Application of NAD(P)H model hantzsch 1,4-dihydropyridine as a mild reducing agent in preparation of cyclo compounds

Full text of DOI:10.1021/jo001434f

344
J . Org. Chem. 2001, 66, 344-347
In our previous paper,8 we reported that (Z)-ethyl
Ap p lica tion of NAD(P )H Mod el Ha n tzsch
R-cyano-â-bromomethylcinnamate was reduced by
NAD(P)H model BNAH in acetonitrile to give a cyclo-
propane derivative, but the yield of the product was low
(about 33%). Recently, we used NAD(P)H model, HEH,
instead of BNAH to react with (Z)-ethyl R-cyano-â-
bromomethylcinnamate and extended the substrate to a
variety of the corresponding analogues. It is surprising
to find that all the yields of the cyclized products are good
or excellent. Here we report the experimental results,
which provides a new and high-yielding route to synthe-
size various cyclopropane, indane, and exopin derivatives.
1,4-Dih yd r op yr id in e a s a Mild Red u cin g
Agen t in P r ep a r a tion of Cyclo Com p ou n d s
Xiao-Qing Zhu,*,† Hong-Yi Wang,‡
J ian-Shuang Wang,† and You-Cheng Liu*,‡,§
Department of Chemistry, National Key Laboratory of
Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, Department of Chemistry and National
Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou 730000, and Department of Chemistry,
University of Science and Technology of China,
Hefei 230026, China
Resu lts a n d Discu ssion
Treatment of allylic and benzylic bromides by Hantzsch
1,4-dihydropyridine (HEH) in anhydrous acetonitrile
under argon atmosphere gave various types of three-,
five-, and seven-membered ring compounds in good or
excellent yields, respectively, which all are very impor-
tant reaction intermediates in organic synthesis. Repre-
sentative reactions are summarized in Table 1.
xqzhu@nankai.edu.cn
Received October 3, 2000
The reduced form of the nicotinamide adenine dinucle-
otide coenzyme [NAD(P)H] plays a vital role in many
bioreductions by transferring a hydride ion or an electron
to the surrounding substrates.1 1-Benzyl-1,4-dihydroni-
cotinamide (BNAH), Hantzsch 1,4-dihydropyridine (HEH),
10-methyl-9,10-dihydroacridine (ArcH2), and many other
1,4-dihydropyridine derivatives have been widely used
as models of NAD(P)H to mimic the reductions of various
unsaturated compounds such as quinones,2 ketones,3
aldehydes,4 imines,5 alkenes,6 etc. Attention of most
research has been focused only on the mechanistic details
of the redox reactions. To our best knowledge, very little
effort has been made toward the application of these
NAD(P)H models in synthetic organic chemistry except
for some chiral NAD(P)H models.7 In fact, the use of
NAD(P)H model compounds as a class of mild reducing
agent in synthetic organic chemistry is also of interest.
As shown in Table 1, when the substrate is an ethyl
R-cyano-â-bromomethylcinnamate derivative (nos. 1 and
2) or a 2-bromo-1-phenylethylidenemalononitrile deriva-
tive (no. 3), the products are cyclopropane derivatives.
When the cases of nos. 1 and 2 are examined, it is
interesting to find that both the (E)-isomer (no. 1) and
the (Z)-isomer (no. 2) of ethyl R-cyano-â-bromomethyl-
cinnamate and its derivatives give (E)-isomers of the
cyclopropane derivatives, i.e., the reaction is stereose-
lective. The main reason could be that the stability of
the (E)-isomers is larger than that of the (Z)-isomers, due
to larger steric hindrance of substituents in the (Z)-
isomers. It is noteworthy that even though the two
isomers of ethyl R-cyano-â-bromomethylcinnamate and
its derivatives all gave the same (E)-isomers of the
products, the reaction rates are different. Kinetic experi-
ments show that the second-order reaction rate constant
for the (Z)-isomer of ethyl R-cyano-â-bromomethylcin-
namate as the substrate (1.43 × 10-1 M-1 s-1) is larger
than that for the (E)-isomer as the substrate (1.29 × 10-1
M-1 s-1), which could be caused by the greater stability
of the (E)-isomer than that of the (Z)-isomer.
