Double Annulation Route to Highly Substituted and Functionalized cis Bicyclic and Tricyclic δ-Lactams and Imides

Full text of DOI:10.1021/jo0000978

J . Org. Chem. 2000, 65, 3255-3258
3255
Sch em e 1a
Dou ble An n u la tion Rou te to High ly
Su bstitu ted a n d F u n ction a lized cis Bicyclic
a n d Tr icyclic δ-La cta m s a n d Im id es
Robert B. Grossman,* Dhananjay S. Pendharkar,
Ravindra M. Rasne, and Melissa A. Varner
Department of Chemistry, University of Kentucky,
Lexington, Kentucky 40506-0055
a
X ) O or H,H; Z1-4 ) CN, CO2Et, NO2, or Me (at least Z2 or
Received J anuary 24, 2000
Z3 ) CN); n ) 0 or 1. (a) HCtCCOMe, cat. NaH in THF or t-BuOK
in CH2Cl2 or Ph3P in CH3CN; (b) NaOEt; EtOH, cat. TsOH, -H2O;
(c) 2-4 atm H2, 5% Pd/C.
Recent reports from this laboratory have established
the wide scope of the double Michael reaction between a
tethered carbon diacid 1 and 3-butyn-2-one (Scheme 1).1-4
We have shown that the highly substituted and func-
tionalized double Michael adducts 2 undergo further
transformations such as Dieckmann reactions and in-
tramolecular reductive aminations in a chemo-, regio-
and, diastereoselective manner to give trans bicyclic
“double annulation” products such as trans-decalins and
trans-hydrindans 3,1,2,4 trans-perhydroisoquinolines and
trans-perhydro-2-pyrindines 4,1,3 and trans-hexahydro-
indoles.2
Ta ble 1. cis Bicyclic Un sa tu r a ted δ-La cta m s a n d Im id es
via Hyd r a tion of 2
The double Michael reaction proceeds only when 1 has
at least one CN group, which becomes axial in the
adducts 2 (Z2 or Z3 in Scheme 1). The further transforma-
tion of 2 into 3 or 4 does not affect that group. For
example, when 2 with one axial and one equatorial CN
group is hydrogenated over Pd/C to give 4, the equatorial
CN group is reduced and the axial CN group remains
unaffected.1,3 By contrast, when 2 with two axial CN
groups is hydrogenated under various conditions, either
no reaction occurs or no identifiable products are ob-
tained. We have been eager to find conditions under
which the axial CN groups are converted into other
functionalities, as the utility of our method for the
synthesis of natural products or potential pharmaceuti-
cals would otherwise be greatly circumscribed. We now
report that axial CN groups in 2-4 and related com-
pounds are smoothly hydrated to CONH2 groups in 75-
80% concentrated H2SO4 in absolute EtOH, and these
groups condense with pendant carbonyl functionality to
provide a variety of highly substituted and functionalized
cis bicyclic and bridged tricyclic δ-lactams and imides in
moderate to good yield. The H2SO4-mediated hydration
of nitriles to amides has of course been known for a very
long time,5 but the reaction is rarely applied to com-
pounds as highly functionalized as 2-4, and it is rather
surprising that such harsh reaction conditions applied
to these compounds give such clean products.
1-ones and cis-tetrahydro-2-pyrindin-1-ones in good yields
(Table 1, entries 1-3), nicely complementing our previ-
ously reported route to the corresponding trans com-
pounds 4.1,3,6 Similarly, hydration of a compound with
two axial CN groups and an equatorial CH2CO2Et group
affords a cis bicyclic amide-imide, reminiscent of the
Kemp’s triacid-derived U-turn compounds of Rebek,7 in
good yield (Table 1, entry 4). Even when a coaxial CO2-
Et or CN group is available in the 3-position (entries 3
and 4), attack of the nascent axial CONH2 group on this
group is much slower than attack on an equatorial
carbonyl group in the 2-position. The direct conversion
of a 4-cyanoketone into a 3,4-dihydropyridin-2-one has
been described in the literature only a handful of
times.8-12 Of course, the conversion of a 4-carbamoyl
ketone to a 3,4-dihydropyridin-2-one is relatively com-
mon, so the transformation reported here is not remark-
Adducts 2 with one axial CN group and an equatorial
acetonyl group are hydrated to cis-hexahydroisoquinolin-
* To whom correspondence should be addressed. E-mail: rbgros1@
pop.uky.edu.
(1) Grossman, R. B.; Varner, M. A.; Skaggs, A. J . J . Org. Chem.
1999, 64, 340.
(2) Grossman, R. B.; Rasne, R. M.; Patrick, B. O. J . Org. Chem. 1999,
64, 7173.
(3) Grossman, R. B.; Pendharkar, D. S.; Patrick, B. O. J . Org. Chem.
1999, 64, 7178.
(4) Grossman, R. B.; Skaggs, A. J .; Kray, A. E.; Patrick, B. O. Org.
Lett. 1999, 1, 1583.
