Synthesis of polysubstituted pyrroles from nitroso-diels-alder cycloadducts

Article abstract of DOI:10.1055/s-2005-918457

Nitroso-Diels-Alder cycloaddition of various dienes combined with a straightforward sequence including N-O bond cleavage and oxidation reaction of the resulting (Z)-γ-aminoenone (or enal) leads to polysubstituted pyrrolic units. Georg Thieme Verlag Stuttg

Full text of DOI:10.1055/s-2005-918457

3346
PAPER
Synthesis of Polysubstituted Pyrroles from Nitroso-Diels–Alder Cycloadducts
S
ynthesis of Polys
é
ubstituted P
r
yrroles
f
a
rom Nitros
l
o-Diels
d
–Alde
r
C
yc
l
i
oadduc
n
ts e Calvet, Nicolas Blanchard, Cyrille Kouklovsky*
Laboratoire de Synthèse des Substances Naturelles, ICMMO, UMR 8615, Batiment 410, Université d’Orsay, 91400 Orsay, France
Fax +33(1)69154679; E-mail: cykouklo@icmo.u-psud.fr
Received 2 May 2005
Dedicated with much respect and admiration to Professor Steven V. Ley, FRS, on the occasion of his 60th birthday
cursors. The latter are easily obtained by nitroso-Diels–
Abstract: Nitroso-Diels–Alder cycloaddition of various dienes
Alder cycloaddition of electron-rich 1,3-dienes 1 with ni-
combined with a straightforward sequence including N–O bond
cleavage and oxidation reaction of the resulting (Z)-g-aminoenone
(or enal) leads to polysubstituted pyrrolic units.
troso dienophiles 2 (Scheme 1).15 These cycloadducts can
be converted into pyrrole 4 photochemically (when
R = Ar);16 under high temperature and pressure;17 rutheni-
um or rhodium catalysis,18 Lewis acid,19 Brönsted acid,20
or silica gel activation;21 fluoride-mediated desilylation of
6-silyl-3,6-dihydro-1,2-oxazine;22 or base-mediated rear-
rangement of 3,6-dihydro-1,2-oxazine bearing an electron
withdrawing group in the 6-position.23 These methods
suffer either from a lack of generality, drastic conditions,
or require very specific substitution of the nitroso-Diels–
Alder cycloadduct.
Key words: nitroso-Diels–Alder reactions, oxidations, pyrroles,
ring closure
The chemistry of the pyrrole nucleus has been under close
investigation due to the occurrence of this unique hetero-
cycle in naturally and/or biologically active compounds.1
Numerous methods for the synthesis of pyrroles have
been reported in the literature and can be classified, for ex-
ample, according to the bond disconnections (Figure 1).1a–c
The N–C2 disconnection method includes cyclization re-
actions,2 metal-mediated cyclization reactions (catalytic3
or non-catalytic4), and N–H insertion reactions.5 The clas-
sical Knorr and Hantzch pyrrole synthesis (N–C2, C3–
C4 disconnections) or the Paal–Knorr cyclocondensation
(N–C2, N–C5 disconnections) are still the object of active
research aimed at increased efficiency and simplicity.6
New methods for the synthesis of pyrroles include multi-
component reactions based on Stetter (or sila-Stetter)
Paal–Knorr domino processes7 or the sequential rear-
rangement of enol-protected propargylic alcohols.8 Cy-
cloadditions (involving C2–C3, C4–C5 disconnections)
of azomethine ylides,9 isonitriles,10 or oxazolium oxides
(münchnones)11 are also an important class of reactions
which allow a straightforward access to polysubstituted
pyrroles. Recently, a metathesis reaction12 (with rutheni-
um trichloride as co-catalyst)13 has been studied, allowing
the efficient conversion of diallylamines to 3-pyrrolines,
which could be dehydrogenated in situ to pyrrole.
conditions
(see text)
nitroso-
Diels–Alder
O
N
O
N
+
N
R
4
R
R
1
2
3
Scheme 1 Literature synthesis of pyrroles 4 from 3,6-dihydro-1,2-
oxazines 316–23
To the best of our knowledge, no systematic studies have
been reported to explore the scope of pyrrole formation
from diversely substituted dihydrooxazine 6 under mild
conditions. The latter can be viewed as a latent pyrrole: a
simple two-step sequence, namely N–O bond cleavage
followed by an oxidation–spontaneous cyclization reac-
tion, should lead directly to pyrrolic units (Scheme 2).
Since substitution of the starting 1,3-diene directly trans-
lates into the pyrrole, this approach should also be quite
flexible. Moreover, regiochemical control during the
[4+2] cycloaddition step is not considered to be an issue.
In continuation of our interest in nitroso-Diels–Alder cy-
cloadditions,24 we would like to report a general and
straightforward access to the pyrrole nucleus from cy-
cloadducts 6.
C3–C4
C5–C4
C5–N
C2–C3
N–C2
N
R
R4
R4
N–O bond
cleavage
and oxidation
R2
spontaneous
cyclization
Figure 1 Bond disconnections for pyrrole synthesis
R3
R3
R2
R3
R2
O
N
O
NHR
R1
R
R4
Contraction of an existing heterocyclic ring into pyrrole
has also been reported. In this regard, 1,2-diazines14 or
3,6-dihydro-1,2-oxazines 3 can be viewed as direct pre-
N
R
5
R1
6
R1
R = acyl
R1, R2, R3, R4 = H, alkyl, aryl
SYNTHESIS 2005, No. 19, pp 3346–3354
Advanced online publication: 04.11.2005
x
x.
x
x
.
2
0
0
5
DOI: 10.1055/s-2005-918457; Art ID: C04905SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 A straightforward two-step synthesis of polysubstituted

PAPER
Synthesis of Polysubstituted Pyrroles from Nitroso-Diels–Alder Cycloadducts
3347
or Bu4NIO4, CH2Cl2, 0 °C (conditions B)25 (Scheme 3,
Table 1).