When the substrate is o-bromomethylbenzylidenema-
lononitrile (no. 4) and its analogues (nos. 5 and 6), indane
structure compounds were obtained. It is surprising to
note that when the substrate is the compound of no. 7 in
Table 1, a seven- rather than a five-membered ring
compound was formed (see eq 3 in Scheme 1). As is well-
known, seven-membered ring structures are, generally,
more difficult to form than the corresponding five-
membered ring, since the ring-strain of the former is
* To whom correspondence should be addressed. Fax: 86-22-
23502458. Phone: 86-22-23508548.
† Nankai University.
‡ Lanzhou University.
§ University of Science and Technology of China.
(1) Murakami, Y.; Kikuchi, J .; Hisaeda, Y.; Hayashida, O. Chem.
Rev. 1996, 96, 721.
(2) Coleman, C. A.; Rose, J . G.; Murray, C. J . J . Am. Chem. Soc.
1992, 114, 9755-9762. (b) Fukuzumi, S.; Nishizawa, N.; Tanaka, T.;
J . Org. Chem. 1984, 49, 3571-3578. (c) Fukuzumi, S.; Yorisue, T. Bull.
Chem. Soc. J pn. 1992, 65, 715-719.
(3) Fukuzumi, S.; Mochizuki, S.; Tanaka, T. J . Am. Chem. Soc. 1989,
111, 1497-1499. (b) Tanner, D. D.; Singh, H. K.; Kharrat, A.; Stein,
A. R. J . Org. Chem. 1987, 52, 2141. (c) Tanner, D. D.; Stein, A. R. J .
Org. Chem. 1988, 53, 1642. (d) Beijer, N. A.; Vekemans, J . A. J . M.;
Buck, H. Recl. Trav. Chim. Pays-Bas 1990, 109, 434-436.
(4) Kanomata, N.; Suzuki, M.; Yoshida, M.; Nakata, T. Angew.
Chem., Int. Ed. Engl. 1998, 37, 1410-1412. (b) Fukuzumi, S.; Ish-
ikama, M.; Tanaka, T. Tetrahedron 1984, 42, 1021-1034.
(5) Lu, Y.; Liu, B.; Cheng, J .-P. Chem. J . Chin. Univ. 1997, 18, 391.
(b) Merjer, H. P.; Van Niel, J . C. G.; Pandit, U. K. Tetrahedron 1984,
40, 5185. (c) De Nie-Sarink, M. J .; Pandit, U. K. Tetrahedron Lett. 1979,
26, 2449-2452. (d) Singh, S.; Sharma, V. K. Tetrahedron Lett. 1979,
29, 2733-2734.
(6) Zhu, X.-Q.; Liu, Y.-C. J . Org. Chem. 1998, 63, 2786. (b) Zhu, X.-
Q.; Liu, Y.-C.; Cheng, J .-P. J . Org. Chem. 1999, 64, 8980. (c) Zhu, X.-
Q.; Liu, Y.-C.; Wang, H.-Y.; Wang W. J . Org. Chem. 1999, 64, 8983.
(d) Zhu, X.-Q.; Zou, H.-L.; Yang, P.-W.; Liu, Y.; Cao, L.; Cheng, J .-P.
J . Chem. Soc., Perkin Trans 2 2000, 1875-1861. (e)Wang, H.-Y.; Liu,
Y.-C.; Zhu, X.-Q.; Guo, Q.-X. Chin. J . Chem. 1999, 17, 1884. (f) Li, B.;
Liu, Y.-C.; Guo, Q.-X. J . Photochem. Photobiol. A: Chem. 1997, 103,
101. (g) Liu, Y.-C.; Li, B.; Guo, Q.-X. Tetrahedron 1995, 51, 9671;
Tetrahedron Lett. 1994, 53, 1642.
