Silver-catalyzed hydroamination: Synthesis of N-bridgehead pyrroles, incorporating a protection-deprotection strategy for preparation of cyclic secondary vinylogous carbamates

Article abstract of DOI:10.1002/ejoc.200400598

N-Bridgehead pyrroles are efficiently prepared from cyclic secondary vinylogous carbamates using a two-step sequence. This sequence involves C-propargylation followed by a silver-catalyzed intramolecular hydroamination. Hydroamination is brought about using microwave irradiation and affords the desired N-bridgehead pyrroles rapidly and in good yield. Cyclic secondary vinylogous carbamates are prepared using a mild, economical procedure. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400598

FULL PAPER
Silver-Catalyzed Hydroamination: Synthesis of N-Bridgehead Pyrroles,
Incorporating a Protection-Deprotection Strategy for Preparation of Cyclic
Secondary Vinylogous Carbamates
Ross S. Robinson,[a] Martin C. Dovey,*[a] and David Gravestock[a]
Keywords: Hydroamination / Pyrroles / Microwaves
N-Bridgehead pyrroles are efficiently prepared from cyclic
secondary vinylogous carbamates using two-step se-
quence. This sequence involves C-propargylation followed
by a silver-catalyzed intramolecular hydroamination. Hy-
droamination is brought about using microwave irradiation
and affords the desired N-bridgehead pyrroles rapidly and
in good yield. Cyclic secondary vinylogous carbamates are
prepared using a mild, economical procedure.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
a
alkaloids in animals.[7] Subsequent to that finding, several
syntheses of these types of compounds have appeared in the
literature,[8] a list to which we now add our method.
Introduction
Pyrroles are amongst the most recognisable structures in
organic chemistry; this being due to the enormous amount
of research focussed on their synthesis and reactivity,[1] as
well as their abundance in nature either as monopyrrolic
compounds[2] or cyclic tetrapyrroles (porphyrins, chlorins
etc.).[3]
Results and Discussion
We have recently reported a novel one-pot synthesis of
pyrroles via the silver-mediated reaction of secondary vi-
nylogous amides or carbamates with propargyl bromide.[4]
This procedure has been improved upon by employing a
two-step procedure which incorporates a silver-catalyzed
hydroamination as its second step.[5] We have now extended
this methodology to N-bridgehead pyrroles (Figure 1; 1, 2,
and 3), the pyrrole analogues of pyrrolizidines, indolizid-
ines, and pyrroloazepines (the term “lehmizidine“ has been
suggested by Garraffo et al.[6] to describe the “5–7-izid-
ines”).
In order to access the N-bridgehead pyrroles in question,
it was necessary to prepare cyclic secondary vinylogous car-
bamates 4 and, although their acyclic analogues 5 can be
readily obtained in high yield,[9] synthesis of the cyclic com-
pounds can be problematic (Figure 2).
Figure 2. Secondary yinylogous carbamates
They have been prepared from lactim ethers,[10] from az-
ido dicarbonyl compounds,[11] from alkenyl-substituted β-
enamino esters,[12] and by lithiation of ketimines[13]
amongst others. However, the most common method used
for preparation of these compounds is the Eschenmoser sul-
phide contraction (also known as the Eschenmoser coup-
ling reaction).[14] A typical synthetic strategy (Scheme 1)
would entail thionation of an appropriate lactam (6) to give
the corresponding thiolactam (7), which would be treated,
sequentially, with an activated alkyl halide (BrCH2CO2Et),
a weak base (Et3N) and a thiophile (Ph3P) to give the vi-
nylogous carbamate (8) at ambient temperature.
Figure 1. N-Bridgehead pyrrole skeletons
It is interesting to note that the pyrrole analogues of pyr-
rolizidine alkaloids have been identified as the metabolites
actually responsible for the hepatotoxicity of pyrrolizidine
[a]
Warren Research Laboratory, School of Chemistry, University
of KwaZulu-Natal,
Private Bag X01, Scottsville, Pietermaritzburg, South Africa,
3209
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DOI: 10.1002/ejoc.200400598
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
505

R. S. Robinson, M. C. Dovey, D. Gravestock
FULL PAPER
tions described above.[19] These two-step reactions are typi-
cally complete after 12–16 hours and in good yield
(Table 1).
Table 1. Preparation of secondary vinylogous carbamates
(Scheme 2)
Entry
10a
Starting material
n
Yield (%)
9a
1
2
3
1
2
3
1
2
3
1
2
3
97
92
89
70
58
90
83
84
23
63
86
83
10b
10c
12a
12b
12c
13a
13b
13c
11a
11b
11c
9b
9c
10a
10b
10c
12a
12b
12c
13a
13b
13c
Scheme 1. (i) Lawesson’s reagent, MW; (ii) BrCH2CO2Et, Et3N,
Ph3P, MeCN
However, if a secondary thiolactam (10) is employed in
the sulphide contraction, much harsher conditions are re-
quired.[14] Typical conditions for this form of the reaction
are the use of potassium tert-butoxide, a large excess of thio-
phile (4 equivalents) and long reaction times at high tem-
perature (72 hours in refluxing xylene).[15] This aside, the
Eschenmoser sulphide contraction is an efficient reaction
and it was deemed important to investigate ways of simpli-
fying the reaction conditions in order to prepare the desired
secondary vinylogous carbamates (Scheme 2).
Michael and Parsons have shown that acrylonitrile can
be successfully removed from a similar adduct 14 by treat-
ment with excess potassium tert-butoxide.[17] However,
when employing this method to remove methyl acrylate
from adduct 13a, the only product isolated was, rather sur-
prisingly, the transesterification product 15 (Figure 3).