pyrroles 5 from 3,6-dihydro-1,2-oxazines 6
We first examined the cycloaddition reaction of the ni-
troso dienophile derived from tert-butyl-N-hydroxycar-
bamate with mono- or disubstituted 1,3-dienes 7a–i. The
substitution of these dienes was chosen as representative
of alkyl groups (7a–c), aromatic group (7d), hydroxy-
methyl (7e–g), and aminomethyl functions (7h–i). Two
sets of oxidation conditions were evaluated according to
the diene solubility: NaIO4, MeOH, 0 °C (conditions A)
Symmetrical 1,3-dienes were reacted first (Table 1, en-
tries 1 and 2). In line with previous work, the correspond-
ing cycloadducts 8a and 8b were obtained with moderate
to good yields. Dissymmetrical 1,3-dienes 7c–i were then
submitted to the nitroso-Diels–Alder cycloaddition
(Table 1, entries 3–9). Good yields of the corresponding
cycloadducts were obtained, except for 8c, as has been
previously noted. The regioisomeric ratios ranges from
Table 1 Synthesis of 3,6-Dihydro-1,2-oxazines 8 and 9 by Nitroso-Diels–Alder Cycloaddition
Entry
1
Diene
Cycloadducts
Yielda
Ratio 8/9
Me
Conditions A: 84%
–
Me
O
N
Boc
Me
7ab
Me
8ac
2
Conditions A: 42%
–
Me
Me
O
N
Me
Me
Boc
7b
8b
3
4
5
Conditions A: 25%
Conditions B: 38%
45:55
20:80
67:33
Me
Boc
Boc
Me
Me
N
O
O
N
Boc
7c
9c
8c
Ph
Conditions A: 80%
Conditions B: 84%
Ph
Ph
O
N
N
O
Boc
7d
8d
9d
Conditions B: 80%
OH
OH
OH
Boc
O
N
N
O
Boc
Me
Me
Me
8e
7e
9e
6
7
Conditions A: 51%
Conditions B: 97%
87:13
2:98
OTBS
OTBS
OTBS
Boc
N
O
O
N
Boc
Me
Me
Me
7f
8f
9f
Conditions B: 74%
OTBS
OTBS
OTBS
Boc
O
N
N
O
Boc
Ph
Ph
8g
Ph
7g
9g
8
9
Conditions B: 89%
Conditions B: 67%
73:27
2:98
NHTs
NHTs
NHTs
Boc
O
N
N
Boc
Me
O
Me
Me
7h
8h
9h
NHTs
NHTs
NHTs
Boc
N
O
O
N
Boc
Ph
Ph
Ph
7i
8i
9i
a Isolated yield. Conditions A: NaIO4, MeOH, 0 °C; Conditions B: Bu4NIO4, CH2Cl2, 0 °C to r.t.
b As commercially available 70:30 (E,E)/(Z,E) mixture.
c With 20% trans isomer.
Synthesis 2005, No. 19, 3346–3354 © Thieme Stuttgart · New York

3348
G. Calvet et al.
PAPER
55:45 (Table 1, entry 3) to 2:98 (Table 1, entries 7 and 9), Table 2 N–O Bond Cleavage of 3,6-Dihydro-1,2-oxazines 8 and 9
depending on the diene. The structure of each regioisomer
Entry
Oxazine Carbamates 10
and 11
Yield
was unambiguously deduced from multidimensional
NMR experiments (HMBC and HSQC). The presence of
a phenyl substituent on C2 in diene 7d led to an increase
in the regioisomeric ratio of the corresponding cycload-
ducts compared to the C2-methyl substituted dienes 7c
(Table 1, entries 4 and 3, 20:80 vs. 45:55). That the phenyl
moiety was a stronger directing group than the methyl
group in this cycloaddition was confirmed with 1,3-dienes
7g and 7i. The regioisomeric ratio of nitroso-Diels–Alder
cycloadducts was 87:13 and 73:27 with 5-methyl-1,3-
dienes 7f and 7h (Table 1, entries 6 and 8) whereas a 2:98
ratio was observed with 5-phenyl-1,3-dienes 7g and 7i
(Table 1, entries 7 and 9). It has been previously shown
for the nitroso-Diels–Alder cycloaddition that a substitu-
ent at the C1-position had a stronger directing effect than
a substituent at C2.26
1
8a
67%
Me
OH
NHBoc
Me
10a
2
8b
81%
Me
OH
NHBoc
Me
10b
3
4
5
8c + 9c
8d + 9d
8e + 9e
65%
76%
60%
Me
Me
OH
NHBoc
NHBoc
OH
10c
Ph
11c
Ph
OH
NHBoc
NHBoc
OH
10d
11d
OH
OH
R4
R4
R4
NHBoc
OH
OH
NHBoc
Boc-NHOH
Method A or B
R3
R2
R3
R2
R3
Boc R2
Boc
O
N
N
O
+
Me
Me
11e
10e
R1
R1
R1
6
7
8
9
8f + 9f
8g + 9g
8h + 9h
8i + 9i
70%
85%
85%
68%
OTBS
OTBS
7
8
9
OH
NHBoc
NHBoc
OH
Scheme 3
Me
Me
10f
11f
3,6-Dihydro-1,2-oxazines 8a–i and 9c–i were then sub-
jected to N–O bond cleavage, mediated by Mo(CO)6 in
aqueous acetonitrile.27 The corresponding (Z)-hydroxy-
carbamate were obtained as mixture of regioisomers, in
good yields (Scheme 4, Table 2).
OTBS
OTBS
NHBoc
OH
OH
NHBoc
Ph
Ph
11g
10g
NHTs
NHTs
R4
R4
OH
NHBoc
NHBoc
OH
NaBH4, Mo(CO)6
CH3CN–H2O, 90 °C
R3
R2
R3
R2
OH
NHBoc
OH
+
8 + 9
Me
Me
NHBoc
10h
11h
R1
R1
11
NHTs
NHTs
10
OH
NHBoc
NHBoc
OH
Scheme 4
Ph
Ph
10i
11i
Hydroxycarbamates 10a–d and 11c–d were oxidized with
MnO2 in dichloroethane (Table 3, conditions A); a
smooth oxidation occurred, followed by a spontaneous
cyclization reaction. In some cases, it was necessary to
heat the reaction mixture to promote the ring closure. Both
2,5- and 3,4-disubstituted pyrroles 12a and 12b were ob-
tained in 60% isolated yield under these conditions
(Table 3, entries 1 and 2). Monosubstituted pyrrole could
also be obtained in good yield (Table 3, entry 3) except in
the case of the 3-phenyl substitution which proved detri-
mental to the yield (Table 3, entry 4, conditions A, 28%).
Hydroxycarbamates 10e and 11e, possessing a primary al-
cohol moiety, led to a complex mixture of products
(Table 3, entry 5).
clean conversion to the corresponding (Z)-g-aminoenone
took place (89% yield). However, the latter decomposed
under neutral, acidic, or basic cyclization conditions
2d
(MnO2, CH2Cl2, 90 °C; anhyd HCl, CH2Cl2 KHMDS,
THF, –78 °C). Therefore, a second set of oxidation condi-
tions using Dess–Martin periodinane was evaluated
(Table 3, conditions B). Reactions were generally cleaner
and better yields were obtained (Table 3, entry 4, 28% un-
der conditions A, compared to 98% under conditions B;
entry 6, 47% under conditions A, compared to 68% under
conditions B). Under these modified conditions the sensi-
tive pyrrole 12g was obtained in 69% yield at 45 °C
In some cases, pyrrole synthesis by MnO2 oxidation (Table 3, entry 7). The yield dropped to 33% when the ox-
proved unsuccessful. When hydroxycarbamates 10g and idation took place at 90 °C, highlighting the sensitive na-
11g (Table 2, entry 7) were treated with MnO2 at 30 °C, a ture of the transient (Z)-g-aminoenone and/or pyrrole 12g
Synthesis 2005, No. 19, 3346–3354 © Thieme Stuttgart · New York

PAPER
Synthesis of Polysubstituted Pyrroles from Nitroso-Diels–Alder Cycloadducts
3349
(vide supra). It is interesting to note that 10h and 11h led addition combined with a straightforward sequence
to the same pyrrole in different yields. Regioisomer 10h including N–O bond cleavage and oxidation reaction of
leads to 12h in quantitative yield whereas 11h gave only the resulting (Z)-g-aminoenone (or enal) leading directly
a 51% yield (Table 3, entry 8). Pyrrole 12i was obtained to the desired pyrrole. Two sets of oxidation conditions
in 61% yield, allowing further functionalization of the have been successfully applied: MnO2 or Dess–Martin
phenyl or tosylamino moieties (Table 3, entry 9).
periodinane according to the sensitivity of the reactants
and/or the products. Owing to the mild conditions re-
quired and the diversity of substitution attainable, this
transformation should prove useful for the synthesis of
polysubstituted pyrrolic units.
