Enantioselective alkynylation reactions to substituted benzaldehyde and salicylaldehyde derivatives: The effect of substituents upon the efficiency and enantioselectivity

Article abstract of DOI:10.1055/s-2007-966045

Asymmetric alkynylation reactions to mono-, di-, and trisubstituted aromatic aldehydes have been accomplished in good yields and with a range of selectivities. For salicylaldehyde derivatives both the yield and the enantioselectivity of the alkynylation r

Full text of DOI:10.1055/s-2007-966045

PAPER
1491
Enantioselective Alkynylation Reactions to Substituted Benzaldehyde and
Salicylaldehyde Derivatives: The Effect of Substituents upon the Efficiency
and Enantioselectivity
Enantioselective
l
Alkyn
i
ylation
z
Reactionsabeth Tyrrell,*a Kibur Hunie Tesfa,a Alastair Mann,a Kuldip Singhb
a
School of Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston, Surrey, KT1 2EE, UK
E-mail: e.tyrrell@kingston.ac.uk
Department of Chemistry, George Porter Building, University of Leicester, Leicester, LE1 7RH, UK
b
Received 6 December 2006
Abstract: Asymmetric alkynylation reactions to mono-, di-, and
trisubstituted aromatic aldehydes have been accomplished in good
yields and with a range of selectivities. For salicylaldehyde deriva-
tives both the yield and the enantioselectivity of the alkynylation re-
action appears to depend not only upon the electron-donating/
electron-withdrawing nature of substituents but also upon their po-
sition in the ring relative to the carbonyl. For benzaldehyde deriva-
tives this observation is exemplified with nitrobenzaldehyde
wherein asymmetric alkynylation with 3-nitrobenzaldehyde occurs
in virtually quantitative yield and enantioselectivity. In contrast our
attempts at asymmetric alkynylations with 4-nitrobenzaldehyde
failed.
i. Co2(CO)8
ii. HBF4
OH
F
R
R
iii. CAN
O
O
1
2
Scheme 1
O
H
R
Key words: asymmetric alkynylation reaction, aromatic aldehydes,
N-methylephedrine, substituent effects, position effects
O
3
Figure 1
The enantioselective addition of terminal alkynes to car-
bonyl compounds continues to attract significant interest1
largely attributed to the industrial importance of chiral
propargyl alcohols2 and their use in the enantioselective
synthesis of more complex molecules.3
that were present in the substrates based upon the salicyl-
aldehyde derivative 3 (Figure 1).
We have been unable to make any direct comparisons of
our results as most reported asymmetric alkynylation re-
actions are, in general, performed upon simpler monosub-
stituted benzaldehyde derivatives. Furthermore, as any
results that are disseminated tend to focus upon the appli-
cations of novel catalysts in asymmetric alkynylation re-
actions any slight variations in either the yields or the
enantiomeric excesses are overlooked and, thus, not com-
mented upon.
In recent years a focal point has been in the development
of novel catalysts based upon amino alcohols,4 oxazo-
lidines,5 a bis(hydroxycamphorsulfonamide)–copper(II)
complex,6 and Boc-proline.7 In an earlier communication8
we revealed a highly diastereoselective cobalt-mediated
synthesis of benzopyrans 2, from the propargyl alcohol 1,
using a novel variation of an intramolecular Nicholas
reaction9 in the key step (Scheme 1). The Nicholas reac-
tion is the reaction of a hexacarbonyldicobalt-complexed
propargyl carbocation with a nucleophile.
We were very keen to investigate the generality of any
causal link between substituent effects and enantiomeric
excess and the results of these studies are discussed here-
in.
Our interests in the chemistry of asymmetric alkynylation
reactions lay in the application of the resulting enantio-
merically pure propargyl alcohols for an enantiospecific
Nicholas reaction.10
Alkynylation reactions of benzaldehyde derivatives usu-
ally require longer reaction times, compared to nonaro-
matic aldehydes, and provide the corresponding propargyl
alcohols in good to excellent yields.1c The enantiomeric
excesses, however, are significantly lower and seldom ex-
ceed 93%12 with typical optimised values appearing in the
ranges 70–85%. The method of choice for effecting the
Most recently we disclosed the results from our investiga-
tions into a range of asymmetric alkynylation reactions of
aldehydes.11 During the course of our investigations we
observed that the enantioselectivity and, to a lesser de-
gree, the efficiency of the alkynylation reaction appeared
to be sensitive to the nature of the aromatic substituents
OH
O
i. Zn(OTf)2,
(+)-N-methylephedrine
Et3N, then
H
R
R
SYNTHESIS 2007, No. 10, pp 1491–1498
Advanced online publication: 02.05.2007
x
x.
x
x
.
