Ruthenium-Catalyzed [2+2+2] Bis-Homo-Diels-Alder Cycloadditions of 1,5-Cyclooctadiene with Alkynyl Phosphonates

Article abstract of DOI:10.1055/s-0039-1690612

The ruthenium-catalyzed [2+2+2] bis-homo-Diels-Alder cycloaddition between 1,5-cyclooctadiene and alkynyl phosphonates was investigated. Various alkynyl phosphonate moieties were found to be compatible with the cycloaddition to give the tricyclo[4.2.2.0 <

Full text of DOI:10.1055/s-0039-1690612

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
paper
A
en
D. Petko et al.
Paper
Synthesis
Ruthenium-Catalyzed [2+2+2] Bis-Homo-Diels–Alder Cycloadditions
of 1,5-Cyclooctadiene with Alkynyl Phosphonates
Dina Petko
O
OR2
OR2
cat. A = Cp*RuCl(COD)
or
cat. B = [CpRu(CH3CN)3]PF6
P
Austin Pounder
William Tam*
R1
O
EtOH
70 °C, 72 h
P
R1
Guelph-Waterloo Centre for Graduate Work in Chemistry and
Biochemistry, Department of Chemistry, University of Guelph,
Guelph, Ontario, N1G 2W1, Canada
R2O OR2
R1 = alkyl, aryl
R2 = Me, Et, Ph
10 examples
yields up to 97%
wtam@uoguelph.ca
Received: 16.07.2019
Diels–Alder
cycloaddition
Accepted after revision: 31.07.2019
Published online: 21.08.2019
DOI: 10.1055/s-0039-1690612; Art ID: ss-2019-m0399-op
Abstract The ruthenium-catalyzed [2+2+2] bis-homo-Diels–Alder cyc-
loaddition between 1,5-cyclooctadiene and alkynyl phosphonates was
investigated. Various alkynyl phosphonate moieties were found to be
compatible with the cycloaddition to give the tricyclo[4.2.2.02,5]dec-7-
ene tricyclic compounds in yields of 46–97%.
homo-Diels–Alder
cycloaddition
Key words 1,5-cyclooctadiene, bis-homo-Diels–Alder reaction, cyclo-
addition, ruthenium-catalyzed, alkynyl phosphonate
bis-homo-Diels–Alder
cycloaddition
1
Cycloadditions are amongst the most powerful in the
repertoire of ring-forming reactions producing multiple
carbon–carbon bonds in a single step. Cycloadditions are
achieved under photochemical or thermal conditions or
promoted by Lewis acids. Transition-metal catalysts ex-
panded the scope of the cycloaddition and have been used
for construction of a wide array of four- to eight-membered
rings.1 Transition-metal-catalyzed [2+2],2 [3+2],3 Diels–
Alder [4+2],4 and homo-Diels–Alder [2+2+2]5 are all well
described in literature; however, very few examples of the
bis-homo-Diels–Alder [2+2+2]6–8 cycloaddition exist. The
bis-homo-Diels–Alder (BHDA) reaction was first reported
by Trost et al. in 1993 as a cycloaddition between 1,5-cy-
clooctadiene (COD, 1) and an alkyne resulting in the forma-
tion of the tricyclo[4.2.2.02,5]dec-7-ene bicyclic framework
2 (Scheme 1).7 Unlike the Diels–Alder and homo-Diels–
Alder cycloadditions, which can both occur thermally or by
transition metal catalysts such as Ni, Co, Rh, and Pd,1 the
BHDA cycloaddition has only been achieved using a Ru cata-
lyst6–8 (Scheme 1).
2
Scheme 1 Diels–Alder, homo-Diels–Alder, and bis-homo-Diels–Alder
cycloadditions
compounds such as mitindomide9 and kingianin C10 (Figure
1). Both mitindomide and kingianin C have been shown to
have anticancer activity. For instance, mitindomide is
tricyclo[4.2.2.02,5]dec-7-ene
O
NHEt
O
O
O
O
O
HN
NH
NHEt
O
O
O
O
The BHDA cycloaddition provides a facile method of
synthesis of the tricyclo[4.2.2.02,5]dec-7-ene bicyclic frame-
works, which can be found in several biologically active
mitindomide
kingianin C
Figure 1 Two biologically active compounds containing the tricyclo-
[4.2.2.02,5]dec-7-ene framework
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
D. Petko et al.
Paper
Synthesis
known to be an inhibitor of DNA topoisomerase II, which is
needed for DNA replication and cell proliferation.9 Addi-
tionally, kingianin C has been shown to have inhibitory ef-
fects on anti-apoptotic protein Bcl-xL, which is commonly
found in cancer cells, particularly those that are resistant to
conventional chemotherapies.10
In the past, our research group has investigated rutheni-
um-catalyzed [2+2]11 and homo-Diels–Alder [2+2+2] cyclo-
additions12 between bicyclic alkenes and alkynyl phospho-
nates to generate cyclobutene and deltacyclanes adducts,
respectively (Scheme 2).
activation of Cp*RuCl(COD) in aprotic solvents. Pleasingly,
the addition of silver salts promoted the cycloaddition us-
ing cat. A in the previously noneffective aprotic solvents al-
though only in a 72–80% yield (entries 5–7, 9, 11, 13). The
yield of 4a was improved with the use of polar protic sol-
vents (entries 3 and 4) as high as 93%. EtOH was found to be
the optimal solvent to promote the formation of the BHDA
cycloadduct for both Ru catalysts in high yields.
Table 1 Optimization of Solvent for the Ru-Catalyzed BHDA [2+2+2]
Cycloaddition of COD 1 with 1-Hexynylphosphonate 3a
O
OR2
OR2
P
cat. A = Cp*RuCl(COD)
1
or
cat. B = [CpRu(CH3CN)3]PF6
nBu
O
+
P
O
R1
solvent
70 °C, 72 h
nBu
P
EtO OEt
[2+2]
[2+2+2]
EtO OEt
4a
3a
O
OR2
OR2
Entry
Solvent
Silver salta
Yield (%)b
Cat. A
P
Cat. B
R1
O
P
R1
1
2
neat
–
0 (51)c
0 (93)c
91
48
85
93
89
–
R2O OR2
NMP
–
Scheme 2 [2+2] and homo-Diels–Alder [2+2+2] reactions of bicyclo-
[2.2.1]hepta-2,5-diene and alkynyl phosphonates
3
EtOH
MeOH
–
4
–
91
To date, the development of new biologically active
compounds depends heavily on organic synthetic chemis-
try. Thus, the introduction of new functional groups into
these attractive polycyclic frameworks would offer more
opportunities to discover new intriguing, and possibly
pharmaceutically relevant molecules.
Vinyl phosphonates have been found to be important
biomolecules in metabolic processes, as anticancer and an-
tiviral drugs, and as antibacterial and antifungal com-
pounds.13–18 The vinyl phosphonate group can be further
modified by established procedures. The alkene can under-
go cyclopropanation,19 ozonolysis,20 or Diels–Alder cyclo-
additions21 while the phosphonate can be converted to a
variety of other phosphorus groups including phosphines.22
To the best of our knowledge, there are no examples of the
BHDA cycloaddition involving alkynes directly attached to a
heteroatom. The formation of the BHDA cycloadduct con-
taining a vinyl phosphonate is thus desirable, and investiga-
tions into the Ru-catalyzed BHDA cycloaddition were fur-
ther pursued.
