Highly regio- And stereoselective synthesis of nine- to twelve-membered cyclic compounds by a Pd°-catalyzed cyclization reaction between alienes with a nucleophilic functionality and organic halides

Article abstract of DOI:10.1002/chem.200900972

A study was conducted to demonstrate highly regio- and stereoselective synthesis of nine- to twelve-membered cyclic compounds by [Pd(PPh ₃)₄]-catalyzed cyclization reaction between allenes with a nucleophilic functionality and organi

Full text of DOI:10.1002/chem.200900972

COMMUNICATION
DOI: 10.1002/chem.200900972
Highly Regio- and Stereoselective Synthesis of Nine- to Twelve-Membered
Cyclic Compounds by a Pd0-Catalyzed Cyclization Reaction between Allenes
with a Nucleophilic Functionality and Organic Halides
Xinpeng Jiang,[a] Qing Yang,[b] Yihua Yu,[c] Chunling Fu,[a] and Shengming Ma*[a]
Eight- to twelve-membered carbocycles and heterocycles
are extremely important subunits of a large variety of natu-
ral products.[1] The attractive properties of these cyclic com-
pounds have encouraged organic chemists to develop vari-
ous efficient methods for their synthesis.[1,2] However, there
are only limited strategies for the preparation of this class of
compound, which is mainly due to the fact that their forma-
tion is usually hampered by entropic/enthalpic factors.[3]
Recently, the reactions of allenes have attracted much at-
tention due to the interesting chemical properties associated
with their cumulated double bonds.[4] Some methodologies
have been developed to form eight-membered rings from al-
lenes, the most notable of which are: 1) intramolecular car-
bopalladation of w-haloallenes;[5] 2) cyclization of bromoal-
lenes with an oxygen, nitrogen, or carbon nucleophilic func-
tionality;[6] 3) intermolecular heteroannulation of a variety
of allenes that have aryl and vinylic iodides with tosylamide
and amine functionalities;[7] and 4) base-catalyzed intramo-
lecular Michael addition of carbanion species to sulfonylal-
lenes.[8] In these reports, it was noted that the formation of
nine-membered and even larger rings was more sluggish be-
cause of competing side reactions, especially dimerization,
which were avoided by applying high-dilution conditions[5b]
or longer reaction times[7] to obtain reasonable yields. In ad-
dition, the cycloisomerization of allenes with carbon nucleo-
philic functionality was reported to afford 9–17-membered
rings under high-dilution conditions.[9] Therefore, it is still of
current interest to develop efficient methodologies for the
preparation of nine- to twelve-membered ring compounds
under mild conditions based on the chemistry on allenes.
It is known that the carbopalladation of allenes may
afford a p-allyl palladium intermediate that can easily be
further trapped by a nucleophilic unit to provide three- to
six-membered carbocycles (Scheme 1).[10] The formidable
[a] X. Jiang, 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
Scheme 1.
[b] Q. Yang
State Key Laboratory of Inorganic Synthesis and Preparative Chemis-
try
challenge here is the regioselective formation of cyclic prod-
ucts A or B and the stereoselectivity for the formation of
the C=C bond in B. Herein, we wish to disclose our recent
observation that this type of transformation may be easily
applied for the regioselective synthesis of nine- to twelve-
membered cycloalkenes with a stereodefined C=C bond in
the ring in high yields (Scheme 1, route b).
Initially, we conducted a treatment of methyl 3-{2-[2,2-
bis(methoxycarbonyl)hexa-4,5-dienyl]phenyl}-2-(methoxy-
carbonyl)propionate 1a with PhI under the conditions we
Jilin University
Changchun 130012, Jilin (P.R. China)
[c] Y. Yu
Shanghai Key Laboratory of Functional Magnetic Resonance Imag-
ing
Department of Physics, East China Normal University
Shanghai 200062 (P.R. China)
Supporting information for this article contains full experimental de-
tails, copies of H and 13C NMR spectra of all compounds and is
1
available on the WWW under http://dx.doi.org/10.1002/
chem.200900927.
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7283

