Pd(0)-catalyzed alkene oxy- and aminoalkynylation with aliphatic bromoacetylenes

Article abstract of DOI:10.1021/jo400254q

Tetrahydrofurans and pyrrolidines are among the most important heterocycles found in bioactive compounds. Cyclization-functionalization domino reactions of alcohols or amines onto olefins constitute one of the most efficient methods to access them. In this context, oxy- and aminoalkynylation are especially important reactions, because of the numerous transformations possible with the triple bond of acetylenes, yet these methods have been limited to the use of silyl protected acetylenes. Herein, we report the first palladium-catalyzed oxy- and aminoalkynylation using aliphatic bromoalkynes, which proceeded with high diastereoselectivity and functional group tolerance. A one-pot hydrogenation of the triple bond gave then access to alkyl-substituted tetrahydrofurans and pyrroldines. Finally, a detailed study of the side products formed during the reaction gave a first insight into the reaction mechanism.

Full text of DOI:10.1021/jo400254q

Article
pubs.acs.org/joc
Pd(0)-Catalyzed Alkene Oxy- and Aminoalkynylation with Aliphatic
Bromoacetylenes
Stefano Nicolai, Raha Sedigh-Zadeh, and Jerome Waser*
́
̂
́ ́
Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique Federale de Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015
Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: Tetrahydrofurans and pyrrolidines are among
the most important heterocycles found in bioactive com-
pounds. Cyclization-functionalization domino reactions of
alcohols or amines onto olefins constitute one of the most
efficient methods to access them. In this context, oxy- and
aminoalkynylation are especially important reactions, because of the numerous transformations possible with the triple bond of
acetylenes, yet these methods have been limited to the use of silyl protected acetylenes. Herein, we report the first palladium-
catalyzed oxy- and aminoalkynylation using aliphatic bromoalkynes, which proceeded with high diastereoselectivity and
functional group tolerance. A one-pot hydrogenation of the triple bond gave then access to alkyl-substituted tetrahydrofurans and
pyrroldines. Finally, a detailed study of the side products formed during the reaction gave a first insight into the reaction
mechanism.
desirable. This transformation requires the use of an electro-
philic acetylene source. Recent years produced impressive
progress in the field of electrophilic alkynylation of aromatic
and aliphatic C−H bonds using Pd catalysis.7 In these
processes, acetylenes bearing bulky silyl groups have been
used most often, followed by aryl acetylenes. On the other
hand, the use of aliphatic acetylenes has been much more
limited. Several reasons concur to make this class of substrates
more challenging: the different electronic properties change the
kinetic of key catalytic steps, especially reductive elimination;
the triple bond is more accessible for direct reaction with the
metal catalyst; and finally, the presence of hydrogen or
functional groups at the propargylic position open the way
for isomerization side reactions.
INTRODUCTION
■
Saturated heterocycles are essential substructures in a large
variety of natural and synthetic bioactive compounds.
Tetrahydrofurans and pyrrolidines substituted with function-
alized aliphatic chains on positions C2 and/or C5 are of
particular interest due to their presence in natural products
exhibiting significant biological and pharmacological activity.
Eminent examples include trans-2,5-disubstituted tetrahydro-
furans in antitumoral annonaceous acetogenins, such as
gigantecin (1)1 or cis-2,5-disubstituted pyrrolidines in antiviral
broussonetines, such as broussonetine G (2)2 or in the
antifungal preussin (3) (Figure 1).3
In 2011, we reported the first example of intramolecular
Pd(0)-catalyzed oxy- and aminoalkynylation of γ-hydroxy
alkenes using electrophilic bromoacetylenes (Scheme 1).8
These transformations were complementary to the oxy- and
aminoalkynylation methods we previously developed for the
synthesis of propargyl lactones and lactams under Pd(II)/
Scheme 1. Extending the Scope of Heteroalkynylation to
Aliphatic Alkynes
Figure 1. Examples of biologically active natural products containing
2,5-disubstituted tetrahydrofurans and pyrrolidines.
One important approach for the synthesis of functionalized
tetrahydrofurans and pyrrolidines relies on the Pd-catalyzed
cyclization of an oxygen or nitrogen nucleophile onto a
tethered alkene followed by further C−O, C−C or C−N bond
formation.4−6 When considering the large variety of available
subsequent transformations for the CC triple bond, the
formation of a sp3−sp bond in this process would be highly
Received: February 5, 2013
© XXXX American Chemical Society
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Pd(IV)-catalysis using the hypervalent iodine reagent TIPS-
EBX.9 Nevertheless, both methods were limited to the use of
silylated alkynyl bromides as electrophiles. This limitation
makes the method less attractive for the convergent synthesis of
alkyl-substituted tetrahydrofurans and pyrrolidines after reduc-
tion of the triple bond. In principle, similar products could be
accessed also via an olefin heterovinylation or heteroalkylation
approach. However, the former has been realized only with
unfunctionalized aliphatic substituents on the alkene so far,6i,k,l
and the latter is an unknown process.
Herein, we would like to report the first successful Pd-
catalyzed oxy- and aminoalkynylation of aliphatic bromo
acetylenes (Scheme 1). The method was successfully applied
to both alcohols and N-Boc protected amines with high
diastereoselectivity. For the first time, we were able to use
bromoacetylenes bearing functionalized aliphatic chains. The
obtained alkynes can be easily reduced to the alkyl chains in a
practical one-pot process. Finally, a detailed study of the side
products formed during oxyalkynylation allowed us to gain a
first insight into the reaction mechanism.
of the palladium source was further evaluated. The use of
PdCl2(PPh3)2 (entry 2) or Pd(OAc)2 (entry 3) as precatalysts
led to lower yields. A significant improvement was observed
with N-heterocyclic carbene Pd-complex 8, which gave the
product in 56% yield in the presence of DPEPHos (entry 4).
However, no conversion could be observed when the same Pd
complex was used in the absence of DPEPHos (entry 5),
suggesting that the carbene ligand had no influence on the
reaction. Similar yields were obtained when the reaction was
performed with complexes bearing only weakly coordinated
ligands, such as [Pd(allyl)(cod)](BF4)2 (entry 6). [Pd-
(cinnamyl)Cp)], a reported clean source of Pd0 for catalysis,10
led to the same result obtained with [Pd(allyl)(cod)](BF4)2
(entry 7). The use of Pd(dba)2 also resulted in a slight
improvement of the yield when compared to Pd2(dba)3 (entry
8). This result raises the question whether enone ligands have a
favorable effect on the reaction. However, when dba was added
to [Pd(allyl)(cod)](BF4)2, no increase in yield was observed
(entry 9). The use of other enone ligands led to a decrease in
yield.11 Overall, this series of experiments demonstrated that
the source of Pd had only a limited influence on the reaction
outcome. At this point, Pd(dba)2 was identified as the best
compromise between price and efficiency for the screening of
reaction conditions.
We decided to focus our attention next on the screening of
different diphosphines as ligands. DPEPHos was optimal for
the cyclization reaction with octynyl bromide 6a. An excess of
this ligand was important to prevent a drop of the yield (entry
10). Other ligands were much less efficient than DPEPHos.
Low yields were obtained with XantPhos and dppf (entries 11
and 12). While the former has similar electronic properties as
DPEPHos, the latter displays a similar bite angle, but lacks the
oxygen atom, which is a potential further weak coordination
site. The bite angle of the chelating ligand is known to be a
crucial parameter to favor reductive elimination over β-hydride
elimination.12 In fact, no product was obtained with ligands
having a smaller bite angle, such as SegPhos or BINAP (entries
13 and 14). The efficiency of different alkynyl halides was
investigated next. Both octynyl chloride (6b) and iodide (6c)
exhibited low reactivity and gave the desired product in low
yields only (entries 15 and 16).
RESULTS AND DISCUSSION
■
Commercially available 4-penten-1-ol (5a) was initially selected
as the model substrate to investigate the oxyalkynylation with
aliphatic bromo acetylenes. A complex mixture had been
observed when phenylethyl ethynyl bromide had been used as
the alkynylating reagent.8 In order to eliminate any potential
negative influence of the phenyl group in close proximity to the
triple bond, 1-bromooctyne (6a) was examined in the reaction.
Indeed, the desired 2-nonynyl tetrahydrofuran 7aa could be
obtained in 44% yield using Pd2(dba)3 as palladium source and
bis(2-diphenylphosphinophenyl)ether (DPEPHos) as ligand
(Table 1, entry 1). Starting from this lead result, the influence
Table 1. Screening of Pd Catalysts and Alkynyl Reagents
a
entry
X
catalyst
Pd2(dba)3
ligand
yield (%)
1
Br (6a)
Br (6a)
Br (6a)
Br (6a)
Br (6a)
Br (6a)
Br (6a)
Br (6a)
Br (6a)
Br (6a)
Br (6a)
Br (6a)
Br (6a)
Br (6a)
Cl (6b)
I (6c)
DPEPHos
DPEPHos
DPEPHos
DPEPHos
44
31
30
56
0
The choice of the base also had a strong influence on the
outcome of the reaction. The use of NaOtBu was essential for
success. Both KOtBu and LiOtBu gave the cyclized product
only in traces. A modest yield (24%) was obtained with
NaHMDS, which further supported the importance of sodium
as countercation. Moreover, a base strong enough to
significantly deprotonate the alcohol was required, and no
reactivity was observed with weaker bases such as sodium
carbonate or sodium acetate. While no significant effect was
observed in the presence of different additives,13 the reaction
temperature was found to be important: running the reaction at
lower temperature (50 °C) led to a significantly slower
transformation, with low conversion of octynyl bromide (6a).
By contrast, the reaction reached 45% yield after just one hour
at higher temperature (110 °C), but without further improve-
ment after a longer reaction time.
2
PdCl2(PPh3)2
Pd(OAc)2
3
b
4
NHC-Pd (8)
NHC-Pd (8)
b
5
6
[Pd(allyl)(cod)]BF4
[Pd(cinnamyl)Cp]
Pd(dba)2
DPEPHos
DPEPHos
DPEPhos
DPEPHos
DPEPHos
XantPhos
dppf
50
50
51
47
7
8
9
[Pd(allyl)(cod)]BF4/dba
Pd(dba)2
c
10
11
12
13
14
15
16
38
Pd(dba)2
29
16
0
Pd(dba)2
Pd(dba)2
SegPhos
BINAP
Pd(dba)2
0
Pd(dba)2
DPEPHos
DPEPHos
traces
16
Pd(dba)2
We concluded our studies on the optimization of the
reaction with solvents and concentration effects (Table 2). The
use of nonaromatic solvents resulted in very low yield (entries
1−5). Moderate yields were obtained with solvents similar to
toluene, such as trifluorotoluene (entry 6) or xylene (entry 7).
Finally, the reaction concentration had a strong effect on the
a
Reaction conditions: 0.15 mmol 5a, 0.006 mmol catalyst (based on
Pd content, 4 mol %), 0.012 mmol DPEPHos (8 mol %), 0.225 mmol
1-halooct-1-yne 6 (1.5 equiv), 0.225 mmol NaOtBu (1.5 equiv), 0.8
mL of toluene, 3 h, 80 °C. Yield was determined by GC−MS.
b
(NHC)Pd(allyl)Cl (8) = Allyl[1,3-bis(mesityl)imidazol-2-ylidene]
c
palladium chloride. 0.0060 mmol DPEPHos (4 mol %).
B
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pentynyl bromides bearing different functional groups in the
terminal position, giving products bearing a silyl-protected
alcohol (7ad, 67% yield), a phenyl group (7ae, 64% yield), a
chloride group (7af, 56%) or a protected alkyne (7ag, 59%).
The tolerance to a halogen atom is particularly interesting, as a
Williamson etherification could have been expected in this case.
For the first time, bromo acetylenes 6h−k derived from
propargylic alcohols could be used in the oxyalkynylation
reaction to produce products 7ah−7ak. This result was of
particular interest when considering the prevalence of hydroxy
substituents in bioactive natural products and also constituted a
major breakthrough in the field, as propargylic or allylic
alcohols had never been obtained in the oxyfunctionalization of
alkenes before. Both benzyl and triisopropyl silyl protected
groups could be used in the reaction to give tertiary (products
7ah and 7ai) and secondary (products 7aj and 7ak) propargylic
alcohols in 63−85% yield. We then decided to examine
secondary alcohols 5b and 5c as substrates.16 The reaction is
especially interesting in this case because the resulting 2,5-
disubstituted tetrahydrofurans are often encountered in bio-
logically active natural compounds (Figure 1). 2-Phenyl-
pentenol (5b) smoothly reacted with tertiary alkynyl bromide
6h to deliver trans-substituted tetrahydrofuran 7bh as the only
diastereoisomer in 72% yield. Alcohol 5c, bearing a propargyl
group on the carbinol position, was less reactive, and complete
conversion could not be achieved. Nonetheless, the oxy-
alkynylation with octynylbromide 6a resulted in the formation
of the C2-symmetric product 7ca, in 55% isolated yield and a
87:13 trans selectivity.
The reaction of aliphatic alkynyl bromides with N-protected
γ-amino alkenes was then investigated (Scheme 3).17 Amines at
primary position gave the corresponding 2-propargyl pyrroli-
dines in 60−77% yields. In addition to octynyl bromide 6a
(product 10aa), the reaction worked well with both
bromoacetylenes bearing a protected alcohol or a phenyl
group on the terminal position (products 10ad and 10ae) and
bromo derivatives of tertiary and secondary propargylic
alcohols (products 10ah and 10aj). Amines on a secondary
position gave full conversion and high diastereoselectivity in
favor of the cis-2,5-disubstituted pyrrolidines. The trans-
formation was compatible with both aromatic (product 10ba)
and aliphatic substituents (product 10ca) on the secondary
position. The presence of a double bond in the lateral chain was
well tolerated, and compound 10da was isolated in 60% yield.
Polycyclic nitrogen heterocycles constitute the core of a
multitude of bioactive natural alkaloids. The potential of the
method to access polycyclic systems were consequently
examined in more detail. cis-2-Allyl cyclopentyl, cyclohexyl
and cycloheptenyl amines 9e−g were good substrates for
aminoalkynylation and give access to [5,5], [5,6] and [5,7]
bicyclic heterocycles (products 10ea, 10fa, 10fl and 10ga).
Aminoalkynylation with brominated alkynyl bromide 6l also
worked well to produce amine 10fl, without alkylation of the
carbamate. The aminoalkynylation was also highly effective in
the case of N-Boc protected 2-allyl aniline (9h), showcasing the
possibility of applying our method for the preparation of
propargylic indoline heterocycles such as 10ha. Finally, the
reaction was not limited to N-Boc-protected amines: under the
same conditions, N-aryl substituted pyrrolidines 10ia and 10ja
could be obtained in 79 and 59% yield respectively.
Table 2. Influence of Solvents and Concentration
a
entry
solvent
concentration (M)
yield (%)
1
THF
0.19
0.19
0.19
0.19
0.19
0.19
0.19
0.50
0.19
0.075
0.019
0.075
8
2
Dioxane
CH3CN
DMSO
DCE
nr
nr
nr
nr
32
42
35
51
65
62
3
4
5
6
CF3Ph
7
Xylene
Toluene
Toluene
Toluene
Toluene
Toluene
8
9
10
11
12
b
69
a
Reaction conditions: 0.15 mmol 5a, 0.006 mmol catalyst (4 mol %),
0.012 mmol DPEPHos (8 mol %), 0.225 mmol 6a (1.5 equiv), 0.225
mmol NaOtBu (1.5 equiv), solvent, 3 h, 80 °C. Yield was determined
b
by GC−MS. 0.40 mmol 5a, 0.52 mmol 1-bromooctyne (6a) (1.3
equiv), 0.52 mmol NaOtBu (1.3 equiv), 0.020 mmol catalyst (5 mol
%), 0.030 mmol DPEPHos (7.5 mol %), solvent, 3 h, 80 °C, isolated
yield after column chromatography.
reaction outcome. The yield dropped to 35% or less when the
reaction was performed at higher concentration (entry 8) than
the usual reaction (entry 9). On the contrary, a significant
improvement up to 65% was observed under more diluted
conditions (0.075 M) (entry 10). Further dilution did not lead
to higher yields (entry 11). Under the optimized conditions,
tetrahydrofuran 7aa could finally be isolated in 69% yield on
preparative scale (entry 12).14
With optimized conditions in hand, we then examined the
scope of the reaction. We started with variation of the bromo
alkyne 6 (Scheme 2). The required aliphatic bromo acetylenes
were readily prepared by bromination of terminal alkynes with
a slight excess of NBS, in the presence of catalytic AgNO3.15 In
addition to octynyl bromide 6a, the reaction worked well with
Scheme 2. Scope of the Oxyalkynylation of γ-
Hydroxyalkenes with Aliphatic Alkynyl Bromides
a
a
Reaction conditions: 0.40 mmol alcohol 5, 0.52 mmol alkynyl
bromide 6 (1.3 equiv), 0.52 mmol NaOtBu (1.3 equiv), 0.020 mmol
Pd(dba)2 (5 mol %), 0.030 mmol DPEPHos (7.5 mol %), 4.6 mL of
toluene, 80 °C, under N2 for 3 h, isolated yield after column
Having effectively developed an extension of our method to
aliphatic acetylenes, we turned to the reduction of the triple
bond to obtain the alkyl chain contained in most natural
b
chromatography. 0.040 mmol Pd(dba)2 (10 mol %), 0.060 mmol
DPEPHos (15 mol %), 15 h.
C
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secondary alcohol 5b with propargylic ether 6h (Scheme 5).
On a 1.85 mmol scale, tetrahydrofuran 7bh could be isolated in
Scheme 3. Scope of the Oxyalkynylation Reaction with N-
Boc γ-Aminoxyalkenes
a
Scheme 5. Large-Scale Reaction between Alcohol 5b and
Alkynyl Bromide 6h and Identification of Side Products
55% yield. Three further products originating from alcohol 5b
could also be isolated: recovered 5b itself (13% yield), ketone
13 (4% yield) and hydroxy ketone 14 (12% yield). In addition,
two products derived from alkynyl bromide 6h were obtained:
reduced alkyne 15 (5% yield) and dimer 16 (36% yield).
The high number of isolated side products further
emphasizes the challenging nature of the oxyalkynylation
process. On the other hand, it also constitutes a fascinating
footprint for the potential intermediates of the catalytic cycle
(Scheme 6). A probable first step would be oxidative addition
Scheme 6. Working Model for the Reaction Mechanism of
the Oxyalkynylation Reaction
a
Reaction conditions: 0.40 mmol amine 9, 0.52 mmol alkynyl bromide
6 (1.3 equiv), 0.52 mmol NaOtBu (1.3 equiv), 0.020 mmol Pd(dba)2
(5 mol %), 0.030 mmol DPEPHos (7.5 mol %), 4.6 mL of toluene, 80
°C, under N2 for 3 h.
products. In particular, a one-pot transformation without
isolation and purification of the alkyne would provide very
efficient access to this class of compounds, especially when
considering that the oxy- or aminoalkylation of olefins is still an
unknown process. A simple switch of solvent to methanol,
addition of Pd/C (5 mol %) and hydrogenation under a H2
atmosphere resulted in the smooth and complete in situ
reduction to compounds 11aa and 12aa within 12 h (Scheme
4).18 In addition, the reaction worked by simply adding
Scheme 4. Oxy- and Aminoalkynylation Followed by in Situ
Hydrogenation with Pd/C
of a Pd(0) complex I on alkynyl bromide 6h to give alkynyl-Pd
intermediate II. This kind of organometallic intermediate can
potentially undergo ligand exchange to form a bis-alkynyl
complex, and subsequent reductive elimination would give the
observed diyne 16.19 In fact, preventing the homocoupling of
the alkynyl bromide is one of the major challenges of the
oxyalkynylation process. Ligand exchange on Pd followed by
intramolecular oxypalladation on III to give intermediate IV
would be in agreement with the excellent trans diastereose-
lectivity observed, if the two substituents are in pseudoequa-
torial position in the transition state V. It allows also
rationalizing the cis selectivity observed for pyrrolidines, as in
this case a strong A1,3 interaction with the Boc group would
methanol and Pd/C to the reaction mixture, but it was much
slower (more than 48 h). Therefore, the removal of toluene
prior to the addition of methanol, although not strictly
required, was more convenient.
The developed methodology is of high interest because it
allows the convergent combination of alcohols or amines and
alkynyl bromides of similar complexity, without using a large
excess of one of the two partners. In order to gain deeper
insight into the reaction mechanism for future improvements,
we decided to study the especially challenging coupling of
D
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Figure 2. Influence of reagent stoichiometry on the formation of tetrahydrofuran 7bh.
make a pseudoaxial position of the adjacent substituent more
favorable.20 Furthermore, a base strong enough to form the
alkoxide to allow ligand exchange would be required for this
step, as it has been observed during the optimization of the
reaction. However, if oxypalladation is too slow, β-hydride
elimination can occur on intermediate III, leading to the
formation of the observed ketone 13 and alkyne 15. Finally, the
last step of the catalytic cycle is reductive elimination to give
oxyalkynylation product 7bh and regenerate the active Pd(0)
catalyst I. Again, β-hydride elimination is possible on
intermediate IV, which would lead to the formation of enol
ether 17. Although 17 was not isolated from the reaction
mixture, hydroxy ketone 14 could reasonably have been formed
during aqueous workup or on silica gel during column
chromatography.21 The formation of 14 is also in agreement
with insertion of the olefin into the Pd−O bond from III to
form intermediate IV. An alternative mechanism involving first
insertion into the Pd-alkynyl bond does not allow rationalizing
the formation of 14.
When considering the complexity of the reaction, the
required reaction temperature, the short reaction time and
the high sensitivity to air, obtaining a precise kinetic profile for
the reaction constitutes a formidable challenge. Nevertheless,
interesting preliminary results were already obtained by
studying the effect of reagents stoichiometry on the rate of
formation of oxyalkynylation product 7bh (Figure 2). Although
the many side reactions do not allow a better understanding of
the reaction mechanism,22 important practical conclusions
could already be drawn from these experiments: (1) Increasing
the excess of alkynyl bromide only slightly accelerates the
reaction and does not lead to a significant increase in yield.
Furthermore, the alkynyl bromide was not completely
consumed in the case the reaction had stopped before
completion. (2) In the presence of a large excess of base,
product formation became much slower. As no extensive
decomposition of starting material 5b and 6h was observed, this
outcome is probably due to catalyst deactivation. (3) The
reaction is accelerated when the catalyst loading is increased
and, more importantly, higher yields of product can be
obtained, as for example in the case of the oxyalkynylation of
propargylic alcohol 5c (Scheme 2, yield with 5 mol % catalyst:
21% yield, with 10 mol % catalyst 55%). Taken together, these
results indicate that catalyst deactivation is a major issue in the
developed process and increasing catalyst stability will be
important in the future.
