Glycine catalyzed diastereoselective domino-synthesis of 6-imino-2,7-dioxabicyclo[3.2.1]octane-4,4,5-tricarbonitriles in water

Article abstract of DOI:10.1039/c5gc00909j

The first example of glycine-catalyzed direct domino synthesis of 6-imino-2,7-dioxabicyclo[3.2.1]octane-4,4,5-tricarbonitriles in aqueous medium is described, giving products in excellent yields and moderate to excellent diastereoselectivities. This appro

Full text of DOI:10.1039/c5gc00909j

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: O. V. Ershov, M. Y.
Ievlev, V. Tafeenko and O. E. Nasakin, Green Chem., 2015, DOI: 10.1039/C5GC00909J.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/greenchem

Please do not adjust margins
Green Chemistry
Page 1 of 6
View Article Online
DOI: 10.1039/C5GC00909J
Green Chemistry
ARTICLE
Glycine catalyzed diastereoselective domino-synthesis of 6-imino-
,7-dioxabicyclo[3.2.1]octane-4,4,5-tricarbonitriles in water
2
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
b
a
O. V. Ershov *, M. Yu. Ievlev , V.A. Tafeenko and O.E. Nasakin
DOI: 10.1039/x0xx00000x
The first example of glycine catalyzed directly domino- synthesis of 6-imino-2,7-dioxabicyclo[3.2.1]octane-4,4,5-
tricarbonitriles in aqueous medium was described, giving products in excellent yields and up to excellent
diastereoselectivities. This approach provides a highly efficient and environmentally benign access to cyano substituted
www.rsc.org/
2
,7-dioxabicyclo[3.2.1]octane.
5
d
biosynthesis in glial cells, the ability to inhibit cholinesterase
5
e
Introduction
activity also include 2,7ꢀoxabicyclo[3.2.1]octane moiety.
Dioxabicyclo[3.2.1]octanes have also been used as keyꢀ
intermediates in total synthesis of natural products
1
Water is the Nature solvent for syntheses. Using water as a
solvent makes the synthesis more environmentally friendly and
safe, which corresponds to the principles of green сhemistry.
Furthermore, water is also known to enhance the rates and to
affect the selectivity of a wide variety of organic reactions, that
(
Versicolorin, Amipurimycin) and to access other classes of
6
important heterocycles such as pyrans and furans.
The most of the methods for the synthesis of 2,7ꢀ
dioxabicyclo[3.2.1]octanes is based on the reactions of
7
a,b
2
carbohydrates cyclization,
on the formation of the
increases their synthetic utility in organic chemistry. Water
also plays an important role as an alternative solvent replacing
hazardous organic solvents for the synthesis of various
7
c
intramolecular acetals from dihydroxyaldehydes, on the
intramolecular
hydroxymethylꢀ2Hꢀpyrans
substituted furans containing 1,5ꢀdiol moiety.
heterocyclization
of
3,4ꢀdihydroꢀ4ꢀ
7
d
3
and on the dehydration of
heterocycles.
7
e
Catalytic
In this paper a new method of glycine catalyzed directly
methods are also wideꢀpresented in the scientific literature, they
include diol and triple bond cyclization in the presence of a
synthesis
of
6ꢀiminoꢀ2,7ꢀdioxabicyclo[3.2.1]octaneꢀ4,4,5ꢀ
tricarbonitriles in aqueous medium is described. 2,7ꢀ
Dioxabicyclo[3.2.1]octane moiety is an important fragment of
natural compounds. There are many illustrative examples such
as Colomitides
Polyrhaphins etc.
5
a,7f
catalyst AuCl3,
dicobalt octacarbonyl catalyzed double
2+2+1] carbonylative cycloaddition reaction of triynes,
7
g
[
platinumꢀcatalyzed [4+2]cycloadditions and annulations of
, Aplytangene-1, Macfarlandins, Aplyviolene,
4
7
h
enynals with allylic alcohols,
cycloisomerization hydrogenation
acetalization arylꢀsubstituted alkynyl allyl alcohols and
rhodium catalyzed
–
–
isomerization –
7
i
heterocyclization
dioxepines by Bu SnH.
of
2ꢀbromomethylꢀ4,7ꢀdihydroꢀ1,3ꢀ
7
j
3
Results and discussion
Figure
1
.
