Synthesis of 1,3-Amino Alcohols, 1,3-Diols, Amines, and Carboxylic Acids from Terminal Alkynes

Article abstract of DOI:10.1021/acs.joc.5b01220

The half-sandwich ruthenium complexes 1-3 activate terminal alkynes toward anti-Markovnikov hydration and reductive hydration under mild conditions. These reactions are believed to proceed via addition of water to metal vinylidene intermediates (4). The functionalization of propargylic alcohols by metal vinylidene pathways is challenging owing to decomposition of the starting material and catalytic intermediates. Here we show that catalyst 2 can be employed to convert propargylic alcohols to 1,3-diols in high yield and with retention of stereochemistry at the propargylic position. The method is also amenable to propargylic amine derivatives, thereby establishing a route to enantioenriched 1,3-amino alcohol products. We also report the development of formal anti-Markovnikov reductive amination and oxidative hydration reactions to access linear amines and carboxylic acids, respectively, from terminal alkynes. This chemistry expands the scope of products that can be prepared from terminal alkynes by practical and high-yielding metal-catalyzed methods.

Full text of DOI:10.1021/acs.joc.5b01220

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Synthesis of 1,3-aminoalcohols, 1,3-diols, amines, and carboxylic acids from terminal
alkynes.
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Mingshuo Zeng and Seth B. Herzon*. Department of Chemistry, Yale University, New
Haven, Connecticut, 06520 USA
Correspondence: seth.herzon@yale.edu
TOC Graphic:
Abstract: The half-sandwich ruthenium complexes 1–3 activate terminal alkynes toward
anti-Markovnikov hydration and reductive hydration under mild conditions. These
reactions are believed to proceed via addition to metal vinylidene intermediates (8). The
functionalization of propargylic alcohols by metal–vinylidene pathways has remained an
unsolved challenge owing to decomposition of the starting material and catalytic
intermediates. Here we show that the catalyst 2 can be employed to convert propargylic
alcohols to 1,3-diols in high yield and with retention of stereochemistry at the propargylic
position. The method is also amenable to propargylic amine derivatives, thereby
establishing a route to enantioenriched 1,3-diol and 1,3-aminoalcohol products. We also
report the development of formal anti-Markovnikov reductive amination and oxidative
hydration reactions to access linear amines and carboxylic acids, respectively, from
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terminal alkynes. This chemistry expands the scope of products that may be prepared
from terminal alkynes by practical and high-yielding metal-catalyzed methods.
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Introduction: The metal-catalyzed addition of heteroatom nucleophiles to alkynes
represents valuable methods to access aldehydes, ketones, imines, enamides, and enol
1
esters, among other products. Several catalysts have been reported to effect the anti-
2
Markovnikov addition of water to terminal alkynes. Recently, our group developed the
half-sandwich ruthenium complexes 1–3, which mediate the anti-Markovnikov hydration
3
of terminal alkynes under mild conditions (Figure 1). When catalysts 1 or 2
+
PF6−
CF
3
–
PF
6
Ru
N
Ru
Ru
N
N
N
Cl
CH3
3
CH CN
N
N
N
3 2
(CH ) N
CH3
CF3
1
2
3
1
, 2, or 3
NMP–H
hydration
1 or 2
HCO
reduction
O
OH
R
R
R
2
O
2
H
Figure 1. Structures of the catalysts 1–3 and the overall sequence for the anti-
Markovnikov reductive hydration of alkynes.
are used in conjunction with formic acid, the aldehyde intermediate is reduced in situ, to
3
a,3c
provide linear alcohol products (a reaction we refer to as reductive hydration).
High
conversions are achieved at ambient temperature within 8–48 h in the presence of 2–10
mol% metal. The catalysts display compatibility with a range of functional groups
including alkyl halides, esters, carboxylic acids, ketones, alkenes, and alcohols. The
connection between unsaturated hydrocarbon starting materials and heteroatom-
substituted products established by these catalysts has strategic merit, as these two
4
classes of functional groups display orthogonal reactivity under many conditions.
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A.
OH
O
+H
+
O
H
[
Ru]
Ru]
2
H O
[
R
R
–
H+
R
[Ru]
R
[Ru] –[Ru]
R
4
B.
O
Ru
Ru
HCO
2
H
–CO
2
N
N
1
or 2
H
O
H
N
N
(
CH
3
)
2
HN
(CH
3
)
2
HN
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n
n
5 (n = 1, 2)
6 (n = 1, 2)
Scheme 1. A. Proposed pathway for the anti-Markovnikov hydration of terminal alkynes
by the catalysts 1–3. B. Pathway for generation of the ruthenium hydride 6 from the
catalysts 1 or 2 and formic acid.
The specific mechanism of alkyne activation by 1–3 is not yet known but may
5
involve the generation of metal vinylidene intermediates (4, Scheme 1A). The addition
of water, followed by tautomerization and protonolysis, would complete the hydration
3c
step. We provided evidence that the hydrogenation mediated by 1 and 2 proceeds via
heterolytic activation of formic acid, to generate the ruthenium formate 5 (Scheme 1B).
The formate 5 is believed to undergo decarboxylation to the monohydride 6, which
6
effects outer-sphere reduction of the aldehyde. Given the high activity of these
catalysts, it was of interest to determine if their substrate scope could be broadened to
access other important classes of products. Specifically, the functionalization of
propargylic alcohols by pathways involving metal vinylidene species has remained an
7
unsolved problem owing to the instability of the catalytic intermediates (vide infra).
These substrates are readily-accessible by asymmetric acetylide additions to carbonyl
8
compounds, and their successful transformation would establish a route to 1,3-diol
products. In addition, we sought to access other product classes and have developed
methods to affect the formal reductive hydroamination and oxidative hydration of alkynes
to access linear amines and carboxylic acids, respectively. Collectively, these reactions
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expand the scope of products that can be formed from terminal alkynes under mild and
practical conditions.
Results and Discussion:
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Syntheses of 1,3-diols and 1,3-aminoalcohols.
The stereoretentive reductive
hydration of enantioenriched propargylic amines and alcohols would provide access to
1,3-aminoalcohols and 1,3-diols. Although Hintermann and Bolm reported an efficient
9
method for the anti-Markovnikov hydration of propargylic sulfonylimines, the anti-
7
Markovnikov hydration of propargylic alcohols is notoriously difficult, and only a handful
of examples have been reported. As shown by Wakatsuki and co-workers, propargylic
alcohols are converted to α,β-unsaturated aldehydes (11) in high yield using classical
1
0
alkyne hydration catalysts (Scheme 2). These may form by in situ dehydration of the
Meyer–Schuster rearrangement
3
R
1
H2O
–Ru
–H2O
H2O
[Ru]
ruthenium
allenylidene (9)
[Ru]
OH
OH
O
[
Ru]
R
R
R
H
8
7
11
OH
O
H2O
[Ru]
–H2O
–
R
H
1
0
hydrogenation
OH
R
OH
12
Scheme 2. Potential reaction pathways in the anti-Markovnikov reductive
hydration of propargylic alcohols.
11
β-hydroxyaldehyde 10 or by a Meyer–Schuster rearrangement proceeding
directly from the starting material 7. An additional complication arises from the reversible
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dehydration of 3-hydroxy vinylidene intermediates 8 to form allenylidene complexes 9,
which abolishes the stereochemistry of the starting material. This facile mode of
reactivity has been leveraged toward the development of metal-catalyzed substitution
1
3
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reactions of propargylic alcohols. Addition of water to the C-1 position of the
allenylidene 9 constitutes an additional route to the unsaturated aldehyde 11.