CONCLUSION
■
In conclusion, we have described the first examples of
intramolecular oxy- and aminoalkynylation of alkenes using
aliphatic bromoacetylenes. The successful use of functionalized
acetylenes in particular was unprecedented for the functional-
ization of olefins and led to a highly convergent synthesis of
important tetrahydrofuran and pyrrolidine building blocks for
organic synthesis. The obtained products can be easily
hydrogenated in a one-pot transformation to give alkyl-
substituted furans and pyrrolidines. A careful study of the
side products formed during the reaction finally led to a first
speculative model for the mechanism of the oxyalkynylation
process.
EXPERIMENTAL SECTION
1-Phenylpent-4-en-1-ol (5b).
■
Following a reported procedure,16a a solution of 4-bromobutene (18)
(2.30 mL, 22.8 mmol, 1.15 equiv) in Et2O (9 mL) was added dropwise
to a suspension of Mg turnings (972 mg, 40.0 mmol, 2.05 equiv) in
Et2O (18 mL) at rt. The mixture was then stirred at rt for 1 h and
further refluxed for 1 h. A solution of benzaldehyde (2.00 mL, 20.0
mmol, 1.0 equiv) in Et2O (9 mL) was then added dropwise, and the
mixture was refluxed for 2 h. It was then poured onto ice (ca. 10 g)
and treated by dropwise addition of HCl (aqueous solution 2.0 M).
E
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The two layers were separated, and the aqueous one was extracted
with Et2O (2 × 20 mL). The combined organic layers were washed
with aqueous NaHCO3 (saturated solution, 20 mL) and brine, dried
over MgSO4, filtered, and the solvent was removed in vacuo.
Purification by column chromatography (SiO2, pentane/EtOAc 95/
5) afforded benzyl alcohol 5b as a colorless oil (1.96 g, 12.1 mmol,
60% yield): Rf 0.30 (Hexane/EtOAc 20/3); 1H NMR (400 MHz,
CDCl3) δ 7.38−7.33 (m, 3 H), 7.29 (m, 2 H), 5.85 (ddt, 1 H, J = 16.9,
10.2, 6.6 Hz), 5.05 (ddd, 1 H, J = 17.1, 3.4, 1.6 Hz), 4.99 (ddd, J =
10.1, 3.1, 1.2 Hz), 4.70 (ddd, 1 H, J = 7.9, 5.5, 3.4 Hz), 2.15 (m, 2 H),
1.97−1.75 (m, 3 H); 13C NMR (101 MHz, CDCl3) δ 144.6, 138.1,
128.5, 127.6, 125.9, 114.9, 74.0, 38.0, 30.0; IR 3359 (br, w), 2932 (w),
1721 (w), 1721 (w), 1642 (w), 1603 (w), 1591 (w), 1493 (w), 1453
(w), 1416 (w), 1416 (w), 1400 (w), 1305 (w), 1270 (w), 1239 (w),
1239 (w), 1200 (w), 1200 (w), 1175 (w), 1104 (w), 1061 (m), 1023
(m), 1013 (m), 913 (m), 760 (m), 701 (s), 675 (m), 668 (m), 667
(m), 650 (m), 638 (m), 629 (w), 616 (w), 606 (w). The values for the
characterization of 5b correspond to the ones reported in literature.16a
Tetradec-1-en-7-yn-5-ol (5c).
under stirring to the Etheral solution of the amine. In this case,
removal of the solvent in vacuo afforded the 4-pentenamine
hydrochloride (23) as a colorless solid (930 mg, 7.64 mmol, 81%
yield).
Following a slightly modified version of a reported procedure,17d
Et3N (3.25 mL, 23.4 mmol, 2.2 equiv) was added to a solution of
Boc2O (2.55 g, 11.7 mmol, 1.1 equiv) in CH2Cl2 (16 mL), and the
mixture was stirred at 0 °C for 5 min. 4-Pentenamine (23) (0.907 g,
10.6 mmol, 1.0 equiv) in CH2Cl2 (16 mL) was then added at 0 °C,
and the resulting mixture was stirred at rt overnight. The solution was
then washed with aqueous citric acid (0.1 M, 20 mL). The aqueous
layer was extracted with CH2Cl2 (3 × 20 mL); the combined organic
layers were washed with aqueous NaHCO3 (saturated solution, 20
mL) and brine, dried over MgSO4, filtered, and the solvent was
removed in vacuo. Purification by column chromatography (SiO2,
Pentane/EtOAc 95/5 to 80/20) afforded protected pentenamine 9a as
a pale yellow oil (1.73 g, 9.33 mmol, 88% yield): Rf 0.32 (Hexane/
EtOAc 20/2); 1H NMR (400 MHz, CDCl3) δ 5.80 (ddt, 1 H, J = 16.9,
10.2, 6.7 Hz), 5.03 (dq, 1 H, J = 17.1, 1.7 Hz), 4.97 (ddd, 1 H, J = 11.3,
2.0, 1.1 Hz), 4.52 (m, 1 H), 3.13 (q, 2 H, J = 6.6 Hz), 2.08 (m, 2 H),
1.58 (quint, 1 H, J = 7.4 Hz), 1.44 (s, 9 H); 13C NMR (101 MHz,
CDCl3) δ 155.9, 137.7, 114.9, 78.9, 40.0, 30.9, 29.1, 28.3; IR 3349 (w),
2978 (m), 2933 (m), 2870 (w), 1692 (s), 1643 (w), 1525 (m), 1453
(w), 1392 (w), 1367 (m), 1271 (m), 1252 (m), 1173 (s), 1044 (w),
995 (w), 977 (w), 913 (m), 874 (w), 782 (w), 666 (w), 638 (w). The
1H NMR values for the characterization for 9a correspond to the ones
reported in literature.17d
Following a reported procedure,16b 1-octyne (19) (1.94 mL, 13.0
mmol, 1.3 equiv) was dissolved in THF (20 mL), and nBuLi (2.5 M in
hexane, 4.8 mL, 12 mmol, 1.2 equiv) was added at −78 °C. The
resulting mixture was stirred for 15 min at this temperature and then
warmed to 0 °C and stirred for 1 h. A solution of epoxide 20 (1.13 mL,
10.0 mmol, 1.0 equiv) in THF (5 mL) was added with stirring at −78
°C, followed by BF3·Et2O (freshly distilled on CaH2, 1.52 mL, 12.0
mmol, 1.2 equiv). After 7 h, the reaction was quenched with aqueous
NH4Cl (saturated solution, 30 mL). Upon warming to rt, the aqueous
layer was extracted with Et2O (3 × 20 mL). The combined organic
layers were washed with brine, dried over MgSO4, and the solvent was
removed in vacuo. Purification by column chromatography (SiO2,
Pentane/Et2O 10/1) afforded secondary alcohol 5c as a colorless oil
tert-Butyl 1-phenylpent-4-enylcarbamate (9b).
Following a reported procedure,17e a solution of 4-bromobutene (18)
(1.6 mL, 16 mmol, 1.0 equiv) in THF (18 mL) was added dropwise to
a suspension of Mg turnings (397 mg, 16.3 mmol, 1.02 equiv) in THF
(2 mL) at rt; the resulting mixture was then stirred at rt for 1 h. CuI
(152 mg, 0.798 mmol, 0.05 equiv) was added to a solution of benzoyl
chloride (1.9 mL, 16 mmol, 1.0 equiv) in THF (17 mL) at −15 °C,
and the resulting mixture was stirred at the same temperature for 10
min. The Grignard reagent previously prepared was then added
dropwise over 1 h at −15 °C. The mixture was stirred at −15 °C for
additionally 2 h and then allowed to warm to rt. THF was removed by
distillation under reduced pressure, and the residue was treated with
CH2Cl2 (30 mL) and aqueous HCl (1.0 M, 20 mL). The two layers
were separated, and the aqueous one was extracted with CH2Cl2 (3 ×
30 mL). The combined organic layers were washed with aqueous
NaHCO3 (saturated solution), dried over MgSO4, filtered, and the
solvent was removed in vacuo. Purification by column chromatography
(SiO2, Pentane/EtOAc 95/5) afforded ketone 24 as a pale yellow oil
(2.44 g, 15.2 mmol, 95% yield).
Ketone 24 (2.30 g, 14.3 mmol, 1.0 equiv) was dissolved in MeOH
(43 mL). Ammonium acetate (18.0 g, 233 mmol, 16.3 equiv),
NaBH3CN (1.53 g, 24.4 mmol, 1.7 equiv) and activated molecular
sieves 4 Å were added, and the resulting mixture was stirred at rt for 24
h. The reaction was then quenched by dropwise addition of aqueous
HCl (37% w/v, ca. 20 mL) until pH 2. The organic solvent was
removed under reduced pressure, and the residue diluted with water
(15 mL). The aqueous layer was washed with Et2O (2 × 35 mL) and
treated by addition of solid KOH until pH 12. It was then extracted
with Et2O (4 × 25 mL), the combined organic layers were dried over
KOH, filtered, and the solvent was removed in vacuo to afford
secondary amine 25 as a colorless oil (1.44 g, 8.95 mmol 62% yield),
which was not further purified.
1
(1.07 g, 5.13 mmol, 51% yield): Rf 0.56 (Hexane/EtOAc 5/1); H
NMR (400 MHz, CDCl3) δ 5.83 (ddt, 1 H, J = 16.9, 10.2, 6.6 Hz),
5.05 (dq, 1 H, J = 17.1, 1.5 Hz), 4.97 (ddd, 1 H, J = 10.0, 2.5, 1.5 Hz),
3.71 (dddd, 1 H, J = 11.6, 6.5, 5.1, 5.1 Hz, 1 H), 2.41 (dddd, 1 H, J =
16.4, 4.7, 2.3, 2.3 Hz), 2.29 (dddd, J = 16.1, 6.5, 2.0, 2.0 Hz), 2.25−
2.09 (m, 2 H), 2.17 (tt, 2 H, J = 7.0, 2.3 Hz), 1.95 (d, 1 H, J = 5.0 Hz),
1.62 (dt, J = 8.0, 6.5 Hz), 1.49 (quint, 2 H, J = 6.9 Hz), 1.42−1.33 (m,
2 H), 1.33−1.23 (m, 4 H), 0.89 (t, 3 H, J = 6.8 Hz); 13C NMR (101
MHz, CDCl3) δ 138.2, 114.8, 75.8, 69.6, 65.8, 35.3, 31.3, 29.9, 28.9,
28.5, 27.8, 22.5, 18.7, 14.0; IR 3374 (w), 3080 (w), 2956 (m), 2931
(s), 2872 (w), 2858 (m), 1642 (w), 1467 (w), 1466 (w), 1455 (w),
1436 (w), 1418 (w), 1331 (w), 1120 (w), 1119 (w), 1081 (w), 1080
(w), 1062 (w), 1061 (w), 1026 (w), 994 (w), 912 (s); HRMS (ESI)
calcd for C14H25O+ [M + H]+ 209.1900, found 209.1903.
tert-Butyl pent-4-enylcarbamate (9a).
Following a reported procedure,17f a suspension of LiAlH4 (1.72 g,
45.1 mmol, 1.7 equiv) in Et2O (45 mL) was slowly added to a solution
of 4-pentenamide (21) (2.65 g, 26.5 mmol, 1.0 equiv) in Et2O (26
mL) at 0 °C. The resulting mixture was stirred at rt overnight and then
diluted with Et2O (300 mL). Aqueous NaOH (10.0 M) was cautiously
added dropwise, until complete precipitation of the insoluble materials.
After filtration, the solids were washed with Et2O (3 × 100 mL). The
combined organic layers were dried over MgSO4, filtered, and the
solvent was removed in vacuo. Purification by column chromatography
(SiO2, CH2Cl2/ULTRA 95/5 to 50/50) afforded 4-pentenamine (22
as a colorless oil (0.907 g, 10.5 mmol, 40% yield). An improved yield
was obtained when HCl in MeOH (1.25 M, ca. 9 mL) was added
Secondary amine 25 (0.564 g, 3.50 mmol, 1.0 equiv) was dissolved
in CH2Cl2 (10.5 mL). Et3N (1.1 mL, 7.7 mmol, 2.2 equiv) was added,
and the solution was cooled to 0 °C. Boc2O (0.840 g, 3.85 mmol, 1.1
equiv) was added in two portions, and the resulting mixture was stirred
at rt overnight. The solution was then washed with aqueous citric acid
(0.1 M, 10 mL). The aqueous layer was extracted with CH2Cl2 (3 × 12
mL); the combined organic layers were washed with aqueous
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Article
NaHCO3 (saturated solution, 12 mL) and brine, dried over MgSO4,
filtered, and the solvent was removed in vacuo. Purification by column
chromatography (SiO2, Pentane/EtOAc 98/2 to 95/5) afforded
protected amine 9b as a colorless solid (0.815 g, 3.11 mmol, 89%
30 min at rt, and then CHCl3 (18 mL) was added, and the mixture was
washed with an aqueous HCl 1% solution (2 × 37 mL, 0−5 °C). The
combined organic layers were dried over MgSO4, filtered, and the
solvent was removed in vacuo, and the mixture was purified by column
chromatography (SiO2, Pentane/EtOAc 20/1) to afford the protected
secondary amine 9c as a colorless oil (287 mg, 1.07 mmol, 57% yield):
1
yield): Rf 0.51 (Pentane/EtOAc 20/3); H NMR (400 MHz, CDCl3)
δ 7.33 (m, 2 H), 7.25 (m, 3 H), 5.81 (ddt, 1 H, J = 16.8, 10.2, 6.5 Hz),
5.01 (ddd, J = 16.1, 3.5, 2.0 Hz), 4.99−4.96 (m, 1 H), 4.78 (m, 1 H),
4.64 (m, 1 H), 2.09 (m, 2 H), 1.78 (m, 2 H), 1.42 (s, 9 H); 13C NMR
(101 MHz, CDCl3) δ 155.2, 142.7, 137.6, 128.5, 127.2, 126.3, 115.2,
79.3, 55.1, 36.0, 30.4, 28.4; IR 3382 (w), 3078 (w), 3064 (w), 3030
(w), 3004 (w), 2978 (w), 2933 (w), 2360 (w), 2342 (w), 1685 (s),
1643 (w), 1519 (s), 1452 (w), 1414 (w), 1391 (w), 1365 (m), 1321
(w), 1297 (m), 1254 (m), 1213 (w), 1175 (s), 1122 (w), 1047 (m),
1026 (w), 1018 (w), 1000 (w), 912 (m), 868 (w), 779 (w), 765 (m),
752 (m), 703 (s), 686 (w), 670 (w), 660 (w), 648 (w), 632 (w), 613
(w); mp 81.9−84.4 °C. The values for the characterization for 9b
correspond to the ones reported in literature.23
1
Rf 0.76 (Hexane/EtOAc 5/1); H NMR (400 MHz, CDCl3) δ 5.81
(ddt, 1 H, J = 16.9, 10.2, 6.7 Hz), 5.01 (dq, 1 H, J = 17.1, 1.7 Hz), 4.95
(ddd, 1 H, J = 10.1, 2.0, 1.3 Hz), 4.24 (m, 1 H), 3.55 (m, 1 H), 2.08
(m, 2 H), 1.43 (s, 9 H), 1.36−1.22 (m, 12 H), 0.87 (t, 3 H, J = 6.7
Hz); 13C NMR (101 MHz, CDCl3) δ 155.6, 138.3, 114.6, 78.8, 50.3,
35.6, 34.8, 31.8, 30.2, 29.2, 28.4, 25.8, 22.6, 14.1; IR 3353 (w), 2978
(w), 2957 (w), 2931 (m), 2872 (w), 2859 (w), 1692 (s), 1642 (w),
1524 (m), 1506 (m), 1455 (w), 1391 (w), 1366 (m), 1266 (w), 1248
(w), 1247 (w), 1173 (s), 1105 (w), 1045 (w), 1021 (w), 995 (w), 910
+
(m), 857 (w); HRMS (ESI) calcd for C16H32NO2 [M + H]+
270.2428, found 270.2428.
Nona-1,8-dien-5-ol (30).
tert-Butyl undec-1-en-5-ylcarbamate (9c).
Following a reported procedure,17g a solution of 4-bromobutene (18)
(2.0 mL, 20 mmol, 2.5 equiv) in THF (16 mL) was added dropwise to
a suspension of Mg turnings (486 mg, 20.0 mmol, 2.5 equiv) in THF
(2 mL) at rt. After stirring the resulting mixture for 1 h at rt, it was
cooled to 0 °C, and a solution of ethyl formate (0.65 mL, 8.0 mmol,
1.0 equiv) in THF (10 mL) was added dropwise. The mixture was
stirred at rt for 4 h, and then the reaction was quenched with aqueous
NH4Cl (saturated solution, 30 mL). The two layers were separated,
and the aqueous one was extracted with Et2O (3 × 30 mL). The
combined organic layers were washed with brine, dried over MgSO4,
filtered, and the solvent was removed in vacuo. Purification by column
chromatography (SiO2, Pentane/EtOAc 90/10 to 70/30) afforded
secondary alcohol 30 as a colorless oil (1.03 g, 7.38 mmol, 92% yield):
Following a reported procedure,17g 4-bromobutene (18) (2.0 mL, 20
mmol, 2.5 equiv) in THF (10 mL) was added dropwise to a
suspension of Mg turnings (486 mg, 20.0 mmol, 2.5 equiv) in THF (2
mL). The resulting mixture was stirred overnight, and then a solution
of heptaldehyde (1.1 mL, 8.0 mmol, 1.0 equiv) in THF (10 mL) was
added dropwise at 0 °C. The reaction was stirred for 3.5 h and then
quenched with aqueous NH4Cl (saturated solution). The aqueous
layer was extracted with Et2O (3 × 20 mL). The combined organic
layers were washed with brine, dried over MgSO4, filtered, and the
solvent was removed in vacuo. Purification by column chromatography
(SiO2, Pentane/EtOAc 98/2) afforded the secondary alcohol 27 as a
pale yellow oil (1.05 g, 6.17 mmol, 77% yield).
1
Rf 0.29 (Hexane/EtOAc 20/3); H NMR (400 MHz, CDCl3) δ 5.83
(ddt, 2 H, J = 16.9, 10.2, 6.7 Hz), 5.04 (ddd, 2 H, J = 17.1, 3.4, 1.7
Hz), 4.96 (ddd, 2 H, J = 10.2, 3.2, 1.5 Hz), 3.64 (m, 1 H), 2.16 (m, 4
H), 1.68−1.45 (m, 5 H); 13C NMR (101 MHz, CDCl3) δ 138.5,
114.7, 70.9, 36.4, 30.0; IR 3359 (w), 3078 (w), 2997 (w), 2979 (w),
2934 (m), 2869 (w), 2850 (w), 1642 (w), 1450 (w), 1416 (w), 1338
(w), 1317 (w), 1126 (w), 1126 (w), 1080 (w), 1061 (w), 1053 (w),
994 (m), 947 (w), 910 (s), 736 (w), 650 (w), 650 (w), 636 (w), 624
(w), 614 (w). The values for the characterization of 30 correspond to
the ones reported in literature.17g
Following a reported procedure,17c phthalimide (1.05 g, 7.11 mmol,
1.4 equiv) and triphenyl phosphine (1.87 g, 7.11 mmol, 1.40 equiv)
were dissolved in THF (37 mL). Secondary alcohol 27 (865 mg, 5.08
mmol, 1.0 equiv) was added; DEAD (40% solution in toluene, 3.1 mL,
7.11 mmol, 1.4 equiv) was then added dropwise at rt over 20 min. The
reaction mixture was stirred at rt for 24 h. The solvent was evaporated,
and the mixture was directly purified by column chromatography
(SiO2, pentane/EtOAc 20/1) to afford phthalimide 28 as a pale yellow
oil (1.17 g, 3.91 mmol, 77% yield).
Phthalimide 28 (1.16 g, 3.86 mmol, 1.0 equiv) was dissolved in
EtOH (34 mL). Hydrazine hydrate (0.39 mL, 8.0 mmol, 2.07 equiv)
was added, and the mixture was refluxed for 7 h. The mixture was
allowed to cool to rt. Concentrated HCl (37% w/w, ca. 10 mL) was
added dropwise to quench the reaction, and the mixture was filtered
through a pad of Celite. The aqueous solution was extracted with Et2O
(2 × 20 mL) and treated with solid NaOH until pH 12. It was then
extracted with CH2Cl2 (4 × 50 mL). The combined organic layers
were washed with brine and dried over Na2SO4, filtered, and the
solvent was removed in vacuo to afford the secondary amine 29 (315
mg, 1.86 mmol, 48% yield) as a viscous colorless oil, which did not
require further purification.
Secondary amine 29 (315 mg, 1.86 mmol, 1.0 equiv) was dissolved
in CH2Cl2 (4.3 mL). Et3N (freshly distilled on CaH2, 0.65 mL, 4.6
mmol, 2.5 equiv) was added, and the solution was cooled to 0 °C.
Boc2O (567 mg, 2.60 mmol, 1.4 equiv) was added in two portions, and
the resulting mixture was stirred at rt overnight. The solution was then
washed with aqueous citric acid (0.1 M, 4 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 10 mL), and the combined organic layers
were washed with aqueous NaHCO3 (saturated solution, 10 mL) and
brine, dried over MgSO4, filtered, and the solvent was removed in
vacuo. In order to remove the excess of Boc2O,24 crude N-protected
amine 9c was dissolved in EtOH (7.5 mL), and imidazole was added
(633 mg, 9.30 mmol, 5.0 equiv). The resulting mixture was stirred for
tert-Butyl nona-1,8-dien-5-ylcarbamate (9d).
Following a reported procedure,17c phthalimide (1.93 g, 13.1 mmol,
1.40 equiv) and triphenyl phosphine (3.44 g, 13.1 mmol, 1.40 equiv)
were dissolved in THF (74 mL). Secondary alcohol 30 (1.59 g, 10.5
mmol, 1.0 equiv) was added; DEAD (40% solution in toluene, 6.6 mL,
15 mmol, 1.4 equiv) was then added dropwise at rt over 20 min. The
reaction mixture was stirred at rt for 23 h. The solvent was removed
under reduced pressure, and the resulting crude oil was triturated with
petroleum ether/Et2O (2:1 mixture) until complete precipitation of
the solids. The latter were filtered off and washed with the same
mixture of solvents. The organic layers were combined, and the
solvents were removed in vacuo. Purification by column chromatog-
raphy (SiO2, Pentane/EtOAc 98/2 to 95/5) afforded phthalimide 31
as a colorless oil (2.32 g, 8.61 mmol, 82% yield).