The conjugate addition of thiolactams to acrylates has
been widely employed as a method of functionalising the
nitrogen atom of these compounds.[16] It has also been dem-
onstrated that this addition can be reversed by the addition
of a strong base.[17] Both of these reactions are reported to
give high yields (Ͼ90 %).
Thiolactams 10 can be easily prepared from the corre-
sponding lactam[18] and subsequent treatment with methyl
acrylate and a catalytic amount of sodium hydroxide gives
the acrylate adducts 12 in good yield (Table 1) and short
reaction time (2 h).[16] These adducts, being tertiary thiolac-
tams, can be converted to tertiary vinylogous carbamates
Figure 3. Related adducts
It was found that by using potassium hexamethyl disilaz-
13 using the mild Eschenmoser sulphide contraction condi- ide (KHMDS), in a similar fashion to previous work in
Scheme 2. (i) Lawesson’s reagent, MW; (ii) BrCH2CO2Et, tBuOK, Ph3P, xylene; (iii) CH2=CHCO2Me, NaOH, THF; (iv) BrCH2CO2Et,
Et3N, Ph3P, MeCN; (v) KHMDS, THF
506
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Eur. J. Org. Chem. 2005, 505–511

Silver-Catalyzed Hydroamination: Synthesis of N-Bridgehead Pyrroles
FULL PAPER
our group involving a vinylogous amide adduct 16,[17] that afford the thermodynamically more stable N-bridgehead
methyl acrylate was cleaved rapidly and efficiently to give pyrrole 20. It is believed that the low yields observed for this
secondary vinylogous carbamates 11 in good yields. The reaction are due to the many potential reaction pathways
secondary compounds adopt the energetically more favour- subsequent to the initial hydroamination.
able Z configuration due to hydrogen bonding, a fact that
is evident from the chemical shift of the amino proton of proved upon by carrying out the procedure in two discrete
the prepared compounds. steps (Scheme 4). C-Propargylation of vinylogous carbam-
As mentioned above, this one-pot method has been im-
These vinylogous carbamates 11 were treated with pro- ates 11 using n-butyllithium affords propargyl adducts 21.
pargyl bromide and silver nitrate, in the one-pot manner A bisadduct (13 %), arising from addition of two equiva-
originally reported,[4] to afford N-bridgehead pyrroles 20 al- lents of propargyl bromide to the carbamate, is noted dur-
beit in low yield (Table 2). This reaction is believed to pro- ing the preparation of 21b. The C-propargyl adducts 21 un-
ceed via silver-mediated hydroamination of the triple bond dergo silver-catalyzed (0.2 equivalents) hydroamination to
of propargyl bromide (17, Scheme 3), followed by nucleo- afford N-bridgehead pyrroles 20. The mechanism proposed
philic substitution via the enaminone functionality (18). Re- for this transformation is in keeping with the generally ac-
arrangement of the cyclic enamine intermediate 19 would cepted mechanism of nucleophilic addition to metal-acti-
vated carbon-carbon multiple bonds.[20] Hydroamination is
performed using a domestic microwave oven and, as such,
is extremely rapid (1 minute).
Table 2. Preparation of N-bridgehead pyrroles (Scheme 4)
This two-step procedure shows an improvement in over-
Entry
20a
Method[a] Starting material
Yield, % (Overall)
all yields compared to the one-pot approach with the added
bonus that the hydroamination is catalytic with respect to
silver (I) whereas the one-pot procedure requires a full stoi-
chiometric equivalent.
A
A
A
–
11a
11b
11c
11a
11b
11c
21a
21b
21c
13
19
20b
20c
21a
21b
21c
20a
20b
20c
14[b]
66
–
–
B
B
B
35[c]
24
75 (50)
75 (26)
71 (17)
Conclusions
In conclusion, we have developed a mild and efficient
means of preparing secondary cyclic vinylogous carbamates
in a relatively short time compared to other common meth-
[a] Method A: One-pot procedure, Method B: Two-step procedure.
[b] Isolated as a mixture of starting material and product. [c] Bisad-
duct also isolated as by-product (13 %).
Scheme 3
Scheme 4
Eur. J. Org. Chem. 2005, 505–511
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507

R. S. Robinson, M. C. Dovey, D. Gravestock
FULL PAPER
film, CHCl ): ν = 2934, 1736, 1682, 1594, 1130 cm–1. MS (EIMS):
˜
ods. We have also shown that these compounds can be
rapidly converted into the corresponding N-bridgehead pyr-
roles utilizing readily available materials and an inexpensive
catalyst system. We are currently attempting to optimize the
C-propargylation reaction discussed above in order to
3
m/z (%) = 241 [M+] (78), 196 (77), 182 (77), 169 (79), 154 (40), 136
(50), 110 (100). HRMS: found m/z = 241.1314 [M+], C12H19NO4
requires 241.1314.
Methyl 3-[(2E)-2-(2-Ethoxy-2-oxoethylidene)piperidin-1-yl]propano-
achieve further overall improvement. We are also exploring ate (13b): 12b (1.32 g, 6.56 mmol) was treated with ethyl bromoace-
tate (1.46 mL, 2.19 g, 13.1 mmol), NEt3 (1.10 mL, 0.80 g,
7.87 mmol), and PPh3 (2.06 g, 7.87 mmol) to afford 13b as a
colourless oil (1.40 g, 5.48 mmol, 84 %) after radial chromatogra-
phy (CH2Cl2/Hex, 1:1); Rf 0.43 (EtOAc/Hex, 1:1). 1H NMR
(500 MHz, CDCl3): δ (ppm) = 1.19 (t, J = 7.1 Hz, 3 H, OCH2CH3),
1.58 (m, 2 H, NCH2CH2CH2), 1.71 (m, 2 H, NCH2CH2CH2), 2.59
(t, J = 7.2 Hz, 2 H, CH2CO2CH3), 3.04 (t, J = 6.8 Hz, 2 H,
CH2C=CH), 3.21 (t, J = 6.3 Hz, 2 H, NCH2CH2CH2), 3.45 (t, J
= 7.2 Hz, 2 H, NCH2CH2CO2CH3), 3.65 (s, 3 H, OCH3), 4.01 (q,
J = 7.2 Hz, 2 H, OCH2CH3), 4.49 (s, 1 H, C=CH). 13C NMR
the possibility of using this strategy in the total synthesis of
bicyclic alkaloids.
