Correlation between functionality preference of ru carbenes and exo / endo product selectivity for clarifying the mechanism of ring-closing enyne metathesis

Article abstract of DOI:10.1021/jo401420f

Functionality preferences of metathesis Ru carbenes to various alkenes and alkynes with electronic and steric diversity were determined by using time-dependent fluorescence quenching. The functionality preferences depend not only on the properties of mult

Full text of DOI:10.1021/jo401420f

Featured Article
pubs.acs.org/joc
Correlation between Functionality Preference of Ru Carbenes and
exo/endo Product Selectivity for Clarifying the Mechanism of Ring-
Closing Enyne Metathesis
Ok Suk Lee,† Kyung Hwan Kim,‡,§ Jinwoo Kim,‡ Kuktae Kwon,‡ Taedong Ok,∥ Hyotcherl Ihee,*,‡,§
Hee-Yoon Lee,*,‡ and Jeong-Hun Sohn*,†
†Department of Chemistry, College of Natural Sciences, Chungnam National University, Daejeon 305-764, Korea
‡Department of Chemistry, KAIST, Daejeon 305-701, Korea
§Center for Nanomaterials and Chemical Reactions, Institute for Basic Science, Daejeon 305-701, Korea
∥College of Medicine, Yonsei University, Seoul 120-752, Korea
S
* Supporting Information
ABSTRACT: Functionality preferences of metathesis Ru car-
benes to various alkenes and alkynes with electronic and steric
diversity were determined by using time-dependent fluorescence
quenching. The functionality preferences depend not only on the
properties of multiple bonds but also on the ligands on Ru. There
was a good correlation between functionality preference and the
metathesis reaction outcome. The correlation between function-
ality preference and exo/endo product ratio offers a solution to
resolve the mechanistic issue related with alkene- vs alkyne-
initiated pathway in ring-closing enyne metathesis. The correlation
indicates the preference is likely to dictate the reaction pathway and eventually the outcome of the reaction. The Ru catalyst
favoring alkyne over alkene provides more endo product, indicating that the reaction mainly initiates at the alkyne. By changing
the substitution pattern, the preference can be reversed to give an exclusive exo product.
functional groups, which reflects the early event in the reaction,
can be determined. In metal-catalyzed coupling reactions with
multiple functionalities, the catalyst-functionality complex
formation might be critical to determine overall reaction
pathway and final product. Using this FRET-based method, we
have endeavored to solve the mechanistic ambiguity in ring-
closing enyne metathesis (enyne RCM) that provides
undisputed efficiencies in producing synthetically versatile
cyclic 1,3-dienes.2 Mo or Ru carbene complexes for metathesis
reaction have absorbance bands at visible range and do not emit
fluorescence. We previously demonstrated that these catalysts
act as fluorescence quenchers for the dyes conjugated with
terminal alkene, alkyne, and allene through the formation of
catalyst−substrate complexes.3
INTRODUCTION
■
Fluorescence resonance energy transfer (FRET) is a distance-
dependent interaction and is detected by the fluorescence
appearance from the fluorescence acceptor or by quenching of
the fluorescence from the fluorescence donor.1 Many transition
metal complexes exhibit their own visible colors, meaning that
their absorbance or emission bands are at the visible light range.
We conceived that the colored metal complex could act as
either fluorescence donor, acceptor, or quencher for dyes due
to FRET phenomenon, when complexed with a dye-conjugated
functional group (Figure 1). By measurement of fluorescence
quenching as a function of time, both kinetic and
thermodynamic preference of the metal complex toward the
The mechanistic ambiguity of the enyne RCM reactions,
especially catalyzed by Ru complexes, has attracted much
attention and debate for the following reasons.2g,4 First, there
exist two equally plausible mechanisms for the formation of the
same exo product via the reaction initiation either at the alkene
(Route A of Scheme 1)5 or at the alkyne (Route B).6 Second,
extensive research on enyne RCM has established that the exo
product is formed exclusively.2 There has been no report on the
Figure 1. Schematic illustration of the FRET-based method to
determine the functionality preference of metal complexes having
visible colors. The metal complexes could act as either fluorescence
donor, acceptor, or quencher for dyes due to FRET phenomenon,
when complexed with a dye-conjugated functionality.
Received: July 2, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo401420f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
of alkyne to 1,3-diene2,13 occur at ambient temperature, the
FRET-based method would allow detection of not only the
initial coordinated species (FQ-1) but also the functionality-
transformed species (FQ-2 and FQ-3 in Figure 2). For
Scheme 1. Plausible Mechanisms of Enyne RCM Reaction
Catalyzed by Ru Carbenes
a
a
There exist two equally plausible mechanisms for the formation of
the same exo product vi via the reaction initiation either at alkene
(Route A) or at alkyne (Route B). The endo product xiii can be
formed via only the reaction initiation at alkyne (Route C).
Figure 2. Functionality preferences of the metathesis Ru carbenes
toward diverse alkenes and alkynes were determined by using the
FRET-based method. Catalysts Ru-1 and Ru-2 act as quenchers of the
Dapoxyl fluorophore when Ru-substrate complexes, FQ-1, FQ-2, or
FQ-3, are formed by the reaction of the Ru catalysts with the dapoxyl-
conjugated substrates. The method is not sensitive to whether the
phosphine group is detached or intact, but it is sensitive to whether the
functional group (alkene or alkyne) tagged with the fluorophore is
detached or attached to the catalyst.
formation of the endo product as the major product, which
should be formed only through the reaction initiation at alkyne
(Route C) in Ru-catalyzed reactions.4a,6c In addition to these
characteristics of the reaction, the mechanistic study providing
the true reaction pathway is hampered by the reversible nature
of the reaction routes. Theoretical studies on enyne RCM using
simplified Ru models have been attempted, but no
comprehensive mechanistic explanation has been proposed.7
To resolve the actual reaction pathway of enyne RCM, it is
critical to establish the relationship between the early event and
the final product outcome of the reaction. Schrock and
Hoveyda reported selective formation of endo products from
RCM reactions of enynes having terminal alkene and alkyne
groups using Mo- or W-based carbenes.8 These findings can be
rationalized only with the reaction initiating at the alkyne. By
using the FRET-based method, we found that the Mo catalysts
preferred the terminal alkyne over the terminal alkene.3b These
two results together indicate that the alkyne preference of Mo
determines the reaction pathway initiated at the alkyne in Mo-
based enyne RCM. This outcome agrees with the previous
theoretical study.9 Herein we report the success in linking the
relative alkene/alkyne preference of Ru catalysts, which governs
the early catalyst−substrate complex formation event, and the
exo/endo selectivity of the products, the final outcome of the
reaction. We first studied the functionality preference of Ru
catalysts toward diversely substituted alkenes and alkynes by
using the FRET-based method.3,10 Then, we examined the exo/
endo selectivity in the enyne RCM reactions of substrates
having various pairs of alkenes and alkynes under standardized
reaction conditions.11
substrates having steric and electronic diversity, we prepared
Dapoxyl-conjugated alkenes and alkynes: monomethylated (2−
4), dimethylated (5), and electron-deficient (6) alkenes, and
ethoxylated (8), methylated (9), and silylated (10) alkynes, as
well as a terminal alkene (1), a terminal alkyne (7), and the
control alkane (11). The functional groups were connected to
the dye moiety via an amide bond with an identical three
carbon tether (Figure 2).
