Type 2 Ring-Opening Reactions of Cyclopropanated 7-Oxabenzonorbornadienes with Carboxylic Acid Nucleophiles

Article abstract of DOI:10.1055/s-0035-1560565

Ring-opening reactions of strained heterocyclic compounds provide efficient routes to various organic frameworks. In this work, the ability of carboxylic acid nucleophiles to promote ring-opening of cyclopropanated 7-oxabenzonorbornadienes was investigated. Reactions proceeded smoothly to yield 2-naphthylmethyl esters in moderate yields, and optimal conditions were found with the use of 10 mol% p-toluenesulfonic acid monohydrate in dichloroethane heated to 90 °C. The amount of nucleophile could be decreased from a large excess to 8 equivalents without diminishing the yield. When varying the structure of the acid catalyst or carboxylic acid nucleophile, reaction rates showed a marked dependence on acidity of these species. Ring-opening was well tolerated by functionalized substrates, with substitution on the bridgehead or aromatic portions of the molecule. The present work is the second account of this type of reaction, and provides a new route to 2-naphthylmethyl esters. The transformations observed in this work should be useful in predicting the reactivity of similar fused-ring systems.

Full text of DOI:10.1055/s-0035-1560565

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
E. Carlson et al.
Paper
Synthesis
Type 2 Ring-Opening Reactions of Cyclopropanated 7-Oxabenzo-
norbornadienes with Carboxylic Acid Nucleophiles
Emily Carlson
Daniel Hong
William Tam*
O
X
Z
X
O
Z
Y
Y
Y
p-TsOH (10 mol%)
O
Y
RCO2H, DCE, 90 °C
Z
14 examples
up to 76%
X
R = Me, n-Pr, c-Pent,
X
Z
Guelph-Waterloo Centre for Graduate Work in Chemistry and
Biochemistry, Department of Chemistry, University of Guelph,
Guelph, Ontario, N1G 2W1, Canada
X = H, OMe
Y = H, OMe
Z = H, Me
t-Bu, Ph, CH=CH ,
C
CH,
2
CH2OMe, CH2ONp, CH2Cl, CH2Br
wtam@uoguelph.ca
Received: 20.06.2016
Accepted after revision: 20.07.2016
Published online: 24.08.2016
ford cyclopropane 6 instead.10 We have also observed that
in the absence of an alkyne, Cp*Ru(COD)Cl promotes isom-
erization of 1 to its naphthalene oxide 7 or naphthol 8.11,12
Furthermore, asymmetric cyclodimerization of 1 can pro-
duce the polycyclic system 9 in excellent enantioselectivity
(up to 99% ee) with the use of a cationic Rh(I) catalyst.13
DOI: 10.1055/s-0035-1560565; Art ID: ss-2016-m0441_op
Abstract Ring-opening reactions of strained heterocyclic compounds
provide efficient routes to various organic frameworks. In this work, the
ability of carboxylic acid nucleophiles to promote ring-opening of cy-
clopropanated 7-oxabenzonorbornadienes was investigated. Reactions
proceeded smoothly to yield 2-naphthylmethyl esters in moderate
yields, and optimal conditions were found with the use of 10 mol% p-
toluenesulfonic acid monohydrate in dichloroethane heated to 90 °C.
The amount of nucleophile could be decreased from a large excess to 8
equivalents without diminishing the yield. When varying the structure
of the acid catalyst or carboxylic acid nucleophile, reaction rates
showed a marked dependence on acidity of these species. Ring-open-
ing was well tolerated by functionalized substrates, with substitution on
the bridgehead or aromatic portions of the molecule. The present work
is the second account of this type of reaction, and provides a new route
to 2-naphthylmethyl esters. The transformations observed in this work
should be useful in predicting the reactivity of similar fused-ring sys-
tems.
R1
R2
O
3
H
H
H
O
R1
Ru catalyst
R2
O
5
2
O
H
O
MeOH
9
Ru catalyst
O
OEt
OH
Rh catalyst
O
O
silica
EtO
4
Ru catalyst
1
OH
THF
O
Ru catalyst
Key words 7-oxabenzonorbornadiene, cyclopropane, ring-opening,
fused-ring systems, acid catalysis
neutral
alumina
O
OEt
Ru catalyst
8
O
6
O
Bridged or fused-ring compounds have been popular
systems of study in many areas of chemical research. Due to
their innate strain, bridged heterocyclic compounds in par-
ticular are valued as synthetic tools to prepare more com-
plex structures.1 One such example is the use of 7-oxaben-
zonorbornadiene (1) to arrive at various highly substituted
organic frameworks (Scheme 1).2,3 In the presence of alkyne
2 and Cp*Ru(COD)Cl, we have found that [2+2] cycloaddi-
tion with 1 proceeds to form cyclobutene 3,4,5 which is also
observed when using alkynyl halides6 or ynamides.7 Reac-
tion of 1 with secondary propargylic alcohol 4 in MeOH
leads to production of isochromene 5, which is also ob-
7
Scheme 1 Transition-metal-catalyzed transformations of 7-oxabenzo-
norbornadiene (1)
7-Oxabenzonorbornadiene (1) is known to undergo
several stereoselective ring-opening reactions depending
on the transition metal catalyst and nucleophile of choice.
