Synthesis of substituted adamantylzinc reagents using a Mg-insertion in the presence of ZnCl2 and further functionalizations

Article abstract of DOI:10.1021/ol500781j

The LiCl-mediated Mg-insertion in the presence of ZnCl₂ allows an efficient synthesis of adamantylzinc reagents starting from the corresponding functionalized tertiary bromides. The highly reactive adamantylzinc species readily undergo a broad

Full text of DOI:10.1021/ol500781j

Letter
pubs.acs.org/OrgLett
Synthesis of Substituted Adamantylzinc Reagents Using a Mg-
Insertion in the Presence of ZnCl2 and Further Functionalizations
Christoph Samann,† Vasudevan Dhayalan,† Peter R. Schreiner,‡ and Paul Knochel*,†
̈
†Department of Chemistry, Ludwig-Maximilians-Universitat, Butenandtstr. 5-13, 81377 Munich, Germany
̈
‡Institute of Organic Chemistry, Justus-Liebig-Universitat, Heinrich-Buff-Ring 58, 35392 Giessen, Germany
̈
S
* Supporting Information
ABSTRACT: The LiCl-mediated Mg-insertion in the pres-
ence of ZnCl2 allows an efficient synthesis of adamantylzinc
reagents starting from the corresponding functionalized
tertiary bromides. The highly reactive adamantylzinc species
readily undergo a broad variety of functionalizations such as
Negishi cross-couplings, Cu(I)-catalyzed acylations and
allylations, and 1,4-addition reactions leading to the expected
products in excellent yields. Furthermore, the adamantyl
moiety could be introduced as α-substituent in terthiophene, increasing its solubility due to the higher lipophilicity and the
prevention of π-stacking.
damantane derivatives have found numerous applications
method should be especially attractive for the preparation of
tertiary organozincs. Hence, we now report a mild and
convenient preparation of functionalized adamantylzinc
reagents starting from readily available adamantyl bromides
bearing for the first time sensitive functional groups.
Moreover, this method has been used to attach an adamantyl
moiety to terthiophene to increase its solubility.
Thus, 1a undergoes a smooth magnesium insertion using
commercially available magnesium turnings (2 equiv, 0 to
25 °C, 2 h) in the presence of LiCl (1.1 equiv) and ZnCl2
(1.1 equiv), leading to the corresponding zinc reagent 2a in
85% yield as determined via titration.12 Remarkably, also the
functionalized adamantylzinc reagents 2b and 2c13 have been
obtained for the first time in 57−63% yield, following this
procedure (Scheme 1).
1
Ain medicinal chemistry and drug development. More-
over, they have shown promising use in the fields of medicine,
supramolecular chemistry, and nanotechnologies.1c Adaman-
tane also is the parent of the so-called diamondoids,2 which
are readily available (from crude oil) nanometer-size diamond-
like building blocks that resemble many of the unique
properties of diamond (e.g., electron emission3). Until now,
no general method has been reported for the preparation of
adamantyl or diamondoid organometallic reagents. The
synthesis of tertiary organometallics is not straightforward
due to side reactions such as proton abstraction or β-hydride
elimination. However, Dubois developed a so-called “static”
method whereby the reaction of 1-bromo-adamantane (1a)
with magnesium turnings was conducted without stirring of
the reaction medium, leading to 1-adamantylmagnesium
bromide in 58% yield.4 Even the reaction of 1a with highly
reactive magnesium (Mg*) generated in situ by the standard
method of Rieke5 did not furnish traces of the organo-
magnesium compound. Instead, a 60% yield of hydrolyzed
adamantane and a 30% yield of homocoupling product were
isolated.6 Noteworthy, by using highly active Rieke-zinc (Zn*)
prepared via reduction of ZnCl2 with lithium naphthalide;
adamantylzinc bromide was obtained in 65% yield.7
The resulting adamantylzinc reagents 2a−c readily undergo
a broad variety of functionalization reactions in the presence
of an appropriate catalyst. Hence, zinc reagent 2a smoothly
reacts in a Pd-catalyzed Negishi cross-coupling14 with aryl
Scheme 1. Mg-Insertion in the Presence of ZnCl2 and LiCl
into the Functionalized Adamantyl Bromides 1a−c
Recently, we have developed a practical method for the
synthesis of alkyl-,8 aryl-,9 benzyl-,9,10 and alkenylzinc11 halides
via LiCl-mediated metal insertion into the corresponding
chlorides and bromides. These preparations are based either
on the use of commercially available zinc powder in
combination with LiCl or magnesium turnings in the presence
of ZnCl2 and LiCl. Especially the second approach proceeds
under exceedingly mild conditions, since magnesium acts as a
stronger reducing agent than zinc (faster electron transfer in
the insertion mechanism). Therefore, we anticipated that this
Received: March 14, 2014
Published: April 15, 2014
© 2014 American Chemical Society
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Letter
halides 3a−k.15 Using 1% Pd(OAc)2 and 2% of the ligand
SPhos introduced by Buchwald16 as a catalytic system, zinc
reagent 2a reacts within 2 h at 50 °C with the ester-
substituted aryl halides 3a−c to provide the corresponding
cross-coupling product 4a in 83−87% yield (Scheme 2).
