Are multicomponent strecker reactions of diketones with diamines under high pressure amenable to heterocyclic synthesis?

Article abstract of DOI:10.3987/COM-05-S(K)69

Employing double Strecker strategy, two new heterocyclic compounds, 5,6,11,12-tetrahydro-6,11-dimethyldibenzo[b,f][1,4]diazocine-6,11-dicarbonitrile and 1,2,3,4,5,10-hexahydrophenazine-4a, 10a-dicarbonitrile, were prepared in one step albeit in low yields. The reaction has proven to be very limited, but such a sterically hindered amine as N-methylaniline underwent Strecker reaction with benzaldehyde and TMSCN to give the corresponding α-amino nitriles.

Full text of DOI:10.3987/COM-05-S(K)69

HETEROCYCLES, Vol. 66, 2005
675
HETEROCYCLES, Vol. 66, 2005, pp. 675 – 681. © The Japan Institute of Heterocyclic Chemistry
Received, 11th October, 2005, Accepted, 24th November, 2005, Published online, 29th November, 2005. COM-05-S(K)69
ARE MULTICOMPONENT STRECKER REACTIONS OF DIKETONES WITH
DIAMINES UNDER HIGH PRESSURE AMENABLE TO HETEROCYCLIC
SYNTHESIS?
a
b
b
a
Koji Kumamoto, Hirokazu Iida, Hiroshi Hamana, Hiyoshizo Kotsuki,*
*
b
and Kiyoshi Matsumoto
a Faculty of Science, Kochi University, Kochi 780-8520, Japan
(e-mail: kotsuki@cc.kochi-u.ac.jp)
b
Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Chiba
288-0025, Japan (e-mail: kmatsumoto@cis.ac.jp)
Abstract –Employing double Strecker strategy, two new heterocyclic compounds,
5,6,11,12-tetrahydro-6,11-dimethyldibenzo[b,f][1,4]diazocine-6,11-dicarbonitrile
and 1,2,3,4,5,10-hexahydrophenazine-4a,10a-dicarbonitrile, were prepared in one
step albeit in low yields. The reaction has proven to be very limited, but such a
sterically hindered amine as N-methylaniline underwent Strecker reaction with
benzaldehyde and TMSCN to give the corresponding α-amino nitriles.
INTRODUCTION
Reactions in which more than two starting compounds react to form a product in such a way that the
majority of the atoms of the material can be found in the product are called multicomponent reactions
(MCRs).1-4 In multistep syntheses the temporal and preparative complexity increases in proportion to
the number of steps in a first approximation. These aspects are reflected in many isolation and
purification operations, such as crystallization, extraction, distillation, or chromatography.
Besides the
multistep, sequential synthesis of a target molecule, the desired product can also be obtained in one-pot
reactions of three or more starting compounds, e.g. multicomponent reactions (MCRs), in many cases.
Therefore, MCRs are very efficient in organic synthesis and have represented a rapid upsurge at the
literature. MCRs are often amenable to synthesis of heterocyclic compounds. Notably, classical examples
are illustrated by Hantzsch synthesis of 1,4-dihydropyridine and pyrrole synthesis, Radziszeski imidazole
Dedicated to the memory of Professor Kenji Koga, Professor Emeritus of University of Tokyo.