2
0
0
7
Ph
ii. phenylacetylene
DOI: 10.1055/s-2007-966045; Art ID: P14606SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

1492
E. Tyrrell et al.
PAPER
asymmetric alkynylation reaction involves the addition of In our initial investigations we studied the influence of C2
a zinc acetylide to the aldehyde in the presence of a stoichi- substituents, based upon 3, on both the efficiency and enan-
ometric chiral ligand such as N-methylephedrine tioselectivity of the asymmetric alkynylation reaction and
(Scheme 2).12,13
compared these results with analogous substrates that were
Table 1 Comparative Asymmetric Alkynylation Reactionsa
Entry Propargyl alcohols 4–11
Yield (%)
ee (%)b
Entry
1b
Propargyl alcohols 12–19c
Yield (%) ee (%)b
H
HO
H
HO
1a
2a
3a
80d,e
81
89
55
63
45
25
23
Ph
Ph
OR
(R)-12g
(R)-4
(R)-5
H
HO
HO
H
78e
53
80
99
2b
3b
Ph
Ph
OR
(R)-13
H
HO
H
HO
Ph
Ph
MeO
MeO
OR
(R)-6
(R)-14
H
H
HO
HO
4a
5a
6a
7a
8a
97
98
90
92
98
83
85
99
99
99
4b
5b
6b
7b
8b
91
88
99
99
85
56
59
99
90
91
Ph
Ph
OR
OMe
(R)-15
HO
OMe
(R)-7
H
H
HO
Ph
Ph
OR
F
F
(R)-8
(R)-16g
H
H
HO
HO
F
F
Ph
Ph
OR
F
F
(R)-9
(R)-17
H
H
HO
HO
Cl
Cl
Ph
Ph
OR
Cl
Cl
(R)-10
(R)-18g
OH
H
H
HO
Br
Br
Ph
Ph
OR
Br
Br
(R)-19g
(S)-11f
a Unless otherwise stated, the reaction conditions were: 1. Zn(OTf)2, (+)-(1S,2R)-N-methylephedrine, Et3N, toluene; 2. phenylacetylene; 3. benz-
aldehyde derivative.
b The ee values were determined by HPLC with Chiralcel OD-H column and confirmed by NMR studies.
c R = CH2CH=CMe2.
d Optimised yields were obtained with 3 equiv of phenylacetylene.
e The yields were significantly increased with longer reaction times.
f (–)-(1R,2S)-N-Methylephedrine was used.
g From ref. 11.
Synthesis 2007, No. 10, 1491–1498 © Thieme Stuttgart · New York

PAPER
Enantioselective Alkynylation Reactions
1493
devoid of the C2 substituent. The results from these syn- between entries 3a and 3b reveal a significant 76% reduc-
theses for the propargyl alcohols 4–19 are summarised tion in the enantioselectivity. In contrast for the regioiso-
(Table 1).
mers, entries 4a/4b, the difference in enantiomeric excess
is less at 27%. Analysis of entries 1a/1b and 2a/2b again
reveal a significant 36% and 55% reduction in the enan-
tioselectivity of the asymmetric alkynylation reaction as a
consequence of the C2 substituent.
Provided a threefold excess of phenylacetylene was used
and the reaction maintained for seven days, very good
yields were obtained; a reaction time of 72 hours saw a
significant reduction in the yield. Comparison of these
data reveals some consistency in the yields apart from en- In general, the differences in the enantioselectivity be-
tries 3a and 3b, which are 30–40% less efficient than the tween aldehydes that contain two electron-withdrawing
corresponding isomers (4a and 4b). In general, the yields groups on the aromatic ring (entries 6–8), are less signifi-
for the asymmetric alkynylation reactions with halogenat- cant. Furthermore, the presence of two electron–with-
ed salicylaldehyde derivatives occur in excellent yields.
drawing groups on the ring provides enhanced levels of
enantioselectivity compared to only one halogen, i.e. en-
try 5b with 59% ee compared to 6b with 99% ee.