Method A
R2
R3
or
Method B
10 + 11
R1
R4
N
Boc
12
All reactions were conducted in flame-dried or oven dried glass-
ware under an atmosphere of dry nitrogen. All solvents were puri-
fied before use unless otherwise indicated. THF, Et2O, and toluene
were distilled over Na/benzophenone ketyl anion under argon.
CH2Cl2 was distilled over CaH2 under argon. All other reagents
were purchased and used without further purification. Analytical
TLC was performed on Kieselgel 60 F254 glass precoated with 0.25
mm of silica gel. Flash chromatography was performed on Kiesel-
gel 60 (230–400 mesh) silica gel. IR spectra were recorded as thin
films on NaCl plates using a Perkin-Elmer Spectrum One FT-IR
spectrophotometer. 1H NMR spectra were measured at 360 MHz on
a Bruker AC360, at 250 MHz on a Bruker AC250 or AM250 and at
200 MHz on a Brucker AC200 using CDCl3 as solvent. Chemical
shifts are reported to 0.01 ppm precision with coupling constants re-
ported to 0.1 Hz precision using residual CHCl3 (7.27 ppm) as an
internal reference. MS were measured on a MAT 95S Finnigan-
Thermo spectrometer at the Institut de Chimie Moléculaire d’Orsay
(ICMMO) Mass Spectrometry Laboratory. Elemental analyses
were performed at the ICSN, CNRS, Gif sur Yvette, France. Spec-
troscopic data were in agreement with literature data for compounds
8a,28 8c,29 9c,29 10a,24 10b,24 11c,31 12a,2d and 12c.30
Scheme 5
Table 3 Synthesis of Pyrroles 12 from Carbamates 10 and 11
Entry Carbamates
Pyrrole 12
Yielda
10 and 11
1
2
10a
Conditions A: 60%
Me
Me
N
Boc
12a
10b
Conditions A: 60%
Conditions A: 63%
Me
Me
N
Boc
12b
Me
3
4
10c + 11c
10d + 11d
N
Boc
12c
Ph
Conditions A: 28%
Conditions B: 98%
Nitroso-Diels–Alder Cycloaddition – Method A; Typical Proce-
dure
N
To a soln of 2,6-hexadiene 7a (E,E/E,Z = 70:30 as determined by 1H
NMR analysis of the commercial compound, 0.27 mL, 2.3 mmol)
in MeOH (15 mL) at 0 °C was added portionwise NaIO4 (497 mg,
2.3 mmol) and BocNHOH (310 mg, 2.3 mmol) over 4 h. The reac-
tion mixture was stirred at 0 °C for 2 h and then quenched with a sat.
aq soln of Na2S2O3 (10 mL). The aqueous phase was extracted with
EtOAc (3 × 20 mL), the combined organic phases were washed with
brine (30 mL), dried over MgSO4, filtered, and concentrated. The
crude oil was purified by flash chromatography (heptane–EtOAc,
90:10) to give 8a (412 mg, 84%) as a colorless oil.
Boc
12d
–
b
5
6
10e + 11e
10f + 11f
Conditions A: 47%
Conditions B: 68%
OTBS
OTBS
OTBS
NHTs
Me
12f
Ph
N
Boc
7
8
9
10g + 11g
10h + 11h
10i + 11i
Conditions B: 69%
N
Boc
12g
Ph
Nitroso-Diels–Alder Cycloaddition – Method B; Typical Proce-
dure
Conditions B: 100%c
Conditions B: 51%d
N
To a soln of diene 7h (603 mg, 2.4 mmol) and BocNHOH (320 mg,
2.4 mmol) in CH2Cl2 (7 mL) at 0 °C was added a soln of Bu4NIO4
(520 mg, 1.2 mmol) in CH2Cl2 (5 mL) dropwise over 40 min. The
reaction mixture was stirred at 0 °C for 1.5 h and at r.t. for 2 h before
being quenched with a sat. aq Na2S2O3 soln (5 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 10 mL), the combined organ-
ic phases were washed with brine (15 mL), dried over MgSO4, fil-
tered, and concentrated. The crude oil was purified by flash
chromatography (heptane–EtOAc, 90:10) to give 8h (32.2 mg) and
a mixture of 8h and 9h (782 mg, 89% combined yield) as colorless
oils.
Boc
12h
Me
Conditions B: 61%
N
Boc
12i
a Isolated yield of pyrrole; Conditions A: MnO2, 1,2-dichloroethane,
30 °C; Conditions B: Dess–Martin periodinane, CH2Cl2–H2O, 90 °C.
b Complex mixture of products was obtained.
c Carbamate 10h alone was used as starting material.
d Carbamate 11h alone was used as starting material.
tert-Butyl 4,5-Dimethyl-3,6-dihydro-2H-1,2-oxazine-2-carboxy-
late (8b)
Rf 0.27 (heptane–EtOAc, 90:10).
In conclusion, we have shown that protected 3,6-dihydro-
1,2-oxazines can be viewed as latent pyrroles. Benefits in-
clude the wide scope of the nitroso-Diels–Alder cyclo-
IR: 2979, 2930, 1728, 1708, 1393, 1368, 1239, 1173, 1140, 1089,
865 cm–1.
Synthesis 2005, No. 19, 3346–3354 © Thieme Stuttgart · New York

3350
G. Calvet et al.
PAPER
1H NMR (benzene-d6, 250 MHz): d = 4.03 (s, 2 H), 3.86 (s, 2 H),
1.42 (s, 6 H, CH3-4, CH3-5), 1.24 (s, 9 H, 3 × CH3).
HRMS-ESI: m/z calcd for C11H19NO4Na [M + Na]+: 252.1206;
found: 252.1209.
13C NMR (benzene-d6, 100 MHz): d = 155.2, 147.9, 123.2, 122.3,
84.5, 80.6, 70.9, 48.6, 28.3, 27.1, 14.9, 13.4.
tert-Butyl 3-Hydroxymethyl-6-methyl-3,6-dihydro-2H-1,2-
oxazine-2-carboxylate (9e)
Rf 0.18 (heptane–EtOAc, 70:30).
IR: 3430, 1683, 1704, 1695, 1369, 1164 cm–1.
tert-Butyl 5-Methyl-3,6-dihydro-2H-1,2-oxazine-2-carboxylate
(8c)
Isolated as a mixture with 9c; Rf 0.22 (heptane–EtOAc, 90:10).
