Phenylboronic acid-mediated synthesis of 2H-Chromenes

Article abstract of DOI:10.1055/s-1998-2042

Condensation of phenols with but-2-enal and 3-methyl-but-2-enal in the presence of phenylboronic acid in acetic acid-toluene solution leads to substituted and condensed 2H-chromenes, constituting a mild and advantageous complement to classical routes for this class of heterocycles.

Full text of DOI:10.1055/s-1998-2042

March 1998
279
Phenylboronic Acid-Mediated Synthesis of 2H-Chromenes
a
b
b
b
a
Brian A. Chauder, Claudio C. Lopes, * Rosangela S. C. Lopes, * Alcides J. M. da Silva, Victor Snieckus *
a
Guelph-Waterloo Centre for Graduate Work in Chemistry, University of Waterloo, Waterloo, Ontario, Canada, N2L 3G1
Fax + 1(519)7465884
b
0
Instituto de Quimica, Universidade Federal do Rio de Janeiro, Departamento de Quimica Analitica, CT, BI A 5 Andar, S-508.
Rio De Janeiro-R. J., Brazil, 21949 900
Received 5 May 1997
Abstract: Condensation of phenols with but-2-enal and 3-methyl- The reaction may be extended to the preparation of con-
but-2-enal in the presence of phenylboronic acid in acetic acid–tol-
uene solution leads to substituted and condensed 2H-chromenes,
from phenanthrols (entry 16). Both crotonaldehyde and
constituting a mild and advantageous complement to classical
densed 2H-chromenes from naphthols (entries 13–15) and
senecioaldehyde undergo smooth condensation with the
same phenols to give useful yields of products (compare
routes for this class of heterocycles.
Key words: 2H-chromene, phenylboronic acid, condensation of
entries 3 and 4 and entries 11 and 12).
phenols with unsaturated aldehydes
The described procedure shows promising advantage over
The central position of the 2H-chromene ring system in
similar reported cyclization procedures. Thus precocene
large and diverse classes of naturally occurring and bio-
logically active heterocycles1,2 has led to the development
of a number of regimens for their preparation: a) Claisen
II, an insecticide (entry 9) previously synthesized in nine
steps and 16% overall yield starting from ethyl 4-acetyl-
16
3
butyrate, was obtained in one step in 91% isolated
rearrangement of propargyl phenyl ethers; b) Pd-cata-
11
4
yield.
lyzed ring closure of 2-isoprenyl phenols, and c) compre-
hensive Lewis acid catalyzed methods.5 Formulated on
,6
In summary, the phenylboronic acid procedure for the
condensation of phenols with unsaturated aldehydes con-
the basis of the important Nagata procedure for ortho-re-
7
giospecific electrophilic substitution of phenols, general,
stitutes a convenient, mild, and general complement to
multigram-scale boron Lewis-acid chelation-controlled
5,6,12
8
other methods
for the synthesis of 2H-chromenes.
preparation of o-substituted phenols and anilines has
been extensively developed and applied to the construc- Mps were determined on a Büchi-20 apparatus and are uncorrected.
tion of tetrahydrocannabinols and their 5-aza analogs.9 IR spectra were obtained on a Perkin-Elmer 983 spectrometer. H and
1
1
3
C NMR spectra were recorded on Bruker AM-250 and AC-200 in-
Recently, Murphy showed that condensation of citronellal
with phenols in the presence of phenylboronic acid fur-
nishes some hexahydrocannabinoids in good yields.
Herein, we report a general phenylboronic acid procedure
for the preparation of substituted and condensed 2H-
struments with TMS as internal standard. Mass spectra (MS) were de-
termined on a high-resolution Varian MAT-CH7 instrument at 70 eV.
Microanalyses were performed by M-H-W Laboratories, Phoenix,
Ariz. With the exception of N,N-diethyl-3-hydroxybenzamide, all
commercial materials were purchased from Aldrich Chemical Co. or
10,11
18
chromenes 2 by condensation of phenols 1 with unsatur- Lancaster Synthesis Ltd.
