Directed ortho metalation reactions of aryl O-carbamates; a regiospecific synthesis of 2,2-disubstituted 2H-1-benzopyrans

Article abstract of DOI:10.1055/s-2001-9747

A one-pot regiocontrolled synthesis of 2,2-disubstituted 2H-1-benzopyrans 5 from aryl O-carbamates 4 using the directed ortho metalation reaction is described and constitutes an advantageous complement to classical routes for this class of heterocycles.

Full text of DOI:10.1055/s-2001-9747

140
PAPER
Directed ortho Metalation Reactions of Aryl O-Carbamates; A Regiospecific
Synthesis of 2,2-Disubstituted 2H-1-Benzopyrans
Brian A. Chauder,a Alexey V. Kalinin,b Victor Snieckus*a
a Queen’s University, Kingston, ON, Canada, K7L 3N6
Fax +(613)5332837; E-mail: snieckus@chem.queensu.ca
bGuelph-Waterloo Centre for Graduate Work in Chemistry, University of Waterloo, Waterloo, ON, Canada, N2L 3G1
Received 21 June 2000; revised 13 September 2000
O
Abstract: A one-pot regiocontrolled synthesis of 2,2-disubstituted
PhB(OH)2
2H-1-benzopyrans 5 from aryl O-carbamates 4 using the directed
ortho metalation reaction is described and constitutes an advanta-
geous complement to classical routes for this class of heterocycles.
HOAc / PhMe
reflux
HO
O
G
G
1
2
3
Key words: 2H-1-benzopyran, chromene, directed ortho metala-
tion, aryl-O-carbamates, carbamoyl migration
Scheme 2
2H-Chromenes are key heterocyclic units in a variety of
polyoxygenated natural products and bioactive mole-
cules.1,2 Of the numerous construction motifs for
chromenes,3 the Friedel-Crafts (F. C.) approach (Scheme
1) is by far the most widely used but, as expected, is com-
promised by poor reactivity for electron-withdrawing
substituents and is regiochemically dictated by electro-
philic aromatic substitution rules. Recently, we developed
a 2H-chromene synthesis, 1+2 Æ 3 (Scheme 2), which de-
pends upon this regiochemical control but which may be
carried out under relatively mild PhB(OH)2/HOAc condi-
tions compared to the Lewis-acid catalyzed conditions
previously reported.4 As a starting point for the total syn-
thesis of plicadin, a coumestan natural product,5 we de-
vised a facile synthesis of the chromene 5 (R = OCONEt2)
(Scheme 3) which is based on the Directed ortho Metal-
ation (DoM) reaction of aryl O-carbamates.6 Since, to the
best of our knowledge, only two previous reports of
chromene construction by DoM chemistry have been
reported7 and since this strategy provides derivatives dif-
ficult to obtain by classical routes, we undertook to gener-
alize this anionic route to chromenes. Herein we report
our results which provide a practical synthetic protocol for
2H-chromenes, 4 Æ 5 (Scheme 3, Table).
1. t-BuLi / THF
-78 °C
O
R
2.
Et2NOCO
R
O
4
5
3. HOAc / 0 °C
Scheme 3
In a typical procedure, the resorcinol dicarbamate8 (entry
1, Table), when subjected to standard metalation with
t-BuLi at -78 °C for 1 hour, followed by senecialdehyde
quench, afforded product 5a in 54-58% yields after dis-
tillation. Similarly, O-carbamates bearing other synergis-
tically (1,3-) Directed Metalation Groups (DMGs)
(entries 2-4, 7-10) led to 2H-chromene derivatives in
21-58% yields. Although clean reactions were observed
(no significant side reactions by GC) and chromenes were
the only isolable products, yields were not improved by
repetitive experiments. Attempts to do so via mediating
basicity of the anion by Li-Mg transmetalation9 were not
successful. Nevertheless, for the dicarbamate (entry 1),
the reaction was easily scaled to 100 mmol (0.5 M in
THF) providing ten-gram quantities of the chromene 5a.
