Silver(I)-Catalyzed Addition of Phenols to Alkyne Cobalt Cluster Stabilized Carbocations

Article abstract of DOI:10.1002/chem.201600288

A smooth catalytic method to use phenols as the nucleophilic partner in the Nicholas reaction has been developed. The method uses either Ag^Ior Au^Icatalysts with AgClO₄or AgBF₄as the most efficient catalysts tested. Neither additional additives nor cocatalysts were required and the formation of the corresponding phenol adducts occurred in excellent yields. The process has the single limitation of the inability of less nucleophilic phenols (4-nitrophenol) to generate the corresponding adducts. Additionally, the reaction is highly diastereoselective. DFT calculations allow a catalytic cycle to be proposed that involves trimetallic intermediates; the rate-determining step of the reaction is hydroxy-group elimination in a cobalt–silver trimetallic intermediate.

Full text of DOI:10.1002/chem.201600288

DOI: 10.1002/chem.201600288
Full Paper
&
Reaction Mechanisms
Silver(I)-Catalyzed Addition of Phenols to Alkyne Cobalt Cluster
Stabilized Carbocations
Carolina Valderas,[a, b, d] Luis Casarrubios,[a, d] Agusti Lledos,[c, d] Manuel A. OrtuÇo,[c, d]
María C. de la Torre,*[b, d] and Miguel A. Sierra*[a, d]
Abstract: A smooth catalytic method to use phenols as the
nucleophilic partner in the Nicholas reaction has been devel-
oped. The method uses either AgI or AuI catalysts with
AgClO4 or AgBF4 as the most efficient catalysts tested. Nei-
ther additional additives nor cocatalysts were required and
the formation of the corresponding phenol adducts oc-
curred in excellent yields. The process has the single limita-
tion of the inability of less nucleophilic phenols (4-nitrophe-
nol) to generate the corresponding adducts. Additionally,
the reaction is highly diastereoselective. DFT calculations
allow a catalytic cycle to be proposed that involves trimetal-
lic intermediates; the rate-determining step of the reaction
is hydroxy-group elimination in a cobalt–silver trimetallic in-
termediate.
Introduction
(allyl silanes, aromatic, and heteroaromatic) nucleophiles were
compatible with the catalytic process (Scheme 1).
The Nicholas reaction, namely, the reaction of a cation adjacent
to an alkyne–Co2(CO)6 cluster with nucleophiles, is among the
most powerful and widely used synthetic reaction based on an
stoichiometric transition-metal complex.[1] The main shortcom-
ing of this otherwise versatile reaction is the necessity of using
an acid to generate the carbocation from the corresponding
propargylic alcohol–Co2(CO)6 complex.[2] Different strategies
have been developed to circumvent this limiting factor.[3] Re-
cently, we reported the possibility of using gold(I) and silver(I),
in particular, as catalysts for the Nicholas reaction.[4] The cata-
lyzed reaction proceeds smoothly at room temperature in
good to excellent yield and the use of the catalyst minimizes
the formation of byproducts. Oxygen (alcohols) and carbon
Scheme 1. The catalytic Nicholas reaction.
However, the “classical” Nicholas reaction is not suitable for
phenols due to the poor nucleophilicity of such systems and
the incompatibility of using more nucleophilic phenolate
anions under the conditions required to generate the cation
adjacent to the alkyne–Co2(CO)6 cluster. Our catalytic reaction
would offer the opportunity to close this gap in the synthetic
applications of this reaction. Moreover, we have segregated
the catalyzed reaction mechanistically from the classical pro-
cess. In the only example in which a phenol has been produc-
tively used in a Nicholas reaction, the reaction proceeded by
C-arylation in a Friedel–Crafts-type reaction, instead of an O-al-
kylation.[5] Herein, we report the development of a general cat-
alytic AgI approach to the addition of phenols to different
propargylic–Co2(CO)6 clusters, together with a preliminary DFT
study of the mechanism of these processes. Moreover, it is
demonstrated that gold(I) is also an efficient catalyst in these
processes.
[a] Dr. C. Valderas, Prof. Dr. L. Casarrubios, Prof. Dr. M. A. Sierra
Departamento de Química Orgµnica I, Facultad de Química
Universidad Complutense, 28040 Madrid (Spain)
E-mail: sierraor@ucm.es
[b] Dr. C. Valderas, Dr. M. C. de la Torre
Instituto de Química Orgµnica General
Instituto de Química Orgµnica
Consejo Superior de Investigaciones Científicas (CSIC)
Juan de la Cierva 3, 28006 Madrid (Spain)
E-mail: mc.delatorre@csic.es
[c] Prof. Dr. A. Lledos, Dr. M. A. OrtuÇo
Departament de Química, Universitat Autònoma de Barcelona
08193 Cerdanyola del Vall›s (Spain)
[d] Dr. C. Valderas, Prof. Dr. L. Casarrubios, Prof. Dr. A. Lledos, Dr. M. A. OrtuÇo,
Dr. M. C. de la Torre, Prof. Dr. M. A. Sierra
Centro de Innovación en Química Avanzada (ORFEO-CINQA)
Results and Discussion
Supporting information for this article and ORCIDs for some of the authors
are available on the WWW under http://dx.doi.org/10.1002/
chem.201600288. The Supporting Information contains experimental details
for compounds 5; TMS-propargyl alcohol precursors of 7a, 12a, 13a, 20A,
and 20B; a complete collection of NMR spectra; and coordinates of the
DFT-calculated structures.
The viability of the catalytic reaction between a metal-cluster-
stabilized cation and a phenol was tested in the reaction of
the propargylic alcohol–Co2(CO)6 complex 1a and 4-methoxy-
phenol as a nucleophile (Scheme 2). The reaction was initially
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Scheme 2. Initial tests of the catalytic Nicholas reaction with phenolic nucleophiles.
tested under the reaction conditions developed by us to add
non-phenol nucleophiles to cobalt-stabilized carbocations.
