Efficient preparation of α-ketoacetals

Article abstract of DOI:10.3390/molecules171213864

The Weinreb amides 2a,b were prepared from the a,a-dimethoxyacetic acids 1c,d. A number of representative nucleophilic additions (RMgX and RLi) on 2 afforded a-ketoacetals 3a-j in 70-99% yield. These compounds represent a versatile arrangement of functional groups of significant synthetic value, as demonstrated in the synthesis of (±)-salbutamol.

Full text of DOI:10.3390/molecules171213864

Molecules 2012, 17, 13864-13878; doi:10.3390/molecules171213864
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Efficient Preparation of α-Ketoacetals
Francisco Ayala-Mata, Citlalli Barrera-Mendoza, Hugo A. Jiménez-Vázquez, Elena Vargas-Díaz
and L. Gerardo Zepeda *
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas del IPN,
Prol. de Carpio y Plan de Ayala S/N, Col. Santo Tomás, Deleg. Gustavo A. Madero, México,
DF 11340, Mexico
* Author to whom correspondence should be addressed; E-Mail: lzepeda@woodward.encb.ipn.mx;
Tel.: +52-55-5729-6300 (ext. 62412); Fax: +52-55-5396-3503.
Received: 22 October 2012; in revised form: 31 October 2012 / Accepted: 19 November 2012 /
Published: 22 November 2012
Abstract: The Weinreb amides 2a,b were prepared from the α,α-dimethoxyacetic acids
1c,d. A number of representative nucleophilic additions (RMgX and RLi) on 2 afforded
α-ketoacetals 3a–j in 70–99% yield. These compounds represent a versatile arrangement of
functional groups of significant synthetic value, as demonstrated in the synthesis of
(±)-salbutamol.
Keywords: α,α-dimethoxyacids; Weinreb amide; Grignard reagents; α-ketoacetals; salbutamol
1. Introduction
The α-ketoacetals constitute a strategic array of functional groups of great value in synthetic organic
chemistry. They offer the possibility of performing the selective functionalization of a keto group over
the more reactive aldehyde, as the latter is protected as an acetal. For instance, α-ketoacetals are key
intermediates in the preparation of chiral cyanohydrins [1], nicotine derivatives [2], chiral sulfoxides [3],
α-hydroxy acetals [4–6], chiral 1,2-diols [7] and, of particular importance for our research group, of
several myrtenal-derived chiral auxiliaries [8–10]. A number of methods have been described for the
preparation of α-ketoacetals, including the classic acetalization of monoalkyl-substituted glyoxals with
trialkylorthoformate [1], treatment of α,α-dichloroketones with MeONa [11], selenium-catalyzed
conversion of terminal alkynes [12] and methyl aryl ketones [13] in the presence of MeOH,
transformation of methoxystyrenes with Ce(IV) ammonium nitrate [14], treatment of methylketones

Molecules 2012, 17
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with alkylnitrite [15], rearrangement of 1,3-dimethoxy-2-alkanones [16], oxidation of arylketones by
thallium(III) and halogens [17], nucleophilic addition to α,α-dialkoxyacetyl chlorides [18] as well as
addition of RMgX and RLi to ethyl α,α-diethoxyacetate [19]. From our own experience, direct
treatment of either α,α-dialkoxyacetates 1a or 1b with Grignard reagents [19] gave the desired
α-ketoacetals invariably accompanied by the corresponding tertiary alcohols. Hence, a protocol for the
separation of the latter must be implemented in order to obtain pure α-ketoacetals. While some
methods lack generality because they need specific substrates, others involve elaborate protocols or the
formation of byproducts which are hard to separate from the reaction mixture. In addition, there is a
scarcity of commercially available α-ketoacetals, which is essentially limited to the existence of
2,2-diethoxyacetophenone and 1,1-dialkoxyacetone [20]. These facts prompted us to develop a general,
easy, and efficient procedure to prepare a wide variety of α-keto-acetals. Therefore, we describe herein
the preparation of Weinreb amides [21] (WAs) 2a,b (Scheme 1) as key reagents for the synthesis of a
wide range of α-ketoacetals through the addition of nucleophiles such as Grignard reagents or
alkyllithiums. The synthetic versatility of α-ketoacetals is demonstrated in the synthesis of rac-salbutamol.
Scheme 1. Commercial α,α-dialkoxyacetates 1a,b, available starting materials for the
synthesis of Weinreb amides 2a,b.
O
O
O
O
R
OMe
R
OR
R
N
O
O
R
2a
2b R = Et
1a
1b R = Et
R = Me
R = Me
2. Results and Discussion
The preparation of WAs 2a and 2b was conceived starting from either commercially
available methyl α,α-dimethoxyacetate (1a) or ethyl α,α-diethoxyacetate (1b) (Scheme 2). Thus,
transesterification of 1a or 1b with the N-magnesium chloride salt of methoxymethyl amine [22–24]
[formed by treatment of N,O-dimethylhydroxylamine (DMHA) with iPrMgCl] in anh. THF at −78 °C
gave WA 2a in 30% yield (R = Me), while 2b (R = Et) was only obtained in trace amounts (i pathway,
Scheme 2). In order to increase the yield of the WAs 2a and 2b, the Ki-Jong [25] protocol was
followed, which made use of the also commercially available [26] α,α-diethoxyacetic acids 1c or 1d as
starting materials.
Thus, using triphosgene in CH2Cl2 at 0 °C, followed by the treatment of the carboxylic acid
chloride intermediate with MeO(Me)NH-HCl and TEA [25], these compounds were readily converted
to their respective WAs 2a and 2b in 88 and 75% yield, respectively (ii pathway, Scheme 2). The WAs
2a and 2b are stable enough to be freely handled without any decomposition under the experimental
procedure. Their purification was achieved by distillation using a Kugelrohr apparatus at 40 °C and
0.5 mmHg, or by column chromatography on silica gel.

