Enantioselective alkynylation reactions to aldehydes: The effects of aromatic substituents upon the enantioselectivity

Article abstract of DOI:10.1055/s-2006-950205

Asymmetric alkynylation reactions to linear alkyl and substituted aromatic aldehydes have been accomplished in good yields and with a range of selectivities. For aromatic aldehydes we observed that the selectivity of the alkynylation reaction appears to d

Full text of DOI:10.1055/s-2006-950205

PAPER
3099
Enantioselective Alkynylation Reactions to Aldehydes: The Effects of
Aromatic Substituents upon the Enantioselectivity
E
nantioselective
l
Alkyn
i
ylation
z
Reactions
a
to Aldehyd
b
es eth Tyrrell,* Kibur Hunie Tesfa, Julien Millet, Christophe Muller
School of Pharmacy and Chemistry, Kingston University, Penrhyn Road, Kingston, Surrey, KT1 2EE, UK
Fax +44(20)85477562; E-mail: e.tyrrell@kingston.ac.uk
Received 19 April 2006
in 1994.6 In the same year the rapid racemisation of a co-
balt-stabilised cation was exploited to afford a stereose-
lective synthesis of fused-ring systems.7
Abstract: Asymmetric alkynylation reactions to linear alkyl and
substituted aromatic aldehydes have been accomplished in good
yields and with a range of selectivities. For aromatic aldehydes we
observed that the selectivity of the alkynylation reaction appears to
depend upon the substituents on the aromatic ring. Thus with elec-
tron-withdrawing substituents both the yield and enantioselectivi-
ties were good to excellent. In contrast to this, the presence of
electron-donating groups provided excellent conversions; however,
these were coupled with poor enantioselectivities.
Chiral propargyl alcohols may be prepared via the asym-
metric reduction of ynones8 or from the asymmetric addi-
tion of alkynes to aromatic aldehydes.9 Although the
catalytic enantioselective addition reaction of dialkyl and
alkenyl zinc reagents to aldehydes may be carried out ef-
ficiently, using a wide range of catalysts, advancements
with the corresponding asymmetric alkynylation reaction
appears to be far less developed.10 The major limitations
seem to be based upon a combination of factors such as
the need to employ stoichiometric amounts of catalyst/
ligand, limitations in the availability of appropriate re-
agents such as chiral ligands and, in some examples, the
production of significant quantities of by-products.11
Key words: asymmetric alkynylation reaction, aromatic aldehydes,
N-methylephedrine, organozinc, substituent effects, citronellal
In a recent paper1 we revealed a diastereoselective cobalt-
mediated synthesis of benzopyrans using a novel variation
of an intramolecular Nicholas2 reaction in the key step.
Using this chemistry we were able to access a number of
functionalised benzopyran derivatives 2, which were then
subsequently screened against cromakalim3 3, a known
modulator of potassium channels (Scheme 1).
From our inspection of the existing literature, in this inter-
esting area of asymmetric synthesis, we were able to cor-
roborate the inconsistencies in the percentage yields and/
or enantioselectivities for asymmetric alkynylation reac-
tions. For instance with aldehydes such as 4 (Figure 1),
with R = alkyl, good to excellent yields for the alkynyla-
tion reaction have been reported with enantiomeric excess
(ee) ranging from good 79%12 to excellent 99%.13 With
benzaldehyde derivatives, based upon 5, longer reaction
times appear to be the norm affording the corresponding
propargyl alcohols in good to excellent yields.14,15 As a
general observation the enantiomeric excesses recorded
for benzaldehyde derivatives are significantly lower than
the previous examples. These seldom exceed 93%13c and
typical optimised values appear in the 70–85% range. Sig-
nificantly fewer examples of asymmetric alkynylation
reactions to derivatives based upon 6 have been forth-
coming. In general the selectivity of alkynylations with
substrates such as these provide lower levels of enantio-
In our efforts to achieve an enantioselective Nicholas
reaction4 we have focussed upon the synthesis of optically
active propargyl alcohols, based upon 1, for use in
benzopyran synthesis. The ability to transfer the stereo-
chemical information, contained within a dicobalt hexa-
carbonyl complexed chiral propargyl alcohol, into the
resulting product still remains a challenge to the synthetic
chemist. This limitation has been explained by the flux-
ional nature of a cobalt-stabilised carbocation that ex-
poses both faces to the incoming nucleophile5 thus leading
to racemisation. One solution to this racemisation process
lies in the ability to rapidly quench the cation before delo-
calisation effects take place. The first example of an enan-
tiospecific Nicholas reaction, a process which provided
chiral products from chiral substrates, was disseminated
O
CH3
CH3
i. Co2(CO)8
ii. HBF4
iii. CAN
N
NC
OH
OH
R
F
R
O
O
O
1
2
3
Scheme 1
SYNTHESIS 2006, No. 18, pp 3099–3105
x
x.
x
x
.
2
0
0
6
Advanced online publication: 21.08.2006
DOI: 10.1055/s-2006-950205; Art ID: P04806SS
© Georg Thieme Verlag Stuttgart · New York

3100
E. Tyrrell et al.
PAPER
selectivity. Thus when R2 = Cl, Br or NO2 yields of 95%
and ee values of 89% have been recorded.14 However for
R2 = OMe or Me, results have varied between yields of
70% with ee values of 37–69%12 to 82–90% yields with
71–74% ee.14
OH
Zn(OTf)2, toluene,
O
R
Et3N, (–)-N-methylephedrine
R
8a–d
H
As far as we have been able to ascertain few if any exam-
ples that have focused upon the asymmetric alkynylation
reaction of O-substituted derivatives, based upon 7, have
been revealed.
