Gold-Catalyzed Hydroamination of Propargylic Alcohols: Controlling Divergent Catalytic Reaction Pathways to Access 1,3-Amino Alcohols, 3-Hydroxyketones, or 3-Aminoketones

Article abstract of DOI:10.1021/acs.joc.9b00988

A versatile approach to the valorization of propargylic alcohols is reported, enabling controlled access to three different products from the same starting materials. First, a general method for the hydroamination of propargylic alcohols with anilines is described using gold catalysis to give 3-hydroxyimines with complete regioselectivity. These 3-hydroxyimines can be reduced to give 1,3-amino alcohols with high syn selectivity. Alternatively, by using a catalytic quantity of aniline, 3-hydroxyketones can be obtained in high yield directly from propargylic alcohols. Further manipulation of the reaction conditions enables the selective formation of 3-aminoketones via a rearrangement/hydroamination pathway. The utility of the new chemistry was exemplified by the one-pot synthesis of a selection of N-arylpyrrolidines and N-arylpiperidines. A mechanism for the hydroamination has been proposed on the basis of experimental studies and density functional theory calculations.

Full text of DOI:10.1021/acs.joc.9b00988

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Article
Gold-Catalyzed Hydroamination of Propargylic Alcohols:
Controlling Divergent Catalytic Reaction Pathways to Access
1,3-Aminoalcohols, 3-Hydroxyketones or 3-Aminoketones
Victor Laserna, Michael J Porter, and Tom David Sheppard
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00988 • Publication Date (Web): 16 Aug 2019
Downloaded from pubs.acs.org on August 17, 2019
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Gold-Catalyzed Hydroamination of Propargylic Alcohols:
Controlling Divergent Catalytic Reaction Pathways to Access
1,3-Aminoalcohols, 3-Hydroxyketones or 3-Aminoketones.
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Victor Laserna, Michael J. Porter and Tom D. Sheppard*
*Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London,
WC1H 0AJ, UK
tom.sheppard@ucl.ac.uk
Ar
NH
OH
12 examples
R2
R1
R3
Hydroamination pathway
O
OH
OH
cat. [Au]
R2
R1
25 examples
R2
Ar NH2
R3
R3
R1
·High Chemoselectivity
·Mild Conditions
·Functional Group Tolerance
Ar
O
HN
R2
R1
11 examples
Meyer-Schuster Rearrangement pathway
R3
A versatile approach to the valorization of propargylic alcohols is reported, enabling controlled
access to three different products from the same starting materials. Firstly, a general method
for the hydroamination of propargylic alcohols with anilines is described using gold catalysis to
give 3-hydroxyimines with complete regioselectivity. These 3-hydroxyimines can be reduced to
give 1,3-aminoalcohols with high syn selectivity. Alternatively, by using a catalytic quantity of
aniline, 3-hydroxyketones can be obtained in high yield directly from propargylic alcohols.
Further manipulation of the reaction conditions enables the selective formation of 3-
aminoketones via a rearrangement/hydroamination pathway. The utility of the new chemistry
was exemplified by the one-pot synthesis of a selection of N-arylpyrrolidines and
N-arylpiperidines. A mechanism for the hydroamination has been proposed on the basis of
experimental studies and DFT calculations.
Introduction
Nitrogen atoms play a key role in many biologically active compounds including natural products
and pharmaceuticals, and this has encouraged the development of new synthetic strategies to
construct C-N bonds.1 Hydroamination of alkenes or alkynes is an atom economical and direct
method to generate C-N bonds which has attracted considerable interest.2 Although alkenes
yield amines directly, the transformation has often proved challenging. In contrast, the
hydroamination of alkynes can be mediated by a range of catalysts based on elements from
across the periodic table.2a,3 This offers an alternative strategy, yielding imines or enamines
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which can be further transformed through sequential reactions to access useful products.4 Two
key limitations of the hydroamination of alkynes are the low reactivity of internal alkynes and
the poor regioselectivity usually observed with these substrates in intermolecular reactions
(Scheme 1).5 Catalyst design has allowed improved regiocontrol for hydroamination of terminal
alkynes, with late transition-metal catalysts usually affording Markovnikov products,6 whereas
early transition-metal catalysts predominantly afford anti-Markovnikov products.3b,7 Internal
alkyne hydroamination selectivity has proved to be more challenging, with reactions usually
giving mixtures of isomers.5 A rare exception is the hydroamination of alkynes bearing strongly
electron-withdrawing groups,8 which give high regioselectivities favoring amine attack on the
more electron deficient atom of the π-system. The intermolecular hydroamination of internal
alkynes using gold catalysts has been challenging, requiring elevated temperatures and yielding
mixtures of isomeric products.5b,6a
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Scheme 1: Hydroamination of Alkynes
Previous work
Schafer,4c,4d Doye4e
R
HN
R
R2/R1
R2
[Au, Zr, Ti]
R1/R2
N
R1
or
O
R1/R2
RNH2
R2/R1
R1/R2
R1/R2
Kawatsura8c
mixtures of isomers
R
R
EWG
N
[Cu]
HN
R1
EWG
RNH2
R1
R1
EWG
This work
HO R3
R2
O
[H2O]
[H]
OH
Ar
R1
R2
R3
HO R3
R2
[Au]
ArNH2
N
HO R3
ArHN
R1
R1
R1
R2
O
NHAr
R2
ArNH2
[Au]
R1
MeOH
To date, the intermolecular hydroamination of propargylic alcohols to yield 3-hydroxyimines has
not been reported, despite the potential utility of the products. The hydroamination of O-
protected propargyl alcohol to give hydroxyacetone hydrazone derivatives has been described,9a
as well as the synthesis of benzodiazepines9b or quinolines9c via reaction of propargylic alcohols
with nitrogen nucleophiles. In this paper, we describe a highly regioselective method for the
hydroamination of propargylic alcohols under mild conditions, which can be controlled to
provide three different products by varying the reaction conditions. This provides an unusual
example of divergent catalysis10 which employs the same reactant and catalyst to access
different products with high levels of selectivity.
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Results and Discussion
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Propargylic alcohols are readily available alkynes with an adjacent alcohol group which are
versatile building blocks due to their diverse reactivity.11 Through a wide array of different
catalytic transformations, using transition metals12 or organocatalysis,13 important synthetic
targets can be accessed including enones,14 furans,15 carbonates,16 N-heterocycles17 or geminal
dihalides.18 In a preliminary screen of conditions for hydroamination, we observed that reaction
of propargylic alcohol 1a, aniline and 2 mol% of PPh3AuNTf219 catalyst at room temperature in
CH2Cl2 led to complete conversion of starting material within 24 h (Scheme 2), with the
formation of three products: 3-hydroxyimine 1b, 3-hydroxyketone 1c and 3-aminoketone 1d in
a ratio of 47:47:6 (1b:1c:1d).‡ No traces of the regioisomeric products (-hydroxyimine, -
hydroxyketone) resulting from an addition of the aniline to the proximal carbon of the
propargylic alcohol were detected. We then decided to explore the reaction conditions to
determine if it was possible to selectively obtain each of the three products.
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Scheme 2 Initial Discovery of the Hydroamination Reaction
NPh OH
n-C4H9
n-C4H9
n-C6H13
1b, 47%
OH
O
OH
2.5 mol% [Au]
PhNH2
r.t. 24 h
CH2Cl2
n-C6H13
n-C6H13
1c, 47%
NHPh
n-C6H13
n-C4H9
1a
O
n-C4H9
1d, 6%
Synthesis of 1,3-Aminoalcohols
During the optimization process (Supporting information), we identified conditions to selectively
generate the 3-hydroxyimine 1b by performing the reaction in chloroform in the presence of
molecular sieves. In order to trap the imine intermediate, we carried out a sequential reduction
by adding Et2O and 2 eq of NaCNBH3 at 0 °C. As anticipated, we found that the reduction took
place in a stereoselective manner yielding the syn-1,3-aminoalcohol in high yield and with
excellent selectivity.20
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Scheme 3: Synthesis of syn-1,3-aminoalcohols via one-pot hydroamination/reduction of propargylic alcohols.
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8
9
OH
2.5 mol% PPh3AuNTf2
CHCl3, rt
HO R3
Add Et2O
NaBH3CN
ArHN
R1
R2
R3
1a-9a
R2
R1
4 Å sieves, 1 eq ArNH2 2 h, 0 ºC
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1ba-9bh
ArHN
OH
OH
Cl
PhHN
n-C4H9
OH
PhHN
n
-C H
n-C4H9
1ba: Ar = Ph, 78%a
n-C6H13
4
9
2ba 48%
PhHN
3ba 67%
1bb: Ar = 4-F-C6H4 64%
PhHN
Ph
OH
1bc: Ar = 3,5-Me2-C6H3 78%,
1bd: Ar = 4-MeO-C6H4 89%,
1be: Ar = 3,5-Cl2-C6H3 68%
1bf: Ar = 3-CF3-C6H4 51%,
1bg: Ar = 2-CH3-C6H4 53%,
1bh: Ar = 2-Br-C6H4 42%
HO
n-C4H9
n
-C H
6
13
4ba 78%a
5ba 51%
Cl
HO
OH
PhHN
Ph
PhHN
EtO
6ba 73%
7ba 74%
OEt
OEt
OH
PMPHN
PhHN
Ph
OH
Ph
OEt
8ba 81%
9bd 67%
Reactions performed on a 0.5 mmol scale; Yields given are isolated yields of the syn diastereoisomer
(stereochemistry shown in reaction assumes R3 is smaller than R2); (PMP = p-methoxyphenyl); aThe relative
stereochemistry was confirmed by conversion to the corresponding cyclic urethane and analysis of the NOESY
spectra (Supporting Information).
We examined a series of different anilines to explore the functional group tolerance of the
method (Scheme 3).‡ The reaction tolerates a variety of substitution patterns on the aniline,
with groups at the ortho (1bg and 1bh), meta (1bc, 1be and 1bf) or para (1bb and 1bd) position,
with slightly lower yields observed in the first case probably due to steric hindrance. Electron
withdrawing groups (1bb, 1be, 1bf and 1bh) and electron donating groups (1bc, 1bd and 1bg)
are well tolerated. No hydroamination was observed with alkylamines, presumably because
they cause greater deactivation of the cationic gold catalyst.21 A range of substrates including
primary (7ba), secondary (3ba, 5ba, 8ba, 9bd), tertiary (2ba, 4ba, 6ba) and benzylic (3ba, 4ba)
propargylic alcohols can be transformed into the corresponding amino alcohols effectively.
Terminal alkynes did not undergo hydroamination when subjected to the reaction conditions,
and only unreacted starting material was observed with these substrates. We were also able to
access a primary aminoalcohol 1bi by oxidative deprotection of p-methoxyphenylamine 1bd
using trichloroisocyanuric acid (Scheme 4).22
Scheme 4: Synthesis of a primary aminoalcohol via deprotection of a p-methoxyphenylamine
(PMP = p-methoxyphenyl; TCCA = trichloroisocyanuric acid).
PMPHN
n-C4H9
OH
NH2 OH
TCCA
MeCN-H2O
n-C6H13
n-C4H9
n-C6H13
1bd
1bi
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Synthesis of 3-Hydroxyketones
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During the optimization of the hydroamination reaction we observed that raising the
temperature and performing the reaction in non-dried solvents under air favoured the
hydrolysis of the imine to yield the 3-hydroxyketone. We hypothesized that in situ imine
hydrolysis would liberate the aniline, allowing it to participate in further hydroamination
reactions. It should therefore be possible to achieve the reaction with a substoichiometric
quantity of amine. After examining a small selection of anilines in combination with the gold
catalyst (Supporting information), 3-trifluoromethylaniline was identified as a suitable co-
catalyst to promote formation of the 3-hydroxyketone. The proposed hydroamination/imine
hydrolysis pathway is supported by the fact that in the absence of aniline, Meyer-Schuster
rearrangement of the propargylic alcohol is predominant and only small quantities of 3-
hydroxyketone are formed.14a, 23 With these conditions in hand we explored the scope of the
hydroamination/hydrolysis reaction for preparing 3-hydroxyketones (Scheme 5). The reaction
tolerates a range of substituents on the propargylic alcohol, including carbocycles (2c, 14c, 17c
and 23c) and branched chains (9c, 13c), and is compatible with primary (7c and 20c), secondary
(1c, 3c, 5c, 9c-17c, 19c, 21c, 23c-26c, 28c, 29c), tertiary (2c, 4c, 6c, 18c, 22c and 27c) and benzylic
(3c, 4c, 9c, 11c, 12c, 17c, 21c, 24c and 26c) propargylic alcohols, even though the latter products
are often prone to elimination of water to give the corresponding enones.23 Electron
withdrawing (cyano: 24c, nitro: 16c, halide: 3c/17c) or electron donating (methoxy: 10c, methyl:
21c) substituents could be present on the benzene rings, and alternative aromatic systems such
as furan (11c), naphthalene (26c) or thiophene (12c) were also tolerated, as were alkenes (27c),
protected alcohols (27c), esters (28c) and acetals (6c, 23c, 25c and 29c).
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Scheme 5 Synthesis of 3-hydroxyketones via catalytic hydroamination of propargylic alcohols with in situ imine
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hydrolysis.
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9
NH2
0.2 eq
F3C
OH
R3
O
OH
R3
2.5 mol% PPh3AuNTf2
R2
R2
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R1
CHCl3, 50 ºC
R1
1c-29c
1a-29a
O
OH
O
O
OH
Cl
O
OH
O
OH
O
OH
OH
EtO
n-C6H13
n-C4H9
n-C6H13 n-C4H9
n-C4H9
n-C4H9
OEt
Cl
1c 91%a (71%b)
OH
2c 81%c
n-C4H9
4c 43%c
6c 68%c
3c 86%
5c 81%
O
O
OH
O
OH
O
OH
O
OH
O
OH
O
OH
O
S
Ph
Ph
PMP n-C4H9
10c 52%d
n-C4H9
n-C4H9
n-C4H9
7c 74%
9c 71%
11c 77%
12c 61%
13c 92%
n-C4H9
14c 94%
OH
O
O
OH
O
OH
O
OH
O
OH
O
OH
O
OH
n-C6H13
n-C6H13 Ph
PNP
n-C4H9
Et
Et
Ph Et
4
15c 81%
16c 76%
17c 59%
OH
18c 32%c
19c 82%d
20c 74%
Br
O
OH
O
OH
Et
O
O
OH
O
OH
EtO
EtO
Et
n-C4H9
n-C6H13
OEt
OEt
CN
21c 71%d
22c 75%c
23c 77%
24c 89%
25c 74%
O
O
OH
O
O
OH
F
OH
O
OH
EtO
TBSO
O
n-C4H9
OEt
26c 69%
27c 54%c
28c 77%
29c 84%
Reactions performed on a 0.5 mmol scale; Undried solvents were used for these reactions; (PMP = p-methoxyphenyl; PNP =
p-nitrophenyl). aIn other solvents, the yields of 1c obtained were as follows: MeCN (88%), PhF (86%), MeOCO2Me (85%),
PhMe (88%), EtOAc (82%); b 5 mmol scale reaction; c0.5 eq of aniline used; dReaction carried out at room temperature for 40
h.
