Nitrone Cycloadditions of 1,2-Cyclohexadiene

Article abstract of DOI:10.1021/jacs.5b13304

We report the first 1,3-dipolar cycloadditions of 1,2-cyclohexadiene, a rarely exploited strained allene. 1,2-Cyclohexadiene is generated in situ under mild conditions and trapped with nitrones to give isoxazolidine products in synthetically useful yields. The reactions occur regioselectively and exhibit a notable endo preference, thus resulting in the controlled formation of two new bonds and two stereogenic centers. DFT calculations of stepwise and concerted reaction pathways are used to rationalize the observed selectivities. Moreover, the strategic manipulation of nitrone cycloadducts demonstrates the utility of this methodology for the assembly of compounds bearing multiple heterocyclic units. These studies showcase the exploitation of a traditionally avoided reactive intermediate in chemical synthesis.

Full text of DOI:10.1021/jacs.5b13304

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Communication
Nitrone Cycloadditions of 1,2-Cyclohexadiene
Joyann S. Barber, Evan D. Styduhar, Hung V. Pham, Travis C. McMahon, K. N. Houk, and Neil K. Garg
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b13304 • Publication Date (Web): 08 Feb 2016
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Nitrone Cycloadditions of 1,2-Cyclohexadiene
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Joyann S. Barber, Evan D. Styduhar, Hung V. Pham, Travis C. McMahon, K. N. Houk,* and Neil K.
Garg*
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Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
E-Mail: houk@chem.ucla.edu, neilgarg@chem.ucla.edu
isoxazolidine products (Figure 1, 7 + 10 à 11). The
resulting products contain significant sp3-character9 and
are obtained with high regio- and diastereoselectivities.
Computational studies suggest that stepwise and con-
certed reaction pathways are operative in the cycloaddi-
tions and predict the observed selectivity trends.
ABSTRACT: We report the first 1,3-dipolar cycloaddi-
tions of 1,2-cyclohexadiene, a rarely exploited strained
allene. 1,2-Cyclohexadiene is generated in situ under
mild conditions and trapped with nitrones to give isoxa-
zolidine products in synthetically useful yields. The re-
actions occur regioselectively, and exhibit a notable en-
do preference, thus resulting in the controlled formation
of two new bonds and two stereogenic centers. DFT
calculations of stepwise and concerted reaction path-
ways are used to rationalize the observed selectivities.
Moreover, the strategic manipulation of nitrone cy-
cloadducts demonstrates the utility of this methodology
for the assembly of compounds bearing multiple hetero-
cyclic units. These studies showcase the exploitation of
a traditionally avoided reactive intermediate in chemical
synthesis.
Figure 1. Strained intermediates, known cycloadditions of 1,2-
cyclohexadiene (7), and nitrone cycloadditions of 7 described in
the present study.
Synthetically Useful Strained Intermediates
N
R
N
R
5
N
N
R
1
2
3
4
6
In situ generated building blocks for the construction
of heterocycles and natural product scaffolds
Various Cycloadditions of 1,2-Cyclohexadiene
O
O
Ph
The synthesis of heterocycles and natural product
Ph
H
[2+2]
cycloadditions
[4+2]
cycloadditions
,
scaffolds remains a vital area of study.1 2 One approach
8
9
7
to construct such important compounds involves the use
of strained intermediates such as benzyne, hetarynes,
and cyclic alkynes (1–6, Figure 1).3 Although initially
viewed as undesirably reactive species several decades
ago, these intermediates can now be used to prepare me-
dicinally-privileged scaffolds and stereochemically
complex natural products.3a,3d–i,3m Likewise, our under-
standing of the structure and reactivity of arynes and
R
O
R'
Nitrone [3+2]
cycloadditions
(Present Study)
10
N
R''
R
R'
First 1,3-dipolar
cycloaddition
