Diazocinones: Synthesis and conformational analysis

Article abstract of DOI:10.1021/jo052577a

1,2,4,5-Tetrazines (prepared from aryl nitriles) condense with isoxazolylcyclobutanones (prepared from 3-benzenesulfonyl-3-vinylcyclobutanol) in methanolic KOH to give conformationally restricted 6-isoxazol-5-yl-6,7- dihydro-5H-[1,2]diazocin-4-ones. The s

Full text of DOI:10.1021/jo052577a

Diazocinones: Synthesis and Conformational Analysis
Lori I. Robins,† Richard D. Carpenter,† James C. Fettinger,† Makhluf J. Haddadin,‡
Dino S. Tinti,*,† and Mark J. Kurth*,†
Department of Chemistry, One Shields AVenue, UniVersity of California, DaVis, California 95616, and
Department of Chemistry, American UniVersity of Beirut, Beirut, Lebanon
mjkurth@ucdaVis.edu; dstinti@ucdaVis.edu
ReceiVed December 14, 2005
1,2,4,5-Tetrazines (prepared from aryl nitriles) condense with isoxazolylcyclobutanones (prepared from
3-benzenesulfonyl-3-vinylcyclobutanol) in methanolic KOH to give conformationally restricted 6-isoxazol-
5-yl-6,7-dihydro-5H-[1,2]diazocin-4-ones. The solution 1H NMR spectra of dihydrodiazocinone 1a with
phenyl moieties at C3 and C8 reveal two conformations of the eight-membered heterocycle that are
non-interconverting on the NMR time scale at ambient temperature. The kinetics of the conversion process,
1
followed by H NMR between 21 and 70 °C in DMSO solution, yield an activation energy of ∼21
kcal/mol relative to the kinetic conformer and show an equilibrated ratio of ∼5:1 of the thermodynamic
to the kinetic conformers. The electronic structure calculations on a model dihydrodiazocinone predict
geometries for the two conformations. One of these geometries agrees with the X-ray crystallographic
analysis of the thermodynamic conformation of 1a.
Introduction
ular clefts,1g isopyrazoles,1h as well as other aza-containing
systems.2 Furthermore, the various chemistries involved with
1,2,4,5-tetrazines are the subject of numerous theoretical
1,2,4,5-Tetrazines (2) are versatile precursors to semibullval-
enes,1a homotropylidenes,1b diazanorcaradienes,1c tetrahetero-
cyclic azepines,1d C60-monoadducts,1e azapagodanes,1f molec-
(2) (a) Imming, P.; Kuemmell, A.; Seitz, G. Heterocycles 1993, 35, 299-
304. (b) Sakamoto, T.; Funami, N.; Kondo, Y.; Yamanaka, H. Heterocycles
1991, 32, 1387-1390. (c) Kuemmel, A.; Seitz, G. Tetrahedron Lett. 1991,
32, 2743-2746. (d) Atfah, M. A. J. Heterocycl. Chem. 1989, 26, 717-
719. (e) Takahashi, M.; Hikita, Y.; Fukui, M. Heterocycles 1989, 29, 1379-
1382. (f) Hartmann, K. P.; Heuschmann, M. Angew. Chem., Int. Ed. Engl.
1989, 28, 1267-1268. (g) Marcelis, A. T. M.; Van der Plas, H. C. J.
Heterocycl. Chem. 1987, 24, 545-548. (h) Hunter, D.; Neilson, D. G.;
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Hunter, D.; Neilson, D. G. J. Chem. Soc., Perkin Trans. 1 1985, 1081-
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1983, 1601-1603. (m) Balcar, J.; Chrisam, G.; Huber, F. X.; Sauer, J.
Tetrahedron Lett. 1983, 24, 1481-1484. (n) Figeys, H. P.; Mathy, A.;
Dralants, A. Synth. Commun. 1981, 11, 655-662. (o) Anastassiou, A. G.;
Girgenti, S. J. Angew. Chem., Int. Ed. Engl. 1975, 14, 814-815. (p)
Takahashi, M.; Suzuki, N.; Igari, Y. Bull. Chem. Soc. Jpn. 1975, 48, 2605-
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* Corresponding author.
† Deparment of Chemistry, University of California.
‡ Department of Chemistry American University of Beirut.