We posited that a general reductive hydration of propargylic alcohols may be
realized if the hydration could be conducted at or below ambient temperature and if the
residence time of the intermediate β-functionalized aldehyde could be suppressed. Our
previous studies established that the rate of decarboxylation of formic acid to provide the
2
3
key monohydride intermediate 6 is faster using the κ -complex 2 than using the κ -
3
c
complex 1. This suggested that the complex 2 may provide higher selectivity for the
desired 1,3-diol product 12 through an increased rate of reduction of the aldehyde
intermediate. To test this hypothesis, the reductive hydration of 1-cyclohexylprop-2-yn-1-
ol (7a) was evaluated using 4.5 mol% of 1, 2, or 3 and 4 equiv of formic acid in aqueous
3
N,N-dimethylformamide (DMF) at 25 °C (Table 1). The κ -complex 1 provided 1-
cyclohexylpropane-1,3-diol (12a) in 36% yield, along with 23% of (E)-3-
2
cyclohexylacrylaldehyde (11a) and 27% of unreacted 7a. By comparison, the κ -
complex 2 provided an 80% yield of the desired 1,3-diol 12a. Although the unsaturated
aldehyde 11a was not observed when catalyst 2 was employed, (E)-3-cyclohexylprop-2-
en-1-ol (13a) was formed in 17% yield. A control experiment demonstrated that 13a is
generated by 1,2-reduction of 11a. In accord with our hypothesis the ratio of product
1
2a to undesired rearranged products 11a and 13a is higher using complex 2 than with
complex 1. The bipyridine ruthenium complex 3, which displays negligible hydrogenation
activity at ambient temperature, provided the unsaturated aldehyde 11a in 84% yield,
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demonstrating the instability of the β-hydroxyaldehyde (10a) under the conditions of the
reductive hydration.
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Table 1. Reductive hydration of 1-cyclohexylprop-2-yn-1-ol (7a)
a
using catalysts 1, 2, or 3.
catalyst
(
4.5 mol%)
HCO2H
OH
OH
Cy
O
Cy
OH
Cy
Cy
OH
DMF–H2O
2
5 °C, 48 h
7a
12a
11a
13a
b
yield
12a:
entry
1
catalyst
12a 11a 13a (11a+13a)
+
PF6−
Ru
CH3
N
N
36% 23% <1%
80% <1% 17%
<1% 84% <1%
1.6:1
4.7:1
–
N
CH3
1
PF6–
Ru
N
c
3
CH CN
2
N
(
CH3)2N
2
CF3
Ru
N
N
Cl
3
CF3
3
a
All reactions were conducted on a 250 µmol scale and employed
b
1
4
.5 mol% of 1, 2, or 3 and 4 equiv of formic acid. Determined by H
c
NMR spectroscopy using mesitylene as an internal standard. 2 was
prepared in situ from [CpRu(CH CN) ]PF and the iminopyridine
ligand, see the Supporting Information.
3
3
6
It was deemed valuable from a practical standpoint to develop the reductive
hydration of C-trimethylsilyl-propargylic alcohols, as these can be formed from the
addition of the liquid reagent trimethylsilylacetylene (as opposed to gaseous acetylene
itself) to an aldehyde. We have previously shown that silylalkynes undergo a
3
a
desilylation–reductive hydration sequence at elevated temperatures. In order to
conduct the reaction at ambient temperature, we evaluated the addition of various
reagents to promote the desilylation of 1-cyclohexyl-3-(trimethylsilyl)prop-2-yn-1-ol (7b)
under the conditions of the reductive hydration reaction (Table 2). In the absence of any
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additive, a 57% yield of 12a was obtained, but the conversion of starting material 7b was
incomplete (entry 1). The addition of acetic acid, methanol, or phosphoric acid, which
were expected to promote cleavage of the trialkylsilyl substituent, did not improve the
conversion of 7b (entries 2–4). Aqueous hydrochloric acid impeded the reaction
completely, likely due to saturation of the catalyst by excess chloride anion (entry 5). We
found that the addition of tetra-n-butylammonium fluoride (TBAF) increased the
conversion of starting material 7b to 80%, and 57% of 12a was obtained (entry 6). It is
possible that the TBAF is deactivated by the aqueous formic acid, or that the fluoride ion
itself reduces the activity of the catalyst. Consequently, we conducted an experiment
wherein TBAF was added to the starting material 7b in anhydrous DMF, prior to the
addition of water, formic acid, and catalyst 2. Under these conditions, full conversion of
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7
b was observed, and the reductive hydration proceeded smoothly to provide 12a in
7
9% yield (entry 7).
Table 2. Optimization of the desilylative reductive hydration of 1-
a
cyclohexyl-3-(trimethylsilyl)prop-2-yn-1-ol (7b).
2
(4.5 mol%)
additive (1.0 equiv)
OH
HCO2H
OH
Cy
DMF–H2O
Cy
OH
TMS
2
5 °C, 48 h
7
b
12a
b
b
entry
additive
none
AcOH
yield 12a
57%
60%
59%
40%
0%
conv. 7b
66%
69%
1
2
3
4
5
6
CH
3
OH
68%
63%
H
3
PO
4
HCl (1 N aqueous)
TBAF
0%
80%
57%
79%
c
7
TBAF
>99%
a
All reactions were conducted on a 250 µmol scale and employed
.5 mol% of 2, 4 equiv of formic acid, and 1 equiv of additive.
4
b
1
Yields and conversion were determined by H NMR spectroscopy
c
using mesitylene as an internal standard. 7b was stirred with TBAF
2
in anhydrous DMF for 30 min before the addition of H O, formic
acid, and 2.
Representative C-trimethylsilyl propargylic alcohols that undergo the reductive
hydration reaction are shown in Table 3. As the configurational stability of the
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propargylic center was not assured (see Scheme 2 above), the substrates 7b–f were
prepared in stereoisomerically-enriched form by asymmetric acetylide addition reactions
8
c,8d
14
to the corresponding aldehyde (7b, 7c, and 7d)
or imine (7f) derivatives, or by
1
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metalloenamine addition to an aldehyde (7e).
Table 3. Scope of the reductive hydration of propargylic alcohols
a
and amines.
TBAF, DMF;
X
2
(5 mol%), HCO2H
X
R
DMF–H2O, 25 °C, 48 h
X = OH or NHR
R
OH
TMS
7
b–g
12a–g
b
entry
1
substrate
product
yield
OH
OH
OH
77%
71%
89%
TMS
7
b (99:1 er)
12a (99:1 er)
OH
OH
BnO
BnO
OH
2
3
CH3 CH3
TMS
CH3 CH3
7
c (97:3 er)
OH
12c (98:2 er)
OH
PMBO
PMBO
OH
CH3
d (>20:1 dr)
TMS
CH3
7
12d (>20:1 dr)
t-Bu
t-Bu
S
S
O
NH OH
O
NH OH
c
4
87%
OH
TMS
7
e (>20:1 dr)
12e (>20:1 dr)
O
O
O
O
S
S
HN
t-Bu
HN
t-Bu
c
O
O
5
OH
81%
89%
TMS
f (97:3 er)
OH
7
12f (98:2 er)
OH
OH
6
CF3
CF3
7g (+/–)
12g (+/–)
OH
O
d
7
8
22%
1
1h
7h (+/–)
OH
OH
d
OH
<1%
e
69%
7
i
12i
a
All reactions were conducted on a 250 µmol scale and employed
equiv of TBAF, 5.0 mol% of 2, and 4 equiv of formic acid.
1
b
Entries 6–8 did not employ TBAF. Isolated yields after purification
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c
by flash-column chromatography.
The deprotection was
dconducted at 0 °C for 15 min and 7.0 mol% of 2 was employed.
Yield determined by 1H NMR spectroscopy using mesitylene as
an internal standard. Employing 9 mol% of catalyst 1.
e
3c
Each substrate was stirred with TBAF (1 equiv) in anhydrous DMF for 30 min at
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2
5 °C before the addition of water, formic acid, and the catalyst 2 (5 mol%). The
enantiomeric excess of the propargylic alcohol 7b was conserved after the reductive
hydration, suggesting that allenylidene intermediates (9, Scheme 2) are not formed from
7
b and the catalyst 2, and the product was obtained in 77% yield (entry 1). The
sterically-hindered enantioenriched alcohol 7c was also smoothly transformed to the 1,3-
diol 12c with retention of stereochemistry (71%, entry 2). It is noteworthy that the
synthesis of 12c by this approach proceeds in four steps overall, and compares
1
6
favorably with the published six-step sequence. The diastereomerically pure diol 12d
and aminodiol 12e were obtained in 89% and 87% yields, respectively, from the
corresponding propargylic alcohol derivatives (entries 3, 4, respectively).