Table 2. Negishi Cross-Couplings of Adamantylzinc
Reagent 2a with Heteroaryl Bromides
Scheme 2. Negishi Cross-Coupling of Adamantylzinc
Reagent 2a with Aryl Halides of Type 3
Various electron-rich and -poor electrophiles (0.9 equiv)
were used in the cross-coupling performed at 50 °C, affording
the corresponding arylated adamantyl derivatives 4b−h in
62−95% yield, tolerating functional groups such as a nitrile,
an aldehyde, a ketone, or a carbamate (Table 1, entries 1−7).
Noteworthy, also a double cross-coupling has been achieved
under these reaction conditions, furnishing the corresponding
product 4i in 82% yield (entry 8).
a
Yield of analytically pure isolated product based on the amount of
b
electrophile used. Obtained after a Negishi cross-coupling (Pd(OAc)2
(1 mol %) and SPhos (2 mol %)) with heteroaryl bromide (0.9 equiv).
Table 1. Negishi Cross-Couplings of Adamantylzinc
Reagent 2a with Aryl Bromides
Adamantylzinc reagent 2a also undergoes Cu(I)-catalyzed
acylations,17 leading to the desired ketones 4o−r in good to
excellent yields (Scheme 3 and Table 3). Thus, 2a reacts with
4-fluorobenzoyl chloride (3q, 0.9 equiv) and 20%
CuCN·2LiCl to afford the corresponding ketone 4o in 89%
yield (Scheme 3).
Scheme 3. Cu(I)-Catalyzed Acylation of Adamantylzinc
Reagent 2a with 4-Fluorobenzoyl Chloride (3q)
Under the same reaction conditions, also the acid chlorides
3r−t were good substrates in the Cu(I)-catalyzed acylation.
The substituted benzoyl chlorides 3r and 3s undergo the
acylation with adamantylzinc species 2a in 70−80% yield
(Table 3, entries 1 and 2). Also the heteroaromatic 6-chloro-
nicotinoyl chloride (3t) reacts with 2a to afford the
corresponding ketone 4r in 44% yield (entry 3). Furthermore,
the highly reactive adamantylzinc reagent 2a furnishes in a
Cu(I)-catalyzed allylation17 with ethyl 2-(bromomethyl)-
acrylate (3u, 0.9 equiv) the desired product 4s in 91% yield
(entry 4). Moreover, the copper-catalyzed alkynylation18 of 2a
with bromoacetylene 3v18 (0.9 equiv) affords the function-
alized acetylene 4t in 66% yield (entry 5). Furthermore, the
adamantylzinc reagent 2a reacts smoothly with S-phenyl
benzenesulfonothioate (3w, 0.9 equiv) to give thioether 4u in
98% yield (entry 6). Additionally, the Cu(I)-mediated 1,4-
addition19 with cyclohex-2-enone (3x, 0.9 equiv) affords the
desired 1,4-addition product 4v in 91% yield (entry 7).
