Palladium catalyzed direct benzylation/allylation of malonates with alcohols-: In situ C-O bond activation

Article abstract of DOI:10.1039/c6gc00163g

High step- and atom-economy are the endlessly pursued in organic and pharmaceutical syntheses. Herein, a new method for directly coupling benzyl/allyl alcohols with malonates via a palladium catalyzed Tsuji-Trost type reaction was developed. The reaction was carried out in an organic carbonate solvent which would activate alcohols in situ, replacing the traditional pre-synthesized carbonates. The new process demonstrated high efficiency, high selectivity and high generality. A wide variety of mono-substituted and bis-substituted malonates were selectively produced under different conditions, and this method represents a more step- and atom-economical and environmentally benign synthetic protocol.

Full text of DOI:10.1039/c6gc00163g

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DOI: 10.1039/C6GC00163G
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ARTICLE
Palladium Catalyzed Direct Benzylation/Allylation of Malonates
with Alcohols -- in-situ C-O Bond Activation
Received 00th January 20xx,
Accepted 00th January 20xx
a
a,*
Xueqin Cao and Yugen Zhang
DOI: 10.1039/x0xx00000x
High step- and atomic-economy are the endless pursuit in organic and pharmaceutical synthesis. Herein, a new method for
directly coupling of benzyl/allyl alcohols with malonates via palladium catalyzed Tsuji-Trost type reaction was developed.
The reaction was carried in organic carbonate solvent which would activate alcohols in situ, replacing the traditional pre-
synthesized carbonates. The new process demonstrated high efficiency, high selectivity and high generality. A wide variety
of mono-substituted and bis-substituted malonates were selectively produced under different conditions, and it
represents a more step- and atom-economic and environmentally benign synthetic protocol.
www.rsc.org/
[
11]
The use of naturally abundant and environmentally benign hydroxyl benzyl alcohol an active electrophile. With that, it is proposed to
group in organic synthesis has drawn much attention as it directly apply alcohols as electrophiles for the C-C coupling
represents1-3]a more green and step- and atomic-economic reactions in carbonate solvents. The equilibrium in scheme 1 would
[
synthesis.
Palladium-catalyzed Tsuji-Trost type benzylation and be pushed to right side as carbonate intermediate is converted to
allylation reactions are efficient and widely used synthetic the coupling product (scheme 1(c)).
approaches in organic synthesis, especially for C-C bond
[4,5]
formations.
Typically, in this type of reaction, a benzyl/allyl
halide/acetate/carbonate/phosphonate is used as activated alcohol
with proper leaving group to react with nucleophile in chemo- and
[6]
stereoselective way. These activated alcohol reagents require an
additional synthetic step as compared to the use of alcohols directly
and yet generate stoichiometric amounts of waste during the
coupling reaction. In this context, the development of new method
to directly apply alcohols as electrophiles for benzylation/allylation
of nucleophiles under mild and environmental benign conditions Scheme 1. (a) Typical synthetic method for alcohol protection
[
7]
and activation with carbonate; (b) Equilibrium between alkyl
alcohol and carbonate; (c) Hypothesis for directly applying
alcohol as electrophile for C-C coupling reaction.
would be highly desirable. Herein, it is demonstrated that
benzyl/allyl alcohols can act as effective electrophiles in palladium-
catalyzed C-C bond formation reactions in which the C-O bonds are
in-situ activated by organic carbonate. The direct transformation of
The alkylation of active methylene compounds is a fundamental
reaction in organic synthesis, and has usually been carried out
alcohol represents
a more step- and atom-economic and
environmentally benign protocol.
Dimethyl carbonate is stable and represents a low-cost, low
toxicity and easy availability solvent. Organic carbonates are also
considered as green solvents as they are completely biodegradable
[
12]
under basic condition. The above hypothesis is firstly tested in
the reaction of palladium-catalyzed benzylation/allylation of
malonates. Typically, benzylation of 2-substituted malonates was
carried by using benzyl carbonates and base with
[8]
[
9]
and can be synthesized from carbon dioxide.
Carbonate
[13]
palladium/phosphine catalyst under heating condition.
Herein,
protected/activated benzyl/allyl alcohols were typically synthesized
by the reaction of alcohols and chloroformate (scheme 1(a)). While,
it is also known that there is an equilibrium between alcohol and
carbonate under basic condition, scheme 1(b). The formation of
benzyl carbonate will activate the benzylic C-O bond and make
benzyl alcohol was used instead of benzyl carbonate in the reaction.
Control reaction for benzyl alcohol and dimethyl methylmalonate
(DMMM) with Pd-dppp (diphenylpropylphosphine) catalyst and
[10]
t
NaO Bu in N,N’-dimethylformaldehyde (DMF) did not give any
product and starting materials were fully recovered (Table 1, entry
1
4). When Cs CO was used as base, a lousy result was obtained
2 3
a.
with low selectivity toward benzylated manolate (29%) (Table 1,
entry 15). This result indicates that inorganic carbonate could also
have equilibrium with benzyl alcohol to form benzyl methyl
carbonate. However, this equilibrium is not useful for synthetic
application. Subsequently, the reaction mediate was changed to
Dr. X. Cao, Dr. Y.G. Zhang.
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
Singapore 138669, Singapore. E-mail: ygzhang@ibn.a-star.edu.sg
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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ARTICLE
Journal Name
dimethylcarbonate (DMC). In this case, almost quantitative amount
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DOI: 10.1039/C6GC00163G
of benzylated DMMM was obtained when 2 mol% of Pd(OAc) , 4.8
2
mol% of dppp and 2 equiv. of base were applied (Table 1, entry 6).
A control reaction with methyl-benzylcarbonate as starting material
[
13]
(
Kuwano’s method ) was also carried and 75% yield of benzylated
DMMM was obtained. It indicates that the in-situ generated
benzylcarbonate intermediate could be more active in the reaction
with DMMM. Further condition optimization showed that bi-
dentate phosphine ligands gave better results than other ligands
t
(
Table 1, entries 1-6). NaO Bu and Cs CO gave better results among
2
3
those bases have been tested (Table 1, entries 6-11). The reaction
can also be carried in the mixture solvents of DMC and Tol or DMF
with the yield of product decreased 17-28% (Table 1, entries 12-13).
With the optimized conditions in hand (Table S1), substrate scope
was then screened.
Table 1. Reaction conditions screening for the benzylation of
[a]
DMMM.
[
b]
Entry Ligand,
mol%
Base
Sol.
Yield
%
(equiv.)
Cs CO (2)
Scheme 2. Substrate scope of alcohols in palladium catalyzed
benzylation/allylation of dimethyl methylmalonate.
[c]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
dba
DMC
DMC
DMC
DMC
DMC
DMC
80
60
79
20
83
90
87
47
57
30
72
73
62
0
2
3
[
d]
Ph3P
P Ph , 4.8
Cs CO (2)
2 3
Cs CO (2)
2
2
5
3
Table 2. Palladium catalyzed benzylation/allylation of dimethyl
malonate to selectively produce mono-substitued and bis-
substituted malonates.
PPh CH , 4.8 Cs CO (2)
2
3
2
3
dcype, 4.8
dppp, 4.8
dppp, 4.8
dppp, 4.8
dppp, 4.8
dppp, 4.8
dppp, 4.8
dppp, 4.8
dppp, 4.8
dppp, 4.8
dppp, 4.8
Cs CO (2)
2 3
Cs CO (2)
2
3
t
NaO Bu (2) DMC
KOH (2)
DMC
DMC
DMC
DMC
DMC/Tol
DMC/DMF
K CO (2)
2
3
0
1
2
3
4
5
NaOAc (2)
Na PO (2)
3
4
Cs CO (2)
2
3
Cs CO (2)
2
3
t
NaO Bu (2) DMF
Cs CO (2) DMF
29
2
3
[a]
[a]
Alcohols Yield of
5
Yield of 6
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
85
93
92
94
69
71
68
<5
72
60
60
65
62
94[
53
83
77
61
68
76
73
78
0
62
51
60
85
0
90
67
[
a] General reaction conditions: Benzyl alcohol (1 mmol),
b
DMMM (1 mmol), Pd(OAc) (2 mol%), solvent (2 mL). [b] NMR
yield. [c] Tris(dibenzylideneacetone)dipalladium was used as
catalyst. [d] (Ph P) Pd was used as catalyst. dcype = 1,2-
2
3
4
b
bis(dicyclohexylphosphino)ethane.