When AgSbF6 was used as the catalyst (5%), compound 2 was
isolated in 54% yield together with compound 3 derived from
an elimination reaction (3%), alcohol 4 (3%), and ether 5 (<
3%). It is remarkable that no C-alkylation products are ob-
served at the phenolic aromatic ring.
Once we demonstrated that the AgI catalyst formed the O-
alkylation product in good yields, we tested several AgI salts.
The most relevant results obtained in the optimization tests
are compiled in Table 1.
Finally, we tested the reaction of complex 1a under stan-
dard conditions for the Nicholas reaction. Thus, complex 1a
was treated with 4-methoxyphenol at À208C in the presence
of BF3·Et2O (1.3 equiv). A 1:0.7 mixture of compounds 2 and 4
was recovered in very low yield (ꢀ15%). Clearly, the advantag-
es of using silver(I) or gold(I) in these reactions is demonstrat-
ed. Due to the lower cost of silver catalysts than gold catalysts,
we continued this study by using silver(I) derivatives.
Once the suitability of the AgI-catalyzed addition of phenols
to propargylic alcohol–Co2CO6 complexes was demonstrated,
the versatility of the process with different phenols was consid-
ered. Thus, complex 1a was reacted with phenol and
4-methoxyphenol in the presence of 5 mol% of
AgClO4 in CH2Cl2 and in a 1:2 molar ratio of Co com-
plex/phenol, forming the corresponding adducts 6
and 2 in 50 and 51% yield, respectively. Complex 7a,
which lacked a terminal alkyne hydrogen, also react-
ed smoothly with 4-methoxyphenol, 3,5-dimethyl-
phenol, 4-chlorophenol, and estrone, in the presence
of a 5 mol% of AgBF4, leading to the corresponding
adducts 8, 9, 10, and 11, respectively, in good to ex-
Table 1. Results for catalyst optimization in the Nicholas reaction.
Entry
Catalyst
([mol%])
Phenol
[equiv]
Ratio[a]
2
3
4
5
1
2
3
4
5
AgSbF6 (10)
AgBF4 (5)
AgClO4 (5)
AgClO4 (5)
AgSbF6, AgClO4
1
1
1
2
–
1
1
1
1[b]
–
0.3
–
0.1
–
0.4
0.4
0.2
–
0.4
0.3
0.2
–
detected in variable proportions
[a] Determined by the integration of well-resolved signals in the 1H NMR spectra of
the crude reaction mixtures. [b] Compound 2 was isolated in 51% yield.
cellent yields. In the case of estrone (AgClO4
5 mol%), adduct 11 was obtained in low yield due to
extensive decomposition of the product during pu-
rification (Scheme 3).
The use of silver(I) catalysts led to the formation of up to
four different isolable reaction products (Table 1). Compound 2
was the desired product, whereas compounds 3–5 were the
products derived from elimination of the alcohol (3), the rear-
ranged alcohol (4), and the product (5) derived from the reac-
tion of Co2(CO)6–1a with rearranged alcohol 4, respectively. As
seen from the results in Table 1, the use of either AgSbF6 or
AgBF4 produced desired product 2 together with variable
amounts of compounds 3–5 (Table 1, entries 1 and 2). The use
of AgClO4 and a 1:1 ratio of Co complex/4-methoxyphenol pro-
duced cleaner reaction mixtures, but products 3, 4, and 5
could still be detected. By increasing the Co complex/4-me-
thoxyphenol molar ratio to 1:2, compound 2 was obtained as
a single reaction product. It should be noted that, in the ab-
sence of nucleophile, the reaction of 1a with AgSbF6 or
AgClO4 produced mixtures of compounds 3–5, the relative
proportions of which were dependent on the catalysts
(Table 1, entry 5). Furthermore, the use of Ph3PAuCl (5%)/
NaBArF (7%) led to Nicholas product 2 together with 4. Due to
1
badly resolved H NMR spectra, the ratio of 2/4 could not be
determined, and the mixture was purified by column chroma-
tography to allow for the isolation of 2 in a respectable yield
of 76%.
Scheme 3. The scope of the catalytic Nicholas reaction. TMS=trimethylsilyl.
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Complex 12a, which lacked both Me groups at the cyclo-
hexene ring, and the open-chain complex 13a also reacted
smoothly with 4-methoxyphenol in the presence of AgClO4
(5 mol%), leading to the corresponding adducts 14 and 15, re-
spectively, in excellent yields (Scheme 4).
cohol was complexed to form Co derivatives and reacted with
4-methoxyphenol by using AgClO4 as the catalyst under stan-
dard conditions. Compound 20A was much more reactive
(4 h) than 20B (48 h). Complex 21b was unstable and was re-
acted with TMANO to eliminate the Co moiety, forming 22 in
essentially quantitative yield.[8] Notably, both reactions were
completely diastereoselective. The reasons behind the different
reactivities of both diastereomeric alcohols 20 can be traced to
the director effect of the alcohol during the first stages of the
catalytic cycle and is discussed below.
Finally, the reactions of aromatic Co complex 23a with dif-
ferent phenols were addressed. Complex 23a lacks an enyne
system in its structure; hence it should broaden the scope of
this catalytic processes. In this regard, the reactions of complex
23a with phenol, 4-methoxyphenol, and 4-chlorophenol
formed adducts 24–26, respectively, in excellent yields, al-
though in these cases it was necessary to increase the amount
of phenol to a molar ratio of 3:1 relative to the Co complex. In
addition, AgBF4 gave cleaner crude reaction mixtures than
AgClO4. Analogously, the reaction of complex 27a, with the
TMS group, and 4-methoxyphenol formed adduct 28 in 77%
yield (Scheme 7). Interestingly, complex 29a was unreactive
under all tested conditions (this behavior has been previously
observed in our studies).[4]
Scheme 4. Expanding the scope of the catalytic Nicholas reaction.