(1) (a) Sauer, J.; Bauerlein, P.; Ebenbeck, W.; Schuster, J.; Sellner, I.;
Sichert, H.; Stimmelmayr, H. Eur. J. Org. Chem. 2002, 791-801. (b) Sauer,
J.; Bauerlein, P.; Ebenbeck, W.; Dyllick-Brenzinger, R.; Gousetis, C.;
Sichert, H.; Troll, T.; Wallfahrer, U. Eur. J. Org. Chem. 2001, 2639-2657.
(c) Sauer, J.; Bauerlein, P.; Ebenbeck, W.; Gousetis, C.; Sichert, H.; Troll,
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Sammelson, R. E.; Olmstead, M. M.; Haddadin, M. J.; Kurth, M. J. J. Org.
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10.1021/jo052577a CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/23/2006
2480
J. Org. Chem. 2006, 71, 2480-2485

Diazocinones: Synthesis and Conformational Analysis
SCHEME 1. 1,2,4,5-Tetrazines as Precursors to
Dihydrodiazocinone (7) and Isoxazolyl-Substituted
Dihydrodiazocinone (1)
FIGURE 1. Synthesized dihydrodiazocinones 1a-h were obtained
in crude conformational ratios (kinetic vs thermodynamic) varying from
∼1:1 to ∼4:1.
regiochemical issues, this R group is best placed at C3 of the
enolate, which should then deliver 7 (via 2 + 3 f 7) with the
R group at C6, as depicted. Given our experience with various
isoxazolylcyclobutanone syntheses,7 we set out to prepare a
series of novel isoxazolyl-substituted dihydrodiazocinones (2
+ 3 f 1a-h; Figure 1) in the belief that the eight-membered
ring diaza heterocycles would have relatively few low-energy,
conformationally accessible states and, in turn, limited confor-
mational flexibility, a concept that is important in understanding
small molecule-receptor interactions.8 If correct, the rigidity of
the dihydrodiazocinone skeleton would cause the adorning
functional groups (Ar1 and R2) to be displayed in reliable spatial
arrangements about the eight-membered ring.
investigations.3 In earlier work, as shown in Scheme 1, we
reported that 1,2,4,5-tetrazines (2) condense with acyclic enolate
nucleophiles (4) in prototic solvent to give, after nitrogen
extrusion and dehydration, pyridazine 5.4a Conversely, when
the carbon nucleophile is derived from cyclobutanone (6),
condensation is followed by nitrogen extrusion and [4.2.0] ring
expansion to 7.4b
The biological connotations5 of cyclooctyl-based compounds
coupled with the rich and diverse implications of cyclooctyl-
based conformational effects6 have interested us in both the
chemistry and structural implications of modifying the conden-
sation of 1,2,4,5-tetrazines 2 with enolate 6 (route to 7) by
placing a substituent on enolate 6 (R * Η). To avoid
Results and Discussion
Following literature methods,4,5 the 1,2,4,5-tetrazine deriva-
tives required for this study were prepared as depicted in Scheme
2. Aryl nitriles were treated with hydrazine and catalytic
elemental sulfur in refluxing ethanol to give dihydro-[1,2,4,5]-
tetrazines 8a-d. These crude dihydro intermediates were
subsequently oxidized with sodium nitrite in acetic acid to yield
the vibrantly purple tetrazines 2a-d.
Concurrently, the requisite isoxazolylcyclobutanones 3 were
synthesized following protocols developed in our laboratory
(Scheme 3).7 Briefly, treatment of allyl phenyl sulfone with 2
equiv of n-butyllithium, followed by addition of epichlorohydrin,
delivered 3-benzenesulfonyl-3-vinylcyclobutanol 9. Next, em-
ploying the Huisgen method for in situ nitrile oxide generation
(oxime + sodium hypochlorite),9 the alkene moiety of 9
underwent a 1,3-dipolar cycloaddition to give 10 (phenyl- and
4-methoxyphenyl-oximes were employed). At this point, the
cyclobutanol was oxidized to the cyclobutanone under Swern
(3) (a) Hughes, G.; Wang, C.; Batsanov, A. S.; Fern, M.; Frank, S.; Bryce,
M. R.; Perepichka, I. F.; Monkman, A. P.; Lyons, B. P. Org. Biomol. Chem.
2003, 1, 3069-3077. (b) Soloducho, J.; Doskocz, J.; Cabaj, J.; Roszak, S.
