Solvent- or temperature-controlled diastereoselective aldol reaction of methyl phenylacetate

Article abstract of DOI:10.1021/ol301782s

Unlike the enolboration-aldolization of methyl propanoate, the choice of either the solvent or temperature determines the diastereoselectivity during the enolboration-aldolization of methyl phenylacetate. In CH₂Cl ₂, the reaction favors the anti-pathway at -78 °C and the syn-pathway at rt. Conversely, the reaction produces the anti-isomer up to rt and the syn-isomer at refluxing temperatures in nonpolar solvents.

Full text of DOI:10.1021/ol301782s

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4346–4349
Solvent- or Temperature-Controlled
Diastereoselective Aldol Reaction of
Methyl Phenylacetate
P. Veeraraghavan Ramachandran* and Prem B. Chanda
Herbert C. Brown Center for Borane Research, Department of Chemistry,
Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-2084, United States
chandran@purdue.edu
Received June 28, 2012
ABSTRACT
Unlike the enolborationꢀaldolization of methyl propanoate, the choice of either the solvent or temperature determines the diastereoselectivity
during the enolborationꢀaldolization of methyl phenylacetate. In CH2Cl2, the reaction favors the anti-pathway at ꢀ78 °C and the syn-pathway at rt.
Conversely, the reaction produces the anti-isomer up to rt and the syn-isomer at refluxing temperatures in nonpolar solvents.
The yield and selectivity in chemical reactions depend on
the reaction conditions. It is particularly critical in diaster-
Scheme 1. Synthesis of β-Hydroxyl R-Phenyl Formyl Moiety via
Higher Crotylboration or EnolborationꢀAldolization
eoselective CꢀC bond forming reactions. During the syn-
thesis of phenyl analogs of certain bioactive natural prod-
ucts,1 we were faced with the diastereoselective synthesis of
β-hydroxyl R-phenyl formyl moieties. Our interest in orga-
noborane reagents and reactions2 led to two possible ap-
proaches to achieve the necessary synthon: (i) Brown’s3
“higher crotylboration”ꢀozonolysis using (E)-dicyclohexyl-
(3-phenylallyl)borane (cinnamyldicyclohexylborane) derived
from 1-phenyl-1,2-propadiene (phenylallene) or (ii) enoli-
zationꢀaldolizationꢀreduction of phenylacetate (Scheme 1).4
The former procedure is limited to the preparation of the
E-isomer of the reagent and anti-isomer of the product.
Although the boron-mediated cross-aldol reaction of
carbonyls ranks high among important CꢀC bond forming
thioesters,7 and imides8 has been thoroughly examined and
well-exploited for organic syntheses,5 a similar application
(1) Ramachandran, P. V.; Srivastava, A.; Hazra, D. Org. Lett. 2007,
reactions5 and the enolborationꢀaldolization of ketones,6
9, 157.
(2) (a) Ramachandran, P. V. Aldrichimica Acta 2002, 35, 23.
(b) Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C. Pure Appl.
Chem. 2003, 75, 1263.
(3) Brown, H. C.; Narla, G. Tetrahedron Lett. 1997, 38, 219.
(4) A similar approach via allylic organometallic compounds has
been reported. (a) Yamamoto, Y. Acc. Chem. Res. 1987, 20, 243.
(b) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
(5) (a) Cowden, C. J.; Paterson, I. Organic Reactions; John Wiley &
Sons: New York, 1997; Vol. 51, pp 1ꢀ209. (b) Mahrwald, R. Modern Aldol
Reactions; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2004.
(c) Mahrwald, R. Aldol Reactions; Springer: Dordrecht, Heidelberg, 2009.
(6) (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) Brown, H. C.;
Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.; Singaram, B. J. Am.
Chem. Soc. 1989, 111, 3441.
of the carboxylic acid ester enolates remained relatively
unexplored9 until reports by the Corey10 and Brown11
(7) Hirama, M.; Masamune, S. Tetrahedron Lett. 1979, 20, 2225.
(8) (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.
