Asymmetric addition of phenylacetylene to aldehydes catalyzed by β-sulfonamide alcohol-titanium complex

Article abstract of DOI:10.1002/adsc.200505453

A series of β-sulfonamide alcohol ligands were synthesized from L-phenylalanine. Titanium complexes of these compounds were used to catalyze the asymmetric addition of phenylacetylene to a number of aldehydes. When the conditions were optimized, 20 mol % of ligand 8a catalyzed the reaction with high enantioselectivity (up to 98% ee) and good yield (up to 92%). When a small amount of MeOH was added to the reaction as a modifier, as little as 5 mol % of ligand was required to efficiently catalyze the reaction under very mild conditions, resulting in an ee of up to 99% and good yield.

Full text of DOI:10.1002/adsc.200505453

FULL PAPERS
DOI: 10.1002/adsc.200505453
Asymmetric Addition of Phenylacetylene to Aldehydes
Catalyzed by b-Sulfonamide Alcohol-Titanium Complex
Zhaoqing Xu,a Li Lin,a Jiangke Xu,a Wenjin Yan,a Rui Wanga, b,*
a
Department of Biochemistry &Molecular Biology, School of Life Science, Lanzhou University, Lanzhou 730000,
Peopleꢀs Republic of China
Fax: (þ86)-931-891-2561, e-mail: wangrui@lzu.edu.cn
b
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences, Lanzhou 730000, Peopleꢀs Republic of China
Received: November 24, 2005; Accepted: January 16, 2006
Abstract: A series of b-sulfonamide alcohol ligands MeOH was added to the reaction as a modifier, as lit-
were synthesized from l-phenylalanine. Titanium tle as 5 mol % of ligand was required to efficiently
complexes of these compounds were used to catalyze catalyze the reaction under very mild conditions, re-
the asymmetric addition of phenylacetylene to a num- sulting in an ee of up to 99% and good yield.
ber of aldehydes. When the conditions were opti-
mized, 20 mol % of ligand 8a catalyzed the reaction
with high enantioselectivity (up to 98% ee) and Keywords: asymmetric alkynylation; C C bond for-
good yield (up to 92%). When a small amount of mation; N,O ligands; sulfonamides; titanium; zinc
À
Introduction
by combining ZnEt2 and the alkyne at high tempera-
tures. Without this separate step, the ethyl addition
Asymmetric carbon-carbon bond formation is an area of product was the main product. Concurrently, Chan
intense research in organic chemistry.[1] One of the most et al. reported[7] that the BINOL-Ti complex successful-
powerful methods for the catalytic asymmetric genera- ly catalyzed this asymmetric reaction in high ee with N-
tion of carbon-carbon bonds is the enantioselective ad- p-toluenesulfonylephedrine as the additive.
dition of organometallic reagents to aldehydes or ke-
tones. In recent years there has been great interest in
asymmetric catalytic addition reactions of terminal al-
kynes to aldehydes.[2,3] The acidity of a terminal alkynyl
proton makes it easy to prepare alkynyl-metal reagents
as good functional carbon nucleophiles and the resulting
products, chiral propargylic alcohols, are important pre-
cursors to many chiral organic compounds.[4]
Carreira et al.[5] developed an efficient in situ method
for the generation of zinc acetylides from terminal al-
kynes, utilizing Zn(OTf)2, and an amine base via p-com-
plex formation. They successfully used this method for ditional metal amides (MNR2), the sulfonamide nitro-
the enantioselective alkynylation of an aliphatic alde- gen atom is a poor electron donor and the N H group
hyde using N-methylephedrine (1; 22 mol %) as a cata- of the sulfonamide-Ti complex is a Lewis acid, owing
lyst. However, because of the strongly basic conditions, to the highly electron-withdrawing nature of the sulfon-
aromatic aldehydes may not be used (Carreira reported yl group.[8] Amino alcohols derived from natural amino
Cannizzaro reaction as a significant side reaction). Fur- acids are among the best and most economical chiral li-
thermore, the high temperatures used in the reaction gands available.[9] We introduced the sulfonyl group to
À
The N H group of sulfonamides is acidic. Unlike tra-
À
may also limit the scope of the reaction.
b-amino alcohols derived from amino acids to prepare
Pu et al. reported[6] that the titanium complex of BI- b-sulfonamide alcohols.[10] As a result of the presence
À
À
NOL (2; 20 mol %) catalyzed the asymmetric alkynyla- of acidic N H and O H groups, the titanium complex
tion of aldehydes with high ee and good yield. They used was readily formed from these compounds when they
a separate step for the preparation of the zinc acetylide were combined with Ti(O-i-Pr)4 under basic conditions.