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HETEROCYCLES, Vol. 66, 2005
synthesis, Biginelli reaction of dihydropyrimidinone synthesis, and Bucherer-Bergs hydantoin synthesis.
More recently, the tricyclic diamino ketone from octahydro-2H-quinolin-2-one was prepared by Scheiber
and Nemes using a double Mannich condensation.5 Ihara and Fukumoto developed an efficient synthesis
of polycyclic compounds employing the intramolecular double Michael reaction.6 The development of
this type of synthetic method can lead to a reduction in the amount of undesired by-products, thereby
contributing to the protection of the environment. However, MCRs under high pressure were hardly
studied.7,8 Quite recently, we have developed a highly efficient method for the synthesis of acyclic
α-amino nitriles in high yields employing the high-pressure-mediated three-component Strecker reactions
of ketones without using any catalyst, including two types of double Strecker reactions.9 Encouraged by
these results, it was envisioned that this strategy might be applicable to the synthesis of heterocycles
using suitably substituted substrates such as diamines and 1,2-diketones. Thus, we describe results at this
purpose.
RESULTS AND DISCUSSION
First, Strecker reaction was investigated with 1,2-diacetylbenzene (1), 1,2-diaminobenzene (2) and
o
Me3SiCN (TMSCN) in acetonitrile at 0.6 GPa and 30 C for 24 h. Acetonitrile was chosen as a solvent,
since it has proven in the previous work of double Strecker reaction with 1,4-diacetylbenzene, aniline,
and TMSCN that acetonitrile was a choice of solvent.9c Thus, 1 equivalent of 1 with 2 and TMSCN (2.4
equivalents) afforded 5,6,11,12-tetrahydro-6,11-dimethyldibenzo[b,f][1,4]diazocine-6,11-dicarbonitrile
(3), albeit only in 17% yield in one step.10
CN
NH
(2.4 equiv.) TMSCN
H2N
H2N
O
O
CH3CN
0.6 GPa, 30 oC, 24 h
17%
N
H
CN
1
2
3
Encouraged by this result of double Strecker strategy for synthesis of novel heterocycles, a similar
reaction of cyclohexane-1,2-dione (4) with 2 and TMSCN was investigated under high pressure
conditions, producing 1,2,3,4,5,10-hexahydrophenazine-4a,10a-dicarbonitrile (5) in 13% yield along with
the aromatized product, 1,2,3,4-tetrahydrophenazine (6).11 It is not clear whether 6 was formed by
bisdehydrocyanation of 5 or by a direct dehydrative condensation of 4 with 2 (see below).

HETEROCYCLES, Vol. 66, 2005
677
H
N
NC
NC
O
O
N
N
(2.4 equiv.) TMSCN
2
CH3CN
0.6 GPa, 30 °C, 24 h
N
H
4
6
5
3 %
13%
However, quite unfortunately, further attempts to prepare such novel heterocyles employing diketones
and 1,2-diamines have met with failure. For example, 2,5-hexanedione (7) with 2 and TMSCN under
same conditions only gave a complex mixture of products.
(2.4 equiv.) TMSCN
O
a complex mixture of products
2
O
CH3CN
0.6 GPa, 30 °C, 24 h
7
Much more disappointedly, 2,3-butanedione (8) and 9,10-phenanthrenequinone (9) with 2 and TMSCN
gave very well known, yet commercially available products, 2,3-dimethylquinoxaline (10) and
dibenzo[a,c]phenazine (11), respectively. Indeed, the reactions have proven to proceed without TMSCN
at room temperature, probably due to aromatic stabilization of the products.
N
O
O
(2.4 equiv.) TMSCN
+
2
CH3CN
0.8 GPa, 30 °C, 24 h
N
10
8
88%
N
N
O
O
(2.4 equiv.) TMSCN
+
2
CH3CN
0.8 GPa, 30 °C, 24 h
98%
11
9
Furthermore, the reaction of 1,2-diphenylethanedione (12) with 1,8-diaminonaphthalene (13) also has met
failure, affording a diastereomeric mixture of cyanotrimethylsilylation products (14).12
CN
Ph
Ph
O
O
Ph
Ph
OTMS
H2N
H2N
(2.4 equiv.) TMSCN
+
CH3CN
0.8 GPa, 30 °C, 24 h
OTMS
CN
14
a diastereomeric mixture of products
~95%
13
12

