Thermal 1,3-Trityl migrations in diels-alder domino reactions of 1-Trityl-4-vinyl-1 H-imidazoles

Article abstract of DOI:10.1021/jo100416c

(Figure presented) Under thermal conditions, tritylimidazoles have been shown to undergo sterically driven N→N trityl migrations, in disagreement with previously published reports. These migrations are a key step in several highly diastereoselective domin

Full text of DOI:10.1021/jo100416c

pubs.acs.org/joc
the sponge Agelas coniferin)8 and cyclo-aplysinopsin A
Thermal 1,3-Trityl Migrations in Diels-Alder
Domino Reactions of 1-Trityl-4-vinyl-1H-imidazoles
(isolated from an unidentified dendrophylliid coral from
the Comoros islands).9 These compounds may arise via
head-to-head (ageliferin) or head-to-tail (cyclo-aplysinopsin
A) D-A reactions followed by rearomatization of the
heteroaromatic component (Figure 1).10
Lynsey J. Cotterill, Ross W. Harrington, William Clegg, and
Michael J. Hall*
School of Chemistry, Newcastle University, Newcastle upon
Tyne NE1 7RU, U.K.
m.hall@ncl.ac.uk
Received March 5, 2010
FIGURE 1. Ageliferin and cyclo-aplysinopsin A.
As part of an extensive investigation into the synthesis and
biosynthesis of ageliferin (and related oroidin alkaloids),
several research groups have examined the D-A reactions
of a range of 3- and 4-vinyl-substituted imidazoles,5 as well as
the D-A reactions of imidazolones.6
These reports not only provided a valuable insight into
alkaloid synthesis and biosynthesis but also contained dis-
cussion of a number of intriguing and unexpected bypro-
ducts arising from D-A initiated domino reactions.
Domino reactions are of increasing value in synthetic
chemistry as they can allow the regio- and stereoselective
construction of multiple C-C and C-X bonds in one
reaction vessel. This leads to both highly efficient synthesis
(through the minimization of isolation steps) and application
through rapid library generation for use in medicinal chemi-
stry and chemical biology.11
Under thermal conditions, tritylimidazoles have been
shown to undergo sterically driven NfN trityl migra-
tions, in disagreement with previously published reports.
These migrations are a key step in several highly diastereo-
selective domino reaction sequences (Diels-Alder, [1,3]-H
shift, [1,3]-trityl migration and Diels-Alder, [1,3]-H shift,
[1,3]-trityl migration, Michael reaction) leading to archi-
tecturally complex molecules.
Diels-Alder (D-A) and hetero-Diels-Alder (h-D-A)
reactions have long been used in both synthetic1 and bio-
synthetic2 approaches for the construction of complex natu-
ral product architectures. Within this field, vinyl-substituted
heteroaromatics have been utilized extensively as dienes in
inter- and intramolecular D-A and h-D-A reactions.3-7
D-A dimerization reactions of both vinylimidazoles and
vinylindoles have been implicated in the biosynthesis of a
number of marine alkaloids such as ageliferin (isolated from
(5) Selected vinylimidazole examples: (a) Lovely, C. J.; Du, H.; Rasika
Dias, H. V. Org. Lett. 2001, 3, 1319–1322. (b) Lovely, C. J.; Du, H.; Rasika
Dias, H. V. Heterocycles2003, 60, 1–7. (c) He, Y.; Chen, Y.; Wu, H.; Lovely, C.
J. Org. Lett. 2003, 5, 3623–3626. (d) Lovely, C. J.; Du, H.; He, Y.; Rasika Dias,
H. V. Org. Lett. 2004, 6, 735–738. (e) Du, H.; He, Y.; Sivappa, R.; Lovely, C. J.
Synlett 2006, 965–992. (f) Lovely, C. J.; Du, H.; Sivappa, R.; Bhandari, M. R.;
He, Y.; Rasika Dias, H. V. J. Org. Chem. 2007, 72, 3741–3749. (g) Sivappa, R.;
Mukherjee, S.; Rasika Dias, H. V.; Lovely, C. J. Org. Biomol. Chem. 2009, 7,
€
3215–3218. (h) Poverlein, C.; Breckle, G.; Lindel, T. Org. Lett. 2006, 8, 819–
821. (i) Hoffmann, H.; Lindel, T. Synthesis 2003, 12, 1753–1783.
