Annulated isoxazoles via [3 + 2] cycloaddition of alkenyl bromides and oximoyl chlorides and Ag(I) promoted elimination

Article abstract of DOI:10.1021/jo501376q

Substituted salicylaldehydes are converted to fused tetracyclic isoxazoles through a synthetic sequence incorporating substitution of 2-bromo-2-cyclohexen- 1-ol, formation of an oxime function, conversion to an oximoyl chloride, intramolecular [3 + 2] cycloaddition, and elimination of an equivalent of hydrogen bromide using silver(I) carbonate. Six examples of this sequence are presented.

Full text of DOI:10.1021/jo501376q

Note
pubs.acs.org/joc
Annulated Isoxazoles via [3 + 2] Cycloaddition of Alkenyl Bromides
and Oximoyl Chlorides and Ag(I) Promoted Elimination
Emmanuel B. Castillo-Contreras, Alexander M. Stahl,† and Gregory R. Dake*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, B. C., Canada, V6T 1Z1
S
* Supporting Information
ABSTRACT: Substituted salicylaldehydes are converted to fused tetracyclic isoxazoles
through a synthetic sequence incorporating substitution of 2-bromo-2-cyclohexen-1-ol,
formation of an oxime function, conversion to an oximoyl chloride, intramolecular [3 +
2] cycloaddition, and elimination of an equivalent of hydrogen bromide using silver(I)
carbonate. Six examples of this sequence are presented.
t is well-established that [3 + 2] dipolar cycloaddition
I
reactions provide straightforward access to a variety of
functionalized heterocyclic ring systems.1 Indeed, the effective-
ness of this specific strategy has led to its frequent application
in the generation of heterocyclic lead compounds for potential
treatments in human disease.2 On a tangent within a broader
synthetic project, we became interested in the construction of
isoxazole and isoxazoline heterocycles connected to substituted
[4.4.0]-bicyclooxacyclodecane ring systems (Figure 1). The
with a small number of substituted salicylaldehydes to produce
ethers 3b−f. The reaction of 4-bromosalicylaldehyde was
particularly low yielding; extended efforts to improve the
reaction yields were not made.
The aldehyde functions in 3a−f were converted to oximes
using established reaction conditions (NH2OH, water, 100 °C,
Scheme 1). No unexpected reactivity was noted. The Suzuki
Figure 1. Strategy for annulated isoxazoles.
experimental record suggested that a synthetic approach
incorporating a dipolar cycloaddition would be viable. First,
dipolar cycloadditions of nitrones and nitrile oxides had been
described previously in substrates, where Q = H.3 In addition,
alkenyl halides (e.g., if Q = Cl or Br) had been used as
dipolarophiles in [3 + 2] cycloadditions,4 although not in this
specific context. Finally, an example of an elimination of a
bromo-substituted isoxazoline to generate an unstrained
isoxazole had been carried out some time ago.5 Consequently,
the proposed route seemed to have validity. This report
summarizes our brief investigation in this matter.
Scheme 1
Substituted salicylaldehydes (1a−f) were selected as starting
materials for the sequence. The alkylation of the phenol
function of these salicylaldehydes with an appropriate electro-
phile was more challenging than anticipated. Extensive
experimentation established that 2-bromo-2-cyclohexen-1-ol
(2) could be reacted with methanesulfonyl anhydride and
triethylamine to generate a (putative) methanesulfonate.6 A
direct interception of this intermediate required DBU and
salicylaldehyde (1a) in dichloromethane to generate 3a in 72%
yield (eq 1). Attempted substitutions using Mitsunobu
conditions (side reactions), p-toluenesulfonate electrophiles
(reagent instability), or chloride electrophiles (low yields) had
significant disadvantages. This procedure was used to react 2
Received: June 19, 2014
Published: July 22, 2014
© 2014 American Chemical Society
7250
dx.doi.org/10.1021/jo501376q | J. Org. Chem. 2014, 79, 7250−7255

The Journal of Organic Chemistry
Note
are recorded in parts per million (ppm) and are referenced to the
group has disclosed a highly effective method to convert oximes
to oximoyl chlorides using N-chlorosuccinimide in basic
conditions, followed by cycloaddition.7 In our hands, this
procedure was most efficient. Isolation of these intermediates
was not required; direct [3 + 2] cycloaddition occurred in the
presence of triethylamine to generate the expected heterocyclic
adducts in excellent yield.
The cleavage of the N−O bond of the isoxazoline
heterocycles8 using hydrogen gas and Raney nickel was
complicated by the generation of a large number of undesired
side products resulting from the reactivity of the C−Br bond.
The elimination of an equivalent of hydrogen bromide from
each of the compounds 5a−f could be accomplished using
silver carbonate in DMSO at 80 °C (eq 2). A number of
annulated isoxazoles 6a−f was generated. A solid-state
molecular structure obtained using X-ray crystallography
confirmed the structure of 6a.
1
centerline of deuterochloroform (δ 7.27 ppm H NMR; δ 77.2 ppm
13C NMR). High-resolution mass spectra were obtained on a time-of-
flight instrument using electrospray ionization.
Representative Procedure of Salicylaldehyde Alkylation
Using 2. 2-((2-Bromocyclohex-2-en-1-yl)oxy)benzaldehyde
(3a). Triethylamine (1.96 g, 15.2 mmol, 1.5 equiv) was added to a
solution of 2-bromo-2-cyclohexene-1-ol (1.77 g, 10 mmol, 1 equiv) in
50 mL of CH2Cl2 at 0 °C. A solution of methanesulfonic anhydride
(2.72 g, 15.2 mL, 1.5 equiv) in 50 mL of CH2Cl2 was added dropwise
over 30 min. The reaction mixture was stirred at 0 °C for 30 min and
then warmed to rt for 1 h. A solution of 3.78 g (30.3 mmol, 3 equiv) of
salicylaldehyde and 4.68 g (30.2 mmol, 3 equiv) of DBU in 50 mL of
CH2Cl2 was then slowly added dropwise over 30 min. The reaction
mixture was stirred at rt for 1 h and then heated to reflux for 16 h.
After it was cooled to rt, the reaction mixture was poured into a
separatory funnel and washed successively with aqueous 2 M HCl
solution (twice), aqueous 2 M NaOH solution (twice), and water
(twice). Drying over sodium sulfate and concentration by rotary
evaporation in vacuo produced a yellowy thick oil that, after
purification using chromatography over silica gel (hexanes:ethyl
acetate 9:1 to 4:1), yielded 2.0 g (72%) of the title compound as a
white solid, mp 78−79 °C. IR (neat): 2932, 1682, 1596, 1229, 653
cm−1. 1H NMR (300 MHz, CDCl3): δ 10.56 (s, 1H), 7.85 (dd, J = 7.7,
1.5 Hz, 1H), 7.54 (td, J = 7.9, 1.4 Hz, 1H), 7.11−7.03 (m, 2H), 6.42
(dd, J = 4.7, 3.1 Hz, 1H), 4.89 (s, 1H), 2.30−2.07 (m, 3H), 2.00−1.90
(m, 1H), 1.84−1.68 (m, 2H). 13C NMR (75 MHz; CDCl3): δ 190.2,
161.0, 135.9, 135.5, 128.4, 126.4, 121.6, 120.2, 114.9, 77.6, 29.6, 27.8,
17.1. MS (ESI+): 305.2 (M + Na)+. HRMS (ESI+): Calculated for
C13H13O2Na79Br (M + Na)+: 302.9997, found: 302.9990.