(5) The earliest mention of this reaction seems to be in: Engelhardt,
A. Ann. 1858, 108, 341.
(6) Only one conformer of each compound is shown in the table;
however, the two chair conformers of each bicyclic compound are close
in energy, and conformational flexibility is expected.
(7) For example: Wintner, E. A.; Conn, M. M.; Rebek, J ., J r. J . Am.
Chem. Soc. 1994, 116, 8877.
(8) Kohler, E. P.; Graustein, A.; Merrill, D. R. J . Am. Chem. Soc.
1922, 44, 2536.
(9) Kohler, E. P.; Souther, B. L. J . Am. Chem. Soc. 1922, 44, 2908.
(10) Allen, C. F. H. J . Am. Chem. Soc. 1925, 47, 1733.
(11) Allen, C. F. H. J . Am. Chem. Soc. 1927, 49, 1112.
(12) Kayukova, L. A.; Chernova, N. V.; Manchuk, Z. N.; Erzhanov,
K. B. J . Org. Chem. USSR (Engl. Transl.) 1990, 26, 1389.
10.1021/jo0000978 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/21/2000

3256 J . Org. Chem., Vol. 65, No. 10, 2000
Notes
Ta ble 2. Tr icyclic N,N′-Dia cyla m in a ls via Hyd r a tion of 2
Ta ble 3. Bicyclic P r im a r y Am id es a n d Br id ged Tr icyclic
Im id es via Hyd r a tion of tr a n s Bicyclic Com p ou n d s
able in itself. Still, it is somewhat surprising that despite
abundant opportunities for side reactions involving the
other functional groups in the starting materials (retro-
Claisen and retro-Dieckmann reactions or hydrolysis of
the CO2Et or CONH2 groups and subsequent decarboxy-
lation), the reported products are obtained cleanly and
in good yield.
a
A 2:1 mixture of amide and imide is obtained initially.
b
Isolated yield of pure amide after chromatography; a 1:1 mixture
of amide and imide is also obtained. c Isolated yield of pure imide
derived from further hydration of a 1:1 mixture of amide and
imide.
Adducts 2 with two CN groups and an acetonyl group
are hydrated to tricyclic N,N′-diacylaminals in moderate
yield (Table 2). The structures of the aminals are as-
signed from their spectral characteristics, including their
3 and 4 (Scheme 1) leaves the axial CN group of the
starting materials unchanged.1-4 Geometric constraints
require that the nascent axial CONH2 group obtained
upon hydration of such trans bicyclic compounds combine
with a coaxial group or with no group at all (Table 3).
Thus, hydration of a trans-perhydroisoquinoline with
coaxial CO2Et and CN groups affords a tricyclic imide
(entry 1). Hydration of a trans-octalone with coaxial CO2-
Et and CN groups under the same conditions and for the
same period of time affords mostly a bicyclic amide, along
with some of the tricyclic imide (entry 2), but the amide
is converted completely to the imide after standing longer
in ethanolic H2SO4. Attack of the nascent CONH2 group
on the coaxial CO2Et group probably occurs more slowly
in entry 2 than in entry 1 because of the electron-
withdrawing effect of the alkenone, as molecular models
show no differences in the spatial orientations of the
CONH2 and CO2Et groups in the two cases. Similarly,
hydration of a trans-hydrindanone with two coaxial CN
groups affords a 1:1 mixture of a bicyclic diamide and a
tricyclic imide, which are separated by chromatography
(entry 3). The tricyclic imide is slightly contaminated
with a small amount of a similar compound that is
probably the transposed â-ethoxy enone. The bicyclic
diamide is also slightly contaminated with a small
amount of a greasy impurity, but attempted repurifica-
tion on silica gel causes its partial conversion to the
imide.
1
symmetry in the H and 13C NMR spectra (entries 1 and
2), the absence of ketone and CN resonances in the 13C
NMR and IR spectra, the upfield shift of the 13C NMR
resonance of the former pendant ketone (ca. 140 ppm)
1
and the upfield shift of the H NMR resonance of the Me
group adjacent to it (ca. 0.7 ppm), and the presence of
NMR and IR absorbances characteristic of CO2Et groups
and secondary amides. In addition, the structure of one
tricyclic N,N′-diacylaminal (entry 2) was confirmed by
X-ray crystallography. A plausible mechanism for the
formation of the aminals involves hydrolysis of one CN
group to the amide, condensation of the amide with the
pendant ketone to give the bicyclic N-acylimine, hydroly-
sis of the second CN group, and closure to the tricyclic
product. Again, attack of a nascent axial CONH2 group
on the acetonyl group or the N-acylimine is much faster
even than attack on a coaxial CO2Et group (entry 4).
N,N′-Diacylaminals with bicyclo[2.2.2]octane skeletons
such as the product in entry 4 have occasionally appeared
in the literature,13-15 as have fused bicyclic N,N′-
diacylaminals,16-20 but the products in entries 1-3 are
to our knowledge the first such compounds with a cage
structure.
