Directed Zincation with TMPZnCl·LiCl and Further Functionalization of the Tropolone Scaffold

Article abstract of DOI:10.1021/acs.orglett.6b03270

The directed zincation of tropolone derivatives was achieved using TMPZnCl·LiCl. Various functionalizations of the zincated intermediates by halogenation, acylation, allylation, and Negishi cross-coupling were successfully performed. Additionally, 1,8-conjugate addition-elimination reactions with a variety of arylmagnesium and secondary alkylzinc reagents were carried out to further elaborate the tropolone core.

Full text of DOI:10.1021/acs.orglett.6b03270

Letter
pubs.acs.org/OrgLett
Directed Zincation with TMPZnCl·LiCl and Further Functionalization
of the Tropolone Scaffold
Diana Haas,† Daniela Sustac-Roman,† Sophia Schwarz, and Paul Knochel*
Department of Chemistry, Ludwig-Maximilians-University Munich, Butenandtstr. 5-13, 81377 Munich, Germany
S
* Supporting Information
ABSTRACT: The directed zincation of tropolone derivatives was achieved using TMPZnCl·LiCl. Various functionalizations of
the zincated intermediates by halogenation, acylation, allylation, and Negishi cross-coupling were successfully performed.
Additionally, 1,8-conjugate addition−elimination reactions with a variety of arylmagnesium and secondary alkylzinc reagents
were carried out to further elaborate the tropolone core.
he structures of tropolone (1) and the related natural
product hinokitiol (β-thujaplicin, 2) were proposed by
coordination to TMPZnCl·LiCl10 may enable the desired
metalation and thus would afford zinc reagents 5 corresponding
to tropolone derivatives of type 4 (Scheme 1). Herein we
report the functionalization of tropolone derivatives by
zincation using TMPZnCl·LiCl followed by reaction with
various electrophiles (E−X).
T
Dewar1 and Nozoe.2 More than 200 natural products are
currently reported to contain a troponoloid core.3 Among
them, colchicine (3) is used for the treatment of gout and
familial Mediterranean fever (Figure 1).4 These cyclic
Scheme 1. Zincation of Tropolone Derivatives Using
TMPZnCl·LiCl
Treatment of benzyl-protected tropolone derivative 4a with
TMPZnCl·LiCl (2.0 equiv, 10 min, 0 °C) leads to the
quantitative formation of the corresponding zincated tropolone
5a. The intermediate zinc reagent can then be quenched by
various electrophiles, furnishing tropolones of type 6 (Table 1).
Quenching of 5a with either iodine or bromine provides the
halogenated tropolones 6a and 6b, respectively, in 89% and
83% yield (entries 1 and 2). The addition of aryl or alkyl acyl
chlorides in the presence of catalytic amounts of Pd(PPh3)4 (3
mol %) allows the formation of ketones 6c and 6d in 68−76%
yield (entries 3 and 4). Additionally, Negishi cross-coupling
reactions14 proceed with various aryl iodides containing
electron-withdrawing or -donating groups as coupling partners
in the presence of 2−3 mol % Pd(dba)2 as the catalyst and 4−6
mol % tris(o-furyl)phosphine (Farina’s ligand),15 affording a
variety of arylated tropolone derivatives 6e−h in 77−91% yield
(entry 5). Furthermore, 2-iodothiophene undergoes a Negishi
Figure 1. Structures of tropolone derivatives.
molecules are of interest because of their non-benzenoid,
planar, seven-membered ring structure showing aromatic-like
properties5 as well as their biological properties.6
Nonetheless, the synthesis of highly substituted tropones and
tropolones is still a synthetic challenge. The tropolone core was
shown to decompose in the presence of strong bases such as
LDA.7 We recently reported the functionalization of an array of
aromatic and heteroaromatic substrates using various TMP-
derived bases (TMP = 2,2,6,6-tetramethylpiperidyl).8 However,
preliminary studies in our laboratory have shown that TMPLi
and TMPMgCl·LiCl9 lead to decomposition of various
protected tropolones even at low temperatures. TMP-Zn
bases, such as TMPZnCl·LiCl,10 TMP2Zn·2MgCl2·2LiCl,11
and TMPZnOPiv·LiCl,12 have proven to be especially efficient
for performing metalations of sensitive (hetero)arenes, as these
metalations produce organozinc derivatives that tolerate a range
of functional groups.8 As it is known that the tropolonato anion
coordinates to the Zn(II) center,13 we envisioned that
Received: October 31, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03270
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Table 1. Zincation of O-Benzyltropolone (4a) and Reactions
with Electrophiles
Table 2. Zincation of Bromotropolone 4c and Reactions
with Electrophiles
a
Negishi cross-coupling in the presence of 3 mol % Pd(dba)2 and 6
mol % P(o-furyl)3.
reagent 5c with iodine or bromine provides the corresponding
products 6m and 6n in 74−98% yield (entries 1 and 2).
Negishi cross-coupling reactions of 5c with aryl iodides
containing substituents such as methoxy, cyano, dimethylami-
no, nitro, or ester afford the desired tropolone derivatives 6o−s
in 63−89% yield (entries 3−7).
a
b
Acylation in the presence of 3 mol % Pd(PPh3)4. Negishi cross-
coupling performed in the presence of 2−3 mol % Pd(dba)2 and 4−6
mol % P(o-furyl)3. Allylation performed in the presence of CuCN·
2LiCl (1.1 equiv). Starting from O-benzyl-4-isopropyltropolone (4b);
see the Supporting Information.
c
d
