Studies on the tandem reaction of 4-aryl-2,3-allenoates with organozinc reagents: A facile route to polysubstituted naphthols

Article abstract of DOI:10.1002/chem.200901779

A highly efficient tandem reaction of easily available 4-aryl-2,3- allenoates with organozinc reagents was developed to afford the diversified polysubstituted anaphthols in moderate to excellent yields. A solution of 4-bromophenyl zinc iodide and xylenes

Full text of DOI:10.1002/chem.200901779

COMMUNICATION
DOI: 10.1002/chem.200901779
Studies on the Tandem Reaction of 4-Aryl-2,3-allenoates with Organozinc
Reagents: A Facile Route to Polysubstituted Naphthols
Guobi Chai, Zhan Lu, Chunling Fu, and Shengming Ma*[a]
Substituted naphthalenes and their derivatives are impor-
tant classes of organic compounds[1] with wide applications
in academic laboratory and industry.[2] They are also basic
skeletons of many biologically active natural products and
pharmaceuticals, such as nanaomycin A, a member of the
family of pyranonaphthoquinone antibiotics, and rifampicin,
used as an antibacterial and antiviral agent.[3] Thus, the de-
velopment of efficient and general methods for the synthesis
of this class of compounds has received much attention.[4]
However, the synthesis of these compounds with different
substituents at specific locations starting from easily avail-
able materials are far from being well-established. In this
Scheme 1. Non-catalyzed conjugate addition and cyclization of
2,3-allenoates with organozinc reagents.
communication, we wish to report an unexpected tandem
reaction of 4-aryl-2,3-allenoates with organozinc reagents af-
fording polysubstituted naphthols, which have been demon-
strated to be percursors for the efficient synthesis of naph-
thalenes with location-defined substituents from organozinc
reagents and 4-aryl-2,3-allenoates (Scheme 1).
Rencently, we reported a domino intermolecular double
Michael addition/cyclization of 4-aryl-2,3-allenoates with di-
alkyl zinc to afford 5-benzylidenecyclohex-2-enones with
high regio- and stereoselectivities (Scheme 1).[5] The reactiv-
ity of the intermediate involved towards the second mole-
cule of 2,3-allenoate is very high: we tried to add many elec-
trophiles or Michael acceptors to trap this intermediate, but
all failed. However, when we studied the reaction of ethyl 2-
methyl-4-phenyl-2,3-butadienoate with diphenyl zinc in tolu-
ene, the corresponding 5-benzylidenecyclohex-2-enone ob-
tained in our previous work was not formed! Instead, a new
Figure 1. ORTEP representation of 3aa.
product was isolated unexpectedly. It was confirmed to have
a naphthol skeleton[6] through careful NMR spectroscopy,
MS, and X-ray diffraction analysis (Figure 1).[7] However,
the yield was still quite low (entry 1, Table 1). To improve
the yield of new transformation, we studied the effect of the
amount of diphenyl zinc, solvent, and temperature on the
reaction of 1a with Ph2Zn (2a) and the results are summar-
ized in Table 1. The yield of 3aa decreased when smaller
amounts of diphenyl zinc was used (entries 1–3, Table 1).
Other solvents such as Et2O, THF, n-hexane, benzene,
DMSO, and 1,4-dioxane failed to give better results (en-
[a] G. Chai, Dr. Z. Lu, Prof. Dr. C. Fu, Prof. Dr. S. Ma
Laboratory of Molecular Recognition and Synthesis
Department of Chemistry, Zhejiang University
Hangzhou 310027, Zhejiang (P.R. China)
Fax : (+86)21-6260-9305
E-mail: masm@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901779.
Chem. Eur. J. 2009, 15, 11083 – 11086
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11083