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Asymmetric Addition of Phenylacetylene to Aldehydes
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Initially, we expected these complexes to behave simi-
larly to BINOL-Ti complexes, and that they could be
straightforwardly applied to the enantioselective addi-
tion of phenylacetylene to aldehydes.[11] To our astonish-
ment, this kind of titanium complex had a very different
catalytic activity than the BINOL-Ti complex in this
type of reaction. The separate step to prepare the zinc
acetylide by combining ZnEt2 and alkyne at high tem-
perature was not required. After the conditions had
been optimized, these ligands could efficiently catalyze
the asymmetric alkynylation of aldehydes with high ees
and high yields in one step.[12] Herein, we describe the
details of our research.
Scheme 2. Addition of phenylacetylene to benzaldehyde by
different methods.
Table 1. Addition of phenylacetylene to benzaldehyde by dif-
ferent methods.[a]
[b]
Entry Method Ligand
Ligand/Ti(O-i-Pr)4 3/4[c]
Results and Discussion
1
2
3
4
5
6
7
A
B
B
B
B
B
B
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
(S)-BINOL
1/3
1/1
1/2
1/3
1/4
1/5
98/2
At room temperature, the reaction to produce the zinc
acetylide directly by combining ZnEt2 and alkyne is
very slow. Hence, in the titanium-based catalytically in-
duced asymmetric addition of alkynylzinc to aldehyde
when the ZnEt2, the alkyne and the aldehyde are com-
bined together at room temperature, multiple products
will result. When benzaldehyde is used as the represen-
tative substrate, two possible products would form: the
alkynylzinc addition product 3, and the ethylzinc addi-
tion product 4 (Scheme 1).
<1/99
<1/99
3/97
5/95
6/94
(þ)-TADDOL 1/3
62/38
[a]
[b]
[c]
Phenylacetylene:Et2Zn:benzaldehyde¼3: 3: 1.
Toluene as solvent and Ti(O-i-Pr)4 was freshly distilled.
The ratio of 3/4 was measured by a calibrated HPLC meth-
od.
alyst compounds was increased, the Lewis acidity of the
catalyst decreased and a small amount of compound 3
was formed. This result led us to question whether the
metalꢀs Lewis acidity or rigidity affected the reactionꢀs
selectivity.
TADDOL is another classical diol ligand, but the
acidity of the hydroxy group in TADDOL is weaker
than that of the BINOL hydroxy group. It forms a Ti
complex when combined with Ti(O-i-Pr)4.[14] The Lewis
acidity of the resulting TADDOL-Ti complex is weaker
Scheme 1. Titanium-based catalyst may give two possible
products.
In order to determine the effect of the catalyst on the than that of the BINOL-Ti complex and metal center is
selectivity of the two possible products, we used two dif- softer. We decided to employ this catalytic system in an
ferent methods: A) pre-preparation of the alkynylzinc effort to explore whether the Lewis acidity of the metal
followed by addition of the aldehyde according to Puꢀs center influences the chemical selectivity. When this sys-
method and B) combination of ZnEt2 (3 equivs.) with tem was utilized following method B, we obtained prod-
the alkyne (3 equivs.) and aldehyde (1 equiv.) at room ucts 3 and 4 in a ratio of 62/38 (entry 7).
temperature (Scheme 2). Using method A, we got a
Encouraged by above experimental results, we sup-
3/4 ratio of>98/2 (Table 1, entry 1). Following process posed that a weak Lewis acid catalyst prefers to promote
B, compound 4 was the main product. Under conditions addition of the alkyne to the aldehyde rather than addi-
B, the ligand to metal ratio was varied from 1/1 to 1/5 tion of the ethyl group. Hence, in an effort to further
(entries 2–6).