Examples
of
naturally
occurring
compounds
with
We reported that 6ꢀiminoꢀ2,7ꢀdioxabicyclo[3.2.1]octaneꢀ4,4,5ꢀ
tricarbonitriles 2 can be produced from appropriate 4ꢀоxoalkaneꢀ
2
,7-dioxabicyclo[3.2.1]octane moiety
Among the compounds with 2,7ꢀoxabicyclo[3.2.1]octane
moiety substances having potent antibiotic,
antifungal and antibacterial activities were found. Therapeutic
compounds for the treatment of cancer, selective inhibition of
1
1
,1,2,2ꢀtetracarbonitriles 1 and 1,3,5ꢀtrisubstituted 2,4ꢀdiazapentaꢀ
,4ꢀdienes, and catch much interest as compounds with cytotoxic
5
a
noticeable
8
a
4
а
8b
activity and capability to suppress the tumor cell growth.
5
b
In continuation of our research work on the construction of 2,7ꢀ
dioxabicyclo[3.2.1]octane moiety, we described herein the first
example of synthesis in water. This approach provides an easy
access to the highly functionalized 2,7ꢀdioxabicyclo[3.2.1]octane
derivatives in environmentally friendly and mild conditions.
5
c
αꢀmannosidase,
potent activity in neurotrophic factor
a.
Chuvash State University, Moskovskiy pr. 15, Cheboksary, Russia.
E-mail: oleg.ershov@mail.ru.
b.
Lomonosov Moscow State University, Leninskie gory 1, Moscow, Russia
CCDC 1062055. For crystallographic data in CIF or other electronic format see
†
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 2015
Green. Chem., 2015, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 6
View Article Online
DOI: 10.1039/C5GC00909J
ARTICLE
Journal Name
Table 2. Domino diastereoselective synthesis of 6ꢀiminoꢀ2,7ꢀ
dioxabicyclo[3.2.1]octaneꢀ4,4,5ꢀtricarbonitriles 2
Scheme 1. Domino approach to 2,7-dioxabicyclo[3.2.1]octanes
Target compounds was not yield in the absence of a catalyst, so for
the initiation of the first stage (Knoevenagel addition of CHꢀacid 1 to
the carbonyl group of aldehyde) basic catalysis was used. A series of
organic and inorganic catalysts were screened for this reaction, and
the obtained results are summarized in Table 1. Generally, as
catalysts, inorganic and organic bases gave bad yields and led to the
formation of byproducts. Reported that 4ꢀоxoalkaneꢀ1,1,2,2ꢀ
Entry
1
Substrate
Aldehyde
Product
Yield, %
91
1
a
2a
2b
9a,b
9cꢀe
tetracarbonitriles 1 easily react with hydroxideꢀanion or amines
.
Among all the catalysts screened, glycine emerged as the best,
affording the product 2b in a quantitative yield for 1ꢀ5 minutes.
2
3
98
96
1
a
a
Table 1. Screening of organic and inorganic catalysts of reaction 1ꢀ
(
2ꢀoxocyclohexyl)ethaneꢀ1,1,2,2ꢀtetracarbonitrile
1a
with
a
acetaldehyde
1
Entry
Catalyst
None
Yield, %
2c
1
2
3
4
5
6
7
8
9
–
–
Sodium hydroxide (10%)
Sodium hydroxide (0.5%)
Potassium carbonate
Sodium acetate
Ammonia
21
17
56
2
12
34
98
4
97
1a
2d
Diethylamine
Triethylamine
5
6
82
94
1
1
b
b
2
e
Glycine
a) Reaction conditions: 0.001 mol of ketone 2b, 0.001 mol of
acetaldehyde, 0.0005 mol of catalyst (2 drops for entry 2, 3 and 6)
stirred at 25 °C in 8 ml of water.
