Functionalized triarylcarbenium ions as catalysts in mukaiyama aldol addition: Effects of counter ions and silyl groups on the intervention of silyl catalysis

Article abstract of DOI:10.1055/s-1998-1815

Stereochemical studies have indicated that functionalized Tr⁺SbCl₆^- may serve as efficient aldol reaction catalysts by judicious choice of a silyl component. The aldol addition between TMS ketene acetal derived from γ-butyrolactone and benzaldehyde provided the silyl aldolates with high syn diastereoselectivities.

Full text of DOI:10.1055/s-1998-1815

924
LETTERS
SYNLETT
Functionalized Triarylcarbenium Ions as Catalysts in Mukaiyama Aldol Addition: Effects of
Counter Ions and Silyl Groups on the Intervention of Silyl Catalysis
Chien-Tien Chen,* Shi-Deh Chao, and Kuao-Chung Yen
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 117
FAX 011-886-2-29324249; INTERNET chefv043@scc.ntnu.edu.tw
Received 20 February 1998
Abstract. Stereochemical studies have indicated that functionalized
contrast to triethyloxonium salts, clean delivery of all trityl
+
–
Tr SbCl may serve as efficient aldol reaction catalysts by judicious
hexachloroantimonates except 3d was achieved by the employment of
6
+
–
choice of a silyl component. The aldol addition between TMS ketene
acetal derived from γ-butyrolactone and benzaldehyde provided the silyl
aldolates with high syn diastereoselectivities.
Me O SbC1 . The optimal procedure involved treatment of the
3 6
+
–
individual trityl methyl ether with Me O SbCl (1.0 equiv.) in a mixed
3
6
solvent of EtNO /CH Cl (1/3). The reaction proceeded with full
2
2
2
strength in less than 4 hours. In all cases but 3d, the resultant trityl
alcohols were recovered essentially in a quantitative sense.
Triphenylcarbenium ions (trityl salts) constitute a unique mode of
carbon-centered Lewis acids for the Mukaiyama-type aldol addition.
1
The reaction profiles in catalytic Mukaiyama aldol addition were
6
So far, the precise nature of the catalytic species in this system remains
examined with 3. Benzaldehyde and silyl ketene acetals derived from
2
elusive in view of several documented facile silyl-mediated pathways.
γ-butyrolactone were selected as test substrates. The stereochemical
Recently, a cogent mechanistic study by Bosnich strongly suggests that
results in the final aldolates serve as indicators to assess the extent of
7
Me Si-X species is the real catalyst in the trityl perchlorate and triflate-
intervention of silyl catalysis, Table 1. Product compositions were
3
3
1
mediated reactions. Their results disagree with our previous
determined by H NMR analysis both before and after column
mechanistic findings by the employment of trityl ions based on a
dibenzosuberane scaffold. One reasonable hypothesis for this
chromatography.
4
When TMS ketene acetal was employed, silyl aldolates 4a (R = Me)
were all obtained (entry 1-5) in moderate yields (30–55%) with
diastereoselectivities in a range of 90/10 to >95/<5 in favor of the syn
isomer (δ = 5.38, J = 2 Hz). In addition, moderate amounts of
desilylated β-hydroxylactones 4b appeared in crude products in all
instances. The chemical yields of the latter components ranged from
36% to 56%. Strikingly, the diastereoselectivities in 4b fall within a
narrow span of 85/15 to 91/9, but predominantly in the opposite anti
discrepancy is that our trityl ions are more catalytically active due to the
peculiar confinements of two of the three aryl groups in a seven-
membered ring. An alternative explanation is that the operation of silyl
catalysis requires a matched use of silyl group and counter ion (e.g.,
TMS and triflate). To support the conjectures, we have conducted a
more thorough stereochemical study of this catalyzed process with
functionalized triarylcarbenium ions.
8
To gain insights into the effects of substituents and counter ions on the
reactivity of trityl ions and extent of silyl catalysis, triarylcarbinols with
5 different aryl appendages of varying electronic and/or steric demands
were synthesized by treatment of dibenzosuberone with the respective
aryllithium. The trityl alcohols were all delivered in good yields ranging
isomer (δ = 4.82, J = 8.8 Hz). It is important to note that when 1/1 (syn/
anti) mixture of 4a was subjected to the similar aldol conditions, no
significant changes in the product composition were observed (85%
recovered, syn/anti = 56/44). This result rules out the possibility that the
opposite anti selectivity in 4b arises from a preferential hydrolysis of the
5
9
from 71 to 91% even in the 2,6-disubstituted cases (1d–f), Scheme 1.
anti silyl aldolate 4a under reaction conditions. Therefore, the opposite
Their structural identities (1d–f) were further proven by X-ray
crystallographic analysis.
sense of diastereocontrol in 4a and 4b are indeed kinetically established
under the reaction conditions.
These findings also indicate that a species related to SbCl might act as
5
a mediator in this aldol process, thus responsible for the origin of the
free aldolates 4b. As expected, essentially 1:1 diastereomeric mixture of
4b were furnished in 57% yield when 20 mol% of SbCl was
5
administered in the aldol reaction (entry 6). Similar results both in terms
of selectivity and chemical yield were obtained when either TMSCl–
+
–
SbCl (20 mol%, 1/1) or Me O SbCl (20 mol%) was subjected to the
5
3
6
same reaction conditions (entry 7 and 8). To probe the possible
influence of ionic clusters on the stereochemical outcome in the aldol
3
process as suggested by Bosnich, the selectivity of the reaction
promoted by TMSCl–SbCl was monitored with increasing loading of
Scheme 1
5
+
–
Bu N SbCl (up to 20 mol%). Virtually no change in stereocontrol was
4
6
sensed in these experiments, thus precluding any ionic strength–
stereocontrol effects. More importantly, we were delighted to find that
no silyl aldolates 4a were detected with these four mediators (entry 6-9).
We have recently developed a novel way of accessing carbenium ions
with functionalized aryl groups, which involves Meerwein salt-
promoted ionization of the corresponding trityl methyl ethers 2. The
requisite ethers can be produced in good to excellent yield (70–97%) by
Drastically opposite results were however obtained when TBS ketene
the standard Williamson etherification procedure (NaH/CH I). Three
acetal was employed. An 1:1 mixture of silyl aldolates 4a (R Si = TBS)
3
3
+
–
+
–
commercial
Meerwein
salts (Et O BF
,
Et O PF ,
6
and
was afforded without contamination of β-hydroxylactones 4b as
illustrated in two representative trityl ion (3b and 3e) mediated aldol
processes (entry 10 and 11). Virtually the same selectivities in 4a were
3
4
3
+
–
Me O SbCl ) have been examined to transform the respective trityl
3
6
methyl ethers into the corresponding triarylcarbenium ions. The
efficiency of this process was assessed by the recovery yield of trityl
alcohols on column chromatography and on HPLC analysis after
buffered, aqueous quenching of the resulting trityl salts. In marked
+
–
observed in the Me O SbCl , TBSCl–SbCl , and SbCl promoted
3
6
5
5
reactions, although free aldols-4b was also isolated in 10% yield in the
last case due to slight SbCl catalysis. Apparently, silyl catalysis
5