Molecules 2012, 17
Scheme 2. Two explored synthetic routes for preparing Weinreb amides 2a,b.
13866
1a
1b
2a
2b
O
O
(30%)
(7%)
i
RO
OCH3
RO
N
OR1
1c
1d
2a
2b
(88%)
(75%)
OR
2a
CH3
OR
ii
R = Me
1a R = R1 = Me
2b R = Et
1b
R = R1 = Et
1c R = Me; R1 = H
1d
R = Et; R1 = H
Reaction conditions for conversion 1a,b  2a,b: (i) a. MeO(Me)NMgCl, THF, −78 °C; b. NH4Cl.
Reaction conditions for conversion 1c,d  2a,b: (ii) a. (Cl3CO)2C=O, CH2Cl2, 0 °C; b. TEA,
MeO(Me)NH-HCl.
A representative series of nucleophilic additions performed on WA 2a yielded only the
corresponding α-ketoacetals 3a–j, with yields ranging from good to excellent (Table 1). Both Grignard
reagents and alkyllithiums led to essentially the same results, as revealed through trials 1 and 6, and 4
and 8, where these different pairs of nucleophiles gave the same product in very similar yields. The
α-ketoacetals were obtained in excellent yields and no further purification was required. In the same
sense, no substantial differences in the reactivity of WAs 2a and 2b were observed, as the latter gave
essentially the same result as the former under nucleophilic addition conditions (see entries 1 and 2, 3
and 4, as well as 6 and 7) giving compounds 4a and 4b. Although some WAs suffer demethoxylation
under the action of LDA or some alkyllithiums (via an E2 reaction) [27], with the concomitant loss of
formaldehyde and formation of the corresponding N-alkylamide, no such behaviour was observed in
this case.
In order to illustrate the synthetic utility of α-ketoacetals they were used for the synthesis of
1,2-aminoalcohols in a protocol similar to that previously described (Scheme 3) [28], a method which
represents a synthetic alternative to that described by using addition of amines to epoxides [29].
For instance, α-ketoacetal 3c was reduced in quantitative yield to the corresponding secondary
carbinol, which was hydrolyzed to the cyclic dimer of the corresponding α-hydroxyaldehyde 6. The
latter was directly treated, without isolation, with primary amines followed by reduction of the imine
intermediate 6 with NaBH4 to afford the corresponding 1,2-aminoalcohols 7a–d in 82–93% yield. This
protocol was then successfully implemented for the total synthesis of (±)-salbutamol, a β2-adrenergic
receptor agonist used for the treatment of chronic obstructive pulmonary disease. Thus, starting from
6-bromosalicylic acid (8), bromobenzodioxane 9 was obtained after reduction of the carboxyl group of
8 and after the successive formation of the dioxane functionality (Scheme 4). Treatment of 9 with Li in
dry THF gave the corresponding organolithium which was subsequently added to Weinreb amide 2a
affording the new α-ketoacetal 10 in 55% global yield from salicylic acid 8. Then, 10 was converted to
carbinol 11 with NaBH4 in MeOH. Finally, after hydrolysis of 11 and successive treatment of the
α-hydroxyaldehyde intermediate with tBuNH2 and reduction of the corresponding ketoimine with
NaBH4, (±)-salbutamol was obtained in 81% yield.

Molecules 2012, 17
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Table 1. Results of the addition of a representative number of nucleophiles to
Weinreb amides 2a,b.
O
O
R1M
RO
RO
OCH3
R1
N
THF, -78 ºC
1.5-2.0 eq.
OR
OR CH3
2a R = Me
2b R = Et
3a-j
4a-b
R = Me
R = Et
Entry
R1M
MeLi
R1
-CH3
Product (% yield)
1
2
3a (95)
4a (90) *
3b (99)
4b (89) *
3c (92)
3a (97)
4a (93)*
4b (91)*
3d (97)
3e (78)
3f (83)
MeLi
-CH3
3
EtLi
-CH2CH3
-CH2CH3
-C6H5
4
EtLi
5
PhLi
6
MeMgBr
MeMgBr
EtMgBr
nPrMgBr
CH3CCMgBr
PhCCMgBr
-CH3
7
-CH3
8
-CH2CH3
-(CH2)2CH3
-C≡C-CH3
-C≡C-C6 H5
-pC6H4-CH3
-pC6H4-F
-mC6H4-OCH3
-CH2C6H5
9
10
11
12
13
14
15
4-MeC6H5MgBr
4-FC6H5MgBr
3-MeOC6H5MgBr
BnMgBr
3g (79)
3h (92)
3i (77)
3j (81)
* Compounds obtained from 2b (R = Et).
Scheme 3. Synthesis of 1,2-aminoalcohols 11a–d from α-ketoacetal 3c.
OH
O
Ph
MeO
1) NaBH4
O
2) HCl, THF
O
OMe
Ph
OH
3c
5
RNH2 neat
OH
OH
H
N
N
NaBH4
MeOH
82-93% global
R
R
7a
=
R
tBu
7b R = CH2CH2OH
7c
6
R = Bn
7d R = CH2-2-THF

