Synthesis of 2-hydroxymethyl-2,3-dihydrobenzofurans

Article abstract of DOI:10.3987/COM-14-13030

A one-pot protocol toward 2-hydroxymethyl-2,3-dihydrobenzofurans (1) starting with oxygenated o-allylbenzaldehydes (3) was described. The facile one-pot process was carried out by the oxidation of o-allylbenzaldehydes (3) with Oxone in the co-solvent of acetone and DMF in the presence of aqueous EDTA solution and then intramolecular ring-closure of the resulting o-allylphenols (2) in acceptable yields.

Full text of DOI:10.3987/COM-14-13030

HETEROCYCLES, Vol. 89, No. 8, 2014
1905
HETEROCYCLES, Vol. 89, No. 8, 2014, pp. 1905 - 1912. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 17th May, 2014, Accepted, 16th June, 2014, Published online, 20th June, 2014
DOI: 10.3987/COM-14-13030
SYNTHESIS OF 2-HYDROXYMETHYL-2,3-DIHYDROBENZOFURANS
Meng-Yang Chang,* Shin-Ying Lin, and Chieh-Kai Chanp
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung 807, Taiwan. Email: mychang@kmu.edu.tw
Abstract – A one-pot protocol toward 2-hydroxymethyl-2,3-dihydrobenzofurans
(1) starting with oxygenated o-allylbenzaldehydes (3) was described. The facile
one-pot process was carried out by the oxidation of o-allylbenzaldehydes (3) with
Oxone in the co-solvent of acetone and DMF in the presence of aqueous EDTA
solution and then intramolecular ring-closure of the resulting o-allylphenols (2) in
acceptable yields.
Functionalized 2,3-dihydrobenzofurans (coumaran) have been studied extensively since this ring system
possesses various potential biological and pharmaceutical Substituted
activities.1-3
2-hydroxymethyl-2,3-dihydrobenzofuran (1) is an important core structure of naturally occurring oxygen
heterocycles.4 Thus, some synthetic routes to access this scaffold have been developed.5 Among these
methods, m-CPBA/K2CO3 system-mediated intramolecular cyclization of o-allylphenol (2) is the most
frequently employed method for generating the skeleton of 2,3-dihydrobenzofuran with a
C2-hydroxymethyl group (Scheme 1). In the course of our efforts with the application of
o-allylbenzaldehyde (3),6 the Oxone-mediated synthesis of skeleton (1) with oxygenated groups on the
benzene ring position was chosen as the key focus.
R
R
3
R
Oxone
m-CPBA,
K CO
2
K CO , EDTA
O
2
3
2
3
OH
CHO
OH
(our work)
3
1
2
Scheme 1. Route toward skeleton (1)
Oxone (2KHSO5·KHSO4·K2SO4) is a mild, stable, non-toxic, inexpensive, easy-operation, and
environmentally benign oxidation regent.7 It has largely been employed as the co-oxidant in the presence
of a metal catalyst for a variety of oxidation transformations.8,9 Webb and Ruszkay reported that
treatment of electron-withdrawing and electron-neutral aromatic aldehydes with Oxone afforded

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HETEROCYCLES, Vol. 89, No. 8, 2014
carboxylic acids. However, when electron-donating substrates, such as p-anisaldehyde, salicylaldehyde or
piperonal, were reacted with Oxone, p-methoxyphenol, catechol or sesamol were isolated.9a This
observation was noted by Borhan9b and Chang,9c as shown in Scheme 2. The majority of electron-rich
benzaldehydes was converted to Dakin products.10 For Oxone-mediated oxidation of non-aromatic
ketones, Baeyer-Villiger esterification was a major route.11 With this idea in mind, treatment of
o-allylbenzaldehyde 3a with the 3,4-dimethoxy group was examined.
