Copper-catalyzed tandem C-N bond formation: An efficient annulative synthesis of functionalized cinnolines

Article abstract of DOI:10.1002/anie.201201529

Cinn-tillating synthesis: The combination of a readily available copper catalyst, a simple hydrazide nucleophile, and established difunctionalized building blocks provides a new, flexible route to an under-developed class of aromatic heterocycles, cinnolines (see scheme). Copyright

Full text of DOI:10.1002/anie.201201529

Angewandte
Chemie
DOI: 10.1002/anie.201201529
Heterocycle Synthesis
ꢀ
Copper-Catalyzed Tandem C N Bond Formation: An Efficient
Annulative Synthesis of Functionalized Cinnolines**
Catherine J. Ball, Jeremy Gilmore, and Michael C. Willis*
[1]
ꢀ
Transition metal-catalyzed aryl C N bond formation has
become an important tool in the synthesis of heterocycles.[2]
Mild conditions, readily accessible starting materials and user-
friendly procedures are among the advantages that such
a strategy offers compared to classical syntheses. However,
the development of general and flexible routes to a wider
variety of heterocycles remains an important goal.
synthesis based on a tandem copper-catalyzed annulation that
employs a simple hydrazide nucleophile.
Cinnolines are classically formed using cyclization of
a phenyldiazonium ion onto an ortho functionality.[8] In the
classic von Richter synthesis[9] this cyclization involves an
activated ortho-alkyne (1!2, route A in Scheme 2). How-
Cinnolines, and cinnoline derivatives, are known to
exhibit anti-cancer,[3] fungicidal and bactericidal,[4] and anti-
inflammatory[5] activity as well as luminescent and optical
properties (Scheme 1).[6] Yet these structures remain rela-
Scheme 2. Retrosynthetic routes for cinnoline formation. PG=protect-
ing group.
ever, such a route usually presents significant limitations;
strongly acidic conditions are required, potentially unstable
and difficult to handle diazonium intermediates are needed,
and the construction of the cinnoline framework necessarily
results in substitution at the 4- and often 3-positions.
Extensive transformations and harsh reaction conditions are
often required to produce cinnolines lacking these substitu-
ents.[10] Alternative routes to cinnolines include cyclizations
involving aryl hydrazones,[11] aryl hydrazines,[12] and nitriles,[13]
and intermolecular cycloadditions.[14] However, none of these
routes represent a general synthesis or allow for complete
control of the substituent pattern incorporated.
We have previously demonstrated that 2-(2-haloalkenyl)-
aryl halides 3 can serve as useful precursors to a number of
heterocycles, using two sequential transition metal-catalyzed
reactions. For example, tandem aminations, the first inter-
molecular, the second intramolecular, provide efficient routes
to a range of N-functionalized indoles.[15] An aminocarbony-
lation step can also be incorporated to produce quinolones
and isoquinolones.[16] Benzofurans have also been prepared
using related chemistry.[17] Given the versatility of these
difunctionalized backbones we envisaged that they could also
provide an efficient synthetic route to cinnolines. Our
proposed route involved the catalytic annulation of aryl-
alkenyl dihalides 3 with an N,N’-disubstituted hydrazide
nucleophile 4 to provide a dihydrocinnoline derivative 5,
which could then be simply converted to the corresponding
aromatic core (route B in Scheme 2).
Scheme 1. Cinnoline and representative biologically active analogues.
tively unfamiliar in modern-day organic chemistry; when
compared with their quinoline isostere, the cinnoline sub-
structure is considerably less exploited. However, in a number
of cases where the pharmacological profiles of these two
structures have been directly compared, the cinnoline ana-
logue has often exhibited superior properties.[3d,5,7] Given the
promising biological profile of many cinnolines it is puzzling
that these structures have not been explored more thoroughly.
One reason for this is presumably the lack of efficient and
accessible synthetic routes. In this Communication, we
address this issue and report an efficient and flexible cinnoline
[*] C. J. Ball, Dr. M. C. Willis
Department of Chemistry, University of Oxford, Chemistry Research
Laboratory
Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: michael.willis@chem.ox.ac.uk
Homepage: http://mcwillis.chem.ox.ac.uk/MCW/Home.html
Dr. J. Gilmore
Lilly Research Centre, Eli Lilly and Company Ltd.
Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH
(UK)
[**] This work was supported by the EPSRC and Eli Lilly.
Supporting information for this article (experimental details) is
available on the WWW under http://dx.doi.org/10.1002/anie.
201201529.
