On the [3 + 2] annulation of cyclic allylsilanes with N -phenyltriazolinedione: An enantio- and diastereoselective synthesis of cis -1,3-diaminocyclitols

Article abstract of DOI:10.1021/jo100724w

(Figure presented) Improved conditions were found to trigger [3 + 2] annulation of cyclic allylsilanes with N-phenyltriazolinedione (PTAD); the products from this reaction were readily tailored into cis-1,3-diaminocyclitols in highly enantioenriched form with full stereochemical control of up to four contiguous stereogenic centers.

Full text of DOI:10.1021/jo100724w

pubs.acs.org/joc
On the [3 þ 2] Annulation of Cyclic Allylsilanes with
N-Phenyltriazolinedione: An Enantio- and Diastereoselective Synthesis
of cis-1,3-Diaminocyclitols
Raudra T. Dey and Tarun K. Sarkar*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
tksr@chem.iitkgp.ernet.in
Received April 14, 2010
Improved conditions were found to trigger [3 þ 2] annulation of cyclic allylsilanes with N-phenyl-
triazolinedione (PTAD); the products from this reaction were readily tailored into cis-1,3-diaminocyclitols
in highly enantioenriched form with full stereochemical control of up to four contiguous stereogenic centers.
Introduction
Aminocyclitols represent a wide class of compounds with
an attractive range of biological properties.1,2 Several dia-
minocyclitols have been synthesized and reported to possess
strong antibiotic activity.3 These include the natural strepta-
mine (1) and 2-deoxystreptamine (2), which feature a 1,3-
arrangement of their amino groups (Figure 1). Moreover,
there are applications of these compounds as substrates for
mutasynthesis of new antibiotics4 and as ligands in cytosta-
tically active PtII-complexes.5 In recent years, chemists from
far-flung laboratories have also reported preparation of cis-1,3-
diaminocyclopentitols, e.g., 36,7 and trans-1,2-diaminocyclitols,
FIGURE 1. Some natural and non-natural diaminocyclitols.
e.g., 48 and 5.8 Incidentally, over the years, the natural trans-1,4-
diaminocyclitol sporamine (6)9 has received intense interest from
synthetic and medicinal chemists alike. Clearly, development of new
and general synthetic strategies to these families of diaminocyclitols
constitutes an important objective to allow a broader investigation
of the utility of such compounds in biology and medicine.
(1) (a) Chapleur, Y. Carbohydrate Mimics; Wiley-VCH: Weinheim, 1998.
(b) Mahmud, T. Nat. Prod. Rep. 2003, 20, 137–166.
(2) For some recent work, see: (a) Mehta, G.; Lakshminath, S.; Talukdar,
P. Tetrahedron Lett. 2002, 43, 335–338. (b) Alegret, C.; Benet-Buchholz, J.;
Riera, A. Org. Lett. 2006, 8, 3069–3072. (c) Serrano, P.; Casas, J.; Zucco, M.;
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Emeric, G.; Egido-Gabas, M.; Llebaria, A.; Delgado, A. J. Comb. Chem.
2007, 9, 43–52. (d) Pandey, G.; Tiwari, K. N.; Puranik, V. G. Org. Lett. 2008,
10, 3611–3614.
In this paper, we report a novel route that provides access
to both diaminocyclohexitols and diaminocyclopentitols in a
highly enantio- and diastereocontrolled fashion. Our strategy
to these species hinges on an efficient [3 þ 2] annulation10-12 of
(3) (a) Sakairi, N.; Hayashida, M.; Amano, A.; Kuzuhara, H. J. Chem. Soc.,
Perkin Trans.1 1990, 1301–1313. (b) Schurrle, K.; Beier, B.; Piepersberg, W. J.
Chem. Soc., Perkin Trans.1 1991, 2407–2412.
(4) (a) Distler, J.; Klier, K.; Piendl, W.; Werbitzky, O.; Bock, A.; Kresze,
G.; Piepersberg, W. FEMS Microbiol. Lett. 1985, 30, 145–150. (b) Sepulchre,
A. M.; Quiclet, B.; Gero, S. D. Bull. Soc. Chim. Fr. 1980, 1-2, 56–65.
(c) Rinehart, K. L., Jr. Pure Appl. Chem. 1977, 49, 1361–1384.
(5) Suami, T.; Shiio, T., Jap. Patent 61,286,396; Appl. 85/127 551, 12 June
1985; Chem. Abstr., 1986, 107, 191010p.
(9) Knapp, S.; Patel, D. V. J. Am. Chem. Soc. 1983, 105, 6985–6986.
(10) For some early and pioneering work on [3 þ 2] annulation of
allylsilanes, see: (a) Colvin, E. W.; Monteith, M. J. Chem. Soc., Chem. Commun.
(6) Bournaud, C.; Bonin, M.; Micouin, L. Org. Lett. 2006, 8, 3041–3043.
ꢀ
(7) (a) Perez Luna, A.; Ceschi, M.-A.; Bonin, M.; Micouin, L.; Husson,
H.-P.; Gougeon, S.; Estenne-Bouhtou, G.; Marabout, B.; Sevrin, M.;
€
1990, 1230–1232. (b) Knolker, H.-J.; Jones, P. G.; Pannek, J.-B. Synlett 1990,
429–430. (c) Danheiser, R. L.; Dixon, B. R.; Gleason, R. W. J. Org. Chem. 1992,
€
57, 6094–6097. (d) Knolker, H.-J.; Foitzik, N.; Graf, R.; Goesmann, H. Angew.
George, P. J. Org. Chem. 2002, 67, 3522–3524. (b) Bournaud, C.; Chung,
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F.; Perez Luna, A.; Pasco, M.; Errasti, G.; Lecourt, T.; Micouin, L. Synthesis
2009, 869–887.
(8) Cong, X.; Liao, Q.-J.; Yao, Z.-J. J. Org. Chem. 2004, 69, 5314–5321.
€
Chem., Int. Ed. 1993, 32, 1081–1083. (e) Knolker, H.-J.; Graf, R. Tetrahedron
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Lett. 1993, 34, 4765–4768. (f) Knolker, H.-J.; Foitzik, N.; Graf, R.; Pannek,
J.-B.; Jones, P. G. Tetrahedron 1993, 49, 9955–9972.
DOI: 10.1021/jo100724w
r
Published on Web 06/03/2010
J. Org. Chem. 2010, 75, 4521–4529 4521
2010 American Chemical Society

Dey and Sarkar
JOCArticle
SCHEME 1. Strategy for the Synthesis of cis-1,3-Diamino-
cyclitols
TABLE 1. Reactivity Profile of Cyclic Allylsilanes with PTAD
[3 þ 2] adduct 14a
H-ene 15a
(%)
M-ene 16a
(%)
allylsilane 13
(%)
13a, R=R0=Et
13b, R=R0=Ph
13c,R=Me, R0=Ph
25
10
46
70
90
31
5
0b
23c
aBy NMR spectroscopy. bThis reaction was run in CHCl3. c2.5 equiv
of PTAD was used.
SCHEME 2. [3 þ 2] Annulation of Acyclic Allylsilanes with
PTAD
enantioenriched cyclic allylsilanes 7 with N-phenyltriazo-
linedione (PTAD) leading to the cycloadducts 8,13 which
after saponification followed by oxidation would produce
the diazene 9. Further elaboration including reductive ring-
opening of the diazene intermediates 9, protection of the result-
ing diamine, and ultimately Tamao-Fleming oxidation gives
access to various diaminocyclitols 10 in protected form (route 1,
Scheme 1). Alternatively, Tamao-Fleming oxidation of the
[3 þ 2] adducts would produce the diols 11 (route 2, Scheme 1),
which can be converted to the corresponding diazenes via
saponification and oxidation. Finally, reductive ring-opening
of the diazenes would produce the free diaminocyclitols 12.
annulation product drops to a meagre 10%.15 Our own
independent studies with allylsilane 13c showed that a higher
yield of the [3 þ 2] adduct (46%) is possible only when an
excess (2.5 equiv) of PTAD is used in the reaction, but even
here significant amounts of H-ene (31%) and M-ene (23%)
products accompany the annulation product. Second, in
bridged ring compounds where the silyl group is positioned
next to the bridgehead carbon as in 14 Tamao oxidation is
usually fraught with difficulties.16
Results and Discussion
To address both these issues, we decided to replace the
phenyl group (Φ = Ph) in 7 by an electron-rich o-methoxy-
phenyl group on the premise that the latter group may facilitate
both the Tamao oxidation17 as well as the [3 þ 2] annulation.