For instance, dihydronaphthalenols with trans substitution
are obtained when using rhodium catalysts with heteroat-
omic nucleophiles, or copper catalysts with alkyl nucleo-
philes, while cis substitution is obtained using rhodium,
palladium, or nickel catalysts with carbon-based nucleo-
served when using
a
cationic Ru catalyst [Cp-
Ru(CH3CN)3]+PF6–.8,9 The same reagents in THF, however, af-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
E. Carlson et al.
Paper
Synthesis
philes.2,14 The resulting frameworks allow for facile prepa-
rations of biologically active compounds, such as sertraline
(10) or arnottin I (11) (Scheme 2).15,16
OH
X
14 Nu
OH
Nu
X
Nu = alkyl,
aryl
14 examples
up to 95% yield
Rh cat.
Nu = alkoxy, amino
NHMe
type 1
or
O
Nu
Nu
12: X = O
13: X = NR
Cu cat.
OH
HN
O
Nu = alkyl
Nu
Nu
10
Ni cat.
Nu = H
1
Cl
15
Nu
Cl
O
OH
12 examples
up to 98% yield
OMe
Rh/Pd/Ni cat.
OMe
Nu = alkyl, aryl
H
OH
O
O
Nu
Nu = alkoxy
type 2
Nu
O
O
Nu
11
12
16
Scheme 2 Ring-opening reactions of 7-oxabenzonorbornadiene (1) in
natural product synthesis
10 examples
up to 91% yield
Scheme 3 Currently known ring-opening reactions of cyclopropanat-
ed heterobenzonorbornadienes
Our group has recently been expanding this area of re-
search through the creation of cyclopropanated analogues
12,17–19 in order to examine their involvement in ring-open-
ing reactions (Figure 1). Since these compounds have only
been developed in the last couple of years, not much is
known yet about their chemical behavior. It is, however,
projected that derivatives 12 should show similar reactivity
to their uncyclopropanated parent alkenes 1.20 To date, we
have discovered ‘type 1’ ring-opening reactions of cyclopro-
panated oxa- and azabenzonorbornadienes 12 and 13 with
organocuprates, which were found to produce cis-1,2-dihy-
dro-2-methylnaphthalenols 14 from oxacyclic precursors,21
as well as polycyclic γ-lactams 15 in the case of the aza
compounds (Scheme 3).22 Thus far, ‘type 2’ ring-opening re-
actions have only been observed as acid-catalyzed opening
of 12 using alcohol nucleophiles, to produce 2-
(alkoxymethyl)naphthalenes (16).23 It was felt that the par-
ticipation of other heteroatom nucleophiles in the ring-
opening of these novel substrates should be pursued and as
such, in this work we decided to explore the reactivity of
weaker carboxylic acid nucleophiles with cyclopropanated
oxabenzonorbornadienes. We began by investigating the
formerly successful acid-mediated conditions.23
The effects of external acid catalyst and temperature on
type 2 ring-opening reactions of 12 using acetic acid as
both nucleophile and solvent are summarized in Table 1. In
the absence of an acid catalyst and at room temperature,
the reaction did not proceed (Table 1, entry 1). In fact, even
after 10 days at 90 °C it was found that no reaction took
place when an acid catalyst was not supplied (entry 2).
Some inorganic acid catalysts were then investigated, of
which sulfuric acid showed the fastest effect at room tem-
perature, where moderate yields of 16a were obtained after
only 1 hour (entry 3). When nitric acid was used as the cat-
alyst, the reaction took a much longer time to proceed, and
yields were slightly worse (entry 4). At the expense of time,
tetrafluoroboric acid gave improved yield of 65% at room
temperature (entry 5), although no appreciable improve-
ment in yield could be made by increasing the reaction
temperature (entry 6). With the organic acid catalysts
screened, camphorsulfonic acid showed slow conversion
when the reaction was heated to 40 °C (entry 7), while pyr-
idinium p-toluenesulfonate required heating to 90 °C to ob-
tain similar results (entry 8). Finally, use of p-toluenesul-
fonic acid monohydrate showed decent conversion at room
temperature (entry 9), which was enhanced at higher tem-
peratures (entries 10–12). The best conditions among these
optimizations was thus found to be with the use of catalytic
p-toluenesulfonic acid at 90 °C for 20 hours, giving 70%
yield (entry 12).
O
O
1
12
Figure 1 Structural comparison between conventional alkene 1 and
novel cyclopropane system 12
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
E. Carlson et al.
Paper
Synthesis
Table 1 Effect of Acid Catalyst and Reaction Temperature on Type 2
Ring-Opening Reactions of 12
ate yields after one week. Although the use of 1,4-dioxane
resulted in reasonable yields, the reaction took two days to
complete (entry 5), whereas similar results were seen with
the use of 1,2-dichloroethane (DCE, entry 6), which gave
74% of product after only 28 hours. When the amount of
acetic acid was reduced to 8 equivalents (entry 7), the reac-
tion showed comparable results as to when acetic acid was
used in large excess (entry 6). However, when smaller
equivalents of acetic acid were used, the yield of 16a was
seen to suffer (entries 8 and 9).
