A coupling reaction between tetrahydrofuran and olefins by Rh-catalyzed/Lewis acid-promoted C-H activation

Article abstract of DOI:10.1016/j.tetlet.2008.05.057

A novel coupling reaction between tetrahydrofuran and olefins is discovered, in which the consecutive C-C and C-Cl bond-forming process takes place via Rh-catalyzed/lewis acid-promoted C-H activation. This reaction could be developed into a straightforward and effective method for rapid access to 2-(2-chloro-2-arylethyl)-tetrahydrofuran compounds.

Full text of DOI:10.1016/j.tetlet.2008.05.057

Tetrahedron Letters 49 (2008) 4652–4654
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A coupling reaction between tetrahydrofuran and olefins by
Rh-catalyzed/Lewis acid-promoted C–H activation
b
Ke Cao a, Yi-Jun Jiang a, Shu-Yu Zhang a, Chun-An Fan a, Yong-Qiang Tu a, , Yuan-Jiang Pan
*
a State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, PR China
b Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel coupling reaction between tetrahydrofuran and olefins is discovered, in which the consecutive
C–C and C–Cl bond-forming process takes place via Rh-catalyzed/lewis acid-promoted C–H activation.
This reaction could be developed into a straightforward and effective method for rapid access to 2-(2-
chloro-2-arylethyl)-tetrahydrofuran compounds.
Received 1 March 2008
Revised 8 May 2008
Accepted 13 May 2008
Available online 15 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
THF
C–H activation
Coupling reaction
Lewis acid
1. Introduction
Table 1
Optimization of reaction conditiona
The tetrahydrofuran (THF) moiety is the key structure feature
of a large number of biologically active natural products.1 Thus,
synthesis of substituted THF has long been attractive to organic
chemists. Recently, many groups have reported transition metal
catalyzed intramolecular cyclization and tandem addition–cycliza-
tion to achieve THF derivatives.2 However, direct transformation of
commercially available THF to THF derivates has been a challeng-
ing subject and has rarely been reported.3 In connection with our
recent interest in sp3 C–H bond activation of alcohols,4 we specu-
lated that the same transformation could occur on ethers.5 Among
the ethers we screened, cyclic ether (especially THF) coupled with
styrene successfully under the catalylsis of RhCl(PPh3)3 and the
promotion of TiCl4. To our surprise, an additional C–Cl bond was
formed during this course (Eq. 1). This interesting result provides
a direct and convenient procedure for preparation of 2-(2-chloro-
2-arylethyl)-tetrahydrofuran derivatives with synthetically useful
C–Cl bond, promoting us to investigate this cross-coupling protocol
in detail.
O
O
catalyst (0.05 eq.)
ð1Þ
+
Cl
3a
TiCl4, additive
70 oC
1a
2a
Entry
Catalyst
1a (equiv)
Additive (equiv)
% Yieldb (% Conv.)c
1d
2d
3d
4
5
6
7
8
9
10
RhCl(PPh3)3
—
50
50
50
50
50
50
50
20
40
40
—
—
21 (80)
—
33 (95)
56 (100)
—
RhCl(PPh3)3
RhCl(PPh3)3
Pd(OAc)2
Pd(PPh3)4
RhCl3
RhCl(PPh3)3
RhCl(PPh3)3
RhCl(PPh3)3
TBHP (0.5)
TBHP (1.1)
TBHP (1.1)
TBHP (1.1)
TBHP (1.1)
TBHP (1.1)
TBHP (1.1)
Bz2O2 (1.0)
—
Trace
23 (70)
65 (100)
16 (80)
a
Reaction condition: styrene 2a (1.0 mmol), THF 1a (20–50 mmol), catalyst
(0.05 mmol), TiCl4 (4.0 mmol), and TBHP (0.2 ml, ꢀ1.1 mmol, ꢀ5.5 M in decane) at
70 °C for 5 h.
b
Initially, the coupling of styrene with excessive THF was con-
ducted in the presence of a catalytic amount of RhCl(PPh3)3 and
two equivalents of TiCl4, wherein only 21% isolated yield with
80% reaction conversion was obtained (Table 1, entry 1). The de-
sired cross-coupling, however, did not proceed at all in the absence
of RhCl(PPh3)3, and only the polymerization of starting styrene was
Isolated yields based on the consumed styrene.
Reaction conversion determined by GC analysis.
Using 2 mmol of TiCl4.
c
d
observed (Table 1, entry 2). To our delight, when substoichiometric
amount of tert-butyl hydroperoxide (TBHP) was employed,6 both
reaction conversion and product yield were improved (Table 1,
entry 3). The yield increased to 56% when 4 equiv of TiCl4 and
1.1 equiv of TBHP were employed (Table 1, entry 4). However,
* Corresponding author. Fax: +86 931 8912582/5557.