(6) Selected vinylimidazolone examples: (a) Dilley, A. S.; Romo, D. Org.
Lett. 2001, 3, 1535–1538. (b) Poullennec, K.; Kelly, A. T.; Romo, D. Org.
Lett. 2002, 4, 2645–2648. (c) Poullennec, K.; Romo, D. J. Am. Chem. Soc.
2003, 125, 6344–6345. (d) Dransfield, P. J.; Wang, S.; Dilley, A.; Romo, D.
Org. Lett. 2005, 7, 1679–1682.
(7) Selected vinylpyrrole examples: (a) Xiao, D.; Ketcha, D. M. J.
Heterocycl. Chem. 1995, 32, 499–503. (b) Noland, W. E.; Lanzatella, N. P.
J. Heterocycl. Chem. 2009, 46, 1285–1295.
(1) Recent reviews: (a) Takao, K.; Munakata, R.; Tadano, K. Chem. Rev.
2005, 105, 4779–4807. (b) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698. (c)
Brocksom, T. J.; Nakamura, J.; Ferreira, M. L.; Brocksom, U. J. Braz.
Chem. Soc. 2001, 12, 597–622.
(2) Oikawa, H.; Tokiwano, T. Nat. Prod. Rep. 2004, 21, 321–352.
(3) Selected vinylindole examples: (a) Bleile, M.; Otto, H.-H. Monatsh.
Chem. 2005, 136, 1799–1809. (b) Le Strat, F.; Maddaluno, J. Org. Lett. 2002,
4, 2791–2793. (c) Kinsman, A. C.; Kerr, M. A. Org. Lett. 2001, 3, 3189–3191.
(d) Eitel, M.; Pindur, U. J. Org. Chem. 1990, 55, 5368–5374. (e) Eitel, M.;
Pindur, U. Heterocycles 1988, 27, 2353–2362. (f) Gonzalez, E.; Pindur, U.;
Schollmeyer, D. J. Chem. Soc., Perkin Trans. 1 1996, 1767–1771. (g) Grieco,
P. A.; Kaufman, M. D. J. Org. Chem. 1999, 64, 7586–7593. (h) Grieco, P. A.;
Kaufman, M. D. J. Org. Chem. 1994, 59, 7197–7198. (i) Ohno, M.; Shimizu,
S.; Eguchi, S. Tetrahedron Lett. 1990, 31, 4613–4616. (j) Joseph, B.; Da
(8) Rinehart, K. L. Pure Appl. Chem. 1989, 61, 525–528. Kobayashi, J.;
Tsuda, M.; Murayama, T.; Nakamura, H.; Ohizuma, Y.; Ishibashi, M.;
Iwamura, M.; Ohta, T.; Nozoe, S. Tetrahedron 1990, 46, 5579–5586.
Williams, D. H.; Faulkner, D. J. Tetrahedron 1996, 52, 5381–5390.
(9) Mancini, I.; Guella, G.; Zibrowius, H.; Pietra, F. Tetrahedron 2003,
59, 8757–8762.
(10) Note:ageliferinbiosynthesismayinvolveeither aD-Adimerizationor
a ringexpansion of the related compound sceptrin. (a) Mourabit, A. A.; Potier,
P. Eur. J. Org. Chem. 2001, 237–243. (b) O’Malley, D. P.; Li, K.; Maue, M.;
Zografos, A. L.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 4762–4775.