study the effect of the relative strength of the Lewis acid-
When BINOL and Ti(O-i-Pr)4 were combined in the ic catalyst on the reaction, a weaker Lewis acid catalytic
ratio of 1/1, the resulting (BINOLate)Ti(O-i-Pr)2 is a system was sought. In non-protonic solvents, the acidity
stronger Lewis acid than at other ratios. In addition, of the sulfonamide hydrogen is much weaker than that
the metal center is hardest.[13] Use of this catalyst result- of the hydroxy group in TADDOL or BINOL. In fact,
ed in the formation of nearly all 4 following completion it will not react with Ti(O-i-Pr)4 in the absence of
of the reaction. However, when the ratio of the two cat- ZnEt2.[8] Furthermore, the sulfonyl oxygen is chelated
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Table 2. Addition of phenylacetylene to benzaldehyde cata-
lyzed by 8.[a, b]
Entry
Method
Ligand
ZnEt2 and
3/4[c]
[mol %]
phenylacetylene
[equivs.]
1
2
3
4
5
6
7
B
C
C
C
C
C
C
8a (20%)
8a (20%)
8a (20%)
8a (20%)
8b (20%)
8a (10%)
8a (5%)
3
3
2
1
3
3
3
93/7
>99/1
94/6
93/7
99/1
99/1
99/1
[a]
20 mol% 8 was used and the ratio 8:Ti(O-i-Pr)4 ¼1: 3.
Toluene was solvent and Ti(O-i-Pr)4 was freshly distilled.
The ratio of 3/4 was measured by a calibrated HPLC meth-
od.
[b]
[c]
Scheme 3. Preparation of p-toluenesulfonylamino alcohol
from l-Phe.
action and found that the best ee was obtained when the
8a/Ti(O-i-Pr)4 ratio was 1:3 (Table 3, entries 2–6). We
also found that this reaction was strongly influenced
by the solvent. Low enantioselectivities were found
when CH2Cl2 and THF were used as the reaction solvent
(Table 3, entries 7 and 8). When the amount of ligand
was increased from 10% to 20% in increments of 5%,
Scheme 4. Addition of phenylacetylene to benzaldehyde by the ee values improved slightly (Table 3, entries 9 and
method C.
10), but no significant changes in ee values were ob-
served when the temperature of the reaction was de-
creased from room temperature to 08C (Table 3, entry
to Ti, making the metal center much softer and its Lewis 11).
acidity weaker.[15]
In the sulfonamide alcohol-titanium complex, the sul-
We have synthesized two N-Ts sulfonamide alcohols fonyl oxygen atom of the sulfonamide group is also che-
(Ts¼p-toluenesulfonyl), 8a and 8b, from l-phenylala- lated to metal center.[17] We wondered whether changing
nine[16] in three straightforward steps in overall yields the sulfonamide groupin the ligand wouldaffectthe out-
of 67% and 62%, respectively (Scheme 3). When com- come of the reaction. Hence, we synthesized two addi-
pound 8a was utilized as catalyst (Table 2), following tional ligands, 11a and 11b, from l-phenylalanine methyl
protocol B, a 3/4 product ratio of 93/7 was obtained (en- ester (Scheme 5) which differ from 8a and 8b in that they
try 1). An improved preparation method C was devel- are methanesulfonamides.