Initial studies began screening a series of solvents for
the BHDA cycloaddition of COD with diethyl 1-hexynyl-
phosphonate (3a) using two commercially available Ru-cat-
alysts: Cp*RuCl(COD) (cat. A) and [CpRu(CH3CN)3]PF6 (cat.
B). Several polar protic, polar aprotic, and nonpolar solvents
were investigated. Using NMP, 1,4-dioxane, THF, or DCE as a
solvent (Table 1, entries 2, 8, 10, 14) or running the reaction
neat (entry 1) produced the desired cycloadduct in a 48–
85% yield but only using cat. B. Next, we turned to additives
to see if the introduction of silver salts would facilitate the
5
1,4-dioxane
AgSbF6
AgBF4
AgOTf
–
80
6
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
78
–
7
79
–
8
0 (90)c
77
83
–
9
AgSbF6
–
10
11
12
13
14
THF
0
60
–
toluene
toluene
DCE
AgSbF6
–
72
0
0 (79)c
AgSbF6
–
77
–
DCE
0
85
a Silver salts were only added to reactions containing cat. A Cp*RuCl(COD).
b Isolated yield.
c Percentage of starting material recovered.
After establishing the above optimized condition, the
scope of the Ru-catalyzed BHDA cycloaddition of COD and
alkynyl phosphonates was investigated. First, the effects of
the substituent on the phosphonate moiety were explored
(Table 2). Alkynyl phosphonates 3a–c were synthesized us-
ing known literature procedures11,23–25 and subjected to op-
timized BHDA conditions to produce cycloadducts 4a–c in
yields up to 97%. The reaction was found to be amenable to
the size of the phosphonate moiety with yields decreasing
as substituent size was increased. The effect of increasing
steric bulk and replacing an aliphatic group with an aro-
matic functionality on the phosphonate is demonstrated by
4c (R = Ph, Table 2, entry 3). Because the OMe moiety (entry
1) produced the cycloadduct 4b in the greatest yield for
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

C
D. Petko et al.
Paper
Synthesis
both catalysts, it was chosen as the model phosphonate
moiety for further exploration into the scope of the BHDA
cycloaddition.
mopropargylic alcohols usually gave higher yields and react
faster in the Ru-catalyzed BHDA cycloadditions.6 It is likely
that the ruthenium may bind to the hydroxyl group and en-
hance the reactivity of the alkynyl phosphonate 3i in the
Ru-catalyzed BHDA cycloaddition, which outweighs the
steric hindrance of the tertiary propargylic alcohol group.
Table 2 Ru-Catalyzed BHDA [2+2+2] Cycloadditions of COD 1 with
Alkynyl Phosphonates 3a–c
Table 3 Ru-Catalyzed BHDA [2+2+2] Cycloadditions of COD 1 with
Alkynyl Phosphonates 3b and 3d–i
cat. A = Cp*RuCl(COD)
or
cat. B = [CpRu(CH3CN)3]PF6
1
nBu
O
P
EtOH
70 °C, 72 h
O
R2O OR2
nBu
P
cat. A = Cp*RuCl(COD)
R2O OR2
4a–c
or
1
cat. B = [CpRu(CH3CN)3]PF6
R1
O
P
3a–c
O
EtOH
70 °C, 72 h
MeO OMe
R1
P
4b,d–i
MeO OMe
3b,d–i
Entry
R2
Cycloadduct
Yield (%)a
Cat. A
Cat. B
Entry
R1
Cycloadduct Yield (%)a
Cat. A
1
2
3
Me
4b
4a
4c
95
91
78
97
93
86
Cat. B
Et
Ph
1
2
3
4
5
6
7
n-Bu
4b
4d
4e
4f
95
0 (35)b
97
80
a Isolated yield.
Cy
t-Bu
0 (78)b
0 (35)b
0 (69)b
Ph
46
66
68
43c
The effects of alkyne substitution were examined with
several examples of primary, secondary, and tertiary alkyl
and aryl substituents (Table 3). The reaction was found to
be susceptible to the steric bulk of the alkyne substituent
with yields decreasing with increased steric hindrance. This
effect was particularly significant with cat. A with no reac-
tion proceeding when substituents lacked a methylene
group (entries 2, 3, 4, and 7). When using cat. B, the BHDA
cycloaddition showed compatibility with various function-
al groups including phenyls, benzyls, and protected alco-
hols (Table 3, entries 4–6). Unfortunately, the reaction did
not proceed with either catalysts when the alkyne was sub-
stituted with a tertiary carbon (entry 3). Interestingly,
when an unprotected alcohol (entry 7) underwent the
BHDA cycloaddition, an unexpected cycloadduct was
formed (Scheme 3). It is believed that cycloadduct 4i is
formed initially and undergoes an intramolecular cycliza-
tion to form the unpredicted tetracyclic cycloadduct 5a. We
have previously shown that propargylic alcohols and ho-
BnOCH2
BnOCH2CH2
Me2C(OH)
4g
4h
4i
58
66
0
a Isolated yield after chromatography.
b Percentage of starting material recovered.
c Unexpected cycloadduct 5a formed (see Scheme 3).
Examining the effects of the aromatic substituents, a se-
ries of ortho-, meta-, and para-substituted dimethyl 1-
phenylethynyl phosphonates were synthesized using
known literatures procedures.23–25 Since Cp*RuCl(COD)
originally failed the catalyze the BHDA cycloaddition with
Ph as an alkyne substituent (Table 3, entry 4), only [Cp-
Ru(CH3CN)3]PF6 was used for further trials. The reaction
was found to be affected by the electronic density of the ar-
omatic substituent. When electron-withdrawing substitu-
ents were placed at the meta- or para-position (Table 4, en-
tries 2, 3, 5) yields were increased from 46% (Table 4, entry
1) to as high as 79%. Unsurprisingly, the BHDA cycloaddition
did not proceed when substituents were placed at the or-
tho-position, most likely due to the steric hindrance (en-
tries 4, 6, 8). Continuing with this trend, electron-donating
substituents failed to undergo the BHDA cycloaddition with
neither product nor starting material being recovered (en-
tries 7 and 8). Interestingly, a similar observation was noted
in our groups previous investigations of the homo-Diels–
Alder cycloaddition of alkynyl phosphonates with bicyclo-
[2.2.1]hepta-2,2-diene where electron-donating aryl sub-
stituents promoted thermal decomposition of the final
cycloadduct.11
O
P
1
HO
OMe
MeO
O
4i
P
OMe
O
OH
OMe
P
3i
O
OMe
5a
Scheme 3 Formation of unexpected cycloadduct 5a via intramolecular
cyclization
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

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D. Petko et al.
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Synthesis
Table 4 Ru-Catalyzed BHDA [2+2+2] Cycloadditions of COD 1 with
Alkynyl Phosphonates 3c and 3e; General Procedure
Alkynyl Phosphonates 3f and 3k–q
i-Pr2NH (reaction scale 0.50–4.0 mmol, 1.5 equiv) was dissolved in
THF ( 0.8 M) at 0 °C in a flame dried round-bottomed flask (RBF). A
1.35 M solution of n-BuLi (1 equiv) in hexanes was added and the
solution stirred at r.t. for 1 h. The mixture was then added via cannula
to a second RBF containing the terminal alkyne (1 equiv) in THF ( 0.6
M) at –78 °C, which was then stirred while warming to r.t. for 2 h. In a
third RBF, the chlorophosphate (2 equiv) was dissolved in THF ( 0.6
M) and cooled to –78 °C. The deprotonated alkyne was then added
dropwise via cannula to the electrophile. The reaction mixture was
then stirred at –78 °C for 1 h, 0 °C for 1 h, and r.t. for 4 h or until com-
plete; the reaction progress was followed by TLC. When the reaction
was complete the solution was quenched with sat. aq NH4Cl. The
aqueous layer was separated and extracted with Et2O (3 ×). The com-
bined organic fractions were dried (MgSO4), filtered, and concentrat-
ed by rotary evaporation. The resulting product was then purified by
flash column chromatography on 230–400 mesh silica gel with hex-
anes/EtOAc mixture as the mobile phase.
