Synthesis of multifunctionalized furans from diazoallenes: Rearrangement of 6-methylenebicyclo[3.1.0] hexanes

Article abstract of DOI:10.1055/s-2006-950215

The synthesis of annulated tetrasubstituted furans using diazoallene precursors is described. This reaction provides efficient access to synthetically useful furan intermediates, which are otherwise difficult to obtain. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950215

PAPER
3605
Synthesis of Multifunctionalized Furans from Diazoallenes: Rearrangement of
6-Methylenebicyclo[3.1.0]hexanes
T
etrasubstituted
u
A
nnulated F
a
urans nli Yao, Allen Hong, Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, CA 94720, USA
Fax +1(510)6429675; E-mail: rsarpong@berkeley.edu
Received 30 May 2006
Dedicated to Professor Martin F. Semmelhack on the occasion of his 65th birthday
stage, valence recombination of 2 followed by alkene
isomerization was expected to give aromatic tetrasubsti-
tuted furan 3.
Abstract: The synthesis of annulated tetrasubstituted furans using
diazoallene precursors is described. This reaction provides efficient
access to synthetically useful furan intermediates, which are other-
wise difficult to obtain.
To test this hypothesis, we embarked on a synthesis of di-
Key words: diazoallene, [3+2] cycloaddition, multifunctionalized azoallenes 1, which began with the synthesis of alcohol 7
furans
as outlined in Scheme 2.
The synthesis of 7 commenced with the addition of the
lithium acetylide generated from alkyne 4 to 4-tert-bu-
Substituted furans are found in a wide range of natural
tyldimethylsilyloxybutanal to provide propargylic alcohol
products and also serve as important synthetic intermedi-
5 in excellent yield. Sequential treatment of 5 with o-ni-
trobenzenesulfonyl hydrazide (o-NBSH), diethyl azodi-
ates.1 As a result of the ubiquitous nature of furans, many
strategies have emerged to address their installation. For
carboxylate (DEAD) and PPh3, following the Myers
example, the Feist–Bénary2 and Paal–Knorr3 furan syn-
theses are readily applied to the synthesis of annulated
furans. However, tetrasubstituted annulated furans have
been especially challenging to access, and often require
multiple functionalizations of an initially installed furan
core. As part of a general program to define new strategies
for annulating five-membered carbo- and heterocycles to
other rings,4 we envisioned a sequence that would accom-
plish both the construction and annulation of tetrasubsti-
tuted furans. As a starting point for our studies, we
targeted the synthesis of bicycles such as 3 (Scheme 1),
which could be directly applied to the synthesis of a vari-
ety of natural products.
protocol,6 gave allenol 7 after deprotection of the primary
hydroxyl group. A Swern oxidation of alcohol 7
(Scheme 3) yielded an intermediate aldehyde, which was
reacted with ethyl diazoacetate in the presence of DBU to
provide 8. Direct oxidation of alcohol 8 to the correspond-
ing ketone proved to be difficult, consistent with the ob-
servations of others.7 This unanticipated hurdle was
circumvented by the treatment of 8 with Rh2(OAc)4 to af-
ford b-keto ester 9. At this stage, diazo installation using
p-acetamidobenzenesulfonyl azide (p-ABSA) furnished
10 in good yield.
Access to 10 set the stage for the key annulation/cycliza-
tion sequence to access tetrasubstituted furans such as 13.
In the event, dropwise addition of 10 into a CH2Cl2 solu-
tion of Rh2(OAc)4 (3 mol%) at 23 °C yielded methyle-
necyclopropane 11 as an inconsequential mixture of
isomers in 73% yield after stirring for 4 hours. Upon heat-
ing at 120 °C for 12 hours in toluene, 11 was smoothly
converted to furan 13 in excellent yield, presumably via
the intermediacy of 12 (Scheme 4).