OH
Zn(OTf)2, toluene,
Et3N, (+)-N-methylephedrine
R
R
8e–f
O
up to 98% de
O
H
R
R
Scheme 2
H
H
4
5
The important stereochemical outcome, resulting from re-
actions such as these, have been systematically correlated
by the Carreira group and shown to be highly dependant
upon the choice of chiral ligand. Thus addition reactions
using (+)-N-methylephedrine affords adducts exclusively
with a R configuration whereas (–)-N-methylephedrine
affords the corresponding adduct with a S configuration.
To date no exceptions to this generalisation have been
highlighted despite its use with a variety of different aro-
matic and non-aromatic aldehydes. The results from these
propargylation reactions are summarised in Table 1.
O
O
O
H
H
R
R
R2
6
7
Figure 1
As well as attempting the asymmetric synthesis of propar-
gyl alcohols using analogues of 7, to serve as cyclisation
precursors in an intramolecular Nicholas reaction, we also
focused upon compounds based upon 8a–8f. The main ad-
vantages with these substrates are that they are readily ac-
cessible from citronellal. In addition we have previously
shown that the racemic analogues readily undergo in-
tramolecular Nicholas cyclisation reactions.16 The method
of choice for effecting the asymmetric alkynylation reac-
tion was the procedure described by Carreira.13c This in-
volves the addition of a zinc acetylide, derived from zinc
triflate, to the aldehyde in the presence of a stoichiometric
amount of a chiral ligand (Scheme 2).
In comparison to the corresponding racemic alkynylation
reaction (2 h, 95–98% yield), the picture that emerges
from these data is that the use of an alkynylzinc reagent,
in the presence of a chiral ligand, tends to favour longer
reaction times, typically about 30 hours, coupled with a
reduction in yield. However, good to excellent levels of
diastereoselectivity are observed regardless of the nature
of the alkyne. With regard to the stereochemistry of the re-
sulting propargyl alcohols we have tentatively assigned
the configuration on the basis of the literature precedent.
Table 1 Optically Active Propargylic Alcohols Obtained from (–)-(S)-Citronellala
Entry
Alkyne
Ligand
Yield (%)
% deb
85
Ph
1
2
8a
8b
(–)-N-Methylephedrine
(–)-N-Methylephedrine
66
65
86
H3C
3
4
8c
(–)-N-Methylephedrine
(–)-N-Methylephedrine
58
70
98
84
TMS
8d
CH3O
5
6
8e
8f
(+)-N-Methylephedrine
(+)-N-Methylephedrine
65
55
92
91
Ph
H3C
a Alkynylation of (–)-(S)-citronellal, in the absence of a chiral ligand, gave a 45:55 ratio of diastereoisomers.
b The de values were calculated using GC–MS as well as from a measurement of the integrals obtained from the corresponding 1H NMR spec-
trum of the reaction mixture. The results obtained from these NMR studies corroborated well with data obtained from the Mosher ester17 of the
corresponding diastereomeric mixture.
Synthesis 2006, No. 18, 3099–3105 © Thieme Stuttgart · New York

PAPER
Enantioselective Alkynylation Reactions to Aldehydes
3101
O
Interestingly the analogous racemic propargylation reac-
tion with phenylethynylmagnesium bromide provided the
corresponding propargyl alcohol in high yield (< 95%) in
about two hours.
O
O
R
H
R
H
Br
K2CO3, Kl, DMF
R1
OH
R1
R2
Predictably long reaction times were indeed necessary in
order to obtain the corresponding chiral propargyl alco-
hols; however, the efficiency of the reaction in terms of
the yield and the levels of enantioselectivity varied con-
siderably (compare entries 3 and 5 with entry 4, Table 2).
The picture that emerges from these data is that the forma-
tion of a chiral complex, involving a zinc alkyne, a zinc-
aldehyde complex and the chiral ligand, leads to a consid-
erable increase in the time required for efficient conver-
sion to the chiral propargyl alcohol compared to the
corresponding racemic synthesis. Despite the fact that the
percentage yields for the alkynylations are good to excel-
lent (55–99% yields) the same is not true for the corre-
sponding enantioselectivities and here significant
differences manifest themselves. Thus, the presence of
electron-donating groups on the aromatic ring appears to
reduce the enantioselectivity to the level observed for 10a
(Table 2, entries 3 and 5). However when the methoxy
group is positioned para to the carbonyl, i.e. R1 = OMe,
the ee is halved to 23% (Table 2, entry 4). In contrast to
this observation when R is electron-withdrawing NO2, Cl
or Br, (Table 2, entries 6–8) there is an accompanying en-
hancement in the ee values, which are enhanced even fur-
ther when both R and R2 are halogens (Table 2, entries 9
and 10). For alkynylations with naphthyl derivatives (en-
try 11), the enantioselectivity is comparable to that ob-
served with a p-methoxy group (entry 4).
r.t., 2 h
87–99%
R2
9
10a–i
H
O
H
O
O
OH
Br
K2CO3, Kl, DMF
r.t., 2 h
87%
11
Scheme 3
Thus for the propargyl alcohols, entries 1–4 in Table 1, we
have assigned a S stereochemistry and entries 5 and 6 as R.
A range of additional aldehydes, 10a–i and 11, based
upon 7, were obtained very efficiently via an O-alkylation
of the corresponding salicylaldehyde derivative 9 or naph-
thyl derivative (Scheme 3).
With these aldehydes in hand we were able to investigate
the corresponding asymmetric addition reactions to afford
propargyl alcohols 12 and 13 (Scheme 4).
