Tandem double intramolecular [4+2]/[3+2] cycloadditions of nitroalkenes. The fused/bridged mode

Article abstract of DOI:10.1021/jo034853w

A new class of tandem [4+2]/[3+2] cycloadditions of nitroalkenes is described in which both pericyclic processes are intramolecular. Two subclasses of intra [4+2]/intra [3+2] cycloadditions have been explored in which the dipolarophile is tethered at eith

Full text of DOI:10.1021/jo034853w

Ta n d em Dou ble In tr a m olecu la r [4+2]/[3+2] Cycloa d d ition s of
Nitr oa lk en es. Th e F u sed /Br id ged Mod e
Scott E. Denmark* and Laurent Gomez
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received J une 18, 2003
A new class of tandem [4+2]/[3+2] cycloadditions of nitroalkenes is described in which both pericyclic
processes are intramolecular. Two subclasses of intra [4+2]/intra [3+2] cycloadditions have been
explored in which the dipolarophile is tethered at either C(5) or C(6) of the nitronate. For both
families of precursors, the cycloadditions occur in good yield and are found to be highly regio- and
stereoselective. This method converts linear polyenes to functionalized polycyclic systems bearing
up to six stereogenic centers.
In tr od u ction
principle, four different permutations that arise from the
pairwise combinations of inter- and intramolecularity for
each event. Among these, three modes, the inter/inter,
intra/inter,5 and inter/intra6 tandem [4+2]/[3+2] cycload-
dition, have been extensively documented. Each mode is
uniquely associated with the formation of a particular
class of polycyclic nitroso acetals that can be unmasked
by simple hydrogenation to reveal interesting cyclic
structures.
A recent communication from these laboratories dis-
closed the development of a new class of the tandem
sequence namely the intra [4+2]/intra [3+2] cycloaddi-
tions in which both the dienophile and the dipolarophile
are attached to the nitroalkene.7 The first subclass called
the fused/ bridged mode wherein the dipolarophile is
tethered either at the C(6) or C(5) positions of the
nitronate has been documented. Because of the comple-
mentary electronic demands of the nitroalkene and
intermediate nitronate, the presence of two alkenes in
the molecule is not a complication and we were able to
transform linear trienes into R-hydroxy lactams and
tricyclic amines (Scheme 1).
The stereoselective construction of highly functional-
ized, oxygen-substituted, nitrogen-containing heterocyclic
compounds is a challenging task with many potential
rewards in the fields of medicinal and natural product
chemistry. In recent years, the hetero Diels-Alder reac-
tion has emerged as a powerful method for the construc-
tion of this class of compounds.1 This process allows for
the rapid and predictable formation of complex ring
systems with remarkably high regio-, diastereo-, and
enantiocontrol. The utility of this method can be further
enhanced if the resulting cycloadduct is poised to undergo
a second reaction in tandem. Tandem pericyclic reactions
allowing for the simultaneous construction of carbon-
carbon and carbon-heteroatom bonds are extremely
valuable for the expedient and efficient construction of
highly functionalized polycyclic compounds.2 In these
laboratories, the tandem [4+2]/[3+2] cycloaddition of
nitroalkenes has been developed as a general approach
for the synthesis of a variety of nitrogen-containing
heterocycles.3 In this sequence, the Lewis acid-promoted
[4+2] cycloaddition provides nitronates which undergo
[3+2] cycloaddition.4 The structural diversity of the
tandem [4+2]/[3+2] cycloaddition sequence derives from
the number of permutations possible for attachment of
the various components (dienophile and dipolarophile) to
the nitroalkene as well as the length of the tethers. As
for any tandem cycloaddition sequence, there are, in
(3) (a) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137.
(b) Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J . Am. Chem.
Soc. 1996, 118, 8266. (c) Denmark, S. E.; Thorarensen, A. J . Am. Chem.
Soc. 1997, 119, 125. (d) Denmark, S. E.; Hurd, A. R.; Sacha, H. J . J .
Org. Chem. 1997, 62, 1668. (e) Denmark, S. E.; Marcin, L. R. J . Org.
Chem. 1997, 62, 1675. (f) Denmark, S. E.; Dixon, J . A. J . Org. Chem.
1997, 62, 7086. (g) Denmark, S. E.; Martinborough, E. A. J . Am. Chem.
Soc. 1999, 121, 3046.
(4) For a recent review of the chemistry of nitronates see: Denmark,
S. E.; Cottell, J . J . In The Chemistry of Heterocyclic Compounds;
Padwa, A., Pearson, W. H., Eds.; Wiley-Interscience: New York, 2002;
Vol. 59, Chapter 2.
(1) (a) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology
in Organic Synthesis; Academic Press: New York, 1987. (b) Carruthers,
W. Cycloaddition Reactions in Organic Synthesis; Pergamon: New
York, 1990. (c) Boger, D. L. In Comprehensive Organic Chemistry,
Combining C-C π-Bonds; Paquette, L. A., Ed.; Pergamon Press:
Oxford, UK, 1991; Vol. 5, pp 451-512. (d) Ho, T.-L. Tandem Organic
Reactions; Wiley: New York, 1992. (e) Ziegler, F. E. In Comprehensive
Organic Synthesis Combining C-C π-Bonds; Paquette, L. A., Ed.;
Pergamon Press: Oxford, UK, 1991; Vol. 5, Chapter 7.3. (f) Tietze, L.
F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
(2) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) Ziegler, F. E. In Comprehensive Organic Synthesis, Combining C-C
π-Bonds; Paquette, L. A., Ed.; Pergamon Press: Oxford, UK, 1991; Vol.