1H NMR (CDCl3, 400 MHz): d = 5.81 (d, J = 10.4 Hz, 1 H), 5.77
(ddd, J = 10.4, 3.8, 1.8 Hz, 1 H), 4.64 (m, 1 H), 4.46 (m, 1 H), 3.77–
3.71 (2 H, CH2OH), 2.36 (br s, 1 H, OH), 1.48 (s, 9 H, 3 × CH3),
1.24 (d, J = 6.8 Hz, 3 H, CH3-6).
1H NMR (CDCl3, 400 MHz): d = 5.54 (m, 1 H, H-4), 4.24 (br s, 2
H, H-6), 4.02 (br s, 2 H, H-3), 1.65 (s, 3 H, CH3-5), 1.49 (s, 9 H,
3 × CH3).
13C NMR (CDCl3, 100 MHz): d = 154.8 or 154.7 (CO), 131.3 or
130.0 (C-5), 116.2, 81.3, 70.9, 44.5, 28.0, 18.0.
13C NMR (CDCl3, 100 MHz): d = 155.1, 131.2, 130.2, 81.9, 72.3,
63.3, 56.1, 28.2, 18.7.
MS (ESI, Na+): m/z (%) = 252.1 ([M + Na]+, 100), 196 (75).
HRMS-ESI: m/z calcd for C11H19NO4Na [M + Na]+: 252.1206;
tert-Butyl 4-Methyl-3,6-dihydro-2H-1,2-oxazine-2-carboxylate
(9c)
Isolated as a mixture with 8c; Rf 0.22 (heptane–EtOAc, 90:10).
found: 252.1209.
IR: 1728, 1704, 1393, 1367, 1243, 1165, 1102, 858, 760 cm–1.
tert-Butyl 6-[(tert-Butyldimethylsilyl)oxy]methyl-3-methyl-3,6-
dihydro-2H-1,2-oxazine-2-carboxylate (8f)
Rf 0.37 (heptane–EtOAc, 90:10).
1H NMR (CDCl3, 400 MHz): d = 5.54 (m, 1 H, H-5), 4.35 (br s, 2
H, H-6), 3.93 (m, 2 H, H-3), 1.72 (s, 3 H, CH3-4), 1.49 (s, 9 H, 3 ×
CH3).
13C NMR (CDCl3, 100 MHz): d = 154.8 or 154.7 (CO), 131.3 or
130.0 (C-5), 117.8, 81.3, 67.7, 48.3, 28.0, 19.5.
IR: 2957, 2930, 1728, 1704, 1393, 1367, 1313, 1256, 1174, 1118,
839, 778 cm–1.
1H NMR (CDCl3, 400 MHz): d = 5.85 (ddd, J = 10.2, 4.4, 2.2 Hz, 1
H), 5.76 (d, J = 10.2 Hz, 1 H), 456 (br s, 1 H, H-6), 4.43 (br s, 1 H,
H-3), 3.75 (dd, J = 10.7, 5.6 Hz, 1 H, CHHOSi), 3.59 (dd, J = 10.7,
5.4 Hz, 1 H, CHHOSi), 1.48 (s, 9 H, 3 × CH3), 1.28 (d, J = 6.8 Hz,
3 H, CH3-3), 0.88 (s, 9 H, 3 × CH3), 0.06 (s, 6 H, 2 × CH3).
13C NMR (CDCl3, 100 MHz): d = 154.4, 129.3, 124.8, 81.1, 77.6,
63.7, 50.1, 28.3, 25.8, 18.2, 18.0, –5.4, –5.5.
MS (ESI, Na+): m/z (%) = 366.2 ([M + Na]+, 46), 310.2 (31), 244.2
(100).
HRMS-ESI: m/z calcd for C17H33NO4SiNa [M + Na]+: 366.2071;
found: 366.2084.
tert-Butyl 5-Phenyl-3,6-dihydro-2H-1,2-oxazine-2-carboxylate
(8d)
Rf 0.23 (heptane–EtOAc, 90:10).
IR: 2978, 1704, 1367, 1246, 1165, 749, 693 cm–1.
1H NMR (CDCl3, 250 MHz): d = 7.36–7.26 (5 H, Ar), 6.19 (m, 1 H,
H-4), 4.78 (dd, J = 4.0, 2.0 Hz, 2 H, H-6), 4.25 (dd, J = 9.2, 4.0 Hz,
2 H, H-3), 1.52 (s, 9 H, 3 × CH3).
13C NMR (CDCl3, 90 MHz): d = 154.9, 136.5, 134.5, 128.6, 127.9,
124.7, 118.4, 81.7, 69.2, 45.1, 28.2.
tert-Butyl 4-Phenyl-3,6-dihydro-2H-1,2-oxazine-2-carboxylate
(9d)
Rf 0.23 (heptane–EtOAc, 90:10).
IR: 2978, 1704, 1367, 1246, 1165, 749, 693 cm–1.
1H NMR (CDCl3, 250 MHz): d = 7.39–7.28 (5 H, Ar), 6.19 (m, 1 H,
H-5), 4.61 (dd, J = 5.3, 2.6 Hz, 2 H, H-6), 4.48 (dd, J = 4.0, 2.1 Hz,
2 H, H-3), 1.52 (s, 9 H, 3 × CH3).
13C NMR (CDCl3, 90 MHz): d = 154.9, 137.1, 133.1, 128.6, 127.9,
124.7, 120.0, 81.7, 68.1, 46.2, 28.2.
tert-Butyl 3-[(tert-Butyldimethylsilyl)oxy]methyl-6-methyl-3,6-
dihydro-2H-1,2-oxazine-2-carboxylate (9f)
Rf 0.34 (heptane–EtOAc, 90:10).
IR: 2931, 2858, 1704, 1367, 1255, 1111, 838, 777 cm–1.
1H NMR (CDCl3, 400 MHz): d = 5.91 (ddd, J = 10.3, 4.2, 1.9 Hz, 1
H), 5.77 (d, J = 10.3 Hz, 1 H), 4.62 (m, 1 H), 4.42 (m, 1 H), 3.81
(dd, J = 9.8, 7.5 Hz, 1 H, CHHOSi), 3.66 (dd, J = 9.8, 6.9 Hz, 1 H,
CHHOSi), 1.48 (s, 9 H, 3 × CH3), 1.24 (d, J = 6.8 Hz, 3 H, CH3-6),
0.89 (s, 9 H, 3 × CH3), 0.06 (s, 6 H, 2 × CH3).
MS (ESI, Na+): m/z (%) = 545.3 ([2 M + Na]+, 36), 284.2 ([M +
13C NMR (CDCl3, 100 MHz): d = 154.3, 130.4, 123.9, 81.2, 72.5,
63.8, 55.3, 28.3, 25.8, 18.8, 18.3, –5.4 (2 C).
Na]+, 100), 162.1 (68).
HRMS-ESI: m/z calcd for C15H19NO3Na [M + Na]+: 284.1257;
MS (ESI, Na+): m/z (%) = 366.2 ([M + Na]+, 100), 310.1 (69), 266.1
found: 284.1259.
(44)
HRMS-ESI: m/z calcd for C17H33NO4SiNa [M + Na]+: 366.2071;
found: 366.2080.
tert-Butyl 6-Hydroxymethyl-3-methyl-3,6-dihydro-2H-1,2-
oxazine-2-carboxylate (8e)
Rf 0.14 (heptane–EtOAc, 70:30).