2f
The syntheses of 2,7ꢀdioxabicyclo[3.2.1]octanes were carried out in
water at room temperature where the 4ꢀоxoalkaneꢀ1,1,2,2ꢀ
tetracarbonitrile 1 component was reacted in a 1 : 1.2 ratio with the
aldehyde in the presence of glycine. The resulting precipitate was
isolated and gave microanalytical data supporting the formulation of
the desired compound (Figure 2).
7
8
92
97
1
b
2g
1
b
2
h
To increase wettability of 4ꢀоxoalkaneꢀ1,1,2,2ꢀtetracarbonitriles 1
and to enhance the reaction rate a few drops of ethanol should be
added better. After the complete conversion of 4ꢀоxoalkaneꢀ1,1,2,2ꢀ
tetracarbonitrile 1 (indicated by TLC), the waterꢀinsoluble product 2
was isolated in highly pure form just by simple filtration and washed
with 1% sodium bicarbonate solution. The yields of the molecules
Figure 2. The molecular structure of 2f with the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level and H atoms are drawn
as small spheres of arbitrary radii. Distances and angles in the molecule are
unexceptional and match those found in similar molecules. The crystal structure is
stabilized by a N1-H1…O1*(0.5-X, 0.5+X, 1.5-Z) intermolecular (H1…O1* - 2.25Å, angle
N1-H1…O1* 155.8°) interaction.
8a
are improvement over those previously reported for 2c,g . The high
yields obtained using this route may be due to the amphoteric nature
of glycine in water, thereby promoting the condensation reaction
much more effectively than using sequential acid and base reagents.
Under glycine catalysis during the interaction of 4ꢀоxoalkaneꢀ
1
,1,2,2ꢀtetracarbonitriles 1 with aldehydes only the one diastereomer
2
| Green. Chem., 2015, 00, 1-3
This journal is © The Royal Society of Chemistry 2015
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 3 of 6
View Article Online
DOI: 10.1039/C5GC00909J
Journal Name
ARTICLE
is obtained, despite the presence of four asymmetric carbon atoms Conclusions
including already existing in the starting compound 1. To explain the
We have developed glycine catalyzed efficient synthesis of 6ꢀ
iminoꢀ2,7ꢀdioxabicyclo[3.2.1]octaneꢀ4,4,5ꢀtricarbonitriles from
reasons of this fact Scheme 3 is proposed. We assume that C is more
favorable for the formation of the pyran moiety than other variants,
because steric repulsions are minimal in it. Furthermore, at the
approach of aldehyde to 4ꢀoxoalkaneꢀ1,1,2,2ꢀtetracarbonitrile 1, as
shown Scheme 3 (C), pyran was formed with equatorial substituents
and axial hydroxyl stabilized by anomeric effect in E (Scheme 2).
appropriate
aldehydes
and
4ꢀоxoalkaneꢀ1,1,2,2ꢀ
tetracarbonitriles in aqueous medium. This transformation
constitutes the first example of synthesis such 2,7ꢀ
dioxabicyclo[3.2.1]octanes in water. This protocol is direct,
operationally simple (room temperature and solventꢀfree
purification of products) for synthesis of highly functionalized
2
,7ꢀdioxabicyclo[3.2.1]octane derivatives in excellent yields
and up to excellent diastereoselectivities.
Experimental
The progress of reactions and the purity of the products were
monitored by TLC on Sorbfil plates (spots were visualized under
UV light, by treatment with iodine vapor, or by heating). The IR
spectra were recorded on an FSMꢀ1202 spectrometer with Fourier
transform from samples dispersed in mineral oil. The NMR spectra
of
2
were measured in DMSOꢀd
6
on a Bruker DRXꢀ500
spectrometer using tetramethylsilane as an internal reference. The
mass spectra were obtained on a Bruker Ultraflex MALDIꢀTOF
mass spectrometer. Crystals of compound 2f suitable for Xꢀray
analysis were grown at room temperature from chloroform solution.