Phthalimide 31 (2.32 g, 8.61 mmol, 1.0 equiv) was dissolved in
EtOH (76 mL). Hydrazine hydrate (0.870 mL, 17.8 mmol, 2.07 equiv)
was added, and the mixture was refluxed for 7 h (during this time a
white solid precipitated). The mixture was allowed to cool down to rt,
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and concentrated HCl (37% w/w, ca. 20 mL) was added dropwise to
quench the reaction. The solvent was removed by distillation under
reduced pressure, and the residual aqueous solution was washed with
Et2O (2 × 30 mL) and treated with solid NaOH until pH 12. It was
then extracted with Et2O (4 × 100 mL). The combined organic layers
were washed with brine and dried over Na2SO4, filtered, and the
solvent was removed in vacuo. Purification by column chromatography
(SiO2, CH2Cl2/ULTRA 95/5 to 50/50) afforded secondary amine 32
as a colorless oil (0.631 g, 4.53 mmol, 53% yield).
PET/Et2O (2:1 mixture) until complete precipitation of the solids.
The latter were filtered off and washed with the same mixture of
solvents. The organic layers were combined, and the solvents were
removed in vacuo. Purification by column chromatography (SiO2,
Pentane/EtOAc 95/5) afforded the corresponding phthalimide as a
pale yellow oil (1.21 g, 4.73 mmol, 77% yield), which was used for the
next step without characterization.
The phthalimide obtained in the previous step (1.21 g, 4.73 mmol,
1.0 equiv) was dissolved in EtOH (46 mL). Hydrazine hydrate (0.48
mL, 9.9 mmol, 2.1 equiv) was added, and the mixture was refluxed for
3 h (during this time a white solid precipitated). The mixture was
allowed to cool down to rt, and concentrated HCl (37% w/w, ca. 20
mL) was added dropwise to quench the reaction. The solvent was
removed by distillation under reduced pressure, and the residual
aqueous solution was washed with Et2O (2 × 30 mL) and treated with
solid NaOH until pH 12. It was then extracted with Et2O (4 × 100
mL). The combined organic layers were washed with brine and dried
over Na2SO4, filtered, and the solvent was removed in vacuo. Crude
amine 35 was obtained as a pale yellow oil (ca. 590 mg, 4.71 mmol,
quantitative), which was used for the next step without further
purification.
Crude secondary amine 35 (590 g, 4.71 mmol, 1.0 equiv) was
dissolved in CH2Cl2 (18 mL). Et3N (1.9 mL, 13 mmol, 2.7 equiv) was
added, and the solution was cooled to 0 °C. Boc2O (1.48 g, 6.77
mmol, 1.4 equiv) was added in two portions, and the resulting mixture
was stirred at rt overnight. The solution was then washed with aqueous
citric acid (0.1 M, 20 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 20 mL); the combined organic layers were washed with
aqueous NaHCO3 (saturated solution, 20 mL) and brine, dried over
MgSO4, filtered, and the solvent was removed in vacuo. Purification by
column chromatography (SiO2, Pentane/EtOAc 97/3 to 95/5)
afforded N-Boc protected amine 9e as a colorless solid (560 mg,
2.48 mmol, 53% yield): Rf 0.48 (Hexane/EtOAc 5/1); mp 43.0−45.2
°C; 1H NMR (400 MHz, CDCl3, 65 °C) δ 5.82 (m, 1 H), 5.02 (ddd, 1
H, J = 17.1, 3.4, 1.6 Hz), 4.97 (dddd, 1 H, J = 10.2, 2.1, 1.1, 1.1 Hz),
4.34 (m, 1 H), 4.03 (m, 1 H), 2.23 (m, 1 H), 2.01 (m, 1 H), 1.97−1.86
(m, 2 H), 1.80 (m, 1 H), 1.68 (m, 1 H), 1.62−1.46 (m, 2 H), 1.46 (m,
9 H), 1.36−1.23 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ 155.6,
137.8, 115.2, 79.0, 54.4, 42.6, 34.2, 32.6, 29.4, 28.5, 21.6; IR 3451 (w),
3336 (br w), 3332 (w), 3076 (w), 2970 (m), 2874 (w), 1696 (s), 1642
(w), 1507 (m), 1454 (w), 1388 (m), 1365 (m), 1311 (w), 1248 (m),
1169 (s), 1089 (w), 1045 (w), 1000 (m), 911 (m), 864 (w); HRMS
(ESI) calcd for C13H23NNaO2+ [M + Na]+ 248.1621, found 248.1626.
2-Allylcyclohexanol (37).
Secondary amine 32 (0.631 g, 4.53 mmol, 1.0 equiv) was dissolved
in CH2Cl2 (10.5 mL). Et3N (1.6 mL, 11 mmol, 2.5 equiv) was added,
and the solution was cooled to 0 °C. Boc2O (1.38 g, 6.34 mmol, 1.4
equiv) was added in two portions, and the resulting mixture was stirred
at rt overnight. The solution was then washed with aqueous citric acid
(0.1 M, 10 mL). The aqueous layer was extracted with CH2Cl2 (3 × 10
mL); the combined organic layers were washed with aqueous
NaHCO3 (saturated solution, 10 mL) and brine, dried over MgSO4,
filtered, and the solvent was removed in vacuo. Purification by column
chromatography (SiO2, Pentane/EtOAc 95/5 to 90/10) afforded
protected amine 9d as a colorless solid (0.749 g, 3.13 mmol, 69%
yield): Rf 0.59 (Hexane/EtOAc 20/3); 1H NMR (400 MHz, CDCl3) δ
5.81 (ddt, 2 H, J = 16.9, 10.2, 6.6 Hz), 5.02 (ddd, 2 H, J = 17.1, 3.2, 1.5
Hz), 4.96 (d, 2 H, J = 10.2 Hz), 4.25 (m, 1 H), 3.59 (m, 1 H), 2.10 (m,
4 H), 1.56 (m, 4 H), 1.44 (s, 9 H); 13C NMR (101 MHz, CDCl3) δ
155.6, 138.2, 114.8, 78.9, 49.9, 34.8, 30.2, 28.4; IR 3439 (w), 3341 (w),
3077 (w), 3002 (w), 2978 (m), 2933 (m), 2853 (w), 1685 (s), 1642
(w), 1525 (m), 1452 (w), 1391 (w), 1366 (m), 1302 (w), 1269 (w),
1248 (m), 1172 (s), 1102 (w), 1046 (w), 1023 (w), 994 (w), 910 (s),
875 (w), 861 (w), 778 (w), 748 (w), 681 (w), 664 (w), 644 (w), 631
(w), 610 (w); mp found, 38.5−40.5 °C; reported, 35.8−36.8 °C. The
values for the characterization for 9d correspond to the ones reported
in literature.25
2-Allylcyclopentanol (34).
Following a reported procedure,17a allyl magnesium bromide (1.0 M in
Et2O, 20 mL, 20 mmol, 2.5 equiv) was diluted with Et2O (20 mL).
Cyclopentene oxide (33) (0.70 mL, 8.0 mmol, 1.0 equiv) was added
dropwise to the resulting solution at rt over 15 min. The mixture was
refluxed for 2.5 h. It was the cooled to 0 °C, and then the reaction was
quenched by addition of aqueous NH4Cl (saturated solution, 20 mL).
The two layers were separated, and the aqueous one was extracted
with Et2O (3 × 30 mL). The combined organic layers were washed
with water (3 × 20 mL) and brine, dried over MgSO4, filtered, and the
solvent was removed in vacuo. 2-Allyl cyclopentanol (34) was
obtained as a colorless oil (777 mg, 6.16 mmol, 77% yield), which
1
Following a reported procedure,17a allyl magnesium bromide (1.0 M in
Et2O, 20 mL, 20 mmol, 3.0 equiv) was diluted with Et2O (16 mL).
Cyclohexene oxide 36 (0.67 mL, 6.6 mmol, 1.0 equiv) was added
dropwise to the resulting solution at rt over 15 min. The mixture was
refluxed for 3 h, and then the reaction was quenched by addition of
aqueous NH4Cl (saturated solution, 30 mL). The two layers were
separated, and the aqueous one was extracted with Et2O (3 × 30 mL).
The combined organic layers were washed with water (3 × 20 mL)
and brine, dried over MgSO4, filtered, and the solvent was removed in
vacuo. Purification by column chromatography (SiO2, CH2Cl2/MeOH
99/1 to 96/4) afforded secondary alcohol 37 as a colorless oil (0.838
did not require further purification: H NMR (400 MHz, CDCl3) δ
5.85 (dddd, 1 H, J = 17.0, 10.1, 6.8, 6.8 Hz), 5.06 (dddd, J = 17.0, 2.1,
1.4, 1.4 Hz), 5.00 (ddd, 1 H, J = 10.1, 1.0, 1.0 Hz), 3.86 (m, 1 H), 2.18
(ddd, J = 14.1, 7.0, 7.0 Hz), 2.03 (m, 1 H), 1.91 (m, 2 H), 1.80 (m, 1
H), 1.71 (m, 1 H), 1.65−1.51 (m, 2 H), 1.49 (d, 1 H, J = 3.1 Hz), 1.22
(m, 1 H); 13C NMR (101 MHz, CDCl3) δ 137.5, 115.2, 78.0, 47.1,
37.8, 34.0, 29.2, 21.5. The values for the characterization for 34
correspond to the ones reported in literature.26
tert-Butyl (2-allylcyclopentyl)carbamate (9e).
1
g, 5.98 mmol, 90% yield): Rf 0.44 (Hexane/EtOAc 20/3); H NMR
(400 MHz, CDCl3) δ 5.89 (ddt, 1 H, J = 17.2, 10.1, 7.4 Hz), 5.09 (m,
1 H), 5.05 (m, 1 H), 3.30 (m, 1 H), 2.48 (m, 1 H), 2.09−1.92 (m, 2
H), 1.79 (m, 2 H), 1.65 (m, 2 H), 1.43−1.12 (m, 4 H), 0.98 (m, 1 H);
13C NMR (101 MHz, CDCl3) δ 137.5, 115.9, 74.5, 44.8, 37.4, 35.5,
30.3, 25.5, 24.9; IR 3332 (w), 2927 (s), 2856 (s), 1639 (w), 1462 (w),
1462 (w), 1449 (m), 1415 (w), 1352 (w), 1308 (w), 1234 (w), 1214
(w), 1195 (w), 1151 (w), 1132 (w), 1081 (w), 1061 (s), 1037 (s), 997
(w), 965 (w), 965 (w), 940 (w), 908 (m), 844 (w), 824 (w), 790 (w),
736 (m), 709 (w), 697 (w), 687 (w), 666 (w), 647 (m), 638 (m), 629
Following a reported procedure,17c phthalimide (1.18 g, 8.00 mmol,
1.3 equiv) and triphenyl phosphine (2.10 g, 8.00 mmol, 1.3 equiv)
were dissolved in THF (43 mL). Secondary alcohol 34 (777 mg, 6.16
mmol, 1.0 equiv) was added; DEAD (40% solution in toluene, 3.9 mL,
8.6 mmol, 1.4 equiv) was then added dropwise at rt over 20 min. The
reaction mixture was stirred at rt for 23 h. The solvent was removed
under reduced pressure, and the resulting crude oil was triturated with
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(w), 629 (w), 620 (w), 611 (m). The values for the characterization
for 37 correspond to the ones reported in literature.27
tert-Butyl (2-allylcyclohexyl)carbamate (9f).
reaction was quenched by addition of aqueous NH4Cl (saturated
solution, 18 mL). The two layers were separated, and the aqueous one
was extracted with Et2O (3 × 25 mL). The combined organic layers
were washed with water (3 × 25 mL) and brine, dried over MgSO4,
filtered, and the solvent was removed in vacuo. Column chromatog-
raphy (SiO2, CH2Cl2/EtOAc 97/3 to 93/7) afforded the pure 2-allyl
cycloheptanol (40) as a colorless oil (978 mg, 6.34 mmol, 91% yield),
which was used directly in the next step.
Following a reported procedure,17c phthalimide (1.06 g, 7.20 mmol,
1.3 equiv) and triphenyl phosphine (1.89 g, 7.20 mmol, 1.3 equiv)
were dissolved in THF (38 mL). Secondary alcohol 40 (855 mg, 5.54
mmol, 1.0 equiv) was added; DEAD (40% solution in toluene, 3.5 mL,
7.8 mmol, 1.4 equiv) was then added dropwise at rt over 20 min. The
reaction mixture was stirred at rt for 23 h. The solvent was removed
under reduced pressure, and the resulting crude oil was triturated with
PET/Et2O (2:1 mixture) until complete precipitation of the solids.
The latter were filtered off and washed with the same mixture of
solvents. The organic layers were combined, and the solvents were
removed in vacuo. Purification by column chromatography (SiO2,
Pentane/EtOAc 95/5 to 93/7) afforded the corresponding phthali-
mide as a colorless solid (1.32 g, 4.66 mmol, 84% yield), which was
used directly for the next step.
Following a reported procedure,17c phthalimide (1.38 g, 9.36 mmol,
1.3 equiv) and triphenyl phosphine (2.45 g, 9.36 mmol, 1.3 equiv)
were dissolved in THF (50 mL). 2-Allyl cyclohexanol (37) (1.00 g,
7.20 mmol, 1.0 equiv) was added; DEAD (40% solution in toluene, 4.6
mL, 10 mmol, 1.4 equiv) was then added dropwise at rt over 20 min.
The reaction mixture was stirred at rt for 23 h. The solvent was
removed under reduced pressure, and the resulting crude oil was
triturated with PET/Et2O (2:1 mixture) until complete precipitation
of the solids. The latter were filtered off and washed with the same
mixture of solvents. The organic layers were combined, and the
solvents were removed in vacuo. Purification by column chromatog-
raphy (SiO2, Pentane/EtOAc 95/5 to 90/10) afforded the
corresponding phthalimide as a pale yellow solid (835 mg, 3.10
mmol, 44% yield), which was used for the next step without
characterization.
The phthalimide obtained in the previous step (1.09 g, 3.86 mmol,
1.0 equiv) was dissolved in EtOH (34 mL). Hydrazine hydrate (0.47
mL, 9.6 mmol, 2.5 equiv) was added, and the mixture was refluxed for
3 h (during this time a white solid precipitated). The mixture was
allowed to cool down to rt, and concentrated HCl (37% w/w, ca. 20
mL) was added dropwise to quench the reaction. The solvent was
removed by distillation under reduced pressure, and the residual
aqueous solution was washed with Et2O (2 × 30 mL) and treated with
solid NaOH until pH 12. It was then extracted with Et2O (4 × 100
mL). The combined organic layers were washed with brine and dried
over Na2SO4, filtered, and the solvent was removed in vacuo. Crude
amine 41 was obtained as a pale yellow oil (468 mg, 3.05 mmol, 79%
yield), which was used for the next step without further purification.
Crude secondary amine 41 (460 mg, 3.00 mmol, 1.0 equiv) was
dissolved in CH2Cl2 (8.8 mL). Et3N (freshly distilled on CaH2, 0.92
mL, 6.6 mmol, 2.2 equiv) was added, and the solution was cooled to 0
°C. Boc2O (785 mg, 3.60 mmol, 1.4 equiv) was added in two portions,
and the resulting mixture was stirred at rt overnight. In order to
remove the excess of Boc2O,24 the solvent was then removed by
evaporation under reduced pressure, and the residue was dissolved in
EtOH (12 mL). Imidazole (1.02 g, 15.0 mmol, 5.0 equiv) was added,
and the mixture was stirred at rt for 15 min. The mixture was then
concentrated in vacuo and diluted with CHCl3 (30 mL). The organic
solution was then washed with aqueous HCl (1% v/v, 8.8 mL, 0 °C),
dried over MgSO4, filtered, and the solvent was removed in vacuo.
Purification by column chromatography (SiO2, pentane/EtOAc 95/5)
afforded N-Boc protected amine 9g as a colorless viscous oil (596 mg,
2.35 mmol, 78% yield): Rf 0.57 (Hexane/EtOAc 5/1); 1H NMR (400
MHz, CDCl3) δ 5.77 (dddd, 1 H, J = 17.1, 10.0, 7.2, 7.2 Hz), 5.00
(ddd, 1 H, J = 14.4, 3.3, 1.5 Hz), 4.97 (ddd, 1 H, J = 5.8, 1.8, 1.8 Hz),
4.51 (d, 1 H, J = 7.9 Hz), 3.89 (m, 1 H), 2.12 (m, 1 H), 1.90 (m, 1 H),
1.75 (m, 1 H), 1.65 (m, 2 H), 1.62−1.42 (m, 6 H), 1.42 (s, 9 H), 1.25
(m, 2 H); 13C NMR (101 MHz, CDCl3) δ 155.4, 137.6, 115.8, 78.8,
52.6, 42.6, 37.3, 33.1, 28.9, 28.4, 27.7, 26.3, 23.4; IR 3455 (w), 3344
(br w), 3075 (w), 2977 (w), 2926 (m), 2859 (w), 1696 (s), 1642 (w),
1500 (m), 1456 (w), 1389 (m), 1366 (m), 1341 (w), 1319 (w), 1246
(m), 1169 (s), 1106 (w), 1047 (w), 1021 (w), 998 (w), 955 (w), 911
The phthalimide obtained in the previous step (835 mg, 3.10 mmol,
1.0 equiv) was dissolved in EtOH (27 mL). Hydrazine hydrate (0.32
mL, 6.5 mmol, 2.1 equiv) was added, and the mixture was refluxed for
3 h (during this time a white solid precipitated). The mixture was
allowed to cool down to rt, and concentrated HCl (37% w/w, ca. 10
mL) was added dropwise to quench the reaction. The solvent was
removed by distillation under reduced pressure, and the residual
aqueous solution was washed with Et2O (2 × 20 mL) and treated with
solid NaOH until pH 12. It was then extracted with Et2O (4 × 50
mL). The combined organic layers were washed with brine and dried
over Na2SO4, filtered, and the solvent was removed in vacuo. Crude
amine 38 was obtained as a pale yellow oil (366 mg, 2.63 mmol, 85%
yield), which was used for the next step without further purification.
Crude secondary amine 38 (366 mg, 2.63 mmol, 1.0 equiv) was
dissolved in CH2Cl2 (7.7 mL). Et3N (freshly distilled on CaH2, 0.80
mL, 5.8 mmol, 2.2 equiv) was added, and the solution was cooled to 0
°C. Boc2O (632 mg, 2.89 mmol, 1.1 equiv) was added in two portions,
and the resulting mixture was stirred at rt overnight. The solution was
then washed with aqueous citric acid (0.1 M, 15 mL). The aqueous
layer was extracted with CH2Cl2 (3 × 15 mL); the combined organic
layers were washed with aqueous NaHCO3 (saturated solution, 15
mL) and brine, dried over MgSO4, filtered, and the solvent was
removed in vacuo. Purification by column chromatography (SiO2,
Pentane/EtOAc 97/3) afforded N-Boc protected amine 9f as a
colorless solid (438 mg, 1.83 mmol, 69% yield): Rf 0.75 (Hexane/
EtOAc 4/1); mp 46.9−49.2 °C ;1H NMR (400 MHz, CDCl3) δ 5.79
(dddd, 1 H, J = 17.0, 10.2, 7.3, 7.3 Hz), 5.02 (m, 1 H), 4.98 (m, 1 H),
4.60 (br m, 1 H), 3.83 (m, 1 H), 2.09 (m, 1 H), 1.91 (m, 1 H), 1.77−
1.46 (m, 6 H), 1.45 (s, 9 H), 1.41−1.20 (m, 2 H), 1.13 (m, 1 H); 13C
NMR (101 MHz, CDCl3) δ 155.4, 137.1, 115.8, 78.9, 49.2, 39.7, 36.2,
30.8, 28.4, 27.3, 24.3, 21.7; IR 3461 (w), 3348 (br w), 3284 (br w),
3135 (w), 3074 (w), 2976 (w), 2929 (m), 2859 (w), 2858 (w), 1814
(w), 1697 (s), 1643 (w), 1500 (m), 1456 (m), 1388 (m), 1365 (m),
1338 (w), 1312 (w), 1247 (m), 1170 (s), 1106 (w), 1067 (m), 975
(w), 944 (w), 911 (m), 873 (w); HRMS (FT-Orbitrap) calcd for
+
C14H26NO2 [M + H]+ 240.1958, found 240.1949.
+
(m), 889 (w); HRMS (ESI) calcd for C15H28NO2 [M + H]+
tert-Butyl (2-allylcycloheptyl)carbamate (9g).
254.2115, found 254.2117.
tert-Butyl 2-allylphenylcarbamate (9h).
Following a reported procedure,17a allyl magnesium bromide (1.0 M in
Et2O, 17.5 mL, 17.5 mmol, 2.5 equiv) was diluted with Et2O (16.8
mL). Cycloheptene oxide 39 (0.81 mL, 7.0 mmol, 1.0 equiv) was
added dropwise to the resulting solution at rt over 15 min. The
mixture was refluxed for 2 h. It was the cooled to 0 °C, and then the
Following a reported procedure,17h 2-iodonitrobenzene (42) (1.74 g,
7.00 mmol, 1.0 equiv) was dissolved in THF (10 mL), and the
solution was cooled to −40 °C. Phenyl magnesium bromide (1.0 M in
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THF, 7.7 mL, 7.7 mmol, 1.1 equiv) was added dropwise, and the
resulting mixture was stirred at −40 °C for 15 min before a solution of
CuCN (627 mg, 7.00 mmol, 1.0 equiv) and LiCl (593 mg, 14.0 mmol,
2.0 equiv) in THF (4.0 mL) was also added. The mixture was stirred
for further 15 min, and then allyl bromide (0.67 mL, 7.7 mmol, 1.1
equiv) was added. The mixture was stirred at −40 °C for 2 h, and then
allowed to warm to rt and quenched by the addition of aqueous
NH4Cl (saturated solution, ca. 10 mL). The aqueous layer was
extracted with Et2O (3 × 20 mL), and the combined organic extracts
were treated with activated charcoal. After the latter was filtered off,
the organic solution was dried over over MgSO4, filtered, and the
solvent removed by evaporation under reduced pressure. Purification
by column chromatography (SiO2, Pentane/CH2Cl2 100/0 to 95/5)
afforded 2-allyl nitrobenzene (43) as a pale yellow oil (590 mg, 3.60
mmol, 52% yield): 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, 1 H, J =
8.6, 1.4 Hz), 7.55 (d, 1H, J = 7.6, 1.2, Hz), 7.41−7.32 (m, 2 H), 5.97
(dddd, 1 H, J = 16.7, 10.1, 6.5, 6.5 Hz), 5.12 (m, 1 H), 5.08 (m, 1 H),
3.69 (d, 2 H, J = 6.5 Hz).
dropwise. The resulting mixture was allowed to warm to rt and stirred
overnight. It was then cooled back to 0 °C, and water (0.43 mL),
aqueous NaOH (10% w/w, 0.86 mL) and again water (1.3 mL) were
added under vigorous stirring in order to induce the complete
precipitation of lithium salts. The solids were filtered off and washed
with Et2O several times. The organic solution was concentrated in
vacuo to afford N-(pent-4-en-1-yl)aniline (9i) (585 mg, 3.63 mmol,
93% yield) as a colorless oil, which did not require further purification:
1
Rf 0.43 (Hexane/EtOAc 10/1); H NMR (400 MHz, CDCl3) δ 7.22
(m, 2 H), 6.74 (t, 1 H, J = 7.2 Hz), 6.64 (m, 2 H), 5.89 (dddd, 1 H, J =
16.9, 10.2, 6.7, 6.7 Hz), 5.11 (ddd, 1 H, J = 17.1, 3.3, 1.7 Hz), 5.05
(ddd, 1 H, J = 10.5, 3.5, 1.5 Hz), 3.65 (br s, 1 H), 3.17 (dd, 2 H, J =
7.0, 7.0 Hz), 2.22 (m, 2 H), 1.76 (quint, 2 H, J = 7.3 Hz); 13C NMR
(101 MHz, CDCl3) δ 148.3, 138.0, 129.2, 117.1, 115.0, 112.6, 43.3,
31.3, 28.6; IR 3411 (br w), 3077 (w), 3054 (w), 3053 (w), 3021 (w),
3001 (w), 2976 (w), 2930 (w), 2858 (w), 1641 (w), 1603 (s), 1507
(s), 1477 (w), 1433 (w), 1371 (w), 1320 (m), 1279 (w), 1259 (m),
1180 (w), 1153 (w), 1102 (w), 993 (m), 912 (m), 869 (w), 837 (w).