We have shown previously that the transformation of
2 into rigid, trans bicyclic “double annulation” products
(13) Davies, L. B.; Leci, O. A.; Sammes, P. G.; Watt, R. A. J . Chem.
Soc., Perkin Trans. 1 1978, 1293.
As noted above, it is not difficult to imagine a host of
side reactions that could occur when the very highly
functionalized 2-4 are dissolved in ethanolic H2SO4.
Instead, smooth reactions occur to afford highly func-
tionalized bicyclic and tricyclic compounds in moderate
to good yield. The new compounds described herein may
be useful scaffolds for displaying functionalized side
(14) ten Hoeve, W.; Wynberg, H. J . Org. Chem. 1980, 45, 2754.
(15) Kalme, Z. A.; Liepin’sh, E. E.; Pelcher, Y. E.; Dubur, G. Y. Chem.
Heterocycl. Compd. (Engl. Transl.) 1989, 25, 516.
(16) Stoll, A. P.; Niklaus, P.; Troxler, F. Helv. Chim. Acta 1971, 54,
1994.
(17) Roeber, H.; Hartke, K. Chem. Ber. 1975, 108, 3262.
(18) Hartke, K.; Roeber, H.; Matusch, R. Chem. Ber. 1975, 108, 3256.
(19) Metz, G. Arch. Pharm. (Weinheim, Ger.) 1987, 320, 285.
(20) Grubmayr, K.; Wagner, U. G. Monatsh. Chem. 1988, 119, 813.

Notes
J . Org. Chem., Vol. 65, No. 10, 2000 3257
62.2, 61.9, 56.5, 44.1, 41.5, 39.5, 33.2, 33.0, 20.0, 19.4, 19.3, 13.8.
IR (KBr): 2229, 1744, 1725, 1675, 1627 cm-1. Anal. Calcd for
chains in fixed mutual orientations. Future reports from
this laboratory will describe the synthesis of natural
products via 2 and 3 and further extension of the scope
of the double annulation reaction.
C
18H23N2O5: C, 64.85; H, 6.95. Found: C, 64.77; H, 6.99.
Gen er a l P r oced u r e for Hyd r a tion . Concentrated sulfuric
acid (4 mL) was slowly added to a solution of the substrate in
absolute ethanol (1 mL) with constant stirring at 0 °C. The
reaction mixture was then allowed to warm to room tempera-
ture. After 15-48 h, the mixture was neutralized with saturated
aqueous NaHCO3 solution and extracted three times with CH2-
Cl2. The combined organic extracts were dried over MgSO4 and
concentrated to give a white solid. Recrystallization from hot
ethanol or flash chromatography afforded the pure hydration
product.
Eth yl (1R*,6S,7S)-4,7-Dim eth yl-7-n itr o-3-azabicyclo[4.4.0]-
d eca n -2-on e-1-ca r boxyla te (Ta ble 1, en tr y 1). Hydration of
ethyl (1R*,2S,3S)-1-cyano-3-methyl-3-nitro-2-(2-oxopropyl)-1-cy-
clohexanecarboxylate2 (100 mg, 0.34 mmol) afforded the title
compound (59 mg, 0.20 mmol, 59% yield) as a white solid, mp
132-133 °C. 1H NMR (300 MHz, CDCl3): δ 6.96 (s, 1H), 4.78
(dm, J d ) 6.3 Hz, 1H), 4.21 (m, 2H), 3.72 (d, 6.2 Hz, 1H), 2.67
(d, 11.6 Hz, 1H), 2.09 (m, 2H), 1.82 (s, 3H), 1.79 (m, 1H), 1.62
(m, 2H), 1.54 (s, 3H), 1.23 (t, 7.1 Hz, 3H). 13C{H} NMR (50 MHz,
CDCl3): δ 171.3, 169.3, 135.9, 100.0, 91.2, 62.1, 53.6, 42.0, 37.3,
28.9, 19.6, 18.7, 17.7, 13.9. IR (KBr): 3437, 3214, 1736, 1696,
1675 cm-1. Anal. Calcd for C14H20N2O5: C, 56.75; H, 6.80.
Found: C, 56.81; H, 6.75.
Eth yl (1R*,6S,7S)-4,7-Dim eth yl-7-n itr o-3-azabicyclo[4.3.0]-
n on a n -2-on e-1-ca r boxyla te (Ta ble 1, en tr y 2). Hydration of
ethyl (1R*,2S,3S)-1-cyano-3-methyl-3-nitro-2-(2-oxopropyl)-1-cy-
clopentanecarboxylate2 (82 mg, 0.29 mmol) afforded the title
compound (46 mg, 0.16 mmol, 56% yield) as a white solid, mp
125-126 °C. 1H NMR (300 MHz, CDCl3): δ 7.01 (s, 1H), 4.85 (d
quintet, J d ) 6.1 Hz, J quintet ) 1.3 Hz, 1H), 4.20 (m, 2H), 3.73
(dm, J d ) 5.0 Hz, 1H), 2.68 (m, 1H), 2.57 (m, 2H), 1.97 (dd, 13.1
Hz, 6.3 Hz, 1H), 1.91 (t, 1.3 Hz, 3H), 1.47 (s, 3H), 1.25 (t, 7.1
Hz, 3H). 13C{H} NMR (50 MHz, CDCl3): δ 170.9, 168.6, 134.6,
96.7, 95.8, 62.3, 56.7, 51.4, 37.3, 31.2, 21.2, 19.1, 13.9. IR (KBr):
3241, 1733, 1673 cm-1. Anal. Calcd for C13H18N2O5: C, 55.31;
H, 6.43. Found: C, 55.19; H, 6.47.