Furthermore, this protocol provides an expeditious route
to simple (entries 2-8), unusual (entry 11) and unknown
chromenes, bearing selected electron-withdrawing and
-donating groups, from a variety of commercially avail-
able phenols. With the exception of 5g and the phenols
corresponding to 5a (5h) and 5e, the prepared chromenes
are new compounds. While the phenol of 5e is conve-
niently available in higher yields (66%, 1 step) by classi-
cal methods,10 some of the other systems, in particular the
5- substituted derivatives (e. g., 5a, b, e, g, i, j) are less
efficiently accessible (e. g., phenol derived from 5a, 5g, or
5h was prepared in 28% overall yield).11 Furthermore,
most of the derived chromenes are poised for further DoM
chemistry.12
Lewis Acid
O
G
G
Et2NOCO
DMG
HO
EDG
O
E+
F.C. - Route to 2H-Chromenes
DoM - Route to 2H-Chromenes
Scheme 1
Synthesis 2001, No. 1, 140–144 ISSN 0039-7881 © Thieme Stuttgart · New York

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Directed ortho Metalation Reactions of Aryl O-Carbamates
141
Table Synthesis of 2H-Chromenes 5 by Directed ortho Metalation
Entry
1
carbamate
product a
Entry
7
carbamate
product a
OCONEt2
O
OMe
O
O
O
OCONEt2
OCONEt2
Et2NOCO
Et2NOCO
OMe
Et2NOCO
4a
5a (54-58%)
4g
4h
4i
5g (40-54%)
2
O
OCONEt2
8
9
OMOM
Ph
Ph
OMOM
Et2NOCO
Et2NOCO
5b (36%) b
4a
5h (52%)
Me
Me
F
3
4
OCONEt2
O
F
OCONEt2
Et2NOCO
5i (43%) c
5c (54%)
4c
OMe
OMe
10
CONEt2
O
CONEt2
Et2NOCO
Et2NOCO
OCONEt2
O
5j (36%)
4j
OCONEt2
OCONEt2
Et2NOCO
5d (22%)
OCONEt2
4d
O
11
N
TBS
5
6
O
N
TBS
Et2NOCO
5k (23%) c
4k
5e (28%)
4e
Et2NOCO
O
Et2NOCO
Et2NOCO
5f (21%)
4f
aYields represent isolated yields for purified products.
bb-phenylcinnamaldehyde was used as the aldehyde.
cReaction conditions: s-BuLi/TMEDA/-78 °C/THF.
In view of the recalcitrance of the O-carbamate to both to-O-migration of the carbamoyl moiety which is driven
acid- and base-mediated hydrolysis,13 the ready formation by the phenolate leaving group ability. The resulting inter-
of the chromene by HOAc quench (as a part of the work- mediate 8 undergoes acid-catalyzed solvolysis to the al-
up procedure) deserves a comment. Several experiments lylic cation 9, which is rapidly trapped by the phenolic OH
were carried out in order to gain insight into the low yields to give product 10. An alternative pathway, via the ortho-
of the reaction. No regioisomers of products 5 were ob- quinone methide 11, formed directly from 8 or via 9, fol-
served. The low yields of products are not due to incom- lowed by electrocyclic ring closure, cannot be excluded.14
plete metalation. This was established by CD3OD quench
experiment (84% incorporation by NMR). Attempts to
isolate intermediates corresponding to protio-7 and depro-
tio-8 by MeI or NH4Cl quench experiments at low temper-
ature gave only final product 5. Thus, we envisage that the
initially formed adduct 7 (Scheme 4) undergoes facile O-
In summary, a DoM protocol, 4 Æ 5, for 2H-chromene
derivatives has been developed which takes advantage of
the synergistic effect of a 1,3-diDMG arrangement to set
the regiochemical consequence by the DoM reaction.
While the yields are low to modest, this procedure allows
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142
B. A. Chauder et al.
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1H NMR (250 MHz, CDCl3): d = 1.15-1.35 (m, 12H), 2.33 (s, 3H),
3.30-3.50 (m, 8H), 6.79 (br s, 3H).
13C NMR (62.9 MHz, CDCl3): d = 153.9, 151.6, 139.6, 119.0,
112.6, 42.1, 41.8, 21.2, 14.1, 13.3.
H+
R
HO
R
O
O
EIMS: m/z (%) = 322 (M+, 17), 101 (8), 100 (100), 72 (63).
O
O
Et2N
OH+
HRMS: calcd. for C17H26N2O4: 322.1894. Found: 322.1887.
Et2N
7
8
5-Methoxyphenyl-1,3-bis(N,N-diethylcarbamate) (4d)
Column chromatography: EtOAc/hexanes (1:4); colorless oil;
yield: 95%.