August 1998
SYNLETT
925
SbCl catalyzed aldol process may be influenced by the presence of
5
TrCl. Presumably, the TrCl causes subtle changes both in ionic strength
and steric environment around SbCl due to TrCl–SbCl ion pairing
5
5
13
effect. Fourth, the extent of participation of silyl catalysis is governed
by the extent of polarization of the R Si–Cl bond by SbCl . A larger
3
5
polarization in TBS–Cl which allows for its competitive operation of
silyl catalysis can be expected in view of the larger stereoelectronic
effect exerted by the tert-butyl group as compared with the methyl
14
group in TMS–Cl.
In summary, we have documented that the intervention of silyl catalysis
in trityl ion-mediated aldol process highly depends on the propensity of
counter ions and silyl groups. Searches for a better counter ion that can
completely suppress both silyl catalysis and any unproductive (e.g.,
SbCl ) catalytic pathway are currently underway.
5
Acknowledgment. We are grateful to Prof. Scott E. Denmark
(University of Illinois, USA) for his support and advice during the early
stages of this work. The National Science Council of the Republic of
China for generous support of this research is greatly acknowledged.
References and Notes
1
(a) Kobayashi, S. Kagaku To Kogyo 1989, 42, 245 and references
therein. (b) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1997,
119, 10049.
2
For selected R SiOTf mediated aldols: (a) Mukai, C.; Hashizume,
3
S.; Nagami, K.; Hanaoka, M. Chem. Pharm. Bull. 1990, 38, 1509.
(b) Murata, S.; Suzuki, M.; Noyori, R. Tetrahedron 1988, 44,
4259.
3
4
5
Hollis, T. K.; Bosnish, B. J. Am. Chem. Soc. 1995, 117, 4570.
Denmark, S. E.; Chen, C.-T. Tetrahedron Lett. 1994, 35, 4327.
All new compounds gave satisfactory spectroscopic and elemental
analyses.
6
7
(a) Olah, G. A.; Liang, G. J. Org. Chem. 1975, 40, 2108. (b)
+
–
Tr BF , 3, were not fully examined since it was found that BF -
4
3
mediated aldol addition completely took over (see ref. 2).
A representative experimental procedure for Meerwein salt-
mediated generation of triarylcarbenium ions and subsequent
aldol addition is as follows: In a 2-necked flask was placed
+
–
Me O SbCl (99 mg, 0.25 mmol, 20 mol%) in anhydrous EtNO
2
3
6
(2.6 mL). The reaction flask was cooled to -78 °C and a solution
of trityl methyl ether 3e (94.2 mg, 0.26 mmol, 21 mol%) in
anhydrous CH Cl (7.8 mL) was added slowly over 5 min. The
2
2
Scheme 2
resultant brownish orange trityl ion was stirred for 4 h. Freshly
distilled benzaldehyde (127 µL, 1.25 mmol) was then added. After
having been stirred for 10 min, the reaction mixture was treated
with a solution of silyl (TMS) ketene acetal (236.5 mg, 1.49
mmol, 1.2 equiv) in anhydrous CH Cl (5.2 mL) over 10 min. The
2 2
resulting reaction mixture was stirred for another 4 h. Saturated
(TBSCl–SbCl ) efficiently took over in the model reaction although one
5
can not rule out an accidental match of diastereocontrols in both
10
processes.
There are several important features emerging from these studies. First,
no interruption of silyl catalysis may be achieved by judicious selections
aqueous NaHCO (10 mL) or pH 7 buffer was added and the
3
reaction mixture was warmed to room temperature. After usual
workup, the crude yellowish oil was purified by column
chromatography (EtOAc/hexane, 1/4) on silica gel to afford 131.2
mg (55 %) of β-hydroxy ester 4b as a mixture of anti/syn (86/14)
isomers along with 4a (45%, anti/syn = <5/>95).
–
of silyl groups (e.g., TMS) and counter ions (e.g., SbCl ) of the trityl
6
11
+
–
salts. In addition, the delicate balance between Tr SbCl and TrCl–
6
+
12
SbCl allow both the Tr and SbCl act independently as Lewis acids.
5
5
Thus, these two catalytic pathways lead to silyl (4a) and free (4b)
aldolates, respectively, and exhibit different diastereocontrols in 4a and
4b. Second, the high syn selectivity in 4a (entry 1-5) is consistent with
an antiperiplanar transition state assembly between trityl ion-activated
aldehyde and TMS ketene acetal (Scheme 2). Third, the large
difference in the diastereoselectivities of 4b between entry 1-5 (anti/syn,
8
9
Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.; Flippin, L. A. J.
Org. Chem. 1986, 51, 3027.
1
Under the same reaction solvent system, silyl aldolates 4a are
found stable when exposed to neutral (pH 7 buffer) or weakly
85/15–91/9) and entry 6-9 (anti/syn, 50/50) strongly suggested that the
basic aqueous (NaHCO ) solution for 12 hours.
3