Exp er im en ta l Section
St a r t in g m a t er ia ls were reported previously,1-3 with the
exception of the following compounds.
Dieth yl (1R,2r ,3S)-1,3-Dicyan o-2-(2-eth oxycar bon yleth yl)-
1,3-cycloh exa n ed ica r boxyla te (Ta ble 1, en tr y 4 sta r tin g
m a ter ia l). To a solution of KOH (150 mg, 2.58 mmol) in EtOH
(3 mL) was added a solution of diethyl 2,6-dicyanopimelate21
(2.15 g, 8.08 mmol) in THF (10 mL). The resulting solution was
allowed to stir at room temperature for 20 min, and it was then
diluted with THF (10 mL). After the reaction mixture cooled to
0 °C, ethyl propiolate (920 µL, 8.9 mmol) was slowly added. The
reaction was allowed to warm at room temperature and was
allowed to stir overnight. The solvent was evaporated, and the
residue was taken up in ether. This solution was shaken once
with dilute HCl and then twice with water. The aqueous layers
were combined and extracted twice with ether. The organic
layers were combined, shaken once with brine, dried over
MgSO4, filtered, and concentrated. The crude product was
purified by flash chromatography (15% EtOAc in petroleum
ether as eluant), and further recrystallization from hot ethanol
afforded the title compound (1.35 g, 3.72 mmol, 46% yield) as a
white solid, mp 60-61 °C. 1H NMR (400 MHz, CDCl3): δ 4.25
(dq, J d ) 10.7 Hz, J q ) 7.2 Hz, 2H), 4.24 (dq, J d ) 10.7 Hz, J q
) 7.2 Hz, 2H), 4.08 (q, 7.2 Hz, 2H), 3.16 (t, 5.3 Hz, 1H), 2.70 (d,
5.3 Hz, 2H), 2.34 (m, 1H), 2.31 (m, 1H), 2.00 (m, 4H), 1.32 (t,
7.2 Hz, 6H), 1.24 (t, 7.2 Hz, 3H). 13C{H} NMR (50 MHz,
CDCl3): δ 169.9, 167.5 (× 2), 116.1 (× 2), 63.7 (× 2), 61.3, 49.3
(× 2), 38.8, 36.6, 33.5 (× 2), 18.5, 13.9, 13.7 (× 2). IR (KBr): 2239,
1752, 1737, 1728 cm-1. Anal. Calcd for C18H24N2O6: C, 59.33;
H, 6.64. Found: C, 59.20; H, 6.78.
Dieth yl (1R*,6R,9R)-6-Cyan o-9-ph en yl-8-azabicyclo[4.4.0]-
d eca n e-2,2-d ica r boxyla te (Ta ble 3, en tr y 1 sta r tin g m a te-
r ia l). This compound was prepared in two steps from diethyl
(4,4-dicyanobutyl)malonate1,21 and phenyl ethynyl ketone22 using
procedures analogous to those previously reported for the
preparation of diethyl (1R*,6R,9S)-6-cyano-9-methyl-8-azabicyclo-
[4.4.0]decane-2,2-dicarboxylate.1 Details will be reported in a
future publication.23
Dieth yl (1R*,6R)-1,4-Dim eth yl-3-azabicyclo[4.3.0]n on an e-
2,9-d ion e-7,7-d ica r boxyla te (Ta ble 1, en tr y 3). Hydration of
ethyl (2R*,3R)-3-cyano-3-methyl-2-(2-oxopropyl)-4-cyclopentanone-
1,1-dicarboxylate3 (100 mg, 0.31 mmol) afforded the title com-
pound (73 mg, 0.23 mmol, 74% yield) as a white solid, mp 153-
1
154 °C. H NMR (300 MHz, CDCl3): δ 7.37 (broad, 1H), 5.02 (d
quintet, J d ) 5.8 Hz, J quintet ) 1.3 Hz, 1H), 4.22 (m, 4H), 3.21
(dd, 5.8 Hz, 1.1 Hz, 1H), 3.05 (d, 18.9 Hz, 1H), 2.51 (d, 18.9 Hz,
1H), 1.83 (t, 1.1 Hz, 3H), 1.41 (s, 3H), 1.29 (t, 7.1 Hz, 3H), 1.21
(t, 7.1 Hz, 3H). 13C{H} NMR (50 MHz, CDCl3): δ 207.9, 170.3,
170.1, 167.3, 133.8, 96.5, 62.1, 61.9, 59.1, 52.5, 48.8, 43.0, 23.8,
18.9, 13.9, 13.8. IR (KBr): 3221, 3175, 3099, 1766, 1736, 1663
cm-1. Anal. Calcd for C16H21NO6: C, 59.43; H, 6.55. Found: C,
59.25; H, 6.50.
