Tandem five membered-ring selective Prins reaction and Friedel-Crafts reaction

Article abstract of DOI:10.1016/j.tetlet.2011.12.113

A tandem reaction consisting of five membered-ring selective Prins cyclization and subsequent Friedel-Crafts cyclization was developed. The reactions of phenyl homoallylic alcohol 3 and benzaldehyde derivatives 6 afforded tetrahydroindenofurans 7 or penta

Full text of DOI:10.1016/j.tetlet.2011.12.113

Tetrahedron Letters 53 (2012) 1337–1340
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Tetrahedron Letters
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Tandem five membered-ring selective Prins reaction and Friedel–Crafts reaction
Yuji Suzuki a, Takanori Niwa a, Eiko Yasui a, Megumi Mizukami b, Masaaki Miyashita a, Shinji Nagumo a,
⇑
a Department of Applied Chemistry, Kogakuin University, Nakano 2665-1, Hachioji, Tokyo 192-0015, Japan
b Hokkaido Pharmaceutical University, School of Pharmacy, Katsuraoka 7-1, Otaru 047-0264, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A tandem reaction consisting of five membered-ring selective Prins cyclization and subsequent Friedel–
Crafts cyclization was developed. The reactions of phenyl homoallylic alcohol 3 and benzaldehyde deriv-
atives 6 afforded tetrahydroindenofurans 7 or pentacyclic products 8, depending upon the quantity of 6.
Also homoallylic alcohol 12 having an alkyne–cobalt moiety reacted with 6 to give rise to tetra-
hydroindenofurans 13 in good yields.
Received 5 December 2011
Revised 24 December 2011
Accepted 26 December 2011
Available online 8 January 2012
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tandem cyclization
Five membered-ring selective Prins
cyclization
Friedel–Crafts cyclization
Phenyl homoallylic alcohol
Alkyne–cobalt complex
The Prins cyclization, which is a facile coupling of a homoallylic
alcohol and an aldehyde promoted by an acid catalyst, has been ap-
plied to the stereoselective synthesis of many natural products hav-
ing a tetrahydropyran ring.1 Recently, several tandem cyclizations
including the Prins cyclization have been developed, wherein annu-
lated tetrahydropyran derivatives were obtained.2 Reddy and Yadav
et al. reported a tandem Prins/Friedel–Crafts cyclization furnishing
polycyclic compounds containing a tetrahydropyran ring.2a The
exclusive formation of tetrahydropyrans observed in many exam-
ples of the Prins reaction is attributed to the transition state taking
a chair form, which is more stable than that of a tetrahydrofuran
ring formation. On the contrary, reversal of the relative stability
between six membered and five membered transition states makes
it possible to form tetrahydrofuran derivatives exclusively. In fact,
the reaction of tri-substituted alkene prefers the formation of tetra-
hydrofuran to tetrahydropyran derivative.3 Although di-substituted
E-homoallylic alcohol usually undertakes the preferential formation
of tetrahydropyran, the reaction of Z-homoallylic alcohol has been
reported to give a mixture of tetrahydropyran and tetrahydrofuran.4
The ring-size selectivity in products has often been controlled by
linking a suitable functional group stabilizing carbocation interme-
diates to an alkene. For example, treatment of allylsilane 1 with
Ce(NBu4)4(NO3)6 (CTAN) resulted in the preferential formation of
tetrahydrofuran 2 (Scheme 1).5
CTAN
83%
O
O
O
O
TMS
TMS
TMS
SnBu3
Bn
Bn
Bn
Bn
1
2
9-anthrylCHO
SnBr4, TMSBr
salicylaldehyde
SnCl4
H
O
H
O
OH
O
-78 °C
92%
H
H
3
Ph
88%
Ph
4
5
Scheme 1. Five membered-ring selective Prins reaction.
⇑
Corresponding author.
E-mail address: bt13071@ns.kogakuin.ac.jp (S. Nagumo).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.113