Tetrahedron 2003, 59, 4761-4766. (c) Pintore, M.; Piclin, N.; Benfenati,
E.; Gini, G.; Chretien, J. R. EnViron. Toxicol. Chem. 2003, 22, 983-991.
(d) Zhou, X.; Kovalev, E. G.; Klug, J. T.; Khodorkovsky, V. Org. Lett.
2001, 3, 1725-1727. (e) Rusinov, G. L.; Ishmetova, R. I.; Latosh, N. I.;
Ganebnych, I. N.; Chupakhin, O. N.; Potemkin, V. A. Russ. Chem. Bull.
2000, 49, 355-362. (f) Spanget-Larsen, J.; Thulstrup, E. W.; Waluk, J.
Chem. Phys. 2000, 254, 135-149. (g) Trifonov, R. E.; Zubarev, V. Y.;
Malin, A. A.; Ostrovskii, V. A. Chem. Heterocycl. Compd. (N.Y.) 1998,
34, 111-114.
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44, 629-630.
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Ahorney, D.; Masek, B. B.; Dembofsky, B. T.; Koether, G. M.; Potts, W.;
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Rao, R. B.; Balaram, P.; Shamala, N. J. Pept. Sci. 2004, 10, 160-172. (b)
Paquette, L. A.; Hartung, R. J. Comput. Chem. 2003, 80, 1201-1208. (c)
Wiberg, K. B. J. Org. Chem. 2003, 68, 9322-9329. (d) Dos Santos, H. F.;
Rocha, W. R.; De Almeida, W. B. Chem. Phys. 2002, 280, 31-42. (e)
Kahn, K.; Bruice, T. C. J. Comput. Chem. 2002, 23, 977-996. (f)
Bharadwaj, R. K. Mol. Phys. 2000, 98, 211-218. (g) Pawar, D. M.; Moody,
E. M.; Noe, E. A. J. Org. Chem. 1999, 64, 4586-4589. (h) Rocha, W. R.;
Pliego, J. R., Jr.; Resende, S. M.; Dos Santos, H. F.; De Oliveira, M. A.;
De Almeida, W. B. J. Comput. Chem. 1998, 19, 524-534.
(7) (a) Cheng, W.-C.; Wong, M.; Olmstead, M. M.; Kurth, M. J. Org.
Lett. 2002, 4, 741. (b) Cheng, W.-C.; Olmstead, M. M.; Kurth, M. J. J.
Org. Chem. 2001, 66, 5528. (c) Cheng, W.-C.; Halm, C.; Evarts, J. B.;
Olmstead, M. M.; and Kurth, M. J. J. Org. Chem. 1999, 64, 8557. (d) Halm,
C.; Kurth, M. J. Tetrahedron Lett. 1997, 38, 7709.
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nasinitt, M. Org. Lett. 2005, 7, 3401-3404. (b) Geney, R.; Sun, L.; Pera,
P.; Bernacki, R. J.; Xia, S.; Horwitz, S. B.; Simmerling, C. L.; Ojima, I.
Chem. Biol. 2005, 12, 339-348. (c) Lin, J.-H.; Perryman, A. L.; Schames,
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J. Org. Chem, Vol. 71, No. 6, 2006 2481

Robins et al.
SCHEME 2. Tetrazine Synthesis
FIGURE 2. 1H NMR data for dihydrodiazocinone 1a (JC4′H,C6H ) ∼1
Hz). (a-c) Isoxazole peaks for 1a at 25 °C (CDCl3), 50 °C (DMSO-
d6), and 119 °C (DMSO-d6), respectively. (d) Thermodynamic con-
former isolated by recrystallization (CDCl3).
The 1H NMR spectrum of column chromatographed 1a was
suggestive of two conformations of the dihydrodiazocinone
heterocycle, which were noninterconverting on the NMR time
scale at ambient temperature. Indeed, this observation was
strengthened by the doubling of signals in the 13C NMR. The
clearest indication that 1a existed in two noninterconverting
(NMR time scale) conformations was found in the proton data
where two distinct singlets were observed for the proton at C4
of the isoxazole ring (viz., C4′H; Figure 2a, singlets at 6.34
and 6.38 ppm in CDCl3; Figure 2b, singlets at 6.74 and 6.86
ppm in DMSO-d6). That this doubling of signals is the
consequence of conformational isomers as opposed to configu-
SCHEME 3. Isoxazolylcyclobutanone Synthesis (a, Ar2 )
C6H5; b, Ar2 ) 4-MeOC6H4)
1
rational isomers was established by variable temperature H
NMR experiments. Specifically, heating a 1.4:1 mixture of these
1
isomers at 119 °C for 20 min led to the H NMR spectrum
depicted in Figure 2c, where the two conformations have
equilibrated to a 10:1.8 mixture. Recrystallization of the crude
reaction mixture (1.4:1 ratio) led to the isolation of the
thermodynamic isomer in pure form (see Figure 2d).