E-mail address: tuyq@lzu.edu.cn (Y.-Q. Tu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.057

K. Cao et al. / Tetrahedron Letters 49 (2008) 4652–4654
4653
Bz2O2 was not effective in this coupling (Table 1, entry 10). Among
the catalysts further examined, RhCl3 gave trace amount of the
desired product (Table 1, entry 7), and the use of other transition
metal catalyst such as Pd(OAc)2 or Pd(PPh3)4 resulted in no reac-
tion (Table 1, entries 5 and 6). It should be noted that the THF load-
ing also has somewhat influence on this reaction (Table 1, entries 8
and 9), and currently the employment of 40 equiv of THF afforded
the best result with an increasing isolated yield of 65%. Among the
lewis acids investigated such as AlCl3, SnCl4 and SbCl5,7 only TiCl4
was found to be successful for this transformation.
compatible with this coupling reaction. Vinyl-substituted arenes
containing the electron-donating group proved to be effective
and the corresponding products 3 were formed in moderate to
good yields (entries 1–6). When a styrene bearing an electron-
withdrawing substituent such as para-chloro styrene was used
(entry 7); however, the starting alkene could not be consumed
completely, even with longer reaction time (8 h), giving product
3g only in 30% yield with 60% of the substrate recovered, which
clearly demonstrated the unfavorable electronic effect on the aro-
matic ring of styrene. Moreover, vinyl-substituted naphthalenes
(entries 8 and 9) and indene (entry 10) also proved to be effective,
and the desired products 3h–j were obtained in moderate yields. In
Based on the above-optimized conditions (Table 1, entry 9), the
scope of this reaction was then examined and different vinyl-
substituted arenes 2 were subjected to the reaction with 1. As
shown in Table 2, different substituents on the aromatic ring were
addition, reaction of a-methyl substituted styrene with THF 1a was
tested (entry 11), but the expected product was not obtained.
Instead, the terminal olefin 3k was formed through the kinetically
controlled elimination process. Furthermore, THP as a cyclic ether
was investigated in this coupling reaction, and the desired product
3l was obtained in a lower yield (35%). The dimerization of the
alkene was the main side reaction.8 However, while using 1,4-diox-
ane and 1,3,5-trioxane as cyclic ether, the coupling reaction did not
occur under the present conditions. Acyclic aliphatic ether such as
diethyl ether was not effective, affording the coupling product in
very low yield (ꢀ10%).
Table 2
Coupling reaction of olefins and ethersa
R1
O
O
RhCl(PPh3)3, TiCl4
TBHP, 70 oC
R1
+
( )n
( )n
Cl
1
2
3
Entry
1
Substrate
Product
% Yieldb
O
Ph
To propose a possible reaction mechanism, some supporting
experiments were then conducted. As shown in Scheme 1, the
known 2-chlorotetrahydrofuran 49 instead of THF was subjected
to the current coupling reaction, and the desired addition product
3d could be achieved in 91% yield, which partially demonstrated
that may be the alpha-C–H activation of THF was firstly involved
in this coupling reaction in the presence of catalyst RhCl(PPh3)3.
Additionally, it was found that addition of PPh3 (0.01 equiv) has a
large detrimental effect on the catalytic performance,7 implying
that the presence of PPh3 could prohibit the ligand dissociation
and exchange.
n = 1, R1 = Ph
65 (1:0.5)
3a
Cl
O
o
-C6H4Me
2
n = 1, R1 = o-C6H4Me
55 (1:0.5)
3b
Cl
O
O
O
O
O
m
-C6H4Me
3
4
5
6
7
n = 1, R1 = m-C6H4Me
n = 1, R1 = p-C6H4Me
n = 1, R1 = o-C6H4OMe
n = 1, R1 = m-C6H4OMe
n = 1, R1 = p-C6H4Cl
45 (1:0.7)
75 (1:0.5)
60 (1:0.7)
Cl
Cl
Cl
Cl
Cl
3c
p
-C6H4Me
3d
Based on the above experimental results, a tentative mecha-
nism was thus proposed in Scheme 2. Firstly, oxygen atom of
THF could preferentially coordinate with Lewis acid TiCl4,10 and
then Rh-catalyzed alpha-C–H activation of THF could take place
o-C6H4OMe
3e
m
-C6H4OMe
63 (1:0.8)
30(40)c (1:0.6)
Cl
O
3f
RhCl(PPh3)3
O
Cl
+
CH2Cl2 , rt, 1h
91%
p
-C6H4Cl
3g
4
3d
Scheme 1. Cross-coupling of 2-chlorotetrahydrofuran and p-methyl styrene. Using
5 mmol of 2-chlorotetrahydrofuran and 1 mmol of p-methyl styrene in 4 mL CH2Cl2.
