Overriding effect of temperature over reagent and substrate size for boron-mediated aldol reaction of methyl phenylacetate

Article abstract of DOI:10.1016/j.tetlet.2013.08.106

The enolization temperature overrides all other aspects, including the sterics of the alkyl group of the boron reagent and the alkoxy group of the ester during the enolboration-aldolization of phenylacetates. This study has led to the first n-Bu₂

Full text of DOI:10.1016/j.tetlet.2013.08.106

Tetrahedron Letters 54 (2013) 5886–5888
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Overriding effect of temperature over reagent and substrate size
for boron-mediated aldol reaction of methyl phenylacetate
⇑
P. Veeraraghavan Ramachandran , Prem B. Chanda
Herbert C. Brown Center for Borane Research, Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The enolization temperature overrides all other aspects, including the sterics of the alkyl group of the
boron reagent and the alkoxy group of the ester during the enolboration–aldolization of phenylacetates.
This study has led to the first n-Bu2BOTf-mediated anti-selective aldol reaction of an ester.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 24 July 2013
Revised 20 August 2013
Accepted 23 August 2013
Available online 31 August 2013
Keywords:
Enolboration
Aldolization
Methyl phenylacetate
Di-n-butylboron triflate
b-Hydroxy-a-phenyl ester
The boron-mediated cross-aldol reactions of carbonyls have
become routine for the stereoselective construction of C–C bonds
of syn/anti-b-hydroxy-a-methyl moiety in natural and unnatural
1) n-Bu2BOTf (1)
i-Pr2NEt, -78°C
CH2Cl2
OH
O
OMe
>97% syn-aldol
2) i-PrCHO
organic molecules.1 Early development of this reaction focused
on ketones,2 thioesters,3 and imides.4 Nevertheless, the ubiquitous
carboxylates were believed to be unreactive substrates for boron-
mediated aldol reaction.5 This was subsequently established to
be erroneous and the enolboration–aldolization of alkyl propano-
ates was soon added to the repertoire of stereoselective reactions.6
The factors controlling the stereoselectivity of ester aldol reac-
tion were reported to be the bulk of the alkyl group on the boron
reagent, the amine used, and the alkoxy group of the esters.6 In
general, a combination of less bulky reagent and ester; for exam-
ple, di-n-butylboron triflate (n-Bu2BOTf, 1) and methyl propano-
ate in the presence of i-Pr2NEt yielded the syn-aldols and a
bulkier reagent–ester combination; for example, dicyclohexylbo-
ron triflate (Chx2BOTf, 2) and tert-butyl propanoate in the
presence of Et3N yielded anti-aldols (Scheme 1).6c Recognizing
the utility of aldols derived from arylacetates for bio-active mol-
ecules,7 we recently developed a simple protocol for the stereose-
O
OR
R = Me or t-Bu
OH
O
1) Chx2BOTf (2)
Et3N, -78°C
CH2Cl2
OtBu
>97% anti-aldol
2) i-PrCHO
Scheme 1. Optimum conditions for syn- and anti-selective aldol reaction of
propanoates.
typical high selectivity obtained with 2, 95–99% selectivity was
achieved for the anti-aldols. However, the unexpected syn-selec-
tivity (76–90%) was less than satisfactory. This prompted the
examination of the ‘syn-favoring’ reagent, 1 under established
syn-favoring solvent and temperature conditions (CH2Cl2, 0 °C)
to achieve maximum selectivity.8 We were curious whether this
‘syn-favoring’ reagent would also provide anti-aldols under the
recently established anti-favoring solvent and temperature
(pentane, ꢀ78 °C). It became our objective to ascertain the critical
aspects, reagent or reaction conditions, which influence the stere-
oselectivity for the aldol reaction of methyl phenylacetate and we
undertook a systematic study.
This study has revealed that (i) contrary to the reaction of
propanoates, the nature of the alkyl group on the boron reagent
and the alkoxy group of ester has less influence on the diastereose-
lectivity (ds) of the aldol reaction of phenylacetates; (ii) the enoli-
zation temperature controls the ds significantly, and (iii) the less
lective preparation of b-hydroxy-a-phenyl moiety via the
Chx2BOTf-mediated aldol reaction of methyl phenylacetate (3).8
Contrary to the established procedures for propanoates described
in Scheme 1, the temperature and solvent played a dominant role
and either the anti- or syn-aldol can be realized from the methyl
ester 3 even using the bulkier reagent 2. In compliance with the
⇑
Corresponding author.