Analogous to the unfunctionalized adamantylzinc reagent
2a, the ester-substituted adamantylzinc derivative 2b readily
reacts in a Pd-catalyzed Negishi cross-coupling with 4-
bromothioanisole (3y, 0.9 equiv) at 50 °C within 2 h to
a
Yield of analytically pure isolated product based on the amount of
b
electrophile used. Obtained after Negishi cross-coupling (Pd(OAc)2
(1 mol %) and SPhos (2 mol %)) with ArBr (0.9 equiv). Obtained
after Negishi cross-coupling (Pd(OAc)2 (1 mol %) and SPhos (2 mol
%)) with 2,7-dibromo-fluorene (0.45 equiv) (Ad = 1-adamantyl).
c
A broad variety of heteroaryl bromides (3l−p) as
electrophiles produce the desired products 4j−n under
standard conditions in excellent yields (Table 2). In particular,
benzofuran, benzothiazole, protected indole, and an ester-
substituted thiophene have successfully been employed in the
cross-coupling reaction furnishing the corresponding hetero-
arylated adamantanes 4j−n in 53−91% yield (entries 1−5).
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Table 3. Further Functionalizations of Adamantylzinc
Reagent 2a with Various Electrophiles
Table 4. Negishi Cross-Couplings of Adamantylzinc
Reagents 2b−c with (Hetero)aryl Bromides
a
Yield of analytically pure isolated product based on the amount of
b
electrophile used. Obtained after a Negishi cross-coupling (Pd(OAc)2
(1 mol %) and SPhos (2 mol %)) with (hetero)aryl bromide (0.9
equiv).
functionalized cross-coupling products 5d−e have been
obtained in 71−73% yield (entries 3 and 4).
The synthesis and investigation of well-defined model
oligomers is of high interest due to the structural and
electronic properties of these molecules. Depending on their
size and substitution pattern oligothiophenes are usually more
soluble than polymers, allowing the precise characterization of
the electronic and geometric structures both in solution and
in the solid state.20
The solubility of oligothiophenes decreases dramatically
with increasing chain length, which is due to the stiffness of
the conjugated π-system and the strong interactions between
the chains. The solubility issue can be solved with the
synthesis of corresponding oligothiophenes bearing alkyl
substituents.21 Several α-alkyl-substituted oligothiophenes
were prepared and characterized by various research groups.
Especially monosubstituted derivatives are attractive candi-
dates since they offer the possibility of dimerization leading to
the corresponding α,α′-disubstituted oligothiophenes with a
double conjugated chain length.20
a
Yield of analytically pure isolated product based on the amount of
b
electrophile used. Obtained after acylation (CuCN·2LiCl (0.2
equiv)) with an acid chloride (0.9 equiv). Obtained after allylation
(CuCN·2LiCl (0.2 equiv)) with ethyl 2-(bromomethyl)acrylate (0.9
equiv). Obtained after alkynylation (CuCN·2LiCl (0.2 equiv)) with
ethyl 3-bromopropiolate (0.9 equiv). Obtained after addition to S-aryl
benzenethiosulfonate (0.9 equiv). Obtained after 1,4-addition
c
d
e
f
(CuCN·2LiCl (1.1 equiv) and TMSCl (2.0 equiv)) with cyclohex-2-
enone (0.9 equiv).
Scheme 4. Negishi Cross-Coupling of Adamantylzinc
Reagent 2b with 4-Bromothioanisole (3y)
Following this idea, adamantylzinc reagent 2a was
submitted to a Negishi cross-coupling with the 5-bromo-
terthiophene 6, furnishing the corresponding α-substituted
oligothiophene 7 in 64% yield (Scheme 5).
Noteworthy, α-adamantyl-terthiophene 7 displays an
excellent solubility in chloroform. Its solubility is
17.0·10−2 M in CHCl3 compared to 5.6·10−2 M of the
unsubstituted derivative (ca. 3 fold increase). The higher
solubility arises most probably from two reasons; on one
hand, the apolar adamantyl-moiety is known to strongly
afford the highly functionalized adamantyl drivative 5a in 87%
yield (Scheme 4).