2-((2-Bromocyclohex-2-en-1-yl)oxy)-3-methoxybenz-
aldehyde (3b). The reaction was performed with 3.64 g (20.6 mmol)
of 2-bromo-2-cyclohexenol, 5.59 g (31.1 mmol) of methanesulfonic
anhydride, 3.19 g (31.6 mmol) of triethylamine, 9.54 g (62.1 mmol) of
o-vanillin, and 9.57 g (61.6 mmol) of DBU. After purification, 6.40 g
(98% yield) of the title compound was isolated as an off-white solid,
mp 64−65 °C. IR (neat): 2950, 1687, 1243, 572 cm−1. 1H NMR (300
MHz, CDCl3): δ 10.49 (s, 1H), 7.37 (dd, J = 7.2, 2.1 Hz, 1H), 7.09−
7.00 (m, 2H), 6.29 (dd, J = 4.6, 3.0 Hz, 1H), 4.88 (s, 1H), 3.82 (s,
3H), 2.21−2.14 (m, 2H), 2.04 (d, J = 8.1 Hz, 1H), 1.80 (dd, J = 15.3,
7.3 Hz, 2H), 1.64−1.61 (m, 1H). 13C NMR (75 MHz; CDCl3): δ
190.7, 152.3, 150.7, 135.1, 130.3, 123.7, 120.7, 118.8, 117.9, 79.6, 55.9,
30.1, 27.8, 16.5. MS (ESI+): 333.3 (M + Na)+. HRMS (ESI+):
Calculated for C14H15O3Na79Br: 333.0102, found: 333.0099.
An example of the utility of these heterocycles can be
demonstrated using a N−O bond cleavage reaction. The
reduction of the isoxazole N−O bond was expected to be much
simpler due to the increase of ring strain of 6 compared with 5.
Thus, the hydrogenolysis of the N−O bond in 6a and 6b using
hydrogen gas over Raney nickel readily occurred to generate
vinylogous amides 7a and 7b in 98% and 92% yields,
respectively (eq 3). The structure of 7b was confirmed by X-
ray crystallography.
2-((2-Bromocyclohex-2-en-1-yl)oxy)-4-methoxybenz-
aldehyde (3c). The reaction was performed with 1.81 g (10.2 mmol)
of 2-bromo-2-cyclohexenol, 2.81 g (15.8 mmol) of methanesulfonic
anhydride, 1.60 g (15.8 mmol) of triethylamine, 2.40 g (15.5 mmol) of
2-hydroxy-4-methoxybenzaldehyde, and 2.44 g (15.7 mmol) of DBU.
After purification, 1.26 g (40% yield) of the title compound was
obtained as a light yellow oil. IR (neat): 2939, 1675, 1596, 1254, 620
In summary, isoxazole heterocycles appended onto an
oxabicyclo[4.4.0]decane ring could be formed through a
sequence incorporating a intramolecular dipolar cycloaddition
using an alkenyl bromide as a dipolarophile and a silver(I)
promoted elimination. These heterocyclic frameworks, and
nitrogen-containing versions, could prove to be useful structural
motifs for exploratory medicinal chemistry programs.
1
cm−1. H NMR (300 MHz, CDCl3): δ 10.38 (s, 1H), 7.85 (d, J = 8.6
Hz, 1H), 6.62−6.56 (m, 2H), 6.43 (dd, J = 5.1, 3.1 Hz, 1H), 4.87−
4.85 (m, 1H), 3.88 (s, 3H), 2.25−2.14 (m, 3H), 1.98−1.90 (m, 1H),
1.79−1.72 (m, 2H). 13C NMR (75 MHz; CDCl3): δ 188.8, 166.1,
162.7, 135.6, 130.4, 120.6, 120.1, 107.1, 100.9, 77.6, 55.9, 29.6, 27.8,
17.1. MS (ESI+): 333.3 (M + Na)+. HRMS (ESI+): Calculated for
C14H15O3Na79Br: 333.0102, found: 333.0107.
5-Bromo-2-((2-bromocyclohex-2-en-1-yl)oxy)benzaldehyde
(3d). The reaction was performed with 1.77 g (10.0 mmol) of 2-
bromo-2-cyclohexenol, 2.81 g (15.8 mmol) of methanesulfonic
anhydride, 1.60 g (15.8 mmol) of triethylamine, 3.29 g (16.4 mmol)
of 5-bromo-2-hydroxybenzaldehyde, and 2.55 g (16.4 mmol) of DBU.
After purification, 0.25 g (7% yield) of the title product was obtained
as a light yellow solid, mp 117 °C. IR (neat): 2938, 1678, 1598, 1252,
618 cm−1. 1H NMR (300 MHz, CDCl3): δ 10.39 (s, 1H), 7.85 (d, J =
2.5 Hz, 1H), 7.55 (dd, J = 8.9, 2.5 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H),
6.35 (dd, J = 4.5, 3.3 Hz, 1H), 4.80 (s, 1H), 2.24−2.00 (m, 6H), 1.98−
1.87 (m, 2H), 1.71 (dd, J = 15.6, 4.2 Hz, 2H), 1.19 (t, J = 7.1 Hz, 1H).
13C NMR (75 MHz; CDCl3): δ 188.5, 159.8, 138.2, 135.6, 130.8,
EXPERIMENTAL SECTION
■
General Methods. All reactions sensitive to air or moisture were
carried out in flame-dried glassware under a nitrogen atmosphere.
Dichloromethane, pyridine, and triethylamine were distilled from
calcium hydride under an argon atmosphere. Dimethyl sulfoxide was
distilled from calcium chloride under high vacuum and was stored with
molecular sieves under an argon atmosphere. All commercially
available reagents were used without further purification unless
otherwise specified. Reactions were magnetically stirred and monitored
by thin-layer chromatography with 250 μm precoated silica gel plates.
Flash column chromatography was performed using silica gel (230−
400 mesh). Melting points are uncorrected. Proton nuclear magnetic
resonance (1H NMR) and carbon nuclear magnetic resonance (13C
NMR) spectra were recorded in deuterochloroform. Chemical shifts
7251
dx.doi.org/10.1021/jo501376q | J. Org. Chem. 2014, 79, 7250−7255

The Journal of Organic Chemistry
Note
127.5, 119.6, 116.8, 114.2, 77.9, 30.9, 29.5, 27.6, 16.9. MS (ESI−):
359.1 (M − H)−. HRMS (ESI+): Calculated for C13H12O2Na79Br2:
380.9102, found: 380.9103.
mmol) of aldehyde 3c and 0.23 mL (3.8 mmol) of hydroxylamine.