OMe
OMe
9a-b
9a-b
9a,c
Oxone
(58%)
Oxone
(85-97%)
Oxone
(79%)
Y
Y
OH
OH
CHO
CO H
CHO
OMe
OH
CHO
OMe
OH
2
Y = NO , CN, CO Me, H, Me, Br, Cl
2
2
OMe
O
O
OMe
OMe
OH
Oxone, acetone-DMF
OMe
O
O
9a
Oxone
(54%)
K CO , EDTA
(aq)
2
3
O
O
OK
CHO
Dakin reaction
then epoxidation
CHO
OH
1a (78%)
3a
Scheme 2. Oxone-mediated reaction of aromatic aldehydes
Under the EDTA aqueous solution (0.4 mM, 8 mL), treatment of compound (3a) with Oxone and K2CO3
the co-solvent of acetone and DMF (8 mL, v/v = 1:1) produced compound (1a) (78%) via a Dakin
reaction of compound (3a) followed by intramolecular ring-closure of the resulting intermediate of
potassium o-allylphenoxide.12 The present Oxone-mediated oxidation reaction of model substrate (3a)
with the dimethoxy group is consistent with previous reports. Although this work was not originally
intended, a facile route for the present synthesis of skeleton (1) was achieved. The three-step known
approach was employed to create this skeleton (3), starting with isovanillin (4) via (1) O-allylation of
compound (4) with allyl, trans-crotyl or trans-cinnamyl bromides (R1 = H, Me, Ph) in acetone, (2)
Claisen rearrangement of allyl phenyl ether in decalin and (3) O-substitution of the resulting compounds
with halides (5) in acetone (Scheme 3).6
OMe
OMe
OMe
2
2
OH
OR
OR
1
1) K CO ,
2
3
R
Br
+
2) decalin, reflux
2
CHO
CHO
CHO
3) K CO , R X (5)
2
3
1
1
R
R
1
2
4
For R = H, R =
3a, Me
1
2
3g, R = R = Me
1
R = a, H; b, Me; c, Ph
1
2
3b, n-Bu
3c, c-C H
3h, R = Ph, R = c-C H
2
5
9
R X = a, MeI; b, n-BuBr; c, c-C H Br;
5
9
5
9
Br
d, BnBr; e, 4-F-1-NO Ph; f,
3d, Bn
2
3e, 4-NO Ph
3f,
N
N
Ph
2
N
N
N
Ph
N
Scheme 3. Three-step synthesis of skeleton (3)6

HETEROCYCLES, Vol. 89, No. 8, 2014
1907
Table 1. Synthesis of skeleton (1)a
OMe
OMe
OMe
OMe
2
2
2
2
OR
OR
OR
OR
Oxone, acetone-DMF
K CO , EDTA
+
+
2
3
(aq)
O
CHO
CHO
O
HO
1
1
1
R
1
R
R
HO
R
3a-f
3g-h
1g-h
1a-f
entry skeleton 3
skeleton 1, yieldb
1a, 78%
1b, 65%
1
2
3
4
5
3a, R1 = H, R2 = Me
3b, R1= H, R2 = n-Bu
3c, R1 = H, R2 = c-C5H9
3d, R1 = H, R2 = Bn
1c, 62%
1d, 68%
3e, R1 = H, R2 = 4-NO2Ph
3f, R1 = H, R2 =
Ph
1e, 48%c
6
1f, 50%,d (64%)e
N
N
N
7
8
3g, R1 = Me, R2 = Me
1g, 70%
1h, 73%
3h, R1 = Ph, R2 = c-C5H9
aThe reaction was run on a 1.0 mmol scale with scale with skeleton (3), Oxone (1.8 g,
3.0 mmol, in 8 mL of 4 mM EDTA), K2CO3 (550 mg, 4.0 mmol), in the co-solvent of
acetone and DMF (v/v = 1/1, 8 mL), rt. bThe product was >95% pure as determined by
1H-NMR analysis. cProduct (2a) was isolated in 25% yield. dProduct (2b) was isolated
in 10% yield. e5 equiv of Oxone was added.