The data of 2f were collected by using Cadꢀ4 diffractometer (Cu Kα
emission, λ 1.54087Å, ωꢀscan) Cell parameters: a= 7.534(3),
o
3
Scheme 2. Steric interactions of substituents during the formation of product
b=10.682(4), c= 16.411(5)Å , β= 102.32(3) , V=1290.3(8)Å , space
group P2 /n, Z=4. Correction for absorption was not used. The
1
Glycine, except of the role of the Knoevenagel addition stage
11a
structure was solved and refined with SHELX program. The nonꢀ
hydrogen atoms were refined by using the anisotropic full matrix
leastꢀsquare procedure. The hydrogen atoms were located from a
difference Fourier map and refined freely. Molecular geometry
calculations were performed with the SHELX program, and the
10
catalyst, can provide the especial catalysis for the bicycle 2
formation (Scheme 3).
1
1b
molecular graphics were prepared by using DIAMOND software.
Representative procedure for preparation of 1-(2-
oxocyclohexyl)ethane-1,1,2,2-tetracarbonitrile 1a.
To the 1.28 g (0.01 mol) of TCNE 1.96 g (0.02 mol) of
cyclohexanone was added. Then drops of concentrated
2
hydrochloric acid to the wellꢀstirred mixture were added and
continuing stirring. After the rapid selfꢀheating mixture became
solid, important that TCNE had completely dissolved before this
moment. Then 100 ml of iceꢀcold water poured into the reaction
mixture and well stirred. Precipitated product filtered and washed
with water and cooled mixture of propanꢀ2ꢀol : water (1:1), then
Scheme 3. Specific glycine catalysis for the formation of 2,7-dioxabicyclo[3.2.1]octane
moiety
Starting compounds 1 can be easily and quantitatively obtained from
corresponding ketones and tetracyanoethylene (TCNE) in solventꢀ
free conditions (in the excess of liquid ketone) in the presence of
catalytic amount of hydrochloric acid (Scheme 4).
dried in the vacuum desiccator over P
temperature. Yiled 2.03 g (90%), m.p. 132–133°C (dec.) (134°C
ref. 12)).
2 5
O and kept at low
(
Representative procedure for preparation of 3-methyl-4-
oxopentane-1,1,2,2-tetracarbonitrile 1b.
To the 1.28 g (0.01 mol) of TCNE 1.42 g (0.02 mol) of butanꢀ2ꢀone
was added. Then 2 drops of concentrated hydrochloric acid to the
wellꢀstirred mixture were added and continuing stirring at room
Scheme 4. Synthesis of starting 4-oxoalkane-1,1,2,2-tetracarbonitriles 1
Reaction takes place with selfꢀheating and completes in 1ꢀ2 minutes temperature. After the completing reaction (indicated with absence
in the case of cyclohexanone, and continuing for 1 hour at the room of colored complex of TCNE with hydroquinone) Then 100 ml of
temperature in the case of butanꢀ2ꢀone.
iceꢀcold water poured into the reaction mixture and well stirred.
Precipitated product filtered and washed with water and cooled
This journal is © The Royal Society of Chemistry 2015
Green. Chem., 2015, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 6
View Article Online
DOI: 10.1039/C5GC00909J
ARTICLE
Journal Name
ꢀ
1
mixture of propanꢀ2ꢀol : water (1:1), then dried in the vacuum 2g. Yield 0.28 g (92%), m.p. 162ꢀ163°C (dec.). IR: νmax/cm
ꢀ
1
1
desiccator over P
86%), m.p. 134–136°C (dec.) (135ꢀ137°C (dec.) (ref. 12))
Representative procedure for preparation of 12-imino-10,11- q, J 6.9 Hz, CH), 5.65 (1H, s, OCH), 7.54 (3H, m, Ph), 7.64 (2H, m,
2
O
5
and kept at low temperature. Yiled 1.72 g 3259, 2246, 1709 cm ;
H
NMR (500 MHz; DMSOꢀd6,
(
TMS) δ
H 3 3
1.27 (3H, d, J 6.9 Hz, CH ), 1.65 (3H, s, CH ), 3.18 (1H,
1,6
+
dioxatricyclo[5.3.2.0 ]dodecane-7,8,8-tricarbonitrile 2a
To the suspension of 0.23 g (0.001 mol) 1ꢀ(2ꢀoxocyclohexyl)ethaneꢀ 307.1189, found: 307.1191.
