Asymmetric Epoxidation of Alkylidenemalononitriles: Key Step for One-Pot Approach to Enantioenriched 3-Substituted Piperazin-2-ones

Article abstract of DOI:10.1021/acs.orglett.5b02186

The first enantioselective epoxidation of readily available alkylidenemalononitriles has been developed by using a multifunctional cinchona derived thiourea as the organocatalyst and cumyl hydroperoxide as the oxidant. A new simple one-pot asymmetric epox

Full text of DOI:10.1021/acs.orglett.5b02186

Letter
pubs.acs.org/OrgLett
Asymmetric Epoxidation of Alkylidenemalononitriles: Key Step for
One-Pot Approach to Enantioenriched 3‑Substituted Piperazin-2-
ones
Sara Meninno, Andreu Vidal-Albalat, and Alessandra Lattanzi*
̀
Dipartimento di Chimica e Biologia, Universita di Salerno, Via Giovanni Paolo II, 84084, Fisciano, Italy
S
* Supporting Information
ABSTRACT: The first enantioselective epoxidation of readily
available alkylidenemalononitriles has been developed by using
a multifunctional cinchona derived thiourea as the organo-
catalyst and cumyl hydroperoxide as the oxidant. A new simple
one-pot asymmetric epoxidation/SN2 ring-opening reaction
with 1,2-diamines leading to important enantioenriched
heterocycles, i.e. 3-substituted piperazin-2-ones, has been
established.
To address the limitations detailed above and motivated by
our interest in the asymmetric synthesis of epoxides,13 we
embarked in a study aimed at the development of an
enantioselective epoxidation of alkylidenemalononitriles as a
primary goal. Additionally, we planned to demonstrate the
feasibility of an asymmetric epoxidation of alkylidenemalono-
nitriles as a key step for a new and straighforward access to
piperazin-2-ones (Scheme 1). A regioselective SN2 ring-opening
he asymmetric epoxidation of alkenes is a cornerstone
Ttransformation in organic chemistry. Several efforts have
been focused in recent decades toward developing asymmetric
systems for the epoxidation of a variety of substituted alkenes.1
Different metal-based or organocatalytic protocols provide
highly valuable enantioenriched epoxides as synthetic inter-
mediates or products showing different biological activities.1c In
terms of alkene structure, excellent stereoselective systems are
currently used to epoxidize allylic and homoallylic alcohols2 and
unfunctionalized olefins.3 In the area of asymmetric epoxidation
of electron-poor alkenes, several methodologies focused on
trans-enones.4 Despite the success, there is room to expand the
substrate scope of electron-poor alkenes, whose enantioen-
riched epoxides would be potentially highly attractive for
further elaborations such as readily available alkylidenemalono-
nitriles.
Scheme 1. Strategy Comprising an Enantioselective
Epoxidation of Alkylidenemalononitriles Followed by a
Regioselective SN2 Ring-Opening with 1,2-Diamines
These alkenes are challenging Michael acceptors as
demonstrated by the few methodologies reported on
asymmetric carbon−carbon bond formation,5 likely ascribed
to their significant reactive nature6 and weak H-bonding
acceptor ability of the cyano group.7 The only example by
Sekiya and co-workers on an asymmetric epoxidation of
alkylidenemalononitriles using alkyl hydroperoxides or molec-
ular oxygen and stoichiometric amounts of chiral bases afforded
nearly racemic epoxides in low yield.8
reaction of the enantioenriched gem-dicyano epoxides by 1,2-
diamines, followed by an intramolecular attack of the other
amine group to the in situ formed acyl cyanide intermediate,
would lead to enantioenriched piperazin-2-ones.14
It has been demonstrated by a few reports that racemic gem-
dicyano epoxides behave like the synthetic equivalent of
dication ketenes. In the presence of binucleophilic compounds,
they afforded, under reflux conditions, heterocycles such as
imidazoles,9 2-acetylimino-1,3-oxathioles,10 and 1,4-benzoxazin-
2-ones.11 Interestingly, Baudy-Floc’h et al. isolated a 3-aryl
piperazin-2-one in 10% yield working under milder con-
ditions.12 The reaction proceeded at room temperature via
regioselective ring-opening of the corresponding gem-dicyano
epoxide by ethylendiamine as a binucleophile.