oped to optimize the selectivity of the reaction. Method
When 11a and 11b were employed in method C as the
C involves the initial mixing of ZnEt2 and the alkyne at catalyst in the asymmetric addition of phenylacetylene
room temperature for one hour followed by the addition to benzaldehyde (Scheme 6 and Table 4), they catalyzed
of the aldehyde. Using this procedure, we could get a 3/4 the reaction with nearly the same ees as the p-toluene-
ratio>99/1 (Scheme 4, entry 2). It was also determined sulfonamide catalysts, 8a and 8b, but the reaction yields
that the amounts of phenylacetylene and ZnEt2 also af- differed. In an effort to explore this, we varied the ratio
fect the reaction result. When the amounts of these com- of ligand, 11a, and Ti(O-i-Pr)4 (entries 1–5). The best re-
pounds were reduced, more product 4 was obtained (en- sults were obtained when the 11a/Ti(O-i-Pr)4 ratio was
tries 3 and 4). However, reducing the amount of ligand 1/2. Under these conditions, the ee purity of 3 was
did not affect the yield of main product (entries 6 and 7). 92% and the ratio of 3/4 was 92/8 (entry 2). Although
These two sulfonamide ligands, 8a and 8b, were tested 11b and 8b are very similar in structure, they gave very
in the asymmetric addition of phenylacetylene to ben- different enantioselectivities (entries 5–10). When
zaldehyde by method C. Interestingly, compound 8b, 10 mol % of 11b was used, the ee of 3 was 51% and ratio
which has the bulkier, less flexible phenyl substituents of 3/4 was 80/20 (entry 7). It is clear from these experi-
at the hydroxy-bearing carbon atom, resulted in a lower mental results that the sulfonamide not only has an im-
enantioselectivity (Table 3, entry 1) than compound 8a, portant influence on ee (11b vs. 8b, 51% vs. 10%), but
which has the more flexible ethyl substituents (Table 3, also influences the product ratio of 3/4 (11a vs. 8a, 92/8
entry 2). We varied the amount of Ti(O-i-Pr)4 in the re- vs.>99/1).
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Asymmetric Addition of Phenylacetylene to Aldehydes
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Table 3. Asymmetric addition phenylacetylene to benzaldehyde by method C and using 8a and 8b as ligands.[a]
ee [%][c, d]
[b]
Entry
Ligand [mol %]
Ligand/Ti(O-i-Pr)4
Solvent
Temp.
1
2
3
4
5
6
7
8
9
8b (10%)
8a (10%)
8a (10%)
8a (10%)
8a (10%)
8a (10%)
8a (10%)
8a (10%)
8a (15%)
8a (20%)
8a (20%)
1/3
1/3
1/1
1/2
1/4
1/5
1/3
1/3
1/3
1/3
1/3
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
rt
rt
rt
rt
rt
rt
rt
rt
10
90
11
88
85
78
4
6
toluene
toluene
toluene
rt
rt
08C
93
95
95
10
11
[a]
Phenylacetylene:Et2Zn:benzaldehyde¼3: 3: 1.
Ti(O-i-Pr)4 was freshly distilled.
[b]
[c]
The enantiomeric excess was determined by HPLC analysis of the corresponding products on a Chiralcel OD column ac-
cording to the literature method.[6]
[d]
The absolute configuration of the product is R.
Table 4. Asymmetric addition phenylacetylene to benzalde-
hyde using 11a and 11b as ligands.[a]
Entry
Ligand
Ligand/Ti(O-i-Pr)4
3/4
ee [%][b]
1
2
3
4
5
6
7
8
9
11a
11a
11a
11a
11a
11b
11b
11b
11b
11b
1/1
1/2
1/3
1/4
1/5
1/1
1/2
1/3
1/4
1/5
95/5
92/8
37
92
92
90
88
3
51
40
29
14
85/15
79/21
80/20
95/5
80/20
80/20
80/20
80/20
10
[a]
In all entries, solvent is toluene, phenylacetylene:
Et2Zn:benzaldehyde¼3: 3: 1, ligand is 10 mol % and
Ti(O-i-Pr)4 was freshly distilled.
[b]
The absolute configuration of the product is R.
Scheme 5. Preparation of methanesulfonylamino alcohol.
number of enantioselective addition products from phe-
nylacetylene and aldehydes. When aromatic aldehydes
were used, products were obtained with high enantiose-
lectivity (up to 98% ee). The use of aliphatic aldehydes
resulted in lower but acceptable selectivity (Table 5).
A large body of work describing the non-linear effects
of amino alcohol-based catalysts for the asymmetric ad-
dition of alkyl groups to aldehydes exists.[18] Their cata-
lytic activity has been attributed to the monomer-dimer
equilibrium of the catalyst. In contrast, reactions em-
ploying titanium tetraisopropoxide and various ligands
such as BINOL, TADDOL and sulfonamides show a lin-
ear relationship between catalyst ee and product ee. Al-
though the titanium-based catalysts are believed to be
Scheme 6. Asymmetric addition of phenylacetylene to ben-
zaldehyde catalyzed by 11.