This prognosis turned out to be correct. Indeed, a preliminary
investigation of simple acyclic allylsilane 17b bearing an
o-methoxyphenyl ligand with PTAD provided promising re-
sults. Thus, while the reaction of allyldimethylphenylsilane
(17a) with PTAD gave the urazole 18a with a maximum yield
of 20%,11b the reaction of 17b with PTAD under identical
conditions increased the yield of 18b to 50% (Scheme 2). Even
better results were obtained with cyclic allylsilanes. As shown in
Table 2 the cyclic allylsilane 20a18 gave exclusively the [3 þ 2]
adduct 21a (55%), and no traces of either the H-ene and/or the
M-ene products could be detected in the crude reaction product
by 1H NMR. The reason as to why the reaction works well with
systems bearing an o-methoxyphenylsilyl group is probably the
increased electron density around silicon, which increases its
migratory aptitude. This new finding is interesting given that
in all previous studies on [3 þ 2] annulation of allylsilanes in-
creased steric hindrance around silicon was used as the key to
At the outset, we surmised that there could be two issues
with the feasibility of the projected route as outlined in
Scheme 1. First, the [3 þ 2] annulation reaction of cyclic
allylsilane 13 to 14 could be plagued by the accompanying
side products, e.g., the H-ene product 15 and/or the metalla
(M)-ene product 16 (Table 1). Indeed, as shown by Davies
et al., the reaction of allylsilane 13a with PTAD yields the
annulation product as the minor component (25%) in a
mixture containing both the H-ene (70%) and the M-ene
products (5%).14 Furthermore, change of ligands in the reac-
tion can have a deleterious effect on the yield of the [3 þ 2]
adduct. For example, with allylsilane 13b the yield of the
(11) For some recent work on [3 þ 2] annulation of allylsilanes, see:
(a) Romero, A.; Woerpel, K. A. Org. Lett. 2006, 8, 2127–2130. (b) Dey, R. T.;
Haque, Sk. A.; Hazra, A.; Basak, S.; Sarkar, T. K. Tetrahedron Lett. 2007,
€
48, 6671–6673. (c) Schmidt, A. W.; Olpp, T.; Baum, E.; Stiffel, T.; Knolker,
H.-J. Synlett 2007, 2371–2374. (d) Huh, C. W.; Roush, W. R. Org. Lett. 2008,
10, 3371–3374. (e) Orac, M. C.; Bergmeier, S. C. Tetrahedron Lett. 2009, 50,
€
1261–1263. (f) Schmidt, A. W.; Olpp, T.; Schmid, S.; Jager, A.; Knolker,
€
H.-J. Tetrahedron 2009, 65, 5484–5490.
(12) For reviews on annulation reactions of allylsilanes, see: (a) Masse,
C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293–1316. (b) Fleming, I.; Barbero,
€
A.; Walter, D. Chem. Rev. 1997, 97, 2063–2192. (c) Knolker, H.-J. J. Prakt.
Chem. 1997, 339, 304–314. (d) Chabaud, L.; James, P; Landais, Y. Eur. J.
Org. Chem. 2004, 3173–3199.
(13) The configuration of the silyl group is based on our previous
(16) (a) Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem., Int.
Ed. 2000, 39, 4073–4075. (b) Clive, J. L. D.; Cheng, H.; Gangopadhyay, P.;
Huang, X.; Prabhudas, B. Tetrahedron 2004, 60, 4205–4221.
investigation in a related area.11b
(14) Dang, H.-S.; Davies, A. G. J. Chem. Soc., Perkin Trans. 2 1991,
2011–2020.
(15) Cai, J.; Davies, A. G. J. Chem. Soc., Perkin Trans. 2 1992, 1743–1746.
(17) Lee, W. T.; Corey, E. J. Org. Lett. 2001, 3, 3337–3339.
(18) 20a was prepared from cyclohexene by exposure to Schlosser’s base
followed by treatment of the resulting species with ClMe2SiC6H4-o-OMe.
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TABLE 2. [3 þ 2] Annulation of Cyclic Allylsilanes with PTADa
annulation product 21b in high yield showing a clean chirality
transfer. Once again, no H-ene or M-ene product accompanied
the [3 þ 2] annulation product 21b. We then found that with
oxygenated cyclic allylsilanes 20c,20 20d,20 and 20e19 [3 þ 2]
annulation products 21c-e could still be made in high yield, and
the presence of the o-methoxyphenyl ligand on silicon was not
an absolute necessity. While no traces of any H-ene/M-ene
product formed from 20b, little (13%) H-ene product accom-
panied the annulation product from 20c. Incorporation of the
o-methoxyphenyl ligand on silicon in the 5-membered cyclic
β-hydroxyallylsilanes resulted in slight increase in the yields of the
[3 þ 2] adducts as shown by 20f and 20g, which gave 21f (70%)
and 21g (72%), respectively . Again, complete chirality transfer
was shown to take place in the conversion of enantiomerically
enriched allylsilanes 20e, 20f, and 20g to 21e, 21f, and 21g,
respectively.
The beneficial effect of the hydroxy substituent in these
cases is interesting and is in marked contrast to the results ob-
tained by Roberson and Woerpel21 in the [3 þ 2] annulation
of cyclic β-alkoxyallylsilanes with chlorosulfonyl isocyanate
where a deleterious effect of the alkoxy substituent was
noted. However, at present, it is difficult to provide a clear
rationale for the beneficial effect of the hydroxy substituent
in our case. Interestingly, in the case of six-membered cyclic
β-hydroxyallylsilanes, the relative configuration of the hy-
droxy group with respect to the silyl substituent plays a
decisive role in the reaction with PTAD. For example, while
the anti-β-hydroxyallylsilane 20c gives the [3 þ 2] adduct 21c
in high yield, the corresponding syn-isomer 20i19 followed a
completely uncharted pathway thereby giving the R,β-unsaturated
ketone 23 as the only product of the reaction with PTAD
(Scheme 4). We believe that in this case PTAD abstracts the
quasi-axial hydrogen on the carbon carrying the hydroxy
group to give a carbocation 24 stabilized by β-effect of the
neighboring silyl group. Loss of proton gives the R-silyl
ketone 25, which then undergoes H-ene reaction with an-
other molecule of PTAD to give the product 23. On the basis
of this rationale, it is clear why allylsilanes 20e and 20g were
immune to the alternative reaction pathway (Scheme 4) and
instead gave the annulation products 21e and 21g, respec-
tively. Obviously, here the geometry of the ring system
precludes proton abstraction as the hydrogen and the silyl
group are not disposed trans-diaxially, and there is no stabi-
lization of the developing carbocation.
Having been unsuccessful in our attempt to obtain the [3 þ 2]
adduct, e.g., 21i (Scheme 4), from the syn-β-hydroxyallylsilane
20i, we then decided to make it in an indirect way. Thus,
oxidation of the [3 þ 2] adduct 21c available from the anti-β-
hydroxyallylsilane 20c yielded the ketone 26, the steric bias of
which allowed complete stereoselective reduction with NaBH4
to provide 21i in excellent overall yield (Scheme 5).
aAll reactions were carried out in CH2Cl2 with 2.5 equiv of PTAD.
bAll compounds reported here were fully characterized by a complement
of 1H and 13C NMR as well as mass spectra; 21c, 21d, and 21g were
further characterized by single-crystal X-ray crystallography. cYields
refer to chromatographically purified products. d13% H-ene product
accompanied the [3 þ 2] adduct.
After addressing the first issue, that is, the [3 þ 2] annula-
tion, we then turned to the other issue involving Tamao
oxidation. Further work along this line fully justified our
choice of the 2-methoxyphenyl substituent on silicon for
successful Tamao oxidation. Indeed, attempted Tamao-
Fleming oxidation of a host of annulation products, e.g.,
14c, 21c, and 21d, with a phenyl substituent on silicon were
facilitate the [3 þ 2] pathway relative to other side reactions.
Armed with this information, we then proceeded to make [3 þ 2]
adducts from oxygenated cyclic allylsilanes. Thus, the enantio-
merically enriched allylsilanes, e.g., 20b and 20f, were prepared
from 20h and 20g, respectively, via Mitsunobu inversion (PPh3/
DEAD/p-NO2C6H4CO2H), followed by saponification; 20h
and 20g, in turn, were made following Roush’s methodology19
using 17b (Scheme 3). Reaction of 20b with PTAD provided the
(20) Clive, D. L. J.; Zhang, C.; Zhou, Y.; Tao, Y. J. Organomet. Chem.
1995, 489, C35–C37.
(21) Roberson, C. W.; Woerpel, K. A. J. Am. Chem. Soc. 2002, 124,
11342–11348.