of 1,2-
Unconventional
route to
stereochemically-
rich heterocycles
*
N
R"
*
O
cyclohexadiene
H
11
Regio- and stereochemical observations explained
by insight from computational studies
,
cyclic alkynes has evolved considerably.3
l,3m 4
We initiated our study toward the trapping of 1,2-
cyclohexadiene (7) by first accessing a suitable precur-
sor that could allow for allene generation in situ. En-
couraged by Guitián’s synthesis of a trimethylsilyltri-
flate precursor to 7,7e which was used in Diels–Alder
cycloadditions, we prepared the new triethylsilyltriflate
species 12,10 which proved more readily accessible and
could be obtained in gram quantities.11 We initially sur-
veyed the reaction of silyltriflate 12 with 5 equivalents
of commercially available nitrone 13 using different
fluoride sources at ambient temperature (Table 1). Alt-
hough the use of TBAF gave low yields of cycloadduct
14 (entry 1), KF/18-crown-6 gave more promising re-
sults (entry 2). Additionally, the use of CsF cleanly gave
product 14 in modest yield, although the remainder of
the mass was unreacted silyl triflate 12 (entry 3). In all
A less well-studied class of highly-strained interme-
diates is cyclic allenes, such as 1,2-cyclohexadiene (7,
Figure 1). 1,2-Cyclohexadiene (7) was first reported by
Wittig in 1966,5 but has seen little synthetic use since,
especially compared to its aryne and alkyne counter-
parts. Seminal efforts include theoretical studies,6 and
the two C–C bond forming reactions: [2+2]6a,6c, and
7
[4+2]6a,6d,7c,7d,7e,8 cycloadditions to form products such as
8 and 9, respectively. These transformations hint at the
potential utility of 7 as a versatile synthetic building
block, but no other cycloadditions involving 7 have been
reported. Similarly, 7 has not previously been used to
prepare heterocycles.
We now report the first dipolar cycloadditions of
1,2-cyclohexadiene, which allow for a facile entryway to
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Journal of the American Chemical Society
Page 2 of 5
Figure 2. Scope of reaction methodology.a
cases, it should be noted that 14 was formed regioselec-
1
2
3
4
5
6
7
8
R
R'
tively and in approximately 9:1 dr, with the major prod-
uct being the endo isomer (14a). For practical reasons,
we elected to further pursue the use of CsF and ultimate-
ly found that the reaction proceeded smoothly at elevat-
ed temperatures and higher concentration (entries 4 and
5) to give cycloadduct 14 in 4 h (entry 5; compared to 3
d for entry 3). Finally, to probe the necessary stoichiom-
etry, we tested the cycloaddition using just 1 equivalent
of nitrone 13. We were delighted to find that cycload-
duct 14 could be formed in comparable yields under
these conditions (entry 6).
OTf
R
O
R'
CsF
N
R"
+
N
CH3CN, 80 °C
O
SiEt3
R''
H
12
10
11
Ph
Me
t-Bu
N
O
t-Bu
N
t-Bu
N
t-Bu
O
O
H
H
H
14
88% yield
(8.9 : 1 dr)
15
63% yieldb
(11.4 : 1 dr)
S
16
76% yield
(>20 : 1 dr)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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S
N
O
N
t-Bu
N
t-Bu
Table 1. Optimization of nitrone cycloaddition.
N
t-Bu
O
O
O
H
R
H
H
R'
OTf
Ph
H
19
88% yield
(8.4 : 1 dr)
18
77% yieldb
(11.9 : 1 dr)
17
67% yieldb
(12.7 : 1 dr)
conditions
+
N
t-Bu
N
O
SiEt3
O
t-Bu
H
14a: R = Ph, R' = H
14b: R = H, R' = Ph
12
entry
13
7
Ts
N
yield
(14a:14b dr)a
equiv
N
conditions
temp (°C)
conc. (M)
of 13
1
2
3
4
5
6
TBAF, THF
23
23
23
80
80
80
0.025
0.025
0.025
0.025
0.1
5.0
35% (10.8:1)
N
t-Bu
N
t-Bu
KF, 18-crown-6,
CH3CN
5.0
77% (12.1:1)
41% (13.5:1)
90% (9.5:1)
92% (9.3:1)
84% (8.5:1)
O
O
H
H
5.0
20
92% yield
(2.5 : 1 dr)
CsF, CH3CN
CsF, CH3CN
CsF, CH3CN
CsF, CH3CN
21
83% yield
(12.2 : 1 dr)
5.0
Ph
5.0
Ph
Me
H
CF3
Me
0.1
1.0
N
N
Me
N
1
O
a Yields and diastereomeric ratios were determined by H NMR analysis
O
H
22
62% yieldc
(4.9 : 1 dr)
O
H
24
71% yieldb
(9.3 : 1 dr)
H
using 1,3,5-trimethoxybenzene as an external standard.