(11) Domino reactions: Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
Domino reactions for natural products and medicinal chemistry: Tietze,
L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304–322. Tietze, L. F.; Rackelmann,
N. Pure Appl. Chem. 2004, 76, 1967–1983.
ꢀ
ꢀ
Costa, H.; Merour, J.-Y.; Leonce, S. Tetrahedron 2000, 56, 3189–3196.
ꢀ
(4) Selected vinylpyrazole examples: (a) Sepulveda-Arques, J.; Medio-
Simon, M.; Piqueres-Vidal, L. Monatsh. Chem. 1989, 120, 1113–1118. (b)
ꢀ
ꢀ
Medio-Simon, M.; Sepulveda-Arques, J. S. Tetrahedron 1986, 42, 6683–6686.
ꢀ
4604 J. Org. Chem. 2010, 75, 4604–4607
Published on Web 06/09/2010
DOI: 10.1021/jo100416c
r
2010 American Chemical Society

Cotterill et al.
JOCNote
Thus inspired, we embarked upon an investigation of the
D-A reactions of 4-vinyl-1H-imidazoles with a view to
optimizing these reactions to selectively generate unusual
domino reaction products in high yields.
Rapid routes to 4-vinylimidazoles from urocanic acid were
based on the sterically controlled, selective trityl protection
of 3-/4-substituted imidazoles. 1-Trityl-4-vinyl-1H-imid-
azole (1) was accessed via a literature approach involving
thermal decarboxylation of urocanic acid and subsequent
trityl protection of the 1 position (confirmation of the
regiochemistry of 1 was achieved by single-crystal X-ray
analysis, see the Supporting Information).12,13
the newly formed 1-phenylpyrrolidine-2,5-dione ring by the
trityl group, whereas in 4 the trityl group has migrated to give
what appears to be a much less crowded molecule.
In an attempt to rationalize this migration event, struc-
tures 3 and 4 were modeled using a HF/3-21G* level of
theory calculation, performed with Spartan.14 The calcula-
tion showed that 4 is the thermodynamic product, being
approximately 19 kJ mol-1 more stable than 3 (Figure 2).
Lovely et al. have previously reported the thermal D-A
reaction of 1-trityl-4-vinyl-1H-imidazole (1) with N-phenyl-
maleimide (NPM).5a,e,f However, when we re-examined this
reaction, under reaction conditions similar to those reported
(heating in toluene or CHCl3), we discovered that the reac-
tion resulted in the formation of the expected D-A product 2
but only trace quantities of the rearomatized compound 3. In
addition, after prolonged reaction times we observed an
unexpected NfN trityl migrated product 4 in moderate
yield (Table 1).
FIGURE 2. Hartree-Fock optimized structures for regioisomers 3
and 4.
We hypothesized that the observed trityl migration might
arise through addition of an electrophile/proton to the imid-
azole N lone pair of 3, generating an imidazolium cation.
Loss of a trityl cation followed by trapping by another mole-
cule of 3 would result in a ditritylated imidazolium cation of
3, which can in turn lose the most sterically hindered trityl to
give 4 and propagate the reaction.
TABLE 1. Reaction of 1 with NPMa
To explore this proposal, isolated 3 was heated to 45 °C in
CDCl3 and the reaction monitored by 1H NMR. Clean
conversion to 4 was observed after 14 h, along with the forma-
tion of protonated 4 arising from adventitious HCl. How-
ever, removal of HCl, via a K2CO3(aq) wash of the reaction
solvent, resulted in a considerable reduction in reaction rate.
NfC migrations in imidazole systems have previously been
reported under flash vacuum pyrolysis conditions through
concerted [1,5]-sigmatropic rearrangements of alkyl groups,
from the N-1 to the C-5 position.15 Under more standard
reaction conditions, the NfN migrations of Bn, SEM, and
MOM groups have recently been reported to occur with the
addition of catalytic BnCl, SEMCl, or MOMCl, respectively, to
give the least sterically hindered thermodynamic products.16
However, this manuscript is, to our knowledge, the first report
of trityl NfN migration under mild thermal conditions.