SCHEME 4. Synthesis of
6-Isoxazolyl-5H-[1,2]diazocin-4-one, 1a
We investigated the kinetics of this interconversion in DMSO-
1
d6 solution by monitoring the H NMR signal of the C4′H of
both conformers as a function of time at several temperatures,
starting from a mixture rich in the kinetic conformer. No line
broadening or evidence of an intermediate was seen in the NMR
spectra. The results indicate a simple isomerization process
wherein the conformers approach their equilibrium concentra-
tions by a first-order process, with an observed rate of kobs
)
k1 + k-1, where k1 and k-1 are the rates for the forward and
backward reactions, respectively. The latter rates are obtained
from kobs, given the equilibrium constant K ) [thermodynamic]/
[kinetic] ) k1/k-1. Figure 3 (top and middle) shows the kinetic
data at 21, 35, 50, and 70 °C as first-order plots of ln[Rt - R∞]
vs time, where R ) [kinetic]/{[kinetic] + [thermodynamic]}.
The observed rates yield a kinetic to thermodynamic activation
energy of ∼21 kcal/mol (Figure 3, bottom). The equilibrium
constant K does not change over the studied temperature range,
within experimental uncertainties. Its value of ∼10:2 indicates
that the energies of the two conformers differ by e2 kcal/mol.
Coupling constants for the C6 methine proton to the adjacent
C5 and C7 methylene protons in 1a provide further conforma-
tional insight. These coupling constants (Table 1) indicate that
the dihedral angles involving the methine proton and the adjacent
methylene protons differ between the two conformers. This
could result from conformer differences in the geometry of the
dihydrodiazocinone ring and/or in the orientation of the isox-
azole substituent (e.g., pseudo-equatorial or pseudo-axial ori-
entation relative to the ring). To identify the explicit confor-
mations of the eight-membered ring and the orientation of the
conditions,10 with concomitant base-mediated â-sulfinate elimi-
nation and isomerization of the cyclobutenone-isoxazoline to
cyclobutanone-isoxazole, delivering (3-isoxazol-5-yl)cyclobu-
tanones 3a and 3b.
With these tetrazines and cyclobutanones in hand, we turned
our attention to creating the eight-membered dihydrodiazocinone
ring systems and found that treating tetrazine 2a with cyclobu-
tanone 3a in methanolic KOH in THF at room temperature gave
dihydrodiazocinone 1a in 62% yield (Scheme 4). Nitrogen
evolution and the gradual discharge of the purple color of the
tetrazine were indicators of the 2a + 3a f 1a conversion. After
completion, the reaction mixture was concentrated to remove
THF, extracted with ethyl acetate, and purified by column
chromatography. In similar fashion, dihydrodiazocinones 1b-h
were prepared in 35-62% yield.
(10) (a) Mancuso, A.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480-2482. (b) Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976,
41, 3329-3331.
2482 J. Org. Chem., Vol. 71, No. 6, 2006

Diazocinones: Synthesis and Conformational Analysis
FIGURE 4. The two minimum energy (TB and TBC) conformers and
the connecting TS found for the cis,cis isomer of 1a with hydrogens
in place of the aryl and isoxazolyl moieties. Energies in kcal/mol relative
to TB are given in parentheses.
kcal/mol. These results parallel the conformational isomerism
in 1,3-cyclooctadiene, where the cis,cis isomer is considerably
lower in energy than the cis,trans isomer.11,12 Figure 4 shows
the two conformations corresponding to energy minima and their
relative energies for the cis,cis isomer of the model. These
correspond roughly to the twist-boat (TB) and twist-boat-chair
(TBC) conformations of cis,cis-1,3-cyclooctadiene, as described
by Anet and Yavari.11 The TB conformer is lower in energy by
1.5 kcal/mol in the model cis,cis-dihydrodiazocinone, whereas
the TBC conformer is lower by 0.5 kcal/mol in cis,cis-1,3-
cyclooctadiene. The structural parameters associated with the
ring are given in Table 2 for the TB and TBC conformers of
the model.