NO
2
NO
2
OMe
OMe
O
O
O
+
OH
3e
or
3f
Oxone, acetone-DMF
K CO , EDTA
1e (48%)
2a (25%)
HO
Ph
Ph
N
OMe
N
OMe
2
3
(aq)
N
O
N
O
N
N
+
OH
O
1f (50%)
2b (10%)
HO
Scheme 4. Reaction of compounds (3e-f)
As shown in Table 1, compounds (3a-h) were efficiently constructed in moderate yields (48-78%) by the
facile protocol. Different substituents (R1, R2), with aliphatic or aromatic groups, were performed. By
exchanging different substituents (R2 = Me, n-Bu, c-C5H9, Bn), the modest yields of compounds (1a-d)
were isolated (entries 1-4). Entry 5 shows that o-allylphenol (2a) with a 4-nitrophenyl R2 group was
separated in a 25% yield. Compared with epoxidation (terminal olefin  epoxide), a reasonable

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HETEROCYCLES, Vol. 89, No. 8, 2014
explanation could be that the Dakin reaction (formyl  hydroxyl group) is preferred to proceed. For the
isolated yield of compound (2b) with the triazoyl group (~10%), similar results were observed, as shown
in entry 6 and Scheme 4. The structure of o-allylphenol (2b) was determined by single-crystal X-ray
crystallography.12 When the amounts of Oxone were increased to 5.0 equiv., the yield of compound (1f)
was improved. By the above reaction conditions, reaction of compound (3g) or (3h) provided a pair of
enantiomer (1g) or (1h) (entries 7-8) via the stereospecific cyclization.
OMe
OMe
Oxone, acetone-DMF
K CO , EDTA
2
3
(aq)
O
CHO
HO
1i (34%)
3i
Scheme 5. Reaction of compound (1i)
To examine the limitation of this route, the 4-methoxy group of compound (3a) was removed. Under a
similar process, treatment of compound (3i) with a C3-methoxy substituent afforded a 34% yield of
compound (1i) along with some unknown products (Scheme 5). Based on the observation, we believe that
two methoxy groups could increase the yield of the desired skeleton (1) and inhibit the formation of the
unknown products by one-pot methodology. For the one-pot reactions of compounds (3e-f) and (3i), the
reactivity should be affected by the electronic character of the phenol moieties in the intermediates. A
facile synthetic methodology for producing several oxygenated 2-hydroxymethyl-2,3-dihydrobenzofurans
(1) has been successfully presented using Oxone-mediated Dakin reaction of o-allylbenzaldehydes (3)
with acceptable yields. Further investigation regarding one-pot cascade synthesis of functionalized
heterocycles will be conducted and published in due course.
EXPERIMENTAL
General. All other reagents and solvents were obtained from commercial sources and used without further
purification. Reactions were routinely carried out under an atmosphere of dry nitrogen with magnetic
stirring. Products in organic solvents were dried with anhydrous magnesium sulfate before concentration
in vacuo. Melting points were determined with a SMP3 melting apparatus. 1H and 13C NMR spectra were
recorded on a Varian INOVA-400 spectrometer operating at 400 and at 100 MHz, respectively. Chemical
shifts (δ) are reported in parts per million (ppm) and the coupling constants (J) are given in Hertz. High
resolution mass spectra (HRMS) were measured with a mass spectrometer Finnigan/Thermo Quest MAT
95XL. X-Ray crystal structures were obtained with an Enraf-Nonius FR-590 diffractometer (CAD4,
Kappa CCD).
A representative procedure of skeleton (1) is as follows: K2CO3 (550 mg, 4.0 mmol) was added to a

HETEROCYCLES, Vol. 89, No. 8, 2014
1909
solution of skeleton (3) (1.0 mmol) in the co-solvent of acetone and DMF (8 mL, v / v = 1 : 1) at rt.