The substrates were synthesized by amide bond formation
between amines 12−22 and activated dye 23 using Et3N in
CH2Cl2 at 0 °C in the final step. The synthesis of substrates
with terminal alkene (1), terminal alkyne (7), and control
alkane (11) were reported in our previous paper.3a Amines 13−
16, 20, and 21 for substrates 2−5, 9, and 10, respectively, were
prepared by following the literature procedures, and amine 17
with electron-deficient alkene for substrate 6 was obtained by
removal of Boc group from Boc-protected 1714 using
CF3CO2H. Amine 19 with ethoxy alkyne was synthesized
from iodide 2415 in two steps including the substitution of the
iodide with phthalimide followed by amino group deprotection
(Scheme 2).
The prepared alkene and alkyne substrates were used for the
FRET measurements. During the measurement, diverse Ru
species would be generated by the reactions of the catalyst with
the substrate alkenes or alkynes, and they might complicate the
analysis and cause misleading conclusions. Thus, to avoid such
a situation and to accurately compare the functionality
preferences, the FRET measurements were performed under
reaction conditions using more than 1.5 equivalents of the
catalysts relative to the substrates over the span of 20 min. In
this short time interval, the amount of the altered catalyst
species should be negligible, and the functionality preference is
RESULTS AND DISCUSSION
■
For our study, we used the Grubbs first-generation (Ru-1) and
second-generation (Ru-2) Ru catalysts. Catalysts Ru-1 and Ru-
2 have absorbance bands at λmax 527 nm and λmax 499 nm in
CH2Cl2, respectively, both of which are near the fluorescence
band of Dapoxyl dye (λmax 508 nm in CH2Cl2), with no
emission of fluorescence. Thus both catalysts can act as
quenchers of Dapoxyl fluorophore when Ru-substrate com-
plexes are formed. Since olefin metathesis12 and transformation
B
dx.doi.org/10.1021/jo401420f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
For each catalyst, the fluorescence quenching traces were
quantitatively analyzed with a set of parameters to determine
both kinetic and thermodynamic parameters, k, k−1, and ΔG, of
formation of the Ru-substrate complex for a given substrate/
catalyst pair; the results are summarized in Table 1.
Scheme 2. Syntheses of Dapoxyl-Cojugated Alkenes and
Alkynes
Table 1. Kinetic and Thermodynamic Parameters for
a
Alkenes and Alkynes with Ru Catalysts
rel.
stability
b
catalyst substrate k (M−1 s−1
)
k−1 (s−1
)
ΔG (kJ/mol)
−28.9 0.39
Ru-1
1
3.15 ( 0.19) 2.21 ( 0.33)
1
× 103 × 10−2
2.07 ( 0.30) 3.70 ( 0.61)
× 103 × 10−1
1.36 ( 0.22) 2.84 ( 0.49)
× 103 × 10−1
1.27 ( 0.20) 2.93 ( 0.56)
× 103 × 10−1
1.15 ( 0.19) 3.12 ( 0.60)
× 103 × 10−1
6.34 ( 0.97) 1.73 ( 0.37)
× 102 × 10−1
1.44 ( 0.15) 1.33 ( 0.24)
× 103 × 10−1
1.65 ( 0.19) 1.02 ( 0.12)
× 103 × 10−1
1.04 ( 0.14) 2.28 ( 0.37)
× 103 × 10−1
9.80 ( 1.38) 2.30 ( 0.40)
× 102 × 10−1
2.57 ( 0.49) 4.78 ( 1.25)
× 102 × 10−2
1.72 ( 0.92) 5.24 ( 1.79)
× 102 × 10−2
1.84 ( 0.28) 5.27 ( 1.51)
× 102 × 10−2
1.67 ( 0.46) 9.11 ( 1.74)
× 102 × 10−2
1.48 ( 0.50) 1.08 ( 0.43)
× 102 × 10−1
1.10 ( 0.41) 7.16 ( 1.85)
× 102 × 10−2
6.31 ( 2.64) 4.76 ( 0.82)
× 102 × 10−4
3.56 ( 1.48) 1.37 ( 0.47)
× 102 × 10−3
1.58 ( 0.30) 2.81 ( 1.31)
× 102 × 10−2
2.64 ( 0.37) 1.91 ( 0.28)
× 102 × 10−2
2
−21.4 0.54
−21.0 0.59
−20.8 0.61
−20.4 0.63
−20.3 0.65
−22.6 0.40
−24.0 0.41
−20.9 0.52
−20.7 0.55
−21.3 0.65
−19.7 0.85
−20.2 0.71
−18.6 0.47
−17.9 0.99
−18.2 0.64
−34.9 0.43
−30.9 0.85
−21.0 0.81
−23.6 0.36
0.740
0.726
0.720
0.706
0.702
1
3
4
5
for only a single kind of the initial catalyst. We measured the
time-dependent fluorescence quenching of each of various pairs
of ten substrates (10−25 μM) and two catalysts (1.5−3.0
equiv) in CH2Cl2 at 20 °C. An example of the fluorescence
traces is shown in Figure 3. These are the calibrated integrated
values of the corresponding fluorescence spectra for all used
combinations of the ten substrates (20 μM) and the two
catalysts (1.5 equiv) over 20 min.
6
7
8
1.062
0.925
0.916
1
9
10
1
Ru-2
2
0.925
0.950
0.875
0.841
0.855
1
3
4
5
6
7
8
0.885
0.602
0.677
9
10
a
k and k−1 are directly determined as fitting parameters, and ΔG is
calculated as −RT ln(k/k−1). k and ΔG represent the kinetic and
thermodynamic preferences, respectively. Relative thermodynamic
b
stability of the catalyst−substrate complexes. The ΔG values of
catalyst−alkene (1) complexes and catalyst−alkyne (7) complexes are
defined as 1. The thermodynamic functionality preference of Ru-1 is 1
> 8 > 7 > 2 > 3 > 9 > 4 > 10 > 5 > 6, while that of Ru-2 is 7 > 8 > 10
> 1 > 9 > 3 > 2 > 4 > 6 > 5.
