A Copper-Catalyzed N-Alkynylation Route to 2-Substituted N-Alkynyl Pyrroles and Their Cyclization into Pyrrolo[2,1-c]oxazin-1-ones: A Formal Total Synthesis of Peramine

Article abstract of DOI:10.1055/s-0036-1588736

Screening of a variety of ligands and reaction conditions for the copper-catalyzed cross-coupling of alkynyl bromides with pyrroles, reveals that the use of the phenanthroline ligand 4,7-dimethoxy-1,10-phenanthroline affords a range of ynpyrroles in good to moderate yields. Furthermore, the utility of these ynpyrroles is demonstrated in the preparation of a series of pyrrolo[2,1-c][1,4]oxazin-1-ones and a formal total synthesis of the pyrrole natural product peramine.

Full text of DOI:10.1055/s-0036-1588736

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–K
paper
A
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
A Copper-Catalyzed N-Alkynylation Route to 2-Substituted N-Alkynyl
Pyrroles and Their Cyclization into Pyrrolo[2,1-c]oxazin-1-ones:
A Formal Total Synthesis of Peramine
Brandon J. Reinusa
Sean M. Kerwin*b
R1
R1
CuSO4·5H2O (10 mol%)
ligand (20 mol%)
R1
O
N
R2
N
+
Br
N
K2CO3 (200 mol%)
toluene (0.5 M), 135 °C
14 h
O
a Department of Chemistry, University of Texas at Austin, Austin,
TX 78712, USA
b Department of Chemistry & Biochemistry, Texas State University,
San Marcos, TX 78666, USA
H
R2
R2
26 examples
up to 99% yield
6 examples
up to 81% yield
smk89@txstate.edu
ligand:
MeO
OMe
N
N
Received: 01.01.2017
Accepted after revision: 10.02.2017
Published online: 14.03.2017
include examples of N-alkynyl indoles,9–11 benzimidaz-
oles,16,17 carbazoles,18 indazoles,17 pyrazoles,17 and imidaz-
oles.16,17 However, only one report of the preparation of N-
alkynyl pyrroles via cross-coupling has appeared.10
DOI: 10.1055/s-0036-1588736; Art ID: ss-2017-m0001-op
Abstract Screening of a variety of ligands and reaction conditions for
the copper-catalyzed cross-coupling of alkynyl bromides with pyrroles,
reveals that the use of the phenanthroline ligand 4,7-dimethoxy-1,10-
phenanthroline affords a range of ynpyrroles in good to moderate
yields. Furthermore, the utility of these ynpyrroles is demonstrated in
the preparation of a series of pyrrolo[2,1-c][1,4]oxazin-1-ones and a
formal total synthesis of the pyrrole natural product peramine.
Our interest in N-alkynyl azoles as synthetic intermedi-
ates19,20 has led us to explore the chemistry of N-alkynyl
pyrroles (ynpyrroles). Due to the prevalence of pyrrole in
both natural products and pharmaceuticals, we were inter-
ested to establish if ynpyrroles could serve as valuable in-
termediates in the synthesis of unique chemical scaffolds.21
Most of the available syntheses of ynpyrroles involve elimi-
nation of N-halovinyl pyrroles using alkyllithium bases and
thus are very limited in substrate scope.22 We reasoned that
a cross-coupling route to ynpyrroles would be much more
versatile; however, through our investigations, it became
clear that the available cross-coupling protocol for forming
N-alkynyl pyrroles was also limited in scope. In particular,
we found that when using this previously reported meth-
odology, 2-substituted pyrroles did not participate in the
cross-coupling with alkynyl bromides.10 Thus, we set out to
establish conditions that could efficiently cross-couple 2-
substituted pyrroles with alkynyl bromides, and also
demonstrate the synthetic utility of the subsequently
formed ynpyrroles.
Our initial exploration focused on identifying condi-
tions that could efficiently cross-couple 2-carboalkoxypyr-
role 1a and alkynyl bromide 2a (Table 1). We began our
search with a handful of established catalytic systems (Ta-
ble 1, entries 1–5). Conditions previously reported by
Hsung10 for the synthesis of a handful of ynpyrroles (Table
1, entry 1) failed to generate 3a in a detectable amount. We
found that our previous conditions for synthesizing ynimid-
azoles16 gave ynpyrrole 3a in a 15% yield (Table 1, entry 4).