The broad scope of this method for the synthesis of 3-hydroxyketones makes it a useful alternative
approach to traditional approaches such as aldol reactions.24 As chlorinated solvents are often
undesirable from an environmental perspective, we examined the reaction in alternative solvents.25
Pleasingly, the hydroamination/hydrolysis reaction could also be performed efficiently in acetonitrile,
fluorobenzene, dimethyl carbonate, toluene or ethyl acetate.
Synthesis of 3-Aminoketones
Finally, we also sought to develop conditions to access the 3-aminoketone 1d, which was identified as a
minor product in our original experiment (Scheme 2). We hypothesized that its formation was due to
Meyer-Schuster rearrangement of the propargylic alcohol,14 followed by conjugate addition of the
aniline to the resulting enone. To selectively form the 3-aminoketone, we changed the solvent to a
mixture of toluene:MeOH (100:1) which is established to promote gold-catalyzed Meyer-Schuster
rearrangement,14 and then added the aniline to the reaction mixture once the enone had been produced
(Scheme 6). Interestingly, the gold catalyst is involved in both steps of the reaction, as it was observed
to catalyze conjugate addition of the aniline to the enone (Supplementary information), with a
particularly significant effect in the case of less nucleophilic anilines. Whilst the addition of anilines to
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electron-deficient alkenes can be mediated by a variety of catalysts,26 this gold-catalysed variant appears
to be complementary in scope as previous reports have not included internal enones as substrates.26
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Scheme 6: Synthesis of 3-aminoketones via Au-catalyzed Meyer-Schuster rearrangement and enone hydroamination.
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9
OH
2.5 mol% PPh3AuNTf2
1 eq ArNH2
50 ºC, 18 h
O
NHAr
R2
R2
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R1
Tol:MeOH 98:2
rt 5 h
R1
1d-25d
NHPh
1a-25a
O
NHPh
O
NHAr
O
Ph
C6H13
5da 93%
n-C4H9
n-C6H13
Ph
7da 73%
NHPh
1da: Ar = Ph, 91%,
1db: Ar = 4-F-C6H4, 87%,
O
1dc: Ar = 3,5-Me2-C6H3, 95%
1dd: Ar = 4-MeO-C6H4, 94% (a)
1df: Ar = 3-CF3-C6H4, 71%
1dg: Ar = 2-Me-C6H4, 53%
n-C4H9
14da 89%
1dj: ArNH2 = 6-aminoquinoline, 51%
O
NHPh
n-C6H13
Unsuccessful Reactions
EtO
OEt
O
NHPh
O
NHPh
Ph
25da 51%
n-C4H9
Et
Et
n-C4H9
18da 0%b
19da 0%b
Reactions performed on a 0.5 mmol scale; (a) Reaction was filtered through a silica pad after enone formation; (b) The
corresponding enone was obtained as the sole product.
Again, we examined the reaction with a series of different aryl amines on substrate 1a, and explored the
functional group tolerance with respect to the propargylic alcohol component using aniline as the
nucleophile (Scheme 6). Although the reaction proved to be tolerant of both electron-deficient and
electron-rich anilines (1da-1dj), only primary (7da) and secondary (5da, 14da, 25da) propargylic alcohols
were suitable substrates. While tertiary and benzylic alcohols underwent the Meyer-Schuster
rearrangement, no conjugate addition to the resulting enone to give 18da or 19da was observed.
Reaction Mechanisms
Several gold-catalysed reactions of allylic alcohols with nucleophiles have been reported which proceed
via a mechanism in which addition of the nucleophile is concerted with elimination of the adjacent
hydroxyl group.27 In order to exclude the possibility that the hydroamination of propargylic alcohols
proceeds in a similar fashion via a planar achiral intermediate (e.g. via Meyer-Schuster rearrangement),
we examined the reaction of enantioenriched alcohol (S)-9a.28 Pleasingly, alcohol (S)-9a could be
converted into hydroxyketone (S)-9c in excellent yield and with no significant loss in enantiopurity
(Scheme 7). Similarly, hydroamination followed by imine reduction gave the corresponding
aminoalcohol in 72% yield as an 85:15 mixture of diastereomers. We were unable to directly determine
the enantiopurity of the diastereomeric product mixture by HPLC, so recrystallisation was carried out,
affording the aminoalcohol (1S,3R)-9bd as an essentially enantiopure single diastereomer in 59% overall
yield (Scheme 7). As analysis of the crude mixture had indicated that only 61% of this diastereomer was
present (i.e. 0.85 × 72), it could be concluded that the hydroamination reaction and reduction had taken
place without any significant erosion of enantiomeric purity.
Scheme 7: Synthesis of enantioenriched products via hydroamination of an enantioenriched propargylic alcohol.
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OH
O
OH
cat. [Au], cat. ArNH2
CHCl3, rt
86%
94:6 er
Ph
Ph
(S)-9a
95:5 er
(S)-9c
7
8
9
CHCl3 rt
4Å sieves
PMPNH2
PMPHN
Ph
(1S,3R)-9bd
59% from (S)-9a
>99:1 er
OH
PMPHN
Ph
OH
cat. [Au]
recryst
then NaBH3CN
Et2O
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72%
85:15 dr
The alcohol moiety in the propargylic alcohol appears to play an important role in accelerating the
hydroamination reaction (Scheme 8), as a competition experiment between propargylic alcohol 1a and
hex-3-yne illustrates (A). Protection of the propargylic alcohol as a benzyl or trimethylsilyl ether appears
to stop the hydroamination reaction (B).
Scheme 8: Experiments to probe the relative reactivity of propargylic alcohols in the hydroamination reaction in comparison to
other alkyne derivatives.
Et
Et
unreacted
OH
Et
+
Et
(A)
cat. PPh3AuNTf2
+
O
OH
n-C6H13
cat. ArNH2
8 h, CDCl3
n-C4H9
n-C6H13
n-C4H9
1a
1c
89% conversion
OR
cat. PPh3AuNTf2
No Reaction
(B)
n-C6H13
R = Bn, SiMe3
cat. ArNH2
CDCl3
n-C4H9
In order to investigate the reaction mechanism further, DFT calculations were carried out. Several
computational studies into both inter-29 and intramolecular30 hydroamination reactions catalysed by
mononuclear gold complexes have been reported previously; we chose to employ the benchmarked
method of Ciancaleoni et al.29c in which single-point energies are calculated using the hybrid B2PLYP
functional31 on geometries optimized using the GGA functional BP86,32 with the def2-TZVPP basis set33
being used throughout. Solution-phase energies were obtained using the SMD solvation model34 with
gas-phase optimized geometries. All calculations were carried out using Gaussian 09.35
Initial modelling of but-2-yn-1-ol complexed to an [Au-PMe3]+ fragment indicated that the gold-alkyne
complex was slightly lower in energy than a structure with the gold linked to the alcohol oxygen.
Transition states were then modelled for addition of aniline to each carbon of the triple bond in this
adduct. The transition state for addition to the distal carbon (Figure 1), as observed experimentally, lay
only 9.9 kJ mol–1 higher in energy than the isolated starting materials, with a hydrogen bond between
the aniline N-H and the alcohol oxygen. Conversely, the transition state for addition to the proximal
carbon was markedly higher in energy (31.1 kJ mol–1 above starting materials).
The condensed Fukui functions36 k+ for these two carbons in the initial gold complex were found to be
respectively 0.063 and 0.055 indicating only a small difference in the intrinsic electrophilicity of the two
sites. Distortion-interaction analysis37 (see supporting information) suggested that both potential
addition pathways involved similar energetic costs in distorting the starting materials, with the
difference between the pathways arising from the more favourable interaction energy for attack at the
distal carbon. We tentatively assign this difference to a stronger hydrogen-bonding interaction in the
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distal attack, due to a more linear geometry for the hydrogen bond in the incipient six-membered ring:
at the transition state for distal attack, the O-H-N angle is 145.6° while the corresponding angle for
proximal attack is 125.6°.
6
7
8
9
Figure 1: Transition states for addition of aniline to the distal (left) and proximal (right) carbon atoms of a but-2-yn-1-ol/Au-
PMe3 cationic complex, calculated at the B2PLYP/def2TZVPP//BP86/def2TZVPP level.38
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For the corresponding addition of aniline to an unfunctionalized alkyne (but-2-yne), the energy barrier
was higher still (37.7 kJ mol–1 above starting materials), indicating that the hydroxyl substituent plays a
role in facilitating the addition reaction as well as determining its regioselectivity.
Scheme 9: Plausible reaction mechanisms for the formation of the three different products. The diastereoselectivity shown
assumes R2 is larger than R3.
Ar
O
R3
O
HN
[Au]
[Au], MeOH
ref [14]
R3
R2
R1
R2
ArNH2
R1
R3 = H
F
path 3
H
H
N
H
H
Ar
R1
H
O
Ar
H
H
O
R3
R2
N
O
[Au]
R3
R2
R2
R3
ArNH2
R1
[Au]
C
R1
Au
A
B
-[Au]
R3 OH
R2
O
path 1
path 2
H
R1
Ar
H2O
[H]
Ar
Ar
R3 OH
R2
N
R3 OH
N
R3 OH
R2
R1
NH
R1
R2
H
H
H
R1
E
D
These considerations lead us to suggest the mechanisms shown in Scheme 9. Thus, gold-catalysed
addition of the aniline to the complexed alkyne (B) is assisted by hydrogen bonding of the aniline to the
oxygen lone pair, and this hydrogen bond also controls the regioselectivity of the addition step. After
protodeauration of vinylgold intermediate C, the resulting enamine D can tautomerise to the imine E
which undergoes hydrolysis to yield the hydroxyketone when water is present (path 1). Under
anhydrous conditions, the imine is stable and can be subsequently reduced to the syn amino-alcohol
(path 2). Further support for these two pathways was obtained from NMR analysis of a reaction of
propargylic alcohol 18a with 0.5 equivalents of 3-trifluoromethylaniline in the presence of PPh3AuNTf2
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which showed a mixture of 3-hydroxyimine E and 3-hydroxyketone 18c (Supporting Information). The
aminoketone product is generated via hydroamination of the enone F which is formed readily via Meyer-
Schuster rearrangement under conditions similar to those we have previously reported (path 3).14
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Synthesis of Nitrogen Heterocycles
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In order to demonstrate the synthetic potential of the hydroamination reaction, we synthesised a small
selection of N-arylpyrrolidines/piperidines from the corresponding acetal-containing propargylic
alcohols (Scheme 10). We were able to find suitable conditions under which the acetal-containing
aminoalcohol was selectively transformed into the pyrrolidine/piperidine product using trifluoroacetic
acid and NaBH4. Pleasingly, the heterocycle synthesis could be performed without the need to purify
any of the intermediate aminoalcohol compounds.
Scheme 10: Synthesis of N-arylpyrroldines and N-arylpiperidines via one-pot gold-catalysed hydroamination of propargylic
alcohols, followed by reduction and reductive amination. Yields shown are for the isolated product after the three step
sequence.
R1
n
EtO
i) ArNH2, [Au], CHCl3
ii) NaBH3CN, Et2O
OH
R2
N
OH
R1
n
EtO
iii) TFA, NaBH4
R2
n = 1, 2
R
6a, 29a 30a, 31a
HO
HO
HO
N
N
N
Ph
F3C
6ed 75%
6ea 73%
6ef 67%
O
F
HO
OH
OH
N
N
N
Ph
Ph
Ph
Cl
29ea 55%
30ea 63%
31ea 71%
Conclusions
In conclusion, we report a method for the valorization of propargylic alcohols through gold catalysed
hydroamination.39 In the presence of an aniline and a commercially available gold catalyst, propargylic
alcohols undergo regioselective hydroamination yielding
a 3-hydroxyimine which can be
stereoselectively reduced to a syn-1,3-aminoalcohol or hydrolyzed to the corresponding
3-hydroxyketone. By changing to a two-step one-pot process, 3-aminoketones can be obtained via
Meyer-Schuster rearrangement and conjugate addition of the aniline to the resulting enone. The latter
step is formally a hydroamination of the enone, which is also catalysed by gold. Thus, by using the same
substrates and catalyst under different conditions, three different products can be obtained efficiently
with high selectivity. This constitutes a highly unusual divergent catalytic reaction.
Experimental Section
General Experimental Procedures
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All solvents and chemicals were used as received. Column chromatography was carried out using either
Merck Geduran Si 60 (40-63 µm) silica gel or a Biotage purification system using Biotage columns.
Analytical thin layer chromatography was carried out using Merck TLC Silica Gel 60 F254 aluminium-
backed plates. Components were visualised using combinations of ultra-violet lights and potassium
permanganate.
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Proton magnetic resonance spectra (1H NMR) were recorded at 400, 500 or 600 MHz on a Bruker Avance
spectrometer and are reported as follows: chemical shift δ in ppm (number of protons, multiplicity,
coupling constant J in Hz, assignment). The solvent used was deuterated chloroform unless stated
otherwise. Residual protic solvent was used as the internal reference, setting CHCl3 to δ 7.26. The
following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, mulitplet; br, broad or a
combination of these. Carbon magnetic resonance spectra (13C NMR) were recorded at 100, 125 or 150
MHz on a Bruker Avance spectrometer using deuterated chloroform using the central reference of CDCl3
to δ 77.0 as the internal standard. Mass Spectrometry data were collected on either TOF or magnetic
sector analysers at the Department of Chemistry, University College London. The ionization method is
reported in the experimental data.
Preparation of propargylic alcohols
n-Butyllithium (1.6 M in hexanes, 1.2 eq., 3.75 mL) was added dropwise to a stirred solution of the
corresponding alkyne (5 mmol) in anhydrous THF (25 mL) at 78 ˚C under an argon atmosphere. After
30 min aldehyde (1 eq.) was added and the resulting solution was stirred for 5 min at 0 ˚C and then 30
min at rt. The reaction was diluted with aq. saturated NH4Cl and the organic phase extracted with Et2O.
The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in
vacuo. The residue was purified by column chromatography (EtOAc/Petrol) to give the propargylic
alcohol.