A common motif in the D-A chemistry of vinyl imida-
zoles involves the inclusion of a heteroatom-(N- or O-)-
substituted methylene group at the vinyl terminus. These
substrates have been examined in synthetic approaches to
both ageliferin and several other related oroidin alkaloids.5i
Thus, we decided to synthesize 4-((E)-3-((tert-butyl)dimethyl-
silyl)oxyprop-1-enyl)-1-trityl-1H-imidazole (6) to examine its
potential for domino reactions under our conditions. Compound
solvent
temp/°C
time/h
yield of 2b/%
yield of 4b/%
toluene
toluene
toluene
CHCl3
CHCl3
110
110
110
61
1
3
5
16
24
35
78
32
6
51
28
25
61
aReaction conditions: 2.5 equiv of N-phenylmaleimide. bIsolated
yields.
Confirmation of the structures of 3 and 4 was obtained
through single-crystal X-ray analysis of the isolated com-
pounds (see the Supporting Information). Unfortunately, all
attempts to grow X-ray quality crystals of 2 only resulted in
isolation of the rearomatized material 3.13
On comparison with reported spectral data, we believe
that the major compound 4 has been previously misassigned,
due to the NfN trityl migration which has occurred. Thus,
our spectral data for 4 matches data that have been erro-
neously attributed to a compound with structure 3.5a,e,f
We submit that compound 1 undergoes a D-A reaction to
give 2, followed by a [1,3]-H migration to give 3. Examination
of the X-ray structure of 3 shows significant steric crowding of
(14) Spartan 006 for Windows. Wavefunction, Inc.: Irvine, CA, 2006.
(15) NfC migrations: Begg, C. G.; Grimmett, M. R.; Wethey, P. D.
Aust. J. Chem. 1973, 26, 2435–2446. Maquestiau, A.; Tommasetti, A.;
Pedregal-Freire, C.; Elguero, J.; Flammang, R.; Wiersum, U. E.; Bender,
H.; Wentrup, C. J. Org. Chem. 1986, 51, 306–309. Mitsuhashi, K.; Itho, E.-I.;
Kawahara, T.; Tanaka, K. J. Heterocycl. Chem. 1983, 20, 1103–1105. N f C
migrations of trityl: Giesemann, H.; Lettau, H.; Mannsfeldt, H.-G. Chem.
Ber. 1960, 93, 570–576.
(16) NfN migrations: Kuroda, T.; Suzuki, F. Tetrahedron Lett. 1992, 33,
2027–2028. Moores, I. G.; Scriven, E. F. V.; Smalley, R. K.; Suschitzky, H. J.
Fluorine Chem. 1988, 41, 277–288. He, Y.; Chen, Y.; Du, H.; Schmid, L. A.;
Lovely, C. J. Tetrahedron Lett. 2004, 45, 5529–5532. Lovely, C. J.; Sivappa,
R.; Mukherjee, S.; Doundoulakis, T.; Lima, H. M.; Yousufuddin, M.
Heterocycles 2010, 80, 1353–1358.
ꢀ
(12) Synthesis of 4-vinyltritylimidazole: Faler, C. A.; Joullie, M. M. Org.
Lett. 2007, 9, 1987–1990. Based on the original procedures: Overberger,
C. G.; Glowaky, R. C.; Pacansky, T. J.; Sannes, K. N. Macromol. Synth.
1974, 5, 43–49. Burger, A.; Yost, W. L. J. Am. Chem. Soc. 1948, 70, 2198–
2201. Data in agreement with: Kokosa, J. M.; Szafasz, R. A.; Tagupa, E.
J. Org. Chem. 1983, 48, 3605–3607.
(13) The crystallographic coordinates of 1, 3, 4, 7, and 8 have been
deposited with the Cambridge Crystallographic Data Centre, deposition
nos. CCDC 768425, 768426, 768427, 768428, and 768429, respectively. These
data can be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.
html (or from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: (þ44) 1223-336-033; or deposit@
ccdc.cam.ac.uk).