O
O
2-naphthyl
8
9
n = 1, R1 = 2-naphthyl
n = 1, R1 = 1-naphthyl
56 (1:0.9)
50 (1:0.9)
3h
Cl
Cl
O
+
TiCl4
1-naphthyl
O
Cl
O
TiCl4
A
3i
R1
3
Cl
RhCl(PPh3)3
O
10d
11d
n = 1, Indene
51
-L
L
3j
H
Rh Cl
Cl L2
Rh
TiCl4
O
O
O
O
TiCl4
L = PPh3
Ph
3k
L2
R1
n = 1,
a
-methyl styrene
54
Cl
E
C
p
-C6H4Me
TiCl4 + tBuOOH
12d
n = 2, R1 = p-C6H4Me
35 (1:0.8)
3l
Cl
L2
Rh Cl
Cl
a
Standard reaction conditions
1 (40.0 mmol), 2 (1.0 mmol), RhCl(PPh3)3
H2O + TiCl3(OtBu)
R1
O
(0.05 mmol), TiCl4 (4.0 mmol) and TBHP (0.2 ml, ꢀ1.1 mmol) at 70 °C for 5 h.
b
Isolated yields calculated on the basis of alkene 2; the ratio of two diastereoi-
TiCl4
D
somers determined by 1H NMR is given in parentheses.
c
Substrate conversion determined by GC analysis.
Using 2.0 mmol of TiCl4 (1.0 M in CH2Cl2).
d
Scheme 2. Proposed mechanism on the coupling of tetrahydrofuran and olefins.

4654
K. Cao et al. / Tetrahedron Letters 49 (2008) 4652–4654
through intermediate C followed by the cooperation of TiCl4 and
TBHP, generating the key species D. During this process, TBHP
may act as an effective hydride acceptor11 to accelerate the C–H
activation from C to D.12 Subsequently, the alkene coordination/
insertion into the Rh–Cl bond13 in a less hindered fashion could
afford the intermediate E, which could undergo reductive elimina-
tion to provide the desired product 3 with the release of Rh(I)
catalyst into the next cycle.
In conclusion, we have developed a novel Rh-catalyzed/Lewis
acid-promoted coupling reaction between THF and vinyl-substi-
tuted arenes. This reaction may proceed via a process including
the alpha-C–H activation of THF and successive C–C bond and
C–Cl bond formation. A series of 2-(2-chloro-2-arylethyl)-tetrahy-
drofuran have been synthesized from simple and readily available
starting materials. Further studies toward the insight into the
reaction mechanism, the expansion of the substrate scope and
the synthetic application is currently ongoing in our group.
References and notes
1. (a) Westley, J. W. In Polyether Antibiotics: Naturally Occurring Acid
lonophoresIonophores; Marcel Dekker: New York, 1982; Vols. I and II; (b)
Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–540; (c)
Harmange, J. C.; Figadere, B. Tetrahedron: Asymmetry 1993, 4, 1711–1754.
2. (a) Hoffman-Röder, A.; Krause, N. Org. Lett. 2001, 3, 2537–2538; (b) Wolfe, J. P.;
Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620–1621; (c) Qian, H.; Han, X.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 9536–9537; (d) Yao, T.; Zhang,
X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164–11165; (e) Sromek, A. W.;
Kel’in, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2004, 43, 2280–2282; (f)
Hashmi, A. S. K.; Sinha, P. Adv. Synth. Catal. 2004, 346, 432–438; (g) Yang, C. G.;
Reich, N. W.; Shi, Z.; He, C. Org. Lett. 2005, 7, 4553–4556; (h) Antoniotti, S.;
Genin, E.; Michelet, V.; Genêt, J.-P. J. Am. Chem. Soc. 2005, 127, 9976–9977; (i)
Jung, H. H.; Floreancig, P. E. Org. Lett. 2006, 8, 1949–1951; (j) Belting, V.; Krause,
N. Org. Lett. 2006, 8, 4489–4492.
3. (a) Xiang, J.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118, 11986–11987; (b) Clark, A.
