Palladium-catalyzed cyclization of 1,6-enyne with 2-bromoarylaldehyde: domino sequence to [5-7-6] tricyclic ring systems

Article abstract of DOI:10.1016/j.tetlet.2009.11.006

A domino sequence of cyclization of 1,6-enyne with 2-bromoarylaldehyde followed by the intramolecular Aldol-condensation has been realized in the presence of 5 mol % of palladium catalyst. This sequence provides a convenient protocol to access polycyclic ring systems with readily available starting materials under simple Pd(0)-catalyzed conditions. The intramolecular Aldol-condensation has been proposed as the key step for the catalytic cycle.

Full text of DOI:10.1016/j.tetlet.2009.11.006

Tetrahedron Letters 51 (2010) 317–320
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed cyclization of 1,6-enyne with 2-bromoarylaldehyde:
domino sequence to [5-7-6] tricyclic ring systems
*
Xianjie Fang, Xiaofeng Tong
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A domino sequence of cyclization of 1,6-enyne with 2-bromoarylaldehyde followed by the intramolecu-
lar Aldol-condensation has been realized in the presence of 5 mol % of palladium catalyst. This sequence
provides a convenient protocol to access polycyclic ring systems with readily available starting materials
under simple Pd(0)-catalyzed conditions. The intramolecular Aldol-condensation has been proposed as
the key step for the catalytic cycle.
Received 5 September 2009
Revised 2 November 2009
Accepted 3 November 2009
Available online 10 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Palladium catalyst
Domino sequence
1,6-Enyne
[5-7-6] Tricyclic ring
Intramolecular Aldol-condensation
The [5-7-6] tricyclic ring systems are important structural
components and widely occur in a range of polycyclic natural
products, such as Dilatriol,1 Rameswaralide,2 Grayanotoxin,3 Gua-
nacastepene A,4 etc. Inspired by their interesting structure and di-
verse biological activities, a variety of synthetic approaches toward
[5-7-6] tricyclic ring systems has been developed.5 Although the
current methods can efficiently construct the [5-7-6] tricyclic ring
systems, they always require multi-steps synthetic route and some
complex substrates, which are not so easy to obtain. Thus, other
versatile and flexible methodologies to construct [5-7-6] tricyclic
ring systems using readily accessible building blocks are still
needed. Herein, we report an one-pot synthesis of [5-7-6] tricyclic
ring compound 3 from the commercially available 1,6-enyne 1 and
2-bromoarylaldehyde 2 under simple palladium-catalyzed condi-
tions Eq. 1:
A, Scheme 1.6 In general, these reactions are triggered by the oxi-
dative addition of Pd(0) to ArX, which leads to the formation of
Ar-Pd(II) intermediate A1. Then sequential insertion of double
bond to Ar-Pd(II) and selective b-H elimination will afford the eno-
late species C1. Finally, the isomerization of C1 gives the carbonyl
product.7 As part of our program to design new sequence of
cyclization of 1,6-enyne, we are particularly interested in the
transition-metal-catalyzed one-pot processes for both the synthe-
sis of structurally complex molecules and the entry into synthetic
building blocks.8 Intrigued by the mechanism of the above-men-
tioned Heck-isomerization process, we envisioned that the corre-
sponding vinyl-Pd(II) species A2 also would be presumably
formed when 1,6-enyne 1 and 2-bromoarylaldehyde 2 were
encountered with the presence of catalytic amount of Pd(0)-spe-
cies (Part B, Scheme 1). At this stage, we anticipated that the newly
formed enolate intermediate C2 would be trapped by the intramo-
lecular aldehyde group of the substrate 2 to deliver the [5-7-6]
tricyclic ring product 3.
To test our strategy, we start our investigation from the reaction
of 1,6-enyne 1a and 2-bromophenylaldehyde 2a. The treatment of
the substrates by using the combination of Pd(OAc)2 catalyst
(5 mol %), Bu4NBr (2.0 equiv), and NaOAc (2.5 equiv) furnishes
the desired product 3a in 39% yield (Table 1, entry 1). Interestingly,
PPh3 (15 mol %), normally working as the ligand to palladium,
almost has no effect to the yield (entry 2). However, the additive
LiCl takes a positive effect on the yield and the best results is con-
sequently obtained when 1 equiv LiCl is used (entry 3). The nature
of the base also seems to impose an important impact on the reac-
tion results. Other bases, such as NaHCO3, Na2CO3, K2CO3, NaOMe,
CHO
R
CHO
[Pd]
Ar
OH
+
Ar
ð1Þ
X
Br
X
R
1
2
3
The so-called tandem Heck-isomerization process between the
aryl halides (ArX) and allylic or homoallylic alcohols has been
widely utilized to synthesize various aldehydes and ketones as
illustrated by the reaction of bromobenzene with propenol in Part
* Corresponding author. Tel.: +86 21 64253881.
E-mail address: tongxf@ecust.edu.cn (X. Tong).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.006

