Retro iminonitroso Diels-Alder reactions: interconversion of nitroso cycloadducts

Article abstract of DOI:10.1016/j.tetlet.2009.07.121

Retro iminonitroso Diels-Alder reactions were investigated in both solution and solid phase. In thermal or Cu(I)-mediated reactions, interconversion of various nitroso cycloadducts occurred in the presence of separate dienes. Up to 99% of conversion was o

Full text of DOI:10.1016/j.tetlet.2009.07.121

Tetrahedron Letters 50 (2009) 5879–5883
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Tetrahedron Letters
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Retro iminonitroso Diels–Alder reactions: interconversion of nitroso
cycloadducts
*
Baiyuan Yang, Weimin Lin, Viktor Krchnak, Marvin J. Miller
Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall, University of Notre Dame, Notre Dame, IN 46556, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Retro iminonitroso Diels–Alder reactions were investigated in both solution and solid phase. In thermal
or Cu(I)-mediated reactions, interconversion of various nitroso cycloadducts occurred in the presence of
separate dienes. Up to 99% of conversion was observed. Use of chiral ligands in the Cu(I)-mediated reac-
tions gave new cycloadducts enantioselectively.
Received 19 June 2009
Revised 20 July 2009
Accepted 21 July 2009
Available online 25 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Since its discovery in 1947, the nitroso Diels–Alder reaction
(NDA) has become a powerful synthetic tool for the formation of
1-amino-4-hydroxy-2-ene derivatives in one step.1 Many groups
have continued to develop and apply nitroso Diels–Alder reactions
in organic syntheses.2 We successfully used nitroso Diels–Alder
reactions to obtain cycloadducts as versatile building blocks for a
variety of synthetic applications, including preparation of carbocy-
clic nucleoside analogs and novel natural product scaffolds.3
The retro Diels–Alder reaction (retro DA) has been known since
the discovery of the forward DA itself and has been used to gener-
ate a wide variety of reactive species in a synthetically useful man-
ner.4 The retro DA strategy has been of considerable utility in
promoting acylnitroso cycloaddition reactions. For example, it
has been used to store in situ generated transient and unisolable
acylnitroso agents 1 by cycloaddition with dimethylanthracene
(DMA).5 To avoid the direct use of oxidant, the resultant cycload-
ducts can be thermolized at relatively low temperature to release
the free acylnitroso species 1 (Scheme 1). However, very few
examples have been reported regarding retro nitroso Diels–Alder
reactions (retro NDA) related to aryl or heteroaryl nitroso agents.6
Studies of retro NDA reactions would benefit understanding of
reaction mechanisms and extend their synthetic use. We envi-
sioned that the dissociation of nitroso cycloadducts might occur
under thermal or Lewis acid-mediated conditions to generate
new nitroso cycloadduct scaffolds in the presence of added dienes.
Herein we describe the preliminary results of this study in both
solution and solid phase.
noticed that cycloaddition with colchicine was a reversible pro-
cess.3e The experiments were conducted by treating cycloadducts
6a–c with 5.0 equiv of 1,3-cyclohexadiene 7 at both 25 °C and
50 °C.7 As shown in Table 1, dissociations of colchicine adduct 6a
and ergosterol adduct 6c at 25 °C were observed and in situ trapping
of the released nitroso species 2a with 7 gave adduct 8 in 43% and
20% yield, respectively (entries 1 and 5). Not surprisingly, at elevated
temperature (50 °C), complete retro NDA reactions of 6a and 6c oc-
curred within several hours, affording adduct 8 in good yields (en-
tries 2 and 6). In the presence of a large excess of 7, the net
reaction of 6c was accelerated and compound 8 was obtained in
54% yield at 25 °C (entry 7). In contrast, no retro NDA reaction was
detected for adduct 6b at 25 °C or even at high temperature (entries
3and4). Theseobservationsclearlyindicatedthatstructureandcon-
figuration played important roles in the related retro NDA reactions.
Compared to their parent natural products or adduct 6b, NDA ad-
ducts 6a and 6c are more sterically congested.
Heating 6a and 6b in the presence of 7 at 50 °C produced only
89% and 86% of adduct 8 even though no starting compounds (6a
and 6c) were recovered (Table 1, entries 2 and 6). This encouraged
further study and revealed that a small portion of released nitroso
2a underwent reaction to form azo-oxy compound 9.8 To the best
of our knowledge, the formation of 9 directly from a pyridinylnitr-
oso precursor has not been reported. Further analyses of solutions
of 6-methyl-2-nitrosopyridine, 2a, showed that while 2a existed in
equilibrium with the corresponding azodioxy dimer,9 azo-oxy
compound 9 slowly formed upon standing in pure organic sol-
vent10 (Fig. 1).