IR: 3428, 1651, 1369 cm–1.
1H NMR (CDCl3, 400 MHz): d = 5.81 (ddd, J = 10.2, 4.4, 2.2 Hz, 1
H), 5.66 (d, J = 10.2 Hz, 1 H), 4.57 (br m, 1 H, H-6), 4.33 (br m, 1
H, H-3), 3.85 (br s, 1 H, OH), 3.62 (d, J = 5.1 Hz, 2 H, CH2OH),
1.42 (s, 9 H, 3 × CH3), 1.22 (d, J = 6.7 Hz, 3 H, CH3-3).
13C NMR (CDCl3, 100 MHz): d = 154.4, 129.6, 124.1, 81.4, 78.5,
63.2, 50.4, 28.1, 17.8.
MS (ESI, Na+): m/z (%) = 196.0 ([M + Na]+, 100).
tert-Butyl 3-[(tert-Butyldimethylsilyl)oxy]methyl-6-phenyl-3,6-
dihydro-2H-1,2-oxazine-2-carboxylate (9g)
Rf 0.22 (heptane–EtOAc, 98:2).
IR: 2955, 2929, 2857, 1706, 1368, 1254, 1170, 1105, 837, 777, 716,
698 cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.38–7.33 (5 H), 6.09 (ddd,
J = 10.5, 4.3, 2.0 Hz, 1 H), 5.98 (ddd, J = 10.4, 10.4, 1.2 Hz, 1 H),
5.52 (br s, 1 H, H-6), 4.57 (br s, 1 H, H-3), 3.94 (dd, J = 9.9, 7.4 Hz,
1 H, CHHOSi), 3.81 (dd, J = 9.9, 6.8 Hz, 1 H, CHHOSi), 1.54 (s, 9
H, 3 × CH3), 0.93 (s, 9 H, 3 × CH3), 0.10 (s, 6 H, 2 × CH3).
Synthesis 2005, No. 19, 3346–3354 © Thieme Stuttgart · New York

PAPER
Synthesis of Polysubstituted Pyrroles from Nitroso-Diels–Alder Cycloadducts
3351
13C NMR (CDCl3, 100 MHz): d = 154.3, 137.0, 128.7, 128.6, 128.4,
128.0, 124.6, 81.1, 78.1, 63.8, 55.5, 28.2, 25.7, 18.1, –5.4, –5.6.
tert-Butyl (Z)-4-Hydroxy-3-phenylbut-2-en-1-yl Carbamate
(10d)
Isolated as a minor isomer as a mixture with 11d.
MS (ESI, Na+): m/z (%) = 428.4 ([M + Na]+, 42), 306.3 (100).
1H NMR (CDCl3, 250 MHz): d = 7.49 (d, J = 6.8 Hz, 2 H), 7.36–
7.26 (3 H), 5.78 (t, J = 7.8 Hz, 1 H, H-2), 4.98 (s, 1 H), 4.55 (s, 1
H), 3.94 (dd, J = 7.8, 6.1 Hz, 2 H, H-1), 3.74 (s, 1 H), 1.42 (s, 9 H,
3 × CH3).
HRMS-ESI: m/z calcd for C22H35NO4SiNa [M + Na]+: 428.2228;
found: 428.2229.
tert-Butyl 3-Methyl-6-(tosylamino)methyl-3,6-dihydro-2H-1,2-
oxazine-2-carboxylate (8h)
Rf 0.28 (heptane–EtOAc, 70:30).
IR: 3267, 2978, 1699, 1369, 1329, 1161, 1119, 816, 665 cm–1.
tert-Butyl (Z)-4-Hydroxy-2-phenylbut-2-en-1-yl Carbamate
(11d)
IR: 3332, 1689, 1514, 1367, 1251, 1166, 767, 698 cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.74 (d, J = 8.0 Hz, 2 H), 7.30 (d,
J = 8.0 Hz, 2 H), 5.86 (ddd, J = 10.4, 4.4, 2.0 Hz, 1 H), 5.62 (d,
J = 10.4 Hz, 1 H), 5.13 (br s, 1 H, NH), 4.57 (br s, 1 H, H-6), 4.39
(br s, 1 H, H-3), 3.24 (ddd, J = 13.2, 7.3, 3.2 Hz, 1 H, CHHN), 3.01
(ddd, J = 13.2, 7.1, 5.4 Hz, 1 H, CHHN), 2.42 (s, 3 H, CH3Ph), 1.49
(s, 9 H, 3 × CH3), 1.25 (d, J = 6.8 Hz, 3 H, CH3-3).
13C NMR (CDCl3, 100 MHz): d = 154.2, 143.4, 136.8, 130.6, 129.7,
127.0, 123.9, 81.9, 75.8, 50.5, 45.1, 28.2, 21.5, 18.0.
MS (ESI, Na+): m/z (%) = 405.2 ([M + Na]+, 96), 283.2 (100).
HRMS-ESI: m/z calcd for C18H26NO5SNa [M + Na]+: 405.1455;
1H NMR (CDCl3, 250 MHz): d = 7.38–7.26 (m, 5 H), 6.10 (t,
J = 6.8 Hz, 1 H, H-3), 4.87 (s, 1 H), 4.34 (d, J = 7.3 Hz, 2 H), 4.21
(d, J = 5.9 Hz, 2 H), 1.38 (s, 9 H, 3 × CH3).
13C NMR (CDCl3, 100 MHz): d = 156.2, 140.2, 139.3, 129.7, 128.6,
127.7, 126.6, 80.0, 58.0, 38.8, 28.3.
MS (ESI, Na+): m/z (%) = 286.3 ([M + Na]+, 64), 230.2 (45), 186.2
(24).
HRMS-ESI: m/z calcd for C15H21NO3Na [M + Na]+: 286.1414;
found: 286.1420.
found: 405.1462.
tert-Butyl (2S,5S)-(Z)-6-(tert-Butyldimethylsilyl)oxy-5-
hydroxyhex-3-en-2-yl Carbamate (10f)
Rf 0.28 (heptane–EtOAc, 80:20).
tert-Butyl 6-Methyl-3-(tosylamino)methyl-3,6-dihydro-2H-1,2-
oxazine-2-carboxylate (9h)
Isolated as a mixture with 8h; Rf 0.26 (heptane–EtOAc, 70:30).
1H NMR (CDCl3, 250 MHz): d = 7.75 (d, J = 8.1 Hz, 2 H), 7.30 (d,
J = 8.1 Hz, 2 H), 5.81 (d, J = 10.4 Hz, 1 H), 5.71 (ddd, J = 10.4, 4.3,
1.9 Hz, 1 H), 4.83 (m, 1 H, NH), 4.59 (m, 1 H, H-6 or H-3), 4.48 (m,
1 H, H-3 or H-6), 3.17 (ddd, J = 9.3, 5.0, 2.0 Hz, 2 H, CH2N), 2.42
(s, 3 H, CH3-Ph), 1.54 (s, 9 H, 3 × CH3), 1.22 (d, J = 6.8 Hz, 3 H,
CH3-3).
