Palladium-catalyzed cocyclotrimerization of allenes with arynes: Selective synthesis of phenanthrenes

Article abstract of DOI:10.1021/jo900117c

Palladium-catalyzed cocyclotrimerization of allenes with arynes has been developed for selectively synthesizing phenanthrenes. In the presence of [(allyl)PdCl]₂ and P(otol)₃, a variety of allenes, including internal and terminal alle

Full text of DOI:10.1021/jo900117c

SCHEME 1
Palladium-Catalyzed Cocyclotrimerization of
Allenes with Arynes: Selective Synthesis of
Phenanthrenes
Yi-Lin Liu,† Yun Liang,*,† Shao-Feng Pi,†
Xiao-Cheng Huang,† and Jin-Heng Li*,†,‡
Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research (Ministry of Education), Hunan Normal
UniVersity, Changsha 410081, China, and State Key
Laboratory of Chemo/Biosensing and Chemometrics,
Hunan UniVersity, Changsha 410082, China
of benzynes with bicyclic alkenes to give 9,10-dihydrophenan-
threne derivatives.3o However, both regio- and chemoselectivi-
ties of these cycloaddition transformations are unsatisfactory.
As an alternative to these methods, Cheng and co-workers
recently demonstrated a highly chemoselective NiBr2(PPh3)2-
catalyzed cocyclotrimerization of benzynes with allenes to afford
10-methylene-9,10-dihydrophenanthrenes in moderate yields (eq
1, Scheme 1).3p However, an excess amount of Zn was necessary
and only aliphatic terminal allenes were screened. Pd(PPh3)4
was also investigated, and the results showed that it was less
effective for the cocyclotrimerization of benzynes with (propa-
1,2-dienyl)cyclohexane (eq 1, Scheme 1). Thus, the development
of some general and selective routes involving new catalytic
systems for the synthesis of phenanthrenes from the aryne
liangyun1972@126.com; jhli@hunnu.edu.cn
ReceiVed January 18, 2009
Palladium-catalyzed cocyclotrimerization of allenes with
arynes has been developed for selectively synthesizing
phenanthrenes. In the presence of [(allyl)PdCl]2 and P(o-
tol)3, a variety of allenes, including internal and terminal
allenes, underwent the cocyclotrimerization with arynes to
afford the corresponding phenanthrenes in moderate to good
yields. The results showed the selectivity of the reaction
based on allenes.
(3) For selected papers on the cyclotrimerization of arynes with unsaturated
compounds, such as alkynes, allenes, alkenes, or arynes, to construct the
phenanthrene frameworks, see: (a) Pen˜a, D.; Escudero, S.; Pe´rez, D.; Guitia´n,
E.; Castedo, L. Angew. Chem., Int. Ed. 1998, 37, 2659–2661. (b) Pen˜a, D.;
Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Am. Chem. Soc. 1999, 121, 5827–5828.
(c) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Org. Lett. 1999, 1, 1555–
1557. (d) Pen˜a, D.; Cobas, A.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Org. Lett.
2000, 2, 1629–1632. (e) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Org.
Chem. 2000, 65, 6944–6950. (f) Caeiro, J.; Pen˜a, D.; Cobas, A.; Pe´rez, D.;
Guitia´n, E. AdV. Synth. Catal. 2006, 348, 2466–2474. (g) Quintana, I.; Boersma,
A. J.; Pen˜a, D.; Pe´rez, D.; Guitia´n, E. Org. Lett. 2006, 8, 3347–3349. (h) Romero,
C.; Pen˜a, D.; Pe´rez, D.; Guitia´n, E. Chem. Eur. J. 2006, 12, 5677–5684. (i)
Radhakrishnan, K. V.; Yoshikawa, E.; Yamamoto, Y. Tetrahedron Lett. 1999,
40, 7533–7535. (j) Yoshikawa, E.; Yamamoto, Y. Angew. Chem., Int. Ed. 2000,
39, 173–175. (k) Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto, Y. J. Am.
