Lewis base-catalyzed cyanation of Morita-Baylis-Hillman carbonates. Synthesis of allylamine derivatives

Article abstract of DOI:10.1016/j.tetlet.2017.07.038

DABCO-catalyzed cyanation of MBH carbonates via 1,3-proton shift transfer is reported. The adducts of cyanation are converted in one step to allylic amines derivatives. The salient features of this reaction include readily available starting materials, mild conditions, broad substrate scope, high efficiency and valuable further applications. The process of the 1,3-proton shift transfer was conducted by a joint research of NMR and DFT calculation.

Full text of DOI:10.1016/j.tetlet.2017.07.038

Accepted Manuscript
Lewis Base-Catalyzed Cyanation of Morita-Baylis-Hillman Carbonates. Syn-
thesis of Allylamine Derivatives
Hai Ma, Feng Sui, Qing-He Zhao, Ning Zhang, Yi Sun, Jing Xian, Meng-Jiao
Jiao, Yu-ling Liu, Zhi-Min Wang
PII:
S0040-4039(17)30884-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.038
TETL 49120
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 June 2017
7 July 2017
10 July 2017
Please cite this article as: Ma, H., Sui, F., Zhao, Q-H., Zhang, N., Sun, Y., Xian, J., Jiao, M-J., Liu, Y-l., Wang, Z-
M., Lewis Base-Catalyzed Cyanation of Morita-Baylis-Hillman Carbonates. Synthesis of Allylamine Derivatives,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.038
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Lewis Base-Catalyzed Cyanation of Morita-
Baylis-Hillman Carbonates. Synthesis of
Allylamine Derivatives
Leave this area blank for abstract info.
Hai Maa,*, Feng Suia, Qing-He Zhaoa, Yi Suna, Ning Zhangb, Jing Xiana, Meng-Jiao Jiaoa, Yu-Ling Liua, Zhi-
Min Wang a,*
CO2R'
CO2R'
Me
HO
DABCO
4 -12 h
R
R
CN
CN
+
R'O2C
CH2Cl2, rt
CN
2
OBoc
R
1
3
InCl3, NaBH4
THF, rt, 3 h
(Z)
NH
O
R
Me
DABCO-catalyzed cyanation of MBH carbonates via 1,3-proton shift transfer is reported. The adducts of cyanation that are converted in one step
to allylic amines derivatives. The salient features of this reaction include readily available starting materials, mild conditions, broad substrate
scope, high efficiency and valuable further applications. The process of the 1,3-proton shift transfer was conducted by a joint research of NMR
and DFT calculation.