5, Chapter 7.3. (c) Tietze, L. F.; Beifuss, U. A Angew. Chem., Int. Ed.
Engl. 1993, 32, 131. (d) Grigg, R., Ed. Cascade Reactions. In Tetra-
hedron Symp. Print No. 62 1996, 52 (35).
(5) (a) Denmark, S. E.; Hurd, A. R. J . Org. Chem. 1998, 63, 3045.
(b) Denmark, S. E.; Thorarensen, A. J . Org. Chem. 1994, 59, 5672. (c)
Denmark, S. E.; Herbert, B. J . Am. Chem. Soc. 1998, 120, 7357. (d)
Denmark, S. E.; Hurd, A. R. J . Org. Chem. 2000, 65, 2875. (e)
Denmark, S. E.; Herbert, B. J . Org. Chem. 2000, 65, 2887.
(6) (a) Denmark, S. E.; Stolle, A.; Dixon, J . A.; Guagnano, V. J . Am.
Chem. Soc. 1995, 117, 2100. (b) Denmark, S. E.; Schnute, M. E.;
Marcin, L. R.; Thorarensen, A. J . Org. Chem. 1995, 60, 3205. (c)
Denmark, S. E.; Guagnano, V.; Dixon, J . A.; Stolle, A. J . Org. Chem.
1997, 62, 4610. (d) Denmark, S. E.; Dixon, J . A. J . Org. Chem. 1997,
62, 7086. (e) Denmark, S. E.; Middleton, D. S. J . Org. Chem. 1998, 63,
1604.
(7) Denmark, S. E.; Gomez, L. Org. Lett. 2001, 18, 2907.
10.1021/jo034853w CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/25/2003
J . Org. Chem. 2003, 68, 8015-8024
8015

Denmark and Gomez
SCHEME 1
wherein the dipolarophile is tethered at the C(6) and C(5)
positions. We also examined the influence of the geometry
of the dipolarophile. The pronounced reactivity of ni-
troalkenes as Michael acceptors dictated that formation
of the nitroalkene be accomplished at the latest stage of
the synthesis.
C(6) Su bcla ss. This new variant of tandem double
intramolecular [4+2]/[3+2] was first examined with use
of a simple disubstituted alkene as the dienophile and
R,â-unsaturated esters as the activating group for the
dipolarophile in the 1,3-dipolar cycloaddition. All the
different nitroalkenes (E)-1, (E)-2, (Z)-2, and (E)-3 were
prepared from a common starting material, the mono-
protected 1,6-dialdehyde 19 (Scheme 2). The synthesis of
nitroalkene (E)-1 began with the formation of the alkene
by treatment of aldehyde 1 with (3-tert-butyldimethyl-
silanoxypropyl)triphenylphosphonium bromide in a Wit-
tig reaction. Generation of the ylide with potassium
hexamethyldisilazide in a mixture of THF and HMPA
yielded the alkene 2 as a 9/1 mixture of Z/E isomers in
71% yield. Removal of the tert-butyldimethylsilyl ether
with tetrabutylammonium fluoride (TBAF, 1 M in THF)
afforded the primary alcohol 3 in 89% yield.
Oxidation of the homoallylic alcohol was found to be a
difficult task due to the sensitivity of the product. Initial
attempts with Swern or PCC oxidation conditions were
unsuccessful leading to a mixture of R,â- and â,γ-
unsaturated aldehydes in poor yield. Ultimately, treat-
ment of the homoallylic alcohol with Dess-Martin peri-
odinane afforded the target aldehyde 4 in 87% yield.
Conversion to the dienoate 5 was then accomplished by
treatment with (methoxycarbonylmethylene)triphen-
ylphosphorane in 79% yield. Hydrolysis of the dimethoxy
acetal was effected by treatment with pyridinium
p-toluenesulfonate (PPTS) in a THF/H2O mixture to
afford the aldehyde 6 in 94% yield. The final installation
of the nitroalkene moiety employed the Henry reaction10
followed by dehydration. Thus, addition of nitroethane
to aldehyde 6 in the presence of a catalytic amount of
KO-t-Bu led to the formation of nitro alcohol 7 as a 1/1
mixture of syn/anti diastereomers in 89% yield. Dehydra-
tion of the mixture of nitro alcohols began by treatment
with acetic anhydride in the presence of a catalytic
amount of DMAP11 to afford nitro acetate 8 as a 1/1
mixture of syn/anti diastereoisomers. The standard con-
ditions for the elimination reaction (stoichiometric amount
In this report, we provide a detailed account, in full,
of our studies on the scope and limitations of this new
family of tandem cycloadditions.8 This work addresses
several topics related to the fused/ bridged mode tandem
[4+2]/[3+2] cycloaddition process, including (1) the prepa-
ration of the nitroalkenes bearing tethered dienophiles
and dipolarophiles, (2) the feasibility of employing such
a triene in tandem cycloaddition reactions, (3) the effect
of the tether length as well as the nature and the
geometry of the dipolarophile, and (4) the transformation
of the nitroso acetal product into R-hydroxy lactams and
tricyclic amines.