Table 1. Effect of the amount of diphenyl zinc, solvent, and temperature
on tandem reaction of 2,3-allenoate 1a with diphenyl zinc (2a).
substituted aryl and heteroaryl zinc reagents in xylenes, that
is, p-BrC6H4ZnI (2b) and 2-thienyl zinc bromide (2c), could
react with 2,3-allenoates to afford the corresponding naph-
thols 3ab–3bc in 69–89% yields (entries 6–10, Table 2). It is
worth noting that the chlorine atom on the aryl ring of the
substrate 1d did not affect the yield, affording the corre-
sponding naphthol 3db in 70% yield, allowing further elab-
oration (entry 8, Table 2). Furthermore, the reactions of
fully substituted allenoates 1b and 1c with dialkyl zinc re-
agents under these new conditions could also afford the cor-
responding naphthols 3bd–3be in high yields (entries 11–13,
Table 2). However, when p-FC6H4ZnBr (2 f) was used,
naphthol 3bf was only afforded in 40% yield and 40% of
the starting material 1b was recovered under Method B
(entry 14, Table 2). To solve this problem, a solution of 2 f in
mesitylene was prepared as above and the reaction was run
at 1608C (defined as Method C) to get a complete conver-
sion, affording naphthol 3bf in 70% yield (entry 15,
Table 2). It should be noted that compared with 2,4-disubsti-
tuted allenoates 1a and 1d, fully substituted allenoates 1b,
1c, 1e, and 1 f often afforded much better results.
n
Solvent
T [8C]
t [h]
Yield[a] of
3aa [%]
1
2
3
4
5
6
7
8
9
3
2
1
3
3
3
3
3
3
3
3
toluene
toluene
toluene
Et2O
RT
RT
RT
RT
RT
RT
RT
RT
RT
70
16
17
17
19
19
19
19
19
19
1
35
18
12
0
THF
0
n-hexane
benzene
DMSO
1,4-dioxane
toluene
xylenes
17
34
0
0
50
65
10
11
140
0.5
[a] Determined by NMR spectroscopy using dibromomethane as internal
standard.
tries 4–9, Table 1). Fortunately, we found that the product
3aa was formed in 50% yield in toluene at 708C (compare
entry 1 with entry 10, Table 1). Finally, we were able to im-
prove the yield of 3aa to 65% by conducting the corre-
sponding reaction in xylenes with diphenyl zinc at 1408C
(entry 11, Table 1, defined as
This transformation is rationalized as follows: the conju-
gate addition of organozinc reagent with the electron-defi-
cient C=C bond in 2,3-allenoate[5,11] affords intermediate A.
Subsequent 6p electrocyclization involving the aryl group[12]
followed by the elimination of EtOH would afford inter-
Method A).
Table 2. Tandem reaction of 2,3-allenoates 1 with orangozinc reagents 2 affording diversified polysubstituted
a-naphthols.[a]
The scope of the organozinc
reagents and allenoates is sum-
marized in Table 2. Different
4,4-disubstituted, 2,4-disubsti-
tuted allenoates, and fully sub-
stituted allenoates could react
with Ph2Zn affording corre-
sponding polysubstituted naph-
thols in 56–91% yields under
1
Isolated
yield of 3 [%]
R4
n/X/t [h]
Method[a]
R1/R2/R3
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H/Me/H (1a)
Ph/Me/H (1b)
Ph/n-Pr/H (1c)
Ph/H/H (1e)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
3/–[b]/0.5
3/–[b]/1
3/–[b]/1
3/–[b]/0.25
3/–[b]/1
6/I/0.5
6/I/6.5
6/I/1.5
6/Br/1
6/Br/8
A
A
A
A
A
B
B
B
B
B
B
B
B
B
C
56 (3aa)
90 (3ba)
91 (3ca)
81 (3ea)
86 (3 fa)
82 (3ab)
88 (3bb)
70 (3db)
69 (3ac)
89 (3bc)
93 (3bd)
92 (3cd)
68 (3be)
40[d] (3bf)
70 (3bf)
Method A
(entries 1–5,
Table 2). As only limited num-
bers of diaryl zinc reagents
were commercially available
and organozinc reagents of the
type RZnX are easily avail-
able[8] with good thermal sta-
bility, and tolerate functional
groups even at elevated tem-
perature,[9] we prepared solu-
tions of this type of organozinc
reagent in xylenes by adding
RZnX in the original solvent
to anhydrous xylenes and then
distilling off the original sol-
vent with a low boiling point,
such as THF, n-hexane, or n-
heptane, in xylenes at 1408C
for 0.5 h for further use (Meth-
od B).[10] These solutions of
Ph/Ph/H (1 f)[c]
H/Me/H (1a)
Ph/Me/H (1b)
H/Me/Cl (1d)
H/Me/H (1a)
Ph/Me/H (1b)
Ph/Me/H (1b)
Ph/n-Pr/H (1c)
Ph/Me/H (1b)
Ph/Me/H (1b)
Ph/Me/H (1b)
Ph (2a)
p-BrC6H4 (2b)
p-BrC6H4 (2b)
p-BrC6H4 (2b)
2-Thienyl (2c)
2-Thienyl (2c)
Et (2d)
Et (2d)
nBu (2e)
p-FC6H4 (2 f)
p-FC6H4 (2 f)
3/–[b]/2
3/–[b]/1
6/–[b]/10.5
6/Br/12
6/Br/10.5
[a] Method A: A solution of 1 (0.2 mmol) in anhydrous xylenes (2 mL) was quickly added dropwise to a solu-
tion of Ph2Zn in anhydrous xylenes (3 mL) at 1408C; Method B: a solution of R4ZnX in THF (0.5m), a solu-
tion of Et2Zn in n-hexane (0.88m), or a solution of nBu2Zn in n-heptane (1m) was added to anhydrous xylenes
(3 mL), followed by heating up to 1408C to distill off the original solvent. Then, a solution of 1 (0.2 mmol) in
anhydrous xylenes (2 mL) was quickly added dropwise; Method C: a solution of R4ZnX in THF (0.5m) was
added to anhydrous mesitylene (3 mL), followed by heating up to 1608C to distill off the original solvent THF.
Then, a solution of 1 (0.2 mmol) in anhydrous xylenes (2 mL) was quickly added dropwise. See Supporting In-
formation for details. [b] R4 Zn was used. [c] Methyl 2,3-allenoate was used instead of ethyl 2,3-allenoate.
2
[d] The starting material 1b was recovered in 40% yield.
11084
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Chem. Eur. J. 2009, 15, 11083 – 11086