Since formation of the intermediates is reversible in the
enyne RCM, the thermodynamic functionality preference (ΔG)
is more important than the kinetic preference. A more negative
ΔG value indicates a stronger thermodynamic preference. For
alkene substrates, the functionality preferences of both Ru-1
and Ru-2 catalysts follow the substitution number of the
alkenes, as anticipated, i.e., terminal > monomethylated >
dimethylated alkene. On the other hand, the electron-deficient
alkene 6 is least preferred by Ru-1 but is positioned prior to the
dimethylated alkene 5 in the case of Ru-2. Among the three
Figure 3. Time-dependent fluorescence quenching of the substrates
(alkenes 1−6 and alkynes 7−10) by the catalysts, Ru-1 and Ru-2.
Experimental data points are shown as black circles (20:30 μM of
substrates vs catalysts), which correspond to the integrated values of
the fluorescence spectra (see Supporting Information for details). The
theoretical curves from the fitting analysis3 are represented as red (1),
green (2), blue (3), cyan (4), magenta (5), navy (6), orange (7),
purple (8), violet (9), and olive (10).
C
dx.doi.org/10.1021/jo401420f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
monomethylated alkenes, the two catalysts exhibit different
preference orders, i.e., 2-methylated (2) > cis-methylated (3) >
trans-methylated alkene (4) for Ru-1 and cis-methylated (3) >
2-methylated (2) > trans-methylated alkene (4) for Ru-2. The
preference of the catalysts becomes more complex for alkyne
than for alkene substrates. Interestingly, among alkyne
substrates, Ru-1 primarily prefers ethoxylated alkyne 8, whereas
Ru-2 favors terminal alkyne 7, and their preference orders are
completely different. For all alkenes and alkynes investigated in
this study, the overall thermodynamic functionality preference
of Ru-1 is alkene 1 > alkyne 8 > alkyne 7 > alkene 2 > alkene 3
> alkyne 9 > alkene 4 > alkyne 10 > alkene 5 > alkene 6, while
that of Ru-2 is alkyne 7 > alkyne 8 > alkyne 10 > alkene 1 >
alkyne 9 > alkene 3 > alkene 2 > alkene 4 > alkene 6 > alkene
5. It is obvious that substituents on either alkene or alkyne have
strong effects on the functionality preference of both catalysts,
which is partially consistent with the previously calculated
reactivity order for substituted alkenes and alkynes, although
the order is not an exact match.16
were determined by the FRET-based method. If the enynes
react with the catalyst preferring the alkyne over the alkene and
produce more of the endo product and/or the triene relative to
the exo product, then it would be highly likely that the
functionality preference guides the final outcome of the
product. This conclusion would be further strengthened if the
exo/endo selectivity variation correlates well with the change in
the preference caused by the substituent effect. Enyne
substrates 258b and 2619 having terminal alkene/terminal
alkyne and methylated alkene/terminal alkyne, respectively,
were prepared by following the literature procedures.
Previously unknown substrates 27 and 28 containing terminal
alkene/methylated alkyne and electron-deficient alkene/termi-
nal alkyne, respectively, were synthesized as shown in Scheme
4.
Scheme 4. Enyne Substrates for Evaluation of exo/endo
Product Ratio
After identifying the functionality preference, our efforts were
then directed to the design of enyne RCM experiments whose
product outcomes can be linked to the functionality preference.
For this purpose, we considered that fixing the actual catalytic
species as a single species during the reactions is critical to
correlate the exo/endo selectivity with the functionality
preference. Thus, we devised the reaction condition involving
high ethylene pressure to ensure that a single catalytic species,
the Ru-methylidene (A in Scheme 3), is operating during the
Scheme 3. Enyne RCM Reactions under High Ethylene
Pressure
We carried out RCM reactions of the enyne substrates using
5 mol % Ru catalyst in CH2Cl2 under ethylene pressure (100
psi) at 40 °C for 20 h. In addition to the production of the
identical Ru methylidene in all reactions, the high ethylene
pressure makes it possible to intercept intermediate xiv, a
precursor to the exo product xv, as the triene xvi (Scheme 5).
Scheme 5. Possible Product Shift of exo to endo in the
Alkyne-Initiated Pathways
reaction cycles11 and to divert the reaction pathways depending
on the ene/yne preferences of the catalysts where we expect
substrate-dependent exo/endo selectivity.17 Under Ar, the actual
catalytic species is Ru complex, which is identified by enyne
substrates and by the reaction pathway initiated at alkene (B)
or alkyne (C) as shown in Scheme 3. Though the functionality
preference of Ru methylidene complexes is more desirable than
that of the precatalysts, Ru-1 and Ru-2, in establishing the
correlation, the experimental limitation only allowed the
preference of the latter. However, it is likely that there is no
significant deviation between the precatalysts and their
methylidenes in the correlation, because we observed that the
Ru-1 analogue replacing benzylidene of Ru-1 with isopenteny-
lidene shows no change of the order of functionality preference
to Ru-1.18
The triene eventually transforms into the endo product xviii,
resulting in the product shift of exo to endo in Routes B and C
in Scheme 1, both of which are initiated at the alkyne site. The
results of the enyne RCM reactions are summarized in Table 2.
Enyne 25 containing terminal alkene and terminal alkyne
groups has been known to show a strong preference for the exo
product in Ru-based reactions, regardless of the mechanistic
pathway (Route A and B in Scheme 1).20 Catalyst Ru-1, which
prefers the terminal alkene 1 over the terminal alkyne 7,
produced only the exo product 33.8b However, with the alkyne-
To investigate the exo/endo product ratios, we chose four
representative enyne substrates containing different pairs of
alkenes and alkynes, whose preferences toward both catalysts
D
dx.doi.org/10.1021/jo401420f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
a
Table 2. Variation of exo/endo Ratio in Enyne RCM Using Ru-1 and Ru-2
a
b
Reactions were carried out under 100 psi of ethylene with 5 mol % of Ru catalyst in CH2Cl2 at 40 °C for 20 h. Substrate 14 was completely
c
consumed by Ru-2, whereas most remained in the case of Ru-1. Ratios were determined by analysis of integration of the olefinic protons from the
400 MHz H NMR spectra of crude mixtures.
1
favoring Ru-2, some endo product 348b was obtained with an
exo/endo ratio of 94/6 (Table 2, entry 1). The formation of the
endo product in the reaction with Ru-2 has a significant
implication because it indicates that at least 6% of the product
mixture was produced through reaction initiation at the alkyne
(Route C and/or combination of Routes B and C).
The ratios of the products for both catalysts dramatically
changed for enyne 26 having a 1,1-disubstituted alkene and a
terminal alkyne. The reactions with both Ru-1 and Ru-2
yielded endo product 378b as the major product over exo
product 3621 along with triene 38 (entry 2). The product ratios
agree with the higher preference of both catalysts to the
terminal alkyne 7 over the disubstituted alkene 2. The higher
triene ratio with Ru-1 also reflects the higher reactivity of Ru-2
over Ru-1 for the substituted alkene.
remained unreactive toward Ru-1. These results are in line with
the product shift of exo to endo in Routes B and C in Scheme 1
under ethylene atmosphere.