We envisaged that diazoallenes such as 1 could serve as
precursors to 3 via a formal [3+2] cycloaddition/isomer-
ization sequence initiated by rhodium complexes. This
would presumably begin with decomposition of the diazo
group to yield a rhodacarbenoid, which upon interaction
with the allene (via a heterolytic or homolytic process)
would yield either 2a or 2b, respectively, reminiscent of
trimethylenemethane (TMM) intermediates.5 At this
O
O
O
OEt
O
O
O
OEt
O
OEt
OEt
Rh(II)
•
N2
H
O
•
or
•
Ar
Ar
Ar
Ar
3
2a
2b
1
Scheme 1
SYNTHESIS 2006, No. 21, pp 3605–3610
x
x.
x
x
.
2
0
0
6
Advanced online publication: 21.08.2006
DOI: 10.1055/s-2006-950215; Art ID: Z10506SS
© Georg Thieme Verlag Stuttgart · New York

3606
T. Yao et al.
PAPER
O
O
S
NHNH2
1. n-BuLi
MeO
MeO
NO2
MeO
OH
2.
PPh3, DEAD
THF, –15 °C to 23 °C
(72% yield)
TBSO
CHO
THF, –78 °C to 23 °C
(88% yield)
MeO
TBSO
4
5
MeO
MeO
MeO
H
•
OH
H
•
OTBS
TBAF
THF, 0–23 °C
MeO
(98% yield)
7
6
Scheme 2
MeO
EtO
H
O
Rh2(OAc)4
(10 mol%)
1. (COCl)2, DMSO, Et3N
7
OH
N2
•
CH2Cl2
2. DBU, N2CHCO2Et
(52% yield)
(85% yield)
MeO
8
O
S
O
N3
MeO
EtO
H
O
MeO
MeO
EtO
H
O
AcHN
Et3N
O
O
N2
•
MeCN, 23 °C
(78% yield)
•
MeO
9
10
Scheme 3
MeO
MeO
MeO
MeO
Rh2(OAc)4
(3 mol%)
EtO
H
O
120 °C
PhMe
O
O
H
N2
CH2Cl2, 23 °C
(73% yield)
•
OEt
11
O
10
MeO
MeO
OEt
O
OEt
O
O
O
(88% yield)
MeO
MeO
12
13
Scheme 4
Tetrasubstituted furan 13 provided crystals suitable for X- range of substrates as shown in Table 1. A series of aro-
ray crystallography. The ORTEP depiction of 13, shown matic groups are readily tolerated at the terminus of the al-
in Figure 1 corroborates the assigned structure.
lene (entries 1–3) as are alkyl substituents (entries 4 and
5). Additionally, sensitive groups such as acetonides and
activated allylic ethers (entry 5) easily participate in this
A preliminary survey has revealed this conversion of dia-
zoallenes to annulated furans to be quite general for a
Synthesis 2006, No. 21, 3605–3610 © Thieme Stuttgart · New York

PAPER
Tetrasubstituted Annulated Furans
3607
OEt
O
OEt
O
DDQ
O
PhH, 120 °C, 8 h
(51% yield)
OH
17
22
Scheme 5
transformation to provide products poised for further ma-
nipulation.
The furan products (e.g. 17, Scheme 5) can be further
elaborated to isobenzofurans via DDQ-promoted dehy-
drogenation in preparation for further functionalization
(e.g. cycloaddition reactions).
In conclusion, we have developed an efficient strategy for
the synthesis of annulated tetrasubstituted furans, which
possess functionality that should allow for further synthet-
ic operations. The synthesis strategy relies on a formal
[3+2] cycloaddition/isomerization sequence of allenyl
rhodacarbenoids that are generated from diazoallene pre-
cursors.8 The Myers protocol for allene formation pro-
vides a powerful entry to the diazoallene substrates.
Figure 1 ORTEP illustration of furan 13 with thermal ellipsoids
drawn at 50% probability (hydrogens are omitted for clarity).
Table 1 Preparation of Tetrasubstituted Furans from Diazoallenes
Entry
1
Diazoallene
Product
Yield (%)
64
H
H
MeO
OEt
•
O
N2
MeO
O
O
OEt
MeO
OMe
O
13
10
2
3
4
5
56
47
55
52
H
H
OMe
OEt
MeO
•
O
O
N2
O
O
OEt
O
15
17
14
H
H
OEt
•
N2
O
O
OEt
O
16
H
H
OEt
O
•
N2
O
O
OEt
O
19
21
18
H
H
OEt
O
O
•
N2
O
O
O
O
O
OEt
O
20
Synthesis 2006, No. 21, 3605–3610 © Thieme Stuttgart · New York

3608
T. Yao et al.
PAPER
All air- or moisture-sensitive reactions were conducted in flame-
dried glassware under N2 using anhydrous, deoxygenated solvents.