IR (neat): n = 2975, 2936, 1722, 1609, 1467, 1415, 1055, 1001
O
R
R
HO
R
O
cm-1.
1H NMR (250 MHz, CDCl3): d = 1.10-1.30 (m, 12H), 3.25-3.50
(m, 8H), 3.78 (s, 3H), 6.54 (d, 2H, J = 2.0 Hz), 6.58 (d, 1H, J = 2.0
Hz).
13C NMR (62.9 MHz, CDCl3): d = 160.3, 153.5, 152.3, 108.0,
104.6, 55.4, 42.0, 41.7, 14.0, 13.2.
9
10
11
Scheme 4
EIMS: m/z (%) = 338 (M+, 28), 127 (10), 101 (10), 100 (100), 72
(71).
rapid access to substituted 2H-chromenes, which are dif-
ficult to prepare by the classical Friedel-Crafts approach
and, at times, may complement the latter method.4
HRMS: calcd. for C17H26N2O5: 338.1842. Found: 338.1850.
1,4-Bis(N,N-diethylcarbamoyl) benzene (4e)16
Further DoM chemistry on 5 and related 2H-chromene O- Column chromatography: EtOAc/hexanes (1:4); colorless solid; mp
103-105 °C (hexanes/EtOAc); yield: 91%.
carbamates is in progress and will be reported in due
course.
IR (neat): n = 2979, 2938, 1723, 1503, 1472, 1416, 1278, 1190, 955
cm-1.
1H NMR (200 MHz, CDCl3): d = 1.10-1.41 (m, 12H), 3.22-3.59
All experiments were carried out under Ar in dried glassware. THF
was freshly distilled from sodium benzophenone ketyl under Ar pri-
or to use. All reagents and chemicals were purchased from Aldrich.
1H and 13C NMR spectra were recorded on a Bruker AM-250 or
AC-200 spectrometer. Mps were obtained on a Büchi-20 apparatus
and are uncorrected. IR spectra were obtained on a Perkin-Elmer
983 spectrometer. MS were determined on a high resolution Varian
MAT-CH7 instrument at 70 eV.
(m, 8H), 7.09 (s, 4H).
13C NMR (50.3 MHz, CDCl3): d = 153.8, 148.1, 121.9, 41.9, 41.6,
13.9, 13.1.
1,2-Bis(N,N-diethylcarbamoyl) benzene (4f)17
Column chromatography: EtOAc/hexanes (1:4); colorless solid; mp
38-41 °C (hexanes/EtOAc); yield: 86%.
IR (neat): n = 2985, 2935, 1723, 1496, 1410, 1255, 1151, 1097, 960
cm-1.
O-Aryl Carbamates 4; General Procedure8
1H NMR (200 MHz, CDCl3): d = 1.02-1.38 (m, 12H), 3.19-3.54
(m, 8H), 7.17 (s, 4H).
13C NMR (50.3 MHz, CDCl3): d = 153.1, 143.1, 125.5, 123.3, 41.9,
41.6, 17.8, 13.0.
To a stirred suspension of the corresponding phenol (1 mmol) and
K2CO3 (1.5 mmol) in MeCN (0.5 M) was added N,N-diethylcar-
bamoyl chloride (1.5 mmol). (Note: for bis-carbamates of entries
1-6, 3 mmol of both K2CO3 and N,N-diethylcarbamoyl chloride are
required). The reaction mixture was heated to reflux until the reac-
tion was completed (TLC). The mixture was cooled, poured into
H2O (5 mL) and the aqueous layer was extracted with Et2O (3 ¥ 5
mL). The combined Et2O extracts were washed with 10% NaOH
(2 ¥ 5 mL), H2O (2 ¥ 5 mL), brine (2 ¥ 5 mL), dried (Na2SO4), con-
centrated in vacuo, and the crude residue was purified as specified
below.
1,3-Bis(N,N-diethylcarbamoyl) benzene (4a)15
Distillation: bp 235-240 °C (bath temp)/0.02 mmHg; yellow oil;
yield: 86-89%.
IR (neat): n = 2976, 2934, 1706, 876, 752 cm-1.
3-Methoxyphenyl-N,N-diethylcarbamate (4g)
Distillation: bp 115-117 °C/0.05 mmHg; colorless oil; yield: 96%.