Three structurally differentiated nitroso cycloadducts 6a–c were
obtained from NDA reactions between 6-methyl-2-nitrosopyridine
2a and colchicine 3, 1,3-cyclopentadiene 4 and ergosterol 5, respec-
tively (Scheme 2).3e We chose these cycloadducts for initial investi-
gations of the retro NDA reactions since, in our early report, we
The retro iminonitroso Diels–Alder reaction was also observed
when we subjected racemic spirocyclic adduct 11b3d to the cata-
lytic asymmetric iminonitroso Diels–Alder reaction conditions.
Trapping of nitroso agent 2b generated from the degradation of
11b with 1,3-cyclohexadiene 7 in the presence of Cu(I)PF6(MeCN)4
and (S)-BINAP produced cycloadduct 12 with moderate
enantioselectivity (19% yield, 52% ee, Scheme 3).11 The absolute
* Corresponding author. Tel.: +1 574 631 7571; fax: +1 574 631 6652.
E-mail address: mmiller1@nd.edu (M.J. Miller).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.121

5880
B. Yang et al. / Tetrahedron Letters 50 (2009) 5879–5883
R1
R1
NDA
*
*
O
N
O
N
+
R3
R3
retro NDA
R2
O
R2
R
N
O
O
R'4NIO4
Retro NDA
O
+
R
N
O
R
NHOH
1
DMA
Scheme 1. Nitroso Diels–Alder and retro acylnitroso Diels–Alder reaction.
MeO
OMe
MeO
H
MeO
OMe
OMe
O
OMe
N
N
O
N
O
MeO
(2a) (2.0 eq)
MeOH, rt
82%
N
O
HN
HN
6a
O
O
colchicine (3)
O
N
N
+
O
CH2Cl2, rt
N
N
2a (1.5 eq)
quant
1,3-cyclopentadiene
(4)
6b
6c
H
2a (1.1 eq)
O
HO
THF, 0 oC
N
H
N
HO
92%
ergosterol (5)
Scheme 2. Nitroso Diels–Alder reaction with various dienes.
Table 1
extended study was performed using different iminonitroso
reagents 2a–c and chiral phosphine ligands.13 Use of chiral ligand
(S)-DifluoroPhos and 6-methyl-2-nitrosopyridine, 2a, provided
spirocyclic adduct 11a with the highest ee value (96% ee, entry
Retro NDA reaction of iminonitroso cycloadducts 6a–c
O
N
N
5).
A dramatically decreased ee value was observed when
6a-c
+
(5 eq)
O
CHCl3
N
2a
N
5-methyl-3-nitrosoisoxazole, 2c, was used (28% ee, entry 6).
Retro Diels–Alder reactions were also attempted in solid phase
using NDA adducts attached to resin. The adduct resins 13a and
7
8
Entry
Adduct
Temp (°C)
Time (h)
8a (%)
13b,14 derived from
a-terpinene, were exposed to various dienes
1
2
6a
6a
6b
6b
6c
6c
6c
25
50
25
>50
25
50
25
24
5
24
—
24
2
24
43
89
0
in a microwave cavity for 5 min, then products 15 were cleaved
from the resin with TBAF and were analyzed by LC/MS.15 The re-
sults are summarized in Table 3. While the nitrophenyl NDA ad-
duct 13a provided quantitative retro NDA adducts with all tested
dienes, the pyridyl derivative 13b was less reactive under the same
conditions (Table 3, entries 1–6). Reactions with unsymmetric
dienes such as 2,4-hexadien-1-ol, 7b, and 1-methoxy-1,3-cyclo-
hexadiene, 7c, gave cycloadducts as mixtures of two regioisomers
in good to excellent yields (entries 4–6).
3
4b
5
0
20
86
54
6
7c
a
Isolated yields reported.
Temperature was increased from 50 °C to 70 °C (reflux).