The scope of the reaction was then investigated with a
variety of benzyl alcohols and allyl alcohols (Scheme 2). Benzyl
alcohols with electron donating substituents in all 2-, 3-, and 4-
position underwent smooth coupling with DMMM to afford
substituted malonates (3b to 3h) in good to excellent yields.
Electron-deficient benzyl alcohols also underwent smooth
coupling reactions to give good to excellent yields (3i to 3k).
Bulky substitutions on benzyl alcohols did not affect much of
b
b
b
c]
the reaction (3b
good as benzyl alcohols (3n and 3o) in this system.
, 3i and 3m). Allyl alcohols reacted equivalent
[
a] Isolated yields. [b] 48 h. [c] 1:4 = 0.67.
2
| J. Name., 2012, 00, 1-3
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catalyst will undergo oxidative cleavage of C-O bond to form
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DOI: 10.1039/C6GC00163G
B. Meanwhile, malonate is activated by base to
With Pd-dppp catalyst, various bases and solvents were intermediate
further evaluated for the reaction of benzyl alcohol and form intermediate
C
which attach to Pd center forming D.
dimethyl malonate to achieve high chemo-selectivity of mono- Following with that, substituted malonate is released via
or bis-substituted benzyl/allyl malonates (Table S2 and S3). reductive elimination and concurrently, palladium catalyst is
High yield of desired bis-substituted product
6 was obtained regenerated to close the cycle. For allyl alcohol substrates, no
with the combination of Cs CO and DMC. In contrast, reaction allyl methyl carbonate intermediate was observed during the
2
3
conditions need to be carefully adjusted in order to achieving reaction. It may due to the higher activity of allyl alcohol
satisfied yields of mono-substituted products (Table S3). As substrates. In fact, control reaction for allyl alcohol and
shown in Table 2, the same alcohol scope was screened for dimethyl methylmalonate (DMMM) with Pd-dppp
coupling reaction with dimethyl malonate. Both mono- (diphenylpropylphosphine) catalyst and NaO Bu in toluene did
substituted products and bis-substituted products were give significant amount of allyl malonate product.
5
t
5
6
produced in satisfied yields for most of alcohols under
separated reaction conditions. The only exception is alcohol 1h
with amine functionality, very low or no yield was obtained
from two reaction systems. There is also no bis-substituted
product for alcohol 1m, due to its huge steric hindrance.
An interesting bis-alcohol substrate (2,2′-Biphenyl-
dimethanol) was tested in the reaction conditions for product
Conclusions
A new method for directly coupling of benzyl/allyl alcohols with
malonates via palladium catalyzed Tsuji-Trost type reaction was
developed. The reaction was carried in organic carbonate solvent
which would activate alcohols in situ. The new process
demonstrated high efficiency, high selectivity and high generality.
This finding may provide a general method for direct using alcohol
in coupling reactions which represents a more step- and atom-
economic and environmentally benign synthetic protocol.
6
. As expected, a seven-member ring bis-substituted malonate
was synthesized (scheme 3). It may be a useful method for the
synthesis other cyclic products. In addition, acetacetic ester
also works well in current system (Table S4).
Acknowledgements
This work was supported by the Institute of Bioengineering
and Nanotechnology (Biomedical Research Council, Agency
for Science, Technology and Research (A*STAR), Singapore).
Scheme 3. The synthesis of a seven-member ring bis-substituted
malonate.
Notes and references
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DOI: 10.1039/C6GC00163G
TOC:
A method for directly coupling of benzyl/allyl alcohols with
malonates via palladium catalyzed Tsuji-Trost type reaction.
This journal is © The Royal Society of Chemistry 20xx
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Green Chemistry
Page 6 of 64
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DOI: 10.1039/C6GC00163G
Supporting Information
Palladium Catalyzed Direct Benzylation/Allylation of Malonates
with Benzyl-/Allyl-Alcohols – In Situ C-O Bond Activation
Xueqin Cao, Yugen Zhang*
Institute of Bioengineering and Nanotechnology
31 Biopolis Way, The Nanos
Singapore 138669
Eꢀmail: ygzhang@ibn.aꢀstar.edu.sg
Table of Contents
1.General Information
S2
2
. Procedure of the benzylation/allylation of DMMM
. Procedure of the benzylation/allylation of DMM
. References
S2ꢀS5
3
S6ꢀS12
4
5
S15
1
13
. H and C NMR Spectra
S15ꢀS57

Page 7 of 64
Green Chemistry
View Article Online
DOI: 10.1039/C6GC00163G
1. General Information
All anhydrous solvents were purchased from SigmaꢀAldrich and used without further purification. All
other reagents were used as received. All reactions were carried out under an argon or nitrogen
atmosphere.
Analytical thin layer chromatography (TLC) was performed using Merck 60 Fꢀ254 silica gel plates with
visualization by ultraviolet light (254 nm) and/or I . Flash column chromatography was carried out on
2
Kieselgel 60 (0.040ꢀ0.063 mm) supplied by Merck under positive pressure.
1
13
H and C nuclear magnetic resonance (NMR) spectra were recorded on Bruker AVꢀ400 (400 MHz)
spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) with the residual solvent peak of
1
tetramethylsilane used as the internal standard at 0.00 ppm. H NMR data are reported in the following
order: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet and m =
multiplet), coupling constants (J, Hz), integration and assignment. High resolution mass spectra (HRMS)
were recorded on a Bruker micrOTOFꢀQII spectrometer.
1
2
3
1
13
Compounds 3a, 3f, and 5f were identified by comparison with their H and C NMR spectra reported
in the literature.
2. Procedure of the benzylation/allylation of DMMM
General procedure:
O
O
OH
Pd(OAc)2 (2 mol%),dppp (4.8 mol%)
Cs CO (2 eq.) DMC 120 oC, 24h
O
+
DMMM
2
2
3
,
,
R
R
O
1
3
Under nitrogen atmosphere, benzyl alcohol (1.0 mmol), DMMM (1.0 mmol), Pd(OAc) (4.5 mg, 20
2
ꢁ
mol), dppp (20 mg, 48 ꢁmol), Cs CO (652 mg, 2.0 equiv) and dimethylcarbonate (DMC) (2 mL) were
2 3
combined in a 20 mL headspace vial fitted with a suba seal cap. The mixture was stirred at 120 °C for 24
h, then cooled to room temperature. The mixture was filtered and washed by ethyl acetate. The obtained
filtration was evaporated under reduced pressure. The residue was purified by flash column
chromatography (EtOAc/hexane) to give the desired product.
Table S1. Reaction conditions screening for the benzylation of DMMM.
O
OH
Pd(OAc)2 dppp
,
O
+
DMMM
Cs CO , DMC , T, t
2
3
O
O
o
a
Entry Pd(OAc)2 dppp (eq.) Cs CO
DMC Coꢀsolvent T ( C) t (h)
Yield(%)
79
2
3
mol%
2
mol%
4.8
eq.
1
mL
2
mL
ꢀ
1
120
24
S2

Green Chemistry
Page 8 of 64
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DOI: 10.1039/C6GC00163G
2
3
4
5
6
7
8
9
1
1
2
2
2
2
2
2
2
1
2
2
4.8
4.8
4.8
4.8
4.8
4
1.5
2
2
2
2
2
2
2
2
2
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
120
120
120
120
100
120
120
120
24
24
16
20
24
24
24
24
24
24
85
90
76
83
29
85
81
80
< 5
< 5
2
2
2
2
2.5
2
2
2
0
1
4.8
4.8
2
0.34 Toluene (1) 120
2
0.34 DMF (1) 120
a
Reaction conditions: Benzyl alcohol (1.0 mmol), DMMM (1.0 mmol). Yield by NMR.
Dimethyl 2-benzyl-2-methylmalonate (3a)
This compound was prepared according to general procedure and isolated by flash
column chromatography (ethyl acetate/hexane=1/20) as a colourless solid (203 mg,
[1] 1
8
6%). Spectroscopic data were in agreement with the published data.