IR (neat): n = 2963, 2836, 1719, 1417, 969 cm-1.
1H NMR (250 MHz, CDCl3): d = 1.13-1.15 (m, 6H), 3.31-3.51 (m,
4H), 3.79 (s, 3H), 6.68-6.76 (m, 3H), 7.27 (t, 1H, J = 8.0 Hz).
13C NMR (62.9 MHz, CDCl3): d = 159.9, 152.1, 128.9, 113.4,
110.4, 107.3, 54.7, 41.7, 41.4, 13.7, 12.8.
EIMS: m/z (%) = 223 (M+, 42), 178 (4), 127 (20), 100 (100), 91
(50), 72 (100).
HRMS: calcd. for C12H17NO3: 223.1208. Found: 223.1214.
1H NMR (250 MHz, CDCl3): d = 1.16-1.26 (m, 12H), 3.33-3.42
(m, 8H), 6.95-6.98 (m, 3H), 7.27-7.34 (m, 1H).
13C NMR (62.9 MHz, CDCl3): d = 152.7, 150.9, 128.0, 117.2,
114.6, 41.2, 40.8, 13.1, 12.2.
3-Fluorophenyl-N,N-diethylcarbamate (4i)
Distillation: bp 120-125 °C / 0.2 mmHg (Kugelrohr); colorless oil;
yield: 84%.
IR (neat): n = 3091, 2978, 2937, 1720, 1607, 1422, 1257, 1155, 965
EIMS: m/z (%) = 308 (M+, 100), 209 (6), 100 (35).
cm-1.
HRMS: calcd. for C16H24N2O4: 308.1736. Found: 308.1747.
1H NMR (200 MHz, CDCl3): d = 1.02-1.38 (m, 6H), 3.18-3.55 (m,
4H), 6.64-7.11 (m, 3H), 7.18-7.39 (m, 1H).
13C NMR (50.3 MHz, CDCl3): d = 162.5 (d, J = 247.2 Hz), 153.3,
152.2 (d, J = 10.7 Hz), 129.6 (d, J = 9.1 Hz), 117.2 (d, J = 3.1 Hz),
111.6 (d, J = 21.4 Hz), 109.4 (d, J = 23.7 Hz), 42.0, 41.7, 13.8, 12.9.
3-Methylphenyl-1,3-bis(N,N-diethylcarbamate) (4c)
Column chromatography: EtOAc/hexanes (1:1); colorless oil;
yield: quant.
IR (neat): n = 2968, 1720, 1618, 1414, 1152 cm-1.
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Directed ortho Metalation Reactions of Aryl O-Carbamates
143
EIMS: m/z (%) = 211 (M+, 2), 112 (11), 100 (42), 72 (100).
1H NMR (250 MHz, CDCl3): d = 1.15-1.35 (m, 6H), 1.42 (s, 6H),
2.25 (s, 3H), 3.30-3.50 (m, 4H), 5.56 (d, 1H, J = 9.9 Hz), 6.34 (d,
1H, J = 9.9 Hz), 6.48 (s, 2H).
13C NMR (62.9 MHz, CDCl3): d = 153.9, 153.4, 146.9, 139.0,
129.7, 116.4, 115.0, 114.0, 112.0, 75.9, 42.1, 41.8, 27.8, 21.4, 14.3,
13.3.
HRMS: calcd. for C11H14FNO2: 211.1009. Found: 211.1001.
3-[(Diethylamino)carbonyl]phenyl-N,N-diethylcarbamate (4j)
Distillation: bp 130-135 °C / 0.03 mmHg; colorless oil; yield: 80%.
IR (neat): n = 2973, 2844, 1710 cm-1.
1H NMR (250 MHz, CDCl3): d = 1.12-1.29 (m, 12H), 3.26-3.52
(m, 8H), 7.10-7.36 (m, 4H).
EIMS: m/z (%) = 289 (M+, 23), 275 (18), 274 (100), 175 (18), 174
(29), 100 (98), 85 (16), 72 (40).
13C NMR (62.9 MHz, CDCl3): d = 170.0, 153.6, 151.3, 138.1,
129.0, 122.5, 122.1, 119.8, 42.0, 41.2, 40.7, 39.8, 13.4.
HRMS: calcd. for C17H23NO3: 289.1679. Found: 289.1685.
