An efficient aldol-type reaction of ethyl diazoacetate with aldehydes promoted by MgI2 etherate

Article abstract of DOI:10.3184/174751914X14145853961149

The first example of the preparation of α-diazo-β-hydroxy esters by the aldol-type condensation of aldehydes with ethyl diazoacetate using Et₃N as base in the presence of magnesium iodide etherate [MgI₂.(Et₂O)_n] has been achieved in good to excellent yields at room temperature in CH₂Cl₂ in 15-30 min.

Full text of DOI:10.3184/174751914X14145853961149

690 RESEARCH PAPER
VOL. 38 NOVEMBER, 690–691
JOURNAL OF CHEMICAL RESEARCH 2014
An efficient aldol-type reaction of ethyl diazoacetate with aldehydes
promoted by MgI2 etherate
Tengjiang Zhong, Tianpeng Wu and Xingxian Zhang*
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310032, P.R. China
The first example of the preparation of α‑diazo‑β‑hydroxy esters by the aldol‑type condensation of aldehydes with ethyl
diazoacetate using Et3N as base in the presence of magnesium iodide etherate [MgI2.(Et2O)n] has been achieved in good to
excellent yields at room temperature in CH2Cl2 in 15–30 min.
Keywords: aldehyde, ethyl diazoacetate, α‑diazo‑β‑hydroxy esters, magnesium iodide etherate
The chemistry of α‑diazocarbonyl compounds has received
considerable attention because of the diverse range of
synthetically useful transformations that these compounds
can undergo.1 In particular, α‑diazocarbonyl compounds are
considered to be a potential source of amino alcohols and
acids. The application of α‑diazo‑β‑hydroxy esters has been
extensively explored because these compounds are involved
in many organic transformations.2–4 Among the diverse
synthetic routes available to access α‑diazo‑β‑hydroxy esters,
one attractive method is the condensation of diazoacetate
to aldehydes catalysed by Lewis acids.5,6 In addition to these
methods, α‑diazo‑β‑hydroxy esters can also be obtained by
reactions of diazoacetate with aldehydes through nucleophilic
addition in the presence of a strong base, such as butyllithium,7,8
lithium diisopropylamide (LDA),9–11 sodium hydride,12
potassium hydroxide,13–15 1,8‑diazabicyclo [5.4.0] undec‑7‑
ene (DBU),16 quaternary ammonium hydroxide,17 potassium
t‑butoxide (KOtBu).18 Although the anionic species thus
generated can efficiently add to carbonyl compounds, some
of these methods clearly require strongly basic reagents and
anhydrous conditions.
improved (entries 3–9). This yield was optimised to 95%
by using 1.0 equiv. of MgI2.(Et2O)n and 2.0 equiv. of Et3N
(entry 10).
Of various untreated solvents screened, an excellent yield was
obtained in non‑coordinating reaction media CH2Cl2. Moderate
yields (83%) were provided in toluene. The reaction was very
sluggish in the coordinative polar solvents such as Et2O, MeCN
and THF. The reactions did not take place in more polar solvents,
such as DMF, dioxane and MeOH. To examine the halide anion
effect, halogen analogues of MgI2 etherate were compared
under parallel reaction conditions (1.0 equiv. of promoters).
MgCl2 etherate was almost inactive and MgBr2 etherate was less
effective in terms of substrate conversion and yield.
With the best optimal conditions in hand, a variety of
different aldehydes, including aliphatic, aromatic, and
heteroaromatic aldehydes were subjected to this reaction and
the results are summarised in Table 2. There was no need to
exclude moisture and oxygen from the reaction system. As
shown in Table 2, MgI2 etherate‑Et3N promoted aldol coupling
of ethyl diazoacetate (EDA) with aromatic aldehydes in good
to excellent yields in a very short period. Moreover aromatic
aldehydes bearing either electron‑donating or electron‑
withdrawing groups in the aromatic ring reacted smoothly to
afford the desired aldol adducts in very good to excellent yields
(Table 2, entries 1–8).
In a previous paper, we have demonstrated that MgI2.(Et2O)n,
a mild Lewis acid efficiently promoted the direct aldol addition
of methyl ketones to aromatic aldehydes.19 We now report
an efficient and facile method for the synthesis of α‑diazo‑
β‑hydroxy esters by the coupling of aldehydes with ethyl
diazoacetate (EDA) promoted by MgI2.(Et2O)n in the presence
of Et3N at room temperature under atmospheric conditions.