Toluene, MeCN, CH2Cl2, and Et3N were distilled under N2 from
CaH2 immediately prior to use and THF was distilled under N2 from
sodium benzophenone ketyl. All other reagents were purchased
from Aldrich or Lancaster and used without further purification.
Melting points were measured on a Büchi melting point apparatus
and are corrected using vanillin (mp 80–81 °C) as a standard. Reac-
tion temperatures were controlled by an IKAmag temperature mod-
ulator. TLC was performed using Merck silica gel 60 F254
precoated plates (0.25 mm) and visualized by UV and anisaldehyde
stain. Fisher silica gel 240–400 mesh (particle size 0.032–0.063)
was used for flash chromatography. 1H and 13C NMR spectra were
recorded on a Bruker DRX-500 (at 500 MHz and 125 MHz, respec-
tively), on a Bruker AVB-400 (at 400 MHz and 100 MHz, respec-
tively) and AV-300 (at 300 MHz and 75 MHz, respectively) in
CDCl3 at 23 °C, unless otherwise stated. Chemical shifts were ref-
erenced to the residual solvent peak, which was set at 7.26 ppm for
1H and 77.23 ppm (center peak) for 13C spectra. IR spectra were re-
corded on a Nicolet MAGNA-IR 850 spectrometer and are reported
in cm–1. High-resolution mass spectral data were obtained from the
University of California, Berkeley Mass Spectral Facility.
1H NMR (300 MHz, CDCl3): d = 0.02 (s, 6 H), 0.87 (s, 9 H), 1.61–
1.73 (m, 2 H), 2.14–2.22 (m, 2 H), 3.65 (t, J = 6.3 Hz, 2 H), 3.76 (s,
6 H), 5.58 (dt, J = 6.6, 6.3 Hz, 1 H), 6.05 (dt, J = 6.6, 3.0 Hz, 1 H),
6.30 (t, J = 2.1 Hz, 1 H), 6.44 (d, J = 2.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 205.4, 161.1, 137.4, 104.8, 99.2,
95.3, 95.1, 62.7, 55.5, 32.3, 26.2, 25.2, 18.5.
6-(3,5-Dimethoxyphenyl)hexa-4,5-dien-1-ol (7); Typical Proce-
dure
A flame-dried, round-bottom flask was charged with anhyd THF
(20 mL) and allene 6 (0.696 g, 2.0 mmol). The solution was cooled
to 0 °C and TBAF (2.0 mL, 2.0 mmol, 1.0 M in THF) was added
slowly over 30 min. The solution was allowed to stir for 15 min at
0 °C and slowly warmed up to 23 °C. After stirring at 23 °C for 4 h,
sat. aq NH4Cl solution (20 mL) was added slowly and stirring con-
tinued for 15 min. The mixture was diluted with EtOAc (40 mL) and
the aqueous layer was extracted with EtOAc (2 × 20 mL). The com-
bined organic layers were washed with brine and dried (MgSO4).
The solvent was removed under reduced pressure and the concen-
trate was purified by flash column chromatography (1:1 hexanes–
EtOAc) to obtain the pure alcohol 7; yield: 0.460 g (98%); dense
liquid; Rf 0.32 (1:1 hexanes–EtOAc).
IR (neat): 3362, 2937, 1604, 1473, 1204 cm–1.
6-{[tert-Butyl(dimethyl)silyl]oxy}-1-(3,5-dimethoxyphenyl)hex-
1-yn-3-ol (5); Typical Procedure
1H NMR (300 MHz, CDCl3): d = 1.71 (tt, J = 6.6, 7.2 Hz, 2 H),
2.14–2.22 (m, 3 H), 3.65 (t, J = 6.6 Hz, 2 H), 3.75 (s, 6 H), 5.57 (q,
J = 6.6 Hz, 1 H), 6.05 (dt, J = 6.3, 3.0 Hz, 1 H), 6.29 (t, J = 2.1 Hz,
1 H), 6.43 (d, J = 2.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 205.4, 161.0, 137.1, 104.7, 99.2,
95.3, 94.8, 62.2, 55.4, 31.9, 25.0.