7-Methoxy-2,2,-dimethyl-2H-5-chromenyl-N,N-diethylcarbam-
ate (5d)
Column chromatography: EtOAc/hexanes (1:4); yellow oil; yield:
22%.
Anal: calcd. for C16H24N2O3: C, 65.73; H, 8.27; N, 9.58. Found: C,
65.54; H, 8.29; N, 9.74.
Chromenes 5; General Procedure
IR (neat) n = 2974, 2935, 1722, 1624, 1574, 1415, 1268, 1150,
To a cooled (-78 °C) solution of 4 (1 mmol) in THF (0.5 M) was
added t-BuLi solution (1.1 mmol) while keeping the internal
temp <-75 °C (20 min addition time). The mixture was stirred for
15 min, 3-methylbut-2-enal (1.3 mmol) was added over 15 min
(internal temp <-74 °C), and the mixture was stirred for 1 h at
-78 °C. The mixture was allowed to warm to r.t., stirred for 1 h,
cooled to 0 °C, and sequentially treated with HOAc (1.3 mmol)
and brine solution (2 mL), and stirred for 1 h at r.t. The organic
phase was separated, the aqueous phase was extracted with Et2O
(3 ¥ 5 mL), and the combined organic extracts were evaporated in
vacuo. Excess aldehyde was removed under high vacuum (0.1 mm-
Hg), the residue was dissolved in Et2O (10 mL), dried (Na2SO4),
concentrated in vacuo, and the crude residue was purified as speci-
fied below.
1118, 1071 cm-1.
1H NMR (250 MHz, CDCl3): d = 1.15-1.30 (m, 6H), 1.42 (s, 6H),
3.35-3.50 (m, 4H), 3.75 (s, 3H), 5.49 (d, 1H, J = 9.9 Hz), 6.25 (s,
2H), 6.31 (d, 1H, J = 9.9 Hz).
13C NMR (62.9 MHz, CDCl3): d = 160.2, 154.5, 153.7, 148.0,
127.9, 116.3, 108.2, 101.0, 99.6, 76.4, 55.4, 42.2, 41.9, 27.9. 14.3,
13.3.
EIMS: m/z (%) = 305 (M+, 23), 291 (12), 290 (68), 190 (10), 100
(100), 72 (63).
HRMS: calcd. for C17H23NO4: 305.1627. Found: 305.1621.
2,2-Dimethyl-2H-6-chromenyl-N,N-diethylcarbamate (5e)
Column chromatography: EtOAc/hexanes (1:4); yellow oil; yield:
28%.
2,2-Dimethyl-2H-5-chromenyl-N,N-diethylcarbamate (5a)
Distillation: bp 120-130 °C / 0.2 mmHg (Kugelrohr); yellow oil;
yield: 54-58%.
IR (neat): n = 3053, 2982, 2937, 1720, 1636, 1475, 1411, 1257,
1167, 967 cm-1.
IR (neat): n = 2977, 1722, 1638, 1611, 1460, 1418, 1277, 1225,
1H NMR (200 MHz, CDCl3): d = 1.12-1.31 (br m, 6H), 1.42 (s,
6H), 3.28-3.50 (br m, 4H), 5.61 (d, 1H, J = 9.8 Hz), 6.26 (d, 1H,
J = 9.8 Hz), 6.72 (d, 1H, J = 8.7 Hz), 6.75 (d, 1H, J = 2.4 Hz), 6.83
(dd, 1H, J = 8.4, 2.5 Hz).
13C NMR (50.3 MHz, CDCl3): d = 154.5, 149.8, 144.8, 131.2,
121.9, 121.7, 121.5, 119.2, 116.4, 76.1, 42.1, 41.7, 27.7, 14.1, 13.3.
1156, 1116, 1060, 758 cm-1.
1H NMR (250 MHz, CDCl3): d = 1.17-1.29 (m, 6H), 1.43 (s, 6H),
3.37-3.47 (m, 4H), 5.62 (d, 1H, J = 10.0 Hz), 6.38 (d, 1H, J = 10.0
Hz), 6.63 (d, 1H, J = 8.1 Hz), 6.64 (d, 1H, J = 8.1 Hz), 7.06 (t, 1H,
J = 8.1 Hz).
13C NMR (62.9 MHz, CDCl3): d = 153.2, 146.8, 130.3, 127.9,
116.0, 114.3, 114.0, 112.9, 75.4, 41.8, 41.4, 27.4, 13.9, 12.9.