Optimization of the conditions of entry 4 led to the forma-
tion of 3a in a 46% yield, a modest gain by utilizing ligand L1
(Table 1, entry 6). Changing from CuI as a precatalyst to
Key words cross-coupling, alkynes, nitrogen heterocycles, cycliza-
tion, peramine
Nitrogen-substituted alkynes have a relatively long his-
tory and yet have undergone a resurgence of interest re-
cently. In 1892, Bode attempted the synthesis of an N-alky-
nylamine (ynamine).1 However, more than half a century
passed before the first successful synthesis of an ynamine
was reported.2 This was followed by reports of a wealth of
transformations of these ynamines.3 Despite this early in-
terest, the lack of general routes for their preparation and
the general instability of these ynamines diminished their
usefulness in synthetic chemistry. This area has witnessed a
renaissance with a focus on N-alkynylamides (ynamides),
which are more stable than ynamines, yet participate in a
wide range of synthetically useful transformations.4 The
synthetic utility of ynamides was further increased with re-
ports of their preparation utilizing cross-coupling reactions
inspired by Buchwald’s work on copper-catalyzed N-aryla-
tions of amides,5 or via mild oxidative cross-coupling strat-
egies.6 These cross-coupling reactions have been success-
fully applied to the preparation of N-alkynyl sulfon-
amides,7–11 amides,8–12 ureas,8–10,12 carbamates,8–12 imides,13
imines,14 and sulfoximines.15 Application to the preparation
of N-alkynyl heterocycles has been somewhat limited, and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

B
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
CuSO4·5H2O, together with a screen of a variety of phenan-
throline-based ligands led to the formation of 3a in an 88%
yield, using 4,7-dimethoxy-1,10-phenanthroline (L7) and
K2CO3 in toluene at 115 °C (Table 1, entry 7). L7 proved to be
a significantly better ligand than other phenanthrolines un-
der identical conditions (Table 1, entries 8–11); further
changes to the conditions of entry 7 only led to diminished
yields (Table 1, entries 12–16). Considering the CuSO4 pre-
catalyst is a pentahydrate, we were not surprised to find
that distillation of the toluene prior to degassing was not
necessary for obtaining 3a in a good yield (Table 1, entry
17).
With improved conditions for the synthesis of 3a estab-
lished (Table 1, entry 7), the substrate scope was explored.
A variety of alkynyl bromides participated in the cross-
coupling; however, we noticed a significant effect of reac-
tion temperature on the success of the coupling (Scheme 1,
products 3a–d). While the isolated yields of 3a and 3b were
Table 1 Optimization of Ynpyrrole 3a Synthesisa
EtO
O
OEt
+
Br
(CH2)4OTBS
N
N
(CH2)4OTBS
H
O
1a
100 mol%
2a
120 mol%
3a
Entry
Precatalyst
Ligand
Base
Solvent
Temp (°C)
Yield (%)b
1
2c
CuSO4·5H2O
FeCl3
L1
L2
L2
L3
n/a
L1
L7
L1
L4
L5
L6
L7
L7
L7
L7
L7
L7
K3PO4
K2CO3
K3PO4
Cs2CO3
KOH
toluene
toluene
toluene
dioxane
dioxane
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
toluene
toluene
toluene
tolueneh
80
90
<5
<5
<5
15
<5
46
88
24
<5
<5
62
21
42
47
72
26
75
3d
4e,f
5g
6f
CuCN
110
50
CuI
CuO
80
CuI
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
K2CO3
K2CO3
115
115
115
115
115
115
115
115
115
115
95
7
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuI
8
9
10
11
12
13
14
15
16
17
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
115
O
O
NH HN
N
N
L1
L2
L3
MeO
Me
Me
OMe
Me
Me
Me
Me
N
N
N
N
N
N
N
N
Me
L4
L5
L6
L7
Me
a Reactions were run with pyrrole 1a (0.2 mmol), alkynyl bromide 2a (0.24 mmol), Cu catalyst (0.02 mmol), ligand (0.04 mmol), base (0.4 mmol), solvent (0.4
mL), Temp (°C), 14 h.
b Yields were calculated by NMR using TCE (1,1,2,2-tetrachloroethane) as an internal standard.
c Using 1.0 mL of toluene (0.2 M).
d Using CuCN (0.01 mmol), L2 (0.02 mmol), and 2.0 mL of toluene (0.1 M).
e Using CuI (0.01 mmol).
f 3 Å MS were added.
g Using CuO (0.004 mmol) and 0.66 mL of toluene (0.3 M).
h Toluene was used as received and degassed prior to use.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

C
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
moderate at 115 °C, a small gain in yield was observed
when increasing the temperature to 135 °C for 3a and a
rather substantial increase in yield was observed for sub-
strate 3b. Compound 3c, which contains a benzyl propargyl
ether, was formed in good yields at 135 °C, while compound
3d was not formed at 135 °C and was only isolable in poor
yields when the reaction temperature was lowered to 90 °C.