(19) Heo, J.-N.; Micalizio, G. C.; Roush, W. R. Org. Lett. 2003, 5, 1693–1696.
J. Org. Chem. Vol. 75, No. 13, 2010 4523

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SCHEME 3. Preparation of Enantiomerically Enriched Allylsilanes
SCHEME 4. Bizarre Reaction of Allylsilane 20i with PTAD
SCHEME 5. Indirect Route to the Adduct 21i
SCHEME 6. Some Recalcitrant Tamao-Fleming Reactions
uniformly unrewarding. Thus, while use of Hg(OAc)2/
AcOOH22 in the case of 21c (Scheme 6) returned about
80% of the starting materials with no traces of the desired
product, use of KBr/AcOOH22 yielded a complex product
mixture containing none of the of the desired alcohol or the
starting annulation product. Also, exposure of 21c to
CF3COOH in CH2Cl2 showed no sign (TLC) of protodesi-
lylation and returned the starting material quantitatively. At
this stage, we also did a detour as outlined in Scheme 6 and
attempted the Tamao oxidation on the ring-opened product
28 obtained from 21c via exposure to alkali, oxidation,
and then reductive ring-opening of the diazene 27 followed
by acetylation. Once again Tamao-Fleming oxidation22 of
(22) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson,
P. E. J. J. Chem. Soc., Perkin Trans. 1 1995, 317–337.
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SCHEME 7. Tamao-Fleming Oxidation of the [3 þ 2] Adducts
Conclusion
In summary, we have developed an enantioselective route
to the pharmacologically significant cis-1,3-diaminocyclitols
with full stereochemical control of up to four contiguous
stereogenic centers. This strategy hinges on two key reac-
tions: (i) [3 þ 2] annulation and (ii) Tamao oxidation. We
have demonstrated that an appropriate choice of the ligands
on silicon is necessary for overall success.
Experimental Section
General experimental details are provided as Supporting
Information.
SCHEME 8. Synthesis of Aminocyclitols
Allyl(2-methoxyphenyl)dimethylsilane (17b). This allylsilane
was prepared via two routes, both giving excellent yield. Route 1:
To a stirred mixture of chloro(2-methoxyphenyl)dimethylsilane
(7 g, 34.8 mmol) and Mg turnings (1.5 g, 61.7 mmol) in dry THF
(32 mL) was added dropwise a solution of allyl bromide (2.95
mL, 34.8 mmol) in dry THF (10 mL) at room temperature at a
rate sufficient to maintain gentle reflux. After the addition was
over, the mixture was stirred at room temperature for 16 h. The
reaction was then quenched by the addition of 5% aq NH4Cl (80
mL) at 0 °C. The organic layer was separated, and the aqueous
layer was extracted with Et2O (3 ꢀ 30 mL). The organic layers
were combined, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to give a pale yellow oil
which was purified by flash column chromatography (SiO2,
9.5:0.5 petroleum ether/EtOAc eluent) to provide the desired
allylsilane as a colorless oil (6.5 g, 91%). Route 2: To a cooled
(-78 °C) solution of 2-bromoanisole (4 mL, 32.1 mmol) in 100
mL of dry THF was added 21.4 mL (32.1 mmol) of n-BuLi (1.5
M in hexane) at such a rate that the internal temperature did not
rise above -55 °C. After the addition was complete, the clear
colorless solution was allowed to stir at -78 °C for 30 min. Then
allylchlorodimethylsilane (neat, 4.85 mL, 32.1 mmol) was added
via syringe, and the mixture was stirred at -78 °C for 15 min.
The mixture was then allowed to come to room temperature and
concentrated. The residue was subjected to extractive workup
with EtOAc/H2O to provide a pale yellow oil which was purified
by flash column chromatography (SiO2, 9.5:0.5 petroleum
ether/EtOAc eluent) to provide the desired allylsilane as a
colorless oil (6.2 g, 94%): TLC (petroleum ether) Rf 0.48
1
(UV, I2); H (400 MHz, C6D6) δ 7.50 (dd, J = 7.2, 1.6 Hz,
1H), 7.30-7.26 (m, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.0
Hz, 1H), 6.01-5.90 (m, 1H), 5.07-4.99 (m, 2H), 3.35 (s, 3H),
2.01 (d, J = 8.0 Hz, 2H), 0.45 (s, 6H); 13C (100 MHz, C6D6) δ
164.4, 135.4, 135.3, 130.9, 126.0, 120.6, 112.9, 109.5, 54.3, 23.5,
-3.1; HRMS (ESþ) m/z calcd for C12H18SiONa (M þ Na)þ
229.10246, found 229.10191.
28 yielded complex product mixture containing no traces
of the desired alcohol, e.g., 29. The choice of o-methoxy-
phenyl group over phenyl group on silicon was successful at
this stage. Tamao oxidation of the cycloadducts 21a, 21b,
and 21g can now be readily carried out under Corey’s con-
ditions17 to afford the corresponding alcohols 30a, 30b,
and 30g, respectively, in moderate to good overall yields
(Scheme 7).
Finally, different aminocyclitols were synthesized in both
routes as outlined in Scheme 1. The cycloadducts 21a, 21b,
and 21h were first converted to the corresponding diazenes
31a, 31b, and 31h (route 1, Scheme 8), respectively, which
were reduced to the cis-1,3-diamines 32a, 32b, and 32h via
catalytic hydrogenation. Protection of the diamines followed
by modified Tamao-Fleming oxidation gave the aminocy-
clitols 33a, 33b, and 33h in protected form. Alternatively,
route 2 gives direct access to unprotected aminocyclitols. For
example, saponification of 30a followed by oxidation using
CuCl2 gave the diazene 34 (route 2, Scheme 8) which was
reduced to the cis-1,3-diaminocyclitol 35 via catalytic hydro-
genation in good overall yield.
3-[(2-Methoxyphenyl)dimethylsilanyl]octa-1,7-dien-4-ol (22a).
Allyl(2-methoxyphenyl)dimethyl silane 17b (2.267 g, 10.99 mmol)
was dissolved in dry THF (5 mL) and cooled to -78 °C. t-BuOK
(1.5 M solution in THF, 6.69 mL, 10.04 mmol) was added via
syringe followed by dropwise addition of n-BuLi (1.9 M solution
in hexanes, 5.28 mL, 10.04 mmol) over 10 min. The deep red
solution was stirred at -78 °C for 10 min, and then the flask was
transferred into a -45 °C bath and stirred for 2 h. The flask was
returned to the -78 °C bath, and freshly prepared (-)-
Ipc2BOMe23 (10.04 mmol) in dry THF (16 mL) was added
slowly via syringe. The deep orange mixture was stirred at -78 °C
for 30 min. Then BF3 OEt2 (1.66 mL, 13.09 mmol) was added
3
dropwise followed immediately by slow addition of 4-penten-1-al
(12.07 mmol). At this point, the solution became dense and the
color became off-white. After being stirred for 4 h at -78 °C, the
mixture was warmed to 0 °C and treated with 3 N NaOH solution
(23) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401–404.
J. Org. Chem. Vol. 75, No. 13, 2010 4525

Dey and Sarkar
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(16.8 mL) and 30% H2O2 (10.3 mL). After being stirred for 2 h
at room temperature, the mixture was extracted with EtOAc (3 ꢀ
50 mL). The extracts were combined, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by flash
column chromatography (SiO2, 9:1 petroleum ether/EtOAc
eluent) to provide 2.27 g of the β-hydroxyallylsilane 22a as
a colorless oil in 78% yield (80% ee, determined by Mosher ester
analysis24): [R]28D = þ7.2 (c 1.13, CHCl3); TLC (5% EtOAc/
petroleum ether) Rf 0.38 (UV, I2); 1H (400 MHz, C6D6) δ
7.54-7.53 (m, 1H), 7.29-7.25 (m, 1H), 7.00 (t, J=7.2 Hz, 1H),
6.57 (d, J = 8.4 Hz, 1H), 6.11 (dt, J = 17.2, 10.4 Hz, 1H),
5.85-5.75(m, 1H), 5.11(dd, J = 10.0, 2.4Hz, 1H), 5.08-4.98(m,
3H), 3.86-3.81 (m, 1H), 3.35 (s, 3H), 2.27 (dd, J = 10.8, 4.0 Hz,
1H), 2.17-2.09 (m, 2H), 1.62 (app q, J=7.6 Hz, 2H), 0.56 (s, 3H),
0.51 (s, 3H); 13C (100 MHz, C6D6) δ 163.9, 138.7, 136.1, 135.9,
130.9, 125.6, 120.9, 114.5, 114.1, 109.5, 70.6, 54.3, 41.8, 36.3, 30.3,
-3.0, -3.5; HRMS (ESþ) m/z calcd for C17H26SiO2Na (M þ
Na)þ 313.15997, found 313.15880.
