Et2MeN·hi-catalyzed reaction of arylboronic acids with 2-acyl-2,3-dihydro-4 h -pyrans leading to 2-aryltetrahydrocyclopenta[1,3,2] dioxaboroles

Article abstract of DOI:10.1055/s-0030-1260007

The reaction of arylboronic acids with 2-acyl-2,3-dihydro-4H-pyrans proceeded smoothly in the presence of a catalytic amount of Et₂MeNHI to give acyl-substituted 2-aryltetrahydrocyclopenta[1,3,2]dioxaboroles in good yields. The reaction is likely to involve the acid-catalyzed ring-opening reaction of pyrans, an intramolecular aldol reaction, and condensation with boronic acids. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260007

PAPER
1537
Et MeN⋅HI-Catalyzed Reaction of Arylboronic Acids with 2-Acyl-2,3-dihy-
2
dro-4H-pyrans Leading to 2-Aryltetrahydrocyclopenta[1,3,2]dioxaboroles
R
T
ing Contractio
a
n of 2-Acy
k
l-2,3-dihydro
a
-4
H
-pyran
h
s
ide Fukuyama,* Takahiro Okamura, Ilhyong Ryu
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
Fax +81(72)2549695; E-mail: fukuyama@c.s.osakafu-u.ac.jp
Received 8 October 2010; revised 5 November 2010
a catalytic amount of the amine salt, Et MeN·HI, further
accelerated boronic acid formation (entries 3–5), and im-
proved the yields of boronic ester 3a by up to 97% (entry
2
Abstract: The reaction of arylboronic acids with 2-acyl-2,3-dihy-
dro-4H-pyrans proceeded smoothly in the presence of a catalytic
amount of Et MeN·HI to give acyl-substituted 2-aryltetrahydrocy-
2
clopenta[1,3,2]dioxaboroles in good yields. The reaction is likely to 5). The reactions using p-toluenesulfonic acid and trifluo-
involve the acid-catalyzed ring-opening reaction of pyrans, an in- roacetic acid instead of Et MeN·HI gave 3a in 41% and
2
tramolecular aldol reaction, and condensation with boronic acids.
4
3% yield, respectively.
Key words: ring contraction, dihydropyran, boronic acid, cyclo-
pentanediol, boronic ester
Table 1 Ring Contraction Reaction of Dihydropyran 2a in the Pres-
ence of Phenylboronic Acid 1aa
O
The ring contraction reactions of easily available carbo-
and heterocyclic compounds are useful methods in organ-
ic synthesis. A variety of ring-contraction reactions have
PhB(OH)2
+
Ph
B
O
toluene
120 °C
O
O
1
O
1
a
2a
been developed thus far, which include Wolff rearrange-
3a
2
3
ment, Favorskii rearrangement, and Wagner–Meerwein
4
Entry Additive
Time (h) Yield (%)b
rearrangement, to name only a few. Many of these reac-
tions are widely employed in the total synthesis of natural
1
2
3
4
5
–
8
8
4
6
8
38
63
70
95
97
1
,5
products. During the course of our study on the devel-
opment of novel catalytic transformations using enones as
H O (1 equiv)
2
6
a substrate, we found that the 2-acetyl-6-methyl-2,3-di-
H O (1 equiv), Et MeN·HI (5 mol%)
2
2
hydropyran (2a; methyl vinyl ketone dimer) underwent
ring contraction in the presence of boronic acids 1 and a
H O (1 equiv), Et MeN·HI (5 mol%)
2
2
catalytic amount of Et MeN·HI to give boronic acid cis-
2
H O (1 equiv), Et MeN·HI (5 mol%)
2 2
cyclopentanediol esters 3 in high yield and stereoselectiv-
ity (Scheme 1). Herein, we have generalized the reaction
a
Conditions: 1a (0.5 mmol), 2a (0.5 mmol), toluene (2 mL), 120 °C.
Isolated yield after flash chromatography on SiO2.
b
and report a novel Et MeN·HI-catalyzed ring contraction
2
of acyl-substituted dihydropyrans leading to 2-aryltet-
rahydrocyclopenta[1,3,2]dioxaboroles.