Developing asymmetric syntheses of substituted piperazin-2-
ones is highly desirable, given their relevance as pharmaco-
phores showing a wide range of biological activities as HDAC
inhibitors,15 bradykinin receptor antagonists,16 serotonin
receptor antagonists,17 hepatitis C virus replication inhibitors,18
antihelminthics,19 and antagonist GW597599,20 to cite a few.
Additionally, they play a central role in conformationally
Received: July 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02186
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
constrained peptides.21 However, the asymmetric synthesis of
substituted piperazin-2-ones is particularly challenging and only
rare examples have been reported.14f,22 Indeed, current
protocols exclusively rely on classical techniques such as the
use of amino acid derivatives as starting compounds, with clear
limitation on structural diversity or via resolution of
diastereomeric salts.20,23
Table 1. Screening of Catalysts in the Asymmetric
Epoxidation of Alkene 1a
a
Herein, we document our preliminary results on asymmetric
nucleophilic epoxidation of alkylidenemalononitriles catalyzed
by a multifunctional cinchona derived thiourea with cumyl
hydroperoxide as the oxidant (CHP). The epoxides were
obtained in good to high yield and up to 90:10 er. Moreover,
we developed a highly valuable one-pot epoxidation/ring-
opening sequence to enantioenriched 3-substituted piperazin-2-
ones starting from easily accessible alkylidenemalononitriles.
We reasoned that bifunctional catalysts bearing double H-
bonding donors would have been effective in engaging a H-
bonding network with alkylidenemalononitrile. This idea was
supported by our recently disclosed ability of cinchona derived
thioureas to catalyze the enantioselective nucleophilic epox-
idation of electron-poor 1,1-disubstituted terminal alkenes with
tert-butyl hydroperoxide (TBHP).13d Initial experiments were
performed with phenylidenemalononitrile 1a and TBHP in
toluene at room temperature screening different organo-
catalysts at a 10 mol % loading (Table 1). We were pleased
to observe that epi-quinine derived thiourea eQNT satisfac-
torily catalyzed the reaction affording the epoxide with a
67.5:32.5 er value (entry 1). The corresponding urea and
squaramide proved to be slightly less efficient (entries 2 and 3).
The epi-cinconidine thiourea eCDT and epi-hydroquinine
thiourea eHQNT were less effective (entries 4 and 5), whereas
the pseudoenantiomeric epi-quinidine thiourea eQDT afforded
the opposite enantiomer of the epoxide in high yield but with
lower enantioselectivity (entry 6). Catalyst 3, where the
thiourea moiety is positioned in the quinoline ring, proved to
be the worst in the series, indicating that the quinuclidine
nitrogen and hydrogen bonding donating groups are catalyti-
cally more effective when located in proximity (entry 7). The
presence of a chiral amine moiety in the epi-quinine derived
thiourea 4 was detrimental for the enatioselectivity (entry 8).
These results suggested that additional chiral scaffolds could be
exploited for matching effects on the catalyst activity.
Structurally different thiourea amines 5 and 6 (entries 9 and
10) did not improve the result obtained with eQNT (entry 1).
Taking into account the reactive nature of alkylidene
malononitrile, we thought improvements might be achieved
using amine thioureas bearing multiple hydrogen-bonding
donors incorporating chiral aminoalcohol moieties.24 We
investigated the catalytic activity of epi-quinine derived
thioureas 7a−e under the standard conditions (entries 11−
15). Interestingly, promoter 7a proved to be more active and
enantioselective than eQNT (entry 11), with the best matching
effect displayed by the (S,S)-amino alcohol portion. The
absolute configuration of the amino alcohol moiety plays an
important role as the opposite enantiomer of 2a was obtained
when passing from catalyst 7a to 7b, containing the
enantiomeric amino alcohol moiety (entries 11 and 12). The
pseudoenantiomeric catalyst 7e (with respect to 7a) nicely led
to the formation of the opposite enantiomer of product 2a with
the same level of enantioselectivity (entry 15).
b
c
entry
cat.