,1,2,2ꢀtetracarbonitrile 1a in water (8 ml), 1ꢀ2 drops of ethanol (to 2h. Yield 0.30 g (97%), m.p. 165ꢀ166°C (dec.). IR: νmax/cm
15 4 2
Ph), 9.79 (1H, s, NH). HRMS calcd. for C17H N O [M+H] :
ꢀ
1
1
ꢀ
1
1
increase wettability of compound 1a), 0.1 g (0.0013 mol) of 40% 3271, 2259, 1711 cm ;
formaldehyde solution and 4 mg (0.0005 mol) of glycine were TMS) δ
H
NMR (500 MHz; DMSOꢀd6,
1.28 (3H, d, J 6.9 Hz, CH ), 1.66 (3H, s, CH ), 3.31 (1H,
3 3
added. Reaction mixture stirred well at room temperature till the q, J 6.9 Hz, CH), 5.87 (1H, s, OCH), 7.60 (1H, dd, J 8.0 Hz, 4.8
completing reaction (TLC). Product filtered and washed with water, Hz, Pyr), 8.06 (1H, dt, J 8.0 Hz, 2.0 Hz, Pyr), 8.75 (1H, dd, J 8.0
H
3
5
ml of 1% sodium bicarbonate solution and cooled mixture of Hz, 4.7 Hz, Pyr), 8.85 (1H, d, J 2.1 Hz, Pyr), 9.85 (1H, s, NH).
+
14 5 2
propanꢀ2ꢀol : water (1:1), then dried in the vacuum desiccator over HRMS calcd. for C16H N O [M+H] : 308.1142, found: 308.1140.
ꢀ
1
2
CaCl . Yield 0.23 g (91%), m.p. 163ꢀ164°C (dec.). IR: νmax/cm
ꢀ
1 1
3271, 2258, 1711 cm ; H NMR (500 MHz; DMSOꢀd6, TMS) δ
H
Acknowledgements
), 2.82 (1H, dd, J 12.0 Hz, 5.8 Hz, CH), The study was performed in the framework of the basic part of
), 5.02 (1H, d, J 12.7 Hz, OCH
), 9.75 the State contract with the Ministry of Education and Science of
[M+H] : 257.1033, the Russian Federation (project no. 872).
The XRD study was carried out using the equipment purchased
Compounds 2b–h were prepared in a similar manner using from the funds of the Program of development of Moscow
appropriate 4ꢀoxoalkaneꢀ1,1,2,2ꢀtetracarbonitriles 1 and aldehydes.
University and within the framework of the Agreement on
b. Yield 0.26 g (98%). M.p. 142ꢀ143 °C (dec.). IR: νmax/cm 3267, collaboration between the Chemical Department of the
1.03 (1H, m, CH
2
), 1.26 (1H, m, CH
2
), 1.47 (1H, m, CH
2
), 1.72 (3H,
m, CH
2
), 2.02 (2H, m, CH
2
4
(
.16 (1H, d, J 12.7 Hz, OCH
1H, s, NH). HRMS calcd. for C13
found: 257.1035.
2
2
+
13 4 2
H N O
ꢀ
1
2
2
ꢀ
1
1
255, 1716 cm ; H NMR (500 MHz; DMSOꢀd6, TMS) δ
H
1.08 Lomonsov Moscow State University and the Chemicalꢀ
), 1.49 Pharmaceutical Department of the I.N. Ul’yanov Chuvash State
), 2.84 (1H, dd, J University
2
(
1H, m, CH
2
), 1.39 (1H, m, CH
), 1.74 (3H, m, CH
2
), 1.45 (3H, d, J 6.2 Hz, CH
), 2.08 (2H, m, CH
3
(1H, m, CH
2
2
1
2.0 Hz, 5.8 Hz, CH), 4.35 (1H, q, J 6.2 Hz, OCH), 9.78 (1H, s,
+
15 4 2
NH). HRMS calcd. for C14H N O [M+H] : 271.1190, found:
Notes and references
2
2
2
71.1191.