Overall, the results in Tables 1 and 2 show good correlations
between the functionality preference of the Ru catalyst and the
exo/endo product ratio in the enyne RCM reactions. The
correlation exhibits that the former is likely to govern the latter
in Ru-catalyzed enyne RCM reactions. This means that the
reactions proceed through either alkene- or alkyne-initiated
pathways, which is dictated by the functionality preference of
the catalyst (Figure 4). In other words, because the
On the other hand, for enyne 27 having terminal alkene and
methylated alkyne, for which both catalysts prefer the former
functionality (1) to the latter (9), both catalysts yielded only
exo product 3922 with no endo product, and only Ru-2
produced an appreciable amount of triene 4123 (entry 3). This
difference between Ru-1 and Ru-2 in producing the triene
product can be explained by the relative 1/9 functionality
preference difference between Ru-1 and Ru-2. The data in
Table 1 show a preference difference of 4.2 kJ/mol for 1 and 9
for Ru-1, whereas Ru-2 shows a much smaller value of 0.3 kJ/
mol. Therefore, it is highly plausible that Ru-1 allows only
alkene-initiated pathway to form 39, whereas the more reactive
Ru-2 allows both alkene- and alkyne-initiated pathways.
For the RCM of enyne 28 having terminal alkyne and
electron-deficient acrylic alkene, an exo/endo product ratio of
17:83 together with the alkyne-transformed triene 44 was
obtained with Ru-2, whereas starting material 28 was almost
unreactive toward Ru-1 (entry 4). In addition, when the
reaction was evaluated under Ar, only exo product 42 was
observed in a small amount. Instead, the triene 44 was obtained
as the major product for Ru-2; most of the starting material
Figure 4. The correlation between functionality preference of Ru and
exo/endo product ratio in Ru-based enyne RCM reaction. The
correlation exhibited that the former is likely to govern the latter.
functionality preference reflects the feasibility of the generation
of Ru-alkene/alkyne complexes ii−iv or vii−xi, the energetics
for these intermediates determines the reaction pathway and
the final product distribution.
CONCLUSION
■
We have determined the functionality preference of metathesis
Ru catalysts toward diverse alkenes and alkynes by using time-
dependent fluorescence quenching. The relative alkene/alkyne
E
dx.doi.org/10.1021/jo401420f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
nm; Fluorescence λmax (CH2Cl2) 508 nm; HRMS (ESI) (m/z) calcd
for C24H28N3O2 [M + H]+ 390.2182, found 390.2180; IR (film) cm−1
3853, 3748, 3673, 3650, 2922, 2360, 2340, 1734, 1717, 1699, 1652,
1614, 1558, 1540, 1508, 1457, 668.
functionality preference was applied to unravelling the
mechanism of enyne RCM by correlating with exo/endo
product selectivity in the Ru-based reactions. The correlation
clearly shows that the former is likely to govern the latter and
indicates that the reactions proceed through either alkene- or
alkyne-initiated pathways, dictated by the functionality
preference of the catalyst. For the RCM reaction of the
enyne containing terminal alkene and terminal alkyne groups
under identical steric and electronic environments, our results
support the reaction pathway in which the reaction with Ru-1
and Ru-2 initiates preferably at the alkene and the alkyne,
respectively. The results offer a rational design guide for
tandem reaction methodologies using sequential metathesis
processes dictated by the functionality preference of a catalyst,
as well as a unified mechanistic explanation of the Ru-based
enyne RCM reactions.
Compound 4. (2.2 mg, 92%): TLC (EtOAc:n-hexane, 50:50 v/v)
1
Rf = 0.43; H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.4 Hz, 2H),
8.02 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 7.46 (s, 1H), 6.85
(d, J = 9.0 Hz, 2H), 5.18 (dd, J = 6.0, 5.4 Hz, 1H), 3.42 (q, J = 6.6 Hz,
2H), 3.03 (s, 6H), 2.07 (m, 2H), 1.67 (s, 3H), 1.59 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.7, 158.9, 152.8, 150.6, 135.5, 130.4, 130.3,
127.3, 126.0, 125.8, 125.7, 121.0, 115.8, 112.2, 40.3, 39.9, 30.2, 29.7,
29.3, 17.9; UV−vis λmax 366 nm; Fluorescence λmax (CH2Cl2) 508 nm;
HRMS (ESI) (m/z) calcd for C24H28N3O2 [M + H]+ 390.2182, found
390.2183; IR (film) cm−1 3853, 3748, 3673, 3650, 2922, 2360, 2340,
1734, 1717, 1699, 1652, 1614, 1558, 1540, 1508, 1457, 668.
Compound 5. (2.0 mg, 80%): TLC (EtOAc:n-hexane, 50:50 v/v)
Rf = 0.50; 1H NMR (600 MHz, acetone-d6) δ 8.15 (d, J = 8.4 Hz, 2H),
8.03 (d, J = 8.4 Hz, 2H), 7.87 (bs, 1H)), 7.69 (d, J = 8.9 Hz, 2H), 7.46
(s, 1H), 6.85 (d, J = 9.0 Hz, 2H), 5.18 (m, 1H), 3.42 (m, 2H), 3.03 (s,
6H), 2.08 (m, 2H), 1.67 (m, 5H), 1.59 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 167.0, 158.9, 152.8, 135.2, 134.1, 130.3, 127.3, 126.0, 125.6,
121.0, 120.1, 119.5, 112.2, 44.3, 40.3, 30.9, 26.25, 26.20, 17.9; UV−vis
λmax 366 nm; Fluorescence λmax (CH2Cl2) 508 nm; HRMS (ESI) (m/
z) calcd for C25H29NaN3O2 [M + Na]+ 426.2152, found 426.2153; IR
(film) cm−1 3853, 3748, 3673, 3650, 2963, 2925, 2853, 2360, 2340,
1734, 1699, 1652, 1613, 1558, 1540, 1509, 1436, 1363, 1261, 1198,
1110, 951, 859, 816, 668.
EXPERIMENTAL SECTION
■
General Methods. Common solvents were purified before use.
Tetrahydrofuran (THF) and dichloromethane (CH2Cl2) were purified
by distillation from sodium-benzophenone and calcium hydride,
respectively. N,N-Dimethylformamide, acetonitrile and triethylamine
were used as received. All reagents were reagent grade and purified
where necessary. “Water” refers to distilled water. Reactions were
monitored by thin layer chromatography (TLC) using silica gel plates.