1338
Y. Suzuki et al. / Tetrahedron Letters 53 (2012) 1337–1340
Table 1
Tandem cyclization of the phenyl homoallylic alcohol 3 and benzaldehyde 6
H
R1
R2
O
R2
R1
R2
BF3 . OEt2
CH2Cl2
R1
R3
OMe
R3
H
H
+
R3
R2
OH
R3
H
H
O
H
O
O
H
H
R1
7b, d-g
6a-g
8d-e
3
7b'
Entry
Aldehyde
Equiv
Time
Temp.
Product (yield)
1
2
3
4
5
6
7
8
9
6a (R1 = R2 = R3 = H)
1.3
1.3
1.3
1.3
1.3
1.3
1.3
3
15 min
1 h
15 min
3 h
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
rt
Complex mixture
7b (87%)
Complex mixture
7d (82%)
7e (82%)
7f (92%)
6b (R1 = OMe, R2 = R3 = H)
6c (R2 = OMe, R1 = R3 = H)
6d (R1 = R2 = OMe, R3 = H)
6e (R1 = R2 = OEt, R3 = H)
6f (R1 = R3 = OMe, R2 = H)
6g (R1 = R2 = R3 = OMe)
6d (R1 = R2 = OMe, R3 = H)
6e (R1 = R2 = OEt, R3 = H)
7b0 (6%)
8d (7%)
8e (5%)
2 h
15 min
15 min
85 h
7g (90%)
8d (86%)
8e (84%)
3
65 h
rt
Table 1 summarizes the tandem cyclizations of the phenyl
NOE for 8d
homoallylic alcohol 37 and various benzaldehyde derivatives. At
first, we carried out the reaction of 3 (1 equiv) with 6 (1.3 equiv)
in the presence of BF3ꢀOEt2 (3 equiv)8 in CH2Cl2 at 0 °C (entries
1–7).9 Thus, m-methoxybenzaldehyde 6b reacted with 3 smoothly
to afford a regioisomeric mixture of tetrahydroindenofurans 7b10
NOE for 7b
H
15.9%
O
OMe
OMe
OMe
H
H
O
8b
2
Ph
3a
H
4
3
H
10
H
(87%) and 7b0 (6%) (entry 2). On the other hand, treatment of
H
Ph
H
6.7%
7%
benzaldehyde 6a or p-methoxybenzaldehyde 6c under the same
conditions resulted in a complex mixture (entries 1 and 3). There-
fore, the presence of an electron donating group at the C30 position
is essential for the formation of tetrahydroindenofuran. Similarly,
benzaldehydes 6d–g (1.3 equiv) bearing a m-methoxy group re-
acted with 3 to give rise to tetrahydroindenofurans 7d–g10 (entries
4–7) in high yields. Notably, the reactions of 6f and 6g having two
methoxy groups at both the C30 and C50 positions were very fast.
The configuration of a phenyl group was found to be b by NOE
MeO
OMe
Figure 1. NOE correlations of 7b and 8d.
We were interested in a phenyl group and an alkyne–dicobalt
complex as an alternative functional group stabilizing five mem-
bered-ring transition state of the Prins reaction. Furthermore, if
the cation intermediate formed by five membered-ring formation
has a nucleophilic functional group at the other site, the second
cyclization may occur to give a polycyclic system. Just when we
started our project based on such concept, Spivey et al. reported
the polycyclization of phenyl homoallyl alcohol 3 and 9-anthra-
ldehyde or salicylaldehyde.6 We wish to report herein a tandem
five-membered Prins/five-membered Friedel–Crafts cyclization of
homoallylic alcohols linked to a phenyl group or an alkyne–dico-
balt complex and various benzaldehyde derivatives.
correlations between H3a-H3b (7%) and H3 -H4 (6.7%) as shown
a
in Figure 1. The reaction mechanism of the present tandem cycliza-
tion is shown in Scheme 2. At first, the Prins cyclization of 3 and 6
occurred via a five-membered transition state to form trans-cation
B and cis-cation C, which were stabilized by a phenyl group,
respectively. Since the 5-5 bicyclo rings are hard to take trans
juncture, only the cation C in the equilibriums between B and C
can undergo subsequent Friedel–Crafts reaction to form the
OMe
O
OMe
MeO
OMe
Ph
B
MeO
OMe
CHO
MeO
MeO
6f
HO
3'
O
5'
OMe
OMe
H
O
O
Ph
A
H
3
C
7f
5-ring selective Prins reaction
Friedel-Crafts reaction
Scheme 2. Mechanism for the formation of 7.