product was extracted into EtOAc, dried over Na2SO4, and
concentrated under reduced pressure. Purification by flash
column chromatography (SiO2, 9:1 petroleum ether/EtOAc
eluent) gave the desired anti-β-hydroxyallylsilane 20b (165 mg,
42%) as a colorless oil: [R]27 = þ70.9 (c 0.66, CHCl3); TLC
D
(10% EtOAc/petroleum ether) Rf 0.26 (UV, I2); 1H (400 MHz,
CDCl3) δ 7.50 (dd, J = 7.0, 1.2 Hz, 1H), 7.30-7.27 (m, 1H),
7.04-6.98 (m, 1H), 6.58-6.54 (m, 1H), 5.72-5.63 (m, 2H),
4.03-3.99 (m, 1H), 3.34 (s, 3H), 2.31-2.29 (m, 1H), 2.18-2.14
(m, 1H), 1.97-1.92 (m, 1H), 1.78-1.71 (m, 1H), 1.69-1.63 (m,
1H), 0.50 (s, 3H), 0.47 (s, 3H); 13C (100 MHz, C6D6) δ 163.7,
135.5, 131.2, 125.5, 125.0, 124.1, 120.6, 109.5, 67.6, 54.9, 35.7,
29.2, 21.5, -3.4, -4.0; HRMS (ESþ) m/z calcd for C15H22SiO2-
Na (M þ Na)þ 285.1287, found 285.1285.
2-[(2-Methoxyphenyl)dimethylsilanyl]cyclopent-3-enol (20g).
The diene 22b (60 mg, 0.22 mmol) was dissolved in toluene (22
mL) and degassed under argon bubbling with sonication for
10 min. The solution was treated with Grubbs’ second-genera-
tion catalyst (13 mg, 0.015 mmol, 7 mol %) in one portion and
stirred for 1 h at 80 °C. The mixture was cooled to room
temperature and concentrated under reduced pressure. The
residue was purified by flash column chromatography (SiO2,
10% EtOAc/petroleum ether) to provide 38 mg (70%) of
3-[(2-Methoxyphenyl)dimethylsilanyl]hepta-1,6-dien-4-ol (22b).
This β-hydroxyallylsilane was obtained as a colorless oil in 75%
yield following the same procedure as described for 22a using
3-buten-1-al in place of 4-penten-1-al (86% ee, determined by
Mosher ester analysis24): [R]27 = þ6.5 (c 1.13, CHCl3); TLC
D
1
(5% EtOAc/petroleum ether) Rf 0.20 (UV, I2); H (400 MHz,
cyclopentenylsilane 20g as a pale yellow oil: [R]27 = þ54.7
D
CDCl3) δ 7.38-7.34 (m, 2H), 6.97 (t, J = 7.2 Hz, 1H), 6.84 (d,
J = 8.4 Hz, 1H), 5.86 (dt, J = 17.2, 10.4 Hz, 1H), 5.76-5.70 (m,
1H), 5.03-4.88 (m, 4H), 3.82 (s, 3H), 3.79-3.76 (m, 1H),
2.18-2.07 (m, 4H), 0.33 (s, 3H), 0.29 (s, 3H); 13C (100 MHz,
CDCl3) δ 163.7, 135.8, 135.7, 135.5, 131.0, 125.3, 120.8, 117.0,
115.0, 109.6, 70.5, 55.0, 41.6, 41.3, -3.0, -3.6; HRMS (ESþ) m/z
calcd for C16H24SiO2Na (M þ Na)þ 299.1443, found 299.1438.
2-[(2-Methoxyphenyl)dimethylsilanyl]cyclohex-3-enol (20h).
The diene 22a (1 g, 3.45 mmol) was dissolved in CH2Cl2 (340
mL) and degassed under argon bubbling with sonication for
30 min. The solution was treated with Grubbs’ second-genera-
tion catalyst (131.8 mg, 0.155 mmol, 4.5 mol %) in one portion
and stirred for 1 h at 40 °C. The mixture was cooled to room
temperature and concentrated under reduced pressure. The
residue was purified by flash column chromatography (SiO2,
10% EtOAc/petroleum ether) to provide 840 mg (93%) of
(c 2.15, CHCl3); TLC (5% EtOAc/petroleum ether) Rf 0.14
(UV, I2); 1H (400 MHz, CDCl3) δ 7.45-7.43 (m, 1H), 7.38-7.34
(m, 1H), 6.97 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.69-
5.64 (m, 2H), 4.71-4.69 (m, 1H), 3.82 (s, 3H), 2.67-2.57
(m, 2H), 2.28-2.24 (m, 1H), 1.85 (d, J = 5.6 Hz, 1H), 0.40 (s,
3H), 0.35 (s, 3H); 13C (100 MHz, CDCl3) δ 163.8, 135.5, 131.0,
130.8, 126.7, 126.1, 120.7, 109.7, 75.1, 54.9, 43.1, 42.8, -2.2,
-2.6; HRMS (ESþ) m/z calcd for C14H20SiO2Na (M þ Na)þ
271.11302, found 271.11222.
2-[(2-Methoxyphenyl)dimethylsilanyl]cyclopent-3-enol (20f).
To a solution of the syn-β-hydroxyallylsilane 20g (373 mg,
1.5 mmol), PPh3 (787 mg, 3 mmol), and 4-nitrobenzoic acid
(503 mg, 3.1 mmol) in 15 mL of dry THF was added a THF
solution (2M) of DEAD (514 mg, 2.95 mmol) dropwise at 0 °C.
The reaction mixture was allowed to warm to room temperature
and stirred for 4 h. The solvent was then evaporated in vacuo.
The resulting thick oil was diluted with CH2Cl2 (30 mL), washed
with saturated aqueous sodium bicarbonate solution (30 mL)
and brine (30 mL), and dried (Na2SO4). Solvent was removed
under reduced pressure to give the crude product as a yellow
thick oil which was dissolved in MeOH (15 mL), K2CO3 (1.2 g,
8.7 mmol) was added to it, and the resulting mixture was stirred
at room temperature for 3 h. Water was then added, the product
was extracted into EtOAc, dried over Na2SO4, and concentrated
under reduced pressure. Purification by flash column chroma-
tography (SiO2, 9:1 petroleum ether/EtOAc eluent) gave the
desired anti-β-hydroxyallylsilane 20f (149 mg, 40%) as a pale
yellow oil: [R]27D = þ86.9 (c 1.85, CHCl3); TLC (20% EtOAc/
petroleum ether) Rf 0.20 (UV, I2); 1H (200 MHz, CDCl3) δ
7.39-7.32 (m, 2H), 6.99-6.91 (m, 1H), 6.88-6.82 (m, 1H),
5.71-5.68 (m, 1H), 5.58-5.53 (m, 1H), 4.40 (d, J = 5.4 Hz, 1H),
3.81 (s, 3H), 2.58-2.26 (m, 3H), 0.23 (s, 3H), 0.22 (s, 3H); 13C (50
MHz, CDCl3) δ 164.4, 135.6, 131.3, 130.8, 125.5, 124.3, 120.7,
109.8, 74.3, 55.1, 46.6, 43.6, -3.6, -4.1; HRMS (ESþ) m/z calcd
for C14H20SiO2Na (M þ Na)þ 271.11302, found 271.11167.
[3 þ 2] Annulation: General Procedure. To a stirred solution of
PTAD (2.5 mmol) in CH2Cl2 (2.5 mL) was added dropwise a
solution of the allylsilane (1 mmol) in CH2Cl2 (1 mL) at room
temperature. The reaction was monitored by TLC (the reactions
are pretty fast; it usulally takes 1-5 min for complete
conversion). After completion of the reaction, solvent was
removed under reduced pressure, and the crude product was
subjected to flash chromatography to give the desired [3 þ 2]
adduct.
cyclohexenylsilane 20h as a pale yellow oil: [R]27 = þ42.7
D
(c 1.20, CHCl3); TLC (10% EtOAc/petroleum ether) Rf 0.46
(UV, I2); 1H (400 MHz, C6D6) δ 7.60 (dd, J = 7.2, 1.2 Hz, 1H),
7.31-7.26 (m, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.59 (d, J = 8.4 Hz,
1H), 5.77-5.67 (m, 2H), 4.19-4.18 (m, 1H), 3.35 (s, 3H),
2.54-2.52 (m, 1H), 2.24-2.17 (m, 1H), 1.99-1.95 (m, 1H),
1.73-1.67 (m, 1H), 1.63-1.55 (m, 1H), 1.41 (d, J = 4.8 Hz, 1H),
0.69 (s, 3H), 0.59 (s, 3H); 13C (100 MHz, C6D6) δ 164.1, 135.9,
130.7, 126.6, 126.1, 124.1, 120.8, 109.6, 67.7, 54.3, 33.5, 30.2,
21.4, -2.3, -2.4; HRMS (ESþ) m/z calcd for C15H22SiO2Na
(M þ Na)þ 285.12867, found 285.12804.