926
LETTERS
SYNLETT
10 Note added in proof: The chiral version of the Mukaiyama aldol
addition between benzaldehyde and silyl ketene acetal derived
from ethyl acetate showed unsatisfactory but significant
enantioselectivity. (t-butylphenyl: 11 %ee (TMS), 6 %ee (TBS);
2,6-dimethoxyphenyl: 22 %ee (TBS)). Chen, C.-T.; Chao, S.-D.;
Yen, K.-C.; Chen, C.-H.; Chou, I.-C.; Hon, S.-W. J. Am. Chem.
Soc. 1997, 119, 11341.
Gaspard-Iloughmane, H.; Dubac, J.; Jaud, J.; Vignaux, P. J. Org.
Chem. 1993, 58, 1835.
13 (a) Moderate anti selectivity (70%) in 4b has been documented in
a TiCl -mediated aldol reaction: Tomo, Y.; Yamamoto, K.
4
Tetrahedron Lett. 1985, 26, 1061. (b) For the combined use of
TrCl and SnCl in the aldol addition, see: Mukaiyama, T.;
2
Kobayashi, S. Chem. Lett. 1987, 491.
11 Similar diastereocontrols in 4a were observed with three different
14 (a) Olah, G. A.; Heiliger, L.; Li, X.-Y.; Prakash, G. K. S. J. Am.
+
–
aromatic aldehydes and are applicable with Tr PF (3).
6
Chem. Soc. 1990, 112, 5991. (b) TMSCl–SnCl has been used as
2
12 It seems that SbCl is a sub-stoichiometric catalyst. The aldol
an active catalyst in Mukaiyama-type aldol reaction: Iwasama, N.;
5
chemical yield can reach 90% only when > 50 mol% of SbCl was
Mukaiyama, T. Chem. Lett. 1987, 463.
5
employed. For the use of SbX as Lewis acids, see: Le Roux, C.;
3