From our interpretation of the literature coupled with our
experiences with the asymmetric alkynylation reaction
using citronellal we anticipated that the C-2 alkoxy moi-
ety would have an impact upon the reaction in terms of the
overall efficiency of the transformation (% yields), the du-
ration and most importantly the enantioselectivity of the
reaction. Using experimental conditions that had previ-
ously been optimised for the alkynylation of benzalde-
hyde derivatives, such as 5, we observed low conversion
rates and modest enantioselectivities (Table 2, entry 1).
We found, however, that a considerable improvement in
the yield could be achieved by using a three-fold excess of
phenylacetylene although no enhancement in the selectiv-
ity was observed (Table 2, entry 2).
Apart from our own observation suggesting a link be-
tween the enantioselectivity of alkynylation reactions and
the electron-rich/poor nature of substituents in the aromat-
ic ring the only other report of relevance that we could
find was revealed by Kang.15b In their asymmetric addi-
tion of phenylacetylene to benzaldehyde derivatives, us-
ing an oxazolidine promoter, they reported the following
optimised enantioselectivities: the 3-nitro (99%), 3-bro-
mo (90%) compared to 3-tolyl (87%) and 3-methoxy de-
Ph
O
i. Zn(OTf)2,
N-methylephedrine
TEA
R
H
R
OH
R1
O
R1
ii. phenylacetylene
O
R2
R2
10a–i
12a–i
Ph
HO
H
O
i. Zn(OTf)2,
N-methylephedrine
TEA
O
O
ii. phenylacetylene
13
11
Scheme 4
Synthesis 2006, No. 18, 3099–3105 © Thieme Stuttgart · New York

3102
E. Tyrrell et al.
PAPER
Table 2 Optically Active Propargylic Alcohols Derived from 10 Using Phenylacetylene in the Presence of Ligand N-Methylephedrine
O
R
R1
H
O
R2
10
20
Entry
Aldehyde
10a
10a
10b
10c
Time (d)
Yield (%)
12a
12a
12b
12c
% eea
45
[a]D
1
2
R = R1 = R2 = H
3b
7c
7
25
+0.7
+0.7
+0.3
+0.8
–1.7
R = R1 = R2 = H
89
45
3
R = OMe, R1 = R2 = H
R = H, R1 = OMe, R2 = H
R = R1 = H, R2 = OMe
R = NO2, R1 = R2 = H
R = Br, R1 = R2 = H
R = Cl, R1 = R2 = H
R = Br, R1 = H, R2 = Br
R = Cl, R1 = H, R2 = Cl
99
43
4
7
63
23
5
10d
10e
7
12d
12e
91
56
6
7
92
78
+18.1
–0.8
7
10f
7
12f
82
84
8
10g
10h
10i
7
12g
12h
12i
96
75
–2.2
9
7
85
91
–26.3
+14.3
+8.0
10
11
7
99d
55 (71)d
90
11
7
13
25 (24)d
a The ee values were determined by HPLC with Chiracel-OD-H column and, for initial trials, confirmed by NMR studies of the Mosher ester.17
b Initially we used the following quantities: Zn(OTf)2 (1.1 equiv) and pheylacetylene (1.5 equiv).
c Optimised yields were obtained with phenylacetylene (3 equiv).
d Data obtained using (–)-N-methylephedrine.
and were calibrated using a standard polystyrene film. The spectra
were recorded either as thin films between sodium chloride discs for
liquids and oils, or for solids as a Nujol mull.19 All IR data are quot-
ed in wavenumbers (cm–1). 1H NMR spectra19 were recorded at 400
MHz using a JEOL Eclipse 400 MHz spectrometer. Peak positions
are quoted using the d scale relative to tetramethylsilane (d = 0) as
an internal standard. 13C NMR spectra19 were recorded at 100 MHz
on a JEOL Eclipse 400 MHz spectrometer using CDCl3 as an inter-
nal standard. Low-resolution mass spectra were recorded on a VG
TRIO-2 mass spectrometer under electron impact conditions at an
ionising potential of 70 eV and/or with a Hewlett Packard GC–MS
HP5890 (GC) instrument with capillary column and HP 5971 (MS).
Accurate mass analyses were performed and reported on a VG-
ZAB-E instrument under EI conditions by the EPSRC National
Mass Spectrometry Service Centre (Swansea) using the EI Peak
Match on M+ method. Enantiomeric excesses were measured by
HPLC method (Chiralcel-OD-H column) using Waters 996 photo-
diode array diode detector. UV spectra were measured on a Cary
100 Scan UV-Vis spectrometer. TLC analyses were performed us-
ing precoated silica 60 F254 plates purchased from Merck. Column
chromatography was carried out using matrix silica gel 60 (particle
size 35–70 mm) purchased from Fischer Scientific.
rivative (86%), respectively. As the overall
enantioselectivities were excellent the significance of the
small reduction in the ee values associated with a substit-
uent effect was probably missed and as a result not com-
mented upon.
In summary this paper describes a series of asymmetric
alkynylation reactions to provide a range of enantioen-
riched propargylic alcohols for use in attempted asymmet-
ric Nicholas cyclisation reactions.18
As a general observation most alkynylation reactions have
been attempted with relatively simple aliphatic aldehydes
or benzaldehyde derivatives. Our contribution to this area
is in the use of more complex, linear alkyl aldehydes as
well as substituted aromatic derivatives. We have now es-
tablished that with use of an excess of the alkyne the de-
sired propargylic alcohols are accessible in good to
excellent yields. In addition we have observed that the
enantioselectivity that accompanies these addition reac-
tions is very dependent upon the electronic nature of the
aromatic ring with electron-withdrawing groups provid-
ing optimal levels of selectivity. The paradox is that, al-
though high-yielding, the alkynylation reaction itself
remains a lengthy process.