Resu lts
Syn th esis of Nitr oa lk en es. To explore the scope and
limitation of the fused/ bridged mode tandem cycloaddi-
tion process we prepared nitroalkenes having different
tether lengths between the dienophile and the dipolaro-
phile. Among the different possibilities for dipolarophile
attachment, we focused our studies on the subclass
SCHEME 2
8016 J . Org. Chem., Vol. 68, No. 21, 2003

Cycloadditions of Nitroalkenes
of DMAP or triethylamine12) were unsuccessful due to
partial isomerization of the double bond. Simply employ-
ing milder conditions, potassium carbonate in t-BuOH,
cleanly produced nitroalkene (E)-1 in 90% overall yield
(Scheme 2). Although the 2,3- and 11,12-double bonds
were formed selectively, (E)-1 still constituted a 91/9
mixture of Z/E isomers at the 5,6-double bond.
isomerization of the double bond. Thus, treatment of the
nitro acetates with 1.2 equiv of DMAP afforded the target
nitroalkenes (E)-2, (Z)-2, and (E)-3 (Schemes 4 and 5).
All three nitroalkenes constituted 92/8 mixtures of Z/E
isomers at the isolated double bond.
SCHEME 4
The preparation of the higher homologues (E)-2, (Z)-
2, and (E)-3 was accomplished in a similar manner.
Treatment of the monoprotected dialdehyde 1 with the
corresponding ylide (prepared from the phosphonium salt
and potassium hexamethyldisilazide) in a mixture THF
and HMPA afforded alkenes 10a and 10b in 78% and
79% yield as a 9/1 mixture of Z/E isomers (Scheme 3).
The carboxylic acid moiety was then reduced with lithium
aluminum hydride in THF. The resulting alcohols 11a
and 11b were oxidized under Swern conditions to afford
the stable aldehydes 12a and 12b in good yields. The R,â-
unsaturated esters were installed with a Wittig reaction,
using (carbomethoxymethylene)triphenylphosphorane to
afford both 13a and 13b as single isomers. A Z-selective
Horner-Emmons olefination with bis-(2,2,2-trifluoro-
ethyl)-(methoxycarbonylmethyl)phosphonate afforded 14
as a single isomer at the 2,3-double bond.
SCHEME 3
SCHEME 5
C(5) Su bcla ss. For the C(5) model, it was deemed
prudent to employ a vinyl ether as the dienophile to allow
the use of a simple terminal olefin as the dipolarophile
for the [3+2] cycloaddition. Elaboration of a â-disubsti-
tuted vinyl ether bearing a remote terminal double bond
was found to be challenging. The versatile Warren-
olefination process appeared to be an attractive solution.
(8) For an early study on the tandem double intramolecular cy-
cloaddition in a fused/fused mode see: Moon, Y. C. Ph.D. Thesis,
University of Illinois, Urbana, IL, 1991.
(9) Schreiber, S. L. Org. Synth. 1985, 64, 150.
(10) Barrett, A. G. M.; Graboski, G. G.; Russell, M. A. J . Org. Chem.
1985, 50, 2603.
Hydrolysis of the dimethoxy acetal with PPTS gener-
ated the aldehydes 15a , 15b, and 18 which can be
converted into the corresponding nitro alcohols by using
the Henry reaction followed by acetylation to afford nitro
acetates 17a , 17b, and 20. For these substrates, the use
of a stronger base, such as DMAP, did not lead to
(11) (a) Nightingale, D.; J anes, J . R. J . Am. Chem. Soc. 1944, 66,
352. (b) Meyers A. I.; Sircar, J . C. J . Org. Chem. 1967, 32, 4134. (c)
Bachman, G. B.; Maleski, R. J . J . Org. Chem. 1972, 37, 2810. (d)
Fukuda, Y.; Kitasato, H.; Sasai, H.; Suami, T. Bull. Chem. Soc. J pn.
1982, 55, 880. (e) Kametani, T.; Suzuki, Y.; Honda, T. J . Chem. Soc.,
Perkin Trans. 1 1986, 1373. (f) Fuji, M. Bull. Chem. Soc. J pn. 1988,
61, 4029.
J . Org. Chem, Vol. 68, No. 21, 2003 8017

Denmark and Gomez
In this plan, an R-methoxy-â-hydroxy phosphine oxide
(ix, Scheme 6) would be generated by addition of the
appropriate lithiophosphine oxide to a ketone, followed
by base-promoted syn-elimination to afford the â-disub-
stituted vinyl ether x.13 The syntheses of the two C(5)
nitroalkene precursors (one or two methylenes between
the dienophile and the dipolarophile) were quite similar
except for the sequence of steps required for the prepara-
tion of the key R-methoxy-â-hydroxy phosphine oxide ix
(Scheme 6). The lithiophosphine oxide is a basic nucleo-
phile such that in reaction with enolizable ketones,
deprotonation competes with nucleophilic attack on the
carbonyl group. This problem became severe in the case
of the â,γ-unsaturated ketone (n ) 1) wherein a mixture
of the desired product along with a 1,3-diene was
obtained. For that reason, the alternative approach
(C(1)-C(3) bond formation) in which an organometallic
agent is added to a â-keto phosphine oxide was employed.
Scheme 7. Treatment of 21 with 2.2 equiv of the lithiated
diphenylmethoxymethylphosphine oxide afforded the
keto phosphine oxide 22 in 82% yield. The use of 1.0 equiv
of the anion led to only a 20% conversion with an 80%
recovery of starting material. The following step required
the introduction of the allylic moiety. Initial attempts
with allylmagnesium bromide afforded the desired prod-
uct in only 36% yield (as a 1/1 mixture of diastereoiso-
mers) along with a 60% of recovery of starting material.
The less basic combination of allytributyltin and titanium
tetrachloride (at -78 °C) gave similar conversion with
the same diastereomeric ratio. Ultimately we found that
addition of organocerium(III) reagents14 (generated by the
treatment of allylmagnesium bromide with cerium(III)
chloride) to the keto phosphine oxide significantly en-
hanced the conversion to the target alcohol (54% yield
and 46% recovered starting material). A simple aqueous
workup followed by two repetitions of this cycle afforded
23 in 91% yield.