Dieth yl (1R*,6R)-6-Cya n o-7-m eth ylbicyclo[4.4.0]d ec-7-
en -9-on e-2,2-d ica r boxyla te (Ta ble 3, en tr y 2 sta r tin g m a te-
r ia l). A solution of diethyl (1R*,6S)-6-cyano-9-ethoxybicyclo-
[4.4.0]dec-8-en-7-one-2,2-dicarboxylate1 (400 mg, 1.10 mmol) in
dry THF (10 mL) at -78 °C was treated with a 1.6 M solution
of MeLi in ether (0.7 mL, 1.1 mmol). The reaction mixture was
allowed to warm to room temperature. The mixture was acidified
with 6 N HCl (2 mL) and allowed to stir for 24 h. When the
reaction was complete (TLC check),24 the solution was extracted
twice with ether. The combined ether layers were shaken with
brine, dried over MgSO4, and evaporated, and the residue was
purified by flash chromatography (15% EtOAc in petroleum
ether as eluant) to give the title compound (298 mg, 894 µmol,
81% yield) as a white solid, mp 152-153 °C. 1H NMR (400 MHz,
CDCl3): δ 6.00 (quintet, 1.1 Hz, 1H), 4.34 (dq, J d ) 11.8 Hz, J q
) 7.1 Hz, 1H), 4.28 (dq, J d ) 11.8 Hz, J q ) 7.1 Hz, 1H), 4.24
(dq, J d ) 12.0 Hz, J q ) 7.1 Hz, 1H), 4.17 (dq, J d ) 12.0 Hz, J q
) 7.1 Hz, 1H), 3.06 (dd, 17.7 Hz, 14.0 Hz, 1H), 2.74 (dd, 14.0
Hz, 2.6 Hz, 1H), 2.71 (ddd, 17.7 Hz, 2.6 Hz, 1.1 Hz, 1H), 2.59
(ddt, J d ) 13.5 Hz, J t ) 3.4 Hz, J d ) 1.4 Hz, 1H), 2.45 (dm, J d
) 13.5 Hz, 1H), 2.26 (m, 1H), 2.07 (d, 1.4 Hz, 3H), 1.59 (m, 1H),
1.50 (dt, J d ) 13.4 Hz, J t ) 4.0 Hz, 1H), 1.46 (dt, J d ) 13.4 Hz,
J t ) 4.0 Hz, 1H), 1.33 (t, 7.1 Hz, 3H), 1.25 (7.1 Hz, 3H). 13C{H}
NMR (50 MHz, CDCl3): δ 196.6, 170.7, 168.5, 155.7, 129.5, 117.7,
Dieth yl (1R*,5S,6R)-5-Am in ocar bon yl-9-azabicyclo[4.4.0]-
d eca n e-8,10-d ion e-1,5-d ica r boxyla te (Ta ble 1, en tr y 4).
Hydration of diethyl (1R,2R,3S)-1,3-dicyano-2-(2-ethoxy-
carbonylethyl)-1,3-cyclohexanedicarboxylate (200 mg, 551 µmol)
afforded the title compound (151 mg, 426 µmol, 79% yield) as a
1
white solid, mp 205-206 °C. H NMR (400 MHz, DMSO-d6): δ
11.19 (s, 1H), 7.41 (s, 1H), 7.25 (s, 1H), 4.13 (dq, J d ) 14.1 Hz,
J q ) 7.1 Hz, 1H), 4.11 (dq, J d ) 14.1 Hz, J q ) 7.1 Hz, 1H), 3.97
(dq, J d ) 11.2 Hz, J q ) 7.2 Hz, 1H), 3.94 (dq, J d ) 11.2 Hz, J q
) 7.2 Hz, 1H), 3.48 (dd, 13.3 Hz, 4.3 Hz, 1H), 2.80 (dd, 16.8 Hz,
13.3 Hz, 1H), 2.20 (dd, 16.8 Hz, 4.3 Hz, 1H), 2.06 (m, 1H), 1.88
(m, 1H), 1.74 (m, 3H), 1.60 (m, 1H), 1.17 (t, 7.2 Hz, 3H), 1.13 (t,
7.1 Hz, 3H). 13C{H} NMR (50 MHz, DMSO-d6): δ 173.5, 171.6,
171.1, 170.5, 170.0, 61.2, 61.1, 56.9, 53.1, 35.5, 30.8, 26.0, 24.4,
18.7, 13.7, 13.6. IR (KBr): 3440, 3203, 1744, 1721, 1708, 1681,
1642 cm-1. Anal. Calcd for C16H22N2O7: C, 54.23; H, 6.25.
Found: C, 53.98; H, 6.20.
