Copper-Catalyzed Formation of α-Alkoxycycloalkenones from N-Tosylhydrazones

Article abstract of DOI:10.1002/anie.201505993

The combination of 20 mol % of copper iodide and lithium tert-butoxide triggers the formation of a broad range of substituted, functionalized α-alkoxy 2H-naphthalenones from readily available N-tosylhydrazones. The data suggests that this transformation occurs through cycloaddition of a copper carbenoid with an ester, followed by a Lewis acid-catalyzed [1,2] alkyl shift of the in situ generated alkoxyepoxide intermediate. The combination of 20 mol % of copper iodide and lithium tert-butoxide triggers the formation of a broad range of substituted, functionalized α-alkoxy 2H-naphthalenones from readily available N-tosylhydrazones. The reaction proceeds by the cycloaddition of a copper carbenoid with an ester, and a subsequent Lewis acid-catalyzed [1,2] alkyl shift of the in situ generated alkoxyepoxide intermediate.

Full text of DOI:10.1002/anie.201505993

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Angewandte
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International Edition: DOI: 10.1002/anie.201505993
German Edition: DOI: 10.1002/ange.201505993
Carbenes
Copper-Catalyzed Formation of a-Alkoxycycloalkenones from
N-Tosylhydrazones
Naijing Su, Juliana A. Theorell, Donald J. Wink, and Tom G. Driver*
Abstract: The combination of 20 mol% of copper iodide and
lithium tert-butoxide triggers the formation of a broad range of
substituted, functionalized a-alkoxy 2H-naphthalenones from
readily available N-tosylhydrazones. The data suggests that this
transformation occurs through cycloaddition of a copper
carbenoid with an ester, followed by a Lewis acid-catalyzed
[1,2] alkyl shift of the in situ generated alkoxyepoxide inter-
mediate.
T
he reactivity of transition-metal carbene complexes has
spurred significant innovation which dramatically simplifies
the synthesis of complex, functionalized molecules.[1,2] These
divalent reactive intermediates have been widely exploited in
cyclopropanation,[3] cycloaddition,[4] annulation,[5] metathe-
Scheme 1. Divergent reactivity of metal divalent catalytic intermediates.
esp=a,a,a’,a’-tetramethyl-1,3-benzene-diproprionate.
sis,[6] and C H bond functionalization processes.[7] In contrast,
migrations to produce a-acyloxy ketones.[14,15] Herein, we
report the copper-catalyzed transformation of N-tosylhydra-
zones into a-alkoxy ketones through a [1,2] alkyl-shift of an
in situ generated alkoxy-substituted epoxide.[16]
To determine if related reactivity patterns are embedded
in metal carbenoids, the reactivity of the N-tosylhydrazone
11a was investigated (Table 1). N-Tosylhydrazones were
chosen as the carbene precursor because they are well-
established as a safe and nontoxic source of alkyl diazo
compounds,[17,18] and the requisite substrate is rapidly acces-
sible from a Suzuki cross-coupling reaction between the aryl
boronate 10 and vinyl triflate 9. To our delight, exposure of
À
the use of these reactive intermediates to trigger cascade
processes has lagged behind the established transforma-
tions.[8] Our group has pursued the synthesis of N-hetero-
cycles from aryl azides by using transition-metal catalysts to
À
generate and control metal N-aryl nitrenes in C H bond-
amination reactions.[9] Our mechanistic experiments sug-
2
À
gested that C(sp ) H functionalization occurred through
a tandem reaction in which C N bond formation preceded
À
[10]
À
C H bond cleavage, and we exploited this mechanism by
substituting the hydrogen with other migrating groups to
achieve the formation of functionalized 3H-indoles, such as 4,
from trisubstituted styryl azides (1) through an electrocyliza-
tion-[1,2] carboxylate rearrangement (Scheme 1).[11] During
the course of our investigations, we were curious if this
reactivity pattern was unique to rhodium N-aryl nitrenes or if
it was general to other divalent catalytic intermediates, such
as metal aryl carbenes. While metal carbenes are established
to react with ketones and aldehydes to afford epoxides,[12,13]
esters coordinate with the electrophilic carbenes to produce
a dipole which can be captured through a dipolar cyclo-
addition reaction.[4] In the absence of a dipolarophile, we
anticipated that an electrocyclization/migration sequence
might occur to afford the indene 6. Alternatively, a [2+1]
cycloaddition, unprecedented with an ester, could occur to
produce the alkoxy-substituted epoxide 7, which might
rearrange under the reaction conditions because it is well-
established that enol-ester-derived epoxides undergo acyloxy
Table 1: Development of the optimized reaction conditions for 2H-
naphthalenone.
Entry
Catalyst
mol%
T [8C]
Yield [%][a]
1
2
3
4
5
6
7
8
CuI
CuBr
CuCl
(CuOTf)2·PhMe
Cu(OTf)2
CuBr2
[Rh2(O2CMe)4]
AlCl3
20
20
20
20
20
20
5
90
90
90
90
90
90
90
90
90
90
50
98
68
30
43
20
36
dec.
dec.