Asymmetric Addition of Alkynes to (S)-(–)-Citronellal: Sythesis
of (3S,5S)-5,9-Dimethyl-1-phenyldec-8-en-1-yn-3-ol (8a); Typi-
cal Procedure
A suspension of zinc triflate (2.20 g, 6.05 mmol) and (–)-N-methyl-
ephedrine (1.19 g, 6.62 mmol) in 0.3 M Et3N in anhyd toluene was
stirred for 2 h at 25 °C. After 2 h, phenylacetylene (0.56 g, 0.61 mL,
5.52 mmol) was delivered to the suspension via syringe followed by
(S)-(–)-citronellal (0.85 g, 5.52 mmol). The progress of the reaction
Melting points were recorded using a Stuart Scientific SMP3 digital
melting point tube apparatus and are uncorrected. IR spectra were
recorded on a Perkin–Elmer 1600 series FTIR spectrophotometer
Synthesis 2006, No. 18, 3099–3105 © Thieme Stuttgart · New York

PAPER
Enantioselective Alkynylation Reactions to Aldehydes
3103
was monitored by TLC. Upon completion, after ca 30 h, the reaction
mixture was quenched by the addition of a sat. solution of NH4Cl
(30 mL). The mixture was extracted with Et2O (3 × 30 mL) and the
combined organic layers were dried over anhyd MgSO4, filtered
and concentrated in vacuo. Purification by column chromatography
on silica using hexane–EtOAc (8:2) as eluent gave the title com-
pound as a colourless oil (yield: 0.99 g, 66%). The diastereoisomer-
ic excess (de) was determined and corroborated by GC–MS, by
measurement of the integrations of the corresponding 1H NMR
spectrum of the crude reaction mixture and the 1H NMR spectrum
of the corresponding Mosher ester;17 [a]D20 +8.3 (c = 0.4, CHCl3).
CH2CHCH3), 1.65 (s, 3 H, C=CCH3), 1.58 (s, 3 H, C=CCH3), 1.35–
1.44 (m, 1 H, CH3CH), 1.16–1.25 (m, 1 H, CH3CH), 0.93–0.95 (d,
J = 6.2 Hz, 3 H, CHCH3).
13C NMR (100 MHz, CDCl3): d = 138.5, 131.6, 131.4, 129.1, 124.6,
119.7, 89.5, 85.2, 61.6, 45.0, 36.8, 29.4, 25.8, 25.4, 21.5, 19.8, 17.8.
MS: m/z [M + NH4]+ calcd for C19H26O: 288.2322; found:
288.2324.
(3S,5S)-5,9-Dimethyl-1-trimethylsilanyldec-8-en-1-yn-3-ol (8c)
20
The typical procedure for 8a was followed; colourless oil; [a]D
+3.6 (c = 0.3, CHCl3).
IR (neat): 3422, 2929, 2202, 1664, 1489, 1444, 1379, 1285, 1069,
758 cm–1.
IR (neat): 3423, 2963, 2925, 1733, 1448, 1377, 1290, 1250, 1154,
843, 760 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.39–7.42 (m, 2 H, ArH), 7.27–
7.30 (m, 3 H, ArH), 5.07–5.11 [m, 1 H, CH=C(CH3)2], 4.62–4.67
(m, 1 H, HOCH), 1.92–2.06 (m, 2 H, CH2CH=), 1.82–1.83 (dd, J =
1.8, 5.6 Hz, 2 H, CHCH2CH), 1.72–1.80 (m, 1 H, CH3CH), 1.65 (s,
3 H, C=CCH3), 1.58 (s, 3 H, C=CCH3), 1.33–1.40 (m, 1 H,
CHCH2CH2), 1.15–1.24 (m, 1 H, CHCH2CH2), 0.94–0.96 (d, J =
6.4 Hz, 3 H, CHCH3).
13C NMR (100 MHz, CDCl3): d = 131.8, 131.5, 128.4, 128.3, 124.7,
122.8, 90.3, 85.0, 61.8, 45.2, 37.2, 29.5, 25.8, 19.8, 17.8.
MS: m/z [M + NH4]+ calcd for C18H24O: 274.2165; found:
1H NMR (400 MHz, CDCl3): d = 5.05–5.09 [m, 1 H, CH=C(CH3)2],
4.60–4.65 (dd, J = 6.0, 13.5 Hz, 1 H, HOCH), 1.92–2.07 (m, 2 H,
=CHCH2), 1.70–1.87 (m, 3 H, CH2CHCH3), 1.64 (s, 3 H, C=CCH3),
1.58 (s, 3 H, C=CCH3), 1.32–1.40 (m, 1 H, CH3CH), 1.16–1.25 (m,
1 H, CH3CH), 0.92–0.95 (d, J = 6.1 Hz, 3 H, CHCH3), 0.15 [s, 9 H,
Si(CH3)3].
13C NMR (100 MHz, CDCl3): d = 124.0, 119.3, 92.3, 89.5, 60.9,
44.9, 36.8, 29.6, 25.3, 21.4, 19.8, 17.6, –0.04.
MS: m/z [M – H]+ calcd for C15H28SiO: 251.1826; found: 251.1828.
274.2165.
(3S,5S)-1-(6-Methoxynaphthalen-2-yl)-5,9-dimethyldec-8-en-1-
yn-3-ol (8d)
Mosher Ester Derivative of (3S,5S)-5,9-Dimethyl-1-phenyldec-
8-en-1-yn-3-ol (8a)
20
The typical procedure for 8a was followed; colourless oil; [a]D
+18.2 (c = 0.3, CHCl3).