Dieth yl (1R,5S,11r )-8-Meth yl-7,9-d ia za tr icyclo[6.2.2.05,11]-
d od eca n e-6,10-d ion e-1,5-d ica r boxyla te (Ta ble 2, en tr y 1).
Hydration of diethyl (1R,2r,3S)-1,3-dicyano-2-(2-oxopropyl)-1,3-
cyclohexanedicarboxylate1 (580 mg, 1.74 mmol) afforded the title
compound (265 mg, 752 µmol, 43% yield) as a white solid, mp
179-181 °C (dec). 1H NMR (400 MHz, CDCl3): δ 7.29 (s, 2H),
4.22 (m, 4H), 3.23 (t, 3.2 Hz, 1H), 2.72 (dm, 13.2 Hz, 2H), 2.21
(21) Grossman, R. B.; Varner, M. A. J . Org. Chem. 1997, 62, 5235.
(22) Prepared by J ones oxidation of commercially available 1-phenyl-
3-propyn-1-ol.
(23) Grossman, R. B.; Maggard, R. K. Unpublished results.
(24) If the reaction is not allowed to proceed for enough time or the
conditions are insufficiently acidic, the undehydrated aldol is isolated
also.

3258 J . Org. Chem., Vol. 65, No. 10, 2000
Notes
(d, 3.2 Hz, 2H), 1.67 (m, 3H), 1.47 (s, 3H), 1.27 (t, 7.1 Hz, 6H),
1.08 (broad q, 13.7 Hz, 1H). 13C{H} NMR (50 MHz, CDCl3): δ
172.1, 170.3, 66.6, 62.3, 54.4, 37.5, 32.2, 30.6, 27.0, 19.2, 13.9.
(80 mg, 0.24 mmol) and chromatographic purification afforded
the amide (27 mg, 77 µmol, 32% yield) as a white solid, mp 221-
223 °C, plus a 1:1 mixture of the amide and the imide. Further
hydration of this mixture afforded pure imide (33 mg, 0.11 mmol,
45% yield) as a white solid, mp 214-215 °C.
IR (KBr): 3448, 3336, 3262, 3200, 1733, 1691, 1652 cm-1
C17H24N2O6.
.
Dieth yl(1R,4S,10r )-7-Meth yl-6,8-d ia za tr icyclo[5.2.2.04,10]-
u n d eca n e-5,9-d ion e-1,4-d ica r boxyla te (Ta ble 2, en tr y 2).
Hydration of diethyl (1R,2r,3S)-1,3-dicyano-2-(2-oxopropyl)-1,3-
cyclopentanedicarboxylate1 (1.82 g, 5.68 mmol) in concentrated
sulfuric acid (18 mL) and EtOH (6 mL) afforded the title
compound (876 mg, 2.59 mmol, 46% yield) as a white solid, mp
193 °C (dec). 1H NMR (400 MHz, CDCl3): δ 6.96 (s, 2H, chemical
shift varies with concentration), 4.23 (m, 4H), 2.87 (t, 3.4 Hz,
1H), 2.62 (∼q, 6.8 Hz, 2H), 2.40 (d, 3.2 Hz, 2H), 2.19 (∼q, 7.1
Hz, 2H), 1.59 (s, 3H), 1.28 (t, 7.2 Hz, 6H). 13C{H} NMR (100
MHz, CDCl3): δ 170.6, 170.6, 65.9, 62.1, 59.7, 45.9, 33.3, 31.9,
27.5, 14.0. IR (KBr): 3202, 1742, 1686 (w), 1652 cm-1. Anal.
Calcd for C16H22N2O6: C, 56.80; H, 6.55. Found: C, 56.78; H,
6.83.
1
Da ta for th e Am id e. H NMR (300 MHz, CDCl3): δ 5.99 (s,
1H), 5.71 (broad, 2H), 4.18 (m, 4H), 3.47 (dd, 17.8 Hz, 14.1 Hz,
1H), 2.79 (dd, 14.1 Hz, 3.4 Hz, 1H), 2.55 (m, 3H), 2.37 (dm, J d
12.2 Hz, 1H), 2.01 (d, 1.4 Hz, 3H), 1.75 (m, 1H), 1.57 (dt, J t
)
)
13.1 Hz, J d ) 4.2 Hz, 1H), 1.37 (dt, J t ) 13.4 Hz, J d ) 4.5 Hz,
1H), 1.28 (t, 7.2 Hz, 3H), 1.23 (t, 7.1 Hz, 3H). 13C{H} NMR (50
MHz, CDCl3): δ 198.6, 171.8, 171.2, 168.9, 162.1, 128.1, 61.0,
60.1, 55.8, 49.5, 44.8, 38.0, 33.0, 32.1, 19.7, 19.5, 13.4, 13.2. IR
(KBr): 3380, 3174, 1750 (w), 1723, 1693, 1646 cm-1. C18H25NO6.