time/h
yield/%
er/%
1
2
eQNT
eQNU
eQNS
eCDT
eHQNT
eQDT
3
15
16
40
21
24
21
29
15
24
24
21
22
18
17
16
58
48
70
57
63
84
43
72
55
34
90
80
75
74
87
67.5:32.5
65.4:34.6
62.2:37.8
59.5:40.5
56.2:43.8
44.9:55.1
54.2:45.8
52.4:47.6
44.3:55.7
31.3:68.7
77.2:22.8
42.8:57.2
71:29
d
3
4
5
e
6
7
8
4
e
9
5
e
10
6
11
7a
e
12
7b
13
7c
e
14
e
7d
49.8:50.2
23:77
15
7e
a
Reactions were carried out at 0.1 mmol scale of 1a (C 0.2 M) using
b
TBHP (1.2 equiv). Determined by 1H NMR analysis with 1,3,5-
c
(MeO)3C6H3 as an internal standard. Determined by chiral HPLC
analysis. Reaction carried out with 5 mol % of eQNS in CHCl3. The
d
e
opposite enantiomer was preferentially obtained.
oxidant, working in toluene at −20 °C. Under optimized
conditions, we studied the substrate scope of the asymmetric
epoxidation of alkylidenemalononitriles (Table 2). Differently
phenyl substituted alkenes were generally converted into the
corresponding epoxides in good to high yield and moderate to
good enantiomeric ratio irrespective of the substitution pattern.
The ortho-substituted derivative was obtained with only a
slightly decreased enantiomeric ratio (entry 9). In the case of
the 4-cyano substituted derivative, the epoxide was isolated
with up to 90:10 er (entry 6). Access to both enantiomeric
products is an important added value of an asymmetric
methodology, especially in view of the potential biological
activity of the final compounds or their derivatives.
Pseudoenantiomeric cinchona alkaloid catalysts seldom afford
the opposite enantiomer of a product with the same level of
enantioselectivity. When the pseudoenantiomeric catalyst 7e
was used, we were pleased to recover the opposite enantiomer
Extensive screening of the reaction parameters,25 choosing
catalyst 7a as the best performing promoter, enabled
identification of cumyl hydroperoxide (CHP) as the best
B
DOI: 10.1021/acs.orglett.5b02186
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Asymmetric Epoxidation of
Alkylidenemalononitriles with 7a/CHP System
Table 3. One-Pot Asymmetric Epoxidation/Ring-Opening
Reaction to 3-Substituted Piperazin-2-ones
a
a
b
c
entry
R1
time/h
yield 2/%
er 2/%
1
2
3
4
5
Ph
24
28
21
42
26
20
25
22
43
64
67
45
78 (a)
74 (b)
90 (c)
70 (d)
64 (e)
80 (f)
79 (f)
80 (g)
65 (h)
90 (i)
84 (j)
47 (k)
85.2:14.8
86:14
4-CF3C6H4
3-BrC6H4
2-naphthyl
4-NO2C6H4
4-CNC6H4
4-CNC6H4
4-ClC6H4
2-MeC6H4
3-MeOC6H4
cyclohexyl
n-C7H15
83:17
81.6:18.4
85.5:14.5
90.4:9.6
90.1:9.9
87.7:12.3
82.8:17.2
86.6:13.4
82:18
d
6
d,e
7
8
9
10
11
12
74.9:25.1
a
Reactions were carried out at 0.15 mmol scale of 1 (C 0.05 M) using
b
c
a
CHP (1.2 equiv). Isolated yield. Determined by chiral HPLC
analysis. A mixture of toluene/CH2Cl2 3/1. The opposite
enantiomer was preferentially obtained.
Reactions were carried out at 0.15 mmol scale of 1 (C 0.05 M) using
d
e
CHP (1.2 equiv) at −20 °C for the indicated time (t1). After removing
toluene, CH3CN (5 mL) and 1,2-diamine (2.5 equiv) were added,
while stirring was maintained at room temperature for the indicated
b
c
d
time (t2). Isolated yield. Determined by chiral HPLC analysis. The
regioisomeric ratio of 92:8 was determined by 1H NMR analysis.
(1R,2R)-1,2-Diaminocyclohexane (2 equiv) was used.
of epoxide 2f with the same e.r. value (entry 7). Surprisingly,
less reactive and more challenging aliphatic alkylidenemalono-
nitriles were suitable substrates for the epoxidation, which
proceeded with a slight decrease in the enantiocontrol (entries
11 and 12).