23
80% yieldb
(6.2 : 1 dr)
Having identified suitable reaction conditions, we
assessed the scope of the methodology by varying the
nitrone component and evaluating isolated yields and
diastereoselectivities (Figure 2). All reactions were per-
formed using CsF at 80 °C and either 1 or 2 equivalents
of the nitrone trapping agent, as indicated.12 In addition
to the parent experiment, which gave 14 in 88% yield
and roughly 9:1 dr, we were delighted to find that
nitrones derived from acetaldehyde and pivaldehyde
could be employed to give products 15 and 16, respec-
tively. Nitrones derived from aldehydes bearing hetero-
cycles were also tested. As shown by the formation of
products 17–21, furan, thiophene, thiazole, quinoline,13
and indole heterocycles are tolerated in this methodolo-
gy. Finally, several nitrones prepared from ketone or
cyclic amine precursors were tested, resulting in isoxa-
zolidines 22–24.14
a
Major diastereomer is shown. Conditions unless otherwise stated: silyl
triflate (1.0 equiv), nitrone (1.0 equiv), CsF (5.0 equiv), and CH3CN (0.1
M) at 80 °C. The yields reflect the average of two isolation experiments. b
Nitrone (2.0 equiv) was used. c Nitrone (2.0 equiv) and THF (0.1 M) at 60
°C were used.
pathways. However, consistent with our experimental
results, computations show that pathway A is disfavored
for the reaction of 7 and nitrone 13.16 The lower energy
pathway involves attack of the central allene carbon
(C2) on the nitrone, with attack of the nitrone oxygen on
C1 (Pathway B).
Figure 3. DFT calculations (B3LYP/6-31G*) were used to exam-
ine regioselectivites and diastereoselectivities.
ΔG‡ = 15.1–
18.2 kcal/mol
ΔG‡ = 14.4–
14.5 kcal/mol
Ph
H
2
1
+
N
O
t-Bu
Path A
Path B
7
13
Ph
Ph
N
2
2
O
O
DFT calculations were performed to assess mecha-
nistic aspects of the 1,2-cyclohexadiene / nitrone cy-
cloaddition.15 We investigated both the regio- and dia-
stereoselectivity of the cycloaddition. Although Diels-
Alder and (2+2) cycloadditions of 1,2-cyclohexadiene
(7) have been studied computationally, no reports of
(3+2) cycloadditions of 7 are available. We assessed
pathways that could lead to either of two possible con-
stitutional isomers, in addition to all possible stereoiso-
mers, as summarized in Figure 3. Cycloaddition via
pathway A would give diastereomers 25 and 26, whereas
pathway B would furnish 14a and 14b. Previous reports
with linear allenes indicate the plausibility of both
N
t-Bu
N
t-Bu
N
O
t-Bu
t-Bu
1
1
O
H
H
Ph
26
exo
Ph
25
endo
H
H
14a
endo
14b
exo
Disfavored
Favored
To explain the observed diastereoselectivities, we
compared the possible transition states for the formation
of both endo and exo products 14a and 14b (Figure 4).
First examining a concerted reaction mechanism, we
found that the activation energy for the endo reaction is
14.5 kcal/mol (TS1), which presents a plausible path-
way for the formation of 14a. A concerted exo transition
state could not be explicitly located; instead diradical
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Figure 5. Comparison of C2 internal angle for 7 and TS1.
transition state TS2 always resulted, suggesting the con-
1
2
3
4
5
6
7
8
2
certed exo reaction is higher in energy. As we do ob-
serve exo product 14b, we proceeded to examine the
stepwise mechanism through TS2. We found that dirad-
ical 27 can be formed via initial formation of the C–C
bond; an intrinsic reaction coordinate scan and a non-
zero S2 value confirms the diradical nature of this pro-
cess. From diradical 27, cyclization furnishes 14a or 14b
(via TS3a or TS3b); the formation of 14a is favored by
1.2 kcal/mol, which correlates to the observed 10:1 ratio
of products. Therefore, we propose that both stepwise
and concerted mechanisms for cycloaddition are in
competition, a phenomena we have previously observed
in our studies on Diels–Alder reactions with allenes,
which are known to be very reactive and form relatively
stable allylic radical intermediates.
