Adamantylzinc bromides: Direct preparation and application to cross-coupling reaction

Full text of DOI:10.1002/bkcs.10537

Note
DOI: 10.1002/bkcs.10537
BULLETIN OF THE
H.-S. Hwang et al.
KOREAN CHEMICAL SOCIETY
Adamantylzinc Bromides: Direct Preparation and Application to Cross-
Coupling Reaction
Hyung-Seo Hwang,† Seong-Ryu Joo,‡ and Seung-Hoi Kim‡,
*
†School of Integrated Oriental Medical Bioscience, Semyung University, Jecheon 390-711, Korea
‡Department of Chemistry, Dankook University, Cheonan 330-714, Korea.
*E-mail: kimsemail@dankook.ac.kr
Received February 22, 2015, Accepted July 17, 2015, Published online September 28, 2015
Keywords: Active zinc, Direct insertion, Adamantylzincs, Cross-couplings
The cross-coupling reaction of zinc-based organometallic
reagenthasbeen regarded asavalidprotocolforthegeneration
of new carbon–carbon bonds mainly due to the excellent
tolerance of the organic functional groups.1 In addition,
organic fragments of organozinc reagents easily transfer
to the catalyst metal in the course of metal-catalyzed coupling
reactions. Owing to the reliable nature of organozinc chemis-
try, this protocol has become prominent in a wide range of
organic synthesis. For the preparation of organozinc reagents,
both transmetallation of Grignard or organolithium with zinc
halide and direct insertion of zinc metal have been the most
utilized methodologies.2 Tremendous work on the synthesis
and application of organozincs have been accomplished.
Very recently, we have provided several works on the appli-
cations of highly active zinc prepared by the reduction of zinc
halides in the presence of lithium naphthalide in tetrahydrofu-
ran (THF).3 Considering the promising results from our
research, we supposed that the direct preparation of an ada-
mantylzinc reagent would be possible. Since the adamantane
moiety has been frequently found in various fields, such as
medicinal, drug, supramolecular, and nanochemistry,4 devel-
oping a facile pathway to introduce an adamantane scaffold is
a frequently encountered subject in the synthesis of functional
organic molecules, and, until now, this goal has been
mostly achieved by utilizing a limited number of adamantyl-
metallic reagents including as adamantylmagnesium5 and
adamantylzinc.6
Among the previous work, a very recent publication pre-
sented by Knochel et al. has immediately attracted our atten-
tion.7 In this work, the preparation of adamantylzinc reagents
via LiCl-mediated Mg-insertion in the presence of ZnCl2 and
their applications to the coupling reactions were presented.
And, interestingly, an inefficient work on the formation of
1-adamantylzinc bromide from using the Rieke zinc and 1-
bromoadamantane was highly emphasized (65% conversion).
However, on the basis of the several established results from
both Rieke’s6 and our laboratories,8 this citation could be a
potentially controversial subject. Therefore, we decided to
readdress the direct preparation of adamantylzinc reagents
and their applications to cross-coupling reactions in
anticipation of more positive results.
To accomplish the intended goal, an initial investigation
was made, starting with readily available 1-bromoadamantane
and highly active zinc (Zn*) prepared by the literature
procedure.6 To our delight, treatment of 1.0 equiv of
1-bromoadamantane with 2.0 equiv of active zinc at refluxing
temperature for 2 h showed the total consumption of 1-bro-
moadamantane, leading to a peak corresponding to organo-
zinc (A) with over 92% conversion as described in Scheme
1. Prior to the general application of A to cross-coupling reac-
tions, the reactivity of the organozinc reagent was examined
by iodine quenching. An aliquot of the organozinc solution
in THF was treated with iodine and the resultant solution
was analyzed by both gas chromatography (GC) and gas
chromatography–mass spectrometry (GC–MS). Both analy-
sis data conclusively showed the formation of 1-adamantyl
iodide with over 85% yield. To confirm this result, isolation
by flash column chromatography was used and showed
79% isolated yield of 1-adamantyl iodide. Consequently, it
can be concluded that the expected organozinc bromide, 1-
adamantylzinc bromide, was successfully obtained under
the conditions used in this study.