SCHEME 6
An additional benefit that accrued from the use of the
cerium reagent was that the diastereomeric ratio im-
proved to 93/7 erythro/threo (presumably from the che-
lation of the cerium reagent). These results were consis-
tent with those from Luche reduction of similar substrates
with NaBH4/CeCl3.15 Treatment of the adduct with
sodium hydride in DMF at 55°C for 3 h led to the
formation of the desired vinyl ether 24 in 92% yield as a
93/7 mixture of E/Z isomers. Removal of the TBS ether
with TBAF in THF afforded the primary alcohol 25 in
89% yield. The next step called for the oxidation of 25 to
the aldehyde 26 that will be used later on for the
construction of the nitroalkene moiety. However, the 1.4-
diene function containing a vinyl ether was found to be
very sensitive to acidic and basic conditions. Several
oxidation conditions were investigated including Swern,
PDC, TEMPO/Oxone, and 1,1-(azodicarbonyl)dipiperi-
dine,16 as well as catalytic oxidation methods with copper/
O2.17 In all cases only decomposition products were
detected. Fortunately, we found that a catalytic amount
(5 mol %) of tetrapropylammonium perruthenate (TPAP)18
and 1.5 equiv of NMO afforded the aldehyde 26 in 82%
yield. Reaction of the aldehyde 26 with nitroethane in
Similarly, this approach can also be thwarted by eno-
lization if the organometallic agent is too basic.
The preparation of the nitroalkene 29 starting from
the protected hydroxy hexanoate ester 21 is outlined in
SCHEME 7
8018 J . Org. Chem., Vol. 68, No. 21, 2003

Cycloadditions of Nitroalkenes
SCHEME 8
the presence of a catalytic amount of KO-t-Bu afforded
nitro alcohol 27 as a 1/1 mixture of diastereoisomers.
Acetylation with acetic anhydride followed by elimination
reaction in the presence of 1.2 equiv of DMAP afforded
the desired nitroalkene 29 in 90% overall yield.
ability of an unactivated disubstituted alkene to engage
in [4+2] cycloaddition with an R,â-substituted nitroal-
kene with use of tin tetrachloride as the Lewis acid. Thus,
treatment of (E)-1 (91% E at the disubstituted alkene)
with SnCl4 in toluene at -78 °C resulted in the rapid
formation of the more polar nitronate product. Interest-
ingly, analysis of the 1H NMR spectra of the crude
nitronate clearly revealed the presence of approximately
10% of the nitroso acetal 38. The intramolecular [3+2]
cycloaddition was taken to completion by warming the
crude mixture in toluene at 80 °C for 90 min (Scheme
9). The nitroso acetal 38 was isolated as a single dia-
stereomer in 82% overall yield after recrystallization. The
assignment of stereostructure was made by analogy to
nitroso acetal 40, which was fully analyzed by 2D NMR
spectroscopy and nOe studies as described below.
Attempts to prepare the higher homologue alcohol 32
through a similar synthetic scheme were found to be
unsuccessful. Treatment of the keto phosphine oxide 22
with the homoallylic organocerium(III) reagent afforded
complete recovery of the starting material. Modification
of the reaction conditions (reaction time, temperature,
concentration, and stoichiometry) was unsuccessful. These
results show clearly that the basicity of the organome-
tallic species is incompatible with the presence of an
acidic proton in the starting material. Therefore, we
focused our efforts on a modified route wherein the
homoallylic nucleophile is added first followed by addition
of the phosphine oxide to the newly formed ketone
(Scheme 8). Thus, conversion of the methyl ester 21 to
the Weinreb amide19 30 was accomplished in 61% yield.
Addition of 3-butenylmagnesium bromide to 30 proceeded
in excellent yield (85%) to provide the ketone 31. At this
point we were able to add the lithiated phosphine oxide
without concern for the isomerization of the double bond.
This transformation was performed cleanly to afford the
alcohol 32 in 92% yield as a 1/1 mixture of diastereoiso-
mers. Treatment with sodium hydride afforded the
methyl vinyl ether 33 in 87% yield as a 1/1 mixture of
E/Z isomers (ultimately found to be inconsequential).
Removal of the TBS group followed by oxidation of the
primary alcohol with TPAP/NMO afforded the aldehyde
35 in very good yield. Conversion to the nitroalkene was
then accomplished as described above to afford 37 as a
1/1 mixture of E/Z isomers at the vinyl ether double bond
without any trace of nitroalkene double bond isomers.
SCHEME 9
Nitroalkenes (E)-2 and (Z)-2 were similarly converted
to nitronates 39 and 41, respectively, in 98% and 82%
yield (Schemes 10 and 11). However, in contrast to the
lower homologue, these nitronates did not undergo the
(13) (a) Earnshaw, C.; Wallis, C. J .; Warren, S. J . Chem. Soc., Perkin
Trans. 1 1979, 3099. (b) Clayden, J .; Warren, S. Angew. Chem., Int.
Ed. Engl. 1996, 35, 241.
(14) (a) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392. (b) Dimitrov, V.;
Kostova, K.; Genov, M. Tetrahedron Lett. 1996, 37, 6787
(15) (a) Buss, A. D.; Warren, S. J . Chem. Soc., Perkin Trans. 1 1985,
2307. (b) Clayden, J .; Warren, S. Angew. Chem., Int. Ed. Engl. 1996,
35, 241.