(9) It was initially reported that di-n-butylboron triflate fails to
enolize methyl propanoate. Evans, D. A.; Nelson, J. V.; Vogel, E.;
Taber, T. R. J. Am. Chem. Soc. 1981, 103, 3099.
r
10.1021/ol301782s
Published on Web 08/10/2012
2012 American Chemical Society

groups involving a dialkylbromo- and iodoborane, respec-
tively. Subsequently, Masamune and Abiko described12
the successful diastereoselective enolizationꢀaldolization
of alkyl propanoates with dialkylboron triflates to the
corresponding syn- or anti-aldols, through the appropriate
choice of the enolizing agent, alkyl propanoates, and amines.
All of the above studies revealed the effects of the sterics of
the ester moiety, the reagent, and the amine on diastereos-
electivity to establish the optimal conditions in which the
bulky tert-butyl propanoates yielded the anti-aldol (>97%)
with dicyclohexylboron triflate (Chx2BOTf, 1) in the pre-
sence of Et3N and methyl propanoates, affording the syn-
aldols (>97%) with di-n-butylboron triflate (n-Bu2BOTf, 2)
in the presence of i-Pr2NEt. However, benzyl propanoates
provided predominantly syn- or anti-aldols with 1 at differ-
ent reaction temperatures.12
A search of the literature revealed that, unlike the aldol
reaction of propanoates, there has been no systematic
investigation of the boron-mediated aldol reaction of
phenylacetates.12,13 A lone example of a syn-selective aldol
reaction of methyl phenylacetate (3)14 with 2 and one of an
anti-selective aldol reaction of ethyl phenylacetate via a Chx2BI-
mediated reaction11 have been described.15,16 However, Chx2BI
is relatively unstable and very sensitive to ethereal solvents.
This prompted a systematic examination of the stereoselective
boron-mediated enolizationꢀaldolization of phenylacetate17
with 1 (chosen due to its ease of preparation). This study has
revealed the complete control of diastereoselectivity in the
enolization of methyl phenylacetate with 1by modifying either
the temperature or the solvent. The details are as follows.
The enolization of 3 with 1, in CH2Cl2, in the presence of
Et3N at 0 °C, followed by aldolization with benzaldehyde
(6a), at the same temperature provided methyl 3-hydroxy-
2,3-diphenylpropanoate (7a) in 88% yield with a syn/anti
ratio of 80:20 (Table 1, entry 1), as was determined from
1
the H NMR spectrum of the crude reaction mixture.18
The reaction of isopropyl phenylacetate (4) yielded 81%
of isopropyl 3-hydroxy-2,3-diphenylpropanoate (8a) with
an increased anti-diastereomer (syn/anti 58:42, Table 1,
entry 2). On the basis of the reported anti-selectivity for
bulky tert-butyl propanoates12b with 1, a higher anti-
selectivity was expected for the enolizationꢀaldolization
of tert-butyl phenylacetate (5). Unfortunately, the enoliza-
tion of 5 with 1 in CH2Cl2 and aldolization with benzalde-
hyde (6a), under the above conditions, did not yield the
desired aldol product (Table 1, entry 3).
The next approach was to examine the influence of
the solvent on the diastereoselectivity of the reaction.
The basis for our approach was the reported solvent effect
on the diastereoselectivity of the aldol reaction of tertiary
amides.19 Thus the enolization of the methyl ester 3 was
examined with 1 in CCl4, pentane, and ether, and indeed,
the reaction yielded ∼90% anti-7a in all of these solvents
(79ꢀ84% yields, Table 1, entries 4ꢀ6). This demonstrates
that less polar solvents favor anti-selectivity. To the best of
our knowledge, this is the first report of a solvent-controlled,
diastereoselective boron-mediated aldol reaction of esters.
Assuming that lowering the temperature would achieve
higher selectivity, the enolization of 3 with 1 was carried
out in pentane (anti-selective solvent) at ꢀ78 °C, followed
by aldolization with 6a at the same temperature, whereas a
selectivity of 3:97 favoring the anti-isomer was achieved
(Table 1, entry 7). Expecting higher syn-selectivity,12b
a ꢀ78 °C reaction was performed in CH2Cl2 (syn-selective
solvent) when, surprisingly, 98% anti-selectivity was ob-
served for 7a (91% yield, Table 1, entry 8)!
(10) Corey, E. J.; Kim, S. S. J. Am. Chem. Soc. 1990, 112, 4976.
(11) (a) Brown, H. C.; Ganesan, K. Tetrahedron Lett. 1992, 33, 3421.