[CpRu(CH3CN)3]PF6
1
O
EtOH
O
P
70 °C, 72 h
OMe
P
MeO
4f,k–q
R
MeO OMe
3f,k–q
R
Entry
R
Cycloadduct
Yield (%)a
1
2
3
4
5
6
7
8
H
4f
46
p-CF3
m-CF3
o-CF3
m-Cl
o-Cl
4k
4l
79
79
4m
4n
4o
4p
4q
0 (72)b
74
0 (78)b
0
Diphenyl Hex-1-yn-1-ylphosphonate (3c)
p-OMe
o-OMe
The crude product was purified by column chromatography (1:3
EtOAc/hexanes) to provide the alkyne 3c as a clear oil; yield: 106.5 mg
(0.338 mmol, 68%); Rf = 0.31 (1:3, EtOAc/hexanes).
0 (91)b
a Isolated yield.
b Percentage of starting material recovered.
IR (neat): 3491 (s), 3070 (w), 2960 (w), 2934 (w), 2873 (w), 2206 (m),
1590 (m), 1489 (s), 1284 (s), 1212 (s), 1188 (s), 1162 (s), 949 (s), 774
cm–1 (m).
In conclusion, we have demonstrated the first examples
of Ru-catalyzed BHDA [2+2+2] cycloaddition between 1,5-
cyclooctadiene and heteroatom-substituted alkynes. The
desired cycloadducts were obtained in yields ranging from
46 to 97%. The reaction was found to be amenable to the
steric bulk of both the phosphonate and alkynyl moieties.
Further, we demonstrated the compatibility for both ali-
phatic and aromatic substituents, as well as a range of func-
tional groups in poor to excellent yields. Finally, exploration
of the intramolecular variant of this reaction, or the modifi-
cation of the vinyl phosphonate could further expand the
scope and applicability of this reaction.
1H NMR (CDCl3, 400 MHz):  = 7.36–7.31 (m, 4 H), 7.27–7.22 (m, 4 H),
7,21–7.17 (m, 2 H), 2.27 (td, J = 7.0, 4.6 Hz, 2 H), 1.46–1.43 (m, 2 H),
1.31–1.25 (m, 2 H), 0.84 (t, J = 7.3 Hz, 3 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 150.0 (d, J = 7.5 Hz), 129.7, 125.5
(d, J = 1.2 Hz), 120.7 (d, J = 4.7 Hz), 106.6 (d, J = 55.5 Hz), 69.5 (d,
J = 322.2 Hz), 29.0 (d, J = 2.2 Hz), 21.6, 18.9 (d, J = 4.8 Hz), 13.3.
31P{1H} NMR (CDCl3, 121 MHz):  = –16.69.
HRMS: m/z [M+] calcd for C18H19O3P: 314.1072; found: 314.1078.
Dimethyl (3,3-Dimethylbut-1-yn-1-yl)phosphonate (3e)
The crude product was purified by column chromatography (EtOAc)
to provide the alkyne 3e as a clear oil; yield: 291.3 mg (1.53 mmol,
38%); Rf = 0.46 (EtOAc).
IR (neat): 3489 (s), 2973 (m), 2907 (w), 2872 (w), 2853 (w), 2220 (w),
2182 (m), 1269 (s), 1033 (s), 839 (m), 798 cm–1 (s).
1H NMR (CDCl3, 400 MHz):  = 3.70 (d, J = 12.2 Hz, 6 H), 1.22 (s, 9 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 111.3 (d, J = 51.2 Hz), 67.1 (d,
J = 305.1 Hz), 53.1 (d, J = 5.4 Hz), 29.8 (d, J = 1.8 Hz), 28.0 (d, J = 3.8
Hz).
All commercial reagents were used without further purification. Sol-
vent was obtained from an LC-SPS solvent purification system sup-
plied with dry packed columns containing 3Å molecular sieves. Stan-
dard column chromatography was performed on 230–400 mesh silica
gel using flash column chromatography techniques. Analytical TLC
was performed on pre-coated silica gel 60 F254 plates. All reactions
1
31P{1H} NMR (CDCl3, 121 MHz):  = –4.52.
carried out in an atmosphere of dry argon. H NMR spectra were re-
corded on 600 or 400 MHz in CDCl3, 13C{H} NMR spectra were record-
ed on 150 or 100 MHz in CDCl3. Chemical shifts for 1H NMR spectra
are reported in parts per million (ppm) with the solvent resonance as
the internal standard (CHCl3:  = 7.26). Chemical shifts for 13C {H}NMR
spectra are reported in parts per million with the solvent as the inter-
nal standard (CHCl3:  = 77.16). Standard abbreviations are used to
denote signal multiplicities. IR spectra were obtained on thin films on
NaCl disks using a Bomem MB-100 FTIR or Nicolet-380 FTIR spectro-
photometer. HRMS samples were ionized by chemical ionization (CI),
electron impact (EI), or electrospray ionization (ESI) as specified, and
detection of the ions was performed by time of flight (TOF). Alkynyl
phosphonates 3a, 3d, 3f, and 3p are known compounds and were pre-
pared using known literature procedures.11,12,23–25
HRMS: m/z [M + H+] calcd for C8H15O3P: 191.0837; found: 191.0840.
Alkynyl Phosphonates 3b, 3d, and 3f–q; General Procedure
H-Phosphonate (reaction scale 0.080–1.6 mmol), terminal alkyne (1
equiv), CuCl or Cu(OAc)2 (10 mol%), and Et3N (0.2 equiv) were dis-
solved in DMSO (0.5 M) in a flame-dried round-bottomed flask and
stirred for 24 h at 70 °C under an inert atmosphere. The resulting
mixture was extracted using EtOAc (3 ×). The combined organic frac-
tions were dried (MgSO4), filtered, and concentrated by rotary evapo-
ration. The resulting product was then purified by flash column chro-
matography on 230–400 mesh silica gel with hexanes/EtOAc mixture
as the mobile phase.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

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D. Petko et al.
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Synthesis
Dimethyl Hex-1-yn-1-ylphosphonate (3b)
HRMS: m/z [M + H+] calcd for C7H13O4P: 193.0630; found: 193.0624.
The crude product was purified by column chromatography (EtOAc)
to provide the alkyne 3b as a yellow oil; yield: 42.0 mg (0.221 mmol,
65%); Rf = 0.42 (EtOAc).
Dimethyl {[4-(Trifluoromethyl)phenyl]ethynyl}phosphonate (3k)
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 3k as a yellow oil; yield: 140.3
mg (0.626 mmol, 39%); Rf = 0.17 (1:1 EtOAc/hexanes).