A flame-dried, round-bottom flask was charged with anhyd THF
(23 mL) and 1-ethynyl-3,5-dimethoxybenzene (1.15 g, 7.09 mmol).
The solution was cooled to –78 °C and n-BuLi (3.0 mL, 7.5 mmol,
2.5 M in hexanes) was added slowly over 20 min. The solution was
allowed to stir for 15 min at –78 °C and slowly warmed to 0 °C. Af-
ter stirring at 0 °C for 20 min, the solution was cooled down again
to –78 °C. 4-tert-Butyldimethylsilyloxybutanal (1.474 g, 7.80
mmol) was added slowly over 20 min. The mixture was stirred for
an additional 15 min at –78 °C, then the acetone bath was removed
and the mixture was allowed to warm to 23 °C. After 1 h, sat. aq
NH4Cl solution (30 mL) was added slowly and stirring continued
for 15 min. The mixture was diluted with EtOAc (40 mL) and the
aqueous layer was extracted with EtOAc (2 × 20 mL). The com-
bined organic layers were washed with brine and dried (MgSO4).
The solvent was removed under reduced pressure and the concen-
trate was purified by flash column chromatography (2:1 hexanes–
EtOAc) to obtain the pure propargylic alcohol 5; yield: 2.14 g
(86%); dense liquid; Rf 0.37 (2:1 hexanes–EtOAc).
Ethyl 8-(3,5-Dimethoxyphenyl)-3-oxoocta-6,7-dienoate (9);
Typical Procedure
To a solution of oxalyl chloride (0.33 mL, 3.84 mmol) in CH2Cl2
(5.5 mL) at –50 °C was added DMSO (0.53 mL, 3.65 mmol). After
stirring for 15 min, alcohol 7 (0.45 g, 1.92 mmol) in CH2Cl2 (5.5
mL) was added and the mixture was stirred for 30 min. Et3N (1.68
mL, 11.5 mmol) was then added and after stirring for 30 min, the
reaction was warmed to 23 °C over 2 h and quenched with H2O (15
mL) and aq sat. NH4Cl (15 mL). The aqueous phase was extracted
with CH2Cl2 (3 × 30 mL). The combined organic extracts were dried
(MgSO4), filtered and concentrated. The product was filtered
through a plug of silica gel (66% EtOAc in hexanes) to furnish the
corresponding aldehyde as a colorless oil, which was immediately
taken on to the next step. To a solution of this aldehyde in MeCN
(20 mL) was added ethyl diazoacetate (0.53 mL, 3.84 mmol) fol-
lowed by DBU (53.8 mL, 0.37 mmol) dropwise via syringe. The
mixture was stirred at 23 °C overnight and concentrated. The resi-
due was purified by flash column chromatography (2:1 hexanes–
EtOAc) to afford 8 as a light yellow oil in 52% overall yield (0.332
g). To a solution of alcohol 8 (320 mg, 0.97 mmol) in CH2Cl2 (28
mL) was added Rh2(OAc)4 (43 mg, 0.097 mmol). A gaseous evolu-
tion was observed from the green reaction mixture. After 30 min,
the solution was concentrated and the crude material was filtered
through a plug of silica gel (66% EtOAc in hexane) to give 9 as col-
orless oil; yield: 0.25 g (5%); dense liquid; Rf 0.2 (4:1 hexanes–
EtOAc).