Chem. Soc. 2000, 122, 7280–7286. (l) Liu, Z.; Zhang, X.; Larock, R. C. J. Am.
Chem. Soc. 2005, 127, 15716–15717. (m) Liu, Z.-J.; Larock, R. C. J. Org. Chem.
2007, 72, 223–232. (n) Liu, Z.-J.; Larock, R. C. Angew. Chem., Int. Ed. 2007,
46, 2535–2538. (o) Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H. J. Org. Chem.
2004, 69, 8445–8450. (p) Hsieh, J.-C.; Rayabarapu, D. K.; Cheng, C.-H. Chem.
Commun. 2004, 532–533. (q) Bhuvaneswari, S.; Jeganmohan, M.; Cheng, C.-
H. Org. Lett. 2006, 8, 5581–2284. (r) Jayanth, T.-T.; Cheng, C.-H. Chem.
Commun. 2006, 894–896. (s) Henderson, J. L.; Edwards, A. S.; Greaney, M. F.
J. Am. Chem. Soc. 2006, 128, 7426–7427.
(4) For selected recent papers on the use of o-silyl aryltriflates as the benzyne
precursors, see: (a) Huang, X.-C.; Liu, Y.-L.; Liang, Y.; Pi, S.-F.; Wang, F.; Li,
J.-H. Org. Lett. 2008, 10, 1525–1528. (b) Shi, F.; Waldo, J. P.; Chen, Y.; Larock,
R. C. Org. Lett. 2008, 10, 2409–2412. (c) Liu, Z.; Shi, F.; Martinez, P. D. G.;
Raminelli, C.; Larock, R. C. J. Org. Chem. 2008, 73, 219–226. (d) Waldo, J. P.;
Zhang, X.; Shi, F.; Larock, R. C. J. Org. Chem. 2008, 73, 6679–6685. (e) Xie,
C.; Liu, L.; Zhang, Y.; Xu, P. Org. Lett. 2008, 10, 2393–2396. (f) Yoshida, H.;
Morishita, T.; Ohshita, J. Org. Lett. 2008, 10, 3845–3847. (g) Ganta, A.;
Snowden, T. S. Org. Lett. 2008, 10, 5103–5106. (h) Bhuvaneswari, S.;
Jeganmohan, M.; Yang, M.-C.; Cheng, C.-H. Chem. Commun. 2008, 2158–2160.
(i) Bhuvaneswari, S.; Jeganmohan, M.; Cheng, C.-H. Chem. Commun. 2008,
5013–5015. (j) Morishita, T.; Fukushima, H.; Yoshida, H.; Ohshita, J.; Kunai,
A. J. Org. Chem. 2008, 73, 5452–5457. (k) Allan, K. M.; Stoltz, B. M. J. Am.
Chem. Soc. 2008, 130, 17270–17271. (l) Gilmore, C. D.; Allan, K. M.; Stoltz,
B. M. J. Am. Chem. Soc. 2008, 130, 1558–1559. (m) Gerfaud, T.; Neuville, L.;
Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 572–577. (n) Jeganmohan, M.;
Bhuvaneswari, S.; Cheng, C.-H. Angew. Chem., Int. Ed. 2009, 48, 391–394. (o)
Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340–5341.
o-Silyl aryltriflates as benzyne precursors were first reported
by Kobayashi in 1983.1 Shortly after, many efficient methods
were developed on the basis of o-silyl aryltriflates because o-silyl
aryltriflates could be readily converted into benzynes in situ
under mild conditions.1-4 A representative example is cyclot-
rimerization of arynes with unsaturated compounds, such as
alkynes, allenes, alkenes, or arynes, to construct the phenan-
threne frameworks.3 Both the Pe´rez group3a-h and the Yama-
moto group,3i-k for example, have independently reported
palladium-catalyzed cyclotrimerizations of benzynes with alkynes
to afford the corresponding phenanthrenes. Subsequently, Larock
and co-workers have described a novel route to prepare
phenanthrene derivatives by palladium-catalyzed annulation of
arynes with 2-halobiaryls.3l-n Cheng and co-workers have also
developed a palladium-catalyzed [2+2+2] cocylotrimerization
† Hunan Normal University.