Figure 4. DFT calculations (B3LYP/6-31G*) of concerted and
stepwise mechanistic pathways.
1
3
Strain induced
predistorted
internal angle
132.8°
7
t-Bu
t-Bu
N
N
Ph
O
Ph
O
9
H
H
2.70 Å
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
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56
57
58
59
60
2.28 Å
1
2
129.8o'
129.8°
14a
TS1
,
17 18
nitrone cycloaddition with 12. Next, palladium-
catalyzed Suzuki cross-coupling21 with boronic acid 29
afforded product 30 in 65% yield. Of note, 30 contains
three distinct heterocycles (i.e., a furan, pyridine, and
isoxazolidine). In another example, we questioned if
silyltriflate 12 could be used as a building block for the
assembly of polycyclic fused heterocycles, such as 33.
Nitrone cycloaddition with 31 furnished isoxazolidine
32. Subsequent N–O bond cleavage,22 followed by SNAr
cyclization23 gave tricycle 33. The conversion of 12 to
33 allows for the facile construction of three new bonds
and two stereogenic centers. Moreover, the two synthet-
ic applications shown in Figure 6 showcase how the un-
usual intermediate cyclohexadiene (7), despite its high
reactivity, can be used to access varying types of poly-
cyclic heterocycles in a controlled way.
Concerted Pathway
Stepwise Pathway
t-Bu
t-Bu
N δ+
O
H
N
t-Bu
Ph
O
Ph
N δ+
H
13
O δ–
14.5
14.4
Ph
H
t-Bu
H
N
O
TS2
–6.2
–7.4
7
Ph
H
TS1
0.0
t-Bu
TS3a
or
Nδ+
H
δ–
Ph
O
TS3b
–16.5
27
Figure 6. Strategic manipulation of nitrone cycloadducts.
Sequential Cycloaddition and Cross-Coupling
t-Bu
t-Bu
t-Bu
H
H
H
N
N
O
N
O
O
Ph
Ph
Ph
O
H
H
H
O
Cl
N
29
(HO)2B
14a
14a
14b
N
endo product
endo product
exo product
Pd(OAc)2 (5 mol%)
SPhos (12.5 mol%)
(major)
(major)
(minor)
N
t-Bu
K3PO4
PhMe, 100 °C
O
Regardless of the reaction trajectory, the 1,3-dipolar
cycloaddition of 1,2-cyclohexadiene occurs quickly with
mild heating. The low ~15 kcal/mol barriers for these
reactions, compared to the >30 kcal/mol barriers for cy-
cloaddition with linear allenes,17,18 can be attributed to
strain and pre-distortion. The geometry-optimized struc-
ture of 1,2-cyclohexadiene (7) and TS1 (concerted
pathway) are shown in Figure 5. Of note, the C1–C2–C3
angle is nearly identical in both cases (132.8° vs
N
t-Bu
H
O
28
from nitrone
cycloaddition
(65% yield)
H
30
Unconventional Route to Polycyclic Heterocyclic Scaffold
NHt-Bu
OTf
3 steps
SiEt3
O
N
H
3 Bonds & 2
Stereocenters
Formed
12
33
N
31
19
1. Zn, AcOH, H2O
CH2Cl2, 23 °C
(82% yield)
129.8°). Thus, only 3° contraction is necessary to reach
F
N
N
O
t-Bu
the transition state geometry. In contrast, linear allenes
must bend by more than 30° in order to reach their op-
timal transition state geometries (see SI for details). Ex-
F
2. NaH, THF, 50 °C
(58% yield)
CsF, CH3CN, 80 °C
(87% yield)
N
t-Bu
O
H
20
amples of distortion-accelerated reactions are known
32
and explain the facility of these reactions with 1,2-
cyclohexadiene.
