Organic Letters
Letter
a
Table 1. Screening Conditions
Scheme 2. Tricyclic 5,5-Benzannulated Spiroketals with
a
gem-Dibromoalkenes
entry
base
solvent
time (h)
yield (%)
b
1
2
3
4
5
6
7
8
9
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
tBuOK
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMA
DMSO
DMSO
DMSO
6
6
6
6
6
6
6
5
3
2
43
79
c
74
−
−
−
−
79
KOAc
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
87
d
10
78
a
Reaction conditions: 1a (0.38 mmol, 1 equiv), 2a (0.56 mmol, 1.5
equiv), base (1.9 mmol, 5 equiv), TBAB (0.19 mmol, 0.5 equiv),
solvent (3 mL), 90 °C. Yield calculated considering 0.19 mmol of
spiroketal 3a as a 100% yield. Any excess gem-dibromoalkene (2a)
b
transformed into terminal alkyne (2.1a). 2a (0.38 mmol, 1 equiv).
c
d
Cs2CO3 (1.5 mmol, 4 equiv). Without TBAB.
(Table 1, entry 10). Thus, the optimized protocol for the
synthesis of tricyclic 5,5-benzannulated spiroketal 3a in high
yield was found to consist of 2′-hydroxyacetophenone (1
equiv), gem-dibromoalkene (1.5 equiv), Cs2CO3 (5 equiv), and
TBAB (0.5 equiv) in DMSO at 90 °C for 3 h (Table 1, entry
9). Additionally, the larger scale reaction that was carried out
with 3.67 mmol of 1a furnished spiroketal 3a in 61% yield.
After establishing the optimized protocol, we explored the
synthetic scope for the formation of tricyclic 5,5-benzannulated
spiroketals using different gem-dibromoalkenes and 2′-hydrox-
yacetophenones involving 3 h conditions (Scheme 2). It was
found that the o-, m-, and p-methoxy- and p-benzyloxy-
functionalized gem-dibromoalkenes reacted well and delivered
tricyclic benzannulated spiroketals 3b−3e, respectively, in 60−
77% yields. Further reaction of 2′-hydroxy-3′-phenylacetophe-
none 1b with gem-dibromoalkenes provided spiroketals 3f and
3g in moderate yields. gem-Dibromoalkenes derived from
simple benzaldehyde and 1- and 2-naphthaldehyde also reacted
well, furnishing spiroketals 3h−3j, respectively, in 71−74%
yields. Reactions using gem-dibromoalkenes derived from
thiophene-2-carbaldehyde and thiophene-3-carbaldehyde af-
forded tricyclic benzannulated spiroketals 3k and 3l,
respectively, in high yields. Similarly, the reaction with 4-
(2,2-dibromovinyl)-N,N-diphenylaniline also provided spiro-
ketal 3m in good yield. The reaction of 1-(5-bromo-2-
hydroxyphenyl)ethanone 1c with 2-(2,2-dibromovinyl)-
thiophene produced spiroketal 3n in 38% yield. The
carbazole-derived gem-dibromoalkene, 9-benzyl-3-(2,2-dibro-
movinyl)-9H-carbazole, gave spiroketal 3o in moderate yield.
Notably, gem-dibromoalkenes derived from p-halo-benzalde-
hydes reacted to furnish spiroketals 3p−3r in 69−82% yields.
The structure of tricyclic benzannulated spiroketal 3r was also
confirmed by single-crystal X-ray analysis. However, p-cyano-,
p-nitro-, and o-nitro-functionalized electron-deficient gem-
dibromoalkenes with 2′-hydroxyacetophenone did not yield
the spiroketal products.
a
Reaction conditions: 2′-hydroxyacetophenone 1 (0.38 mmol, 1
equiv), gem-dibromoalkene 2 (0.56 mmol, 1.5 equiv), Cs2CO3 (1.9
mmol, 5 equiv), TBAB (0.19 mmol, 0.5 equiv), DMSO (3 mL), 90
°C, 3 h. Yield calculated considering 0.19 mmol of spiroketal 3 as a
100% yield.
We extended the study with challenging 1,3-dienyldibro-
mides derived from functionalized cinnamaldehydes. These
gem-dibromoalkenes showed excellent reactivity under the
optimized conditions (Scheme 3). Thus, the 1,3-dienyldi-
bromides prepared from cinnamaldehydes containing function-
alized phenyls (with R = H, 4-Me, 4-MeO, 4-Cl, and 4-Br)
reacted well with 2′-hydroxyacetophenone to afford tricyclic
benzannulated spiroketals 5a−5e, respectively, in good yields
(Scheme 3, i). 2-Naphthyl-substituted 1,3-dienyldibromide
also furnished spiroketal 5f in 68% yield. Further study using 3-
en-1-ynyldibromide 6a also afforded tricyclic 5,5-benzannu-
lated spiroketal 7a in 50% yield under the established
conditions (Scheme 3, ii). We further demonstrated the
versatility of the protocol with 1,4-disubstituted bis-dibro-
moalkene 8a and 2′-hydroxyacetophenone 1a. This reaction
proceeded smoothly to give terminal acetylene-embedded
tricyclic 5,5-benzannulated spiroketal 9a in high yield (Scheme
3, iii). Interestingly, reaction of 2′-hydroxyacetophenone with
1-bromoalkyne12c 2aa prepared from gem-dibromoalkene 2a
furnished tricyclic spiroketal 3a in 80% yield (Scheme 3, iv).
This reaction clearly indicated the in situ formation of 1-
bromoalkyne during the course of the reaction from gem-
dibromoalkene. It also further indicated the viability for the
B
Org. Lett. XXXX, XXX, XXX−XXX