After purification, 0.31 g (52% yield) of the title compound was
obtained as a light yellow oil, which solidified upon standing, mp 97−
1
2-((2-Bromocyclohex-2-en-1-yl)oxy)-5-nitrobenzaldehyde
(3e). The reaction was performed with 1.78 g (10.0 mmol) of 2-
bromo-2-cyclohexenol, 2.76 g (15.5 mmol) of methanesulfonic
anhydride, 1.52 g (15.1 mmol) of triethylamine, 3.58 g (21.2 mmol)
of 2-hydroxy-5-nitrobenzaldehyde, and 3.36 g (21.6 mmol) of DBU.
After purification, 0.98 g (30% yield) of the title compound was
obtained as a white powder, mp 114−117 °C. IR (neat): 3118, 2953,
115 °C (decomposed). IR (neat): 3240, 2933, 1608, 1265 cm−1. H
NMR (300 MHz, CDCl3): δ 9.55 (br s, 1H), 8.55 (s, 1H), 7.72 (d, J =
9.3 Hz, 1H), 6.56−6.54 (m, 2H), 6.36 (dd, J = 5.1, 3.0 Hz, 1H), 4.76
(s, 1H), 3.80 (s, 3H), 2.22−2.15 (m, 1H), 2.14−2.01 (m, 2H), 1.90−
1.70 (m, 2H), 1.68−1.60 (m, 1H). 13C NMR (75 MHz; CDCl3): δ
162.4, 157.6, 146.4, 135.2, 127.6, 120.4, 115.2, 106.8, 101.2, 77.3, 55.6,
29.3, 27.7, 16.9. MS (ESI+): 328.2 (M + H)+. HRMS (ESI+):
Calculated for C14H17NO379Br: 326.0392, found: 326.0389.
1
1683, 1587, 1342, 1268, 667 cm−1. H NMR (300 MHz, CDCl3): δ
10.51 (s, 1H), 8.72 (d, J = 2.9 Hz, 1H), 8.42 (dd, J = 9.2, 2.9 Hz, 1H),
7.21 (d, J = 9.3 Hz, 1H), 6.49 (dd, J = 5.0, 3.2 Hz, 1H), 5.06 (t, J = 3.6
Hz, 1H), 2.37−2.16 (m, 3H), 2.15−2.02 (m, 1H), 1.82−178 (m, 2H).
13C NMR (75 MHz; CDCl3): δ 187.9, 173.9, 142.0, 136.6, 130.6,
5-Bromo-2-((2-bromocyclohex-2-en-1-yl)oxy)benzaldehyde
Oxime (4d). The reaction was performed with 0.25 g (0.70 mmol) of
aldehyde 3d and 0.09 mL (1.5 mmol) of hydroxylamine. After
purification, 0.19 g (73% yield) of the title compound was obtained as
a light yellow thick oil, which solidified upon standing, mp 105−110
°C (decomposed). IR (neat): 3280, 2951, 1481, 1268, 663, 634 cm−1.
1H NMR (300 MHz, CDCl3): δ 9.09 (br s, 1H), 7.89 (d, J = 2.3 Hz,
125.9, 124.9, 118.7, 114.5, 78.3, 29.6, 27.7, 17.1. MS (ESI−): 324.2 (M
− H)−. HRMS (ESI+): Calculated for C13H11O4N79Br: 323.9871,
found: 323.9878.
2-((2-Bromocyclohex-2-en-1-yl)oxy)-1-naphthaldehyde (3f).
The reaction was performed with 1.81 g (10.2 mmol) of 2-bromo-2-
cyclohexenol, 2.80 g (15.8 mmol) of methanesulfonic anhydride, 1.60
g (15.8 mmol) of triethylamine, 5.40 g (30.7 mmol) of 2-hydroxy-1-
naphthaldehyde, and 4.78 g (30.8 mmol) of DBU. After purification,
2.44 g (72% yield) of the title compound was obtained as an off-white
solid, mp 88−90 °C. IR (neat): 3084, 2952, 1234, 649 cm−1. 1H NMR
(300 MHz, CDCl3): δ 10.97 (s, 1H), 9.31 (d, J = 8.6 Hz, 1H), 8.02 (d,
J = 9.1 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.65−7.60 (m, 1H), 7.44 (t,
J = 7.2 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H), 6.42 (dd, J = 4.9, 3.1 Hz,
1H), 4.99 (s, 1H), 2.29−2.05 (m, 3H), 1.99−1.68 (m, 3H). 13C NMR
(75 MHz; CDCl3): δ 192.6, 163.1, 137.5, 135.6, 131.6, 129.8, 129.1,
128.3, 125.22, 125.10, 119.9, 118.8, 115.7, 78.6, 29.9, 27.7, 16.9. MS
(ESI+): 355.3 (M + Na)+. HRMS (ESI+): Calculated for C17H16-
O279Br: 331.0334, found: 331.0337.
Representative Procedure for Conversion of Substituted
Salicylaldehydes to Oximes. Synthesis of 2-((2-Bromo-
cyclohex-2-en-1-yl)oxy)benzaldehyde Oxime (4a). A solution
of hydroxylamine (0.75 mL, 12.2 mmol, 50% in water, 1.4 equiv) was
added to a cloudy solution of 2.01 g (7.17 mmol, 1 equiv) of aldehyde
3a in 70 mL of water at 100 °C. The reaction mixture was stirred for
16 h. The reaction mixture was cooled to rt and was extracted three
times with ethyl acetate. The combined organic extracts were washed
with brine twice and dried over sodium sulfate. The dried extracts were
filtered and concentrated using rotary evaporation in vacuo to produce
a thick yellow oil. The oil was purified by chromatography on silica gel
(hexanes:ethyl acetate 8:2 to 7:3) to yield 2.1 g (98%) of the title
compound as a white solid, mp. 119−121 °C. IR (neat): 3272, 2931,
1599, 1451, 1233, 642 cm−1. 1H NMR (300 MHz, CDCl3): δ 8.63 (s,
1H), 8.28 (br s, 1H), 7.78 (dd, J = 7.7, 1.8 Hz, 1H), 7.36 (ddd, J = 8.5,
7.3, 1.7 Hz, 1H), 7.04−6.97 (m, 2H), 6.40 (dd, J = 5.1, 3.1 Hz, 1H),
4.81 (d, J = 3.7 Hz, 1H), 2.32−2.05 (m, 3H), 1.93−1.65 (m, 3H). 13C
NMR (75 MHz; CDCl3): δ 156.5, 146.9, 135.2, 131.4, 126.7, 122.5,
121.8, 120.7, 114.7, 77.4, 29.5, 27.9, 17.0. MS (ESI+): 320.3 (M +
Na)+; HRMS (ESI+): Calculated for C13H15NO279Br: 296.0286, found:
296.0282.