Experimental Section
NMR spectra were recorded using a 500 MHz Varian Unity Inova
spectrometer equipped with an Oxford magnet (11.744T) and a
switchable 5 m probe. 1H NMR spectra were recorded at 500 MHz
in deuteriochloroform and referenced against the deuteriochloro-
form singlet at δ = 7.26 ppm. 13C NMR spectra were recorded at
125 MHz in deuteriochloroform and referenced against the central
line of the deuteriochloroform triplet at δ = 77.0 ppm. IR spectra
were recorded as thin films (chloroform) using a Perkin–Elmer
Spectrum One spectrometer. High resolution mass spectra were ob-
tained by the Mass Spectrometry Unit of the University of the
North West using an Autospec-TOF (Micromass) mass spectrome-
ter and the Mass Spectrometry Service at the School of Chemistry
at the University of the Witwatersrand using a Micromass VG 70
SEQ mass spectrometer. THF and acetonitrile were distilled before
use from sodium benzophenone and calcium hydride respectively.
Ethyl acetate and hexane, for chromatography, were distilled before
use. Thin-layer chromatography was carried out using silica gel 60
F254 aluminium backed plates. The plates were viewed under UV
light and developed in iodine thereafter. Silica gel 60 PF254 was
used for radial chromatography. Microwave reactions were carried
out using a National 700 W domestic microwave oven.
(125 MHz, CDCl3):
δ
(ppm)
=
14.6 (OCH2CH3), 19.4
(NCH2CH2CH2), 23.2 (NCH2CH2CH2), 26.3 (CH2C=CH), 30.1
(CH2CO2CH3), 47.4 (NCH2CH2CO2CH3), 50.0 (NCH2CH2CH2),
51.7 (OCH3), 58.1 (OCH2CH3), 82.1 (C=CH), 161.3 (C=CH),
168.7 (CO CH CH ), 172.0 (CO CH ). IR (thin film, CHCl ): ν =
˜
2
2
3
2
3
3
2945, 1736, 1679, 1569, 1133, 1050 cm–1. MS (EIMS): m/z (%) =
255 [M+] (84), 210 (68), 196 (65), 182 (100), 150 (60), 122 (67),
97 (87). HRMS: found m/z = 255.1471 [M+], C13H21NO4 requires
255.1471.
Methyl 3-[(2E)-2-(2-Ethoxy-2-oxoethylidene)azepan-1-yl]propanoate
(13c): 12c (1.40 g, 6.51 mmol) was treated with ethyl bromoacetate
(1.49 mL, 2.25 g, 13.5 mmol), NEt3 (1.13 mL, 0.82 g, 8.09 mmol),
and PPh3 (2.12 g, 8.09 mmol) to afford 13c as a colourless oil
(0.40 g, 1.5 mmol, 23 %) after radial chromatography (EtOAc/Hex,
1:3); R 0.52 (EtOAc/Hex, 1:1). 1H NMR (500 MHz, CDCl3): δ
f
(ppm) = 1.22 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.53 (br., 2 H,
NCH2CH2), 1.61 (br., 4 H, NCH2CH2CH 2CH2), 2.60 (t, J =
7.1 Hz, 2 H, CH2CO2CH3), 3.21 (br., 2 H, CH C=CH), 3.40 (m,
2
Thiolactams (10)[18] and their acrylate adducts (12)[16] were pre-
pared using literature procedures.
2
H, NCH2CH2CH2), 3.53 (t,
J
=
7.1 Hz,
2
H,
NCH2CH2CO2CH3), 3.67 (s, 3 H, OCH3), 4.04 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 4.46 (s, 1 H, C=CH). 13C NMR (125 MHz, CDCl3): δ
Preparation of Vinylogous Carbamate Acrylate Adducts (13). Gene-
[19]
(ppm)
=
14.6 (OCH2CH3), 25.9 (NCH2CH2CH2), 27.0
ral Procedure:
Ethyl bromoacetate (10 mmol) was added to a
(CH2C=CH), 28.7 (NCH2CH2CH2), 29.3 (CH2CH2C=CH), 31.3
(CH2CO2CH3), 48.5 (NCH2CH2CO2CH3), 51.7 (OCH3), 53.0
(NCH2CH2CH2), 58.2 (OCH2CH3), 82.9 (C=CH), 166.3 (C=CH),
solution of 12 (5 mmol) in dry CH3CN (10 mL) and stirred over-
night at room temperature to ensure salt formation. A solution of
NEt3 (6 mmol) and PPh3 (6 mmol) in dry CH2Cl2 (2 mL) was
added to the reaction mixture and stirred until the reaction was
complete according to TLC analysis (1–2 hours). The reaction was
quenched with water (5 mL) and extracted with CH2Cl2 (3 ×
20 mL). The organic layers were combined, dried (MgSO4), and
concentrated in vacuo to afford 13 after chromatography.