H NMR (400
MHz, d ꢀDMSO) δ 7.30ꢀ7.23 (m, 3H, ArH), 7.10ꢀ7.07 (m, 2H, ArH), 3.67 (s, 6H, 2 x
6
1
3
CH ), 3.12 (s, 2H, CH ), 1.22 (s, 3H, CH ); C NMR (101 MHz, d ꢀDMSO) δ 171.8, 135.9, 130.3, 128.4,
27.2, 54.4, 52.8, 40.7, 19.5; HRMS (ESI+) calc. for C H O [M+Na] 259.0941; found 259.0942.
3
2
3
6
+
1
13 16 4
Dimethyl 2-(2-methoxybenzyl)-2-methylmalonate (3b)
This compound was prepared according to general procedure and isolated by flash
column chromatography (ethyl acetate/hexane=1/20) as a colourless solid (242 mg,
1
9
1%). H NMR (400 MHz, d ꢀDMSO) δ 7.22 (ddd, J = 8.3, 7.4, 1.8 Hz, 1H, ArH), 7.00
6
(
3
dd, J = 7.4, 1.8 Hz, 1H, ArH), 6.95 (dd, J = 8.3, 0.8 Hz, 1H, ArH), 6.85 (td, J = 7.4, 1.0 Hz, 1H, ArH),
1
3
.72 (s, 3H, CH ), 3.66 (s, 6H, 2 x CH ), 3.17 (s, 2H, CH ), 1.16 (s, 3H, CH ); C NMR (101 MHz, d ꢀ
3 3 2 3 6
DMSO) δ 172.1, 157.8, 131.5, 128.5, 123.9, 120.2, 110.9, 55.2, 53.8, 52.6, 34.1, 19.2; HRMS (ESI+)
+
calc. for C H O [M+Na] 289.1046; found 289.1049.
14
18
5
Dimethyl 2-(3-methoxybenzyl)-2-methylmalonate (3c)
This compound was prepared according to general procedure and isolated by flash
column chromatography (ethyl acetate/hexane=1/20) as a colourless liquid (255 mg,
1
9
1%). %). H NMR (400 MHz, d ꢀDMSO) δ 7.21ꢀ7.17 (m, 1H, ArH), 6.81 (ddd, J
6
=
8.2, 2.6, 0.9Hz, 1H, ArH), 6.67ꢀ6.63 (m, 2H, ArH), 3.71 (s, 3H, CH ), 3.67 (s, 6H, 2 x CH ), 3.10 (s,
3 3
13
2H, CH ), 1.23 (s, 3H, CH ); C NMR (101 MHz, d ꢀDMSO) δ 171.8, 159.5, 137.4, 129.3, 122.5, 115.9,
2 3 6
+
112.6, 55.3, 54.4, 52.6, 40.6, 19.5; HRMS (ESI+) calc. for C H O [M+Na] 289.1046; found 289.1049.
1
4
18
5
S3

Page 9 of 64
Green Chemistry
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DOI: 10.1039/C6GC00163G
Dimethyl 2-(4-methoxybenzyl)-2-methylmalonate (3d)
This compound was prepared according to general procedure and isolated by flash
column chromatography (ethyl acetate/hexane=1/20) as a colourless liquid (239 mg,
1
9
0%). H NMR (400 MHz, d ꢀDMSO) δ 7.01 (d, J = 8.8Hz, 2H, ArH), 6.83 (d, J =
6
13
8
.8Hz, 2H, ArH), 3.72 (s, 3H, CH ), 3.67 (s, 6H, 2 x CH ), 3.07 (s, 2H, CH ), 1.22 (s, 3H, CH ); C
3 3 2 3
NMR (101 MHz, CDCl ) δ 172.3, 158.4, 131.0, 127.8, 113.5, 55.1, 54.8, 52.4, 40.3, 19.6; HRMS (ESI+)
3
+
calc. for C H O [M+Na] 289.1046; found 289.1051.
14
18
5
Dimethyl 2-methyl-2-(4-(pentyloxy)benzyl)malonate (3e)
This compound was prepared according to general procedure and isolated
by flash column chromatography (ethyl acetate/hexane=1/10) as a
1
colourless liquid (280 mg, 87%). H NMR (400 MHz, d ꢀDMSO) δ 6.88
6
(
d, J = 8.7Hz, 2H, ArH), 6.81 (d, J = 8.7Hz, 2H, ArH), 3.90 (t, J = 6.5Hz, 2H, CH ), 3.66 (s, 6H, 2 x
2
CH ), 3.05 (s, 2H, CH ), 1.72ꢀ1.65 (m, 2H, CH ), 1.40ꢀ1.32 (m, 4H, 2 x CH ), 1.21 (s, 3H, CH ), 0.88 (t, J
3
2
2
2
3
1
3
=
4
7.1Hz, 3H, CH ); C NMR (101 MHz, CDCl ) δ 172.3, 158.0, 130.9, 127.6, 114.0, 67.7, 54.9, 52.4,
3 3
+
0.3, 28.9, 28.1, 22.3, 19.6, 13.9; HRMS (ESI+) calc. for C H O [M+Na] 345.1672; found 345.1678.
18 26 5
Dimethyl 2-(3,5-dimethoxybenzyl)-2-methylmalonate (3f)
O
O
This compound was prepared according to general procedure and isolated by flash
O
O
column chromatography (ethyl acetate/hexane=1/20) as a white solid (240 mg,
1
O
81%). H NMR (400 MHz, d ꢀDMSO) δ 6.38 (t, J = 2.3 Hz, 1H, ArH), 6.23 (t, J =
6
O
2
.5 Hz, 2H, ArH), 3.69 (s, 6H, 2 x CH ), 3.67 (s, 6H, 2 x CH ), 3.06 (s, 2H, CH ),
3 3 2
1
3
1
4
.24 (s, 3H, CH ); C NMR (101 MHz, d ꢀDMSO) δ 171.8, 160.4, 138.4, 108.3, 98.8, 55.2, 54.2, 52.7,
3 6
0.8, 19.4; HRMS (ESI+) calc. for C H O [M+Na] 319.1152; found 319.1160.
+
15
20
6
Dimethyl 2-methyl-2-(4-methylbenzyl)malonate (3g)
This compound was prepared according to general procedure and isolated by flash
column chromatography (ethyl acetate/hexane=1/20) as a colourless liquid (215 mg,
1
8
6%). H NMR (400 MHz, d ꢀDMSO) δ 7.08 (d, J = 7.7 Hz, 2H, ArH), 6.97 (d, J =
6
13
8
.0 Hz, 2H, ArH), 3.67 (s, 6H, 2 x CH ), 3.08 (s, 2H, CH ), 2.26 (s, 3H, ArꢀCH ); 1.21 (s, 3H, CH ); C
3 2 3 3
NMR (101 MHz, d ꢀDMSO) δ 171.7, 136.1, 132.7, 130.0, 128.9, 54.3, 52.6, 40.2, 20.7, 19.3; HRMS
6
+
(
ESI+) calc. for C H O [M+Na] 273.1097; found 273.1101.
14
18
4
Dimethyl 2-(3-aminobenzyl)-2-methylmalonate (3h)
This compound was prepared according to general procedure and isolated by flash
column chromatography (ethyl acetate/hexane=2/5) as a light yellow liquid (193
1
mg, 77%). H NMR (400 MHz, d ꢀDMSO) δ 6.89 (t, J = 7.7Hz, 1H, ArH), 6.41
6
(
2
ddd, J = 8.0, 2.2, 0.9Hz, 1H, ArH), 6.26 (t, J = 1.9Hz, 1H, ArH), 6.20 (d, J = 7.5Hz, 1H, ArH), 5.0 (s,
H, NH ), 3.67 (s, 6H, 2 x CH ), 2.96 (s, 2H, CH ), 1.22 (s, 3H, CH ); C NMR (101 MHz, d ꢀDMSO) δ
2 3 2 3 6
1
3
1
72.1, 148.8, 136.3, 128.7, 117.8, 115.7, 112.6, 54.5, 52.6, 41.0, 19.4; HRMS (ESI+) calc. for
+
C H NO [M+Na] 274.1050; found 274.1040.