(7) Kanomata, N.; Nakata, T. Angew Chem., Int. Ed. Engl. 1997,
36, 1207-1211. (b) Ohno, A.; Tsutsumi, A.; Kawai, Y.; Yamazaki, N.;
Kikata, Y.; Okamura, M. J . Am. Chem. Soc. 1994, 116, 8133. (c) De
Kok, P, M. T.; Bastiaansen, L. A. M.; Van Lier, P. M.; Vekemans, J . A.
J . M.; Buck, H. M. J . Org. Chem. 1989, 54, 1313. (d) Skog, K.;
Wennerstrom, O. Tetrahedron Lett. 1992, 33, 1751. (e) Combret, Y.;
Duflos, J .; Dupas, G.; Bourguignon, J .; Queguiner, G. Tetrahedron:
Asymmetry 1993, 4, 1635. (f). Bedat, J .; Levacher, V.; Dupas, G.;
Queguiner, G.; Bourguignon, J . Chem. Lett. 1995, 327.
(8) Zhu, X.-Q.; Liu, Y.-C.; Li, J .; Wang, H.-Y. J . Chem. Soc., Perkin
Trans 2 1997, 2191.
10.1021/jo001434f CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/08/2000

Notes
J . Org. Chem., Vol. 66, No. 1, 2001 345
Ta ble 1. Cycliza tion s of Som e Allylic a n d Ben zylic Br om id es by HEH in CH3CN u n d er a n Ar gon Atm osp h er ea
a
b
All reactions were carried out as described in Experimental Section. Molar ratio of HEH to the substrate. c Yields of isolated products.
The Z/ E ratio was determined by using 1H NMR integration, and the diastereomeric configuration of (E) was assigned on the basis of
d
Donald J . Cram’s work.9
generally larger than that of the latter. However, the
origin of the seven-membered ring formation can be found
in the following mechanistic analysis.
benzyl position of the substrates10 and the resulting
carbanions undergo, (i) in the cases of nos. 1-3, intramo-
lecular displacement on â-bromomethyl group to produce
cyclopropane derivatives as shown in Scheme 1 (eq 1);
(ii) in the cases of nos. 4-6, intramolecular nucleophilic
substitution on the o-bromomethyl group offered indane
derivatives after initial hydride transfer as shown in eq
2. But in the case of no. 8, the enol anion formed by
hydride transfer has a higher charge density upon oxygen
than carbon. Also, the R,â-unsaturated ketone product,
8a , is resonance stabilized. Thus the enol anion can
undergo intramolecular displacement to form seven-
rather than five-membered ring structure compound as
It is worth noting that in the case of no. 8, when m- or
p-bromomethylbenzylidenemalononitrile was used in place
of o-bromomethylbenzylidenemalononitrile (no. 4), no
cyclized compounds were obtained. For instance, p-
bromomethylbenzylidenemalononitrile, when treated with
HEH under the same experimental conditions as the
corresponding ortho-substituted compound, gave two
open-chain rather than cyclized compounds: p-bromom-
ethylbenzylmalononitrile (8a ) and p-2,2-dicyano-3-(4′-
bromomethyl)phenylpropylbenzylmalononitrile (8b), the
former of which is major product (no. 8).
Concerning the cyclization mechanisms of the sub-
strates listed in Table 1 by HEH, it is reasonable to
propose that the reactions take place via a hydride
transfer mechanism, similar to the proposal in our
previous papers.8 Thus a hydride from HEH added to the
(9) Yankee, E. Y.; Spencer, B.; Howe, N. E.; Cram, D. J . J . Am Chem.
Soc. 1973, 95, 4220.
(10) The addition of p-dinitrobenzene, a known electron-transfer
inhibitor,11 to the reaction mixtures of the substrates and Hantzsch
1,4-dihydropyridine showed no remarkable effects on the reactions,
indicating no electron transfer occurrence in the reaction processes.