To a toluene solution of (3S,5S)-5,9-dimethyl-1-phenyldec-8-en-1-
yn-3-ol (8a; 0.0346 g, 0.13 mmol), were sequentially added (S)-(–)-
a-methoxy-a-(trifluoromethyl)phenylacetic acid (75 mL, 0.40
mmol), 4-dimethylaminopyridine (0.01 g, 0.08 mmol) and anhyd
pyridine (27 mL, 0.33 mmol). The mixture was left to stir at ambient
temperature for about 1 h whereupon H2O was added (1 mL) in or-
der to quench the reaction. The mixture was extracted with EtOAc
(4 × 5 mL), washed with dilute HCl acid (0.5 mL, 10% solution) fol-
lowed by a wash with a sat. solution of aq NaHCO3 (0.5 mL). The
mixture was dried over anhyd MgSO4, filtered and concentrated in
vacuo to afford the desired Mosher ester (yield: 0.06 g, 98%) as a
clear oil.
IR (neat): 3385, 2963, 2926, 1630, 1602, 1498, 1483, 1389, 1245,
1029, 852 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.86 (s, 1 H, ArH), 7.64–7.68 (m,
2 H, ArH), 7.42–7.44 (d, J = 8.4 Hz, 1 H, ArH), 7.13–7.16 (ddd,
J = 0.7, 2.5, 8.9 Hz, 1 H, ArH), 7.09–7.10 (d, J = 2.2 Hz, 1 H, ArH),
5.11–5.13 [m, 1 H, CH=C(CH3)2], 4.69–4.73 (m, 1 H, HOCH),
3.91–3.92 (d, J = 0.7 Hz, 3 H, OCH3), 1.99–2.09 (m, 2 H, =CHCH2),
1.95–1.96 (d, J = 4.0 Hz, 1 H, CHCH3), 1.77–1.87 (m, 2 H,
HOCHCH2), 1.68 (s, 3 H, C=CCH3), 1.61 (s, 3 H, C=CCH3), 1.40–
1.48 (m, 1 H, CH3CH), 1.21–1.30 (m, 1 H, CH3CH), 0.98–0.99 (d,
J = 5.9 Hz, 3 H, CHCH3).
IR (neat): 2953.8, 1749, 1490.9, 1451.8, 1269.9, 1168.9, 1122.4,
1015.5, 991.8, 705.4 cm–1.
13C NMR (100 MHz, CDCl3): d = 158.4, 134.2, 131.5, 129.4, 129.1,
124.6, 128.6, 126.9, 124.7, 119.5, 117.6, 105.8, 89.9, 85.6, 61.9,
55.4, 45.3, 37.2, 29.6, 25.8, 25.4, 19.8, 17.8.
1H NMR (400 MHz, CDCl3): d = 7.48–7.49 (d, J = 6.9 Hz, 2 H,
ArH), 7.22–7.35 (m, 8 H, ArH), 5.73–5.35 (dd, J = 5.1, 8.7 Hz, 1 H,
OCH), 4. 98 [tt, J = 1.2, 7.1 Hz, 1 H, CH=C(CH3)2], 3.50–3.51 (d,
J = 0.9 Hz, 3 H, OCH3), 1.85–2.00 (m, 3 H, CH2CH=, CH3CH),
1.60–1.68 (m, 2 H, CH3CHCH2), 1.58 (s, 3 H, CH3), 1.51 (s, 3 H,
CH3), 1.27–1.36 (m, 1 H, CH3CH2CH), 1.12–1.20 (m, 1 H,
CH2CHCH), 0.89–0.90 (d, J = 6.0 Hz, 3 H, CHCH3).
MS: m/z [M + H]+ calcd for C23H28O2: 337.2162; found: 337.2164.
O-Alkylation of Salicylaldehyde Derivatives: Synthesis of 2-[(3-
Methylbut-2-en-1-yl)oxy]benzaldehyde (10a); Typical Proce-
dure
To a solution of salicylaldehyde (1.00 g, 8.18 mmol) and 4-bromo-
2-methyl-2-butene (1.10 g, 8.99 mmol) in anhyd DMF (25 mL)
were added finely ground anhyd K2CO3 (3.72 g, 27 mmol) and KI
(0.12 g, 0.68 mmol). The reaction mixture was left to stir at r.t. un-
der a nitrogen atmosphere for about 2.5 h, whereupon analysis of
the reaction mixture by TLC showed the presence of a new com-
pound [Rf = 0.48; Et2O–light PE (1:3)]. The reaction mixture was
poured in to H2O and partitioned in Et2O. The aqueous phase was
extracted with Et2O (6 × 15 mL). The organic extracts were com-
bined, dried over anhyd MgSO4, filtered and concentrated in vacuo
to afford the desired product as a yellow oil (yield: 1.10 g; 84%).
13C NMR (100 MHz, CDCl3): d = 165.9, 132.2, 131.8, 131.7, 131.6,
128.6, 128.4, 127.5, 124.3, 122.1, 86.2, 85.5, 65.5, 55.7, 41.7, 36.9,
29.0, 25.8, 25.3, 19.1, 17.7.
MS: m/z [M + NH4]+ calcd for C28H31F3O3: 490.2564; found:
490.2561.
(3S,5S)-5,9-Dimethyl-1-p-tolyldec-8-en-1-yn-3-ol (8b)
The typical procedure for 8a was followed; colourless oil; [a]D
–10.4 (c = 0.6, CHCl3).
20
IR (neat): 3406, 2959, 2926, 2199, 1718, 1664, 1606, 1508, 1378,
1289, 1062, 817, 755 cm–1.
IR (neat): 3034, 1686, 1598, 1286 cm–1.