With the verified reactivity of the organozinc reagent (A) in
hand, we next turned our attention to expanding the scope of
A, which was accomplished by the cross-coupling reactions
with several electrophiles. Our first attempt for the coupling
reactions with a wide range of acid chlorides was to prepare
ketones (results are summarized in Table 1). The coupling
reactions were carried out under typical copper-catalyzed
reaction conditions: 10 mol % CuCN and 20 mol % LiCl at
0 ꢀC in THF. The coupling reaction of 1-adamantylzinc bro-
mide with benzoyl chloride proceeded smoothly to produce
Scheme 1. Preparation of 1-adamantylzinc bromide (A).
Bull. Korean Chem. Soc. 2015, Vol. 36, 2769–2772
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
2769

Note
BULLETIN OF THE
ISSN (Print) 0253-2964 | (Online) 1229-5949
KOREAN CHEMICAL SOCIETY
Table 1. Coupling reaction of A with acid chlorides.
Table 2. Coupling reaction of A with aryl halides.
Yield (%)a
51
Entry ArCoCl
1
Time (h) Product (Ar)
Yield (%)a
40
Entry
1
ArX
Time (h)
24
Product (Ar)
C6H5 2a
5
C6H5 1a
2
3
4
2
1
4-ClC6H4 2b
4-MeOC6H4 2c
3-FC6H4 2d
32
55
26
2
3
4
3
4-ClC6H4 1b
62
42
55
3
2
4-MeOC6H4 1c
4-CH3C6H4 1d
12
5
6
24
24
41
53
2e
5
6
7
24
24
3
39
20
54
2f
1e
1f
7
24
44
2g
a Isolated yield (based on aryl halide).
1g
adamantylzinc reagent, such as 2-adamantylzinc bromide
(B) which has less steric demand. The preparation of B was
carried out under the same conditions used for A. As expected,
treatment of 2-bromoadamantane with active zinc easily con-
verted to the corresponding organozinc (B). Then, the result-
ing organozinc (B) was examined with a variety of
electrophiles inthesamemanneremployedwithA. Theresults
are summarized in Table 3. Again, the coupling reactions with
acid chlorides proceeded smoothly under the mild conditions,
affording the desired ketones (3a–3g) in slightly higher yields
than those obtained from using organozinc reagent A. This
result could be easily understood considering the less steric
demand of the reaction site of the organozinc reagent B, i.e.,
tertiary (A) vs. secondary (B).
Palladium-catalyzed coupling reactions of B with haloge-
nated benzenes (entries 1–4, Table 4) proceeded smoothly,
resulting in the formation of the corresponding aryl-substi-
tuted adamantanes (4a, 4b, 4c, and 4d) in good yields. Reac-
tion with heteroaryl halides also proceeded smoothly to yield
heteroaryl-substituted adamantanes in good yields. 2-Bro-
mothiophene reacted with B to afford 4e with 70% yield (entry
5, Table 4). A good result was obtained from the coupling
reaction using 2-iodo-5-bromopyridine (entry 6, Table 4).
The coupling reaction with 2-bromopyridine also proceeded
well to generate 4g in moderate yield (entry 7, Table 4).
We then attempted the coupling reaction of the organozincs
(A and B) with haloaromatic compounds containing an amine
functional group, and this reaction was more challenging.
Even though there are very limited examples of coupling reac-
tions of organozinc compounds with haloaromatic amines,9 to
a Isolated yield (based on acid chloride).
adamantan-1-yl(phenyl)methanone (1a) in a moderate iso-
lated yield (entry 1, Table 1).
This catalyst system worked well for the other acid chlor-
ides containing an electron-donating group (OCH3 and
CH3) and a halogen (Cl), producing the ketones (1b–1d) in
moderate yields (entries 2–4, Table 1). Heteroaromatic acid
chlorides were also shown to be suitable coupling partners
for the preparation of aryl adamantyl ketones (1e–1g) under
the same conditions. Relatively lower results were obtained
from the coupling reactions with 2-furancarbonyl chloride
(entry 5, Table 1) and 2-thiophenecarbonyl chloride (entry 6, -
Table 1). It is of much interest that the reaction conditions used
for the aforementioned coupling reactions also worked well
for the coupling reaction with 2-chloronicotinyl chloride. As
shown in Table 1, the coupling product (1g) was successfully
produced through the reaction with 2-chloronicotinyl chloride
with a 54% yield (entry 7, Table 1).