The values for the characterization of 9i correspond to the ones
reported in literature.6f
Following a reported procedure,17i Zn (dust, 3.53 g, 54.0 mmol,
15.0 equiv) and acetic acid (3.1 mL, 54 mmol, 15 equiv) were added
to a solution of 2-allyl nitrobenzene (43) (590 mg, 3.60 mmol, 1.0
equiv) in EtOH (36 mL). The resulting suspension was stirred at rt for
1.5 h and then filtered through Celite. After washing the Celite pad
with EtOH, the organic solution was concentrated in vacuo. Aqueous
NaHCO3 (saturated solution, 30 mL) was added to the residue, and
the aqueous layer was extracted with EtOAc (3 × 30 mL). The
combined organic extracts were washed with brine, dried over MgSO4,
filtered, and the solvent was removed in vacuo. The obtained crude oil
was used for the next step without further purification.
Crude 2-allyl aniline (44) (ca. 480 mg, ca. 3.60 mmol, 1.0 equiv)
was dissolved in Et2O (5.8 mL), and Et3N (1.1 mL, 7.9 mmol, 2.2
equiv) was added to the resulting solution, cooled to 0 °C. A solution
of Boc2O (1.65 g, 7.54 mmol, 2.1 equiv) in Et2O (5.8 mL) was then
added, and the mixture was stirred at 0 °C for 10 min and then at rt for
20 h. After filtering the solids off, the resulting solution was
concentrated in vacuo. Purification of the crude oil by column
chromatography (SiO2, pentane/EtOAc 95/5) afforded the pure N-
Boc protected 2-allyl aniline 9h as a colorless oil (365 mg, 1.56 mmol,
43% yield): Rf 0.57 (Hexane/EtOAc 5/1); 1H NMR (400 MHz,
CDCl3) δ 7.78 (d, 1 H, J = 7.9 Hz), 7.24 (m, 2 H), 7.14 (dd, 1 H, J =
7.6, 1.3 Hz), 7.04 (td, 1 H, J = 7.4, 1.0 Hz), 6.43 (br s, 1 H), 5.96
(dddd, 1 H, J = 17.2, 9.9, 5.8, 5.8 Hz), 5.16 (dq, 1 H, J = 9.9, 1.5 Hz),
5.06 (dq, 1 H, J = 17.2, 1.7 Hz), 3.37 (d, 2 H, J = 6.0 Hz), 1.51 (s, 9
H); 13C NMR (101 MHz, CDCl3) δ 153.1, 136.4, 135.8, 129.9, 128.9,
127.3, 123.9, 121.9, 116.5, 80.2, 36.4, 28.3; IR 3430 (br w), 3335 (br
w), 3003 (w), 2976 (w), 2932 (w), 2877 (w), 2876 (w), 2871 (w),
2360 (w), 2342 (w), 2332 (w), 1731 (m), 1688 (m), 1639 (w), 1613
(w), 1589 (w), 1513 (s), 1477 (w), 1452 (m), 1429 (w), 1412 (m),
1392 (w), 1366 (m), 1300 (w), 1299 (w), 1245 (m), 1158 (s), 1119
(m), 1037 (w), 1028 (w), 999 (w), 919 (w), 878 (w), 843 (w), 816
(w). The data for the characterization of compound 9h correspond to
the ones reported in the literature.23
4-Methoxy-N-(pent-4-en-1-yl)aniline (9j).
Following a reported procedure,17b pyridine (0.22 mL, 2.8 mmol, 1.1
equiv) and DMAP (16.0 mg, 0.125 mmol, 0.050 equiv) were added to
a solution of para-anisidine (308 mg, 2.50 mmol, 1.0 equiv) in CH2Cl2
(7.0 mL). The mixture was cooled to 0 °C, and pentenoyl chloride
(45) (0.30 mL, 2.8 mmol, 1.1 equiv) was added dropwise. The mixture
was allowed to warm to rt. The reaction was then quenched by adding
aqueous HCl (10% v/v, 7.0 mL), and the aqueous layer was separated
and extracted with CH2Cl2 (3 × 10 mL). The combined organic
extracts were washed with aqueous NaHCO3 (saturated solution, 10
mL), water and brine, dried over MgSO4, filtered, and the solvent was
removed in vacuo. Purification by column chromatography (SiO2,
CH2Cl2/MeOH 99/1 to 95/5) afforded pentenamide 47 as an off-
white solid (400 mg, 1.95 mmol, 78% yield).
Pentenamide 47 (400 mg, 1.95 mmol, 1.0 equiv) was dissolved in a
mixture of THF (1.4 mL) and Et2O (6.1 mL), and the solution was
cooled to 0 °C. A suspension of LiAlH4 (185 mg, 4.87 mmol, 2.5
equiv) in Et2O (4.9 mL) was added dropwise. The resulting mixture
was allowed to warm to rt and stirred overnight. It was then cooled
back to 0 °C and water (0.20 mL), aqueous NaOH (10% w/w, 0.40
mL) and again water (0.6 mL) were added under vigorous stirring in
order to induce the complete precipitation of lithium salts. The solids
were filtered off and washed with Et2O several times. The organic
solution was concentrated in vacuo to afford 4-methoxy-N-(pent-4-en-
1-yl)aniline (9j) (356 mg, 1.86 mmol, 95% yield) as a brown oil, which
did not require further purification: Rf 0.55 (Hexane/EtOAc 5/1); 1H
NMR (400 MHz, CDCl3) δ 6.78 (d, 2 H, J = 8.6 Hz), 6.58 (d, 2 H, J =
8.6 Hz), 5.84 (ddd, 1 H, J = 17.0, 10.1, 6.7 Hz), 5.06 (d, 1 H, J = 17.2
Hz), 5.00 (d, 1 H, J = 10.1 Hz), 3.75 (s, 3 H), 3.35 (br s, 1 H), 3.10 (t,
2 H, J = 7.0 Hz), 2.17 (dd, 2 H, J = 13.7, 6.7 Hz), 1.71 (quint, 2 H, J =
7.1 Hz); 13C NMR (101 MHz, CDCl3) δ 151.9, 142.6, 138.0, 114.9,
114.8, 114.0, 55.7, 44.3, 31.3, 28.7; IR 3411 (w), 3077 (w), 3054 (w),
3021 (w), 3001 (w), 2976 (w), 2930 (w), 2858 (w), 1641 (w), 1603
(s), 1507 (s), 1477 (w), 1433 (w), 1371 (w), 1320 (m), 1279 (w),
1259 (m), 1180 (w), 1153 (w), 1153 (w), 1102 (w), 1102 (w), 1023
(w), 993 (m), 912 (m), 869 (w), 869 (w). The values for the
characterization of 9j correspond to the ones reported in literature.6f
General Procedure for the Bromination of Terminal
Alkynes.15a The terminal alkyne (1.0 equiv) was dissolved in acetone
(ca. 6.8 mL per mmol of alkyne). N-bromosuccinimide (1.2 equiv) and
AgNO3 (0.1 equiv) were added to the resulting solution in this order,
and the mixture was stirred at rt for 3−6 h, until complete
consumption of the starting material according to TLC. It was then
poured onto iced water. The aqueous layer was extracted with pentane
(3 times), and the combined organic extracts were dried over MgSO4,
N-(Pent-4-en-1-yl)aniline (9i).
Aniline (0.36 mL, 4.0 mmol, 1.0 equiv) was dissolved in CH2Cl2 (12
mL), and the resulting solution was cooled to 0 °C. Et3N (0.83 mL,
6.0 mmol, 1.5 equiv) was added. Pentenoyl chloride (45) (0.44 mL;
4.0 mmol, 1.0 equiv) was then added dropwise, and the mixture was
allowed to warm to rt overnight. It was then diluted with CH2Cl2 (10
mL) and washed with aqueous HCl (1.0 M, 20 mL), aqueous NaOH
(1.0 M, 20 mL), water and brine, dried over MgSO4, filtered, and the
solvent was removed in vacuo. The resulting off-white solid (690 mg,
3.94 mmol, 98% yield) was used in the next step without further
purification.
Pentenamide 46 (683 mg, 3.90 mmol, 1.0 equiv) was dissolved in
THF (4.3 mL), and the solution was cooled to 0 °C. A suspension of
LiAlH4 (430 mg, 11.3 mmol, 2.9 equiv) in Et2O (11.3 mL) was added
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filtered, and the solvent removed by evaporation under reduced
31.3, 28.4, 22.5, 20.8, 14.0, −7.6. The values for the characterization of
6c correspond to the ones reported in literature.29
((5-Bromopent-4-yn-1-yl)oxy)(tert-butyl)diphenylsilane (6d).
pressure. The bromo alkyne was isolated by column chromatography
1
in 95−99% purity as judged by H NMR.
2-Bromo-1-triisopropylsilyl acetylene (4).
4-Pentyn-1-ol (49) (0.46 mL, 5.0 mmol) was dissolved in CH2Cl2 (10
mL), and the solution was cooled to 0 °C. After the addition of
imidazole (442 mg, 6.50 mmol, 1.3 equiv), tert-butyl diphenyl silyl
chloride (1.4 mL. 5.4 mmol, 1.1 equiv) was also added, dropwise. The
mixture was stirred and allowed to warm to rt overnight. The reaction
was then quenched by the addition of water (ca. 10 mL). The aqueous
layer was separated and extracted with CH2Cl2 (3 × 10 mL). The
combined organic extracts were dried over MgSO4, filtered, and the
solvent was removed in vacuo. Purification by column chromatography
(SiO2, Pentane/EtOAc 98/2) afforded the O-silylated pentynol 50 as a
Triisopropylsilylacetylene (48) (813 mg, 4.45 mmol, 1.00 equiv) was
brominated according to the general procedure. Bromoalkyne 4 was
obtained as a colorless oil (1.16 g, 4.43 mmol, 99%) without further
1
purification: H NMR (400 MHz, CDCl3) δ 1.20−0.97 (m, 21 H);
13C NMR (101 MHz, CDCl3) δ 83.5, 61.7, 18.5, 11.3. The values for
the characterization of 4 correspond to the ones reported in
literature.28
1-Bromooct-1-yne (6a).
1
colorless oil (1.33 g, 4.12 mmol, 82% yield): H NMR (400 MHz,
CDCl3) δ 7.67 (m, 4 H), 7.46−7.34 (m, 6 H), 3.75 (t, 2 H, J = 6.0
Hz), 2.35 (td, 2 H, J = 7.2, 2.6 Hz), 1.92 (t, 1 H, J = 2.6 Hz), 1.78
(ddd, 2 H, J = 13.1, 7.1, 6.0 Hz), 1.05 (s, 9 H).
1-Octyne (19) (3.0 mL, 20 mmol, 1.0 equiv) was brominated
according to the general procedure. After purification by column
chromatography (SiO2, pentane), bromoalkyne 6a was obtained as a
O-Silylated alcohol 50 (1.33 g. 4.12 mmol) was brominated
according to the general procedure. After purification by column
chromatography (SiO2, Pentane/EtOAc 98/2), bromoalkyne 6d was
obtained as a pale yellow oil (1.42 g, 3.54 mmol, 86% yield): 1H NMR
(400 MHz, CDCl3) δ 7.68 (m, 4 H), 7.47−7.34 (m, 6 H), 3.74 (t, 2 H,
J = 5.9 Hz), 2.38 (t, 2 H, J = 7.1 Hz), 1.76 (ddd, 2 H, J = 12.9, 6.7, 5.8
Hz), 1.06 (s, 9 H); 13C NMR (101 MHz, CDCl3) δ 135.5, 133.7,
129.6, 127.6, 79.9, 62.1, 37.8, 31.1, 26.8, 19.2, 16.2; IR 3070 (w), 3050
(w), 2954 (w), 2932 (w), 2931 (w), 2893 (w), 2857 (w), 1590 (w),
1470 (w), 1428 (w), 1389 (w), 1361 (w), 1189 (w), 1107 (s), 1063
(m), 1003 (w), 961 (w), 909 (w), 823 (w); HRMS (ESI) calcd for
C2179BrH26OSi+ [M + H]+ 401.0931, found 401.0943.
1
colorless oil (3.33 g, 17.6 mmol, 88% yield): Rf 0.91 (Hexane); H
NMR (400 MHz, CDCl3) δ 2.20 (t, 2 H, J = 7.0 Hz), 1.51 (quint, 2 H,
J = 6.4 Hz), 1.42−1.33 (quint, 2 H, J = 7.1 Hz), 1.33−1.22 (m, 4 H)
0.89 (t, 3 H, J = 6.7 Hz); 13C NMR (101 MHz, CDCl3) δ 80.5, 37.4,
31.3, 28.5, 28.3, 22.5, 19.7, 14.0. The values for the characterization of
6a correspond to the ones reported in literature.29
1-Chlorooct-1-yne (6b).
(5-Bromopent-4-yn-1-yl)benzene (6e).
Following a slightly modified version of a reported procedure,15g N-
Chlorosuccinimide (641 mg, 4.80 mmol, 1.20 equiv) and AgOAc (67.0
mg, 0.400 mmol, 0.10 equiv) were added in this order to a solution of
1-octyne (19) (0.60 mL; 4.0 mmol, 1.0 equiv) in acetone (16.0 mL),
and the solution was heated to reflux overnight. The mixture was
poured onto ice, and the resulting aqueous layer was extracted with
pentane (3 × 20 mL). The combined organic layers were washed with
brine, dried over MgSO4, filtered, and the solvent was removed in
vacuo. Purification by column chromatography (SiO2, Pentane)
afforded chloro alkyne 6b as a smelly colorless oil (577 mg, 3.99
mmol, quantitative): 1H NMR (400 MHz, CDCl3) δ 2.16 (t, 2 H, J =
7.0 Hz), 1.50 (quint, J = 6.9 Hz, 2 H), 1.43−1.24 (m, 6 H), 0.89 (t, 3
H, J = 6.7 Hz); 13C NMR (101 MHz, CDCl3) δ 69.7, 56.9, 31.3, 28.5,
28.4, 22.5, 18.8, 14.0. The values for the characterization of 6b
correspond to the ones reported in literature.30
Pent-4-yn-1-ylbenzene (51) (0.76 mL, 5.0 mmol, 1.0 equiv) was
brominated according to the general procedure. After purification by
column chromatography (SiO2, pentane), bromo alkyne 6e was
obtained as a pale yellow oil (1.05 g, 4.71 mmol, 94% yield): Rf 0.38
(Hexane); 1H NMR (400 MHz, CDCl3) δ 7.33−7.28 (m, 2 H), 7.24−
7.19 (m, 3 H), 2.73 (t, 2 H, J = 7.5 Hz), 2.24 (t, 2 H, J = 7.0 Hz), 1.86
(m, 2 H); 13C NMR (101 MHz, CDCl3) δ 141.3, 128.5, 128.3, 125.9,
79.9, 38.1, 34.7, 29.8, 19.1. The values for the characterization of 6e
correspond to the ones reported in literature.29
1-Bromo-5-chloropent-1-yne (6f).
1-Iodooct-1-yne (6c).
5-Chloropent-1-yne (52) (0.53 mL, 5.0 mmol, 1.0 equiv) was
brominated according to the general procedure. After purification by
column chromatography (SiO2, Pentane), bromoalkyne 6f was
obtained as a colorless oil (805 mg, 4.44 mmol, 89% yield): Rf 0.38
Following a reported procedure,15b a solution of 1-octyne (19) (0.60
mL, 4.0 mmol, 1.00 equiv) in THF (6.5 mL) was cooled to −78 °C,
and nBuLi (2.5 M in hexanes, 1.7 mL, 4.2 mmol, 1.0 equiv) was added
dropwise. The solution was stirred at −78 °C for 15 min and then at 0
°C for 5 min; it was then cooled back to −78 °C, and a solution of
iodine (1.12 g, 4.40 mmol, 1.10 equiv) in THF (6.5 mL) was added
dropwise. The mixture was stirred at rt for 2 h and then diluted with
Et2O and quenched with brine (ca. 15 mL). The organic layer was
separated, washed with aqueous Na2S2O3 (saturated solution, 15 mL),
dried over MgSO4, filtered, and the solvent was removed in vacuo.
Purification by column chromatography (SiO2, Pentane/Et2O 98/2)
afforded iodo alkyne 6c as a smelly colorless oil (932 mg, 3.95 mmol,
1
(Hexane); H NMR (400 MHz, CDCl3) δ 3.64 (t, 2 H, J = 6.3 Hz),
2.41 (t, 2 H, J = 6.8 Hz), 1.97 (quint, 2 H, J = 6.5 Hz); 13C NMR (101
MHz, CDCl3) δ 78.4, 43.4, 39.0, 31.0, 17.1; IR 3000 (w), 2961 (m),
2915 (w), 2914 (w), 2873 (w), 2844 (w), 2843 (w), 2219 (w), 2218
(w), 1455 (w), 1442 (s), 1433 (s), 1354 (w), 1329 (w), 1309 (m),
1290 (s), 1111 (w), 1041 (w), 1040 (w), 1034 (w), 1033 (w), 991
(w), 990 (w), 972 (w), 945 (w), 911 (w), 854 (m). Anal. Calcd. for
C5H6ClBr: C, 33.09%; H, 3.33%. Found: C, 33.13%; H, 3.06%.
(7-Bromohepta-1,6-diyn-1-yl)triisopropylsilane (6g).
1
99%): H NMR (400 MHz, CDCl3) δ 2.35 (t, 2 H, J = 7.0 Hz), 1.50
(quint, J = 7.0 Hz, 2 H), 1.41−1.31 (m, 2 H), 1.33−1.23 (m, 4 H),
0.89 (t, 3 H, J = 6.8 Hz); 13C NMR (101 MHz, CDCl3) δ 94.8, 65.8,
K
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Following a reported procedure,15e 1,6-heptadiyne (53) (0.62 mL, 5.4
mmol, 1.0 equiv) was dissolved in THF (8.0 mL), and the solution was
cooled to −78 °C. A 1.0 M solution of LHMDS in THF (freshly
prepared by treating HMDS (5.3 mmol) with nBuLi (2.5 M in
hexanes, 2.1 mL, 5.3 mmol, 0.98 equiv) was added dropwise over 15
min, and the resulting mixture was stirred at −78 °C for 40 min.
Triisopropyl silyl chloride (1.15 mL, 5.40 mmol, 1.0 equiv) was added
dropwise over 1.5 h at the same temperature and was then warmed to
rt during 3 h. The reaction was quenched by addition of water (10
mL), and the aqueous layer was extracted with Et2O (3 × 15 mL). The
combined organic extracts were washed with aqueous HCl (1.0 M, 10
mL), dried over MgSO4, filtered and concentrated in vacuo. The crude
oil was purified by column chromatography (SiO2, pentane) to furnish
monosilylated diyne 54 as a colorless oil (640 mg, 2.78 mmol, 48%
yield).
Monosilylated diyne 54 (640 mg, 2.78 mmol) was brominated
according to the general procedure, but using 1.3 equiv of NBS (594
mg, 3.34 mmol) and 0.3 equiv of AgNO3 (131 mg, 0.771 mmol). After
purification by column chromatography (SiO2, pentane), bromo
alkyne 6g was obtained as a colorless oil (803 g, 2.45 mmol, 95%
yield): 1H NMR (400 MHz, CDCl3) δ 2.36 (t, 2 H, J = 7.0 Hz), 2.36
(t, 2 H, J = 7.3 Hz), 1.74 (quint, 2 H, J = 7.0 Hz), 1.10−1.02 (m, 21
H); 13C NMR (101 MHz, CDCl3) δ 107.5, 81.1, 79.3, 38.3, 27.6, 19.0,
18.7, 18.6, 11.3; IR 2942 (s), 2893 (m), 2865 (s), 2721 (w), 2172 (m),
1464 (s), 1431 (m), 1384 (w), 1362 (w), 1343 (w), 1326 (w), 1311
(w), 1290 (w), 1241 (w), 1213 (w), 1135 (w), 1070 (w), 1044 (m),
1019 (m), 995 (m), 919 (w), 883 (s), 840 (w); HRMS (ESI) calcd for
C16H2779BrSi+ [M]+ 326.1065, found 326.1058.
organic layers were washed with H2O, dried over MgSO4, filtered, and
the solvent was removed in vacuo. Purification by column
chromatography (SiO2, pentane) afforded TIPS-protected propargyl
alcohol 56 as a colorless oil (622 mg, 2.59 mmol, 74% yield), which
was used directly for the next step.
Propargyl alcohol 56 (603 mg, 2.51 mmol, 1.0 equiv) was
brominated according to the general procedure. After purification by
column chromatography (SiO2, pentane), bromoalkyne 6i was
obtained as a colorless oil (733 mg, 2.30 mmol, 91% yield): Rf 0.91
1
(Hexane); H NMR (400 MHz, CDCl3) δ 1.51 (s, 6 H), 1.18−1.03
(m, 21 H); 13C NMR (101 MHz, CDCl3) δ 85.4, 67.2, 42.7, 32.9, 18.3,
13.0; IR 2982 (w), 2962 (w), 2961 (w), 2943 (m), 2892 (w), 2866
(m), 2214 (w), 1748 (w), 1741 (w), 1740 (w), 1724 (w), 1464 (m),
1379 (w), 1361 (w), 1230 (m), 1205 (w), 1164 (s), 1050 (s), 1016
(w), 997 (w), 996 (w), 953 (w), 937 (w), 909 (m), 882 (s), 842 (w);
HRMS (APPI) calcd for C1479BrH27OSi+ [M]+ 318.1009, found
318.1011.