IR (neat): 3494 (s), 2957 (m), 2874 (w), 2205 (m), 1274 (s), 1034 (s),
838 (m), 784 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 3.72 (d, J = 12.3 Hz, 6 H), 2.31 (td,
J = 7.1, 4.5 Hz, 2 H), 1.54–1.49 (m, 2 H), 1.41–1.36 (m, 2 H), 0.87 (t,
J = 7.3 Hz, 3 H).
IR (neat): 3488 (s), 2958 (w), 2856 (w), 2193 (m), 1325 (s), 1277 (m),
1172 (m), 1130 (s), 1067 (s), 1037 (s), 865 (m), 843 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 7.68–7.61 (m, 4 H), 3.84 (d, J = 12.2 Hz,
13C{1H} NMR (CDCl3, 100 MHz):  = 104.1 (d, J = 53.5 Hz), 69.0 (d,
J = 305.8 Hz), 53.1 (d, J = 5.6), 29.3 (d, J = 2.1 Hz), 21.8, 18.8 (d, J = 4.5
Hz), 13.4.
6 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 133.0 (d, J = 2.3 Hz), 132.4 (d,
J = 33.0 Hz), 125.6 (q, J = 3.8 Hz), 123.4 (d, J = 272.9 Hz), 123.1 (d,
J = 7.6 Hz), 97.5 (d, J = 52.6 Hz), 79.3 (d, J = 299.8 Hz), 53.6 (d, J = 5.4
Hz).
31P{1H} NMR (CDCl3, 121 MHz):  = –2.5.
HRMS: m/z [M + H+] calcd for C8H15O3P: 191.0837; found: 191.0841.
31P{1H} NMR (CDCl3, 121 MHz):  = –3.2.
Dimethyl [3-(Benzyloxy)prop-1-yn-1-yl]phosphonate (3g)
HRMS: m/z [M+] calcd for C11H10F3O3P: 278.0320; found: 278.0318.
The crude product was purified by column chromatography (EtOAc)
to provide the alkyne 3g as a clear oil; yield: 91.8 mg (0.408 mmol,
48%); Rf = 0.45 (EtOAc).
Dimethyl {[3-(Trifluoromethyl)phenyl]ethynyl}phosphonate (3l)
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 3l as a yellow oil; yield: 164.7
mg (0.592 mmol, 43%); Rf = 0.11 (1:1 EtOAc/hexanes).
IR (neat): 3031 (w), 2954 (w), 2853 (w), 2204 (w), 1266 (m), 1022 (s),
837 (m), 784 (m), 739 (m), 698 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 7.34–7.27 (m, 5 H), 4.57 (s, 2 H), 4.24
(d, J = 3.8 Hz, 2 H), 3.76 (d, J = 12.3 Hz, 6 H).
IR (neat): 3477 (s), 2958 (w), 2855 (w), 2192 (m), 1332 (s), 1280 (s),
1219 (s), 1171 (s), 1037 (s), 908 (m), 755 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 7.72–7.67 (m, 2 H), 7.57–7.53 (m, 2 H),
3.83 (d, J = 12.4 Hz, 6 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 135.1 (d, J = 2.7 Hz), 132.8 (d,
J = 31.5 Hz), 131.8, 130.6, 127.1, 126.2 (q, J = 4.9), 123.0 (d, J = 271.5
Hz), 94.9 (d, J = 52.1 Hz), 82.3 (d, J = 295.8 Hz), 53.6 (d, J = 5.6 Hz).
13C{1H} NMR (CDCl3, 100 MHz):  = 136.5, 128.5, 128.2, 128.1, 97.2 (d,
J = 50.0 Hz), 75.1 (d, J = 296.8 Hz), 72.2, 57.0 (d, J = 4.4 Hz), 53.49 (d,
J = 5.5 Hz).
31P{1H} NMR (CDCl3, 121 MHz):  = –3.9.
HRMS: m/z [M + H+] calcd for C12H15O4P: 225.0786; found: 255.0778.
31P{1H} NMR (CDCl3, 121 MHz)  = –3.5.
Dimethyl [4-(Benzyloxy)but-1-yn-1-yl]phosphonate (3h)
HRMS: m/z [M +
H+] calcd for C11H10F3O3P: 279.0398; found:
279.0399.
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 3h as a yellow oil; yield: 150.5
mg (0.559 mmol, 46%); Rf = 0.1 (1:1 EtOAc/hexanes).
Dimethyl {[2-(Trifluoromethyl)phenyl]ethynyl}phosphonate (3m)
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 3m as a yellow oil; yield: 130.1
mg (0.466 mmol, 65%); Rf = 0.24 (1:1 EtOAc/hexanes).
IR (neat): 3029 (w), 2953 (w), 2853 (w), 2207 (m), 1265 (m), 1023 (s),
835 (m), 779 (m), 734 (m), 699 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 7.32–7.23 (m, 5 H), 4.50 (s, 2 H), 3.72
IR (neat): 3485 (s), 2958 (w), 2856 (w), 2194 (m), 1320 (s), 1271 (s),
1178 (s), 1132 (s), 1035 (s), 869 (m), 785 cm–1 (m).
(d, J = 12.3 Hz, 6 H), 3.60 (t, J = 6.7 Hz, 2 H), 2.62 (td, J = 6.8, 4.4 Hz, 2
H).
1H NMR (CDCl3, 400 MHz):  = 7.79 (s, 1 H), 7.70 (dd, J = 15.9, 7.8 Hz, 2
H), 7.50 (t, J = 7.9 Hz, 1 H), 3.83 (d, J = 12.3 Hz, 6 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 135.7, 131.4 (q, J = 33.2 Hz), 129.5
(sext, J = 2.8 Hz), 129.3, 127.4 (q, J = 3.5 Hz), 123.3 (d, J = 272.67 Hz),
120.4 (d, J = 5.8 Hz), 97.5 (d, J = 52.7 Hz), 78.6 (d, J = 299.6 Hz), 53.6 (d,
J = 5.4 Hz).
13C{1H} NMR (CDCl3, 100 MHz):  = 137.6, 128.4, 127.8, 127.6, 100.7
(d, J = 53.2 Hz), 73.1, 70.1 (d, J = 303.5 Hz), 66.8 (d, J = 2.6 Hz), 53.2 (d,
J = 5.4 Hz), 20.7 (d, J = 4.5 Hz).
31P{1H} NMR (CDCl3, 121 MHz):  = –2.9.
HRMS: m/z [M + H+] calcd for C13H17O4P: 269.0943; found: 269.0932.
31P{1H} NMR (CDCl3, 121 MHz):  = –3.2.
Dimethyl (3-Hydroxy-3-methylbut-1-yn-1-yl)phosphonate (3i)
HRMS: m/z [M
+
H+] calcd for C11H10F3O3P: 279.0398; found:
The crude product was purified by column chromatography (EtOAc)
to provide the alkyne 3j as an orange oil; yield: 30.9 mg (0.160 mmol,
57%); Rf = 0.28 (EtOAc).
279.0399.
Dimethyl [(3-Chlorophenyl)ethynyl]phosphonate (3n)
IR (neat): 3360 (s), 2986 (w), 2957 (w), 2854 (w), 2202 (w), 1253 (m),
1220 (m), 1027 (s), 922 (s), 841 (s), 820 (s), 729 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 3.72 (d, J = 12.3 Hz, 6 H), 1.49 (s, 6 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 106.9 (d, J = 49.3 Hz), 69.4 (d,
J = 300.9 Hz), 64.6 (d, J = 4.1 Hz), 53.5 (d, J = 5.7 Hz), 30.4 (d, J = 1.2
Hz).