1
Tetrahedron Letters
Lewis Base-Catalyzed Cyanation of Morita-Baylis-Hillman Carbonates. Synthesis of
Allylamine Derivatives
Hai Maa,*, Feng Suia, Qing-He Zhaoa, Ning Zhangb, Yi Suna, Jing Xiana, Meng-Jiao Jiaoa, Yu-ling Liua,
Zhi-Min Wanga,*
aInstitute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Bejing 100700, China.
bTianjin Institute of Pharmaceutical Research Pharmaceutical Co.,Ltd, Tianjin 300301, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
DABCO-catalyzed cyanation of MBH carbonates via 1,3-proton shift transfer is reported. The
adducts of cyanation that are converted in one step to allylic amines derivatives. The salient
features of this reaction include readily available starting materials, mild conditions, broad
substrate scope, high efficiency and valuable further applications. The process of the 1,3-proton
shift transfer was conducted by a joint research of NMR and DFT calculation.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
cyanation
MBH carbonates
1,3-proton shift transfer
allylamine derivatives
1. Introduction
MBH adducts possess a high potential for use as synthetic
intermediates; therefore, in recent years, several research groups
Allyl amines and allylamine derivatives represent an
important class of compounds due to their potency in medicinal
chemistry given their activities such as chemotherapeutic agents,1
enzyme inhibitors2 and antifungal activities.3 Furthermore, allylic
amines are very important synthetic intermediates4 and functional
groups in many biologically active compounds and natural
products.5 Due to their significance in organic synthesis, much
effort has been exerted to develop efficient methods of allylic
amines or allylamine derivatives.6 The allylamine functionality
can be introduced by nucleophilic substitution at the allylic
position or by direct allylic amination of olefins (Scheme 1a, b)7.
Conversions of alcohols or a better leaving group, for instance,
halide, carboxylate, carbonates, phosphonate, or sulfonate, etc. to
their corresponding nitriles or azides are very important and
essential in functional group transformation for the synthesis of
amino groups.8
have focused their efforts on the modification of the β-position
(the alcohol moiety) of the MBH adducts. In particular, by
converting the hydroxy group into a leaving group, the MBH
adducts, such as acetates and carbonates, can construct a large
variety of multifunctional compounds.9 However, Among them
little attention has been paid to exploring cyanide as viable
nucleophilic substrates in the cyanation of MBH carbonates10 and
there are no effective methods for transforming the adducts of the
cyanation to allylic amines.
Me
CO2Me
Ph
CO2Me
Ph
HO
8 h
DABCO
PhMe
CN
CN
+
MeO2C
Ph
CN
OBoc
3a
5 min
1a
5
Scheme 2. Cyanation of MBH Carbonate 1a.
a)Allylic azidations
azide
transformations
NaN3/TMSN3
R
NH2
R
N3
R
X
Herein, we disclose a new type of organocatalytic approach
towards synthetic of vinyl cyanide moieties via a procedure of
DABCO promoting 1,3-proton shift transfer reaction. The
significance of the present chemistry is: 1) Compared to previous
work mainly with metal catalysts, this work is under metal free
conditions. 2) Acetone cyanohydin as cyanide source was used
which was simple, stable, easy to handle, and readily available
compared with other toxicity, volatility, and hazardous handling
cyanide sources such as HCN, TMSCN or KCN. 3) It is the first
example of a transformation of vinyl cyanide to allylic amines
derivatives. This research not only provides a new approach for
additives/conditions
X = OH, OTs, OAc, SiMe3, Halide
b) Direct allylic amination
R1R2NH
R1
R
X
R
N
R2
additives/conditions
X = OH, OAc, Halide
c) This work
Me
HO
CO2R'
CN
cyano
transformations
CO2R'
NH
CN
R
4 h -12 h
R
O
R'O2C
R
DABCO
(Z)
R
CN
5 min
OBoc
Me
Scheme 1. Different approaches for the synthesis of allyl
amines.