Ligand 8a was chosen to be the best overall chiral li- monomeric throughout the catalytic cycle, the alkoxide
gand to facilitate this alkynyl addition reaction. Method group maybe exchanged to give a better catalyst during
C, employing 20 mol % of 8a, was used to prepare a the process.[20] For example, if an alkoxide was added to a
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Table 5. Asymmetric addition of phenylacetylene to aldehydes promoted by ligand 8a.[a, b,c]
Entry
Aldehydes
Time [h]
Isolated yield [%]
ee [%][d]
95
1
12
92
2
3
12
12
89
90
92
93
4
12
88
90
5
6
7
14
12
12
91
80
87
92
98
93
8
18
18
70
71
90
95
9
10
12
12
86
81
81
70
11
[a]
In all of the entries: Et2Zn:phenylacetylene:aldehyde: Ti(O-i-Pr)4:8a¼3: 3: 1: 0.6: 0.2.
All the reactions were processed under argon and at room temperature.
Ti(O-i-Pr)4was freshly distilled before use.
[b]
[c]
[d]
The ee values were determined by chiral HPLC with a Chiracel OD column according to the literature method.[6]
titanium isopropoxide-based catalyst, it could exchange
When phenylacetylene was added to benzaldehyde
with the isopropoxide and form a new catalyst under the above optimized conditions using 5 mol %
(Scheme 7). The resulting new complex often has differ- of 8a as the catalyst the product had an ee of 81% (Ta-
ent catalytic behavior that sometimes results in a better ble 6, entry 1). In an effort to enhance the efficiency of
outcome. Over the past decade, reports of stoichiomet- the ligand, we tried adding alcohols to the reaction.
ric or sub-stoichiometric quantities of achiral additives When 10 mol % MeOH and EtOH were added, the
to these systems which result in a significant increase ee rose slightly (entries 2 and 7). MeOH had the most
in the rate and/or the enantioselectivity of organic trans- significant effect and could boost the productꢀs ee to
formations have sporadically appeared in the litera- 92% without decreasing the overall yield. We varied
ture.[19]
the ratio of 8a/MeOH from 1/1, 1/2 to 1/5 and found
that the ee was highest when the ratio was 1/2 (entries
2–6). Addition of other achiral molecules including
tert-BuOH, phenol, naphthol and DMPEG all de-
creased the catalystꢀs enantioselectivity (entries 8–
12). Chiral additives such as (R)-BINOL and (S)-BI-
NOL (5 mol %) also resulted in decreased selectivity
(entry 13). It is interesting that when (R)-BINOL was
added, the absolute configuration of product changed
Scheme 7. The alkoxide exchange in titanium-based catalysts. from R to S (Entry 14).
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Asymmetric Addition of Phenylacetylene to Aldehydes
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Table 6. Use of additives in the 8a-catalyzed asymmetric ad-
stronger the Lewis acid, the smaller the percentage of al-
kyne addition product formed.
dition of phenylacetylene to benzaldehyde.[a]
We have prepared a series of b-sulfonamide alcohols
from l-phenylalanine in three steps and in good yield
to act as ligands in this reaction. Among the ligands pre-
pared compound 8a exhibited the best catalytic activity
in the enantioselective addition of phenylacetylene to
aldehydes under very mild conditions, resulting in high
ee and good yield. Furthermore, we found that a small
amount of MeOH used as additive in the reaction en-
hanced the efficiency of the catalyst.
Entry
Additive
Ligand/additive
ee [%][b]
1
2
3
4
5
6
7
8
9
none
–
81
87
92
85
72
60
85
79
77
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
1/1
1/2
1/3
1/4
1/5
1/2
1/2
1/2
t-BuOH
DMPEG
10
1/2
74
Experimental Section
11
1/2
69
General Remarks
All manipulations were carried out under an argon atmosphere
using dried and degassed solvents. Sulfonylamino alcohols 8a
and 8b were synthesized according to literature procedures.[16]
(S)-2-(p-Toluenesulfonylamino)-1,1-diethyl-3-phenyl-1-
propanol [(S)-8a]: White needles; yield: 62%; mp 95–968C;
[a]2D0: À39 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3, TMS):
d¼0.84–0.95 (m, 6H, CH3), 1.43–1.75 (m, 4H, CH2Me), 2.01
12
1/2
63
13
14
(S)-BINOL
(R)-BINOL
1/1
1/1
68
37
[a]
In all of the entries: 5 mol % 8a was used; Et2Zn:phenyl-
acetylene: benzaldehyde:Ti(O-i-Pr)4 ¼3: 3: 1: 0.6.