The catalytic addition of phenols to monoterpene deriva-
tives (more prone to rearrangements) was next tested. (R)-(À)-
Carvone-derived complex 16a reacted with 4-methoxyphenol
and 3,5-dimethylphenol to yield the corresponding adducts 17
and 18 in good yields (Scheme 5). The reaction was highly se-
lective in the case of 17 and yielded a mixture (92:8) of stereo-
isomers, and was completely selective for 18. Again, the reac-
tion of 16a with estrone yielded the hybrid compound 19, al-
though in low yield, due to extensive decomposition during
purification.[6]
To complete this study, a double-catalyzed Nicholas reaction
was effected in complex 30a derived from diol 30 (obtained
by addition of trimethylsilylethynyllithium to terephthalalde-
hyde). Under typical catalysis with AgBF4 (5 mol%), the double
addition product 31 was obtained in nearly quantitative (94%)
yield as a mixture of inseparable isomers (Scheme 8).
To obtain some mechanistic clues and to ascertain the cata-
lytic role of silver(I), we carried out additional experiments.
Thus, the reaction of complex 1a and 4-methoxyphenol (1:3
molar ratio) with NaBF4 or NaClO4 (5 mol%), under identical
conditions to those used above, lead to the quantitative recov-
ery of the starting material; this excludes the possibility of the
An analogous reaction of the corresponding (1R)-(À)-myrte-
nal derivative 20A[7] with Co2(CO)8 and 4-methoxyphenol
formed adduct 21a (Scheme 6).[8]
The reaction of this complex derived from 20A deserves fur-
ther discussion. The addition of lithium acetylide to (1R)-(À)-
myrtenal produces two diastereomeric alcohols, 20A and 20B,
which were separated by chromatography. Each separated al-
À
À
counterion (BF4 or ClO4 ) having some role in the promotion
of the reaction.
Scheme 5. The use of terpene derivatives in the catalytic Nicholas reaction.
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Scheme 6. Diastereoselective process for the catalytic Nicholas reaction. LiHMDS=lithium hexamethyldisilazide, TMANO=trimethylamine N-oxide.
tion-metal chemistry.[10] All reported energies correspond with
Gibbs energies (in kcalmolÀ1) in dichloromethane as a solvent.
The reaction begins with the coordination of 4-methoxyphe-
nol–AgI to form the I1-OMe intermediate (Scheme 9) on the
same face as the alcohol (coordination is according to the ex-
perimental data described above directed by the alcohol). In-
termediate I1-OMe has a trimetallic structure with the silver
atom coordinated to the double bond, the alcohol (loosely),
and the phenol. 4-Methoxyphenol was unreactive towards I1-
OMe, whereas anion 4-MeOC6H4OÀ (formed by the reaction of
the phenol with AgOH species generated in the reaction
media, see below) smoothly added to C3 via TS1-OMe (DG° =
8.6 kcalmolÀ1) to form a second intermediate, I2-OMe, located
8.0 kcalmolÀ1 below I1-OMe. Intermediate I2-OMe evolves to
the reaction product I3-OMe via TS2-OMe (DG° =20.6 kcal
Scheme 7. The use of aromatic propargylic complexes in the catalytic Nicho-
molÀ1). Finally, intermediate I3-OMe extruded AgOH to form
las reaction.
the isolated product and catalyst (AgOH additionally acted as
a base to deprotonate a new phenol molecule to form the re-
More acidic 4-nitrophenol (and subsequently less nucleophil-
ic) was unreactive under standard conditions, as well as the
phenolate salts derived from reactive phenols. The results ob-
tained in these cases indicated that silver phenolate was not
the catalytic species, but inhibited the reaction by quenching
the active silver species.
agent 4-methoxyphenol-AgI; Figure 1 and Scheme 9).
To support this proposal, analogous reaction pathways were
calculated for phenol (reactive) and 4-nitrophenol (unreactive).
The principal difference between the three reagents was found
in the second step of the reaction (the addition of the pheno-
late to I1 depended little on the nature of the phenol). The
process involving TS2-H (DG° =21.1 kcalmolÀ1) is similar to
that reported for TS2-OMe (DG° =20.6 kcalmolÀ1). Interesting-
ly, the breakage of I2-NO2 via TS-NO2 (DG° =24.2 kcalmolÀ1) is
now higher in energy than previously observed,[11] which is
congruent with the lower affinity of 4-nitrophenol for silver,
To gain some insight into the mechanism, we studied this
catalytic reaction by computational means (see the Computa-
tional details section). All calculations were performed at the
DFT level by using the M06 functional,[9] which accounted for
dispersion interactions and delivered good accuracy for transi-
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Scheme 8. The double catalytic Nicholas reaction.
and therefore, a lower ability to stabilize the emerging positive
charge in TS2-NO2. This may justify the inertness of 4-nitrophe-
nol in these reactions, probably coupled to the fact that the in-
creased acidity may poison the silver catalysts.
Conclusion
For the first time, a smooth catalytic method to use phenols as
the nucleophilic partner in the Nicholas reaction has been de-
veloped. The method was general and several silver(I) and
gold(I) catalysts can be employed. Among them, the most effi-
cient were either AgClO4 or AgBF4. Additional additives or co-
catalysts were not required to obtain good to excellent yields.
Both enyne and arylalkyne derivatives were suitable for these
transformations. The only shortcoming of this process was the
inability of the less nucleophilic phenols (4-nitrophenol) to
generate the corresponding adducts. Moreover, by working
with chiral substrates, very high selectivity of the reaction was
demonstrated. The stereochemistry of the addition of the
phenol was directed by the configuration of the alcohol.
DFT calculations gave a preliminary overview of the catalytic
cycle, which involved trimetallic intermediates and explained
the relative reactivities of different phenols that were directly
related to the phenolate substituent.
Experimental Section
General
All reactions were carried out under an argon atmosphere. All sol-
vents used herein were purified by distillation and were freshly dis-
tilled immediately before use. CH2Cl2 was purified by using a Pure
Solv PS-MD-5 system. BF3·Et2O was distilled prior to use. Flame-
dried glassware was used for moisture-sensitive reactions. Silica gel
(Merck: 230–400 mesh) was used as the stationary phase for the
purification of crude reaction mixtures by flash column chromatog-
raphy. Identification of products was made by TLC (Kieselgel 60F-
254). NMR spectra were recorded at 258C in CDCl3 on a Bruker
Avance 300 spectrometer (300 MHz for 1H and 75 MHz for 13C).