The two conformers are distinguished mainly by the dihedral
angles. These angles for the five C-C single bonds of the ring
(Table 2, D3-D7) alternate in sign for the TBC conformer but
not for the TB conformer. The TBC conformer has near C2
symmetry for the eight-membered ring, with the symmetry axis
bisecting the N1-N2 and C5-C6 bonds. The TB conformer
shows more extreme values for the internal ring angles: angle
A7 is small at ∼109°, while angle A3 is large at ∼132°. Both
the TB and TBC conformers are strongly twisted by ∼74° about
the pair of CdN bonds. Although there are similarities in the
geometries of these conformers and those of cis,cis-1,3-
cyclooctadiene,11,12 the detailed geometries of the dihydrodia-
zocinone and cyclooctadiene rings differ due to the shorter bonds
for N relative to C and the influence of the carbonyl substituent
(changed hybridization of C4).
A low-energy transition state (TS) connecting the TB and
TBC conformers of this model was found at 5.9 kcal/mol above
TB. The eight-membered ring has a rough boat conformation
in the TS with a near C2 symmetry axis bisecting the N1-N2
and C5-C6 bonds. The TS structure and its geometrical
parameters are included in Figure 4 and Table 2, respectively.
The near-degeneracy in the calculated energies of the TB and
TBC conformers agrees with the small energy difference
between the kinetic and the thermodynamic conformers implied
by the equilibrium constant. However, the calculated energies
of the conformers and the connecting TS imply a dynamic
FIGURE 3. Plots of ln[Rt - R∞] vs time (top and middle), where R
) [kinetic]/{[kinetic] + [thermodynamic]} at 21, 35, 50, and 70 °C,
and of ln k1 vs inverse temperature (bottom).
TABLE 1. Coupling Constants in Hz for the Proton(s) at C6a of
the Dihydrodiazocinone
H5a
H5b
H7a
H7b
Experimental
thermodynamic conformerb
kinetic conformerc
5.3
11.8
10.7
3.7
2.5
1.0
11.5
3.5
Calculational
thermodynamic conformer
TBC (H6 ax)
TB (H6 eq)
5.23
5.97
11.58
3.11
1.25
7.05
11.53
11.52
kinetic conformer
TB (H6 ax)
TBC (H6 eq)
12.29
2.18
3.52
6.99
0.97
7.05
7.70
1.34
a See TB and TBC structures in Figure 4 for Ha and Hb assignments.
b H5 and H7 assignments based on HSQC, NOE, and 13C chemical shifts.
c H5 and H7 assignments based on the 13C chemical shift correlation with
the thermodynamic isomer.
(11) Anet, F. A. L.; Yavari, I. J. Am. Chem. Soc. 1978, 100, 7814-
7819.
C6-substituent, theoretical calculations were performed on the
dihydrodiazocinone ring system.
(12) (a) Yavari, I.; Kabiri-Fard, H.; Moradi, S. J. Mol. Struct.
(THEOCHEM) 2003, 623, 237-244. (b) Hess, B. A., Jr.; Baldwin, J. E. J.
Org. Chem. 2002, 67, 6025-6033. (c) Rashidi-Ranjbar, P.; Sandstrom, J.
J. Chem. Soc., Perkin Trans. 2 1990, 901-906. (d) Isaksson, R.; Roschester,
J.; Sandstro¨m, J.; Wistrand, L. G. J. Am. Chem. Soc. 1985, 107, 4074-
4075 (e) Oda, K.: Ohnuma, T.; Ban, Y. J. Am. Chem. Soc. 1984, 106,
5378-5379. (f) Gottlieb, H. E.; Mervic, M.; Ghera, E. J. Chem. Soc., Perkin
Trans. 1 1982, 2353-2358. (g) Allinger, N. L.; Viskocil, Jr., J. F.; Burkert,
U.; Yuh, Y. Tetrahedron 1976, 32, 33-35. (h) Zuccarello, F.; Buemi, G.;
Favini, G. J. Mol. Struc. 1973, 18, 295-302.