Oxone (1.8 g, 3.0 mmol) in an aqueous EDTA (4 mM, 8 mL) solution was added to the stirred reaction
mixture solution at rt. The reaction mixture was stirred at rt for 6 h. NaHSO3 (aq) (50%, 10 mL) was added
to the reaction mixture and the mixture was extracted with CH2Cl2 (3 x 20 mL). The combined organic
layers were washed with brine, dried, filtered and evaporated to afford crude product. Purification on
silica gel (hexanes/EtOAc = 10/1~2/1) afforded skeleton (1).
o
Compound (1a). Yield = 78% (164 mg); Colorless solid; mp 52-53 C (recrystallized from hexanes and
1
EtOAc); HRMS (ESI, M++1) calcd for C11H15O4 211.0970, found 211.0977; H NMR (400 MHz,
CDCl3): δ 6.65 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 4.89-4.83 (m, 1H), 3.87 (s, 3H), 3.81 (dd, J =
2.8, 12.4 Hz, 1H), 3.78 (s, 3H), 3.71 (dd, J = 6.4, 12.4 Hz, 1H), 3.28 (dd, J = 9.2, 16.0 Hz, 1H), 3.05 (dd,
J = 7.6, 16.0 Hz, 1H), 2.37 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 154.3, 146.3, 146.2, 118.7, 112.6,
103.0, 83.5, 64.7, 59.8, 56.9, 29.7.
Compound (1b). Yield = 65% (164 mg); Colorless oil; HRMS (ESI, M++1) calcd for C14H21O4 253.1440,
1
found 253.1435; H NMR (400 MHz, CDCl3): δ 6.63 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H),
4.87-4.81 (m, 1H), 4.01 (t, J = 6.8 Hz, 2H), 3.75 (s, 3H), 3.79-3.66 (m, 2H), 3.22 (dd, J = 9.2, 16.0 Hz,
1H), 2.98 (dd, J = 7.6, 16.0 Hz, 1H), 2.70 (br s, 1H), 1.71-1.64 (m, 2H), 1.50-1.41 (m, 2H), 0.94 (t, J =
13
7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 154.1, 146.7, 145.4, 119.5, 112.8, 103.0, 83.5, 72.2, 64.6,
56.9, 32.2, 29.7, 19.0, 13.7.
Compound (1c). Yield = 62% (164 mg); Colorless oil; HRMS (ESI, M++1) calcd for C15H21O4 265.1440,
1
found 265.1442; H NMR (400 MHz, CDCl3): δ 6.61 (d, J = 8.4 Hz, 1H), 6.36 (d, J = 8.4 Hz, 1H),
4.87-4.78 (m, 2H), 3.75 (dd, J = 2.8, 12.4 Hz, 1H), 3.73 (s, 3H), 3.67 (dd, J = 6.4, 12.4 Hz, 1H), 3.18 (dd,
J = 9.2, 16.0 Hz, 1H), 2.94 (dd, J = 7.6, 16.0 Hz, 1H), 2.85 (br s, 1H), 2.01-1.52 (m, 8H); 13C NMR (100
MHz, CDCl3): δ 154.0, 146.9, 144.1, 120.2, 112.8, 102.8, 83.5, 83.4, 64.5, 56.8, 32.8, 32.7, 29.9, 23.3
(2x).
Compound (1d). Yield = 68% (195 mg); Colorless oil; HRMS (ESI, M++1) calcd for C17H19O4 287.1283,
found 287.1285; 1H NMR (400 MHz, CDCl3): δ 7.41-7.29 (m, 5H), 6.70 (d, J = 8.8 Hz, 1H), 6.44 (d, J =
8.8 Hz, 1H), 5.09 (s, 2H), 4.80-4.74 (m, 1H), 3.82 (s, 3H), 3.68-3.57 (m, 2H), 3.02 (dd, J = 9.2, 16.0 Hz,
1H), 2.73 (dd, J = 7.6, 16.0 Hz, 1H), 2.52 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 153.8, 146.8, 144.6,
137.5, 128.2 (4x), 127.9, 120.4, 112.7, 103.5, 83.5, 74.2, 64.6, 56.8, 29.5.