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 3n as a yellow oil; yield: 86.9
mg (0.355 mmol, 44%); Rf = 0.22 (1:1 EtOAc/hexanes).
IR (neat): 3493 (s), 3063 (w), 2999 (w), 2955 (w), 2852 (w), 2194 (m),
1276 (s), 1035 (s), 902 (s), 841 (s), 788 cm–1 (s).
1H NMR (CDCl3, 400 MHz):  = 7.53–7.52 (m, 1 H), 7.44–7.40 (m, 2 H),
7.29 (t, J = 7.9 Hz, 1 H), 3.83 (d, J = 12.2 Hz, 6 H).
31P{1H} NMR (CDCl3, 121 MHz):  = –2.8.
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13C{1H} NMR (CDCl3, 100 MHz):  = 134.5, 132.4 (d, J = 2.6 Hz), 131.2,
130.8 (d, J = 2.5 Hz), 129.9, 121.0 (d, J = 5.6 Hz), 97.8 (d, J = 52.8 Hz),
78.1 (d, J = 300.3), 53.5 (d, J = 5.7 Hz).
1H NMR (CDCl3, 400 MHz):  = 4.06–3.93 (m, 4 H), 2.75 (dd, J = 11.9,
3.4 Hz, 1 H), 2.62–2.57 (m, 2 H), 2.44 (br s, 1 H), 2.17–2.08 (m, 4 H),
2.02–1.85 (m, 4 H), 1.42–1.33 (m, 4 H), 1.28 (td, J = 7.0, 1.8 Hz, 6 H),
1.14–1.10 (m, 2 H), 0.89 (t, J = 7.0 Hz, 3 H).
31P{1H} NMR (CDCl3, 121 MHz):  = –2.9.
13C{1H} NMR (CDCl3, 100 MHz):  = 165.2 (d, J = 10.2 Hz), 125.2 (d,
J = 184.3 Hz), 60.9 (d, J = 5.0 Hz), 39.4 (d, J = 14.2 Hz), 35.6 (d, J = 9.7
Hz), 35.2 (d, J = 2.9 Hz), 34.0 (d, J = 3.2 Hz), 33.4 (d, J = 5.4 Hz), 30.6 (d,
J = 2.5 Hz), 22.9, 20.4 (d, J = 3.1 Hz), 19.8 (d, J = 3.1 Hz), 18.2, 17.63,
16.4, 14.0.
31P{1H} NMR (CDCl3, 121 MHz):  = 19.0.
HRMS: m/z [M+] calcd for C18H31O3P: 326.2011; found: 326.2012.
HRMS: m/z [M
245.0135.
+
H+] calcd for C10H10ClO3P: 245.0134; found:
Dimethyl [(2-Chlorophenyl)ethynyl]phosphonate (3o)
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 3o as an orange oil: yield: 7.4
mg (0.030 mmol, 35%); Rf = 0.18 (1:1 EtOAc/hexanes).
IR (neat): 3454 (s), 3056 (w), 2955 (w), 2853 (w), 2193 (m), 1267 (s),
1038 (s), 869 (m), 737 cm–1 (s).
1H NMR (CDCl3, 400 MHz):  = 7.58 (dd, J = 7.7, 1.6 Hz, 1 H), 7.43 (dd,
J = 4.1, 1.0 Hz, 1 H), 7.38 (td, J = 7.4, 1.6 Hz, 1 H), 7.27 (td, J = 7.6, 1.4
Hz, 1 H), 3.87 (d, J = 12.4 Hz, 6 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 137.1, 134.4 (d, J = 2.3 Hz), 131.8,
129.6, 126.7, 119.7 (d, J = 5.1 Hz), 96.1 (d, J = 52.7 Hz), 81.7 (d,
J = 298.3 Hz), 53.6 (d, J = 5.5 Hz).
Dimethyl (8-Butyltricyclo[4.2.2.02,5]dec-7-en-7-yl)phosphonate
(4b) (Table 2, entry 1)
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 4b as a yellow oil; yield: 58.5
mg (0.196 mmol, 97%); Rf = 0.17 (1:1 EtOAc/hexanes).
IR (neat): 3475 (s), 2951 (s), 2929 (s), 2872 (m), 2855 (m), 1609 (w),
1458 (w), 1248 (s), 1053 (s), 1029 (s), 821 (m), 780 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 3.60 (dd, J = 11.1, 4.7 Hz, 6 H), 2.70–
2.66 (m, 1 H), 2.57–2.53 (m, 2 H), 2.43–2.41 (m, 1 H), 2.13–2.04 (m, 4
H), 1.98–1.79 (m, 4 H), 1.40–1.26 (m, 4 H), 1.11–1.07 (m, 2 H), 0.85 (t,
J = 7.1 Hz, 3 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 166.6 (d, J = 10.6 Hz), 123.9 (d,
J = 184.8 Hz), 51.7 (dd, J = 5.1, 1.4 Hz), 39.4 (d, J = 14.4 Hz), 35.6 (d,
J = 9.7 Hz), 35.1 (d, J = 2.9 Hz), 33.9 (d, J = 3.0 Hz), 33.4 (d, J = 5.5 Hz),
30.6 (d, J = 2.9 Hz), 22.8, 20.3 (d, J = 3.2 Hz), 19.8 (d, J = 3.0 Hz), 18.2
(d, J = 1.1 Hz), 17.5, 13.9.
31P{1H} NMR (CDCl3, 121 MHz):  = –2.9.
HRMS: m/z [M+] calcd for C10H10ClO3P: 244.0056; found: 244.0048.
Dimethyl [(2-Methoxyphenyl)ethynyl]phosphonate (3q)
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 3q as a clear oil; yield: 100.9
mg (0.419 mmol, 56%); Rf = 0.14 (1:1 EtOAc/hexanes).
IR (neat): 3490 (s), 3004 (w), 2954 (w), 2851 (w), 2181 (w), 1289 (m),
1038 (s), 840 (m), 802 cm–1 (s).
1H NMR (CDCl3, 400 MHz):  = 7.24 (t, J = 8.0 Hz, 1 H), 7.12 (d, J = 7.6
Hz, 1 H), 7.03 (t, J = 2.0 Hz, 1 H), 6.96 (qd, J = 8.4, 2.4, 0.9 Hz, 1 H),
3.83–3.76 (m, 9 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 159.3, 129.6, 125.2 (d, J = 2.4 Hz),
120.2, (d, J = 5.6 Hz), 117.7, 117.2 (d, J = 2.2), 99.9 (d, J = 53.4 Hz), 76.6
(d, J = 302.6 Hz), 55.4, 53.5 (d, J = 5.4 Hz).
31P{1H} NMR (CDCl3, 121 MHz):  = 21.8.
HRMS: m/z [M + H+] calcd for C16H27O3P: 299.1776; found: 299.1770.
Diphenyl (8-Butyltricyclo[4.2.2.02,5]dec-7-en-7-yl)phosphonate
(4c) (Table 2, entry 3)
The crude product was purified by column chromatography (1:3
EtOAc/hexanes) to provide the alkyne 4c as a yellow oil; yield: 32.8
mg (0.078 mmol, 86%); Rf = 0.51 (1:3 EtOAc/hexanes).
31P{1H} NMR (CDCl3, 121 MHz):  = –2.3.