(((1-Bromonon-1-yn-3-yl)oxy)methyl)benzene (6j).
Following a slightly modified reported procedure,15d heptaldehyde
(57) (1.22 mL, 8.76 mmol, 1.0 equiv) was added dropwise to a
solution of ethynyl magnesium bromide (0.5 M in THF, 22.8 mL, 11.4
mmol, 1.3 equiv) at 0 °C. After 30 min, the cooling bath was removed
to reach rt, and the solution was stirred for further 2 h. The reaction
was then quenched by addition of aqueous HCl (1.0 M, 15 mL), and
the mixture was extracted with Et2O (3 × 20 mL). The combined
organic layers were washed with brine, dried over MgSO4, filtered, and
the solvent was removed in vacuo. Purification by column
chromatography (SiO2, pentane/EtOAc 20/1) afforded the corre-
sponding propargyl alcohol as a yellow oil (943 mg, 6.73 mmol, 77%
yield).
(((4-Bromo-2-methylbut-3-yn-2-yl)oxy)methyl)benzene (6h).
Following a reported procedure,15c NaH (60% suspension in mineral
oil, 240 mg, 6.00 mmol, 1.2 equiv) was added portionwise to a solution
of 2-methyl-3-butyn-2-ol (55) (0.49 mL, 5.0 mmol, 1.0 equiv) in THF
(24 mL). The mixture was stirred at rt for 1 h, and then TBAI (92.0
mg, 0.250 mmol, 0.050 equiv) and benzyl bromide (0.72 mL, 6.0
mmol, 1.2 equiv) were added in this order. The reaction mixture was
stirred at rt overnight and then diluted with Et2O (18 mL). The
organic solution was washed with water (3 × 15 mL), brine and dried
over MgSO4. Upon filtration, it was concentrated by evaporation
under reduced pressure, and the resulting crude oil was purified by
column chromatography (SiO2, Pentane/Et2O 95/5) to afford the
pure O-benzylated alcohol 15 as a colorless oil (715 mg, 4.10 mmol,
82% yield), which was directly used in the next step.
Following a reported procedure,15c the propargyl alcohol (701 mg,
5.00 mmol, 1.0 equiv) was added dropwise to a suspension of NaH
(168 mg, 7.00 mmol, 1.4 equiv) in THF (24 mL). The solution was
stirred for 2 h, and then TBAI (92.3 mg, 0.250 mmol, 0.05 equiv) and
benzyl bromide (0.84 mL, 7.0 mmol, 1.4 equiv) were added
sequentially. The resulting mixture was stirred overnight and then
quenched by slow addition of H2O. The aqueous layer was extracted
with Et2O (3 × 40 mL), and the combined organic layers were washed
with brine, dried over MgSO4, filtered, and the solvent was removed in
vacuo. Purification by column chromatography (SiO2, pentane/EtOAc
20/1) afforded the O-benzylated propargyl alcohol 58 as a yellow oil
(1.12 mg, 4.86 mmol, 97% yield).
Propargyl alcohol 58 (1.12 g, 4.86 mmol, 1.0 equiv) was brominated
according to the general procedure. After purification by column
chromatography (SiO2, Pentane/EtOAc 98/2), bromoalkyne 6j was
obtained as a pale yellow oil (1.06 g, 3.43 mmol, 71% yield): Rf 0.66
O-Benzylated alcohol 15 (523 mg, 3.00 mmol) was brominated
according to the general procedure. After purification by column
chromatography (SiO2, Pentane/EtOAc 98/2), bromoalkyne 6h was
1
obtained as a pale yellow oil (631 mg, 2.49 mmol, 83% yield): H
1
(Hexane/EtOAc 10/1); H NMR (400 MHz, CDCl3) δ 7.37−7.27
NMR (400 MHz, CDCl3) δ 7.41−7.31 (m, 4 H), 7.27 (m, 1 H), 4.62
(s, 2 H), 1.55 (s, 6 H); 13C NMR (101 MHz, CDCl3) δ 138.7, 128.3,
127.7, 127.4, 82.4, 71.7, 66.7, 44.1, 28.7; IR 3065 (w), 3031 (w), 2985
(w), 2934 (w), 2864 (w), 2210 (w), 1496 (w), 1454 (w), 1436 (w),
1382 (w), 1361 (w), 1235 (m), 1186 (m), 1157 (s), 1086 (m), 1055
(s), 1030 (m), 1003 (w), 960 (w), 894 (w); HRMS (ESI) calcd for
C12H1379BrO+ [M]+ 252.0150, found 252.0144.
(m, 5 H), 4.78 (d, 1 H, J = 11.7 Hz), 4.49 (d, 1 H, J = 11.7 Hz), 4.09
(t, 1 H, J = 6.6 Hz), 1.74 (ddd, 2 H, J = 13.2, 6.6, 2.0 Hz), 1.44 (m, 2
H), 1.35−1.25 (m, 6 H), 0.88 (t, 3 H, J = 6.7 Hz); 13C NMR (101
MHz, CDCl3) δ 137.8, 128.4, 128.0, 127.7, 79.5, 70.7, 69.6, 45.1, 35.6,
31.7, 28.9, 25.2, 22.6, 14.1; IR 3031 (w), 2953 (s), 2928 (s), 2857 (s),
2207 (w), 1726 (w), 1725 (w), 1705 (w), 1497 (w), 1456 (s), 1391
(w), 1377 (w), 1333 (m), 1206 (w), 1120 (w), 1092 (s), 1071 (s),
1029 (m), 990 (w), 910 (w), 846 (w); HRMS (ESI) calcd for
C1679BrH22O+ [M + H]+ 309.0849, found 309.0857.
((4-Bromo-2-methylbut-3-yn-2-yl)oxy)triisopropylsilane (6i).
((1-Bromonon-1-yn-3-yl)oxy)triisopropylsilane (6k).
Following a reported procedure,15h 2-methylbut-3-yn-2-ol (55) (0.34
mL, 3.5 mmol, 1.0 equiv) and 2,6-lutidine (freshly distilled on CaH2,
0.41 mL, 3.5 mmol, 1.0 equiv) were dissolved in CH2Cl2 (12 mL).
TIPSOTf (0.94 mL, 3.5 mmol, 1.0 equiv) was added dropwise to the
solution at 0 °C. The solution was allowed to warm to rt overnight and
then quenched with a saturated aqueous NaHCO3 solution, and the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined
Following a slightly modified reported procedure,15d heptaldehyde
(57) (1.22 mL, 8.76 mmol, 1.0 equiv) was added dropwise to a
solution of ethynyl magnesium bromide (0.5 M in THF, 22.8 mL, 11.4
mmol, 1.3 equiv) at 0 °C. After 30 min, the cooling bath was removed
to reach rt, and the solution was stirred for further 2 h. The reaction
L
dx.doi.org/10.1021/jo400254q | J. Org. Chem. XXXX, XXX, XXX−XXX

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was then quenched by addition of aqueous HCl (1.0 M, 15 mL), and
the mixture was extracted with Et2O (3 × 20 mL). The combined
organic layers were washed with brine, dried over MgSO4, filtered, and
the solvent was removed in vacuo. Purification by column
chromatography (SiO2, pentane/EtOAc 20/1) afforded the corre-
sponding propargyl alcohol as a yellow oil (943 mg, 6.73 mmol, 77%
yield).
28.1, 28.0, 19.6; IR 2951 (m), 2929 (m), 2900 (w), 2856 (m), 1599
(w), 1490 (w), 1471 (w), 1464 (w), 1442 (w), 1433 (w), 1433 (w),
1407 (w), 1389 (w), 1389 (w), 1361 (w), 1361 (w), 1352 (w), 1254
(m), 1223 (w), 1189 (w), 1105 (s), 1071 (m), 1029 (w), 1007 (w),
1007 (w), 982 (w), 954 (w), 912 (w), 835 (s), 816 (w). Anal. Calcd.
for C9H14Br2: C, 38.33%; H, 5.00%. Found: C, 38.69%; H, 5.08%.
General Procedure for the Oxy- and Aminoalkynylation
Reaction. Under inert atmosphere, Pd(dba)2 (11.5 mg, 0.0200 mmol,
0.05 equiv), DPEPHos (16.1 mg, 0.0300 mmol, 0.075 equiv) and
NaOtBu (50.0 mg, 0.520 mmol, 1.3 equiv) were introduced into a 5
mL vial, which was then sealed. Toluene was added (4.6 mL), followed
by the bromo acetylene (0.520 mmol, 1.3 equiv) and the starting
material (0.40 mmol, 1.0 equiv). The mixture was stirred at 80 °C for
3 h and then allowed to cool to room temperature. The solvent was
evaporated under reduced pressure. The crude mixture was then
directly purified by column chromatography (SiO2, pentane/EtOAc
98/2 to 96/4).
General Procedure for the Deprotection of 2-Propargyl N-
Boc Pyrrolidines. The N-Boc pyrrolidines 10 (1.0 equiv) is dissolved
in CH2Cl2 (20 mL per mmol of protected pyrrolidine), and the
resulting solution is cooled to 0 °C. Trifluoroacetic acid (10 mL per
mmol of protected pyrrolidine) was added dropwise, and the mixture
was stirred at 0 °C for 40 min. The volatiles were then removed by
distillation under reduced pressure. The residue was taken up in
CH2Cl2, and the solution as washed with aqueous NaOH (2 M, three
times). The combined organic layers were dried over Na2SO4, filtered
and concentrated under reduced pressure.
TIPSCl (1.36 mL, 6.36 mmol, 1.1 equiv) and DMAP (777 mg, 6.36
mmol, 1.1 equiv) were dissolved in CH2Cl2 (10 mL) at rt and a
solution of propargyl alcohol (810 mg, 5.78 mmol, 1.0 equiv) in
CH2Cl2 (30 mL) was slowly added to the reaction mixture. The
reaction was stirred overnight and then quenched by sequential
addition of H2O (36 mL) and aqueous HCl (2.0 M, 36 mL). The
mixture was extracted with CH2Cl2 (3 × 20 mL), and the combined
organic layers were washed with brine, dried over MgSO4, filtered, and
the solvent was removed in vacuo. Purification by column
chromatography (SiO2, Pentane) afforded the O-silylated propargyl
alcohol 59 as a colorless oil (1.04 g, 3.51 mmol, 61% yield).
O-Silylated propargyl alcohol 59 (890 mg, 3.00 mmol, 1.0 equiv)
was brominated according to the general procedure. After purification
by column chromatography (SiO2, pentane), bromo alkyne 6k was
obtained as a colorless oil (1.04 g, 2.77 mmol, 92% yield): Rf 0.63
1
(Hexane); H NMR (400 MHz, CDCl3) δ 4.48 (t, 1 H, J = 6.3 Hz),
1.69 (m, 2 H), 1.44 (m, 2 H), 1.36−1.26 (m, 6 H), 1.17−1.04 (m, 21
H), 0.89 (t, J = 6.7 Hz); 13C NMR (101 MHz, CDCl3) δ 82.1, 64.0,
43.6, 38.7, 31.8, 29.0, 24.9, 22.6, 18.0, 18.0, 14.1, 12.3; IR 2942 (s),
2928 (s), 2894 (m), 2866 (s), 2212 (w), 1598 (w), 1597 (w), 1597
(w), 1596 (w), 1592 (w), 1591 (w), 1464 (m), 1383 (w), 1367 (w),
1339 (w), 1260 (w), 1259 (w), 1119 (m), 1096 (s), 1067 (s), 1014
(m), 998 (m), 971 (w), 920 (w), 883 (s); HRMS (ESI) calcd for
C1879BrH36OSi+ [M + H]+ 375.1713, found 375.1724.
2-(Non-2-yn-1-yl)tetrahydrofuran (7aa). The title compound was
prepared from 4-penten-1-ol (5a) (34.4 mg, 0.400 mmol) and octynyl
bromide (6a) (98.0 mg, 0.521 mmol). It was obtained as a colorless oil
1
(56.4 mg, 0.291 mmol, 69% yield): Rf 0.54 (Hexane/EtOAc 5/1); H
NMR (400 MHz, CDCl3) δ 3.99 (ddd, 1 H, J = 12.2, 6.7, 6.7 Hz), 3.90
(ddd, 1 H, J = 8.2, 7.0, 7.0 Hz), 3.76 (ddd, 1 H, J = 7.7, 7.7, 6.4 Hz),
2.43 (ddt, 1 H, J = 16.4, 5.1, 2.4 Hz), 2.33 (ddt, 1 H, J = 16.4, 6.7, 2.4
Hz), 2.15 (tt, 2 H, J = 7.0, 2.4 Hz), 2.02 (m, 1 H), 1.90 (m, 2 H), 1.69
(ddt, 1 H, J = 12.0, 8.7, 7.0 Hz), 1.48 (quint, 2 H, J = 7.0 Hz), 1.41−
1.21 (m, 6 H), 0.88 (t, 3 H, J = 6.8 Hz); 13C NMR (101 MHz, CDCl3)
δ 81.6, 77.7, 76.5, 68.4, 31.3, 30.7, 29.0, 28.5, 25.7, 25.6, 22.5, 18.8,
14.0; IR 2956 (m), 2928 (m), 2857 (m), 1690 (w), 1460 (w), 1436
(w), 1435 (w), 1378 (w), 1369 (w), 1183 (w), 1110 (w), 1069 (s),
920 (w), 877 (w), 844 (w), 831 (w), 816 (w); HRMS (ESI) calcd for
C13H23O+ [M + H]+ 195.1743, found 195.1741.
tert-Butyldiphenyl((6-(tetrahydrofuran-2-yl)hex-4-yn-1-yl)oxy)-
silane (7ad). The title compound was prepared from 4-penten-1-ol
(5a) (34.4 mg, 0.400 mmol) and alkynyl bromide 6d (208 mg, 0.519
mmol). It was obtained as a colorless oil (109 mg, 0.269 mmol, 67%
yield): Rf 0.49 (Hexane/EtOAc 5/1); 1H NMR (400 MHz, CDCl3) δ
7.67 (m, 4 H), 7.45−7.34 (m, 6 H), 3.95 (ddd, 1 H, J = 12.3, 6.7, 6.7
Hz), 3.88 (m, 1 H), 3.78−3.70 (m, 1 H), 3.73 (t, 2 H, J = 6.1 Hz), 2.40
(ddd, 1 H, J = 13.7, 5.3, 2.3 Hz), 2.34−2.26 (m, 3 H), 1.98 (m, 1 H),
1.94−1.80 (m, 2 H), 1.74 (quint, 2 H, J = 6.7 Hz), 1.63 (dddd, 1 H, J
= 12.3, 8.8, 7.0, 7.0 Hz), 1.05 (s, 9 H); 13C NMR (101 MHz, CDCl3)
δ 135.9, 134.2, 129.8, 127.9, 81.3, 78.0, 77.1, 68.7, 62.9, 32.2, 31.0,
27.1, 26.0, 25.9, 19.5, 15.7; IR 3070 (w), 3049 (w), 3026 (w), 3015
(w), 2997 (w), 2953 (w), 2931 (m), 2857 (w), 1590 (w), 1488 (w),
1473 (w), 1463 (w), 1446 (w), 1429 (m), 1390 (w), 1361 (w), 1189
(w), 1140 (w), 1108 (s), 1068 (s), 1032 (w), 1009 (w), 999 (w), 975
(w), 963 (w), 938 (w), 911 (m), 910 (m), 823 (m); HRMS (ESI)
calcd for C26H35O2Si+ [M + H]+ 407.2401, found 407.2385.
1,9-Dibromonon-1-yne (6l).
Following a reported procedure,15f NaH (60% suspension in mineral
oil, 1.28 g, 32.0 mmol, 4.0 equiv) was added to ethylene diamine
(freshly distilled from KOH, 14.4 mL), and the resulting mixture was
stirred at rt for 1 h. During this time, it became brown, and after being
stirred at 60 °C during an additional hour, it finally converted into a
turbid violet solution. It was then cooled to 40 °C, and 3-nonyn-1-ol
(60) (1.27 mL, 8.00 mmol, 1.0 equiv) was added dropwise. The
mixture was then heated back to 60 °C and stirred at this temperature
for 2 h. After this time, the mixture was allowed to cool down to rt,
and aqueous HCl (1.0 M, 15 mL) was added. The aqueous layer was
separated and extracted with Et2O (3 × 20 mL). The combined
organic extracts were dried over MgSO4, filtered and concentrated in
vacuo. The crude oil was purified by column chromatography (SiO2,
Pentane/EtOAc 95/5 to 70/30) to furnish 8-nonyn-1-ol (61) as a
yellow oil (856 mg, 6.10 mmol, 76% yield), which was used directly in
the next step.
Alcohol 61 (280 mg, 2.00 mmol, 1.0 equiv) was dissolved in
acetonitrile (6.8 mL). Triphenyl phosphine (787 mg, 3.00 mmol, 1.5
equiv) and tetrabromo methane (997 mg, 3.00 mmol, 1.5 equiv) were
added in this order, and the mixture was stirred at rt for 1 h. The
reaction was quenched by addition of aqueous NaOH (15% w/w)
until pH 9, and the aqueous layer was extracted with Et2O (3 × 10
mL). The combined organic extracts were dried over MgSO4, filtered
and concentrated in vacuo. The crude oil was purified by column
chromatography (SiO2, Pentane/EtOAc 95/5) to furnish the
corresponding alkyl bromide as a yellow oil (404 mg, 1.99 mmol,
quantitative), which was used directly in the following step.
2-(6-Phenylhex-2-yn-1-yl)tetrahydrofuran (7ae). The title com-
pound was prepared from 4-penten-1-ol (5a) (34.4 mg, 0.400 mmol)
and alkynyl bromide 6e (116 mg, 0.520 mmol). It was obtained as a
pale yellow oil (58.0 mg, 0.254 mmol, 64% yield): Rf 0.67 (Hexane/
1
The obtained alkyl bromide (404 mg, 1.99 mmol) was brominated
according to the general procedure. After purification by column
chromatography (SiO2, pentane), dibromo alkyne 6l was obtained as a
EtOAc 5/1); H NMR (400 MHz, CDCl3) δ 7.28 (m, 2 H), 7.21−
7.16 (m, 3 H), 4.01 (ddd, 1 H, J = 13.5, 6.7, 5.5 Hz), 3.92 (ddd, 1 H, J
= 8.2, 7.0, 6.4 Hz), 3.77 (ddd, 1 H, J = 8.1, 7.5, 6.3 Hz), 2.72 (t, 2 H, J
= 7.5 Hz), 2.46 (dddd, 1 H, J = 16.4, 5.4, 2.4, 2.4 Hz), 2.37 (dddd, 1 H,
J = 16.4, 6.7, 2.4, 2.4 Hz), 2.22−2.16 (m, 2 H), 2.05 (m, 1 H), 1.99−
1.86 (m, 2 H), 1.81 (quint, 2 H, J = 6.9 Hz), 1.72 (m, 1 H); 13C NMR
(101 MHz, CDCl3) δ 141.8, 128.5, 128.3, 125.8, 81.0, 77.6, 77.2, 68.4,
1
colorless oil (422 g, 1.49 mmol, 75% yield): Rf 0.44 (Hexane); H
NMR (400 MHz, CDCl3) δ 3.41 (t, 2 H, J = 6.8 Hz), 2.21 (t, 2 H, J =
6.9 Hz), 1.86 (quint, 2 H, J = 6.5 Hz), 1.52 (m, 2 H), 1.47−1.28 (m, 6
H); 13C NMR (101 MHz, CDCl3) δ 80.3, 37.6, 33.9, 32.7, 28.5, 28.2,
M
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The Journal of Organic Chemistry
Article
34.8, 30.7, 30.6, 25.7, 25.6, 18.3; IR 3025 (w), 2973 (w), 2943 (w),
2942 (w), 2929 (w), 2909 (w), 2903 (w), 2885 (w), 2884 (w), 2863
(w), 1603 (w), 1496 (w), 1455 (w), 1434 (w), 1408 (w), 1394 (w),
1370 (w), 1332 (w), 1313 (w), 1251 (w), 1243 (w), 1234 (w), 1233
(w), 1179 (w), 1067 (s), 1032 (w), 1014 (w), 1013 (w), 1009 (w),
996 (w), 984 (w), 967 (w), 945 (w), 911 (w), 880 (w), 873 (w), 844
(w), 838 (w), 832 (w); HRMS (ESI) calcd for C16H21O+ [M + H]+
229.1587, found 229.1586.
2-(6-Chlorohex-2-yn-1-yl)tetrahydrofuran (7af). The title com-
pound was prepared from 4-penten-1-ol (5a) (34.4 mg, 0.400 mmol)
and alkynyl bromide 6f (94.4 mg, 0.520 mmol). It was obtained as a
pale yellow oil (41.5 mg, 0.222 mmol, 56% yield): Rf 0.53 (Hexane/
EtOAc 5/1); 1H NMR (400 MHz, CDCl3) δ 3.98 (quint, 1 H, J = 6.5
Hz), 3.90 (ddd, 1 H, J = 8.5, 7.0, 7.0 Hz), 3.76 (ddd, 1 H, J = 7.5, 6.5,
6.5 Hz), 3.64 (t, 2 H, J = 6.5 Hz), 2.45−2.30 (m, 4 H), 2.03 (m, 1 H),
1.97−1.82 (m, 2 H), 1.92 (quint, 2 H, J = 6.5 Hz), 1.65 (m, 1 H); 13C
NMR (101 MHz, CDCl3) δ 79.4, 77.8, 77.5, 68.4, 43.7, 31.6, 30.7,
25.7, 25.5, 16.2; IR 2961 (w), 2953 (w), 2952 (w), 2951 (w), 2926
(w), 2914 (w), 2869 (w), 1457 (w), 1441 (w), 1435 (w), 1369 (w),
1358 (w), 1357 (w), 1331 (w), 1330 (w), 1307 (w), 1292 (w), 1272
(w), 1110 (w), 1067 (s), 1009 (w), 987 (w), 972 (w), 971 (w), 913
(m), 861 (w); HRMS (ESI) calcd for C1037ClH16O+ [M + H]+
187.0884, found 187.0889.