Molecules 2012, 17
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Scheme 4. α-Ketoacetal 10 as key intermediate for the synthesis of rac-salbutamol.
O
O
R
1) nBuLi, THF,
OH 1) LiAlH4, THF
O
O
-78ºC
OMe
O
2) WA 2a
2) (CH3)2C(OMe)2
dry acetone
55% four steps
MeO
Br
Br
10
8
R = CO2H
8a R = CH2OH
9
1)
O
OH
OH
NaBH4, MeOH
99%
O
1) HCl 10%, THF, rt
OMe
2) a. tBuNH2 neat
b. NaBH4, MeOH
81% two steps
MeO
N
H
OH
OH
11
rac-salbutamol
3. Experimental
3.1. General Procedures
1H and 13C-NMR spectra were recorded on Varian spectrometers at 500/125 and 300/75 MHz using
CDCl3 as solvent and TMS as internal standard. Chemical shift values (δ) are reported in ppm
1
13
(tetramethylsilane δ = 0 ppm for H; chloroform-d δ = 77.0 ppm for C). Proton spectra are reported
as follows: δ (multiplicity, number of protons, coupling constant J). Multiplicities are indicated by s
(singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet), st (sextet), m (multiplet), bs
(broad signal). Infrared spectra were recorded on a Perkin-Elmer Spectrum 2000 spectrophotometer.
High Resolution Mass Spectra (HRMS) were determined with a JEOL GCmate spectrometer by
Electronic Impact (EI) ionization. Thin-layer chromatograms (TLC) were done on precoated TLC
sheets of silica gel Merck 60F-254. Spots on TLC were revealed by using UV lamp, ceric sulfate,
iodine chamber or 2,4-dinitrophenylhydrazine. Purification of compounds was performed by column
chromatography on silica gel (Merck 230–400 mesh). A Kugelrohr SEV 200 apparatus was also used
for liquid samples. THF was freshly distilled from a purple solution of sodium and benzophenone
under nitrogen atmosphere. Some reagents were purchased from Sigma-Aldrich Chemical Co. and
used without further purification.
N-Trimethoxy-N-methyl-acetamide (2a):
Method A
N,O-Dimethylhydroxylamine hydrochloride (6.70 g, 68.6 mmol) in THF (60 mL) was cooled for 10 min.
at −78 °C in a bath of acetone-dry ice. A freshly prepared solution of isopropylmagnesium chloride

Molecules 2012, 17
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(14.12g, 137.28 mmol) was slowly added to the above solution, maintaining a vigorous stirring for 30 min
under nitrogen atmosphere. To the resulting reaction mixture, methyl dimethoxyacetate (1a, 6 mL,
6.58 g, 49.03 mmol) was added dropwise and the reaction mixture was stirred for 1h at −78 °C, then
quenched with 20 wt % NH4Cl. The reaction was extracted with dichloromethane (3 × 30 mL) and the
organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. The product was purified
using a Kugelrohr apparatus at 40 °C (0.5 mmHg), obtaining amide 2a (2.39 g, 30%) as a pale yellow
oil. The same procedure was followed to prepare amide 2b, starting from ethyl diethoxyacetate (1b).
Method B
To a stirred solution of the carboxylic acid 1c (58 mg; 0.48 mmol) in CH2Cl2 (10 mL) at 0 °C;
triphosgene (71.1 mg; 0.24 mmol) and triethylamine (0.334 mL; 2.398 mmol) were added. Then
N,O-dimethylhydroxylamine hydrochloride (51 mg; 0.52 mmol) was added to the solution and the ice
bath removed. The reaction mixture was stirred at room temperature for 1h. The reaction was extracted
with EtOAc (3 × 10 mL). Then; the organic phase was dried with anhydrous Na2SO4 and concentrated
in vacuum. The product was purified by column chromatography on silica gel using EtOAc-n-hexane
(1:1) as eluent to give 2a (69 mg; 88%). Rf = 0.13 n-hexane:EtOAc (4:1). νmax (film): 2940; 1679;
1
1456; 1196; 1066; 977 cm−1. H-NMR (500 MHz; CDCl3): δ 5.22 (bs; 1H) C-1; 3.75 (s; 3H) MeON;
3.45 (s; 6H) (OCH3)2; 3.20 (bs; 3H) N-CH3. 13C-NMR (125 MHz; CDCl3): δ 167.5 (C-1); 96.3 (C-2);
61.5 (N-OCH3); 53.4 ((CH3O)2); 32.1 (N-CH3). EI-HRMS: calculated for C6H13NO4 163.0845;
observed 163.0852.
2,2-Diethoxy-N-methoxy-N-methyl-acetamide (2b). To a stirred solution of carboxylic acid 1d (1.27 g,
8.60 mmol) in CH2Cl2 (35 ml) at 0 °C, triphosgene (1.28 g, 4.3 mmol) and triethylamine (6 mL,
43.0 mmol) were added. Then N,O-dimethylhydroxylamine hydrochloride (923 mg, 9.46 mmol) was
added to the solution and the ice bath removed. The reaction mixture was stirred at room temperature
for 2h, and then filtered, dried with anh. Na2SO4 and concentrated in vacuo. The product was purified
by column chromatography on silica gel using EtOAc-n-hexane (1:1) to give 2b (1.24 g, 75%).
Rf = 0.33 n-hexane-EtOAc (6:4). νmax (film): 2977, 2934, 1683, 1444, 1146, 1062, 987 cm−1.
1H-NMR (500 MHz; CDCl3): δ 5.21 (bs, 1H) H-1, 3.61 (s, 3H) NOCH3, 3.59 (q, 4H, J = 7.0 Hz)
13
2 OCH2, 3.18 (br, 3H) NCH3, 1.22 (t, 6H, J = 7.0 Hz) (CH3)2, C-NMR (125 MHz; CDCl3): δ 168.0
(C-1), 94.6 (C-2), 63.1 (OCH2), 62.2 (NOCH3), 33.3 (NCH3), 14.8 (CH3). EI-HRMS: peak for
molecular ion (C6H12NO4) not observed. Calculated for [M−OMe]+ 160.0974 (C7H14NO3); observed
160.0974.
3.2. General Procedure for the Preparation of α-Ketoacetals
To a solution of amide 2a (100 mg, 0.61 mmol) in THF (6 mL), cooled at −78 °C, the
organometallic reagents (1.5–2.0 eq.) were slowly added, maintaining vigorous stirring under nitrogen
atmosphere for 1 h. Then, the reaction was quenched with a saturated solution of NH4Cl. The reaction
was extracted with dichloromethane (3 × 4 mL). The organic layer was dried over anh. Na2SO4 and
evaporated to dryness. The crude reaction was flash chromatographed (silica gel) using a mixture of
n-hexane-EtOAc (8:2) as eluent.