Y. Suzuki et al. / Tetrahedron Letters 53 (2012) 1337–1340
1339
H
OHC
OMe
OMe
Ph
Ph
Ph
OBF3
OBF3
O
BF3
MeO
MeO
MeO
OMe
7d
OMe
D
OMe
E
H
H
O
O
O
OMe
OMe
Ph
Ph
Ph
H
OMe
OMe
OMe
OMe
MeO
MeO
MeO
OMe
OMe
OMe
F
G
8d
Scheme 3. Mechanism for the formation of 8.
TMS
OH
Co(CO)3
Co(CO)3
TMS
(Ph3P)2PdCl2
CuI, HNiPr2
Co2(CO)8
CH2Cl2
I
TMS
OH
OH
+
0 °C to rt
72%
9
10
11
12
Scheme 4. Preparation of the homoallylic alcohol 12 linked to alkyne dicobalt complex.
corresponding tetrahydroindenofurans 7. The two methoxy groups
at the C30 and C50 positions in C have remarkable accelerating ef-
fect on the subsequent Friedel–Crafts cyclization.
Scheme 3 shows the tentative mechanism for the conversion of
7d into 8d. The reaction started by coordination of BF3 to the oxy-
gen atom on the furan ring of 7d. The methoxy group at the C6
position in 7d might accelerate fragmentation of the C–O bond
leading to D, which was further transformed into E by deprotona-
tion concomitant with aromatization. The intermediate E, which is
a kind of homoallylic alcohol linked to an aryl group, was further
converted into 8d by the sequential Prins and Friedel–Crafts cycli-
zation through intermediates F and G.
Complexation of an alkyne with dicobalt hexacarbonyl Co2(CO)6
has been known to remarkably stabilize cations of a-carbon atom
adjacent to an alkyne moiety. The Nicholas reaction, a coupling
reaction of Co2(CO)6 stabilized cations and nucleophiles, has been
widely used in organic synthesis.11 The alkyne–cobalt complex
Interestingly, a small amount of pentacyclic compounds 8d–e10
were also obtained in the reactions of benzaldehydes bearing a
methoxy group at the C40 position (entries 4 and 5). We confirmed
that indenofuran 7d reacted with 6d very slowly in the presence of
BF3ꢀOEt2 to furnish 8d. On the contrary, the reaction of 7b with 6b
did not occur at all. Based on these results, we investigated the tan-
dem cyclization of 3 with three equivalents of 6d–e in the presence
of BF3ꢀOEt2 in CH2Cl2 at room temperature (entries 8 and 9). In
both cases, pentacyclic compounds 8d–e were obtainable in good
yields as we expected. The stereochemistry of 8d was unambigu-
ously determined by NOE measurements as shown in Figure 1.
Table 2
Tandem cyclization of the homoallylic alcohol 12 and benzaldehyde 6
R2
R2
R3
R1
R1
R3
TMS
OH
Co(CO)3
Co(CO)3
BF3 . OEt2
CH2Cl2
Co(CO)3
Co(CO)3
+
O
O
H
12
0 °C
6d-g (1.2 eq.)
TMS
R2
R2
R1
R1
R3
TMS
R3
TMS
H
H
Co(CO)3
Co(CO)3
Co(CO)3
Co(CO)3
O
O
H
H
13d-g
Entry
Aldehyde
Time (h)
Product (yield)
1
2
3
4
6d (R1 = R2 = OMe, R3 = H)
6e (R1 = R2 = OEt, R3 = H)
6f (R1 = R3 = OMe, R2 = H)
6g (R1 = R2 = R3 = OMe)
6
2
4
4
13d (83%)
13e (76%)
13f (66%)
13g (89%)