Chemical shifts are given in ppm relative to CDCl3 (1H, d=
Scheme 9. Calculated reaction pathway.
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Figure 1. Calculated reaction pathway.
7.27 ppm and 13C, d=77.0 ppm). IR spectra were recorded on
a MIR (8000–400 cmÀ1) spectrometer as solid films by slow evapo-
ration of the solvent by using the attenuated total reflectance
(ATR) technique. MS spectra (HRMS) were acquired on a QTOF
6520: HP-1200 (Agilent Technologies) mass spectrometer.
J=13.6, 8.6, 6.4 Hz, 1H), 1.05 ppm (s, 6H); 13C NMR (126 MHz,
CDCl3): d=199.7, 154.2, 153.0, 136.7, 128.6, 117.7, 114.8, 91.8, 82.0,
72.9, 55.8, 34.3, 34.0, 28.7, 27.1, 21.1 ppm; IR (ATR): n˜ =2093, 2054,
2025, 1504, 1223, 1100, 1034, 824, 800 cmÀ1; HRMS (ESI): m/z calcd
for C23H20Co2NaO8 [M+Na]+: 564.9714; found: 564.9729.
Compounds 1a,[4] 3,[4] 4,[4] 16,[4] 23,[4] and 30[12] were prepared by
Complex 6
following previously described methods.
Following the general procedure, from alkyne–cobalt complex 1a
(51.0 mg, 0.12 mmol), phenol (22.0 mg, 0.23 mmol), and AgClO4
(1.2 mg, 5.8 mmol), and after SiO2 chromatography (hexane/EtOAc
50:1), pure 6 was obtained (30.0 mg, 50%). 1H NMR (300 MHz,
CDCl3): d=7.30 (d, J=8.4 Hz, 2H), 6.94 (t, J=8.4 Hz, 3H), 6.17 (s,
2H), 4.42 (d, J=2.2 Hz, 1H), 2.55–2.18 (m, 2H), 1.77 (ddd, J=13.6,
5.8, 4.6 Hz, 1H), 1.65 (ddd, J=13.6, 8.7, 6.4 Hz, 1H), 1.05 ppm (s,
6H); 13C NMR (75 MHz, CDCl3): d=199.6, 158.9, 136.9, 129.7, 128.2,
120.9, 116.2, 80.65, 72.9, 34.4, 34.0, 28.7, 27.1, 20.9 ppm; IR (ATR):
n˜ =2959, 2925, 1594, 1263, 1153, 1055, 860, 843, 801, 748,
703 cmÀ1; HRMS (ESI): m/z calcd for C22H18Co2NaO7 [M+Na]+:
534.9614; found: 534.9697.
General procedure for the Nicholas reaction
Co2(CO)8 (1.2 equiv) was added to a solution of the corresponding
propargylic alcohol (1.0 equiv) in dry CH2Cl2 (0.1m) under an argon
atmosphere. The mixture was stirred at room temperature over-
night. The crude reaction was filtered through a short pad of Celite
and concentrated in vacuo, and the obtained dicobalt hexacarbon-
yl complex was used without further purification. AgBF4 or AgClO4
(5 mol%) and the corresponding phenol (2.0 or 3.0 equiv) were
added under argon atmosphere at room temperature to a solution
of the propargylic–Co2(CO)6 complex (1.0 equiv) in dry CH2Cl2
(0.03m),. The reaction mixture was stirred until no starting material
was observed by TLC analysis. The crude reaction mixture was fil-
tered through Celite and concentrated in vacuo. Flash column
chromatography on SiO2 of the residue gave pure products. Op-
tional workup and purification implied washing the crude reaction
mixture with 5% NaOH and extraction with CH2Cl2. The combined
organic layers were dried over Na2SO4, filtered, and concentrated
in vacuo to afford pure reaction products.
Complex 8
Following the general procedure, from alkyne–cobalt complex 7a
(52.0 mg, 0.10 mmol), 4-methoxyphenol (24.8 mg, 0.20 mmol), and
AgBF4 (1.0 mg, 5.1 mmol), and after SiO2 chromatography (hexane/
EtOAc 60:1), pure
8
was obtained (67.7 mg, 99%). 1H NMR
(300 MHz, CDCl3): d=6.85 (m, 4H), 6.14 (s, 1H), 4.28 (s, 1H), 3.77 (s,
3H), 2.47–2.24 (m, 2H), 1.83–1.56 (m, 2H), 1.07 (s, 3H), 1.05 (s, 3H),
0.27 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=200.5, 154.3, 152.8,
137.2, 128.4, 118.2, 114.8, 82.2, 79.9, 55.9, 38.1, 34.4, 33.9, 28.9, 27.1,
21.0, 0.8 ppm; IR (ATR): n˜ =2962, 2088, 2050, 2022, 1672, 1506,
Complex 2
1249, 1226, 1035, 841 cmÀ1
;
HRMS (ESI): m/z calcd for
Following the general procedure, from alkyne–cobalt complex 1a
(52.0 mg, 0.12 mmol), 4-methoxyphenol (30.0 mg, 0.24 mmol), and
AgClO4 (1.3 mg, 6.1 mmol), and after SiO2 chromatography (hexane/
C26H28Co2NaO8Si [M+Na]+: 637.0117; found: 637.0120.
EtOAc 50:1), pure
2
was obtained (33.0 mg, 51%). 1H NMR
Complex 9
(500 MHz, CDCl3): d=6.87 (d, J=9.2 Hz, 2H), 6.82 (d, J=9.2 Hz,
2H), 6.17 (s, 1H), 6.15 (s, 1H), 4.28 (s, 1H), 3.77 (s, 3H), 2.44–2.34
(m, 1H), 2.33–2.24 (m, 1H), 1.75 (dt, J=13.6, 5.3 Hz, 1H), 1.62 (ddd,
Following the general procedure, from alkyne–cobalt complex 7a
(52.0 mg, 0.12 mmol), 3,5-dimethylphenol (23.0 mg, 0.19 mmol),
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and AgClO4 (1.0 mg, 4.7 mmol) and after washing with 5% NaOH
and extraction with CH2Cl2, pure 9 was obtained (48.9 mg, 85%).