Table 2. [Pd
ACHTUNGTRENUN(NG PPh3)4]-catalyzed coupling cyclization of 1a with different
previously used for the cyclization of 2-(2’,3’-allenyl)malo-
organic halides under standard conditions.[a]
nates with aryl halides ([PdACTHNUTRGNE(UNG PPh3)4] (5 mol%) and K2CO3
(4 equiv) in THF, 808C).[10e] Unfortunately, the reaction
failed to afford expected products 2a or 3a after 3 days;
84% of 1a was recovered (Table 1, entry 1). Luckily, in
Table 1. Effects of solvent and base in [PdACHTNUTRGEN(UNG PPh3)4]-catalyzed coupling
cyclization of 1a with PhI.[a]
Entry
R
t [h]
Yield of 2[b] [%]
1
2
3
4
5
6
7
8
Ph
11
11.5
14
12
17
14
72
72
91 (2a)
84 (2b)
89 (2c)
90 (2d)
85 (2e)
84 (2 f)
60 (2g)
62 (2h)
p-MeOOCC6H4
p-MeCOC6H4
p-MeC6H4
p-ClC6H4
4-pyridinyl
(E)-1-hexenyl[c,b]
(E)-styryl[d]
Entry
Base
Solvent[b]
t [h]
Yield of 2a[c] [%]
0[d]
76
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
KOAc
THF
72
14.5
11
11
24
11
24
24
DMSO
DMF
DMA
DMA
DMA
DMA
DMA
[a] Reaction conditions: 1a (0.07m), RI (2 equiv), [PdACTHUNTRGNE(UNG PPh3)4] (5 mol%),
K2CO3 (4 equiv). [b] Isolated yield. [c] 1-iodohex-1-(E)-ene (3 equiv) was
used. [d] (E)-styryl iodide (3 equiv).
69
93 (91)
36[e]
58
0
43
KHCO3
iodide (Table 2, entry 6), 1-iodohex-1-(E)-ene (Table 2,
entry 7), and (E)-styryl iodide (Table 2, entry 8) may be
used to afford the corresponding ten-membered rings with
an E C=C bond in high regio- and stereoselectivity.
[a] Reaction conditions: 1a (0.07m), PhI (2 equiv), [PdACTHUNTRGNE(UNG PPh3)4]
(5 mol%), base (4 equiv). [b] THF=tetrahydrofuran, DMSO=dimethyl-
sulfoxide, DMF=N,N-dimethylformamide, DMA=N,N-dimethylaceta-
mide. [c] Determined by using 1H NMR (300 MHz) spectroscopy with
CH2Br2 as the internal standard; yields of the isolated product are given
in parentheses. [d] 84% of starting material 1a was recovered. [e] 43%
of starting material 1a was recovered.
This set of standard reaction conditions may also be used
for the synthesis of nine- to twelve-membered rings
(Table 3, entries 1–5). The reaction of 4c with 4-chlorophen-
yl iodide gave the medium-sized nitrogen-tethered heterocy-
cle 5c in 82% yield (Table 3, entry 3). The structure of this
compound was further established by an X-ray diffraction
study (Figure 2a).[11] Based on these results, we reasoned
that a similar treatment of w-aminoallene with iodobenzene
could also provide an efficient route to similar azacycles. To
our delight, under the same conditions, the expected product
5 f was obtained in 83% yield (Table 3, entry 6), the struc-
ture and the configuration of the C=C bond of this com-
pounds was further established by the X-ray diffraction
study (Figure 2b).[12]
other solvents, such as DMSO (Table 1, entry 2) and DMF
(Table 1, entry 3), the reaction afforded ten-membered cy-
cloalkene (E)-2a as the only product in yields of 76 and
69%, respectively. Surprisingly, when DMA was used, the
NMR yield was improved to 93% (Table 1, entry 4). The
configuration of the C=C bond in 2a was established by a
NOE study (Figure 1). It is also worth noting that the for-
mation of eight-membered car-
bocycle 3a was not observed,
indicating that this reaction is
highly regioselective. With the
addition of a different base,
such as Na2CO3, Cs2CO3,
KOAc, and KHCO3 (Table 1,
entries 5–8), the reaction af-
The stereoselectivity may be explained by the presence of
the R group,[13] which leads to the formation of the anti in-
termediate to avoid steric repulsion between the R group
and the substituent with the nucleophilic functionality.[14]
Subsequent highly regioselective attack of the nucleophilic
moiety to the less substituted terminal affords the final
cyclic products (see Scheme 2).
forded (E)-2a in relatively
lower yields. Thus, [Pd(PPh3)4]
Figure 1. NOE study of (E)-2a
(E=CO2CH3).
G
In conclusion, we have developed an efficient method for
the synthesis of not-readily-available nine- to twelve-mem-
(5 mol%) and K2CO3 (4 equiv)
in DMA at 808C were estab-
bered rings by a [PdACTHNGUTERN(NUG PPh3)4]-catalyzed coupling cyclization
lished as the optimized reaction conditions for further study.
The scope of this reaction of 1a with different organic
halides to give ten-membered rings has been demonstrated,
with typical results summarized in Table 2. The following
issues should be noted: 1) The yields of these reactions
range from 60 to 91%; 2) in addition to electron-deficient
(Table 2, entries 2 and 3), electron-rich (Table 2, entry 4),
and Cl-substituted aryl iodides (Table 2, entry 5), pyridinyl
reaction of functionalized allenes with organic halides in
highly regio- and stereoselectivity without applying highly
diluted technique. Further study in this area is being pur-
sued in our laboratory.
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Chem. Eur. J. 2009, 15, 7283 – 7286