The absolute configuration of the product is R except for
entry 14.
3
(s, 1H, OH), 2.37 (s, 3H, PhCH3), 2.48 (dd, JH,H ¼9.2 Hz,
3
2JH,H ¼14.2 Hz, 1H, PhCHAHB), 2.94 (dd, JH,H ¼6.2 Hz,
[b]
2JH,H ¼14.2 Hz, 1H, PhCHAHB), 4.65 (m, 1H, CHN), 4.75 (s,
1H, NH), 6.93–7.40 (m, 9H, 2Ph); IR (KBr): n¼3512, 3287,
3066, 3028, 2969, 2882, 1648, 1599, 1457, 1321, 1152, 1086,
960, 908, 812, 736, 698 cmÀ1; MS (ESI): m/z¼360 [MÀH]À.
(S)-2-(p-Toluenesulfonylamino)-1,1,3-triphenyl-1-propa-
nol [(S)-8b]: White needles; yield: 67%; mp 122–1238C; [a]2D0:
þ105 (c 1.2, CHCl3); 1H NMR (200 MHz, CDCl3, TMS): d¼
The enantioselective addition of phenylacetylene to a
variety of aldehydes (Table 7) was investigated using
5 mol % of compound 8a as the chiral ligand with
10 mol % of MeOH as additive. In nearly all cases
enantioselectivities>90% could be obtained for aro-
matic aldehydes. Only m-anisaldehyde and a-naphthal-
dehyde gave lower ee, 80% and 86%, respectively. Ali-
phatic aldehydes, however, gave lower ee than the aro-
matic aldehydes, with phenylacetaldehyde showing the
highest ee.
3
2.37 (s, 3H, CH3), 2.53 (s, 1H, OH), 2.86 (dd, JH,H ¼6.0 Hz,
3
2JH,H ¼14.2 Hz, 1H, PhCHAHB), 3.27 (dd, JH,H ¼3.6 Hz,
2JH,H ¼14.2 Hz, 1H, PhCHAHB), 4.69 (m, 1H, CHN), 4.86 (d,
3JH,H ¼8.2 Hz, 1H, NH), 6.96–7.52 (m, 19H, 4Ph); IR (KBr):
n¼3528, 3303, 3066, 3028, 2926, 1660, 1598, 1493, 1448, 1324,
1153, 1087, 968, 908, 811, 740, 700 cmÀ1; MS (ESI): m/z¼
456[MÀH]À.
(S)-Methyl 3-Phenyl-2-(methanesulfonamino)-
propanoate (10)
Conclusion
It is generally accepted that when the chiral ligands of
BINOL, TADDOL, or sulfonamide alcohols are chelat-
ed with titanium tetroisopropoxide, they function equal-
l-Phenylalanine methyl ester hydrochloride (9; 2.16 g,
10 mmol) was suspended in 25 mL dry diethyl ether and stir-
red. After the system was cooled to 08C, NEt3 (4.2 mL,
ly well as catalysts for reactions such as, e.g., the addition 30 mmol) was added. Methanesulfonyl chloride (0.93 mL,
of alkynyl groups to aldehydes.[11] In this paper, we re-
12 mmol) was dissolved in 10 mL dry diethyl ether and added
to the system dropwise during 30 minutes. The system was
port that when these different ligands are combined to
warmed to room temperature and stirred overnight. After
prepare a titanium-based catalyst with ZnEt2 under sim-
the reaction was complete as checked by TLC, the mixture
ilar conditions and at room temperature, the main reac-
was cooled to 08C and washed with 10 mL 5% aqueous
tion product between the alkyne and aldehyde differs.