Flash column chromatography was performed over ultrapure silica gel
(230−400 mesh). 1H NMR and 13C NMR spectra were recorded on a
400 or 600 MHz spectrometer using residual solvent peaks as an
internal standard (CHCl3: δ 7.24 ppm for proton and δ 77.0 ppm for
carbon; acetone: δ 2.05 ppm for proton and δ 29.9 ppm for carbon;
benzene: δ 7.15 ppm for proton and δ 128.0 ppm for carbon; toluene:
δ 2.09 ppm for proton and δ 20.4 ppm for carbon). Multiplicities for
1H NMR are designated as follows: s = singlet, d = doublet, dd =
Compound 9. (2.2 mg, 92%): TLC (EtOAc:n-hexane, 50:50 v/v)
1
Rf = 0.35; H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.5 Hz, 2H),
7.85 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.9 Hz, 2H), 7.26 (s, 1H), 6.74
(d, J = 9.0 Hz, 2H), 6.57 (m, 1H), 3.59 (q, J = 6.4 Hz, 2H), 3.01 (s,
6H), 2.28 (m, 2H), 1.81 (m, 2H), 1.78 (t, J = 2.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.7, 158.9, 152.9, 150.6, 135.4, 130.3, 127.4,
126.0, 125.6, 121.0, 115.8, 112.2, 78.5, 76.9, 40.3, 39.9, 28.2, 16.8, 3.5;
UV−vis λmax 366 nm; Fluorescence λmax (CH2Cl2) 508 nm; HRMS
(ESI) (m/z) calcd for C24H26N3O2 [M + H]+ 388.2025, found
388.2024; IR (film) cm−1 3853, 3748, 3673, 3650, 2959, 2922, 2852,
2360, 2340, 1734, 1699, 1652, 1612, 1557, 1540, 1509, 1363, 1197,
951, 859, 815, 715, 668.
doublet of doublets, ddd = doublet of dd, dt = doublet of triplets, ddt
= doublet of dt, t = triplet, q = quartet, quint = quintet, m = multiplet,
bs = broad singlet. Infrared spectra (IR) were recorded on FT-IR
spectrometer and are reported in reciprocal centimeters (cm−1). UV−
visible spectra were recorded on UV−visible spectrophotometer. High
resolution mass spectra (HRMS) were obtained on TOF-Q.
Compound 10. (2.1 mg, 87%): TLC (EtOAc:n-hexane, 50:50 v/v)
1
Rf = 0.48; H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 2H),
7.84 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 9.0 Hz, 2H), 7.26 (s, 1H), 6.75
(d, J = 9.0 Hz, 2H), 6.44 (m, 1H), 3.59 (q, J = 6.6 Hz, 2H), 3.01 (s,
6H), 2.37 (t, J = 6.8 Hz, 2H), 1.86 (quint, J = 6.7 Hz, 2H), 0.13 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 166.9, 158.9, 152.9, 150.6,
135.3, 130.4, 127.4, 126.0, 125.7, 121.0, 115.8, 112.2, 106.3, 85.9, 40.3,
39.6, 28.1, 17.8, 0.1; UV−vis λmax 366 nm; Fluorescence λmax (CH2Cl2)
508 nm; HRMS (ESI) (m/z) calcd for C26H32N3O2Si [M + H]+
446.2264, found 446.2262; IR (film) cm−1 3853, 3748, 3673, 3650,
2921, 2360, 2340, 2175, 1734, 1699, 1652, 1613, 1558, 1540, 1508,,
1363, 1106, 842, 761.
General Procedure for the Syntheses of Compounds 2−5, 9,
and 10. To a mixture of amine 12,24 13,25 14,25 15,26 20,27 or 2128
(9.0 μmol) and activated dye 23 (6.2 μmol) in CH2Cl2 (0.2 mL) was
added Et3N (27 μmol), and the resulting mixture was stirred for 20
min at 0 °C. The mixture was diluted with EtOAc (3 mL), washed
with saturated NH4Cl (0.5 mL) and brine (0.5 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
product was purified by flash column chromatography or preparative
TLC to give the desired dapoxyl-conjugated product.
Compound 2. (2.1 mg, 87%): TLC (EtOAc:n-hexane, 50:50 v/v)
Synthesis of Compound 6. To a solution of Boc-protected 1714
(9.0 mg, 35 μmol) in CH2Cl2 (1.0 mL) was added CF3CO2H (0.2
mL), and the reaction mixture was stirred at 0 °C for 1 h. After
concentration under reduced pressure, the residue was dissolved in
CH2Cl2 (0.1 mL). To this solution was added a solution of 23 (3.0 mg,
7.4 μmol) in CH2Cl2 (0.1 mL), and the resulting mixture was stirred at
0 °C for 30 min. The mixture was diluted with EtOAc (3 mL), washed
with saturated NH4Cl (0.5 mL) and brine (0.5 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
product was purified by column chromatography to give 6 (2.9 mg,
1
Rf = 0.40; H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H),
7.84 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.9 Hz, 2H), 7.26 (s, 1H), 6.74
(d, J = 9.0 Hz, 2H), 6.21 (m, 1H), 4.75 (m, 2H), 3.47 (q, J = 7.0 Hz,
2H), 3.01 (s, 6H), 2.13 (m, 2H), 1.77 (quint, J = 7.2 Hz, 2H), 1.74 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 166.7, 159.6, 153.4, 151.0,
145.7, 136.1, 130.9, 130.0, 127.9, 126.7, 126.3, 121.7, 113.1, 111.3,
40.5, 40.0, 35.3, 29.7, 22.3; UV−vis λmax 366 nm; Fluorescence λmax
(CH2Cl2) 508 nm; HRMS (ESI) (m/z) calcd for C24H28N3O2 [M +
H]+ 390.2182, found 390.2183; IR (film) cm−1 3853, 3748, 3673,
3650, 2923, 2851, 2359, 2340, 1734, 1699, 1651, 1613, 1558, 1540,
1509, 1364, 1197, 1106, 860, 815.
1
86%): TLC (EtOAc:n-hexane, 50:50 v/v) Rf = 0.23; H NMR (400
MHz, acetone-d6) δ 8.15 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.54 Hz,
2H), 7.95 (bs, 1H), 7.68 (d, J = 9.0 Hz, 2H), 7.45 (s, 1H), 6.98 (dt, J =
7.0, 15.6 Hz, 1H), 6.84 (d, J = 9.0 Hz, 2H), 5.90 (dt, J = 1.6, 15.6 Hz,
1H), 4.12 (q, J = 7.12 Hz, 2H), 3.47 (q, J = 6.8 Hz, 2H), 3.02 (s, 6H),
2.35 (ddd, J = 1.50, 7.2, 14.6 Hz, 2H), 1.82 (quint, J = 7.2 Hz, 2H),
1.23 (t, J = 7.10 Hz, 3H); 13C NMR (100 MHz, acetone-d6) δ 166.6,
159.6, 153.8, 151.8, 149.3, 136.9, 130.8, 128.65, 128.64, 126.3, 122.5,
121.9, 116.5, 114.7, 113.1, 60.3, 40.2, 39.8, 39.6, 28.7, 14.4; UV−vis
Compound 3. (2.3 mg, 95%): TLC (EtOAc:n-hexane, 50:50 v/v)
Rf = 0.40; H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.4 Hz, 2H),
1
7.83 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.9 Hz, 2H), 7.25 (s, 1H), 6.74
(d, J = 8.9 Hz, 2H), 6.18 (m, 1H), 5.51 (m, 1H), 5.41 (m, 1H), 3.47
(q, J = 6.8 Hz, 2H), 3.01 (s, 6H), 2.16 (m, 2H), 1.71 (quint, J = 7.2
Hz, 2H), 1.62 (d, J = 6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
166.7, 158.9, 152.8, 150.6, 135.4, 130.3, 129.4, 127.3, 126.0, 125.6,
125.0, 121.0, 115.8, 112.2, 40.3, 39.9, 29.3, 24.4, 12.8; UV−vis λmax 366
F
dx.doi.org/10.1021/jo401420f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
λmax 366 nm; Fluorescence λmax (CH2Cl2) 508 nm; HRMS (ESI) (m/
z) calcd for C26H29NaN3O4 [M + Na]+ 470.2050, found 470.2046; IR
(film) cm−1 3898, 3732, 3647, 2922, 2362, 2335, 1741, 1678, 1652,
1560, 1517, 1460, 1398, 1259, 1024, 796, 713, 673.