Triisopropyl(8-(tetrahydrofuran-2-yl)octa-1,6-diyn-1-yl)silane
(7ag). The title compound was prepared from 4-penten-1-ol (5a)
(34.4 mg, 0.400 mmol) and alkynyl bromide 6g (170 mg, 0.520
mmol). It was obtained as a pale yellow oil (76.7 mg, 0.230 mmol,
59% yield): Rf 0.34 (Hexane/EtOAc 20/1); 1H NMR (400 MHz,
CDCl3) δ 3.98 (ddd, 1 H, J = 12.2, 6.5, 6.5 Hz), 3.89 (dd, 1 H, J =
14.7, 7.0 Hz), 3.75 (dd, 1 H, J = 14.0, 7.4 Hz), 2.42 (m, 1 H), 2.26−
2.38 (m, 5 H), 2.02 (m, 1 H), 1.90 (m, 2 H), 1.75−1.64 (m, 1 H), 1.70
(quint, J = 7.0 Hz), 0.97−1.13 (m, 21 H); 13C NMR (101 MHz,
CDCl3) δ 108.1, 80.7, 80.5, 77.6, 77.3, 68.4, 30.7, 28.3, 25.7, 25.6, 19.0,
18.6, 17.9, 11.3; IR 2942 (s), 2865 (s), 2361 (w), 2172 (m), 2172 (m),
1684 (w), 1683 (w), 1462 (m), 1374 (w), 1336 (w), 1320 (w), 1070
(s), 999 (w), 921 (w), 883 (m); HRMS (APPI) calcd for C21H36OSi+
[M]+ 332.2535, found 332.2532.
as a pale yellow oil (79.6 mg, 0.253 mmol, 63% yield; inseparable
mixture of diastereoisomers, d.r. 1/1; the differentiation between the
two diastereoisomers is only visible in 13C NMR spectrum): Rf 0.62
(Hexane/EtOAc 5/1); 1H NMR (400 MHz, CDCl3) δ 7.41−7.31 (m,
4 H), 7.28 (m, 1 H), 4.79 (d, 1 H, J = 11.8 Hz), 4.51 (d, 1 H, J = 11.8
Hz), 4.12−4.01 (m, 3 H), 3.92 (ddd, 1 H, J = 7.6, 6.7, 6.7 Hz), 3.78
(dd, 1 H, J = 14.1, 7.4 Hz), 2.56 (ddd, 1 H, J = 16.5, 4.9, 1.8 Hz), 2.44
(dddd, 1 H, J = 16.5, 7.1, 0.9, 0.9 Hz), 2.06 (m, 1 H), 2.01−1.84 (m, 2
H), 1.81−1.66 (m, 3 H), 1.55−1.38 (m, 2 H), 1.40−1.22 (m, 6 H),
0.83 (m, 3 H); 13C NMR (101 MHz, CDCl3) δ 138.2, 128.2, 127.9,
127.5, 82.7, 80.5, 80.5, 77.2, 70.2, 68.9, 68.4, 36.0, 31.7, 30.7, 28.9,
25.7, 25.5, 25.3, 22.5, 14.0; IR 3062 (w), 3027 (w), 2927 (m), 2914
(m), 2908 (m), 2867 (m), 1690 (w), 1651 (w), 1645 (w), 1634 (w),
1624 (w), 1604 (w), 1586 (w), 1557 (w), 1543 (w), 1496 (m), 1454
(s), 1430 (m), 1406 (m), 1381 (w), 1357 (w), 1341 (w), 1249 (w),
1199 (w), 1186 (w), 1156 (m), 1080 (m), 1059 (s), 1031 (m), 1002
(w), 960 (w), 911 (w), 875 (w), 840 (w), 834 (w), 823 (w), 812 (w);
+
HRMS (ESI) calcd for C21H31O2 [M + H]+ 315.2319, found
315.2320.
Triisopropyl((1-(tetrahydrofuran-2-yl)dec-2-yn-4-yl)oxy)silane
(7ak). The title compound was prepared from 4-penten-1-ol (5a)
(34.4 mg, 0.400 mmol) and alkynyl bromide 6k (199 mg, 0.520
mmol). It was obtained as a pale yellow oil (118 mg, 0.310 mmol, 78%
yield; inseparable mixture of diastereoisomers, d.r. 1/1; the differ-
entiation between the two diastereoisomers is only visible in 13C NMR
spectrum): Rf 0.77 (Hexane/EtOAc 5/1); 1H NMR (400 MHz,
CDCl3) δ 4.44 (m, 1 H), 3.99 (ddd, 1 H, J = 13.9, 7.0, 4.7 Hz), 3.88
(m, 1 H), 3.75 (ddd, 1 H, J = 8.2, 7.4, 6.3 Hz), 2.50 (ddd, 1 H, J = 4.6,
2.0, 2.0 Hz), 2.33 (ddd, J = 4.6, 2.0, 2.0 Hz), 2.04 (m, 1 H), 1.98−1.81
(m, 2 H), 1.72 (m, 1 H), 1.69−1.62 (m, 2 H), 1.49−1.38 (m, 2 H),
1.36−1.21 (m, 6 H), 1.18−1.03 (m, 21 H), 0.89 (t, 3 H, J = 6.7 Hz);
13C NMR (101 MHz, CDCl3, resolved signals corresponding to
different diastereoisomers are reported in italics)31 δ 83.5, 83.5, 80.7,
68.4, 68.3, 63.2, 39.2, 31.8, 30.7, 29.1, 25.7, 25.7, 25.6, 25.6, 25.0, 22.6,
18.1, 18.0, 14.1; IR 2942 (s), 2895 (m), 2865 (s), 1464 (m), 1383 (w),
1383 (w), 1367 (w), 1341 (w), 1256 (w), 1250 (w), 1151 (w), 1089
(s), 1070 (s), 1014 (w), 998 (w), 920 (w), 883 (m).); HRMS (ESI)
calcd for C23H45O2Si+ [M + H]+ 381.3183, found 381.3196.
2-(4-(Benzyloxy)-4-methylpent-2-yn-1-yl)tetrahydrofuran (7ah).
The title compound was prepared from 4-penten-1-ol (5a) (34.4
mg, 0.400 mmol) and alkynyl bromide 6h (132 mg, 0.520 mmol). It
was obtained as a pale yellow oil (87.5 mg, 0.338 mmol, 85% yield): Rf
0.53 (Hexane/EtOAc 5/1); 1H NMR (400 MHz, CDCl3) δ 7.44−7.33
(m, 4 H), 7.29 (m, 1 H), 4.66 (s, 2 H), 4.06 (ddd, 1 H, J = 13.7, 6.9,
4.9 Hz), 3.94 (ddd, 1 H, J = 8.2, 7.0, 7.0 Hz), 3.80 (ddd, 1 H, J = 7.4,
7.4, 6.4 Hz), 2.56 (dd, 1 H, J = 16.5, 4.8 Hz), 2.45 (dd, 1 H, J = 16.5,
7.2 Hz), 2.08 (m, 1 H), 2.02−1.85 (m, 2 H), 1.77 (ddt, J = 12.0, 8.8,
7.0 Hz), 1.56 (s, 6 H); 13C NMR (101 MHz, CDCl3) δ 139.2, 128.2,
127.6, 127.2, 83.7, 81.2, 77.2, 70.7, 68.5, 66.3, 30.6, 29.1, 25.7, 25.4; IR
3031 (w), 2980 (w), 2934 (w), 2907 (w), 2866 (w), 2865 (w), 2238
(w), 1497 (w), 1455 (w), 1454 (w), 1379 (w), 1360 (w), 1249 (w),
1187 (w), 1156 (m), 1063 (s), 1030 (w), 921 (w), 873 (w); HRMS
2-(4-(Benzyloxy)-4-methylpent-2-yn-1-yl)-5-phenyltetrahydrofur-
an (7bh). The title compound was prepared from alcohol 5b (65.0
mg, 0.401 mmol) and alkynyl bromide 6h (132 mg, 0.520 mmol). It
was obtained as a colorless oil (96.3 mg, 0.288 mmol, 72% yield):32 Rf
0.65 (Hexane/EtOAc 5/1); 1H NMR (400 MHz, CDCl3) δ 7.40−7.28
(m, 7 H), 7.28−7.20 (m, 3 H), 5.06 (dd, 1 H, J = 7.9, 6.7 Hz), 4.65 (s,
2 H), 4.37 (ddd, 1 H, J = 13.6, 6.9, 4.7 Hz), 2.62 (dd, 1 H, J = 16.6, 4.6
Hz), 2.53 (dd, 1 H, J = 16.5, 7.2 Hz), 2.38 (m, 1 H), 2.21 (m, 1 H),
2.00−1.82 (m, 2 H), 1.54 (s, 6 H); 13C NMR (101 MHz, CDCl3) δ
143.2, 139.2, 128.3, 128.3, 127.6, 127.2, 127.2, 125.5, 84.0, 82.2, 81.1,
77.9, 70.8, 66.4, 35.2, 31.5, 29.2, 25.8; IR 3063 (w), 3030 (w), 2980
(w), 2933 (w), 2912 (w), 2911 (w), 2865 (w), 1604 (w), 1495 (w),
1453 (w), 1380 (w), 1359 (w), 1249 (w), 1186 (w), 1156 (m), 1084
(m), 1057 (s), 1031 (m), 1002 (w), 967 (w), 922 (w), 874 (w), 818
+
(ESI) calcd for C17H23O2 [M + H]+ 259.1693, found 259.1704.
+
(w); HRMS (ESI) HRMS (ESI) calcd for C23H27O2 [M + H]+
Triisopropyl((2-methyl-5-(tetrahydrofuran-2-yl)pent-3-yn-2-yl)-
oxy)silane (7ai). The title compound was prepared from 4-penten-1-ol
(5a) (34.4 mg, 0.400 mmol) and alkynyl bromide 6i (166 mg, 0.520
mmol). It was obtained as a pale yellow oil (94.0 mg, 0.290 mmol,
72% yield): Rf 0.81 (Hexane/EtOAc 5/1); 1H NMR (400 MHz,
CDCl3) δ 3.97 (ddd,1 H, J = 14.4, 6.7, 4.8 Hz), 3.88 (ddd, 1 H, J = 8.2,
7.2, 6.3 Hz), 3.74 (ddd, 1 H, J = 8.3, 7.4, 6.5 Hz), 2.47 (dd, 1 H, J =
16.4, 4.7 Hz), 2.29 (dd, 1 H, J = 16.5, 7.9 Hz), 2.02 (m, 1 H), 1.96−
1.81 (m, 2 H), 1.68 (m, 1 H), 1.18−1.00 (m, 21 H); 13C NMR (101
MHz, CDCl3) δ 87.1, 78.9, 77.3, 68.3, 66.2, 33.4, 30.7, 25.7, 25.6, 18.3,
13.0; IR 2961 (m), 2943 (m), 2942 (m), 2890 (w), 2865 (m), 1754
(w), 1744 (w), 1464 (m), 1435 (w), 1434 (w), 1377 (w), 1360 (w),
1245 (m), 1244 (m), 1162 (s), 1050 (s), 1049 (s), 1017 (w), 996 (w),
969 (w), 956 (w), 935 (w), 920 (w), 904 (w), 882 (m); HRMS (ESI)
calcd for C19H37O2Si+ [M + H]+ 325.2557, found 325.2550.
335.2006, found 335.2006.
2,5-Di(non-2-yn-1-yl)tetrahydrofuran (7ca). The title compound
was prepared from alcohol 5c (77.7 mg, 0.400 mmol) and octynyl
bromide (6a) (98.0 mg, 0.521 mmol) following the general procedure,
but using 0.10 equiv of Pd(dba)2 (23.0 mg, 0.0400 mmol) and 0.15
equiv of DPEPHos (32.3 mg, 0.0600 mmol). It was obtained as a pale
yellow oil (69.9 mg, 0.221 mmol, 55% yield, 95% pure; mixture of
inseparable diastereoisomers, d.r. trans/cis 87/13):33 Rf 0.64 (Hexane/
1
EtOAc 5/1); H NMR (400 MHz, CDCl3) δ 4.14 (m, 2 H), 2.42
(dddd, 2 H, J = 13.1, 7.3, 2.5, 2.5 Hz), 2.30 (dddd, 2 H, J = 16.4, 7.3,
2.4, 2.4 Hz), 2.16−2.06 (m, 4 H), 1.76 (m, 2 H), 1.45 (quint, 4 H, J =
6.8 Hz), 1.35 (m, 2 H), 1.31−1.22 (m, 12 H), 0.87 (t, 6 H, J = 6.7
Hz); 13C NMR (101 MHz, CDCl3, resolved signals corresponding to
the minor diastereoisomer are reported in italics) δ 81.8, 81.6, 78.4,
78.0, 76.5, 76.3, 31.3, 30.9, 30.2, 28.9, 28.9, 28.5, 28.5, 25.8, 25.7, 22.5,
18.7, 14.0; IR 2956 (m), 2929 (s), 2871 (m), 2857 (m), 1581 (w),
1465 (m), 1444 (w), 1435 (w), 1379 (w), 1367 (w), 1359 (w), 1345
2-(4-(Benzyloxy)dec-2-yn-1-yl)tetrahydrofuran (7aj). The title
compound was prepared from 4-penten-1-ol (5a) (34.4 mg, 0.400
mmol) and alkynyl bromide 6j (161 mg, 0.520 mmol). It was obtained
N
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The Journal of Organic Chemistry
Article
(w), 1330 (w), 1314 (w), 1068 (s), 911 (m), 888 (w); HRMS (ESI)
calcd for C22H37O+ [M + H]+ 317.2839, found 317.2847.
(w), 911 (m), 882 (w), 881 (w), 861 (w), 827 (m), 814 (w); HRMS
(ESI) calcd for C16H22N+ [M + H]+ 228.1747, found 228.1749.
tert-Butyl 2-(4-(benzyloxy)-4-methylpent-2-yn-1-yl)pyrrolidine-1-
carboxylate (10ah). The title compound was prepared from N-Boc-4-
pentenamine (9a) (74.5 mg, 0.400 mmol) and alkynyl bromide 6h
(132 mg, 0.520 mmol). It was obtained as a pale yellow oil (106 mg,
0.298 mmol, 74% yield, mixture of rotamers): Rf 0.64 (Hexane/EtOAc
5/1); 1H NMR (400 MHz, CDCl3) δ 7.39−7.29 (m, 3 H), 7.25 (m, 2
H), 4.60 (s, 2 H), 3.94 (m, 1 H), 3.82 (m, 1 H), 3.49−3.29 (m, 2 H),
2.66 (m, 1 H), 2.57 (m, 1 H), 2.45 (m, 1 H), 2.09−1.86 (m, 3 H), 1.79
(m, 1 H), 1.51 (s, 6 H), 1.47 (s, 9 H), 1.46 (m, 9 H); 13C NMR (101
MHz, CDCl3; the signals of resolved rotamers are reported in italics) δ
154.3, 154.2, 139.2, 128.2, 127.6, 127.2, 84.0, 83.6, 81.9, 81.5, 79.3,
79.1, 70.7, 66.3, 56.2, 56.1, 47.1, 46.7, 30.7, 29.9, 29.1, 28.5, 24.2, 23.6,
23.4, 22.9; IR 2979 (w), 2933 (w), 2932 (w), 2931 (w), 2926 (w),
2911 (w), 2910 (w), 2909 (w), 2881 (w), 2880 (w), 2879 (w), 1733
(w), 1696 (s), 1656 (w), 1655 (w), 1654 (w), 1571 (w), 1571 (w),
1570 (w), 1554 (w), 1553 (w), 1512 (w), 1455 (w), 1455 (w), 1396
(s), 1364 (w), 1341 (w), 1281 (w), 1280 (w), 1252 (w), 1251 (w),
1241 (w), 1240 (w), 1164 (m), 1163 (m), 1120 (w), 1096 (w), 1057
(w), 960 (w), 929 (w), 905 (w), 813 (w); HRMS (ESI) calcd for
tert-Butyl 2-(non-2-yn-1-yl)pyrrolidine-1-carboxylate (10aa). The
title compound was prepared from N-Boc-4-pentenamine (9a) (74.5
mg, 0.400 mmol) and octynyl bromide (6a) (98.0 mg, 0.521 mmol). It
was obtained as a pale yellow oil (84.4 mg, 0.288 mmol, 72% yield): Rf
0.60 (Hexane/EtOAc 5/1). The product was obtained as a mixture of
rotamers. In order to characterize it, it was subjected to deprotection
of the amino group according to the general procedure.
2-(Non-2-yn-1-yl)pyrrolidine (10aa′). The title compound was
obtained as a yellow oil (62.6 mg, 0.324 mmol, quantitative): 1H NMR
(400 MHz, CDCl3) δ 3.16 (dt, 1 H, J = 13.0, 6.5 Hz), 3.02 (ddd, 1 H, J
= 10.4, 7.5, 5.6 Hz), 2.85 (ddd, J = 10.3, 7.6, 6.7 Hz), 2.37−2.25 (m, 2
H), 2.14 (tt, 2 H, J = 6.9, 2.4 Hz), 2.05 (m, 1 H, br s), 1.86 (m, 1 H),
1.81−1.68 (m, 2 H), 1.51−1.41 (m, 3 H), 1.41−1.20 (m, 6 H), 0.88 (t,
3 H, J = 6.8 Hz); 13C NMR (101 MHz, CDCl3) δ 81.7, 77.3, 57.7,
46.6, 31.3, 30.7, 29.0, 28.5, 25.5, 25.4, 22.6, 18.7, 14.0; IR 3332 (br w),
2956 (s), 2928 (s), 2857 (s), 2116 (w), 1748 (w), 1748 (w), 1725 (w),
1725 (w), 1692 (w), 1612 (w), 1554 (w), 1462 (w), 1429 (w), 1429
(w), 1403 (w), 1352 (w), 1331 (w), 1283 (w), 1245 (w), 1152 (w),
1092 (w), 957 (w), 956 (w), 911 (w), 810 (w); HRMS (ESI) calcd for
C13H24N+ [M + H]+ 194.19033, found 194.19044.
+
C22H32NO3 [M] 358.2382, found 358.2374.
tert-Butyl 2-(4-(benzyloxy)dec-2-yn-1-yl)pyrrolidine-1-carboxy-
late (10aj). The title compound was prepared from N-Boc-4-
pentenamine (9a) (74.5 mg, 0.400 mmol) and alkynyl bromide 6j
(161 mg, 0.520 mmol). It was obtained as a pale yellow oil (104 mg,
0.251 mmol, 63% yield): Rf 0.54 (Hexane/EtOAc 5/1). The product
was obtained as a mixture of rotamers. In order to characterize it, it
was subjected to deprotection of the amino group according to the
general procedure.
tert-Butyl 2-(6-((tert-butyldiphenylsilyl)oxy)hex-2-yn-1-yl)-
pyrrolidine-1-carboxylate (10ad). The title compound was prepared
from N-Boc-4-pentenamine (9a) (74.5 mg, 0.400 mmol) and alkynyl
bromide 6d (208 mg, 0.519 mmol). It was obtained as a pale yellow oil
(144 mg, 0.288 mmol, 72% yield): Rf 0.50 (Hexane/EtOAc 5/1). The
product was obtained as a mixture of rotamers. In order to characterize
it, it was subjected to deprotection of the amino group according to
the general procedure.
(4-(Benzyloxy)dec-2-yn-1-yl)pyrrolidine (10aj′). The title com-
pound was obtained as a dark yellow oil (76.6 mg, 0.244 mmol, 97%
yield): 1H NMR (400 MHz, CDCl3) δ 7.41−7.30 (m, 4 H), 7.28 (m, 1
H), 4.77 (d, 1 H, J = 11.8 Hz), 4.49 (d, 1 H, J = 11.8 Hz), 4.07 (tt, 1
H, J = 6.5, 1.8 Hz), 3.23 (ddd, 1 H, J = 13.1, 6.5, 6.5 Hz), 3.03 (m, 1
H), 2.88 (ddd, 1 H, J = 10.3, 7.2, 7.2 Hz), 2.42 (dd, 2 H, J = 6.1, 1.8
Hz), 1.97−1.86 (m, 2 H), 1.85−1.61 (m, 3 H), 1.56−1.37 (m, 3 H),
1.35−1.21 (m, 6 H), 0.87 (t, 3 H, J = 6.5 Hz); 13C NMR (101 MHz,
CDCl3) δ 139.9, 128.3, 127.9, 127.6, 81.1, 77.0, 70.4, 69.0, 57.6, 46.3,
36.0, 31.8, 30.6, 29.0, 25.4, 25.1, 24.8, 22.6, 14.1; IR 3395 (br w), 3032
(w), 2953 (s), 2928 (s), 2857 (s), 1737 (m), 1715 (w), 1690 (m),
1679 (m), 1642 (m), 1543 (w), 1497 (w), 1456 (m), 1435 (w), 1385
(w), 1380 (w), 1337 (w), 1313 (w), 1287 (w), 1286 (w), 1236 (w),
1209 (w), 1209 (w), 1169 (w), 1154 (w), 1154 (w), 1089 (s), 1070
(s), 1029 (m), 919 (w), 912 (w), 822 (w); HRMS (ESI) calcd for
C21H32NO+ [M + H]+ 314.2478, found 314.2486.
tert-Butyl 2-(non-2-yn-1-yl)-5-phenylpyrrolidine-1-carboxylate
(10ba). The title compound was prepared from N-Boc amine 9b
(105 mg, 0.402 mmol) and octynyl bromide (6a) (98.0 mg, 0.521
mmol). It was obtained as a pale yellow oil (110 mg, 0.298 mmol, 74%
yield): Rf 0.60 (Hexane/EtOAc 5/1). The product was obtained as a
mixture of rotamers. In order to characterize it, it was subjected to
deprotection of the amino group according to the general procedure.