CHCl3/1,3-cyclohexadiene 7 (10% v:v) as solvent.
b
c
In summary, we found that various iminonitroso cycloadducts
can undergo retro nitroso Diels–Alder reactions in both solution
and solid phase under thermal or Cu(I)-mediated conditions. By
trapping the released nitroso dienophiles with separate dienes,
new adduct scaffolds were generated in an efficient fashion. Use
of chiral ligands in the Cu(I)-mediated reactions gave new cycload-
ducts enantioselectively. We hope that the chemistry we describe
here can help expand the use of retro iminonitroso Diels–Alder
reactions in organic syntheses.
stereochemistry was proposed based on the literature-based
mechanistic model.12
To minimize the competing non-catalytic asymmetric imino-
nitroso Diels–Alder reaction process, work-up temperature was
modified from room temperature to À20 °C. By doing this, cycload-
duct 11b was obtained in 74% yield and with an improved ee value
(Table 2, entries 1 and 2). Under these optimized conditions, an

B. Yang et al. / Tetrahedron Letters 50 (2009) 5879–5883
5881
-
-
O
O
N N
N
Slow
N
N
O
N N
Solvent
Solvent
N
N
N
O
2a
monomer
9
dimer
Figure 1. Solution state equilibrium of 6-methyl-2-nitrosopyridine 2a and generation of 9.
N
O
N
O
CbzN
N
N
2b
12
ee: 52%
CuPF6(MeCN)4
-(S)-BINAP (10 mol%)
+
+
N
Cbz
N
O
CH2Cl2
CbzN
N
-78 oC to rt
( )-11b
(+) 11b
ee: 24%
N
O
10
N
Scheme 3. Retro NDA reaction of spirocyclic adduct 11b.
Table 2
NDA Reaction with various iminonitroso agents and chiral phosphine ligands
CbzN
Cbz
N
CuPF6(MeCN)4
Het
-(S)-ligand (10 mol%)
O
+
Het
N
O
N
CH2Cl2
-78 oC to -20 oC
10
2a-c
(-)-11a-c
Ligand :
O
O
F
F
O
O
PPh2
PPh2
O
O
PPh2
PPh2
PPh2
PPh2
F
F
O
O
(S)-DifluoroPhos
(S)-SynPhos
(S)-BINAP
Entry
1a
Nitroso
Ligand
11c (%)
eed (%)
51
2b
(S)-BINAP
11b, 71
O
N
N
2b
3b
4b
5b
2b
2b
2a
2a
2c
(S)-BINAP
11b, 74
11b, 75
11a, 85
11a, 74
11c, 65
65
86
92
96
28
O
N
N
N
(S)-DifluoroPhos
(S)-SynPhos
O
N
O
O
N
N
N
N
(S)-DifluoroPhos
(S)-DifluoroPhos
6b
O
O
N
N
a
Reaction was worked up at room temperature.
Reaction was worked up at À20 °C.
Isolated yields reported.
b
c
d
Determined by Chiral HPLC.

5882
B. Yang et al. / Tetrahedron Letters 50 (2009) 5879–5883
Table 3
Retro HDA reaction of resin-bounded
a-terpinene adducts with various dienes
O
O
O
O
Microwave
100 oC
L
N
L
N
H
R
+
N
O
H
X
N
O
+
X
DMF
R'
13a: X = C-NO2
13b: X = N
7, 7a-c
O
O
HO
O
L
N
N
TBAF
THF
H
H
R
R
X
N
X
N
O
14
15
O
R'
R'
Entry
1
Adduct
Diene
15a (%)
13a
7
99
2
3
4
5
13b
13a
13a
13a
13b
7
81
7a
7b
7c
7c
99
OH
99 (6:4)
99 (>9:1)
75 (6:4)
OMe
OMe
6
a
Determined by LC/MS.
5. For an early example, see: Horsewood, P.; Kirby, G. W.; Sharma, R. P.; Sweeny, J.
G. J. Chem. Soc., Perkin Trans. 1 1983, 1802.
Acknowledgments
6. (a) Gamenara, D.; Dias, E.; Tancredi, N.; Herinzen, H.; Moyna, P.; Forbes, E. J.
Braz. Chem. Soc. 2001, 4, 489; (b) Wanner, M. J.; Koomen, G. J. J. Chem. Soc.,
Perkin Trans. 1 2001, 16, 1908.
We gratefully acknowledge support from the NIH (GM 075885).
WethanktheLizzadroMagneticResonanceResearchCenteratNotre
Dame for NMR facilities and Nonka Sevova for mass spectrometry
analysis.
7. General procedures: To a solution of cycloadduct 6 (0.05 mmol) in CHCl3 (2 mL)
was added 1,3-cyclohexadiene 7 (24 lL, 0.25 mmol). The reaction mixture was
stirred at room temperature for 24 h, or heated at 50 °C and monitored by TLC
until 6 was consumed. The solvent was removed under reduced pressure and
the crude product was purified by silica gel chromatography (hexanes/
EtOAc = 5:1) to yield compound 8 as a yellowish solid.