IR (neat): 3386, 2954, 1597, 1421, 1254 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.04 (s, 6 H), 0.87 (s, 9 H), 1.64–
1.99 (m, 4 H), 3.60–3.70 (m, 9 H), 4.60 (t, J = 6.0 Hz, 1 H), 6.38 (t,
J = 2.4 Hz, 1 H), 6.53 (t, J = 2.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 160.5, 124.3, 109.5, 101.7, 90.0,
84.6, 63.3, 62.5, 55.4, 35.4, 28.7, 26.0, 18.4, –5.2.
tert-Butyl{[6-(3,5-dimethoxyphenyl)hexa-4,5-dienyl]oxy}di-
methylsilane (6); Typical Procedure
DEAD (0.69 mL, 4.5 mmol) was added to a solution of Ph3P (1.18
g, 4.5 mmol) in THF (12 mL) at –15 °C. After 8 min, a solution of
propargylic alcohol 5 (1.09 g, 3.0 mmol) in THF (9 mL) was added
to the yellow mixture, followed 30 min later by a solution of NBSH
(0.97 g, 4.5 mmol) in THF (12 mL). The resulting suspension was
held at –15 °C for 1 h, after which time TLC analysis indicated
complete consumption of the starting alcohol 5. The mixture was
warmed to 23 °C and allowed to stand for 4 h. Concentration of the
mixture and purification of the residue by flash column chromatog-
raphy (20:1 hexanes–EtOAc) afforded allene 6 as yellow oil; yield:
0.749 g (72%); dense liquid; Rf 0.38 (9:1 hexanes–EtOAc).
IR (neat): 2938, 1742, 1716, 1593, 1205 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.21 (t, J = 7.2 Hz, 3 H), 2.23–2.48
(m, 2 H), 2.69 (dt, J = 1.6, 7.2, Hz, 2 H), 3.30–3.48 (m, 2 H), 3.78
(s, 6 H), 4.11 (q, J = 7.2 Hz, 2 H), 5.59–5.66 (m, 1 H), 6.08 (dt,
J = 6.4, 3.6 Hz, 1 H), 6.29 (t, J = 2.0 Hz, 1 H), 6.39 (d, J = 2.4 Hz,
2 H).
13C NMR (100 MHz, CDCl3): d = 205.1, 202.0, 167.2, 161.1, 136.7,
104.7, 99.5, 96.6, 94.2, 61.5, 55.5, 49.6, 41.4, 34.2, 22.3, 14.2.
IR (neat): 2954, 1604, 1472, 1205, 1155 cm–1.
Synthesis 2006, No. 21, 3605–3610 © Thieme Stuttgart · New York

PAPER
Tetrasubstituted Annulated Furans
3609
HRMS (EI+): m/z calcd for [C18H22O5]+: 318.1467; found:
318.1469.
1H NMR (300 MHz, CDCl3): d (major diastereomer) = 1.20–1.39
(m, 9 H), 2.29–2.37 (m, 2 H), 2.84–3.09 (m, 2 H), 3.57–3.68 (m, 1
H), 4.04–4.10 (m, 1 H), 4.27 (q, J = 9.0 Hz, 2 H), 4.44–4.54 (m, 1
H), 5.15–5.21 (m, 1 H), 5.27–5.38 (m, 1 H).
13C NMR (75 MHz, CDCl3): d (major diastereomer) = 204.9, 191.9,
109.6, 92.4, 92.1, 75.0, 69.6, 61.6, 39.3, 26.9, 26.1, 23.0, 14.6.
8-(3,5-Dimethoxyphenyl)-1-ethoxy-1,3-dioxoocta-6,7-diene-2-
diazonium (10); Typical Procedure
To a solution of keto ester 9 (45.3 mg, 0.15 mmol) in MeCN (2.5
mL) at 0 °C was added Et3N (64.5 mL, 0.45 mmol) followed by p-
acetamidobenzenesufonyl azide (73.5 mg, 0.3 mmol). After 10 min
at 0 °C, the solution was allowed to warm to r.t. over 4 h. The mix-
ture was poured into H2O (10 mL) and extracted with Et2O (3 × 10
mL). The combined organic extracts were washed with brine (10
mL), dried (MgSO4), filtered and concentrated. The product was
purified by flash column chromatography (3:1 hexanes–EtOAc) to
afford 10 as colorless oil in 70% overall yield (38.6 mg); dense liq-
uid; Rf 0.32 (3:1 hexanes–EtOAc).
Tetrasubstituted Furans from Diazoallenes; 1-(3,5-Dimethoxy-
phenyl)-3-ethoxy-6,7-dihydro-2-benzofuran-4(5H)-one (13);
Typical Procedure
A flame-dried, round-bottom flask was charged with CH2Cl2 (12
mL) and Rh2(OAc)4 (1.49 mg, 0.0036 mmol). Allene 10 (38.6 mg,
0.12 mmol) in CH2Cl2 (2 mL) was added over 2 h via syringe pump.