1
3
17
4
S4

Green Chemistry
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DOI: 10.1039/C6GC00163G
Dimethyl 2-methyl-2-(3-(trifluoromethyl)benzyl)malonate (3i)
This compound was prepared according to general procedure and isolated by flash
column chromatography (ethyl acetate/hexane=1/20) as a colourless liquid (283 mg,
1
9
3%). H NMR (400 MHz, d ꢀDMSO) ) δ 7.63ꢀ7.61 (m, 1H, ArH), 7.53 (td, J =
6
8
.0, 0.6Hz, 1H, ArH), 7.44ꢀ7.42 (m, 2H, ArH), 3.67 (s, 6H, 2 x CH ), 3.25 (s, 2H, CH ), 1.25 (s, 3H,
3 2
1
3
2
CH ); C NMR (101 MHz, d ꢀDMSO) δ 171.5, 137.4, 134.4, 129.3, 129.0 (q, J = 31Hz ), 126.5 (q,
3
6
CF
3
1
3
JCF = 4Hz ), 124.3 (q, J = 272Hz ), 123.8 (q, J = 4Hz ), 54.2, 52.6, 40.1, 19.3; HRMS (ESI+) calc.
CF
CF
+
for C H F O [M+Na] 327.0815; found 327.0818.
14
15
3
4
Dimethyl 2-(4-(methoxycarbonyl)benzyl)-2-methylmalonate (3j)
This compound was prepared according to general procedure and isolated by flash
column chromatography (ethyl acetate/hexane=1/5) as a white solid (247 mg,
1
8
4%). H NMR (400 MHz, d ꢀDMSO) δ 7.87 (d, J = 8.4 Hz, 2H, ArH), 7.25 (d, J
6
=
8.4 Hz, 2H, ArH), 3.84 (s, 3H, CH ), 3.67 (s, 6H, 2 x CH ), 3.21 (s, 2H, CH ),
3 3 2
13
1
5
.24 (s, 3H, CH ); C NMR (101 MHz, d ꢀDMSO) δ 171.5, 166.2, 141.7, 130.6, 129.2, 128.5, 54.2, 52.7,
3 6
2.3, 40.5, 19.4; HRMS (ESI+) calc. for C H O [M+Na] 317.0996; found 317.1002.
+
1
5
18
6
Dimethyl 2-(4-cyanobenzyl)-2-methylmalonate (3k)
This compound was prepared according to general procedure and isolated by flash
column chromatography (ethyl acetate/hexane=1/4) as a white solid (212 mg, 81%).
1
%
). H NMR (400 MHz, d ꢀDMSO) δ 7.76 (d, J = 8.5 Hz, 2H, ArH), 7.32 (d, J =
6
1
3
8
.5 Hz, 2H, ArH), 3.67 (s, 6H, 2 x CH ), 3.22 (s, 2H, CH ), 1.23 (s, 3H, CH ); C NMR (101 MHz, d ꢀ
3 2 3 6
DMSO) δ 171.3, 142.0, 132.2, 131.2, 118.8, 110.0, 54.1, 52.7, 40.4, 19.3; HRMS (ESI+) calc. for
+
C H NO [M+Na] 284.0893; found 284.0898.
1
4
15
4
Dimethyl 2-methyl-2-(naphthalen-1-ylmethyl)malonate (3l)
This compound was prepared according to general procedure and isolated by flash
column chromatography (ethyl acetate/hexane=1/15) as a colourless sticky liquid (246
1
mg, 86%). %). H NMR (400 MHz, d ꢀDMSO) ) δ 7.89ꢀ7.82 (m, 3H, ArH), 7.63 (s,
6
1
H, ArH), 7.51ꢀ7.46 (m, 2H, ArH), 7.24 (dd, J = 8.4, 1.8Hz, 1H, ArH), 3.70 (s, 6H, 2 x CH ), 3.31 (s,
3
13
2H, CH ), 1.29 (s, 3H, CH ); C NMR (101 MHz, d ꢀDMSO) δ 171.7, 133.6, 132.9, 132.1 128.7, 128.4,
2 3 6
+
127.7, 127.5, 126.3, 125.9, 54.4, 52.7, 40.8, 19.5; HRMS (ESI+) calc. for C H O [M+Na] 309.1097;
17 18 4
found 309.1098.
Dimethyl 2-(anthracen-9-ylmethyl)-2-methylmalonate (3m)
This compound was prepared according to general procedure and isolated by flash
column chromatography (ethyl acetate/hexane=1/15) as an orange solid (215 mg,
1
6
4%). H NMR (400 MHz, d ꢀDMSO) δ 8.56 (s, 1H, ArH), 8.22ꢀ8.20 (m, 2H, ArH),
6
8
.10ꢀ8.08 (m, 2H, ArH), 7.38ꢀ7.30 (m, 4H, ArH), 4.36 (s, 2H, CH ), 3.61 (s, 6H, 2 x
2
1
3
CH ), 1.05 (s, 3H, CH ); C NMR (101 MHz, d ꢀDMSO) δ 172.2, 131.1, 131.0, 129.2,
3
3
6
+
1
28.7, 127.3, 125.9, 125.1, 124.8, 54.5, 52.9, 30.5, 20.1; HRMS (ESI+) calc. for C H O [M+Na]
21 20 4
359.1254; found 359.1260.
Dimethyl 2-cinnamyl-2-methylmalonate (3n)
S5

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Green Chemistry
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DOI: 10.1039/C6GC00163G
This compound was prepared according to general procedure and isolated by flash
column chromatography (ethyl acetate/hexane=1/20) as a colourless liquid (249 mg,
1
9
5%). H NMR (400 MHz, d ꢀDMSO) δ 7.37ꢀ7.21 (m, 5H, ArH), 6.48 (d, J =
6
1
2
1
5.2Hz, 1H, =CH), 6.11 (dt, J = 15.6, 7.8Hz, 1H, =CH), 3.67 (s, 6H, 2 x CH ), 2.69 (dd, J = 7.5, 1.1Hz,
3
13
H, CH ), 1.36 (s, 3H, CH ); C NMR (101 MHz, CDCl ) δ 171.8, 136.7, 133.9, 128.8, 127.6, 126.1,
2
3
3
+
24.0, 53.5, 52.6, 38.9, 19.7. HRMS (ESI+) calc. for C H O [M+Na] 285.1097; found 285.1110.
1
5
18
4
Dimethyl 2-allyl-2-methylmalonate (3o)
This compound was prepared according to general procedure and isolated by flash column
1
chromatography (ethyl acetate/hexane=1/20) as a colourless liquid (136 mg, 73%). H
NMR (400 MHz, CDCl ) δ 5.73ꢀ5.62 (m, 1H, =CH), 5.12ꢀ5.07 (m, 2H, =CH ), 3.72 (s,
3
2
1
3
6
1
2
H, 2 x CH ), 2.61 (dt, J = 7.4, 1.1Hz, 2H, CH ), 1.39 (s, 3H, CH ); C NMR (101 MHz, CDCl ) δ
3 2 3 3
+
72.3, 132.4, 119.1, 53.4, 52.4, 40.0, 19.7; HRMS (ESI+) calc. for C H O [M+Na] 209.0790; found
9
14
4
09.0793.
3. Procedure of the benzylation/allylation of DMM
General procedure A:
Under nitrogen atmosphere, benzyl alcohol (1.0 mmol), DMM (5.0 mmol), Pd(OAc) (2.3 mg, 10
2
ꢁ
mol), dppp (10 mg, 24 ꢁmol), Cs CO (326 mg, 1.0 equiv) and DMC (2 mL) were combined in a 20 mL
2
3
headspace vial fitted with a suba seal cap. The mixture was stirred at 120 °C for 15 h, then cooled to room
temperature. The mixture was filtered and washed by ethyl acetate, and the obtained solution was
evaporated under reduced pressure. The residue was purified by flash column chromatography
(
EtOAc/hexane) to give the desired product 5.