Having identified optimal conditions, we then investigat-
ed the generality of the present ring contraction reaction,
and the results are shown in Table 2. p-Tolylboronic acid
O
Et2MeN⋅HI
(
1b) and p-methoxyphenylboronic acid (1c) also reacted
ArB(OH)2
Ar
B
+
O
with 2a to give the corresponding bicyclic boronic esters
3b and 3c in 88 and 85% yield, respectively (Table 2, en-
tries 2 and 3). Dihydropyran 2b, a dimer of ethyl vinyl ke-
tone, also worked well to give boronic ester 3d (entry 4).
Dihydropyrans 2c and 2d gave the corresponding bicyclic
boronic esters 3e and 3f in good yields (entries 5 and 6).
In the case of 2e having a terminal alkene moiety, the car-
bon–carbon double bond was tolerated to give boronic es-
ter 3g in 66% yield (entry 7).
O
O
O
1
2a
3
Scheme 1 Formation of boronic acid cis-cyclopentanediol esters
The reaction of phenylboronic acid (1a) with acyl-substi-
tuted dihydropyran 2a in toluene at reflux gave a 38%
yield of the phenylboronic ester of 1-acetyl-1,2-cylopen-
tanediol 3a (Table 1, entry 1). In this reaction, the cis-iso-
mer was formed selectively. The boronic ester formation
was accelerated in the presence of one equivalent of wa-
ter, which gave 3a in 63% yield (entry 2). The addition of
To gain some mechanistic insight into the present ring
contraction, we examined some control experiments.
When the reaction of 2a was carried out in the absence of
boronic acid, 2-hydroxy-1,6-diketone 5 was obtained in a
3
3% yield, whereas cyclic diol 4 was not formed
SYNTHESIS 2011, No. 10, pp 1537–1540
x
x.
x
x
.
2
0
1
1
(Scheme 2). The reaction of isolated 5 with phenylboronic
acid (1a) was tested with or without Et MeN·HI
Advanced online publication: 15.04.2011
DOI: 10.1055/s-0030-1260007; Art ID: F17510SS
Georg Thieme Verlag Stuttgart · New York
2
©

1
538
T. Fukuyama et al.
PAPER
(
Scheme 3). In both cases, boronic ester 3a was obtained, Scheme 4. An acid-catalyzed hydrative ring-opening re-
which strongly suggests the intermediacy of 5.
action would give 2-hydroxy-1,6-diketone 5. An intramo-
lecular aldol reaction of diol 6, the enol form of 5, would
give cis- and trans-cyclic diols 4. The trans-diol cannot
Taking this observation into consideration, we propose a
mechanism for the present reaction, which is shown in
Table 2 Et MeN·HI-Catalyzed Ring Contraction of 2-Acyl-Substituted Dihydropyrans 2 with Arylboronic Acids 1a
2
R2
Et2MeN⋅HI (5 mol%)
O
R1
+
ArB(OH)2
R2
Ar
B
O
H2O (1 equiv)
toluene
1
O
R1
3
O
120 °C, 6 h
O
2
Entry
1
1
1
1
2
3
Yield (%)b
95
O
O
OH
OH
B
B
O
O
O
O
O
a
2
2
2
a
3
3
a
O
O
OH
OH
B
B
2
3
88
85
O
O
b
a
b
O
OH
OH
MeO
B
MeO
B
O
O
O
1
c
a
3
c
O
O
OH
OH
B
B
B
4
5
B
70
75
O
O
O
1
1
a
2
2
b
c
3
3
d
e
O
O
OH
OH
B
O
O
O
O
a
a
O
O
OH
OH
B
Ph
81
66
6
O
O
1
1
2
2
d
Ph
3
f
O
O
B
OH
OH
7
B
O
O
O
a
e
3
g
a
Conditions: 1 (0.5 mmol), 2 (0.5 mmol), Et MeN·HI (5 mol%), H O (0.5 mmol), toluene (2 mL), 120 °C.
Isolated yield after flash chromatography on SiO2.