Using the optimized conditions of 8 equivalents of nuc-
leophile in DCE with catalytic p-toluenesulfonic acid at 90
°C, several different carboxylic acid nucleophiles were then
subjected to type 2 ring-opening reaction (Table 3). This re-
sulted in a large collection of diverse products with decent
yields. Relative to acetic acid (entry 1), the primary n-bu-
tyric acid nucleophile (n-PrCO2H) produced comparable
yield of corresponding ring-opened product 16b after 24
hours (Table 3, entry 2). Use of cyclopentanecarboxylic acid
resulted in similar yield of 16c after an additional day (en-
try 3), and pivalic acid gave comparable yield of 16d after a
further day of reaction (entry 4). When benzoic acid was
used as the nucleophile, once again a very similar yield of
16e could be attained (entry 5), although the reaction was
much faster. Use of 2-propenoic acid resulted in a similar
reaction rate and yield, as well (entry 6). When 2-propynoic
acid was used, the reaction was complete after only 1 hour,
with no starting material observed by NMR, although prod-
uct could only be isolated in 29% yield (entry 7). These fast-
O
acid cat. (10 mol%)
AcOH
OAc
12
16a
Entry
Acid source
(0.1 equiv)
Temp
(°C)a
Time
(h)
Yield (%)b of Yield (%)b of
recovered 12 product 16a
1
2
none
r.t.
90
r.t.
r.t.
r.t.
90
40
90
r.t.
40
60
90
48
240
1
88
64
0
0
0
none
3
H2SO4
59
48
65
69
36
33
41
55
66
70
4
HNO3
120
168
20
12
0
5
HBF4
6c
7
HBF4
0
CSA
168
168
168
30
44
27
36
5
8
PPTS
9
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
10
11
12
24
0
20
0
a Room temperature; r.t. = 19–24 °C.
b Isolated yield after column chromatography.
c Aqueous solution of 48 wt% HBF4.
Next, the effect of solvent and equivalency of acetic acid
were screened (Table 2). It was found that relative to when
acetic acid was the sole reaction medium (Table 2, entry 1),
addition of acetonitrile led to a reduction in yield (entry 2),
which was also suggested with the use of toluene (entry 3).
This reduction in yield was even more pronounced with the
use of dimethyl sulfoxide (entry 4), which only gave moder-
Table 3 Effect of Nucleophile on Type 2 Ring-Opening Reactions of 12
O
O
p-TsOH (10 mol%), DCE
O
R
Table 2 Effect of Solvent and Nucleophile Equivalency on Type 2 Ring-
Opening Reactions of 12
RCO2H (8 equiv), 90 °C
12
16a–k
O
Entry
R
pKa of RCO2Ha Time
(h)
Product
Yield
(%)b
p-TsOH (10 mol%), solvent
OAc
AcOH (x equiv), 90 °C
12
16a
1
2
Me
4.7624
4.8125
4.9826
5.0524
4.1724
4.2524
1.8427
3.5324
3.228
18
16a
16b
16c
16d
16e
16f
73
72
76
70
70
63
29
75
16
37
51
n-Pr
22
48
68
24
32
1
Entry Solvent
AcOH
Time
Yield (%)a of
recovered 12 product 16a
Yield (%)a of
3
c-C5H9
t-Bu
(× equiv) (h)
4
1
2
3
4
5
6
7
8
9
none
>50
>50
>50
>50
>50
>50
8
20
0
0
70
54
67
44
68
74
73
63
48
5
Ph
MeCN
toluene
DMSO
1,4-dioxane
DCE
20
28
6
H2C=CH
HC≡C
MeOCH2
NpOCH2
ClCH2
BrCH2
0
7
16g
16h
16i
168
48
11
7
8
6
9c
10
11
6
28
0
2.8624
2.8624
2
16j
DCE
18
0
2
16k
DCE
4
24
0
a Values according to literature references.
DCE
2
24
0
b Isolated yield after column chromatography.
c Calculated pKa value, as reported in reference.
a Isolated yield after column chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
E. Carlson et al.
Paper
Synthesis
er reaction times were found to correlate with the pKa val-
ues of each carboxylic acid. When methoxyacetic acid
(MeOCH2CO2H) and 2-naphthoxyacetic acid (NpOCH2CO2H)
were subjected to reaction, both transformations were
complete after 6 hours (entries 8 and 9), and a similar cor-
relation in reaction rate with pKa value of the nucleophile
was also noted for chloro- and bromoacetic acid (entries 10
and 11). All reactions were left to react until complete con-
sumption of starting material 12 was confirmed by NMR
analysis. Thus, in trials where lower isolated yields were ob-
tained, it appeared that decomposition of 12 had occurred
under the reaction conditions.