We next investigated the synthetic potential of this class of
epoxides to rapidly and conveniently access the piperazin-2-one
scaffold in an one-pot access,26 as illustrated in Scheme 1. After
performing the asymmetric epoxidation of representative
alkylidenemalononitriles under standard conditions, toluene
was removed under reduced pressure and replaced with
acetonitrile followed by the addition of 2.5 equiv27 of 1,2-
diamines at room temperature (Table 3).
e
On the basis of experimental data, a plausible transition state
model for the oxa-Michael step of the nucleophilic epoxidation
is illustrated in Figure 1. The alkylidenemalononitrile is
We were delighted to isolate in good overall yield the
corresponding N-benzyl substituted heterocycles 8 using N-
dibenzyl-1,2-ethylendiamine and different arylidenemalono-
nitriles 1 (entries 1−3). More importantly, the ring-opening
reaction occurred stereospecifically, according to an SN2
displacement, as attested by the enantiomeric ratio values
observed for compounds 8. N-Unsubstituted piperazin-2-one
8d was also isolated in high overall yield without erosion of
enantioselectivity using ethylendiamine as the binucleophile
(entry 4). Interestingly, when reacting unsymmetric N-benzyl
ethylendiamine with model epoxide 2a, the regioisomer (R2 =
Bn, R3 = H) derived from epoxide ring-opening by the less
sterically demanding nitrogen of the diamine was almost
exclusively obtained (entry 5). On the basis of characterization
data of previously reported compounds 8a,d22a,b the absolute
configuration of the stereocenter was established to be (R) and
consequently the absolute configuration of epoxide as (S)-2a.
Finally, (1R,2R)-1,2-diaminocyclohexane reacted with epoxide
2a affording two enantiomerically pure bicyclic diaster-
eoisomers 8f and 8g in 84% and 14% yield respectively, in
line with the enantiomeric ratio of epoxide 2a. In addition, we
confirmed the (S)-absolute configuration of epoxide 2a,
comparing the data of diastereoisomers 8f,g with data
previously reported for enantiomerically pure diastereoisomer
8g.14c
Figure 1. Postulated transition state model.
activated and oriented by a H-bonding network of the thiourea
NH and the OH bonds.28 The OH group of the CHP is
expected to be strongly engaged in H-bonding interaction with
the basic quinuclidine nitrogen. The attack of the peroxide
would preferentially occur to the Si-face of the alkene, to give
the enolate which after ring closure would provide the (S)-
epoxide.
In conclusion, we disclosed the first asymmetric epoxidation
of readily available alkylidenemalononitriles catalyzed by a
multifunctional cinchona alkaloid thiourea/CHP system. The
epoxidation is applicable to either aromatic and aliphatic
alkylidenemalononitriles achieving the products in both
absolute configurations with a moderate to good level of
enantiocontrol. A relevant synthetic application of these
products has been also documented. Either N-alkylated or N-
unprotected enantioenriched 3-substituted piperazin-2-ones
can be satisfactorily isolated starting from alkylidenemalono-
nitriles, via a one-pot epoxidation/SN2 ring-opening reaction
sequence. Our approach to 3-substituted piperazin-2-ones can
be considered complementary to the asymmetric reduction of
C
DOI: 10.1021/acs.orglett.5b02186
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(12) Hurtaud, D.; Baudy-Floc'h, M.; Robert, A.; Le Grel, P. J. Org.
Chem. 1994, 59, 4701−4703.
(13) (a) Lattanzi, A.; Iannece, P.; Vicinanza, A.; Scettri, A. Chem.
Commun. 2003, 1440−1441. (b) Lattanzi, A. Org. Lett. 2005, 7, 2579−
2582. (c) De Fusco, C.; Tedesco, C.; Lattanzi, A. J. Org. Chem. 2011,
76, 676−679. (d) Russo, A.; Galdi, G.; Croce, G.; Lattanzi, A. Chem. -
Eur. J. 2012, 18, 6152−6157.
(14) For examples on stereospecific ring-opening reactions of
diastereoisomerically or enantiomerically enriched epoxides, by
amines, see: (a) Jackson, R. F. W.; Kirk, J. M.; Palmer, N. J.;
Waterson, D.; Wythes, M. J. J. Chem. Soc., Chem. Commun. 1993, 889−
890. (b) Jackson, R. F. W.; Palmer, N. J.; Wythes, M. J.; Clegg, W.;
Elsegood, M. R. J. J. Org. Chem. 1995, 60, 6431−6440. (c) Aggarwal,
V. K.; Barrell, J. K.; Worrall, J. M.; Alexander, R. J. Org. Chem. 1998,
the aliphatic trichloromethyl ketones/Jocic type reaction
sequence.14f,29 Further work to improve the enantioselectivity
and extend the scope of the synthetic elaborations is underway
in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02186.