The reaction was conducted for 10 h.
2
2
b
c
Synthesis 2011, No. 10, 1537–1540 © Thieme Stuttgart · New York

PAPER
Ring Contraction of 2-Acyl-2,3-dihydro-4H-pyrans
1539
were recorded on a JEOL MS700 spectrometer. Dihydropyrans 2a
and 2b were prepared from methyl vinyl ketone and ethyl vinyl ke-
tone, respectively. Dihydropyrans 2c, 2d, and 2e were prepared
from 2a according to the reported method. The products were pu-
rified by flash chromatography on silica gel (Nacalai Tesque Inc.,
Silica Gel 60, 230–400 mesh).
OH
O
HO
HO
Et2MeNHI (5 mol%)
H2O (1.0 equiv)
O
7
toluene, 120 °C, 6 h
O
O
O
2a
5 33%
4 not formed
Scheme 2 Reaction of 2a with Et MeN·HI in the absence of boronic
acid
2
3
a-Acetyl-6a-methyl-2-phenyl-4H-tetrahydrocyclopen-
ta[1,3,2]dioxaborole (3a); Typical Procedure
Phenylboronic acid (1a; 0.5 mmol, 60.9 mg), dihydropyran (2a; 0.5
mmol, 70.4 mg), Et MeN·HI (5 mol%, 5.2 mg), H O (0.5 mmol, 9
OH
O
O
O
2
2
1a
+
B
mg), and toluene (2 mL) were placed in a screw-capped test tube.
The test tube was purged with argon and sealed. The mixture was
stirred at 120 °C for 6 h. After the reaction, the solvent was removed
under reduced pressure. The residue was purified by flash chroma-
tography on silica gel (hexane–EtOAc, 15:1) to give the boronic es-
toluene
1
20 °C, 6 h
O
5
3a
O
Et2MeN⋅HI (5 mol%)
without Et2MeN⋅HI
65%
54%
ter 3a as a colorless oil; yield: 115.8 mg (95%), R = 0.30 (hexane–
f
EtOAc, 15:1) (Table 2).
–
1
IR (neat): 1714 cm .
Scheme 3 Reaction of 5 with phenylboronic acid
1
H NMR (500 MHz, CDCl ): d = 1.36 (s, 3 H), 1.63–1.80 (m, 3 H),
3
1
.90–1.97 (m, 1 H), 2.06–2.10 (m, 1 H), 2.26–2.34 (m, 1 H), 2.35
(
s, 3 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.50–7.54 (m, 1 H), 7.85–7.89 (m,
+
H , H2O
R1
R1
2 H).
13
R2
R2
O
O
OH
C NMR (125 MHz, CDCl ): d = 22.38, 23.35, 28.14, 38.45, 41.77,
O
3
O
2
9
4.52, 98.55, 127.87, 127.91, 134.95, 211.62.
R2
MS (EI): m/z (%) = 244 (M , 20), 201 (100), 186 (41), 97 (71).
+
OH
O
OH
O
HO
R1
+
HRMS (EI): m/z calcd for C H BO (M ): 244.1271; found:
1
4
17
3
R1
R2
R2
244.1269.
HO
OH
O
R1
6
O
3
a-Acetyl-6a-methyl-2-(4-methylphenyl)-4H-tetrahydrocyclo-
5
trans-4
penta[1,3,2]dioxaborole (3b)
White solid; mp 69–70 °C; R = 0.25 (hexane–EtOAc, 20:1).
f
R2
IR (KBr): 1712 cm–1.
R2
O
HO
1
H NMR (500 MHz, CDCl ): d = 1.34 (s, 3 H), 1.61–1.76 (m, 3 H),
ArB(OH)2
3
Ar
B
1
.90–1.94 (m, 1 H), 2.04–2.06 (m, 1 H), 2.25–2.30 (m, 1 H), 2.32
–
H2O
O
HO
R1
(
s, 3 H), 2.40 (s, 3 H), 7.24 (d, J = 7.5 Hz, 2 H), 7.75 (d, J = 7.5 Hz,
R1
O
O
2 H).
1
3
3
C NMR (125 MHz, CDCl ): d = 21.73, 22.38, 23.34, 28.09, 38.43,
cis-4
3
4
1.80, 94.37, 98.47, 128.64, 128.74, 134.99, 141.94, 211.72.