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HETEROCYCLES, Vol. 66, 2005
Finally, in the previous paper,9c it was found that the Strecker reaction of sterically hindered
N-methylaniline with acetone (or acetophenone) and TMSCN did not take place. Thus, it is in passing
note here that N-methylaniline (15) reacted with benzaldehyde (16) to produce
2-(N-methyl-N-phenylamino)phenylacetonitrile (17) in 47% yield along with two by-products (18 and 19).
The generality of double Strecker reaction of sterically hindered amines with aldehydes is therefore
worthy of further investigation and will be a subject of future communications elsewhere.
CHO
OH
CN
OTMS
CN
NHMe
CN
(1.2 equiv.) TMSCN
+
+
+
N
CH3CN
0.8 GPa, 30 °C, 24 h
Me
47%
37%
16%
15
16
19
17
18
CONCLUSION
High-pressure-mediated single and double Strecker reactions using acyclic diketones and aromatic amines
such as aniline which do not take place without catalysts have proven successful. In contrast, a
heterocyclic version of this strategy was highly limited at present; only a novel type of two heterocycles
was obtained albeit in low yield in one step. However, it should be noted the reaction of aldehydes and
ketones with TMSCN did take place in the absence of such catalysts as Lewis acids, thus this aspect is
also worthy of further investigation in connection with green chemistry.9c Based upon detailed
mechanistic investigations on Strecker reaction under high pressure,9 further work is in progress by
developing such new tactics as microwave techniques, supercritical methods as well as molecular
modeling methods.
EXPERIMENTAL
General Procedure
All high-pressure reactions were performed in a piston-cylinder type apparatus (Hikari Koatsu
HR-15-B3). All melting points were measured on Yanagimoto MP-S3 micro-melting point apparatus and
1
were uncorrected. The NMR spectra were recorded on a JEOL LA 400 (400 MHz for H NMR spectral
13
analysis and 100 MHz for C NMR spectral analysis). All NMR spectra were taken in CDCl3 solution
and were reported in part per millions (δ) downfield from TMS as an internal standard. IR spectra were
measured with a JASCO FT/IR-460 plus Fourier Transform Infrared Spectrophotometer and were
reported in wavenumbers (cm-1). TLC was conducted by using Merck Kieselgel 60F-254 plates (0.25
mm). For column chromatography, Fuji Silicia BW-300 and, for flash chromatography, Merck Kieselgel
(230-400 mesh) was employed.

HETEROCYCLES, Vol. 66, 2005
679
Typical experimental procedure: A mixture of diketone (1, 1.0 mmol), diamine (2, 1.0 mmol), and
TMSCN (2.4 mmol) in MeCN (ca. 1.5 mL) was placed in a Teflon reaction vessel, and the mixture was
allowed to react at 0.6 GPa and 30 °C for 24 h. After the mixture was cooled and the pressure was
released, the mixture was concentrated in vacuo. The crude product was purified by silica gel column
chromatography (elution with hexane-AcOEt, from 4:1 to 1:1) to afford the pure product.
5,6,11,12-Tetrahydro-6,11-dimethyldibenzo[b,f][1,4]diazocine-6,11-dicarbonitrile (3): colorless
solid; Rf 0.28 (hexane/AcOEt, 1:1); mp 165-168 °C (Et2O, decomp); FTIR (KBr) ν 3496, 3393, 2217,
1612, 1499, 1460; 1H NMR: 1.80 (6H, s), 3.98 (2H, br s), 6.84 (1H, dd, J = 8.0, 1.2 Hz), 6.91 (1H, dt, J =
8.0, 1.2 Hz), 7.24 (1H, dt, J = 8.0, 1.2 Hz), 7.47 (2H, m), 7.55 (2H, m), 8.17 (1H, dd, J = 8.0, 1.2 Hz); 13C
NMR: 24.6 (×2), 63.9 (×2), 115.6 (×2), 119.1(5), 119.2(3), 122.5 (×2), 129.6, 130.0, 130.4 (×2), 139.7
(×2), 147.6 (×2); Anal. Calcd for C18H16N4•4/7H2O C, 72.39; H, 5.79; N, 18.76. Found: C, 72.11; H, 5.49;
N, 18.36.
1,2,3,4,5,10-Hexahydrophenazine-4a,10a-dicarbonitrile (5): colorless solid; Rf 0.42 (hexane/AcOEt,
1
2:1); mp 230-240 °C (hexane-Et2O, sublimed); FTIR (KBr) ν 3344, 2233, 1603, 1509, 1469; H NMR:
13
1.84-2.02 (6H, m), 2.27 (2H, dm, J = 12.2 Hz), 4.20 (2H, br s), 6.68 (2H, m), 6.82 (2H, m); C NMR:
21.5 (×2), 32.8 (×2), 57.3 (×2), 116.1 (×2), 117.7 (×2), 121.6 (×2), 129.0 (×2); Anal. Calcd for C14H14N4:
C, 70.57; H, 5.92; N, 23.51. Found: C, 70.38; H, 5.99; N, 23.56.
1,2,3,4-Tetrahydrophenazine (6): yellowish solid; Rf 0.36 (hexane/AcOEt, 2:1); mp 90-92 °C (AcOEt;
lit.,13 90-92 °C); FTIR (KBr) ν 1559, 1483, 1427, 769; H NMR: 2.05 (4H, m), 3.17 (4H, m), 7.67 (2H,
1
m), 7.97 (2H, m); 13C NMR: 22.8 (×2), 33.2 (×2), 128.3 (×2), 128.9 (×2), 141.2 (×2), 154.2 (×2).
2,3-Dimethylquinoxaline (10): colorless solid; Rf 0.32 (hexane/AcOEt, 1:1); mp 103-106°C (MeCN;
lit.,14 104-105 °C); FTIR (KBr) ν 1569, 1491, 1398, 1165, 763; 1H NMR: 2.74 (6H, s), 7.67 (2H, m), 7.98
(2H, m); 13C NMR: 23.2 (×2), 128.3 (×2), 128.8 (×2), 141.0 (×2), 153.4 (×2).
Dibenzo[a,c]phenazine (11): yellowish solid; Rf 0.46 (hexane/AcOEt, 4:1); mp 228-231 °C (MeCN;
lit.,15 227-228 °C); FTIR (KBr) ν 1605, 1499, 1358, 768, 724; 1H NMR: 7.70-7.79 (4H, m), 7.83 (2H, dd,
13
J = 6.5, 3.4 Hz), 8.30 (2H, dd, J = 6.5, 3.4 Hz), 8.52 (2H, d, J = 8.0 Hz), 9.37 (2H, d, J = 7.8 Hz); C
NMR: 122.9 (×2), 126.2 (×2), 127.9 (×2), 129.4 (×2), 129.7 (×2), 130.3 (×4), 132.0 (×2), 142.1 (×2),
142.4 (×2).
2,3-Diphenyl-2,3-bis(trimethylsilyloxy)succinonitrile (14):12 a diastereomeric mixture; Rf 0.42
(hexane/AcOEt, 4:1); FTIR (KBr) ν 2238, 1491, 1449, 1255, 1142, 855; 1H NMR: -0.04 (9H, s), 0.22 (9H,