Ta n d em Dou ble In tr a m olecu la r [4+2]/[3+2] Cy-
cloa d d ition of Nitr oa lk en es. C(6) Su bcla ss. Orienting
experiments (based on prior experience)8 established the
(16) Narasaka, K.; Morikawa, A.; Saigo, K.; Mukaiyama, T. Bull.
Chem. Soc. J pn. 1977, 10, 2773.
(12) (a) Litvinenko, L. M.; Kirichenko, A. I. Dokl. Akad. Nauk SSSR
Ser. Khim. 1967, 176, 97; Chem Abstr. 1968, 68, 68325u. (b) Steglich,
W.; Hofle, G. Angew. Chem., Int. Ed. Engl. 1969, 8, 981. (c) Hofle, G.;
Steglich, W. Synthesis 1972, 619. (d) Hofle, G.; Steglich, W.; Vor-
bruggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569.
(17) Marko´, I.; Gautier, A.; Chelle´-Regnaud, I.; Giles, P. R.; Tsuka-
zaki, M.; Urch, C. J .; Brown, S. M. J . Org. Chem. 1998, 63, 7576.
(18) (a) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 1, 13. (b)
Ley, S. V.; Norman, J .; Griffith, W. P.; Marsen, S. P. Synthesis 1994,
639.
J . Org. Chem, Vol. 68, No. 21, 2003 8019

Denmark and Gomez
TABLE 1. Op tim iza tion of th e In tr a m olecu la r [3+2]
Cycloa d d ition
intramolecular [3+2] cycloaddition at room temperature,
presumably due to the entropically disfavored formation
of the seven-membered ring.
SCHEME 10
entry
solvents
T, °C
80
100
120-160
66
80
100
100
100
time
40, %b
40
1
2
3
4
5
6
7
8
9
toluene
toluene
mesitylene
THF
CH3CN
C2H5CN
CH5NO2
C6H5Cl
DME
5 d
3 d
2 h
5 d
3 d
3 d
3 d
3 d
2 d
50
decomp
<10c
30
30
16
40
20
SCHEME 11
100
a
All reactions were performed in degassed solvents, using
sodium bicarbonate to prevent acidic degradation of the nitronate.
b
The percentage of product was determined by crude 1H NMR in
comparison of integration with recovered starting material. c Small
amounts of byproducts were also detected.
3J HH analysis and nOe experiments. First, the preserva-
Results from optimization of the thermal cycloaddition
of 39 are collected in Table 1. The influence of temper-
ature on the rate of the [3+2] cycloaddition in apolar
solvents was first examined. Heating a toluene solution
of nitronate 39 at 80 °C for 5 days led to a 40% conversion
to 40. Raising the temperature to 100 °C was found to
improve the conversion (50% after 3 days). However,
further increase in the temperature to 120-160 °C
afforded no detectable amount of nitroso acetal and only
decomposition of the starting material. Variation in the
polarity of the solvent brought no significant effect on
the rate of the cycloaddition. For example, 39 was
recovered unchanged after being heated for 5 days in
refluxing THF. Both acetonitrile and propionitrile pro-
vided the cycloadduct in 30% conversion after 3 days.
Nitromethane and DME were ineffective, whereas chlo-
robenzene appeared to be slightly better. These investi-
gations demonstrated that the rate of the [3+2] cycload-
dition was indeed slow but the reaction was found to be
clean because unreacted starting material could be
recovered in almost all cases. Finally, all attempts to
activate the dipolarophile with Lewis acids such as Sc-
(OTf)3, TMSOTf, AlMe3, or Cl2Pd(NCMe)2 were unsuc-
cessful and led to decomposition of the nitronate. Under
the optimal conditions (heating a dilute toluene solution
at 100 °C for 3 days) the pure nitroso acetal 40 could be
isolated as a single isomer in 44% yield along with 40%
of recovered starting material (Scheme 10).
tion of the trans relationship in the dipolarophile was
3
apparent from inspection of the HC(11)/HC(12) J HH
,
which was 5.0 Hz. Moreover, the configuration of the
C(12) center on the newly created ring was confirmed by
irradiation of HC(12) (2.56 ppm), which led to an en-
hancement at H3C(16) of 2.15% and at H3C(18) of 2.08%.
The stereostructures of other nitronates and nitroso
acetals in the C(6) tether series were assigned by
3
comparison of the relevant J HH, which are collected in
Table 2.
TABLE 2. Cou p lin g Con sta n ts (Hz) for Nitr on a tes a n d
Nitr oso Aceta ls
no. compd type
n
HC(6)/HC(7) HC(7)/HC(12) HC(11)/HC(12)
39 nitronate
41 nitronate
38 nitroso acetal
40 nitroso acetal
42 nitroso acetal
1
2
1
2
2
1.0
1.5
15.5
16.9
0.0 (trans)
5.0 (trans)
9.5 (cis)
The stereostructure of 39 was established first by
assignment of all proton and carbon resonances by 2D
NMR experiments (Table 2). With those assignments in
hand, the preservation of the cis relationship in the
dienophile was assured by inspection of the HC(6)/HC-
(7) 3J HH, which was found to be 1.0 Hz. Further, the trans
ring fusion was established by analysis of the HC(7)/HC-
Nitronate (Z)-2 bearing a cis dipolarophile was found
to react even more slowly. Heating the nitronate in
toluene at 100 °C for 3 days provided the nitroso acetal
in 23% yield along with 68% of recovered starting
material (Scheme 11). The effects of dipolarophile geom-
etry on the rate of the intramolecular [3+2] cycloaddition
of cyclic nitronates have been previously noted and will
be discussed below.