HRMS: m/z [M + H+] calcd for C11H13O4P: 241.0630; found: 241.0633.
IR (neat): 2953 (m), 2929 (m), 2871 (w), 1593 (m), 1490 (s), 1262 (m),
1216 (m), 1193 (s), 921 (s), 770 (m), 732 (m), 690 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 7.27 (t, J = 7.8 Hz, 4 H), 7.20–7.16 (m, 4
H), 7.11 (t, J = 7.3 Hz, 2 H), 2.96 (d, J = 12.2 Hz, 1 H), 2.73–2.68 (m, 2
H), 2.48 (br s, 1 H), 2.13–2.04 (m, 4 H), 2.01–1.85 (m, 4 H), 1.37–1.23
(m, 4 H), 1.05 (d, J = 8.8 Hz, 2 H), 0.85 (t, J = 7.0 Hz, 3 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 168.9 (d, J = 11.2 Hz), 150.7 (d,
J = 7.2 Hz), 129.5, 124.6, 124.0 (d, J = 186.1 Hz), 120.5 (d, J = 4.7 Hz),
39.8 (d, J = 15.2 Hz), 35.9 (d, J = 9.5 Hz), 35.0 (d, J = 3.0 Hz), 33.9 (d,
J = 3.1 Hz), 33.6 (d, J = 5.4 Hz), 30.4 (d, J = 2.3 Hz), 22.9, 20.2 (d, J = 3.5
Hz), 19.7 (d, J = 3.0 Hz), 18.2, 17.6, 14.0.
Cationic Ru-Catalyzed Cycloaddition; General Procedure
The alkynyl phosphonate (reaction scale 0.10–0.18 mmol) and 1,5-
cyclooctadiene (1.1–1.3 equiv) were weighed into oven-dried screw
cap vials, purged with argon and imported into a glovebox. Within
the glovebox the alkynyl phosphonate, 1,5-cyclooctadiene, rutheni-
um catalyst (0.04–0.06 equiv), and anhydrous solvent (2 mL) were
combined and mixed in a two-dram screw cap vial equipped with a
small stir bar. The vials were then sealed and exported out of the
glove box and allowed to react for 72 h at 70 °C. Products were puri-
fied using flash column chromatography on 230–400 mesh silica gel
with hexanes/EtOAc mixture as the mobile phase.
31P{1H} NMR (CDCl3, 121 MHz):  = 9.0.
HRMS: m/z [M+] calcd for C26H31O3P: 422.2011; found: 422.2008.
Diethyl (8-Butyltricyclo[4.2.2.02,5]dec-7-en-7-yl)phosphonate (4a)
(Table 2, entry 2)
Dimethyl (8-Cyclohexyltricyclo[4.2.2.02,5]dec-7-en-7-yl)phospho-
nate (4d) (Table 3, entry 2)
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 4a as a yellow-brown oil; yield:
41.8 mg (0.128 mmol, 93%); Rf = 0.46 (1:1 EtOAc/hexanes).
The crude product was purified by column chromatography (EtOAc)
to provide the alkyne 4d as a yellow oil; yield: 36.2 mg (0.112 mmol,
80%); Rf = 0.14 (EtOAc).
IR (neat): 3472 (s), 2950 (m), 2927 (m), 2871 (w), 1725 (w), 1243 (m),
1094 (s), 1052 (s), 950 (s), 785 (m), 565 cm–1 (m).
IR (neat): 3484 (s), 2928 (s), 2851 (m), 1600 (w), 1449 (m), 1246 (s),
1071 (s), 1028 (s), 820 cm–1 (m).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

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1H NMR (CDCl3, 400 MHz):  = 3.64 (dd, J = 11.12, 3.4 Hz, 6 H), 3.34–
3.27 (m, 1 H), 2.78–2.72 (m, 1 H), 2.69–2.67 (m, 1 H), 2.15–2.02 (m, 4
H), 2.01–1.81 (m, 4 H), 1.70–1.64 (m, 3 H), 1.57–1.45 (m, 2 H), 1.37–
1.24 (m, 4 H), 1.15–1.08 (m, 2 H), 1.06–0.99 (m, 1 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 170.3 (d, J = 10.8 Hz), 122.7 (d,
J = 182.7 Hz), 83.0, 51.7 (d, J = 5.1 Hz), 41.8 (d, J = 5.4 Hz), 35.6 (d,
J = 9.8 Hz), 35.0 (d, J = 14.4 Hz), 34.8 (d, J = 2.9 Hz), 34.2 (d, J = 3.0 Hz),
30.8 (d, J = 2.0 Hz), 30.5 (d, J = 1.9 Hz), 26.1, 25.9 (d, J = 5.2 Hz), 20.2,
20.1 (d, J = 3.4 Hz), 18.1, 17.5.
13C{1H} NMR (CDCl3, 100 MHz):  = 163.3 (d, J = 9.6 Hz), 138.5, 128.3,
127.6, 127.4, 126.4 (d, J = 183.4 Hz), 72.7, 69.0 (d, J = 2.7 Hz), 51.8 (d,
J = 5.1 Hz), 39.7 (d, J = 14.1 Hz), 35.7 (d, J = 9.3 Hz), 34.9 (d, J = 2.9 Hz),
33.7 (d, J = 5.5 Hz), 33.6 (d, J = 3.0 Hz), 20.2 (d, J = 2.9 Hz), 19.5 (d,
J = 3.2 Hz), 18.1, 17.5.
31P{1H} NMR (CDCl3, 121 MHz):  = 21.3.
HRMS: m/z [M + H+] calcd for C21H29O4P: 377.1881; found: 377.1883.
Dimethyl {8-[4-(Trifluoromethyl)phenyl]tricyclo[4.2.2.02,5]dec-7-
en-7-yl}phosphonate (4k) (Table 4, entry 2)
31P{1H} NMR (CDCl3, 121 MHz):  = 22.2.
HRMS: m/z [M + H+] calcd for C18H29O3P: 325.1932; found: 325.1934.
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 4k as a yellow oil; yield: 38.4
mg (0.099 mmol, 79%); Rf = 0.19 (1:1 EtOAc/hexanes).
Dimethyl (8-Phenyltricyclo[4.2.2.02,5]dec-7-en-7-yl)phosphonate
(4f) (Table 3, entry 4)
IR (neat): 3455 (s), 2952 (m), 2852 (w), 1326 (s), 1251 (s), 1166 (s),
1124 (s), 1065 (s), 1031 cm–1 (s).
1H NMR (CDCl3, 400 MHz):  = 7.55 (d, J = 8.1 Hz, 2 H), 7.40 (d, J = 8.0
Hz, 2 H), 3.47 (dd, J = 11.1, 2.4 Hz, 6 H), 3.04–2.99 (m, 1 H), 2.73–2.70
(m, 1 H), 2.38–2.33 (m, 2 H), 2.24–2.18 (m, 2 H), 2.10–1.92 (m, 4 H),
1.38–1.31 (m, 2 H).
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 4f as a yellow oil; yield: 2.3 mg
(0.070 mmol, 46%); Rf = 0.14 (1:1 EtOAc/hexanes).
IR (neat): 3462 (s), 2947 (m), 2848 (w), 1236 (m), 1020 (s), 819 (s),
781 (s), 768 (s), 698 cm–1 (s).