318
X. Fang, X. Tong / Tetrahedron Letters 51 (2010) 317–320
Part A: previous work
PdII
OH
insertion
Pd(0)
Ph
PhBr
Ph
OH
Ph-Pd-Br
Ph
OH
CHO
elimination
A1
B1
C1
D1
Part B: this work
CHO
CHO
R
CHO
2
CHO
Aldol
Br
PdII
???
R
R
Pd(0)
X
OH
X
OH
OH
R
X
A2
X
C2
3
1
Scheme 1. New strategy for the tandem Heck-isomerization process.
and Et3N, were much less efficient than NaOAc (entries 7–12).
Bu4NBr exhibits better effect to the yield than Bu4NCl (entry 6).
The yield will dramatically drop without Bu4NBr (entry 5).9
bulk (entry 3). Notably, nitrogen linked 1,6-enynes exhibit similar
reactivity under the reaction conditions (entry 4). With regard to
2-bromoarylaldehyde, both 2b and 2c also are good choices for
the construction of poly-cyclic systems. It is worth noting that
the novel domino sequence can be performed with 1,7-enynes
CHO
Ph
Pd(OAc)2
CHO
Br
(Eqs. 2 and 3). Hence, other two different poly-cyclic systems10
,
OH
NaOAc, LiCl
+
NTs
(
3ea and 3ec, are obtained in 38% and 37% yields, respectively.
These reactions provide valuable products in only one step from
readily available compounds.
Bu4NBr, DMF, 100ºC
)
2
N
Ph
Ts
2a
1e
3ea
ð2Þ
Our mechanistic proposal for the reaction is as follows (Scheme
2). The interaction of 2-bromoarylaldehyde 2 with Pd(0)-species
leads to the formation of the aryl-Pd(II) intermediate. Insertion of
alkyne of 1,6-enyne substrate to aryl-Pd(II) bond produces the
vinylpalladium intermediate A2, which undergoes intramolecular
insertion of olefins to give B2. Then Ha-elimination selectively
occurs to release palladium catalyst and yields enolate intermedi-
ate C2. In the end, the newly formed enolate is expected to be
trapped through the intramolecular Aldol-condensation to give
the desired product 3.11
Ph
CHO
Pd(OAc)2
NaOAc, LiCl
CHO
OH
+
(
N
Bu4NBr, DMF, 100ºC
NTs
)
N
Br
2
N
Ts
Ph
3ec
2c
1e
ð3Þ
With the optimized conditions in hand, we next examined the
In summary, our effort to investigate the sequence of cycliza-
tion of 1,6-enyne has led us to the rational design of a new reaction
to produce [5-7-6] tricyclic ring systems. The feature of this proto-
col is to employ 1,6-enyne 1 and bromoarylaldehyde 2 as starting
materials which are readily available. With regard to the mecha-
generality of this catalytic method for the synthesis of [5-7-6] tri-
cyclic ring using a variety of enynes 1 and 2-bromoarylaldehyde 2
(Table 2). Primary alkyl groups and phenyl group can be used as
substituents on the alkyne. The 1,6-enyne 1c with terminal alkyne
group gives the best results probably due to the smallest stereo
Table 1
Optimizations for Pd(OAc)2-Catalyzd reaction of 1a with 2aa
CHO
Ph
5 mol% Pd(OAc)2
Bu4NBr, DMF, 100ºC
CHO
OH
X
Base, Additive
Br
X
Ph
1a
2a
3a
Entry
Bu4NBr (equiv)
Base (equiv)
Additive (equiv)
Yieldb (%)
1
2
3
2.0
2.0
2.0
2.0
/
2.0
2.0
2.0
2.0
2.0
2.0
2.0
NaOAc (2.5)
NaOAc (2.5)
NaOAc (2.5)
NaOAc (2.5)
NaOAc (2.5)
NaOAc (2.5)
NaHCO3 (2.5)
Na2CO3 (2.5)
K2CO3 (2.5)
NaOMe (2.5)
NEt3 (2.5)
/
39
35
61
45
19
27
17
15
<5
18
17
19
PPh3 (0.15)
LiCl (1.0)
LiCl (3.0)
LiCl (1.0)
LiCl (1.0)
LiCl (1.0)
LiCl (1.0)
LiCl (1.0)
LiCl (1.0)
LiCl (1.0)
LiCl (1.0)
4
5
6c
7
8
9
10
11
12
NEt3 (8.0)
a
b
c
Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), and Pd(OAc)2 (0.015 mmol) in DMF (3 mL) at 100 °C for 24 h.
Isolated yield.
Bu4NCl was used.