3
(12) J HH, which was 15.5 Hz. Nitroso acetal 40 was
shown to possess the fused/ bridged tetracyclic structure
again by full assignment of all resonances with the aid
of 2D NMR spectroscopy. The configurations of the two
new stereocenters were established by a combination of
(19) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(b) Levin, J . I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982, 12,
989.
8020 J . Org. Chem., Vol. 68, No. 21, 2003

Cycloadditions of Nitroalkenes
The intramolecular [4+2] cycloaddition of nitroalkene
(E)-3 proceeded successfully, as was observed with (E)-2
and (Z)-2, to afforded nitronate 43 in 86% yield. However,
all attempts to induce the intramolecular [3+2] cycload-
dition with 43 leading to the formation of an eight-
membered ring failed under an assortment of reaction
conditions (Scheme 12).
SCHEME 12
C(5) Su bcla ss. The reactivity of the C(5) tethered
nitroalkenes in the tandem double intramolecular cy-
cloaddition was next examined. Nitroalkene 29 was
expressly designed to differentiate the pendant alkenes
for their disparate roles in the two cycloaddition pro-
cesses. In the event, the [4+2] cycloaddition of 29 (93%
E at the vinyl ether position) was rapidly promoted by
SnCl4 (20 min at -78 °C) to afford a mixture of the
expected nitronate 45 along with the nitroso acetal 46
in a 3/2 ratio. The intramolecular [3+2] cycloaddition was
taken to completion by stirring the mixture in toluene
at room temperature for 1 h. The nitroso acetal 46 could
then be isolated as a single isomer in 87% yield overall
(Scheme 13). The assignment of the relative configuration
of the tetracyclic nitroso acetal 46 was determined by
assignment of all proton and carbon NMR resonances and
comparison of relevant coupling constants to the higher
homologue 48, which was fully assigned as described
below.
F IGURE 1. Stereochemical assignments for C(5) tether
nitroso acetals.
room temperature but the reaction could be induced by
warming a toluene solution of 47 at 100 °C for 2 h to
provide nitroso acetal 48 as a single stereoisomer in 79%
yield (Scheme 14).
SCHEME 14
SCHEME 13
The determination of the stereostructure of the C(5)
nitroso acetals began by assigning all the carbon and
proton resonances of 2D NMR experiments as sum-
marized in Figure 1. The relative configurations of the
key centers at C(6), C(11), and C(14) were established
by nOe experiments. Most significant was the observation
of an nOe enhancement among HC(10), HC(11), and HC-
(17), which established the endo fold of the tether. Also,
the positive nOe between HC(6) and HC(16) established
the cis fusion in the newly created ring. Assignment of
the stereostructure of 46 was made on the basis of similar
chemical shifts and coupling constants for HC(6), HC-
(10), the acetal proton HC(13/14), and the methoxy group
H3C(15/16).
The triene 37 bearing a two-methylene tether at C(5)
between the dienophile and the dipolarophile was next
evaluated. This substrate, which comprised a 1/1 mixture
of E/Z isomers of the vinyl ether, was treated with SnCl4
in toluene at -78 °C to effect the intramolecular [4+2]
cycloaddition. Surprisingly, the nitronate 47 was isolated
as a single stereoisomer. On the basis of previous studies
in the C(5) bridged mode cycloaddition, this observation
has been rationalized by an isomerization of either the
vinyl ether or the nitronate and will be discussed in detail
below.3f Obviously, 47 in contrast to 45 did not undergo
the intramolecular [3+2] cycloaddition spontaneously at
Hydrogenolytic Cleavage ofNitroso Acetals: P repar-
a tion of r-Hyd r oxy La cta m s. The synthetic utility of
the tandem process is revealed by the facile transforma-
tion of the nitroso acetal by hydrogenolytic N-O
bond cleavage. The conversion of nitroso acetals 38 and
40 to their respective R-hydroxy lactams was accom-
plished with a catalytic amount of Raney nickel in
J . Org. Chem, Vol. 68, No. 21, 2003 8021

Denmark and Gomez
methanol under 160 psi of hydrogen for 12 h to afford
49and 50 as single isomers in 71% and 78% yields,re-
spectively (Scheme 15).
anism of the elimination is beyond the scope of the
present investigation, we have shown that epimerization
does not take place during acetylation as the nitro
acetates are also formed as a 1/1 mixture. Moreover,
previous studies in these laboratories have established
that DMAP and other nucleophiles can isomerize ni-
troalkenes, however, at a rate significantly lower than
the rate of elimination.20 Thus, it would appear most
likely that the elimination takes place via either an E1cb
mechanism or by an E2 mechanism in which the isomeric
nitro acetates can interconvert (Scheme 17).
SCHEME 15
SCHEME 17
P r ep a r a tion of Tr icyclic Am in es. The nitroso acetal
46 was also subjected to hydrogenolysis, under milder
conditions (Raney nickel/MeOH/1 atm H2), to produce a
highly polar amino alcohol. To facilitate purification, the
amino alcohol was acetylated to provide the tricyclic
acetamide 51 in 81% yield along with a minor byproduct
52 (6% yield) (Scheme 16). This byproduct arose from
overreduction of the intermediate aldehyde before it
collapsed to form the imine (vide infra). Attempts to
inhibit the side reaction by using less catalyst failed. On
the other hand, the nitroso acetal 48 reacted cleanly in
methanol at 1 atm of H2 for 12 h to afford after
acetylation the amino acetate 53 in 82% yield.