Due to the instability of complex 9, characterization was accom-
plished for the demetalated analogue 9l.
(300 MHz, CDCl3): d=6.92 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz,
2H), 6.35 (s, 1H), 4.77 (d, J=11.1 Hz, 2H), 4.55 (s, 1H), 3.78 (s, 3H),
2.69–2.46 (m, 2H), 2.28–2.07 (m, 2H), 2.00 (s, 3H), 1.78 (s, 3H),
1.53 ppm (td, J=13.4, J=3.0 Hz, 1H); 13C NMR (126 MHz, CDCl3):
d=199.9, 154.5, 152.7, 148.5, 132.8, 131.1, 118.4, 114.9, 109.4, 88.5,
78.3, 74.8, 55.9, 38.0, 36.4, 32.1, 21.3, 19.7 ppm; IR (ATR): n˜ =2962,
Complex 10
2091, 2051, 2019, 1504, 1259, 1211, 1090, 1031, 796, 750, 702 cmÀ1
;
Following the general procedure, from alkyne–cobalt complex 7a
(52.0 mg, 0.12 mmol), 4-chlorophenol (26.7 mg, 0.21 mmol), and
AgClO4 (1.0 mg, 5.2 mmol), and after SiO2 chromatography (hexane/
EtOAc 50:1), pure 10 was obtained (41.6 mg, 64%). Due to the in-
stability of complex 10, characterization was accomplished for the
demetalated analogue 10l.
HRMS (ESI): m/z calcd for C25H22Co2NaO8 [M+Na]+: 590.9871;
found: 590.9848.
Complex 18
Following the general procedure, from alkyne–cobalt complex 16a
(67.0 mg, 0.14 mmol), 3,5-dimethylphenol (34.0 mg, 0.28 mmol),
and AgClO4 (1.5 mg, 7.2 mmol), and after washing with 5% NaOH
and extraction with CH2Cl2, pure 18 was obtained (61.1 mg, 77%).
1H NMR (300 MHz, CDCl3): d=6.69–6.51 (m, 3H), 6.34 (s, 1H), 4.76
(d, J=10.6 Hz, 2H), 4.68 (brs, 1H), 2.64–2.48 (m, 2H), 2.29 (s, 6H),
2.26–2.14 (m, 2H), 1.96 (s, 3H), 1.77 (s, 3H), 1.59 ppm (td, J=13.7,
4.1 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=199.8, 158.7, 148.5, 139.5,
132.8, 131.0, 123.0, 114.1, 109.4, 74.8, 72.3, 37.8, 36.5, 32.3, 21.6,
21.3, 19.6 ppm; HRMS (ESI): m/z calcd for C26H24Co2NaO7 [M+Na]+:
589.0084; found: 589.0062.
Complex 11
Following the general procedure, from alkyne–cobalt complex 7a
(61.0 mg, 0.12 mmol), estrone (64.8 mg, 0.24 mmol), and AgClO4
(1.2 mg, 6.0 mmol), and after SiO2 chromatography (hexane/EtOAc
50:1), pure 11 was obtained (24.0 mg, 26%). 1H NMR (300 MHz,
CDCl3): d=7.19 (d, J=8.6 Hz, 1H), 6.78–6.70 (m, 1H), 6.70–6.60 (m,
1H), 6.21–6.11 (m, 1H), 4.37 (s, 1H), 2.94–2.80 (m, 2H), 2.51 (dd, J=
18.3, 8.3 Hz, 1H), 2.44–1.91 (m, 8H), 1.81–1.41 (m, 8H), 1.04 (s, 6H),
0.91 (s, 3H), 0.28 (s, 6H), 0.16 ppm (s, 3H); 13C NMR (101 MHz,
CDCl3): d=221.2, 200.2, 156.9, 137.9, 137.3, 132.4, 128.5, 126.5,
116.7, 116.3, 81.0, 50.6, 48.2, 44.2, 38.5, 36.0, 34.5, 33.9, 31.7, 29.8,
28.9, 27.1, 26.7, 26.0, 21.7, 20.8, 14.0, 0.8 ppm; IR (ATR): n˜ =2926,
Complex 19
Following the general procedure, from alkyne–cobalt complex 16a
(83.0 mg, 0.18 mmol), estrone (97.0 mg, 0.36 mmol), and AgClO4
(1.8 mg, 9.0 mmol), and after SiO2 chromatography (hexane/EtOAc
40:1 to 20:1), pure 19 was obtained (15.0 mg, 12%). 1H NMR
(400 MHz, CDCl3): d=7.21 (d, J=8.6 Hz, 1H), 6.78 (dd, J=8.6,
2.6 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 6.34 (s, 1H), 4.76 (d, J=15.5 Hz,
2H), 4.67 (s, 1H), 2.99–2.79 (m, 2H), 2.62–2.53 (m, 1H), 2.53–2.43
(m, 1H), 2.46–2.31 (m, 2H), 2.31–2.01 (m, 6H), 1.95 (s, 3H), 1.77 (s,
3H), 1.68–1.43 (m, 8H), 0.91 ppm (s, 3H); 13C NMR (101 MHz,
CDCl3): d=221.1, 200.0, 156.7, 148.5, 138.1, 132.7, 131.1, 126.6,
116.5, 113.7, 109.4, 88.5, 74.8, 50.5, 48.2, 44.2, 38.5, 38.0, 36.5, 36.0,
32.2, 31.7, 29.8, 26.7, 26.0, 21.7, 21.3, 19.6, 14.0 ppm; IR (ATR): n˜ =
2927, 2858, 2091, 2053, 2025, 1738, 1604, 1573, 1496, 1453, 1279,
1244, 1099, 1053, 1036, 1008 cmÀ1; HRMS (ESI): m/z calcd for
C36H36ClCo2O8 [M+Cl]À: 749.0768; found: 749.0834.