3377, 3291, 2975, 2929, 2893, 1641, 1604, 1447, 1426, 1365, 1202,
1080, 1045, 972, 876.
Measurement of Time-Dependent Fluorescence Quenching
Signal. The time-dependent fluorescence quenching signal was
measured by a Shimadzu RF-5301PC fluorometer with excitation at
350 nm and an excitation and emission slit width of 2 nm. Samples
were prepared with anhydrous CH2Cl2 and measured under Ar. A
solution of a substrate in CH2Cl2 (3.0 mL) in a 10 × 10 mm quartz
cuvette was placed in the temperature-controlled holder of the
fluorometer, and the fluorescence spectrum at time zero was acquired.
A Ru catalyst solution (3.0 mM in CH2Cl2) was added to the substrate
solution using a syringe, and the fluorescence spectra were obtained as
a function of time. The area of the fluorescence curve, designated the
fluorescence intensity, was calculated.
Determination of exo/endo/Triene Ratio in the Enyne RCM
Reaction. Ru catalyst (5 mol %) was added to a CH2Cl2 solution (0.3
M) of an enyne substrate. The reaction mixture was stirred under
ethylene atmosphere (100 psi) at 40 °C for 20 h. The mixture was
filtered through a silica gel pad and washed with diethyl ether. The
filtrate was concentrated in vacuo, and the residue was purified by flash
column chromatography on silica gel to identify the exo, endo, and
triene products. The ratios of these products were determined by
integration of the olefinic protons in the 400 MHz 1H NMR spectra of
the crude mixtures.
Synthesis of Compound 8. To a solution of iodide 2415 (300 mg,
1.26 mmol) in DMF (1.0 mL) were added phthalimide (204 mg, 1.39
mmol) and K2CO3 (261 mg, 1.89 mmol), and the resulting mixture
was stirred overnight at 50 °C. After cooling to room temperature the
mixture was diluted with Et2O (30 mL), washed with brine (5 mL ×
2), dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatography
to give ivory oil (260 mg). To a stirred solution of the obtained oil
(260 mg) in THF (1.0 mL) was added H2NNH2·H2O (80% in H2O,
0.3 mL), and the mixture was allowed to stir overnight at 60 °C. After
cooling to room temperature, the resulting mixture was diluted with
Et2O (25 mL), washed with 1 N NaOH (5 mL) and brine (5 mL),
dried over MgSO4, filtered, and concentrated. The crude product was
purified by column chromatography to give yellow oil (81 mg). To a
stirred solution of 23 (2.5 mg, 6.17 μmol) in CH2Cl2 (0.1 mL) was
added a solution of the obtained yellow oil (10 mg) in CH2Cl2 (0.1
mL), and the resulting mixture was stirred at 0 °C for 30 min. The
mixture was diluted with EtOAc (3 mL), washed with saturated
NH4Cl (0.5 mL) and brine (0.5 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude product was purified
by column chromatography to give 8 (2.1 mg, 90%): TLC (EtOAc:n-
hexane, 50:50 v/v) Rf = 0.36; 1H NMR (600 MHz, acetone-d6) δ 8.15
(d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.94 (bs, 1H), 7.68 (d, J
= 9.0 Hz, 2H), 7.45 (s, 1H), 6.84 (d, J = 9.0 Hz, 2H), 4.02 (q, J = 7.2
Hz, 2H), 3.50 (q, J = 6.6 Hz, 2H), 3.02 (s, 6H), 2.22 (t, J = 7.2 Hz,
2H), 2.07 (m, 2H), 1.77 (quint, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 166.7, 158.9, 152.8, 150.6,
135.4, 130.3, 127.4, 126.0, 125.6, 121.0, 115.8, 112.2, 90.2, 74.1, 40.3,
39.8, 28.9, 15.3, 14.4, 1.03; UV−vis λmax 366 nm; Fluorescence λmax
(CH2Cl2) 508 nm; HRMS (ESI) (m/z) calcd for C25H27NaN3O3 [M
+ Na]+ 440.1945, found 440.1949; IR (film) cm−1 3855, 3748, 3673,
2919, 2850, 2360, 2340, 2271, 1699, 1652, 1612, 1558, 1540, 1509,
1363, 1223, 1197, 1016, 815, 715.
Characterization Data for Compounds 38, 42−44. Com-
1
pound 38. Data: Rf (20% EtOAc/n-hexane) = 0.5; H NMR (400
MHz, benzene-d6) δ 7.68 (d, J = 8.2 Hz, 2H), 6.77 (d, J = 8.2 Hz, 2H),
6.19 (dd, J = 17.8, 11.2 Hz, 1H), 5.39 (d, J = 17.8 Hz, 1H), 5.00−4.84
(m, 3H), 4.71−4.70 (m, 2H), 3.94 (s, 2H), 3.64 (s, 2H), 1.88 (s, 3H),
1.57 (s, 3H); 13C NMR (100 MHz, benzene-d6) δ 142.6, 140.9, 140.8,
138.1, 136.9, 129.5, 128.1, 127.9, 118.3, 115.0, 114.2, 54.0, 49.3, 21.0,
20.1; HRMS (ESI) (m/z) calcd for C16H21NO2S [M + Na]+ 314.1185,
found 314.1187; IR (film) cm−1 2922, 1598, 1341, 1159, 1100, 910,
812, 781, 661.
1
Compound 42. Data: Rf (33% EtOAc/n-hexane) = 0.32; H NMR
(400 MHz, CDCl3) δ 7.33−7.25 (m, 5H), 6.47 (dd, J = 17.5, 10.7 Hz,
1H), 5.92 (s, 1H), 5.46 (d, J = 17.4 Hz, 1H), 5.37 (d, J = 10.6 Hz, 1H),
4.63 (s, 2H), 3.34 (t, J = 7.1 Hz, 2H), 2.44 (td, J = 7.1, 1.3 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 166.0, 148.0, 138.0, 136.9, 129.2,
128.6, 128.0, 123.6, 119.5, 77.8, 50.2, 45.0, 23.8; HRMS (ESI) (m/z)
calcd for C14H15NO [M + Na]+ 236.1046, found 236.1051; IR (film)
cm−1 2925, 1654, 1622, 1586, 1479, 1445, 1423, 1343, 1326, 1247,
1173, 1074, 1029, 989, 924, 875, 798, 730, 699.