1H NMR (400 MHz, CDCl3): d = 10.46 (d, J = 0.7 Hz, 1 H, HC=O),
7.78 (dd, J = 1.8, 7.9 Hz, 1 H, ArH), 7.45–7.50 (m, 1 H, ArH), 6.93–
6.97 (m, 2 H, ArH), 5.43–5.48 (m, 1 H, C=CH), 4.59 (d, J = 6.8 Hz,
2 H, H2CO), 1.76 (s, 3 H, CH3), 1.71 (s, 3 H, CH3).
1H NMR (400 MHz, CDCl3): d = 7.28–7.30 (d, J = 8 Hz, 2 H, ArH),
7.08–7.10 (d, J = 7.8 Hz, 2 H, ArH), 5.08–5.11 [m, 1 H,
CH=C(CH3)2], 4.61–4.66 (dd, J = 6.1, 13.5 Hz, 1 H, HOCH), 2.32
(s, 3 H, ArCH3), 1.92–2.07 (m, 2 H, =CHCH2), 1.71–1.87 (m, 3 H,
Synthesis 2006, No. 18, 3099–3105 © Thieme Stuttgart · New York

3104
E. Tyrrell et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 189.63, 161.12, 138.40, 135.63,
127.94, 124.82, 120.27, 118.80, 112.73, 65.20, 25.53, 18.04.
MS: m/z [M + NH4]+ calcd for C20H19NO4: 355.1652; found:
355.1652.
MS: m/z [M + H]+ calcd for C12H14O2: 191.1067; found: 191.1066.
(1R)-(–)-1-{3,5-Dibromo-2-[(3-methylbut-2-en-1-yl)oxy]phe-
nyl}-3-phenylprop-2-yn-1-ol (12h)
Asymmetric Addition of Phenylacetylene to Aldehyde 10a: Syn-
thesis of (1R)-(+)-1-{2-[(3-Methylbut-2-en-1-yl)oxy]phenyl}-3-
phenylprop-2-yn-1-ol (12a); Typical Procedure
The typical procedure for 12a was followed and 12h was isolated as
a white solid (85%). The enantiomeric excess was determined by
HPLC analysis and found to be 91% (Chiralcel OD-H, 10% i-PrOH
in hexane, 254 nm); tmajor = 6.54 min and tminor = 12.11 min; mp
94.8–95.4 °C; [a]D20 –26.3 (c = 9.4, CHCl3).
A 100 mL flask was charged with Zn(OTf)2 (2.1010 g, 5.78 mmol,
1.1 equiv) and (1S,2R)-(+)-N-methylephedrine (1.1311 g, 6.31
mmol, 1.2 equiv) and purged with nitrogen for 15 min whereupon
anhyd toluene (242 mL) and Et3N (1.76 mL, 1.2770 g, 12.62 mmol,
2.4 equiv) were added via syringe. The resulting mixture was left to
stir for 2 h before phenylacetylene (1.73 mL, 1.6117 g, 15.78 mmol,
3 equiv) was added by syringe in one portion. After 15 min of stir-
ring, 2-[(3-methylbut-2-en-1-yl)oxy]benzaldehyde (1.0 g, 5.26
mmol, 1 equiv) was added in one portion. The progress of the reac-
tion was monitored by TLC analysis where product started to form
after 24 h and optimal results were obtained after 7 d.
IR (mull): 3408, 3068, 2972, 2226, 1672, 1490, 1444, 1380, 1308,
1218, 1144, 1034, 942, 864, 756, 690 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.76 (dd, J = 0.4, 2.4 Hz, 1 H,
ArH), 7.69 (d, J = 2.4 Hz, 1 H, ArH), 7.43–7.47 (m, 2 H, ArH),
7.30–7.37 (m, 3 H, ArH), 5.92 (d, J = 5.9 Hz, 1 H, HCPh), 5.61–
5.66 (m, 1 H, C=CH), 4.61–4.70 (m, 2 H, CH2), 2.89 (d, J = 5.9 Hz,
1 H, OH), 1.81 (d, J = 1.0 Hz, 3 H, CH3), 1.73 (d, J = 1.0 Hz, 3 H,
CH3).
The reaction was quenched by the addition of an aq sat. solution of
NH4Cl (31 mL). The reaction mixture was extracted with Et2O (100
mL). The layers were separated and the aqueous layer was further
extracted with Et2O (3 × 100 mL). The combined organic layers
were washed sequentially with a sat. NH4Cl solution (100 mL) fol-
lowed by sat. brine (100 mL). The organic layers were isolated and
dried over anhyd MgSO4, filtered, and concentrated in vacuo to af-
ford the crude product. Purification by column chromatography on
silica gel using CHCl3–light PE (3:2) gave the pure chiral alcohol as
a clear yellow oil (yield: 0.74 g, 89%). The enantiomeric excess was
determined by HPLC analysis and found to be 45% (Chiralcel OD-
13C NMR (100 MHz, CDCl3): d = 152.97, 140.46, 138.06, 135.99,
131.82 (2 ×), 130.60, 128.94, 128.46 (2 ×), 122.04, 119.25, 118.53,
117.55, 87.92, 87.12, 71.19, 60.88, 25.98, 18.35.
MS: m/z [M + NH4]+ calcd for C20H18Br2O2: 466.0012; found:
466.0013.
(1R)-(+)-1-{2-[(3-Methylbut-2-en-1-yl)oxy]-1-naphthyl}-3-phe-
nylprop-2-yn-1-ol (13)
The typical procedure for 12a was followed and 13 was isolated as
a yellow oil (55%). The enantiomeric excess was determined by
HPLC analysis and found to be 25% (Chiralcel OD-H, 5% i-PrOH
H, 10% i-PrOH in hexane, 254 nm); tmajor = 12.39 min and tminor
=
20
14.81 min; [a]D20 +0.7 (c = 10.3, CHCl3).
in hexane, 254 nm); tmajor = 29.23 min and tminor = 32.43 min; [a]D
8.0 (c = 0.5, CHCl3).