The aldehyde used to prepare propargylic alcohol 8a was synthesized following reported procedures.40
Alkynes used to prepare 6a, 23a, 25a, 26a, 27a, 28a, 29a and 30a were synthesized following reported
procedures.41
Propargylic alcohols 7a and 20a were purchased from commercial suppliers. We have previously
reported the synthesis of propargylic alcohols 9a,18a 17a,18a 21a,18a 22a,23 and 29a.18b Enantioenriched
propargylic alcohol (S)-9a (e.r. 96:4) was synthesized following reported procedures.23,28
Tridec-5-yn-7-ol (1a)42
891 mg, 91%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 4.34 (tt, J = 6.4, 1.9 Hz, 1H), 2.22 (td, J = 7.0, 2.0
Hz, 2H), 1.75–1.58 (m, 2H), 1.53–1.45 (m, 2H), 1.46–1.36 (m, 4H), 1.36–1.22 (m, 6H), 0.91 (t, J = 7.2 Hz,
3H), 0.89 (t, J = 7.3, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 85.6, 81.5, 62.9, 38.3, 31.9, 30.86, 29.1, 25.3,
22.7, 22.0, 18.5, 14.2, 13.7. IR max (solid/cm-1) 3353 (O-H), 2955 (C-H), 2927 (C-H), 2858 (C-H), 1506,
1431, 1145, 1039, 726.
1-(Hex-1-ynyl)cyclohexan-1-ol (2a)43
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774 mg, 86%, colourless oil, H NMR (600 MHz, CDCl3) δ 2.20 (t, J = 9.5, 2H), 1.99 (br s, 1H), 1.83 (m,
2H), 1.70–1.61 (m, 2H), 1.58–1.44 (m, 7H), 1.44–1.34 (m, 2H), 1.25-1.18 (m, 1H), 0.89 (t, J = 7.3 Hz, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 84.8, 84.0, 68.9, 40.4, 31.0, 25.4, 23.57, 22.0, 18.4, 13.7. IR max
(solid/cm-1) 3484 (O-H), 2931 (C-H), 2858 (C-H), 1447, 1340, 1056, 961, 752.
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5
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8
9
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29
30
31
32
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36
37
38
39
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60
1-(2-Chlorophenyl)hept-2-yn-1-ol (3a)44
1
987 mg, 89%, colourless oil, H NMR (600 MHz, CDCl3) δ 7.76 (dd, J = 7.7, 1.7 Hz, 1H), 7.37 (dd, J = 7.9,
1.3 Hz, 1H), 7.31 (td, J = 7.5, 1.3 Hz, 1H), 7.28–7.24 (m, 1H), 5.81 (s, 1H), 2.35 (m, 1H), 2.27 (td, J = 7.1,
2.1 Hz, 2H), 1.57–1.47 (m, 2H), 1.46–1.37 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3)
δ 138.6, 132.9, 129.8, 129.6, 128.5, 127.3, 88.0, 78.9, 62.3, 30.7, 22.1, 18.6, 13.7. IR max (solid/cm-1)
3351 (O-H), 2957 (C-H), 2931 (C-H), 2871 (C-H), 1467, 1442, 1052, 1035, 750.
2-(4-Chlorophenyl)hex-3-yn-2-ol (4a)45
1
898 mg, 77%, colourless oil, H NMR (600 MHz, CDCl3) δ 7.58 (m, 2H), 7.31 (m, 2H), 2.27 (m, 2H), 1.71
(s, 3H), 1.58–1.48 (m, 2H), 1.50–1.37 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). C{1H} NMR (151 MHz, CDCl3) δ
13
144.9, 133.4, 128.4, 126.6, 86.2, 83.5, 69.7, 33.8, 30.8, 22.1, 18.5, 13.7. IR max (solid/cm-1) 3425 (O-H),
2995 (C-H), 2933 (C-H), 2889 (C-H), 1497, 1371, 1025, 819.
1-Phenylnon-1-yn-3-ol (5a)46
1
960 mg, 89%, colourless oil, H NMR (700 MHz, CDCl3) δ 7.45–7.41 (m, 2H), 7.34–7.28 (m, 3H), 4.60 (t, J
= 6.5 Hz, 1H), 1.92 (br s, 1H), 1.84–1.76 (m, 2H), 1.56–1.47 (m, 2H), 1.40–1.34 (m, 2H), 1.35–1.25 (m,
13
4H), 0.93–0.86 (m, 3H). C{1H} NMR (176 MHz, CDCl3) δ 131.8, 128.5, 128.4, 122.8, 90.4, 85.0, 63.2,
38.1, 31.9, 29.1, 25.32, 22.7, 14.2. IR max (solid/cm-1) 3366 (O-H), 2927 (C-H), 2857 (C-H), 1489, 1457,
1062, 755, 690.
7,7-Diethoxy-2-methylhept-3-yn-2-ol (6a)
1
834 mg, 78%, colourless oil, H NMR (400 MHz, CDCl3) δ 4.57 (t, J = 5.7 Hz, 1H), 3.64 (dq, J = 9.3, 7.1 Hz,
2H), 3.49 (dq, J = 9.4, 7.1 Hz, 2H), 2.24 (t, J = 7.3 Hz, 2H), 2.12 (br s, 1H), 1.78 (m, 2H), 1.47 (s, 6H), 1.19
(t, J = 7.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 101.8, 85.5, 81.7, 65.2, 61.5, 32.8, 31.8, 15.4, 14.3. IR max
(solid/cm-1) 3429 (O-H), 2975 (C-H), 2930 (C-H), 2875 (C-H), 1456, 1373, 1127, 1056, 949. HRMS (ESI-
TOF) m/z: [M+NH4]+ Calcd for C12H26O3N+, 232.1907; Found, 232.1907.
5,5-Diethoxy-1-phenylpent-1-yn-3-ol (8a)
1
892 mg, 72%, yellow oil, H NMR (400 MHz, CDCl3) δ 7.46–7.36 (m, 2H), 7.33–7.28 (m, 3H), 4.93 (t, J =
5.7 Hz, 1H), 4.79 (t, J = 5.5 Hz, 1H), 3.87–3.68 (m, 2H), 3.59 (m, 2H), 3.40 (br s, 1H), 2.20–2.10 (m, 2H),
1.25 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 131.7, 128.4, 128.3,
122.7, 101.5, 89.4, 84.8, 62.5, 61.9, 60.0, 40.6, 15.4, 15.4. IR max (solid/cm-1) 3412 (O-H), 2974 (C-H),
2930 (C-H), 2882 (C-H), 1489, 1374, 1119, 1049, 755, 690, 829. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C15H20O3Na+, 271.1305; Found, 232.1305.
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1-(4-Methoxyphenyl)hept-2-yn-1-ol (10a)42
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5
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7
8
1
1021 mg, 94%, colourless oil, H NMR (600 MHz, CDCl3) δ 7.58–7.38 (m, 2H), 6.95–6.86 (m, 2H), 5.40 (s,
1H), 3.81 (s, 3H), 2.27 (td, J = 7.1, 2.0 Hz, 2H), 2.15 (br s, 1H), 1.62–1.49 (m, 2H), 1.47–1.32 (m, 2H), 1.01–
0.83 (m, 3H). C{1H} NMR (151 MHz, CDCl3) δ 159.7, 133.8, 128.2, 114.0, 87.6, 80.2, 64.6, 55.5, 30.8,
13
22.1, 18.6, 13.7. IR max (solid/cm-1) 3403 (O-H), 2956 (C-H), 2932 (C-H), 2836 (C-H), 1610, 1509, 1244,
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1171, 1031, 634.
1-(Furan-2-yl)hept-2-yn-1-ol (11a)14b
1
703 mg, 79%, colourless oil, H NMR (600 MHz, CDCl3) δ 7.41–7.35 (m, 1H), 6.42 (br d, J = 3.2 Hz, 1H),
6.34 (dd, J = 3.2, 1.8 Hz, 1H), 5.43 (s, 1H), 2.32–2.28 (m, 1H), 2.27 (td, J = 7.1, 2.1 Hz, 2H), 1.57–1.48 (m,
2H), 1.41 (m, 2H), 0.96–0.88 (m, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 153.9, 143.0, 110.4, 107.5, 87.0,
77.6, 58.5, 30.6, 22.1, 18.6, 13.7. IR max (solid/cm-1) 3396 (O-H), 2957 (C-H), 2932 (C-H), 2872 (C-H),
1501, 1148, 1005, 735, 598.
1-(Thiophen-2-yl)hept-2-yn-1-ol (12a)47
1
896 mg, 93%, brown oil, H NMR (600 MHz, CDCl3) δ 7.27 (dd, J = 5.1, 1.1 Hz, 1H), 7.16–7.13 (m, 1H),
6.98–6.94 (m, 1H), 5.62 (s, 1H), 2.35(br s, 1H), 2.28 (td, J = 7.1, 2.0 Hz, 2H), 1.63–1.50 (m, 2H), 1.50–1.39
(m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 145.8, 126.8, 125.9, 125.4, 87.2, 79.7,
60.5, 30.7, 22.1, 18.6, 13.7. IR max (solid/cm-1) 3381 (O-H), 2956 (C-H), 2933 (C-H), 2877 (C-H), 906, 728,
698.
2-Methylnon-4-yn-3-ol (13a)42
692 mg, 90%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 4.14 (dt, J = 5.5, 2.0 Hz, 1H), 2.20 (td, J = 7.0, 2.0
Hz, 2H), 1.87–1.79 (m, 1H), 1.55–1.46 (m, 2H), 1.44–1.31 (m, 2H), 0.98 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.7
Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 86.3, 79.9, 68.3, 68.2, 34.8, 34.8, 30.9,
22.0, 18.5, 18.2, 18.2, 17.5, 17.5, 13.7. IR max (solid/cm-1) 3383 (O-H), 2958 (C-H), 2931 (C-H), 2872 (C-
H), 1671 1466, 1381, 1049, 1021, 779.
1-Cyclohexylhept-2-yn-1-ol (14a)42
1
843 mg, 87%, colourless oil, H NMR (600 MHz, CDCl3) δ 4.15–4.09 (m, 1H), 2.26–2.17 (m, 2H), 1.82 (d,
J = 12.3 Hz, 2H), 1.75 (d, J = 12.6 Hz, 2H), 1.70–1.60 (m, 1H), 1.52–1.44 (m, 3H), 1.45–1.36 (m, 2H), 1.28–
1.19 (m, 2H), 1.19–1.09 (m, 2H), 1.09–1.00 (m, 1H), 0.96–0.85 (m, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
86.4, 80.2, 67.6, 44.5, 30.9, 28.7, 28.2, 26.6, 26.0, 22.1, 18.5, 13.7. IR max (solid/cm-1) 3345 (O-H), 2923
(C-H), 2852 (C-H), 1449, 1008, 892.
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Docosa-8,14-diyne-7,16-diol (15a)
5
6
7
8
1
1068 mg, 62%, colourless oil, mixture of diastereoisomers (1:1). H NMR (600 MHz, CDCl3) δ 4.31 (m,
2H), 2.28–2.18 (m, 4H), 1.64 (m, 4H), 1.59–1.56 (m, 4H), 1.46–1.36 (m, 4H), 1.31–1.22 (m, 12H), 0.89–
0.83 (m, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ 84.9, 81.9, 62.79 (diastereomer 1), 62.78 (diastereomer 2)
38.3, 31.9, 29.1, 27.8, 25.3, 22.7, 18.3, 14.2. IR max (solid/cm-1) 3355 (O-H), 2926 (C-H), 2857 (C-H), 1458,
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1329, 1039, 735. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H37O2 , 333.2788; Found, 333.2785.
+
1-(4-Nitrophenyl)-5-phenylpent-2-yn-1-ol (16a)48
1
1231 mg, 88%, colourless oil, H NMR (600 MHz, CDCl3) δ 8.27–8.10 (m, 2H), 7.64–7.50 (m, 2H), 7.33–
7.28 (m, 2H), 7.27–7.22 (m, 1H), 7.20 (dd, J = 7.8, 0.9 Hz, 2H), 5.56–5.45 (m, 1H), 2.85 (t, J = 7.4 Hz, 2H),
2.60 (td, J = 7.4, 2.0 Hz, 2H), 2.33 (d, J = 5.8 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 147.9, 147.8, 140.3,
128.6, 127.5, 127.4, 126.6, 123.8, 88.1, 80.0, 63.9, 34.7, 20.9. IR max (solid/cm-1) 3405 (O-H), 3029 (C-
H), 2930 (C-H), 1519 (C=C), 1343, 1265, 1011, 732, 697.
3-Ethylnon-4-yn-3-ol (18a)49
1
695 mg, 83%, colourless oil, H NMR (600 MHz, CDCl3) δ 2.18 (m, 2H), 1.98 (br s, 1H, OH), 1.61 (m, 4H),
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1.51–1.41 (m, 2H), 1.39 (m, 2H), 0.99 (t, J = 7.20 Hz, 6H), 0.88 (t, J = 7.30 Hz 3H). C NMR (151 MHz,
CDCl3) δ 84.9, 82.7, 72.3, 34.7, 31.0, 22.0, 18.4, 13.7, 8.7. IR max (solid/cm-1) 3341 (O-H), 2993 (C-H),
2933 (C-H), 2852 (C-H), 1459, 1019, 871.
1-Phenylhept-2yn-1-ol (19a)42
1
801 mg, 85%, colourless oil, H NMR (600 MHz, CDCl3) δ 7.59–7.52 (m, 2H), 7.38 (m, 2H), 7.35–7.32 (m,
1H), 5.45 (s, 1H), 2.34–2.25 (m, 2H), 1.56–1.51 (m, 2H), 1.47–1.40 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ 141.4, 128.7, 128.3, 126.8, 87.8, 80.0, 65.0, 30.8, 22.1, 18.6, 13.7. IR max
(solid/cm-1) 3362 (O-H), 2957 (C-H), 2931 (C-H), 2871 (C-H), 1641, 1497, 1314, 999, 696.
1-Cyclohexyl-6,6-diethoxyhex-2-yn-1-ol (23a)
1045 mg, 79%, colourless oil, 1H NMR (400 MHz, CDCl3) δ 4.60 (t, J = 5.7 Hz, 1H), 4.12 (d, J = 5.9 Hz, 1H),
3.66 (dq, J = 9.4, 7.1 Hz, 2H), 3.51 (dq, J = 9.4, 7.1 Hz, 2H), 2.30 (td, J = 7.3, 2.0 Hz, 2H), 1.88–1.80 (m,
4H), 1.78 (s, 1H), 1.71–1.64 (m, 2H), 1.56–1.47 (m, 1H), 1.33–0.97 (m, 12H). C{1H} NMR (101 MHz,
CDCl3) δ 101.8, 85.43, 80.5, 67.5, 61.6, 44.4, 32.9, 28.7, 28.2, 26.5, 25.98, 25.95, 15.4, 14.5. IR max
(solid/cm-1) 3382 (O-H), 2973 (C-H), 2924 (C-H), 2852 (C-H), 1448, 1374, 1118, 1056, 731. HRMS (ESI-
TOF) m/z: [M+NH4]+ Calcd for C16H32O3N+, 286.2377; Found, 286.2376.