ꢀ
1
§ CCDC 1062055 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
c. Yield 0.32 g (96%). M.p. 198ꢀ199 °C (dec.). IR: νmax/cm 3276,
ꢀ
1
1
256, 1714 cm ; H NMR (500 MHz; DMSOꢀd6, TMS) δ
), 1.31 (1H, m, CH ), 1.52 (1H, m, CH
), 1.91 (1H, m, CH ), 2.09 (1H, m, CH ), 3.05 (1H, dd, J 11.9
H
1.10
(1H, m, CH
2
2
2
), 1.77 (2H, m, www.ccdc.cam.ac.uk/data_request/cif.
CH
2
2
2
1
2
P. Ball. H O: A Biography of Water; Phoenix Press: London,
2000.
(a) A. Chanda and V. V. Fokin, Chem
Hz, 5.7 Hz, CH), 5.69 (1H, s, OCH), 7.54 (3H, m, Ph), 7.65 (2H, m,
Ph), 9.87 (1H, s, NH). HRMS calcd. for C19H N O [M+H] :
17 4 2
2
+
. Rev., 2009, 109, 725–
3
2
2
33.1346, found: 333.1343.
d. Yield 0.32 g (97%). M.p. 203ꢀ205 °C (dec.). IR: νmax/cm 3265,
251, 1719 cm ; H NMR (500 MHz; DMSOꢀd6, TMS) δ
), 1.31 (1H, m, CH ), 1.53 (1H, m, CH ), 1.78 (2H, m,
), 1.93 (1H, m, CH ), 2.09 (1H, m, CH ), 3.09 (1H, dd, J 11.8
7
48; (b) C. J. Li and T. H. Chang, Organic Reactions in
ꢀ
1
Aqueous Media WileyꢀVCH: New York, 1997; (c) P. A.
Grieco, Organic Synthesis in Water Blackie Acad.
ꢀ
1
1
H
1.10
Professional: London, 1998; (d) C.ꢀJ. Li, Chem
05, 3095ꢀ3165; (e) A. Lubineau, J. Augé and Y. Queneau,
Synthesis , 1994, 741ꢀ760.
S. P. Siva and C. J. Subhash, Mini-Reviews in Organic
Chemistry, 2011, 8, 455ꢀ464.
. Rev., 2005,
(1H, m, CH
2
2
2
1
CH
2
2
2
Hz, 5.7 Hz, CH), 5.89 (1H, s, OCH), 7.60 (1H, dd, J 8.0 Hz, 4.7
Hz, Pyr), 8.07 (1H, dt, J 8.0 Hz, 1.9 Hz, Pyr), 8.75 (1H, dd, J 4.8
Hz, 1.5 Hz, Pyr), 8.87 (1H, d, J 2.2 Hz, Pyr), 9.93 (1H, s, NH).
3
4
(a) J.ꢀY. Donga, L.ꢀM. Wanga, H.ꢀCh. Song, K.ꢀZ. Shen, Y.ꢀ
+
P. Zhou, L. Wang and K.ꢀQ. Zhang, Chemistry
Biodiversity, 2009, 6, 1216ꢀ1223; (b) R. A. Keyzers, P. T.
Northcote and M. T. DaviesꢀColeman Nat Prod Rep., 2006,
3, 321ꢀ334.
(a) Y.ꢀY. Yeung and E. J. Corey; Org
&
HRMS calcd. for C18
H
16
N
5
O
2
[M+H] : 334.1299, found: 334.1301.
ꢀ
1
2e. Yield 0.19 g (82%), m.p. 157ꢀ158°C (dec.). IR: νmax/cm 3277,
.
.