Table S2. Reaction conditions screening for the benzylation of DMM (I).
a
Pd(OAc)2 dppp
Ratio of
Yield(%)
monoꢀ
o
Entry
1
T( C) t(h)
(
mol%) (mol%) BnOH/DMM
bisꢀ
23
20
9
2
2
2
4.8
4.8
4.8
1:1.2
1:1.2
1:3
120
120
120
24 38
24 44
15 70
b
2
b
3
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Green Chemistry
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DOI: 10.1039/C6GC00163G
b
4
5
6
7
8
9
1
1
1
1
2
4.8
4.8
2.4
2.4
2.4
1.2
2.4
2.4
2.4
2.4
1:5
1:5
1:5
1:8
1:3
1:5
1:5
1:5
1:5
1:5
120
15 78
15 84
15 86
15 86
15 74
15 76
15 80
12 78
18 74
4
6
2
120
120
120
120
120
120
120
120
110
1
7
1
5
1
11
7
0.5
1
b
0
1
2
3
6
1
6
1
8
1
15 74
6
a
b
Reaction conditions: BnOH (1 mmol), Cs CO (1.0 eq.), DMC (2 mL). Yield by NMR. Solvent (1
2
3
mL DMC + 1 mL Dioxane)
General procedure B:
Under nitrogen atmosphere, benzyl alcohol (2.2 mmol), DMM (1.0 mmol), Pd(OAc) (4.5 mg, 20
2
ꢁ
mol), dppp (20 mg, 48 ꢁmol), Cs CO (717 mg, 2.2 equiv) and DMC (2 mL) were combined in a 20 mL
2
3
headspace vial fitted with a suba seal cap. The mixture was stirred at 120 °C for 36 h, then cooled to room
temperature. The mixture was filtered and washed by ethyl acetate, and the obtained solution was
evaporated under reduced pressure. The residue was purified by flash column chromatography
(
EtOAc/hexane) to give the desired product 6.
S7

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Green Chemistry
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DOI: 10.1039/C6GC00163G
Table S3. Reaction conditions screening for the benzylation of DMM (II).
a
Entry Base
(eq.)
DMC
Co-solvent
(mL)
Toluene (2)
t (h)
24
24
24
24
24
29
36
24
24
24
24
24
24
24
24
24
30
Yield(%)
(
mL)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
Cs CO3 (2)
ꢀ
0
2
Cs CO3 (2)
2
1
2
2
2
2
2
2
2
2
1
1
1
1
1
1
ꢀ
56
45
43
67
78
85
54
30
36
11
< 5
12
25
31
43
46
2
Cs CO3 (2)
ꢀ
2
b
Cs CO3 (2)
ꢀ
2
Cs CO3 (2.2)
ꢀ
2
Cs CO3 (2.2)
ꢀ
2
Cs CO3 (2.2)
ꢀ
2
Cs CO3 (2.5)
ꢀ
2
K CO3 (2)
2
ꢀ
0
1
2
3
4
5
6
7
K CO3 (2.2)
2
ꢀ
t
NaO Bu (2)
ꢀ
c
d
e
f
Cs CO3 (2)
ꢀ
2
Cs CO3 (2)
ꢀ
2
Cs CO3 (2)
ꢀ
2
Cs CO3 (2)
ꢀ
2
Cs CO3 (2.2)
DMF (1)
DMF (1)
2
Cs CO3 (2.2)
2
Reaction conditions: Benzyl alcohol (2.2 mmol), DMM (1.0 mmol), Pd(OAc) (2 mol%), dppp (4.8
o
a
b
c
d
mol%), 120 C. Yield by NMR. Pd(OAc) (4 mol%), dppp(10 mol%). TCHP as ligand. DPMP as
e
f
ligand. dppb as ligand. TPAP as ligand.
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DOI: 10.1039/C6GC00163G
Dimethyl 2-benzylmalonate (5a)
This compound was prepared according to general procedure A and isolated by flash
column chromatography (ethyl acetate/hexane=1/5) as a colourless liquid (189 mg,
1
8
1
5%). H NMR (400 MHz, d ꢀDMSO) δ 7.30ꢀ7.19 (m, 5H, ArH), 3.87 (t, J = 8.0 Hz,
6
1
3
H, CH), 3.60 (s, 6H, 2 x CH ), 3.08 (d, J = 7.8 Hz, 2H, CH ); C NMR (101 MHz, d ꢀ
DMSO) δ 169.0, 137.7, 128.8, 128.5, 126.8, 52.8, 52.5, 34.2; HRMS (ESI+) calc. for C H O [M+Na]
3
2
6
+
1
2
14
4
245.0784; found 245.0775.
Dimethyl 2,2-dibenzylmalonate (6a)
This compound was prepared according to general procedure B and isolated by flash
column chromatography (ethyl acetate/hexane=1/20) as a colourless liquid (259 mg,
1
8
3%). H NMR (400 MHz, d ꢀDMSO) δ 7.32ꢀ7.15 (m, 10H, 2 x ArH), 3.58 (s, 6H, 2
6
1
3
x CH ), 3.10 (s, 4H, 2 x CH ); C NMR (101 MHz, d ꢀDMSO) δ 170.6, 135.8, 130.1,
28.4, 127.1, 60.0, 52.3, 38.5; HRMS (ESI+) calc. for C H O [M+Na] 335.1254; found 335.1248.
3
2
6
+
1
1
9
20
4
Dimethyl 2-(2-methoxybenzyl)malonate (5b)
This compound was prepared according to general procedure A and isolated by flash
column chromatography (ethyl acetate/hexane=1/10) as a colourless liquid (234 mg,
1
9
6
3%). H NMR (400 MHz, CDCl ) δ 7.26ꢀ7.19 (m, 1H, ArH), 7.13ꢀ7.11 (m, 1H, ArH),
3
.87ꢀ6.82 (m, 2H, ArH), 3.85 (t, J = 8.1 Hz, 1H, CH), 3.83 (s, 3H, ArꢀOCH ), 3.68 (s,
3
1
3
6
1
H, 2 x CH ), 3.20 (d, J = 7.7 Hz, 2H, CH ); C NMR (101 MHz, d ꢀDMSO) δ 169.1, 157.3, 130.1,
3
2
6
+
28.5, 125.4, 120.4, 110.7, 55.4, 52.4, 51.0, 29.5; HRMS (ESI+) calc. for C H O [M+Na] 275.0890;
13 16 5
found 275.0887.
Dimethyl 2,2-bis(2-methoxybenzyl)malonate (6b)
This compound was prepared according to general procedure B and isolated by flash
O
O
O
column chromatography (ethyl acetate/hexane=1/10) as a colourless sticky liquid (286
1
mg, 77%). H NMR (400 MHz, d ꢀDMSO) δ 7.20 (td, J = 8.1, 1.7 Hz, 2H, 2 x ArH),
6
O
O
O
7
.02 (dd, J = 7.5, 1.7 Hz, 2H, 2 x ArH), 6.92 (dd, J = 8.2, 0.8 Hz, 2H, 2 x ArH), 7.20
(
td, J = 7.4, 1.0 Hz, 2H, 2 x ArH), 3.69 (s, 6H, 2 x ArꢀOCH ), 3.53 (s, 6H, 2 x OCH ),
3
3
13
3
5
.13 (s, 4H, 2 x CH ); C NMR (101 MHz, d ꢀDMSO) δ 170.9, 157.8, 131.1, 128.2, 124.5, 119.9, 110.3,
2 6
8.4, 55.3, 52.4, 33.0; HRMS (ESI+) calc. for C H O [M+Na] 395.1465; found 395.1472.
+
2
1
24
6
Dimethyl 2-(3-methoxybenzyl)malonate (5c)
This compound was prepared according to general procedure A and isolated by
flash column chromatography (ethyl acetate/hexane=1/5) as a colourless liquid (232
1
mg, 92%). H NMR (400 MHz, d ꢀDMSO) δ 7.20ꢀ6.74 (m, 4H, ArH), 3.88 (t, J =
6
8
.1 Hz, 1H, CH), 3.72 (s, 3H, ArꢀOCH ), 3.61 (s, 6H, 2 x CH ), 3.05 (d, J = 7.3 Hz,
3 3
1
3
2
5
H, CH ); C NMR (101 MHz, d ꢀDMSO) δ 169.0, 159.4, 139.4, 129.4, 120.9, 114.4, 112.3, 55.0, 52.7,
2 6
2.5, 34.1; HRMS (ESI+) calc. for C H O [M+Na] 275.0890; found 275.0889.