Conjugate Addition and Cyclization Reactions
COMMUNICATION
mediate C. Of course, intermediate A may also undergo in-
tramolecular Friedel–Crafts cyclization[13] to afford zinc
naphthoxide C. Subsequent hydrolysis of intermediate C
would provide the naphthol product 3 (Scheme 2).
Scheme 4. Synthetic application of 3db. a) TsCl (3 equiv), Et3N (3 equiv),
CH2Cl2, 08C to RT, 24 h; b) p-MeOC6H4B(OH)2 (2 equiv), [Pd
(5 mol%), K3PO4 (2 equiv), toluene, reflux, 3 h; c) m-MeOC6H4B(OH)2
(1.5 equiv), Pd(OAc)2 (5 mol%), SPhos (10 mol%), K3PO4 (2 equiv), tol-
uene, 1108C, 1.5 h; d) PhB(OH)2 (6 equiv), Pd(OAc)2 (5 mol%), XPhos
(12.5 mol%), K3PO4 (7.5 equiv), xylenes, reflux, 25 h. Ar1 =4-(p-meth-
oxyphenyl)phenyl; Ar2 =m-methoxyphenyl.
ACHTUNGTRENNUNG(PPh3)4]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
3-{4’-(p-methoxyphenyl)phenyl}-7-(m-methoxyphenyl)-2-
methyl-1-phenylnaphthalene (9db) by applying the tosyla-
tion and three highly selective sequential Suzuki–Miyaura
coupling reactions (Scheme 4), indicating the potential of
this methodology.[14]
In summary, we have developed a highly efficient tandem
reaction of easily available 4-aryl-2,3-allenoates[15] with orga-
nozinc reagents[8] to afford the diversified polysubstituted a-
naphthols in moderate to excellent yields. Different substitu-
ents may be introduced to different positions of naphthols
by just installing these substituents in 2,3-allenoates and or-
ganozinc reagents. The product 3db has been successfully
applied to the synthesis of polysubstituted naphthalene 9db
utilizing sequential coupling reactions. This method will be
of high interest to synthetic, material, and medicinal chem-
ists. Further studies in this area including the mechanistic
study are being conducted in our laboratory.
Scheme 2. Rationale for this transformation.
We were quite surprised to note that under Method B,
even the reaction of ethyl 2-methyl-4-phenyl-2,3-buta-
ACHTUNGTRENNUNGdienoate 1a with diethyl zinc 2d afforded 3-alkyl-substituted
naphthol 3ad in 20% yield, along with the 5-benzylidenecy-
clohex-2-enone product, which has been generated exclu-
sively in our previous study,[5] in 6% NMR spectroscopic
yield (Scheme 3, top). Furthermore, the reaction of 1a with
Experimental Section
A typical procedure for the preparation of 3db: To a dried Schlenk flask
equipped with a Teflon-coated magnetic stirring bar were added a solu-
tion of 4-bromophenyl zinc iodide (2b; 24 mL, 0.5m in THF, 12 mmol,
3 equiv) and xylenes (30 mL) sequentially with a nitrogen atmosphere at
room temperature. The flask was then submerged in an oil bath preheat-
ed to 1408C to distill off THF with a distillation apparatus for 0.5 h with
a stream of N2. A solution of 1d (0.9485 g, 4.0 mmol) in xylenes (20 mL)
was added with a syringe dropwise quickly at 1408C. After 0.5 h, the re-
action was complete as monitored by TLC and quenched subsequently
by dropwise addition of saturated aqueous NH4Cl (5 mL) at 08C. After
warming up to room temperature and extraction with diethyl ether (3ꢁ
60 mL), the organic layer was washed sequentially with diluted HCl (5%,
aq.), a saturated aqueous solution of NaHCO3, and brine. After being
dried over anhydrous Na2SO4, filtration, evaporation, and column chro-
matography on silica gel (eluent: 30–608C petroleum ether/ethyl ace-
tate=50:1) afforded 3db (0.9710 g, 70%): Solid; m.p. 157.5–159.08C;
1H NMR (300 MHz, CDCl3): d=8.16 (d, J=1.8 Hz, 1H), 7.70 (d, J=
8.4 Hz, 1H), 7.62–7.54 (m, 2H), 7.40 (dd, J1 =8.7 Hz, J2 =1.8 Hz, 1H),
7.30 (s, 1H), 7.25–7.19 (m, 2H), 5.20 (s, 1H), 2.27 ppm (s, 3H); 13C NMR
(CDCl3, 75 MHz): d=148.5, 140.34, 140.28, 131.3, 131.0, 130.6, 129.2,
127.0, 124.1, 121.4, 120.8, 120.6, 115.7, 13.3 ppm; MS (EI): m/z (%): 350
Scheme 3.
diphenyl zinc in toluene at room tempeature[5] also afforded
naphthol 3aa in 35% NMR spectroscopic yield (Scheme 3,
bottom). Thus, the chemistry shown here is mostly due to
the nature of the zinc reagents and substrates. In addition,
the high temperature, which increase the rate of either
cyclic Friedel–Crafts reaction[13] or 6p electrocyclization[12]
of intermediate A with respect to its conjugate addition to
the second molecule of allenoate,[5] may also be partially re-
sponsible.
The reaction can be easily extended to a scale of
4.0 mmol of the substrates 1d with 3 equivalents of 2b af-
fording
(3db) in 70% yield (Scheme 4). Under different conditions,
3db may easily be converted to polysubstituted naphthalene
3-(p-bromophenyl)-7-chloro-2-methyl-1-naphthol
(24.95) [M
[M
+A(79Br35Cl)]; IR (KBr, cmÀ1): n˜ =3407, 2923, 2852, 1636, 1595, 1570,
1489, 1441, 1418, 1393, 1367, 1298, 1270, 1224, 1203, 1168, 1146, 1112,
+A(81Br37Cl)], 348 (100) [M+(79Br37Cl or 81Br35Cl)], 346 (76.80)
CHTUNGTRENNUNG
CTHUNGTRENNUNG
Chem. Eur. J. 2009, 15, 11083 – 11086
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11085