2086, 2047, 2018, 1740, 1605, 1496, 1263, 1250, 841, 733, 701 cmÀ1
;
HRMS (ESI): m/z calcd for C37H42ClCo2O8Si [M+Cl]À: 795.1001;
found: 795.1009.
Complex 14
Following the general procedure, from alkyne–cobalt complex 12a
(54.0 mg, 0.13 mmol), 4-methoxyphenol (32.0 mg, 0.26 mmol), and
AgClO4 (1.4 mg, 6.6 mmol), and after washing with 5% NaOH and
extraction with CH2Cl2, pure 14 was obtained (60.5 mg, 90%).
1H NMR (400 MHz, CDCl3): d=6.89 (d, J=9.1 Hz, 2H), 6.83 (d, J=
9.0 Hz, 2H), 6.25 (s, 1H), 6.20 (s, 1H), 4.71 (s, 1H), 3.77 (s, 3H),
2.45–2.20 (m, 2H), 2.06–1.91 (m, 2H), 1.91–1.68 ppm (m, 2H);
13C NMR (101 MHz, CDCl3): d=199.8, 154.3, 151.8, 138.9, 128.5,
118.1, 114.8, 73.4, 55.8, 31.2, 29.9, 28.3 ppm; IR (ATR): n˜ =2932,
2093, 2053, 2022, 1506, 1225, 1105, 1040, 824 cmÀ1; HRMS (ESI): m/
z calcd for C21H16Co2NaO8 [M+Na]+: 536.9401; found: 536.9397.
Complex 21a
Following the general procedure, from alkyne–cobalt complex 20A
(149.6 mg, 0.28 mmol), 4-methoxyphenol (69.5 mg, 0.56 mmol),
and AgClO4 (3.0 mg, 14.0 mmol), and after SiO2 chromatography
(hexane/EtOAc 80:1), pure 21a was obtained (92 mg, 51%).
1H NMR (300 MHz, CDCl3): d=6.84 (m, 4H), 6.20 (s, 1H), 4.78 (d, J=
7.6 Hz, 1H), 3.76 (s, 3H), 3.32 (t, J=5.3 Hz, 1H), 2.59–2.32 (m, 2H;
4axial), 2.17 (dd, J=14.7, 4.5 Hz, 1H), 2.07 (dd, J=10.0, 4.5 Hz, 1H),
1.92 (d, J=10.0 Hz, 1H), 1.38 (s, 3H), 0.74 (s, 3H), 0.32 ppm (s, 9H);
13C NMR (126 MHz, CDCl3): d=200.3, 154.8, 151.9, 146.3, 125.4,
120.0, 114.8, 97.7, 80.3, 76.4, 55.8, 46.2, 41.9, 40.5, 33.2, 26.9, 25.9,
22.1, 1.2 ppm; IR (ATR): n˜ =2934, 2084, 2046, 2017, 1505, 1248,
1222, 1039, 841 cmÀ1; HRMS (ESI): m/z calcd for C28H30Co2NaO8Si
[M+Na]+: 663.0266; found: 663.0286.
Complex 15
Following the general procedure, from alkyne–cobalt complex 13a
(52.0 mg, 0.09 mmol), 4-methoxyphenol (21.8 mg, 0.18 mmol), and
AgClO4 (0.9 mg, 4.5 mmol), 15 was obtained after several purifica-
tions by chromatography (42 mg, 77%). Due to instability of this
product, only characteristic NMR signals are given. 1H NMR
(300 MHz, CDCl3): d=7.74–7.63 (m, 1H), 7.62–7.53 (m, 2H), 7.39–
7.28 (m, 11 H), 6.97–6.83 (m, 3H), 6.82–6.65 (m, 4H), 6.41 (d, J=
9.3 Hz, 1H), 5.33 (d, J=9.5 Hz, 1H), 3.75 (s, 3H), 0.16 ppm (s, 9H);
13C NMR (75 MHz, CDCl3): d=199.8, 155.0, 142.1, 140.5, 133.9,
128.7, 128.6, 128.5, 128.1, 126.8, 120.0, 114.5, 80.2, 55.8, 0.6 ppm.
Complex 17
Complex 21b
Following the general procedure, from alkyne–cobalt complex 16a
(76.0 mg, 0.16 mmol), 4-methoxyphenol (40.0 mg, 0.32 mmol), and
AgClO4 (1.6 mg, 8.0 mmol), and after SiO2 chromatography (hexane/
EtOAc 60:1), pure 17 was obtained (71.4 mg, 78%). 1H NMR
Following the general procedure, from alkyne–cobalt complex 20B
(112.2 mg, 0.21 mmol), 4-methoxyphenol (52.0 mg, 0.42 mmol),
and AgClO4 (2.2 mg, 10.0 mmol), and after washing with 5% NaOH
and extraction with CH2Cl2, pure 21b was obtained (114.0 mg,
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86%). Due to the instability of complex 21b, characterization was
accomplished for its demetalated analogue 22.
and extraction with CH2Cl2, pure 31 was obtained (87.5 mg, 94%).
1H NMR (300 MHz, CDCl3): d=7.43 (s, 1H), 7.42 (s, 1H), 6.66 (m,
4H), 6.08 (d, J=5.7 Hz, 1H), 3.70 (s, 3H), 0.23–0.13 ppm (m, 9H);
13C NMR (75 MHz, CDCl3): d=200.1, 154.2, 151.6, 142.2, 126.8,
116.9, 114.6, 113.0, 80.8, 55.9, 0.8 ppm; IR (ATR): n˜ =2959, 2089,
2049, 2018, 1505, 1249, 1221, 1042, 837, 775 cmÀ1; HRMS (ESI): m/z
calcd for C44H38ClCo4O16Si2 [M+Cl]À: 1148.8720; found: 1148.872.