2-[(2-Methoxyphenyl)dimethylsilanyl]cyclohex-3-enol (20b).
To a solution of the syn-β-hydroxyallylsilane 20h (394 mg, 1.5
mmol), PPh3 (787 mg, 3 mmol), and 4-nitrobenzoic acid (503
mg, 3.1 mmol) in 15 mL of dry THF was added a THF solution
(2M) of DEAD (514 mg, 2.95 mmol) dropwise at 0 °C. The
reaction mixture was allowed to warm to room temperature and
stirred for 4 h. The solvent was then evaporated in vacuo. The
resulting thick oil was diluted with CH2Cl2 (30 mL), washed
with saturated aqueous sodium bicarbonate solution (30 mL)
and brine (30 mL), and dried (Na2SO4). Solvent was removed
under reduced pressure to give the crude product as a yellow
thick oil which was dissolved in MeOH (15 mL), K2CO3 (1.2 g,
8.7 mmol) was added to it, and the resulting mixture was stirred
at room temperature for 3 h. Then water was added, and the
(24) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543–
2549.
4526 J. Org. Chem. Vol. 75, No. 13, 2010

Dey and Sarkar
JOCArticle
11-(Dimethylphenylsilanyl)-4-phenyl-2,4,6-triazatricyclo[5.3.1.02.6]-
undecane-3,5-dione (14c): white solid; mp 168-170 °C; TLC
(30% EtOAc/petroleum ether) Rf 0.48 (UV, I2); 1H (400 MHz,
CDCl3) δ 7.60-7.33 (m, 10H), 4.60 (t, J = 4 Hz, 2H), 1.97-1.94
(m, 2H), 1.86-1.77 (m, 1H), 1.72-1.65 (m, 2H), 1.59-1.58 (m,
2H), 0.50 (s, 6H); 13C (100 MHz, CDCl3) δ 155.7, 136.0, 133.5,
131.7, 129.8, 129.0, 128.3, 128.0, 125.4, 60.2, 41.2, 27.1, 18.2,
-1.5; HRMS (ESþ) m/z calcd for C22H25SiN3O2Na (M þ Na)þ
414.1614, found 414.1610.
1.67 (m, 1H), 1.58-1.50 (m, 1H), 0.40 (s, 3H), 0.39 (s, 3H); 13
C
(100 MHz, CDCl3) δ 163.7, 158.9, 157.1, 134.9, 132.1, 131.5,
129.1, 128.3, 125.4, 123.2, 121.0, 109.7, 70.4, 69.5, 64.4, 55.0,
41.5, 37.7, -2.08, -2.09; HRMS (ESI) m/z calcd for C22H26-
N3O4Si (M þ H)þ 424.1693, found 424.1693.
8-Hydroxy-10-[(2-methoxyphenyl)dimethylsilanyl]-4-phenyl-
2,4,6-triazatricyclo[5.2.1.02.6]decane-3,5-dione (21g): [R]28
=
D
þ5.6 (c 1.35, CHCl3); TLC (40% EtOAc/petroleum ether) Rf
0.42 (UV, I2); 1H (400 MHz, CDCl3) δ 7.46-7.33 (m, 7H), 6.97
(t, J = 7.2 Hz, 1H), 6.86 (d, J = 8 Hz, 1H), 4.84 (s, 1H), 4.49 (s,
1H), 4.26 (d, J = 6.4 Hz, 1H), 3.85 (s, 3H), 2.28-2.23 (m, 1H),
1.68-1.62 (m, 2H), 0.45 (s, 3H), 0.41 (s, 3H); 13C (100 MHz,
CDCl3) δ 163.5, 157.4, 157.2, 135.1, 131.53, 131.50, 129.1, 128.2,
125.5, 125.2, 120.8, 109.6, 71.4, 68.4, 63.2, 54.9, 39.8, 39.0, -1.0,
-1.5; HRMS (ESI) m/z calcd for C22H26N3O4Si (M þ H)þ
424.1693, found 424.1691.
11-[(2-Methoxyphenyl)dimethylsilanyl]-4-phenyl-2,4,6-triazatri-
cyclo[5.3.1.02.6]undecane-3,5-dione (21a): pale yellow gum; TLC
(30% EtOAc/petroleum ether) Rf 0.43 (UV, I2); H (400 MHz,
1
CDCl3) δ 7.49-7.32 (m, 7H), 6.99 (t, J = 7.4 Hz, 1H), 6.86 (d, J =
8.4 Hz, 1H), 4.62 (t, J = 4 Hz, 2H), 3.82 (s, 3H), 1.97-1.94 (m,
2H), 1.89-1.66 (m, 5H), 0.47 (s, 6H); 13C (50 MHz, CDCl3) δ
163.8, 156.2, 135.0, 132.0, 131.9, 129.1, 128.0, 125.5, 124.1, 120.9,
109.8, 61.0, 54.8, 40.5, 27.0, 18.4, -1.2; HRMS (ESþ) m/z calcd
for C23H27SiN3O3Na (MþNa)þ 444.1719, found 444.1711.
8-Hydroxy-11-[(2-methoxyphenyl)dimethylsilanyl]-4-phenyl-
2,4,6-triazatricyclo[5.3.1.02.6]undecane-3,5-dione (21b): white solid;
mp 168-170 °C; [R]27D = þ8.6 (c 1.45, CHCl3); TLC (50%
EtOAc/petroleum ether) Rf 0.53 (UV, I2); 1H (400 MHz, CDCl3)
δ 7.45-7.39 (m, 5H), 7.37-7.32 (m, 2H), 6.99 (t, J = 7.4 Hz, 1H),
6.87 (d, J = 8 Hz, 1H), 4.58-4.57 (m, 2H), 3.96 (t, J=8 Hz, 1H),
3.84(s, 3H), 2.17-2.11(m, 1H), 2.04-1.95 (m, 2H), 1.76-1.56 (m,
3H), 0.46 (s, 3H), 0.45 (s, 3H); 13C (100 MHz, CDCl3) δ 163.6,
157.5, 156.5, 134.8, 132.0, 131.6, 129.0, 128.1, 125.4, 123.6, 120.9,
109.8, 67.6, 67.0, 60.1, 54.8, 39.5, 29.1, 27.1, -1.1, -1.5; HRMS
(ESI) m/z calcd for C23H28N3O4Si (M þ H)þ 438.18436, found
438.18396.
11-(Dimethylphenylsilanyl)-8-hydroxy-4-phenyl-2,4,6-triazatri-
cyclo[5.3.1.02.6]undecane-3,5-dione (21c): white solid; mp 206-
208 °C; TLC (50% EtOAc/petroleum ether) Rf 0.32 (UV, I2); 1H
(400 MHz, CDCl3) δ 7.50-7.34 (m, 10H), 4.58-4.55 (m, 2H),
3.89-3.86 (m, 1H), 2.23 (br s, 1H), 2.12-2.06 (m, 1H), 1.97-1.94
(m, 1H), 1.69-1.53 (m, 3H), 0.49 (s, 6H); 13C (100 MHz, CDCl3)
δ 157.2, 156.1, 135.5, 133.5, 131.5, 130.0, 129.0, 128.4, 128.2,
125.3, 67.0, 66.8, 59.4, 40.2, 28.9, 27.4, -1.82, -1.88; HRMS
(ESþ) m/z calcd for C22H25SiN3O3Na (M þ Na)þ 430.1563,
found 430.1566.