Synthesis of Compound 27. To a stirred solution of 2929 (284
mg, 1.19 mmol) in CH3CN (10 mL) were added 3030 (267 mg, 1.26
mmol) and K2CO3 (329 mg, 2.38 mmol), and the resulting mixture
was refluxed for 2 days. After cooling to room temperature, NH4Cl (30
mL) was added, and the layers were separated. The aqueous layer was
extracted with EtOAc (20 mL × 3). Combined organic layer was dried
over MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by column chromatography to give 27
(178 mg, 54%) as colorless oil: TLC (EtOAc:n-hexane, 17:83 v/v) Rf
1
Compound 43. Data: Rf (33% EtOAc/n-hexane) = 0.34; H NMR
(400 MHz, CDCl3) δ 7.32−7.25 (m, 5H), 6.46 (d, J = 12.7 Hz, 1H),
5.95 (d, J = 12.6 Hz, 1H), 5.19 (s, 1H), 5.06 (p, J = 1.6 Hz, 1H), 4.67
(s, 2H), 3.40−3.32 (m, 2H), 2.54−2.48 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 167.8, 144.7, 138.6, 137.9, 129.2, 128.8, 128.1, 124.9,
122.3, 77.8, 52.3, 46.8, 36.3, 30.3; HRMS (ESI) (m/z) calcd for
C14H15NO [M + Na]+ 236.1046, found 236.1042; IR (film) cm−1
2922, 1635, 1612, 1578, 1481, 1435, 1356, 1261, 1227, 1196, 1159,
1094, 1026, 947, 913, 834, 802, 743, 700.
1
= 0.4; H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.4 Hz, 2H), 7.26
(d, J = 7.9 Hz, 2H), 5.62 (ddt, J = 16.5, 10.0, 6.4 Hz, 1H), 5.17−5.11
(m, 2H), 3.80 (d, J = 6.5 Hz, 2H), 3.25−3.17 (m, 2H), 2.39 (s, 3H),
2.34 (ddt, J = 7.6, 6.6, 2.5 Hz, 2H), 1.70 (t, J = 2.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 143.2, 136.9, 133.0, 129.6, 127.1, 118.9, 77.4,
75.6, 51.0, 46.5, 21.4, 19.4, 13.3; HRMS (ESI) (m/z) calcd for
C15H19NO2S [M + Na]+ 300.1029, found 300.1029; IR (film) cm−1
2920, 1600, 1441, 1336, 1156, 1090, 985, 919, 812, 740, 661.
1
Compound 44. Data: Rf (33% EtOAc/n-hexane) = 0.5; H NMR
(400 MHz, toluene-d8) δ 7.05−6.97 (m, 5H), 6.35−6.30 (m, 2H),
6.16 (dd, J = 17.6, 10.8 Hz, 1H), 5.30 (dd, J = 8.2, 4.7 Hz, 1H), 5.15
(d, J = 17.6 Hz, 1H), 4.90−4.84 (m, 2H), 4.77 (s, 1H), 4.37 (s, 2H),
3.32 (t, J = 7.8 Hz, 2H), 2.31 (t, J = 7.8 Hz, 2H); 13C NMR (100
MHz, toluene-d8) δ 166.1, 144.6, 138.9, 138.7, 129.0, 127.6, 126.9,
116.8, 113.8, 51.0, 47.1, 31.5; HRMS (ESI) (m/z) calcd for C16H19NO
[M + Na]+ 264.1359, found 264.1358; IR (film) cm−1 2931, 1644,
1605, 1433, 1365, 1220, 1159, 978, 902, 797, 736, 698.
Synthesis of Compound 28. To a stirred solution of amine 3131
(388 mg, 2.44 mmol) in CH2Cl2 (10 mL) were added i-Pr2NEt (640
μL, 3.67 mmol) and acryloyl chloride (200 μL, 2.46 mmol) at 0 °C,
and the mixture was warmed to room temperature. After 4 h, NH4Cl
(20 mL) was added, and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (15 mL × 3). Combined organic layer was
dried over MgSO4, filtered, and concentrated under reduced pressure.
The crude product was purified by column chromatography to give
compound 28 (480 mg, 93%) as colorless oil: TLC (EtOAc:Hexane,
20:80 v/v) Rf = 0.2; 1H NMR (400 MHz, toluene-d8) δ 7.09−6.97 (m,
5H), 6.31−6.26 (m, 2H), 5.29 (dd, J = 7.4, 5.5 Hz, 1H), 4.40 (s, 2H),
3.28 (t, J = 6.5 Hz, 2H), 2.16 (bs, 2H), 1.73 (t, J = 2.6 Hz, 1H); 13C
NMR (100 MHz, toluene-d8) δ 166.3, 138.4, 137.7, 129.0, 128.8,
127.7, 127.4, 81.9, 70.5, 51.0, 46.3, 18.7; HRMS (ESI) (m/z) calcd for
C14H15NO [M + Na]+ 236.1046, found 236.1050; IR (film) cm−1
ASSOCIATED CONTENT
■
S
* Supporting Information
Time-dependent change of the fluorescence spectra, time-
dependent quenching traces at various conditions, global fitting
1
analysis of FRET data, and H and 13C NMR spectra of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
G
dx.doi.org/10.1021/jo401420f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(9) Poater, A.; Solans-Monfort, X.; Clot, E.; Coperet, C.; Eisenstein,
O. J. Am. Chem. Soc. 2007, 129, 8207.
(10) Other FRET-based method for the detection of Pd complex
formation was reported. Lim, S.-G.; Blum, S. A. Organometallics 2009,
28, 4643.
(11) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63,
6082.
(12) Hoveyda, A. H.; Zhugralin, A. R. Nature 2007, 450, 243.
(13) Lee, J.; Lee, H.; Sohn, J.-H. Bull. Korean Chem. Soc. 2011, 32,
3213.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sohnjh@cnu.ac.kr; leehy@kaist.ac.kr; hyotcherl.ihee@
kaist.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(14) Perron, J.; Joseph, B.; Mer
6553.
́
our, J.-Y. Tetrahedron Lett. 2003, 44,
This work was supported by the NRF grant (No. 20110013842
and No. 20110029194) funded by Korean Ministry of
Education, Science and Technology (MEST) and the Research
Center Program (CA1201) of Institute for Basic Science (IBS)
in Korea.
(15) Funk, R. L.; Bolton, G. L.; Brummond, K. M.; Ellestad, K. E.;
Stallman, J. B. J. Am. Chem. Soc. 1993, 115, 7023.