In summary, we have discovered the first 1,3-
dipolar cycloadditions of 1,2-cyclohexadiene. The trans-
formation involves in situ generation of the strained in-
termediate under mild conditions, and trapping with
nitrones to give isoxazolidine products in synthetically
useful yields. The reactions occur regioselectively, with
a notable endo preference, thus resulting in the con-
trolled formation of two new bonds and two stereogenic
The nitrone cycloaddition of 1,2-cyclohexadiene
(7), when used sequentially with other transformations,
provides new and unique strategies for preparing com-
pounds bearing multiple heterocyclic units (Figure 6).
For example, isoxazolidine 28 was synthesized via a
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centers. DFT calculations suggest that stepwise and con-
Page 4 of 5
1
2
3
4
5
6
7
8
certed reaction pathways are operative in the cycloaddi-
tions and predict the observed selectivity trends. Moreo-
ver, the strategic manipulation of nitrone cycloadducts
demonstrates the utility of this methodology for the as-
sembly of compounds bearing multiple heterocyclic
units. These studies are expected to prompt the further
exploitation of traditionally avoided reactive intermedi-
ates in chemical synthesis.
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Chem. Soc. 2014, 136, 14706–14709. (c) McMahon, T. C.; Medina, J. M.;
Yang, Y.-F.; Simmons, B. J.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc.
2015, 137, 4082–4085.
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6
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ASSOCIATED CONTENT
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Supporting Information Available. Detailed experimental
and computational procedures, compound characterization,
Cartesian coordinates, electronic energies, entropies, en-
thalpies, Gibbs free energies and lowest frequencies of the
calculated structures. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
houk@chem.ucla.edu and neilgarg@chem.ucla.edu
7
(a) Moore, W. R.; Moser, W. R. J. Org. Chem. 1970, 35, 908–912. (b)
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ACKNOWLEDGMENT
The authors are grateful to the NIH-NIGMS (R01
GM090007 for N.K.G.), the NSF (CHE-1361104 for
K.N.H.), Bristol–Myers Squibb, the A. P. Sloan Founda-
tion, the Dreyfus Foundation, the University of California,
Los Angeles, the Foote Family (H. V. P. and E.D.S.), and
the Chemistry–Biology Interface training program (J.S.B.,
9
Another attractive aspect of using 1,2-cyclohexadiene (7) as a synthetic
intermediate is the potential to access sp3-rich heterocycles, especially in
comparison to benzyne cycloadducts. The synthesis of sp3-rich heterocy-
cles is a current priority area in medical chemistry; see: a) Lovering, F.;
Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752–6756. b) Ritchie,
T. J.; Macdonald, S. J. F. Drug Discov. Today 2009, 14, 1011–1020. c)
Lovering, F. Med. Chem. Commun. 2013, 4, 515–519.
10
USPHS
National
Research
Service
Award
Our efforts to prepare the known trimethylsilyl counterpart of 12 were
thwarted by complications associated with the synthesis and purification
of 2-(trimethylsilyl)cyclohexanone.
5T32GM008496-20) for financial support. These studies
were supported by shared instrumentation grants from the
NSF (CHE-1048804) and the NIH NCRR (S10RR025631).
Computations were performed with resources made availa-
ble from the Extreme Science and Engineering Discovery
Environment (XSEDE), which is supported by the National
Science Foundation (OCI-1053575), as well as the UCLA
Institute of Digital Research and Education (IDRE).
11 See Supporting Information for the synthesis of silyltriflate 12.
12
In some cases, improved yields were obtained using 2 equiv of the
nitrone trapping agent. Optimal conditions used for each substrate are
indicated.
The modest dr observed in the formation of 20 is currently not well
13
understood.
We also explored the use of nitrones bearing chiral auxiliaries. Use of
14
Vasella’s mannose-derived nitrones led to modest dr’s, whereas the use of
phenethylamine derivatives gave the corresponding cycloadducts in 1.5:1
dr. For Vasella’s mannose derivative, see: Vasella, A. Helv. Chim. Acta
1977, 60, 1273–1295.
15 All geometries were optimized using the density functional B3LYP with
a 6-31G(d) basis set. Free energies were then determined using B3LYP
single point calculations with the D3 correction (with no Becke-Johnson
damping) to account for dispersion, in conjunction with the larger 6-
311+G(d,p) basis set. The conductor-like polarizable continuum model
(CPCM) for acetonitrile was used to simulate implicit solvent. Minima
and transition states were located and verified with 0 and 1 imaginary
frequencies, respectively.