The type 2 ring-opening reactions were then applied to
transformations using more diversely substituted variants
of cyclopropanated oxabenzonorbornadiene (Table 4). As
with the parent compound 12 (Table 4, entry 1), substrate
17a bearing bridgehead methyl groups underwent ring-
opening smoothly, furnishing expected product 18a in 60%
yield after 20 hours (entry 2). Substrate 17b with p-dimeth-
oxy substitution was found to undergo a more rapid trans-
formation (entry 3), while the same substituents in the or-
tho orientation (17c) resulted in an even faster reaction (en-
try 4).
lyst << pKa of carboxylic acid nucleophile). Following elec-
trophilic opening of the ether bridge in 19, an equivalent of
carboxylic acid then attacks at the external cyclopropane
carbon of 20, and subsequent dehydration produces naph-
thalene 16. Since the increased nucleophilicities of the car-
boxylic acids (having higher pKa values) do not show an en-
hancement in reaction rate, the data do not lend support to
the nucleophilic attack being the slow step in the reaction.
Thus, it is likely that the electrophilic ring-opening and for-
mation of carbocation 19 is the slow step, although the
mechanism of these conversions may be more complicated
than what is currently understood. The present study, how-
ever, does show that the pKa of the carboxylic acid has some
effect on the rate of reaction.
In addition, it was found that 2-propynoic acid (which
had the lowest pKa of all the acids tested in this work, Table
3), could promote ring-opening of 12 even in the absence of
an added catalyst. Relative to the reaction with added p-tol-
uenesulfonic acid (which took only 1 hour to complete), the
same reaction without any catalyst took 3 days to reach
completion (Scheme 5). Since these conditions only utilized
8 equivalents of carboxylic acid diluted in DCE, the reaction
was then repeated in the absence of acid catalyst, but using
a large excess of carboxylic acid as both solvent and nucleo-
phile. In this case, the reaction was much faster, with full
consumption of starting material after 2 hours. This is in
stark contrast to the reaction using pure acetic acid in the
absence of catalyst, whose reaction did not proceed even
after a full week.
The transformation at hand is explained by the follow-
ing mechanism (Scheme 4): the oxygen of 12 becomes pro-
tonated (presumably by the acid catalyst, when pKa of cata-
Table 4 Effect of Substrate Functionalization on Type 2 Ring-Opening
Reactions of Cyclopropanated 7-Oxabenzonorbornadiene
In conclusion, the present work demonstrates the abili-
ty of carboxylic acid nucleophiles to cleave cyclopropanated
oxabenzonorbornadienes in a type 2 fashion, under acid
mediation. The strength and source of the acid catalyst was
seen to affect the rate of ring-opening, and the conversion
took place most efficiently when p-toluenesulfonic acid
monohydrate was used in conjunction with DCE at 90 °C.
The amount of nucleophile could be reduced to 8 equiva-
lents without hampering the reaction yield. This mode of
ring-opening showed successful conversion with diverse
nucleophile and substrate combinations. The benzylic es-
ters produced in this way could be useful in the preparation
O
X
Z
X
Z
O
Z
Y
Y
Y
p-TsOH (10 mol%)
O
Y
AcOH, DCE, 90 °C
12, 17a–c
16a, 18a–c
X
X
Z
Entry
X
Y
Z
Time (h) Product
Yield (%)a
1
2
3
4
H
H
H
18
20
7
16a
18a
18b
18c
73
60
45
40
H
H
H
Me
H
OMe
H
OMe
H
1
a Isolated yield after column chromatography.
O
H-cat.
H
O
OH
O
HO
R
12
19
20
OH2
O
OH
O
O
~ H+
O
R
O
H
R
O
R
H
base
16
Scheme 4 Proposed mechanism for type 2 ring-opening of 12
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
E. Carlson et al.
Paper
Synthesis
Acetic Acid 2-Naphthalenylmethyl Ester (16a)
Yield: 23.8 mg (73%); white solid; mp 50–53 °C (Lit.31,32 mp 53–55
°C); Rf = 0.22 (EtOAc–hexanes, 2:98).
IR (ATR): 3056, 2952, 1732 (C=O), 1223, 1022, 821, 743, 479 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.90–7.86 (m, 4 H), 7.55–7.48 (m, 3 H),
5.30 (s, 2 H), 2.16 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.8, 133.2, 133.1, 133.0, 128.3,
128.0, 127.6, 127.3, 126.2, 1261, 125.8, 66.3, 21.0.
O
O
(pKa = 1.84)
OH
(8 equiv)
O
p-TsOH.H2O (10 mol%)
.
29%
16g
16g
DCE, 90 °C, 1 h
O
O
O
(pKa = 1.84)
OH
(8 equiv)
O
DCE, 90 °C, 3 d
O
O
29%
Spectral data are consistent with those previously reported.31,32
(pKa = 1.84)
12
Butanoic Acid 2-Naphthalenylmethyl Ester (16b)
OH
(>30 equiv)
O
Yield: 39.0 mg (72%); yellow oil; Rf = 0.32 (EtOAc–hexanes, 5:95).