(Bromoethynyl)benzene is a common cross-coupling part-
ner in the synthesis of ynazoles and ynamides and we were
curious why the yield of 3d was so low.
while the yields with pyrrole 1a generally improve as reac-
tion temperatures are increased, the yields with (bro-
moethynyl)benzene diminish with increasing tempera-
tures.
O
standard conditionsa
O
+
Br
Ph
N
Ph
N
H
(eq 1)
1e (100 mol%)
120 mol%
3e 0%, 76%b
CuSO4·5H2O (10 mol%)
OEt
Br
OEt
standard conditionsa
L7 (20 mol%)
OEt
N
+
Br
R
+
+
3d
3b
+
3d
(eq 2)
N
N
H
O
H
K2CO3 (200 mol%)
toluene (0.5 M)
Temp.
O
O
TIPS
100 mol%
120 mol%
88%c
100 mol%
120 mol%
50 mol%
100%
12–14 h
R
Scheme 2 Cross-coupling with (bromoethynyl)benzene. a Reaction
conditions: pyrrole (0.2 mmol), alkynyl bromide (0.24 mmol),
OEt
OEt
OEt
OEt
CuSO4·5H2O (0.02 mmol), L7 (0.04 mmol), K2CO3 (0.4 mmol), toluene
N
N
N
N
(0.4 mL), 135 °C, 12–14 h. b Reaction run at 80 °C. c Percent recovered.
O
O
O
O
TIPS
We also sought to explore the reactivity and substrate
scope of the pyrrole coupling partner (Scheme 3). The high-
ly efficient cross-coupling to generate 3b (Scheme 1)
prompted us to use (bromoethynyl)triisopropylsilane at
135 °C as our standard conditions. In addition to pyrrole 1a,
a variety of esters were tolerated (Scheme 3, products
4a–e,o,p), including esters at both the 2 and 3 positions of
the pyrrole. A modest reduction in yield was observed in
the synthesis of ynpyrrole 4c compared to 3b, likely the re-
sult of the increased sterics of a 2,5-disubstituted pyrrole.
Various functional groups were tolerated in the 2-position
(4f–i), including a bulky ketone (4j). Unsubstituted pyrrole
gave a moderate yield (4k), while 2,5-dimethylpyrrole was
a rather poor substrate (4l). In addition, phenyl-substituted
pyrroles gave poor to moderate yields depending on the
substitution and electronics (4m,n,q). Finally, trisubstitut-
ed ynpyrroles 4o and 4p could be formed in modest yields
under our conditions.
Considering the above results, the substitution on pyr-
role appears to play an important role in this cross-coupling
chemistry. Interestingly, both the most electron-deficient
(4o,r) and the most electron-rich pyrroles gave poor yields
(4k,l). This observed reactivity might be related to the vari-
ation in pKa for these substrates. Pyrroles that are too acidic
may form inactive copper aggregates24 that diminish their
reactivity, whereas substantially less acidic pyrroles may
suffer from poor acid–base chemistry. It seems, for the con-
ditions we have reported, that pyrroles with a single elec-
tron-withdrawing group at the 2-position display the best
reactivity (4a–c,f–j). Thus, for pyrroles with significantly
different electronics or sterics, a separate optimization of li-
gand and coupling conditions may be required.
BnO
OTBS
3d 16% (90 °C)b
3a 66% (115 °C)a
3b 67% (115 °C)a
3c 74% (135 °C)
0% (135 °C)
69% (135 °C)
99% (135 °C)
Scheme 1 Scope of alkynyl bromides coupling to 1a. Reaction condi-
tions: pyrrole (0.2 mmol), alkynyl bromide (0.24 mmol), CuSO4·5H2O
(0.02 mmol), L7 (0.04 mmol), K2CO3 (0.4 mmol), toluene (0.4 mL),
135 °C , 12–14 h. a Reaction run at 115 °C. b Reaction run at 90 °C.