169.0 (CO CH CH ), 172.1 (CO CH ). IR (thin film, CHCl ): ν =
˜
2
2
3
2
3
3
2923, 1733, 1681, 1572, 1443, 1135 cm–1. HRMS: found m/z =
269.1628 [M+], C14H23NO4 requires 269.1627.
tert-Butyl 3-[(2E)-2-(2-Ethoxy-2-oxoethylidene)pyrrolidin-1-yl]pro-
panoate (15): tBuOK (1 m solution in tBuOH, 1.40 mL, 1.40 mmol)
was added to a solution of 12a (0.17 g, 0.70 mmol) in dry THF
(5 mL) and stirred at room temperature for 30 minutes. The reac-
Methyl
3-[(2E)-2-(2-Ethoxy-2-oxoethylidene)pyrrolidin-1-yl]pro-
panoate (13a): 12a (0.50 g, 2.7 mmol) was treated with ethyl bromo-
acetate (0.60 mL, 0.90 g, 5.4 mmol), NEt3 (0.45 mL, 0.32 g, tion was quenched with water (2 mL) and the aqueous layer was
3.2 mmol), and PPh3 (0.84 g, 3.2 mmol) to afford 13a as a colour-
extracted with CH2Cl2 (3 × 20 mL). The organic layers were com-
less oil (0.54 g, 2.2 mmol, 83 %) after radial chromatography
bined, dried (MgSO4) and concentrated in vacuo to afford 15 as a
(CH2Cl2/Hex, 1:1 Ǟ EtOAc/Hex, 1:3); Rf 0.31 (EtOAc/Hex, 1:1). colourless oil (20 mg, 0.071 mmol, 10 %) after radial chromatogra-
1H NMR (500 MHz, CDCl3): δ (ppm) = 1.23 (t, J = 7.1 Hz, 3 H, phy (EtOAc/Hex, 1:4); Rf 0.60 (EtOAc/Hex, 2:1). 1H NMR
OCH2CH 3), 1.91 (m, 2 H, NCH2CH 2CH2), 2.57 (t, J = 6.9 Hz, 2
(500 MHz, CDCl3): δ (ppm) = 1.23 (t, J = 7.2 Hz, 3 H, OCH2CH3),
H, CH 2CO2CH3), 3.12 (t, J = 7.9 Hz, 2 H, CH 2C=CH), 3.38 1.43 (s, 9 H, C[CH3]3), 1.90 (m, 2 H, NCH2CH2CH2), 2.47 (t, J =
(t, J = 7.2 Hz, 2 H, NCH2CH2CH2), 3.48 (t, J = 7.1 Hz, 2 H, 7.0 Hz, 2 H, CH2CO2C[CH3]3), 3.12 (t, J = 7.7 Hz, 2 H,
NCH2CH2CO2CH3), 3.68 (s, 3 H, OCH3), 4.07 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 4.51 (s, 1 H, C=CH). 13C NMR (125 MHz, CDCl3): δ = 7.1 Hz, 2 H, NCH2CH2CO2CCH3), 4.07 (q, J = 7.2 Hz, 2 H,
(ppm)
14.7 (OCH2CH3), 21.1 (NCH2CH2CH2), 30.7 OCH2CH3), 4.51 (s, 1 H, C=CH). 13C NMR (125 MHz, CDCl3):
(CH2C=CH), 32.5 (CH2CO2CH3), 41.9 (NCH2CH2CO2CH3), 51.8 (ppm) 15.0 (OCH2CH3), 21.4 (NCH2CH2CH2), 28.3
(OCH3), 52.8 (NCH2CH2CH2), 58.3 (OCH2CH3), 78.3 (C=CH), (C[CH3]3), 32.5 (CH2C=CH), 32.8 (CH2CO2C[CH3]3), 42.3
164.4 (C=CH), 169.2 (CO2CH2CH3), 171.9 (CO2CH3). IR (thin (NCH2CH2CO2C[CH3]3), 53.0 (NCH2CH2CH2), 58.5 (OCH2CH3),
CH2C=CH), 3.37 (t, J = 7.0 Hz, 2 H, NCH2CH2CH2), 3.43 (t, J
=
δ
=
508
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Silver-Catalyzed Hydroamination: Synthesis of N-Bridgehead Pyrroles
78.4 (C=CH), 81.3 (C [CH3]3), 164.7 (C=CH), 169.6 radial chromatography (EtOAc/Hex, 1:3); Rf 0.57 (EtOAc/Hex,
FULL PAPER
1
(CO CH CH ), 171.0 (CO C[CH ] ). IR (thin film, CHCl ): ν =
1:1). H NMR (500 MHz, CDCl3): δ (ppm) = 1.30 (t, J = 7.2 Hz,
3 H, OCH2CH3), 2.17 (s, 3 H, NCCH3), 2.51 (m, 2 H, NCH2CH2),
3.05 (t, J = 7.4 Hz, 2 H, NCH2CH2CH2), 3.83 (t, J = 7.1 Hz, 2 H,
NCH2CH2), 4.22 (q, J = 7.1 Hz, 2 H, OCH2CH3), 6.26 (s, 1 H,
C=CH). 13C NMR (125 MHz, CDCl3): δ (ppm) = 11.7 (NCCH3),
14.6 (OCH2CH3), 25.9 (NCH2CH2CH2), 26.9 (NCH2CH2), 44.9
(NCH2), 59.1 (OCH2CH3), 106.3 (CCO2CH2CH3), 110.0
(NC=CH), 124.0 (NC=CH), 142.6 (NC=CCO2CH2CH3), 165.4
˜
2
2
3
2
3 3
3
2978, 1725, 1681, 1591, 1130 cm–1. MS (EIMS): m/z (%) = 283
[M+] (42), 182 (71), 154 (32), 110 (100).