A heteroaromatic aldehyde, 2‑thiophenealdehyde, was a
good substrate as well (entry 9). An α,β‑unsaturated aldehyde,
cinnamaldehyde, reacted with EDA to afford the aldol adduct
in excellent yield without any decomposition or polymerisation
Results and discussion
To optimise the reaction (Scheme 1), we chose benzaldehyde
(1a R=Ph) as a model substrate and we determined the yield of
product (3a R=Ph) using various amounts of MgI2.(Et2O)n and
Et3N and 1.2 equiv. EDA in CH2Cl2 at room temperature. As
shown in Table 1, without MgI2.(Et2O)n or Et3N, the reaction
could not be carried out (entries 1 and 2). With increasing
amounts of MgI2.(Et2O)n, the yield of aldol product ethyl
2‑diazo‑3‑hydroxy‑3‑phenylpropanoate successively was
Table 1 Optimisation of the reaction conditions for formation of
ethyl 2‑diazo‑3‑hydroxy‑3‑phenylpropanoate 3a (R=Ph) by reaction of
benzaldehyde 1a (R=Ph) with ethyl diazoacetate (EDA) 2 for various times
a
and under several sets of conditions (Scheme 1)
MgI2.(Et2O)n/
mol%b
Yield of 3a
Entry
Et3N/mol%b
Time/h
(R=Ph)/%c
1
2
3
4
5
6
7
8
9
100
0
15
0
200
200
200
150
200
200
200
200
200
300
12
12
8
8
8
3
3
2
1
0
0
40
62
60
71
78
84
90
95
94
30
50
50
60
70
80
100
100
H
O
O
O
O
MgI2
(OEt2)n , Et3N
H
+
OEt
R
OEt
untreated CH2Cl2, r.t.
R
H
10
11
0.25
0.33
atmospheric condition
N2
N2
aReaction conditions: to a solution of benzaldehyde 1a (R=Ph) (1 mmol)
and EDA (1.2 mmol) in untreated CH2Cl2 (5 mL) was added MgI2.(OEt2)n and
Et3N and the mixture stirred for various times.
1
2
3
Scheme 1
bRelative to benzaldehyde.
* Correspondent. E‑mail: zhangxx@zjut.edu.cn
cIsolated yields after silica gel column chromatographic purification.
JCR1402914_FINAL.indd 690
11/11/2014 17:37:06

JOURNAL OF CHEMICAL RESEARCH 2014 691
Table 2 Yields of ethyl 2‑diazo‑3‑hydroxy‑3‑aryl/alkylpropanoates 3a–l
by reaction of the corresponding aldehydes 1 with ethyl diazoacetate (EDA)
Ethyl 2‑diazo‑3‑(4‑fluorophenyl)‑3‑hydroxypropanoate (3e):17
Yellowish oil; δH 1.29 (t, J=7.1 Hz, 3H), 3.52 (br s, 1H), 4.26 (q,
J=7.1 Hz, 2H), 5.89 (d, J=1.25 Hz, 1H), 7.06–7.09 (m, 2H), 7.40–7.43
(m, 2H).
Ethyl 2‑diazo‑3‑hydroxy‑3‑(4‑nitrophenyl)propanoate (3f):17
Yellowish oil; δH 1.28 (t, J=7.1 Hz, 3H), 3.90 (br s, 1H), 4.26 (q,
J=7.1 Hz, 2H), 5.99 (s, 1H), 7.63 (d, J=8.6 Hz, 2H), 8.21–8.24 (m, 2H).
Ethyl 2‑diazo‑3‑hydroxy‑3‑(4‑(trifluoromethyl)phenyl)propanoate
(3g): Pale yellowish solid, m.p. 52.3–53.1 °C (lit.21 51–53 °C). δH 1.29
(t, J=7.2 Hz, 3H), 3.65 (br s, 1H), 4.27 (q, J=7.2 Hz, 2H), 5.96 (s, 1H),
7.56 (d, J=8.2 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H).
Ethyl 2‑diazo‑3‑hydroxy‑3‑(naphthalen‑1‑yl)propanoate (3h):21
Pale yellowish oil; δH 1.33 (t, J=7.2 Hz, 3H), 3.72 (br s, 1H), 4.32 (q,
J=7.2 Hz, 2H), 6.64 (s, 1H), 7.50–7.56 (m, 3H), 7.83–7.95 (m, 4H).
Ethyl 2‑diazo‑3‑hydroxy‑3‑(thiophen‑2‑yl)propanoate (3i):22
Yellowish oil; δH 1.31 (t, J=7.2 Hz, 3H), 3.39 (br s, 1H), 4.29 (q,
J=7.2 Hz, 2H), 6.12 (s, 1H), 7.02 (d, J=3.9 Hz, 1H), 7.03–7.07 (m, 1H),
7.31 (d, J=3.9 Hz).