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Table 1: Reaction optimization for the formation of diethyldihydro-
cinnoline-1,2-dicarboxylate 8a.[a]
Table 2: Copper-catalyzed tandem C N annulation for the preparation of
dihydrocinnoline derivatives 8.[a]
Entry Cu source
[mol%]
Ligand Metal:Ligand Base
Yield[b]
1
2
3
4
5
6
7
8
9
10
CuI [10]
CuI [10]
CuI [10]
CuI [10]
CuI [10]
CuI [10]
CuTC [10]
Cu(OTf)2.PhH [10]
CuI [10]
A
A
A
A
B
C
A
A
A
A
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1
1:2
K3PO4
Cs2CO3
K2CO3
54%
79%
95%
NaOtBu 0%[c]
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
31%
72%
82%
87%
79%
61%
CuI [5]
[a] Reaction conditions: dihalide (1.0 equiv), diethyl-1,2-hydrazinedicar-
boxylate (2.0 equiv), base (2.5 equiv), dioxane, 908C, 18 h. [b] Yield of
isolated product. [c] Aryl alkyne 6ab was isolated as the sole reaction
product. CuTC=copper(I) thiophene-2-carboxylate.
Our initial investigations to realize this novel route
to cinnolines focused on the combination of 2-(2-bromo-
alkenyl)aryl bromide 6a and diethyl-1,2-hydrazine dicarbox-
ylate 7 (Table 1). Dihalide 6a was synthesized as reported[15]
using simple Wittig chemistry, in good yield, and with high Z-
ꢀ
selectivity. Based on literature precedent for aryl C N bond
formation with hydrazides,[18,19] we focused on a CuI diamine
catalyst system. Treatment of dihalide 6a with a catalyst
generated from CuI and N,N’-dimethylethylenediamine
(ligand A, DMEDA), using K3PO4 as the base in dioxane,
produced the desired diethyldihydrocinnoline-1,2-dicarboxy-
late 8a in moderate yield (Entry 1). Changing the base to
Cs2CO3, and then K2CO3 increased the yield to 95%
(Entries 2–3). When the strong base NaOtBu was employed,
only alkyne 6ab was isolated as a reaction product (Entry 4).
Other types of known Cu ligands were explored, however all
were inferior to diamine A (Entries 5–6). Changing the
copper source away from CuI also resulted in slightly reduced
yields (Entries 7–8). Finally, a metal:ligand ratio of 1:2 with
10 mol% CuI loading was optimal; changing the ratio to 1:1
(Entry 9) and reducing the loading to 5 mol% (Entry 10)
resulted in lower yields of 79% and 61%, respectively.
With the conditions optimized, we sought to explore the
scope of this new process and a variety of diethyldihydrocin-
[a] Conditions: dihalide (1.0 equiv), diethyl-1,2-hydrazinedicarboxyl-
ate (2.0 equiv), CuI (10 mol%), ligand A (20 mol%), K2CO3 (2.5 equiv),
dioxane, 908C, 18 h. Yields of isolated product. Substrates were obtained
with Z:E>10:1, except in cases [b] where this was markedly lower. See
Supporting Information for details. [c] Using aryl chloride substrate.
ents, useful for further functionalization, is also noteworthy
(8i–m). Inclusion of additional alkene-substituents in the
substrates was also possible, leading to C3-substituted dihy-
drocinnoline products (8o–r). A number of heterocycle-based
substrates could be used, leading to the formation of aza
derivative 8s, thiophene derivative 8t, and benzothiophene
derivative 8u. Finally, it should be noted that the E-isomers of
the alkenyl bromide precusors 6 do not produce dihydrocin-
noline products under the present reaction conditions, and
lead instead to the formation of noncyclized byproducts. This
is generally not an issue as the majority of substrates were
obtained with > 10:1 Z:E selectivity. However, for selected
substrates, lower Z:E ratios resulted in reduced yields of
dihydrocinnoline products (8h, 8t, and 8u, for example).
The range of dihydrocinnolines shown in Table 2 illus-
trates the variety of type and position of substituents that can
noline-1,2-dicarboxylate derivatives
8
were prepared
(Table 2). Electron-rich (8b–f), neutral (8g–h) and electron-
poor (8i–n) arene cores were all readily incorporated.