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4-(1-Hydroxyhept-2-yn-1yl)benzonitrile (24a)50
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902 mg, 84%, colourless oil, H NMR (600 MHz, CDCl3) δ 7.72–7.60 (m, 4H), 5.49 (s, 1H), 2.35 (s, 1H),
2.26 (td, J = 7.1, 2.1 Hz, 2H), 1.62–1.46 (m, 2H), 1.50–1.34 (m, 2H), 0.97–0.84 (m, 3H). 13C{1H} NMR (151
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MHz, CDCl3) δ 146.4, 132.5, 127.3, 118.8, 112.0, 88.9, 79.1, 64.1, 30.6, 22.1, 18.6, 13.7. IR max (solid/cm-
1) 3402 (O-H), 2957 (C-H), 2932 (C-H), 2871 (C-H), 2229 (CN) 1608, 1463, 1325, 1134 1013, 887, 562.
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1,1-Diethoxydodec-4-yn-6-ol (25a)
952 mg, 71%, colourless oil. 1H NMR (400 MHz, CDCl3) δ 4.59 (t, J = 5.7 Hz, 1H), 4.33 (m, 1H), 3.75–3.60
(m, 2H), 3.58–3.45 (m, 2H), 2.28 (td, J = 7.3, 1.9 Hz, 2H), 1.81 (m, 2H), 1.65 (m, 2H), 1.48–1.38 (m, 2H),
1.40–1.27 (m, 6H), 1.20 (t, J = 7.1 Hz, 6H), 0.88 (t, J = 6.8 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 101.8,
84.6, 81.8, 62.8, 61.6, 38.3, 32.8, 31.9, 29.1, 25.3, 22.7, 15.4, 14.5, 14.2. IR max (solid/cm-1) 3418 (O-H),
2956 (C-H), 2928 (C-H), 2858 (C-H), 1445, 1375, 1127, 1059. HRMS (ESI-TOF) m/z: [M+NH4]+ Calcd for
C16H34O3N+, 288.2533; Found, 288.2533.
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1-(Naphthalen-1-yl)hept-2-yn-1-ol (26a)51
954 mg, 80%, colourless oil 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.5 Hz, 1H), 7.99–7.80 (m, 3H), 7.63–
7.43 (m, 3H), 6.20–6.06 (m, 1H), 2.36 (d, J = 5.7 Hz, 1H), 2.31 (td, J = 7.1, 3.7 Hz, 2H), 1.67–1.50 (m, 2H),
1.49–1.36 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 136.4, 134.2, 130.7, 129.3,
128.8, 126.4, 125.9, 125.4, 124.6, 124.2, 88.5, 79.8, 63.21, 30.8, 22.1, 18.7, 13.7. IR max (solid/cm-1) 3367
(O-H), 3049, 2956 (C-H), 2930 (C-H), 2870 (C-H), 1687, 1573, 1104, 774.
9-((tert-Butyldimethylsilanyl)oxy)-5-methylnon-1-en-6-yn-5-ol (27a)
944 mg, 67%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 5.87 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.06 (dq, J
= 17.1, 1.7 Hz, 1H), 4.97 (dq, J = 10.2, 1.3 Hz, 1H), 3.70 (t, J = 7.1 Hz, 2H), 2.41 (t, J = 7.1 Hz, 2H), 2.35–
2.21 (m, 2H), 1.79–1.67 (m, 2H), 1.46 (s, 3H), 0.93–0.88 (s, 9H), 0.09–0.04 (s, 6H). 13C{1H} NMR (151 MHz,
CDCl3) δ 138.6, 114.8, 84.8, 81.2, 68.3, 62.0, 42.9, 30.3, 29.4, 26.0, 23.2, 18.4, -5.2. IR max (solid/cm-1)
3397 (O-H), 2953 (C-H), 2929 (C-H), 2857 (C-H), 1641, 1470, 1274, 1103, 909, 834, 775. HRMS (ESI-TOF)
m/z: [M]+ Calcd for C16H30O2Si+, 282.2010; Found, 282.2009.
6,6-Diethoxy-1-(2-fluorophenyl)hex-2-yn-1-ol (29a)
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1134 mg, 81%, yellow oil, H NMR (600 MHz, CDCl3) δ 7.62 (dt, J = 7.6, 1.6 Hz, 1H), 7.33–7.29 (m, 1H),
7.21–7.11 (m, 1H), 7.09–7.02 (m, 1H), 5.71 (t, J = 1.9 Hz, 1H), 4.59 (t, J = 5.7 Hz, 1H), 3.71–3.58 (m, 2H),
3.56–3.44 (m, 2H), 2.34 (td, J = 7.3, 2.0 Hz, 2H), 1.86–1.81 (m, 2H), 1.29–1.15 (m, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 160.2 (d, J C-F= 248.0 Hz), 130.0 (d, JC-F = 8.3 Hz), 128.5 (d, JC-F = 13.1 Hz), 128.3 (d, JC-F = 3.6
Hz), 124.3 (d, JC-F = 3.6 Hz), 115.6 (d, JC-F = 21.3 Hz) 101.8, 86.8, 79.3, 61.7, 59.2 (d, JC-F = 5.0 Hz), 32.6,
15.4, 14.5. IR max (solid/cm-1) 3402 (O-H), 2981 (C-H), 2942 (C-H), 2888 (C-H), 1491, 1337, 1057, 762.
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C16H21FO3Na+, 303.1367; Found, 303.1369.
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2-(4-Chlorophenyl)-7,7-diethoxyhept-3-yn-2-ol (30a)
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1072 mg, 69%, colourless oil, H NMR (400 MHz, CDCl3) δ 7.59–7.53 (m, 2H), 7.35–7.27 (m, 2H), 4.59 (t,
J = 5.7 Hz, 1H), 3.65 (dq, J = 9.4, 7.1 Hz, 1H), 3.50 (dq, J = 9.4, 7.1 Hz, 1H), 2.34 (t, J = 7.3 Hz, 1H), 1.84 (td,
J = 7.3, 5.7 Hz, 1H), 1.70 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 144.8, 133.4, 128.3, 126.6, 101.7, 85.2, 83.7, 69.6, 61.6, 33.6, 32.7, 15.4, 14.4. IR max (solid/cm-1)
3415 (O-H), 2975 (C-H), 2930 (C-H), 2883 (C-H), 1487, 1397, 1054, 829. HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C17H23ClO3Na+, 333.1228; Found, 333.1224.
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8,8-Diethoxy-2-methyloct-3-yn-2-ol (31a)
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923 mg, 81%, colourless oil, H NMR (400 MHz, CDCl3) δ 4.50 (t, J = 5.7 Hz, 1H), 3.64 (dq, J = 9.4, 7.1 Hz,
2H), 3.49 (dq, J = 9.4, 7.1 Hz, 2H), 2.21 (t, J = 7.0 Hz, 2H), 1.91 (br s, 1H), 1.70 (m, 2H), 1.66–1.52 (m, 2H),
1.48 (s, 6H), 1.20 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3) δ 102.6, 85.6, 82.2, 65.4, 61.1, 32.8,
31.9, 24.1, 18.6, 15.5. IR max (solid/cm-1) 3433 (O-H), 2978 (C-H), 2926 (C-H), 2885 (C-H), 1465, 1134,
1056, 949, 761. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C13H25O3 , 251.1626; Found, 251.1623.
+
Preparation of Syn 1,3-Aminoalcohols
The corresponding propargylic alcohol (0.5 mmol, 1 equiv.) was dissolved in CHCl3 (0.5 mL), 4 Å
molecular sieves (300 mg, previously dried overnight at 120 °C) were added to the mixture. PPh3AuNTf2
(8 mg, 2 mol%) was added together with the corresponding amine (0.5 mmol, 1 equiv.) and the reaction
was stirred at room temperature until completion (TLC, 18-66 h). Diethyl ether (1 mL) was added
followed by NaCNBH3 (62 mg, 1 mmol, 2 equiv.) and the reaction stirred for 2 h at 0 °C. After this time
the solvent was removed in vacuo and the product was purified by column chromatography
(EtOAc/Petrol) to give the corresponding aminoalcohol.
Different reducing agents were tested for the reduction step including LiAlH4, NaBH4, DIBAL,
catecholborane, LiBHEt3 and NaBH3CN. With all of them complete reduction of the imine was achieved,
but the best selectivities for the syn amino alcohol were obtained using NaBH3CN, which gave complete
reduction without significant hydrolysis of the imine.
syn-5-(Phenylamino)tridecan-7-ol (1ba)
After amine addition the reaction was stirred for 18h.
113 mg, 78%, pale yellow solid, , mp 61-62 °C; H NMR (600 MHz, CDCl3) δ 7.22–7.15 (m, 2H), 6.77 (t, J
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= 7.3 Hz, 1H), 6.69 (m, 2H), 3.89–3.81 (m, 1H), 3.60–3.54 (m, 1H), 1.75–1.69 (m, 1H), 1.56–1.40 (m, 5H),
1.30 (m, 12H), 0.89 (t, J = 6.8 Hz, 3H), 0.87 (t, J = 6.9, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 147.3, 129.4,
118.8, 115.2, 72.3, 54.6, 41.6, 38.3, 35.4, 32.0, 29.5, 28.0, 25.5, 22.9, 22.7, 14.2, 14.1. IR max (solid/cm-
1) 3367 (O-H), 2923 (C-H), 2853 (C-H), 1598 (C=C), 1497 (C=C), 1463 (C=C), 1317, 745, 691. HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C19H34O+, 292.2635; Found, 292.2633.
syn-5-((4-Fluorophenyl)amino)tridecan-7-ol (1bb)
After amine addition the reaction was stirred for 24h.
98 mg, 64%, white solid, mp 66-67 °C 1H NMR (600 MHz, CDCl3) δ 6.96–6.87 (m, 2H), 6.71–6.62 (m, 2H),
3.92–3.79 (m, 1H), 3.51–3.39 (m, 1H), 1.77–1.67 (m, 1H), 1.54–1.49 (m, 1H), 1.46–1.41 (m, 4H), 1.32–
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1.25 (m, 12H), 0.89 (t, J = 6.8 Hz, 3H), 0.87 (t, J = 6.9, 3H). 13C{1H} NMR (151 MHz, CDCl3) 156.7 (d, JC-F
=
236.7 Hz), 143.4, 116.5 (d, J C-F = 7.5 Hz), 115.9 (d, J C-F = 22.3 Hz), 72.4, 55.9, 41.4, 38.3, 35.25, 32.0, 29.5,
27.9, 25.5, 22.9, 22.7, 14.2, 14.1. IR max (solid/cm-1) 3352 (O-H), 2924 (C-H), 2853 (C-H), 1506 (C=C),
1463 (C=C), 1219, 819. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H33FNO+, 310.2541; Found, 310.2539.
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syn-5-((3,5-Dimethylphenyl)amino)tridecan-7-ol (1bc)
After amine addition the reaction was stirred for 24h.
124 mg, 78%, colourless oil, 1H NMR (700 MHz, CDCl3) δ 6.43 (s, 1H), 6.34 (s, 2H), 3.83 (m, 1H), 3.52 (m,
1H), 2.23 (s, 6H), 1.71 (m, 1H), 1.53–1.46 (m, 1H), 1.45–1.35 (m, 4H), 1.29 (m, 12H), 0.89 (t, J = 6.8 Hz,
3H), 0.87 (t, J = 6.8, 3H). 13C{1H} NMR (176 MHz, CDCl3) δ 147.3, 139.1, 121.0, 113.4, 72.5, 54.9, 41.5,
38.3, 35.4, 32.0, 29.5, 28.0, 25.6, 22.9, 22.8, 21.6, 14.2, 14.2. IR max (solid/cm-1) 3367 (O-H), 2923 (C-H),
2853 (C-H), 1598 (C=C), 1463 (C=C), 1178. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H38NO+, 320.2948;
Found, 320.2945.
syn-5-((4-Methoxyphenyl)amino)tridecan-7-ol (1bd)
After amine addition the reaction was stirred for 48h.
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143 mg, 89%, white solid, mp 65-67 °C. H NMR (400 MHz, CDCl3) δ 6.84–6.74 (m, 2H), 6.75–6.67 (m,
2H), 3.85 (m, 1H), 3.75 (s, 3H), 3.42 (m, 1H), 1.78–1.69 (m, 1H), 1.60–1.48 (m, 1H), 1.46–1.38 (m, 4H),
1.32–1.22 (m, 12H), 0.88 (t, J = 6.8 Hz, 3H), 0.85 (t, J = 6.9, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.4,
140.8, 117.4, 114.9, 72.7, 56.8, 55.8, 41.1, 38.3, 35.3, 31.9, 29.5, 27.9, 25.5, 22.8, 22.7, 14.2, 14.1. IR max
(solid/cm-1) 3271 (O-H), 2920 (C-H), 2852 (C-H), 1507 (C=C), 1462 (C=C), 1230, 1040, 817. HRMS (ESI-
+
TOF) m/z: [M+H]+ Calcd for C20H36NO2 , 322.2741; Found, 322.2739.
syn-5-((3,5-Dichlorophenyl)amino)tridecan-7-ol (1be)
After amine addition the reaction was stirred for 48h.
122 mg, 68%, pale brown oil, 1H NMR (700 MHz, CDCl3) δ 6.66 (s, 1H), 6.49 (s, 2H), 3.81 (br s, 1H), 3.74
(m, 1H), 3.53–3.45 (m, 1H), 1.65 (m, 1H), 1.59–1.51 (m, 3H), 1.50–1.42 (m, 2H), 1.33–1.25 (m, 12H), 0.89
(t, J = 6.9 Hz, 3H), 0.88 (t, J = 6.9, 3H). 13C{1H} NMR (176 MHz, CDCl3) δ 149.4, 135.7, 117.4, 112.0, 71.3,
52.9, 41.9, 38.4, 35.0, 31.9, 29.4, 27.9, 25.5, 22.8, 22.7, 14.2, 14.2. IR max (solid/cm-1) 3449 (O-H), 2924
(C-H), 2853 (C-H), 1583 (C=C), 1507 (C=C), 1451 (C=C), 1110, 725. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
+
C19H32NOCl2 , 360.1855; Found, 360.1855.
syn-5-((3-(Trifluoromethyl)phenyl)amino)tridecan-7-ol (1bf)
After amine addition the reaction was stirred for 48h.
92 mg, 51%, pale yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.27–7.22 (m, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.86
(s, 1H), 6.79 (m, 1H), 3.84–3.77 (m, 1H), 3.57 (m, 1H), 1.70 (m, 1H), 1.54 (m, 3H), 1.49–1.38 (m, 3H),
1.36–1.25 (m, 12H), 0.89 (t, J = 6.8 Hz, 3H), 0.87 (t, J = 6.9, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 147.8,
131.8 (q, J C-F = 31.7 Hz), 129.9, 124.4 (q, JC-F = 272.4 Hz), 117.2, 114.5 (d, JC-F = 3.9 Hz), 110.5 (d, JC-F = 3.9
Hz), 71.6, 53.3, 41.8, 38.3, 35.1, 31.9, 29.4, 27.9, 25.5, 22.8, 22.7, 14.2, 14.1. IR max (solid/cm-1) 3361 (O-
H), 2925 (C-H), 2854 (C-H), 1612 (C=C), 1336 (C=C), 1120, 696. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C20H33F3NO+, 360.2509; Found, 360.2506.