Scheme 4 Possible mechanism for the Et MeN·HI-catalyzed ring
2
+
MS (EI): m/z (%) = 258 (M , 37), 215 (100), 200 (42), 187 (21), 119
(
contraction
25), 97 (92), 69 (22).
+
HRMS (EI): m/z calcd for C H BO (M ): 258.1427; found:
1
5
19
3
undergo condensation with boronic acids; hence, it reverts
back to 6. Eventually, the cis-diol would undergo conden-
sation with boronic acids to give cis-boronic esters 3.
2
58.1426.
3a-Acetyl-6a-methyl-2-(4-methoxyphenyl)-4H-tetrahydrocy-
clopenta[1,3,2]dioxaborole (3c)
White solid; mp 92–93 °C; R = 0.24 (hexane–EtOAc, 20:1).
In conclusion, we have developed a novel Et MeN·HI-
2
f
catalyzed ring contraction of 2-acyl-substituted 2,3-dihy-
dropyrans 2 in the presence of arylboronic acids 1 leading
to arylboronic acid cis-cyclopentanediol esters 3. A vari-
ety of boronic esters can be obtained from easily available
starting materials. The reaction would involve an acid-cat-
alyzed ring opening followed by an intramolecular aldol
reaction and condensation with boronic acids.
–
1
IR (KBr): 1710 cm .
1
H NMR (500 MHz, CDCl ): d = 1.33 (s, 3 H), 1.60–1.74 (m, 3 H),
.88–1.92 (m, 1 H), 2.03–2.08 (m, 1 H), 2.24–2.31 (m, 1 H), 2.32
s, 3 H), 3.84 (s, 3 H), 6.93 (d, J = 7.4 Hz, 2 H), 7.79 (d, J = 7.4 Hz,
3
1
(
2
H).
1
3
C NMR (125 MHz, CDCl ): d = 22.38, 23.34, 28.03, 38.40, 41.79,
5.10, 94.28, 98.41, 113.42, 113.53, 136.74, 162.45, 211.77.
3
5
+
MS (EI): m/z (%) = 274 (M , 46), 231 (46), 216 (100), 135 (25), 97
1
The H NMR spectra were recorded with a JEOL JMN-500 (500
(
71).
MHz) spectrometer in CDCl , and are referenced at 0.00 ppm for
3
+
1
3
HRMS (EI): m/z calcd for C H BO (M ): 274.1376; found:
TMS. Chemical shifts (d) are reported in ppm. C NMR spectra
were recorded with a JEOL JMN-500 (125 MHz) spectrometer in
CDCl and are referenced at 77 ppm for CDCl . IR spectra were ob-
tained on a JASCO FT/IR-4100 spectrometer; absorptions were re-
ported in cm . Both conventional and high resolution mass spectra
15 19
4
2
74.1372.
3
3
6
a-Ethyl-2-phenyl-3a-propanoyl-4H-tetrahydrocyclopen-
–1
ta[1,3,2]dioxaborole (3d)
Colorless oil; R = 0.30 (hexane–EtOAc, 20:1).
f
Synthesis 2011, No. 10, 1537–1540 © Thieme Stuttgart · New York

1
540
T. Fukuyama et al.
PAPER
–
1
IR (neat): 1713 cm .