1340
Y. Suzuki et al. / Tetrahedron Letters 53 (2012) 1337–1340
5. Chen, C.; Mariano, P. S. J. Org. Chem. 2000, 65, 3252.
6. Spivey, A. C.; Laraia, L.; Bayly, A. R.; Rzepa, H. S.; White, A. J. P. Org. Lett. 2010,
12, 900.
7. Compound 3 was prepared by reduction of trans-styrylacetic acid (Aldrich)
with LiAlH4.
was also known to increase the reactivity at the b position of the
neighboring alkene.12 We thus tried the tandem cyclization of
homoallylic alcohol 1210 linked to an alkyne dicobalt complex with
benzaldehyde derivatives. Compound 12 was easily accessible by
treatment of eneyne 11, which was prepared according to the Stol-
tz method,13 with Co2(CO)8 in CH2Cl2 (Scheme 4). As we expected,
12 reacted with aldehydes 6d–g in the presence of BF3ꢀOEt2 in
CH2Cl2 to form tetrahydroindenofurans 13d–g10 having an alkyne
dicobalt moiety in good yields (Table 2). On the other hand, when
11 was treated with 6f under the same conditions, aldehyde 6f was
recovered and 11 was decomposed. Thus, an alkyne–dicobalt com-
plex was also found to serve as an efficient functional group for the
tandem Prins and Friedel–Crafs cyclization.
In conclusion, we have developed the novel tandem cyclizations
of homoallylic alcohols linked to a phenyl group or an alkyne–
dicobalt complex with various benzaldehydes. The tandem
cyclization of 3 with benzaldehyde 6 (1.3 equiv) afforded the tetra-
hydroindenofurans 7 as the major product. On the other hand, the
reaction of 3 with an excess amount of 6 gave rise to pentacyclic
compounds 8 containing a furan ring by repeating the sequential
five membered-ring selective Prins and Friedel–Crafts cyclization
twice. Also, the tandem reaction of 12 with benzaldehydes
proceeded smoothly to afford tetrahydroindenofurans 13 having
an alkyne dicobalt moiety. Further synthetic application of the
present tandem reaction is now in progress.
8. Two equivalents or less of BF3ꢀEt2O was not enough to complete the tandem
cyclization of 3 and 6b.
9. Typical procedure of the tandem cyclization is as follows. To a solution of 3
(0.6 mmol) and 6 (1.3 or 3 equiv) in CH2Cl2 (3 ml) was added BF3ꢀOEt2 (3 equiv)
at 0 °C or room temperature. The mixture was further stirred for hours or
minutes shown in Table, quenched with sat NaHCO3 aq, extracted with AcOEt,
and washed with sat NaCl aq. The organic layer was concentrated under
reduced pressure. The residue was purified by column chromatography on
silica gel to give 7 or 8. If polarities of product and 6 are close, the crude was
subjected to column chromatography on silica gel after treatment with NaBH4
in MeOH.
10. All newly synthesized compounds gave spectroscopic data in agreement with
the assigned structures. Representative data are shown below. Compound 7b:
IR (film) 2941, 2864, 1609, 1491, 1254 cmꢁ1; HRMS calcd for C18H18O2 (M+)
266.1307, found 266.1287; 1H NMR (CDCl3, 400 MHz) d 7.29 (m, 2H), 7.21 (m,
1H), 7.08 (m, 2H), 7.00 (d, J = 2.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.83 (dd,
J = 8.0, 2.0 Hz, 1H), 5.57 (d, J = 6.8 Hz, 1H), 4.16 (d, J = 3.6 Hz, 1H), 3.94 (m, 1H),
3.82 (s, 3H), 3.78 (dt, J = 8.0, 6.4 Hz, 1H), 3.08 (m, 1H), 2.24 (m, 1H), 1.94 (m,
1H); 13C NMR (CDCl3, 100 MHz) d 159.61 (4°), 145.95 (4°), 143.44 (4°), 138.18
(4°), 128.58 (3°, 2C), 127.51 (3°, 2C), 126.35 (3°), 126.08 (3°), 116.55 (3°), 109.05
(3°), 86.64 (3°), 67.64 (2°), 56.73 (3°), 55.34 (1°), 53.55 (3°), 33.82 (2°).
Compound 8d: IR (KBr) 2932, 2882, 2832, 1501 cmꢁ1
; HRMS calcd for
C28H28O5 (M+) 444.1937, found 444.1927; 1H NMR (CDCl3, 400 MHz) d 7.33
(m, 2H), 7.26 (m, 1H), 7.09 (br m, 2H), 6.94 (s, 1H), 6.91 (s, 1H), 6.87 (s, 1H),
6.51 (s, 1H), 5.31 (s, 1H), 4.55 (s, 1H), 4.51 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.87
(s, 3H), 3.87 (m, 1H), 3.72 (s, 3H), 3.66 (dt, J = 8.24, 6.4 Hz, 1H), 1.72 (ddd,
J = 12.8, 6.4, 4.6 Hz, 1H), 1.58 (m, 1H); 13C NMR (CDCl3, 100 MHz) d 150.24 (4°),
149.35 (4°), 149.18 (4°), 148.99 (4°), 142.95 (4°), 136.80 (4°), 136.66 (4°), 136.11
(4°), 133.31 (4°), 128.94 (3°), 128.51 (3°, 2C), 126.71 (3°, 2C), 108.37 (3°), 108.04
(3°), 106.60 (3°), 106.57 (3°), 93.86 (3°), 68.66 (4°), 68.22 (2°), 60.52 (3°), 58.03
(3°), 56.19 (1°), 56.06 (1°), 55.92 (1°, 2C), 35.06 (2°).
References and notes
11. Review on Nicholas reaction, see: Teobald, B. J. Tetrahedron 2002, 58, 4133.
12. For example, to see: (a) Mikami, K.; Feng, F.; Matsueda, H.; Yoshida, A.;
Grierson, D. S. Synlett 1996, 833; (b) Smyth, G. D.; Ohmura, H.; Mikami, K.
Synlett 2001, 509; (c) Kitamura, M.; Ohmori, K.; Suzuki, K. Tetrahedron Lett.
1999, 40, 4563.
1. Review on Prins cyclization, see: Olier, C.; Kaafarani, M.; Gastaldi, S.; Bertrand,
M. P. Tetrahedron 2010, 66, 413.
2. For example, to see: (a) Reddy, B. V. S.; Borkar, P.; Yadav, J. S.; Sridhar, B.; Grée,
R. J. Org. Chem. 76, 7677.; (b) Yadav, J. S.; Chakravarthy, P. P.; Borkar, P.; Reddy,
B. V. S.; Sarma, A. V. S. Tetrahedron Lett. 2009, 50, 5998.
13. Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778.
3. Loh, T.-P.; Hu, Q.-Y.; Tan, K.-T.; Cheng, H.-S. Org. Lett. 2001, 3, 2669.
4. Yang, X.-F.; Mague, J. T.; Li, C.-J. J. Org. Chem. 2001, 66, 739.