The
arylpropargylic sulfonamide 7f also underwent high-yielding reductive hydration to
provide the aminoalcohol 12f with conservation of stereochemistry (84%, entry 5). In the
case of the sulfinamide 7e and the sulfonamide 7f, the deprotection step was performed
1
7
at 0 °C to prevent decomposition of the substrate. Interestingly, allylic alcohols (e.g.,
1
3a, Table 1) were not observed in the reductive hydration of 7b–7f. Instead,
approximately 10–15% of the corresponding terminal alkenes (not shown), presumably
formed by hydrogenation of the deprotected alkyne, were observed. Reductive
hydration of the electron-deficient benzylic alcohol 7g proceeded smoothly to provide the
1
,3-diol 12g in 89% yield (entry 6). A limitation of the reaction is seen in the reductive
hydration of 1-phenylprop-2-yn-1-ol (7h), which provided cinnamaldehyde (11h) in 22%
yield, along with 73% of 7h remaining (entry 7). This deviation in product distribution
may reflect an increased ease of ionization, which promotes Meyer–Schuster
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rearrangment or elimination of the β-hydroxy aldehyde intermediate.
Tertiary
propargylic alcohols such as 1-ethynylcyclohexan-1-ol (7i) were unreactive toward 2
(entry 8), but a 69% of 1-(2-hydroxyethyl)cyclohexan-1-ol (12i) could be obtained when 9
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c
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mol% of catalyst 1 was employed.
Synthesis of amines. We next sought to develop an anti-Markovnikov reductive
hydroamination of terminal alkynes. Although a handful of anti-Markovnikov alkyne
hydroamination catalysts have been reported, these require heating to 120 °C under
18
19
strongly basic conditions, provide variable regioselectivities, or are limited to
2
0
secondary amine nucleophiles (for anti-Markovnikov alkyne hydroamidation, see ref.
2
1
)
.
Several mechanistic possibilities could be envisioned, including trapping of the
vinylidene directly by the nitrogen nucleophile or ruthenium-mediated reductive
2
2
amination of the aldehyde intermediate.
Our studies began with an evaluation of the ability of the ruthenium complexes 1
and 2 to promote the reductive hydroamination of phenylacetylene (7j) to form the linear
amine 14j (Table 4). p-Anisidine was used as nucleophile due to its low volatility and the
2
3
ease of removal of the p-methoxyphenyl substituent. Unfortunately, the product 14j
was only formed in 17–22% yield, even after prolonged heating at 100 °C in the
presence of 1 or 2, and extensive decomposition of the alkyne was observed (entries 1
and 2). We reasoned that the imine ligands of 1 and 2 may be unstable in the presence
3
a
of excess p-anisidine at high temperature, and so the bipyridine complex 15 was
evaluated. The starting material 7j was recovered quantitatively after stirring at 25 °C,
and a 17% yield of the product 14j was obtained after heating to 100 °C (entries 3 and 4,
respectively). Qualitatively similar results were observed when the more active electron-
deficient complex 3 was employed (entry 5). Several potential modes of catalyst
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Table 4. Optimization of the anti-Markovnikov reductive
hydroamination.
a
H
N
catalyst, p-anisidine
Ph
Ph
reductant
NMP–H2O
OCH3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
j
1
4j
catalyst
entry (mol%) reductant (equiv) temp, time yield 13j conv. 7j
b
b
1
2
3
4
5
1 (9)
2 (9)
HCO
HCO
HCO
HCO
HCO
2
2
2
2
2
H (4)
H (4)
H (4)
H (4)
H (4)
72 h, 100 °C
72 h, 100 °C
72 h, 25 °C
72 h, 100 °C
72 h, 100 °C
30 h, 25 °C
22%
17%
0%
17%
21%
55%
69%
79%
67%
15 (9)
15 (9)
3 (9)
<1%
>99%
>99%
>99%
>99%
c
6
3 (2)
PICB (1)
c
7
3 (2) PICB (1), AcOH (1) 30h, 25 °C
+
PF6−
Ru
N
CH3
BH3
NCCH3
N
N
2-picoline•borane
(PICB)
1
5
a
b
All reactions w1ere conducted on
determined by Hc NMR spectroscopy using mesitylene as an
internal standard. PCIB and AcOH (1 equiv each) were added after
a 250 µmol scale Yields
2
4 h. The reaction was stirred for an additional 6 h.
deactivation may have been occurring including displacement of the nitrogen
ligands from ruthenium or the accumulation of catalytically-inactive intermediates. To
probe the latter process, we monitored the reductive hydroamination in entry 2 by
2
4
UPLC/MS analysis. We observed formation of the iminoacyl complex 16 (Figure 2),
and we did
PF6–
Ru
N
Ph
6 R = CH2CH2N(CH3)2
N
N
R
CH3O
1
Figure 2. Structure of the iminoacyl complex 16.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
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5
5
5
5
5
6
not observe product formation even after heating 16 for extended periods. Thus
although the complexes 1 and 2 are competent to promote the direct anti-Markovnikov
addition of amines to alkynes, catalyst turnover appears to be impeded by the formation
of stable iminoacyl complexes that are resistant to protonolysis.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
We reasoned that addition of the amine nucleophile after anti-Markovnikov
25
hydration may provide a means to overcome these challenges. Given that the
hydration proceeds at ambient temperature, such a process may deliver a broader
substrate scope. 2-Picoline–borane (PICB) was chosen as reductant since it has been
reported to selectively reduce imines in the presence of aldehydes and ketones under
2
6
aqueous conditions. In this approach, the substrate would be transformed to an
aldehyde by the ruthenium catalyst, addition of a primary amine, followed by PICB-
mediated reductive amination, would provide the amine product. The addition of 1 equiv
each of PICB and p-anisidine directly to a reaction mixture containing the aldehyde
derived from 7j (obtained using 2 mol% 3) formed the amine 14j in 55% yield, along with
22% of 2-phenylethanol (entry 6). The addition of acetic acid (1 equiv) suppressed
direct reduction of the aldehyde and provided the amine 14j in 69% yield (entry 7).
Under these conditions a range of alkynes undergo reductive hydroamination
with p-anisidine as nucleophile at ambient temperature (Table 5). Aromatic alkynes such
as 7k only required 2 mol% ruthenium to complete the hydration step, and the amine
1
4k was obtained in 61% yield (entry 1). Somewhat higher loadings of ruthenium (5
mol%) were required to obtain full conversion of aliphatic alkynes (7l, entry 2). A broad
range of functional groups, such as imides (7m), esters (7n), and alkylchlorides (7o) are
compatible with the reaction conditions (67–77% yield of product, entries 3–5,
respectively). In addition, we have found that a range of heterocycles are compatible
with the hydration and reduction steps. For example, alkynyl furans (7p), thiophenes
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(
7q), and indoles (7r) are efficiently converted to the linear amine products (60–79%
yield, entries 6–8). Sterically-encumbered alkynes such as 2,4,6-trimethylphenyl (Mes)-
acetylene 7s and the N-(tert-butoxycarbonyl)-protected propargylic amine 7t required 7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Table 5. Scope of the anti-Markovnikov reductive hydroamination.