Analysis of the enantiomeric excess does, however, reveal
a notable difference. In all examples, except for entries 6a/
6b, a noticeable reduction in the enantioselectivity was Analysis of the data for entries 1a–8a reveal significant
observed for the C2-substituted propargyl alcohols. The differences in the efficiency of the alkynylations i.e. 53%,
difference is most noteworthy when the alkynylation reac- entry 3a compared to 98%, entry 8a. Likewise a 19% dif-
tions are performed with comparatively electron-rich de- ference in the enantioselectivity for the asymmetric alky-
rivatives. Thus comparison of the enantiomeric excesses nylation reaction was observed between the naphthyl
Table 2 Effect of Substituted Benzaldehyde Derivatives on the Efficiency and Enantioselectivity of the Asymmetric Alkynylation Reaction
O
HO
H
R1
R2
R1
R2
i. Zn(OTf)2,
H
(+)-N-methylephedrine
Et3N, then
Ph
+
Ph
ii. phenylacetylene
R3
4–26
R3
R1
R2
R3
Yield (%)
eea (%)
[a]D
25
Entry
Propargyl alcohols
4–26
1
2
(R)-4
H
H
H
H
H
H
H
H
H
H
F
H
H
80b
<10d
99
81
–
+5.0c
–
(R)-20
(R)-21
(R)-22
(R)-8
NO2
H
H
3
NO2
H
99
83
85
86
99
99
83
99
99
99
99
99
99
80
+27.0
+8.0
4
F
60
5
H
F
98
+10.0
+8.0
6
(R)-23
(R)-24
(R)-6
Cl
H
97
7
Br
OMe
H
H
97
+10.0
+4.0
8
H
53
9
(R)-7
OMe
H
97
+18.0
+10.0
+11.0
+14.0
–15.0e
–12.0e
+2.0
10
11
12
13
14
15
16
(R)-25
(R)-9
CF3
H
99
F
90
(R)-10
(S)-10
(S)-11
(R)-26
(R)-5
Cl
Cl
Br
H
H
Cl
Cl
Br
F
92
H
93
H
98
OMe
25
(CH=CH)2
H
78
–6.0
a The ee values were determined by HPLC with Chiralcel OD-H column and confirmed by NMR studies using chiral derivatising agents.
b Optimised yields were obtained with 3 equiv of phenylacetylene.
c (c 1, EtOH) in all examples except (R)-26 with CHCl3.
d Result repeated three times.
e (–)-N-Methylephedrine was employed.
Synthesis 2007, No. 10, 1491–1498 © Thieme Stuttgart · New York

1494
E. Tyrrell et al.
PAPER
derivative, entry 2a and the dibromo derivative, entry 8a. ceptions to this generalisation have been highlighted de-
In order to investigate the generality of these observa- spite its use with a variety of aromatic and nonaromatic
tions, we conducted a second study that looked at the ef- aldehydes. The structure of two propargyl alcohols syn-
fect of substituents present in the benzaldehyde derivative thesised during these investigations was confirmed by
on both the efficiency and enantioselectivity of the asym- single-crystal X-ray diffraction analysis (Figure 2).16
metric alkynylation reaction (Table 2).
The data for the asymmetric alkynylation reaction to benz-
aldehyde (Table 2, entry 1) will serve as a useful bench-
mark in our analyses. Thus, provided the alkynylation
reaction is left to run its course an optimised yield of 80%
was obtained (entry 1) with a similar outcome (78%) for
2-naphthaldehyde (entry 16). The enantiomeric excess for
these two examples were both an acceptable 80% and
81%. The effects of para substituents were most notewor-
thy with 4-nitrobenzaldehyde14 (entry 2) failing to under-
go reaction at all.15 In contrast, however, alkynylation of
3-nitrobenzaldehyde (entry 3) occurred in both a quantita-
tive yield and enantiomeric excess. With the 4-halogenat-
ed derivatives (entries 4, 6, 7) an increase in yield and
enantiomeric excess appears to correlate with a reduction
in the electronegativity of the substituent. Thus asymmet-
ric alkynylation of 4-fluorobenzaldehyde (entry 4) occurs
in a 60% yield and 83% ee. For the chloro and bromo de-
Figure 2 X-ray crystal structures of (i) (R)-15 and (ii) (R)-10.16
rivatives the yields are higher at 97% and the enantiomer-
ic excesses increasing from 86% (entry 6) to 99% for the
bromo derivative (entry 7). A comparison of 4-fluorobenz-
aldehyde (entry 4), with the corresponding meta deriva-
tive (entry 5) reveals a significant 38% enhancement in
yield and a modest improvement in the enantioselectivity
of the reaction. Propargylation of the 3,5-dihalogenated
benzaldehydes (entries 11–14) all occurred in excellent
yields and enantiomeric excesses, however, we again ob-
served an increase in the yield as the electronegativity of
the 3,5-substituents decreased. Interestingly the ideal sub-
strate, in terms of yield and enantiomeric excess, was 4-
(trifluoromethyl)benzaldehyde (entry 10), which provid-
ed the propargyl alcohol (R)-25 in virtually quantitative
yield and enantiomeric excess. In sharp contrast to this the
corresponding 4-fluoro derivative (entry 4) was notice-
ably less efficient. The combination of an electron-with-
drawing group at C3 and an electron-donating group at C4
of the aromatic ring (entry 15) leads to a significant reduc-
tion in the yield of the reaction, however, the product was
formed with excellent enantiomeric excess.