Preparation of Secondary Vinylogous Carbamates (11). General
Procedure: KHMDS (1.2 or 2.0 mmol) was added to a stirred solu-
tion of 13 (1 mmol) in dry THF (2 mL) and stirred for 15 minutes
at room temperature. The reaction mixture was quenched with
water (10 mL) and the aqueous layer was extracted with CH2Cl2 (3
× 20 mL). The organic layers were combined, dried (MgSO4), and
concentrated in vacuo to afford, spectroscopically pure 11.
(C=O). IR (thin film, CHCl ): ν = 2978, 1698, 1209, 1078 cm–1.
˜
3
MS (EIMS): m/z (%) = 193 [M+] (44), 164 (100), 148 (41), 120 (33).
HRMS: found m/z = 193.1103 [M+], C11H15NO2 requires 193.1103.
Ethyl (2Z)-Pyrrolidin-2-ylideneacetate (11a): 13a (0.27 g, 1.1 mmol)
was treated with KHMDS (0.47 g, 2.2 mmol) to afford 11a as a
white crystalline solid (m.p. 60–62 °C) (ref.[13] m.p. 61–62 °C)
(0.11 g, 0.71 mmol, 63 %); Rf 0.57 (EtOAc/Hex, 1:1). 1H NMR
(500 MHz, CDCl3): δ (ppm) = 1.24 (t, J = 7.4 Hz, 2 H, OCH2CH3),
1.96 (m, 2 H, NCH2CH2), 2.57 (t, J = 7.5 Hz, 2 H, CH2C=CH),
3.50 (t, J = 6.2 Hz, 2 H, NCH2), 4.09 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 4.52 (s, 1 H, C=CH), 7.90 (br., 1 H, NH). 13C NMR
(125 MHz, CDCl3): δ (ppm) = 14.7 (OCH2CH3), 22.0 (NCH2CH2),
32.2 (CH2C=CH), 47.0 (NCH2), 58.4 (OCH2CH3), 76.6 (C=CH),
166.4 (C=CH), 170.8 (C=O). MS (EIMS): m/z (%) = 155 [M+] (22),
110 (79), 83 (95), 82 (100), 80 (43), 54 (19).
Ethyl 3-Methyl-5,6,7,8-tetrahydro-1-indolizinecarboxylate (20b):
11b (75 mg, 0.44 mmol) was treated with AgNO3 (90 mg,
0.53 mmol) and propargyl bromide (80 % w/w solution in toluene,
0.06 mL, 0.06 g, 0.5 mmol) to afford 20b as a colourless oil (16 mg,
0.077 mmol, 19 %) after radial chromatography (EtOAc/Hex, 1:3);
1
Rf 0.56 (EtOAc/Hex, 1:2). H NMR (500 MHz, CDCl3): δ (ppm)
=
1.31 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.80 (m, 2 H,
NCH2CH2CH2), 1.96 (m, 2 H, NCH2CH2), 2.15 (s, 3 H, NCCH3),
3.06 (t, J = 6.6 Hz, 2 H, CH2C=C), 3.75 (t, J = 6.0 Hz, 2 H,
NCH2CH2), 4.23 (q, J = 7.2 Hz, 2 H, OCH2CH3), 6.26 (s, 1 H,
C=CH). 13C NMR (125 MHz, CDCl3): δ (ppm) = 11.6 (NCCH3),
14.6 (OCH2 CH3), 19.9 (NCH2CH2CH2), 23.0 (CH2C=C), 23.9
(NCH2CH2), 42.9 (NCH2), 59.0 (OCH2CH3), 107.0 (NC=CH),
Ethyl (2Z)-Piperidin-2-ylideneacetate (11b): 13b (0.70 g, 2.7 mmol)
was treated with KHMDS (0.63 g, 3.0 mmol) to afford 11b as a
colourless oil (0.40 g, 2.4 mmol, 86 %); Rf 0.84 (EtOAc/Hex, 1:1).
1H NMR (500 MHz, CDCl3): δ (ppm) = 1.21 (t, J = 6.8 Hz, 3 H,
OCH2CH3), 1.66 (m, 2 H, NCH2CH2CH2), 1.74 (m, 2 H,
NCH2CH2), 2.32 (t, J = 6.2 Hz, 2 H, CH2C=CH), 3.26 (dt, J =
5.8 and 2.4 Hz Hz, 2 H, NCH2), 4.05 (q, J = 7.4 Hz, 2 H,
OCH2CH3), 4.32 (s, 1 H, C=CH), 8.70 (br., 1 H, NH). 13C NMR
(125 MHz, CDCl3): δ (ppm) = 14.6 (OCH2CH3), 19.9 (NCH2CH2),
22.7 (NCH2CH2CH2), 29.1 (CH2C=CH), 41.2 (NCH2), 58.1
(OCH2CH3), 80.1 (C=CH), 162.7 (C=CH), 170.7 (C=O). MS
(EIMS): m/z (%) = 169 [M+] (56), 124 (59), 97 (100), 82 (36).
109.4
(CCO2CH2CH3),
127.1
(NC=CH),
136.2
˜
(NC=CCO CH CH ), 165.5 (C=O). IR (thin film, CHCl ): ν =
2
2
3
3
2923, 1692, 1218, 1185 cm–1. MS (EIMS): m/z (%) = 207 [M+] (40),
178 (100), 134 (79). HRMS: found m/z
C12H17NO2 requires 207.1259.