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syn-5-(o-Tolylamino)tridecan-7-ol (1bg)
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After amine addition the reaction was stirred for 66h.
81 mg, 53%, colourless oil, 1H NMR (700 MHz, CDCl3) δ 7.12 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.3 Hz, 1H),
6.75 (d, J = 8.1 Hz, 1H), 6.70 (t, J = 7.4 Hz, 1H), 3.83 (m, 1H), 3.61 (m, 1H), 3.46 (br s, 1H), 2.15 (s, 3H),
1.76 (m, 1H), 1.55 (m, 1H), 1.50–1.41 (m, 4H), 1.31 (m, 12H), 0.89 (t, J = 6.8 Hz, 3H), 0.87 (t, J = 6.9, 3H).
13C{1H} NMR (176 MHz, CDCl3) δ 145.2, 130.6, 127.3, 123.5, 118.2, 112.4, 72.4, 54.1, 41.7, 38.3, 35.3,
32.0, 29.5, 28.0, 25.6, 22.9, 22.8, 17.9, 14.2, 14.2. IR max (solid/cm-1) 3385 (O-H), 2923 (C-H), 2853 (C-
H), 1603 (C=C), 1510 (C=C), 1476, 743. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H36NO+, 306.2791;
Found, 306.2789.
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syn-5-((2-Bromophenyl)amino)tridecan-7-ol (1bh)
After amine addition the reaction was stirred for 66h.
78 mg, 42%, colourless oil. 1H NMR (700 MHz, CDCl3) δ 7.42 (d, J = 7.9 Hz, 1H), 7.17 (t, J = 7.3 Hz, 1H),
6.77 (d, J = 8.2 Hz, 1H), 6.58 (t, J = 7.6 Hz, 1H), 3.79 (m, 1H), 3.64–3.58 (m, 1H), 1.74–1.69 (m, 1H), 1.62
13
(m, 2H), 1.51–1.39 (m, 3H), 1.29 (m, 12H), 0.93–0.84 (m, 6H). C{1H} NMR (176 MHz, CDCl3) δ 144.5,
132.7, 128.6, 118.5, 113.3, 111.2, 71.2, 53.4, 42.0, 38.3, 35.06, 32.0, 29.5, 27.9, 25.6, 22.9, 22.7, 14.2,
14.2. IR max (solid/cm-1) 3402 (O-H), 2923 (C-H), 2853 (C-H), 1594 (C=C), 1507 (C=C), 1457 (C=C), 1016,
738. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H33NOBr+, 370.1739; Found, 370.1739.
1-(2-(Phenylamino)hexyl)cyclohexan-1-ol (2ba)
After amine addition the reaction was stirred for 18h.
66 mg, 48%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 7.22–7.12 (m, 2H), 6.77 (tt, J = 7.4, 1.0 Hz, 1H),
6.69 (m, 2H), 3.72–3.60 (m, 2H), 1.81 (dd, J = 14.7, 2.5 Hz, 1H), 1.71–1.21 (m, 14H), 0.88–0.83 (m, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 147.0, 129.5, 119.0, 115.4, 71.4, 50.7, 40.5, 40.0, 36.9, 35.6, 28.1, 26.1,
22.9, 22.5, 22.3, 14.2. IR max (solid/cm-1) 3345 (O-H), 2924 (C-H), 2853 (C-H), 1598 (C=C), 1496 (C=C),
1376 (C=C), 1159, 747. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H30NO+, 376.2322; Found, 276.2327.
syn-1-(2-Chlorophenyl)-3-(phenylamino)heptan-1-ol (3ba)
After amine addition the reaction was stirred for 18h.
105 mg, 48%, colourless oil, 1H NMR (700 MHz, CDCl3) δ 7.64 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H),
7.30 (d, J = 7.5 Hz, 1H), 7.22 (t, J = 7.6 Hz, 2H), 7.21–7.18 (m, 1H), 6.82 (t, J = 7.2 Hz, 1H), 6.78 (d, J = 7.9
Hz, 2H), 5.33 (m, 1H), 3.74 (m, 1H), 2.09 (m, 1H), 1.65–1.53 (m, 3H), 1.53–1.47 (m, 1H), 1.35–1.24 (m,
13
3H), 0.86 (t, J = 6.7 Hz, 3H). C{1H} NMR (176 MHz, CDCl3) δ 147.1, 142.2, 131.5, 129.5, 129.4, 128.4,
127.3, 127.1, 119.4, 115.7, 71.5, 55.2, 42.1, 35.2, 27.9, 22.8, 14.2. IR max (solid/cm-1) 3379 (O-H), 2925
(C-H), 2854 (C-H), 1598 (C=C), 1496 (C=C), 990, 749. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H24NOCl+,
318.1619; Found, 318.1614.
(2RS,4RS)-2-(4-Chlorophenyl)-4-(phenylamino)octan-2-ol (4ba)
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129 mg, 78%, colourless oil, 1H NMR (700 MHz, CDCl3) δ 7.43 (d, J = 7.7 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H),
7.22 (t, J = 7.3 Hz, 2H), 6.83 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 7.8 Hz, 2H), 3.78 (m, 1H), 1.99 (d, J = 14.7 Hz,
1H), 1.74 (dd, J = 14.5, 11.1 Hz, 1H), 1.64 (s, 3H), 1.59–1.49 (m, 1H), 1.39 (dd, J = 14.2, 6.9 Hz, 1H), 1.31–
1.19 (m, 4H), 0.84 (t, J = 6.0 Hz, 3H). 13C{1H} NMR (176 MHz, CDCl3) δ 148.3, 146.6, 132.4, 129. 6, 128.4,
126.2, 119.8, 115.8, 74.0, 52.3, 47.4, 35.6, 29.1, 28.0, 22.8, 14.1. IR max (solid/cm-1) 3320 (O-H), 2926 (C-
H), 2854 (C-H), 1598 (C=C), 1496 (C=C), 1091, 750. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H27ClNO+,
332.1776; Found, 332.1773.
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syn-1-Phenyl-1-(phenylamino)nonan-3-ol (5ba)
After amine addition the reaction was stirred for 18h.
79 mg, 51%, colourless oil, 1H NMR (700 MHz, CDCl3) δ 7.37 (m, 5H), 7.22–7.14 (m, 2H), 6.73 (t, J = 7.2
Hz, 1H), 6.65 (m, 2H), 5.06–4.96 (dd, J = 8.2, 2.8 Hz, 1H), 3.60 (m, 1H), 2.12–2.03 (m, 1H), 1.85–1.78 (m,
13
1H), 1.37–1.16 (m, 10H), 0.86 (t, J = 6.8 Hz, 3H). C{1H} NMR (176 MHz, CDCl3) δ 145.1, 129.5, 128.6,
127.5, 125.7, 118.2, 115.9, 114.3, 71.9, 51.3, 43.7, 35.5, 31.9, 29.4, 26.0, 22.7, 14.2. IR max (solid/cm-1)
3377 (O-H), 2951 (C-H), 2853 (C-H), 1588 (C=C), 1506 (C=C), 1452 (C=C), 1315, 749. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C21H30NO+, 312.2322; Found, 312.2326.
7,7-Diethoxy-2-methyl-4-(phenylamino)heptan-2-ol (6ba)
After amine addition the reaction was stirred for 18h.
112 mg, 73%, colourless oil, 1H NMR (700 MHz, CDCl3) δ 7.18 (t, J = 7.9 Hz, 2H), 6.77 (t, J = 7.3 Hz, 1H),
6.71 (d, J = 7.9 Hz, 2H), 4.41 (t, J = 5.4 Hz, 1H), 3.77–3.73 (m, 1H), 3.68 (br s, 1H), 3.59 (m, 2H), 3.46–3.39
(m, 2H), 1.72 (dd, J = 14.6, 2.7 Hz, 1H), 1.68–1.58 (m, 4H), 1.50–1.46 (m, 1H), 1.29 (s, 3H), 1.24 (s, 3H),
1.19–1.13 (m, 6H). 13C{1H} NMR (176 MHz, CDCl3) δ 146.9, 129.5, 119.1, 115.3, 102.9, 70.9, 61.4, 61.1,
51.4, 46.3, 31.5, 30.8, 29.9, 28. 8, 15.4, 15.4. IR max (solid/cm-1) 3364 (O-H), 2968 (C-H), 2927 (C-H), 1599
+
(C=C), 1497 (C=C), 1153, 1055. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H32NO3 , 310.2377; Found,
310.2374.
3-Phenyl-3-(phenylamino)propan-1-ol (7ba)52
After amine addition the reaction was stirred for 18h.
84 mg, 74%, colourless oil, 1H NMR (700 MHz, CDCl3) δ 7.38–7.34 (m, 2H), 7.32 (m, 2H), 7.25–7.22 (m,
1H), 7.09 (m, 2H), 6.66 (t, J = 7.3 Hz, 1H), 6.56 (t, J = 8.6 Hz, 2H), 4.58 (t, J = 6.7 Hz, 1H), 3.79 (m, 2H),
2.13–2.01 (m, 2H).13C{1H} NMR (176 MHz, CDCl3) δ 147.4, 143.7, 129.3, 128.8, 127.21, 126.4, 117.7,
113.9, 60.9, 57.0, 40.8. IR max (solid/cm-1) 3393 (O-H), 2938 (C-H), 1599 (C=C), 1501 (C=C), 1315.
syn-1,1-Diethoxy-5-phenyl-5-(phenylamino)pentan-3-ol (8ba)
After amine addition the reaction was stirred for 18h.
138 mg, 81%, colourless oil, 1H NMR (700 MHz, CDCl3) δ 7.42–7.36 (m, 2H), 7.33 (m, 2H), 7.22 (m, 1H),
7.10–7.02 (m, 2H), 6.66–6.61 (m, 1H), 6.60–6.52 (m, 2H), 4.76–4.61 (m, 1H), 4.59–4.44 (m, 1H), 4.04–
3.95 (m, 1H), 3.79–3.68 (m, 1H), 3.68–3.59 (m, 1H), 3.58–3.45 (m, 2H), 2.04–1.97 (m, 1H), 1.84–1.71 (m,
3H), 1.26–1.19 (m, 6H). 13C{1H} NMR (176 MHz, CDCl3) δ 147.6, 144.3, 129.1, 128.8, 127.2, 126.5, 117.7,
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114.2, 102.4, 68.1, 62.6, 61.9, 58.4, 46.1, 41.0, 15.5, 15.4. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C21H30NO3 , 344.2220; Found, 344.2225.
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syn-1-((4-methoxyphenyl)amino)-4-methyl-1-phenylpentan-3-ol (9bd)
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After amine addition the reaction was stirred for 48h.
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The compound was isolated as a mixture of syn/anti isomers (85:15). The syn isomer was purified by
recrystallisation from n-hexane. 97 mg, 67%, colourless crystals, mp 99-101 °C. 1H NMR (700 MHz, CDCl3)
δ 7.31 (m, 4H), 7.22 (m, 1H), 6.68 (d, J = 8.9 Hz, 2H), 6.55 (d, J = 8.9 Hz, 2H), 4.46–4.40 (m, 1H), 3.69 (s,
3H), 3.64 (m, 1H), 1.84 (m, 2H), 1.71–1.64 (m, 1H), 1.57 (br s, 1H), 0.91 (m, 6H). 13C{1H} NMR (176 MHz,
CDCl3) δ 152.9, 144.2, 141.1, 128.8, 127.2, 126.3, 116.5, 114.8, 76.9, 60.5, 55.8, 42.1, 34.47, 18.5, 17.4.
IR max (solid/cm-1) 3375 (O-H), 2955 (C-H), 1603 (C=C), 1513 (C=C), 1325.
This compound was synthesized from the corresponding racemic propargylic alcohol and from an
enantiomerically enriched sample. From the enantiomerically enriched propargylic alcohol, the yield
after crystallization was 59% (84 mg), []D25 = +14.2 (c = 1.0, CH2Cl2). Only one enantiomer was observed
by chiral HPLC.
cis-4-Butyl-6-hexyl-3-phenyl-1,3-oxazinan-2-one (1ba-URE)
Compound 1ba (29 mg, 0.1 mmol, 1 equiv.) was mixed with carbonyldiimidazole (16 mg, 0.1 mmol, 1
equiv.) and dissolved in MeCN (0.5 mL). The mixture was heated to 80 °C. After 14 h the mixture was
cooled down to rt and the product was purified by flash column chromatography (AcOEt: Hex). The
nOeSY spectrum of the product supports the stereochemical assignment shown above. nOeSY spectrum
is included in the supporting information.
28 mg, 85%, pale yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 10.7, 4.5 Hz, 2H), 7.31–7.27 (m,
1H), 7.24 (t, J = 3.1 Hz, 2H), 4.40–4.26 (m, 1H), 3.88–3.79 (m, 1H), 2.18 (m, 1H), 1.81–1.62 (m, 3H), 1.54–
1.03 (m, 14H), 0.89 (t, J = 7.0 Hz, 3H), 0.79 (t, J = 7.1, 3H). 13C{1H} NMR (176 MHz, CDCl3) δ 154.0, 140.2,
129.2, 128.4, 127.4, 76.0, 57.6, 35.2, 34.3, 33.8, 31.8, 29.3, 26.9, 24.8, 22.7, 22.6, 14.2, 14.0. IR max
(solid/cm-1) 2955 (C-H), 2928 (C-H), 2858 (C-H), 1693 (C=O), 1415, 1297, 766, 696. HRMS (ESI-TOF) m/z:
+
[M+H]+ Calcd for C20H32NO2 , 318.2428; Found, 318.2426.
(4RS,6RS)-4-Butyl-6-(4-chlorophenyl)-6-methyl-3-phenyl-1,3-oxazinan-2-one (4ba-URE)
Compound 4ba (33 mg, 0.1 mmol, 1 equiv.) was mixed with CDI (16 mg, 0.1 mmol, 1 equiv.) and dissolved
in MeCN (0.5 mL). The mixture was heated to 80 °C. After 14 h the mixture was cooled down to rt and
the product was purified by flash column chromatography (AcOEt: Hex). The nOeSY spectrum of the
product supports the stereochemical assignment shown above. nOeSY spectrum is included in the
supporting information.