(b) Brown, H. C.; Ganesan, K. J. Org. Chem. 1994, 59, 2336.
(12) (a) Masamune, S.; Abiko, A.; Liu, J.-F. J. Org. Chem. 1996, 61,
2590. (b) Inoue, T.; Liu, J.-F.; Buske, D. C.; Abiko, A. J. Org. Chem.
2002, 67, 5250.
(13) (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997,
119, 2586. (b) Abiko, A.; Liu, J.-F.; Buske, D. C.; Moriyama, S.;
Masamune, S. J. Am. Chem. Soc. 1999, 121, 7168. (c) Abiko, A. Acc.
Chem. Res. 2004, 37, 387.
The limits of this temperature effect on the reaction
were then examined, and we noticed that increasing the
enolizationꢀaldolization temperature to rt or to reflux, in
CH2Cl2, provided an 88:12 syn/anti ratio for 7a (78ꢀ84%
yields) (Table 1, entries 10 and 14). This effect was not
observed in other solvents, which favored the anti-isomer at
rt (Table 1, entries 11ꢀ13). At reflux temperatures, however,
all of the solvents produced predominantly the syn-product
(Table 1, entries 14ꢀ17). Clearly, all of the solvents favor the
kinetic enolate at very low temperature (ꢀ78 °C) and the
thermodynamic enolate at refluxing temperature. The solvent
effect is pronounced at 0 °C (Table 1, entry 1 vs entries 4ꢀ6)
and rt (Table 1, entry 10 vs entries 11ꢀ13).
(14) Pinheiro, S.; Lima, M. B.; Goncalves, C. B. S. S.; Pedraza, S. F.;
de Farias, F. M. C. Tetrahedron Lett. 2000, 41, 4033.
(15) For the lithium enolates of phenylacetate, see: (a) Tanaka, F.; Fuji,
K. Tetrahedron Lett. 1992, 33, 7885. (b) Corset, J.; Froment, F.; Lautie,
M.-F.; Ratovelomanana, N.; Seyden-Penne, J.; Strzalko, T.; Roux-Schmitt,
M.-C. J. Am. Chem. Soc. 1993, 115, 1684. (c) Solladie-Cavallo, A.; Csaky,
A. G. J. Org. Chem. 1994, 59, 2585. (d) Solladie-Cavallo, A.; Csaky, A. G.;
Gantz, I.; Suffert, J. J. Org. Chem. 1994, 59, 5343. (e) Tanaka, F.; Node, M.;
Tanaka, K.; Mizuchi, M.; Hosoi, S.; Nakayama, M.; Taga, T.; Fuji, K. J.
Am. Chem. Soc. 1995, 117, 12159. (f) Fugi, K.; Mija, A.; Tanaka, K. J. Chem.
Soc., Perkin Trans. 1 1998, 185. (g) Ylioja, P. M.; Mosley, A. D.; Charlot,
C. E.; Carbery, D. R. Tetrahedron Lett. 2008, 49, 1111. (h) Harker, W. R. R.;
Carswell, E. L.; Carbery, D. R. Org. Lett. 2010, 12, 3712.
(16) For the titanium enolates of phenylacetate, see: (a) Bernardi, A.;
Dotti, P.; Poli, G.; Scolastico, C. Tetrahedron 1992, 48, 5597.
(b) Matsumura, Y.; Nishimura, M.; Hiu, H.; Watanabe, M.; Kise, N.
J. Org. Chem. 1996, 61, 2809. (c) Periasamy, M.; Suresh, S.; Ganesan,
S. S. Tetrahedron Lett. 2005, 46, 5521.
(17) Forapplicationsofaldolproducts of aryl acetates, see: (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.
Since there is no literature report on the effect of solvents
for the enolizationꢀaldolization of methyl propanoate
(10), we carried out such a reaction in different solvents,
at varying temperatures, to understand this phenomenon
further. Interestingly, we failed to observe a similar effect
on the diastereoselectivity in the case of 10.20 Obviously,
the presence of the phenyl group controls the stereochem-
istry of enolization.
(18) Chemical shift of the carbinol proton of the syn-isomer is δ 5.30
ppm (J = 7.5 Hz), and that of the anti-isomer is δ 5.16 ppm (J = 9.3 Hz).