=
207.1257 [M+],
Ethyl 3-Methyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-1-car-
boxylate (20c): 11c (0.18 g, 0.98 mmol) was treated with AgNO3
(0.20 g, 1.18 mmol) and propargyl bromide (80 % w/w solution in
toluene, 0.13 mL, 0.14 g, 1.18 mmol) to afford 20c as an insepa-
rable mixture of starting material and product (SM/prod, 2:1)
1
(14 % from H NMR integral values) after radial chromatography
(EtOAc/Hex, 1:3); Rf 0.67 (EtOAc/Hex, 1:1). H NMR (500 MHz,
1
Ethyl (2Z)-Azepan-2-ylideneacetate (11c): 13c (0.32 g, 1.2 mmol)
was treated with KHMDS (0.30 g, 1.4 mmol) to afford 11c as a
white crystalline solid (m.p. 47–50 °C) (ref.[13] m.p. 55–56 °C)
(0.18 g, 0.98 mmol, 83 %); Rf 0.68 (EtOAc/Hex, 1:1). 1H NMR
(500 MHz, CDCl3): δ (ppm) = 1.16 (t, J = 6.9 Hz, 3 H, OCH2CH3),
CDCl3): δ (ppm) = 1.29 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.64 (m,
2 H, NCH2CH2CH2CH2), 1.80 (m, 2 H, NCH2CH2), 2.15 (s, 3 H,
NCCH3), 3.20 (br., 2 H, CH2C=C), 3.84 (m, 2 H, NCH2CH2), 4.20
(q, J = 7.2 Hz, 2 H, OCH2CH3), 6.15 (s, 1 H, C=CH). 13C NMR
(125 MHz, CDCl3): δ (ppm) = 12.2 (NCCH3), 14.4 (OCH2CH3),
25.2 (CH2C=C), 26.8 (NCH2CH2CH2), 28.6 (NCH2CH2CH2CH2),
31.1 (NCH2CH2), 45.3 (NCH2), 58.9 (OCH2CH3), 106.8
(NC=CH), 109.3 (CCO2CH2CH3), 126.9 (NC=CH), 141.7
1.63–1.49 (m,
6 H, NCH2CH2CH 2CH2), 2.21 (br., 2 H,
CH2C=CH), 3.22 (br., 2 H, NCH2), 4.00 (q, J = 6.8 Hz, 2 H,
OCH2CH3), 4.35 (s, 1 H, C=CH), 8.76 (br., 1 H, NH). 13C NMR
(125 MHz, CDCl3):
δ
(ppm)
=
14.3 (OCH2CH3), 26.3
(NC=CCO CH CH ), 165.7 (C=O). IR (thin film, CHCl ): ν =
˜
2
2
3
3
(NCH2CH2CH2), 29.9 (NCH2CH2), 30.2 (CH2CH2C=CH), 34.9
(CH2C=CH), 43.9 (NCH2), 58.0 (OCH2CH3), 80.4 (C=CH), 168.2
(C=CH), 170.6 (C=O). MS (EIMS): m/z (%) = 184 [M+ + 1] (100),
183 [M+] (68), 138 (55), 111 (83), 96 (28).
2928, 1695, 1651, 1602, 1253, 1168, 1116, 1053 cm–1. MS (EIMS):
m/z (%) = 221 [M+] (54), 191 (77), 148 (100). HRMS: found m/z =
221.1416 [M+], C13H19NO2 requires 221.1416.
Preparation of C-Propargyl Vinylogous Amides and Carbamates
(21). General Procedure: nBuLi (2.2 mmol) was added to a solution
of 11 (2 mmol) in dry THF (10 mL) at 0 °C and allowed to warm
to room temperature over 30 minutes. Propargyl bromide (3 mmol)
was added thereafter and the reaction mixture was stirred over-
night. The reaction was quenched by addition of NH4Cl(aq) (5 mL),
and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The
organic layers were combined, dried (MgSO4), and concentrated in
vacuo to afford 21 after chromatography.
Preparation of N-Bridgehead Pyrroles (20). General One-Pot Pro-
cedure: AgNO3 (1.2 mmol) was added to a stirred solution of 11
(1 mmol) and propargyl bromide (1.2 mmol) in dry CH3CN (2 mL)
and stirred overnight. The organic layer was washed with NaI(aq)
,
dried (MgSO4), and concentrated in vacuo to afford 20 after radial
chromatography.
Ethyl 5-Methyl-2,3-dihydro-1H-pyrrolizine-7-carboxylate (20a): 11a
(0.10 g, 0.64 mmol) was treated with AgNO3 (0.13 g, 0.77 mmol)
and propargyl bromide (80 % w/w solution in toluene, 0.09 mL,
0.09 g, 0.8 mmol) to afford 20a as a colourless crystalline solid
Ethyl (2Z)-2-Pyrrolidin-2-ylidenepent-4-ynoate (21a): 11a (0.35 g,
(m.p. 54–56 °C) (ref.[8a] m.p. 58 °C) (16 mg, 0.083 mmol, 13 %) after 2.3 mmol) was treated with nBuLi (1.6 m solution in hexane,
Eur. J. Org. Chem. 2005, 505–511
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509

R. S. Robinson, M. C. Dovey, D. Gravestock
FULL PAPER
1.55 mL, 2.48 mmol) and propargyl bromide (80 % w/w solution in
toluene, 0.38 mL, 0.40 g, 3.4 mmol) to afford 21a as a colourless
oil (0.29 g, 1.5 mmol, 66 %) after radial chromatography (EtOAc/
Hex, 1:3); Rf 0.61 (EtOAc/Hex, 1:1). 1H NMR (500 MHz, CDCl3):
δ (ppm) = 1.26 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.90 (t, J = 2.6 Hz,
1 H, CϵCH), 2.00 (m, 2 H, NCH2CH2), 2.72 (t, J = 7.8 Hz, 2 H,
NCH2CH2CH2), 3.08 (d, J = 2.6 Hz, 2 H, CH2CϵCH), 3.51 (t, J
= 7.0 Hz, 2 H, NCH2), 4.14 (q, J = 7.3 Hz, 2 H, OCH2CH3), 8.14
(br., 1 H, NH). 13C NMR (125 MHz, CDCl3): δ (ppm) = 14.6
(OCH2CH3), 17.0 (CH2CϵCH), 21.8 (NCH2CH2), 30.8
(CH2CH2C=C), 47.2 (NCH2), 58.9 (OCH2CH3), 66.4 (CϵCH),
84.2 (CϵCH), 84.5 (NC=C), 165.2 (NC=C), 169.4 (C=O). IR (thin
Note: Spectral and physical data for the compounds shown below
matched those acquired for the same compounds in prior reactions.