3
(2–9 mol%)
NMP–H2O, 25 °C, 24 h;
R
NHPMP
14k–v
R
p-anisidine, PICB
2
5 °C, 6 h
7
k–v
b
entry
1
substrate, mol% 3
product, yield
NHPMP
CH3O
CH3O
7k
14k
2
mol%
61%
NHPMP
n-octyl
n-octyl
7l
2
3
14l
5
mol%
83%
O
NHPMP
N ( )5
O
N ( )3
O
O
7
m
14m
5 mol%
O
77%
O
NHPMP
CH3O
( )8
CH3O
( )8
4
5
7
n
14n
5
mo%
69%
NHPMP
Cl
( )3
Cl
( )3
7o
14o
5
mol%
67%
OAc
O
O
OAc
6
7
NHPMP
7p
1
4p
5 mol%
79%
OAc
S
S
OAc
NHPMP
7q
1
4q
5
H
N
mol%
73%
H
N
O
O
c
8
HN
HN
NHPMP
7
r
14r
5
mol%
60%
NHPMP
Mes
Mes
9
7
s
14s
7
mol%
86%
BocHN
BocHN
NHPMP
10
7
t
14t
7
mol%
72%
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
BocHN
1
2k
OH
CH3
OH
CH3
NHPMP
H
H
11
H
H
H
H
CH3O
CH3O
1
4u
7u
9 mol%
81%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NHPMP
N
N
d
1
2
7
v
14v
9
mol%
73%
a
All reactions were conducted on a 250 µmol scale and employed 3,
AcOH (1.1 equiv), p-anisidine (1.0 equiv), and PICB (1.0 equiv).
Isolated yield after purification by flash-column chromatography.
Hydration step conducted for 36 h. Hydration step conducted for
8 h.
b
c
d
4
mol% catalyst loading to achieve complete conversion in the hydration step (86%
and 72% yield of amine, entries 9 and 10, respectively). The tertiary propargylic alcohol
7
u and the electron-rich indole 7v were converted to the amines 14u and 14v in 81%
and 73% yields, respectively. Additional experiments revealed that the reaction is also
compatible with other primary and secondary aryl and alkyl amines (see Table S1 in
Supporting Information), although the efficiency of the reaction was lower.
Synthesis of carboxylic acids. The oxidation of organic compounds by
2
7
ruthenium tetroxide was first introduced by Djerassi and Engle in 1953. Since that time,
several protocols employing substoichiometric quantities of ruthenium have been
developed to overcome the cost and waste associated with the use of molar equivalents
28
of metal oxidant. We envisioned that we might be able to modify our ruthenium
complexes in situ by addition of a suitable oxidant to allow for direct conversion of the
hydration product to a carboxylic acid. This two-step, one-flask process would constitute
2
9
a formal anti-Markovnikov oxidative hydration of terminal alkynes.
To test the feasibility of this approach, we evaluated the hydration of
phenylacetylene (7j) using 2 mol% of the catalyst 3 in aqueous N-methyl-2-pyrrolidinone
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(
NMP) at ambient temperature for 24 h, followed by the addition of a terminal oxidant (3
equiv, Table 6). Periodic acid provided a 62% yield of phenylacetic acid (17j) after one
hour (entry 1) while sodium periodate provided a nearly quantitative yield of 17j (entry 2).
Other mildly basic oxidants such as sodium hypochlorite (entry 3) and sodium bromate
(entry 4) were ineffective (<1%, 6% yield of 17j, respectively). Iodosobenzene (entry 5)
and bis(acetoxy)iodobenzene (entry 6) were highly effective and provided a nearly
quantitative yield of 17j. The application of stoichiometric amounts of sodium periodate,
iodosobenzene, or bis(acetoxy)iodobenzene resulted in lower yields of product (26%–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
8%, entries 7–9). Attempted oxidation of phenylacetaldehyde using three equivalents
of bis(acetoxy)iodobenzene alone provided only a 16% yield of 17j, confirming the
intermediacy of a ruthenium-based oxidant.
Table 6. Optimization of the formal anti-Markovnikov oxidative
a
hydration of alkynes.
3 (2 mol%)
NMP–H2O, 25 °C, 24 h;
O
oxidant, 25 °C, 1 h
OH
7
j
17j
b
entry
oxidant
HIO
NaIO
NaClO
equiv
yield
1
2
3
4
5
6
7
8
9
4
3.0
3.0
3.0
3.0
3.0
3.0
1.0
1.0
1.0
62%
>99%
<1%
6%
4
NaBrO
PhIO
3
>99%
>99%
26%
48%
58%
PhI(OAc)
2
NaIO
4
PhIO
PhI(OAc)
2
a
b
All reactions were conducted on a 300 µmol scale. Yields
1
determined by H NMR spectroscopy using mesitylene as an
internal standard.
The scope of this formal anti-Markovnikov oxidative hydration is shown in Table
7. Phenylacetylene (7j, entry 1), electron-rich arylalkynes such as 4-
methoxyphenylacetylene (7k, entry 2), and simple aliphatic alkynes such as 1-decyne
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
7l, entry 3) underwent oxidative hydration in high yield (84%, 82%, and 98%,
respectively). A broad range of functional groups are compatible with these conditions.
For example, phthalimide- (7m, entry 4), ester- (7n, entry 5), and primary alkyl chloride-
(7o, entry 6) containing alkynes underwent oxidative hydration in ≥92% yield. The
sterically-hindered alkyne mesitylacetylene (7s) was smoothly functionalized to provide
the arylacetic acid derivative 17s in 91% yield (entry 7). Although not extensively
investigated, propargylic amine derivatives are also compatible with the reaction
conditions. For example, the propargylic sulfonamide 7t (entry 8) and the propargylic
sulfinamide 7w (entry 9) underwent oxidative hydration to provide the β-aminoacid
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 7. Scope of the two-step one-flask anti-Markovnikov oxidative
a
hydration.
3
(2–7 mol%)
NMP–H2O, 25 °C, 24 h;
O
R
R
7
PhI(OAc)2, 25 °C, 1 h
OH
7j-w
j-w
1
3
yieldb
entry
substrate
product
(mol%) (%)
O
c
1
OH
2
84%
7
j
17j
O
c
2
OH
2
5
82%
98%
H3CO
H3CO
1
7k
7
k
O
n-octyl
n-octyl
3
4
OH
7
l
1
7l
O
O
O
OH
N
N
5
99%
O
O
7
m
17m
O
O
O
CH3O
( )8
5
6
CH O
( )8
5
5
94%
92%
3
OH
7
n
1
7n
O
Cl
(
)3
Cl
( )3
OH
7
o
17o
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7
8
9
O
Mes
d
Mes
7
8
7
91%
91%
OH
7
s
17s
TsHN
TsHN
O
d
7
5
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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7
t
17t
t-Bu
t-Bu
O
S
S
O
NH
NH
O
O
d,e
9
80%
OH
TMS
7
w
17w
a
All reactions conducted on a 600 µmol scale employing 3.0 equiv
b
PhI(OAc)
chromatography. e Emplying 2.0 equiv PhI(OAc)
equiv PhI(OAc) . Hydration conducted at 50 °C.
2
.
Isolated yields after purification by flash-column
c
d
2
. Employing 4.0
2
derivatives 17t and 17w in 91% and 80% yields, respectively. In the case of the
sulfinamide 7w, the first hydration step was conducted at 50 °C to ensure quantitative
desilylation and concurrent oxidation of the sulfur atom was observed in the second
operation.
Conclusion: In this manuscript we have broadened the scope of products that
may be prepared from terminal alkynes using the catalysts 1–3. We have shown that
propargylic alcohols, which have been challenging substrates for anti-Markovnikov
functionalization reactions, can be efficiently converted to 1,3-diol products using the
catalyst 2. 2 also converts propargylic amines to 1,3-aminoalcohols in high yield. The
efficiencies of these transformations are attributed to the mild conditions of the hydration
step and the rapid rate of reduction of the β-functionalized aldehyde intermediates,
which conspire to suppress elimination and rearrangement pathways. These reactions
proceed without erosion of stereochemistry, thereby providing access to enantioenriched
1
,3-difunctionalized products. In addition, we have developed a formal anti-Markovnikov
reductive hydroamination reaction that provides access to linear amines and also
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
described a formal anti-Markovnikov oxidative hydration to provide carboxylic acids.
These advances significantly expand the utility of this chemistry by increasing the
diversity of products that are accessible from alkynes under mild conditions.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Experimental Section: General Experimental Procedures. All reactions were
performed in single-neck, flame-dried, round-bottomed flasks fitted with Teflon-coated
stir bars and rubber septa, or borosilicate vials, under an atmosphere of nitrogen, unless
otherwise noted. Air- and moisture-sensitive liquids were transferred via syringe or
stainless steel cannula, or were handled in a nitrogen-filled drybox (working oxygen level
<
10 ppm). Organic solutions were concentrated by rotary evaporation at 30–33 °C.