(19) Brown, H. C.; Ganesan, K. J. Org. Chem. 1994, 59, 7346.
(20) See Supporting Information for details.
Org. Lett., Vol. 14, No. 17, 2012
4347

Table 1. Optimization of Syn- and Anti-Selectivity by Using Reagent 1
ester
cond.a
enolization
aldol products
yield (%)b
aldolization
temperature
entry
3ꢀ5
R
amine
Et3N
solvent
temperature
7aꢀ9a
syn/antid
1
3
4
5
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
Me
i-Pr
t-Bu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
CH2Cl2
CH2Cl2
CH2Cl2
CCl4
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
ꢀ78 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
ꢀ78 °C
7a
8a
9a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
88
81
NRc
82
84
79
78
91
85
78
80
77
76
84
79
76
77
85
76
78
92
79
80:20
58:42
NRc
2
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
i-Pr2NEt
i-Pr2NEt
3
4
12:88
10:90
9:91
5
Et2O
6
pentane
pentane
CH2Cl2
CH2Cl2
CH2Cl2
CCl4
7
3:97
8
ꢀ78 o
C
ꢀ78 o
C
2:98
9
ꢀ30 °C
rt
ꢀ30 °C
rt
18:82
88:12
22:78
34:66
15:85
88:12
84:16
68:32
68:32
10:90
60:40
88:12
4:96
10
11
12
13
14
15
16
17
18
19
20
21
22
rt
rt
Et2O
rt
rt
pentane
CH2Cl2
CCl4
rt
rt
reflux
reflux
reflux
reflux
ꢀ78 °C
ꢀ78 °C
rt
reflux
reflux
reflux
reflux
0 °C
rt
Et2O
pentane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ꢀ78 °C
ꢀ78 °C
rt
ꢀ78 °C
rt
90:10
a Enolization and aldolization times were 2 and 3 h, respectively. b Combined yield of syn and anti isomers. c NR = No reaction. d Syn and anti ratios
were determined by 1H NMR spectroscopy.
It is noteworthy that aldolization temperature also is
critical for high selectivity. For example, the enolization of
Scheme 2. Optimization of Syn- and Anti-Selective Aldol Re-
actions of Methyl Phenylacetate (3) with 1
3 with 1 at ꢀ78 °C, followed by aldolization at 0 °C, or rt
decreased the diastereoselectivity to 90% and 40% anti,
respectively (Table 1, entries 18and 19). Once the enolate is
formed at rt, cooling the reaction for aldolization had no
effect on the diastereoselectivity (Table 1, entry 20).
We examined the influence of the amine by carrying out
the reaction in CH2Cl2 at ꢀ78 °C and rt in the presence of
i-Pr2NEt and found no major effect, although we obtained
a slightly improved syn-selectivity (syn/anti 90:10, Table 1,
entry 22) at rt. Thus, we have achieved a boron-mediated
aldol reaction of methyl phenylacetate with 1, wherein the
diastereoselectivity can be efficiently controlledbya simple
change of solvent or reaction temperature, the latter con-
dition providing optimal results (Scheme 2).
groups (6b, 6c), or electron-withdrawing 4-fluoro
and 4-nitro groups (6d, 6e), cinnamaldehyde (an R,β-
unsaturated aldehyde, 6f), heteroaromatic thiophene-
2-carbaldehyde (6g), and hindered and unhindered ali-
phatic aldehydes (6hꢀk), provided the corresponding
anti-β-hydroxy-R-phenyl esters (anti-7aꢀ7k) in 81ꢀ96%
yields and95ꢀ99% diastereoselectivity. Thesame seriesof
aldehydes, except pivalaldehyde, provided 76ꢀ90% syn-
aldol in 79ꢀ90% yields with 3 and 1 in the presence of
i-Pr2NEt at ambient temperature. Pivalaldehyde provided
The generality of the reaction was demonstrated under
the standardized conditions for the syn-selection (CH2Cl2,
rt) and anti-selection (CH2Cl2, ꢀ78 °C). A series of alde-
hydes of varying steric and electronic requirements were
converted to the corresponding β-hydroxy-R-phenyl esters
in high yields and diastereoselectivities. Thus, methyl
phenylacetate, when treated with reagent 1 in the presence
of Et3N at ꢀ78 °C, followed by aldolization with benzal-
dehyde bearing electron-donating 4-methyl and 4-methoxy
4348
Org. Lett., Vol. 14, No. 17, 2012

a syn/anti ratio of 62:38. The results are summarized in
Table 2.