Complex 24
Following the general procedure, from alkyne–cobalt complex 23a
(56.0 mg, 0.13 mmol), 4-methoxyphenol (50.0 mg, 0.4 mmol), and
AgBF4 (1.3 mg, 6.7 mmol), and after SiO2 chromatography (hexane/
EtOAc 30:1), pure 24 was obtained (55.0 mg, 75%). 1H NMR
(300 MHz, CDCl3): d=7.52–7.38 (m, 2H), 7.38–7.27 (m, 3H), 6.85 (d,
J=8.9 Hz, 2H), 6.77 (d, J=8.9 Hz, 2H), 6.15 (s, 1H), 6.01 (s, 1H),
3.73 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=199.2, 154.2, 151.8,
142.1, 128.8, 128.3, 125.8, 116.8, 114.7, 80.6, 72.1, 55.8 ppm; IR
(ATR): n˜ =2927, 2094, 2052, 2014, 1734, 1503, 1265, 1241, 1220,
1037, 822, 755, 700 cmÀ1; HRMS (ESI): m/z calcd for C22H14ClCo2O8
[M+Cl]À: 558.9047; found: 558.9056.
Demetalation procedure
Up to 10.0 equivalents of TMANO were added at 08C in small por-
tions in an open flask to a solution of the corresponding cobalt
complex (1.0 equiv) in CH2Cl2 (0.02m). The reaction mixture was
stirred until no starting material was observed by TLC analysis (re-
action mixture turned blue). The crude reaction was filtered
through a mixture of Celite/SiO2 (1:1) and concentrated in vacuo to
obtain pure metal-free compounds 9l, 10l, and 22.
Complex 25
Following the general procedure, from alkyne–cobalt complex 23a
(25.0 mg, 60.0 mmol), phenol (17.0 mg, 0.18 mmol), and AgBF4
(0.6 mg, 3.0 mmol), and after washing with 5%NaOH and extraction
with CH2Cl2, pure 25 was obtained (23.5 mg, 79%). 1H NMR
(300 MHz, CDCl3): d=7.49–7.40 (m, 2H), 7.39–7.29 (m, 3H), 7.25–
7.18 (m, 2H), 6.98–6.87 (m, 3H), 6.26 (s, 1H), 6.03 ppm (s, 1H);
13C NMR (75 MHz, CDCl3): d=199.5, 157.7, 141.9, 129.6, 128.9,
128.3, 125.8, 121.3, 115.8, 79.8, 72.0 ppm; IR (ATR): n˜ =2922, 2852,
2096, 2056, 2026, 1738, 1598, 1492, 1262, 1220, 772 cmÀ1; HRMS
(ESI): m/z calcd for C21H12ClCo2O7 [M+Cl]À: 528.8941; found:
528.8967.
Compound 9l
Following the general procedure, cobalt complex 9 (48.9 mg,
80.0 mmol) was treated with TMANO (18.0 mg, 0.24 mmol) in
CH2Cl2 (5 mL). Pure compound 9l was obtained as a yellow solid
1
(22.2 mg 85%). H NMR (300 MHz, CDCl3): d=6.58 (s, 1H), 6.54 (s,
2H), 6.12 (s, 1H), 4.39 (s, 1H), 2.36–2.15 (m, 8H), 1.70–1.43 (m, 2H),
1.02 (s, 3H), 1.02 (s, 3H), 0.17 ppm (s, 9H); 13C NMR (75 MHz,
CDCl3): d=158.5, 139.4, 133.6, 123.3, 122.6, 113.5, 105.6, 93.5, 79.1,
34.0, 33.2, 29.8, 27.3, 27.3, 21.6, 20.8, 1.18 ppm; IR (ATR): n˜ =2959,
2922, 2871, 2144, 1611, 1594, 1473, 1302, 1288, 1250, 1187, 1153,
860, 843, 760 cmÀ1; HRMS (ESI): m/z calcd for C21H31OSi [M+H]+:
327.2139; found: 327.2123.
Complex 26
Following the general procedure, from alkyne–cobalt complex 23a
(26.0 mg, 60.0 mmol), 4-chlorophenol (23.0 mg, 0.18 mmol), and
AgBF4 (0.6 mg, 3.0 mmol), and after washing with 5% NaOH and ex-
traction with CH2Cl2, pure 26 was obtained (24.5 mg, 77%).
1H NMR (300 MHz, CDCl3): d=7.48–7.30 (m, 5H), 7.17 (d, J=7.4 Hz,
2H), 6.83 (d, J=7.4 Hz, 2H), 6.20 (s, 1H), 6.02 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3): d=199.1, 156.2, 141.4, 129.5, 129.0, 128.5, 126.2,
125.7, 117.1, 97.4, 80.4, 72.0 ppm; IR (ATR): n˜ =2962, 2924, 2095,
Compound 10l
Following the general procedure, cobalt complex 10 (41.6 mg,
67.0 mmol) was treated with TMANO (15.1 mg, 0.2 mmol) in CH2Cl2
(3.3 mL). Pure compound 10l was obtained as a yellow solid
(21.3 mg, 96%). 1H NMR (300 MHz, CDCl3): d=7.22 (d, J=8.9 Hz,
2H), 6.83 (d, J=8.9 Hz, 2H), 6.06 (s, 1H), 4.35 (q, J=2.3 Hz, 1H),
2.30–2.13 (m, 2H), 1.67–1.46 (m, 2H), 1.02 (s, 3H), 1.01 (s, 3H),
0.17 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=157.2, 132.5, 129.5,
125.7, 124.0, 117.2, 105.3, 94.0, 80.0, 33.8, 33.3, 29.8, 27.3, 27.1,
20.9, 1.2 ppm; IR (ATR): n˜ =2959, 2926, 2871, 2144, 1594, 1489,
1238, 1025, 1006, 843, 760 cmÀ1; HRMS (ESI): m/z calcd for
C19H26ClOSi [M+H]+: 333.1363; found: 333.1367.
2056, 2024, 1487, 1260, 1230, 1089, 1012, 796, 737, 700 cmÀ1
;
HRMS (ESI): m/z calcd for C21H11Cl2Co2O7 [M+Cl]À: 562.8551; found:
562.8566.