E-mail address: chandran@purdue.edu (P.V. Ramachandran).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.106

P. V. Ramachandran, P. B. Chanda / Tetrahedron Letters 54 (2013) 5886–5888
5887
1) 1/i-Pr2NEt
0°C, 30 min.
bulky boron reagent, 1, can indeed provide anti-aldol products for
the aldol reaction of methyl ester 3. The details follow.
OH
O
Ph
OMe
syn-5a
65%, 93% syn
OH
CH2Cl2
2) PhCHO, -78°C, 45 min.
The project was initiated with the enolization of 3 by 1 in ‘syn-
favoring solvent’,8 CH2Cl2, in the presence of ‘syn-favoring amine’,6c
i-Pr2NEt, at 0 °C, followed by aldolization of benzaldehyde (4a), at
0 °C, when methyl 3-hydroxy-2,3-diphenylpropanoate (5a) was
obtained in 41% yield and 89:11 syn:anti selectivity (Table 1, entry
1). Although the syn-selectivity improved from 80% to 89% com-
pared to reaction with 2, the yield was considerably lower. Carry-
ing out the enolization at 0 °C and aldolization at ꢀ78 °C improved
the yield to 65% and the selectivity to 93:7 favoring the syn-isomer
(Table 1, entry 2).9 The enolization temperature was increased to
probe whether the syn-selectivity could be improved further.
However, the reactions at room temperature (rt) or at reflux did
not alter the selectivity much (Table 1, entries 3 and 4).
The improved syn-selectivity with the less bulkier reagent 1
accomplished one of our goals. However, we were interested in
exploring whether 1 is capable of enolizing bulky esters, such as
tert-butyl phenylacetate (8) for a complimentary anti-selective al-
dol reaction. This became important since reagent 2 had failed to
enolize 8.8 A reaction of 8 with 1, under similar conditions (CH2Cl2,
i-Pr2NEt, enolization: 0 °C, aldolization: ꢀ78 °C), yielded the corre-
sponding product with 55% anti-selectivity (Table 1, entry 7).
Clearly, the bulk on the ester favored the anti-product; albeit not
prominently. We then carried out the enolization–aldolization of
ethyl- (6) and isopropyl (7) phenylacetate and the trend was
clearly established (Table 1, entries 5 and 6). Encouraged by this
result, 8 was enolized with 1 at ꢀ78 °C, which improved anti-selec-
tivity significantly to 92%, in 75% yield (Table 1, entry 8), validating
the importance of enolization temperature in controlling the
diastereoselectivity for the aldol reaction of phenylacetates. This
indeed is, to the best of our knowledge, the first example of an
anti-selective ester aldol reaction facilitated by n-Bu2BOTf (1). Unfor-
tunately, contrary to 5a, the diastereomers of tert-butyl 3-hydroxy-
2,3-diphenylpropanoate (11a) could not be readily separated by
column chromatography. Not knowing whether the smaller
methyl ester will also provide similar anti-selectivity at low tem-
perature, 3 was enolized and aldolized at ꢀ78 °C. We were elated
to isolate an 87% yield of the aldol with 85% anti-selectivity
O
Ph
Ph
OMe
1) 1/i-Pr2NEt
3
O
-78 oC, 30 min.
Ph
OMe
5a
Solvent
2) PhCHO, -78°C, 45 min.
Ph
anti-
CH2Cl2: 87%, 85% anti
Toluene: 74%, 93% anti
Scheme 2. Optimum conditions for syn- and anti-selective aldol reaction of 3 using 1.
(Table 1, entry 9). This demonstrates that, unlike the propanoate
ester (Scheme 1), the combination of less bulky alkyl group on
enolborating agent (2) and smaller alkoxy group of ester (3) also
avors the anti-selectivity (Scheme 2).