NaOH three times and with brine two times, dried over
BINOL-Ti and TADDOL-Ti prefer to add the ethyl
Na2SO4, and concentrated under vacuum. The residue was pu-
group of ZnEt2 to the aldehyde, whereas the sulfona-
rified by flash column chromatography (silica gel, 30% EtOAc
mide alcohol-Ti complex favors the addition of alkyne
to the substrate. We found that the Lewis acidity of the
in hexane) to give the product; yield: 85%; white needles; mp
48–508C; [a]2D0: À25 (c 1.1, CHCl3); 1H NMR (400 MHz,
3
ligand correlated well with chemical selectivity: the CDCl3, TMS): d¼2.55 (s, 3H, CH3), 2.95 (dd, JH,H ¼4.8 Hz,
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Table 7. 8a-catalyzed asymmetric addition of phenylacetylene to aldehydes using MeOH as additive.[a, b,c]
Entry
1
Aldehyde
Time [h]
Isolated yield [%]
ee [%][d]
12
12
95
92
92
95
2
3
12
89
80
4
5
6
12
12
12
91
83
83
95
94
92
7
12
86
90
8[e]
18
18
62
67
86
97
9[e]
10
11
15
15
89
91
76
68
12
15
83
99
[a]
In all of the entries: 5 mol % 8a and 10 mol % MeOH were used; Et2Zn:phenylacetylene:aldehyde:Ti(O-i-Pr)4:8a¼
3: 3: 1: 0.6: 0.05.
[b]
[c]
[d]
[e]
All the reactions were processed under argon and at room temperature.
Ti(O-i-Pr)4 was freshly distilled before use.
The ee values were determined by chiral HPLC with a Chiracel OD column according to the literature method.[6]
We found a significant amount of ethyl-added product when naphthaldehyde was the substrate.
2JH,H ¼12.8 Hz, 1H, PhCHAHB), 3.12 (dd, 3JH,H ¼4.8 Hz, 2JH,H
¼
TLC, the mixture was cooled to 08C and quenched by saturat-
ed aqueous NH4Cl. The mixture was extracted with ether. The
organic layer was washed with brine, dried over Na2SO4, and
concentrated under vacuum. The residue was purified by flash
column chromatography (silica gel, 30% EtOAc in hexane) to
give the product; yield: 86%; white crystals; mp 101–1038C;
[a]2D0: À73 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS):
d¼0.95–1.0 (m, 6H, 2CH3), 1.54–1.79 (m, 4H, 2CH2), 1.90
12.8 Hz, 1H, PhCHAHB), 3.69 (s, 3H, CH3), 4.32 (m, 1H, CH),
5.73 (d, 1H, NH), 7.18–7.28 (m, 5H, Ph); 13C NMR
(100 MHz, CDCl3, TMS): d¼171.8, 135.7, 129.3, 129.1, 126.9,
57.1, 52.3, 40.9, 38.8; MS (FAB): m/z¼258 [MþH]þ; anal.
calcd. for C11H14NO4S: C 51.35, H 5.88; found: C 51.39, H,
5.76.
3
(s, 3H, CH3), 1.95 (brs, 1H, OH), 2.55 (dd, JH,H ¼12 Hz,
3
2
2JH,H ¼14 Hz, 1H, PhCHAHB), 3.05 (dd, JH,H ¼3.2 Hz, JH,H
¼
(S)-2-(Methanesulfonylamino)-1,1-diethyl-3-phenyl-1-
propanol [(S)-11a]:
14 Hz, 1H, PhCHAHB), 3.65 (m, 1H, CH), 4.71 (d, 1H, NH),
7.22–7.35 (m, 5H, Ph); 13C NMR (100 MHz, CDCl3, TMS):
d¼139.3, 130.0, 128.8, 127.0, 76.4, 62.2, 40.9, 36.4, 27.9, 7.6;
HR-MS (ESI): m/z¼303.1743, calcd. for [MþNH4]þ:
303.1737.