Density functional theory calculations at the B3LYP/
6-311+G(2d,p)//B3LYP/6-31G(d) level were carried out on a
model dihydrodiazocinone substituted with Ar1 ) R2 ) H (see
1 in Figure 1). The calculations show several conformations
for the dihydrodiazocinone ring. The lower energy conforma-
tions have a cis,cis orientation of the two CdN double bonds.
The cis,trans and trans,cis isomers are higher in energy by 7-15
J. Org. Chem, Vol. 71, No. 6, 2006 2483

Robins et al.
TS
crystalb
TABLE 2. Selected Interatomic Distances and Angles
parametera
TB
TBC
TS
crystalb
parametera
TB
1.549
1.558
1.501
1.282
TBC
1.546
1.553
1.510
1.280
Bond Lengths/Ångstro¨ms
B1
B2
B3
B3*
B4
N1N2
N2C3
C3C4
C4O
1.353
1.368
1.371
1.389
1.279
1.517
1.212
1.514
B5
B6
B7
B8
C5C6
C6C7
C7C8
C8N1
1.558
1.552
1.501
1.281
1.544
1.554
1.511
1.293
1.285
1.507
1.221
1.522
1.278
1.523
1.213
1.526
1.278
1.517
1.217
1.537
C4C5
Bond Angles/Degrees
A1
A2
A3
A4
A5
C8N1N2
N1N2C3
N2C3C4
C3C4C5
C4C5C6
121.566
124.992
131.694
121.849
114.976
120.216
119.058
125.888
114.650
113.866
118.586
119.154
127.041
123.563
125.175
118.85
118.99
122.74
114.20
110.60
A6
A7
A8
A4*(3)
A4*(5)
C5C6C7
C6C7C8
C7C8N1
C3C4O
OC4C5
115.458
109.188
124.894
116.796
121.246
115.557
111.902
128.119
122.149
123.200
119.688
111.965
125.603
117.316
118.838
113.80
113.16
124.95
122.90
122.86
Dihedral Angles/Degrees
D1
D2
D3
D3*
D4
C8N1N2C3
N1N2C3C4
N2C3C4C5
N2C3C4O
C3C4C5C6
-73.901
10.472
-72.644
6.722
90.228
-90.833
-80.972
-75.460
0.177
72.421
-113.771
-22.149
-72.35
D4*
D5
D6
D7
D8
OC4C5C6
C4C5C6C7
C5C6C7C8
C6C7C8N1
C7C8N1N2
-110.619
-59.432
-40.632
83.614
100.101
53.713
-78.514
88.876
5.906
164.131
-5.992
-52.213
91.685
7.346
93.215
51.98
-81.45
91.93
5.70
7.090
97.91
-80.65
-85.35
-176.659
65.468
14.203
6.635
a See Figure 1 for atom numbering. b Average of the two molecules in the unit cell.
difference, 4.2 Hz). These correspond to TBC-eq and TB-eq
for 1a, respectively, where ax and eq refer to the orientation of
the isoxazolyl substituent at C6. Better agreement is obtained
if the thermodynamic conformer is assigned as 0.85 TBC-eq
and 0.15 TB-ax (rms difference, 0.55 Hz) and the kinetic
conformer as 0.15 TBC-ax and 0.85 TB-eq (rms difference, 3.5
Hz), following the system proposed in Figure 5. The experi-
mental and calculated coupling constants are in significantly
better agreement for the thermodynamic conformer than the
kinetic conformer and may be associated with a greater
contribution of the axially substituted conformer in the kinetic
isomer and/or the inherent dihedral angle changes implicated
by placement of the isoxazole substituent in the TBC-ax, TB-
ax, and TB-eq conformers. An equatorial orientation of the
isoxazolyl substituent at C6 in TBC should not cause large
changes in the dihedral angles at C6 compared to the corre-
sponding angles of the model dihydrodiazocinone ring; conse-
quently, the calculated coupling constants agree well with the
experimental values. However, an axial orientation of the
isoxazolyl substituent in TBC and either an axial or equatorial
orientation of the substituent in TB should cause greater
geometry changes; consequently, the coupling constants calcu-
lated for the unperturbed dihydrodiazocinone ring show poorer
agreement with experiment.