Molecules 2012, 17
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1,1-Dimethoxypropan-2-one (3a). (A) Following the General Procedure described above, N-methoxy-
N-methylacetamide (2a, 100 mg, 0.61 mmol) was treated with MeMgBr (0.92 mmol), affording
α-ketoacetal 3a (70 mg, 97%) as a pale yellow liquid. (B) N-methoxy-N-methylacetamide (2a, 100 mg,
0.61 mmol) was treated with MeLi (0.92 mmol), affording α-ketoacetal 3a (68.7 mg, 95%) as a pale
yellow liquid. Rf = 0.66 n-hexane-EtOAc (8:2). 1H-NMR (300 MHz; CDCl3): δ 4.47 (s, 1H) H-1, 3.42
(s, 6H) (OCH3)2, 2.22 (s, 3H) H-3 [11,30–33].
1,1-Dimethoxybutan-2-one (3b). Following the General Procedure described above, N-methoxy-N-
methylacetamide (2a, 100 mg, 0.61 mmol) was treated with EtLi (0.92 mmol), affording α-ketoacetal
1
3b (80 mg, 99%) as a pale yellow liquid. Rf = 0.63 n-hexane-EtOAc (4:1). H-NMR (300 MHz;
CDCl3): δ 4.49 (s, 1H) H-1, 3.40 (s, 6H) (OCH3)2, 2.58 (q, 2H, J = 7.5 Hz) H-3, 1.05 (t, 3H, J = 7.5 Hz)
H-4 [11,30–33].
1,1-Diethoxypropan-2-one (4a). (A) Following the General Procedure described above, N-methoxy-N-
methylacetamide (2b, 100 mg, 0.52 mmol) was treated with MeMgBr (0.78 mmol), affording
α-ketoacetal 4a (71 mg, 93%). (B) N-methoxy-N-methylacetamide (2b, 100 mg, 0.52 mmol) was
treated with MeLi (0.78 mmol), affording α-ketoacetal 4a (69 mg, 90%). Rf = 0.33 n-hexane-EtOAc
1
(85:15). H-NMR (500 MHz; CDCl3): δ 4.25 (s, 1H) H-1, 3.7–3.5 (q, 4H, J = 7.0 Hz) (OCH2)2, 2.18
(s, 3H) H-3, 1.22 (t, 6H, J = 7.0 Hz) 2CH3 [17,34–36].
1,1-Diethoxybutan-2-one (4b). (A) Following the General Procedure described above, N-methoxy-N-
methylacetamide (2b, 100 mg, 0.52 mmol) was treated with EtMgBr (0.78 mmol), affording
α-ketoacetal 4b (75 mg, 90%). (B) N-methoxy-N-methylacetamide (2b, 100 mg, 0.52 mmol) was
treated with EtLi (0.78 mmol), affording α-ketoacetal 4b (74 mg, 89%). Rf = 0.30 n-hexane-EtOAc
1
(85:15). H-NMR (500 MHz; CDCl3): δ 4.53 (s, 1H) H-1, 3.45–3.75 (m, 4H) (OCH2)2, 2.59 (q, 2H,
J = 7.5 Hz) H-3, 1.20 (t, 6H, J = 7.0 Hz) 2CH3, 1.01 (t, 3H, J = 7.5 Hz) H-4 [11,19,36].
1,1-Dimethoxy-2-phenylethan-2-one (3c). Following the General Procedure described above,
N-methoxy-N-methylacetamide (2a, 100 mg, 0.61 mmol) was treated with PhLi (0.92 mmol),
1
affording α-ketoacetal 3c (101 mg, 92%) as a colorless liquid. Rf = 0.51 n-hexane-EtOAc (4:1). H-
NMR (500 MHz; CDCl3): δ 8.11 (dd, 2H, J = 7.8, 1.4 Hz) H-o, 7.57 (td, 1H, J = 7.8, 1.4 Hz) H-p, 7.44
(dd, 2H, J = 7.8, 1.4 Hz) H-m, 5.22 (s, 1H) H-1, 3.47 (s, 6H) (OCH3)2. 13C-NMR (125 MHz; CDCl3):
δ 193.4 (C-2), 133.8 (C-i), 133.6 (C-p), 129.5 (C-o), 128.4 (C-m), 103.3 (C-1), 54.5 (OCH3)2 [1,11,12].
1,1-Dimethoxypentan-2-one (3d). Following the General Procedure described above, N-methoxy-N-
methylacetamide (2a, 100 mg, 0.61 mmol) was treated with n-PrMgBr (0.92 mmol), affording
α-ketoacetal 3d (86 mg, 97%) as a pale yellow liquid. Rf = 0.66 n-hexane-EtOAc (4:1). 1H-NMR (300
MHz; CDCl3): δ 4.47 (s, 1H) H-1, 3.41 (s, 6H) (OCH3)2, 2.54 (t, 2H, J = 7.5 Hz) H-3, 1.61 (qui, 2H,
J = 7.5 Hz) H-4, 0.93 (t, 3H, J = 7.5 Hz) H-5. 13C-NMR (75 MHz; CDCl3): δ 205.7 (C-2), 103.9 (C-1),
54.6 (OCH3), 39.2 (C-3), 16.3 (C-4), 13.7 (C-5) [11].
1,1-Dimethoxypent-3-yn-2-one (3e). Following the General Procedure described above, N-methoxy-N-
methylacetamide (2a, 100 mg, 0.61 mmol) was treated with CH3CCMgBr (0.92 mmol), affording