To further investigate the low yield of 3d, we looked to a
previously established pyrrole coupling partner for (bro-
moethynyl)benzene, pyrrole 1e. Ynpyrrole 3e (Scheme 2)
has been reported by Hsung and co-workers via the cou-
pling of (bromoethynyl)benzene and 1e.10 Using our newly
established conditions from Table 1 at a reaction tempera-
ture of 135 °C, ynpyrrole 3e (Scheme 2, eq 1) was not
formed; however, running the cross-coupling at 80 °C, the
desired ynpyrrole 3e was isolated in a 76% yield. This sug-
gests the poor yield of 3d (Scheme 1), even at lower reac-
tion temperatures, is an issue specific to pyrrole 1a with
(bromoethynyl)benzene rather than a general issue of (bro-
moethynyl)benzene as a coupling partner. Investigating the
low yields of 3d even further, we sought to determine if yn-
pyrrole 3d could inhibit catalysis through an undesirable
interaction with copper.23 By running a cross-coupling in
the presence of 3d (Scheme 2, eq 2), we found ynpyrrole 3b
was formed quantitatively and 3d was recovered in an ex-
cellent yield. These results suggest the low cross-coupling
yields of 3d were not from an undesirable interaction with
copper or due to its decomposition under the reaction con-
ditions, but due to an issue with generating the ynpyrrole.
Considering the results, pyrrole 1a and (bromoethynyl)ben-
zene are poor cross-coupling partners, likely due to incom-
patible reactivities under our standard conditions, i.e.,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

D
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
R1
R
R1
1) standard conditionsa
OTMSE
O
R
CuSO4·5H2O (10 mol%)
Br
R2
N
N
+
N
L7 (20 mol%)
N
+
Br
TIPS
2) TBAF, DMF, 0 °C to r.t.
2 hb,c
H
O
O
N
H
K2CO3 (200 mol%)
toluene (0.5 M), 135 °C
12–14 h
100 mol%
120 mol%
R3
100 mol%
120 mol%
TIPS
O
O
O
O
O
N
Me
ii
OMe
N
N
N
O
H
O
O
OtBu
OTMSE
OEt
Me
NH
Me
N
N
N
N
H
O
O
O
H2N
X
N
H
R2 = TIPS
5a, 58%
R2 = TIPS
R2 = (CH2)3OTBS
peramine
4a, 96%
4b, 85%
4c, 74%
4d, 37%
5b, 56%
X = OH, 5c, 43%
X = Cl, 5d
O
i
OMe
OMe
Me
H
NEt2
O
O
N
Me
CN
Me
N
N
N
N
N
N
H
O
O
O
O
O
4e, 24%
4f, 68%
4g, 98%
4h, 99%
H
O
BnO
MeO
BnO
5f, 81%
5g,75%
5e, 55%
Me
tBu
Me
Scheme 4 Synthesis of substituted pyrrolo[2,1-c]oxazin-1-ones.
N
N
N
N
a Reaction conditions: pyrrole (0.2 mmol), alkynyl bromide (0.24 mmol),
CuSO4·5H2O (0.02 mmol), L7 (0.04 mmol), K2CO3 (0.4 mmol), toluene
(0.4 mL), 135 °C, 12–14 h. b 1.25 equiv of TBAF per silyl protecting
group. c Yields calculated over two steps. (i) CH2Cl2, r.t., CCl4 (9 equiv),
PPh3 (3 equiv), 70%; (ii) See ref. 27.
O
O
4i, 95%
4j, 99%
4k, 57%
4l, 5%
O
O
Ph
OMe
OMe
O
TBSO
Ph
Me
Me
N
N
N
N
several herbivore-toxic alkaloids produced by epichloae
fungi associated with cool-season grasses.26 Using our two-
step sequence, alcohol 5c was obtained in a modest yield.
Subsequent chlorination of 5c gave pyrrolo[2,1-c][1,4]oxa-
zin-1-one 5d, an intermediate in the total synthesis of the
natural product peramine.27 This route to 5d obviates diffi-
culties encountered in the preparation of this compound
from alkylation and cyclization of 2-(trichloroacetyl)pyr-
role, which affords only 15% of the cyclized product on large
scale.27
In conclusion, we have demonstrated a new set of con-
ditions for the synthesis of 2-substituted ynpyrroles and
applied them to an expanded scope of substrates. This work
also illustrates the advantages of optimizing and tailoring
the cross-coupling conditions for separate classes of pyrrole
coupling partners. Finally, we also demonstrated the use of
ynpyrroles toward the synthesis of pyrrolo[2,1-c][1,4]oxa-
zin-1-ones, applying this strategy to the formal synthesis of
peramine and to the unique elaboration of ethinyl estradiol
analogues.