X. Fang, X. Tong / Tetrahedron Letters 51 (2010) 317–320
319
Table 2
Synthesis of [5-7-6] tricyclic ring compound 3 from 1 and 2a
CHO
X
R
Pd(OAc)2
NaOAc, LiCl
CHO
Ar
OH
Ar
Bu4NBr, DMF, 100ºC
Br
X
R
1
2
3
a
Entry
1
1
2
3
Yieldb (%)
CHO
Br
CHO
2a
2a
1a R = Ph X = O
3aa 61
O
Ph
Bu
CHO
Br
CHO
2
3
4
1b R = Bu, X = O
1c R = H, X = O
3ba 53
3ca 77
3da 55
O
CHO
Br
CHO
2a
2a
O
CHO
CHO
Br
1d R = Bu, X = NTs
NTs
CHO
Bu
CHO
O
O
O
2b
2b
5
6
7
8
1a R = Ph, X = O
1d R = Bu, X = NTs
1a R = Ph, X = O
1d R = Bu, X = NTs
3ab 31
3db 48
3ac 30
3dc 45
Br
O
O
Ph
Bu
CHO
Br
CHO
O
O
O
O
NTs
CHO
CHO
2c
Br
N
N
N
O
Ph
CHO
Br
CHO
2c
N
NTs
Bu
a
Reaction conditions: 1 (0.3 mmol), 2 (0.45 mmol), Pd(OAc)2 (0.015 mmol), NaOAc (0.75 mmol), Bu4NBr (0.6 mmol), and LiCl (0.3 mmol) in DMF (3 mL) at 100 °C for 24 h.
Isolated yield.
b
CHO
PdX
nism, we believe that the intramolecular Aldol-condensation is a
key step to fulfill the whole of design plan. Further studies on
the application of products are ongoing in our laboratories and will
be reported in due course.
base
2
Pd-H
Pd(0)
CHO
X
OH
R
1
C2
Acknowledgment
- H2O
Financial support from Shanghai Municipal Committee of Sci-
ence and Technology is greatly appreciated (09ZR1408500).
CHO
PdII
PdII
CHO
Ha
product 3
R
R
OH
OH
Supplementary data
X
X
B2
A2
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.006.
Scheme 2. Proposed mechanism for the formation of 3.