ated aldehydes (Scheme 1). The advantages of this meth-
od in terms of mildness of conditions and efficiency over General Procedure:
other Lewis acid5 and base
,6
12,13,15
induced processes an-
A solution of phenol 1 (2.7 mmol), aldehyde (2.7 mmol), phenylbo-
ronic acid (2.7 mmol) and glacial HOAc (13.5 mL) in anhyd toluene
ticipates its broader application and is recently demon-
strated in the synthesis of naturally occurring
pyroxanthones from our laboratories.14
(
100 mL) was refluxed for 16 h under N in an apparatus fitted with a
2
Dean–Stark trap. Optimization of product formation was effected by
TLC monitoring. The mixture was cooled, concentrated in vacuo, and
the residue was extracted with several portions of CH Cl (3 mL). The
2
2
combined extract was washed successively with H O (15 mL),
2
NaHCO (20 mL), and brine (15 mL), dried (Na SO ), the solvent
3
2
4
was evaporated in vacuo, and the crude product was purified by flash
chromatography on silica gel (EtOAc–hexane 1:9 eluent).
2
,2,5, 7-Tetramethyl-2H-1-benzopyran (entry 1): bp 98–102 °C/0.2
Torr.
1
H NMR (CDCl ) d = 1.40 (s, 6H), 2.22 (s, 3H), 2.24 (s, 3H), 5.57 (d,
3
Scheme 1
J = 10 Hz, 1H), 6.45–6.50 (m, 3H).
13
C NMR (CDCl ) d = 152.9, 138.5, 133.5, 129.3, 123.2, 119.2,
3
1
17.1, 114.8, 27.7 (two), 21.3, 18.2.
The results are summarized in the Table. Treatment of
phenols 1 with either but-2-enal (crotonaldehyde) or 3-
–1.
IR (neat) n = 2974, 2922, 1613, 1564, 1311, 1212 cm
MS (rel intensity) m/e 188(10), 173(100), 128(7), 155(7), 91(5), 79(5).
methylbut-2-enal (senecioaldehyde) in the presence of Anal. Calcd. for C H O: C, 82.93; H, 8.56; Found: C, 82.74; H,
13 16
PhB(OH)2 (1 equiv) in HOAc-toluene solution under re- 8.70.
flux afforded the respective 2H-chromene derivatives 2 in
2
,2-Dimethyl-7-(N,N-diethylcarboxamido)-2H-1-benzopyran (entry
modest to excellent yields. As expected on the basis of
mechanistic considerations,7 electron-donating groups
facilitate the reaction (entries 3–6, 9–12) while electron-
,11
2): oil, bp 136–140°C/0.2 Torr.
–1.
IR (neat) n = 2950, 1728, 1623, 1556, 1503, 1446, 1215 cm
1
H NMR (CDCl ) d = 1.06–1.26 (br m, 6H), 1.42 (s, 6H), 3.28–3.50
3
withdrawing substituents give less satisfactory results (br), 5.64 (d, J = 10 Hz, 1H), 6.31 (d, J – 10 Hz, 1H), 6.76 (s, 1H),
(
entries 2, 8) and 4-nitrophenol is recovered unchanged. 6.82 (dd, J = 1.5, 7.5 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H).

2
80
Papers
SYNTHESIS
Table. Synthesis of Substituted 2H-Chromenes (2)
Entry
1
ArOH
RCHO
Product
Yield (%)
65
2
25
3
4
70
70
5
6
83
50
7
8
67
35
1
3
C NMR(CDCl ) d = 153.5, 153.3, 151.8, 129.3, 126.0, 121.3, 117.9,
1H), 6.27 (d, J = 16 Hz, 1H), 6.37–6.43 (m, 2H), 6.88 (d, J = 6 Hz, 1H).
3
3
1
1
13.4, 109.6, 75.9, 41.7, 27.7, 13.8, 13.0.
C NMR(CDCl ) d = 160.6, 154.1, 127.5, 126.7, 121.7, 114.4, 106.3,
3
MS (rel intensity) m/e 259(50), 244(100), 187(95), 144(90), 115(60);
HRMS Calcd. for C H NO : 259.15721; Found: 259.15678.
101.9, 76.0, 54.9, 27.8. HRMS Calcd. for C12
Found: 190.09860.
H O : 190.09937,
14 2
16
21
2
6
-Methoxy-2-methyl-2H-1-benzopyran (entry 3):
8-Methoxy-2,2-dimethyl-2H-1-benzopyran (entry 6): bp 80–84°C/
17
13
bp 70–74°C/0.22 Torr (lit. bp 86 °C/0.9 Torr).