S. Ma et al.
1074, 1011 cmÀ1
found: 345.9761.
;
HRMS Calcd for C17H12O35Cl79Br [M+]: 345.9760;
[7] Crystal data for compound 3aa: (C17H14O)6, MW =1405.69; mono-
clinic, space group C2/c; final R indices [I>2s(I)], R1=0.0401,
wR2=0.1065, R indices (all data) R1=0.0519, wR2=0.1189; a=
24.2231(4), b=13.8166(2), c=23.8007(4) ꢄ, a=90, b=112.8660(10),
g=908, V=7339.7(2) ꢄ3, T=123(2) K, Z=4; reflections collected/
unique: 65774/8538 (Rint =0.0279), number of observations [I>
2s(I)] 7013, parameters: 535. CCDC 727474 contains the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif..
[8] a) E. Lorthiois, C. Meyer in The Chemistry of Organozinc Com-
pounds (Eds.: Z. Rappoport, I. Marek), Wiley, New York, 2006,
pp. 863–977; b) P. Knochel, H. Leuser, L.-Z. Gong, S. Perrone, F. F.
Kneisel in Handbook of Functionalized Organometallics (Ed.: P.
Knochel), Wiley-VCH, Weinheim, 2005, pp. 251–346; c) A. Krasov-
skiy, V. Malakhov, A. Gavryushin, P. Knochel, Angew. Chem. 2006,
118, 6186; Angew. Chem. Int. Ed. 2006, 45, 6040.
Acknowledgements
Financial support from the National Basic Research Program of China
(2009CB825300) and Major State Basic Research and Development Pro-
gram (2006CB806105) is greatly appreciated. S.M. is a Qiu Shi Adjunct
Professor at Zhejiang University. We thank Mr. Guofei Chen in our
group for reproducing the results presented in entries 1, 9, and 15 of
Table 2.
Keywords: allenes · cross-coupling · cyclization · Michael
addition · zinc
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Received: June 27, 2009
Published online: September 18, 2009
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Chem. Eur. J. 2009, 15, 11083 – 11086