346 J . Org. Chem., Vol. 66, No. 1, 2001
Notes
Sch em e 1
from calcium hydride before use. 1H and 13C NMR spectra were
measured on a Bruker AM-400 spectrometer operating at 400.13
MHz for 1H and 100 MHz for 13C, using TMS as reference for
spectra recorded in CDCl3. Mass spectra were obtained on a
VGZAB-HS mass spectrometer at an ionization potential of
70 eV.
shown in eq 3. When the substrate is p- or m-bromo-
methylbenzylidenemalononitrile, the carbanion formed
by hydride transfer cannot be cyclized by intramolecular
displacement to form ring structure species as the final
products, since the rigid benzene ring in the carbanion
can prevent the carbanion from the cyclization. Thus, the
final products are only two chain products (8a and 8b)
as shown in eq 4 (Scheme 1).
In summary, we present a convenient method for the
preparation of three-, five-, and seven-membered ring
compounds using NAD(P)H mimic reactions. The most
advantageous features of the synthetic procedure: (i) the
starting materials are readily available; (ii) the reaction
yields are very high, and the reaction conditions are mild;
(iii) the workup of the reaction mixtures is simple. Even
so, the main purpose of this article is not only to provide
a nice synthetic method, but also to demonstrate the
application of NAD(P)H mimic reactions in organic
synthesis, so as to attract more attention to the applica-
tion of biomimetic reactions in organic synthesis.
Gen er a l P r oced u r e for th e Cycliza tion of th e Allylic a n d
Ben zylic Br om id es by HEH. A mixture of the bromide (0.4
mmol) and HEH (0.8 mmol) in 40 mL of deaerated acetonitrile
was set in dark at room temperature for 7-20 h. Solvent was
then rotary evaporated, and the products were separated by
column chromatography on silica gel with petroleum ether-ethyl
acetate as eluent. The product structures were determined by
NMR and mass spectrometry. The data of the representative
products are shown below.
(E)-E t h yl 1-cya n o-2-p h en ylcyclop r op a n eca r b oxyla t e
(1a ): 1H NMR (400 MHz, CDCl3): δ 1.39 (t, 3H, J ) 7 Hz), 2.15
(dd, 2H, J ) 8 and 1.86 Hz), 3.20 (br t, 1H, J ) 8 Hz), 4.33 (q,
2H, J ) 7 Hz), 7.36 (br s, 5H); MS: m/ z ) 215 (M+., 17). Anal.
Calcd for C13H13NO2: C, 72.54;, H, 6.09; N, 6.51. Found: C,
72.69; H, 6.12; N, 6.60.
2-P h en ylcyclop r op a n ed ica r bon itr ile (3a ): 1H NMR (400
MHz, CDCl3): δ 2.23 (d, 2H, J ) 9 Hz), 3.29 (t, 1H, J ) 9 Hz),
7.38 (s, 5H); MS: m/z ) 168 (M+.). Anal. Calcd for C11H8N2: C,
78.57; H, 4.76; N, 16.67. Found: C, 78.53; H, 4.71; N, 16.69.
Exp er im en ta l Section
Ma ter ia ls a n d Ap p a r a tu s. Hantzsch 1,4-dihydropyridine12
and the substrates (nos. 1-3)13 were prepared according to the
literatures. o-Bromomethylbezylidenemalononitrile and its ana-
logues (nos. 5 and 6) were prepared by Knoevenagel condensa-
tion of o- and p-tolualdehyde with malononitrile, R-cyanoacetate,
and R-cyano sulfone followed by bromination with NBS/AIBN,
respectively.14 The other reagents were purchased from Aldrich
Chemical Co. HPLC grade acetonitrile was dried and distilled
(11) Kerber, R. C.; Urry, G. W.; Kornblum, N. J . Am. Chem. Soc.
1964, 86, 3904; 1965, 87, 4520. (b) Korblum, N.; Michel, R. E.; Kerber,
R. C. J . Am. Chem. Soc. 1966, 88, 5560, 5562.
(12) Hinkel, L. E.; Agling, E. E.; Morgan, H. J . Chem. Soc. 1931,
1835. (b) Hinkel, L. E.; Madel, W. R. J . Chem. Soc. 1929, 750.
(13) Lehnert, W. Tetrahedron 1973, 29, 634.
(14) Kolsaker, P.; Ellingsen, P. O. Acta Chem. Scand. B 1979, 33,
138.