1H), 7.40 (dd, J = 8.8, 2.3 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 6.36 (dd,
J = 4.9, 3.1 Hz, 1H), 4.72 (s, 1H), 2.27−2.09 (m, 3H), 1.90−1.61 (m,
3H). 13C NMR (75 MHz; CDCl3): δ 155.4, 145.5, 135.4, 133.7, 129.2,
124.4, 120.1, 116.4, 114.2, 77.8, 60.8, 29.4, 27.7, 16.9. MS (ESI+):
398.1 (M + Na)+. HRMS (ESI+): Calculated for C13H14NO279Br2:
373.9391, found: 373.9389.
2-((2-Bromocyclohex-2-en-1-yl)oxy)-5-nitrobenzaldehyde
Oxime (4e). The reaction was performed with 0.96 g (2.9 mmol) of
aldehyde 3e and 0.36 mL (5.9 mmol) of hydroxylamine. After
purification, 0.74 g (74% yield) of the title compound was obtained as
a light yellow oil, which solidified upon standing, mp 134.5−141 °C
(decomposed). IR (neat): 3413, 2929, 1511, 1339, 1269, 674 cm−1. 1H
NMR (300 MHz, CDCl3): δ 8.67 (d, J = 2.9 Hz, 1H), 8.54 (s, 1H),
8.24 (dd, J = 9.2, 2.9 Hz, 1H), 7.07 (d, J = 9.4 Hz, 1H), 6.45 (dd, J =
5.1, 3.1 Hz, 1H), 4.96 (m, 1H), 2.29 (m, 4.6 Hz, 1H), 2.21−2.07 (m,
2H), 2.05−1.93 (m, 1H), 1.83−1.70 (m, 2H). 13C NMR (75 MHz;
CDCl3): δ 160.7, 145.0, 141.9, 136.2, 126.6, 122.90, 122.8, 119.2,
113.4, 77.8, 29.5, 27.7, 17.0. MS (ESI−): 339.2 (M − H)−. HRMS
(ESI+): Calculated for C13H13N2O4Na79Br: 362.9956, found:
362.9962.
2-((2-Bromocyclohex-2-en-1-yl)oxy)-1-naphthaldehyde
Oxime (4f). The reaction was performed with 2.44 g (7.4 mmol) of
aldehyde 3f and 0.72 mL (11.1 mmol) of hydroxylamine. After
purification, 1.26 g (50% yield) of the title compound was obtained as
a light yellow thick oil. IR (neat): 3312, 2935, 1588, 1509, 1234, 637
cm−1. 1H NMR (300 MHz; CDCl3): δ 9.00 (s, 1H), 8.93 (s, 1H), 8.86
(dd, J = 8.7, 0.9 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.82 (dt, J = 8.0, 0.6
Hz, 1H), 7.58 (ddd, J = 8.6, 6.9, 1.5 Hz, 1H), 7.44 (ddd, J = 8.1, 6.9,
1.2 Hz, 1H), 7.36 (d, J = 9.2 Hz, 1H), 6.41 (dd, J = 5.1, 3.0 Hz, 1H),
4.90 (d, J = 3.5 Hz, 1H), 2.23−2.20 (m, 1H), 2.15−2.08 (m, 2H),
1.90−1.82 (m, 2H), 1.70−1.66 (m, 1H). 13C NMR (75 MHz;
CDCl3): δ 155.8, 148.0, 135.3, 132.1, 131.7, 129.8, 128.4, 128.0, 125.8,
124.7, 120.6, 116.4, 116.3, 78.8, 29.7, 27.8, 16.9. MS (ESI+): 348.3 (M
+ H)+. HRMS (ESI+): Calculated for C17H17NO279Br: 346.0443,
found: 346.0446.
Representative Procedure of Conversion to Oximoyl
Chlorides and in Situ Cycloaddition. Synthesis of 2a1-
Bromo-2a,2a1,3,4,5,5a-hexahydroxantheno[9,1-cd]isoxazole
(5a). Pyridine (0.14 mL, 1.7 mmol 0.2 equiv) was added to a solution
of oxime 4a (2.48 g, 8.4 mmol, 1 equiv) in 85 mL of chloroform. The
reaction mixture was heated to 40 °C. N-Chlorosuccinimide (1.28 g,
9.4 mmol, 1.1 equiv) was added in small portions over a period of 30
min. The reaction mixture was further stirred at 40 °C for 3 h.
Triethylamine (1.2 mL, 8.6 mmol, 1 equiv) was added, converting the
yellow-orange solution to a dark red fuming one. The reaction mixture
was stirred at 40 °C for 2 h. The mixture was diluted with 100 mL of
CH2Cl2. The organic layer was washed with aqueous 1 M hydrochloric
acid (once) and water (twice) and dried over sodium sulfate.
Concentration by rotary evaporation in vacuo yielded an orange solid.
Purification using column chromatography on silica gel (hexanes:ethyl
acetate 8:2 to 7:3) yielded 1.54 g (63%) the title compound as a white
solid, mp 170−173 °C. IR (neat): 2933, 1611, 1462, 1209, 665 cm−1.
2-((2-Bromocyclohex-2-en-1-yl)oxy)-3-methoxybenz-
aldehyde Oxime (4b). The reaction was performed with 3.88 g (12.5
mmol) of aldehyde 3b and 1.10 mL (17.8 mmol) of hydroxylamine.
After purification, 3.79 g (94% yield) of the title compound was
obtained as a light yellow thick oil, which solidified upon standing, mp
159−164 °C (decomposed). IR (neat): 3284, 2937, 1475, 1438, 1266
1
cm−1. H NMR (300 MHz, CDCl3): δ 8.65 (s, 1H), 7.36 (d, J = 7.8
Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.36 (dd, J
= 4.8, 2.9 Hz, 1H), 4.83 (s, 1H), 3.86 (s, 3H), 2.30−2.22 (s, 1H),
2.18−2.09 (m, 3H), 1.96−1.83 (m, 1H), 1.68−1.25 (m, 2H). 13C
NMR (75 MHz; CDCl3): δ 152.7, 147.3, 145.9, 135.2, 126.9, 124.2,
121.3 118.1, 113.9, 79.3, 56.0, 29.9, 28.1, 16.8. MS (ESI+): 350.3 (M +
Na)+. HRMS (ESI+): Calculated for C14H17NO379Br: 326.0392, found:
326.0396.
2-((2-Bromocyclohex-2-en-1-yl)oxy)-4-methoxybenz-
aldehyde Oxime (4c). The reaction was performed with 0.57 g (1.8
7252
dx.doi.org/10.1021/jo501376q | J. Org. Chem. 2014, 79, 7250−7255

The Journal of Organic Chemistry
Note
1H NMR (300 MHz; CDCl3): δ 7.88 (dd, J = 7.8, 1.6 Hz, 1H), 7.41
9.13 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.80 (dt, J = 8.0, 0.6
Hz, 1H), 7.65 (td, J = 7.8, 1.5 Hz, 1H), 7.49−7.44 (m, 1H), 7.19 (d, J
= 9.0 Hz, 1H), 5.15−5.10 (m, 1H), 4.99 (dd, J = 11.7, 5.9 Hz, 1H),
2.29−2.21 (m, 1H), 2.15−2.06 (m, 1H), 1.68−1.62 (m, 1H), 1.50−
1.23 (m, 3H). 13C NMR (75 MHz; CDCl3): δ 152.8, 152.3, 134.5,
130.8, 129.6, 128.9, 128.7, 127.0, 125.1, 118.9, 103.7, 88.3, 81.4, 68.7,
30.5, 28.7, 16.6. MS (ESI+): 346.2 (M + H)+. HRMS (ESI+):
Calculated for C17H15NO279Br: 344.0286, found: 344.0291.