10
5
[*] N. Su, J. A. Theorell, Prof. Dr. D. J. Wink, Prof. Dr. T. G. Driver
Department of Chemistry, University of Illinois at Chicago
845 West Taylor Street, Chicago, IL 60607 (USA)
E-mail: tgd@uic.edu
9
10
11
none
CuI
CuI
n.a.
10
20
76
20
[a] Determined using 1H NMR spectroscopy with CH2Br2 as an internal
standard. DME=dimethoxyethane, OTf=trifluoromethylsulfonate,
Ts =4-methyltoluenesulfonate.
Homepage: http://www2.chem.uic.edu/driver
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505993.
12942
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11a to LiOtBu (1.1 equiv) and 20 mol% of CuI produced
a single product in 98% (entry 1), and it was established to be
the a-methoxy-2H-naphthalenone 12a by X-ray crystallog-
raphy. The expected indene was not observed. The identity of
the copper catalyst proved critical to obtaining the indene in
good yield (entries 2–6). In comparison to CuI, lower reaction
yields were obtained with CuBr, CuCl, and (CuOTf)2·PhMe
as well as copper(II) salts. [Rh2(OAc)4] as well as Lewis acids,
such as AlCl3, were also examined as potential catalysts but
only decomposition was observed (entries 7 and 8).[19] In the
absence of a metal salt, 12a was observed in only 10%
(entry 9). Lowering the catalyst loading of CuI to 10 mol% or
reducing the reaction temperature to 508C also led to
diminished 12a formation (entries 10 and 11). Changing the
solvent or the counterion of the alkoxide base also had
a deleterious effect on 2H-naphthalenone formation.[19]
By using the optimal reaction conditions, the scope of this
transformation was interrogated by adding substituents to the
aryl portion of the hydrazone (Table 2). The electronic nature
of the substrate was modified through substituting the 4-
position with a range of different functional groups (entries 1–
6). This reaction appears insensitive to the electronic nature
of the R1 group, thus resulting in good conversions with
electron-donating groups as well as electron-withdrawing
groups. This reaction also tolerates substitution at the 5-
position of 11 without attenuation of the yield of the 2H-
naphthalenone (entries 7–9). While the reaction is insensitive
to changes to the electronic nature of the substrate, increasing
the steric environment, by adding a second ortho substituent,
attenuated the yield of the reaction (entry 10). Because 2,6-
disubstituted aryl hydrazones are competent substrates in
carbene and carbenoid reactions,[17b,d] we attribute this
adverse effect to the destabilizing steric interactions that
might occur in a co-planar transition state specific to the
reaction. The thiophene N-tosylhydrazone 11k was also
found to be competent in this transformation to enable
access to the heterocycle 12k (entry 11).
Next, the identity of the ortho-substituent of the aryl
hydrazone was varied to further survey the scope of this new
reaction (Table 3). The effect on changing the steric environ-
ment around the reaction center was investigated first
(entries 1 and 2). As expected from Table 2, we found an
inverse correlation between the reaction yield and the size of
Table 3: Effect of the o-alkenyl substituent identity on 2H-naphthalenone
formation.
Entry 13
N-tosylhydrazone 2H-naphthalenone Yield [%][a]
1
2
13a
13b
58, R1 =Et
30, R1 =iPr
3
13c
61
60, n=0,
R2 =Et
65, n=2
R2 =Me
78, n=3,
R2 =Me[b]
4
5
6
13d
13e
13 f
7
8
9
13g
13h
13i
50, E=O
50, E=NBoc
55, E=NTs
Table 2: Examination of the scope and limitations of the tandem
reaction.
10
11
13j
35
Entry
11
R1
R2
R3
Yield [%][a]
1
2
3
4
5
6
7
8
9
10
11a
11b
11c
11d
11e
11 f
11g
11h
11i
H
H
H
H
H
H
H
OMe
Me
Cl
H
H
H
H
H
H
H
H
93
60
72
67
87
68
64
77
87
25
MeO
Ph
F
Cl
F3C
H
H
H
H
82
13k
d.r.=60:40[c]
40
12
13
13l
d.r. ꢀ 95:5[d,e]
H
OMe
11j
H
11
11k
53
71
13m
d.r. ꢀ 95:5[d,e]
[a] Yield of 12 isolated after neutral alumina chromatography, only
product obtained.
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Table 3: (Continued)
Entry 13
N-tosylhydrazone 2H-naphthalenone Yield [%][a]
quant.
14
13n
d.r. 55:45[d]
15
13o
40[f]
[a] Yield of 14 isolated after neutral alumina chromatography, only
product obtained. [b] Reaction performed in PhH. [c] Determined using
1H NMR spectroscopy. [d] Determined using SFC-MS. [e] Identity of the
major diastereomer determined by nOe spectroscopic experiments.
[f] Styrene elimination product formed in 23%. Ac=acetyl, Boc=tert-
butyloxycarbonyl.