References and notes
8. Spectral data of 9 (yellowish solid): mp: 85–87 °C; 1H NMR (500 MHz, CDCl3) d
8.22 (d, J = 8.2 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.80 (m, 1H), 7.76 (m, 1H), 7.42
(d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 2.70 (s, 3H), 2.63 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 158.8, 158.7, 157.1, 155.8, 139.2, 138.2, 127.0, 123.8, 115.6,
114.9, 24.6, 24.5; (FAB) MS: 229 [M+1]+.
1. (a) Wichterle, O. Collect. Czech. Chem. Commun. 1947, 12, 292; (b) Arbuzov, Y. A.
Dokl. Akad. Nauk SSSR 1948, 60, 993.
2. For reviews, see: (a) Streith, J.; Defoin, A. Synthesis 1994, 11, 1107; (b) Vogt, P.
F.; Miller, M. J. Tetrahedron 1998, 54, 1317; (c) Yamamoto, H.; Momiyama, N.
Chem. Commun. 2005, 3514; (d) Yamamoto, Y.; Yamamoto, H. Eur. J. Org. Chem.
2006, 2031; (e) Samarakoon, T.; Hanson, R. R. Chemtracts 2007, 20, 220.
3. For relevant publications, see: (a) Ghosh, A.; Ritter, A.; Miller, M. J. J. Org. Chem.
1995, 60, 5808; (b) Zhang, D. Y.; Sueling, C.; Miller, M. J. J. Org. Chem. 1998, 63,
885; (c) Li, F. Z.; Brogan, J. B.; Gage, J. L.; Zhang, D. Y.; Miller, M. J. J. Org. Chem.
2004, 69, 4538; (d) Lin, W. M.; Gupta, A.; Kim, K. H.; Mendel, D.; Miller, M. J.
Org. Lett. 2009, 11, 449; (e) Li, F. Z.; Yang, B. Y.; Miller, M. J.; Zajicek, J.; Noll, B.
C.; Möllmann, U.; Dahse, H.-M.; Miller, P. A. Org. Lett. 2007, 7, 2923; (f) Krchnak,
V.; Waring, K. R.; Noll, Br. C.; Möllmann, U.; Dahse, H.-M.; Miller, M. J. J. Org.
Chem. 2008, 73, 4559.
4. For reviews, see: (a) Kwart, H.; King, K. Chem. Rev. 1968, 68, 415; (b) Ripoll, J.
L.; Rouessac, A.; Rouessac, F. Tetrahedron 1978, 34, 19; (c) Rickborn, B. Org.
React. 1998, 53, 223; (d) Stajer, G.; Csede, F.; Fulop, F. Curr. Org. Chem. 2003,
7, 1423; For recent examples, see: (e) Boul, P. J.; Reutenauer, P.; Lehn, J. M.
Org. Lett. 2005, 7, 15; (f) Snyder, S. A.; Kontes, F. J. Am. Chem. Soc. 2009, 131,
1745.
9. Gowenlock, B. G.; Maidment, M. J.; Orrell, K. G.; Sik, V.; Giuseppe, M.; Vasapollo,
G.; Hursthouse, M. N.; Malik, K. M. A. J. Chem. Soc., Perkin Trans. 2 2000, 2280.
10. For detailed discussions of formation of azo-oxy compounds from
nitrosobenzene, see: Zuman, P.; Shah, B. Chem. Rev. 1994, 94, 1621.
11. Cu(I)-mediated retro NDA reaction with spirocyclic adduct 11b: To an oven-dried
round-bottomed flask were added anhydrous CH2Cl2 (5 mL), Cu(I)PF6(CH3CN)4
(9 mg, 0.025 mmol) and (S)-BINAP (16 mg, 0.025 mmol) in order. After stirring
for 0.5 h under Ar, the reaction mixture was cooled to À78 °C, racemic
compound 11b (94 mg, 0.25 mmol) and 1,3-cyclohexadiene (0.1 mL) were
added. The solution was gradually warmed to room temperature over 2 h. The
crude product was chromatographed on silica gel (hexanes/EtOAc = 5:1) to
afford 11b (70 mg, yield 75%, ee = 24%) as a white solid and 12 (9 mg, yield 19%,
ee = 52%) as a colorless oil, respectively. Enantiomeric excess was determined
by HPLC with Chiralcel AD-H column (95:5 hexanes/2-propanol), 1.0 mL/min,
for 11b, major enantiomer tR = 19.6 min, minor enantiomer tR = 18.0 min; for
12, major enantiomer tR = 14.8 min, minor enantiomer tR = 10.9 min.