33 mg, 92%, colourless oil,1H NMR (400 MHz, CDCl3) δ 7.46–7.39 (m, 2H), 7.34–7.28 (m, 2H), 7.21 (dd, J
= 8.5, 7.4 Hz, 2H), 6.83 (t, J = 7.4 Hz, 1H), 6.72 (dd, J = 8.6, 1.0 Hz, 2H), 3.78 (td, J = 6.7, 3.3 Hz, 1H), 1.99
(dd, J = 14.7, 2.7 Hz, 1H), 1.78–1.68 (m, 1H), 1.63 (s, 3H), 1.41 (d, J = 6.8 Hz, 2H), 1.30–1.19 (m, 4H), 0.84
(m, 3H). 13C{1H} NMR (176 MHz, CDCl3) δ 150.4, 146.6, 139.4, 132.9, 129.4, 129.2, 128.8, 128.6, 126.3,
73.9, 58.5, 46.8, 34.4, 30.4, 29.0, 22.6, 14.1. IR max (solid/cm-1) 2964 (C-H), 2929 (C-H), 2859 (C-H) 1685
(C=O), 1596 (C=C), 1495 (C=C), 1215, 754, 696. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C21H25NO2Cl+,
358.1568; Found, 358.1568.
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syn-5-Aminotridecan-7-ol (1bi)
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To a solution of aminoalcohol 1bd (118 mg, 0.5 mmol) in MeCN/H2O (10 mL, 1:1) trichloroisocyanuric
acid (0.13 g, 0.27 mmol) and 1 M aqueous H2SO4 (0.5 mL) were added. The mixture was stirred for 16 h.
at rt and then the product was extracted with CH2Cl2 (3 x 50 mL) and the combined organic extracts
concentrated. The amino alcohol was purified using flash column chromatography.
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78 mg, 72%, brown oil, H NMR (400 MHz, CDCl3) δ 3.81 (m, 1H), 3.29 (m, 1H), 1.79 (m, 1H), 1.67 (m,
2H), 1.54 (m, 1H), 1.42 (m, 2H), 1.38–1.22 (m, 12H), 0.89 (t, J = 6.8, 1.9 Hz, 3H), 0.87 (t, J = 6.9, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 72.6, 53.2, 38.8, 38.6, 34.7, 31.9, 29.4, 27.8, 25.7, 22.7, 22.5, 14.1, 14.0.
IR max (solid/cm-1) 3371 (O-H), 3195 (N-H) 2955 (C-H), 2912 (C-H), 1154, 1092, 752, 692. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C13H30NO+, 216.2322; Found, 216.2323.
Preparation of Hydroxyketones
The corresponding propargylic alcohol (0.5 mmol, 1 equiv.) was dissolved in undried CHCl3 (0.5 mL). After
the substrate was completely dissolved, PPh3AuNTf2 (8 mg, 2 mol%) and 3-trifluoromethylaniline (16
mg, 0.2 equiv.) were added to the solution. The reaction was then stirred at 50 °C for 18 h. The solvent
was removed in vacuo and the product was purified by column chromatography (AcOEt:Hex, 1:4).
7-Hydroxytridecan-5-one (1c)
96 mg, 91%, pale yellow solid, mp 47-49 °C; 1H NMR (600 MHz, CDCl3) δ 4.08–3.93 (m, 1H), 3.04 (d, J =
3.0 Hz, 1H), 2.58 (dd, J = 17.5, 2.7 Hz, 1H), 2.48 (dd, J = 17.5, 9.2 Hz, 1H), 2.42 (t, J = 7.6 Hz, 2H), 1.59–
1.52 (m, 2H), 1.51–1.45 (m, 1H), 1.42–1.35 (m, 2H), 1.33–1.22 (m, 9H), 0.90 (t, 7.3 Hz, 3H), 0.87 (t, 7.2
Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 212.8, 67.8, 49.0, 43.5, 36.6, 31.9, 29.3, 25.8, 25.5, 22.7, 22.4,
14.2, 13.9. IR max (solid/cm-1) 3397 (O-H), 2956 (C-H), 2928 (C-H), 2857 (C-H), 1705 (C=O), 1465, 1378,
1164, 732. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C13H27O2 , 215.2006; Found, 215.2006.
+
1-(1-Hydroxycyclohexyl)hexan-2-one (2c)
80 mg, 81%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 3.77 (br s, 1H), 2.56 (s, 2H), 2.41 (t, J = 7.4 Hz, 2H),
1.72–1.61 (m, 5H), 1.59–1.52 (m, 3H), 1.45–1.23 (m, 6H), 0.91 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (151 MHz,
CDCl3) δ 213.8, 70.8, 44.7, 37.7, 37.7, 25.9, 25.7, 22.4, 22.1, 14.0. IR max (solid/cm-1) 3497 (O-H), 2931
(C-H), 2859 (C-H), 1698 (C=O), 1447, 1406, 996. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H23O2 ,
199.1693; Found, 199.1692.
+
1-(2-Chlorophenyl)-1-hydroxyheptan-3-one (3c)
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103 mg, 86%, yellow oil, H NMR (600 MHz, CDCl3) δ 7.62 (dd, J = 7.8, 1.6 Hz, 1H), 7.34–7.28 (m, 2H),
7.23–7.18 (m, 1H), 5.49 (dt, J = 9.6, 2.7 Hz, 1H), 3.66 (d, J = 3.3 Hz, 1H), 2.97 (dd, J = 17.6, 2.3 Hz, 1H),
2.63 (dd, J = 17.6, 9.6 Hz, 1H), 2.44 (m, 2H), 1.58 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 212.1, 140.3, 131.2, 129.4, 128.7, 127.3, 127.2, 66.9, 49.0, 43.4, 25.8, 22.4, 13.9. IR max
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(solid/cm-1) 3449 (O-H), 2958 (C-H), 2931 (C-H), 2872 (C-H), 1703 (C=O), 1439, 1047, 1032, 753. HRMS
(ESI-TOF) m/z: [M]+ Calcd for C13H17ClO2 , 240.0912; Found, 240.0911.
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55 mg, 43%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.39–7.33 (m, 2H), 7.30–7.27 (m, 2H), 4.71 (s, 1H),
3.10 (d, J = 17.1 Hz, 1H), 2.80 (d, J = 17.1 Hz, 1H), 2.36 (m, 1H), 2.26 (m, 1H), 1.48 (s, 3H), 1.47–1.40 (m,
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2H), 1.20 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). C{1H} NMR (151 MHz, CDCl3) δ 213.1, 146.1, 132.7, 128.5,
126.0, 73.2, 53.0, 44.5, 30.7, 25.4, 22.2, 13.8. IR max (solid/cm-1) 3470 (O-H), 2958 (C-H), 2931 (C-H),
2872 (C-H), 1696 (C=O), 1489, 1401, 1164, 1094, 1012, 829, 555. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C14H19ClO2Na+, 277.0967; Found, 277.0967.
3-Hydroxy-1-phenylnonan-1-one (5c)53
95 mg, 81%, yellow oil, 1H NMR (400 MHz, CDCl3) δ 8.00–7.91 (m, 2H), 7.63–7.55 (m, 1H), 7.50–7.44 (m,
2H), 4.22 (m, 1H), 3.17 (dd, J = 17.7, 2.6 Hz, 1H), 3.04 (dd, J = 17.7, 9.0 Hz, 1H), 1.68–1.57 (m, 1H), 1.50
(m, 2H), 1.35–1.24 (m, 7H), 0.89 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 201.1, 136.9, 133.6,
128.7, 128.1, 67.9, 45.1, 36.6, 31.9, 29.3, 25.6, 22.7, 14.2. IR max (solid/cm-1) 3452 (O-H), 2957 (C-H),
2931 (C-H), 2872 (C-H), 1703 (C=O), 1493, 1379, 1068, 698.
1,1-Diethoxy-6-hydroxy-6-methylheptan-4-one (6c)
60 mg, 78%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 4.48 (t, J = 5.3 Hz, 1H), 3.83 (s, 1H), 3.63 (dq, J = 9.4,
7.1 Hz, 2H), 3.55–3.40 (m, 2H), 2.61 (s, 2H), 2.51 (t, J = 7.2 Hz, 2H), 1.89 (td, J = 7.2, 5.4 Hz, 2H), 1.23 (s,
6H), 1.18 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (151 MHz, CDCl3) δ 212.6, 102.0, 69.8, 61.9, 53.2, 39.3, 29.5,
27.5, 15.4. IR max (solid/cm-1) 3475 (O-H), 2973 (C-H), 2931 (C-H), 2896 (C-H), 1700 (C=O), 1444, 1373,
1123, 1055. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C12H24O4Na+, 255.1567; Found, 255.1567.
3-Hydroxy-1-phenylpropan-1-one (7c)54
56 mg, 74%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 8.03–7.93 (m, 2H), 7.63–7.56 (m, 1H), 7.50–7.46 (m,
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2H), 4.03 (m, 2H), 3.28–3.20 (m, 2H), 2.65 (t, J = 6.5 Hz, 1H); C{1H} NMR (151 MHz, CDCl3) δ 200.7,
136.8, 133.7, 128.8, 128.2, 58.2, 40.5. IR max (solid/cm-1) 3403 (O-H), 2925 (C-H), 1677 (C=O), 1492,
1327, 1177, 1057, 688.
3-Hydroxy-4-methyl-1-phenylpentan-1-one (9c)23
72 mg, 82%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 7.96 (dt, J = 8.5, 1.5 Hz, 2H), 7.62–7.56 (m, 1H),
7.52–7.44 (m, 2H), 4.04–3.97 (m, 1H), 3.21–3.12 (m, 2H), 3.03 (dd, J = 17.4, 9.6 Hz, 1H), 1.86–1.76 (m,
1H), 1.01 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (176 MHz, CDCl3) δ 201.5, 137.1, 133.6,
128.8, 128.2, 72.5, 42.1, 33.3, 18.7, 18.0. IR max (solid/cm-1) 3488 (O-H), 2961 (C-H), 2911 (C-H), 2867
(C-H), 1704 (C=O), 1467, 1355, 1235, 995, 737.
This compound was synthesized from the corresponding racemic propargylic alcohol and from an
enantiomerically enriched sample. From the enantiomerically enriched propargylic alcohol, the yield
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was 86%, []D = +6.3 (c = 1.0, CH2Cl2). An e.r. of 94:6 was observed by chiral HPLC (supporting
information).
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1-Hydroxy-1-(4-methoxyphenyl)heptan-3-one (10c)55
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61 mg, 52%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 7.27 (m, 2H), 6.99–6.77 (m, 2H), 5.09 (dd, J = 9.2,
3.0 Hz, 1H), 3.79 (s, 3H), 3.29 (br s, 1H), 2.84 (dd, J = 17.3, 9.3 Hz, 1H), 2.75(dd, J = 17.3, 3.2 Hz, 1H), 2.42
(t, J = 7.6 Hz, 2H), 1.57–1.51 (m, 2H), 1.40–1.24 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 211.8, 159.2, 135.2, 127.0, 114.0, 69.8, 55.4, 51.1, 43.6, 25.8, 22.4, 13.9. IR max (solid/cm-1)
3433 (O-H), 2957 (C-H), 2931 (C-H), 2872 (C-H), 1704 (C=O), 1611, 1512, 1245, 1033, 830.
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1-(Furan-2-yl)-1-hydroxyheptan-3-one (11c)56
75 mg, 77%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.36 (dd, J = 1.8, 0.8 Hz, 1H), 6.32 (dd, J = 3.2, 1.8 Hz,
1H), 6.25 (d, J = 3.2 Hz, 1H), 5.16 (m, 1H), 3.31 (br s, 1H), 3.02 (dd, J = 17.5, 8.9 Hz, 1H), 2.89 (dd, J = 17.5,
3.3 Hz, 1H), 2.45 (t, J = 7.4 Hz, 2H), 1.63–1.53 (m, 2H), 1.38–1.26 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (151 MHz, CDCl3) δ 211.2, 155.2, 142.2, 110.4, 106.4, 64.0, 47.2, 43.5, 25.8, 22.4, 13.9. IR max
(solid/cm-1) 3451 (O-H), 2958 (C-H), 2933 (C-H), 2873 (C-H), 1709 (C=O), 1378, 1012, 739.
1-Hydroxy-1-(thiophen-2-yl)heptan-3-one (12c)57
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60 mg, 61%, brown oil, H NMR (600 MHz, CDCl3) δ 7.25–7.22 (m, 1H), 6.97–6.94 (m, 2H), 5.40 (dt, J =
8.6, 3.5 Hz, 1H), 3.51 (d, J = 3.7 Hz, 1H), 2.98 (dd, J = 17.6, 3.6 Hz, 1H), 2.92 (dd, J = 17.6, 8.6 Hz, 1H), 2.45
(t, J = 7.4 Hz, 2H), 1.65–1.52 (m, 2H), 1.35–1.28 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 211.3, 146.7, 126.8, 124.8, 123.6, 66.4, 50.9, 43.5, 25.7, 22.4, 13.9. IR max (solid/cm-1) 3433 (O-
H), 2957 (C-H), 2931 (C-H), 2872 (C-H), 1706 (C=O), 1404, 1126, 1036, 699.
3-Hydroxy-2-methylnonan-5-one (13c)58
79 mg, 92%, colourless oil, 1H NMR (400 MHz, CDCl3) δ 3.84–3.77 (m, 1H), 2.63–2.55 (dd, J = 17.6, 2.3
Hz, 1H), 2.48 (dd, J = 17.6, 9.6 Hz, 1H), 2.44 (t, J = 7.4 Hz, 2H), 1.67 (m, 1H), 1.61–1.51 (m, 2H), 1.37–1.26
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(m, 2H), 0.95–0.88 (m, 9H). C{1H} NMR (101 MHz, CDCl3) δ 212.9, 72.4, 46.0, 43.5, 33.1, 25.8, 22.3,
18.4, 17.8, 13.9. IR max (solid/cm-1) 3397 (O-H), 2959 (C-H), 2932 (C-H), 2873 (C-H), 1702 (C=O), 1333,
1164, 1125, 1070 698.
1-Cyclohexyl-1-hydroxyheptan-3-one (14c)55
99 mg, 94%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 3.79 (m, 1H), 2.96 (d, J = 3.5 Hz, 1H), 2.59 (dd, J
= 17.3, 2.4 Hz, 1H), 2.50 (dd, J = 17.3, 9.6 Hz, 1H), 2.43 (t, J = 7.5 Hz, 2H), 1.87–1.80 (m, 1H), 1.74 (m, 2H),
1.68–1.60 (m, 2H), 1.60–1.51 (m, 2H), 1.38–1.27 (m, 3H), 1.26–1.09 (m, 3H), 1.07–0.96 (m, 2H), 0.90 (t,
J = 7.4 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 213.1, 71.9, 46.2, 43.6, 43.1, 29.0, 28.4, 26.6, 26.2, 25.9,
22.4, 14.0. IR max (solid/cm-1) 3458 (O-H), 2991 (C-H), 2933 (C-H), 2859 (C-H), 1703 (C=O), 1417, 1106,
796.