Although the majority of substrates featured an alkenyl
bromide/aryl bromide combination of activating groups, it
was also possible to employ aryl chloride units, as used in the
preparation of dihydrocinnolines 8d, 8e, and 8g. The ability
to tolerate the incorporation of additional halogen substitu-
2
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Table 3: NaOH mediated conversion of dihydrocinnoline derivatives 8
be introduced using this synthesis. In particular, we have
shown that a Cl-substituent can be incorporated at each
position of the benzo core. We have also prepared derivatives
featuring a substituent at each position of the heterocycle,
except C4. The difficulty in making C4-substituted products
results from the use of Wittig chemistry for the preparation of
the alkenyl bromide substrates 6.[20] However, the inherent
reactivity of diethyldihydrocinnoline dicarboxylates 8 can be
used to produce C4 substituents in an efficient manner. For
example, formylation of dihydrocinnoline 8g using classic
Vilsmeier–Haack conditions led exclusively to 4-formyl
derivative 9, and chlorination using NCS provided 4-chloro
derivative 10, both in good yields (Scheme 3). Capitalizing on
into cinnolines 11.[a]
Scheme 3. Dihydrocinnoline functionalization and elaboration using
a Suzuki coupling. NCS=N-chlorosuccinimide, XPhos=2-dicyclohexyl-
phosphino-2’,4’,6’-triisopropylbiphenyl.
the introduction of a Cl substituent, Suzuki conditions were
developed utilizing Buchwaldꢀs electron-rich biaryl phos-
phine ligand, XPhos,[21] which allowed 4-aryl dihydrocinno-
lines 8v–x to be prepared in excellent yields.
Next, our focus turned to the crucial transformation of the
dihydrocinnoline derivatives 8 into their aromatic cinnoline
counterparts. We found that a simple system of aqueous
sodium hydroxide in ethanol left open to air led to the
formation of cinnolines 11, in generally good yields (Table 3).
Cinnolines with strongly electron-donating substituents were
readily prepared, presumably because of their increased
propensity for oxidation. For example, cinnolines 11a, 11b,
and 11e were obtained in yields of 94%, 98%, and 90%,
respectively. Less electron-rich substrates were transformed
with lower efficiency, but still in generally good yields. Slightly
modified conditions were required for the F containing
cinnoline 11i and for the strongly electron-deficient products
(for example, 11n). Under the standard conditions 11i was
observed to undergo an SNAr reaction to yield the corre-
sponding ethoxy-substituted product, and attempts to form
11n resulted in decomposition. However, simply stirring the
reactions at room temperature (as opposed to 708C) for an
extended period of time (36 h) allowed formation of the
desired cinnolines, albeit with reduced yields. The hetero-
cycle-derived examples were also transformed into the
corresponding aromatic systems, delivering the unusual aza
cinnoline analogue 11s,[22] and the novel thiophene-contain-
ing analogues 11t and 11u.[23]
[a] Reaction conditions: diethyldihydrocinnoline-1,2-dicarboxylates (8,
1.0 equiv), 5m NaOH(aq) (5.0 equiv), ethanol, 708C, 16 h. Yields of
isolated product. [b] Left at room temperature for 36 h.
The cinnoline-forming conditions could also be performed
as a “one-pot” process, without isolation of the intermediate
dihydrocinnoline derivatives. Instead, the crude reaction
mixture from the Cu-catalyzed transformation was simply
filtered through Celite, concentrated under vacuum, and
subjected directly to the cinnoline-forming conditions. As
such, we prepared cinnoline 11a on a gram scale in 87% yield
(Scheme 4).
Finally, to fully demonstrate the utility of our cinnoline
synthesis, we have prepared a medicinally important cinno-
line derivative. Cinnoline 13 is an intermediate in the
synthesis of a series of cinnoline-based Topoisomerase-
targeting agents[7] (Scheme 5). Its previous synthesis relied
on diazotization chemistry; however, we predicted that our
direct annulation route would eliminate the need for a diazo-
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anticipate that cinnolines will no longer be under represented
in the literature.
Received: February 24, 2012
Revised: March 21, 2012
Published online: && &&, &&&&
Scheme 4. Gram scale “one-pot” formation of cinnoline 11a.
Keywords: annulation · cinnolines · copper catalysis ·
.
heterocycles · tandem processes
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4
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Communications
Heterocycle Synthesis
C. J. Ball, J. Gilmore,
M. C. Willis*
&&&& — &&&&
ꢀ
Copper-Catalyzed Tandem C N Bond
Formation: An Efficient Annulative
Synthesis of Functionalized Cinnolines
Cinn-tillating synthesis: The combination
of a readily available copper catalyst,
a simple hydrazide nucleophile, and
established difunctionalized building
blocks provides a new, flexible route to an
under-developed class of aromatic het-
erocycles, cinnolines (see scheme).
6
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