2-Dimethylaminotropone (7) also undergoes metalation with
TMPZnCl·LiCl (2.0 equiv, 10 min, 0 °C), providing the
corresponding zinc reagent quantitatively. The organozinc
reagent reacts in a Cu-mediated allylation with 3-bromocyclo-
hexene as well as a Negishi cross-coupling reaction with phenyl
iodide to afford the tropolone derivatives 8a and 8b,
respectively, in 91% and 80% yield (Scheme 2).
Interestingly, when carbamate 9 was subjected to the
optimized metalation conditions using TMPZnCl·LiCl (2.0
equiv, 0 °C, 10 min) followed by addition of bromine as an
electrophile, the desired main product 10 was obtained in 81%
cross-coupling reaction with zinc species 5a to afford 6i in 80%
yield (entry 6). The alkenyl iodide (E)-1-iodooct-1-ene
undergoes cross-coupling with 5a, giving tropolone 6j in 75%
yield (E:Z = 97:3; entry 7). Additionally, a Cu-mediated
allylation reaction with 3-bromocyclohexene affords the desired
tropolone 6k in 94% yield (entry 8). Also, O-benzyl-4-
isopropyltropolone (4b), derived from the commercially
available natural compound β-thujaplicin by benzylation,16
also undergoes smooth metalation with TMPZnCl·LiCl at the
position α to the keto group (2.0 equiv, 0 °C, 10 min), and in
situ Negishi cross-coupling of the corresponding zinc reagent
with 1-fluoro-4-iodobenzene affords tropolone 6l in 76% yield
(entry 9).
Scheme 2. Zincation of 2-Dimethylaminotropone (7) and
Reactions with Electrophiles Leading to Tropones 8a and 8b
We further explored the scope of this zincation using
TMPZnCl·LiCl on other tropolone derivatives. Bromotropo-
lone 4c, a precursor to Fitzgerald’s compound,17 which has
been shown to have similar biological activities as colchicine, is
metalated with TMPZnCl·LiCl at low temperatures (1.4 equiv,
0.5 h, −30 °C; Table 2). Halogenation of the intermediate zinc
B
DOI: 10.1021/acs.orglett.6b03270
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Letter
yield, with bromination occurring at the position α to the
ketone (Scheme 3).18
Scheme 6. 1,8-Conjugate Addition−Elimination Using
Secondary Mixed Zinc Reagents
Scheme 3. Zincation of Carbamate 9 and Reaction with
Bromine
In order to further elaborate the tropolone core, we have
performed various additions of organomagnesium and -zinc
reagents to several tropone derivatives. Reaction of tropolone
or its methylated derivative with phenylmagnesium bromide or
phenyllithium has been proposed to occur via a 1,8-conjugate
addition−elimination mechanism.19 Thus, the addition of
various arylmagnesium chloride reagents to 2-aryltropolones
(6f−h) provides the diarylated tropones 11a−c with
substitution of the −OBn group, presumably via the 1,8-
conjugate addition−elimination mechanism (Scheme 4).
conditions to produce the desired 1,8-addition−elimination
products 14d and 14e, respectively, in 40−64% yield.
In summary, we have developed a new general method for
the regioselective zincation of various tropolone derivatives
using TMPZnCl·LiCl. The generated organozinc reagents
reacted with a variety of electrophiles in Cu-mediated allylation
reactions as well as in Pd-catalyzed Negishi cross-coupling and
acylation reactions, providing substituted seven-membered
tropones. Additionally, to further elaborate the tropolone
core, 1,8-conjugate addition−elimination reactions of various
tropolone derivatives were carried out using a variety of
organometallic reagents, such as arylmagnesium or secondary
alkylzinc reagents. Further extension of this method toward the
synthesis of biologically active tropolones is currently underway
in our laboratory.
Scheme 4. 1,8-Addition−Elimination of Tropolone
Derivatives Using Arylmagnesium Reagents
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03270.
Surprisingly, even tropone derivative 12 containing an iodide
substituent preferentially undergoes a formal substitution of the
dimethylamino group with p-tolylMgBr·LiCl instead of I/Mg
exchange,20 thus providing the substituted tropone 13 in 67%
yield (Scheme 5).21
1
Full experimental details and H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*paul.knochel@cup.uni-muenchen.de
ORCID
Scheme 5. 1,8-Addition−Elimination of 2-
Dimethylaminotropone 12 Using p-TolylMgBr·LiCl
Paul Knochel: 0000-0001-8167-272X
Author Contributions
†D.H. and D.S.-R. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Additionally, we have performed conjugate addition−
elimination reactions of various secondary mixed alkylzinc
reagents22 with benzyl-protected tropolone 4a to obtain
numerous α-alkylated tropone derivatives of type 14 (Scheme
6). The reaction of benzylated tropolone 4a with various cyclic
alkylzinc reagents proceeded within 0.5 h at −30 °C in the
presence of TMSBr (2.0 equiv), followed by a reaction with
TBAF, to afford the alkylated products 14a−c in 54−71% yield.
Surprisingly, even a benzyl-protected 4-piperidinylzinc reagent
and a benzylic zinc derivative reacted under our reaction
■
We thank Ludwig-Maximilians-University Munich for financial
support and BASF SE (Ludwigshafen) and Albemarle
Corporation (Hoechst-Frankfurt) for generous gifts of
chemicals. D.S.-R. thanks the Fonds de recherche du Quebec-
́
Nature et technologies (FRQNT) for a postdoctoral fellowship.
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