1H NMR (CDCl3, 400 MHz):  = 7.31–7.25 (m, 5 H), 3.42 (dd, J = 11.1,
1.1 Hz, 6 H), 3.02–2.98 (m, 1 H), 2.76–2.75 (m, 1 H), 2.39–3.33 (m, 2
H), 2.21–2.18 (m, 2 H), 2.07–1.91 (m, 4 H), 1.39–1.27 (m, 2 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 161.2 (d, J = 7.2 Hz), 140.4 (d,
J = 6.7 Hz), 127.8, 127.7, 127.6 (d, J = 186.1 Hz), 127.6 (d, J = 1.6 Hz),
51.8 (d, J = 6.5 Hz), 42.7 (d, J = 13.1 Hz), 36.5 (d, J = 9.4 Hz), 34.7 (d,
J = 3.0 Hz), 34.2 (d, J = 3.0 Hz), 19.9, 19.9, 18.1, 17.6.
13C{1H} NMR (CDCl3, 100 MHz):  = 159.9 (d, J = 6.9 Hz), 143.9 (d,
J = 6.8 Hz), 129.8, 128.5, 127.9 (d, J = 1.6 Hz), 124.6 (q, J = 3.7 Hz),
124.1 (d, J = 272.1 Hz), 51.9, 42.7 (d, J = 12.8 Hz), 36.5 (d, J = 9.0 Hz),
34.5 (d, J = 3.0 Hz), 34.1 (d, J = 3.0 Hz), 19.9 (d, J = 3.2 Hz), 19.8 (d,
J = 3.5 Hz), 17.9, 17.5.
31P{1H} NMR (CDCl3, 121 MHz):  = 19.3.
HRMS: m/z [M
+
H+] calcd for C19H22F3O3P: 387.1336; found:
31P{1H} NMR (CDCl3, 121 MHz):  = 20.0.
387.1342.
HRMS: m/z [M + H+] calcd for C18H23O3P: 319.1463; found: 319.1465.
Dimethyl {8-[3-(Trifluoromethyl)phenyl]tricyclo[4.2.2.02,5]dec-7-
en-7-yl}phosphonate (4l) (Table 4, entry 3)
Dimethyl {8-[(Benzyloxy)methyl]tricyclo[4.2.2.02,5]dec-7-en-7-
yl}phosphonate (4g) (Table 3, entry 5)
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 4l as a yellow oil; yield: 40.4
mg (0.105 mmol, 79%); Rf = 0.14 (1:1 EtOAc/hexanes).
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 4g as a yellow oil; yield: 24.5
mg (0.068 mmol, 66%); Rf = 0.17 (1:1 EtOAc/hexanes).
IR (neat): 3454 (s), 2952 (s), 2875 (w), 2851 (w), 1321 (s), 1249 (s),
1165 (s), 1072 (s), 1030 (s), 824 cm–1 (s).
1H NMR (CDCl3, 400 MHz):  = 7.52–7.48 (m, 3 H), 7.43–7.39 (m, 1 H),
3.46 (dd, J = 11.1, 1.5 Hz, 6 H), 3.05–3.01 (m, 1 H), 2.74–2.72 (m, 1 H),
2.41–2.30 (m, 2 H), 2.27–2.17 (m, 2 H), 2.11–1.91 (m, 4 H), 1.38–1.32
(m, 2 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 159.6 (d, J = 6.6 Hz), 141.0 (d,
J = 6.8 Hz), 131.1, 130.2, 128.6, 128.1, 124.4, 124.4, 124.1 (d, J = 272.4
Hz), 51.9 (d, J = 10.4 Hz), 42.6 (d, J = 12.6 Hz), 36.5 (d, J = 9.3 Hz), 34.6
(d, J = 3.0 Hz), 34.2 (d, J = 3.0 Hz), 19.9 (d, J = 3.2 Hz), 19.8 (d, J = 3.4
Hz), 18.0, 17.5.
IR (neat): 3462 (s), 2948 (m), 2872 (w), 2849 (w), 1454 (s), 1244 (s),
1047 (s), 1017 (m), 819 (m), 780 (m), 736 cm–1 (m).
1H NMR (CDCl3, 400 MHz):  = 7.31–7.24 (m, 5 H), 4.59–4.51 (m, 2 H),
4.49 (s, 2 H), 3.65 (dd, J = 11.1, 6.1 Hz, 6 H), 2.87 (br s, 1 H), 2.77 (d,
J = 11.7 Hz, 1 H), 2.18–2.12 (m, 4 H), 2.04–1.87 (m, 4 H), 1.23–1.12 (m,
2 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 161.6 (d, J = 9.3 Hz), 138.5, 128.3,
128.2 (d, J = 183.5 Hz), 127.6, 127.5, 72.4, 68.4 (d, J = 5.4), 52.0 (d,
J = 3.7 Hz), 36.5 (d, J = 13.4 Hz), 35.9 (d, J = 8.7 Hz), 34.8 (d, J = 2.7 Hz),
33.9 (d, J = 3.1 Hz), 20.2 (d, J = 3.3 Hz), 19.6 (d, J = 2.9 Hz), 18.0, 17.5.
31P{1H} NMR (CDCl3, 121 MHz):  = 19.4.
31P{1H} NMR (CDCl3, 121 MHz):  = 20.0.
HRMS: m/z [M + H+] calcd for C20H27O4P: 363.1725; found: 363.1716.
HRMS: m/z [M
+
H+] calcd for C19H22F3O3P: 387.1336; found:
387.1349.
Dimethyl {8-[2-(Benzyloxy)ethyl]tricyclo[4.2.2.02,5]dec-7-en-7-
yl}phosphonate (4h) (Table 3, entry 6)
Dimethyl [8-(3-Chlorophenyl)tricyclo[4.2.2.02,5]dec-7-en-7-
yl]phosphonate (4n) (Table 4, entry 5)
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 4h as a yellow oil; yield: 30.6
mg (0.0813 mmol, 68%); Rf = 0.17 (1:1 EtOAc/hexanes).
The crude product was purified by column chromatography (1:1
EtOAc/hexanes) to provide the alkyne 4n as a yellow oil; yield: 28.3
mg (0.080 mmol, 74%); Rf = 0.08 (1:1 EtOAc/hexanes).
IR (neat): 3408 (s), 2947 (m), 2851 (w), 1496 (m), 1242 (m), 1020 (s),
IR (neat): 3442 (s), 2950 (s), 1249 (w), 1071 (s), 1053 (s), 1029 (s), 824
cm–1 (m).
818 (m), 729 (s), 697 (m) cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.29–7.23 (m, 5 H), 4.48 (s, 2 H), 3.61–
3.58 (m, 8 H), 3.03–2.91 (m, 2 H), 2.71 (d, J = 11.8 Hz, 1 H), 2.52 (br s, 1
H), 2.12–2.07 (m, 4 H), 2.01–1.83 (m, 4 H), 1.18–1.08 (m, 2 H).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

H
D. Petko et al.
Paper
Synthesis
1H NMR (CDCl3, 400 MHz):  = 7.28–7.19 (m, 4 H), 3.48 (d, J = 11.1 Hz,
6 H), 3.04–3.00 (m, 1 H), 2.73–2.72 (m, 1 H), 2.37–2.32 (m, 2 H), 2.23–
2.19 (m, 2 H), 2.08–1.91 (m, 4 H), 1.35–1.31 (m, 2 H).