1-[3-(Dimethylphenylsilanyl)-4-oxocyclohex-2-enyl]-4-phenyl-
[1,2,4]triazolidine-3,5-dione (23). To a stirred solution of PTAD
(0.1 g, 0.6 mmol) in CH2Cl2 (2 mL) was added dropwise a
solution of the allylsilane 20i (0.06 g, 0.26 mmol) in CH2Cl2 (0.5
mL) at room temperature. The mixture was stirred at room
temperature for 2 h. Then solvent was removed under reduced
pressure, and the crude product was subjected to flash chroma-
tography (SiO2, 6:4 petroleum ether/EtOAc eluent) to give the
ketone 23 (0.063 g, 60%) as a pale yellow gum: [R]26D = þ31.8
(c 0.80, CHCl3); TLC (50% EtOAc/petroleum ether) Rf 0.42
(UV,I2); 1H (400 MHz, CDCl3) δ 7.49-7.30 (m, 10H), 6.78 (s,
1H), 5.05-5.01 (m, 1H), 2.63-2.58 (m, 1H), 2.54-2.45 (m, 1H),
2.30-2.24 (m, 2H), 0.41 (s, 3H), 0.40 (s, 3H) ; 13C (100 MHz,
CDCl3) δ 199.8, 154.7, 154.4, 152.9, 145.6, 136.3, 134.2, 130.6,
129.3, 129.2, 128.7, 127.8, 125.7, 54.6, 36.6, 26.1, -3.0, -3.2;
HRMS (ESþ) m/z calcd for C22H23SiN3O3Na (M þ Na)þ
428.1406, found 428.1402.
11-(Dimethylphenylsilanyl)-4-phenyl-2,4,6-triazatricyclo[5.3.1.02.6]-
undecane-3,5,8-trione (26). To a solution of the [3 þ 2] adduct 21c
(0.2 g, 0.5 mmol) in dry CH2Cl2 (5 mL) was added PCC (0.13 g, 0.6
mmol) at room temperature. The mixture was stirred for an addi-
tional 6 h at room temperature. Ether (15 mL) was added, and the
mixture was filtered. Removal of solvents followed by flash chloumn
chromatography (SiO2, 7:3 petroleum ether/EtOAc eluent) afforded
the ketone 26 (0.16 g, 80%) as a white solid: mp 214-216 °C; TLC
10-(Dimethylphenylsilanyl)-8-hydroxy-4-phenyl-2,4,6-triazatri-
cyclo[5.2.1.02.6]decane-3,5-dione (21d): white solid; mp 192-
194 °C; TLC (50% EtOAc/petroleum ether) Rf 0.39 (UV, I2);
1H (500 MHz, CDCl3) δ 7.06-6.92 (m, 10H), 4.21 (d, J = 2 Hz,
1H), 4.15 (s, 1H), 3.75 (dd, J=7, 3 Hz, 1H), 2.50 (br s, 1H),
1.58-1.53 (m, 1H), 1.26 (t, J=1.5 Hz, 1H), 1.11-1.07 (m, 1H),
0.006 (s, 6H); 13C (100 MHz, CDCl3) δ 158.3, 156.4, 135.3,
133.3, 131.5, 130.1, 129.1, 128.4, 128.3, 125.5, 70.5, 68.6, 63.5,
41.9, 37.3, -2.60, -2.64; HRMS (ESþ) m/z calcd for C21H23Si-
N3O3Na (M þ Na)þ 416.1406, found 416.1408.
1
(30% EtOAc/petroleum ether) Rf 0.44 (UV, I2); H (400 MHz,
CDCl3) δ 7.49-7.38 (m, 10H), 4.69-4.66 (m, 2H), 2.80-2.74 (m,
1H), 2.40-2.33 (m, 2H), 1.97-1.92 (m, 2H), 0.45 (s, 3H), 0.43
(s, 3H); 13C (100 MHz, CDCl3) δ 201.6, 155.8, 155.5, 134.4, 133.6,
131.3, 130.2, 129.1, 128.4, 125.3, 67.8, 59.2, 41.0, 34.7, 28.9, -2.8,
-3.4; HRMS (ESþ) m/z calcd for C22H23SiN3O3 Na (M þ Na)þ
428.1406, found 428.1410.
11-(Dimethylphenylsilanyl)-8-hydroxy-4-phenyl-2,4,6-triaza-
tricyclo[5.3.1.02.6]undecane-3,5-dione (21i). To a solution of 26
(0.15 g, 0.4 mmol) in THF-MeOH (1:1, 5 mL) was added
NaBH4 (0.08 g, 2.0 mmol) at 0 °C (ice-water bath), and the
mixture was stirred for 5 min. Water was added and the mixture
extracted with CH2Cl2. The combined organic layers were dried
(Na2SO 4) and concentrated. The residue was purified by flash
column chromatography (SiO2, 7:3 petroleum ether/EtOAc
eluent) to obtain the alcohol 21i (0.14 g, 93%) as a white solid:
mp 179-181 °C; TLC (30% EtOAc/petroleum ether) Rf 0.35
(UV,I2); 1H (400 MHz, CDCl3) δ 7.53-7.50 (m, 2H), 7.48-7.43
(m, 4H), 7.37-7.34 (m, 4H), 4.68 (s, 1H), 4.53-4.51 (m, 1H),
4.18 (s, 1H), 2.06-2.00 (m, 1H), 1.94-1.88 (m, 2H), 1.67-1.65
(m, 2H), 1.42 (s, 1H), 0.55 (s, 3H), 0.51 (s, 3H); 13C (100 MHz,
CDCl3) δ 155.7, 155.6, 138.5, 133.5, 131.5, 129.3, 129.1, 128.2,
128.0, 125.4, 66.1, 63.4, 59.9, 38.8, 27.1, 24.6, -0.6, -0.5;
HRMS (ESþ) m/z calcd for C22H25SiN3O3Na (M þ Na)þ
430.1563, found 430.1568.
10-(Dimethylphenylsilanyl)-8-hydroxy-4-phenyl-2,4,6-triaza-
tricyclo[5.2.1.02.6]decane-3,5-dione (21e): white solid; mp 112-
114 °C; [R]29D = þ5.9 (c 0.86, CHCl3); TLC (30% EtOAc/
petroleum ether) Rf 0.40 (UV, I2); 1H (500 MHz, CDCl3) δ
7.46-7.44 (m, 2H), 7.39-7.35 (m, 4H), 7.32-7.27 (m, 4H), 4.68
(d, J = 2.5 Hz, 1H), 4.45 (s, 1H), 4.23 (d, J = 6 Hz, 1H),
2.17-2.12 (m, 1H), 1.81 (br s, 1H), 1.55-1.47 (m, 2H), 0.40 (s,
6H) ; 13C (100 MHz, CDCl3) δ 156.9, 156.7, 137.4, 133.6, 131.4,
129.5, 129.1, 128.3, 128.1, 125.2, 71.2, 67.8, 62.4, 40.0, 38.7,
-1.3, -1.4; HRMS (ESþ) m/z calcd for C21H23SiN3O3Na (M þ
Na)þ 416.1406, found 416.1402.
8-Hydroxy-10-[(2-methoxyphenyl)dimethylsilanyl]-4-phenyl-
2,4,6-triazatricyclo[5.2.1.02.6]decane-3,5-dione (21f): white solid;
mp 138-142 °C; [R]27D = þ6.7 (c 1.00, CHCl3); TLC (30%
EtOAc/petroleum ether), Rf 0.15 (UV, I2); 1H (200 MHz,
CDCl3) δ 7.47-7.28 (m, 7H), 6.99 (t, J = 7.2 Hz, 1H), 6.87
(d, J = 8.2 Hz, 1H), 4.69-4.68 (m, 1H), 4.63 (s, 1H), 4.29-4.24
(m, 1H), 3.84 (s, 3H), 2.24 (br s, 1H), 2.17-2.08 (m, 1H), 1.69-
Synthesis of the Diazene: General Procedure. A solution of the
cycloadduct (0.5 mmol) in 2-propanol (15 mL) was sonicated
J. Org. Chem. Vol. 75, No. 13, 2010 4527

Dey and Sarkar
JOCArticle
under argon bubbling for 15 min. To this solution was added
solid potassium hydroxide (powder, 10 mmol), and the mixture
was stirred at 80 °C for 2 h. The reaction mixture was then
cooled to room temperature, and water (25 mL) was added to it
at 0 °C (ice-water bath). The resulting solution was stirred at
room temperature for 15 min (during this time the oxidation
of the hydrazino intermediates was complete by the dissolved
oxygen present in the medium) and then extracted with dichloro-
methane (4 ꢀ 25 mL). The combined organic extracts were dried
(Na2SO4) and evaporated in vacuo to give the crude diazene,
which was purified by flash column chromatography.
CD3OD) δ 7.40-7.37 (m, 2H), 6.99-6.95 (m, 2H), 3.80-3.75 (m,
3H), 3.50-3.47 (m, 1H), 3.30 (s, 3H), 1.82-1.70 (m, 4H), 0.41
(s, 6H); 13C (100 MHz, CD3OD) δ 164.0, 135.1, 131.5, 123.7,
120.5, 109.6, 67.5, 54.1, 52.5, 33.6, 27.1, 22.1, -2.8, -2.9; HRMS
(ESþ) m/z calcd for C15H27SiN2O2 (M þ H)þ 295.1842, found
295.1842.