FIGURE 5. Schematic representation of the proposed interconversion
between the kinetic and the thermodynamic conformers of the dihy-
drodiazocinone 1a.
interconversion of the TB and TBC conformers at ambient
temperature. We assume that this also holds for 1a, even with
the aryl and isoxazolyl substituents. Hence, the experimental
kinetic and thermodynamic conformers cannot simply be TB
and TBC conformers.
Because a substituent at C6 can assume a pseudoaxial or
pseudoequatorial orientation relative to the ring, two distinct
conformations for 1a result for each of the model conformations
(and TSs), depending on the orientation of the isoxazolyl
substituent relative to the ring. A consideration of these
geometries shows that the TB conformer with an axial sub-
stituent at C6 is connected by a TS to the TBC conformer with
an equatorial substituent at C6. The energy difference between
an axial or an equatorial substituent at C6 for a given conformer
or TS is anticipated to be similar to the energy differences
among unsubstituted TB, TBC, and TS structures. However,
the conversion between the pseudoaxially (ax) and pseudoequa-
torially (eq) substituted isomers for a particular model conformer
(TB or TBC) is expected to involve a high-energy TS. These
ideas are shown schematically in Figure 5, where the top process
can be associated with the kinetic conformer, and the bottom
process can be associated with the thermodynamic conformer
(vide infra).
Finally, X-ray crystallography analysis of 1a yields the TBC-
eq conformation (Figure 6), in agreement with the major
contributor of the thermodynamic conformer. The data in Table
2 show that the calculated internal ring bond distances, bond
angles, and dihedral angles in the model are in good agreement
with the crystallography results. The average rms differences
are 0.009 Å, 1.6°, and 3.8°, respectively.
Conclusions
The calculated coupling constants for the protons on C6 to
the protons on C5 and C7 for the minimum-energy conforma-
tions of the model are included in Table 1, with the two protons
on C6 in the model distinguished by their pseudoaxial or
pseudoequatorial orientation relative to the ring. The best
agreement between the calculated results for a single conformer
and the experimental data occurs if the thermodynamic con-
former is assigned to TBC with H6 axial (rms difference, 1.5
Hz), and the kinetic conformer to TB with H6 axial (rms
We have achieved a general route to novel isoxazole-
substituted dihydrodiazocinones (1), which proceeds by the
condensation of tetrazines (2) with cyclobutanones (3) in
methanolic KOH in THF at room temperature. These eight-
membered ring diaza heterocycles exist in relatively few low-
energy, conformationally accessible states and experience
limited conformational flexibility. Conformational analyses of
these dihydrodiazocinones by spectral, crystallographic, kinetic,
2484 J. Org. Chem., Vol. 71, No. 6, 2006

Diazocinones: Synthesis and Conformational Analysis
of CH2Cl2, cyclobutanol 10a (1.0 g, 2.7 mmol) was added dropwise
to the solution and stirred for 15 min, followed by the addition of
Et3N (1.87 mL, 13.5 mmol). The reaction was monitored by TLC
(50% EtOAc in hexanes) and quenched by the addition of water
after 20 min. The organic layer was diluted with CH2Cl2, and the
aqueous layer was washed once with 60 mL CH2Cl2. The organic
extracts were combined, dried (MgSO4), vacuum filtered, and
concentrated. The crude material was purified by column chroma-
tography (50% EtOAc in hexanes) to give the isoxazolylcyclobu-
tanone 3a (470 mg, 75%): mp 95-96 °C; IR 1783, 1442, 1290;
1H NMR δ 3.49-3.57 (d, 4H), 3.82 (m, 1H), 6.43 (s, 1H), 7.42 (d,
2H), 7.44 (t, 2H), 7.8, (t, 1H); 13C NMR δ 203.9, 174.21, 162.9,
130.4, 129.2, 126.9, 99.3, 53.7, 21.6.7
General Route to Dihydrodiazocinones: 3,8-Diphenyl-6-(3-
phenylisoxazol-5-yl)-6,7-dihydro-5H-[1,2]diazocin-4-one (1a).