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7,16-Dihydroxydocosane-9,14-dione (15c)
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149 mg, 81%, yellow oil, mixture of diastereoisomers (overlapped cannot differentiate most peaks) H
NMR (600 MHz, CDCl3) δ 4.06–3.99 (m, 2H), 2.63–2.54 (m, 2H), 2.54–2.48 (m, 2H), 2.42 (m, 4H), 2.13 (s,
2H), 1.61–1.55 (m, 4H), 1.52–1.47 (m, 2H), 1.44–1.37 (m, 4H), 1.34–1.23 (m, 14H), 0.88 (t, J = 6.7 Hz, 6H).
13C{1H} NMR (151 MHz, CDCl3) δ 212.0 (diastereomer 1), 208.8 (diastereomer 1), 67.8, 49.2, 43.5, 36.6,
31.9, 29.3, 25.5, 22.7, 14.2. IR max (solid/cm-1) 3326 (O-H), 2926 (C-H), 2856 (C-H), 1702 (C=O), 1332,
1166, 1127, 667. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H42O4Na+, 393.2975; Found, 393.2983.
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1-Hydroxy-1-(4-nitrophenyl)-5-phenylpentan-3-one (16c)
113 mg, 76%, yellow oil, 1H NMR (400 MHz, CDCl3) δ 8.28–8.18 (m, 2H), 7.56–7.45 (m, 2H), 7.29 (m, 2H),
7.24–7.19 (m, 1H), 7.18–7.15 (m, 2H), 5.24 (m, 1H), 3.56 (d, J = 3.3 Hz, 1H), 2.93 (m, 2H), 2.79 (m, 4H);
13C{1H} NMR (101 MHz, CDCl3) δ 209.9, 150.0, 147.4, 140.4, 128.7, 128.35, 127.1, 126.5, 123.8, 69.1,
51.0, 45.1, 29.6. IR max (solid/cm-1) 3464 (O-H), 2927 (C-H), 1706 (C=O), 1601, 1515, 1342, 854, 697.
HRMS (ESI-TOF) m/z: [M+Cl]+ Calcd for C17H17ClNO4 , 334.0846; Found, 334.0851.
+
3-(4-Bromophenyl)-1-cyclopropyl-3-hydroxypropan-1-one (17c)
79 mg, 59%, pale yellow solid, mp 93-94 °C 1H NMR (400 MHz, CDCl3) δ 7.52–7.44 (m, 2H), 7.29–7.20 (m,
2H), 5.12 (m, 1H), 3.58 (d, J = 3.0 Hz, 1H), 2.98–2.93 (m, 2H), 1.91 (tt, J = 7.8, 4.5 Hz, 1H), 1.16–1.06 (m,
2H), 1.01–0.90 (m, 2H); C{1H} NMR (101 MHz, CDCl3) δ 211.2, 141.9, 131.7, 127.5, 121.4, 69.4, 51.4,
21.4, 11.6, 11.4. IR max (solid/cm-1) 3433 (O-H), 2920 (C-H), 2900 (C-H), 1686 (C=O), 1420, 1055, 1027,
819, 532. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C12H13O2BrNa+, 290.9991; Found, 291.0001.
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3-Ethyl-3-hydroxynonan-5-one (18c)
30 mg, 32%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 3.81 (s, 1H), 2.55 (s, 2H), 2.43 (t, J = 7.4 Hz, 2H), 1.61–
1.47 (m, 6H), 1.35–1.31 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H), 0.85 (t, J = 7.5 Hz, 6H). 13C{1H} NMR (151 MHz,
CDCl3) δ 214.2, 74.3, 48.7, 44.7, 31.2, 25.7, 22.4, 14.0, 8.2. IR max (solid/cm-1) 3463 (O-H), 2960 (C-H),
2930 (C-H), 2874 (C-H), 1698 (C=O), 1488, 1459, 1407, 1126, 1061, 976. HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C11H22O2Na+, 209.1517; Found, 209.1514.
1-Hydroxy-1-phenylheptan-3-one (19c)55
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84 mg, 82%, colourless oil, H NMR (400 MHz, CDCl3) δ 7.42–7.32 (m, 4H), 7.28 (m, 1H) 5.16 (m, 1H),
3.37 (d, J = 3.1 Hz, 1H), 2.92–2.71 (m, 2H), 2.43 (t, J = 7.4 Hz, 2H), 1.64–1.51 (m, 2H), 1.40–1.23 (m, 2H),
0.90 (t, J = 7.2 Hz, 3H). C{1H} NMR (101 MHz, CDCl3) δ 211.8, 142.9, 128.6, 127.7, 125.7, 70.0, 51.1,
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43.5, 25.7, 22.3, 13.9. IR max (solid/cm-1) 3485 (O-H), 2959 (C-H), 2932 (C-H), 2873 (C-H), 1703 (C=O),
1494, 1128, 905, 725, 699.
1-Hydroxyhexan-3-one (20c)58
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43 mg, 74%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 3.84 (t, J = 5.4 Hz, 2H), 2.72–2.62 (m, 2H), 2.53–2.36
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(m, 2H), 1.71–1.55 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); C{1H} NMR (151 MHz, CDCl3) δ 212.1, 58.0, 45.4,
44.4, 17.2, 13.8. IR max (solid/cm-1) 3397 (O-H), 2963 (C-H), 2932 (C-H), 1704 (C=O), 1349, 1226, 1189,
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1-Cyclopropyl-3-hydroxy-3-p-tolylpropan-1-one (21c)
72 mg, 71%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.28–7.24 (m, 2H), 7.16 (d, J = 7.9 Hz, 2H), 5.12 (dd,
J = 8.7, 3.5 Hz, 1H), 3.52–3.37 (m, 1H), 3.04–2.90 (m, 1H), 2.34 (s, 1H), 1.92 (m, 1H), 1.14–1.04 (m, 2H),
0.94–0.89 (m, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 211.5, 140.0, 137.4, 129.3, 125.7, 69.9, 51.7, 21.5,
21.2, 11.5, 11.2. IR max (solid/cm-1) 3430 (O-H), 3009 (C-H), 2923 (C-H), 1686 (C=O), 1514, 1387, 1103,
1056, 815. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C13H16O2Na+, 227.1043; Found, 227.1049.
3-Ethyl-3-hydroxy-1-p-tolylpentan-1-one (22c)
83 mg, 75%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 7.90–7.81 (m, 2H), 7.30–7.24 (m, 2H), 4.14 (s, 1H),
3.06 (s, 2H), 2.41 (s, 3H), 1.65–1.54 (m, 4H), 0.90 (t, J = 7.5 Hz, 6H); C{1H} NMR (151 MHz, CDCl3) δ
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202.3, 144.7, 135.2, 129.5, 128.3, 74.6, 44.0, 31.4, 21.8, 8.3. IR max (solid/cm-1) 3473 (O-H), 2966 (C-H),
2936 (C-H), 2880 (C-H), 1663 (C=O), 1605, 1407, 1122, 781. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
+
C14H21O2 , 221.1542; Found, 221.1540.
1-Cyclohexyl-6,6-diethoxy-1-hydroxyhexan-3-one (23c)
110 mg, 77%, yellow oil, 1H NMR (600 MHz, CDCl3) δ 4.48 (t, J = 5.3 Hz, 1H), 3.80 (m, 1H), 3.63 (m, 2H),
3.53–3.43 (m, 2H), 2.93 (d, J = 3.6 Hz, 1H), 2.64–2.58 (dd, J = 17.1, 2.6 Hz, 1H), 2.53 (m, 3H), 1.91 (td, J =
7.2, 5.3 Hz, 2H), 1.84 (m, 1H), 1.79–1.71 (m, 2H), 1.69–1.61 (m, 2H), 1.39–1.31 (m, 1H), 1.27–1.21 (m,
2H), 1.19 (t, J = 6.9 Hz, 3H), 1.18 (t, J = 6.9 Hz, 3H), 1.15 (m, 1H), 1.02 (m, 2H). 13C{1H} NMR (151 MHz,
CDCl3) δ 212.2, 102.1, 71.9, 61.9, 61.8, 46.5, 43.2, 38.5, 29.0, 28.4, 27.7, 26.6, 26.3, 26.2, 15.4. IR max
(solid/cm-1) 3463 (O-H), 2971 (C-H), 2926 (C-H), 2853 (C-H), 1706 (C=O), 1484, 1407, 1123, 1058. HRMS
Found 309.2038, [C16H30O4+Na]+ requires 309.2036. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C16H30O4Na+, 309.2036; Found, 309.2038.
4-(1-Hydroxy-3-oxoheptyl)benzonitrile (24c)
103 mg, 89%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 7.65 (m, 2H), 7.48 (m, 2H), 5.26–5.12 (m, 1H),
3.79–3.56 (br s, 1H), 2.93–2.71 (m, 2H), 2.58–2.37 (m, 2H), 1.60–1.50 (m, 2H), 1.35–1.26 (m, 2H), 0.89
(t, J = 7.6 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 211.3, 148.3, 132.5, 126.5, 118.9, 111.5, 69.3, 50.7,
43.5, 25.7, 22.3, 13.9. IR max (solid/cm-1) 3472 (O-H), 2958 (C-H), 2932 (C-H), 2872 (C-H), 2228 (CN), 1705
(C=O), 1608, 1328, 1124, 832, 566. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C14H17O2Na+, 254.1158;
Found, 254.1148.
1,1-Diethoxy-6-hydroxydodecan-4-one (25c)
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106 mg, 74%, yellow oil, 1H NMR (400 MHz, CDCl3) δ 4.47 (t, J = 5.3 Hz, 1H), 4.01 (m, 1H), 3.62 (m, 2H),
3.46 (m, 2H), 2.60 (dd, J = 17.2, 2.8 Hz, 1H), 2.55–2.43 (m, 3H), 1.90 (m, 2H), 1.54–1.22 (m, 8H), 1.18 (m,
6H), 0.89–0.84 (m, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 211.9, 102.0, 67.9, 61.9, 61.8, 49.3, 38.4, 36.6,
31.9, 29.3, 27.7, 25.5, 22.7, 15.4, 14.2. IR max (solid/cm-1) 3453 (O-H), 2956 (C-H), 2927 (C-H), 2857 (C-
H), 1708 (C=O), 1409, 1373, 1122, 1057. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C16H32O4Na+, 311.2193;
Found, 311.2197.
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1-Hydroxy-1-(naphthalen-1-yl)heptan-3-one (26c)55
88 mg, 69%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 8.01 (d, J = 8.4 Hz, 1H), 7.94–7.87 (m, 1H), 7.78
(t, J = 8.8 Hz, 1H), 7.69 (d, J = 7.1 Hz, 1H), 7.60–7.44 (m, 3H), 5.96 (dt, J = 8.4, 2.9 Hz, 1H), 3.47 (d, J = 3.1
Hz, 1H), 3.09–2.85 (m, 2H), 2.59–2.40 (m, 2H), 1.73–1.53 (m, 2H), 1.42–1.27 (m, 2H), 0.90 (t, J = 7.3 Hz,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 212.0, 138.5, 133.9, 130.0, 129.2, 128.2, 126.3, 125.7, 125.7, 123.1,
122.9, 67.0, 50.5, 43.6, 25.8, 22.4, 13.9. IR max (solid/cm-1) 3451 (O-H), 2957 (C-H), 2931 (C-H), 2872 (C-
H), 1706 (C=O), 1264, 1050, 800, 778.
1-((tert-Butyldimethylsilanyl)oxy)-5-hydroxy-5-methylnon-8-en-3-one (27c)
81 mg, 54%, colourless oil, 1H NMR (400 MHz, CDCl3) δ 5.80 (m, 1H), 4.98 (m, 2H), 3.88 (m, 2H), 3.82 (s,
1H), 2.68 (d, J = 17.1 Hz, 1H), 2.61 (m, 3H), 2.15–2.07 (m, 2H), 1.62–1.53 (m, 2H), 1.21 (s, 3H), 0.87 (s,
9H), 0.05 (s, 6H). 13C{1H} NMR (176 MHz, CDCl3) δ 212.4, 138.8, 114.6, 71.7, 58.8, 52.9, 47.4, 41.3, 28.4,
26.9, 26.0, 18.4, -5.4. IR max (solid/cm-1) 3498 (O-H), 2955 (C-H), 2930 (C-H), 2857 (C-H), 1702 (C=O),
1375, 1331, 1125, 835, 812. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C16H32O3SiNa+, 323.2013; Found,
323.2014.
Ethyl 3-hydroxy-5-oxo-5-p-tolylpentanoate (28c)
97 mg, 77%, yellow solid, mp 86-87 °C 1H NMR (700 MHz, CDCl3) δ 7.86 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 7.8
Hz, 2H), 4.65 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.61 (s, 1H), 3.24–3.16 (m, 2H), 2.62 (d, J = 6.4 Hz, 2H), 2.42
(s, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (176 MHz, CDCl3) δ 199.3, 172.0, 144.7, 134.3, 129.5, 128.4,
64.9, 60.9, 44.2, 41.0, 21.8, 14.3. IR max (solid/cm-1) 3451 (O-H), 2975 (C-H), 2957 (C-H), 2855 (C-H), 1731
(C=O), 1679 (C=O), 1606 (C=C), 1407, 1181, 1059, 810. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C14H18O4Na+, 273.1097; Found, 274.1096.
6,6-Diethoxy-1-(2-fluorophenyl)-1-hydroxyhexan-3-one (29c)
125 mg, 84%, yellow oil, 1H NMR (400 MHz, CDCl3) δ 7.58–7.48 (m, 1H), 7.26–7.20 (m, 1H), 7.15 (td, J =
7.5, 1.1 Hz, 1H), 7.06–6.94 (m, 1H), 5.44 (m, 1H), 4.48 (t, J = 5.3 Hz, 1H), 3.70–3.54 (m, 3H), 3.54–3.42
(m, 2H), 2.91 (dd, J = 17.4, 2.9 Hz, 1H), 2.81 (dd, J = 17.4, 9.2 Hz, 1H), 2.64–2.46 (m, 2H), 1.92 (m, 2H),
1.18 (m, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 211.0, 159.4 (d, JC-F = 245.4 Hz), 129.9 (d, J C-F = 13.1 Hz),
129.0 (d, JC-F = 8.2 Hz), 127.3 (d, JC-F = 4.3 Hz), 124.4 (d, JC-F = 3.4 Hz), 115.2 (d, JC-F = 21.5 Hz), 102.0, 64.3
(d, J C-F = 2.8 Hz), 61.8, 61.8, 49.8, 38.2, 27.7, 15.3. IR max (solid/cm-1) 3433 (O-H), 2974 (C-H), 2930 (C-
H), 2897 (C-H), 1710 (C=O), 1487, 1372, 1119, 1055, 757. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C16H23NFO4Na+, 321.1473; Found, 321.1480.