After stirring at rt for 4 h, the solution was concentrated and the
crude material was filtered through a plug of florisil (66% EtOAc in
hexane) to give the corresponding 6-methylenebicyclo[3.1.0]hex-
ane 11 (E/Z = 7.6:1) as a colorless oil. A flame-dried 25 mL Schlenk
flask equipped with a Teflon screw-top cap was charged with 11 (as
obtained above) in anhyd toluene (0.038 M). The mixture was
flushed with N2 by sparging over 1 min and capped tightly. The
flask was placed in an oil bath which was heated to 120 °C (ca. 20
min) and held at this temperature overnight. At the completion of
the reaction (determined by TLC analysis), the solvent was re-
moved by evaporation under reduced pressure and the concentrate
was purified by flash chromatography (1:1 hexanes–EtOAc) to af-
ford furan 13 in 64% overall yield (23 mg); white solid; mp 104–
105 °C; Rf 0.33 (1:1 hexanes–EtOAc).
IR (neat): 2938, 1716, 1653, 1593 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.2 Hz, 3 H), 2.34–2.63
(m, 2 H), 2.89 (dt, J = 17.1, 6.6 Hz, 1 H), 3.16 (dt, J = 16.8, 6.9 Hz,
1 H), 3.76 (s, 6 H), 4.20 (q, J = 7.2 Hz, 2 H), 5.63 (dt, J = 6.0, 6.0
Hz, 1 H), 6.07 (dt, J = 6.3, 3.3 Hz, 1 H), 6.28–6.30 (m, 1 H), 6.38–
6.40 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 205.4, 192.1, 161.5, 161.1, 137.0,
104.7, 99.6, 96.5, 94.5, 61.6, 55.5, 38.5, 23.4, 14.5.
The allenes 14, 16 and 18 were prepared by the same sequence of
reactions starting from appropriate alkynes (Table 1). The proper-
ties of the final products, allenes 14, 16 and 18 are given below.
IR (neat): 2941, 1741, 1679, 1576, 1205, 1157 cm–1.
14
1H NMR (300 MHz, CDCl3): d = 1.50 (t, J = 7.1 Hz, 3 H), 2.02 (tt,
J = 6.6, 6.0 Hz, 2 H), 2.44 (t, J = 6.3 Hz, 2 H), 2.85 (t, J = 6.3 Hz, 2
H), 3.81 (s, 6 H), 4.60 (q, J = 7.1 Hz, 2 H), 6.34 (t, J = 2.4 Hz, 1 H),
6.61 (J = 2.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 193.4, 161.2, 159.6, 136.9, 132.4,
122.2, 102.6, 100.4, 98.5, 68.2, 55.6, 39.4, 23.9, 22.6, 15.2.
Dense liquid; Rf 0.47 (3:1 hexanes–EtOAc).
IR (neat): 3400, 1716, 1653, 1303 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.2 Hz, 3 H), 2.35–2.59
(m, 2 H), 2.92 (dt, J = 16.8, 6.6 Hz, 1 H), 3.11 (dt, J = 16.8, 7.2 Hz,
1 H), 3.80 (s, 3 H), 4.20 (q, J = 7.2 Hz, 2 H), 5.59 (dt, J = 6.3, 6.3
Hz, 1 H), 6.55 (dt, J = 6.6, 3.3 Hz, 1 H), 6.80–6.90 (m, 2 H), 7.14
(dt, J = 1.5, 7.4 Hz, 1 H), 7.31 (dd, J = 1.5, 6.0 Hz, 1 H).
HRMS (EI+): m/z calcd for [C18H20O5]+: 316.1311; found:
316.1304.
13C NMR (75 MHz, CDCl3): d = 205.6, 192.2, 161.5, 156.0, 128.1,
127.8, 123.1, 120.9, 111.0, 93.4, 90.1, 61.5, 55.7, 38.9, 23.6, 14.4.
15
Colorless oil; Rf 0.29 (1:1 hexanes–EtOAc).