0.2 Torr (lit. bp 115 °C/2 Torr).
1
1
H NMR (CDCl ) d= 1.41 (d, J = 6 Hz, 3H), 3.74 (m, 3H), 4.89–4.94
H NMR (CDCl ) d = 1.48 (s, 6H), 3.85 (s, 3H), 5.61 (d, J = 10 Hz,
3
3
(m, 1H), 5.68 (dd, J = 9.7, 3.0 Hz, 2H), 6.34 (d, J = 9.7 Hz, 1H), 6.54
d, J = 3.0 Hz, 1H), 6.63–6.73 (m, 2H).
1H), 6.30 (d, J = 10 Hz, 1H), 6.59–6.68 (m, 1H), 6.77–6.78 (m, 2H).
(
HRMS Calcd. for C H O : 176.08372; Found: 176.08368.
2,2-Dimethyl-7-(N,N-diethyl O-carbamoyl)-2H-1-benzopyran (entry
11 12 2
7
): oil.
1
6
-Methoxy-2,2-dimethyl-2H-1-benzopyran (entry 4):
H NMR (CDCl ) d = 1.15–1.29 (br m, 3H), 1.41 (s, 6H), 3.33–3.44
3
19
bp 62–65°C/0.22 Torr (lit. bp 132–136°C/15 Torr).
(br m, 4H), 5.54 (d, J = 9.8 Hz, 1H), 6.29 (d, J = 9.8 Hz, 1H), 6.56 (d,
J = 2.5 Hz, 1H), 6.61 (dd, J = 2.3, 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz,
1H).
1
H NMR (CDCl ) d = 1.40 (s, 6H), 5.53 (d, J = 10 Hz, 1H), 6.28 (d, J
3
=
10 Hz, 1H), 6.54 (d, J = 2.3 Hz, 1H), 6.67–6.69 (m, 2H).
1
3
C NMR (CDCl ) d = 13.0, 13.8, 27.7, 41.7, 75.9, 109.6, 113.4,
3
7
-Methoxy-2,2-dimethyl-2H-1-benzopyran11 (entry 5): colorless oil.
117,9, 121.3, 126.0, 129.3, 151.8, 153.3, 153.5.
HRMS Calcd. for C16 : 275.15213; Found: 275.15201.
1
H NMR (CDCl ) d = 1.42 (s, 6H), 3.78 (s, 3H), 5.46 (d, J = 16 Hz,
H21NO
3
3

March 1998
SYNTHESIS
281
Table. (continued)
Entry
ArOH
RCHO
Product
Yield (%)
91
9
1
0
70
1
1
60
85
1
1
2
3
60
95
1
4
1
1
5
6
95
48
6
0
-Bromo-2,2-dimethyl-2H-1-benzopyran (entry 8): oil, bp 93–96 °C/ 2,2-Dimethyl-6-isopropoxy-7-methoxy-2H-1-benzopyran (entry 10):
.2 Torr (lit.21 bp 116 °C/5 Torr).
bp 130–135 °C/0.5 Torr.
1
–1
H NMR(CDCl ) d = 1.41 (s, 6H), 5.63 (d, J = 10 Hz, 1H), 6.24 (d, J IR (neat) n = 2974, 1614, 1572, 1503, 1362, 1124 cm .
3
1
=
10 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 7.07 (br s, 1H).
H NMR (CDCl ) d = 1.31 (d, J = 6 Hz, 6H), 1.41 (s, 6H), 3.79 (s, 3H),
3
4
.33 (m, 1H), 5.46 (d, J = 10 Hz, 1H), 6.21 (d, J = 10 Hz, 1H), 6.39
,7-Dimethoxy-2,2-dimethyl-2H-1-benzopyran (entry 9): mp 43– (s, 1H), 6.57 (s, 1H).
6
16
4
5°C, Et O/Hexanes (lit. mp 46–47 °C).
MS (rel intensity) m/e 248(20), 233(25), 191(100), 176(10), 91(10).
2
1
H NMR (CDCl ) d = 1.41 (s, 6h), 3.82 (s, 3H), 3.84 (s, 3H), 5.48 (d, Anal. Calcd. for C H O : C, 72.55; H, 8.11; Found: C, 72.46; H, 7.96.
3
15 20 3
J = 9.7 Hz, 1H), 6.24 (d, J = 9.7 Hz, 1H), 6.42 (s, 1H), 6.53 (s, 1H).