EIMS: m/z (%) = 275 (M+,16), 260 (67), 189 (24), 161 (19), 132
(37), 100 (100).
EIMS: m/z (%) = 275 (M+, 55), 260 (100), 175 (8), 161 (26).
HRMS: calcd. for C16H21NO3: 275.1521. Found: 275.1532.
HRMS: calcd. for C16H21NO3: 275.1521. Found: 275.1518.
2,2-Dimethyl-2H-8-chromenyl-N,N-diethylcarbamate (5f)
Column chromatography: EtOAc/hexanes (1:4); colorless oil;
yield: 21%.
IR (neat) n = 3068, 2980, 2925, 1726, 1459, 1417, 1272, 1150 cm-1.
1H NMR (200 MHz, CDCl3): d = 1.08-1.28 (br m, 6H), 1.40 (s,
6H), 3.32-3.53 (br m, 4H), 5.60 (d, 1H, J = 9.9 Hz), 6.32 (d, 1H,
J = 9.8 Hz), 6.74-7.03 (m, 3H).
13C NMR (50.3 MHz, CDCl3): d = 154.0, 144.9, 139.9, 130.9,
123.0, 122.9, 122.6, 122.1, 120.0, 72.6, 42.3, 28.0, 14.0, 13.5.
EIMS: m/z (%) = 275 (M+,8), 260 (100), 189 (11), 161 (18), 132 (4).
2,2-Diphenyl-2H-5-chromenyl-N,N-diethylcarbamate (5b)
Column chromatography: EtOAc/hexanes (1:4); colorless solid;
yield: 36%.
IR (neat): n = 3063, 3033, 2926, 1721, 1607, 1482, 1446, 1237, 987,
754 cm-1.
1H NMR (200 MHz, CDCl3): d = 1.17-1.31 (m, 6H), 3.33-3.51 (m,
4H), 6.16 (d, 1H, J = 9.8 Hz), 6.61 (d, 1H, J = 9.8 Hz), 6.79-7.15
(m, 3H), 7.20-7.45 (m, 10H).
13C NMR (50.3 MHz, CDCl3): d = 152.6, 152.3, 144.9, 129.5,
128.8, 128.1, 127.4, 127.0, 126.5, 123.3, 121.1, 121.0, 116.4, 82.5,
42.1, 41.7, 14.1, 13.3.
HRMS: calcd. for C16H21NO3: 275.1521. Found: 275.1508.
5-Methoxy-2,2-dimethyl-2H-chromene (5g)18
Column chromatography: Et2O/hexanes (1:9); colorless oil; yield:
40-54%.
IR (neat): n = 2971, 2838, 1635, 1620 cm-1.
1H NMR (250 MHz, CDCl3): d = 1.40 (s, 6H), 3.78 (s, 3H), 5.55 (d,
1H, J = 10.0 Hz), 6.37 (d, 1H, J = 8.2 Hz), 6.42 (d, 1H, J = 8.2 Hz),
6.65 (d, 1H, J = 10.0 Hz), 7.05 (t, 1H, J = 8.2 Hz).
HRMS: calcd. for C26H25NO3: 399.1834. Found: 399.1842.
2,2,7-Trimethyl-2H-5-chromenyl-N,N-diethylcarbamate (5c)
Column chromatography: EtOAc/hexanes (1:4); yellow oil; yield:
54-55%.
IR (neat): n = 2976, 2933, 1720, 1627, 1566, 1416, 1266, 1152,
1118, 1072 cm-1.
13C NMR (62.9 MHz, CDCl3): d = 155.2, 153.7, 128.8, 128.7,
116.8, 110.6, 109.5, 102.9, 75.6, 55.5, 27.7.
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B. A. Chauder et al.
PAPER
5-(Methoxymethoxy)-2,2-dimethyl-2H-chromene (5h)
Column chromatography: EtOAc/hexanes (1:9); colorless solid;
yield: 52%.
References
(1) Schweizer, E. E.; Meeder-Nycz, D. In Chromenes,
Chromanones and Chromones; Ellis, G. P., Ed.; John Wiley:
New York, 1977; Chapter 2.
Hepworth, J. D. In Comprehensive Heterocyclic Chemistry,
Vol. 3; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New
York, 1984, pp 665-675, 741-756.