J. Org. Chem. Vol. 75, No. 13, 2010 4605

Cotterill et al.
JOCNote
6 was synthesized via methylation of urocanic acid (5), selective
tritylation of the 1 position, DIBAL-H reduction to the
primary alcohol, and TBS protection (Scheme 1).17
We have demonstrated a number of novel domino reac-
tion routes for the rapid formation of complex molecules.
For example, the formation of 8 generates four contiguous
stereocenters, including a quaternary center, three new C-C
bonds, and one C-N bond. Thus, this sets the scene for the
construction of natural product scaffold libraries with po-
tential medicinal chemistry application. We have also shown
a facile, thermal NfN migration of trityl-protected imid-
azole systems to give the least sterically hindered thermo-
dynamic product. The NfN trityl-migration is difficult to
observe by NMR, our efforts to use NOESY and ROESY
experiments to track the location of the trityl group proved
inconclusive, thus X-ray crystallography has played a key
role in this study. The observation of NfN trityl migrations
has important implications on account of the extensive use of
trityl and trityl-derived groups in imidazole-based medicinal
compounds, such as the antifungal agents clotrimazole,
fluotrimazole, and bifonazole, as well as in the field of
synthetic chemistry.
SCHEME 1. Synthesis of 6a
aReaction conditions: (i) MeOH, SOCl2, reflux, 16 h (81%); (ii) TrCl,
Et3N, THF, rt, 16 h (97%); (iii) 3 equiv of DIBAL-H, DCM, -78 °C, 1 h
(67%); (iv) TBSCl, imidazole, DCM, 16 h (68%).
Under standard conditions, 6 reacts with NPM to give 7,
arising from an endo-D-A, [1,3]-H migration, [1,3]-Tr mi-
gration domino reaction sequence. However, with extended
reaction times an additional compound 8 was also observed
(Table 2). Again, confirmation of the structures of 7 and 8
was obtained through single-crystal X-ray analysis of the
isolated compounds (see the Supporting Information).13
Ongoing work in our group is aimed at optimizing and
extending these domino reaction pathways to develop new,
efficient routes to highly complex, natural product-inspired
substrates.
TABLE 2. Reaction of 6 with N-Phenylmaleimidea
Experimental Section
(()-(5aS,8aS)-7-Phenyl-1-trityl-5,5a,7,8b-tetrahydroimidazo-
[4,5-e]isoindole-6,8(7H,8aH)-dione (2). To 1-trityl-4-vinyl-1H-
imidazole (1) (264 mg, 0.52 mmol) in toluene (10 mL) was added
N-phenylmaleimide (224 mg, 1.30 mmol) and the solution
stirred at reflux for 3 h. The solvent was removed, and the crude
residue was chromatographed on silica gel (ethyl acetate-
petroleum ether 40/60, 40:60) to yield the title compound
as a white solid, 207 mg (78%): Rf 0.42 (UV active, ethyl
acetate-petroleum ether 40/60, 40:60); mp 208-211 °C; 1H
NMR (300 MHz, CDCl3) δH 7.55-7.51 (6H, m), 7.47-7.34
(13H, m), 7.13 (2H, dd, J = 7.0, 1.6 Hz), 5.65 (1H, ddd, J = 5.4,
3.8, 3.8 Hz), 4.37 (1H, ddd, J = 6.0, 3.1, 3.1 Hz), 2.98 (1H, ddd,
J = 15.4, 7.8, 1.1 Hz), 2.77 (1H, ddd, J = 8.2, 8.1, 0.7 Hz), 2.00
(2H, m); 13C NMR (101 MHz, CDCl3) δC 178.0, 174.0, 162.2,
155.5, 142.2, 131.6, 130.4, 129.1, 128.7, 128.1, 127.7, 126.6,
102.2, 75.0, 58.9, 42.0, 36.8, 26.3; IR 2362, 1709, 1381, 1160,
750, 701; HRMS calcd for C34H27N3O2 (M þ Na)þ 532.1995,
found 532.2007.
solvent
temp/°C
time/h
yield of 7b/%
yield of 8b/%
toluene
toluene
110
110
16
72
63
10
9
57
aReaction conditions: 2.5 equiv of N-phenylmaleimide. bIsolated
yields.