ꢀ
1
1
2
249, 1709 cm ; H NMR (500 MHz; DMSOꢀd6, TMS) δ
), 1.54 (3H, s, CH ), 2.94 (1H, q, J 6.8 Hz,
CH), 4.11 (1H, d, J 12.8 Hz, OCH ), 5.02 (1H, d, J 12.8 Hz,
OCH ), 9.65 (1H, s, NH). HRMS calcd. for C11
31.0877, found: 231.0876.
f. Yield 0.23 g (94%), m.p. 124ꢀ125°C (dec.). IR: νmax/cm 3275,
H
1.18
2
(3H, d, J 6.8 Hz, CH
3
3
5
. Lett., 2008, 10, 3877ꢀ
3878; (b) Ch. Salomon, Y. Kawakami, A. Bagchi, Y.
Rusman, R. Blanchette, B. Held and A. Spike, Patent
WO2014018671, 2014; Chem. Abstr. 2014, 160, 272657; (c)
R. S. Mane, S. Ghosh, Sh. Singh, B. A. Chopade and D. D.
2
+
2
11 4 2
H N O [M+H] :
2
2
2
ꢀ
1
Dhavale, Bioorg
Kikuchi, Y. Miyagawa, Y. Sahashi, S. Inato, A. Haganuma,
N. Nakahata and Y. Oshima, Org Chem., 2004, 69, 352ꢀ
56; (e) N. H. Grieg, A. Brossi, W. Luo, Q.ꢀS. Yu and H. W.
Holloway, Patent WO2006060082, 2006; Chem Abstr. 2006,
45, 27973.
(a) T. L. Graybill, E. G. Casillas, K. Pal and C. A. Townsend,
. Med. Chem., 2011, 19; 6720ꢀ6725; (d) H.
ꢀ
1
1
261, 1719 cm ; H NMR (500 MHz; DMSOꢀd6, TMS) δ
), 1.51 (3H, d, J 6.0 Hz, CH ), 1.54 (3H, s,
), 2.90 (1H, q, J 6.8 Hz, CH), 4.53 (1H, q, J 6.0 Hz, OCH),
H
1.19
(3H, d, J 6.8 Hz, CH
3
3
J
.
.
3
CH
3
+
.
9.71 (1H, s, NH). HRMS calcd. for C12
13 4 2
H N O [M+H] : 245.1033,
1
found: 245.1035.
6
J
.
Am
.
Chem
.
Soc., 1999, 121, 7729ꢀ7746; (b) R. S. Mane, S.
4
| Green. Chem., 2015, 00, 1-3
This journal is © The Royal Society of Chemistry 2015
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 5 of 6
View Article Online
DOI: 10.1039/C5GC00909J
Journal Name
ARTICLE
Ghosh, B. A. Chopade, O. Reiser and D. D. Dhavale,
J.
Org
.
Chem., 2011, 76, 2892ꢀ2895.
7
(a) S. J. Angyal, Carbohydr
. Res. 1991, 216, 171ꢀ178; (b) P.
Siegfried, W. L. Frieder and H. J. Lindner, Tetrahedron
:
Asymmetry, 2003, 14, 2475–2479; (c) M. Aquino, I. Safir, Z.
Elkhayat, Z. Gandara, M. Perez, P. Retailleau, S. Arseniyadis,
Org
Saylor and J. F. Sebastian, Synth
12; (e) M. Dai, I. J. Krauss and S. J. Danishefsky,
Chem., 2008, 73, 9576ꢀ9583; (f) S. Antoniotti, E. Genin, V.
.
Lett., 2009, 11, 3610ꢀ3613; (d) F. T. Oakes, R. W.
Commun., 1982, 12, 607ꢀ
Org
.
6
J.
.
Michelet and J.ꢀP. Gene,
J.
Am
.
Chem
.
Soc., 2005, 127, 9976ꢀ
9
977; (g) S. U. Son, Y. A. Yoon, D. S. Choi, J. K. Park, B.
M. Kim and Y. K. Chung, Org
.