IR (neat): n = 3072, 3045, 2974, 2930, 1639, 1606, 1579, 1245,
1157, 1053, 758 cm-1.
1H NMR (200 MHz, CDCl3): d = 1.43 (s, 6H), 3.49 (s, 3H), 5.18 (s,
2H), 5.59 (d, 1H, J = 9.9 Hz), 6.48 (d, 1H, J = 8.1 Hz), 6.60 (d, 1H,
J = 8.3 Hz), 6.68 (d, 1H, J = 10.0 Hz), 7.02 (t, 1H, J = 8.4 Hz).
13C NMR (50.3 MHz, CDCl3): d = 153.7, 152.9, 129.3, 128.9,
116.8, 111.5, 110.4, 106.6, 94.8, 75.7, 56.1, 27.8.
(2) For a recent review, see: Lévai, A.; Tímár, T.; Sebõk, P.;
Eszenyi, T. Heterocycles 2000, 53, 1193.
(3) Via Claisen rearrangement of propargyl phenyl ethers: Bell,
D.; Davies, M. R.; Geen, G. R.; Mann, I. S. Synthesis 1995,
707.
EIMS: m/z (%) = 220 (M+,6), 205 (100), 175 (52), 161 (57).
For a Pd-catalyzed route: Larock, R. C.; Wei, L.; Hightower,
T. R. Synlett 1998, 522.
Lewis-acid catalyzed methods: Cossy, J.; Rakotoarisoa, H.;
Kahn, P.; Desmurs, J. -R. Tetrahedron Lett. 1998, 39, 9671.
Pozzo, J. L.; Lokshin, V. A.; Guglielmetti, R. J. Chem. Soc.
Perkin Trans. 1 1994, 2591.
HRMS: calcd. for C13H16O3: 220.1099. Found: 220.1106.
5-Fluoro-2,2-dimethyl-2H-chromene (5i)
Column chromatography: EtOAc/hexanes (1:9); colorless oil;
yield: 43%.
1H NMR (200 MHz, CDCl3): d = 1.44 (s, 6H), 5.63 (d, 1H, J = 9.9
Hz), 6.52-6.60 (m, 3H), 6.96-7.08 (m, 1H).
13C NMR (50.3 MHz, CDCl3): d = 158.6 (d, J = 251.5 Hz), 154.1
(d, J = 15.1 Hz), 130.6 (d, J = 2.3 Hz), 128.8 (d, J = 9.9 Hz), 125.6,
115.1 (d, J = 4.6 Hz), 112.1 (d, J = 3.0 Hz), 107.2 (d, J = 21.4 Hz),
76.3, 27.8.
Via ring-closing metathesis: Chang, S.; Grubbs, R. H. J. Org.
Chem. 1998, 63, 864.
(4) Chauder, B. A.; Lopes, C. C.; Lopes, R. S. C.; da Silva, A. J.
M.; Snieckus, V. Synthesis 1998, 279.
(5) Chauder, B. A.; Kalinin, A. V.; Taylor, N. J.; Snieckus, V.
Angew. Chem., Int. Ed. Engl. 1999, 38, 1435.
(6) Snieckus, V. Chem. Rev. 1990, 90, 879.
(7) For the preparation of chromenes via a metal halogen
exchange on o-bromophenols, see: Talley, J. Synthesis 1983,
845.
EIMS: m/z (%) = 178 (M+,1), 163 (100), 115 (13).
HRMS: calcd. for C11H11FO: 178.0794. Found: 178.0787.
N,N-Diethyl-2,2-dimethyl-2H-5-chromenecarboxamide (5j)
Column chromatography: EtOAc/hexanes (1:9); colorless oil;
yield: 36%.
For an aromatic lithiation route to chromenes, see: Cruz-
Almanza, R.; Pérez-Flores, F.; Cárdenas, J.; Vázques, C.;
Fuentes, A. Synth. Commun. 1994, 24, 1009.
For a THP protected phenol homocuprate approach to
chromenes, see: Luteijn, J. M.; Spronck, H. J. W. J. Chem.
Soc., Perkin Trans. 1 1979, 201.
IR (neat): n = 3056, 2976, 2931, 1630, 1443, 1379, 1295, 1115, 767
cm-1.
