
elevated concentration (entry 20, Condition A).
The identity of 3ga was determined by spectral analysis
and further confirmed by X-ray crystallographic analysis.13
When ortho-brominated (1i) or ortho-chlorinated (1j) sub-
strates were used, no corresponding dihydrophthalazine
product could be isolated, and an intramolecular annulation
reaction was accomplished to give 3-phenyl-1-tosyl-1H-
indazole (3i) in high yields. It is worth mentioning that
N-methyl or N-phenyl sulfonylhydrazones could also pro-
duce the corresponding products (3ka, 3la) in good yields.
However, attempts to replace the tosyl group with amide or
aryl groups failed under the same conditions, which sug-
gested that the acidity of the NꢀHiscriticaltothereaction.9d
To define the scope of this reaction better, we further
applied other alkenes as the coupling partners for this
oxidative olefination/annulation process (Scheme 3). Re-
actions involving alkenes conjugated with an alkyl or aryl
acrylate led to good to excellent product yields (3abꢀ3af).
For acrylate esters bearing an allyl group (2e), the electron-
rich CdC double bond remained intact under optimized
conditions and resulted in the formation of 3ae in high
yield. It should be noted that substrates bearing an acrylic
acid or an unsubstituted amide group could be tolerated
in this reaction and afforded products in good yields
(3ag, 3ah); the free ꢀCOOH or ꢀCONH2 group remained
untouched in the reaction. N,N-Disubstituted amide and
acrylonitrile could also be employed in this transformation
and afforded the desired products in good yields (3ai, 3aj).
With the optimized reaction conditions in hand, we
then extended the reaction with a range of substrates.
As illustrated in Scheme 2, hydrazones containing both
electron-donating (3ba, 3ea) and electron-withdrawing
groups (3ca, 3da, and 3fa) or bearing para- (3baꢀ3da)
and meta-groups (3ea, 3fa) proceeded efficiently with good
to excellent yields. The regioselectivity of this reaction
mainly depends on the steric hindrance of substrates. For
example, moderate regioselectivity of 3fa-A/3fa-B (1.4:1)
was observed for a meta-fluoro containing substrate (1f),
and the major product (3fa-A) corresponds to the CꢀC
coupling at a less hindered position. Notably, the methyl
and methoxyl substituent at the ortho position retarded the
reaction, and the products were obtained in moderate
yields with high regioselectivity (3ga, 3ha).
Scheme 2. Reaction of Hydrazones with n-Butyl Acrylatea,b
Scheme 3. Reaction of N-Tosylhydrazone with Alkenesa,b
a Reaction conditions: 1a (0.3 mmol), 2 (3.0 equiv), [RhCp*Cl2]2
(2.5 mol %), and Cu(OAc)2 H2O (2.0 equiv) in DMF (1.0 mL), 80 °C,
3
b
under nitrogen. Isolated yield. The yield based on 69% conversion
c
of 1a. d Cu(OAc)2 H2O (4.0 equiv) was used. The yield based on 84%
conversion of 1a.
3
a Reaction conditions: 1 (0.3 mmol), 2a (3.0 equiv), [RhCp*Cl2]2
(2.5 mol %), and Cu(OAc)2 H2O (2.0 equiv) in DMF (1.0 mL), 80 °C,
(13) Crystal data for 3ga: C28H30N2O4S, MW = 490.60, Monoclinic,
P21/n, final R indices [I > 2σ(I)], R1 = 0.0812, wR2 = 0.2240, a =
11.5309(16) A, b = 8.3030(12) A, c = 27.839(4) A, R = 90°, β =
98.030(2)°, γ = 90°, V = 2639.2(7) A3, Crystal size = 0.40 ꢁ 0.20 ꢁ 0.20
mm, T = 293(2) K, Z = 4, reflections collected/unique = 15995/5991
[R(int) = 0.0387]; Data, 5991; restraints, 0; parameters, 317.