4m, 13%
4n, 54%
4o, 28%
4p, 19%
OMe
O
O
N
N
OMe
4q, 0%
4r, 0%
Scheme 3 Scope of the pyrroles in cross-coupling
During our investigations, we were intrigued to find
that deprotection of ynpyrrole 4b with TBAF afforded com-
pound 5a as the sole product (Scheme 4). The pyrrole[2,1-
c]oxazin-1-one 5a is presumably formed by cyclization of
the initially formed carboxylate (5b′,c′,e′–g′, see the experi-
mental section). We decided to explore this result by exam-
ining this two-step cross-coupling/cyclization sequence for
a variety of pyrrole and alkynyl bromide coupling partners
(Scheme 4). Both 2-(trimethylsilyl)ethylcarboxylate- and
5-methyl-2-(trimethylsilyl)ethylcarboxylate-substituted
ynpyrroles participate in this reaction (5a,b). In addition, a
variety of alkynyl bromides were also tolerated, including
those with large alkyne substituents. This procedure al-
lowed for the synthesis of the novel estradiol analogue 5g in
a high yield in only four steps from ethinyl estradiol.
All pyrroles were commercially available or synthesized using stan-
dard chemistry. Pyrroles purchased commercially were purified by
column chromatography prior to use. For the synthesis of known pyr-
roles: ethyl 5-methyl-1H-pyrrole-2-carboxylate,28a methyl 2-methyl-
To further explore the utility of this two-step cross-
coupling/cyclization procedure, we used this transforma-
tion to complete a formal total synthesis of the rye grass
endophytic fungal alkaloid peramine.25 Peramine is one of
1H-pyrrole-3-carboxylate,28b
N,N-diethyl-1H-pyrrole-2-carboxam-
ide,28c 2,2-dimethyl-1-(1H-pyrrol-2-yl)propan-1-one,28d 2-phenyl-
1H-pyrrole,28e 3-phenyl-1H-pyrrole,28f see referenced materials. All
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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B. J. Reinus, S. M. Kerwin
Paper
Synthesis
reactions were run under argon unless otherwise stated. Column
chromatography was carried out on SiliaFlash P60 silica gel (230-400
mesh). Reactions were monitored by TLC on Merck silica gel 60 W
F245 aluminium-backed TLC plates. Optical rotations were measured
using a Perkin-Elmer 241 MC polarimeter. Melting points were re-
corded on a Buchi B-540 melting point apparatus and are uncorrect-
ed. IR spectra were obtained using a PerkinElmer Spectrum 100 FT-IR
spectrophotometer using a diamond anvil ATR accessory. NMR spec-
tra were recorded in ppm at 400 MHz (1H) and 100 MHz (13C) using
an Agilent MR spectrometer. The following abbreviations are used to
explain the multiplicities: s = singlet, d = doublet, dd = doublet of dou-
blets, t = triplet, q = quartet, quin = quintet, m = multiplet, br s = broad
singlet. NMR yields were calculated using 1,1,2,2-tetrachloroethane
as internal standard. HRMS was performed using an Agilent 6530 Q-
TOF spectrometer.
1H NMR (400 MHz, CDCl3): δ = 8.51 (br s, 1 H, H-1), 6.31 (d, J = 2.8 Hz,
1 H, H-4), 4.58 (s, 2 H, CH2), 3.77 (s, 3 H, CO2CH3), 2.48 (s, 3 H, CH3),
0.89 (s, 9 H, tBu), 0.05 (s, 6 H, Si-CH3).
13C NMR (100 MHz, CDCl3): δ = 166.0, 135.3, 129.1, 111.1, 107.1, 58.3,
50.6, 25.8, 18.3, 13.1, –5.3.
HRMS (ESI): m/z [M + H]+ calcd for C14H26NO3SiNa: 284.1676; found:
284.1677.
2-(Trimethylsilyl)ethyl 1H-Pyrrole-2-carboxylate (1d)
Ethyl pyrrole-2-carboxylate (278 mg, 2.0 mmol) was added to 2-
(trimethylsilyl)ethanol (2.0 mL), followed by KOtBu (24 mg, 0.2
mmol). The mixture was then heated to 110 °C and stirred for 5 h. Af-
ter completion, the mixture was diluted with H2O (100 mL) and ex-
tracted with EtOAc (3 × 35 mL), the combined extracts were washed
with brine (30 mL) and dried over Na2SO4. Removal of the solvent and
purification by column chromatography (hexanes/EtOAc, 20:1) gave
the product as a white solid (270 mg, 64%); mp 67–68 °C.
Pyrrole Starting Materials
IR: 3311, 2954, 1679, 1555, 1414, 1316, 1168, 1127, 1031, 963, 837,
Methyl 5-Formyl-2-methyl-1H-pyrrole-3-carboxylate (1b)
744 cm–1
.