‡ Hunan University.
(1) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211–1214.
(2) For reviews, see: (a) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59,
701–730. (b) Wenk, H. H.; Winkler, M.; Sander, W. Angew. Chem., Int. Ed.
2003, 42, 502–528. (c) Guitia´n, E.; Pe´rez, D.; Pen˜a, D. Top. Organomet. Chem.
2005, 14, 109–146.
10.1021/jo900117c CCC: $40.75
Published on Web 03/18/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3199–3202 3199

TABLE 1. Palladium-Catalyzed Cocyclotrimerization of Ethyl
4-Phenylbuta-2,3-dienoate (1a) with 2-(Trimethylsilyl)phenyl
Triflate (2a)a
TABLE 2. Selective Cocyclotrimerization of Allene 1 with Triflate
a
2 in the Presence of [(allyl)PdCl]2 and P(o-tol)3
entry
[Pd]
t (°C)
time (h)
yield (%)b
1c
2
3
4
5
6
7
8
Pd(dba)2
Pd(dba)2
PdCl2
Pd(PPh3)4
Pd(OAc)2
[(allyl)PdCl]2
[(allyl)PdCl]2
[(allyl)PdCl]2
[(allyl)PdCl]2
Pd(OAc)2
80
80
80
80
80
80
60
0
0 to 60
0 to 60
0 to 60
0 to 60
20
20
10
10
6
30
39
8
23
38
40
54
12
71
49
0
6
24
24
3
12
20
20
9d
10d
11
12e
[(allyl)PdCl]2
17
a Reaction conditions: 1a (0.2 mmol), 2a (2 equiv), [Pd] (5 mol %),
P(o-tol)3 (10 mol %), and CsF (3 equiv) in MeCN (2 mL). b Isolated
yield. The benzyne cyclotrimerization product was observed by GC-MS
analysis. c Without P(o-tol)3. d At 0 °C for 2 h, then at 60 °C for 1 h.
e In THF (2 mL) instead of MeCN.
partners is still a challenging area. Here, we report a selective
cocyclotrimerization of benzynes with allenes to synthesize
phenanthrenes in moderate yields using [(allyl)PdCl]2 and P(o-
tol)3 catalytic systems (eq 2, Scheme 1).
The reaction between ethyl 4-phenylbuta-2,3-dienoate (1a)
and 2-(trimethylsilyl)phenyl triflate (2a) was conducted to
optimize the reaction conditions, and the results are summarized
in Table 1. Initially, a set of the Pd catalytic systems were
investigated (entries 1-6). Without ligands, treatment of allene
1a with triflate 2a and Pd(dba)2 at 80 °C afforded the
corresponding product 3 in a 30% yield (entry 1). The yield of
3 was enhanced to 39% in the presence of P(o-tol)3 (entry 2).
Identical results were obtained with either Pd(OAc)2 or [(al-
lyl)PdCl]2 (entries 5 and 6). However, both PdCl2 and Pd(PPh3)4
were less effective (entries 3 and 4). The reaction temperature
was subsequently examined in the presence of [(allyl)PdCl]2
and P(o-tol)3. The screening results demonstrated that the
reaction temperature affected the reaction (entries 6-9). The
yield of the target product 3 was enhanced to 54% at 60 °C
(entry 7), and 12% yield was still isolated at 0 °C (entry 8).
Interestingly, the yield of 3 was increased to 71% when the
reaction was conducted at 0 °C for 2 h, then at 60 °C for 1 h
(entry 9). However, Pd(OAc)2 displayed less activity under the
same conditions (entry 10). It is worthy noting that no desired
product is observed by GC-MS analysis without Pd catalysts
(entry 11).3 Another solvent, THF, was also tested, and the
results showed that it was inferior to MeCN (entry 12).