IR (ATR): 3056, 2964, 2875, 1731 (C=O), 1169, 814, 473 cm–1
90 °C, 2 h
26%
.
16g
1H NMR (600 MHz, CDCl3): δ = 7.83–7.80 (m, 4 H), 7.48–7.43 (m, 3 H),
5.26 (s, 2 H), 2.35 (t, J = 7.5 Hz, 2 H), 1.70–1.66 (m, 2 H), 0.94 (t, J = 7.3
Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 173.6, 133.6, 133.2, 133.1, 128.4,
128.0, 127.7, 127.3, 126.3, 126.2, 125.9, 66.2, 36.3, 18.5, 13.7.
O
(pKa = 4.76)
OH
no reaction
90 °C, 10 d
Scheme 5 Ability of 2-propynoic acid to react in the absence of added
catalyst
HRMS: m/z [M]+ calcd for C15H16O2: 228.1150; found: 228.1155.
of biologically active frameworks, through transformations
such as cross-coupling reactions.29 The chemistry intro-
duced in this work may show appeal in further transforma-
tions of similarly strained fused-ring systems.
Cyclopentanecarboxylic Acid 2-Naphthalenylmethyl Ester (16c)
Yield: 38.0 mg (76%); clear oil; Rf = 0.27 (EtOAc–hexanes, 5:95).
IR (ATR): 3055, 2955, 2870, 1726 (C=O), 1601, 1508, 1451, 1173, 1145,
815, 472 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.88–7.84 (m, 4 H), 7.53–7.49 (m, 3 H),
5.30 (s, 2 H), 2.84 (pent, J = 8.0 Hz, 1 H), 1.96–1.85 (m, 4 H), 1.78–1.72
(m, 2 H), 1.63–1.60 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 176.7, 133.7, 133.2, 133.1, 128.4,
128.0, 127.7, 127.2, 126.3, 126.2, 125.8, 66.2, 43.9, 30.1 (2 C), 25.8 (2
C).
All commercial reagents were used without further purification. Cy-
clopropanated oxabenzonorbornadiene was prepared as previously
reported.17,18 Dichloroethane was obtained from an LC-SPS solvent
purification system supplied with dry packed columns containing 3Å
molecular sieves. Standard column chromatography was performed
on 230–400 mesh silica gel using flash column chromatography tech-
niques.30 Analytical TLC was performed on precoated silica gel 60
F254 plates. Melting points were measured using a Mel-Temp appara-
tus. IR spectra were acquired as solids or as neat oils on a Bruker AL-
PHA platinum single reflection diamond ATR spectrophotometer and
are reported in wave numbers (cm–1). 1H and 13C NMR spectra were
recorded on a Bruker Avance 600 MHz or 400 MHz spectrometer
equipped with a Cryoplatform® Prodigy cryoprobe, and reported as
chemical shift (δ) values in parts per million (ppm) from TMS with
the solvent resonance as the internal standard (CDCl3 1H: 7.24 ppm;
13C: 77.0 ppm).
HRMS: m/z [M]+ calcd for C17H18O2: 254.1307; found: 254.1301.
2,2-Dimethylpropanoic Acid 2-Naphthalenylmethyl Ester (16d)
Yield: 30.3 mg (70%); clear oil; Rf = 0.23 (EtOAc–hexanes, 5:95).
IR (ATR): 3056, 2971, 2872, 1725 (C=O), 1478, 1279, 1141, 814, 733,
472 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.83–7.78 (m, 4 H), 7.48–7.41 (m, 3 H),
5.24 (s, 2 H), 1.22 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 178.4, 133.9, 133.2, 133.0, 128.3,
128.0, 127.7, 126.9, 126.3, 126.2, 125.6, 66.2, 38.9, 27.2 (3 C).
Spectral data are consistent with those previously reported.33
Acid-Catalyzed Ring-Opening Reaction of Cyclopropanated
7-Oxabenzonorbornadiene; General Procedure
Benzoic Acid 2-Naphthalenylmethyl Ester (16e)
In a small screw-cap vial equipped with a stir bar, cyclopropanated
oxabenzonorbornadiene 12 (0.19 mmol, 1.0 equiv) was dissolved in
dichloroethane (0.25 mL). p-TsOH·H2O (0.1 equiv) was added as a sol-
id, and carboxylic acid nucleophile (8.0 equiv) was introduced, rins-
ing with dichloroethane (0.25 mL). The vial was sealed tightly and
heated to 90 °C with continuous stirring for 1–168 h. The crude prod-
uct was quenched with sat. aq NaHCO3, extracted with CH2Cl2 (3 × 10
mL), and the combined organic layers were dried (MgSO4): The sol-
vent was removed by rotary evaporation, and the crude mixture was
purified by column chromatography (EtOAc–hexanes, 2:98 to 5:95) to
give the corresponding ring-opened product (Tables 3, 4).
Yield: 41.5 mg (70%); white solid; mp 45–47 °C; Rf = 0.21 (EtOAc–hex-
anes, 5:95).