3
under nitrogen. b Isolated yield. c At 120 °C. d The yield based on 39%
e
conversion of 1h. N0-((2-Bromophenyl)(phenyl)methylene)-4-methyl-
benzenesulfonohydrazide (1i) was used. f N0-((2-Chlorophenyl)(phenyl)-
methylene)-4-methylbenzenesulfonohydrazide (1j) was used.
Org. Lett., Vol. XX, No. XX, XXXX
C

Two key compounds are proposed as possible intermedi-
ates for this reaction (Scheme 4), intermediate A generated
through a Wacker-type mechanism9k or intermediate B via
a Heck-type mechanism.8d To define the possible inter-
mediate and pathway, several control experiments were
performed. From intermediate A, which could be synthe-
sized by palladium-catalyzed oxidative coupling of 1a with
n-butyl acrylate,14 no annulation product 3aa was obtained
under Condition A (Scheme 4). This result implied that the
reaction did not mainly proceed via intermediate A. When
the reaction time was shortened to 40 min under Condition
A, with 58% conversion of 1a, intermediate B was isolated
in 31% yield together with 25% yield of 3aa, and 3aa was
further produced in 90% yield from synthesized B after
reacting for 6 h under condition A (Scheme 4).
in Scheme 5. Coordination of hydrazone 1a to a Rh(III)
species facilitates the formation of the NꢀRh bond,
which in turn promotes the generation of a rhodacycle
(I). This rhodacycle can coordinate 1 equiv of alkene
and then undergo alkene insertion to give intermediate
II. Subsequently, reductive elimination of II yields the
intermediate B and a Rh(I) species, which is then re-
oxidized by Cu(II) to regenerate Rh(III). The formed
intermediate B presumably reacts with copper acetate
to afford intermediate III with concomitant elimination
of HOAc. Intermediate III likely undergoes a Michael
addition followed by subsequent enolate protonation to
give dihydrophthalazine 3aa.
Scheme 5. Plausible Mechanism for Synthesis of 3aa from 1a
Scheme 4. Formation of B and 3aa under Condition Aa
a Condition A: [RhCp*Cl2]2 (2.5 mol %) and Cu(OAc)2 H2O
(2.0 equiv) in DMF (1.0 mL), 80 °C, 6 h, under nitrogen.
3
In summary, we have developed an efficient rhodium-
catalyzed tandem CꢀH olefination and copper acetate
promoted intramolecular CꢀN bond-forming protocol
for the straightforward synthesis of l,2-dihydrophtha-
lazines. This approach provides one of the easiest path-
ways for accessing this class of valuable compounds
from easily accessible sulfonylhydrazones and alkenes.
The characteristics of excellent functional group
tolerance and synthesis modularity will provide the
described reaction with broad utility in organic synth-
esis. Further applications are under investigation in
our group.
To probe the role of rhodium and copper catalysts in this
tandem process, several experiments were performed un-
der the optimized reaction conditions. A trace amount of
dihydrophthalazine 3aa was produced without using cop-
per acetate (eq 1), while an 89% yield of 3aa was isolated in
the absence of a rhodium catalyst (eq 2), which indicated
that the Cu(OAc)2 was crucial to facilitate this reaction.15
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Nos. 20972093 and
21272149) is gratefully acknowledged. The authors thank
Prof. Hongmei Deng (Laboratory for Microstructures,
SHU) for spectral support.
Supporting Information Available. Experimental pro-
cedures and characterization data for all compounds,
and X-ray structure of compound 3ga (CIF). This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
On the basis of these investigations, we proposed a
plausible mechanism for this tandem reaction as depicted
(14) Elliott, L. D.; Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G. C.;
Booker-Milburn, K. I. Org. Lett. 2011, 13, 728.
(15) Kantam, M. L.; Neeraja, V.; Kavita, B.; Neelima, B.; Chaudhuri,
The authors declare no competing financial interest.
M. K.; Hussain, S. Adv. Synth. Catal. 2005, 347, 763.
D
Org. Lett., Vol. XX, No. XX, XXXX