13
C NMR (CDCl ) d = 149.3, 146.9, 142.7, 127.7, 121.6, 112.6, 6,7-Dioxymethylene-2-methyl-2H-1-benzopyran (entry 11): mp 70–
3
1
09.5, 100.6, 75.4, 56.0, 55.4, 27.2; HRMS Calcd. for C H O : 72°C, Et O/Hexanes.
13
16
3
2
–
1
2
20.10913; Found: 220.10904.
IR (film) n = 2983, 2901, 2842, 1642, 1615, 1603, 1256, 1208 cm .

2
82
Papers
SYNTHESIS
1
We thank NSERC Canada for support under the Research Grant and
Industrial Research Chair programs. We are most grateful to CNPq
Brazil for a CAPES fellowship to A. da Silva (1993–95) without which
this work would not have been possible. VS thanks Glaxo Wellcome
for a Visiting Professorship at Duke University and Michael Pirrung
and Ned Porter for collegial hospitality during which time this man-
uscript was prepared.
H NMR (CDCl3) d = 1.40 (d, J = 6.6 Hz, 3H), 4.86–4.89 (m, 1H),
5
.52 (dd, J = 3, 10 Hz, 1H), 5.87 (s, 2H), 6.26 (d, J = 10 Hz, 1H), 6.38
(s, 1H), 6.46 (s, 1H).
MS (rel intensity) m/e 190(20), 175(100), 117(5), 77(10).
Anal. Calcd. for C H O : C, 69.46; H, 5.29; Found: C, 69.46; H,
5
11 10 3
.32.
2
,2-Dimethyl-6,7-dioxymethylene-2H-1-benzopyran4 (entry 12): bp
(
(
(
1) Ellis, G. P. Chromenes, Chromanones and Chromones. In The
1
13–116°C/0.2 Torr.
Chemistry of Heterocyclic Compounds, Wiley: New York,
1
H NMR (CDCl3) d = 1.39 (s, 6H), 5.46 (d, J = 10 Hz, 1H), 5.87 (s,
1
977, Ch. 2.
2
H), 6.19 (d, J = 10 Hz, 1H), 6.37 (s, 1H), 6.46 (s, 1H).
2) Katrizky, A.; Brogden, P. J.; Gabbutt, C. D.; Hepworth, J. D. In
13
C NMR (CDCl ) d = 148.1, 147.5, 128.0, 122.2, 114.1, 105.5,
3
Comprehensive Heterocyclic Chemistry, Pergamon: 1984, vol.
1
00.8, 98.9, 27.4 (two).
3
, Ch. 22.
3) Hlubucek, J.; Ritchie, E.; Taylor, W. C. Tetrahedron Lett. 1969,
369.
–1
IR (neat) n = 2975, 2894, 1613, 1476, 1370, 1259, 1200 cm .
MS (rel intensity) m/e 204(15), 189(100), 159(5), 131(10), 77(10).
Anal. Calcd. for C H O: C, 70.57; H, 5.92; Found: C, 70.68, H,
1
12 12
Bohlmann, F.; Büchmann, U. Chem. Ber. 1972, 105, 863.
4) Iyer, M.; Trivedi, G. R. Synth. Commun. 1990, 20, 1347.
5) Talley, J. J. Synthesis 1983, 845.
6
.03.
(
(
2
-Methyl-2H-naphtho[1,2-b]pyran (entry 13): colorless oil.
(6) Cruz-Almanza, R.; Pérez-Flores, F.; Cárdenas, J.; Vázques, C.;
Fuentes, A. Synth. Commun. 1994, 24, 1009.
(7) Nagata, W.; Okada, K. Synthesis 1979, 365.
(8) Sugasawa, T. in Yoshida, Z.-i. New Synthetic Methodology and
Functionally Interesting Compounds, Kodasha: Tokyo and
Elsevier: Amsterdam, 1986, p 63.
1
H NMR (CDCl ) d = 1.53 (d, J = 6.6 Hz, 3H), 5.16–5.70 (m, 1H),
3
5
.69 (dd, J = 3.3, 9.7 Hz, 1H), 6.49 (dd, J = 1.6, 9.7 Hz, 1H), 7.13 (d,
J = 8.3 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.39–7.44 (m, 2H), 7.70–
7
.74 (m, 1H), 8.14–8.18 (m, 1H).
1
3
C NMR (CDCl ) d = 148.7, 134.4, 127.5, 126.1, 125.2, 124.7,
3
1
24.5, 124.1, 121.8, 120.1, 116.0, 71.9, 21.1.