In our attempt to obtain suitable crystalline material for
these analyses, we synthesised both enantiomeric forms of
selected propargyl alcohols, (Table 2, entries 12, 13).17 In-
terestingly the 1H NMR spectra for the enantiomeric pro-
pargyl alcohols, (R)-10 and (S)-10, showed significant
differences, for example, we observed no coupling be-
tween the propargylic hydrogen atom and the hydroxy
group for the R-enantiomer (R)-10, however, a clear cou-
pling was observed with the corresponding S-enantiomer
(S)-10 (Figure 3).18
In summary, this paper describes a series of asymmetric
alkynylation reactions to provide a range of enantioen-
riched propargyl alcohols for use in attempted asymmetric
Nicholas cyclisation reactions.
As a general observation most alkynylation reactions that
appear in the current literature have been attempted with
relatively simple aliphatic aldehydes or benzaldehyde de-
rivatives. These have tended to focus upon the develop-
ment of a new ligand or catalyst for applications in
asymmetric alkynylation reactions with the emphasis on
optimising the activity of the reagent. Our contribution to
this area is in the use of more complex, aromatic alde-
hydes, where we have established that with use of an ex-
cess of the alkyne the desired propargylic alcohols are
accessible in good to excellent yield. We observed that for
alkynylations performed upon C2-substituted aldehydes,
such as 3 (Table 1), both the enantioselectivity and the ef-
ficiency of the reaction may be compromised by the posi-
tion of substituents on the aromatic ring. The presence of
a dihalogenated ring was accompanied by optimum levels
of enantioselectivity and overall conversions.
For electron-rich aromatics, we observed that the efficien-
cy again depended upon the position in the ring of the sub-
stituent. Thus although p-anisaldehyde (entry 8)
underwent asymmetric alkynylation with a high degree of
enantioselectivity, the yield was only a modest 53%. In
contrast m-anisaldehyde (entry 9), provided the propargyl
alcohol (R)-7 in excellent yield (97%) but a somewhat re-
duced enantiomeric excess.
Carreira13 has developed a correlation between the ob-
served configuration of the resulting chiral centre and the
choice of chiral ligand. Thus with the use of (+)-N-meth-
ylephedrine the resulting propargyl alcohols are formed
with R-configuration. In contrast (–)-N-methylephedrine
provides the corresponding S-enantiomer. To date no ex-
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Enantioselective Alkynylation Reactions
1495
Figure 3 1H NMR spectrum of (R)-10 (upper spectrum) and (S)-10 (lower spectrum).
All compounds provided satisfactory spectral data that were consis-
tent with the assigned structures. Optical rotation data and HPLC re-
tention times are included for all relevant examples. The syntheses
and spectral characteristics of compound (R)-12–(R)-15 and (R)-18,
(R)-19 are available in a previous publication.11
With benzaldehyde derivatives (Table 2) the outcomes
are more polarised, such that alkynylations with the p-ni-
tro derivative failed whereas the corresponding meta de-
rivative underwent smooth alkynylation in quantitative
yield and enantiomeric excess. In contrast to the situation
with the p-nitro group, the corresponding trifluoromethyl
derivative (entry 10) underwent smooth alkynylation in
quantitative yield and enantiomeric excess. Apart from
entry 2, all the alkynylation reactions occurred with high
levels of enantioselectivity.
(+)-(1R)-1,3-Diphenylprop-2-yn-1-ol [(R)-4]; Typical Proce-
dure
A 100-mL flask was charged with Zn(OTf)2 (2.6427 g, 7.27 mmol,
1.1 equiv) and (+)-(1S,2R)-N-methylephedrine (1.4215 g, 7.93
mmol, 1.2 equiv) and purged with N2 for 15 min whereupon toluene
(52 mL) and Et3N (2.20 mL, 1.6048 g, 15.86 mmol, 2.4 equiv) was
added via syringe. The resulting mixture was left to stir for 2 h be-
fore the phenylacetylene (2.18 mL, 2.0254 g, 19.83 mmol, 3.0
equiv) was added by syringe in one portion. After 15 min of stirring
benzaldehyde (0.701 g, 6.61 mmol, 1 equiv) was added in one por-
tion. After completion, 7 d, the reaction was quenched by the addi-
tion of sat. NH4Cl soln (38 mL). The mixture was extracted with
Et2O (3 × 40). The combined organic layers were washed sequen-
tially with sat. NH4Cl soln (100 mL) and brine (100 mL), dried (an-
hyd MgSO4), filtered, and concentrated in vacuo to afford the crude
product. Purification by chromatography (silica gel) gave (R)-4 as a
low melting point yellow crystalline solid; yield: 1.10 g (80%); 81%
ee; HPLC analysis (Chiralcel OD-H, 10% i-PrOH–hexane, 254
nm): tR = 15.06 (major), 24.09 min (minor); mp 35.5–36.6 °C.