Unlike other reported 2:1 adducts, compound 8 did not
arise through intermolecular ene reactions with additional
NPM but instead through a previously unobserved Michael
addition of the enol form of 7 to an NPM unit. We have
demonstrated that compound 8 may be formed through such
a Michael addition. Purified 7 was dissolved in CDCl3,
treated with 1 equiv of NaH, and quenched with D2O. This
led to selective deuteration of the tertiary carbon R to the
imidazole ring. Thus, deprotonation of 7, with NaH fol-
lowed by addition of NPM, gave compound 8 in 61%
isolated yield (Scheme 2).
(()-(5aS,8aS)-5,5a-Dihydro-7-phenyl-1-tritylimidazo[4,5-e]-
isoindole-6,8(1H,4H,7H,8aH)-dione (3). To 1-trityl-4-vinyl-1H-
imidazole (1) (1.0 g, 2.97 mmol) in toluene (37 mL) was added
N-phenylmaleimide (1.29 g, 7.43 mmol) and the solution stirred
at reflux for 3 h. The reaction mixture was concentrated to a low
volume and cooled. The resulting colorless crystals were filtered,
yielding the title compound, 80 mg (5%): Rf 0.29 (UV active,
SCHEME 2. Formation of 8 from 7 via Michael Additiona
1
methanol-diethyl ether, 2:98); mp 190 °C dec; H NMR (400
MHz, DMSO-d6) δH 7.43-7.30 (12H, m), 7.29 (1H, s),
7.17-7.14 (6H, m), 7.09-7.07 (2H, m), 2.56 (1H, ddd, J =
19.2, 4.8, 4.8 Hz), 2.37 (1H, ddd, J = 19.7, 14.6, 5.4 Hz), 2.13
(1H, ddd, J = 12.0, 8.2, 4.2 Hz), 1.53-1.44 (2H, m); 13C NMR,
(101 MHz, CDCl3) δC 177.7, 173.7, 142.4, 142.2, 142.0, 141.8,
141.0, 130.8, 129.1, 128.5, 128.2, 127.9, 126.4, 77.3, 42.4, 40.8,
24.9, 23.0; IR 2970, 2360, 1716, 1379, 1174, 823, 751, 703;
HRMS calcd for C34H27N3O2 (M þ Na)þ 532.1995, found
532.2006. Anal. Calcd for C34H27N3O2: C, 80.13; H, 5.34; N,
8.25. Found: C, 80.00; H, 5.26; N, 8.20.
aReaction conditions: NaH, toluene, rt, 1 h, then NPM, reflux 6 h (61%).
(17) Dolensky, B.; Kirk, K. L. J. Org. Chem. 2002, 67, 3468–3473.
Pirrung, M. C.; Pei, T. J. Org. Chem. 2000, 65, 2229–2230. Kosaka, K.;
Maruyama, K.; Nakamura, H.; Ikeda, M. J. Heterocycl. Chem. 1991, 28,
1941–1944. Uenishi, J.; Motoyama, M.; Takahashi, K. Tetrahedron: Asym-
metry 1994, 5, 101–110.
(()-(5aS,8aS)-5,5a-Dihydro-7-phenyl-3-tritylimidazo[4,5-e]-
isoindole-6,8(3H,4H,7H,8aH)-dione (4). To 1-trityl-4-vinyl-1H-
imidazole (1) (500 mg, 0.98 mmol) in toluene (18.5 mL) was
added N-phenylmaleimide (425 mg, 2.45 mmol) and the solution
4606 J. Org. Chem. Vol. 75, No. 13, 2010

Cotterill et al.