Notes
J . Org. Chem., Vol. 66, No. 1, 2001 347
2,2-In d a n ed ica r bon itr ile (4a ): yellow solid; mp 130-131
MS: m/z ) 248 (100), 191 (26), 189 (23), 133 (46), 115 (32), 105
(48), 104 (54), 77 (31), 76 (42). Anal. Calcd for C17H12O2: C, 82.24;
H, 4.88. Found: C, 82.19; H, 4.91.
°C; 1H NMR (400 MHz, CDCl3): δ 3.70 (s, 4H), 7.2 (s, 4H). MS:
m/z ) 168 (100), 141 (91), 114 (7). Anal. Calcd for C11H8N2: C,
78.55; H, 4.79; N, 16.66. Found: C, 78.62; H, 4.81; N, 16.63.
Eth yl 2-cya n o-2-in d a n eca r boxyla te (5a ): mp: 78-80 °C;
1H NMR (400 MHz, CDCl3): δ 1.33 (t, 3H, J ) 7.2 Hz), 3.59 (s,
4H), 4.27 (q, 2H, J ) 7.2 Hz), 7.20 (s, 4H); MS: m/z: 215 (22),
2-(p-Br om om eth ylben zyl)m a lon on itr ile (8a ): mp: 82-84
1
°C; H NMR (400 MHz, CDCl3): δ ) 3.30 (d, J ) 6.0 Hz, 2H),
3.9 (t, J ) 6.0 Hz, 1H), 4.5 (s, 2H), 7.32 (m, 4H); MS: m/z 248/
250 (M+), 169, 104. Anal. Calcd for C11H9N2Br: C 53.03, H 3.64,
N 11.25. Found: C 53.01, H 3.68, N 11.21.
188 (4), 160 (18), 142 (100), 115 (32). Anal. Calcd for C13H13
-
NO2: C, 72.53; H, 6.09; N, 6.51. Found: C, 72.54; H, 6.15; N,
6.46.
2-(p-Br om om eth ylben zyl)-2-[p-(2′,2′-dicyan oeth ylben zyl)]-
m a lon on itr ile (8b): mp: 138-140 °C; 1H NMR (400 MHz,
CDCl3): δ 3.26 (s, 2H), 3.27 (s, 2H), 3.33 (d, 2H, J ) 6.5 Hz),
3.95 (t, 1H, J ) 6.5 Hz), 4.5 (s, 2H), 7.40-7.47 (m, 8H); MS:
m/z: 416/418 (M+), 415/417, 337, 183/185, 169, 104. Anal. Calcd
for C22H18N4Br: C, 63.17; H, 4.31; N, 13.40. Found: C, 63.12;
H, 4.36; N, 13.33.
2-Cya n o-2-p h en ylsu lfon ylin d a n e (6a ): mp: 138-141 °C;
1H NMR (400 MHz, CDCl3): δ 3.95 (d, 2H, J ) 16.6 Hz) 7.23 (s,
4H), 8.15-7.73 (m, 5H),; MS: m/z: 283 (5), 265 (76), 141 (100),
115 (36). Anal. Calcd for C16H13NO2S: C, 67.83; H, 4.63; N, 4.95.
Found: C, 67.80; H, 4.61; N, 4.97.
5H-Ben z[e]in d en o[1,2-b]oxep in -11-on e (7a ): 92% yield;
yellow solid; mp 138-139 °C; IR (KBr, cm-1): 1693, 1620, 1584,
1463, 1477, 1301, 1155, 935, 921, 770, 713; 1H NMR (400 MHz,
CDCl3): δ 3.80 (s, 2H) 5.61 (s, 2H), 7.36 (m, 8H); 13C NMR (100
MHz, CDCl3): δ 26.3, 72.8, 107.8, 118.0, 120.9, 127.2, 128.6,
129.6, 129.9, 130.3, 131.9, 132.2, 133.9, 139.7, 141.8, 173.3, 194.2;
Ackn owledgm en t. This work was possible by grants
from the Natural Science Foundation of China (NSFC
No. 29972028).
J O001434F