o
Compound (1e). Yield = 48% (152 mg); Colorless solid; mp 85-86 C (recrystallized from hexanes and
1
EtOAc); HRMS (ESI, M++1) calcd for C16H16NO6 318.09778, found 318.0979; H NMR (400 MHz,
CDCl3): δ 8.16 (d, J = 9.2 Hz, 2H), 6.93 (d, J = 9.2 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz,
1H), 4.94-4.87 (m, 1H), 3.81 (dd, J = 3.2, 9.2 Hz, 1H), 3.70 (s, 3H), 3.69 (dd, J = 6.0, 9.2 Hz, 1H), 3.07
(dd, J = 9.2, 16.0 Hz, 1H), 2.88 (dd, J = 7.2, 16.0 Hz, 1H), 2.30 (br s, 1H); 13C NMR (100 MHz, CDCl3):

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HETEROCYCLES, Vol. 89, No. 8, 2014
δ 162.5, 154.5, 146.1, 142.4, 139.0, 125.9 (2x), 121.0, 115.3 (2x), 112.9, 106.2, 83.9, 64.5, 56.8, 29.2.
o
Compound (1f). Yield = 50% (184 mg); Colorless solid; mp 61-62 C (recrystallized from hexanes and
1
EtOAc); HRMS (ESI, M++1) calcd for C20H22N3O4 368.1610, found 368.1615; H NMR (400 MHz,
CDCl3): δ 7.45 (s, 1H), 7.38-7.33 (m, 3H), 7.23-7.18 (m, 2H), 6.62 (d, J = 8.4 Hz, 1H), 6.41 (d, J = 8.4
Hz, 1H), 5.51 (d, J = 15.2 Hz, 1H), 5.47 (d, J = 14.8 Hz, 1H), 5.20 (s, 2H), 4.79-4.72 (m, 1H), 3.74 (s,
3H), 3.70 (dd, J = 3.2, 12.0 Hz, 1H), 3.60 (dd, J = 6.0, 12.0 Hz, 1H), 3.04 (dd, J = 9.2, 16.0 Hz, 1H), 2.81
13
(dd, J = 6.8, 16.0 Hz, 1H), 2.28 (br s, 1H); C NMR (100 MHz, CDCl3): δ 154.0, 146.7, 144.9, 144.0,
134.5, 129.1 (2x), 128.7, 127.9 (2x), 123.0, 120.5, 112.4, 103.8, 83.6, 65.2, 64.6, 56.7, 54.0, 29.6.
Compound (1g). Yield = 70% (157 mg); Colorless gum; HRMS (ESI, M++1) calcd for C12H17O4
225.1127, found 225.1128; 1H NMR (400 MHz, CDCl3): δ 6.72 (s, 1H), 6.40 (s, 1H), 4.66 (dt, J = 3.6, 8.4
Hz, 1H), 4.10-4.08 (m, 1H), 3.79 (s, 6H), 3.15 (dd, J = 8.4, 15.2 Hz, 1H), 3.03 (dd, J = 9.6, 15.2 Hz, 1H),
13
2.18 (br s, 1H), 1.19 (d, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl3): δ 153.5, 149.1, 143.3, 116.5,
109.2, 94.6, 87.0, 68.2, 56.8, 56.0, 29.5, 17.6.
Compound (1h). Yield = 73% (248 mg); Colorless gum; HRMS (ESI, M++1) calcd for C21H25O4
341.1753, found 341.1758; 1H NMR (400 MHz, CDCl3): δ 7.46-7.34 (m, 5H), 6.58 (s, 1H), 6.51 (s, 1H),
4.75 (d, J = 8.0 Hz, 1H), 4.71-4.67 (m, 1H), 4.15-4.10 (m, 1H), 3.80 (s, 3H), 3.00 (dd, J = 5.2, 15.6 Hz,
1H), 2.84 (dd, J = 8.8, 15.6 Hz, 1H), 1.96-1.53 (m, 8H), 1.60 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ
147.8, 147.4, 144.5, 138.1, 128.8 (2x), 128.7, 127.2 (2x), 113.3, 110.3, 103.4, 81.8, 80.3, 68.4, 56.8, 32.8,
32.7, 32.4, 24.0 (2x).