REFERENCES
1
In 2013, 15 of the top 20 small molecule pharmaceuticals contain heter-
ocycles. For discussions, see: (a) Vitaku, E.; Smith, B. R.; Smith, D. T.;
Njardarson,
http://njardarson.lab.arizona.edu/sites/njardarson.lab.arizona.edu/files/Top
%20US%20Pharmaceutical%20Products%20of%202013.pdf (accessed
J.
T.
December 13, 2015). (b) McGrath, N. A.; Brichacek, M.; Njardarson, J. T.
J. Chem. Educ. 2010, 87, 1348–1349.
16
2
Stepwise and concerted reaction mechanisms were evaluated; see the
Supporting Information for details.
Heterocycles are also prevalent motifs in agrochemicals and materials
chemistry; see: (a) Dinges, J., Lamberth, C., Eds. Bioactive Heterocyclic
Compounds Classes: Agrochemicals; Wiley-VCH: Weinheim, 2012. (b)
Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1999, 2849–2866.
17 Schmidt, Y.; Lam, J. K.; Pham, H. V.; Houk, K. N.; Vanderwal, C. D. J.
Am. Chem. Soc. 2013, 135, 7339–7348.
18 Pham, H. V.; Houk, K. N. J. Org. Chem. 2014, 79, 8968-8976.
19
The C1–C2–C3 angle in the diradical transition state (TS2) is very
3
For reviews of arynes and hetarynes, see: (a) Pellissier, H.; Santelli, M.
Tetrahedron 2003, 59, 701–730. (b) Wenk, H. H.; Winkler, M.; Sander,
W. Angew. Chem., Int. Ed. 2003, 42, 502–528. (c) Sanz, R. Org. Prep.
Proced. Int. 2008, 40, 215–291. (d) Bronner, S. M.; Goetz, A. E.; Garg, N.
K. Synlett 2011, 2599–2604. (e) Tadross, P. M.; Stoltz, B. M. Chem. Rev.
2012, 112, 3550–3557. (f) Gampe, C. M.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2012, 51, 3766–3778. (g) Bhunia, A.; Yetra, S. R.; Biju, A. T.
Chem. Soc. Rev. 2012, 41, 3140–3152. (h) Yoshida, H.; Takaki, K. Synlett
2012, 1725–1732. (i) Dubrovskiy, A. V.; Markina, N. A.; Larock, R. C.
Org. Biomol. Chem. 2013, 11, 191–218. (j) Wu, C.; Shi, F. Asian J. Org.
Chem. 2013, 2, 116–125. (k) Hoffmann, R. W.; Suzuki, K. Angew. Chem.,
Int. Ed. 2013, 52, 2655–2656. (l) Goetz, A. E.; Garg, N. K. J. Org. Chem.
similar as well (i.e., 129.5°).
20 For examples of distortion-accelerated reactions, see: (a) Gordon, C. G.;
Mackey, J. L.; Jewett, J. C.; Sletten, E. M.; Houk, K. N.; Bertozzi, C. R. J.
Am. Chem. Soc. 2012, 134, 9199–9208. (b) Lopez, S. A.; Houk, K. N. J.
Org. Chem. 2013, 78, 1778–1783. (c) Hong, X.; Liang, Y.; Griffith, A. K.;
Lambert, T. H.; Houk, K. N. Chem. Sci. 2014, 5, 471-475.
21
Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358–
3366.
22 Swift, P. A.; Stagnito, M. L.; Mullen, G. B.; Palmer, G. C.; Ceorgiev, V.
S. Eur. J. Med. Chem. 1988, 23, 465–471.
23 Saitton, S.; Kihlberg, J.; Luthman, K. Tetrahedron 2004, 6113–6120.
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SYNOPSIS TOC
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R
R'
R
O
R'
+
*
N
13 examples
62–92% yield
R"
N
*
O
R''
5
6
H
Experimental and Computational Studies of
First 1,3-Dipolar Cycloaddition of 1,2-Cyclohexadiene
7
8
9
NHt-Bu
New Tool to Access
3 Steps
*
Stereochemically-rich
polycyclic heterocycles
*
O
N
H
10
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