IR (neat): 3529, 3425, 3067, 3035, 2929, 2202, 1664, 1489, 1444,
1379, 1285, 1069, 758 cm–1.
IR (neat): 3422, 3056, 2972, 2920, 2226, 1672, 1624, 1596, 1510,
1464, 1440, 1378, 1236, 1072, 1014, 956, 808, 756, 692 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.62 (dd, J = 1.7, 7.5 Hz, 1 H,
ArH), 7.46–7.50 (m, 2 H, ArH), 7.29–7.33 (m, 4 H, ArH), 7.00 (dt,
J = 1.1, 7.5 Hz, 1 H, ArH), 6.95 (dd, J = 0.7, 8.2 Hz, 1 H, ArH), 5.91
(d, J = 6.4 Hz, 1 H, OHCH), 5.50–5.55 (m, 1 H, HC=C), 4.63 (d,
J = 6.8 Hz, 2 H, OCH2), 3.31 (d, J = 6.4 Hz, 1 H, OH), 1.79 (s, 3 H,
CH3), 1.75 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 156.35, 138.57, 131.86, 129.69,
129.22, 128.43, 128.31, 128.17, 122.94, 120.93, 119.51, 112.25,
88.48, 86.13, 65.41, 62.25, 25.88, 18.38.
1H NMR (400 MHz, CDCl3): d = 8.44–8.46 (d, J = 8.6 Hz, 1 H,
ArH), 7.54–7.84 (dd, J = 2.9, 8.6 Hz, 2 H, ArH), 7.54–7.57 (t, J =
7.5 Hz, 1 H, ArH), 7.39–7.41 (m, 3 H, ArH), 7.24–7.31 (m, 4 H,
ArH), 6.66 (s, 1 H, HCPh), 5.58–5.62 (m, 1 H, C=CH), 4.72–4.80
(m, 2 H, CH2), 3.92 (br s, 1 H, OH), 1.80 (s, 3 H, CH3), 1.77 (s, 3 H,
CH3).
13C NMR (100 MHz, CDCl3): d = 154.07, 138.86, 131.44, 130.42,
129.78, 128.72, 128.72, 128.29, 128.27, 126.97, 124.05, 123.77,
123.19, 122.58, 119.70, 115.52, 90.26, 85.01, 67.14, 58.64, 25.95,
18.44.
MS: m/z [M – H]+ calcd for C20H20O2: 291.1380; found: 291.1376.
UV (i-PrOH): lmax = 243 (e = 1.33) nm.
MS: m/z [M + NH4]+ calcd for C24H22O2: 365.1512; found:
365.1512.
(1R)-(+)-1-{2-[(3-Methylbut-2-en-1-yl)oxy]-5-nitrophenyl}-3-
phenylprop-2-yn-1-ol (12e)
(1R)-(+)-1-{2-[(3-Methylbut-2-en-1-yl)oxy]-5-methoxyphenyl}-
3-phenylprop-2-yn-1-ol (12b)
The typical procedure for 12a was followed and 12e was isolated as
a yellow oil (92%). The enantiomeric excess was determined by
HPLC analysis and found to be 78% (Chiralcel OD-H, 15% i-PrOH
in hexane, 254 nm); tmajor = 12.13 min and tminor = 66.87 min; [a]D
+18.1 (c = 3.1, CHCl3).
The typical procedure for 12a was followed and 12b was isolated as
a yellow crystalline solid (99%). The enantiomeric excess was de-
termined by HPLC analysis and found to be 43% (Chiralcel OD-H,
10% i-PrOH in hexane, 254 nm); tmajor = 12.73 min and tminor = 16.54
min; mp 42.8–43.2 °C (from IMS); [a]D20 +0.3 (c = 7.2, CHCl3).
20
IR (neat): 3420, 3082, 2975, 2202, 1674, 1592, 1514, 1490,1384,
1268, 1086, 974 cm–1.
(1R)-(+)-1-{2-[(3-Methylbut-2-en-1-yl)oxy]-4-methoxyphenyl}-
3-phenylprop-2-yn-1-ol (12c)
1H NMR (400 MHz, CDCl3): d = 8.58 (d, J = 2.9 Hz, 1 H, ArH),
8.24 (dd, J = 2.9, 9.2 Hz, 1 H, ArH), 7.44–7.51 (m, 2 H, ArH), 7.30–
7.35 (m, 3 H, ArH), 6.99 (d, J = 9.2 Hz, 1 H, ArH), 5.94 (d, J = 6.0
Hz, 1 H, HCPh), 5.47–5.52 (m, 1 H, C=CH), 4.73 (d, J = 6.6 Hz, 2
H, CH2), 2.94 (d, J = 6.0 Hz, 1 H, OH), 1.81 (s, 3 H, CH3), 1.76 (s,
3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 161.05, 141.34, 140.10, 131.91,
130.28, 128.85, 128.43, 125.88, 124.02, 122.26, 118.20, 111.75,
87.18, 86.84, 65.32, 60.83, 25.89, 18.47.
The typical procedure for 12a was followed and 12c was isolated as
a yellow oil (23%). The enantiomeric excess was determined by
HPLC analysis and found to be 23% (Chiralcel OD-H, 5% i-PrOH
20
in hexane, 254 nm); tmajor = 13.18 min and tminor = 20.28 min; [a]D
+0.8 (c = 3.5, CHCl3).