Ta n d em In tr a [4+2]/In tr a [3+2] Cycloa d d ition of
Nitr oa lk en es. Mech a n ism of [4+2] Cycloa d d ition .
One of the central mechanistic questions in the Lewis
acid-induced [4+2] cycloaddition of nitroalkenes is the
timing of the bond formation, i.e., concerted or stepwise?
The results described in this report do not allow an un-
ambiguous conclusion. However, in the intramolecular
[4+2] cycloaddition of nitroalkenes tethered at the C(6)
position, we have shown that the cis-alkene (dienophile)
reacted with the nitroalkene to afford nitronates with a
complete preservation of the dienophile configuration and
thus a cis relationship between HC(6) and HC(5). These
results are consistent with previous studies from these
laboratories and support the conclusion that these reac-
tions are stereochemically coupled but not necessarily
concerted.21 Furthermore, we have also shown that a 1/1
E/Z mixture of vinyl ethers in the C(5) tethered nitroalk-
ene mode was cleanly converted into its corresponding
nitronate as a single isomer. This result is clearly
inconsistent with a concerted pathway unless the isomer-
ization were occurring after the cycloaddition. We have
previously noted the facile isomerization of C(6) alkoxy
nitronates in the presence of tin tetrachloride in inter-
molecular [4+2] cycloadditions and we presume that the
same process is operative in these substrates.22
SCHEME 16
Discu ssion
P r ep a r a tion of Nitr oa lk en es. Under the conditions
of the Henry reaction,10 an approximately 1/1 mixture of
syn and anti nitro alcohols was produced. Acetylation by
acetic anhydride and a catalytic amount of 4-N,N-
dimethylamiopyridine (DMAP, 5-10 mol %) followed by
dehydroacetylation with DMAP or triethylamine (1.2
equiv) produced E-nitroalkenes exclusively (>98%) and
in high yield (>90%). If the elimination occurs stereospe-
cifically by an anti-process, since it is an intermolecular
reaction, a 1/1 mixture of nitroalkenes will result. The
fact that the DMAP-Ac2O method produced the E-
nitroalkene exclusively implies that epimerization of
intermediates of products must occur at some stage of
the reaction. Although a thorough analysis of the mech-
Ster eoch em ica l Cou r se of th e Ta n d em In tr a -
[4+2]/In tr a [3+2] Cycloa d d ition of Nitr oa lk en es. A
key stereochemical issue in the intramolecular [4+2]
cycloaddition is the configuration at the ring fusion that
arises from the relative orientation of the dienophile and
the nitroalkene. This feature is, in turn, controlled by
the folding of the side chain. The main factors that
influence the preference for side chain folding are (1) the
(20) (a) Cramer, C. J . Ph.D. Thesis, University of Illinois, Urbana,
IL, 1989. (b) Moon, Y. C. Ph.D. Thesis, University of Illinois, Urbana,
IL, 1991
(21) Denmark, S. E.; Moon, Y.-C.; Cramer, C. J .; Dappen, M. S.;
Senanayake, C. B. W. Tetrahedron 1990, 46, 7373.
(22) Denmark, S. E.; Dixon, J . A. J . Org. Chem. 1998, 63, 6178.
8022 J . Org. Chem., Vol. 68, No. 21, 2003

Cycloadditions of Nitroalkenes
substitution on and configuration of the nitroalkene and
(2) any mechanistically dictated interactions between the
termini of the reacting double bonds (Figure 2). Inde-
pendent of double bond geometry, a trans ring fusion
arises from an exo fold (side chain away from diene)
whereas a cis ring fusion arises from an endo fold (side
chain under diene). Examination of models of the exo
transition structure clearly shows steric interactions
between the methyl group and the R2 substituent in the
dienophile as between the tin complex and the R3 sub-
stituent in the dienophile. In the endo mode, the steric
interactions that the methyl group experiences are more
severe, now including the allylic methylene group on the
dienophile and another methylene in the tether. The tin
complex in this mode now experiences steric interactions
with the R1 substituent on the dienophile.
respect to the dipolarophile is controlled by the limited
degrees of freedom and the constraints imposed by
effective overlap with the cyclic nitronate.
The nitronate containing a short tether (n ) 1) was
heated at 80 °C for 90 min to afford the corresponding
nitroso acetal 38 in 82% yield. However, the nitronate
39 bearing a longer chain (n ) 2) suffers from a greater
entropic cost in reaching the cycloaddition transition
state. Additionally, this substrate must overcome the
disfavored enthalpy contribution in forming a seven-
member ring.23 Indeed, the intramolecular [3+2] cycload-
dition was found to be very slow; the nitroso acetal 40
was isolated in 44% yield after 3 days at 100 °C in
toluene. These factors became prohibitively severe in the
intramolecular [3+2] cycloaddition in the nitronate 43
bearing a longer tether (n ) 3). All our attempts to form
the eight-membered ring failed. We also noticed a
significant effect of dipolarophile geometry on the rate
of the intramolecular [3+2] cycloaddition. The nitronate
41 containing a Z dipolarophile reacted more slowly than
39; only a 23% yield of the nitroso acetal 43 was obtained
after 3 days at 100 °C. This trend has been observed
previously and can be understood in view of the increased
steric interactions between the nitronate ring and the
methyl ester that must be oriented directly above.24
The trans ring fusion that results from the exo [4+2]
transition structure in the C(5) systems played a signifi-
cant role in facilitating the intramolecular [3+2] cycload-
dition. An important consequence of the trans fusion is
the placement of the dipolarophile in an axial orientation
in close proximity to the nitronate dipole (Scheme 19).