4-Methoxymethoxy-2-[(2-methoxyphenyl)dimethylsilanyl]-
cyclopentane-1,3-diamine (32h): colorless oil; [R]26 = -3.34
D
(c 1.25, MeOH); 1H (400 MHz, CD3OD) δ 7.41-7.30 (m, 2H),
6.98-6.88 (m, 2H), 4.63-4.56 (m, 2H), 3.82 (s, 3H), 3.79-3.74
(m, 1H), 3.33 (s, 3H), 3.26-3.23 (m, 1H), 3.02-2.99 (m, 1H),
1.79-1.76 (m, 2H), 1.00-0.96 (m, 1H), 0.36 (s, 6H); 13C (100
MHz, CD3OD) δ 164.0, 135.1, 131.2, 124.6, 120.5, 109.4, 95.7,
84.9, 59.7, 54.2, 54.0, 51.0, 42.0, 40.0, -4.8, -4.9; HRMS (ESþ)
m/z calcd for C16H29SiN2O3 (M þ H)þ 325.1947, found 325.1943.
Tamao-Fleming Oxidation: General Procedure. To a stirred
solution of the [3 þ 2] adduct (0.15 mmol) in 1.5 mL of CH2Cl2
was added CF3COOH (2.3 mmol) at room temperature. The
solution was allowed to stir at room temperature for 10 h. The
solvent and excess CF3COOH were then removed under re-
duced pressure, and the crude was redissolved in 5 mL of
THF-MeOH (1:1). KF (0.8 mmol) and KHCO3 (0.8 mmol)
were added, followed by dropwise addition of 30% H2O2
(3 mmol) at 0 °C (ice-water bath). The resulting mixture was
allowed to warm to room temperature and stirred for 48 h, and
then the reaction mixture was diluted with water (10 mL) and
extracted with ethyl acetate (5 ꢀ 10 mL). The organic extracts
were combined, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. Purification by flash
column chromatography gave the desired alcohol.
8-(Dimethylphenylsilanyl)-6,7-diazabicyclo[3.2.1]oct-6-en-2-ol
(27): white solid; mp 89-91 °C dec; TLC (50% EtOAc/petro-
leum ether) Rf 0.30 (UV, I2); 1H (400 MHz, C6D6) δ 7.23-7.21
(m, 2H), 7.18-7.16(m, 3H), 5.12 (t, J = 3.6 Hz, 1H), 4.69-4.68
(m, 1H), 3.58-3.54 (m, 1H), 1.60-1.55 (m, 1H), 1.35-1.31 (m,
2H), 0.97-0.81 (m, 3H), 0.063 (s, 3H), 0.060 (s, 3H); 13C (100
MHz, C6D6) δ 137.9, 134.1, 130.0, 128.1, 87.8, 80.9, 64.9, 34.5,
28.8, 19.0, -1.3, -1.4; HRMS (ESþ) m/z calcd for C14H20Si-
N2ONa (M þ Na)þ 283.1242, found 283.1245.
8-[(2-Methoxyphenyl)dimethylsilanyl]-6,7-diazabicyclo[3.2.1]-
oct-6-ene (31a): pale yellow gum; TLC (15% EtOAc/petroleum
ether), Rf 0.34 (UV, I2); 1H (400 MHz, CDCl3) δ 7.40-7.34 (m,
2H), 6.97 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 8 Hz, 1H), 4.93 (t, J =
3.6 Hz, 1H), 3.80 (s, 3H), 1.62-1.57 (m, 2H), 1.50-1.42 (m, 2H),
1.36-1.25 (m, 1H), 1.21-1.18 (m, 1H), 1.01-0.91 (m, 1H), 0.43
(s, 6H); 13C (100 MHz, CDCl3) δ 163.8, 134.9, 131.3, 125.3,
120.6, 109.4, 81.4, 54.6, 33.6, 18.6, 16.7, -0.9, -1.1; HRMS
(ESþ) m/z calcd for C15H22SiN2ONa (M þ Na)þ 297.1399,
found 297.1395.
8-[(2-Methoxyphenyl)dimethylsilanyl]-6,7-diazabicyclo[3.2.1]-
11-Hydroxy-4-phenyl-2,4,6-triazatricyclo[5.3.1.02,6]undecane-
3,5-dione (30a): white solid; mp 230-234 °C; TLC (50% EtOAc/
petroleum ether) Rf 0.20 (UV,I2); 1H (200 MHz, CDCl3) δ 7.52-
7.33 (m, 5H), 4.37-4.24 (m, 3H), 2.15-1.99 (m, 2H), 1.94-1.83
(m, 2H), 1.75-1.53 (m, 2H); 13C (100 MHz, CDCl3) δ 154.6,
131.6, 129.1, 128.1, 125.5, 70.6, 57.5, 21.9, 17.1; HRMS (ESI) m/z
calcd for C14H15N3O3Na (M þ Na)þ 296.1011, found 296.1007.
8,11-Dihydroxy-4-phenyl-2,4,6-triazatricyclo[5.3.1.02,6]undecane-
3,5-dione (30b): white solid; mp >320 °C; [R]29D = þ26.1 (c 0.25,
MeOH); TLC (EtOAc) Rf 0.15 (UV,I2); 1H (200 MHz, DMSO-d6)
δ 7.48-7.36 (m, 5H), 6.00 (d, J = 3.8 Hz, 1H), 4.88 (d, J = 5.2 Hz,
1H), 4.43-4.36 (m, 1H), 4.15-4.11 (m, 1H), 4.06-3.99 (m, 2H),
1.97-1.81 (m, 2H), 1.66-1.40 (m, 2H); 13C (100 MHz, DMSO-d6)
δ 155.8, 155.3, 132.3, 129.2, 128.5, 126.9, 70.8, 64.2, 63.3, 57.2, 27.4,
21.9; HRMS (ESI) m/z calcd for C14H15N3O4Na (M þ Na)þ
312.0960, found 312.0958.
oct-6-en-2-ol (31b): pale yellow gum; [R]29 = þ35.9 (c 0.75,
D
CHCl3); TLC (50% EtOAc/petroleum ether) Rf 0.27 (UV, I2);
1H (400 MHz, acetone-d6) δ 7.41-7.34 (m, 2H), 6.98-6.93 (m,
2H), 4.99-4.98 (m, 1H), 4.87 (s, 1H), 3.87 (s, 3H), 3.73-3.69 (m,
1H), 1.69-1.64 (m, 1H), 1.51-1.44 (m, 2H), 1.16-1.14 (m, 1H),
0.75-0.65 (m, 1H), 0.41 (s, 3H), 0.40 (s, 3H); 13C (100 MHz,
acetone-d6) δ 164.6, 135.4, 132.0, 125.7, 121.2, 110.3, 64.3, 55.0,
34.6, 28.1, 18.4, -1.1, -1.2; HRMS (ESþ) m/z calcd for
C15H22SiN2O2Na (M þ Na)þ 313.1348, found 313.1347.
5-Methoxymethoxy-7-[(2-methoxyphenyl)dimethylsilanyl]-
2,3-diazabicyclo[2.2.1]hept-2-ene (31h): pale yellow gum; [R]29
=
D
-47.8 (c0.73, CHCl3); TLC (20% EtOAc/petroleum ether) Rf 0.35
(UV, I2); 1H (400 MHz, CDCl3) δ 7.36-7.26 (m, 2H), 6.93 (t, J =
7.6 Hz, 1H), 6.83 (d, J= 8.4 Hz, 1H), 5.28 (s, 1H), 5.17 (s, 1H), 4.39
(d, J = 6.8 Hz, 1H), 4.26 (d, J = 6.8 Hz, 1H), 3.83 (s, 3H),
3.44-3.42 (m, 1H), 3.22 (s, 3H), 1.31-1.29 (m, 3H), 0.35 (s, 3H),
0.33 (s, 3H); 13C (100 MHz, CDCl3) δ 163.5, 135.1, 131.0, 126.1,
120.4, 109.2, 94.6, 83.6, 77.8, 70.3, 55.4, 54.8, 42.3, 27.1, -1.3, -1.7;
HRMS (ESþ) m/z calcd for C16H25SiN2O3 (M þ H)þ 321.1634,
found 321.1636.