(ddd, J = 8.3, 7.4, 1.6 Hz, 1H), 7.08−7.02 (m, 2H), 5.13 (t, J = 8.5 Hz,
1H), 4.90 (dd, J = 11.6, 6.0 Hz, 1H), 2.28−2.20 (m, 1H), 2.14−2.05
(m, 1H), 1.70−1.65 (m, 1H), 1.39−1.20 (m, 3H); 13C NMR (75
MHz; CDCl3): δ 152.3, 151.5, 133.4, 125.9, 122.3, 118.4, 110.5, 89.6,
81.6, 67.1, 30.6, 29.0, 16.9; MS (ESI+): 294.3 (M + H)+. HRMS
(ESI+): Calculated for C13H13NO279Br: 294.0130, found: 294.0135
2 a 1 - B r o m o - 7 - m e t h o x y - 2 a , 2 a 1 , 3 , 4 , 5 , 5 a - h e x a -
hydroxantheno[9,1-cd]isoxazole (5b). The reaction was per-
formed with 4.56 g (14.0 mmol) of oxime 4b, 0.22 mL of pyridine
(2.7 mmol), 2.10 g (15.4 mmol) of N-chlorosuccinimide, and 2.0 mL
(14.0 mmol) of triethylamine. After purification, 4.04 g (89% yield) of
the title compound was obtained as a white solid, mp 170−172 °C. IR
(neat): 2941, 1572, 1489, 1211, 626 cm−1. 1H NMR (300 MHz;
CDCl3): δ 7.41 (dd, J = 5.6, 3.7 Hz, 1H), 6.95−6.93 (m, 2H), 5.08 (t, J
= 8.3 Hz, 1H), 4.97 (dd, J = 11.3, 5.9 Hz, 1H), 3.81 (s, 4H), 2.20−2.07
(m, 2H), 1.60 (dd, J = 7.1, 3.7 Hz, 1H), 1.36−1.09 (m, 3H). 13C NMR
(75 MHz; CDCl3): δ 151.2, 149.1, 141.8, 121.8, 117.0, 114.3, 110.8,
89.6, 81.7, 77.7, 77.2, 76.8, 66.7, 56.1, 30.3, 28.7, 16.6. MS (ESI+):
326.3 (M + H)+. HRMS (ESI+): Calculated for C14H15NO379Br,
324.0235, found: 324.0238.
Representative Procedure of Elimination to Form 6.
Synthesis of 3,4,5,5a-Tetrahydroxantheno[9,1-cd]isoxazole
(6a). To a solution of 0.30 g (1.0 mmol, 1 equiv) of 5a in 10 mL
of DMSO at 100 °C was added 0.32 g (1.1 mmol, 1.1 equiv) of silver
carbonate. The reaction mixture was stirred at 100 °C for 16 h. The
reaction mixture was cooled to rt and filtered through Celite. The filter
cake was washed with water. The solution was extracted with ethyl
acetate (three times). The combined organic extracts were washed
with brine (twice), dried over sodium sulfate, and concentrated using
rotary evaporation in vacuo to yield a brown solid. Purification using
chromatography on silica gel (hexanes:ethyl acetate 8:2 to 7:3) yielded
0.17 g (78%) of the title compound as a white solid, mp 94.5 °C. IR
(neat): 2943, 1685, 1498, 1200 cm−1. 1H NMR (400 MHz; CDCl3): δ
7.78 (dd, J = 7.6, 1.4 Hz, 1H), 7.33 (td, J = 7.8, 1.3 Hz, 1H), 7.04 (dd,
J = 14.2, 7.8 Hz, 2H), 5.11−5.07 (m, 1H), 2.81 (ddt, J = 17.8, 6.4, 1.8
Hz, 1H), 2.69 (dddd, J = 17.5, 11.1, 6.2, 2.3 Hz, 1H), 2.49−2.43 (m,
1H), 2.26−2.22 (m, 1H), 1.87 (ddddd, J = 17.0, 14.1, 11.2, 6.0, 2.9 Hz,
1H), 1.68−1.59 (m, 1H). 13C NMR (100 MHz; CDCl3): δ 166.2,
156.1, 153.2, 132.1, 125.0, 122.4, 118.6, 115.7, 113.1, 70.0, 29.3, 22.4,
20.7. MS (ESI+): 214.4 (M + H)+. HRMS (ESI+): Calculated for
C13H12NO2: 214.0868, found: 214.0876.
7-Methoxy-3,4,5,5a-tetrahydroxantheno[9,1-cd]isoxazole
(6b). The reaction was performed with 1.63 g (5.0 mmol) of
bromoisoxazoline 5b and 1.55 g (5.6 mmol) of silver carbonate. After
purification, 0.97 g (79% yield) of the title compound was obtained as
a white powder, mp 142−143 °C. IR (neat): 2961, 1684, 1575, 1263
cm−1. 1H NMR (400 MHz; CDCl3): δ 7.42 (dd, J = 7.5, 1.8 Hz, 1H),
7.03 (t, J = 7.8 Hz, 1H), 6.98 (dd, J = 8.2, 1.7 Hz, 1H), 5.19−5.14 (m,
1H), 3.91 (s, 3H), 2.85 (ddt, J = 17.7, 6.3, 1.7 Hz, 1H), 2.72 (dddd, J =
17.5, 11.1, 6.2, 2.6 Hz, 1H), 2.60 (dddd, J = 12.1, 5.8, 3.7, 2.4 Hz, 1H),
2.32−2.24 (m, 1H), 1.90 (tddd, J = 14.0, 11.0, 6.3, 2.8 Hz, 1H), 1.72
(dddd, J = 14.1, 12.2, 9.5, 2.8 Hz, 1H). 13C NMR (101 MHz; CDCl3):
δ 166.3, 149.5, 145.3, 122.1, 116.7, 116.2, 114.2, 112.9, 70.3, 56.1, 29.3,
22.3, 20.6. MS (ESI+): 244.5 (M + H)+. HRMS (ESI+): Calculated for
C14H14NO3: 244.0974, found: 244.0977.