Molecules 2012, 17
13871
α-ketoacetal 3e (67.6 mg, 78%) as a pale yellow liquid. Rf = 0.40 n-hexane-EtOAc (4:1). νmax (film):
1
2931, 2216, 1683, 1455, 1260, 1187, 1118, 1074, 847 cm−1. H-NMR (500 MHz; CDCl3): δ 4.60
(s, 1H) H-1, 3.35 (s, 6H) (OCH3)2, 2.09 (s, 3H) H-5. 13C-NMR (125 MHz; CDCl3): δ 182.1 (C-2),
103.2 (C-1), 94.7 (C-3), 78.3 (C-4), 54.5 (OCH3), 4.5 (C-5). EI-HRMS: calculated for C7H10O3
142.0630; observed 142.0621.
1,1-Dimethoxy-4-phenylbut-3-yn-2-one (3f). Following the General Procedure described above, N-
methoxy-N-methylacetamide (2a, 100 mg, 0.61 mmol) was treated with PhCCMgBr (0.92 mmol),
affording α-ketoacetal 3f (103.3 mg, 83%) as a pale yellow solid. Rf = 0.40 n-hexane-EtOAc (4:1).
1
νmax (film): 2918, 2204, 1679, 1489, 1444, 1070, 758, 689 cm−1. H-NMR (500 MHz; CDCl3):
δ 7.27–7.43 (m, 5H) Ar, 4.76 (s, 1H) H-1, 3.50 (s, 6H) (OCH3)2. 13C-NMR (125 MHz; CDCl3): δ 182.3
(C-2), 133.4 (C-o), 131.1 (C-p), 128.6 (C-m), 119.6 (C-i), 103.00 (C-1), 94.9 (C-4), 86.4 (C-3), 54.4
(OCH3)2. EI-HRMS: calculated for [M-OMe]+· (C11H9O3) 173.0603; observed 173.0607.
1,1-Dimethoxy-2-(4-methylphenyl)-ethan-2-one (3g). Following the General Procedure described
above, N-methoxy-N-methylacetamide (2a, 100 mg, 0.61 mmol) was treated with 4-Me-C6H4MgBr
(0.92 mmol), affording α-ketoacetal 3g (94 mg, 79%) as a pale yellow liquid. Rf = 0.46
1
n-hexane-EtOAc (4:1). H-NMR (500 MHz; CDCl3): δ 8.12 (d, 2H, J = 8.1 Hz) H-o, 7.36 (d, 2H,
13
J = 8.1 Hz) H-m, 5.23 (s, 1H) H-1, 3.48 (s, 6H) (OCH3)2, 2.43 (s, 3H) CH3. C-NMR (125 MHz;
CDCl3): δ 193.0 (C-2), 144.6 (C-p), 131.3 (C-i), 129.6 (C-o), 129.2 (C-m), 103.1 (C-1), 54.4 (OCH3)2,
21.7 (CH3) [37–39].
1,1-Dimethoxy-2-(4-fluorophenyl)-ethan-2-one (3h). Following the General Procedure described
above, N-methoxy-N-methylacetamide (2a, 100 mg, 0.61 mmol) was treated with 4-F-C6H4MgCl
(0.92 mmol), affording α-ketoacetal 3h (112 mg, 92%) as a pale yellow liquid. Rf = 0.44
1
n-hexane-EtOAc (4:1). H-NMR (500 MHz; CDCl3): 8.17 (m, 2H) H-o, 7.13 (m, 2H) H-m, 5.12 (s,
1H) H-1, 3.48 (s, 6H) (OCH3)2. 13C-NMR (125 MHz; CDCl3): δ 191.9, (C-2), 167.0 (1J (C-F) = 254.3 Hz,
C-p), 132.4 (3J (C-F) = 9.3 Hz, C-o), 130.1 (4J (C-F) = 3 Hz, C-i), 115.5 (2J (C-F) = 21.6 Hz, C-p),
104.1 (C-1), 54.1 (OCH3)2 [37–39].
1,1-Dimethoxy-2-(3-methoxyphenyl)ethan-2-one (3i). Following the General Procedure described
above, N-methoxy-N-methylacetamide (2a, 100 mg, 0.61 mmol) was treated with 3-MeO-C6H4MgBr
(0.92 mmol), affording α-ketoacetal 3i (99 mg, 77%) as a pale yellow liquid. Rf = 0.37
1
n-hexane-EtOAc (4:1). H-NMR (500 MHz; CDCl3): δ 7.72 (dd, 1H, J = 8.0, 1.5 Hz) H-6', 7.61 (dd,
1H, J = 2.7, 1.5 Hz) H-2', 7.37 (t, 1H, J = 8.0 Hz) H-5', 7.13 (dd, 1H, J = 8.0, 2.7 Hz) H-4', 5.23 (s,
13
1H) H-1, 3.86 (s, 3H) ArOCH3, 3.47 (s, 6H) (OCH3)2. C-NMR (125 MHz; CDCl3): δ 193.2 (C-2),
159.6 (C-3'), 135.0 (C-1'), 129.4 (C-5'), 122.2 (C-6'), 120.3 (C-4’), 113.5 (C-2'), 103.0 (C-1), 55.3
(-C6H4-OCH3), 54.4 (OCH3)2 [40,41].
1,1-Dimethoxy-3-phenilpropan-2-one (3j). Following the General Procedure described above,
N-methoxy-N-methylacetamide (2a, 100 mg, 0.61 mmol) was treated with BnMgCl (0.92 mmol),
affording α-ketoacetal 3j (96 mg, 81%) as a pale yellow liquid. Rf = 0.44 n-hexane-EtOAc (4:1).
1H-NMR (500 MHz; CDCl3): δ 7.15–7.35 (m, 5H) Ar, 4.53 (s, 1H) H-1, 3.86 (s, 2H) H-3, 3.41 (s, 6H)