IR: 3334, 2957, 2931, 1689, 1520, 1367, 1252, 1174, 1115, 1055,
837, 778 cm–1.
1H NMR (CDCl3, 360 MHz): d = 5.51 (dd, app. br t, J = 9.2 Hz, 1
H, H-4), 5.31 (br t, J = 10.1 Hz, 1 H, H-3), 4.58–4.50 (3 H, H-5, H-
2, OH or NH), 3.97 (br s, 1 H, OH or NH), 3.65 (m, 1 H, H-6), 3.57
(dd, J = 9.4, 5.6 Hz, 1 H, H-6), 1.42 (s, 9 H, 3 × CH3), 1.18 (d,
J = 6.8 Hz, 3 H, H-1), 0.89 (s, 9 H, 3 × CH3), 0.08 (s, 6 H, 2 × CH3).
13C NMR (CDCl3, 90 MHz): d = 155.4, 134.5, 130.7, 79.9, 67.4,
66.8, 44.0, 28.4, 25.9, 21.1, 18.3, –5.3 (2 C).
13C NMR (CDCl3, 62.5 MHz): d = 154.0, 143.4, 136.8, 131.7,
129.7, 127.1, 122.7, 82.4, 72.3, 65.9, 45.0, 28.3, 18.7, 15.3.
MS (ESI, Na+): m/z (%) = 713.5 ([2 M + Na]+, 4), 368.2 ([M + Na]+,
tert-Butyl 6-Phenyl-3-(tosylamino)methyl-3,6-dihydro-2H-1,2-
oxazine-2-carboxylate (9i)
Rf 0.31 (heptane–EtOAc, 70:30).
100), 246.2 (12).
HRMS-ESI: m/z (%) calcd for C17H35NO4SiNa [M + Na]+:
368.2228; found: 368.2242.
IR: 3278, 2978, 1704, 1395, 1369, 1331, 1161, 1094, 815, 757, 700,
662 cm–1.
tert-Butyl (2S,5S)-(Z)-1-(tert-Butyldimethylsilyl)oxy-5-
hydroxyhex-3-en-2-yl Carbamate (11f)
Isolated as a mixture with 10f.
1H NMR (CDCl3, 360 MHz): d = 5.58 (dd, app. br t, J = 9.5 Hz, 1
H), 5.37 (dd app. t, J = 10.3 Hz, 1 H), 4.69–4.66 (2 H), 4.11 (m, 1
H), 3.70 (dd, J = 9.7, 4.0 Hz, 1 H, H-1), 3.56 (m, 1 H, H-1), 1.40 (s,
9 H, 3 × CH3), 1.22 (d, J = 6.1 Hz, 3 H, H-6), 0.88 (s, 9 H, 3 × CH3),
0.08 (s, 6 H, 2 × CH3).
1H NMR (CDCl3, 250 MHz): d = 7.72 (d, J = 8.3 Hz, 2 H), 7.36–
7.29 (7 H), 6.01 (d, J = 10.3 Hz, 1 H), 5.93 (ddd, J = 10.4, 4.1, 2.3
Hz, 1 H), 5.49 (m, 1 H, H-6), 4.99 (m, 1 H, NH), 4.60 (m, 1 H, H-
3), 3.25 (t, J = 6.0 Hz, 2 H, CH2N), 2.40 (s, 3 H, CH3-Ph), 1.52 (s,
9 H, 3 × CH3).
13C NMR (CDCl3, 100 MHz): d = 154.5, 143.2, 136.8, 136.4, 129.5,
129.4, 129.0, 128.5, 128.2, 126.9, 123.9, 82.3, 78.0, 53.0, 45.0,
28.1, 21.3.
13C NMR (CDCl3, 90 MHz): d = 156.0, 136.8, 127.8, 80.0, 64.9,
62.0, 49.1, 28.3, 25.8, 22.3, 18.2, –5.6 (2 C).
MS (ESI, Na+): m/z (%) = 467.3 ([M + Na]+, 79), 411.2 (47), 345.3
(100).
tert-Butyl (2S,5S)-(Z)-5-Hydroxy-5-phenyl-1-(tert-butyl-
dimethylsilyl)oxyhex-3-en-2-yl Carbamate (11g)
HRMS-ESI: m/z calcd for C23H28N2O5SNa [M + Na]+: 467.1611;
found: 467.1619.
IR: 3442, 1692, 1493, 1367, 1253, 1171, 1101, 837, 778, 700 cm–1.
1H NMR (CDCl3, 250 MHz): d = 7.42–7.25 (m, 5 H), 5.80 (dd,
J = 10.5, 9.0 Hz, 1 H), 5.67 (d, J = 9.3 Hz, 1 H), 5.53 (t, J = 10.5 Hz,
1 H), 5.18 (br d, J = 6.0 Hz, 1 H), 4.64 (m, 1 H), 3.78 (dd, J = 10.1,
3.6 Hz, 1 H, CHHOSi), 3.61 (dd, J = 10.1, 3.9 Hz, 1 H, CHHOSi),
1.46 (s, 9 H, 3 × CH3), 0.91 (s, 9 H, 3 × CH3), 0.07 (s, 6 H, 2 × CH3).
13C NMR (CDCl3, 62.5 MHz): d = 156.1, 143.0, 135.3, 128.3,
127.1, 126.0, 80.3, 68.3, 64.8, 49.1, 28.4, 25.8, 18.3, –5.5.
N–O Bond Cleavage; Typical Procedure
To a soln of 8g (626 mg, 1.54 mmol) in CH3CN–H2O (7:1, 12 mL)
was added Mo(CO)6 (653 mg, 2.47 mmol). After 10 min at r.t.,
NaBH4 (29 mg, 0.77 mmol) was added and the suspension was heat-
ed at 90 °C overnight. The reaction mixture was cooled and Et2O
(10 mL) was added. The suspension was filtered through a bed of
celite and thoroughly rinsed with Et2O (3 × 5 mL). The filtrate was
concentrated and the crude oil was purified by flash chromatogra-
phy (heptane–EtOAc, 85:15 to 80:20) to give 11g (535 mg, 85%) as
a colorless oil.
MS (ESI, Na+): m/z (%) = 430.4 ([M + Na]+, 60), 290.3 (100).
HRMS-ESI: m/z calcd for C22H37NO4SiNa [M + Na]+: 430.2384;
found: 430.2389.
Synthesis 2005, No. 19, 3346–3354 © Thieme Stuttgart · New York

3352
G. Calvet et al.
PAPER
tert-Butyl (2S,5S)-(Z)-6-Tosylamino-5-hydroxyhex-3-en-2-yl
Carbamate (10h)
Rf 0.26 (heptane–EtOAc, 60:40).
IR: 3364, 2978, 1683, 1516, 1506, 1328, 1161, 914, 815, 734 cm–1.
1H NMR (CDCl3, 400 MHz): d = 5.80 (s, 2 H, H-3, H-4), 2.39 (s, 6
H, CH3-2, CH3-5), 1.60 (s, 9 H, 3 × CH3).
13C NMR (CDCl3, 100 MHz): d = 150.5, 131.2, 110.1, 83.2, 28.1,
16.5.