With the hope of improving the anti-selectivity further by tak-
ing advantage of the solvent effect on diastereoselectivity, a reac-
tion was attempted in pentane. Unfortunately, we were unable to
obtain any product in this solvent. The melting point of CCl4 pre-
vented the examination of this solvent below ꢀ23 °C. Adopting tol-
uene as the non-polar solvent improved the anti-selectivity to 93%
(Table 1, entry 10) in 74% yield; thus it became our solvent of
choice for anti-aldols.The bold face data in Table 1 correspond to
the optimal conditions for the reaction.
We also attempted to improve the anti-selectivity further by
using the ‘anti-favoring amine’,6c Et3N. Again, we were concerned
since it has been reported that ‘the combination of a smaller bor-
on-triflate (1) and a smaller amine (Et3N) failed to enolize the pro-
panoate esters’.6c The enolization of phenylacetate 3 with 1, in the
presence of Et3N, followed by aldolization of 4a, provided 40% iso-
lated yield of 5a. Surprisingly, the ds was very poor (Table 1, entry
11).
We demonstrated the overriding effect of the temperature on
the aldol reaction of 3 by carrying out the reaction with another
less bulky reagent, 9-borabicyclo[3.3.1]nonyl triflate (9-BBNOTf,
12) at ꢀ78 °C (Scheme 3). We achieved a 50% yield of the product
in 81% anti-selectivity.
With the optimum conditions for the syn- and anti-selective
enolboration–aldolization of methyl phenylacetate (3) with 1 in
hand, the generality of our protocol was demonstrated. A series
of aldehydes of varying steric and electronic requirements were
tested under both conditions. As can be seen from Table 2, both
aromatic and aliphatic aldehydes were aldolized with similar effi-
ciency. Electron-withdrawing or -donating substituents on the aro-
matic ring did not affect the selectivity or yield. A heteroaromatic
Table 1
Optimization of syn- and anti-selectivity using 1
OH
O
1) n-Bu2BOTf/i-Pr2NEt
temp.; 30 min.
OH
O
O
+
Ph
OR
Ph
OR
Ph
OR
CH2Cl2
2) PhCHO,
temp.; 45 min.
Ph
Ph
3
6
5a 9a
R = Me ( ), Et ( ),
i-Pr (10a), and t-Bu (11a)
R = Me ( ), Et ( ),
i-Pr (7), and t-Bu (8)
aldehyde also gave similar results. An
a,b-unsaturated aldehyde
(cinnamaldehyde) provided only 1,2-addition product. The bulk
of the aldehyde (pivalaldehyde) was detrimental only for the syn-
selection; however the anti-aldols were obtained in high diastereo-
meric excess.
In conclusion, the first detailed study of the effects of tempera-
ture, solvents, amines, and alkoxy groups of esters for the diaste-
reoselective aldol reaction of phenylacetates using a less bulky
boron triflate reagent, (n-Bu2BOTf, 1), has been accomplished. We
have achieved a higher syn-selectivity for the aldol products com-
pared to Chx2BOTf (2). Further, in contrast to the general under-
Entry
Ester
Enol. (°C)
Aldol. (°C)
Aldol.
#
Yielda (%)
syn:antib
1
2
3
4
5
6
7
8
9
3
3
3
3
6
7
8
8
3
3
3
0
0
5a
5a
5a
5a
41
65
62
89:11
93:7
92:8
86:14
88:12
67:33
45:55
8:92
0
rt
ꢀ78
rt
Reflux
0
0
Reflux
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
40
c
9a
c
c
10a
11a
11a
5a
5a
5a
0
ꢀ78
ꢀ78
ꢀ78
ꢀ78
75
87
74
40
15:85
7:93
47:53
10d
11e
1) 12/i-Pr2NEt
-78°C, 30 min.
CH2Cl2
2) PhCHO, -78°C, 45 min.
OH
O
O
a
b
c
Ph
Combined yields of syn and anti-isomers.
Ph
OMe
anti-5a
50%, 81% anti
OMe
Syn and anti ratios were determined by 1H NMR spectroscopy.
Not isolated.
3
Ph
d
e
Toluene was used as solvent.
Et3N was used as amine.
Scheme 3. anti-Selective aldol reaction of 3 using 12.