Molecules 2012, 17
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13
(OCH3)2. C-NMR (125 MHz; CDCl3): δ 202.6 (C-2), 133.4 (C-i), 129.7 (C-m), 128.5 (C-o), 126.9
(C-p), 103.6 (C-1), 54.7 (OCH3)2, 44.1 (C-3) [12,17,42].
3.3. General Procedure for the Synthesis of β-Aminoalcohols
To a cooled (0 °C) solution of α,α-dimethoxyacetophenone (3c, 2 g, 11.09 mmol) in EtOH (100 mL)
839.3 mg (22.18 mmol) of NaBH4 were added and the resulting mixture was stirred for 30 min. The
reaction was quenched with acetone, the solvent was evaporated and 100 mL of hot water was added
to the crude reaction. The latter was extracted with dichloromethane (3 × 5 mL), the organic layer was
dried over anh. Na2SO4 and evaporated to dryness giving the corresponding carbinol (1.98 g, 96%).
This compound (500 mg, 2.74 mmol) was treated with 0.2 mL of HCl 37% diluted in 2 mL of THF
and stirred for 15 min. The reaction mixture was washed with a sat. solution of NaHCO3 (3 × 10 mL),
extracted with dichloromethane (3 × 15 mL) and the organic layer was dried over anh. Na2SO4 and
evaporated to dryness, giving 285.9 mg (74%) of 5 as a white solid.
The amine (7.34 mmol) was added to a solution of α-hydroxyaldehyde 5 (200 mg, 1.49 mmol) in
THF and the resulting mixture was stirred for 30 min. The crude reaction was dissolved in 3 mL of
ethanol and treated with NaBH4 (2.94 mmol) under vigorous stirring for 30 min. After this time, the
reaction was quenched with acetone and the solvent was evaporated. The crude syrup was treated with
5 mL of hot water, extracted with dichloromethane and (3 × 5 mL), the organic layer was dried over
anh. Na2SO4 and evaporated to dryness giving the corresponding β-aminoalcohol.
2-(tert-Butylamino)-1-pheny-1-phenylethanol (7a). Following the General Procedure as described
above, intermediate 5 (200 mg, 1.49 mmol) was treated with t-BuNH2 (7.3 mmol). The product was
purified by column chromatography on silica gel using ethanol-dichloromethane (3:7) to give 7a (254 mg,
90%) as a white solid. 1H-NMR (300 MHz; CDCl3): δ 7.38 (m, 5H) Ar-H, 4.62 (dd, 1H, J = 8.8, 3.7 Hz)
H-1, 2.90 (dd, 1H, J = 12.0, 3.7 Hz) H-2a, 2.89 (s, 1H) OH, 2.60 (dd, 1H, J =12.0, 8.8 Hz) H-2b, 1.10
(s, 9H) t-Bu [18,43–45].
2-(2-Hydroxyethyl)-1-phenylethanol (7b). Following the General Procedure described above,
α-hydroxyaldehyde 5 (200 mg, 1.49 mmol) was treated with ethanolamine (7.3 mmol). The product
was recrystallized using n-hexane, giving 7b (218 mg, 82%). 1H-NMR (300 MHz; CDCl3): δ 7.35 (m,
5H) Ar-H, 4.76 (dd, 1H, J = 8.8, 3.7 Hz) H-1, 3.69 (t, 2H, J = 5.1 Hz) H-3, 2.90 (m, 4H) H-2 and H-4,
2.30 (bs, 3H) NH, 2OH [46,47].
2-(Benzylamino)-1-phenylethanol (7c). Following the General Procedure described above,
α-hydroxyaldehyde 5 (200 mg, 1.49 mmol) was treated with benzylamine (7.3 mmol). The product
was recrystallized using n-hexane and a small amount of dichloromethane, giving 7c (311 mg, 93%) as
a white solid. 1H-NMR (300 MHz; CDCl3): δ 7.5–7.10 (m, 10H) Ar-H, 4.73 (dd, 1H, J = 8.9, 3.6 Hz)
H-1, 3.85 (m, 2H) H-3, 2.94 (dd, 2H, J = 12.2, 3.6 Hz) H-2a, (dd, 2H, J = 12.2, 8.9 Hz) H-2b, 2.24 (bs,
2H) OH, NH [48–51].
1-Phenyl-2-((tetrahydrofuran-2-yl)methylamino) ethanol (7d). Following the General Procedure
described above, α-hydroxyaldehyde 5 (200 mg, 1.49 mmol) was treated with 2-tetrahydrofurfurylamine