1
Da ta for Th e Im id e. H NMR (300 MHz, CDCl3): δ 8.34 (s,
1H), 6.04 (d, 1.3 Hz, 1H), 4.28 (q, 7.2 Hz, 1H), 4.27 (q, 7.1 Hz,
1H), 2.52 (m, 4H), 2.26 (d, 1.4 Hz, 3H), 2.21 (m, 1H), 2.04 (m,
1H), 1.65 (m, 3H), 1.32 (t, 7.2 Hz, 3H). 13C{H} NMR (50 MHz,
CDCl3): δ 195.0, 171.7, 169.9, 168.7, 160.7, 128.8, 62.2, 55.8,
47.9, 44.7, 38.2, 32.3, 32.1, 22.3, 19.4, 13.9. IR (KBr): 3241, 1743,
1692, 1673 cm-1. C16H19NO5.
E t h yl (1R*,4S,7S,10R)-4,7-Dim et h yl-6,8-d ia za t r icyclo-
[5.2.2.04,10]u n d eca n e-3,5,9-tr ion e-1-ca r boxyla te (Ta ble 2,
en tr y 3). Hydration of ethyl (1R*,2R,3R)-1,3-dicyano-3-methyl-
2-(2-oxopropyl)-4-cyclopentanone-1-carboxylate3 (298 mg, 1.05
mmol) afforded the title compound (172 mg, 584 µmol, 54% yield)
as a white solid, mp 238-239 °C. 1H NMR (300 MHz, CDCl3):
δ 7.87 (s, 1H), 7.59 (s, 1H), 4.26 (m, 2H), 3.37 (d, 20.2 Hz, 1H),
3.18 (d, 20.2 Hz, 1H), 2.73 (t, 3.2 Hz, 1H), 2.59 (dd, 13.5 Hz, 2.8
Hz, 1H), 2.19 (dd, 13.4 Hz, 2.5 Hz, 1H), 1.62 (s, 3H), 1.43 (s,
3H), 1.31 (t, 7.1 Hz, 3H). 13C{H} NMR (50 MHz, CDCl3): δ 207.5,
170.4, 170.1, 167.1, 65.7, 62.8, 57.1, 54.0, 45.8, 45.2, 30.6, 27.2,
E t h yl (1R*,6R,7R)-1,7-Bis(a m in oca r b on yl)-4-et h oxyb i-
cyclo[4.3.0]n on -3-en -2-on e-7-ca r boxyla te a n d Eth yl (1R*,-
2R,7R)-4-Eth oxy-9-a za tr icyclo[5.3.2.02,7]d od ec-4-en e-6,8,10-
tr ion e-1-ca r boxyla te (Ta ble 3, en tr y 3). Hydration of ethyl
(1R*,6S,7S)-1,7-dicyano-4-ethoxybicyclo[4.3.0]non-3-en-2-one-7-
carboxylate (100 mg, 331 µmol) afforded the diamide (27 mg, 80
µmol, 32% yield) as a white solid, mp 170-171 °C, and the imide
(24 mg, 75 µmol, 30% yield) as a white solid, mp 128-129 °C.
1
Da ta for th e Dia m id e. H NMR (400 MHz, CDCl3): δ 6.08
22.7, 14.1. IR (KBr): 3205, 3071, 1754, 1731, 1683, 1644 cm-1
.
(s, 2H), 5.48 (s, 2H), 5.32 (d, 1.5 Hz, 1H), 4.21 (m, 2H), 3.93 (m,
2H), 3.49 (dd, 17.2 Hz, 12.3 Hz, 1H), 2.90 (dd, 12.4 Hz, 4.6 Hz,
1H), 2.78 (dd, 17.2 Hz, 4.6 Hz, 1H), 2.54 (dd, 10.5 Hz, 4.3 Hz,
1H), 2.25 (dt, J d ) 12.5 Hz, J t ) 4.3 Hz, 1H), 1.92 (m, 2H), 1.37
(t, 7.0 Hz, 3H), 1.27 (t, 7.1 Hz, 3H). 13C{H} NMR (50 MHz,
CDCl3): δ 197.9, 181.2, 173.5, 172.4, 171.8, 101.8, 65.4, 63.1,
62.1, 61.2, 48.2, 32.1, 31.0, 14.0, 13.9, one resonance obscured.
IR (KBr): 3442, 3348, 1730, 1671 cm-1. C16H22N2O6.
Anal. Calcd for C14H18N2O5: C, 57.13; H, 6.16. Found: C, 56.93;
H, 6.30.