1H NMR (CDCl3, 360 MHz): d = 7.70 (d, J = 8.3 Hz, 2 H), 7.24 (d,
J = 8.3 Hz, 2 H), 5.41–5.34 (m, 2 H, H-4, OH or NH), 5.20 (t,
J = 10.4 Hz, 1 H, H-3), 4.89–4.82 (m, 2 H, NH, OH), 4.53 (m, 1 H,
H-5), 4.32 (br s, 1 H, H-2), 3.02 (ddd, J = 12.3, 7.8, 3.5 Hz, 1 H, H-
6), 2.84 (ddd, J = 12.3, 7.6, 4.6 Hz, 1 H, H-6), 2.35 (s, 3 H, CH3Ph),
1.33 (s, 9 H, 3 × CH3), 1.09 (d, J = 6.8 Hz, 3 H, H-1).
13C NMR (CDCl3, 90 MHz): d = 155.6, 143.1, 136.8, 135.3, 129.5,
129.1, 126.9, 80.0, 64.5, 47.6, 43.6, 28.1, 21.3, 20.1.
MS (ESI, Na+): m/z (%) = 407.3 ([M + Na]+, 100), 184.2 (43).
HRMS-ESI: m/z calcd for C18H28N2O5SNa [M + Na]+: 407.1611;
MS (ESI, Na+): m/z (%) = 413.2 ([2 M + Na]+, 100), 219.1 (32), 138
(53), 118 (32).
tert-Butyl 2-(tert-Butyldimethylsilyloxymethyl)-5-Methyl-1H-
pyrrole-1-carboxylate (12f) – Method B; Typical Procedure
To a soln of 10f and 11f (73.2 mg, 0.21 mmol) in CH2Cl2 (4.2 mL)
was added Dess–Martin periodinane (180 mg, 0.42 mmol) and the
resulting suspension was stirred at 90 °C for 8 h. The reaction mix-
ture was cooled and poured into a sat. aq soln of NaHCO3 (5 mL).
The aqueous phase was extracted with CH2Cl2 (3 × 5 mL), the com-
bined organic phases were washed with a sat. aq soln of Na2S2O3
(10 mL), dried over MgSO4, filtered, and concentrated. The crude
oil was purified by flash chromatography (heptane–EtOAc, 98:2) to
give 12f (47 mg, 68%) as colorless oil.
found: 407.1621.
tert-Butyl (2S,5S)-(Z)-1-Tosylamino-5-hydroxyhex-3-en-2-yl
Carbamate (11h)
Rf 0.28 (heptane–EtOAc, 60:40).
IR: 3364, 2978, 1683, 1516, 1506, 1328, 1161, 914, 815, 734 cm–1.
1H NMR (CDCl3, 250 MHz): d = 7.72 (d, J = 8.3 Hz, 2 H), 7.29 (d,
J = 8.3 Hz, 2 H), 5.64–5.53 (m, 2 H), 5.26 (d, J = 7.5 Hz, 1 H), 5.13
(t, J = 10.4 Hz, 1 H), 4.58–4.44 (m, 2 H), 4.05 (br s, 1 H), 2.97 (t,
J = 6.4 Hz, 2 H, H-1), 2.41 (s, 3 H, CH3Ph), 1.38 (s, 9 H, 3 × CH3),
1.18 (d, J = 6.5 Hz, 3 H, H-6).
13C NMR (CDCl3, 62.5 MHz): d = 156.0, 143.6, 137.8, 136.6,
129.8, 127.3, 126.9, 80.4, 62.3, 47.7, 46.1, 28.2, 22.4, 21.5.
Rf 0.40 (heptane–EtOAc, 95:5).
IR: 2980, 1767, 1716, 1369, 1153 cm–1.
1H NMR (CDCl3, 250 MHz): d = 6.06 (d, J = 2.7 Hz, 1 H), 5.84 (d,
J = 2.7 Hz, 1 H), 4.81 (s, 2 H, CH2O), 2.38 (s, 3 H, CH3-5), 1.58 (s,
9 H, 3 × CH3), 0.91 (s, 9 H, 3 × CH3), 0.05 (s, 6 H, 2 × CH3).
13C NMR (CDCl3, 62.5 MHz): d = 150.1, 135.0, 110.4, 109.8, 83.4,
60.6, 28.0, 25.9, 18.5, 16.2, –5.3.
MS (ESI, Na+): m/z (%) = 348.2 ([M + Na]+, 100), 301.2 (41), 275.1
(57), 231.1 (38).
MS (ESI, Na+): m/z (%) = 407.3 ([M + Na]+, 100), 250.2 (22), 184.2
(29).
HRMS-ESI: m/z calcd for C18H28N2O5SNa [M + Na]+: 407.1611;
found: 407.1622.
tert-Butyl 3,4-Dimethyl-1H-pyrrole-1-carboxylate (12b)
Prepared under conditions A; yield: 60%; Rf 0.10 (heptane).
IR: 2980, 2934, 1738, 1402, 1345, 1254 cm–1.
1H NMR (CDCl3, 400 MHz): d = 6.94 (s, 2 H, H-2, H-5), 1.98 (s, 6
H, CH3-3, CH3-4), 1.57 (s, 9 H, 3 × CH3).
tert-Butyl (2S,5S)-(Z)-5-Hydroxy-5-phenyl-1-tosylaminohex-3-
en-2-yl Carbamate (11i)
Rf 0.25 (heptane–EtOAc, 80:20).
13C NMR (CDCl3, 100 MHz): d = 148.9, 122.7, 117.0, 82.6, 28.0,
10.1.
IR: 3362, 2978, 1689, 1516, 1328, 1161, 1093, 815, 743, 701, 662
cm–1.
MS (ESI, Na+): m/z (%) = 413.2 ([2 M + Na]+, 68), 301 (28), 250
(45), 234 (100), 178 (55), 150 (48), 134 (51).
1H NMR (CDCl3, 250 MHz): d = 7.70 (d, J = 7.8 Hz, 2 H), 7.32–
7.24 (7 H), 5.74 (dd, J = 10.8, 9.3 Hz, 1 H), 5.65 (t, J = 6.4 Hz, 1 H),
5.50 (d, J = 8.8 Hz, 1 H), 5.34 (d, J = 7.0 Hz, 1 H), 5.23 (t, J = 10.4
Hz, 1 H), 4.63 (m, 1 H), 4.40 (br s, 1 H), 3.01–2.92 (2 H), 2.39 (s, 3
H, CH3Ph), 1.41 (s, 9 H, 3 × CH3).
13C NMR (CDCl3, 62.5 MHz): d = 156.0, 143.6, 142.6, 136.5,
136.2, 129.8, 128.4, 127.8, 127.3, 126.9, 126.0, 80.4, 68.5, 47.7,
46.0, 28.3, 21.4.
tert-Butyl 3-Methyl-1H-pyrrole-1-carboxylate (12c)
Prepared under conditions A; yield: 63%.
IR: 3151, 1741, 1343, 1251, 972 cm–1.
1H NMR (CDCl3, 400 MHz): d = 7.13 (t, J = 2.5 Hz, 1 H, H-2 or H-
5), 6.97 (m, 1 H, H-5 or H-2), 6.05 (m, 1 H, H-4), 2.06 (s, 3 H, CH3-
3), 1.58 (s, 9 H, 3 × CH3).