Molecules 2012, 17
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(7.3 mmol). The product was recrystallized using n-hexane, giving 7d (283 mg, 87%) as a white solid.
1H-NMR (300 MHz; CDCl3): δ 7.35 (m, 5H) Ar-H, 4.70 (dd, 1H) H-1, 4.01 (m, 1H) H-4, 3.79 (m, 2H)
H-7a,b, 2.92 (m, 1H) H-2a, 2.71 (m, 3H) H-3a,b and H-2b, 2.40 (br, 2H) NH and OH, 2.00–1.42
(m, 4H) H-5a,b and H-6a,b [52].
Bromo-2-(hydroxymethyl)phenol (8a). A solution of LiAlH4 (3.5 g, 90 mmol) in 50 mL of ether was
cooled for 30 min. at −78 °C in a bath of acetone-dry ice. After that, a solution of 5-bromosalicylic
acid (8, 16 g, 0.078 mmol) in ether (20 mL) was added dropwise and the reaction mixture was stirred
for 2.5 h under nitrogen atmosphere and was quenched with EtOAc and water (ice). Then, to the
reaction mixture a solution of hydrochloric acid 50% v/v (200 mL) was added. The reaction was
extracted with dichloromethane (3 × 20 mL) and washed with sat. NaHCO3 (3 × 30 mL) and the
organic layer was dried over anh. Na2SO4 and evaporated to dryness. The crude was dissolved in EtOAc
1
and n-hexane was added to obtain a precipitate, obtaining 8a (8.6 g, 57%) as a white solid. H-NMR
(500 MHz; CDCl3): δ 9.80 (br, 1H) OH, 7.31 (d, 1H, J = 2.5 Hz) H-3, 7.20 (dd, 1H, J = 8.6, 2.5 Hz)
H-5, 6.82 (d, 1H, J = 8.6 Hz) H-6, 5.08 (br, 1H) OH, 4.42 (s, 2H) CH2 [53–55].
6-Bromo-2,2-dimethyl-4H-benzo[d][1,3]dioxane (9). To a stirred solution of 8a (5 g, 24.62 mmol),
p-TsOH (450 mg, 0.24 mmol) and sodium sulfate (9.6 g) in acetone (95 mL) 2,2-dimethoxypropane
(121 mmol) were added. The reaction was maintained with a vigorous stirring for 72 h at 40 °C. After
that, the reaction was extracted with CH2Cl2 (120 mL) and washed with sat. NaHCO3 (3 × 30 mL).
The organic layer was dried over anh. Na2SO4 and evaporated to dryness giving 9 (5.65 g, quantitative
1
yield) as an amber liquid. H-NMR (500 MHz; CDCl3): δ 7.21 (dd, 1H, J = 8.5, 2.5 Hz) Hb, 7.03 (d,
1H, J = 2.5 Hz) Hc, 6.70 (d, 1H, J= 8.6 Hz) Ha, 4.78 (s, 2H) CH2, 1.51 (s, 6H) 2CH3 [56].
1-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2,2-methoxyethanone (10). To a solution of 9 (163 mg,
67 mmol) in THF (7 mL) at −78 °C, 1.6 M nBuLi (0.92 mL 1.47 mmol) was slowly added maintaining
a vigorous stirring under nitrogen atmosphere for 45 min. This solution was added dropwise to a
solution of 2a (109 mg, 0.67 mmol) in 10 mL of THF cooled at −78 °C. The reaction was stirred under
nitrogen atmosphere for 1 h. Then the reaction was quenched with a saturated solution of NH4Cl. The
reaction was extracted with dichloromethane (3 × 5 mL), the organic layer was dried over anh. Na2SO4
and evaporated to dryness giving 10 (176 mg, quantitative yield) as a yellow syrup. νmax (film): 1693,
1
1497, 1375, 1272, 1204, 1110, 1067, 955, 433 cm−1. H-NMR (300 MHz; CDCl3): δ 7.98 (dd, 1H,
J = 7.5, 2.3 Hz) H-2', 7.83 (d, 1H, J = 2.3 Hz) H-6', 6.85 (d, 1H, J = 7.5 Hz) H-3', 5.15 (s, 1H) H-1,
4.88 (s, 2H) H-7, 3.46 (s, 6H) (OCH3)2, 1.56 (s, 6H) 2CH3. 13C-NMR (75 MHz; CDCl3): δ 191.9 (C-2),
156 (C-1'), 130.2 (C-5'), 127.1 (C-6'), 126.1 (C-4'), 118.9 (C-2'), 117.0 (C-3'), 103.6 (C-1), 100.5
(C-8'), 60.6 (C-7'), 54.5 ((OCH3)2), 24.7 (2 CH3). EI-HRMS: calculated for C14H18O5 266.1154;
observed 266.1154.
1-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2,2-dimethoxyethanol (11). To a cooled solution (0 °C)
of 10 (161 mg, 0.6 mmol) in ethanol (10 mL) NaBH4 (46 mg, 1.22 mmol) was added. The reaction
mixture was stirred for 30 min. Then it was quenched with acetone, the solvent was evaporated and 5 mL
of hot water was added to the reaction crude. The reaction was extracted with dichloromethane (3 × 5 mL),
the organic layer was dried over anh. Na2SO4 and evaporated to dryness giving 11 (160 mg,