2-(Non-2-yn-1-yl)-5-phenylpyrrolidine (10ba′). The title com-
pound was obtained as a dark yellow oil (76.6 mg, 0.244 mmol,
97% yield; mixture of inseparable diastereoisomers, d.r. trans/cis 10/
90):34 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 2 H), 7.31 (m, 2 H),
7.23 (m, 2 H), 4.17 (dd, J = 7.4, 7.4 Hz), 3.36 (ddd, J = 13.2, 6.1, 6.1
Hz), 2.45 (dddd, 1 H, J = 16.4, 5.8, 2.3, 2.3 Hz), 2.38 (m, 1 H), 2.20−
2.11 (m, 3 H), 1.98 (m, 1 H), 1.79−1.63 (m, 2 H), 1.48 (quint, 2 H, J
= 7.0 Hz), 1.43−1.32 (m, 2 H), 1.33−1.22 (m, 4 H), 0.88 (t, J = 7.0
Hz); 13C NMR (101 MHz, CDCl3) δ 144.7, 128.2, 126.7, 126.6, 81.7,
77.6, 62.7, 57.9, 34.2, 31.3, 30.7, 29.0, 28.5, 26.0, 22.5, 18.7, 14.0; IR
3063 (w), 3028 (w), 2955 (m), 2924 (s), 2853 (s), 1738 (w), 1603
(w), 1492 (w), 1458 (m), 1434 (w), 1400 (w), 1399 (w), 1377 (w),
1250 (w), 1109 (w), 1075 (w), 1028 (w), 910 (s), 828 (w); HRMS
(ESI) calcd for C19H28N+ [M + H]+ 270.2216, found 270.2225.
tert-Butyl 2-heptyl-5-(non-2-yn-1-yl)pyrrolidine-1-carboxylate
(10ca). The title compound was prepared from N-Boc amine 9c
(108 mg, 0.400 mmol) and octynyl bromide (6a) (98.3 mg, 0.520
2-(6-((tert-Butyldiphenylsilyl)oxy)hex-2-yn-1-yl)pyrrolidine
(10ad′). The title compound was obtained as a yellow oil (117 mg,
0.288 mmol, quantitative): 1H NMR (400 MHz, CDCl3) δ 7.73 (dd, 4
H, J = 7.4, 1.6 Hz), 7.42−7.33 (m, 6 H), 3.71 (t, 2 H, J = 5.7 Hz), 3.09
(ddd, 1 H, J = 12.8, 6.2, 6.2 Hz), 3.05−2.86 (m, 2 H), 2.94 (ddd, 1 H,
J = 10.5, 7.5, 5.5 Hz), 2.76 (ddd, 2 H, J = 10.5, 7.0, 7.0 Hz), 2.34−2.20
(m, 3 H), 1.76−1.62 (m, 2 H), 1.71 (quint, 2 H, J = 6.5 Hz), 1.41
(dddd, 1 H, J = 12.5, 7.5, 7.5, 7.5 Hz), 1.05 (s, 9 H); 13C NMR (101
MHz, CDCl3) δ 135.5, 133.8, 129.6, 127.6, 83.4, 74.0, 62.4, 58.6, 45.9,
31.6, 29.6, 26.8, 23.3, 22.1, 19.2, 15.2; IR 3341 (w), 3069 (w), 3049
(w), 2953 (m), 2932 (m), 2889 (m), 2888 (m), 2856 (m), 1688 (m),
1591 (w), 1468 (m), 1429 (s), 1393 (w), 1393 (w), 1359 (w), 1359
(w), 1334 (w), 1305 (w), 1304 (w), 1259 (w), 1238 (w), 1204 (w),
1204 (w), 1191 (w), 1191 (w), 1145 (w), 1111 (s), 1063 (m), 1004
(w), 1004 (w), 970 (w), 936 (w), 876 (m), 876 (m), 822 (m); HRMS
(ESI) calcd for C26H36NOSi+ [M + H]+ 406.2561, found 406.2562.
tert-Butyl 2-(7-phenylhept-2-yn-1-yl)pyrrolidine-1-carboxylate
(10ae). The title compound was prepared from N-Boc-4-pentenamine
(9a) (74.5 mg, 0.400 mmol) and alkynyl bromide 6e (116 mg, 0.520
mmol). It was obtained as a pale yellow oil (101 mg, 0.308 mmol, 77%
yield): Rf 0.52 (Hexane/EtOAc 5/1). The product was obtained as a
mixture of rotamers. In order to characterize it, it was subjected to
deprotection of the amino group according to the general procedure.
2-(6-Phenylhex-2-yn-1-yl)pyrrolidine (10ae′). The title compound
1
was obtained as a yellow oil (52.3 mg, 0.230 mmol, 74% yield): H
NMR (400 MHz, CDCl3) δ 7.31 (m, 2 H), 7.23−7.18 (m, 3 H), 3.80
(br s, 1 H), 3.28 (ddd, 1 H, J = 13.3, 7.0, 6.4 Hz), 3.10 (ddd, 1 H, J =
10.5, 7.5, 5.8 Hz), 2.95 (ddd,1 H, J = 10.6, 7.9, 6.7 Hz), 2.73 (t, 2 H, J
= 7.5 Hz), 2.44−2.39 (m, 2 H), 2.20 (tt, 2 H, J = 7.0, 2.3 Hz), 1.96 (m,
1 H), 1.90−1.74 (m, 4 H), 1.83 (quint, 2 H, J = 6.9 Hz), 1.56 (m, 1
H); 13C NMR (101 MHz, CDCl3) δ 141.7, 128.4, 128.3, 125.8, 81.5,
77.4, 57.8, 46.4, 34.8, 30.6, 30.6, 25.2, 24.9, 18.2; IR 3087 (w), 3078
(w), 3063 (w), 3062 (w), 3026 (w), 3008 (w), 2995 (w), 2939 (s),
2932 (s), 2861 (m), 2860 (m), 2112 (w), 2111 (w), 2108 (w), 2107
(w), 2091 (w), 2090 (w), 2089 (w), 1950 (w), 1949 (w), 1944 (w),
1943 (w), 1687 (s), 1635 (w), 1603 (w), 1496 (m), 1455 (s), 1430
(m), 1408 (m), 1353 (w), 1352 (w), 1334 (w), 1294 (w), 1229 (w),
1201 (s), 1176 (s), 1175 (s), 1130 (m), 1101 (w), 1090 (w), 1089
(w), 1082 (w), 1057 (w), 1050 (w), 1032 (w), 965 (w), 954 (w), 943
O
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The Journal of Organic Chemistry
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mmol). It was obtained as a pale yellow oil (77.0 mg, 0.204 mmol,
51% yield): Rf 0.89 (Hexane/EtOAc 5/1). The product was obtained
as a mixture of rotamers. In order to characterize it, it was subjected to
deprotection of the amino group according to the general procedure.
2-Heptyl-5-(non-2-yn-1-yl)pyrrolidine (10ca′). The title com-
pound was obtained as a dark yellow oil (52.3 mg, 0.188 mmol,
94% yield; mixture of inseparable diastereoisomers, d.r. trans/cis > 3/
97):35 1H NMR (400 MHz, CDCl3) δ 3.13 (dddd, 1 H, J = 7.5, 6.0,
6.0, 6.0 Hz), 2.97 (dddd, J = 8.0, 6.5, 6.5, 6.5 Hz), 2.32 (m, 2 H), 2.13
(tt, 2 H, J = 6.9, 2.3 Hz), 1.88−1.77 (m, 3 H), 1.53−1.42 (m, 5 H),
1.41−1.21 (m, 14 H), 0.91−0.83 (m, 6 H); 13C NMR (101 MHz,
CDCl3) δ 81.8, 77.3, 59.6, 57.7, 36.7, 31.8, 31.7, 31.4, 30.3, 29.5, 29.0,
28.5, 27.4, 25.5, 22.6, 22.6, 18.7, 14.1, 14.0; IR 2957 (m), 2927 (m),
2856 (m), 2184 (w), 2183 (w), 1464 (w), 1434 (w), 1433 (w), 1404
(w), 1403 (w), 1379 (w), 1127 (w), 1122 (w), 1100 (w), 1084 (w),
991 (w), 990 (w), 962 (w), 909 (s), 879 (w).1032 (w), 965 (w), 954
(w), 943 (w), 911 (m), 882 (w), 881 (w), 861 (w), 827 (m), 814 (w);
HRMS (ESI) calcd for C19H36N+ [M + H]+ 278.2842, found
278.2846.
tert-Butyl 2-(but-3-en-1-yl)-5-(non-2-yn-1-yl)pyrrolidine-1-car-
boxylate (10da). The title compound was prepared from N-Boc
amine 9d (95.0 mg, 0.397 mmol) and octynyl bromide (6a) (98.0 mg,
0.521 mmol). It was obtained as a pale yellow oil (83.4 mg, 0.240
mmol, 60% yield): Rf 0.58 (Hexane/EtOAc 5/1). The product was
obtained as a mixture of rotamers. In order to characterize it, it was
subjected to deprotection of the amino group according to the general
procedure.
2-(But-3-en-1-yl)-5-(non-2-yn-1-yl)pyrrolidine (10da′). The title
compound was obtained as a dark yellow oil (59.1 mg, 0.239 mmol,
99% yield; mixture of inseparable diastereoisomers, d.r. trans/cis 5/
95):36 1H NMR (400 MHz, CDCl3) δ 5.81 (m, 1 H), 5.00 (dddd, 1 H,
J = 17.1, 6.5, 2.0, 2.0 Hz), 4.92 (m, 1 H), 3.14 (ddd, 1 H, J = 18.6, 6.0,
6.0 Hz), 3.00 (ddd, 1 H, J = 19.6, 5.5, 5.5 Hz), 2.35 (dddd, 1 H, J =
16.1, 8.0, 2.5, 2.5 Hz), 2.27 (m, 1 H), 2.18−2.03 (m, 4 H), 1.96 (br s, 1
H), 1.90−1.76 (m, 2 H), 1.59 (dddd, 1 H, J = 13.6, 8.5, 7.0, 7.0 Hz),
1.55−1.40 (m, 4 H), 1.40−1.20 (m, 7 H), 0.86 (t, 3 H, J = 6.2 Hz);
13C NMR (101 MHz, CDCl3) δ 138.6, 114.3, 81.7, 77.3, 58.9, 57.7,
35.7, 31.6, 31.5, 31.3, 30.2, 29.0, 28.5, 25.6, 22.5, 18.7, 14.0; IR 3076
(w), 2956 (m), 2928 (s), 2857 (m), 1714 (w), 1698 (w), 1682 (w),
1661 (w), 1641 (w), 1457 (w), 1435 (w), 1406 (w), 1379 (w), 1278
(w), 1177 (w), 1135 (w), 1115 (w), 995 (w), 910 (s); HRMS (ESI)
calcd for C17H30N+ [M + H]+ 248.2373, found 248.2371.
tert-Butyl 2-(non-2-yn-1-yl)octahydro-1H-indole-1-carboxylate
(10fa). The title compound was prepared from N-Boc amine 9f
(96.0 mg, 0.401 mmol) and octynyl bromide (6a) (98.0 mg, 0.521
mmol). It was obtained as a pale yellow oil (88.3 mg, 0.254 mmol,
64% yield): Rf 0.60 (Hexane/EtOAc 5/1). The product was obtained
as a mixture of rotamers. In order to characterize it, it was subjected to
deprotection of the amino group according to the general procedure.
2-(Non-2-yn-1-yl)octahydro-1H-indole (10fa′). The title com-
pound was obtained as a yellow oil (61.7 mg, 0.249 mmol, 98%
yield; mixture of inseparable diastereoisomers, d.r. trans/cis 6/94):37
1H NMR (400 MHz, CDCl3) δ 3.25 (dddd, 1 H, J = 8.0, 8.0, 6.0, 6.0
Hz), 3.05 (dd, 1 H, J = 10.8, 5.4 Hz), 2.43 (dddd, 1 H, J = 16.1, 5.0,
2.5, 2.5 Hz), 2.37 (dddd, 1 H, J = 16.1, 4.5, 2.0, 2.0 Hz), 2.16 (tt, 2 H, J
= 6.9, 2.3 Hz), 2.04 (m, 1 H), 1.93 (m, 1 H), 1.78 (s, 1 H), 1.65 (m, 2
H), 1.57−1.42 (m, 6 H), 1.42−1.20 (m, 9 H), 0.88 (t, 3 H, J = 6.8
Hz); 13C NMR (101 MHz, CDCl3) δ 81.8, 77.5, 57.8, 56.9, 38.3, 36.6,
31.3, 29.1, 29.0, 28.6, 28.6, 26.3, 23.9, 22.5, 22.0, 18.8, 14.0; IR 2926
(s), 2854 (m), 1451 (w), 1403 (w), 1377 (w), 1377 (w), 1347 (w),
1347 (w), 1332 (w), 1332 (w), 1285 (w), 1285 (w), 1284 (w), 1284
(w), 1216 (w), 1083 (w), 1083 (w), 1028 (w), 1028 (w), 910 (w), 818
(w).; HRMS (ESI) calcd for C17H30N+ [M + H]+ 248.2373, found
248.2369.
tert-Butyl 2-(10-bromodec-2-yn-1-yl)octahydro-1H-indole-1-car-
boxylate (10fi). The title compound was prepared from N-Boc amine
9f (96.0 mg, 0.401 mmol) and alkynyl bromide 6i (147 mg, 0.520
mmol). It was obtained as a pale yellow oil (112 mg, 0.253 mmol, 63%
yield, mixture of inseparable diastereoisomers, d.r. trans/cis < 5/95): Rf
0.69 (Hexane/EtOAc 5/1). The product was obtained as a mixture of
rotamers. In order to characterize it, NMR spectra were acquired at 55
1
°C: H NMR (400 MHz, CDCl3) δ 3.83−3.68 (m, 2 H), 3.39 (t, J =
6.8 Hz), 2.76 (m, 1 H), 2.46 (dddd, J = 16.1, 7.7, 2.3, 2.3 Hz), 2.25−
2.10 (m, 3 H), 2.03−1.91 (m, 3 H), 1.87 (quint, 2 H, J = 6.9 Hz), 1.73
(m, 1 H), 1.69−1.58 (m, 3 H), 1.56−1.24 (m, 13 H), 1.46 (s, 9 H),
1.17 (tt, 1 H, J = 13.1, 3.0 Hz); 13C NMR (101 MHz, CDCl3) δ 154.5,
81.9, 78.9, 77.5, 58.1, 57.0, 36.0, 33.8, 33.3, 32.9, 29.2, 28.9, 28.6, 28.3,
28.1, 26.3, 25.7, 25.3, 24.2, 20.9, 18.8; IR 2929 (m), 2856 (w), 1690
(s), 1454 (w), 1394 (s), 1363 (m), 1295 (w), 1251 (w), 1164 (m),
1116 (m), 1096 (w), 971 (w), 907 (w), 863 (w), 862 (w); HRMS
(ESI) calcd for C2379BrH39NO2+ [M + H]+ 440.2159, found 440.2166.
tert-Butyl 2-(non-2-yn-1-yl)octahydrocyclohepta[b]pyrrole-
1(2H)-carboxylate (10ga). The title compound was prepared from
N-Boc amine 9g (101 mg, 0.399 mmol) and octynyl bromide (6a)
(98.0 mg, 0.521 mmol). It was obtained as a pale yellow oil (82.3 mg,
0.227 mmol, 57% yield): Rf 0.60 (Hexane/EtOAc 5/1). The product
was obtained as a mixture of rotamers. In order to characterize it, it
was subjected to deprotection of the amino group according to the
general procedure.
tert-Butyl 2-(non-2-yn-1-yl)hexahydrocyclopenta[b]pyrrole-
1(2H)-carboxylate (10ea). The title compound was prepared from
N-Boc amine 9e (90.1 mg, 0.400 mmol) and octynyl bromide (6a)
(98.0 mg, 0.521 mmol). It was obtained as a pale yellow oil (98.5 mg,
0.295 mmol, 74% yield): Rf 0.55 (Hexane/EtOAc 5/1). The product
was obtained as a mixture of rotamers. In order to characterize it, it
was subjected to deprotection of the amino group according to the
general procedure.
2-(Non-2-yn-1-yl)decahydrocyclohepta[b]pyrrole (10ga′). The
title compound was obtained as a dark yellow oil (53.4 mg, 0.204
mmol, 90% yield; mixture of inseparable diastereoisomers, d.r. trans/cis
> 10/90):38 1H NMR (400 MHz, CDCl3) δ 4.86 (br s, 1 H), 3.41
(ddd, 1 H, J = 11.6, 9.5, 4.0 Hz), 3.20 (ddd, J = 11.4, 11.4, 6.0 Hz),
2.42 (dt, 2 H, J = 5.9, 2.4 Hz), 2.33 (m, 1 H), 2.15 (m, 1 H), 2.11 (tt, J
= 6.7, 2.2 Hz, 2 H), 1.89 (m, 1 H), 1.84−1.75 (m, 2 H), 1.63 (m, 1 H),
1.55 (dd, 1 H, J = 23.1, 11.1 Hz), 1.45 (m, 2 H), 1.39−1.11 (m, 11 H),
0.87 (t, 3 H, J = 6.8 Hz); 13C NMR (101 MHz, CDCl3) δ 82.6, 75.8,
63.0, 57.9, 42.8, 39.7, 31.5, 31.4, 31.3, 31.1, 29.2, 28.9, 28.5, 26.4, 23.2,
22.5, 18.7, 14.0; IR 2921 (m), 2854 (w), 2853 (w), 2246 (w), 1680
(m), 1457 (w), 1445 (w), 1431 (w), 1430 (w), 1380 (w), 1202 (m),
1183 (m), 1182 (m), 1139 (m), 1036 (w), 1028 (w), 1016 (w), 1008
(w), 998 (w), 909 (s), 835 (w); HRMS (ESI) calcd for C18H32N+ [M
+ H]+ 262.2529, found 262.2519.
tert-Butyl 2-(non-2-yn-1-yl)indoline-1-carboxylate (10ha). The
title compound was prepared from N-Boc aniline 9h (93.3 mg, 0.400
mmol) and octynyl bromide (6a) (98.0 mg, 0.521 mmol). It was
obtained as a pale yellow oil (109 mg, 0.319 mmol, 80% yield): Rf 0.55
(Hexane/EtOAc 5/1). The product was obtained as a mixture of
rotamers. In order to characterize it, it was subjected to deprotection
of the amino group according to the general procedure.
2-(Non-2-yn-1-yl)octahydrocyclopenta[b]pyrrole (10ea′). The
title compound was obtained as a dark yellow oil (61.2 mg, 0.263
mmol, 89% yield; mixture of inseparable diastereoisomers, d.r. trans/cis
1
> 5/95): H NMR (400 MHz, CDCl3) δ 3.62 (dd, 1 H, J = 7.1, 7.1
Hz), 2.98 (ddd, 1 H, J = 16.2, 5.4, 5.4 Hz), 2.54 (dddd, J = 17.1, 8.0,
8.0, 2.5 Hz), 2.38 (dddd, 1 H, J = 16.4, 5.0, 2.4, 2.4 Hz), 2.28 (dddd, 1
H, J = 16.4, 4.9, 2.3, 2.3 Hz), 2.13 (tt, 2 H, J = 6.9, 2.3 Hz), 2.05 (ddd,
1 H, J = 12.2, 8.9, 5.2 Hz), 1.86 (br s, 1 H), 1.68−1.48 (m, 6 H), 1.46
(quint, 2 H, J = 7.0 Hz), 1.36 (dt, 2 H, J = 16.1, 7.0 Hz), 1.31−1.21
(m, 6 H), 1.01 (ddd, 1 H, J = 11.8, 10.8, 8.9 Hz), 0.88 (t, 3 H, J = 6.7
Hz); 13C NMR (101 MHz, CDCl3) δ 82.0, 77.0, 63.5, 58.8, 43.1, 39.8,
34.2, 33.1, 31.3, 29.0, 28.6, 24.1, 23.7, 22.5, 18.7, 14.0; IR 3344 (br w),
2951 (s), 2950 (s), 2930 (s), 2858 (s), 1696 (w), 1695 (w), 1694 (w),
1693 (w), 1692 (w), 1689 (w), 1683 (w), 1682 (w), 1641 (w), 1640
(w), 1465 (m), 1451 (m), 1434 (m), 1402 (w), 1379 (w), 1359 (w),
1348 (w), 1326 (w), 1298 (w), 1286 (w), 1277 (w), 1221 (w), 1179
(w), 1165 (w), 1126 (w), 1112 (w), 1091 (w), 1072 (w), 1046 (w),
1045 (w), 993 (w), 977 (w), 931 (w), 930 (w), 909 (m), 891 (w), 890
(w), 840 (w); HRMS (ESI) calcd for C16H28N+ [M + H]+ 234.2216,
found 234.2218.
P
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Article
2-(Non-2-yn-1-yl)indoline (10ha′). The title compound was
obtained as an orange oil (74.7 mg, 0.309 mmol, 90% yield): 1H
NMR (400 MHz, CDCl3) δ 7.07 (d, 1 H, J = 7.3 Hz), 7.01 (td, 1 H, J
= 7.6, 0.5 Hz), 6.69 (m, 1 H), 6.62 (d, 1 H, J = 7.8 Hz), 4.10 (br s, 1
H), 3.95 (ddd, 1 H, J = 13.4, 8.6, 6.2 Hz), 3.17 (dd, 1 H, J = 15.7, 8.7
Hz), 2.75 (dd, 1 H, J = 15.7, 6.1 Hz), 2.38 (dd, 1 H, J = 4.8, 2.4 Hz),
2.35 (dd, 1 H, J = 3.8, 2.4 Hz), 2.16 (tt, 2 H, J = 6.9, 2.3 Hz), 1.49
(quint, 2 H), 1.44−1.20 (m, 6 H), 0.90 (t, 3 H, J = 6.7 Hz); 13C NMR
(101 MHz, CDCl3) δ 150.2, 128.0, 127.3, 124.8, 118.6, 109.2, 82.2,
77.0, 58.6, 35.5, 31.3, 28.9, 28.5, 26.3, 22.5, 18.7, 14.0; IR 3372 (w),
2954 (w), 2929 (m), 2856 (w), 1731 (w), 1692 (m), 1610 (m), 1591
(w), 1514 (m), 1485 (m), 1466 (m), 1455 (m), 1411 (w), 1366 (w),
1322 (w), 1301 (w), 1245 (s), 1158 (s), 1119 (w), 1049 (w), 1023
(w), 918 (w), 898 (w), 879 (w), 842 (w); HRMS (ESI) calcd for
C17H24N+ [M + H]+ 242.1903, found 242.1901.
2-(Non-2-yn-1-yl)-1-phenylpyrrolidine (10ia). The title compound
was prepared from N-phenyl amine 9i (64.5 mg, 0.400 mmol) and
octynyl bromide (6a) (97.8 mg, 0.520 mmol). It was obtained as a pale
yellow oil (85.3 mg, 0.317 mmol, 79% yield): Rf 0.55 (Hexane/EtOAc
10/1); 1H NMR (400 MHz, CDCl3) δ 7.21 (dd, 2 H, J = 8.4, 7.4 Hz),
6.67 (t, 1 H, J = 7.3 Hz), 6.60 (d, 2 H, J = 8.1 Hz), 3.86 (m, 1 H), 3.43
(m, 1 H), 3.17 (m, 1 H), 2.58 (dd, 1 H, J = 16.4, 2.3 Hz), 2.17 (tt, 2 H,
J = 6.9, 2.3 Hz), 2.14−1.95 (m, 5 H), 1.49 (q, 2 H, J = 6.8 Hz), 1.40
(m, 2 H), 1.35−1.24 (m, 4 H), 0.90 (t, 3 H, J = 6.7 Hz); 13C NMR
(101 MHz, CDCl3) δ 146.8, 129.2, 115.6, 111.8, 81.9, 77.6, 58.3, 48.3,
31.4, 30.3, 29.0, 28.6, 23.0, 22.9, 22.6, 18.8, 14.1; IR 2955 (m), 2930
(s), 2929 (s), 2856 (m), 1699 (w), 1599 (s), 1505 (s), 1483 (w), 1482
(w), 1463 (w), 1366 (s), 1347 (m), 1346 (m), 1296 (w), 1244 (w),
1216 (w), 1215 (w), 1179 (w), 1178 (w), 1161 (w), 1036 (w), 1036
(w), 994 (w), 958 (w), 958 (w), 911 (w), 858 (w); HRMS (ESI) calcd
for C19H28N+ [M + H]+ 270.2216, found 270.2222.