(16) García-Fandino, R.; Castedo, L.; Granja, J. R.; Car
Dalton Trans. 2007, 2925.
́
denas, D. J.
̃
(17) Na, Y.; Song, J.-A.; Han, S.-Y. Bull. Korean Chem. Soc. 2011, 32,
3164.
(18) Dye-conjugated substrates 1, 2, 6, 7, and 9, whose functionalites
are the components of enynes in Table 2, were tested; see Supporting
Information.
REFERENCES
■
(1) For selected reviews on FRET, see: (a) Yuan, L.; Lin, W.; Zheng,
K.; Zhu, S. Acc. Chem. Res. 2013, 46, 1462. (b) Gell, D. A.; Grant, R.
P.; MacKay, J. P. Adv. Exp. Med. Biol. 2012, 747, 19. (c) Miyawaki, A.
Annu. Rev. Biochem. 2011, 80, 357. (d) Wu, J.; Liu, W.; Ge, J.; Zhang,
H.; Wang, P. Chem. Soc. Rev. 2011, 40, 3483. (e) Sapsford, K. E.; Berti,
L.; Medintz, I. L. Angew. Chem., Int. Ed. 2006, 45, 4562. (f) Haugland,
R. P. The Handbook. A Guide to Fluorescent Probes and Labeling
Technologies, 10th ed.; Invitrogen: San Diego, CA, 2005.
(19) Trost, B. M.; Breder, A.; O’Keefe, B. M.; Rao, M.; Franz, A. W. J.
Am. Chem. Soc. 2011, 133, 4766.
(20) Nunez-Zarur, F.; Solans-Monfort, X.; Rodríguez-Santiago, L.;
̃
Sodupe, M. ACS Catal. 2013, 3, 206.
(21) Ferrer, C.; Raducan, M.; Nevado, C.; Claverie, C. K.;
Echavarren, A. M. Tetrahedron 2007, 63, 6306.
(2) For selected reviews on enyne RCM, see: (a) Li, J.; Lee, D. Eur. J.
Org. Chem. 2011, 2011, 4269. (b) Fischmeister, C.; Bruneau, C.
Beilstein J. Org. Chem. 2011, 7, 156. (c) Mori, M. Materials 2010, 3,
2087. (d) Kotha, S.; Meshram, M.; Tiwari, A. Chem. Soc. Rev. 2009, 38,
2065. (e) Mori, M. Adv. Synth. Catal. 2007, 349, 121. (f) Diver, S. T.
Coord. Chem. Rev. 2007, 251, 671. (g) Villar, H.; Frings, M.; Bolm, C.
Chem. Soc. Rev. 2007, 36, 55. (h) Diver, S. T.; Giessert, A. J. Chem. Rev.
2004, 104, 1317.
(3) (a) Sohn, J.-H.; Kim, K. H.; Lee, H.-Y.; No, Z. S.; Ihee, H. J. Am.
Chem. Soc. 2008, 130, 16506. (b) Kim, K. H.; Ok, T.; Lee, K.; Lee, H.-
S.; Chang, K. T.; Ihee, H.; Sohn, J.-H. J. Am. Chem. Soc. 2010, 132,
12027.
(22) Sashuk, V.; Grela, K. J. Mol. Catal. A: Chem. 2006, 257, 59.
(23) Li, Q.; Yu, Z. -X. Organometallics 2012, 31, 5185.
(24) Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1998, 63, 8983.
(25) Scheideman, M.; Wang, G.; Vedejs, E. J. Am. Chem. Soc. 2008,
130, 8669.
(26) Tietze, L. F.; Bratz, M. Chem. Ber. 1989, 122, 977.
(27) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 9295.
(28) Diaz, L.; Bujons, J.; Casas, J.; Llebaria, A.; Delgado, A. J. Med.
Chem. 2010, 53, 5248.
(29) Fang, F.; Vogel, M.; Hines, J. V.; Bergmeier, S. C. Org. Biomol.
Chem. 2012, 10, 3080.
(30) Teichert, J. F.; Zhang, S.; van Zijl, A. W.; Slaa, J. W.; Minnaard,
A. J.; Feringa, B. L. Org. Lett. 2010, 12, 4658.
(31) Hess, W.; Burton, J. W. Chem.Eur. J. 2010, 16, 12303.
(4) (a) Kitamura, T.; Sato, Y.; Mori, M. Adv. Synth. Catal. 2002, 344,
678. (b) Hansen, E. C.; Lee, D. Acc. Chem. Res. 2006, 39, 509.
(c) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1.
(5) (a) Hoye, T. R.; Donaldson, S. M.; Vos, T. J. Org. Lett. 1999, 1,
277. (b) Schramm, M. P.; Reddy, D. S.; Kozmin, S. A. Angew. Chem.,
Int. Ed. 2001, 40, 4274. (c) Lloyd-Jones, G. C.; Margue, R. G.; de
Vries, J. G. Angew. Chem., Int. Ed. 2005, 44, 7442. (d) Diver, S. T.;
Galan, B. R.; Giessert, A. J.; Keister, J. B. J. Am. Chem. Soc. 2005, 127,
5762. (e) Kim, S. H.; Bowden, N.; Grubbs, R. H. J. Am. Chem. Soc.
1994, 116, 10801. (f) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2003,
125, 9582.
(6) (a) Kinoshita, A.; Mori, M. Synlett 1994, 1020. (b) Stragies, R.;
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2518.
(c) Kitamura, T.; Sato, Y.; Mori, M. Chem. Commun. 2001, 1258.
(d) Lee, H. -Y.; Kim, B. G.; Snapper, M. L. Org. Lett. 2003, 5, 1855.
(e) Nunez, A.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J. Chem.
́
̃
Commun. 2006, 2690. (f) Dieltiens, N.; Moonen, K.; Stevens, C. V.
Chem.Eur. J. 2007, 13, 203.
(7) The previous theoretical studies on enyne RCM using simplified
models for the Ru complexes proposed that the alkene-initiated
pathway is more favorable because the step of ix or xii formation
displayed higher intrinsic barrier than that of iii formation in their
calculation.7a However, more recent computation suggested different
conclusions that the higher bulk included in the Ru model, the lower
the preference for the alkene-initiated pathway is.7b (a) Lippstreu, J. J.;
Straub, B. F. J. Am. Chem. Soc. 2005, 127, 7444. (b) Nunez-Zarur, F.;
̃
Solans-Monfort, X.; Rodríguez-Santiago, L.; Pleixats, R.; Sodupe, M.
Chem.Eur. J. 2011, 17, 7506.
(8) (a) Lee, Y.-J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 10652. (b) Zhao, Y.; Hoveyda, A. H.; Schrock, R. R. Org.
Lett. 2011, 13, 784.
H
dx.doi.org/10.1021/jo401420f | J. Org. Chem. XXXX, XXX, XXX−XXX