Under argon at 0 °C, POCl3 (2.83 mL, 30 mmol) was added to DMF
(2.71 mL, 35 mmol) dropwise and the mixture allowed to warm to r.t.
After 20 min, the mixture was cooled back to 0 °C and methyl 2-
methyl-1H-pyrrole-3-carboxylate (2.28 g, 16.4 mmol) was added in
portions and the mixture subsequently warmed to r.t. and stirred for
3 h. Following completion, the mixture was diluted with H2O and
quenched with NaOAc·3H2O (12 g), then Na2CO3 (5 g) was added care-
fully in portions. The resulting solid was filtered and washed with
H2O. Purification by column chromatography (hexanes/EtOAc, 1:1)
gave the title compound as a white solid (1.86 g, 56%), which could be
further purified by recrystallization from toluene; mp 154–156 °C.
1H NMR (400 MHz, CDCl3): δ = 9.30 (br s, 1 H, H-1), 6.96–6.94 (m, 1 H,
H-3), 6.91–6.89 (m, 1 H, H-5), 6.26–6.24 (m, 1 H, H-4), 4.39–4.35 (m,
2 H, O-CH2), 1.12–1.07 (m, 2 H, Si-CH2), 0.07 (s, 9 H, Si-CH3).
13C NMR (100 MHz, CDCl3): δ = 161.4, 123.1, 122.6, 114.9, 110.3, 62.5,
17.4, –1.4.
HRMS (ESI): m/z [M + Na]+ calcd for C10H17NO2SiNa: 234.0921; found:
234.0912.
2-(Trimethylsilyl)ethyl 5-Methyl-1H-pyrrole-2-carboxylate (1f)
Following the procedure outlined above for 2-(trimethylsilyl)ethyl
1H-pyrrole-2-carboxylate, the title compound was synthesized as a
white solid (135 mg, 50%); mp 83–84 °C.
IR: 3254, 1713, 1651, 1567, 1475, 1416, 1243, 1138, 1094, 1012, 868,
776, 684 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.43 (br s, 1 H, H-1), 9.42 (s, 1 H,
CHO), 7.35 (d, J = 2.8 Hz, 1 H, H-4), 3.84 (s, 3 H, CO2CH3), 2.63 (s, 3 H,
CH3).
13C NMR (100 MHz, CDCl3): δ = 179.2, 164.6, 144.0, 130.4, 124.2,
115.0, 51.1, 13.4.
IR: 3306, 2952, 1662, 1491, 1329, 1228, 1142, 990, 836, 771 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.45 (br s, 1 H, H-1), 6.79 (s, 1 H, H-3),
5.94 (t, J = 3.2 Hz, 1 H, H-4), 4.40–4.30 (m, 2 H, O-CH3), 2.31 (s, 3 H,
CH3), 1.12–1.06 (m, 2 H, Si-CH2), 0.07 (s, 9 H, Si-CH3).
13C NMR (100 MHz, CDCl3): δ = 161.7, 134.0, 121.3, 115.9, 108.7, 62.2,
17.4, 13.0, –1.4.
HRMS (ESI): m/z [M + Na]+ calcd for C8H9NO3Na: 190.0475; found:
190.0473.
HRMS (ESI): m/z [M + Na]+ calcd for C11H19NO2SiNa: 248.1077; found:
248.1081.
Methyl 5-{[(tert-Butyldimethylsilyl)oxy]methyl}-2-methyl-1H-
pyrrole-3-carboxylate (1c)
Alkynyl Bromides 2; General Procedure
To a solution of methyl 5-formyl-2-methyl-1H-pyrrole-3-carboxylate
(168 mg, 1.0 mmol) in MeOH (2.0 mL) was added NaBH4 (76 mg, 2.0
mmol). Following reaction completion (TLC), the mixture was diluted
with sat. NH4Cl (20 mL) and extracted with CH2Cl2 (3 × 20 mL),
washed with brine (20 mL) and dried over Na2SO4. Removal of the sol-
vent gave the alcohol, which was taken forward without further puri-
fication. To the residue was added CH2Cl2 (5.0 mL), Et3N (600 μL, 4.0
mmol), and DMAP (12 mg, 0.1 mmol). After cooling to 0 °C, TBSCl
(200 mg, 1.3 mmol) was added, and the solution was allowed to warm
to r.t. After reaction completion (TLC), the mixture was diluted with
sat. NH4Cl (20 mL) and extracted with CH2Cl2 (3 × 25 mL), the com-
bined extracts were washed with brine (20 mL) and dried over Na2-
SO4. Removal of the solvent and purification by column chromatogra-
phy (hexanes/EtOAc, 5:1) gave the title compound as a white solid
(123.5 mg, 44%); mp 55–58 °C.