Intermediates were purified by flash-column chromatography, as described by Still et
30
al. employing silica gel (60 Å, 40–63 µm particle size) purchased from Sorbent
Technologies (Atlanta, GA).
Analytical thin-layered chromatography (TLC) was
performed using glass plates pre-coated with silica gel (0.25 mm, 60 Å pore size)
impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by
exposure to ultraviolet light (UV) and/or submersion in aqueous potassium
4
permanganate solution (KMnO ) or aqueous bromocresol solution, followed by brief
heating on a hot plate (120 °C, 10–15 s).
Materials. Commercial solvents and reagents were used as received with the
following exceptions. Dichloromethane, N,N-dimethylformamide, ether, tetrahydrofuran,
3
1
triethylamine, and toluene were purified according to the method of Pangborn et al.
Distilled water, N-methyl-2-pyrrolidinone, N,N-dimethylformamide, and formic acid were
5
deoxygenated by sparging with nitrogen for 30 min before use. Tris(acetonitrile) (η -
3
2
33
cyclopentadienyl)ruthenium hexafluorophosphate (S5), the iminopyridine ligand S6,
3
3
33
the tridentate ruthenium complex 1, the bidentate ruthenium complex 2, the
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ruthenium chloride complex 3, 1-cyclohexylprop-2-yn-1-ol (7a), (R)-1-cyclohexyl-3-
3
6
37
38
(
trimethylsilyl)-2-propyn-1-ol (7b), the aldehyde S1, the t-butylsulfinyl imine S3, (S)-
3
9
N-(1-(2-furanyl)-prop-2-yn-1-yl)2-methylpropane-2-sulfonamide
(7f),
α-ethynyl-4-
4
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(trifluoromethyl)-benzenemethanol (7g),
N-(2-propyn-1-yl)-1H-indole-2-carboxamide
4
1
33
(
7r), 2-ethynyl-1,3,5-trimethylbenzene (7s), tert-butyl(1-ethynylcyclohexyl)carbamate
42
43
(
7t), 1-(2-propynyl)-1H-indole (7v), and 2-methyl-N-((R)-1-phenyl-3-(trimethylsilyl)2-
39
propyn-1-yl)propane-2-sulfinamide (7w)
were prepared according to published
procedures.
1
Instrumentation. Proton nuclear magnetic resonance spectra ( H NMR) were
recorded at 400, 500, or 600 MHz at 24 °C, unless otherwise noted. Chemical shifts are
expressed in parts per million (ppm, δ scale) downfield from tetramethylsilane and are
3 2 6 6
referenced to residual protium in the NMR solvent [CHCl , δ 7.26; CHDCl , δ 5.32; C H ,
δ 7.16]. Data are represented as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, quin = quintet, m = multiplet and/or multiple resonances,
br = broad, app = apparent), integration, coupling constant in Hertz, and assignment.
13
Proton-decoupled carbon nuclear magnetic resonance spectra ( C NMR) were recorded
at 101, 126 or 151 MHz at 24 °C, unless otherwise noted. Chemical shifts are
expressed in parts per million (ppm, δ scale) downfield from tetramethylsilane and are
3 2 2
referenced to the carbon resonances of the solvent (CDCl , δ 77.0; CD Cl , δ 54.0).
Attached proton test (APT) were recorded at 101 or 151 MHz at 24 °C, unless otherwise
13
noted. C NMR and APT data are combined and represented as follows: chemical shift,
carbon type [obtained from APT experiments]. Attenuated total reflectance Fourier
transform infrared spectra (ATR-FTIR) were obtained using a FTIR spectrometer
referenced to a polystyrene standard. Data are represented as follows: frequency of
–
1
absorption (cm ), intensity of absorption (s = strong, m = medium, w = weak, br = broad.
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High-resolution mass spectrometry (HRMS) were obtained using a UPLC/HRMS
instrument equipped with a dual API/ESI quadropole high-resolution mass spectrometry
detector and photodiode array detector.
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For clarity, synthetic intermediates not described in the manuscript are
numbered in the Experimental Section beginning with S1.
O
BnO
H
CH3 CH3
S1
Synthesis of the propargylic alcohol 7c. Following the procedure of Carreira and co-
8
c
workers, (+)-N-methylephedrine (670 mg, 3.74 mmol, 1.20 equiv) and triethylamine
(
520 µL, 3.74 mmol, 1.20 equiv) were added in sequence to a solution of zinc
trifluoromethanesulfonate (1.29 g, 3.54 mmol, 1.10 equiv) in toluene (10 mL) at 25 °C.
The resulting solution was stirred for 2 h at 25 °C. Trimethylsilylacetylene (533 µL, 3.74
mmol, 1.20 equiv) was then added via syringe, and the resulting mixture was stirred for
4
4
15 min at 25 °C. The aldehyde S1 (599 mg, 3.12 mmol, 1 equiv) was then added and
the resulting mixture was stirred for 19 h at 25 °C. The product mixture was diluted with
saturated aqueous ammonium chloride solution (50 mL) and the layers that formed were
separated. The aqueous layer was extracted with dichloromethane (3 × 50 mL) and the
organic layers were combined. The combined organic layers were dried over sodium
sulfate and the dried solution was filtered. The filtrate was concentrated and the residue
obtained was purified by flash-column chromatography (eluting with 5% acetone–
f
pentane) to afford the propargylic alcohol 7c as a colorless oil (625 mg, 69%): R = 0.29
1
(
5% acetone–pentane; UV, KMnO
4
). H NMR (500 MHz, CDCl
3
) δ 7.38-7.27 (m, 5H),
4
.52 (q, J = 12 Hz, 2H), 4.20 (d, J = 7.1 Hz, 1H), 3.65 (d, J = 8.8 Hz, 1H), 3.38 (d, J = 7.2
1
3
Hz, 1H), 3.29 (d, J = 8.8 Hz, 1H), 1.09 (s, 3H), 0.97 (s, 3H), 0.18 (s, 9H). C NMR (101
MHz, CDCl
3
) δ 138.0 (C), 128.6 (CH), 127.9 (CH), 127.7 (CH), 105.6 (C), 90.1 (C), 78.3
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(
CH
2
), 73.8 (CH
2
), 71.0 (CH), 39.3 (C), 22.2 (CH
3
), 21.2 (CH
3
), 0.10 (CH
3
). IR (ATR-
–
1
+
FTIR), cm : 1250 (m), 1060 (m), 1005 (m), 838 (s). HRMS-ESI(m/z): [M–OH] calcd for
+
45
C
17
H
25OSi , 273.1669; found, 273.1648. Mosher ester analysis of 7c indicated a 97:3
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ratio of enantiomers. The absolute stereochemistry of the major enantiomer was
8
c
assigned by analogy to that obtained by Carreira and co-workers.
O
PMBO
H
CH3
S2
Synthesis of the propargylic alcohol 7d. Following the procedure of Marshall and co-
8d
workers, a solution of diethylzinc in hexanes (1.0 M, 2.40 mL, 2.40 mmol, 4.80 equiv)
was added to a solution of trimethylsilylacetylene (454 µL, 3.21 mmol, 6.40 equiv) in
toluene (2.5 mL) at 25 °C. The reaction vessel was fitted with a reflux condenser and
then placed in an oil bath that had been preheated to 120 °C. The mixture was stirred
and heated for 1 h at 120 °C. The solution was cooled to 25 °C and the cooled solution
was diluted sequentially with ether (6.0 mL) and titanium isopropoxide (178 µL, 601 µmol,
1
.20 equiv). The resulting mixture was stirred for 1 h at 25 °C. A solution of the
4
6
aldehyde S2 (97.4 mg, 501 µmol, 1 equiv) in ether (4.0 mL) was then added. The
resulting mixture was stirred for 15 h at 25 °C. The product mixture was diluted with
aqueous tartaric acid solution (1.0 M, 10 mL) and the resulting biphasic mixture was
stirred for 30 min at 25 °C. The stirred biphasic mixture was transferred to a separatory
funnel, and the aqueous layer was extracted with ether (3 × 20 mL). The organic layers
were combined and the combined organic layer was washed with saturated aqueous
sodium chloride solution (35 mL). The washed organic layer was dried over sodium
sulfate and the dried solution was filtered. The filtrate was concentrated and the residue
obtained was purified by flash-column chromatography (eluting with 20% ether–pentane)
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6
1
to afford the propargyl alcohol 7d as a white solid (210 mg, 23%, >20:1 dr). H NMR
spectroscopic data for the propargylic alcohol 7d prepared in this way were identical to
4
7
literature values.