1
(ddd, J = 18.8, 8.3, 6.4 Hz, 1 H), 2.92 (ddd, J = 18.8, 8.3, 6.0 Hz, 1
H), 4.90 (d, J = 10.5 Hz, 1 H), 4.98 (d, J = 17.0 Hz, 1 H), 5.75 (ddt,
J = 17.0, 10.5, 6.4 Hz, 1 H), 7.35 (t, J = 7.3 Hz, 2 H), 7.42–7.48 (m,
H NMR (500 MHz, CDCl ): d = 0.94 (t, J = 6.7 Hz, 3 H), 1.06 (t,
J = 6.4 Hz, 3 H), 1.47–1.58 (m, 1 H), 1.57–1.64 (m, 4 H), 1.67–1.72
m, 1 H), 1.75–1.79 (m, 1 H), 1.91–1.95 (m, 1 H), 2.06–2.11 (m, 1
H), 2.17–2.23 (m, 1 H), 2.67 (dq, J = 19.3, 6.4 Hz, 1 H), 2.84 (dq,
J = 19.3, 6.4 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 2 H), 7.51 (t, J = 7.4 Hz,
3
1
H), 7.79 (d, J = 7.2 Hz, 2 H).
(
1
3
C NMR (125 MHz, CDCl ): d = 22.37, 23.44, 27.11, 38.81, 39.33,
3
41.80, 94.66, 98.44, 115.31, 127.86, 131.66, 134.95, 137.14,
212.26.
1
H), 7.86 (d, J = 7.2 Hz, 2 H).
1
3
+
C NMR (125 MHz, CDCl ): d = 7.07, 8.55, 22.25, 29.57, 33.50,
MS (EI): m/z (%) = 284 (M , 22), 201 (100), 97 (59).
3
3
9.32, 39.46, 97.82, 98.53, 127.75, 126.78, 131.54, 134.93, 213.86.
+
HRMS (EI): m/z calcd for C H BO (M ): 284.1584; found:
1
7
21
3
+
MS (EI): m/z (%) = 272 (M , 26), 215 (100), 200 (34), 111 (52).
284.1587.
+
HRMS (EI): m/z calcd for C H BO (M ): 272.1584; found:
1
6
21
3
2
72.1583.
Acknowledgment
6
a-Methyl-2-phenyl-3a-propanoyl-4H-tetrahydrocyclopen-
We thank JSPS and MEXT for financial support of this work.
ta[1,3,2]dioxaborole (3e)
Colorless oil; R = 0.30 (hexane–EtOAc, 20:1).
f
References
–1
IR (neat): 1713 cm .
1
(1) For reviews on ring-contraction reactions, see:
H NMR (500 MHz, CDCl ): d = 1.06 (t, J = 6.78 Hz, 3 H), 1.31 (s,
3
(a) Redmore, D.; Gutsche, C. D. Carbocyclic Ring
3
2
H), 1.68–1.78 (m, 3 H), 1.90–1.96 (m, 1 H), 2.03–2.10 (m, 1 H),
Contraction Reactions, In Advances in Alicyclic Chemistry,
Vol. 3; Hart, H.; Karabastos, G. J., Eds.; Academic Press:
New York, 1971, 1–138. (b) Silva, L. F. Jr. Tetrahedron
.27–2.34 (m, 1 H), 2.58 (dq, J = 19.3, 6.8 Hz, 1 H), 2.88 (dq,
J = 19.3, 6.8 Hz, 1 H), 7.41 (t, J = 7.4 Hz, 2 H), 7.52 (t, J = 7.4 Hz,
H), 7.86 (d, J = 7.3 Hz, 2 H).
1
1
2002, 58, 9132.
3
C NMR (125 MHz, CDCl ): d = 7.10, 22.37, 23.39, 23.42, 33.34,
3
(2) For a review on Wolff rearrangement, see: Gill, G. B. The
Wolff Rearrangement, In Comprehensive Organic Synthesis,
Vol. 3; Trost, B. M.; Fleming, I., Eds.; Pergamon Press:
Oxford, 1991, 887–912.
3
8.65, 41.77, 94.53, 98.58, 127.81, 127.88, 131.60, 134.93, 213.54.
+
MS (EI): m/z (%) = 258 (M , 42), 201 (100), 200 (69), 105 (25), 97
(
94).
(
3) For a review on Favorskii rearrangement, see: Mann, J. The
Favorskii Rearrangement, In Comprehensive Organic
Synthesis, Vol. 3; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991, 839–859.
+
HRMS (EI): m/z calcd for C H BO (M ): 258.1427; found:
2
1
5
19
3
58.1423.