Melting point determinations were recorded using a Stuart Scientif-
ic SMP3 digital melting point apparatus tube apparatus and are un-
corrected. IR spectra were recorded on a Perkin-Elmer 1600 series
FTIR spectrophotometer and were calibrated using a standard poly-
styrene film. The spectra were recorded either as thin films for liq-
1
uids, between NaCl discs or for solids as a Nujol mull. H NMR
were recorded at 400 MHz using a JEOL Eclipse 400 MHz spec-
trometer with TMS as internal standard. 13C NMR were recorded at
100 MHz on a JEOL Eclipse 400 MHz spectrometer using CDCl3
as internal standard. LR-MS were recorded on a VG TRIO-2 mass
spectrometer under EI (70 eV) and/or with a Hewlett Packard GC-
MS HP5890 (GC) with capillary column and HP 5971 (MS). Accu-
rate mass analyses were performed and reported on a VG-ZAB-E
by the EPSRC National Mass Spectrometry Service Centre
(Swansea) using the EI Peak Match on M+ method. Enantiomeric
excesses were measured by an HPLC method (Chiralcel OD-H col-
umn) using Waters 996 photodiode array diode detector.
[a]D25 +5 (c 1, EtOH).
IR (thin film): 3332, 2230, 1598, 1490 cm–1.
Synthesis 2007, No. 10, 1491–1498 © Thieme Stuttgart · New York

1496
E. Tyrrell et al.
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1H NMR (400 MHz, CDCl3): d = 7.64–7.61 (m, 2 H, H-Ar), 7.50–
7.47 (m, 2 H, H-Ar), 7.44–7.29 (m, 6 H, H-Ar), 5.70 (d, 1 H, J = 5.8
Hz, H-CPh), 2.38 (d, 1 H, J = 5.8 Hz, OH).
1H NMR (400 MHz, CDCl3): d = 7.50 (dd, J = 0.6, 2.1 Hz, 2 H, H-
Ar), 7.49–7.46 (m, 2 H, H-Ar), 7.39–7.31 (m, 4 H, H-Ar), 5.65 (s, 1
H, H-Ph), 2.46 (br s, 1 H, OH).
13C NMR (100 MHz, CDCl3): d = 140.72, 131.86 (2), 128.79 (2),
128.72, 128.57 (2), 128.42 (2), 128.85, 122.49, 88.78, 86.78, 65.17.
13C NMR (100 MHz, CDCl3): d = 143.84, 135.26 (2), 131.91 (2),
129.11, 128.54, 128.51 (2), 125.30 (2), 121.87, 87.57, 87.39, 63.95.
HRMS: m/z [M – H]+ calcd for C15H11O: 207.0804; found:
HRMS: m/z [M – H]+ calcd for C15H9Cl2O: 275.0025; found:
207.0807.
275.0024.
UV (i-PrOH): lmax = 240.5 nm.
(–)-(1S)-1-(3,5-Dichlorophenyl)-3-phenylprop-2-yn-1-ol [(S)-
10]
Compound (S)-10 was synthesised according to the typical proce-
dure using (–)-(1R,2S)-N-methylephedrine and was isolated as
white needles; yield: 93%; 99.8% ee; HPLC (Chiralcel OD-H, 10%
i-PrOH–hexane, 254 nm): tR = 9.80 (minor), 61.35 min (major); mp
86.7–87.1 °C (hexane).
[a]D25 –15 (c 1.0, EtOH).
1H NMR (400 MHz, CDCl3): d = 7.50 (dd, J = 0.7, 2.0 Hz, 2 H, H-
Ar), 7.48–7.46 (m, 2 H, H-Ar), 7.39–7.31 (m, 4 H, H-Ar), 5.64 (d,
J = 6.0 Hz, 1 H, H-Ph), 2.41 (d, J = 6.0 Hz, 1 H, OH).
(–)-(1R)-1-(2-Naphthyl)-3-phenylprop-2-yn-1-ol [(R)-5]
Compound (R)-5 was synthesised according to the typical proce-
dure and was isolated as a white solid; yield: 78%; 80% ee; HPLC
(Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 17.28 (ma-
jor), 57.56 min (minor); mp 106.3–107.6 °C.
[a]D25 –6 (c 1, EtOH).
HRMS: m/z [M]+ calcd for C19H14O: 258.1039; found: 258.1037.
UV (i-PrOH): lmax = 221.7 nm.
(+)-(1R)-1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-ol [(R)-6]
Compound (R)-6 was synthesised according to the typical proce-
dure and was isolated as white needles; yield: 53%; 99% ee; HPLC
(Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 13.57 (ma-
jor), 28.08 min (minor); mp 95.5–95.8 °C.