(E)‑Ethyl 2‑diazo‑3‑hydroxy‑5‑phenylpent‑4‑enoate (3j):17 Yellowish
oil. δH 1.32 (t, J=7.1 Hz, 3H), 2.87 (br s, 1H), 4.27 (q, J=7.1 Hz,
2H), 5.46 (d, J=5.3 Hz, 1H), 6.28 (dd, J=5.6, 16.0 Hz, 1H), 6.82 (d,
J=15.6 Hz, 1H), 7.29–7.42 (m, 5H).
2 using Et3N as base in the presence of magnesium iodide etherate [MgI2.
a
(Et2O)n] for various times (Scheme 1)
Entry
R
t/min
Product
Yields of 3a–l/%b
1
2
3
4
5
6
7
8
9
C6H5
15
15
20
20
20
25
15
15
15
30
15
15
3a
3b
3c
3d
3e
3f
3g
3h
3i
95
92
93
94
93
97
96
93
93
89
90
88
4‑MeOC6H4
2‑MeC6H4
4‑ClC6H4
4‑FC6H4
4‑NO2C6H4
4‑CF3C6H4
1‑Naphthyl
2‑Thienyl
trans‑PhCH=CH
Cyclohexyl
t‑Bu
10
11
12
3j
3k
3l
aReaction conditions: To a solution of aldehyde 1 (R=various) (1 mmol)
and EDA (1.2 mmol) in untreated CH2Cl2 (5 mL) was added MgI2.(OEt2)n
(1 mmol) and Et3N (2 mmol) and the mixture stirred for various times.
bIsolated yields after silica gel column chromatographic purification.
Ethyl 3‑cyclohexyl‑2‑diazo‑3‑hydroxypropanoate (3k):17 Pale
yellowish oil; δH 0.92–1.31 (m, 8H), 1.45–1.80 (m, 5H), 2.0 (d,
J=12 Hz, 1H), 3.23 (br s, 1H), 4.19 (q, J=7.02 Hz, 2H), 4.26 (d,
J=9.34 Hz, 1H).
Ethyl 2‑diazo‑3‑hydroxy‑4,4‑dimethylpentanoate (3l):21 Pale
yellowish oil. δH 0.97 (s, 9H), 1.28 (t, J=7.1 Hz, 3H), 2.94 (br s, 1H),
4.19–4.23 (m, 3H).
(entry 10). In addition to aromatic aldehydes, aliphatic
aldehydes also reacted efficiently under the same conditions
(entries 11 and 12). Note that the addition to the more sterically
hindered aldehyde, t‑butyl aldehyde, gave the product in good
yield (88%). However, ketones did not react, even prolonging
the reaction time.
In conclusion, we have demonstrated the unique reactivity
of MgI2 etherate in the aldol coupling of aldehydes with EDA.
This magnesium‑promoted aldol addition is mild, efficient and
operationally simple. Further investigation on the reactivity
of MgI2 etherate in other C−C bond constructing reactions is
underway.
We are grateful to the National Natural Science Foundation of
China (No. 21372203 and 21272076).
Received 24 September 2014; accepted 23 October 2014
Paper 1402914 doi: 10.3184/174751914X14145853961149
Published online: 13 November 2014
Experimental
References
All reagents were obtained from commercial suppliers, and were used
without further purification unless otherwise indicated. Silica gel
for column chromatography was purchased from Qingdao Haiyang
Chemical Co., Ltd. Melting points were determined using a Büchi
B‑540 capillary melting‑point apparatus. 1H NMR spectra were
recorded with a Bruker Avance instrument at 500 MHz in CdCl3 with
tetramethylsilane as the internal standard.
1
2
T. Ye and M.A. McKervey, Chem. Rev., 1994, 94, 1091.
M.P. Doyle, M.A. McKervey and T. Ye, Modern catalytic methods for
organic synthesis with diazo compounds. Wiley–Interscience, New York,
1998.
3
4
5
6
M.C. Pirrung and J.A. Werner, J. Am. Chem. Soc., 1986, 108, 6062.
D.J. Miller and C.J. Moody, Tetrahedron, 1995, 51, 10811.
W. Yao and J. Wang, Org. Lett., 2003, 5, 1527.
M.E. Dudley, Md. M. Morshed, C.L. Brennan, M.S. Islam, M.S. Ahmad,
M.‑R. Atuu, B. Branstetter and M.M. Hossain, J. Org. Chem., 2004, 69,
7599.