Synthesis 2006, No. 18, 3099–3105 © Thieme Stuttgart · New York

PAPER
Enantioselective Alkynylation Reactions to Aldehydes
3105
(1R)-(–)-1-{2-[(3-Methylbut-2-en-1-yl)oxy]-3-methoxyphenyl}-
3-phenylprop-2-yn-1-ol (12d)
SFB Symposium, October 10–11, 2005, Aachen, Germany;
Abstract 226.
(5) Schreiber, S. L.; Klimas, M. T.; Sammakia, T. J. Am. Chem.
Soc. 1987, 20, 207.
(6) Muehldorf, A. V.; Guzman-Perez, A.; Kluge, A. F.
Tetrahedron Lett. 1994, 35, 8755.
(7) Grove, D. D.; Corte, J. R.; Spencer, R. P.; Pauly, M. E.; Rath,
N. P. J. Chem. Soc., Chem. Commun. 1994, 49.
(8) Using asymmetric hydroboration techniques: (a) Corey, E.
J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153. (b)Parker,
K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3214.
(c) Using transition-metal-catalysed hydrogenation, see:
Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1997, 119, 8738.
The typical procedure for 12a was followed and 12d was isolated as
a yellow crystalline solid (91%). The enantiomeric excess was de-
termined by HPLC analysis and found to be 56% (Chiralcel OD-H,
10% i-PrOH in hexane, 254 nm); tmajor = 12.69 min and tminor = 18.40
min; mp 66.6–67.8 °C; [a]D20 –1.7 (c = 3.0, CHCl3).
(1R)-(–)-1-{2-[(3-Methylbut-2-en-1-yl)oxy]-5-bromophenyl}-3-
phenylprop-2-yn-1-ol (12f)
The typical procedure for 12a was followed and 12f was isolated as
a yellow oil (82%). The enantiomeric excess was determined by
HPLC analysis and found to be 84% (Chiralcel OD-H, 10% i-PrOH
20
in hexane, 254 nm); tmajor = 9.0 min and tminor = 14.16 min; [a]D
–0.8 (c = 3.5, CHCl3).
(9) Lu, G.; Li, Y.-M.; Li, X.-S.; Chan, A. S. C. Coord. Chem.
Rev. 2005, 249, 1736.
(1R)-(–)-1-{2-[(3-Methylbut-2-en-1-yl)oxy]-5-chlorophenyl}-3-
phenylprop-2-yn-1-ol (12g)
(10) Katritzky, A. R.; Meth-Cohn, O.; Rees, C. W.
Comprehensive Organic Functional Group
The typical procedure for 12a was followed and 12g was isolated as
a yellow oil (96%). The enantiomeric excess was determined by
HPLC analysis and found to be 75% (Chiralcel OD-H, 10% i-PrOH
Transformations, Vol. 1; Elsevier Sciences Ltd.:
Amsterdam, 2005, 1.21.
(11) Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757.
(12) Watts, C. C.; Thoniyot, P.; Hirayama, L. C.; Romano, T.;
Singaram, B. Tetrahedron: Asymmetry 2005, 16, 1829.
(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. 2001, 123, 9687. (c) Boyall, D.; Frantz, D.
E.; Carreira, E. M. Org. Lett. 2002, 4, 2605.
(14) (a) Lu, G.; Li, X.; Zhou, Z.; Chan, W. L.; Chan, A. S. C.
Tetrahedron: Asymmetry 2001, 12, 2147. (b) Li, Z.;
Upahhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P. J.
Synthesis 1999, 1453.
(15) (a) Pizzuti, M. G.; Superchi, S. Tetrahedron: Asymmetry
2005, 16, 2263. (b) Kang, Y.-F.; Wang, R.; Liu, L.; Da C, S.;
Yan, W.-J.; Xu, Z.-Q. Tetrahedron Lett. 2005, 46, 863.
(16) Tyrrell, E.; Tillett, C. Tetrahedron Lett. 1998, 39, 9535.
(17) (a) Dale, J. A.; Dull, D.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543. (b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc.
1973, 95, 512.
20
in hexane, 254 nm); tmajor = 9.11 min and tminor = 14.29 min; [a]D
–2.2 (c = 6.9, CHCl3).
(1S)-(+)-1-{2-[(3-Methylbut-2-en-1-yl)oxy]-3,5-dichlorophe-
nyl}-3-phenylprop-2-yn-1-ol (12i)
The typical procedure for 12a was followed and 12i was isolated as
an opaque white waxy solid (99%). The enantiomeric excess was
determined by HPLC analysis and found to be 90% (Chiralcel OD-
H, 10% i-PrOH in hexane, 254 nm); tmajor = 11.38 min and tminor
6.35 min; mp 86.6–87.3 °C (from IMS); [a]D +14.3 (c = 1.4,
CHCl3).
=
20
Acknowledgment
The authors wish to thank the EPSRC National Mass Spectrometry
Service Centre, University of Swansea, for high-resolution mass
spectra.
(18) The results from these studies will be disseminated at a later
date (although see ref. 4).
(19) All compounds provided satisfactory spectral data that were
consistent with the assigned structures. For succinctness we
have limited the experimental section to a representative
example of salicylaldehyde derivatives, e.g. non-substituted,
mono- and di-substituted and naphthyl derivatives. Optical
rotation data and HPLC retention times are included for all
relevant examples.
References
(1) Mann, A.; Muller, C.; Tyrrell, E. J. Chem. Soc., Perkin
Trans. 1 1998, 1427.
(2) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207.
(3) Review: Roxburgh, C. J. Synthesis 1996, 3, 307.
(4) Tyrrell, E.; Millet, J.; Tesfa, K. H. Asymmetric Synthesis
with Chemical and Biological Methods; 9th International
Synthesis 2006, No. 18, 3099–3105 © Thieme Stuttgart · New York