1
Experimental details, analytical data, copies of H, 13C
NMR spectra and HPLC traces (PDF)
́
63, 7128−7129. (d) Agut, J.; Vidal, A.; Rodríguez, S.; Gonzalez, F. V. J.
Org. Chem. 2013, 78, 5717−5722. (e) Meninno, S.; Napolitano, L.;
Lattanzi, A. Catal. Sci. Technol. 2015, 5, 124−128. (f) Perryman, M. S.;
Earl, M. W. M.; Greatorex, S.; Clarkson, G. J.; Fox, D. J. Org. Biomol.
Chem. 2015, 13, 2360−2365.
(15) Chetan, B.; Bunha, M.; Jagrat, M.; Sinha, B. N.; Saiko, P.;
Graser, G.; Szekeres, T.; Raman, G.; Rajendran, P.; Moorthy, D.; Basu,
A.; Jayaprakash, V. Bioorg. Med. Chem. Lett. 2010, 20, 3906−3910.
(16) Kam, Y. L.; Rhee, S.-J.; Choo, H.-Y. P. Bioorg. Med. Chem. 2004,
12, 3543−3552.
(17) Bromidge, S. M.; Brown, A. M.; Clarke, S. E.; Dodgson, K.;
Gager, T.; Grassam, H. L.; Jeffrey, P. M.; Joiner, G. F.; King, F. D.;
Middlemiss, D. N.; Moss, S. F.; Newman, H.; Riley, G.; Routledge, C.;
Wyman, P. J. Med. Chem. 1999, 42, 202−205.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lattanzi@unisa.it.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank MIUR and University of Salerno for financial
support. We thank Dr. P. Iannece (University of Salerno) for
assistance with MS spectra and elemental analyses. A.V.-A.
thanks Generalitat Valenciana for a Ph.D. research grant under
the VALi+D Program. A.L. thanks the European COST Action
CM0905-Organocatalysis (ORCA).
(18) Kakarla, R.; Liu, J.; Naduthambi, D.; Chang, W.; Mosley, R. T.;
Bao, D.; Steuer, H. M. M.; Keilman, M.; Bansal, S.; Lam, A. M.; Seibel,
W.; Neilson, S.; Furman, P. A.; Sofia, M. J. J. Med. Chem. 2014, 57,
2136−2160.
(19) Roszkowski, P.; Maurin, J. K.; Czarnocki, Z. Tetrahedron:
Asymmetry 2006, 17, 1415−1419.
REFERENCES
■
(1) (a) Adolfsson, H. Modern Oxidations Methods; Backvall, J.-E., Ed.;
̈
(20) Guercio, G.; Bacchi, S.; Goodyear, M.; Carangio, A.; Tinazzi, F.;
Curti, S. Org. Process Res. Dev. 2008, 12, 1188−1194.
WILEY-VCH: Weinheim, 2004; pp 21−49. (b) De Faveri, G.;
Ilyashenko, G.; Watkinson, M. Chem. Soc. Rev. 2011, 40, 1722−1760.
(c) Zhu, Y.; Wang, Q.; Cornwall, R. G.; Shi, Y. Chem. Rev. 2014, 114,
8199−8256.
(2) For allylic alcohols, see: (a) Johnson, R. A.; Sharpless, K. B. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; WILEY-VCH:
New York, 2000; pp 231−280. (b) Hoshino, Y.; Yamamoto, H. J. Am.
Chem. Soc. 2000, 122, 10452−10453. (c) Egami, H.; Oguma, T.;
Katsuki, T. J. Am. Chem. Soc. 2010, 132, 5886−5895. For selected
examples on homoallylic alcohols, see: (d) Rossiter, B. E.; Sharpless, K.
B. J. Org. Chem. 1984, 49, 3707−3711. (e) Wang, C.; Yamamoto, H. J.
Am. Chem. Soc. 2014, 136, 1222−1225.
(21) For selected examples, see: (a) Giannis, A.; Kolter, T. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1244−1267. (b) Beshore, D. C.;
Dinsmore, C. J. Org. Lett. 2002, 4, 1201−1204. (c) Herrero, S.; García-
́
Lopez, M. T.; Latorre, M.; Cenarruzabeitia, E.; Del Rio, J.; Herranz, R.