MgI2 etherate‑promoted aldol reaction; general procedure
Freshly prepared MgI2 etherate20 was added to a stirred solution of
aldehyde (1.0 mmol), EDA (127 mg, 1.2 mmol) and Et3N (121 mg,
1.2 mmol) in CH2Cl2 (5 mL) (1.0 mmol) at room temperature. The
resulting reaction mixture was stirred at room temperature for
15–30 min and quenched with saturated aqueous Na2SO3. Extractive
workup with ether and chromatographic purification of the crude
product on silica gel gave the desired aldol adduct.
Ethyl 2‑diazo‑3‑hydroxy‑3‑phenylpropanoate (3a):17 Pale yellowish
oil; δH 1.31 (t, J=7.2 Hz, 3H), 3.26 (br s, 1H), 4.29 (q, J=7.2 Hz, 2H),
5.93 (d, J=2.5 Hz, 1H), 7.28–7.45 (m, 5H).
7
8
9
U. Schçllkopf, H. Frasnelli and D. Hoppe, Angew. Chem. Int. Ed., 1970, 9,
300.
U. Schçllkopf, B. Banhidai, H. Frasnelli, R. Meyer and H. Beckhaus, Eur.
J. Org. Chem., 1974, 1767.
R. Pellicciari and B. Natalini, J. Chem. Soc., Perkin Trans. 1, 1977, 1882.
10 R. Pellicciari, B. Natalini, B.M. Sadeghpour, M. Marinozzi, J.P. Snyder,
B.L. Williamson, J.T. Kuethe and A. Padwa, J. Am. Chem. Soc., 1996, 118, 1.
11 C.J. Moody and R.J. Taylor, Tetrahedron Lett., 1987, 28, 5351.
12 N. Jiang, Z. Qu and J. Wang, Org. Lett., 2001, 3, 2989.
13 E. Wenkert and C.A. McPherson, J. Am. Chem. Soc., 1972, 94, 8084.
14 T.L. Burkoth, Tetrahedron Lett., 1969, 57, 5049.
15 N.F. Woolsey and M.H. Khalil, J. Org. Chem., 1972, 37, 2405.
16 N. Jiang and J. Wang, Tetrahedron Lett., 2002, 43, 1285.
17 R. Varala, R. Enugala, S. Nuvula and S.R. Adapa, Tetrahedron Lett., 2006,
47, 877.
Ethyl 2‑diazo‑3‑hydroxy‑3‑(4‑methoxyphenyl)propanoate (3b):17
Yellowish oil; δH 1.33 (t, J=7.3 Hz, 3H), 3.00 (br s, 1H), 3.83 (s, 3H),
4.29 (q, J=7.3 Hz, 2H), 5.88 (s, 1H), 6.93 (d, J=7.0 Hz, 2H), 7.36 (d,
J=7.0 Hz, 2H).
Ethyl 2‑diazo‑3‑hydroxy‑3‑(o‑tolyl)propanoate (3c):16 Pale yellowish
oil; δH 1.29 (t, J=7.1 Hz, 3H), 3.75 (br s, 1H), 3.84 (s, 3H), 4.25 (q,
J=7.1 Hz, 2H), 5.96 (d, J=4.8 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 7.00
(m, 1H), 7.31 (m, 1H), 7.47 (d, J=7.3 Hz, 1H).
Ethyl 3‑(4‑chlorophenyl)‑2‑diazo‑3‑hydroxypropanoate (3d):17
Pale yellowish oil; δH 1.29 (t, J=7.1 Hz, 3H), 3.69 (br s, 1H), 4.25 (q,
J=7.1 Hz, 2H), 5.87 (s, 1H), 7.34–7.38 (m, 4H).
18 B. Sreebdhar, V. Balasubrahmanyam, C. Sridhar and M.N. Prasad, Catal.
Commun., 2005, 6, 517.
19 Y. Liu, H. Shen and X. Zhang, Main Group Met. Chem., 2012, 35, 111.
20 V. Arkley, J. Attenburrow, G.I. Gregory and T. Walker, J. Chem. Soc.,
1962, 1260.
21 K. Hasegawa, S. Arai and A. Nishida, Tetrahedron, 2006, 62, 1390.
22 S. Kanemasa, T. Araki, T. Kanai and E. Wada, Tetrahedron Lett., 1999, 40,
5059.
JCR1402914_FINAL.indd 691
11/11/2014 17:37:06

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and
its content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.