1-(4-Methoxyphenyl)-2-(non-2-yn-1-yl)pyrrolidine (10ja). The
title compound was prepared from N-para-methoxyphenyl amine 9j
(76.5 mg, 0.400 mmol) and octynyl bromide (6a) (97.8 mg, 0.520
mmol). It was obtained as a yellow oil (71.0 mg, 0.237 mmol, 59%
yield): Rf 0.79 (Hexane/EtOAc 5/1); 1H NMR (400 MHz, CDCl3) δ
6.85 (m, 2 H), 6.56 (m, 2 H), 3.83−3.74 (m, 1 H), 3.76 (d, 2 H, J =
1.6 Hz), 3.41 (m, 1 H), 3.12 (m, 1 H), 2.55 (ddd, 1 H, J = 16.5, 2.3,
2.3 Hz), 2.17 (m, 2 H), 2.13−1.95 (m, 5 H), 1.52 (m, 2 H), 1.46−1.24
(m, 6 H), 0.91 (t, 3 H, J = 6.8 Hz); 13C NMR (101 MHz, CDCl3) δ
150.9, 141.8, 115.1, 112.6, 81.8, 77.7, 58.8, 56.0, 49.0, 31.4, 30.4, 29.0,
28.6, 23.2, 22.6, 18.8, 14.1; IR 3045 (w), 2952 (m), 2930 (m), 2857
(w), 2834 (w), 1622 (w), 1574 (w), 1515 (s), 1485 (w), 1463 (w),
1365 (w), 1340 (w), 1329 (w), 1284 (w), 1242 (s), 1179 (w), 1044
(m), 980 (w), 961 (w), 960 (w), 911 (w), 888 (w), 813 (m); HRMS
(ESI) calcd for C20H30NO+ [M + H]+ 300.2322, found 300.2319.
General Procedure for the Oxy- and Aminoalkynylation/in
Situ Complete Hydrogenation. Under inert atmosphere, Pd(dba)2
(11.5 mg, 0.0200 mmol, 0.05 equiv), DPEPHos (16.1 mg, 0.0300
mmol, 0.075 equiv) and NaOtBu (50.0 mg, 0.520 mmol, 1.3 equiv)
were introduced into a 5 mL vial, which was then sealed. Toluene was
added (4.6 mL), followed by the bromo acetylene 6 (0.520 mmol, 1.3
equiv) and the starting material 5 or 9 (0.40 mmol, 1.0 equiv). The
mixture was stirred at 80 °C for 3 h and then allowed to cool to rt.
Toluene was removed under reduced pressure, and MeOH was added
(2.5−3.0 mL) followed by palladium on charcoal (two portions of ca.
50 mg). The mixture was purged with H2 over 10 min and stirred
under a H2-atmosphere for 24 h. Upon filtration through Celite, the
solvent was removed in vacuo, and the crude mixture was then directly
purified by column chromatography (SiO2, pentane/EtOAc 98/2 to
96/4).
14.1; IR 2957 (m), 2923 (s), 2872 (m), 2854 (s), 1489 (w), 1465 (w),
1379 (w), 1189 (w), 1180 (w), 1179 (w), 1178 (w), 1177 (w), 1174
(w), 1173 (w), 1070 (m), 1039 (w), 1026 (w), 943 (w), 922 (w), 904
(w), 870 (w), 861 (w), 850 (w); HRMS (ESI) calcd for C13H27O+ [M
+ H]+ 199.2056, found 199.2056.
tert-Butyl 2-nonylpyrrolidine-1-carboxylate (12aa). The title
compound was prepared from N-Boc-4-pentenamine (9a) (74.5 mg,
0.400 mmol) and octynyl bromide (6a) (98.3 mg, 0.520 mmol). It was
obtained as a pale yellow oil (87.1 mg, 0.293 mmol, 73% yield): Rf 0.83
(Hexane/EtOAc 5/1). The product was obtained as a mixture of
rotamers. In order to characterize it, it was subjected to deprotection
of the amino group according to the general procedure.
2-Nonylpyrrolidine (12aa′). The title compound was obtained as a
1
yellow oil (61.1 mg, 0.310 mmol, quantitative): H NMR (400 MHz,
CDCl3) δ 4.98 (br s, 1 H), 3.13−3.04 (m, 2 H), 2.94 (ddd, 1 H, J =
10.9, 8.3, 6.4 Hz), 1.95 (m, 1 H), 1.89−1.72 (m, 2 H), 1.58 (m, 1 H),
1.50−1.40 (m, 1 H), 1.39−1.20 (m, 15 H), 0.86 (t, 3 H, J = 6.6 Hz);
13C NMR (101 MHz, CDCl3) δ 59.7, 45.7, 34.9, 31.9, 31.3, 29.6, 29.5,
29.5, 29.3, 27.2, 24.7, 22.6, 14.1; IR 3424 (w), 2957 (m), 2924 (s),
2873 (w), 2854 (s), 1678 (s), 1525 (w), 1524 (w), 1460 (m), 1414
(m), 1379 (w), 1344 (w), 1201 (s), 1176 (s), 1133 (s), 1047 (w),
1036 (w), 1026 (w), 937 (w), 930 (w), 929 (w), 909 (w), 908 (w),
899 (w), 831 (m), 815 (w); HRMS (ESI) calcd for C13H28N+ [M +
H]+ 198.2216, found 198.2219.
[Pd(allyl)(cod)](BF4)2.
Following a reported procedure,39 [Pd(allyl)Cl]2 (300 mg, 0.820
mmol, 1.0 equiv) and AgBF4 (314 mg, 1.61 mmol, 2.0 equiv) were
introduced into a 2-necked flask under N2. CH2Cl2 (8.0 mL) was then
added, and the solution stirred at room temperature for 15 min. Cod
(0.33 mL, 1.6 mmol, 2.0 equiv) was then added, and the solution was
stirred for 1 h. Upon removal of the formed precipitate by filtration
through Celite, the resulting solution was treated with Et2O (50 mL)
in order to induce the precipitation of the product. The latter was
removed by filtration and washed with Et2O (3 × 10 mL) and dried in
vacuo. The solid was taken up in CH2Cl2 and passed through a cotton
wool plug; Et2O (2 × 15 mL) was again added to precipitate out the
product, which was dried in vacuo. Complex [Pd(allyl)(cod)](BF4)2
was finally obtained as a colorless solid (354 mg, 1.04 mmol, 63%
yield): 1H NMR (400 MHz, CDCl3) δ 6.28 (broad d, 4 H), 6.10 (tt, J
= 13.4, 7.3 Hz, 1 H), 4.98, (d, J = 7.3 Hz, 2 H), 3.98 (d, J = 13.4 Hz, 2
H), 2.75−2.55 (m, 6 H), 2.36 (m, 2 H); 13C NMR (101 MHz, CDCl3)
δ 125.6, 114.0, 112.9, 29.4. The values for the characterization
correspond to the ones reported in literature.40
[(Cinnamyl)PdCp].
Following a slightly modified version of a reported procedure,10
[Pd(cinnamyl)Cl]2 (300 mg, 0.579 mmol, 1.0 equiv) was dissolved in
THF (10 mL), and the solution was cooled to −78 °C. A solution
prepared by diluting NaCp (2.0 M, 0.72 mL, 1.4 mmol, 2.5 equiv) with
THF (10 mL) was then added dropwise, and the resulting purple
mixture was stirred at −78 °C for 5 min. It was then allowed to warm
to rt and subsequently cooled to 0 °C. The solvent was removed from
the cooled solution under reduced pressure and hexane (10 mL) was
added. The dissolved solids were filtered off, and the filtrate was
concentrated in vacuo to obtain an oily purple solid. Upon addition of
hexane (1.5 mL), crystallization at −40 °C afforded [(Cinnamyl)-
PdCp] (317 mg, 0.550 mmol, 95% yield) as a dark-purple crystalline
2-Nonyltetrahydrofuran (11aa). The title compound was prepared
from 4-penten-1-ol (5a) (34.4 mg, 0.400 mmol) and octynyl bromide
(6a) (98.3 mg, 0.520 mmol). It was obtained as a pale yellow oil (40.0
mg, 0.202 mmol, 51% yield): Rf 0.83 (Hexane/EtOAc 5/1); 1H NMR
(400 MHz, CDCl3) δ 3.85 (ddd, 1 H, J = 8.5, 7.0, 6.0 Hz), 3.77 (ddd,1
H, J = 14.6, 7.0, 6.0 Hz), 3.70 (ddd, 1 H, J = 7.5, 7.5, 6.0 Hz), 1.95 (m,
1 H), 1.91−1.79 (m, 2 H), 1.56 (m, 1 H), 1.48−1.20 (m, 14 H), 1.47−
1.38 (m, 2 H), 0.87 (t, 3 H, J = 6.6 Hz); 13C NMR (101 MHz, CDCl3)
δ 79.5, 67.6, 35.7, 31.9, 31.4, 29.8, 29.6, 29.6, 29.3, 26.4, 25.7, 22.7,
1
solid: H NMR (400 MHz, C7D8) δ 7.28−7.22 (m, 2 H), 7.04−6.96
(m, 3 H), 5.63 (s, 5 H), 5.14 (ddd, 1 H, J = 10.3, 10.3, 6.2 Hz), 3.84
(d, 1 H, J = 9.8 Hz), 3.36 (d, 1 H, J = 6.1 Hz), 2.16 (d, 1 H, J = 10.5
Hz). The values for the characterization of [(Cinnamyl)PdCp]
correspond to the ones reported in literature.10
Q
dx.doi.org/10.1021/jo400254q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Large Scale Reaction for the Synthesis of 7bh. Under inert
atmosphere, Pd(dba)2 (53.2 mg, 0.0925 mmol, 0.05 equiv), DPEPHos
(74.9 mg, 0.139 mmol, 0.075 equiv) and NaOtBu (232 mg, 2.41
mmol, 1.3 equiv) were introduced into a 50 mL one-neck flask.
Toluene (21.3 mL) was added under an argon atmosphere, followed
by the bromo acetylene 6h (610 mg, 2.41 mmol, 1.3 equiv) and
alcohol 5b (300 mg, 1.85 mmol, 1.0 equiv). The mixture was stirred at
80 °C for 3 h and then allowed to cool to room temperature. The
solvent was evaporated under reduced pressure. The crude mixture
was then directly purified by column chromatography (SiO2, pentane/
EtOAc 99/1). Fractions containing the inseparable mixture of alkyne
15 and dimer 16 were collected and purified again (SiO2, 98/2
pentane/Et2O). The isolation and identification showed that 13% of
5b (39.5 mg, 0.243 mmol) was recovered, 55% of 7bh (338 mg, 1.01
mmol) was formed, and the following side-products were generated:
ketone 13 (12.8 mg, 0.0799 mmol, 4%), hydroxy ketone 14 (40.9 mg,
0.230 mmol, 12%), alkyne 15 (21.9 mg, 0.126 mmol, 5%) and dimer
16 (152 mg, 0.438 mmol, 36%).
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41, 4165.
1-Phenylpent-4-en-1-one (13). Rf 0.37 (Pentane/EtOAc 20/1); 1H
NMR (400 MHz, CDCl3) δ 7.96 (m, 2 H), 7.56 (m, 1 H), 7.46 (m, 2
H), 5.91 (m, 1 H), 5.09 (dd, 1 H, J = 17.1, 1.5 Hz), 5.01 (d, 1 H, J =
10.2 Hz), 3.07 (ddd, 2 H, J = 7.3, 7.3, 2.0 Hz), 2.50 (m, 2 H); 13C
NMR (101 MHz, CDCl3) δ 199.4, 137.3, 136.9, 133.0, 128.6, 128.0,
115.2, 37.7, 28.1. The data for the characterization of compound 13
correspond to the ones reported in the literature.41
5-Hydroxy-5-phenylpentan-2-one (14). Rf 0.05 (Pentane/EtOAc
20/1); 1H NMR (400 MHz, CDCl3) δ 7.37−7.30 (m, 3 H), 7.27 (m, 2
H), 4.72 (t, 1 H, J = 6.3 Hz), 2.55 (t, 2 H, J = 7.0 Hz), 2.13 (s, 3 H),
2.02 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ 209.1, 143.9, 128.2,
127.2, 125.4, 73.1, 39.5, 32.3, 29.7. The data for the characterization of
compound 14 correspond to the ones reported in the literature.42
(((2-Methylbut-3-yn-2-yl)oxy)methyl)benzene (15). Rf 0.47 (Pen-
1
tane/EtOAc 20/1); H NMR (400 MHz, CDCl3) δ 7.41−7.31 (m, 4
H), 7.27 (m, 1 H), 4.65 (s, 2 H), 2.49 (s, 1 H), 1.57 (s, 6 H); 13C
NMR (101 MHz, CDCl3) δ 138.9, 128.3, 127.7, 127.3, 86.1, 72.2, 70.5,
66.5, 28.8. The data for the characterization of compound 15
correspond to the ones reported in the literature.43
(((4-Bromo-2-methylbut-3-yn-2-yl)oxy)methyl)benzene (16). Rf
0.40 (Pentane/EtOAc 20/1); Mp 51.6−53.4 °C; 1H NMR (400
MHz, CDCl3) δ 7.37 (m, 8 H), 7.28 (m, 2 H), 4.65 (s, 4 H), 1.59 (s,
12 H); 13C NMR (101 MHz, CDCl3) δ 138.6, 128.3, 127.7, 127.4,
81.7, 71.0, 68.5, 66.8, 28.7; IR 3091 (w), 3067 (w), 3066 (w), 3063
(w), 3048 (w), 3033 (w), 2985 (m), 2934 (w), 2905 (w), 2865 (w),
2864 (w), 2838 (w), 2374 (w), 2357 (w), 2150 (w), 1948 (w), 1871
(w), 1810 (w), 1745 (w), 1705 (w), 1606 (w), 1517 (w), 1498 (w),
1464 (w), 1456 (m), 1438 (w), 1382 (m), 1360 (w), 1339 (w), 1330
(w), 1330 (w), 1312 (w), 1303 (w), 1223 (m), 1185 (m), 1157 (s),
1122 (w), 1105 (w), 1086 (m), 1054 (s), 1030 (m), 1003 (w), 941
(w), 925 (w), 912 (w), 883 (m), 847 (w), 828 (w), 821 (w); HRMS
+
(ESI) calcd for C24H26NaO2 [M + Na]+ 369.1830, found 369.1836.
ASSOCIATED CONTENT
■
S
* Supporting Information
General methods, reaction optimization, kinetic studies and
characterization data, including NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(8) Nicolai, S.; Waser, J. Org. Lett. 2011, 13, 6324.
́ ́
(9) (a) Nicolai, S.; Erard, S.; Fernandez Gonzalez, D.; Waser, J. Org.
Lett. 2009, 12, 384. (b) Nicolai, S.; Piemontesi, C.; Waser, J. Angew.
Chem., Int. Ed. 2011, 50, 4680.
(10) Fraser, A. W.; Besaw, J. E.; Hull, L. E.; Baird, M. C.
Organometallics 2012, 31, 2470.
(11) See Table S3 in the Supporting Information for a full list of
tested enone ligands.
(12) (a) Kranenburg, M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Eur. J. Inorg. Chem. 1998, 1998, 155. (b) Dierkes, P.; W. N. M. van
Leeuwen, P. J. Chem. Soc., Dalton Trans. 1999, 1519. (c) van Leeuwen,
P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P. Chem. Rev.
2000, 100, 2741. (d) Birkholz, M.-N.; Freixa, Z.; van Leeuwen, P. W.
N. M. Chem. Soc. Rev. 2009, 38, 1099.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jerome.waser@epfl.ch.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
EPFL, F. Hoffmann-La Roche, Ltd., and SNF (Grant No.
200021_119810) are acknowledged for financial support.
(13) See Supporting Information for a list of tested additives.
R
dx.doi.org/10.1021/jo400254q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(14) On larger scale, reoptimization of the catalyst and ligand
loadings led to the use of 5 mol % Pd(dba)2 and 7.5 mol % DPEPHos.
See Supporting Information for more details.
(32) The trans-stereochemistry of the tetrahydrofuran products and
the cis-stereochemistry of the pyrrolidine products had been assigned
in our previous work with silyl acetylenes.8 The stereochemistry in this
work was deduced by analogy and comparison of the NMR spectra.
(33) Diastereoisomeric ratio calculated by integration of peaks at δ
4.14 (Major diastereoisomer) and δ 4.00 (Minor diastereoisomer).
(34) Diastereoisomeric ratio calculated by integration of peaks at δ
3.36 (Major diastereoisomer) and δ 3.56 (Minor diastereoisomer).
(35) Diastereoisomeric ratio calculated by integration of peaks at δ
3.13 (Major diastereoisomer) and δ 3.31 (Minor diastereoisomer).
(36) Diastereoisomeric ratio calculated by integration of peaks at δ
3.14 (Major diastereoisomer) and δ 3.31 (Minor diastereoisomer).
Full assignment based on COSY.
(37) Diastereoisomeric ratio calculated by integration of peaks at δ
3.05 (Major diastereoisomer) and δ 2.97 (Minor diastereoisomer).
(38) Diastereoisomeric ratio calculated by integration of peaks at δ
3.20 (Major diastereoisomer) and δ 3.07 (Minor diastereoisomer).
(39) Mccormick, J. B.; Jaynes, E. N.; Kaplan, R. I.; Clark, H. C.;
Ruddick, J. D. In Inorganic Synthesis; John Wiley & Sons, Inc.:
Hoboken, NJ, 2007; p 216.
(15) (a) Mu, F.; Lee, D. J.; Pryor, D. E.; Hamel, E.; Cushman, M. J.
Med. Chem. 2002, 45, 4774. The halogenoalkynes used in these
studies were synthesized using known procedures: (b) Cossy, J.;
Tresnard, L.; Pardo, D. G. Eur. J. Org. Chem. 1999, 1925. (c) Trost, B.
M.; Fandrick, D. R.; Dinh, D. C. J. Am. Chem. Soc. 2005, 127, 14186.
(d) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614.
(e) Gramlich, P. M. E.; Warncke, S.; Gierlich, J.; Carell, T. Angew.
Chem., Int. Ed. 2008, 47, 3442. (f) Sui, B.; Yeh, E. A. H.; Curran, D. P.
J. Org. Chem. 2010, 75, 2942. (g) Schmidt, R. G.; Bayburt, E. K.;
Latshaw, S. P.; Koenig, J. R.; Daanen, J. F.; McDonald, H. A.; Bianchi,
B. R.; Zhong, C.; Joshi, S.; Honore, P.; Marsh, K. C.; Lee, C.-H.;
Faltynek, C. R.; Gomtsyan, A. Bioorg. Med. Chem. Lett. 2011, 21, 1338.
(h) Nishimura, T.; Nagaosa, M.; Hayashi, T. Tetrahedron Lett. 2011,
52, 2185.
(16) Alcohols 5b and 5c were synthesized using known procedures:
(a) Janza, B.; Studer, A. J. Org. Chem. 2005, 70, 6991. (b) Habel, A.;
Boland, W. Org. Biomol. Chem. 2008, 16, 1601.
(17) The protected amines used in this study were synthesized using
known procedures: see ref 6f. (a) Schomaker, J. M.; Travis, B. R.;
Borhan, B. Org. Lett. 2003, 5, 3089. (b) Dolman, S. J.; Schrock, R. R.;
Hoveyda, A. H. Org. Lett. 2003, 5, 4899. (c) Ma, S.; Ni, B. Chem.
Eur. J. 2004, 10, 3286. (d) Michael, F. E.; Cochran, B. M. J. Am. Chem.
Soc. 2006, 128, 4246. (e) Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J.
Am. Chem. Soc. 2006, 128, 3748. (f) Bertrand, M. B.; Leathen, M. L.;
(40) Hegedus, L. S; McKearin, J. M. J. Am. Chem. Soc. 1982, 104,
2444.
(41) Hok, S.; Schore, N. E. J. Org. Chem. 2006, 71, 1736.
(42) Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2001, 57, 4817.
(43) Jiang, M. X.-W.; Rawat, M.; Wulff, W. D. J. Am. Chem. Soc. 2004,
126, 5970.
̀
Wolfe, J. P. Org. Lett. 2007, 9, 457. (g) Lemiere, G.; Gandon, V.;
Cariou, K.; Hours, A.; Fukuyama, T.; Dhimane, A.-L.; Fensterbank, L.;
Malacria, M. J. Am. Chem. Soc. 2009, 131, 2993. (h) Gresser, M. J.;
Wales, S. M.; Keller, P. A. Tetrahedron 2010, 66, 6965. (i) Li, X.; Li,
C.; Zhang, W.; Lu, X.; Han, S.; Hong, R. Org. Lett. 2010, 12, 1696.
(18) For an example of one-pot metathesis-hydrogenation, see:
Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003, 42, 308. The
̈
formation of the alkane product was not observed in the absence of
Pd/C, which indicated that the heterogenous catalyst was required for
hydrogenation.
(19) (a) Liu, Q.; Burton, D. J. Tetrahedron Lett. 1997, 38, 437.
(b) Damle, S. V.; Seomoon, D.; Lee, P. H. J. Org. Chem. 2003, 68,
7085. An alternative mechanism would be insertion of II onto the
triple bond of 6h followed by β-bromide elimination. Overall, this
process is a reductive coupling leading to Pd(II). The active Pd(0)
catalyst would be most probably regenerated after one of the β-hydride
elimination proposed in the catalytic cycle.
(20) A similar explanation has also been proposed in the case of
oxyarylation, see ref 6h.
(21) Another possibility for the formation of 14 would be direct
Wacker-like oxidation of the olefin. However, as special care has been
taken to exclude air and moisture during the reaction, this mechanism
appears less probable.
(22) Crude analysis of the initial rate of the reactions would give
reaction orders of 0.6, 0.6 and 1.4 for alcohol 5b, alkynyl bromide 6h
and Pd(dba)2, respectively. However, the many side reactions and the
catalyst deactivation occurring during oxyalkynylation limit the
significance of these results.
(23) Bertrand, M. B.; Wolfe, J. P. Tetrahedron 2005, 61, 6447.
(24) Basel, Y.; Hassner, A. Synthesis 2001, 550.
(25) Legeay, J. C.; Lewis, W.; Stockman, R. A. Chem. Commun. 2009,
2207.
(26) Curran, D. P.; Liu, H. J. Chem. Soc., Perkin Trans. 1 1994, 1377.
(27) Wang, L.; Thai, K.; Gravel, M. Org. Lett. 2009, 11, 891.
(28) Rubin, Y.; Lin, S. S.; Knobler, C. B.; Anthony, J.; Boldi, A. M.;
Diederich, F. J. Am. Chem. Soc. 1991, 113, 6943.
(29) Yamagishi, M.; Nishigai, K.; Hata, T.; Urabe, H. Org. Lett. 2011,
13, 4873.
(30) Salvi, L.; Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am.
Chem. Soc. 2007, 129, 16119.
(31) The peaks at 18.1 and 18.0 ppm correspond to the rotamers of
the TIPS protecting group.
S
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