J. Org. Chem. 2002, 67, 3866−3873.
(22) (a) Baek, J.; Jang, J. I.; Park, Y. S. Bull. Korean Chem. Soc. 2011,
32, 4067−4070. (b) Jang, J. I.; Kang, S. Y.; Kang, K. H.; Park, Y. S.
Tetrahedron 2011, 67, 6221−6226. (c) Hsieh, S.-Y.; Binanzer, M.;
Kreituss, I.; Bode, J. W. Chem. Commun. 2012, 48, 8892−8894.
(d) Korch, K.; Eidamshaus, C.; Behenna, D. C.; Nam, S.; Horne, D.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2015, 54, 179−183.
(3) (a) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T.
Tetrahedron Lett. 1990, 31, 7345−7348. (b) Jacobsen, E. N.; Zhang,
W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113,
7063−7064.
̀
(23) For an excellent review, see: De Risi, C.; Pela, M.; Pollini, G.;
Trapella, C.; Zanirato, V. Tetrahedron: Asymmetry 2010, 21, 255−274.
(24) For a recent review, see: Fang, X.; Wang, C.-J. Chem. Commun.
2015, 51, 1185−1197.
(4) For a recent review, see: Colonna, S.; Perdicchia, D. In Science of
Synthesis, Stereoselective Synthesis; De Vries, J. G., Molander, G. A.,
Evans, P. A., Eds.; Thieme: Stuttgart, 2011; Vol. 1, pp 123−153.
(5) (a) Yue, L.; Du, W.; Liu, Y.-K.; Chen, Y.-C. Tetrahedron Lett.
2008, 49, 3881−3884. (b) Xiao, H.; Chai, Z.; Zheng, C.-W.; Yang, Y.-
Q.; Liu, W.; Zhang, J.-K.; Zhao, G. Angew. Chem., Int. Ed. 2010, 49,
4467−4470. (c) Ding, D.; Zhao, C.-G. Tetrahedron Lett. 2010, 51,
1322−1325. (d) Li, J.-L.; Yue, C.-Z.; Chen, P.-Q.; Xiao, Y.-C.; Chen,
Y.-C. Angew. Chem., Int. Ed. 2014, 53, 5449−5452.
(25) See Tables S1−S4 in the Supporting Information.
(26) For notable examples of organocatalytic pot-economic synthesis
of biologically active products, see: (a) Ishikawa, H.; Suzuki, T.;
Hayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1304−1307. (b) Hayashi,
Y.; Umemiya, S. Angew. Chem., Int. Ed. 2013, 52, 3450−3452.
(c) Weng, J.; Wang, S.; Huang, L.-J.; Luo, Z.-Y.; Lu, G. Chem.
Commun. 2015, 51, 10170−10173.
(27) A slight excess of the diamine was used to remove HCN formed
in the course of the reaction.
(6) Lemek, T.; Mayr, H. J. Org. Chem. 2003, 68, 6880−6886.
(7) Sagawa, N.; Shikata, T. Phys. Chem. Chem. Phys. 2014, 16,
13262−13270.
(28) Hydrogen bonding between each cyano group with a single NH
of the thiourea moiety was reported to be less plausible by a recent
DFT study; see: Qi, Z.-H.; Zhang, Y.; Ruan, G.-Y.; Zhang, Y.; Wang,
Y.; Wang, X.-W. RSC Adv. 2015, 5, 34314−34318.
(8) Nanjo, K.; Suzuki, K.; Sekiya, M. Chem. Pharm. Bull. 1981, 29,
336−343.
(29) Jocic, Z. Zh. Russ. Fiz. Khim. Ova. 1897, 29, 97−103.
(9) Guinamant, J. L.; Robert, A. Tetrahedron 1986, 42, 1169−1177.
́
(10) Le Marechal, A. M.; Robert, A.; Leban, I. J. Chem. Soc., Perkin
Trans. 1 1993, 351−356.
(11) Gaz, A.; Ammadi, F.; Boukhris, S.; Souizi, A.; Coudert, G.
Heterocycl. Commun. 1999, 5, 413−418.
D
DOI: 10.1021/acs.orglett.5b02186
Org. Lett. XXXX, XXX, XXX−XXX