Much to our delight, the unactivated vinyl group under-
went the intramolecular [3+2] cycloaddition readily at
room temperature.24a Clearly, the rate of intramolecular
[3+2] cycloaddition is dependent not only on the reactiv-
ity of the dipolarophile but also on the ability to easily
access reactive conformation in the proximity of the
nitronate. The marked difference in the rates of the
intramolecular [3+2] cycloadditions between 45 and 47
may be rationalized again by the greater entropic cost of
achieving suitable alignment that attends the increased
length of the dipolarophile tether from one to two
methylene units.
F IGURE 2. Steric interactions responsible for the stereose-
lectivity of the intramolecular [4+2] cycloaddition.
In the C(6)-tethered systems, R2 and R3 are hydrogen,
so the exo transition structure is clearly more favorable
and this was the exclusive outcome of this mode. The
trans relationship was assured by the magnitude of the
vicinal coupling constant in the1H NMR spectra of nitro-
nates 39, 41, and 43. This trans selectivity from an exo
fold is well-precedented in other intramolecular [4+2]
cycloadditions of nitroalkenes with simpler dienophiles.21
In the C(5)-tethered systems, wherein R2 is a methylene
group, the exo mode is also expected to be favored. The
formation of a single cycloadduct, assigned as the trans
nitronate (or nitroso acetal), was confirmed by nOe stud-
ies as the new quaternary center precluded analysis of
vicinal coupling constants.
SCHEME 19
H yd r ogen olyt ic Clea va ge of Nit r oso Acet a ls.
P r ep a r a tion of r-Hyd r oxy La cta m s a n d Tr icyclic
Am in es. The conversion of nitroso acetals 38 and 40 to
their respective R-hydroxy lactams was accomplished by
using a suspension of Raney nickel in methanol at 160
psi of hydrogen. After 12 h, their corresponding lactams
49 and 50 were isolated in good yield as single isomers.
The deconvolution of these nitroso acetals is relatively
straightforward as the products arise directly from the
The facial selectivity of the intramolecular [3+2] cy-
cloaddition is controlled by predisposition of the tethered
dipolarophile to fold to one side of the nitronate. In the
C(6) mode with a one-methylene-unit tether (n ) 1), the
trans ring fusion places the dipolarophile in an axial
orientation, which favors the 1,3-dipolar cycloaddition
(Scheme 18). In addition, the facial selectivity with
SCHEME 18
(23) (a) Padwa, A. In 1,3-DipolarCycloaddition Chemistry; Padwa,
A., Ed.; Wiley-Interscience: New York, 1984; Vol. 2, Chapter 12. (b)
Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1.
(24) (a) Denmark, S. E.; Senanayake, C. B. W. Tetrahedron 1996,
52, 11579. (b) Denmark, S. E.; Seierstad, M. J .; Herbert, B. J . Org.
Chem. 1999, 64, 884.
J . Org. Chem, Vol. 68, No. 21, 2003 8023

Denmark and Gomez
insertion of two molecules of hydrogen followed by the
spontaneous lactamization of the generated amino ester.
It is noteworthy that the creation of these tricyclic
lactams as single stereoisomers bearing six contiguous
stereogenic centers in three steps from linear trienes
constitutes a remarkable increase in molecular complex-
ity and control.
slow compared to the direct reduction of the aldehyde to
produce amino diol 55. Support for this hypothesis is
found in the absence of the related reduction product
from hydrogenolysis of 48. In this case the intramolecular
imine formation creates a less strained azabicyclic [3.2.1]
system that leads readily to the observed tricyclic amine
53 (after acetylation).
In a similar manner, nitroso acetals 46 and 48 were
treated with a catalytic amount of Raney nickel under
only 1 atm of hydrogen to afford the tricyclic amines in
good yield. The formation of these amines is believed to
proceed through a number of discrete intermediates as
postulated in Scheme 20. Hydrogenolytic N-O bond
cleavage of 46 should form hemiacetal xiii, which upon
loss of methanol should afford amino aldehyde xiv. This
compound can undergo intramolecular imine formation
(to xv) that, under the reducing atmosphere, would lead
to amine 54. However, the imine formation requires the
construction of an azabicyclic [2.2.1] system and may be
Con clu sion
The novel class of tandem double intramolecular [4+2]/
[3+2] cycloadditions called the fused/ bridged mode has
been documented. Families of nitroalkenes bearing di-
polarophiles tethered both at C(6) and at C(5) can
participate in this process. In addition, simple alkenes
as well as vinyl ethers can serve as dienophiles. The
stereochemical course of the intramolecular [4+2] cy-
cloaddition is determined by the folding of the side chain,
which minimizes interactions with the nitroalkene moi-
ety. Unsaturated esters and simple vinyl groups function
well as dipolarophiles depending upon the location of the
tether. The disposition and the geometry of the tethered
dipolarophile have significant effects on the rates of the
intramolecular [3+2] cycloadditions. Hydrogenolysis of
the nitroso acetals provides polycyclic lactams and tri-
cyclic amines in high yields and remarkable stereoselec-
tivities.
SCHEME 20
Extension of this new class of reactions to other
families wherein the attachment of the dipolarophiles
extends from other positions along with applications of
these reactions in target oriented synthetic endeavors are
underway.
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM30938) for generous financial
support. L.G. also thanks the Association pour la
Recherche sur le Cancer (ARC) for a postdoctoral
fellowship.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details for the preparation of all intermediates and products,
as well as complete spectroscopic and analytical data for all
characterized compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O034853W
8024 J . Org. Chem., Vol. 68, No. 21, 2003