Scheme 2. Possible mechanisms for 2H-naphthalenone formation.
natively, 18 could be formed through a noncarbene mecha-
nism.[22] In this mechanism, the copper catalyst activates the
ester for attack by 15 to produce 22.[23] Loss of N2 forms the
benzyl cation 23, which is attacked by the copper alkoxide to
produce 18. Ring-opening of the epoxide generates the
oxocarbenium ion 19, which triggers a [1,2] methyl shift to
afford 20.[16] Dissociation of the copper catalyst produces the
product 12a.
Several experiments were performed in an attempt to gain
insight into the reactivity of the proposed catalytic inter-
mediates.[19] First, the addition of TEMPO (2,2,6,6-tetrame-
thylpiperidine 1-oxyl) to the reaction mixture did not produce
any new products to indicate that radical intermediates, if
formed, did not escape the solvent sheath. Attempts to trap
either 17 or 19 with a dipolarophile (DMAD; dimethylace-
tylenedicarboxylate)[4] or an external nucleophile (Et3SiH)
did not change the reaction outcome: only the 2H-naphtha-
lenone 12 was formed.[19] Next, we surveyed the reactivity of
the N-tosylhydrazones 24 to determine if the o-alkenyl group
was required for a successful reaction (Scheme 3). Irrespec-
tive of the potential ring formed, only b-hydride elimination
was observed. Finally, to examine the potential for an alkoxy-
substituted epoxide to rearrange, 27 was synthesized and its
reactivity toward Lewis and Brønsted acids was tested. We
found that while it remained inert toward mixtures of CuI and
the hydrazone R1 group. When the aldehyde-derived 13c was
submitted to the reaction conditions, the naphthalenol 14c
was produced (Table 3, entry 3). Next, the composition of the
ortho-alkenyl substituent was modified (entries 4–12). While
shrinking the ring-size led to an attenuated yield (entry 4),
substrates containing medium-sized o-cycloalkenyl rings were
smoothly converted into the a-methoxy-2H-naphthalenones
14e and 14 f (entries 5 and 6). The reaction also tolerated o-
heterocyclic substituents to afford 14g–i (entries 7–9). This
reaction does tolerate acyclic o-alkenyl groups: the hydrazone
13j was efficiently converted into the 2H-naphthalenone 14j
albeit with a reduced yield (entry 10). The diastereoselectivity
of the reaction was next probed (entries 11–14). While
exposure of the hydrazone 13k to the reaction conditions
provided a 3:2 mixture of diastereomers, the chiral, non-
racemic o-norbornyl 13l afforded the 2H-naphthalenone
product as a single diastereomer. Next, the effect of moving
the one of the bridge attachments from the allylic to the
homoallylic position was examined with the b-pinene-derived
13m (entry 13). Alleviating the steric pressure around the
carboxylate substituent improved the yield of the trans-
formation without the loss of stereoselectivity to produce
14m in 71% as a single diastereomer. In contrast, no
diastereoselectivity was observed with the (À)-menthol-
derived carboxylate 13n (entry 14). This reaction could also
be extended to the hydrazone 13o, which contained an o-aryl
group, to produce 14o in 40% (entry 15). Elimination,
however, also occurred to form the 2-substituted styrene in
23%.[19]
The conversion of the N-tosylhydrazones into a-methoxy-
2H-naphthalenones is proposed to occur through the tandem
cycloaddition/[1,2] rearrangement of
a copper carbene
(Scheme 2). The reaction of N-tosylhydrazone with tert-
butoxide generates the diazo 15,[20] which is decomposed by
the copper(I) salt to produce the copper carbene 16.[21] The
epoxide 18 could be produced through either a stepwise
reaction with the proximal methyl carboxylate via the ylide 17
or directly through a [2+1] cycloaddition reaction.[12] Alter-
Scheme 3. Experiments to elucidate the mechanism of the tandem
reaction.
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tert-butanol,[22] exposure of 27 to 5 mol% of a stronger Lewis
acid, AlCl3, at room temperature triggered the formation of
the a-methoxymethyl ketone 28. We interpret this result to
mean that epoxides, such as 18, can rearrange provided that
a strong enough Lewis acid is formed during the reaction.
In conclusion, we have discovered a new reactivity pattern
for metal aryl carbenes toward pendant carboxylates to
transform readily accessible aryl N-tosylhydrazones into
functionalized a-alkoxy 2H-naphthalenones. Currently, we
are working towards understanding the mechanism of this
reaction to exploit the reactivity of these metal aryl carbenes
and trigger additional tandem reactions to facilitate access to
complex functionalized carbocycles.
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Acknowledgements
We are grateful to the Office of the Vice Chancellor of
Research at the University of Illinois at Chicago for their
generous support.
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Keywords: carbenes · copper · cyclizations · hydrazones ·
synthetic methods
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[24] Exposure of the epoxide 27 to stoichiometric amounts of LiCl
and tert-butanol produced only the hydrolyzed a-hydroxy phenyl
ketone. See the Supporting Information for more details.
Received: June 30, 2015
Revised: July 22, 2015
Published online: September 7, 2015
12946 www.angewandte.org
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Angew. Chem. Int. Ed. 2015, 54, 12942 –12946