13C NMR (100 MHz, CDCl3): d = 143.85, 135.25 (2), 131.91 (2),
129.10, 128.53, 128.50 (2), 125.29 (2), 121.87, 87.58, 87.39, 63.96.
HRMS: m/z [M – H]+ calcd for C15H9Cl2O: 275.0025; found:
275.0024.
[a]D25 +4 (c 1, EtOH).
HRMS: m/z [M]+ calcd for C16H14O2: 238.0988; found: 238.0985.
(–)-(1S)-1-(3,5-Dibromophenyl)-3-phenylprop-2-yn-1-ol [(S)-
11]
Compound (S)-11 was synthesised according to the typical proce-
dure using (–)-(1R,2S)-N-methylephedrine and was isolated as fine
white needles; yield: 98%; 99.9% ee; HPLC (Chiralcel OD-H, 10%
i-PrOH–hexane, 254 nm): tR = 31.11 min (major); mp 95.4–95.7 °C.
[a]D25 –12 (c 1.0, EtOH).
HRMS: m/z [M – H]+ calcd for C15H9Br2O: 363.9093; found:
UV (i-PrOH): lmax = 240.5 nm.
(+)-(1R)-1-(3-Methoxyphenyl)-3-phenylprop-2-yn-1-ol [(R)-7]
Compound (R)-7 was synthesised according to the typical proce-
dure and was isolated as a yellow oil; yield: 97%; 83% ee; HPLC
(Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 15.57 (ma-
jor), 26.32 min (minor).
363.9095.
[a]D25 +18 (c 1, EtOH).
HRMS: m/z [M]+ calcd for C16H14O2: 238.0988; found: 238.0985.
(+)-(1R)-1-{3-Fluoro-2-[(3-methylbut-2-enyl)oxy]phenyl}-3-
phenylprop-2-yn-1-ol [(R)-16]11
Compound (R)-16 was synthesised according to the literature
procedure11 and isolated as a low-melting-point waxy solid; yield:
88%; 59% ee; HPLC (Chiralcel OD-H, 10% i-PrOH–hexane, 254
nm): tR = 7.31 (minor), 11.36 min (major).
[a]D25 +9.0 (c 1, CHCl3).
IR (neat): 3414, 2228, 1672,1602, 1476, 1270 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.47–7.44 (m, 2 H, H-Ar), 7.40–
7.37 (m, 1 H, ArH), 7.33–7.29 (m, 3 H, ArH), 7.11–7.02 (m, 2 H,
ArH), 5.88 (d, J = 6.6 Hz, 1 H, HCPh), 5.61–5.56 (m, 1 H, C=CH),
4.74 (d, J = 7.3 Hz, 2 H, CH2), 3.11 (d, J = 6.6 Hz, 1 H, OH), 1.77
(s, 3 H, CH3), 1.71 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 156.76, 154.30, 139.94, 135.77,
131.78 (2), 128.63, 128.37 (2), 123.88, 123.19, 122.59, 119.79,
117.19, 88.59, 86.28, 70.77, 61.59, 25.91, 18.13.
(+)-(1R)-1-(3-Fluorophenyl)-3-phenylprop-2-yn-1-ol [(R)-8]
Compound (R)-8 was synthesised according to the typical proce-
dure and was isolated as white needles; yield: 98%; 85% ee; HPLC
(Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 10.31 (ma-
jor), 25.23 min (minor); mp 43.4–44.5 °C.
[a]D25 +10 (c 1, EtOH).
HRMS: m/z [M – H]+ calcd for C15H10FO: 225.0710; found:
225.0710.
(+)-(1R)-1-(3,5-Difluorophenyl)-3-phenylprop-2-yn-1-ol [(R)-9]
Compound (R)-9 was synthesised according to the typical proce-
dure and was isolated as white needles; yield: 90%; 99.8% ee;
HPLC (Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 10.25
min (major); mp 79.8–80.4 °C.
[a]D25 +11 (c 1, EtOH).
HRMS: m/z [M – H]+ calcd for C15H9F2O: 243.0616; found:
HRMS: m/z [M + NH4]+ calcd for C20H19FO2·NH4: 328.1707;
found: 328.1708.
243.0616.
UV (i-PrOH): lmax = 241.7 nm.
(+)-(1R)-1-(3,5-Dichlorophenyl)-3-phenylprop-2-yn-1-ol [(R)-
10]
Compound (R)-10 was synthesised according to the typical proce-
dure and was isolated as white needles; yield: 92%; 99.7% ee;
HPLC (Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 9.69
(major), 14.31 min (minor); mp 90.5–90.7 °C.
(+)-(1R)-1-{3,5-Difluoro-2-[(3-methylbut-2-enyl)oxy]phenyl}-3-
phenylprop-2-yn-1-ol [(R)-17]11
Compound (R)-17 was synthesised according to the literature
procedure11 as fine white hair-like crystals; yield: 99%; 99% ee;
HPLC (Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 7.15
(minor), 10.89 min (major); mp 65.4–65.6 °C (hexane).