+
13
16
5
Dimethyl 2,2-bis(3-methoxybenzyl)malonate (6c)
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DOI: 10.1039/C6GC00163G
This compound was prepared according to general procedure B and isolated
by flash column chromatography (ethyl acetate/hexane=1/10) as a colourless
1
sticky liquid (227 mg, 71%). %). H NMR (400 MHz, d ꢀDMSO) δ 7.23 (t, J
6
=
8.0 Hz, 2H, 2 x ArH), 6.83 (ddd, J = 8.3, 2.5, 0.6 Hz, 2H, 2 x ArH), 6.71 (d,
J = 7.6 Hz, 2H, 2 x ArH), 6.67 (t, J = 2.0 Hz, 2H, 2 x ArH), 3.72 (s, 6H, 2 x ArꢀOCH ), 3.61 (s, 6H, 2 x
3
1
3
CH ), 3.08 (s, 4H, 2 x CH ); C NMR (101 MHz, d ꢀDMSO) δ 170.6, 159.1, 137.4, 129.4, 122.3, 115.7,
3
2
6
+
1
12.5, 59.9, 54.9, 52.5, 38.5; HRMS (ESI+) calc. for C H O [M+Na] 395.1465; found 395.1473.
21 24 6
Dimethyl 2-(4-methoxybenzyl)malonate (5d)
This compound was prepared according to general procedure A and isolated by
flash column chromatography (ethyl acetate/hexane=1/5) as a colourless liquid (237
1
mg, 94%). H NMR (400 MHz, d ꢀDMSO) δ 7.11 (d, J = 8.8 Hz, 2H, ArH), 6.83
6
(
d, J = 8.8 Hz, 2H, ArH), 3.81 (t, J = 8.0 Hz, 1H, CH), 3.71 (s, 3H, ArꢀOCH ),
3
1
3
3
1
2
.60 (s, 6H, 2 x CH ), 3.01 (d, J = 8.0 Hz, 2H, CH ); C NMR (101 MHz, d ꢀDMSO) δ 169.1, 158.2,
3
2
6
+
30.0, 129.6, 114.0, 55.1, 53.2, 52.5, 33.6; HRMS (ESI+) calc. for C H O [M+Na] 275.0890; found
1
3
16
5
75.0891.
Dimethyl 2,2-bis(4-methoxybenzyl)malonate (6d)
This compound was prepared according to general procedure B and isolated
by flash column chromatography (ethyl acetate/hexane=1/10) as a white solid
1
(
253 mg, 71%). H NMR (400 MHz, CDCl ) δ 7.07 (d, J = 8.8 Hz, 4H, 2 x
3
ArH), 6.81 (d, J = 8.8 Hz, 4H, 2 x ArH), 3.80 (s, 6H, 2 x ArꢀOCH ), 3.66 (s,
3
1
3
6
6
H, 2 x CH ), 3.16 (s, 4H, 2 x CH ); C NMR (101 MHz, d ꢀDMSO) δ 171.5, 158.5, 131.1, 128.2, 113.7,
3 2 6
+
0.5, 55.4, 52.1, 38.3; HRMS (ESI+) calc. for C H O [M+Na] 395.1465; found 395.1474.
2
1
24
6
Dimethyl 2-(4-(pentyloxy)benzyl)malonate (5e)
This compound was prepared according to general procedure A and
isolated by flash column chromatography (ethyl acetate/hexane=1/10) as a
1
colourless liquid (213 mg, 69%). H NMR (400 MHz, d ꢀDMSO) δ 7.09 (d,
6
J = 8.1 Hz, 2H, ArH), 6.81 (d, J = 8.1 Hz, 2H, ArH), 3.90 (t, J = 6.6 Hz,
2
H, CH ), 3.80 (t, J = 8.0 Hz, 1H, CH), 3.60 (s, 6H, 2 x CH ), 3.01 (d, J = 7.7 Hz, 2H, CH ), 1.72ꢀ1.64
2
3
2
1
3
(
m, 2H, CH ), 1.41ꢀ1.32 (m, 4H, CH CH ), 0.88 (t, J = 7.0 Hz, 3H, CH ); C NMR (101 MHz, d ꢀ
2 2 2 3 6
DMSO) δ 168.9, 157.3, 130.0, 129.4, 114.3, 67.2, 53.0, 52.2, 33.6, 28.6, 28.0, 22.0, 14.1; HRMS (ESI+)
+
calc. for C H O [M+Na] 331.1516; found 331.1523.
17
24
5
Dimethyl 2,2-bis(4-(pentyloxy)benzyl)malonate (6e)
This compound was prepared according to general procedure
B and isolated by flash column chromatography (ethyl
acetate/hexane=1/10) as a colourless sticky liquid (368 mg,
1
7
6%). %). H NMR (400 MHz, d ꢀDMSO) δ 7.04 (d, J = 8.7
6
Hz, 4H, 2 x ArH), 6.84 (d, J = 8.7 Hz, 4H, 2 x ArH), 3.91 (t, J = 6.5 Hz, 4H, 2 x CH ), 3.58 (s, 6H, 2 x
2
CH ), 3.00 (s, 4H, 2 x CH ), 1.72ꢀ1.65 (m, 4H, 2 x CH ), 1.42ꢀ1.30 (m, 8H, 2 x CH CH ), 0.89 (t, J = 7.1
3
2
2
2
2
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1
3
Hz, 6H, 2 x CH ); C NMR (101 MHz, d ꢀDMSO) δ 170.9, 157.8, 131.3, 127.6, 114.3, 67.5, 60.2, 52.4,
3
6
+
3
7.6, 28.6, 27.9, 22.0, 14.2; HRMS (ESI+) calc. for C H O [M+Na] 507.2717; found 507.2724.
29 40 6
Dimethyl 2-(3,5-dimethoxybenzyl)malonate (5f)
This compound was prepared according to general procedure A and isolated by
flash column chromatography (ethyl acetate/hexane=1/5) as a colourless liquid (200
1
mg, 71%). %). H NMR (400 MHz, d ꢀDMSO) δ 6.36ꢀ6.33 (m, 3H, ArH), 3.88 (t, J
6
=
8.2 Hz, 1H, CH), 3.70 (s, 6H, 2 x ArꢀOCH ), 3.62 (s, 6H, 2 x CH ), 3.01 (d, J =
3 3
1
3
8
3
.2 Hz, 2H, CH ); C NMR (101 MHz, d ꢀDMSO) δ 168.8, 160.6, 140.1, 106.7, 98.3, 55.2, 52.6, 52.5,
2 6
4.3; HRMS (ESI+) calc. for C H O [M+Na] 305.0996; found 305.1000.
+
14
18
6
Dimethyl 2,2-bis(3,5-dimethoxybenzyl)malonate (6f)
This compound was prepared according to general procedure B and isolated
by flash column chromatography (ethyl acetate/hexane=1/5) as a white solid
1
(
315 mg, 73%). H NMR (400 MHz, d ꢀDMSO) δ 6.40 (d, J = 2.2 Hz, 2H, 2
6
x ArH), 6.24 (d, J = 2.2 Hz, 4H, 2 x ArH),3.71 (s, 12H, 4 x ArꢀOCH ), 3.63
3
1
3
(
s, 6H, 2 x CH ), 3.04 (s, 4H, 2 x CH ); C NMR (101 MHz, d ꢀDMSO) δ
3 2 6
+
1
70.5, 160.3, 137.8, 108.1, 99.0, 59.6, 55.1, 52.5, 38.6; HRMS (ESI+) calc. for C H O [M+Na]
23 28 8
455.1676; found 455.1685.
Dimethyl 2-(4-methylbenzyl)malonate (5g)
This compound was prepared according to general procedure A and isolated by flash
column chromatography (ethyl acetate/hexane=1/5) as a colourless liquid (160 mg,
1
6
8%). H NMR (400 MHz, d ꢀDMSO) δ 7.08 (s, 4H, ArH), 3.83 (t, J = 8.1 Hz, 1H,
6
13
CH), 3.60 (s, 6H, 2 x CH ), 3.03 (d, J = 7.5 Hz, 2H, CH ), 2.25 (s, 3H, Arꢀ CH ),; C
3
2
3
NMR (101 MHz, d ꢀDMSO) δ 169.0, 136.0, 134.9, 129.1, 128.7, 52.9, 52.5, 33.8, 20.8; HRMS (ESI+)
6
+
calc. for C H O [M+Na] 259.0941; found 259.0937.