Molecules 2012, 17
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quantitative yield) as a yellow and viscous liquid. 1H-NMR (300 MHz; CDCl3): δ 7.18 (dd, 1H, J = 8.4,
1.6 Hz) H-2', 7.02 (d, 1H, J = 1.6 Hz) H-6', 6.78 (d, 1H, J = 8.4 Hz) H-3', 4.83 (s, 2H) H-7', 4.50 (d,
1H, J = 6.5 Hz) H-2, 4.24 (d, 1H, J = 6.5 Hz) H-1, 3.45 (s, 3H) OCH3, 3.25 (s, 3H) OCH3, 2.90 (br,
13
1H) OH, 1.52 (s, 6H) 2CH3. C-NMR (75 MHz; CDCl3): δ 150.7 (C-4'), 131.2 (C-1'), 126.9 (C-2'),
123.2 (C-6'), 118.9 (C-5'), 116.6 (C-3'), 107.5 (C-1), 99.3 (C-8'), 73.3 (C-2), 60.7 (C-7'), 55.7 (OCH3),
54.7 ((OCH3)2), 24.7 (2CH3), 24.4 (CH3). EI-HRMS: calculated for C14H18O5 268.1311; observed
268.1311.
(±)-Salbutamol. To a solution of hydroxyacetal 11 (160 mg, 0.59 mmol) 37% HCl (0.16 mL) diluted
in THF (1 mL) was added. After 15 min the reaction finished and the reaction mixture was washed
with a solution of NaHCO3 sat (3 × 2 mL). The reaction was extracted with dichloromethane and
(3 × 3 mL) the organic layer was dried over anh. Na2SO4 and evaporated to dryness, giving the
corresponding α-hydroxyaldehyde (80 mg as crude). To this crude t-BuNH2 (0.76 mL, 7.3 mmol) was
added and the reaction mixture was stirred for 30 min. The reaction crude was dissolved in ethanol (3 mL)
and treated with NaBH4 (109.7 mg, 2.9 mmol) under vigorous stirring for 30 min. The reaction was
then quenched with acetone and the solvent was evaporated. After this, hot water (5 mL) was added to
the crude. The reaction was extracted with dichloromethane and (3 × 5 mL). The organic layer was
dried over anh. Na2SO4 and evaporated to dryness giving (rac)-salbutamol (85.3 mg, 81% yield).
1H-NMR (300 MHz; CDCl3): δ 7.11 (dd, 1H, J = 8.1, 1.8 Hz) H-2', 7.03 (d, 1H, J = 1.8 Hz)
H-6', 6.8 (dd, 1H, J = 8.1Hz) H-3', 4.53 (dd, 1H, J = 8.8, 3.7 Hz) CHOH, 3.90 (s, 2H) CH2OH, 2.90
(dd, 1H, J = 12.0, 3.7 Hz) NHCH2, 2.60 (dd, 1H, J = 12.0, 8.8 Hz) NHCH2, 2.2 (br, 4H) NH and
3(OH), 1.10 (s, 9H) t-Bu [57].
4. Conclusions
In conclusion, it has been shown that WAs 2a,b represent an efficient and practical alternative for
obtaining a wide variety of α-ketoacetals, which in turn represent an array of functional groups in high
demand in synthetic organic chemistry. A practical synthetic application of α-ketoacetals was
developed for the synthesis of some 1,2-aminoalcohols, including the total synthesis of (±)-salbutamol.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/17/12/13864/s1.
Acknowledgments
This work was supported by CONACyT (grant 105601) and CGPI-IPN (grants 20110372 and
20120857). FAM and CCBM thank CONACyT (202120 and 202175, respectively) and CGPI/IPN
(PIFI) for graduate fellowships. LGZ and HAJV are fellows of the COFAA and EDI programs of the IPN.

Molecules 2012, 17
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Sample Availability: Samples of the compounds 2a, 2b, 3a–j, 4a, 4b, 7a–d, 9, 10, 11 and
rac-salbutamol are available from the authors.
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