Synthesis of Nine- to Twelve-Membered Cyclic Compounds
COMMUNICATION
Table 3. [PdACHTUNGTRENNUNG(PPh3)4]-catalyzed coupling cyclization of 4 with PhI under
standard conditions.[a]
Entry 4[b]
5[b]
t
Isolated yield of 5
[h] [%]
1
2
11.5 70
16.7 89
3[c]
8
82
73
4
11
5
13
16
73
83
6[d]
[a] The reactions were carried out at 808C in DMA with 4 (c=0.07m),
K2CO3 (4 equiv) and PhI (2.0 equiv) in the presence of [Pd(PPh3)4]
AHCTUNGTRENNUNG
(5 mol%). [b] E=CO2Me. [c] ArI=4-chlorophenyl iodide (2.0 equiv)
was used. [d] E=CO2Et.
Figure 2. ORTEP drawing of a) 5c and b) 5 f. Thermal ellipsoids are
drawn at the 30% probability level.
Experimental Section
[PdACHTUNGTRENNUNG(PPh3)4] (5.7 mg, 0.005 mmol), 1a (41.8 mg, 0.1 mmol), iodobenzene
(40.9 mg, 0.2 mmol), and DMA (1.5 mL) were added sequentially to a
Schlenk tube containing potassium carbonate (55.6 mg, 0.4 mmol) under
nitrogen. The Schlenk tube was cooled by using a dry-ice/acetone bath
and back-filled with nitrogen three times. The reaction was stirred at
808C for 11 h until completion, as monitored by TLC (eluent: petroleum
ether/ethyl acetate 5:1). The resulting mixture was quenched with H2O
(10 mL) and extracted with diethyl ether (3ꢁ30 mL), then washed with
water and brine and dried over anhydrous Na2SO4. After filtration and
evaporation of the solvent, chromatography on silica gel (eluent: petrole-
um ether/ethyl acetate/dichloromethane 5:1:1) gave 2a as a white solid
(44.9 mg, 91%). M.p. 204–2058C (CH2Cl2/n-hexane); 1H NMR
(300 MHz, CDCl3) d=7.34–7.18 (m, 5H), 7.18–7.08 (m, 2H), 6.90–6.78
(m, 2H), 5.19 (dd, J1 =12.8, J2 =4.4 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H),
3.79 (s, 3H), 3.60 (d, J=14.7 Hz, 1H), 3.47 (d, J=15.0 Hz, 1H), 3.29–3.11
(m, 3H), 2.95 (d, J=14.7 Hz, 1H), 2.88 (s, 3H), 2.63 (dd, J1 =14.3 Hz,
J2 =4.4 Hz, 1H), 2.44 ppm (t, J=13.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=172.2, 171.8, 171.2, 170.8, 142.4, 140.2, 135.6, 135.4, 129.8,
129.41, 129.37, 127.8, 127.6, 127.1, 127.0, 126.9, 58.6, 57.9, 52.8, 52.6, 52.5,
Scheme 2.
51.8, 33.1, 32.5, 31.2, 30.2 ppm; IR (KBr): n=1734, 1496, 1433, 1270,
1206, 1179, 1111, 1068 cmÀ1; EI MS (70 eV): m/z (%): 494.2 (57.22) [M+],
115 (100); elemental analysis calcd (%) for C28H30O8: C 68.00, H 6.11;
found: C 68.09, H 6.18.
CCDC 721795 (5c) and 702170 (5 f) contain the supplementary crystallo-
graphic 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
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www.chemeurj.org
7285

S. Ma et al.
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Acknowledgements
Financial support from the National Natural Science Foundation of
China (no. 20732005), the State Key Basic Research Development
(2006CB806105), and the Science and Technology commission of Shang-
hai Municipality, STCSM (no. 07DZ22937) is greatly appreciated.
Shengming Ma is a Qiu Shi adjunct professor at Zhejiang University. We
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Keywords: allenes · cyclization · medium-ring compounds ·
palladium · stereoselectivity
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¯
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Received: April 13, 2009
Published online: June 19, 2009
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