13
16
4
Dimethyl 2,2-bis(4-methylbenzyl)malonate (6g)
This compound was prepared according to general procedure B and isolated by
flash column chromatography (ethyl acetate/hexane=1/20) as a colourless liquid
1
(
265 mg, 78%). H NMR (400 MHz, d ꢀDMSO) δ 7.11 (d, J = 7.8 Hz, 4H, 2 x
6
ArH), 7.03 (d, J = 8.0 Hz, 4H, 2 x ArH),3.59 (s, 6H, 2 x CH ), 3.03 (s, 4H, 2 x
3
1
3
CH ), 2.27 (s, 6H, 2 x ArꢀCH ); C NMR (101 MHz, d ꢀDMSO) δ 170.8, 136.3,
2
3
6
+
1
32.8, 130.3, 129.2, 60.0, 52.5, 37.9, 20.9; HRMS (ESI+) calc. for C H O [M+Na] 363.1567; found
21 24 4
363.1570.
Dimethyl 2-(3-aminobenzyl)malonate (5h)
This compound was prepared according to general procedure A and isolated by
flash column chromatography (ethyl acetate/hexane=1/3) as a colourless liquid (12
1
mg, 5%). H NMR (400 MHz, d ꢀDMSO) δ 6.89 (t, J = 7.7 Hz, 1H, ArH), 6.40ꢀ
6
6
.35 (m, 2H, ArH), 6.30 (t, J = 7.5 Hz, 1H, ArH), 5.00 (s, 2H, NH ), 3.72 (t, J =
2
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1
3
8
.0 Hz, 1H, CH), 3.62 (s, 6H, 2 x CH ), 2.91 (d, J = 8.3 Hz, 2H, CH ); C NMR (101 MHz, d ꢀDMSO) δ
3 2 6
1
69.1, 148.8, 138.2, 129.1, 116.0, 114.0, 112.5, 53.0, 52.5, 34.5; HRMS (ESI+) calc. for C H NO
4
1
2
15
+
[
M+Na] 260.0893; found 260.0888.
Dimethyl 2-(3-(trifluoromethyl)benzyl)malonate (5i)
This compound was prepared according to general procedure A and isolated by
flash column chromatography (ethyl acetate/hexane=1/20) as a colourless liquid
1
(
209 mg, 72%). H NMR (400 MHz, d ꢀDMSO) δ 7.59ꢀ7.51 (m, 4H, ArH), 3.99 (t,
6
13
J = 8.0 Hz, 1H, CH), 3.60 (s, 6H, 2 x CH ), 3.18 (d, J = 7.3 Hz, 2H, CH ); C
NMR (101 MHz, CDCl ) δ 168.7, 138.5, 132.2, 130.8 (q, J = 32Hz ), 128.9, 125.4 (q, J = 4Hz ),
3
2
2
3
3
CF
CF
1
3
1
[
23.9 (q, J = 272Hz), 123.6 (q, J = 4Hz), 53.2, 52.6, 34.3; HRMS (ESI+) calc. for C H F O
CF CF 13 13 3 4
+
M+Na] 313.0658; found 313.0664.
Dimethyl 2,2-bis(3-(trifluoromethyl)benzyl)malonate (6i)
This compound was prepared according to general procedure B and isolated
O
O
O
by flash column chromatography (ethyl acetate/hexane=1/20) as a colourless
F3C
1
CF3
liquid (278 mg, 62%). %). H NMR (400 MHz, d ꢀDMSO) δ 7.64 (d, J = 7.6
O
6
Hz, 2H, 2 x ArH), 7.56 (t, J = 7.8 Hz, 2H, 2 x ArH), 7.49 (d, J = 7.6 Hz,
2
H, 2 x ArH), 7.43 (s, 2H, 2 x ArH), 3.57 (s, 6H, 2 x CH ), 3.25 (s, 4H, 2 x
3
1
3
2
3
CH ); C NMR (101 MHz, CDCl ) δ 170.5, 136.7, 133.3, 130.6 (q, J = 33Hz ), 128.7, 126.6 (q, J =
CF
2
3
CF
3
1
4
Hz ), 124.0 (q, J = 4Hz), 123.9 (q, J = 272Hz), 60.2, 52.3, 39.5; HRMS (ESI+) calc. for C H
CF CF 21 18
+
F O [M+Na] 471.1001; found 471.1003.
6
4
Dimethyl 2-(4-(methoxycarbonyl)benzyl)malonate (5j)
O
This compound was prepared according to general procedure A and isolated by
O
flash column chromatography (ethyl acetate/hexane=1/3) as a white solid (160 mg,
H
O
O
1
O
57%). H NMR (400 MHz, d ꢀDMSO) δ 7.88 (d, J = 8.1 Hz, 2H, ArH), 7.37 (d, J
6
O
=
8.1 Hz, 2H, ArH), 3.95 (t, J = 8.0 Hz, 1H, CH), 3.83 (s, 3H, ArꢀCOOCH ), 3.61
3
1
3
(
1
s, 6H, 2 x CH ), 3.16 (d, J = 8.0 Hz, 2H, CH ); C NMR (101 MHz, d ꢀDMSO) δ 168.8, 166.1, 143.5,
3 2 6
+
29.4, 129.3, 128.2, 52.6, 52.3, 52.2, 34.0; HRMS (ESI+) calc. for C H O [M+Na] 303.0839; found
14 16 6
303.0846.
Dimethyl 2,2-bis(4-(methoxycarbonyl)benzyl)malonate (6j)
This compound was prepared according to general procedure B and
isolated by flash column chromatography (ethyl acetate/hexane=1/5) as a
1
white solid (218 mg, 51%). H NMR (400 MHz, CDCl ) δ 7.95 (d, J =
3
8
.4 Hz, 4H, 2 x ArH), 7.21 (d, J = 8.4 Hz, 4H, 2 x ArH), 3.92 (s, 6H, 2 x
1
3
ArꢀCOOCH ), 3.65 (s, 6H, 2 x CH ), 3.27 (s, 4H, 2 x CH ); C NMR
3
3
2
(
101 MHz, CDCl ) δ 170.7, 166.8, 141.2, 129.9, 129.5, 128.9, 60.1, 52.3, 52.0, 39.6; HRMS (ESI+) calc.
3
+
for C H O [M+Na] 451.1363; found 451.1371.
23
24
8
Dimethyl 2-(4-cyanobenzyl)malonate (5k)
This compound was prepared according to general procedure A and isolated by flash
column chromatography (ethyl acetate/hexane=1/3) as a colourless liquid (148 mg,
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1
6
3
0%). H NMR (400 MHz, d ꢀDMSO) δ 7.76 (d, J = 8.8 Hz, 2H, ArH), 7.44 (d, J = 8.8 Hz, 2H, ArH),
6
1
3
.99 (t, J = 8.0 Hz, 1H, CH), 3.61 (s, 6H, 2 x CH ), 3.17 (d, J = 8.0 Hz, 2H, CH ); C NMR (101 MHz,
3
2
d ꢀDMSO) δ 168.8, 143.9, 132.6, 130.1, 119.0, 109.8, 52.9, 52.1, 34.1; HRMS (ESI+) calc. for
6
+
C H NO [M+Na] 270.0737; found 270.0729.
1
3
13
4
Dimethyl 2,2-bis(4-cyanobenzyl)malonate (6k)
This compound was prepared according to general procedure B and isolated
by flash column chromatography (ethyl acetate/hexane=1/5) as a a white solid
1
(
217 mg, 60%). H NMR (400 MHz, d ꢀDMSO) δ 7.69 (d, J = 8.6 Hz, 4H, 2
6
x ArH), 7.36 (d, J = 8.6 Hz, 4H, 2 x ArH), 3.57 (s, 6H, 2 x CH ), 3.22 (s, 4H,
3
13
2
x CH ); C NMR (101 MHz, d ꢀDMSO) δ 170.0, 141.9, 132.4, 131.2, 118.9, 110.1, 59.8, 52.6; 39.2;
2 6
+
HRMS (ESI+) calc. for C H N O [M+Na] 385.1159; found 385.1161.