6
a-Methyl-2-phenyl-3a-(3-phenylpropanoyl)-4H-tetrahydrocy-
(
4) For a review on Wagner–Meerwein rearrangement, see:
Hanson, J. R. The Wagner-Meerwein Rearrangement, In
Comprehensive Organic Synthesis, Vol. 3; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 705–719.
clopenta[1,3,2]dioxaborole (3f)
Colorless oil; R = 0.30 (hexane–EtOAc, 20:1).
f
–1
IR (neat): 1712 cm .
1
(5) For recent examples on total synthesis of natural product
using ring contraction, see: (a) Jana, C. K.; Scopelliti, R.;
Gademann, K. Chem. Eur. J. 2010, 16, 7692. (b) Fu, L.;
Gribble, G. W. Tetrahedron Lett. 2010, 51, 537.
H NMR (500 MHz, CDCl ): d = 1.17 (s, 3 H), 1.58–1.70 (m, 3 H),
3
1
2
(
.83–1.87 (m, 1 H), 1.97–2.02 (m, 1 H), 2.18–2.28 (m, 1 H), 2.75–
.90 (m, 3 H), 3.10–3.16 (m, 1 H), 7.07–7.15 (m, 3 H), 7.17–7.22
m, 3 H), 7.33 (t, J = 7.4 Hz, 2 H), 7.43 (t, J = 7.9 Hz, 1 H), 7.76 (d,
(
c) Carnerio, V. M. T.; Ferraz, H. M. C.; Vieira, T. O.;
Ishikawa, E. E.; Silva, L. F. Jr. J. Org. Chem. 2010, 75,
877. (d) Lee, H.-Y.; Murugan, R. N.; Moon, D. K. Eur. J.
J = 7.9 Hz, 2 H).
1
3
C NMR (125 MHz, CDCl ): d = 19.98, 22.34, 23.23, 29.14, 38.84,
3
2
4
1
1.80, 94.64, 98.40, 126.00, 127.82, 128.35, 128.42, 131.64,
Org. Chem. 2009, 5028. (e) Silva, L. F. Jr.; Craveiro, M. V.
Org. Lett. 2008, 10, 5417. (f) Pouysegu, L.; Marguerit, M.;
Gagnepain, J.; Lyvinec, G.; Eatherton, A. J.; Quideau, S.
Org. Lett. 2008, 10, 5211. (g) Angeles, A. R.; Waters, S. P.;
Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 13765.
6) (a) Fukuyama, T.; Yamaura, R.; Higashibeppu, Y.;
Okamura, H.; Ryu, I.; Kondo, T.; Mitsudo, T. Org. Lett.
34.95, 141.00, 212.06.
+
MS (EI): m/z (%) = 334 (M , 18), 201 (100), 97 (64).
+
HRMS (EI): m/z calcd for C H BO (M ): 334.1740; found:
3
2
1
23
3
34.1737.
(
3
a-(But-4-enoyl)-6a-methyl-2-phenyl-4H-tetrahydrocyclopen-
2
005, 7, 5781. (b) Fukuyama, T.; Higashibeppu, Y.;
Yamaura, R.; Ryu, I. Org. Lett. 2007, 9, 587.
c) Fukuyama, T.; Doi, T.; Minamino, S.; Omura, S.; Ryu, I.
Angew. Chem. Int. Ed. 2007, 46, 5559.
(7) Chaquin, P.; Morizur, J.-P.; Kossanyi, J. J. Am. Chem. Soc.
977, 99, 903.
ta[1,3,2]dioxaborole (3g)
Colorless oil; R = 0.30 (hexane–EtOAc, 20:1).
f
(
–1
IR (neat): 1713 cm .
1
H NMR (500 MHz, CDCl ): d = 1.25 (s, 3 H), 1.59–1.74 (m, 3 H),
3
1
1
.85–1.88 (m, 1 H), 1.97–2.04 (m, 1 H), 2.17–2.34 (m, 3 H), 2.57
Synthesis 2011, No. 10, 1537–1540 © Thieme Stuttgart · New York