13C{1H} NMR (CDCl3, 100 MHz):  = 159.7 (d, J = 6.7 Hz), 142.1 (d,
J = 6.7 Hz), 133.5, 129.0 (d, J = 186.3 Hz), 128.9, 127.8, 127.5 (d, J = 1.8
Hz), 126.0 (d, J = 1.6 Hz), 51.9, 42.6 (d, J = 12.7 Hz), 36.5 (d, J = 9.3 Hz),
34.6 (d, J = 3.0 Hz), 34.1 (d, J = 3.0 Hz), 19.9 (d, J = 3.6 Hz), 19.8, 18.0
(d, J = 1.0 Hz), 17.6.
(3) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 1. (b) Trost,
B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1979, 101, 6429. (c) Trost,
B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1983, 105, 2326.
(4) (a) Hilt, G.; Lüers, S.; Harms, K. J. Org. Chem. 2004, 69, 624.
(b) Hilt, G.; Smolko, K. I. Angew. Chem. Int. Ed. 2003, 42, 2795.
(c) Carmona, D.; Lamata, M. P.; Oro, L. A. Coord. Chem. Rev. 2000,
200, 717. (d) Murakami, M.; Ubukata, M.; Itami, K.; Ito, Y.
Angew. Chem. Int. Ed. 1998, 37, 2248. (e) O’Mahoney, D. J. R.;
Belanger, D. B.; Livinghouse, T. Synlett 1998, 443. (f) Jolly, R. S.;
Luedtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem. Soc. 1990,
112, 4965. (g) Wender, P. A.; Jenkins, T. E. J. Am. Chem. Soc. 1989,
111, 6432.
31P{1H} NMR (CDCl3, 121 MHz):  = 19.6.
HRMS: m/z [M+] calcd for C18H22ClO3P: 352.0995; found: 352.0990.
(5) (a) Tenaglia, A.; Gaillard, S. Org. Lett. 2007, 9, 3607. (b) Lautens,
M.; Tam, W.; Lautens, J. C.; Edwards, L. G.; Crudden, C. M.;
Smith, A. C. J. Am. Chem. Soc. 1995, 117, 6863. (c) Lautens, M.;
Edwards, L. G.; Tam, W.; Lough, A. J. J. Am. Chem. Soc. 1995, 117,
10276. (d) Lautens, M.; Tam, W.; Sood, C. J. Org. Chem. 1993, 58,
4513. (e) Lautens, M.; Lautens, J. C.; Smith, A. C. J. Am. Chem. Soc.
1990, 112, 5627. (f) Lautens, M.; Crudden, C. M. Organometallics
1989, 8, 2733. (g) Lyons, J. E.; Myers, H. K.; Schneider, A. J. Chem.
Soc., Chem. Commun. 1978, 636.
1-Methoxy-3,3-dimethyl-1,3,4,4a,5,6,6a,7-octahydro-4,7-ethano-
cyclobuta[4,5]benzo[1,2-c][1,2]oxaphosphole 1-Oxide (5a) (Table
3, entry 7; Scheme 3)
The crude product was purified by column chromatography (EtOAc)
to provide the alkyne 5a as a clear oil; yield: 21.4 mg (0.079 mmol,
43%); Rf = 0.34 (EtOAc).
IR (neat): 3457 (s), 2977 (m), 2951 (m), 2932 (m), 2229 (w), 1615 (w),
1267 (s), 1252 (s), 1048 (s), 959 (s), 901 (s), 795 cm–1 (s).
1H NMR (CDCl3, 400 MHz):  = 3.71–3.64 (m, 3 H), 2.94–2.90 (m, 1 H),
2.65–2.63 (m, 1 H), 2.32–2.09 (m, 4 H), 2.06–1.97 (m, 4 H), 1.45 (t,
J = 22.2 Hz, 6 H), 1.31–1.05 (m, 2 H).
(6) Petko, D.; Stratton, M.; Tam, W. Can. J. Chem. 2018, 96, 1115.
(7) Trost, B. M.; Imi, K.; Indolese, A. F. J. Am. Chem. Soc. 1993, 115,
8831.
13C{1H} NMR (CDCl3, 100 MHz):  = 171.62 (dd, J = 18.9, 5.8 Hz), 126.1
(dd, J = 168.4, 4.7 Hz), 85.8 (dd, J = 7.1, 2.3 Hz), 52.9 (d, J = 6.5 Hz),
35.4 (d, J = 2.7 Hz), 35.0 (dd, J = 5.5, 2.7 Hz), 33.6 (dd, J = 12.5, 2.4 Hz),
32.1 (dd, J = 9.5, 1.0 Hz), 27.1 (dd, J = 22.3, 2.1 Hz), 26.0 (dd, J = 22.1,
1.7 Hz), 20.3 (dd, J = 3.2, 2.3 Hz), 20.2 (d, J = 3.6 Hz), 17.5 (dd, J = 4.2,
1.8 Hz), 17.1 (d, J = 13.4 Hz).
(8) Alvarez, P.; Gimeno, J.; Lastra, E.; García-Granda, S.; Van der
Maelen, J. F.; Bassetti, M. Organometallics 2001, 20, 3762.
(9) Hasinoff, B. B.; Creighton, A. M.; Kozlowska, H.; Thampatty, P.;
Allan, W. P.; Yalowich, J. C. Mol. Pharmacol. 1997, 52, 839.
(10) Leverrier, A.; Awang, K.; Guéritte, F.; Litaudon, M. Phytochemis-
try 2011, 72, 1443.
(11) Cockburn, N.; Karimi, E.; Tam, W. J. Org. Chem. 2009, 74, 5762.
(12) Kettles, T. J.; Cockburn, N.; Tam, W. J. Org. Chem. 2011, 76, 6951.
(13) Chrobak, E.; Bebenek, E.; Kadela-Tomanek, M.; Latocha, M.;
Jelsch, C.; Wenger, E.; Boryczka, S. Molecules 2016, 21, 1123.
(14) Smith, P. W.; Chamiec, A. J.; Chung, G.; Cobley, K. N.; Duncan, K.;
Howes, P. D.; Whittington, A. R.; Wood, M. R. J. Antibiot. (Tokyo)
1995, 48, 73.
31P{1H} NMR (CDCl3, 121 MHz):  = 35.9, 35.9.
HRMS: m/z [M + H+] calcd for C14H21O3P: 269.1306; found: 269.1301.
Funding Information
This work was supported by the Natural Sciences and Engineering
Council of Canada (NSERC).()
(15) Holstein, S. A.; Cermak, D. M.; Wiemer, D. F.; Lewis, K.; Hohl, R.
J. Bioorg. Med. Chem. 1998, 6, 687.
(16) Ouahrouch, A.; Taourirte, M.; Schols, D.; Snoeck, R.; Andrei, G.;
Engels, J. W.; Lazrek, H. B. Arch. Pharm. (Weinheim) 2016, 349,
30.
Supporting Information
(17) East, J. E.; Carter, K. M.; Kennedy, P. C.; Schulte, N. A.; Toews, M.
L.; Lynch, K. R.; Macdonald, T. L. Med. Chem. Commun. 2011, 2,
325.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690612.
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orit
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orti
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gInformati
o
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(18) Prakash, T. P.; Lima, W. F.; Murray, H. M.; Li, W.; Kinberger, G.
A.; Chappell, E.; Gaus, H.; Seth, P. P.; Bhat, B.; Crooke, S. T.;
Swayze, E. Nucleic Acid Res. 2015, 43, 2993.
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H