5888
P. V. Ramachandran, P. B. Chanda / Tetrahedron Letters 54 (2013) 5886–5888
Table 2
References and notes
Examination of various aldehydes for n-Bu2BOTf-mediated syn- and anti-selective
aldol reaction of 3
1. (a) Cowden, C. J.; Paterson, I. Organic Reactions In ; John Wiley & Sons: New
York, 1997; Vol. 51, pp 1–200; (b) Mahrwald, R. Modern Aldol Reactions; Wiley-
1) n-Bu2BOTf/i-Pr2NEt
O
OH
O
OH O
VCH Verlag GmbH
& Co: KGaA, Weinheim, 2004; (c) Mahrwald, R. Aldol
Cond.
Ph
+
OMe
OMe
OMe
R'
R'
Reactions; Springer Dordrecht: Heidelberg London New York, 2009.
2. (a) Mukaiyama, T.; Inoue, T. Chem. Lett. 1976, 559; (b) Van Horn, D. E.;
Masamune, S. Tetrahedron Lett. 1979, 20, 2229; (c) Inoue, T.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 1980, 53, 174; (d) Paterson, I.; Lister, M. A.; McClure, C. K.
Tetrahedron Lett. 1986, 27, 4787; (e) Paterson, I.; Goodman, J. M. Tetrahedron
Lett. 1989, 30, 997; (f) Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.;
Singaram, B. J. Am. Chem. Soc. 1989, 111, 3441.
Solvent
Ph
Ph
3
2) R'CHO, Cond.
5a 5j
-
Entry
Conda
R0CHO
R0
Aldol.
4
5
Yieldb (%)
syn:antic
3. Hirama, M.; Masamune, S. Tetrahedron Lett. 1979, 20, 2225.
1
2
3
4
5
6
7
8
9
10
11
12d
13
14
15
16
17
18
19e
20d
S
A
S
A
S
A
S
A
S
A
S
A
S
A
S
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
4f
C6H5
C6H5
5a
5a
5b
5b
5c
5c
5d
5d
5e
5e
5f
65
74
60
72
52
55
52
66
51
66
67
53
57
55
58
73
63
67
55
68
93:7
7:93
95:5
4:96
91:9
8:92
92:8
7:93
93:7
9:91
91:9
10:90
90:10
10:90
62:38
7:93
90:10
12:88
94:6
10:90
4. (a) Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartoli, J.
Pure Appl. Chem. 1981, 53, 1109; (b) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am.
Chem. Soc. 1981, 103, 2127; (c) Oppolzer, W.; Blagg, J.; Rodriguez, I.; Walther, E.
J. Am. Chem. Soc. 1990, 112, 2767.
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-FC6H4
4-FC6H4
4-NO2C6H4
4-NO2C6H4
(E)-PhCH@CH
(E)-PhCH@CH
2-Thioph
2-Thioph
t-Bu
5. Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc. 1981, 103, 3099.
6. (a) Corey, E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976; (b) Brown, H. C.;
Ganesan, K. J. Org. Chem. 1994, 59, 2336; (c) Inoue, T.; Liu, J.-F.; Buske, D. C.;
Abiko, A. J. Org. Chem. 2002, 67, 5250; (d) Abiko, A. Acc. Chem. Res. 2004, 37,
387; (e) Ramachandran, P. V.; Pratihar, D. Org. Lett. 2009, 11, 1467.
7. (a) van Aardt, T. G.; van Heerden, P. S.; Ferreira, D. Tetrahedron Lett. 1998, 39,
3881; (b) van Aardt, T. G.; van Rensburg, H.; Ferreira, D. Tetrahedron 2001, 57,
7113; (c) McNulty, J.; Nair, J. J.; Griffin, C.; Pandey, S. J. Nat. Prod. 2008, 71, 357;
(d) McNulty, J.; Nair, J. J.; Singh, M.; Crankshaw, D. J.; Holloway, A. C. Bioorg.
Med. Chem. Lett. 2010, 20, 2335; (e) McNulty, J.; Nair, J. J.; Vurgun, N.;
DiFrancesco, B. R.; Brown, C. E.; Tsoi, B.; Crankshaw, D. J.; Holloway, A. C. Bioorg.
Med. Chem. Lett. 2012, 22, 718.
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Ramachandran, P. V.; Chanda, P. B. Chem. Commun. 2013, 49, 3152.
9. A lone example of syn-selective aldol reaction of 3 with 1 under this condition
in 97% syn-selectivity has been reported with no details. Pinheiro, S.; Lima, M.