J.; Rooke, S.; Sparey, T. J.; Taylor, P. C. Tetrahedron Lett. 1996, 37, 909–912; (c)
Xiang, J.; Jiang, W.; Gong, J.; Fuchs, P. L. J. Am. Chem. Soc. 1997, 119, 4123–4129;
(d) Davies, H. M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122,
3063–3070; (e) Díaz-Requejo, M. M.; Belderra´ın, T. R.; Nicasio, M. C.;
Trofimenko, S.; Pérez, P. J. J. Am. Chem. Soc. 2002, 124, 896–897; (f) Hirano,
K.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2002, 43, 3617–3620; (g) Jang, Y. J.;
Shih, Y. K.; Liu, J. Y.; Kuo, W. Y.; Yao, C. F. Chem. Eur. J. 2003, 9, 2123–2128; (h)
Zhang, Y.; Li, C. J. Tetrahedron Lett. 2004, 45, 7581–7584; (i) Albone, D. P.;
Challenger, S.; Derrick, A. M.; Fillery, S. M.; Irwin, J. L.; Parsons, C. M.; Takada,
H.; Taylor, P. C.; Wilson, D. J. Org. Biomol. Chem. 2005, 3, 107–111; (j) Fructos, M.
R.; Trofimenko, S.; Díaz-Requejo, M. M.; Pérez, P. J. J. Am. Chem. Soc. 2006, 128,
11784–11791; (k) He, L.; Yu, J.; Zhang, J.; Yu, X. Q. Org. Lett. 2007, 9, 2277–2280.
4. For Rh-catalyzed sp3 C–H bond activation see: (a) Shi, L.; Tu, Y. Q.; Wang, M.;
Zhang, F. M.; Fan, C. A.; Zhao, Y. M.; Xia, W. J. J. Am. Chem. Soc. 2005, 127,
10836–10837; (b) For Pd-catalyzed sp3 C–H bond activation see: Jiang, Y. J.; Tu,
Y. Q.; Zhang, E.; Zhang, S. Y.; Cao, K.; Shi, L. Adv. Synth. Catal. DOI: 10.1002/
adsc.200700439.
2 General procedure
To the freshly distilled cooled (ꢁ78 °C) THF (3.2 mL, 40.0 mmol)
was added TiCl4 (4.4ꢂ10ꢁ1 mL, 4.0 mmol) carefully under argon.
The resulting light yellow mixture was stirred and warmed to
0 °C within 30 min, then RhCl(PPh3)3 (46.3 mg, 0.5ꢂ10ꢁ1 mmol),
styrene (117.0
lL, 1.0 mmol), and TBHP (0.2 mL, ꢀ1.1 mmol) were
sequentially added. After the reaction mixture was stirred at 70 °C
until the substrate was consumed completely (ꢀ5 h), the reaction
mixture was cooled to rt and filtered through a short silica gel col-
umn using CH2Cl2/Et2O as eluent. After evaporation of the solvent,
the residue was purified by flash chromatography (petroleum
ether/AcOEt = 20:1) to afford 3a (136.5 mg, 65% yield, diastereo-
meric ratio 1:0.5).
5. For Ir-catalyzed sp3 C–H bond activation of ether see: (a) Lin, Y.; Ma, D.; Lu, X.
Tetrahedron Lett. 1987, 28, 3249–3252. For Lewis acid catalyzed sp3 C–H bond
activation of ether see: (b) Pastine, S. J.; McQuaid, K. M.; Sames, D. J. Am. Chem.
Soc. 2005, 127, 12180–12181.
6. Caution! Mixing a metal salt and peroxide can cause an explosion.
7. For details, see Supplementary data.
8. Tsuchimoto, T.; Kamiyama, S.; Negoro, R.; Shirakawa, E.; Kawakami, Y. Chem.
Commun. 2003, 852–853.
9. Fuchigami, T.; Sato, T.; Nonaka, T. J. Org. Chem. 1986, 51, 366–369.
10. Shi, M.; Jiang, J. K.; Cui, S. C. Tetrahedron 2001, 57, 7343–7347.
11. Li, Z.; Bohle, D. S.; Li, C. J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928–8933 and
reference cited therein.
12. D might also be the active intermediate from 4 to 3d in supporting experiment
in Scheme 1.
13. For allene insertion into Pd–Cl bond see: (a) Hegedus, L. S.; Kambe, N.; Tamura,
R.; Woodgate, P. D. Organometallics 1983, 2, 1658–1661. For alkyne insertion
into Rh–Cl bond see: (b) Hua, R.; Shimada, S.; Tanaka, M. J. Am. Chem. Soc. 1998,
120, 12365–12366; (c) Kashiwabara, T.; Kataoka, K.; Hua, R.; Shimada, S.;
Tanaka, M. Org. Lett. 2005, 7, 2241–2244.
Acknowledgements
This work was supported by the NSFC (Nos. 20621091,
20672048, 20732002) and the Chang Jiang Scholars program.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.057.