8,10-Dihydroxy-4-phenyl-2,4,6-triazatricyclo[5.2.1.02,6]decane-
3,5-dione (30g): [R]29 = þ12.6 (c 0.50, CHCl3); TLC (50%
D
EtOAc/petroleum ether) Rf 0.18 (UV,I2); 1H (400 MHz, CDCl3)
δ 7.47-7.35 (m, 5H), 4.53-4.51 (m, 2H), 4.34 (s, 1H), 4.28 (d,
J = 6.4 Hz, 1H), 3.57 (br s, 2H), 2.46-2.41 (m, 1H), 2.13 (d, J =
14.4 Hz, 1H); 13C (100 MHz, CDCl3) δ 155.7, 155.5, 131.0, 129.2,
128.6, 125.4, 77.1, 71.0, 62.2, 61.3, 37.1; HRMS (ESI) m/z calcd
for C13H13N3O4Na (M þ Na)þ 298.0804, found 298.0810.
Diol 33b. To a solution of the diamine 32b (150 mg, 0.5 mmol),
pyridine (427 mg, 5.4 mmol), and DMAP (cat.) in dichloro-
methane (7 mL) was added benzoyl chloride (379 mg, 2.7 mmol)
at 0 °C (ice-water bath). The resulting solution was allowed to
warm to room temperature and stirred for 6 h. Water (10 mL)
was added to the reaction mixture, the organic layer was
separated, and the aqueous layer was extracted with ethyl
acetate (3 ꢀ 5 mL). The organic extracts were combined, dried
over anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure to afford a yellow oil which was dissolved in
Synthesis of the cis-1,3-Diaminocycloalkanes: General Proce-
dure. The diazene (0.5 mmol) was dissolved in methanol (20
mL), and 10% Pd-on-carbon (150 mg) was added. The mixture
was stirred at room temperature under hydrogen (60 psi) for 9 h.
The catalyst was then removed by filtration (Celite) and washed
with methanol, and the solvent was evaporated in vacuo to give
the diamine, which was sufficiently pure to be used in the next
step.
2-[(2-Methoxyphenyl)dimethylsilanyl]cyclohexane-1,3-diamine
(32a): colorless oil; 1H (400 MHz, CD3OD) δ 7.40-7.36 (m, 2H),
6.95-6.92 (m, 2H), 3.79 (s, 3H), 3.33-3.32 (m, 2H), 2.88-2.84
(m, 1H), 1.89-1.74 (m, 3H), 1.59-0.86 (m, 4H), 0.41 (s, 6H); 13
C
(100 MHz, CD3OD) δ 163.8, 134.4, 131.1, 126.3, 120.6, 109.5,
53.9, 49.7, 42.2, 34.5, 20.5, -2.1; HRMS (ESþ) m/z calcd for
C15H27SiN2O (M þ H)þ 279.1892, found 279.1889.
CH2Cl2 (5 mL). HBF4 OEt2 (268 mg, 1.65 mmol) was added to
3
the solution at 0 °C (ice-water bath). The resulting mixture was
allowed to warm to room temperature and stirred for 6 h. The
reaction was quenched by dropwise addition of satd aq NaHCO3
2,4-Diamino-3-[(2-methoxyphenyl)dimethylsilanyl]cyclohexanol
(32b):colorless oil; [R]28D =þ4.65 (c0.65, MeOH); 1H (400MHz,
4528 J. Org. Chem. Vol. 75, No. 13, 2010

Dey and Sarkar
JOCArticle
(at 0 °C). The organic layer was separated, and the aqueous
layer was extracted with dichloromethane (3 ꢀ 10 mL). The
organic extracts were combined, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure to give the
crude fluorosilane which was dissolved in THF-MeOH (1:1,
10 mL). KF (145 mg, 2.5 mmol) and KHCO3 (250 mg, 2.5 mmol)
were added, and then 30% aq H2O2 (1 mL, 8.8 mmol) was added at
0 °C (ice-water bath). The resulting mixture was allowed to warm
to room temperature and stirred for 48 h. Then the reaction
mixture was diluted with water (10 mL) and extracted with ethyl
acetate (5 ꢀ 10 mL). The organic extracts were combined, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. Purification by flash column chromatography (SiO2, 8:2
EtOAc/petroleum ether eluent) gave the diol 33b as a white solid
(109 mg, 60%): [R]27D = þ26.7 (c 1.13, MeOH); mp 238-240 °C;
(Na2SO4) and evaporated in vacuo to give a brown oil which was
purified by flash column chromatography (SiO2, 1:1 EtOAc/
petroleum ether eluent) to give the diazene 34 (90 mg, 64%) as a
pale brown oil: TLC (50% EtOAc/petroleum ether) Rf 0.22 (I2);1H
(400 MHz, CDCl3) δ 4.60 (t, J = 4.4 Hz, 2H), 4.12 (t, J = 5.2 Hz,
1H), 2.12 (br s, 1H), 1.79-1.71 (m, 2H), 1.58-1.52 (m, 2H),
1.48-1.41 (m, 1H), 0.98-0.85 (m, 1H); 13C (100 MHz, CDCl3) δ
78.0, 70.6, 16.2, 15.1; HRMS (ESI) m/z calcd for C6H10N2ONa (M
þ Na)þ 149.0691, found 149.0690.
2,6-Diaminocyclohexanol (35). The diazene 34 (30 mg, 0.24
mmol) was dissolved in methanol (15 mL), and 10% Pd-on-
carbon (50 mg) was added. The mixture was stirred at room
temperature under hydrogen (60 psi) for 9 h. The catalyst was
then removed by filtration (Celite) and washed with methanol,
and the solvent was evaporated in vacuo to give the diamino
alcohol 35 (30 mg, 97%) as a colorless oil: 1H (400 MHz,
CD3OD) δ 2.78 (t, J = 9.2 Hz, 1H), 2.50-2.44 (m, 2H),
1.86-1.83 (m, 2H), 1.70-1.66 (m, 1H), 1.38-1.31 (m, 1H),
1.23-1.16 (m, 2H); 13C (50 MHz, CD3OD) δ 81.4, 54.8, 32.4,
22.2; HRMS (ESI) m/z calcd for C6H14N2ONa (M þ Na)þ
153.1004, found 153.1008.
1
TLC (80% EtOAc/petroleum ether), Rf 0.25 (UV, I2); H (400
MHz, CD3OD) δ 7.89-7.83 (m, 4H), 7.53-7.50 (m, 2H),
7.47-7.42 (m, 4H), 4.17 (s, 1H), 4.06-4.03 (m, 2H), 3.95-3.92
(m, 1H), 1.90-1.76 (m, 4H); 13C (100 MHz, CD3OD) δ 169.1,
169.0, 134.5, 134.4, 131.1, 131.0, 128.1, 128.0, 126.99, 126.97, 70.4,
68.1, 57.9, 54.5, 29.4, 24.7; HRMS (ESþ) m/z calcd for
C20H22N2O4Na (M þ Na)þ 377.1477, found 377.1476.
6,7-Diazabicyclo[3.2.1]oct-6-en-8-ol (34). A solution of the
alcohol 30a (305 mg, 1.12 mmol) in 2-propanol (15 mL) was
sonicated under argon bubbling for 15 min. To this solution was
added solid potassium hydroxide (1.2 g, 21.4 mmol), and the
mixture was stirred at 80 °C for 2 h. The reaction mixture was
cooled to room temperature, and water (25 mL) was added to it at
0 °C (ice-water bath). Concentrated HCl was added dropwise,
and the pH was adjusted to 1-2. Then 12% aq NH4OH was added
to the mixture, and the pH was brought to 5-6 followed by
addition of 15 mL of 2 N aq CuCl2 solution. The resulting dark
brown mixture was treated with 50 mL of 12% aq NH4OH and
75 mL of hexane. The color immediately changed to deep blue.
This was stirred at room temperature for 30 min. The organic layer
was separated, and the aqueous layer was extracted with dichloro-
methane (4 ꢀ 25 mL). The combined organic extracts were dried
Acknowledgment. This work was supported by DST &
CSIR, Government of India. R.T.D. is grateful to CSIR,
Government of India, for a Senior Research Fellowship. DST
is thanked for the creation of a 400 MHz NMR facility under the
IRPHA program and DST-FIST for the single-crystal X-ray
facility. We are also thankful to Prof. R. V. Venkateswaran
(IACS, Kolkata), Prof. S. Ghosh (IACS, Kolkata), Dr. S. W.
Djuric (Abbott Laboratories, Abbott Park, IL), and Dr. C. Fehr
(Firmenich, Geneva) for their continued help and support.
Supporting Information Available: Experimental details and
full spectral and X-ray crystallographic data (CCDC 768163-
768165). This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 13, 2010 4529