IR (ATR): 3403, 3058, 2975, 1706, 1599, 1506, 1450, 1311, 1274, 1261,
819, 699, 679 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.12 (m, 2 H), 7.94 (s, 1 H), 7.89 (m, 3
H), 7.60–7.47 (m, 6 H), 5.56 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 166.5, 133.4, 133.2, 133.14, 133.10,
130.1, 129.8 (2 C), 128.5, 128.4 (2 C), 128.0, 127.8, 127.4, 126.4, 126.3,
125.9, 66.9.
HRMS: m/z [M]+ calcd for C18H14O2: 262.0994; found: 262.0999.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
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Synthesis
2-Propenoic Acid 2-Naphthalenylmethyl Ester (16f)
HRMS: m/z [M]+ calcd for C13H11ClO2: 234.0448; found: 234.0441.
Yield: 28.8 mg (63%); clear oil; Rf = 0.30 (EtOAc–hexanes, 1:9).
IR (ATR): 3055, 2954, 2108, 1719 (C=O), 1405, 1176, 967, 809 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.86–7.83 (m, 4 H), 7.51–7.47 (m, 3 H),
6.47 (dd, J = 17.3 Hz, 1.4 Hz, 1 H), 6.19 (dd, J = 17.3 Hz, 10.4 Hz, 1 H),
5.87 (dd, J = 10.4 Hz, 1.4 Hz, 1 H), 5.36 (s, 2 H).
Bromoacetic Acid 2-Naphthalenylmethyl Ester (16k)
.
Yield: 22.6 mg (51%); white solid; mp 48–49 °C; Rf = 0.48 (EtOAc–hex-
anes, 25:75).
IR (ATR): 3024, 2964, 2108, 1916, 1750, 1718 (C=O), 1270, 1230, 966,
816 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 166.1, 133.3, 133.2, 133.1, 131.3,
128.4, 128.3, 128.0, 127.7, 127.4, 126.4, 126.3, 125.9, 66.5.
1H NMR (600 MHz, CDCl3): δ = 7.87–7.84 (m, 4 H), 7.51–7.50 (m, 2 H),
7.47–7.46 (m, 1 H), 5.37 (s, 2 H), 3.90 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 167.1, 133.3, 133.2, 132.4, 128.6,
HRMS: m/z [M]+ calcd for C14H12O2: 212.0837; found: 212.0842.
128.1, 127.8 (2 C), 126.52, 126.46, 125.9, 68.1, 25.9.
HRMS: m/z [M]+ calcd for C13H11BrO2: 277.9942; found: 277.9948.
2-Propynoic Acid 2-Naphthalenylmethyl Ester (16g)
Yield: 17.9 mg (29%); white solid; mp 89–92 °C; Rf = 0.18 (EtOAc–hex-
anes, 5:95).
Acetic Acid 1,4-Dimethyl-2-naphthalenylmethyl Ester (18a)
IR (ATR): 3402, 3246, 3061, 2940, 2112, 1703 (C=O), 1227, 822, 749,
716 cm–1
.
Yield: 24.1 mg (60%); yellow oil; Rf = 0.19 (EtOAc–hexanes, 5:95).
IR (ATR): 3072, 2942, 2254, 1732 (C=O), 1224, 1021, 729 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.90–7.87 (m, 4 H), 7.54–7.49 (m, 3 H),
1H NMR (400 MHz, CDCl3): δ = 8.15–8.12 (m, 1 H), 8.04–8.01 (m, 1 H),
7.59–7.56 (m, 2 H), 7.33 (s, 1 H), 5.33 (s, 2 H), 2.71 (s, 3 H), 2.70 (s, 3
H), 2.14 (s, 3 H).
5.41 (s, 2 H), 2.93 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 152.6, 133.3, 133.1, 131.9, 128.6,
128.1, 128.0, 127.8, 126.6, 126.5, 125.9, 75.2, 74.5, 68.1.
13C NMR (100 MHz, CDCl3): δ = 171.1, 132.9, 132.7, 132.4, 131.6,
HRMS: m/z [M]+ calcd for C14H10O2: 210.0681; found: 210.0688.
130.2, 128.3, 125.81, 125.78, 124.8, 124.6, 65.3, 21.1, 19.4, 14.2.
Methoxyacetic Acid 2-Naphthalenylmethyl Ester (16h)
HRMS: m/z [M]+ calcd for C15H16O2: 228.1150; found: 228.1156.
Yield: 32.4 mg (75%); white solid; mp 30–32 °C; Rf = 0.14 (EtOAc–hex-
anes, 5:95).
Acetic Acid 5,8-Dimethoxy-2-naphthalenylmethyl Ester (18b)
Yield: 13.5 mg (45%); yellow oil; Rf = 0.38 (EtOAc–hexanes, 1:4).
IR (ATR): 3000, 2938, 2835, 1733 (C=O), 1603, 1462, 1365, 1270, 1214,
IR (ATR): 3467, 3053, 2994, 2927, 2889, 2869, 2827, 1737 (C=O), 1449,
1212, 1192, 1124, 829, 740 cm–1
.