Ethyl 5-Methyl-2,3-dihydro-1H-pyrrolizine-7-carboxylate (20a): 21a
(0.25 g, 1.29 mmol) was treated with AgNO3 (44 mg, 0.26 mmol)
and irradiated to afford 20a as a colourless crystalline solid (0.19 g,
0.97 mmol, 75 %).
Ethyl 3-Methyl-5,6,7,8-tetrahydro-1-indolizinecarboxylate (20b):
21b (48 mg, 0.23 mmol) was treated with AgNO3 (8 mg,
0.05 mmol) and irradiated to afford 20b as a colourless oil (36 mg,
0.17 mmol, 75 %).
Ethyl 3-Methyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepine-1-car-
boxylate (20c): 21c (98 mg, 0.44 mmol) was treated with AgNO3
(15 mg, 0.09 mmol) and irradiated to afford 20c as a colourless oil
(70 mg, 0.32 mmol, 71 %).
film, CHCl ): ν = 3362, 3307, 2972, 2104, 1654, 1596, 1248,
˜
3
1212 cm–1. MS (EIMS): m/z (%) = 193 [M+] (35), 164 (100), 120
(74), 118 (46), 91 (22). HRMS: found m/z = 193.1091 [M+],
C11H23NO2 requires 193.1103.
Ethyl (2Z)-2-Piperidin-2-ylidenepent-4-ynoate (21b): 11b (0.38 g,
2.25 mmol) was treated with nBuLi (1.6 m solution in hexane,
1.54 mL, 2.47 mmol) and propargyl bromide (80 % w/w solution in
toluene, 0.38 mL, 0.40 g, 3.37 mmol) to afford 21b as a colourless
oil (0.16 g, 0.79 mmol, 35 %) and ethyl 2-prop-2-ynyl-2-(3,4,5,6-
tetrahydropyridin-2-yl)pent-4-ynoate as a colourless oil (70 mg,
0.29 mmol, 13 %) after radial chromatography (EtOAc/Hex, 1:9);
Rf 0.37 and 0.30 (EtOAc/Hex, 1:4) respectively. 1H NMR
(500 MHz, CDCl3): δ (ppm) = 1.27 (t, J = 7.4 Hz, 3 H, OCH2CH3),
1.78–1.72 (m, 4 H, NCH2CH2CH2), 1.91 (t, J = 2.5 Hz, 1 H,
CϵCH), 2.58 (t, J = 6.2 Hz, 2 H, CH2CH2C=C), 3.12 (d, J =
2.4 Hz, 2 H, CH2CϵCH), 3.31 (m, 2 H, NCH2), 4.13 (q, J =
[1] a) T. L. Gilchrist, Heterocyclic Chemistry, Addison Wesley
Longman Ltd., UK, 1997, 3rd Edition, pp. 193–207; b) R. A.
Jones, Pyrroles and their Benzo Derivatives: (ii) Reactivity, in:
Comprehensive Heterocyclic Chemistry, (Eds.: A. R. Katritsky,
C. W. Rees), Pergamon Press: New York, 1984, vol. 4, pp. 201–
312; c) R. J. Sundberg, Pyrroles and their Benzo Derivatives:
(i) Synthesis and Applications, ibid, pp. 313–376.
[2] A. Gossauer, Monopyrrolic Natural Compounds Including
Tetramic Acid Derivatives, in: Progress in the Chemistry of Or-
ganic Natural Products (Eds.: W. Herz, H. Falk, G. W. Kirby),
Springer-Verlag,Vienna, 2003, vol. 86, pp. 2–188.
7.4 Hz, 2 H, OCH2CH3), 9.65 (br., 1 H, NH). 13C NMR (125 MHz, [3] F.-P. Montforts, M. Glasenapp-Breiling, Naturally Occurring
Cyclic Tetrapyrroles, in: Progress in the Chemistry of Organic
Natural Products (Eds.: W. Herz, H. Falk, G. W. Kirby),
Springer-Verlag, Vienna, 2002, vol. 85, pp. 1–55.
[4] a) D. Gravestock, M. C. Dovey, Synthesis 2003, 523–530. b)
See also: D. Gravestock, M. C. Dovey, Synthesis 2003, 1470.
[5] R. S. Robinson, M. C. Dovey, D. Gravestock, Tetrahedron Lett.
2004, 45, 6787–6789.
[6] H. M. Garraffo, P. Jain, T. F. Spande, J. W. Daly, T. H. Jones,
L. J. Smith, V. E. Zottig, J. Nat. Prod. 2001, 64, 421–427.
[7] A. R. Mattocks, Nature 1968, 217, 723–728.
[8] For recent examples see: a) L. Calvo, A. González, M. C.
Sañudo, Synthesis 2002, 2450–2456; b) P. D. Croce, C. La Rosa,
Heterocycles 2001, 55, 1843–1858; c) J. Barluenga, M. Tomás,
V. Kouznetsov, A. Suárez-Sobrino, E. Rubio, J. Org. Chem.
1996, 61, 2185–2190.
[9] B. Rechsteiner, F. Texier-Boullet, J. Hamelin, Tetrahedron Lett.