8-Methoxy-3,4,5,5a-tetrahydroxantheno[9,1-cd]isoxazole
(6c). The reaction was performed with 0.15 g (0.5 mmol) of
bromoisoxazoline 5c and 0.26 g (1.0 mmol) of silver carbonate. After
purification, 0.087 g (77% yield) of the title compound was obtained
as a white powder, mp 151.5−155.0 °C. IR (neat): 2935, 1687, 1616,
1254 cm−1. 1H NMR (300 MHz; CDCl3): δ 7.69 (d, J = 8.5 Hz, 1H),
6.62 (dd, J = 8.5, 2.5 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 5.11−5.04 (m,
1H), 3.80 (s, 3H), 2.80 (ddt, J = 17.7, 6.4, 1.6 Hz, 1H), 2.67 (dddd, J =
17.4, 11.0, 6.1, 2.4 Hz, 1H), 2.45 (dddd, J = 12.0, 5.7, 3.6, 2.4 Hz, 1H),
2.27−2.22 (m, 1H), 1.95−1.79 (m, 1H), 1.70−1.57 (m, 1H). 13C
NMR (75 MHz; CDCl3): δ 165.8, 162.9, 157.6, 130.1, 126.0, 122.1,
109.1, 108.4, 103.6, 77.2, 70.4, 55.5, 29.3, 22.4, 20.8. MS (ESI+): 244.4
(M + H)+. HRMS (ESI+): Calculated for C14H14NO3: 244.0974,
found: 244.0978.
8-Bromo-3,4,5,5a-tetrahydroxantheno[9,1-cd]isoxazole
(6d). The reaction was performed with 0.14 g (0.4 mmol) of
bromoisoxazoline 5d and 0.21 g (0.8 mmol) of silver carbonate. After
purification, 0.073 g (69% yield) of the title compound was obtained
as a white powder, mp 124−125 °C. IR (neat): 3060, 2937, 1684,
1496, 1202 cm−1. 1H NMR (300 MHz; CDCl3): δ 7.88 (d, J = 2.4 Hz,
1H), 7.40 (dd, J = 8.8, 2.5 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 5.08 (ddt,
J = 9.7, 5.6, 2.2 Hz, 1H), 2.83 (ddt, J = 17.8, 6.4, 1.7 Hz, 1H), 2.69
(dddd, J = 17.5, 11.0, 6.1, 2.5 Hz, 1H), 2.50−2.42 (m, 1H), 2.31−2.21
(m, 1H), 1.96−1.80 (m, 1H), 1.62 (dddd, J = 14.0, 12.2, 9.5, 2.8 Hz,
1H). 13C NMR (75 MHz; CDCl3): δ 166.7, 155.1, 152.4, 134.8, 127.6,
120.4, 117.4, 114.6, 112.8, 70.4, 29.3, 22.5, 20.7. MS (ESI+): 294.2 (M
2 a 1 - B r o m o - 8 - m e t h o x y - 2 a , 2 a 1 , 3 , 4 , 5 , 5 a - h e x a -
hydroxantheno[9,1-cd]isoxazole (5c). The reaction was performed
with 0.31 g (1.0 mmol) of oxime 4c, 0.02 mL of pyridine (0.2 mmol),
0.15 g (1.1 mmol) of N-chlorosuccinimide, and 0.14 mL (1.0 mmol)
of triethylamine. After purification, 0.15 g (49% yield) of the title
compound was obtained as a thick clear oil, which solidified upon
standing, mp 131−135.5 °C. IR (neat): 2942, 1614, 1591, 1437, 1197,
1
634 cm−1. H NMR (300 MHz; CDCl3): δ 7.75 (d, J = 8.7 Hz, 1H),
6.63 (dd, J = 8.8, 2.5 Hz, 1H), 6.51 (s, 1H), 5.09−5.03 (m, 1H), 4.86
(dd, J = 11.4, 5.9 Hz, 1H), 3.80 (s, 3H), 2.22−2.14 (m, 1H), 2.10−
2.02 (m, 1H), 1.68−1.63 (m, 1H), 1.40−1.18 (m, 3H). 13C NMR (75
MHz; CDCl3): δ 163.9, 153.9, 130.1, 127.5, 127.0, 122.0, 110.5, 103.0,
102.0, 89.0, 81.8, 55.6, 30.4, 29.0, 17.0. MS (ESI+): 326.2 (M + H)+.
HRMS (ESI+): Calculated for C14H15NO379Br: 324.0235, found:
324.0241.
2a1,9-Dibromo-2a,2a1,3,4,5,5a-hexahydroxantheno[9,1-cd]-
isoxazole (5d). The reaction was performed with 0.19 g (0.5 mmol)
of oxime 4d, 0.01 mL of pyridine (0.1 mmol), 0.08 g (0.6 mmol) of N-
chlorosuccinimide, and 0.07 mL (0.5 mmol) of triethylamine. After
purification, 0.14 g (72% yield) of the title compound was obtained as
a foamy clear thick oil. IR (neat): 2952, 1459, 1440, 1213, 728, 680
1
cm−1. H NMR (300 MHz; CDCl3): δ 7.99 (d, J = 2.5 Hz, 1H), 7.48
(dd, J = 8.9, 2.5 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 5.15 (d, J = 8.8 Hz,
1H), 4.90−4.86 (m, 1H), 2.28−2.19 (m, 1H), 2.13−2.04 (m, 1H),
1.68−165 (m, 1H), 1.37−1.14 (m, 4H). 13C NMR (75 MHz; CDCl3):
δ 151.2, 150.5, 136.1, 128.2, 120.3, 114.5, 112.2, 89.9, 81.8, 66.2, 30.5,
28.9, 16.7. MS (ESI+): 374.0 (M + H)+. HRMS (ESI+): Calculated for
C13H12NO279Br2: 371.9235, found: 371.9233.
2a1-Bromo-9-nitro-2a,2a1,3,4,5,5a-hexahydroxantheno[9,1-
cd]isoxazole (5e). The reaction was performed with 0.74 g (2.2
mmol) of oxime 4e, 0.04 mL of pyridine (0.4 mmol), 0.33 g (0.6
mmol) of N-chlorosuccinimide, and 0.3 mL (2.2 mmol) of
triethylamine. After purification, 0.56 g (76% yield) of the title
compound was obtained as a white powder, mp 166−167.5 °C. IR
(neat): 3107, 2944, 1617, 1460, 1338, 1229, 685 cm−1. 1H NMR (300
MHz; CDCl3): δ 8.82 (d, J = 2.8 Hz, 1H), 8.28 (dd, J = 9.2, 2.8 Hz,
1H), 7.17 (d, J = 9.2 Hz, 1H), 5.22 (t, J = 8.5 Hz, 1H), 5.07−5.01 (m,
1H), 2.35−2.26 (m, 1H), 2.23−2.16 (m, 1H), 1.78−1.71 (m, 1H),
1.35−1.20 (m, 3H). 13C NMR (75 MHz; CDCl3): δ 156.7, 150.1,
134.9, 128.1, 122.4, 119.3, 110.9, 90.5, 82.8, 64.9, 30.6, 29.4, 16.6. MS
(ESI+): 341.1 (M + H)+. HRMS (ESI+): Calculated for C13H12-
N2O479Br: 338.9980, found: 338.9977.