B. Yang et al. / Tetrahedron Letters 50 (2009) 5879–5883
5883
12. (a) Yamamoto, Y.; Yamamoto, H. J. Am. Chem. Soc. 2004, 41, 4128; (b)
Yamamoto, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44, 7082.
2.04 (m, 4H); 13C NMR (75 MHz, CDCl3) d 147.1, 146.8, 139.2, 137.3, 134.1, 130.3,
128.3, 127.8, 127.6, 125.5, 118.5, 116.8, 111.7, 86.2, 69.9, 66.8, 60.0, 42.0, 41.4;
Compound 11c (colorless oil): 1H NMR (500 MHz, CDCl3) d 7.35 (m, 5H), 6.33 (m,
1H), 6.22 (m, 1H), 5.65 (s, 1H), 5.13 (s, 2H), 4.69 (s, 1H), 4.64 (s, 1H), 3.44 (m, 4H),
2.30 (s, 3H), 1.97 (m, 1H), 1.90 (m, 1H), 1.63 (m, 2H); 13C NMR (125 MHz, CDCl3) d
169.4, 169.0, 136.7, 134.2, 131.7, 128.5, 128.0, 95.6, 85.7, 67.1, 61.4, 42.2, 41.5;
HPLC: Chiralcel AD-H column (88:12 hexanes:2-propanol), 1.0 mL/min, major
enantiomer tR = 26.1 min, minor enantiomer tR = 31.0 min.
13. General procedures: To
a oven-dried round-bottomed flask were added
anhydrous CH2Cl2 (4 mL), Cu(I)PF6(CH3CN)4 (9 mg, 0.025 mmol), and chiral
phosphine ligand (0.025 mmol) in order under Ar. After stirring for 1 h, the
reaction mixture was cooled to À78 °C, nitroso compound 2 (0.30 mmol) was
added. The resulting dark blue mixture was stirred for 10 min, then spirocyclic
diene 10 (0.10 g, 0.36 mmol) in CH2Cl2 (0.5 mL) was added dropwise. The
solution was gradually warmed to À20 °C over 2 h and chromatographed
immediately on silica gel to afford nitroso-Diels–Alder adduct 11. Compound
11a (colorless oil): 1H NMR (300 MHz, CDCl3) d 7.31 (m, 6H), 6.64 (d, J = 6.9 Hz,
1H), 6.58 (d, J = 7.2 Hz, 1H), 5.14 (s, 3H), 4.74 (s, 1H), 3.59 (m, 4H), 2.43 (s, 3H),
2.03 (m, 4H); 13C NMR (75 MHz, CDCl3) d 137.7, 134.3, 130.2, 128.5, 128.0, 127.9,
116.4, 108.7, 86.2, 70.4, 67.0, 60.1, 42.2, 41.7, 29.2; HPLC: Chiralcel AD-H column
(95:5 hexanes:2-propanol), 1.0 mL/min, major enantiomer tR = 14.6 min, minor
enantiomer tR = 15.6 min; Compound 11b (white solid, mp: 123–124 °C): 1H
NMR (300 MHz, CDCl3) d 8.19 (dd, J = 3.9, 4.8, 1H), 7.49 (m, 1H), 7.36 (m, 6H), 6.78
(d, J = 12 Hz, 1H), 6.21 (m, 1H), 6.04 (m, 1H), 5.14 (s, 3H), 4.74 (s, 1H), 3.52 (m, 4H),
14. (a) Krchnak, V.; Möllmann, U.; Dahse, H.-M.; Miller, M. J. J. Comb. Chem. 2008,
10, 94; (b) Krchnak, V.; Möllmann, U.; Dahse, H.-M.; Miller, M. J. J. Comb. Chem.
2008, 10, 104.
15. Gerneral procedures: Resin-bounded
a-terpinene HDA adduct 13 (ꢀ50 mg) was
washed three times with THF, then 2 mL of a 0.25 M solution of diene in DMF
was added. The resin slurry was transfered to a vial and exposed to 100 °C in a
microwave cavity for 5 min. The resultant resin was washed five times with
THF and the product was released by treatment with 0.1 M TBAF in 1 mL of THF
for 30 min. The obtained product was analyzed by LC/MS. For analytical data of
compounds 15, see Ref. 14.