Table 2. Temperature-Controlled Preparation of Syn- and Anti-
Aldols from Methyl Phenylacetate in CH2Cl2 with 1
In conclusion, a detailed study of the effects of tempera-
ture, solvent, amine, and an ester alkyl group for diastereo-
selective aldol reactions of phenylacetates with 1 has revealed
that the aldol reaction of methyl phenylacetate can provide
either the anti- orsyn-aldol product by the appropriate choice
of solvent and/or temperature.21 This methodology will
provide ready access to molecular synthesis containing a
β-hydoxy-R-phenyl moiety. The role of the phenyl group in
influencing the stereochemistry in different solvents and at
variable temperature is being probed further. An asymmetric
version of this reaction will be reported in due course.
R0CHO
aldol
yield
(%)b
syn/
antic
entry
cond.a
6
R0
7
1
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
6a
6b
6c
6d
6e
6f
C6H5
7a
7b
7c
7d
7e
7f
91
87
81
81
93
82
92
89
86
96
90
79
83
88
83
79
89
87
89
82
87
90
2:98
2:98
2
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-NO2C6H4
E-PhCH=CH
2-Thioph
t-Bu
Acknowledgment. We thank the Herbert C. Brown Cen-
ter for Borane Research for financial assistance of this project.
3
3:97
4
4:96
5
4:96
Supporting Information Available. Experimental details
and spectral data of compounds. This material is available
free of charge via the Internet at http://pubs.acs.org
6
5:95
7
6g
6h
6i
7g
7h
7i
4:96
8
4:96
9
i-Pr
4:96
10
11
12
13
14
15
16
17
18
19
20
21
22
6j
n-Pr
7j
2:98
(21) Typical procedure for anti- or syn-selective aldol reaction. Freshly
prepared dicyclohexylborane (Chx2BH) (0.267 g, 1.5 mmol) was trans-
ferred to a 50 mL round-bottom flask and suspended in 3 mL of
dichloromethane. Trifluoromethanesulfonic acid (TfOH) (0.15 mL, 1.69
mmol) was then added dropwise at 0 °C. The reaction mixture was stirred at
rt for 1 h followed by cooling to ꢀ78 °C. Methyl phenylacetate (1 mmol),
dissolved in 1 mL of dichloromethane, was slowly added to the cooled
reaction mixture. Triethylamine (0.30 mL, 2.2 mmol) was then added
dropwise to the reaction mixture and stirred for 2 h at ꢀ78 °C. Aldehyde
(1.5 mmol) was added dropwise to the solution of enolate and stirred for 3 h
at the same temperature (ꢀ78 °C). The reaction was quenched by addition
of pH 7 buffer solution (2 mL). The mixture was diluted with MeOH (2 mL)
followed by slow addition of 30% hydrogen peroxide (2 mL) and stirred for
4 h at rt. The organic layer was separated, and the aqueous layer was
washed with dichloromethane (3 ꢁ 10 mL). Combined organic layers were
then 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 anti-aldol product. A similar reaction was
carried out at rt and in the presence of N,N-diisopropylethylamine to obtain
pure syn-aldol product.
6k
6a
6b
6c
6d
6e
6f
TBSO-(CH2)2
C6H5
7k
7a
7b
7c
7d
7e
7f
1:99
90:10
85:15
79:21
87:13
85:15
81:19
76:24
62:38
85:15
89:11
88:12
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-NO2C6H4
E-PhCH=CH
2-Thioph
t-Bu
6g
6h
6i
7g
7h
7i
i-Pr
6j
n-Pr
7j
6k
TBSO-(CH2)2
7k
a Anti-selective condition A = Enolization: ꢀ78 °C, Et3N, 2 h; aldoliza-
tion: ꢀ78 °C, 3 h. Syn-selective condition B = Enolization: rt, i-Pr2NEt, 2 h;
aldolization: rt, 3 h. b Combined yield of syn and anti isomers. c Syn and anti
ratios were determined by 1H NMR or GC analysis.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4349