2a1-Bromo-2a,2a1,3,4,5,5a-hexahydrobenzo[7,8]xantheno-
[9,1-cd]isoxazole (5f). The reaction was performed with 0.37 g (2.2
mmol) of oxime 4f, 0.02 mL of pyridine (0.2 mmol), 0.16 g (1.2
mmol) of N-chlorosuccinimide, and 0.15 mL (1.1 mmol) of
triethylamine. After purification, 0.27 g (73% yield) of the title
compound was obtained as a very thick yellow oil. IR (neat): 3058,
1
2951, 1620, 1442, 1226, 726 cm−1. H NMR (300 MHz; CDCl3): δ
7253
dx.doi.org/10.1021/jo501376q | J. Org. Chem. 2014, 79, 7250−7255

The Journal of Organic Chemistry
Note
+ H)+. HRMS (ESI+): Calculated for C13H11NO279Br: 291.9973,
found: 291.9960.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gdake@chem.ubc.ca.
9-Nitro-3,4,5,5a-tetrahydroxantheno[9,1-cd]isoxazole (6e).
The reaction was performed with 0.35 g (1.0 mmol) of bromoisoxazo-
line 5e and 0.58 g (2.1 mmol) of silver carbonate. After purification,
0.17 g (65% yield) of the title compound was obtained as a white
powder, mp 195−196 °C. IR (neat): 2968, 1684, 1619, 1499, 1265
Present Address
†Undergraduate research student. Department of Orthopedic
Surgery, Stanford University, 300 Pasteur Drive, Edwards R163,
Stanford, CA 94305.
1
cm−1. H NMR (300 MHz; CDCl3): δ 8.53 (d, J = 2.8 Hz, 1H), 8.09
(dd, J = 9.1, 2.8 Hz, 1H), 7.03 (d, J = 9.1 Hz, 1H), 5.16 (ddt, J = 9.7,
5.5, 2.1 Hz, 1H), 2.79 (ddt, J = 18.0, 6.5, 1.6 Hz, 1H), 2.64 (dddd, J =
17.6, 11.0, 6.3, 2.4 Hz, 1H), 2.42 (tdd, J = 7.9, 4.2, 2.0 Hz, 1H), 2.27−
2.17 (m, 1H), 1.84 (ddd, J = 10.7, 6.4, 2.8 Hz, 1H), 1.57 (dddd, J =
13.9, 12.2, 9.6, 2.8 Hz, 1H). 13C NMR (75 MHz; CDCl3): δ 167.5,
160.7, 151.4, 142.0, 127.0, 120.6, 119.1, 116.5, 116.4, 116.4, 115.5,
112.0, 71.3, 28.9, 22.1, 20.3. MS (ESI+): 259.3 (M + H)+. HRMS
(ESI+): Calculated for C13H11N2O4: 259.0719, found: 259.0723.
3,4,5,5a-Tetrahydrobenzo[7,8]xantheno[9,1-cd]isoxazole
(6f). The reaction was performed with 0.27 g (0.8 mmol) of
bromoisoxazoline 5f and 0.44 g (1.6 mmol) of silver carbonate. After
purification, 0.069 g (34% yield) of the title compound was obtained
as a white powder, mp 186−187 °C. IR (neat): 2940, 1617, 1592,
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Brian O. Patrick (U.B.C.) for the solution of
solid-state molecular structures in this paper. E.B.C-C. thanks
CONACYT of Mexico for a doctoral fellowship (172270). The
authors thank the University of British Columbia, the Natural
Sciences and Engineering Research Council (NSERC) of
Canada (Discovery and Undergraduate Student Research
Assistant programs), and the Canada Foundation for
Innovation (CFI) for the financial support of our programs.
1
1526, 1209 cm−1. H NMR (300 MHz; CDCl3): δ 8.82 (dd, J = 8.4,
0.6 Hz, 1H), 7.79 (dd, J = 8.5, 3.8 Hz, 2H), 7.63 (ddd, J = 8.4, 7.0, 1.4
Hz, 1H), 7.44 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H),
5.19−5.13 (m, 1H), 2.83 (ddt, J = 17.6, 6.3, 1.7 Hz, 1H), 2.70 (dddd, J
= 17.3, 10.8, 6.1, 2.5 Hz, 1H), 2.49 (dddd, J = 11.7, 5.7, 3.7, 2.1 Hz,
1H), 2.29−2.20 (m, 1H), 1.85 (tddd, J = 14.0, 10.5, 6.3, 2.4 Hz, 1H),
1.70 (dddd, J = 14.1, 11.7, 9.3, 2.5 Hz, 1H). 13C NMR (75 MHz;
CDCl3): δ 165.0, 155.4, 153.7, 132.5, 130.3, 129.6, 128.2(0), 128.1(8),
126.5, 124.9, 119.3, 113.1, 109.8, 70.3, 29.3, 22.3, 20.7. MS (ESI+):
264.4 (M + H)+. HRMS (ESI+): Calculated for C17H14NO2: 264.1025,
found: 264.1024.
REFERENCES
■
(1) (a) Martinez-Ariza, G.; Dietrich, J.; De Moliner, F.; Hulme, C.
Synlett 2013, 24, 1801−1804. (b) Arigela, R. K.; Samala, S.; Mahar, R.;
Shukla, S. K.; Kunda, B. J. Org. Chem. 2013, 78, 10476−10484.
(c) Novak, A.; Testen, A.; Bezensek, J.; Groselj, U.; Hrast, M.;
Kasunic, M.; Gobec, S.; Stanovnik, B.; Svete, J. Tetrahedron 2013, 69,
6648−6665. (d) Xiao, Y.; Zhang, L. Org. Lett. 2012, 14, 4662−4665.
(e) Lu, C.; Dubrovskiy, A. V.; Larock, R. C. J. Org. Chem. 2012, 77,
2279−2284. (f) Wirtz, L.; Kazmaier, U. Eur. J. Org. Chem. 2011, 2011,
3467−3473. (g) Zhou, F.; Liu, J.; Ding, K.; Liu, J.; Cai, Q. J. Org.
Chem. 2011, 76, 5346−5353. (h) Cui, P.; Xu, L.; Shi, Z.; Gan, L. J. Org.
Chem. 2011, 76, 4210−4212. (i) Li, R.; Jansen, D. J.; Datta, A. Org.
Biomol. Chem. 2009, 7, 1921−1930.
(2) (a) Akritopoulou-Zanze, I.; Wakefield, B. D.; Gasiecki, A.; Kalvin,
D.; Johnson, E. F.; Kovar, P.; Djuric, S. W. Bioorg. Med. Chem. Lett.
2011, 21, 1476−1479. (b) Quinn, J. F.; Gregg, B. T.; Kitchen, D. B.;
Lewis, R. M.; Razzano, D. A.; Kayser, L. E.; Schilling, L. J.; Golden, K.