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8
9
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1
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CH3
S
CH3
S
CH3
CH3
CH3
CH3
O
N
O
N
OH
CH3
TMS
S3
S4
Synthesis of the propargylic alcohol S4. Following the procedure of Ellman and co-
15
workers, a solution of n-butyllithium in hexanes (2.5 M, 880 µL, 2.20 mmol, 1.10 equiv)
was added to a solution of diisopropylamine (336 µL, 2.40 mmol, 1.20 equiv) in
tetrahydrofuran (8.3 mL) at 0 °C. The resulting mixture was stirred for 30 min at 0 °C.
48
The solution was cooled to –78 °C and a solution of the t-butylsulfinyl imine S3 (447
mg, 2.00 mmol, 1 equiv) in tetrahydrofuran (4.0 mL) was added dropwise via syringe.
The resulting mixture was stirred for 45 min at –78 °C. Zinc bromide (901 mg, 4.00
mmol, 2.00 equiv) and 3-trimethylsilylpropynal (384 µL, 2.60 mmol, 1.30 equiv) were
then added in sequence. The resulting mixture was stirred for 3 h at –78 °C. A solution
of acetic acid (580 µL, 10.0 mmol, 5.00 equiv) in tetrahydrofuran (5.0 mL) that had been
precooled to –78 °C was then added to the cold reaction mixture. The product mixture
was diluted with saturated aqueous sodium chloride solution (25 mL) and the layers that
formed were separated. The aqueous layer was extracted with ethyl acetate (2 × 25 mL)
and the organic layers were combined. The combined organic layer was dried over
sodium sulfate, and the dried solution was filtered. The filtrate was concentrated and the
residue obtained was purified by flash-column chromatography (eluting with 60% ether–
pentane) to afford the propargyl alcohol S4 as a yellow oil (900 mg, 56%, >20:1 dr). The
15
relative configuration of S4 was assigned by analogy to related addition products:
f
R =
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0
7
.20 (25% ether–pentane; UV). H NMR (600 MHz, CDCl
3
) δ 7.86 (d, J = 7.9 Hz, 2H),
.53-7.38 (m, 3H), 5.09 (d, J = 9.2 Hz, 1H), 4.49 (m, 1H), 3.76 (t, J = 12.6 Hz, 1H), 3.51
1
3
(dd, J = 3.0, 13.2 Hz, 1H), 1.36 (s, 9H), 0.16 (s, 9H). C NMR (151 MHz, CDCl
3
) δ 174.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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29
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57
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59
60
(
(
C), 136.9 (C), 132.2 (CH), 128.9 (CH), 127.7 (CH), 106.3 (C), 88.7 (CH), 59.4 (C), 59.3
–1
CH), 41.4 (CH
2
), 23.3 (CH
3
), 0.03 (CH
3
). IR (ATR-FTIR), cm :3322 (w, br), 1035 (m),
+
+
8
39 (s). HRMS-ESI(m/z): [M-OH] calcd for C18
H
26NOSSi , 332.1499; found, 332.1474.
Syntheses of the aminoalcohol 7e. Following the procedure of Ellman and co-
1
5
workers, a solution of lithium triethylborohydride in tetrahydrofuran (1.0 M, 3.80 mL,
3.77 mmol, 2.50 equiv) was added to a solution of the propargylic alcohol S4 (528 mg,
1
.51 mmol, 1 equiv) in tetrahydrofuran (2.0 mL) at –78 °C. The resulting solution was
stirred for 2 h at –78 °C. The cold product mixture was diluted with saturated aqueous
ammonium chloride solution (3.0 mL) and the diluted product mixture was gradually
warmed to 25 °C. The warmed product mixture was diluted with saturated aqueous
sodium chloride solution (15 mL) and the layers that formed were separated. The
aqueous layer was extracted with dichloromethane (3 × 15 mL) and the organic layers
were combined. The combined organic layer was dried over sodium sulfate, and the
dried solution was filtered. The filtrate was concentrated and the residue obtained was
purified by flash-column chromatography (eluting with 30% ethyl acetate–pentane) to
afford the propargylic alcohol 7e as a white solid (403 mg, 76%, >20:1 dr). The relative
configuration of 7e was determined by conversion to the corresponding cyclic carbamate,
15
followed by NMR analysis, as previously described:
R
f
= 0.40 (50% ethyl acetate–
) δ 7.38-7.23 (m, 5H),
1
pentane; UV, KMnO
4
). mp 129–131 °C. H NMR (400 MHz, CDCl
3
4
.81 (quint, J = 4.8 Hz, 1H), 4.51 (t, br, J = 5.2 Hz, 1H), 4.14 (d, J = 5.1 Hz, 1H), 3.59 (s,
1
3
1H), 2.19 (dddd, J = 21.0, 14.4, 7.6, 4.0 Hz, 2H), 1.22 (s, 9H), 0.18 (s, 9H). C NMR
(
151 MHz, CDCl
3
) δ 142.6 (C), 128.7 (CH), 127.6 (CH), 126.8 (CH), 105.8 (C), 90.6 (C),
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6
–1
6
3
0.4 (CH), 56.9 (CH), 55.9 (C), 45.7 (CH
2
), 22.8 (CH
3
), 0.02 (CH
3
). IR (ATR-FTIR), cm :
+
307 (w, br), 1008 (s), 839 (s), 703 (m). HRMS-ESI(m/z): [M–OH] calcd for
+
C
18
H
30NO
2
SSi , 352.1761; found, 352.1736.
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8
9
0
4
9
Synthesis of the alkyne 7p. A solution of 2-propynylmagnesium bromide in ether
(0.90 M, 12.0 mL, 10.8 mmol, 2.16 equiv) was added dropwise via syringe to a solution
of furfural (480 mg, 5.00 mmol, 1 equiv) in ether (5.0 mL) at 0 °C. The reaction mixture
was stirred for 10 min at 0 °C. The cooling bath was removed and the reaction mixture
was allowed to warm to 25 °C. The mixture was stirred for 45 min at 25 °C and then was
cooled to 0 °C. Acetic anhydride (773 µL, 7.00 mmol, 1.40 equiv) was then added
dropwise via syringe. The resulting solution stirred for 20 min at 0 °C. The cooling bath
was removed, and the reaction mixture was stirred for 1 h. The product mixture was
cooled to 0 °C and the cooled product mixture was diluted with saturated aqueous
ammonium chloride solution (25 mL). The diluted product mixture was transferred to a
separatory funnel and extracted with ether (3 × 15 mL). The organic layers were
combined and the combined layer was dried over sodium sulfate. The dried solution
was filtered and the filtrate was concentrated. The residue obtained was purified by
flash-column chromatography (eluting with 50% dichloromethane–pentane) to afford the
f
alkyne 7p as an orange oil (747 mg, 84%): R = 0.31 (50% methylene chloride–pentane;
1
UV, KMnO
4
). H NMR (400 MHz, CDCl
3
) δ 7.40 (dd, J = 1.8, 0.9 Hz, 1H), 6.43 (dd, J =
3
2
.2, 0.9 Hz, 1H), 6.36 (dd, J = 3.3, 1.8 Hz, 1H), 5.99 (t, J = 6.9 Hz, 1H), 2.86 (dd, J = 6.9,
1
3
3
.7 Hz, 2H), 2.09 (s, 3H), 1.99 (t, J = 2.6 Hz, 1H). C NMR (101 MHz, CDCl ) δ 170.1
(
C), 151.1 (C), 143.0 (CH), 110.5 (CH), 109.3 (CH), 79.0 (C), 70.8 (CH), 66.7 (CH), 23.1
–
1
2 3
(CH ), 21.1 (CH ). IR (ATR-FTIR), cm : 3293 (br, m), 1737 (s), 1221 (s), 1013 (m).