With the optimal reaction conditions in hand, the scope of
the cocyclotrimerzation reaction was screened (Table 2 and
Scheme 2). As shown in Table 2, a variety of internal allenes
1b-i were first evaluated by reacting with triflate2a, [(allyl)P-
dCl]2, and P(o-tol)3 (entries 1-8). The results demonstrated that
the structures of the allenes affected the yield and selectivity to
some extent. While ethyl 4-(4-methoxyphenyl)buta-2,3-dienoate
1b, for instance, was treated with triflate 2a, [(allyl)PdCl]2, and
P(o-tol)3 to afford the desired product 4 in a 77% yield (entry
1), substrate 1d with an o-methoxyphenyl group reduced the
yield of the corresponding product 6 to 53% under the same
a Reaction conditions: 1 (0.2 mmol), 2 (2 equiv), [(allyl)PdCl]2 (5 mol
%), P(o-tol)3 (10 mol %), and CsF (3 equiv) in MeCN (2 mL) at 0 °C
for 2 h, then at 60 °C for 1 h. b Isolated yield. c (Z)/(E) isomers ) 2:1
1
determined by H NMR spectra.
conditions (entry 3). In the presence of [(allyl)PdCl]2 and P(o-
tol)3, the other disubstituted allenes 1c, 1e, and 1g also provided
the target phenanthrene products in satisfactory yields (entries
2 and 4-6). Surprisingly, 9,10-dihydro-9-methylenephenan-
3200 J. Org. Chem. Vol. 74, No. 8, 2009

SCHEME 2. Cocyclotrimerization of Terminal Allenes 1j-l
species with allene 1 and benyne A, which is generated from
the reaction of 2 with CsF, occurs readily to afford
intermediate B. Subsequently, intermediate B undergoes cis-
addition to give intermediate C, followed by insertion with
another benzyne A to yield intermediate D. Finally, reductive
elimination of intermediate D takes place to provide the target
9,10-dihydro-9-methylenephenanthrene product and regener-
ate the active Pd(0) species. Intermediate D to intermediate
D readily occurs by isomerization to give the phenanthrene
product due to the electronic effect of allenes. However, the
formation of 9,10-dihydro-9-methylenephenanthrenes from
allenes 1f, 1h, and 1i may be because the steric hindrance
effect preponderates over the electronic effect. The identical
effects are presented among the reactions of the electron-
neutral and electron-deficient terminal allenes.
with Triflate 2a
SCHEME 3. A Possible Mechanism
In summary, we have developed a selective protocol for the
synthesis of phenanthrenes by palladium-catalyzed cocyclotri-
merization of allenes with benzynes. This method allows for a
wide range of various allenes, including internal and terminal
allenes, to proceed the cocyclotrimerization with arynes. It is
noteworthy that the products, phenanthrenes, are the common
structural motifs in both naturally occurring biological com-
pounds with antimalarial, anticancer and emetic activities,5 and
materials with photoconducting, photochemical, and electrolu-
minescent properties.
Experimental Section
Typical Experimental Procedure for the Palladium-Cata-
lyzed Cocyclotrimerization of Allenes with Benzynes. A mixture
of allene 1 (0.2 mmol), 2-(trimethylsilyl)phenyl triflate 2 (2 equiv),
[(allyl)PdCl]2 (5 mol %), P(o-tol)3 (10 mol %), and CsF (3 equiv)
was stirred in MeCN (2 mL) at 0 °C for 2 h, then at 60 °C for 1 h
until complete consumption of starting material as monitored by
TLC and GC-MS analysis. Then the mixture was filtered by crude
flash column chromatography with diethyl ether, and evaporated
under vacuum. The residue was purified by flash column chroma-
tography to afford the pure product (hexane/ethyl acetate).