320
X. Fang, X. Tong / Tetrahedron Letters 51 (2010) 317–320
6. For selected reviews, see: (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000,
References and notes
100, 3009–3066; (b) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945–
2964; (c) Muzart, J. Tetrahedron 2005, 61, 4179–4212.
1. Pettit, G. R.; Ode, R. H.; Herald, C. L.; Von Dreele, R. B.; Michel, C. J. Am. Chem.
Soc. 1976, 98, 4677–4678.
2. Ramesh, P.; Reddy, N. S.; Venkateswarlu, Y.; Reddy, M. V. R.; Faulkner, D. J.
Tetrahedron Lett. 1998, 39, 8217–8220.
3. Kan, T.; Hosokawa, S.; Nara, S.; Oikawa, M.; Ito, S.; Matsuda, F.; Shirahama, H. J.
Org. Chem. 1994, 59, 5532–5534.
4. (a) Brady, S. F.; Singh, M. P.; Janso, J. E.; Clardy, J. J. Am. Chem. Soc. 2000, 122,
2116–2217; (b) Brady, S. F.; Bondi, S. M.; Clardy, J. J. Am. Chem. Soc. 2001, 123,
9900–9901.
5. (a) Trost, B. M.; Shen, H. C. Angew. Chem., Int. Ed. 2001, 40, 2313–2315; (b) Tan,
D. S.; Dudley, G. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41, 2185–
2188; (c) Shi, B.; Hawryluk, N. A.; Snider, B. B. J. Org. Chem. 2003, 68, 1030–
1042; (d) Mehta, G.; Umarye, J. D.; Srinivas, K. Tetrahedron Lett. 2003, 44, 4233–
4237; (e) Du, X.; Chu, H. V.; Kwon, O. Org. Lett. 2003, 5, 1923–1926; (f)
Brummond, K. M.; Gao, D. Org. Lett. 2003, 5, 3491–3494; (g) Srikrishna, A.;
Dethe, D. H. Org. Lett. 2004, 6, 165–168; (h) Mandal, M.; Danishefsky, S. J.
Tetrahedron Lett. 2004, 45, 3831–3833; (i) Chiu, P.; Li, S. Org. Lett. 2004, 6, 613–
616; (j) Boyer, F. D.; Hanna, I.; Ricard, L. Org. Lett. 2004, 6, 1817–1820; (k) Li, C.
C.; Liang, S.; Zhang, X. H.; Xie, Z. X.; Chen, J. H.; Wu, Y. D.; Yang, Z. Org. Lett.
2005, 7, 3709–3712; (m) Yao, L.; Shi, M. Eur. J. Org. Chem. 2009, 4036–
4040.
7. (a) Melpolder, J. B.; Heck, R. F. J. Org. Chem. 1976, 41, 265–272; (b) Chalk, A. J.;
Magennis, S. A. J. Org. Chem. 1976, 41, 273–278; (c) Tietze, L. F.; Kahle, K.;
Raschke, T. Chem. Eur. J. 2002, 8, 401–407; (d) Berthiol, F.; Doucet, H.; Santelli,
M. Tetrahedron 2006, 62, 4372–4383; (e) Crawley, M. L.; Phipps, K. M.; Goljer, I.;
Mehlmann, J. F.; Lundquist, J. T.; Ullrich, J. W.; Yang, C. J.; Mahaney, P. E. Org.
Lett. 2009, 11, 1183–1185.
8. (a) Liu, H.; Yu, J.; Wang, L.; Tong, X. Tetrahedron Lett. 2008, 49, 6924–6928; (b)
Fang, X.; Li, C.; Tong, X. Chem. Commun. 2009, 5311–5313; (c) Tong, X.; Beller,
M.; Tse, M. J. Am. Chem. Soc. 2007, 129, 4906–4907; (d) Tong, X.; Li, D.; Zhang,
Z.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 7601–7607.
9. (a) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287–1289; (b) Larock, R. C.;
Leung, W.-Y.; Stolz-Dunn, S. Tetrahedron Lett. 1989, 30, 6629–6632; (c) Taylor,
E. C.; Gillepsie, P.; Patel, M. J. Org. Chem. 1992, 57, 3218–3225; (d) Larock, R. C.;
Yum, E. K.; Yang, H. Tetrahedron 1994, 50, 305–321; (e) Basavaiah, D.;
Muthukumaran, K. Tetrahedron 1998, 54, 4943–4948.
10. (a) Majetich, G.; Grove, J. L. Org. Lett. 2009, 11, 2904–2907; (b) Majetich, G.;
Zou, G. Org. Lett. 2008, 10, 81–84; (c) Majetich, G.; Zou, G.; Grove, J. Org. Lett.
2008, 10, 85–87.
11. (a) Dyker, G.; Thöne, A. J. Prakt. Chem. 1993, 341, 138–141; (b) Dyker, G.;
Grundt, P. Tetrahedron Lett. 1996, 37, 619–622.