+
+
8 7
HRMS-ESI(m/z): [M–OAc] calcd for C H O , 119.0491; found, 119.0492.
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Synthesis of the alkyne 7q. Following the procedure above using 2-
thiophenecarboxaldehyde (561 mg, 5.00 mmol, 1 equiv). Purification by flash-column
chromatography (eluting with 50% dichloromethane–pentane) afforded the alkyne 7q as
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
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45
46
47
48
49
50
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54
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56
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60
f 4
a yellow oil (966 mg, 99%): R = 0.29 (50% methylene chloride–pentane; UV, KMnO ).
1
H NMR (400 MHz, CDCl
3
) δ 7.29 (dd, J = 5.1, 1.2 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 6.98
(
dd, J = 5.1, 3.6 Hz, 1H), 6.19 (t, J = 6.7 Hz, 1H), 2.84 (dd, J = 6.6, 2.7 Hz, 2H), 2.10 (s,
1
3
3
3
H), 2.03 (t, J = 2.6 Hz, 1H). C NMR (101 MHz, CDCl ) δ 170.1 (C), 141.6 (C), 126.7
(CH), 126.3 (CH), 125.8 (CH), 79.2 (C), 71.2 (CH), 69.2 (CH), 26.7 (CH
2
), 21.2 (CH
3
). IR
–
1
+
(ATR-FTIR), cm : 3289 (br, m), 1735 (s), 1221 (s), 1018 (s). HRMS-ESI(m/z): [M–OAc]
+
calcd for C
8
H
7
S , 135.0263; found, 135.0259.
CH3
N
N
CH3
N
S6
Synthesis of the 1,3-diol 12a (Table 3, entry 1). In a nitrogen-filled drybox, a 4-mL vial
equipped with a magnetic stirring bar was charged with the propargylic alcohol 7b (105
mg, 500 µmol, 1 equiv) and N,N-dimethylformamide (1.0 mL). The vial was sealed with
a Teflon-lined cap and the sealed vial was removed from the drybox. A solution of tetra-
n-butylammonium fluoride in tetrahydrofuran (1.0 M, 500 µL, 500 µmol, 1.00 equiv) was
then added with exclusion of oxygen (nitrogen-filled bag). The vial was sealed with a
Teflon-lined cap and the sealed vial was removed from the nitrogen-filled bag. The
reaction mixture was stirred for 30 min at 25 °C. Formic acid (76.0 µL, 2.00 mmol, 4.00
5
equiv), water (500 µL), and a solution of (η -cyclopentadienyl) tris(acetonitrile)ruthenium
3
2
3c
hexafluorophosphate (S5) and the iminopyridine ligand S6 in N,N-dimethylformamide
(25 mM, 1.00 mL, 25.0 µmol, 0.0500 equiv) were then added in sequence with exclusion
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5
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of oxygen (nitrogen-filled bag). The vial was sealed with a Teflon-lined cap and the
sealed vial was removed from the nitrogen-filled bag. The reaction mixture was stirred
for 48 h at 25 °C. The product mixture was diluted with ethyl acetate (15 mL) and the
diluted solution was transferred to a separatory funnel. Saturated aqueous ammonium
chloride solution (25 mL) was added, and the layers that formed were separated. The
aqueous layer was extracted with ethyl acetate (3 × 20 mL) and the organic layers were
combined. The combined organic layers were washed with saturated aqueous sodium
chloride solution (3 × 30 mL). The washed organic layer was dried over sodium sulfate.
The dried solution was filtered and the filtrate was concentrated. The residue obtained
was purified by flash-column chromatography (eluting with 60% ethyl acetate–pentane)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
to afford the product 12a as a colorless oil (61.2 mg, 77%). H NMR spectroscopic data
5
0
for the diol 12a prepared in this way were identical to literature values.
Synthesis of the 1,3-diol 12c (Table 3, entry 2). Following the procedure for 12a using
the propargylic alcohol 7c (145 mg, 500 µmol, 1 equiv). Purification by flash-column
chromatography (eluting with 60% ether–pentane) afforded the diol 12c as a white solid
1
(
85.0 mg, 71%, 98:2 er). H NMR spectroscopic data for the 1,3-diol 12c prepared in this
1
6
way were identical to literature values. The enantiomeric excess of 12c was
5
1
determined to be 92% by the James method.
Synthesis of the 1,3-diol 12d (Table 3, entry 3). Following procedure for 12a using the
propargylic alcohol 7d (146 mg, 500 µmol, 1 equiv). Purification by flash-column
chromatography (eluting with 60% ether–pentane) afforded the 1,3-diol 12d as a
1
colorless oil (106 mg, 89%, >20:1 dr): R
NMR (500 MHz, CDCl
9.6, 11.3, 2H), 3.93 (dt, J = 9.7, 3.4 Hz, 1H), 3.84 (t, J = 5.6 Hz, 2H), 3.81 (s, 3H), 3.52
f
= 0.11 (50% ethyl acetate–pentane; UV). H
3
) δ 7.26 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.6, 2H), 4.50 (dd, J =
6
13
(
dq, J = 6.4, 2.7 Hz, 1H), 1.79-1.60 (m, 2H), 1.18 (d, J = 6.4 Hz, 3H).
C NMR (151
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MHz, CDCl
3
) δ159.3 (C), 130.4 (C), 129.4 (CH), 113.9 (CH), 77.3 (CH), 73.3 (CH), 70.5
–
1
(
CH ), 61.4 (CH ), 55.4 (CH ), 33.8 (CH ), 14.1 (CH ). IR (ATR-FTIR), cm : 3373 (w, br),
2
2 3 2 3
+
+
2926 (w, br), 1245 (s), 1030 (s). HRMS-ESI(m/z): [M+Na] calcd for C13
4
H20NaO ,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
263.1254.1434; found, 263.1250.
Synthesis of the 1,3-diol 12e (Table 3, entry 4). A 4-mL vial equipped with a magnetic
stir bar was charged with the propargylic alcohol 7e (87.9 mg, 250 µmol, 1 equiv) and
N,N-dimethylformamide (500 µL) under an atmosphere of argon. The mixture was
cooled to 0 °C and then a solution of tetra-n-butylammonium fluoride in tetrahydrofuran
(1.0 M, 250 µL, 250 µmol, 1.00 equiv) was added dropwise via syringe. The resulting
mixture was stirred for 15 min at 0 °C. The vial was transferred to a nitrogen-filled bag
and then formic acid (38.0 µL, 1.00 mmol, 4.00 equiv), water (250 µL), and a solution of
5
(
η -cyclopentadienyl) tris(acetonitrile)ruthenium hexafluorophosphate (S5) and the
iminopyridine ligand S6 in N,N-dimethylformamide (35 mM, 500 µL, 17.5 µmol, 0.0700
equiv) were added in sequence. The vial was sealed with a Teflon-lined cap and the
sealed vial was removed from the nitrogen-filled bag. The reaction mixture was stirred
for 48 h at 25 °C. The product mixture was diluted with ethyl acetate (15 mL) and the
diluted solution was transferred to a separatory funnel. Aqueous saturated ammonium
chloride solution (25 mL) was added, and the layers that formed were separated. The
aqueous layer was extracted with ethyl acetate (3 × 20 mL) and the organic layers were
combined. The combined organic layers were washed with saturated aqueous sodium
chloride solution (3 × 30 mL). The washed organic layer was dried over sodium sulfate.