All the alkynyl bromides were synthesized from the respective alkyne
using the following general procedure: To a solution of alkyne (1.0
equiv) in acetone (0.2 M) was added NBS (1.2 equiv) and AgNO3 (0.1
equiv). The mixture was allowed to stir open to the air for 4 h. Follow-
ing completion, the acetone was removed and the residue taken up in
hexanes. The organics were washed with sat. NH4Cl, H2O (× 2), and
brine, and dried over Na2SO4. Removal of the solvent gave the previ-
ously reported, pure alkynyl bromides: [(6-bromohex-5-yn-1-
yl)oxy](tert-butyl)dimethylsilane,29a
2-bromo-1-triisopropylsilyl
acetylene,29b
{[(4-bromo-2-methylbut-3-yn-2-yl)oxy]methyl}ben-
zene,29c and 1-bromo-2-phenylacetylene.16
{[(5-Bromopent-4-yn-1-yl)oxy]methyl}benzene (2b)
Pale yellow oil (1.36 g, 93%).
IR: 3302, 2951, 2856, 1675, 1596, 1530, 1450, 1339, 1224, 1134,
IR: 2931, 2860, 1718, 1602, 1452, 1364, 1272, 1203, 1175, 1104,
1060, 1001, 834, 776 cm–1
.
1070, 909, 736, 712, 697 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

F
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.40–7.29 (m, 5 H, Ar-H), 4.52 (s, 2 H,
Ph-CH2), 3.56 (t, J = 5.6 Hz, 2 H, O-CH2), 2.35 (t, J = 7.2 Hz, 2 H, CC-
CH2), 1.82 (quin, J = 6.4 Hz, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 138.3, 128.3, 127.58, 127.55, 79.6,
72.9, 68.5, 37.9, 28.4, 16.5.
1H NMR (400 MHz, CDCl3): δ = 7.04 (dd, J = 2.8, 1.6 Hz, 1 H, H-3), 6.93
(dd, J = 3.6, 1.6 Hz, 1 H, H-5), 6.18 (dd, J = 3.6, 2.8 Hz, 1 H, H-4), 4.32 (q,
J = 7.2 Hz, 2 H, O-CH2), 1.34 (t, J = 7.2 Hz, 3 H, OCH2-CH3), 1.16–1.12
(m, 21 H, Si-iPr).
13C NMR (100 MHz, CDCl3): δ = 159.2, 131.9, 126.1, 118.2, 110.3, 94.6,
68.3, 60.3, 18.6, 14.4, 11.3.
HRMS (ESI): m/z [M + Na]+ calcd for C18H29NO2SiNa: 342.1860; found:
HRMS (ESI): m/z [M + Na]+ calcd for C12H13BrONa: 275.0042; found:
275.0040.
342.1854.
(8R,9S,13S,14S,17S)-17-(Bromoethynyl)-3,17-dimethoxy-13-meth-
yl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenan-
threne (2c)
Ethyl 1-[3-(Benzyloxy)-3-methylbut-1-yn-1-yl]-1H-pyrrole-2-car-
boxylate (3c)
Pale yellow solid (980 mg, 96%); mp 113–115 °C; [α]D –23.4 (c 1.0,
Clear oil (45.8 mg, 74%).
CH2Cl2).
IR: 2984, 2269, 1716, 1422, 1262, 1207, 1154, 1100, 731, 696 cm–1
.
IR: 2931, 2195, 1609, 1575, 1498, 1452, 1379, 1279, 1254, 1236,
1H NMR (400 MHz, CDCl3): δ = 7.44–7.24 (m, 5 H, Ph), 7.01 (dd, J = 2.8,
1.6 Hz, 1 H, H-3), 6.96 (dd, J = 4.0, 1.6 Hz, 1 H, H-5), 6.21 (dd, J = 4.0,
2.8 Hz, 1 H, H-4), 4.75 (s, 2 H, Ph-CH2), 4.33 (q, J = 7.2 Hz, 2 H, O-CH2),
1.67 (s, 6 H, CH3), 1.36 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.4, 139.1, 131.3, 128.2, 127.7,
127.2, 126.0, 118.3, 110.3, 71.1, 70.8, 66.6, 60.3, 28.8, 14.4.