2
allylic amines derivatives in organic synthesis, but also offers
Yield (%)b
Entry
Cyanide
Solvent
(E/Z)c
valuable mechanistic insights into this novel 1,3-proton shift
transfer reaction.
Table 1. Optimization of Reaction Conditions.a
3a
4
1
2
3
4
5
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
96
80
n.r.
78
87
－
－
－
－
－
1.7:1
1:1
6
7
8
－
Me
CO2Me
Ph
HO
CO2Me
CN
DABCO
PhMe
CN
CN
+
MeO2C
1.2:1
1:1
+
Ph
OBoc
TMSCN
3a
Yield (%)b
a Reactions were performed with MBH carbonate 1a (0.5 mmol), cyanide (2.0
equiv) in 1.0 mL of solvent for 2 h at room temperature.
1a
4
5
Entry Base (mol %)
Solvent
(E/Z)c
b Yield after column chromatography.
3a
4
c E:Z ratio of the product determined by yield after column chromatography.
1
2
DABCO (10)
Et3N (10)
toluene
toluene
toluene
toluene
toluene
toluene
THF
85
45
23
－
－
－
90
96
40
－
92
80
96
－
－
64
－
－
83
－
－
－
－
－
－
－
1.5:1
1:1
A series of other cyanide sources were screened in Table 2. In
general, silyl cyanide reagent (87% yield) was found to be
superior to benzophenone cyanohydrin (6; 80% yield) and 8
(78% yield) in this reaction (entries 5 vs. 2 and 4), whereas
chalcone cyanohydrin 7 gave no conversion (entry 3). Of the
cyanide reagents, 5 exhibited the best yield 96%.
3
DBU (10)
1.2:1
4
DMAP (10)
Ph3P (10)
5
6
K2CO3 (10)
DBACO (10)
DABCO (10)
DABCO (10)
DABCO (10)
DABCO (10)
DABCO (5)
DABCO (20)
7
1.5:1
1.7:1
1.1:1
Having identified optimized reaction conditions for the
cyanation of MBH carbonate, we explored the substrate scope of
this process. The results are summarized in Table 3. A variety of
aromatics with electron-donating and electron-withdrawing
groups in the 3-, or 4-position were tolerated (Table 2, entries 2–
10). MBH carbonates bearing electron-withdrawing groups on
the aromatic ring participate in the reaction, affording the
cyanation products in good yields within 4 h (entries 4–7, 9–10).
The substrates bearing electron-donating groups on the aromatic
ring participate in the slower transformation, delivering the
sequential products in excellent yields after 12 h (entries 2–3, 8).
Heteroaromatic substrates were also suitable under these
conditions (entries 15, 16). In addition, the reaction worked well
with 1- and 2-naphthyl MBH carbonates to give the desired
products 3m and 3n in 88% and 86%, respectively (entries 13,
14). Due to the steric effect, substrates substituted in the 2-
position on the aromatic rings afforded the desired products in
lower yields (entries 11, 12). The reaction also worked well by
changing the ester group in the MBH carbonates, providing the
corresponding product 3q in 96% yield (entry 17). Subsequently,
in the case of aliphatic substrate, the reaction proceeded smoothly
at room temperature. However, the final product obtained was 2r
not transformational product even prolonged reaction time to 24
h (entry 18).
8
CH2Cl2
DMF
9
10
11
12
13
CH3OH
CHCl3
CH2Cl2
CH2Cl2
1.6:1
1.7:1
1.6:1
a Reactions were performed with MBH carbonate 1a (0.5 mmol), acetone
cyanohydin (2.0 equiv) in 1.0 mL of solvent for 2 h at room temperature.
b Yield after column chromatography.
c E:Z ratio of the product determined by yield after column chromatography.
Our study commenced with MBH carbonate 1a and acetone
cyanohydin in the presence of 10 mol % of DABCO in toluene at
room temperature. Gratifyingly, the final product of cyanation
was thermodynamically-favored compound 3a containing the
vinyl cyanide moiety, a precursor of allylic amine transforming
from kinetic-favored product 2 envisaged initially which could be
detected in the reaction system. As indicated in Table 1, among
various bases evaluated in the cyanation of MBH carbonate 1a,
the strong nucleophilic base DABCO showed the best
regioselectivity, affording 3a in 85% yield (E/Z=1.5/1, Entry 1).
Regioisomer 4 was obtained when using inorganic base K2CO3
(Entry 6). Mixture of both products were obtained employing the
DBU (Entry 3). Further optimization on the other reaction
conditions (including solvent and base’s loading) led to the
discovery that the regioisomer of 3a was formed exclusively in
96% yield (E/Z=1.7/1) when CH2Cl2 was used as solvent and
base’s loading was 10 mol % (Entry 11).
Table 3. Substrate Scope for the Cyanation of MBH
Carbonates.a
Me
CO R'
CO R'
2
2
HO
DABCO
CH Cl , rt
CN
R
R
CN
R'O C
2
+
2
2
R
CN
2
OBoc
5
1
3
Time
(h)
Yield
(%)b
Entry
1 (R, R’)
Product 3
(E/Z)c
1.7:1
2.3:1
Table 2. Different cyanide sources effect on the Cyanation of
MBH Carbonates.a
1
2
1a (C6H5, Me)
3a
3b
8
97
1b (4-MeOC6H4, Me)
1c (4-MeC6H4, Me)
1d (4-FC6H4, Me)
12
94
Me
cyanide (2.0 equiv.)
DABCO (0.1 equiv.)
CO2Me
Ph
CO2Me
CN
CN
3
4
5
6
7
8
3c
3d
3e
3f
12
4
97
88
84
83
81
96
1.7:1
1.5:1
1.9:1
1.7:1
3.2:1
2.0:1
+
MeO2C
CH2Cl2, rt
Ph
OBoc
1a
3a
4
1e (4-ClC6H4, Me)
1f (4-BrC6H4, Me)
1g (4-CF3C6H4, Me)
1h (3-MeOC6H4, Me)
4
HO
HO
CN
O
CN
HO
CN
4
NC
O
3g
3h
4
5
6
7
8
12