The application of A to the coupling reactions was not only
limited to the preparation of ketones. In our next effort to
expand the scope of 1-adamantylzinc bromide, a palladium-
catalyzed carbon–carbon bond was also used. In this applica-
tion, a Pd(OAc)2 and SPhos-catalyst system was selected after
a catalyst-screening test. It worked well to provide 1-aryl-
substituted adamantane derivatives and the results are sum-
marized in Table 2.
The promising observation from the applications of 1-
adamantylzinc bromide (A) allowed us to explore other
Bull. Korean Chem. Soc. 2015, Vol. 36, 2769–2772
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2770

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
Table 3. Coupling reaction of B with acid chlorides.
Table 4. Coupling reaction of B with arylhalides.
Entry
1
ArX
Time (h)
24
Product (Ar)
Yield (%)a
67
Entry ArCoCl
1
Time (h) Product (Ar)
Yield (%)a
58
C6H5 4a
5
C6H5 3a
2
3
4
2
4
4
4-ClC6H4 4b
4-MeOC6H4 4c
3-FC6H4 4d
85
83
82
2
3
4
5
4-ClC6H4 3b
65
62
59
5
5
4-MeOC6H4 3c
4-CH3C6H4 3d
5
6
24
24
70
81
4e
4f
5
6
7
24
24
3
43
28
54
3e
3f
7
24
57
4g
a Isolated yield (based on ArX).
3g
a Isolated yield (based on acid chloride).
the best of our knowledge, no report revealed the coupling
reaction with adamantylzinc halides. As illustrated in
Figure 1, the reaction of A with 4-iodoaniline in the presence
of 2 mol % Pd(OAc)2 and 4 mol % SPhos gave rise to the
cross-coupling product, 4-(adamantan-1-yl)aniline (5a), with
53% isolated yield. 3-Iodoaniline was also coupled with
A under the same conditions, affording 5b in a similar manner.
More successful coupling reactions were achieved using
B under the same conditions, yielding 5c and 5d in 73%
and 84% isolated yields, respectively.
Figure 1. Coupling reaction with iodoanilines.
In conclusion, we have demonstrated an efficient synthetic
route for the direct preparation of adamantylzinc bromides
(A and B) from active zinc and adamantyl bromides, as well
as their applications to the cross-coupling reactions with a
variety of electrophiles. The direct oxidative addition of active
zinc into 1- and 2-bromoadamantanes and the subsequent cou-
pling reactions were completed under mild reaction condi-
tions. From these observations, it can be concluded that the
synthetic strategy of using highly active zinc and bromoada-
mantanes for the preparation of the corresponding adamantyl-
zinc reagents can be effective.
equipped with a stir bar was added 6.54 g of active zinc (Zn*,
100.0 mmol) in 100 mL of THF. Next, 1-bromoadamantane
(10.5 g, 50.0 mmol) was cannulated into the flask at room tem-
perature. The resulting mixture was then allowed to reflux for
2 h. The solution was cooled to room temperature and settled
down. Then the supernatant was used for the subsequent
coupling reactions.
Preparation of adamantan-1-yl-(4-methoxyphenyl)metha-
none (1c): Into a 25 mL round-bottomed flask were placed
CuCN (0.02 g, 10 mol %) and LiCl (0.02 g, 20 mol %). The
flask was pumped down and recharged with argon gas. Then,
2.0 mL of THF was added to dissolve. The flask was cooled to
0 ꢀC using an ice-bath. 4-Methoxybenzoyl chloride (0.24 g,
1.4 mmol) dissolved in 2.0 mL of THF was added into the
flask. Next, 4.0 mL of 1-adamantylzinc bromide (0.5 M in
Experimental
Representative Procedures. Preparation of 1-adamantylzinc
bromide (A): In an oven-dried 250 mL round-bottomed flask
Bull. Korean Chem. Soc. 2015, Vol. 36, 2769–2772
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2771

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
3. Recent examples: (a) Recent applications of highly active zinc,
see: (a) H. S. Jung, S. H. Kim, Tetrahedron Lett. 2015, 56,
1004; (b) H. S. Jung, S. H. Kim, Synlett 2015, 26, 666;
(c) H. H. Cho, S. H. Kim, Bull. Korean Chem. Soc. 2015, 36,
1274; (d) H. H. Cho, S. H. Kim, Bull. Korean Chem. Soc.