1086, 801 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.87 (m, 4 H), 7.54 (m, 3 H), 5.40 (s, 2
1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 8.8 Hz, 1 H), 8.19 (s, 1 H),
7.48 (dd, J = 8.6 Hz, 1.8 Hz, 1 H), 6.71 (s, 2 H), 5.27 (s, 2 H), 3.96 (s, 3
H), 3.95 (s, 3 H), 2.13 (s, 3 H).
H), 4.13 (s, 2 H), 3.49 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.2, 133.19, 133.15, 132.8, 128.5,
128.0, 127.8, 127.7, 126.5, 126.4, 126.0, 69.9, 66.8, 59.5.
13C NMR (100 MHz, CDCl3): δ = 171.0, 149.42, 149.40, 133.3, 126.1,
HRMS: m/z [M]+ calcd for C14H14O3: 230.0943; found: 230.0949.
126.0, 125.9, 122.4, 121.5, 103.62, 103.60, 66.7, 55.8, 55.7, 21.1.
Naphthoxyacetic Acid 2-Naphthalenylmethyl Ester (16i)
HRMS: m/z [M]+ calcd for C15H16O4: 260.1049; found: 260.1055.
Yield: 13.2 mg (16%); white solid; mp 98–100 °C; Rf = 0.10 (EtOAc–
hexanes, 5:95).
Acetic Acid 6,7-Dimethoxy-2-naphthalenylmethyl Ester (18c)
Yield: 8.6 mg (40%); white solid; mp 66–68 °C; Rf = 0.24 (EtOAc–hex-
anes, 1:9).
IR (ATR): 3054, 2971, 2116, 1738 (C=O), 1597, 1272, 1215, 1190, 1170,
1061, 841 cm–1
.
IR (ATR): 3004, 2955, 2831, 1736, 1492, 1254, 1227, 1163 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.84–7.79 (m, 6 H), 7.64 (d, J = 8.1 Hz, 1
H), 7.52 (m, 2 H), 7.44 (m, 3 H), 7.28 (m, 1 H), 7.07 (d, J = 2.5 Hz, 1 H),
5.46 (s, 2 H), 4.85 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 168.8, 155.7, 134.2, 133.2, 133.1,
132.5, 129.8, 129.4, 128.5, 129.1, 127.8, 127.73, 127.68, 126.9, 126.54,
126.47, 126.4, 125.9, 124.2, 118.6, 107.1, 67.2, 65.4.
1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 7.9 Hz, 1 H), 7.68 (s, 1 H),
7.32 (dd, J = 8.4 Hz, 1.6 Hz, 1 H), 7.12 (s, 2 H), 5.23 (s, 2 H), 4.006 (s, 3
H), 4.003 (s, 3 H), 2.12 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.1, 149.8, 131.6 (2 C), 128.9 (2 C),
126.8, 126.2, 124.5, 106.3, 106.1, 66.7, 55.9 (2 C), 21.2.
HRMS: m/z [M]+ calcd for C23H18O3: 342.1256; found: 342.1263.
HRMS: m/z [M]+ calcd for C15H16O4: 260.1049; found: 260.1053.
Chloroacetic Acid 2-Naphthalenylmethyl Ester (16j)
Yield: 16.2 mg (37%); white solid; mp 50–51 °C; Rf = 0.44 (EtOAc–hex-
anes, 25:75).
Acknowledgment
This work was supported by Natural Sciences and Engineering Coun-
cil of Canada (NSERC).
IR (ATR): 3479, 3059, 3026, 2955, 1747 (C=O), 1310, 1185, 962, 828
cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.84 (m, 4 H), 7.51–7.49 (m, 2 H), 7.46–
7.45 (m, 1 H), 5.37 (s, 2 H), 4.11 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 167.3, 133.3, 133.2, 132.3, 128.6,
128.1, 127.9, 127.8, 126.6, 126.5, 125.9, 68.1, 41.0.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560565.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
E. Carlson et al.
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Synthesis
References
3538. (g) Lautens, M.; Hiebert, S. J. Am. Chem. Soc. 2004, 126,
1437. (h) Wu, M. S.; Jeganmohan, M.; Cheng, C.-H. J. Org. Chem.
2005, 70, 9545.
(1) (a) Lautens, M.; Ma, S.; Chiu, P. J. Am. Chem. Soc. 1997, 119,
6478. (b) Chiu, P.; Lautens, M. Top. Curr. Chem. 1997, 190, 1.
(c) Edmunds, M.; Raheem, M. A.; Boutin, R.; Tait, K.; Tam, W.
Beilstein J. Org. Chem. 2016, 12, 239. (d) Okada, M.; Sumitomo,
H.; Yamada, S.; Atsumi, M. Macromolecules 1986, 19, 953.
(e) Bertolini, F.; Macchia, F.; Pineschi, M. Tetrahedron Lett. 2006,
47, 9173. (f) Crotti, S.; Bussolo, V. D.; Pineschi, M. Synthesis
2012, 44, 1511.