JOCNote
stirred at reflux for 5 h. The solvent was removed, and the crude
residue was chromatographed on silica gel (ethyl acetate-
petroleum ether 40/60, 60:40) to yield the title compound as a
white solid, 240 mg (32%): Rf 0.10 (UV active, methanol-
diethyl ether, 2:98); mp >232 °C dec; 1H NMR (400 MHz,
CDCl3) δH 7.40-7.35 (2H, m), 7.31 (1H, s), 7.27-7.23 (10H, m),
7.15-7.12 (2H, m), 7.05-7.02 (6H, m), 4.21 (1H, d, J = 10.4
Hz), 3.31 (1H, ddd, J = 10.4, 6.0, 6.0 Hz), 2.12-2.06 (1H, m),
1.72 (1H, ddd, J = 19.8, 5.3, 4.8 Hz), 1.67-1.59 (1H, m), 1.43
(1H, ddd, J = 19.6, 12.7, 5.3 Hz); 13C NMR (101 MHz, CDCl3)
Supporting Information for an alternative procedure from 7.) To
1-trityl-4-((E)-3-(tert-butyldimethylsilyloxy)prop-1-enyl)-1H-imi-
dazole (6) (430 mg, 0.9 mmol) in toluene (20 mL) was added
N-phenylmaleimide (387 mg, 2.2 mmol) and the solution stirred at
reflux for 72 h. The solvent was removed, and the crude residue
was chromatographed on silica gel (ethyl acetate-petroleum ether
40/60, 5% increasing to 60%) to yield the title compound as a
brown solid, 420 mg (57%), and a minor amount of 7, as a yellow
solid, 59 mg (10%): Rf 0.68 (UV active, ethyl acetate-petroleum
ether 40/60, 35:65); mp 185-188 °C; 1H NMR, (400 MHz,
CDCl3) δH 7.39 (6H, ddd, J = 9.6, 8.9, 1.6 Hz), 7.34-7.33 (1H,
m), 7.31-7.30 (5H, m), 7.29-7.27 (3H, m), 7.26-7.23 (3H, m),
7.16-7.14 (2H, m), 7.04 (6H, ddd, J = 4.4, 1.6, 1.6 Hz), 4.83 (1H,
dd, J = 12.1, 8.9 Hz), 3.93 (1H, dd, J = 12.9, 7.9 Hz), 3.58 (1H, dd,
J = 12.6, 9.9 Hz), 3.22 (1H, d, J = 5.1 Hz), 3.11 (1H, dd, J = 23.0,
12.2 Hz,), 2.79 (1H, dd, J = 23.0, 8.9 Hz), 2.13 (1H, dd, J = 20.3,
4.3 Hz), 2.03-1.95 (1H, m), 1.10 (1H, dd, J = 20.3, 15.1 Hz), 0.66
(9H, s), -0.14 and -0.21 (3H, s); 13C NMR (101 MHz, CDCl3) δC
176.4, 175.3, 174.5, 174.5, 141.2, 139.9, 133.5, 132.0, 131.5, 131.0,
129.7, 129.3, 129.1, 128.9, 128.7, 128.5, 128.3, 126.8, 126.4, 75.3,
63.9, 49.3, 44.8, 44.2, 40.6, 32.0, 25.9, 24.1, 18.2, -5.3 and -5.4; IR
2325, 1781, 1711, 1498, 1378, 1185, 1089, 837, 747, 700; HRMS
calcd for C51H50N4O5Si (M þ Na)þ 849.3443, found 849.3450.