2014, 35, 3081; (e) H. S. Jung, S. H. Kim, Bull. Korean Chem.
Soc. 2014, 35, 280; (f ) H. S. Jung, H. H. Cho, S. H. Kim, Tetra-
hedron Lett. 2013, 54, 960; (g) S. H. Kim, R. D. Rieke, J. Org.
Chem. 2013, 78, 1984.
4. L. Wanka, K. Iqbal, P. R. Schreiner, Chem. Rev. 2013, 113, 3516.
5. (a) R. D. Rieke, S. E. Bales, J. Am. Chem. Soc. 1974, 96, 1775;
(b)G. Molle, P. Bauer, J. E. Dubois, J. Org. Chem. 1982, 47, 4120.
6. (a) R. D. Rieke, M. V. Hanson, J. D. Brown, J. Org. Chem. 1996,
61, 2726; (b) M. V. Hanson, J. D. Brown, R. D. Rieke, Q. J. Niu,
Tetrahedron Lett. 1994, 35, 7205; (c) L. Zhu, R. M. Wehmeyer,
R. D. Rieke, J. Org. Chem. 1991, 56, 1445.
THF, 2.0 mmol) was cannulated into the flask under argon
atmosphere at 0 ꢀC, then the whole mixture was allowed to
warm up gradually to room temperature over 3 h while being
stirred. Quenched with saturated 3 M HCl solution, then
extracted with ethyl ether (10 mL × 3). Washed with saturated
NaHCO3, 8% NH4OH solutions, and brine, then dried over
anhydrous MgSO4. Purification by flash column chromatog-
raphy (hexanes/ethylacetate) afforded 0.16 g of 1c in 42% iso-
1
lated yield as a pale yellow solid (mp 91–94 ꢀC); H NMR
(CDCl3, 500 MHz) δ = 7.77 (d, J = 9.0 Hz, 2H), 6.88 (d, J =
9.0 Hz, 2H), 3.85 (s, 3H), 2.09–2.05 (m, 9H), 1.76 (br s,
6H); 13C NMR (CDCl3, 125 MHz) δ = 207.2, 161.6, 131.6,
131.0, 55.3, 46.8, 39.5, 36.6, 28.3.
Acknowledgment. This work was supported in part by DAN-
KOOK ChemBio Specialization for Creative Korea (CK)-II.
7. C. Sämann, V. Dhayalan, P. R. Schreiner, P. Knochel, Org. Lett.
2014, 16, 2418.
8. (a) U. S. Shin, K. W. Cho, S. H. Kim, Bull. Korean Chem. Soc.
2013, 34, 1575; (b) K. W. Cho, S. H. Kim, Bull. Korean Chem.
Soc. 2013, 34, 983; (c) S. H. Kim, R. D. Rieke, J. Org. Chem.
2013, 78, 1984; (d) R. D. Rieke, S. H. Kim, Tetrahedron Lett.
2012, 53, 3478.
9. (a) G. Manolikakes, C. M. Hernandez, M. A. Schade, A. Metzger,
P. Knochel, J. Org. Chem. 2008, 73, 8422; (b) C. I. Stathakis,
S. Berhardt, V. Quint, P. Knochel, Angew. Chem. Int. Ed. 2012,
51, 9428; (c) J. R. Colombe, S. Bernhardt, C. Stathakis,
S. L. Buchwald, P. Knochel, Org. Lett. 2013, 15, 5754.
References
1. (a) E.-I. Negishi, Handbook of Organopalladium Chemistry for
Organic Synthesis, Vol. 1, Wiley-Interscience, New York,
2002, p. 229; (b) M. Uchiyama, T. Furuyama, M. Kobayashi,
Y. Matsumoto, T. Tanaka, J. Am. Chem. Soc. 2006, 128, 8404.
2. (a) J. Hartwig, Organotransition Metal Chemistry; From Bonding
to Catalysis, University Science Books, Sausalito, 2010;
(b) J. J. Li, G. W. Gribble, Palladium in Heterocyclic Chemistry.
A
Guide for the Synthetic Chemist, 2nd ed., Elsevier,
Oxford, 2007.
Bull. Korean Chem. Soc. 2015, Vol. 36, 2769–2772
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 2772