1H NMR (200 MHz, CDCl3): d = 1.16-1.30 (m, 6H), 1.43 (s, 6H),
3.09-3.20 (m, 4H), 5.65 (d, 1H, J = 9.8 Hz), 6.28 (d, 1H, J = 9.8
Hz), 6.73 (d, 1H, J = 7.9 Hz), 6.82 (d, 1H, J = 7.9 Hz), 7.10 (t, 1H,
J = 7.9 Hz).
13C NMR (50.3 MHz, CDCl3): d = 169.9, 152.9, 134.4, 131.8,
128.9, 119.0, 117.9, 117.6, 116.7, 74.2, 42.9, 38.9, 27.8, 14.0, 12.9.
(8) For the preparation of O-arylcarbamate in entry 8 (4h, Table),
see: Tsukazaki, M.; Snieckus, V. Can. J. Chem. 1992, 70,
1486.
For the preparation of 4k (entry 11), see: Griffen, E. J.; Roe,
D.; Snieckus, V. J. Org. Chem. 1995, 60, 1484.
(9) Sibi, M. P.; Miah, M. A. J.; Snieckus, V. J. Org. Chem. 1984,
49, 737.
EIMS: m/z (%) = 259 (M+,4), 244 (37), 173 (100), 144 (19), 115
(23).
(10) Garcías, X.; Ballester, P.; Saá, J. M. Tetrahedron Lett. 1991,
32, 7739.
(11) Schuda, P. F.; Price, W. A. J. Org. Chem. 1987, 52, 1972.
(12) Chauder, B. A. studies in progress.
HRMS: calcd. for C16H21NO2: 259.1572. Found: 259.1560.
3-[1-(tert-Butyl)-1,1-dimethylsilyl]-7,7-dimethyl-3,7-dihydro-
pyrano[3,2-e]indole (5k)
Column chromatography: EtOAc/hexanes (1:9); colorless solid; mp
63-65 °C (hexanes/EtOAc); yield: 23%.
1H NMR (200 MHz, CDCl3): d = 0.56 (s, 6H), 0.91 (s, 9H), 1.44 (s,
6H), 5.61 (d, 1H, J = 9.8 Hz), 6.57 (d, 1H, J = 3.0 Hz), 6.60 (d, 1H,
J = 8.9 Hz), 6.62 (d, 1H, J = 9.8 Hz), 7.14 (d, 1H, J = 3.4 Hz), 7.22
(d, 1H, J = 8.9 Hz).
13C NMR (50.3 MHz, CDCl3): d = 146.5, 136.3, 132.0, 129.3,
128.3, 120.1, 113.8, 111.8, 111.6, 101.6, 75.4, 27.6, 26.3, 19.4,
-4.0.
(13) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935.
For a circumvention of this problem, see: Metallinos, C.;
Nerdinger, S.; Snieckus, V. Org. Lett. 1999, 1, 1183.
(14) Migneault, D.; Bernstein, M. A.; Lau, C. K. Can. J. Chem.
1995, 73, 1506; and references cited therein.
Murphy, W. S.; Tuladhar, S. M.; Duffy, B. J. Chem. Soc.,
Perkin Trans. 1 1992, 605.
Talley, J. J. Org. Chem. 1985, 50, 1695.
(15) Kalinin, A. V.; Da Silva, A. J. M.; Lopes, C. C., Lopes, R. S.
C.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4995.
(16) Mills, R. J.; Horvath, R. F.; Sibi, M. P.; Snieckus, V.
Tetrahedron Lett. 1985, 26, 1145.
(17) Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.;
Snieckus, V. J. Org. Chem. 1992, 57, 4066.
EIMS: m/z (%) = 313 (M+,13), 298 (100), 183 (24), 120 (10).
HRMS: calcd. for C19H27NOSi: 313.1862. Found: 313.1873.
(18) Tímár, T.; Sebõk, P.; Kover, K. E.; Jaszgerenyi, J. C. Magn.
Reson. Chem. 1989, 27, 303.
Acknowledgement
We are grateful to NSERC Canada and Monsanto for support under
the Industrial Research Chair tenure at Waterloo (1992-98) and the
continuing NSERC support of our synthetic programs at Queen’s
University.
Article Identifier:
1437-210X,E;2001,0,01,0140,0144,ftx,en;M00800SS.pdf
Synthesis 2001, No. 1, 140–144 ISSN 0039-7881 © Thieme Stuttgart · New York