δ
C 177.6, 174.8, 141.5, 139.1, 132.1, 131.6, 129.9, 129.4, 129.1,
128.5, 128.3, 128.2, 126.5, 75.1, 41.5, 40.3, 22.6, 21.0; IR 2962,
2360, 1712, 1380, 1177, 701; HRMS calcd for C34H27N3O2 (M þ
Na)þ 532.1995, found 532.2003. Anal. Calcd for C34H27N3O2:
C, 80.13; H, 5.34; N, 8.25. Found: C, 79.96; H, 5.33; N, 8.15.
(()-(5S,5aS,8aS)-5-((tert-Butyldimethylsilyloxy)methyl)-7-
phenyl-3-trityl-5,5a,7,8-tetrahydroimidazo[4,5-e]isoindole-6,8-
(3H,4H)-dione (7). To 1-trityl-4-((E)-3-(tert-butyldimethylsilyl-
oxy)prop-1-enyl)-1H-imidazole (6) (600 mg, 1.2 mmol) in toluene
(28 mL) was added N-phenylmaleimide (520 mg, 3.0 mmol) and
the solution stirred at reflux for 20 h. The solvent was removed, and
the crude residue was chromatographed on silica gel (ethyl acetate-
petroleum ether 40/60, 60:40) to yield the title compound as a pale
yellow solid, 496 mg (63%): Rf 0.48 (UV active, ethyl acetate-
1
petroleum ether 40/60, 80:20); mp 119-121 °C; H NMR (400
Acknowledgment. The authors would like to thank
Newcastle University and the EPSRC for PhD funding
(L.J.C.), EPSRC (EP/F03637X/1) for X-ray crystallography
facilities, the EPSRC National Mass Spectrometry Service
(University of Swansea), Prof. William McFarlane and
Dr. Corinne Wills (Newcastle) for NMR studies, and Beverly
Stewart (Newcastle) for computational studies.
MHz, CDCl3) δH 7.42 (2H, ddd, J= 9.6, 9.6, 0.7 Hz), 7.35 (2H, dd,
J= 9.3, 0.7 Hz), 7.30-7.27 (9H, m), 7.12 (2H, dd, J= 9.4, 2.2 Hz),
7.09-7.07 (6H, m), 4.27 (1H, d, J = 9.6 Hz), 3.93 (1H, dd, J =
12.5, 7.8 Hz), 3.65 (1H, dd, J= 12.4, 9.9 Hz), 3.50 (1H, dd, J=9.8,
4.8 Hz), 2.12-2.08 (2H, m), 1.10 (1H, ddd, J = 18.0, 16.0, 1.0 Hz),
0.72 (9H, s), -0.09, -0.17 (3H, s); 13C NMR (101 MHz, CDCl3)
δC 176.1, 174.5, 141.2, 139.1, 132.2, 131.9, 129.7, 129.3, 129.0,
128.4, 128.2, 128.1, 126.4, 75.0, 64.1, 42.8, 41.4, 38.9, 25.8, 23.8, 18.,
-5.5, -5.6; IR 2925, 2316, 1710, 1384, 1085, 700; HRMS calcd for
C41H43N3O3Si (M þ H)þ 654.3146, found 654.3145. Anal. Calcd
for C41H43N3O3Si: C, 75.31; H, 6.63; N, 6.43. Found: C, 75.21;
H, 6.57; N, 6.37.
Supporting Information Available:
Experimental proce-
dures for the synthesis of 1 and 6. 1H, 13C spectra for compounds
1-4 and 6-8. Crystallographic information files (CIFs) for
compounds 1, 3, 4, 7, and 8. Experimental details, optimized
atomic coordinates, and final energies for Hartree-Fock model
of 3 and 4. This material is available free of charge via the
Internet at http://pubs.acs.org.
(()-((5S,5aS,8aS)-5-((tert-Butyldimethylsilyloxy)methyl)-8a-
((R)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-7-phenyl-3-trityl-5,5a,7,
8a-tetrahydroimidazo[4,5-e]isoindole-6,8(3H,4H)-dione (8). (See the
J. Org. Chem. Vol. 75, No. 13, 2010 4607