(15) Lautens, M.; Rovis, T. Tetrahedron 1999, 55, 8967.
(16) Madan, S.; Cheng, C.-H. J. Org. Chem. 2006, 71, 8312.
(17) McKee, M.; Haner, J.; Carlson, E.; Tam, W. Synthesis 2014, 46,
1518.
(18) (a) Carlson, E.; Duret, G.; Blanchard, N.; Tam, W. Synth. Commun.
2016, 46, 55. (b) Lough, A. J.; Carlson, E.; Tam, W. IUCrData
2016, 1, x160341.
(2) Rayabarapu, D. K.; Cheng, C.-H. Acc. Chem. Res. 2007, 40, 971.
(3) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48.
(4) For a review of tranisiton-metal-catalyzed [2+2] cycloadditions
between bicyclic alkenes and alkynes, see: Tam, W.; Jack, K.;
Goodreid, J.; Cockburn, N. Adv. Org. Synth. 2013, 6, 59.
(5) (a) Burton, R. R.; Tam, W. J. Org. Chem. 2007, 72, 7333.
(b) Burton, R. R.; Tam, W. Tetrahedron Lett. 2006, 47, 7185.
(6) Allen, A.; Villeneuve, K.; Cockburn, N.; Fatila, E.; Riddell, N.;
Tam, W. Eur. J. Org. Chem. 2008, 4178.
(7) Villeneuve, K.; Riddell, N.; Tam, W. Tetrahedron 2006, 62, 3823.
(8) Villeneuve, K.; Tam, W. Eur. J. Org. Chem. 2006, 5449.
(9) Villeneuve, K.; Tam, W. Organometallics 2007, 26, 6082.
(10) Villeneuve, K.; Tam, W. Organometallics 2006, 25, 843.
(11) Villeneuve, K.; Tam, W. J. Am. Chem. Soc. 2006, 128, 3514.
(12) Ballantine, M.; Menard, M. L.; Tam, W. J. Org. Chem. 2009, 74,
7570.
(19) Carlson, E.; Tam, W. Synthesis 2016, 48, 2449.
(20) de Meijere, A. Angew. Chem., Int. Ed. Engl. 1979, 18, 809.
(21) Carlson, E.; Haner, J.; McKee, M.; Tam, W. Org. Lett. 2014, 16,
1776.
(22) Carlson, E.; Tam, W. Org. Lett. 2016, 18, 2134.
(23) Tigchelaar, A.; Haner, J.; Carlson, E.; Tam, W. Synlett 2014, 25,
2355.
(24) Jencks, W. P.; Regenstein, J. In Ionization Constants of Acids and
Bases, Handbook of Biochemistry; Sober, M. A., Ed.; Chemical
Rubber Company: Cleveland, 1968, 305.
(25) Harris, D. C. Quantitative Chemical Analysis, 8th ed.; W. H.
Freeman and Company: New York, 2010, AP11.
(26) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory Chem-
icals, 6th ed.; Elsevier Inc: Oxford, 2009, 194.
(27) Carey, F. A.; Sundberg, R. A. Advanced Organic Chemistry Part A:
Structure and Mechanisms, 5th ed.; Springer: New York, 2007, 1.
(28) Velkov, T.; Horne, J.; Laguerre, A.; Jones, E.; Scanlon, M. J.;
Porter, C. J. H. Chem. Biol. 2007, 14, 452.
(13) Allen, A.; Le Marquand, P.; Burton, R. R.; Villeneuve, K.; Tam, W.
J. Org. Chem. 2007, 72, 7849.
(14) (a) Leong, P.; Lautens, M. J. Org. Chem. 2004, 69, 2194.
(b) Bertozzi, F.; Pineschi, M.; Moacchia, F.; Arnold, L. A.;
Minnaard, A. J.; Feringa, B. L. Org. Lett. 2002, 4, 2703. (c) Fan, E.;
Shi, W.; Lowary, T. J. Org. Chem. 2007, 72, 2917. (d) Lautens, M.;
Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311.
(e) Duan, J.; Cheng, C.-H. Tetrahedron Lett. 1993, 34, 4019.
(f) Feng, C.; Nandi, T. S.; Cheng, C.-H. J. Org. Chem. 1999, 64,
(29) Konev, M. O.; Hanna, L. E.; Jarvo, E. R. Angew. Chem. Int. Ed.
2016, 55, 6730.
(30) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(31) Ly, T.; Krout, M.; Pham, D. K.; Tani, K.; Stoltz, B. M.; Julian, R. R.
J. Am. Chem. Soc. 2007, 129, 1864.
(32) Guan, B.-T.; Xiang, S.-K.; Wiang, B.; Sun, Z.; Wang, Y.; Zhao, K.;
Zhang, J. J. Am. Chem. Soc. 2008, 130, 3268.
(33) Rao, C. B.; Chinnababu, B.; Venkateswarlu, Y. J. Org. Chem. 2009,
74, 8856.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G