Under the same reaction conditions, also ethyl 4-bromo-
benzoate (3b, 0.9 equiv) and 5-bromo-2-methyl-benzothiazole
(3n, 0.9 equiv) were used in the Pd-catalyzed Negishi reaction
with the ester-substituted adamantylzinc species 2b. The
corresponding cross-coupling products 5b and 5c were
obtained in 70−84% yield (Table 4, entries 1 and 2).
Similarly, the adamantylzinc reagent 2c was functionalized by
Pd-catalyzed Negishi cross-coupling reactions with both
electron-poor and -rich aryl bromides. Thus, the highly
Scheme 5. Synthesis of α-adamantyl-terthiophene 7
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(9) (a) Metzger, A.; Schade, M. A.; Knochel, P. Org. Lett. 2008, 10,
1107. (b) Boudet, N.; Sase, S.; Sinha, P.; Liu, C.-Y.; Krasovskiy, A.;
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its bulkiness prevents π-stacking of the oligothiophene
molecules. Therefore 7 should be an ideal candidate for the
synthesis of a highly soluble α,α′-substituted diadamantyl
oligothiophene via literature known procedures.20
In summary, we have developed a mild and convenient
procedure for the selective synthesis of adamantylzincs,
tolerating for the first time functional groups on the
adamantyl scaffold using a LiCl-mediated Mg insertion in
the presence of ZnCl2. The highly reactive adamantylzinc
species 2a−c readily undergo a broad variety of functionaliza-
tion reactions in the presence of an appropriate catalyst.
Furthermore, the adamantyl moiety was introduced as an α-
substituent in an oligothiophene, increasing its solubility (ca. 3
fold). Further extensions of this work are currently underway
in our laboratories.
(10) (a) Metzger, A.; Piller, F. M.; Knochel, P. Chem. Commun.
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(14) (a) Negishi, E.-i.; King, A. O.; Okukado, N. J. Org. Chem.
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ASSOCIATED CONTENT
* Supporting Information
(15) For 1-adamantyl halides used as electrophiles in cross-coupling
■
S
reactions, see: (a) Brase, S.; Waegell, B.; de Meijere, A. Synthesis
̈
1998, 148. (b) Ghorai, S. K.; Jin, M.; Hatakeyama, T.; Nakamura, M.
Org. Lett. 2012, 14, 1066. (c) Someya, H.; Yorimitsu, H.; Oshima, K.
Tetrahedron Lett. 2009, 50, 3270. (d) Zultanski, S. L.; Fu, G. C. J.
Experimental procedures and characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
Am. Chem. Soc. 2013, 135, 624. (e) Lohre, C.; Droge, T.; Wang, C.;
̈
AUTHOR INFORMATION
Corresponding Author
Glorius, F. Chem.Eur. J. 2011, 17, 6052.
(16) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126,
13028.
(17) Yeh, M. C. P.; Berk, S. C.; Talbert, J.; Knochel, P. J. Org.
Chem. 1988, 53, 2390.
■
*E-mail: paul.knochel@cup.uni-muenchen.de.
Notes
(18) (a) Yeh, M. C. P.; Knochel, P. Tetrahedron Lett. 1989, 30,
4799. (b) Cahiez, G.; Gager, O.; Buendia, J. Angew. Chem., Int. Ed.
2010, 49, 1278.
(19) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I.
Tetrahedron Lett. 1986, 34, 4029.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the German-Israel project cooperation (DIP) and
the European Research Council under the European
Community’s Seventh Framework Programme (FP7/2007−
2013; ERC Grant Agreement No. 227763) for financial
support. We also thank BASF SE (Ludwigshafen), W. C.
Heraeus (Hanau), and Rockwood Lithium GmbH (Frankfurt)
for the generous gift of chemicals.
(20) Bauerle, P. The Synthesis of Oligothiophenes. In Handbook of
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Oligo- and Polythiophenes; Fichou, D., Ed.; Wiley-VCH: Weinheim,
1999.
(21) (a) Delabouglise, D.; Hmyene, M.; Horowitz, G.; Yassar, A.;
Garnier, F. Adv. Mater. 1992, 4, 107. (b) Otani, T.; Hachiya, M.;
Hashizume, D.; Matsuo, T.; Tamao, K. Chem.Asian J. 2011, 6, 350.
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