13C NMR (CDCl3, 100 MHz): d = 148.9, 122.4, 119.9, 117.1, 114.0,
83.1, 28.0, 11.9.
MS (ESI, Na+): m/z (%) = 469.3 ([M + Na]+, 100), 329.3 (23).
HRMS-ESI: m/z calcd for C23H30N2O5SNa [M + Na]+: 469.1768;
found: 469.1772.
tert-Butyl 3-Phenyl-1H-pyrrole-1-carboxylate (12d)
Prepared under conditions B; yield: 98%; Rf 0.24 (heptane–EtOAc,
98:2).
IR: 1743, 1392, 1355, 1142, 975 cm–1.
tert-Butyl 2,5-Dimethyl-1H-Pyrrole-1-carboxylate (12a) –
Method A; Typical Procedure
To a soln of 10a (55.4 mg, 0.26 mmol) in CH2Cl2 (2.6 mL) was add-
ed MnO2 (1.12 g, 12.9 mmol) and the resulting suspension was
stirred at 30 °C overnight. The reaction mixture was filtered through
a bed of celite and rinsed with CH2Cl2 (3 × 5 mL). The filtrate was
concentrated and the crude oil was purified by flash chromatogra-
phy (heptane–EtOAc, 95:5) to give 12a (29.8 mg, 60%) as a color-
less oil.
1H NMR (CDCl3, 400 MHz): d = 7.55 (d, J = 6.8 Hz, 4 H), 7.43 (t,
J = 6.8 Hz, 2 H), 7.35 (m, 1 H, H-2 or H-5), 6.59 (m, 1 H, H-4), 1.65
(s, 9 H, 3 × CH3).
13C NMR (CDCl3, 100 MHz): d = 148.8, 134.3, 128.7, 127.8, 126.6,
125.5, 120.9, 115.7, 110.4, 83.8, 28.0.
MS (EI): m/z (%) = 243.1 ([M]+, 9), 143.0 (100), 115 (34), 57 (65).
HRMS-EI: m/z (%) calcd for C23H30N2O5SNa [M]+: 243.1254;
found: 243.1265.
Rf 0.13 (heptane).
IR: 2978, 2930, 1739, 1371, 1335, 1313, 1125 cm–1.
Synthesis 2005, No. 19, 3346–3354 © Thieme Stuttgart · New York

PAPER
Synthesis of Polysubstituted Pyrroles from Nitroso-Diels–Alder Cycloadducts
3353
tert-Butyl [2-(tert-Butyldimethylsilyl)oxy]methyl-5-phenyl-1H-
pyrrole-1-carboxylate (12g)
Prepared under conditions B; yield: 69%; Rf 0.45 (heptane–EtOAc,
95:5); mp < 50 °C (waxy solid).
References
(1) (a) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001,
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IR: 2930, 1737, 1339, 1313, 1256, 1148, 1061, 838, 777, 698 cm–1.
1H NMR (CDCl3, 250 MHz): d = 7.29–7.21 (m, 5 H), 6.20 (d,
J = 3.5 Hz, 1 H), 6.08 (d, J = 3.5 Hz, 1 H), 4.87 (s, 2 H, CH2O), 1.21
(s, 9 H, 3 × CH3), 0.90 (s, 9 H, 3 × CH3), 0.07 (s, 6 H, 2 × CH3).
13C NMR (CDCl3, 62.5 MHz): d = 149.8, 136.6, 135.5, 135.2,
128.7, 127.6, 126.8, 112.4, 110.0, 83.5, 59.9, 27.3, 25.9, 18.3, –5.3.
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MS (ESI, Na+): m/z (%) = 410.2 ([M + Na]+, 100), 301.2 (27).
HRMS-ESI: m/z calcd for C22H33NO3SiNa [M + Na]+: 410.2122;
found: 410.2118.
Anal. Calcd for C22H33NO3Si: C, 68.17; H, 8.58; N, 3.61. Found: C,
68.19; H, 8.58; N, 3.46.
tert-Butyl 2-(Tosylamino)methyl-5-methyl-1H-pyrrole-1-
carboxylate (12h)
Prepared under conditions B; yield: 100% (from 10h), 51% (from
11h); Rf 0.43 (heptane–EtOAc, 70:30); mp 73 °C.
IR: 3304, 1733, 1392, 1338, 1260, 1163, 1129, 1093, 850, 814, 790,
737 cm–1.
1H NMR (CDCl3, 250 MHz): d = 7.57 (d, J = 8.1 Hz, 2 H), 7.16 (d,
J = 8.1 Hz, 2 H), 5.91 (d, J = 3.2 Hz, 1 H), 5.67–5.61 (m, 2 H), 4.21
(d, J = 6.5 Hz, 2 H, CH2N), 2.37 (s, 3 H, CH3-Ar), 2.18 (s, 3 H, CH3-
5), 1.53 (s, 9 H, 3 × CH3).
13C NMR (CDCl3, 62.5 MHz): d = 150.3, 142.4, 137.7, 132.3,
129.7, 129.5, 129.1, 126.7, 113.6, 110.6, 84.4, 41.7, 27.8, 21.3,
16.5.
MS (ESI, Na+): m/z (%) = 387.2 ([M + Na]+, 100).
HRMS-ESI: m/z calcd for C18H24N2O4SNa [M + Na]+: 387.1349;
found: 387.1353.
Anal. Calcd for C18H24N2O4S: C, 59.32; H, 6.64; N, 7.69. Found: C,
59.30; H, 6.71; N, 7.50.
tert-Butyl 2-(Tosylamino)methyl-5-phenyl-1H-pyrrole-1-
carboxylate (12i)
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Prepared under conditions B; yield: 61%; Rf 0.25 (heptane–EtOAc,
80:20).
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IR: 3305, 1732, 1371, 1318, 1149, 1693, 812, 759, 735, 700 cm–1.
1H NMR (CDCl3, 250 MHz): d = 7.65 (d, J = 8.3 Hz, 2 H), 7.32–
7.26 (m, 3 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.08 (d, J = 7.5 Hz, 2 H),
6.08 (d, J = 2.9 Hz, 1 H), 5.93 (d, J = 2.9 Hz, 1 H), 5.83 (dd, app. t,
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CH3-Ar), 1.12 (s, 9 H, 3 × CH3).
13C NMR (CDCl3, 62.5 MHz): d = 150.3, 142.7, 138.0, 134.9,
131.2, 129.2, 128.5, 127.6, 126.9, 113.6, 112.4, 84.5, 41.4, 27.1,
21.4.
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(23).
HRMS-ESI: m/z calcd for C23H26N2O4SK [M + K]+: 465.1245;
found: 465.1258.
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Acknowledgment
We would like to thank Friederike Tewes for preliminary experi-
ments. We thank the Ministère de la Recherche et de la Technologie
for a grant (G.C.), the Université Paris-XI and the CNRS-UMR
8615 for financial support.
(19) McClure, K. F.; Danishefsky, S. J. J. Org. Chem. 1991, 56,
850.
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