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HETEROCYCLES, Vol. 66, 2005
s), 7.01 (2H, d, J = 7.6 Hz), 7.16 (2H, t, J = 7.6 Hz), 7.29 (1H, t, J = 7.6 Hz), 7.42-7.49 (4H, m), 7.70-7.74
(1H, m); 13C NMR: 0.2 (×3), 0.6 (×3), 81.1, 81.4, 117.8, 118.9, 127.2 (×2), 127.5 (×2), 127.7 (×2), 127.8
(×2), 129.5, 129.8, 134.1, 136.1.
2-(N-Methyl-N-phenylamino)phenylacetonitrile (17): colorless oil; Rf 0.49 (hexane/AcOEt, 4:1); FTIR
(neat) ν 2231, 1599, 1499, 1451; 1H NMR: 2.75 (3H, s), 5.86 (1H, s), 6.98 (1H, t, J = 7.3 Hz), 7.04 (2H, d,
J = 7.8 Hz), 7.34 (2H, m), 7.41-7.47 (3H, m), 7.55-7.58 (2H, m); 13C NMR: 34.6, 58.6, 116.1, 116.7 (×2),
121.2 (×2), 127.2 (×2), 129.0, 129.1, 129.5 (×2), 133.4, 149.1.
2-Hydroxy-2-phenylacetonitrile (18):16 colorless oil; Rf 0.18 (hexane/AcOEt, 4:1); FTIR (neat) ν 3416,
2251, 1495, 1455, 1193, 1040, 1026; 1H NMR: 2.89 (1H, br s), 5.54 (1H, s), 7.43-7.47 (3H, m), 7.52-7.55
(2H, m); 13C NMR: 63.7, 118.7, 126.7 (×2), 129.2 (×2), 129.9, 135.2.
2-Phenyl-2-(trimethylsilyloxy)acetonitrile (19):17colorless oil; Rf 0.58 (hexane/AcOEt, 4:1); FTIR
1
(neat) ν 2240, 1495, 1455, 1255, 1196, 1097, 1072; H NMR: 0.23 (9H, s), 5.50 (1H, s), 7.38-7.49 (5H,
m); 13C NMR: –0.3 (×3), 63.7, 119.2, 126.3 (×2), 128.9 (×2), 129.3, 136.2.
ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Science, Culture, Sports, Science, and Technology, Japan (to H. K. and K. M.). This work was also
supported in part by Grant-in-Aid for Encouragement of Young Scientists (B, No. 16710157) from the
Japan Society for the Promotion of Science (to H. I.). H. I. extends his gratitude for Sasakawa Scientific
Research Grants (Nos. 6-182 and 7-199K) and Sasakawa Grants for Science Fellows (No. F02-109) from
the Japan Science Society for supports of this research.
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