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Preparation of Aminoketones
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The corresponding propargylic alcohol (0.5 mmol, 1 equiv) was dissolved in a mixture of toluene:MeOH
(98:2, 0.5 mL), and PPh3AuNTf2 (8 mg, 2 mol%) was added into the reaction mixture. The mixture was
stirred for 5 h and then the corresponding amine (0.5 mmol, 1 equiv.) was added and the reaction heated
to 50 °C overnight. The solvent was removed in vacuo and the product was purified by column
chromatography (EtOAc/Petrol).
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7-(Phenylamino)tridecan-5-one (1da)
131 mg, 91%, pale brown oil, 1H NMR (400 MHz, CDCl3) δ 7.19–7.02 (m, 2H), 6.75–6.66 (m, 1H), 6.59 (m,
2H), 3.96–3.77 (m, 1H), 3.67 (s, 1H), 2.67 (dd, J = 16.3, 5.0 Hz, 1H), 2.55 (dd, J = 16.3, 6.5 Hz, 1H), 2.38 (t,
J = 7.4 Hz, 2H), 1.53 (m, 4H), 1.36–1.17 (m, 10H), 0.88 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.0, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 210.7, 147.4, 129.5, 117.5, 113.5, 49.9, 47.1, 43.6, 35.4, 31.9, 29.3, 26.4, 25.8, 22.7,
22.4, 14.2, 14.0. IR max (solid/cm-1) 3367 (N-H), 2924 (C-H), 2854 (C-H), 1704 (C=O), 1599 (C=C), 1498
(C=C), 746. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H32NO+, 290.2478; Found, 290.2478.
7-((4-Fluorophenyl)amino)tridecan-5-one (1db)
133 mg, 87%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 6.89–6.84 (m, 2H), 6.56–6.51 (m, 2H), 3.79–3.71
(m, 1H), 2.63 (dd, J = 16.4, 5.2 Hz, 1H), 2.55 (dd, J = 16.4, 6.2 Hz, 1H), 2.38 (t, J = 7.4 Hz, 2H), 1.59–1.49
(m, 4H), 1.32–1.22 (m, 10H), 0.88 (t, J = 7.0 Hz, 3H), 0.87 (t, J = 7.1, 3H). 13C{1H} NMR (151 MHz, CDCl3)
δ 210.7, 155.9 (d, J C-F = 245.0 Hz) 143.8 (d, J C-F = 1.5 Hz), 115.9 (d, J C-F = 22.3 Hz), 114.5 (d, J C-F = 7.4 Hz),
50.9, 46.9, 43.7, 35.3, 31.9, 29.3, 26.4, 25.8, 22.7, 22.4, 14.2, 13.9. IR max (solid/cm-1) 3361 (N-H), 2915
(C-H), 2822 (C-H), 1703 (C=O), 1601 (C=C), 1517 (C=C), 746. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C19H31FNO+, 308.2384; Found, 308.2385.
7-((3,5-Dimethylphenyl)amino)tridecan-5-one (1dc)
150 mg, 95%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 6.35 (s, 1H), 6.23 (s, 2H), 3.80 (m, 1H), 3.59 (br
s, 1H), 2.65 (dd, J = 16.3, 4.8 Hz, 1H), 2.54 (dd, J = 16.3, 6.8 Hz, 1H), 2.39 (m, 2H), 2.22 (s, 6H), 1.52 (m,
4H), 1.30 (m, 10H), 0.89 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 210.8,
147.4, 139.1, 119.5, 111.4, 49.9, 47.2, 43.6, 35.4, 31.9, 29.3, 26.3, 25.9, 22.7, 22.4, 21.6, 14.2, 14.0. IR
max (solid/cm-1) 3387 (N-H), 2952 (C-H), 2853 (C-H), 1704 (C=O), 1597 (C=C), 1463 (C=C), 819. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C21H36NO+, 318.2791; Found, 318.2797.
7-((4-Methoxyphenyl)amino)tridecan-5-one (1dd)
Propargylic alchohol 1a (98 mg, 0.5 mmol, 1 equiv) was dissolved in a mixture of toluene:MeOH (98:2,
0.5 mL), and PPh3AuNTf2 (8 mg, 2 mol%) was added into the reaction mixture. The mixture was stirred
for 5 h and then filtered through a silica pad. The solvent was removed in vacuo and anisidine (62 mg,
0.5 mmol, 1 equiv.) was added and the mixture was dissolved in toluene (0.2 mL) and heated to 50 °C
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overnight. The solvent was removed in vacuo and the product was purified by column chromatography
(EtOAc/Petrol) to give the amino ketone.
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149 mg, 94%, colourless oil, 1H NMR (400 MHz, CDCl3) δ 6.86–6.68 (m, 2H), 6.63–6.52 (m, 2H), 3.73 (s,
3H), 3.71 (m, 1H), 2.63 (dd, J = 16.2, 5.2 Hz, 1H), 2.53 (dd, J = 16.2, 6.4 Hz, 1H), 2.37 (t, J = 7.4 Hz, 2H),
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1.60–1.46 (m, 4H), 1.37–1.22 (m, 10H), 0.87 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.2, 3H). C{1H} NMR (101
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MHz, CDCl3) δ 210.9, 152.3, 141.5, 115.2, 115.0, 55.9, 51.2, 47.0, 43.6, 35.3, 31.8, 29.3, 26.3, 25.8, 22.7,
22.3, 14.1, 13.9. IR max (solid/cm-1) 3365 (N-H), 2925 (C-H), 1703 (C=O), 1508 (C=C), 1462 (C=C), 1233.
+
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H34NO2 , 320.2584; Found, 320.2587.
7-((3-(Trifluoromethyl)phenyl)amino)tridecan-5-one (1df)
126 mg, 71%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 7.23 (t, J = 7.9 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H),
6.77 (s, 1H), 6.73 (dd, J = 8.2, 2.0 Hz, 1H), 3.97 (br s, 1H), 3.86–3.77 (m, 1H), 2.66 (dd, J = 16.6, 5.0 Hz,
1H), 2.59 (dd, J = 16.6, 6.1 Hz, 1H), 2.39 (t, J = 7.4 Hz, 2H), 1.61–1.49 (m, 4H), 1.35–1.22 (m, 10H), 0.89
(t, J = 7.3 Hz, 3H), 0.88 (t, J = 7.1, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 210.4, 147.6, 131.8 (q, J C-F = 31.6
Hz), 129.9, 124.4 (q, J C-F = 272.4 Hz), 116.1, 113.8 (q, J = 3.9 Hz), 109.5 (q, J C-F = 3.9 Hz), 49.8, 46.6,
C-F
43.7, 35.2, 31.8, 29.3, 26.4, 25.8, 22.7, 22.4, 14.1, 13.9. IR max (solid/cm-1) 3378 (N-H), 2925 (C-H), 2855
(C-H), 1704 (C=O), 1612 (C=C), 1339 (C=C), 1119. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H31F3NO+,
358.2353; Found, 358.2352.
7-(o-Tolylamino)tridecan-5-one (1dg)
80 mg, 53%, colourless oil, 1H NMR (600 MHz, CDCl3) δ 7.10 (t, J = 8.3 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H),
6.66–6.57 (m, 2H), 3.91–3.83 (m, 1H), 2.70 (dd, J = 16.4, 4.8 Hz, 1H), 2.60 (dd, J = 16.4, 6.6 Hz, 1H), 2.40–
2.37 (m, 2H), 2.12 (s, 3H), 1.62–1.57 (m, 2H), 1.57–1.49 (m, 2H), 1.35–1.23 (m, 10H), 0.89 (t, J = 7.3, 3H),
0.88 (t, J = 7.3, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 210.8, 145.2, 130.4, 127.3, 122.3, 116.8, 110.1, 49.6,
47.0, 43.7, 35.4, 31.9, 29.3, 26.4, 25.8, 22.7, 22.4, 17.7, 14.2, 14.0. IR max (solid/cm-1) 3369 (N-H), 2924
(C-H), 2871 (C-H), 1705 (C=O), 1587 (C=C), 1489 (C=C), 767. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C20H34NO+, 304.2635; Found, 304.2639.
7-(Quinolin-6-ylamino)tridecan-5-one (1dj)
86 mg, 51%, pale brown oil. 1H NMR (600 MHz, CDCl3) δ 8.59 (dd, J = 4.2, 1.5 Hz, 1H), 7.88 (d, J = 7.9 Hz,
1H), 7.85 (d, J = 9.0 Hz, 1H), 7.28–7.20 (m, 1H), 7.05 (dd, J = 9.0, 2.6 Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 3.98–
3.92 (m, 1H), 2.73 (dd, J = 16.6, 4.8 Hz, 1H), 2.63 (dd, J = 16.6, 6.4 Hz, 1H), 2.43–2.34 (m, 2H), 1.64–1.58
(m, 2H), 1.56–1.49 (m, 2H), 1.43 (m, 1H), 1.34–1.21 (m, 9H), 0.89 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.3, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 210.6, 146.3, 145.3, 143.3, 133.9, 130.5, 130.3, 121.8, 121.5, 103.5,
49.9, 46.7, 43.8, 35.3, 31.9, 29.3, 26.4, 25.8, 22.69, 22.4, 14.2, 13.9. IR max (solid/cm-1) 3380 (N-H), 2952
(C-H), 2923 (C-H), 1703 (C=O), 1620 (C=C), 1517 (C=C), 1377, 826. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C22H33N2O+, 341.2587; Found, 341.2584.
1-Phenyl-3-(phenylamino)nonan-1-one (5da)
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143 mg, 93%, colourless oil, 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.59–7.51 (m, 1H), 7.50–7.42 (m,
2H), 7.20–7.13 (m, 2H), 6.74–6.66 (m, 1H), 6.62 (m, 2H), 4.03 (m, 1H), 3.77 (br s, 1H), 3.24 (dd, J = 16.6,
4.4 Hz, 1H), 3.13 (dd, J = 16.6, 6.9 Hz, 1H), 1.75–1.54 (m, 2H), 1.47 (m, 1H), 1.39 (m, 1H), 1.32–1.20 (m,
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6H), 0.87 (t, J = 6.8 Hz, 3H); C{1H} NMR (176 MHz, CDCl3) δ 199.7, 147.4, 137.4, 133.3, 129.5, 128.8,
128.2, 117.5, 113.5, 50.2, 42.9, 35.6, 31.9, 29.4, 26.5, 22.7, 14.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C21H28NO+, 310.2165; Found, 310.2168.
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1-Phenyl-3-(phenylamino)propan-1-one (7da)59
82 mg, 73%, colourless oil, 1H NMR (700 MHz, CDCl3) δ 7.95 (d, J = 7.7 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H),
7.46 (t, J = 7.5 Hz, 2H), 7.18 (t, J = 7.4 Hz, 2H), 6.71 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 7.8 Hz, 2H), 3.62 (t, J =
6.0 Hz, 2H), 3.29 (t, J = 6.0 Hz, 2H). 13C{1H} NMR (176 MHz, CDCl3) δ 199.5, 147.9, 136.9, 133.5, 129.5,
128.8, 128.2, 117.7, 113.2, 38.9, 37.8. IR max (solid/cm-1) 3403 (N-H), 3051 (C-H), 1675 (C=O), 1598 (C=C),
1504 (C=C), 1446.
1-Cyclohexyl-1-(phenylamino)heptan-3-one (14da)
127 mg, 89%, yellow oil; 1H NMR (700 MHz, CDCl3) δ 7.14 (m, 2H), 6.65 (t, J = 6.8 Hz, 1H), 6.58 (d, J = 7.9
Hz, 2H), 3.72 (m, 1H), 2.62 (dd, J = 16.2, 5.0 Hz, 1H), 2.56 (dd, J = 16.2, 6.3 Hz, 1H), 2.38 (t, J = 7.4 Hz, 2H),
2.05-1.86 (m, 2H), 1.75 (m, 3H), 1.68–1.61 (m, 3H), 1.50 (m, 3H), 1.26 (m, 3H), 1.23–1.15 (m, 1H), 0.86
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(t, J = 7.3 Hz, 3H); C{1H} NMR (176 MHz, CDCl3) δ 210.8, 147.8, 129.5, 117.2, 113.3, 54.7, 44.8, 43.4,
42.1, 29.7, 29.6, 26.6, 26.4, 25.9, 22.4, 14.0. IR max (solid/cm-1) 3492 (O-H), 2921 (C-H), 2849 (C-H), 1702
(C=O), 1598 (C=C), 1446 (C=C), 745. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H30NO+, 288.2322; Found,
288.2329.
1,1-Diethoxy-6-(phenylamino)dodecan-4-one (25da)
93 mg, 51%, colourless oil, 1H NMR (700 MHz, CDCl3) δ 7.15 (t, J = 7.4 Hz, 2H), 6.67 (t, J = 7.2 Hz, 1H),
6.58 (d, J = 7.9 Hz, 2H), 4.45 (t, J = 5.2 Hz, 1H), 3.85–3.79 (m, 1H), 3.65 (br s, 1H), 3.63–3.56 (m, 2H), 3.49–
3.40 (m, 2H), 2.67 (dd, J = 16.2, 5.0 Hz, 1H), 2.58 (dd, J = 16.2, 6.3 Hz, 1H), 2.49 (t, J = 7.2 Hz, 2H), 1.86
(m, 2H), 1.53 (m, 2H), 1.44–1.37 (m, 1H), 1.27 (m, 9H), 1.17 (t, J = 7.0 Hz, 6H), 0.86 (t, J = 6.8 Hz, 3H).
13C{1H} NMR (176 MHz, CDCl3) δ 209.9, 147.4, 129.5, 117.5, 113.5, 102.1, 61.8, 50.0, 47.27, 38.6, 35.4,
31.9, 29.4, 27.6, 26.4, 22.7, 15.4, 14.2. IR max (solid/cm-1) 3355 (N-H), 2914 (C-H), 2848 (C-H), 1698 (C=O),
1595 (C=C), 1469 (C=C), 1367, 1054 746. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H38NO3 , 290.2478;
Found, 290.2478.
+
Preparation of Heterocycles
The corresponding propargylic alcohol (0.5 mmol, 1 equiv.) and aniline (0.5 mmol, 1 equiv.) were
dissolved in CHCl3 (0.5 mL) and oven-dried molecular sieves were added to the mixture followed by
PPh3AuNTf2 (8 mg, 2 mol%). The reaction was stirred at room temperature until completion (TLC). Once
the reaction was complete, Et2O (1 mL) and NaCNBH3 (62 mg, 1 mmol, 2 equiv.) were added and the
reaction was stirred for 2 h at 0 °C. After this time the mixture was filtered and the solvent removed in
vacuo. The residue was dissolved in CH2Cl2:TFA (50:1, 2.5 mL) and NaBH4 (46 mg, 1.25 mmol, 2.5 equiv.)
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