Dieth yl 8-Meth yl-9,12-d ia za tr icyclo[6.2.2.01,6]d od eca n e-
10,11-d ion e-5,5-d ica r boxyla te (Ta ble 2, en tr y 4). Hydration
of diethyl 3,3-dicyano-2-(2-oxopropyl)-1,1-cyclohexanedicarboxy-
late1 (280 mg, 838 µmol) afforded the title compound (121 mg,
343 µmol, 41% yield) as a white solid, mp 251-252 °C. 1H NMR
(300 MHz, CDCl3): δ 7.48 (s, 1H), 7.08 (s, 1H), 4.15 (m, 4H),
2.72 (dd, 12.6 Hz, 5.8 Hz, 1H), 2.48 (dd, 10.2 Hz, 5.7 Hz, 1H),
2.35 (m, 2H), 2.17 (dd, 12.5 Hz, 10.3 Hz, 1H), 1.83 (m, 3H), 1.61
(s, 3H), 1.56 (dd, 13.8 Hz, 3.4 Hz, 1H), 1.25 (t, 7.2 Hz, 3H), 1.24
(t, 7.2 Hz, 3H). 13C{H} NMR (50 MHz, CDCl3): δ 174.3, 171.9,
171.4, 169.3, 65.2, 61.7, 61.2, 56.9, 53.6, 39.8, 39.2, 32.7, 22.9,
1
Da ta for th e Im id e. H NMR (400 MHz, CDCl3): δ 7.89 (s,
1H), 5.46 (d, 1.6 Hz, 1H), 4.31 (q, 7.3 Hz, 1H), 4.30 (q, 7.1 Hz,
1H), 3.92 (q, 7.0 Hz, 2H), 2.96 (dd, 17.6 Hz, 4.7 Hz, 1H), 2.73
(dd, 11.8 Hz, 4.8 Hz, 1H), 2.61 (m, 2H), 2.37 (m, 2H), 2.21 (m,
1H), 1.36 (t, 7.1 Hz, 3H), 1.34 (t, 7.1 Hz, 3H). 13C{H} NMR (50
MHz, CDCl3): δ 192.1, 175.6, 170.7, 170.4, 168.2, 102.7, 65.4,
62.2, 60.3, 60.2, 46.5, 30.7, 30.1, 26.4, 14.1, 14.0. IR (KBr): 3227,
3103, 1733, 1705, 1670 cm-1. C16H19NO6.
21.6, 18.4, 13.9, 13.8. IR (KBr): 3435, 3189, 1728, 1668 cm-1
.
Anal. Calcd for C17H24N2O6: C, 57.94; H, 6.86. Found: C, 57.90;
H, 7.06.
Eth yl (1R*,2R,4R,7R)-4-P h en yl-5,9-diazatr icyclo[5.3.3.02,7]-
tr id eca n e-8,10-d ion e-1-ca r boxyla te (Ta ble 3, en tr y 1). Hy-
dration of diethyl (1R*,6R,9R)-6-cyano-9-phenyl-8-azabicyclo-
[4.4.0]decane-2,2-dicarboxylate (384 mg, 1.00 mmol) afforded the
title compound (179 mg, 503 µmol, 50% yield) as a white solid,
mp 197-198 °C. 1H NMR (300 MHz, CDCl3): δ 8.48 (broad, 1H),
7.29 (broad, 1H), 7.28 (m, 5H), 4.21 (q, 7.2 Hz, 1H), 4.20 (q, 7.1
Hz, 1H), 3.81 (d, 12.2 Hz, 1H), 3.65 (dd, 11.3 Hz, 2.8 Hz, 1H),
2.58 (d, 12.2 Hz, 1H), 2.19 (m, 2H), 2.15 (dd, 12.7 Hz, 4.1 Hz,
1H), 1.84 (m, 3H), 1.54 (m, 3H), 1.23 (t, 7.2 Hz, 3H). 13C{H} NMR
(50 MHz, CDCl3): δ 174.3, 170.7, 169.4, 143.1, 128.4, 127.5,
126.4, 61.6, 61.0, 56.2, 53.4, 45.8, 44.8, 35.1, 32.9, 32.8, 19.1,
14.0. IR (KBr): 3315, 3170, 1731, 1698 cm-1. Anal. Calcd for
C20H24N2O4: C, 67.40; H, 6.79. Found: C, 67.24; H, 6.94.
Dieth yl (1R*,6R)-6-Am in ocar bon yl-7-m eth ylbicyclo[4.4.0]-
d ec-7-en -9-on e-2,2-d ica r b oxyla t e a n d E t h yl (1R*,2R,7R)-
6-Meth yl-9-a za tr icyclo[5.3.3.02,7]tr id ec-5-en e-4,8,10-tr ion e-
1-car boxylate (Table 3, en tr y 2). Hydration of diethyl (1R*,6R)-
6-cyano-7-methylbicyclo[4.4.0]dec-7-en-9-one-2,2-dicarboxylate
Ack n ow led gm en t. This work was generously sup-
ported by the National Science Foundation (CAREER
award to R.B.G., CHE-9733201). NMR instruments
used in this research were obtained with funds from the
CRIF program of the National Science Foundation
(CHE-997841) and the Research Challenge Trust Fund
of the University of Kentucky. The authors thank Dr.
Brian O. Patrick for determining the X-ray structure
of the product in Table 2, entry 2.
Su p p or tin g In for m a tion Ava ila ble: A thermal ellipsoid
plot of the product in Table 2, entry 2, and 1H and 13C NMR
spectra of all compounds for which elemental analyses are not
reported. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O0000978