Douglas, A. W.; Abramson, N. L.; Houpis, I. N.; Karady, S.;
Molina, A.; Xavier, L. C.; Yasuda, N. Tetrahedron Lett. 1994,
HRMS Calcd. for C H O: 196.08880; Found: 196.08911.
14 12
3
5, 6807 and refs cited therein.
(
9) Migneault, D.; Bernstein, M. A.; Lau, C. K. Can. J. Chem.
6
6
-Methoxy-2,2-dimethyl-2H-naphtho[1,2-b]pyran (entry 14): mp 61–
20
1995, 73, 1506.
4°C, Et O/Hexanes (lit. 62°C).
2
1
(10) Murphy, W. S.; Tuladhar, S. M.; Duffy, B. J. Chem. Soc., Per-
kin Trans I 1992, 605.
11) For a related example of a PhB(OH) -propanoic acid mediated
H NMR d = 1.48 (s, 6H), 3.94 (s, 3H), 5.64 (d, J = 10 Hz, 1H), 6.30
(d, J = 10 Hz, 1H), 6.50 (s, 1H), 7.38–7.49 (m, 2H), 8.12–8.15 (m,
(
2
H).
2
condensation leading to precocene I and II, naturally occurring
chromenes, see Bissada, S.; Lau, C. K.; Bernstein, M. A.; Du-
fresne, C. Can. J. Chem. 1994, 72, 1866.
2
,2-Dimethyl-2H-naphtho[2,1-b]pyran15 (entry 15): oil.
1
H NMR (CDCl ) d = 1.48 (s, 3H), 1.49 (s, 3H), 5.71 (d, J = 9.6 Hz,
3
(
(
(
12) Crombie, L.; Ponsford, R. J. Chem. Soc. C 1971, 788.
13) Hepworth, J. D.; Livingstone, R. J. Chem. Soc. 1966, 2013.
14) Familoni, O. B.; Ionica, I.; Bower, J.; Snieckus, V. Synlett 1997,
081.
15) Lamcharfi, E.; Menguy, L.; Zamarlik, H. Synth. Commun. 1993,
3, 3019.
16) Solladie, G.; Boeffel, D.; Maignan, J. Tetrahedron Lett. 1996,
065 and refs. cited therein.
1
H), 7.02 (d, J = 9.6 Hz, 1H), 7.31–7.35 (m, 1H), 7.43–7.49 (m, 1H),
7
1
.64 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.6 Hz,
H).
1
1
3
C NMR (CDCl ) d = 150.9, 129.8, 129.2, 129.1, 128.4, 126.3,
3
(
(
1
23.2, 121.1, 118.3, 118.1, 113.5, 75.8, 27.5.
2
HRMS Calcd. for C H O: 210.10445; Found: 210.10367.
15 14
2
2
,2-Dimethyl-2H-phenanthro[9,10-b]pyran (entry 16): oil.
(17) Anderson, W. K.; LaVoie, E. J. J. Org. Chem. 1973, 38, 3832.
(18) N,N-Diethyl 3-hydroxybenzamide was obtained by BBr de-
1
H NMR (CDCl ) d = 1.59 (s, 6H), 5.81 (d, J = 9.9 Hz, 1H), 7.10 (d,
3
3
J = 9.9 Hz, 1H), 7.42–7.65 (m, 4H), 8.02–8.07 (m, 1H), 8.37–8.44 (m,
methylation (CH Cl /-78°C) of the corresponding m-anisamide:
2
2
1
H), 8.61–8.69 (m, 2H).
Billedeau, R. J.; Sibi, M. P.; Snieckus, V. Tetrahedron Lett.
1983, 4515.
13
C NMR (CDCl ) d = 146.7, 131.0, 129.3, 128.8, 126.9, 126.4, 126.3,
3
1
25.9, 124.0, 123.0, 122.6, 122.4, 121.8, 118.7, 110.3, 76.2, 27.4.
(19) Livingstone, R; Watson, R. B. J. Chem. Soc. 1957, 1509.
(20) Livingstone, R.; Whiting, M. C. J. Chem. Soc. 1955, 3631.
HRMS Calcd. for C H O: 260.12010; Found: 260.11955.
19 16
(21) Livingstone, R.; Miller, D.; Morris, S. J. Chem. Soc., 1960,
3
094.