IR (neat): 3391, 294, 1678, 1580, 1247 cm–1.
16
Dense liquid; Rf 0.48 (3:1 hexanes–EtOAc).
1H NMR (300 MHz, CDCl3): d = 1.48 (t, J = 6.9 Hz, 3 H), 1.97 (tt,
J = 6.3, 6.0 Hz, 2 H), 2.43 (t, J = 6.3 Hz, 2 H), 2.64 (t, J = 6.3 Hz, 2
H), 3.85 (s, 3 H), 4.56 (q, J = 6.9 Hz, 2 H), 6.92–7.01 (m, 2 H),
7.24–7.31 (m, 1 H), 7.35 (d, J = 7.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 193.8, 160.1, 156.2, 134.7, 129.2,
123.4, 120.8, 119.6, 111.5, 100, 67.9, 55.6, 39.7, 24.1, 22.8, 15.3.
IR (neat): 2982, 1723, 1711, 1658, 1304 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.2 Hz, 3 H), 2.36–2.64
(m, 2 H), 2.91 (dt, J = 16.8, 6.6 Hz, 1 H), 3.16 (dt, J = 16.8, 7.2 Hz,
1 H), 4.20 (q, J = 7.2 Hz, 2 H), 5.64 (dt, J = 6.3, 6.0 Hz, 1 H), 6.15
(dt, J = 6.3, 3.3 Hz, 1 H), 7.14–7.37 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 205.3, 192.1, 161.5, 134.9, 128.8,
127.1, 126.9, 96.4, 94.3, 76.7, 61.6, 38.7, 23.6, 14.5.
HRMS (EI+): m/z calcd for [C17H18O4]+: 286.1205; found:
286.1201.
18
17
Dense liquid; Rf 0.51 (4:1 hexanes–EtOAc).
White solid; mp 98–99 °C; Rf 0.18 (2:1 hexanes–EtOAc).
IR (neat): 2940, 1678, 1612, 1580, 1264 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.51 (t, J = 7.2 Hz, 3 H), 1.97 (tt,
J = 6.4, 6.0 Hz, 2 H), 2.45 (t, J = 6.4 Hz, 2 H), 2.86 (t, J = 6.0 Hz, 2
H), 4.61 (q, J = 6.8 Hz, 2 H), 7.19–7.24 (m, 1 H), 7.38 (t, J = 7.6 Hz,
2 H), 7.47 (d, J = 8.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3). d = 193.5, 159.7, 137.1, 130.8, 128.9,
126.6, 124.1, 121.6, 100.3, 68.1, 39.4, 23.9, 22.5, 15.2.
HRMS (EI+): m/z calcd for [C16H16O3]+: 256.1099; found:
IR (neat): 2959, 1719, 1654, 1292 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.85 (t, J = 7.2 Hz, 3 H), 1.21–1.37
(m, 7 H), 1.87–1.96 (m, 2 H), 2.24–2.32 (m, 2 H), 2.93 (t, J = 7.2
Hz, 2 H), 4.26 (q, J = 7.2 Hz, 2 H), 5.04–5.14 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 203.9, 192.3, 161.5, 92.5, 89.8,
76.2, 61.5, 39.5, 31.5, 28.8, 23.5, 22.4, 14.5, 14.1.
20
Mixture of diastereomers (dr = 4.5:1); dense liquid; Rf 0.52 (2:1
hexanes–EtOAc).
256.1102.
IR (neat): 2985, 1717, 1655, 1372 cm–1.
Synthesis 2006, No. 21, 3605–3610 © Thieme Stuttgart · New York

3610
19
T. Yao et al.
PAPER
1H NMR (500 MHz, CDCl3): d = 0.82 (t, J = 7.2 Hz, 3 H), 4.03 (q,
J = 7.2 Hz, 2 H), 6.79 (d, J = 7.5 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1 H),
7.42 (t, J = 7.5 Hz, 2 H), 7.48–7.56 (m, 2 H), 7.75 (d, J = 8.0 Hz, 2
H), 11.1 (s, 1 H).
Colorless oil; Rf 0.25 (3:1 hexanes–EtOAc).