Ethyl 2-(10-phenylphenanthren-9-yl)acetate (3): pale yellow
solid, mp 105.8 °C (uncorrected); 1H NMR (500 MHz) δ 8.76 (d,
J ) 9.5 Hz, 1H), 8.72 (d, J ) 8.0 Hz, 1H), 8.01 (d, J ) 9.0 Hz,
1H), 7.67-7.63 (m, 2H), 7.59 (t, J ) 7.5 Hz, 1H), 7.51-7.43 (m,
3H), 7.42-7.40 (m, 1H), 7.38-7.35 (m, 3H), 4.11-4.06 (m, 2H),
3.90 (s, 2H), 1.15 (t, J ) 7.5 Hz, 3H); 13C NMR (125 MHz) δ
171.7, 139.7, 139.1, 132.1, 131.1, 130.2, 130.0, 128.4, 128.2, 128.0,
127.7, 127.4, 127.1, 127.0, 126.4, 126.3, 124.7, 123.0, 122.4, 60.7,
threne 8 was obtained from the reaction of allene 1f (entry 5).
We were interested to find that the chemoselectivities of
trisubstituted allenes were shifted toward 9,10-dihydro-9-
methylenephenanthrenes (entries 7 and 8). In the presence of
[(allyl)PdCl]2 and P(o-tol)3, the reaction of 2-methyl-1,4-
diphenylbuta-2,3-dien-1-one (1h) with triflate 2a was conducted
smoothly to afford a mixture of (Z)- and (E)-9,10-dihydro-9-
methylenephenanthrene 10 in a 60% total yield (Z/E ) 2:1; entry
7). It was found that a 29% yield was still achieved from the
reaction between ethyl 4-methylpenta-2,3-dienoate (1i) and
triflate 2a under the standard conditions (entry 8). Another
triflate 2b was investigated by the reaction with allenes 1a, 1b,
or 1e in the presence of [(allyl)PdCl]2 and P(o-tol)3, and the
results indicated that these reactions were carried out selectively
in moderate yields (entries 9-11). However, triflate 2c reacted
with allene 2a provided a mixture of products (entry 12).
As shown in Scheme 2, three terminal allenes 1j-l were also
examined under the standard conditions. Treatment of aliphatic
allenes 1j or 1k with triflate 2a, [(allyl)PdCl]2, and P(o-tol)3
afforded the corresponding 9,10-dihydro-9-methylenephenan-
threnes 16 and 17, respectively, in moderate yields, whose
selectivity is identical to Cheng’s Pd results.3p We were pleased
to find that the reaction of the electron-deficient terminal allene
1l with triflate 2a was also conducted smoothly in a 57% total
yield under the same conditions. However, the regioselectivity
was not satisfactory, and a mixture of 18 and 19 was obtained
in a 1:1 ratio.
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A possible mechanism as outlined in Scheme 3 for the
palladium-catalyzed cocyclotrimerization reaction is proposed
on the basis of the present results and the previously reported
mechanisms.1-4 Initially, complexation of the active Pd(0)Ln
J. Org. Chem. Vol. 74, No. 8, 2009 3201

37.0, 14.1; IR (KBr, cm-1) 1727; LRMS (EI, 70 eV) m/z (%) 340
(M+, 55), 294 (29), 267 (100), 252 (28); HRMS (EI) for C24H20O2
(M+) calcd. 340.1463, found 340.1461.
Chinese Medicine Research (Ministry of Education of China)
(No. KLCBTCMR2008-11), and Hunan Normal University (No.
080605) for financial support.
Acknowledgment. We thank the Opening Fund of the State
Key Laboratory of Chemo/Biosensing and Chemometrics (No.
2006016), New Century Excellent Talents in University (No.
NCET-06-0711), Scientific Research Fund of Hunan Provincial
Education Department (Nos. 08B053 and 08A037), Opening
Fund of Key Laboratory of Chemical Biology and Traditional
Supporting Information Available: General experimental
procedures, characterization data for 3-19, and copies of
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO900117C
3202 J. Org. Chem. Vol. 74, No. 8, 2009