The dried solution was filtered and the filtrate was concentrated. The residue obtained
was purified by flash-column chromatography (eluting with 5% methanol–
f
dichloromethane) to afford the diol 12e as a white solid (65.0 mg, 87%, >20:1 dr): R =
1
0.16 (5% methanol–methylene chloride; UV). mp 83–85 °C. H NMR (500 MHz, CDCl
3
) δ
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.34–7.22 (m, 5H), 5.04 (m, br, 1H), 4.73 (dt, J = 8.7, 3.9 Hz, 1H), 4.66 (s, br, 1H), 4.10
1
3
(
(
m, 1H), 3.91 (m, 1H), 3.77 (m, 1H), 1.93 (m, 3H), 1.65 (m, 1H), 1.21 (s, 9H). C NMR
151 MHz, CDCl ) δ 143.3 (C), 128.6 (CH), 127.4 (CH), 126.9 (CH), 68.2 (CH), 60.9
), 56.4 (CH), 55.8 (C), 44.9 (CH
3
–
1
0
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(CH
), 37.9 (CH
), 22.8 (CH
). IR (ATR-FTIR), cm :
2
2
2
3
+
3
340 (w, br), 2955 (w), 1034 (s), 699 (m). HRMS-ESI(m/z): [M+Na] calcd for
+
C
15
H
25NNaO
3
S , 322.1447; found, 322.1436.
Synthesis of the sulfonamide 12f (Table 3 entry 5). Following procedure for 12e using
the propargylic alcohol 7f (78.4 mg, 250 µmol, 1 equiv). Purification by flash-column
chromatography (eluting with 50% ether–pentane) afforded the alcohol 12f as a white
1
solid (53.2 mg, 81%): R
NMR (500 MHz, CDCl
.24 (d, J = 3.3 Hz, 1H), 4.77 (td, J = 9.2, 4.3 Hz, 1H), 4.52 (d, J = 9.7 Hz, 1H), 3.90 (ddd,
J = 11.9, 10.1, 3.2 Hz, 1H), 3.73 (dt, J = 11.8, 4.3 Hz, 1H), 2.37, (s, br, 1H), 2.15 (ddt, J
f
= 0.31 (50% ethyl acetate–pentane; KMnO
4
). mp 72–75 °C. H
3
) δ 7.38 (dd, J = 1.9, 0.8 Hz, 1H), 6.34 (dd, J = 3.3, 1.9 Hz, 1H),
6
1
3
= 14.6, 10.1, 4.6 Hz, 1H), 1.98–1.86 (m, 1H), 1.36 (s, 9H). C NMR (151 MHz, CDCl
3
) δ
1
54.3 (C), 142.2 (CH), 110.4 (CH), 106.5 (CH), 60.3 (C), 58.5 (CH ), 50.2 (CH), 38.7
2
–1
(
2 3
CH ), 24.3 (CH ). IR (ATR-FTIR), cm : 3453 (w, br), 3176 (w, br), 1121 (s), 508 (s).
+
+
4
HRMS-ESI(m/z): [M+Na] calcd for C11H19NNaO S , 284.0927; found, 284.0903. The
enantiomeric excess of the alcohol 12f was determined to be 96% by chiral stationary
phase HPLC analysis (Chiralpak IA, 10% ethanol–hexane, flow rate 1.0 mL/min, 210
nm).
Synthesis of the 1,3-diol 12g (Table 3, entry 6). In a nitrogen-filled drybox, a 4-mL vial
5
equipped with
a
magnetic stir bar was charged with (η -cyclopentadienyl)
tris(acetonitrile)ruthenium hexafluorophosphate (S5, 10.9 mg, 25.0 µmol, 0.0500 equiv),
the ligand S6 (4.4 mg, 25.0 µmol, 0.050 equiv), and N,N-dimethylformamide (2.0 mL).
The propargylic alcohol 7g (100 mg, 500 µmol, 1 equiv) was then added. The vial was
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sealed with Teflon-lined cap and the sealed vial was removed from the drybox. Formic
acid (76.0 µL, 2.00 mmol, 4.00 equiv) and water (500 µL) were added sequentially with
exclusion of oxygen (nitrogen-filled bag). The vial was sealed with a Teflon-lined cap
and the sealed vial was removed from the nitrogen-filled bag. The reaction mixture was
stirred for 48 h at 25 °C. The product mixture was diluted with ethyl acetate (15 mL) and
the diluted solution was transferred to a separatory funnel. Saturated aqueous
ammonium chloride solution (25 mL) was added, and the layers that formed were
separated. The aqueous layer was extracted with ethyl acetate (3 × 20 mL) and the
organic layers were combined. The combined organic layers were washed with
saturated aqueous sodium chloride solution (3 × 30 mL). The washed organic layer was
dried over sodium sulfate. The dried solution was filtered and the filtrate was
concentrated. The residue obtained was purified by flash-column chromatography
10
11
12
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14
15
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48
49
50
51
52
53
54
55
56
57
58
59
60
(
eluting with 3% methanol–dichloromethane) to afford the 1,3-diol 12g as white solid
1
(
97.5 mg, 89%). H NMR spectroscopic data for the diol 12g prepared in this way were
5
2
identical to literature values.
Synthesis of the unsaturated aldehyde 11h (Table 3, entry 7). In a nitrogen-filled
5
drybox, a 4-mL vial equipped with a magnetic stir bar was charged with (η -
cyclopentadienyl) tris(acetonitrile)ruthenium hexafluorophosphate (S5, 5.4 mg, 13 µmol,
0
.050 equiv), the ligand S6 (2.2 mg, 13 µmol, 0.050 equiv), and N,N-dimethylformamide
(
1.0 mL). The propargylic alcohol 7h (33.0 mg, 250 µmol, 1 equiv) was then added. The
vial was sealed with Teflon-lined cap and the sealed vial was removed from the drybox.
Formic acid (38.0 µL, 1.00 mmol, 4.00 equiv) and water (250 µL) were added
sequentially with exclusion of oxygen (nitrogen-filled bag). The vial was sealed with a
Teflon-lined cap and the sealed vial was removed from the nitrogen-filled bag. The
reaction mixture was stirred for 48 h at 25 °C. 1,3,5-trimethoxybenzene (16.9 mg, 100
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µmol, 0.402 equiv) was added to the product mixture. An aliquot of this mixture (~100
µL) was removed and diluted with chloroform-d (2.0 mL). The diluted mixture was dried
over sodium sulfate and the dried solution was filtered. The filtrate was transferred to an
1
0
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NMR tube. Analysis by H NMR spectroscopy indicated 27% conversion of 7h and 22%
5
3
yield of the aldehyde 11h.
Synthesis of the 1,3-diol 12i (Table 3, entry 8). In a nitrogen-filled drybox, a 4-mL vial
5
equipped with
a
magnetic stir bar was charged with (η -cyclopentadienyl)
tris(acetonitrile)ruthenium hexafluorophosphate (S5, 5.4 mg, 13 µmol, 0.050 equiv), the
ligand S6 (2.2 mg, 13 µmol, 0.050 equiv), and N,N-dimethylformamide (1.0 mL). The
propargylic alcohol 7i (31.0 mg, 250 µmol, 1 equiv) was then added. The vial was sealed
with Teflon-lined cap and the sealed vial was removed from the drybox. Formic acid
(
38.0 µL, 1.00 mmol, 4.00 equiv) and water (250 µL) were added sequentially with
exclusion of oxygen (nitrogen-filled bag). The vial was sealed with a Teflon-lined cap
and the sealed vial was removed from the nitrogen-filled bag. The reaction mixture was
stirred for 48 h at 25 °C. Mesitylene (20.0 µL, 144 µmol, 0.575 equiv) was added to the
product mixture. An aliquot of this mixture (~100 µL) was removed and diluted with
chloroform-d (2.0 mL). The diluted mixture was dried over sodium sulfate and the dried
solution was filtered. The filtrate was transferred to an NMR tube. Analysis of the
1
mixture by H-NMR spectroscopy indicated 9% conversion of the starting material 7i.
The 1,3-diol product 12i could not be detected.
Synthesis of the amine 14j (Table 4, entry 7). In a nitrogen-filled drybox, a 4-mL vial
was charged sequentially with a Teflon-coated stirbar, the ruthenium complex 3 (3.0 mg,
6
.0 µmol, 0.020 equiv), N-methyl-2-pyrrolidinone (1.5 mL), and phenylacetylene (7j, 30.6
mg, 300 µmol, 1 equiv). The vial was sealed with Teflon-lined cap and the sealed vial
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