Cyclobutanone 3a (0.1 g, 0.46 mmol) and tetrazine 2a (0.109 g,
0.46 mmol) were dissolved in THF. To this solution was added
KOH/MeOH (1.5 equiv), and the resulting mixture was stirred at
room temperature for 3 h. The workup consisted of a dilution with
ethyl acetate (40 mL) and washing sequentially with water (30 mL)
and brine (30 mL). The organic layer was dried over MgSO4 and
concentrated. The crude material was purified by column chroma-
tography (hexanes/ethyl acetate, 9:1) and recrystallized from MeOH
to give compound 1a (0.116, 62%): mp 125-126 °C; IR (neat)
1714, 1599, 1428, 1252 cm-1; 1H NMR δ 2.86-2.90 (dd, 1H, J )
5.3, 12.3 Hz), 3.05-3.11 (dd, 1H, J ) 10.4, 12.5 Hz), 3.17-3.23
(dd, 1H, J ) 10.9, 13.2 Hz), 3.28-3.35 (m, 1H), 3.46-3.51 (dd,
1H, J ) 2.56, 13.4 Hz), 6.37-6.38 (d, 1H, J ) 1 Hz), 7.44-7.46
(m, 9H), 7.66-7.71 (m, 4H), 7.87-7.89 (m, 2H); 13C NMR δ 203.8,
173.3, 162.9, 153.6, 150.4, 135.0, 131.4, 131.2, 130.8, 130.5, 129.4,
129.2, 129.0, 128.8, 127.5, 127.2, 127.0, 99.6, 45.2, 31.244, 31.1.
ESI MS (M + H) m/z calcd, 419.16; found, 420.08. Purity was
determined to be 95% by HPLC analysis on the basis of the
absorption at 220 nm.
FIGURE 6. X-ray crystal structure of the thermodynamic conformer
of 1a and, for comparison, the calculated structure of the model TBC-
eq.
and computational means allow us to confidently assign the
conformation TBC as the major contributor to the thermody-
namic isomer.
Experimental Section
5-(1-Benzenesulfonyl-3-hydroxycyclobutyl)-3-phenyl-4,5-di-
hydroisoxazole (10a). The allylcyclobutanol 9 (1.5 g, 6.25 mmol)
and benzaldehyde oxime (3.025 g, 25 mmol) were dissolved in
CH2Cl2 (60 mL) at 0 °C, and aqueous NaOCl (35 mL, 25 mmol,
5.25% of solution) was added dropwise with stirring at 6 drops/
sec. The solution was warmed to room temperature overnight, and
the organic layer was separated, dried (MgSO4), vacuum filtered,
and concentrated. The crude reaction mixture was recrystallized
from ethyl acetate and hexanes to yield 10a as a white powder
(1.4 g, 60% yield): mp 170-171 °C; IR (neat) 1445, 1302, 1245,
Acknowledgment. We thank the National Science Founda-
tion and the U.C.sDavis President’s Undergraduate Fellowship
(R.D.C.) for support of this work. M.J.H. thanks the American
University of Beirut for a paid research leave. The NMR
spectrometers used in this study were funded in part by grants
from NSF (CHE-9808183) and NIH (RR-11973).
1
1130, 1147; H NMR δ 2.58-2.64 (m, 2H), 2.76-2.83 (m, 2H),
3.42-3.45 (d, 2H, J ) 9.9 Hz), 4.37-4.41 (m, 1H), 4.64-4.68 (t,
1H, J ) 9.9 Hz), 7.38-7.44 (m, 4H), 7.60-7.65 (m, 2H), 7.71-
7.75 (m, 2H), 7.88-7.90 (dd, 2H, J ) 1.3, 8.4 Hz; d, 1H), 5.32 (d,
1H), 5.91 (m, 1H), 7.53 (m, 2H), 7.59 (t, 1H), 7.78 (d, 2H); 13C
NMR δ 136.1, 134.8, 130.8, 129.8, 129.7, 129.1, 128.8, 127.0, 62.1,
61.8, 38.4, 38.2, 33.6.7
Supporting Information Available: Detailed experimental
procedures for 2a-d, 3b, 9, 8a-d, and 10b, spectra for 1a-h, 3a,
and 10a (1H NMR, 13C NMR, and HPLC), crystallographic data
for 1a, and details of the electronic structure calculations. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
5-(3-Oxocyclobutyl)-3-phenylisoxazole (3a). Oxalyl chloride
(284 µL, 24 mmol) and DMSO (520 µL, 6.75 mmol) were dissolved
in CH2Cl2 (20 mL) with stirring at -78 °C for 40 min. In 10 mL
JO052577A
J. Org. Chem, Vol. 71, No. 6, 2006 2485