3
9
1i (3-ClC6H4, Me)
1j (3,4-Cl2C6H3, Me)
1k (2-MeOC6H4, Me)
1l (2-BrC6H4, Me)
1m (1-Naphthyl, Me)
1n (2-Naphthyl, Me)
1o (2-Furanyl, Me)
1p (2-thienyl, Me)
1q (C6H5, Et)
3i
3j
4
4
80
81
60
78
88
86
85
84
96
65
1.6:1
2.2:1
6:1
10
11d
12
13
14
15
16
17
18
3k
3l
12
12
8
1.5:1
1.3:1
1.4:1
1.6:1
2.3:1
1.4:1
-
3m
3n
3o
3p
3q
2r
8
4
4
8
1r (isopropyl, Me)
24
aReactions were performed with MBH carbonate 1 (0.5 mmol), acetone
cyanohydin (2.0 equiv), and 10 mol % of DABCO in 1.0 mL of CH2Cl2 for 4-
24 h at room temperature.
bYield after column chromatography.
cE:Z ratio of the product determined by yield after column chromatography.
dE:Z ratio of the product determined by NMR analysis.
Figure 2. DFT Profile of 1,3-hydrogen Transfer
We next turned our attention to the application of the
cyanation products to the synthesis of the allylic amines
derivatives. The adducts 3a and 3c were readily transformed into
corresponding unsaturated lactam 4a and 4c by reductive
amidation using InCl3 and NaBH4 with good yields (Scheme 3).11
To gain additional insight into the transformation of
dynamically-favored product 2 to thermodynamically favored
product 3a, the reaction of 1a under standard reaction conditions
1
in CDCl3 was monitored by H NMR spectroscopy (Figure 1).
After reacting with acetone cyanohydin for 5 min, the signals A,
B, C and D were assigned to the hydrogen of MBH carbonate 1a,
which weakened gradually and disappeared after 15 min (Figure
1). The characteristic peaks E and F were assigned to 2, which
appeared and increased after 5 min along with the decrease of 1a.
The peaks of 2 became weak at 2 h, and completely disappeared
at 12 h as it was converted into the characteristic peaks G, H and
I, J of final product 3a (Figure 1).
Scheme 3. Transformation of Cyanation Adducts 3a and 3c to
Unsaturated Lactam 4a and 4c.
E
HO
Ar
CN
CO
+
tBuO
2
N
N
I
E
CN
O
Ar
E
+
tBuOH
Ar
OBoc
1
CN
3
CN
Ar
N
N
E
H
N
CN
E
Ar
N
IN2
2
Figure 1. Dynamically-favored Product 2 Detected by NMR
Analysis.
CN
N
N
E
N
N
Ar
H
H
II
NC
Ar
E
IN1
In order to explain this astonishing transformation of
dynamically-favored product 2 to the thermodynamically favored
product 3a, DFT calculation was conducted on the M06-2X/6-
31G(d) level (Figure 2). The combination of 2 and DABCO is
endothermic by 2.8 Kcal/mol in gas phase. Then, acidic β-H was
snatched by Lewis base DABCO furnishing an allylic anion IN2.
This procedure is endothermic by 3.7 Kcal/mol. The subsequent
step is the releasing of proton from proton shuttle H-DABCO to
sp2-hybidized carbon after overcoming an activation Gibbs free
energy barrier of 21.6 kcal/mol to get the final product and is
exergonic by -1.1 kcal/mol.
Scheme 4. Possible reaction mechanism for the formation of 3.
On the basis of above experimental results, previous work and
computational data,12 a plausible reaction mechanism has been
outlined in Scheme 4. The nucleophilicity of the catalyst plays an
important role in the mechanism of the reaction. The reaction
might be initiated with the in situ formation of a quaternary
ammonium ion
I
from
1
via an addition-elimination-
deprotonation process. The deprotonation of acetone cyanohydin

4
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proton shift transfer process under metal free conditions. This
novel protocol provided an efficient method for the construction
of vinyl cyanide moieties, which could be easily transformed into
allylamine derivatives, in good to excellent yields and
regioselectivities.
Remarkably,
the
transformation
of
dynamically-favored product to the thermodynamically favored
product was conducted by a joint research of NMR and DFT
calculation. Efforts are currently underway in our laboratory to
explore medicinal applications of the products, and the results of
which will be reported in due course.
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Acknowledgments
We thank the Voluntary Program of China Academy of
Chinese Medical Sciences (ZZ0908028) for financial support.
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5
Highlights
Organocatalytic approach towards synthetic of
vinyl cyanide moieties is disclosed.
A procedure of DABCO promoting 1,3-proton
shift transfer reaction is mentioned.
1,3-proton shift transfer is conducted by
researching of NMR and DFT calculation.
Vinyl cyanide is transformed into allylic amines
derivatives.
Mechanism relies on addition-elimination-
deprotonation and 1,3-proton shift transfer.