2
1
18
2
4
Dimethyl 2-(naphthalen-1-ylmethyl)malonate (5l)
This compound was prepared according to general procedure A and isolated by flash
column chromatography (ethyl acetate/hexane=1/6) as a colourless liquid (177 mg,
1
6
5%). H NMR (400 MHz, d ꢀDMSO) δ 7.88ꢀ7.83 (m, 3H, ArH), 7.03 (d, J = 0.7 Hz,
6
1
H, ArH), 7.50ꢀ7.45 (m, 2H, ArH), 7.40 (dd, J = 8.5, 1.7 Hz, 1H, ArH), 4.00 (t, J =
1
3
8
.0 Hz, 1H, CH), 3.60 (s, 6H, 2 x CH ), 3.26 (d, J = 7.8 Hz, 2H, CH ); C NMR (101 MHz, d ꢀDMSO) δ
3 2 6
1
69.1, 135.5, 133.2, 132.0, 128.0, 127.63, 127.57, 127.3, 127.1, 126.3, 125.8, 52.7, 52.5, 34.5; HRMS
+
(
ESI+) calc. for C H O [M+Na] 295.0941; found 295.0939.
16
16
4
Dimethyl 2,2-bis(naphthalen-1-ylmethyl)malonate (6l)
This compound was prepared according to general procedure B and isolated by
flash column chromatography (ethyl acetate/hexane=1/20) as a white solid (350
1
mg, 85%). H NMR (400 MHz, d ꢀDMSO) δ 7.93ꢀ7.86 (m, 6H, 2 x ArH), 7.74 (s,
6
2
H, 2 x ArH), 7.54ꢀ7.49 (m, 4H, 2 x ArH), 7.33 (dd, J = 8.5, 1.8 Hz, 2H, 2 x
1
3
ArH), 3.62 (s, 6H, 2 x CH ), 3.33 (s, 4H, 2 x CH ); C NMR (101 MHz, CDCl )
3
2
3
δ 171.3, 133.6, 133.2, 132.3, 128.9, 128.0, 127.7, 127.6, 127.5, 126.0, 125.6, 60.5, 52.2, 39.6; HRMS
+
(
ESI+) calc. for C H O [M+Na] 435.1567; found 435.1574.
27 24 4
Dimethyl 2-(anthracen-9-ylmethyl)malonate (5m)
This compound was prepared according to general procedure A and isolated by flash
column chromatography (ethyl acetate/hexane=1/6) as a yellow solid (200 mg,
1
6
2%). H NMR (400 MHz, d ꢀDMSO) δ 8.56 (s, 1H, ArH), 8.27ꢀ8.24 (m, 2H, ArH),
6
8
.11ꢀ8.09 (m, 2H, ArH), 7.60ꢀ7.51 (m, 4H, ArH), 4.18 (d, J = 7.8 Hz, 2H, CH ), 3.87
2
1
3
(
1
t, J = 7.8 Hz, 1H, CH), 3.47 (s, 6H, 2 x CH ); C NMR (101 MHz, d ꢀDMSO) δ 169.0, 131.2, 129.6,
3 6
+
29.5, 129.3, 127.1, 126.4, 125.3, 124.1, 52.5, 52.4, 26.2; HRMS (ESI+) calc. for C H O [M+Na]
20 18 4
345.1097; found 345.1105.
Dimethyl 2-cinnamylmalonate (5n)
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This compound was prepared according to general procedure A and isolated by
flash column chromatography (ethyl acetate/hexane=1/5) as a colourless liquid (219
1
mg, 94%). H NMR (400 MHz, d ꢀDMSO) δ 7.37ꢀ7.28 (m, 4H, ArH), 7.25ꢀ7.20
6
(
m, 1H, ArH),6.46 (d, J = 16.3 Hz, 1H, = CH), 6.23ꢀ6.15 (m, 1H, =CH), 3.73 (t, J =
1
3
7
.5 Hz, 1H, CH), 3.66 (s, 6H, 2 x CH ), 2.67 (td, J = 7.3, 1.2 Hz, 2H, CH ); C NMR (101 MHz, d ꢀ
3
2
6
DMSO) δ 169.2, 136.8, 132.2, 128.7, 127.5, 126.1, 125.9, 52.6, 51.1, 32.1; HRMS (ESI+) calc. for
+
C H O [M+Na] 271.0941; found 271.0934.
1
4
16
4
Dimethyl 2,2-dicinnamylmalonate (6n)
This compound was prepared according to general procedure B and isolated
by flash column chromatography (ethyl acetate/hexane=1/20) as a colourless
1
sticky liquid (328 mg, 90%). H NMR (400 MHz, d ꢀDMSO) δ 7.42ꢀ7.40 (m,
6
4
H, 2 x ArH), δ 7.34ꢀ7.30 (m, 4H, 2 x ArH), δ 7.26ꢀ7.22 (m, 2H, 2 x ArH),
6
.52 (d, J = 15.8 Hz, 2H, 2 x = CH), 6.16 (dt, J = 15.8, 8.2 Hz, 2H, 2 x =CH), 3.68 (s, 6H, 2 x CH ), 2.75
3
13
(
d, J = 7.4 Hz, 4H, 2 x CH ); C NMR (101 MHz, d ꢀDMSO) δ 171.0, 136.7, 134.0, 128.8, 127.6, 126.5,
2 6
+
1
24.0, 58.1, 52.7, 36.1; HRMS (ESI+) calc. for C H O [M+Na] 387.1567; found 387.1571.
23 24 4
Dimethyl 2-allylmalonate (5o)
This compound was prepared according to general procedure A and isolated by flash
column chromatography (ethyl acetate/hexane=1/10) as a colourless liquid (91 mg, 53%).
1
H NMR (400 MHz, CDCl ) δ 5.81ꢀ5.71 (m, 1H, =CH), 5.14ꢀ5.05 (m, 2H, =CH ), 3.74 (s,
3
2
1
3
6
H, 2 x CH ), 3.46 (t, J = 7.6 Hz, 1H, CH), 2.67ꢀ2.62 (m, 2H, CH ); C NMR (101 MHz,
3 2
+
CDCl ) δ 169.5, 133.7, 117.8, 52.5, 51.3, 32.8; HRMS (ESI+) calc. for C H O [M+Na] 195.0628;
3
8
12
4
found 195.0630.
Dimethyl 2,2-diallylmalonate (6o)
This compound was prepared according to general procedure B and isolated by flash
column chromatography (ethyl acetate/hexane=1/20) as a colourless liquid (142 mg, 67%).
1
H NMR (400 MHz, d ꢀDMSO) δ 5.67ꢀ5.58 (m, 2H, 2 x =CH), 5.15ꢀ5.09 (m, 4H, 2 x
6
1
3
=
CH ), 3.65 (s, 6H, 2 x CH ), 2.53 (d, J = 8.0 Hz, 4H, 2 x CH ); C NMR (101 MHz, d ꢀ
2 3 2 6
+
DMSO) δ 170.5, 132.4, 119.6, 57.1, 52.5, 36.5; HRMS (ESI+) calc. for C H O [M+Na] 235.0941;
1
1
16
4
found 235.0942.
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Table S4. Primary screening for other substrates.
4. References
[
[
1] F. Bjoerkling, J. Boutelje, S. Gatenbeck, K. Hult, T. Norin, P.Szmulik, Tetrahedron 1985, 41, 1347.
2] E. Fillion, D. Fishlock, A. Wilsily, J. M. Goll. J. Org. Chem. 2005, 70, 1316ꢀ1327.
[
3] T. Ke, C. R. Wescott, A. M. Klibanov. J. Am. Chem. Soc. 1996, 118, 3366ꢀ3374.
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1
13
5
. H and C NMR Spectra of malonates
1
H NMR, d ꢀDMSO, 400 MHz
6
13
C NMR, d ꢀDMSO, 101 MHz
6
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1
H NMR, d ꢀDMSO, 400 MHz
6
13
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