B.; Goncalves, C. B. S. S.; de Pedraza, S. F.; Farias, F. M. C. Tetrahedron Lett. 2000,
41, 4033.
10. Typical procedure for syn-selective aldol reaction. Di-n-butylboron triflate (n-
Bu2BOTf, 1) (1.1 mmol) (1 M in CH2Cl2) was transferred to a 50 mL oven dried
round-bottom flask, under inert atmosphere, and CH2Cl2 (1 mL) was added.
The solution was cooled to 0 °C and N,N-diisopropylethylamine (0.21 mL,
1.2 mmol) was added slowly. Methyl phenylacetate 3 (1 mmol), dissolved in
1 mL CH2Cl2, was then added, dropwise, and the resulting reaction mixture was
stirred at 0 °C for 30 min. After enolization, the mixture was cooled to ꢀ78 °C
and aldehyde 4 (1.5 mmol) was added, dropwise, and stirred for 45 min at the
same temperature (ꢀ78 °C). The reaction was quenched by the addition of pH 7
buffer solution (2 mL), diluted with MeOH (2 mL), followed by the slow
addition of H2O2 (30%, 2 mL) and was stirred for 4 h at room temperature. The
organic layer was separated and the aqueous layer was extracted with CH2Cl2
(3 ꢁ 10 mL). The combined organic layers were washed with saturated brine
solution (5 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo,
and purified by silica gel column chromatography to obtain pure syn-aldol
products 5a–5j.
4f
5f
4g
4g
4h
4h
4i
4i
4j
4j
5g
5g
5h
5h
5i
5i
5j
5j
A
S
A
S
t-Bu
i-Pr
i-Pr
n-Pr
A
n-Pr
a
S = syn-selective condition: enolization: 0 °C, 30 min; aldolization: ꢀ78 °C,
45 min in CH2Cl2. A = anti-selective condition: enolization: ꢀ78 °C, 30 min; aldol-
ization: ꢀ78 °C, 45 min in toluene.
b
Combined yields of syn and anti isomers.
Syn and anti ratios were determined by 1H NMR spectroscopy.
c
Syn and anti ratios were determined by 13C NMR spectroscopy.
d
e
Syn and anti ratios were determined by GC analysis.
standing on the boron-mediated aldol reaction of esters, we have
demonstrated that the less sterically hindered and relatively
inexpensive reagent 1 can, indeed, be used for the formation of
anti-aldol products from phenylacetates. We have established
that the enolization temperature is the most critical parameter
to control the diastereoselectivity for the aldol reaction of
phenylacetates.10
Typical procedure for anti-selective aldol reaction. Di-n-butylboron triflate (n-
Bu2BOTf, 1) (1.5 mmol) (1 M in CH2Cl2) was transferred to a 50 mL oven dried
round-bottom flask, under inert atmosphere, and the solvent was replaced
with anhydrous toluene (3 mL). The solution was cooled to ꢀ78 °C and methyl
phenylacetate 3 (1 mmol), dissolved in 1 mL toluene, was slowly added to the
cooled reaction mixture. (Caution: too viscous to stir, requires agitation). N,N-
Diisopropylethylamine (0.38 mL, 2.2 mmol) was then added, dropwise, and the
Acknowledgment
resulting reaction mixture was stirred for 30 min at ꢀ78 °C. Aldehyde
4
We thank the Herbert C. Brown Center for Borane Research for
financial assistance of this project.
(1.5 mmol) was then added, dropwise, to the above enolate solution, and the
mixture was stirred for 45 min at the same temperature (ꢀ78 °C). The reaction
was quenched by the addition of pH 7 buffer solution (2 mL). The mixture was
diluted with MeOH (2 mL), then H2O2 (30%, 2 mL) was slowly added, and
stirred for 4 h at room temperature. The toluene layer was separated and
washed with saturated brine solution (2 mL). The aqueous layer was extracted
with CH2Cl2 (3 ꢁ 10 mL) and washed with saturated brine solution (5 mL).
Finally, the combined organic layers were dried over anhydrous Na2SO4,
filtered, concentrated in vacuo, and purified by silica gel column
chromatography to obtain pure anti-aldol products 5a–5j.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
08.106.