Compound (1i). Yield = 34% (61 mg); Colorless oil; HRMS (ESI, M++1) calcd for C10H13O3 181.0865,
found 181.0851; 1H NMR (400 MHz, CDCl3): δ 7.08 (t, J = 8.0 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 6.41 (d,
J = 8.0 Hz, 1H), 4.95-4.89 (m, 1H), 3.82 (s, 3H), 3.82-3.69 (m, 2H), 3.18 (dd, J = 9.2, 16.0 Hz, 1H), 2.90
13
(dd, J = 7.6, 16.0 Hz, 1H), 2.55 (br s, 1H); C NMR (100 MHz, CDCl3): δ 160.4, 156.5, 129.0, 113.4,
103.0, 102.7, 83.6, 64.9, 55.2, 28.7.
Compound (2a). Yield = 25% (19 mg); Colorless gum; HRMS (ESI, M++1) calcd for C16H16NO5
302.1029, found 302.1032; 1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 9.2 Hz, 2H), 6.89 (d, J = 9.2 Hz,
2H), 6.81 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 5.88-5.79 (m, 1H), 5.11 (br s, 1H), 5.04-4.99 (m,
13
2H), 3.68 (s, 3H), 3.35 (dt, J = 1.2, 6.0 Hz, 2H); C NMR (100 MHz, CDCl3): δ 163.3, 148.9, 146.0,
142.2, 140.7, 134.9, 126.8 (2x), 120.9, 116.5, 115.2 (2x), 113.1, 111.5, 56.3, 28.5.
o
Compound (2b). Yield = 10% (35 mg); Colorless solid; mp 61-62 C (recrystallized from hexanes and
1
EtOAc); HRMS (ESI, M++1) calcd for C20H22N3O3 352.1661, found 352.1667; H NMR (400 MHz,
CDCl3): δ 7.50 (s, 1H), 7.40-7.34 (m, 3H), 7.26-7.23 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 8.4
Hz, 1H), 5.91-5.81 (m, 1H), 5.52 (s, 2H), 5.41 (br s, 1H), 5.13 (s, 2H), 5.02-4.97 (m, 2H), 3.76 (s, 3H),
13
3.37 (dt, J = 1.6, 6.0 Hz, 2H); C NMR (100 MHz, CDCl3): δ 148.9, 146.7, 145.8, 145.1, 136.2, 134.5,

HETEROCYCLES, Vol. 89, No. 8, 2014
1911
129.1 (2x), 128.7, 128.0 (2x), 122.9, 120.6, 115.6, 111.1, 110.9, 66.2, 56.2, 54.1, 28.5. Single-crystal
X-ray diagram: crystal of compound 2b was grown by slow diffusion of EtOAc into a solution of
compound 2b in CH2Cl2 to yield colorless prisms. The compound crystallizes in the monoclinic crystal
system, space group P C 2/c, a = 30.00(4) Å, b = 6.608(8) Å, c = 18.39(2) Å, V = 3643(8) Å3, Z = 8, dcalcd
= 1.281 g/cm3, F(000) = 1488, 2θ range 1.358~27.376o, R indices (all data) R1 = 0.2467, wR2 = 0.3585.
ACKNOWLEDGEMENTS
The authors would like to thank the National Science Council of the Republic of China for its financial
support (NSC 102-2113-M-037-005-MY2).
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12. CCDC 996277 (2b) contains the supplementary crystallographic data for this paper. This data can be
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Road, Cambridge CB2 1EZ, UK; fax: 44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
SUPPLEMENTARY MATERIAL
Scanned photocopies of 1H and 13C NMR spectral data were supported.