1993, 34, 5071–5074.
[10] J.-P. Célérier, E. Deloisy, G. Lhommet, P. Maitte, J. Org. Chem.
1979, 44, 3089–3089.
[11] P. H. Lambert, M. Vaultier, R. Carrié, J. Org. Chem. 1985, 50,
5352–5356.
[12] H. M. C. Ferraz, E. O. de Oliveira, M. E. Payret-Arrua, C. A.
Brandt, J. Org. Chem. 1995, 60, 7357–7359.
CDCl3): δ (ppm) = 14.6 (OCH2CH3), 15.6 (CH2CϵCH), 19.8
(NCH2CH2), 22.0 (NCH2CH2CH2), 25.9 (CH2CH2C=C), 41.3
(NCH2), 58.7 (OCH2CH3), 66.3 (CϵCH), 84.8 (CϵCH), 85.3
(NC=C), 161.2 (NC=C), 169.7 (C=O). IR (thin film, CHCl ): ν =
˜
3
3280, 2939, 2857, 2109, 1690, 1637, 1591, 1207 cm–1. MS (EIMS):
m/z (%) = 207 [M+] (44), 178 (100), 162 (23), 134 (60), 132 (33).
HRMS: found m/z = 207.1245 [M+], C12H17NO2 requires 207.1259.
Ethyl (2Z)-2-Azepan-2-ylidenepent-4-ynoate (21c): 11c (0.34 g,
1.9 mmol) was treated with nBuLi (1.6 m solution in hexane,
1.28 mL, 2.04 mmol) and propargyl bromide (80 % w/w solution in
toluene, 0.31 mL, 0.33 g, 2.8 mmol) to afford 21c as a colourless
oil (0.10 g, 0.45 mmol, 24 %) after radial chromatography (EtOAc/
Hex, 1:9); Rf 0.69 (EtOAc/Hex, 1:1). 1H NMR (500 MHz, CDCl3):
δ (ppm) = 1.27 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.61–1.56 (m, 2 H,
NCH2CH2), 1.73–1.66 (m, 4 H, NCH2CH2CH2CH2), 1.92 (t, J =
2.6 Hz, 1 H, CϵCH), 2.59 (m, 2 H, CH2CH2C=C), 3.21 (d, J =
2.8 Hz, 2 H, CH2CϵCH), 3.32 (m, 2 H, NCH2), 4.13 (q, J =
7.1 Hz, 2 H, OCH2CH3), 9.67 (br., 1 H, NH). 13C NMR (125 MHz,
CDCl3): δ (ppm) = 14.6 (OCH2CH3), 16.6 (CH2CϵCH), 25.3
(NCH2CH2CH2), 29.1 (CH2CH2C=C), 30.0 (NCH2CH2), 30.4
(CH2CH2C=C), 44.0 (NCH2), 59.0 (OCH2CH3), 66.5 (CϵCH), [13] G. Bartoli, C. Cimarelli, R. Dalpozzo, G. Palmieri, Tetrahedron
1995, 51, 8613–8622.
85.6 (CϵCH), 86.2 (NC=C), 167.8 (NC=C), 170.2 (C=O). IR (thin
film, CHCl ): ν = 3291, 2928, 2109, 1643, 1591, 1248, 1196 cm–1.
[14] K. Shiosaki, The Eschenmoser Coupling Reaction, in: Compre-
hensive Organic Synthesis (Eds.: B. M. Trost, I. Fleming), Per-
gamon Press: Oxford, 1991, vol. 2, pp. 865–892.
[15] H. W. Pinnick, Y.-H. Chang, J. Org. Chem. 1978, 43, 4662–
4663.
˜
3
MS (EIMS): m/z (%) = 221 [M+] (42), 192 (100), 148 (84), 146 (41),
120 (32). HRMS: found m/z = 221.1401 [M+], C13H19NO2 requires
221.1416.
[16] For examples see: a) F. G. Fang, M. Prato, G. Kim, D. Danish-
efsky, Tetrahedron Lett. 1989, 30, 3625–3628; b) A. S. Howard,
G. C. Gerrans, J. P. Michael, J. Org. Chem. 1980, 45, 1713–
1715.
Preparation of N-Bridgehead Pyrroles (20). General Two-Step Pro-
cedure: AgNO3 (0.2 mmol) was added to a Pyrex test tube contain-
ing a solution of 21 (1 mmol) in dry CH3CN (1 mL). The test tube
was sealed and subjected to microwave irradiation (700 W, low) for
[17] a) J. P. Michael, A. S. Parsons, Tetrahedron 1996, 52, 2199–
2216; b) Z. Mkhize, M.Sc. Dissertation, University of Natal
(Pmb), 2002.
60 seconds (30, 30). The organic layer was washed with NaI(aq)
,
dried (MgSO4), and concentrated in vacuo. The crude material was
filtered (MeOH) through a short plug of silica gel to afford 20.
[18] R. S. Varma, D. Kumar, Org. Lett. 1999, 1, 697–700.
510
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 505–511

Silver-Catalyzed Hydroamination: Synthesis of N-Bridgehead Pyrroles
FULL PAPER
[19] For examples of the preparation of related compounds see: a)
D. Ma, W. Zhu, Org. Lett. 2001, 3, 3927–3929; b) A. S. How-
ard, G. C. Gerrans, C. A. Meerholz, Tetrahedron Lett. 1980,
21, 1373–1374.
[20] K. E. Harding, T. H. Tiner, Electrophilic Heteroatom Cycliza-
tions, in: Comprehensive Organic Synthesis (Eds.: B. M. Trost,
I. Fleming); Pergamon Press: Oxford, 1991.
Received: August 23, 2004
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