[a]D25 +14 (c 1.0, EtOH).
[a]D25 +38.0 (c 1, CHCl3).
Synthesis 2007, No. 10, 1491–1498 © Thieme Stuttgart · New York

PAPER
Enantioselective Alkynylation Reactions
1497
IR (neat): 3412, 2228, 1672, 1602, 1488, 1210 cm–1.
(+)-(1R)-1-(3-Fluoro-4-methoxyphenyl)-3-phenylprop-2-yn-1-
ol [(R)-26]
Compound (R)-26 was synthesised according to the typical proce-
dure and isolated as white needles; yield: 25%; 99% ee; HPLC
(Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 14.09 (ma-
jor), 39.09 min (minor); mp 67.5–67.8 °C.
[a]D25 +2 (c 1, CHCl3).
HRMS: m/z [M]+ calcd for C16H13FO2: 256.0894; found: 256.0892.
1H NMR (400 MHz, CDCl3): d = 7.47–7.43 (m, 2 H, ArH), 7.36–
7.29 (m, 3 H, ArH), 7.17 (ddd, J = 1.8, 2.7, 8.6 Hz, 1 H, ArH), 6.84
(ddd, J = 3.1, 8.0, 11.2 Hz, 1 H, ArH), 5.88 (d, J = 6.0 Hz, 1 H, H-
CPh), 5.58–5.53 (m, 1 H, C=CH), 4.67 (d, J = 8.0 Hz, 2 H, CH2),
2.97 (d, J = 6.0 Hz, 1 H, OH), 1.77 (s, 3 H,CH3), 1.70 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 207.39, 159.57, 156.51, 140.26,
136.82, 131.80 (2), 128.82, 128.41 (2), 122.27, 119.53, 109.91,
104.99, 87.87, 86.60, 70.93, 60.85, 25.90, 18.90.
UV (i-PrOH): lmax = 240.5 nm.
HRMS: m/z [M + NH4]+ calcd for C20H18F2O2·NH4: 346.1613;
found: 346.1614.
Acknowledgment
UV (i-PrOH): lmax = 241.7 nm.
The authors wish to thank the EPSRC National Mass Spectrometry
Service Centre, University of Swansea for High Resolution Mass
Spectra.
(+)-(1R)-1-(3-Nitrophenyl)-3-phenylprop-2-yn-1-ol [(R)-21]
Compound (R)-21 was synthesised according to the typical proce-
dure and isolated as a yellow oil; yield: 99%; 99.7% ee; HPLC
(Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 17.14 min
(major),
References
[a]D25 +27 (c 1, EtOH).
HRMS: m/z [M – H]+ calcd for C15H10NO3: 252.0655; found:
(1) (a) Pu, L. Tetrahedron 2003, 59, 9873. (b) Gao, G.; Xie, R.-
G.; Pu, L. Proc. Natl. Acad. Sci. U.S.A. 2004, 15, 5417.
(c) Xu, Z.; Chen, C.; Xu, J.; Miao, M.; Yan, W.; Wang, R.
Org. Lett. 2004, 6, 1193. (d) Lu, G.; Li, Y.-M.; Li, X.-S.;
Chan, A. S. C. Coord. Chem. Rev. 2005, 249, 1736.
(2) Modern Acetylene Chemistry; Strang, P. J.; Diederich, F.,
Eds.; VCH: Weinheim, 1995.
(3) (a) Nicolaou, K. C.; Webber, S. E. J. Am. Chem. Soc. 1984,
106, 5734. (b) Vourloumis, D.; Kim, K. D.; Petersen, J. L.;
Margriotis, P. A. J. Org. Chem. 1996, 61, 4848.
(4) (a) Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.;
Reider, P. J. Synthesis 1999, 1453. (b) Lu, G.; Zhou, Z.;
Chan, W. L.; Chan, A. S. C. Tetrahedron: Asymmetry 2001,
12, 2147. (c) Watt, C. C.; Thoniyot, P.; Hirayama, L. C.;
Romano, T.; Singaram, B. Tetrahedron: Asymmetry 2005,
16, 1829. (d) Pizzuti, M. G.; Superchi, S. Tetrahedron:
Asymmetry 2005, 16, 2263. (e) Trost, B. M.; Weiss, A. H.;
von Wangelin, A. J. J. Am. Chem. Soc. 2006, 128, 8.
(5) (a) Kang, Y.-f.; Wang, R.; Liu, L.; Da C, s.; Yan, W.-j.; Xu,
Z.-q. Tetrahedron Lett. 2005, 46, 863. (b) Braga, A. L.;
Appelt, H. R.; Silveira, C. C.; Wessjohann, L. A.; Schneider,
P. H. Tetrahedron 2002, 58, 10413.
(6) Liu, L.; Wang, R.; Kang, Y.-F.; Cai, H.-Q.; Chen, C. Synlett
2006, 1245.