Ester 10 (1.1 g, 4.3 mmol) was dissolved in 20 mL dry diethyl
ether and stirred at 08C. Then 4 equivs. of EtMgBr were added
to the mixture dropwise and the system was warmed to room
temperature. After the reaction was complete as checked by
512
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Adv. Synth. Catal. 2006, 348, 506 – 514

Asymmetric Addition of Phenylacetylene to Aldehydes
FULL PAPERS
(S)-2-(Methanesulfonylamino)-1,1,3-triphenyl-1-
propanol [(S)-11b]:
General Procedure for the Addition of
Phenylacetylene to Aldehydes using MeOH as
Additive
Ester 10 (1.1 g, 4.3 mmol) was dissolved in 20 mL dry diethyl
ether and stirred at 08C. Then 4 equivs. of PhMgBr were added
into the mixture dropwise and the system was warmed to room
temperature. After the reaction was complete as checked by
TLC, the mixture was cooled to 08C and quenched by saturat-
ed aqueous NH4Cl. The mixture was extracted with ether. The
organic layer was washed with brine, dried over Na2SO4, and
concentrated under vacuum. The residue was purified by flash
column chromatography (silica gel, 30% EtOAc in hexane) to
give the product; yield: 78%; white crystals; mp 184–1868C;
[a]2D0: þ106 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3,
TMS): d¼1.81 (s, 3H, CH3), 2.06 (brs, 1H, OH), 2.80 (dd,
Under argon, the ligand 8b (9 mg, 0.025 mmol) and Ti(O-i-Pr)4
(20.5 mL, 0.075 mmol) were mixed in dry toluene at room tem-
perature. Then, a solution of Et2Zn (1.0 M in toluene, 1.5 mL),
was added. After the mixture had been stirred at room temper-
ature for 1 h, phenylacetylene (165 mL, 1.5 mmol) was added
and stirred for 30 min. Then, MeOH (2 mL, 0.05 mmol) was
added to the system and stirred for another 30 min. The rest
of the procedure was the same as described in method C.
Acknowledgements
2
3JH,H ¼10.4 Hz, JH,H ¼14.4 Hz, 1H, PhCHAHB), 2.98 (dd,
We are grateful for the grants from the National Natural Science
Foundation of China (Nos. 20525206, 20372028 and 20472026),
the Chang Jiang Program of the Ministry of Education of China
for financial support.
2
3JH,H ¼2.4 Hz, JH,H ¼14.4 Hz, 1H, PhCHAHB), 4.90 (m, 1H,
CH), 5.75 (d, 1H, NH), 7.15–7.42 (m, 10H, 2Ph), 7.72–7.79
(m, 5H, Ph); 13C NMR (100 MHz, CDCl3, TMS): d¼146.7,
140.2, 130.8, 129.1, 128.7, 127.6, 127.5, 127.0, 81.8, 64.4, 42.0,
38.9; HR-MS (ESI): m/z¼399.1741; calcd. for [MþNH4]þ:
399.1737.
References and Notes
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Method A: Under argon, a solution of Et2Zn (1.0 M in toluene,
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bined in 2 mL toluene and refluxed for 5 hours. Then, the sys-
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was complete as checked by TLC, the mixture was cooled to
08C and quenched by 5% aqueous HCl. The mixture was ex-
tracted with ether. The organic layer was washed with brine,
dried over Na2SO4, and concentrated under vacuum. The resi-
due was purified by flash column chromatography (silica gel,
12.5% EtOAc in hexane) to give the product.
Method B: Under argon, the ligand (0.05 mmol) and Ti(O-i-
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temperature. Then, a solution of Et2Zn (1.0 M in toluene,
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1.5 mmol) and aldehyde (0.5 mmol) were added together and
stirred at room temperature. After the reaction was complete
as checked by TLC, the mixture was quenched and purified
by the same procedure as method A.
Method C: Under argon, the ligand and Ti(O-i-Pr)4 were
mixed in dry toluene at room temperature. Then, a solution
of Et2Zn was added. After the mixture had been stirred at
room temperature for 1 h, phenylacetylene was added and stir-
red for another 1 hour. The orange solution was cooled to 08C
and treated with aldehyde, then, the resultant mixture was al-
lowed to warm up to room temperature. After the reaction
was complete as checked by TLC, the mixture was quenched
and purified by the same procedure as for method A.
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Adv. Synth. Catal. 2006, 348, 506 – 514