IR (neat): 2934, 2871, 1680, 1582, 1068 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 7.2 Hz, 3 H), 1.18–1.35
(m, 2 H), 1.41 (t, J = 6.9 Hz, 2 H), 1.51 (tt, J = 7.2, 7.5 Hz, 2 H),
1.91 (tt, J = 6.6, 6.3 Hz, 2 H), 2.35 (t, J = 6.6 Hz, 2 H), 2.41–2.61
(m, 2 H), 4.47 (q, J = 6.9 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 196.2, 169.4, 162.0, 137.3, 135.2,
133.4, 129.6, 128.7, 119.2, 118.7, 62.3, 13.2.
13C NMR (75 MHz, CDCl3): d = 193.6, 159.1, 139.3, 119.0, 67.8,
Acknowledgment
39.7, 30.5, 257, 24.1, 22.3, 20.6, 15.2, 14.0.
The authors thank UC Berkeley, GlaxoSmithKline, Eli Lilly, and
the Elsa U. Pardee Foundation for generous funding.
21
Colorless oil; Rf 0.29 (1:1 hexanes–EtOAc).
IR (neat): 2985, 1683, 1580, 1061 cm–1.
References
1H NMR (300 MHz, CDCl3): d = 1.40–1.47 (m, 9 H), 1.95 (tt,
J = 6.3, 6.0 Hz, 2 H), 2.37 (t, J = 6.6 Hz, 2 H), 2.51–2.70 (m, 2 H),
4.04 (t, J = 8.1 Hz, 1 H), 4.14 (t, J = 7.5 Hz, 1 H), 4.51 (q, J = 6.9
Hz, 2 H), 4.98 (t, J = 4.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 193.1, 160.1, 133.4, 125.6, 109.8,
99.0, 69.7, 68.1, 66.9, 39.6, 26.3, 26.1, 23.8, 20.5, 15.2.
(1) Joule, J. A.; Mills, K. Heterocyclic Chemistry; 4th ed.,
Blackwell: Oxford, 2000, 296.
(2) For an application to annulated furan synthesis, see:
Zambias, R.; Caldwell, C.; Kopka, I.; Hammond, M. J. Org.
Chem. 1988, 53, 4135.
(3) Koenig, B. In Science of Synthesis, Vol. 9; Maas, G., Ed.;
Thieme: Stuttgart, 2002, 183.
(4) For recent reports from our group in this regard, see:
(a) Bhanu Prasad, B. A.; Yoshimoto, F. K.; Sarpong, R. J.
Am. Chem. Soc. 2005, 127, 12468. (b) Pujanauski B. G.,
Bhanu Prasad B. A., Sarpong R.; J. Am. Chem. Soc.; 2006,
128: 6786.
(5) For a pertinent, recent review on the trimethylmethylene-
methane diyl, see: Allan, A. K.; Carroll, G. L.; Little, R. D.
Eur. J. Org. Chem. 1998, 1.
(6) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492.
(7) See, for example: Hughes, C. C.; Kennedy-Smith, J. J.;
Trauner, D. Org. Lett. 2003, 5, 4113.
(8) The diazoallene compounds were found to be unstable using
EI techniques for mass spectrometry measurements.
3-Ethoxy-1-phenyl-2-benzofuran-4-ol (22)
A flame-dried 25 mL Schlenk flask equipped with a Teflon screw-
top cap was charged with 17 (12 mg, 0.0468 mmol) and DDQ (22
mg, 0.097 mmol) in anhyd benzene (0.024 M). The mixture was
flushed with N2 by sparging over 1 min and capped tightly. The
flask was placed in an oil bath which was heated to 120 °C (ca. 20
min) and held at this temperature overnight. At the completion of
the reaction (determined by TLC analysis), the solvent was re-
moved by evaporation under reduced pressure and the concentrate
was purified by preparative TLC (3:1 hexanes–EtOAc) to afford 22;
yield: 6.1 mg (51%); white solid; mp 72–73 °C; Rf 0.47 (3:1 hex-
anes–EtOAc).
IR (neat): 2984, 1674, 1599, 1275, 1193 cm–1.
Synthesis 2006, No. 21, 3605–3610 © Thieme Stuttgart · New York