(7) Zhou, Y.-f.; Wang, R.; Xu, Z.-q.; Yan, W.-j.; Lei, L.; Gao,
Y.-f.; Da, C.-s. Tetrahedron: Asymmetry 2004, 15, 589.
(8) Mann, A.; Muller, C.; Tyrrell, E. J. Chem. Soc., Perkin
Trans. 1 1998, 1427.
(9) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207.
(10) Muehldorf, A. V.; Guzman-Perez, A.; Kluge, A. F.
Tetrahedron Lett. 1994, 35, 8755.
252.0656.
(+)-(1R)-1-(4-Fluorophenyl)-3-phenylprop-2-yn-1-ol [(R)-22]
Compound (R)-22 was synthesised according to the typical proce-
dure and isolated as white needles; yield: 60%; 83% ee; HPLC
(Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 9.95 (major),
23.54 min (minor); mp 38.8–39.3 °C.
[a]D25 +8 (c 1, EtOH).
HRMS: m/z [M]+ calcd for C15H11FO: 226.0788; found: 226.0788.
(+)-(1R)-1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-ol [(R)-23]
Compound (R)-23 was synthesised according to the typical proce-
dure and isolated as a yellow crystalline solid; yield: 97%; 86% ee;
HPLC (Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 10.91
(major), 32.95 min (minor); mp 58.5–59.3 °C.
[a]D25 +8 (c 1, EtOH).
HRMS: m/z [M]+ calcd for C15H11OCl: 242.0493; found: 242.0492.
UV (i-PrOH): lmax = 240.5 nm.
(+)-(1R)-1-(4-Bromophenyl)-3-phenylprop-2-yn-1-ol [(R)-24]
Compound (R)-24 was synthesised according to the typical proce-
dure and isolated as a white crystalline solid; yield: 97%; 99% ee;
HPLC (Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 11.55
(major), 37.03 min (minor); mp 68.8–71.3 °C.
[a]D25 +10 (c 1, EtOH).
HRMS: m/z [M – H]+ calcd for C15H10BrO: 284.9910; found:
(11) Tyrrell, E.; Tesfa, K. H.; Millet, J.; Muller, C. Synthesis
2006, 3099.
(12) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4,
2605.
(13) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem.
Soc. 2000, 122, 1806. (b) Anand, N. K.; Carreira, E. M. J.
Am. Chem. Soc. 2002, 124, 2605.
(14) The effects of ortho substituents upon yield and
enantiomeric excess has recently been highlighted.4e With a
dinuclear Zn catalyst and Me2Zn a yield of 91% was
recorded for the analogous reaction.
284.9912.
UV (i-PrOH): lmax = 251, 242 nm.
(+)-(1R)-3-Phenyl-1-[4-(trifluoromethyl)phenyl]prop-2-yn-1-ol
[(R)-25]
Compound (R)-25 was synthesised according to the typical proce-
dure and isolated as a white powder; yield: 99.9%; 99% ee; HPLC
(Chiralcel OD-H, 10% i-PrOH–hexane, 254 nm): tR = 9.75 (major),
32.86 min (minor); mp 70.4–70.7 °C.
[a]D25 +10 (c 1, EtOH).
HRMS: m/z [M]+ calcd for C16H11F3O: 276.0757; found: 276.0756.
(15) This reaction was repeated 3 times with the same result.
Interestingly, exposure of the same aldehyde to
phenylethynylmagnesium bromide gave the racemic
propargyl alcohol in a modest 30% yield.
UV (i-PrOH): lmax = 240.5 nm.
Synthesis 2007, No. 10, 1491–1498 © Thieme Stuttgart · New York

1498
E. Tyrrell et al.
PAPER
significant difference in crystal morphology between
(16) CCDC 628668 [(R)-10] and CCDC 628669 [(R)-15] contain
the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
enantiomeric propargyl alcohols.
(18) In addition to the differences in the 1H NMR spectra of these
enantiomers, we observed differences in mp 90.5–90.7 °C
(R-enantiomer) and 86.7–87.1 °C (S-enantiomer) and the
corresponding HPLC retention time tR = 9.69 (major), 14.31
min (minor) R-enantiomer and tR = 61.35 (major), 9.80 min
(minor) S-enantiomer.
www.ccdc.cam.ac.uk/data_request/cif.
(17) We have used both forms of N-methylephedrine in some
selected examples in our studies in an attempt to obtain
crystals suitable for X-ray analysis. We observed a
Synthesis 2007, No. 10, 1491–1498 © Thieme Stuttgart · New York