Complex 28
Following the general procedure, from alkyne–cobalt complex 27a
(66.0 mg, 0.13 mmol), 4-methoxyphenol (48.4 mg, 0.4 mmol), and
AgBF4 (1.3 mg, 6.7 mmol), and after SiO2 chromatography (hexane/
EtOAc 60:1), pure 28 was obtained (59.6 mg, 77%). 1H NMR
(300 MHz, CDCl3): d=7.47–7.39 (m, 2H), 7.39–7.27 (m, 3H), 6.81 (d,
J=9.2 Hz, 2H), 6.74 (d, J=9.2 Hz, 2H), 6.14 (s, 1H), 3.71 (s, 3H),
0.22 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=200.1, 154.1, 151.9,
141.9, 128.9, 128.5, 126.3, 116.6, 114.7, 81.2, 55.8, 0.8 ppm; IR (ATR):
n˜ =2957, 2089, 2049, 2018, 1505, 1248, 1221, 1038, 838, 758,
700 cmÀ1; HRMS (ESI): m/z calcd for C25H22ClCo2O8Si [M+Cl]À:
630.9442; found: 630.9471.
Compound 22
Following the general procedure, cobalt complex 21b (114 mg,
0.18 mmol) was treated with TMANO (40.5 mg, 0.54 mmol) in
CH2Cl2 (9.0 mL). Pure compound 22 was obtained as colorless oil
1
(46.0 mg, 72%). H NMR (300 MHz, CDCl3): d=6.82 (s, 4H), 5.49 (s,
1H), 4.75 (d, J=7.4 Hz, 1H), 3.77 (s, 3H), 3.22 (t, J=5.4 Hz, 1H),
2.56 (dt, J=6.4, 3.1 Hz, 1H), 2.30 (dd, J=14.4, 7.5 Hz, 2H), 2.21–
2.10 (m, 1H), 2.14–1.99 (m, 2H), 1.82 (d, J=10.1 Hz, 1H), 1.36 (s,
3H), 0.74 (s, 3H), 0.17 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=
157.2, 154.3, 151.8, 118.0, 114.8, 108.7, 102.3, 99.3, 74.0, 55.9, 47.8,
41.9, 40.1, 32.7, 27.0, 26.3, 22.0, À0.4 ppm; IR (ATR): n˜ =2952, 2915,
1630, 1505, 1249, 1223, 1104, 1039, 1009, 844, 760 cmÀ1; HRMS
(ESI): m/z calcd for C22H31O2Si [M+H]+: 355.2088; found: 355.2085.
Complex 31
Following the general procedure, from alkyne–cobalt complex 30a
(74.7 mg, 0.083 mmol), 4-methoxyphenol (41.2 mg, 0.33 mmol),
and AgBF4 (0.8 mg, 4.1 mmol) and after washing with 5% NaOH
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[6] Assignment of the absolute stereochemistry of carbon C2 in com-
pounds 17, 18, and 19 was established by NMR spectroscopy by using
a similar method to that employed in our previous work.[4]
Computational details
All calculations were performed at the DFT level by using the M06
functional[9,10] with an ultrafine integration grid,[13] as implemented
in Gaussian 09.[14] Cobalt and silver atoms were described by using
the scalar relativistic Stuttgart–Dresden SDD pseudopotential[15]
and its associated double-z basis set complemented with a set of
f-polarization functions.[16] The 6-31G** basis set was used for the
H, C, N, and O atoms.[17] All structures of reactants, intermediates,
transition states, and products were fully optimized in dichlorome-
thane (e=8.93) by using the SMD continuum model.[18] Transition
states were identified by one imaginary frequency in the Hessian
matrix. It was confirmed that transition states connected with the
corresponding intermediates by means of application of the eigen-
vector corresponding to the imaginary frequency and subsequent
optimization of the resulting structures. All energy values given in
the text were Gibbs energies in dichloromethane at 298 K.
[7] The absolute configuration of the newly formed chiral centers of 20A
and 20B was established by the reaction of 20A with both (R)- and (S)-
(À)-a-methoxy-a-(trifluoromethyl)phenylacetyl chloride Mosher’s acid
chlorides, according to the procedure described by T. R. Hoye, C. S. Jef-
frey, F. Shao, Nat. Protoc. 2007, 2, 2451. A comparison of the 1H NMR
spectroscopy data of the corresponding (S)- and (R)-esters unambigu-
ously showed the R configuration for alcohol 20A, and subsequently,
the S configuration for 20B (Scheme 6). These data were obtained as
a reviewer suggestion during paper revision and fully supported the
proposed reaction mechanism (Scheme 9) based on theoretical calcula-
tions.
[8] For an extensive study on the stereochemical outcome of the Nicholas
reaction, see: a) E. lvaro, M. C. de La Torre, M. A. Sierra, Org. Lett. 2003,
5, 2381; b) E. lvaro, M. C. de La Torre, M. A. Sierra, Chem. Eur. J. 2006,
12, 6403. According to this procedure, selective irradiation under NOE
conditions of the olefinic proton H-10 (d=6.23 ppm) of compound
21a was performed. An intensity increase in the signal of H-3 con-
firmed the E stereochemistry of the double bond. Another NOE experi-
ment to irradiate H-3 (d=4.81 ppm) produced a NOE in the pro-S
methyl group (d=0.75 ppm), which confirmed the syn relationship be-
tween this methyl and H-3. In a similar manner, the stereochemistry of
compounds 21b and 22 was also elucidated.
Acknowledgements
Financial support from the Spanish MINECO (CTQ2013-46459-
C2-1P;
CTQ2013-46459-C2-1P;
CTQ2014-54071-P,
and
[9] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215.
CTQ2014-51912-REDC) and the CAM (S2009/PPQ-1634-AVAN-
CAT) is acknowledged.
Keywords: density functional calculations
· homogeneous
catalysis · Nicholas reaction · reaction mechanisms · silver
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in a fivefold decrease in the reaction rate for a 1 kcalmolÀ1 increase in
the DG of activation.
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CT, 2009.
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Acta 1990, 77, 123.
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[5] a) R. C. J. Atkinson, L. J. Hope-Weeks, M. J. Mays, G. A. Sloan, J. Organo-
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Received: January 21, 2016
Published online on May 17, 2016
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