C. Lett. Drug Des. Discovery 2012, 9, 2−7. (c) Pardin, C.; Roy, I.;
Lubell, W. D.; Keillor, J. W. Chem. Biol. Drug Des. 2008, 72, 189−196.
(3) (a) Raihan, M. J.; Kavala, V.; Kuo, C.-W.; Raju, B. R.; Yao, C.-F.
Green Chem. 2010, 12, 1090−1096. (b) Pal, A.; Bhattacharjee, A.;
Bhattacharjya, A.; Patra, A. Tetrahedron 1999, 55, 4123−4132.
(c) Arai, N.; Iwakoshi, M.; Tanabe, K.; Narasaka, K. Bull. Chem. Soc.
Jpn. 1999, 72, 2277−2285. (d) Broggini, G.; Zecchi, G. Synthesis 1996,
1280−1282. (e) Broggini, G.; Folcio, F.; Sardone, N.; Zecchi, G.
Tetrahedron 1996, 52, 11849−11856. (f) Hassner, A.; Lokanatha Rai,
K. Heterocycles 1990, 30, 817−830. (g) Oppolzer, W.; Keller, K.
Tetrahedron Lett. 1970, 11, 1117−11120.
(4) (a) Tranmer, G. K.; Tam, W. J. Org. Chem. 2001, 66, 5113−5123.
(b) Shirahase, M.; Kanemasa, S.; Oderaotoshi, Y. Org. Lett. 2004, 6,
675−678. (c) Jakowiecki, J.; Loska, R.; Makosza, M. J. Org. Chem.
2008, 73, 5436−5441. (d) Piperno, A.; Rescifina, A.; Corsaro, A.;
Chiacchio, M. A.; Procopio, A.; Romeo, R. Eur. J. Org. Chem. 2007,
1517−1521. (e) Hems, W. P.; Tan, C. H.; Stork, T.; Feeder, N.;
Holmes, A. B. Tetrahedron Lett. 1999, 40, 1393−1396. (f) Keirs, D.;
Moffat, D.; Overton, K.; Tomanek, R. J. Chem. Soc., Perkin Trans 1
1991, 1041−1051.
(5) Hansen, J. F.; Kim, Y. I.; McCrotty, S. E.; Strong, S. A.; Zimmer,
D. E. J. Heterocyclic Chem. 1980, 17, 475−479.
(6) Yagoubi, M.; Cruz, A. C. F.; Nichols, P. L.; Elliott, R. L.; Willis,
M. C. Angew. Chem., Int. Ed. 2010, 49, 7958−7962.
Sample Procedure for the Preparation of 9-Amino-2,3,4,4a-
tetrahydro-1H-xanthen-1-ones. 9-Amino-2,3,4,4a-tetrahydro-
1H-xanthen-1-one (7a). Raney nickel (30 mg, 30% by weight in
water) was added to isoxazole 6a (0.12 g, 0.6 mmol, 1 equiv). After
removal of water in vacuo, 10 mL of methanol was added under a
hydrogen atmosphere (using a balloon filled with hydrogen gas). The
reaction mixture was stirred at rt for 24 h. The solvent was removed
using rotary evaporation in vacuo. Purification using chromatography
over silica gel yielded 0.12 g (98% yield) of the title product as a
yellow powder, mp 164.5−165.5 °C. IR (neat): 3304, 3154, 2942,
1
1614, 1598 cm−1. H NMR (400 MHz; CDCl3): δ 10.25 (br s, 1H),
7.45 (dd, J = 7.9, 1.5 Hz, 1H), 7.28 (td, J = 7.8, 1.2 Hz, 1H), 6.95 (td, J
= 7.6, 1.0 Hz, 1H), 6.89 (dd, J = 8.2, 1.0 Hz, 1H), 5.86 (br s, 1H), 4.77
(dd, J = 9.5, 5.8 Hz, 1H), 2.35−2.25 (m, 3H), 1.92−1.79 (m, 2H),
1.64−1.53 (m, 1H). 13C NMR (101 MHz; CDCl3): δ 196.2, 157.9,
152.1, 132.8, 123.5, 121.6, 119.3, 117.4, 100.1, 75.3, 37.8, 29.8, 18.6.
MS (ESI+) (m/z): 216.3 (M + H)+. HRMS (ESI+): Calculated for
C13H14NO2: 216.1025, found: 216.1021.
9-Amino-5-methoxy-2,3,4,4a-tetrahydro-1H-xanthen-1-one
(7b). The reaction was performed with 0.09 g (0.4 mmol) of isoxazole
6b and ∼25 mg of Raney nickel. After purification, 0.080 g (92% yield)
of the title compound was obtained as a light yellow thick oil. IR
1
(neat): 3401, 3233, 2944, 1610, 1572, 1465 cm−1. H NMR (400
MHz; CDCl3): δ 10.28 (br s, 1H), 7.05 (t, J = 4.6 Hz, 1H), 6.92 (d, J =
4.5 Hz, 2H), 5.76 (br s, 1H), 4.79 (dd, J = 9.3, 5.9 Hz, 1H), 3.82 (s,
3H), 2.35 (dd, J = 10.6, 5.3 Hz, 3H), 1.95 (ddd, J = 24.0, 11.2, 3.1 Hz,
2H), 1.66−1.55 (m, 1H). 13C NMR (101 MHz; CDCl3): δ 196.3,
152.3, 148.8, 147.6, 121.3, 120.0, 115.0, 114.5, 99.9, 75.8, 56.1, 37.8,
29.8, 18.6. MS (ESI+): 268.4 (M + Na)+. HRMS (ESI+): Calculated
for C14H16NO3: 246.1130, found: 246.1126.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of spectra and X-ray data for previously unreported
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
7254
dx.doi.org/10.1021/jo501376q | J. Org. Chem. 2014, 79, 7250−7255

The Journal of Organic Chemistry
Note
(7) (a) Bode, J. W.; Hachisu, Y.; Matsuura, T.; Suzuki, K. Org. Lett.
2003, 5, 391−394. (b) Illescas, B. M.; Martin, N. J. Org. Chem. 2000,
65, 5986−5995. (c) Sanders, B. C.; Friscourt, F.; Ledin, P. A.; Mbua,
N. E.; Arumugam, S.; Guo, J.; Boltje, T. J.; Popik, V. V.; Boons, G.-J. J.
Am. Chem. Soc. 2011, 133, 949−957.
(8) (a) Baldwin, S. W.; Chen, P.; Nikolic, N.; Weinseimer, D. C. Org.
Lett. 2000, 2, 1193−1196. (b) R Nagireddy, J.; Raheem, M.-A.; Haner,
J.; Tam, W. Curr. Org. Synth. 2011, 8, 659−700. (c) Curran, D. P. J.
Am. Chem. Soc. 1982, 104, 4024−4026. (d) Curran, D. P. J. Am. Chem.
Soc. 1983, 105, 5826−5833. (e) Casnati, G.; Ricca, A. Tetrahedron Lett.
1967, 8, 327−330.
7255
dx.doi.org/10.1021/jo501376q | J. Org. Chem. 2014, 79, 7250−7255