Lett., 2001, 3, 1065ꢀ1067; (h)
Am Chem Soc.,
009, 131, 2090ꢀ2091; (i) N. Koerber, F. Rominger and T. J.
J. Mueller, Adv Synth Catal., 2009, 351, 2921ꢀ2935; (i) N.
Koerber, F. Rominger and T. J. J. Mueller, Adv Synth Catal.,
009, 351, 2921ꢀ2935; (j) A. C. Hindson, F. MacCorquodale
and J. C. Walton, Chem Soc., Perkin Trans. 2, 1993, 871ꢀ
77.
Y.ꢀC. Hsu, C.ꢀM. Ting and R.ꢀS. Liu,
J.
.
.
2
.
.
.
.
2
J.
.
8
8
9
(a) M. Yu. Ievlev, O. V. Ershov, Ya. S. Kayukov, M. Yu.
Belikov, S. V. Fedoseev, O. E. Nasakin, Patent RU2545459
C1, 2015; Chem. Abstr. 2015, 517051; (b) O. E. Nasakin, A.
N. Lyshchikov, Ya. S. Kayukov, V. P. Sheverdov Pharm.
Chem. J. 2000, 4, 170ꢀ185.
(а) S. V. Fedoseev, O. V. Ershov, M. Yu. Belikov, K. V.
Lipin, I. N. Bardasov, O. E. Nasakin, V. A. Tafeenko,
Tetrahedron Lett. 2013, 54, 2143ꢀ2145; (b) S. V. Fedoseev,
O. V. Ershov, M. Yu. Belikov, K. V. Lipin, O. E. Nasakin, V.
A. Tafeenko, Rus. J. Org. Chem., 2013, 49, 1661ꢀ1665 (c) M.
Yu. Belikov, O. V. Ershov, A. V. Eremkin, O. E. Nasakin, V.
A. Tafeenko, E. V. Nurieva, Tetrahedron Lett. 2011, 52,
6
407ꢀ6410; (d) M. Yu. Belikov, O. V. Ershov, A. V.
Eremkin, Ya. S. Kayukov, O. E. Nasakin, Rus. J. Org. Chem.
,
2
010, 46, 597ꢀ598. (e) M. Yu. Belikov, O. V. Ershov, A. V.
Eremkin, Ya. S. Kayukov, O. E. Nasakin, Rus. J. Org. Chem.
,
2010, 46, 615ꢀ616.
1
0 (a) S. Shafqat, M. Khan, A. Zulkharnain, S. Hamdan, A. H.
Rigit and A. Khan Asian J. Chem., 2014, 26, 8463ꢀ8466; (b)
M. Chowdhry, D. Mingos, A. White and D. Williams J.
Chem. Soc., Perkin Trans. 1, 2000, 3495–3504.
1
1 (a) G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112ꢀ122,
(b) K. Brandenburg, DIAMOND, Release 2.1d; Crystal
Impact GbR: Bonn, Germany, 2000.
2 W. J. Middleton, R. E. Heckert, E. L. Little and C. G.
Krespan, J. Am. Chem. Soc., 1958, 80, 2783ꢀ2788
1
This journal is © The Royal Society of Chemistry 2015
Green. Chem., 2015, 00, 1-3 | 5
Please do not adjust margins

Green Chemistry
Page 6 of 6
View Article Online
Glycine catalyzed diastereoselective domino-synthesis of 6-im
D
in
OI: 10.1039/C5GC00909J
o
-
2
,7-dioxabicyclo[3.2.1]octane-4,4,5-tricarbonitriles in water
O. V. Ershov, M. Yu. Ievlev, V.A. Tafeenko and O.E. Nasakin
The first example of glycine catalyzed directly synthesis of 6-imino-2,7-dioxabicyclo[3.2.1]octane-4,4,5-
tricarbonitriles in aqueous medium was described, giving products in excellent yields and up to excellent
diastereoselectivities. This approach provides a highly efficient and environmentally benign access to cyano
substituted 2,7-dioxabicyclo[3.2.1]octanes