1096, 1041, 975, 860, 813, 781, 736, 673 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.20 (d, J = 8.4 Hz, 1 H, H-1), 6.71 (dd,
J = 8.8, 3.2 Hz, 1 H, H-2), 6.62 (d, J = 2.8 Hz, 1 H, H-4), 3.77 (s, 3 H, O3-
CH3), 3.40 (s, 3 H, O17-CH3), 2.90–2.82 (m, 2 H, C6-H2), 2.38–2.29 (m,
1 H, C9-H), 2.28–2.18 (m, 2 H), 2.03–1.66 (m, 6 H), 1.52–1.31 (m, 4 H),
0.86 (s, 3 H, C13-CH3).
13C NMR (100 MHz, CDCl3): δ = 157.3, 137.7, 132.3, 126.2, 113.6,
111.3, 86.8, 81.1, 55.0, 53.3, 49.5, 47.7, 46.3, 43.3, 39.0, 36.2, 34.1,
29.7, 27.1, 26.4, 22.6, 12.6.
HRMS (ESI): m/z [M + Na]+ calcd for C19H21NO3Na: 334.1414; found:
334.1431.
Ethyl 1-(Phenylethynyl)-1H-pyrrole-2-carboxylate (3d)
HRMS (CI): m/z [M + H]+ calcd for C22H28O2Br: 403.1273; found:
403.1203.
Pale yellow oil (7.9 mg, 16%).
IR: 2981, 2261, 1713, 1459, 1423, 1263, 1169, 1101, 754 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.52 (m, 2 H, o-Ar-H), 7.38–7.30
(m, 3 H, m-,p-Ar-H), 7.13 (dd, J = 3.2, 1.6 Hz, 1 H, H-5), 7.00 (dd, J = 3.6,
1.6 Hz, 1 H, H-3), 6.25 (dd, J = 3.6, 3.2 Hz, 1 H, H-4), 4.35 (q, J = 7.2 Hz,
2 H, O-CH2), 1.36 (t, J = 7.2 Hz, 3 H, OCH2-CH3).
13C NMR (100 MHz, CDCl3): δ = 159.5, 131.4, 131.0, 128.2, 128.1,
125.9, 122.1, 118.3, 110.5, 81.3, 69.4, 60.3, 14.3.
Ynpyrroles 3 and 4; General Procedure
An 8 mL vial was charged with K2CO3 (55 mg, 0.4 mmol) and flame-
dried and allowed to cool under vacuum. Once cooled, the vial was
rapidly charged with CuSO4·5H2O (5 mg, 0.02 mmol), 4,7-dimethoxy-
1,10-phenanthroline (L7) (9.6 mg, 0.04 mmol), ethyl 1H-pyrrole-2-
carboxylate 1 (27.8 mg, 0.2 mmol) and an oven-dried stir bar. To the
vial was then added freshly distilled toluene (0.4 mL) and the mixture
sparged with argon for 10 min. Finally, the alkynyl bromide 2 was
added and the mixture sparged for an additional 10 min. Following
degassing, the vial was rapidly sealed with a Teflon cap and placed in
an oil bath at 135 °C. After reaction completion, the mixture was al-
lowed to cool to r.t. and directly loaded onto a silica gel column and
purified with hexanes/EtOAc.
HRMS (ESI): m/z [M + Na]+ calcd for C15H13NO2Na: 262.0838; found:
262.0840.
1-(Phenylethynyl)-1,5,6,7-tetrahydro-4H-indol-4-one (3e)
Pale yellow solid (35.7 mg, 76%); mp 101–103 °C.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.46 (m, 2 H, o-Ar-H ), 7.40–7.32
(m, 3 H, p-,m-Ar-H), 6.84 (d, J = 3.2 Hz, 1 H, H-2), 6.58 (d, J = 3.2 Hz, 1
H, H-3), 2.91 (t, J = 6.0 Hz, 2 H, H-5), 2.50 (t, J = 5.6 Hz, 2 H, H-7), 2.24–
2.15 (m, 2 H, H-6).
13C NMR (100 MHz, CDCl3): δ = 193.7, 147.1, 131.5, 128.7, 128.4,
124.7, 121.4, 121.3, 107.1, 79.4, 70.6, 37.6, 23.2, 21.8.
Ethyl 1-{6-[(tert-Butyldimethylsilyl)oxy]hex-1-yn-1-yl}-1H-pyr-
role-2-carboxylate (3a)
Pale yellow oil (48.3 mg, 69%).
IR: 2930, 2274, 1721, 1465, 1422, 1259, 1104, 835, 733 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.00 (dd, J = 2.8, 2.0 Hz, 1 H, H-3), 6.90
(dd, J = 3.6, 1.6 Hz, 1 H, H-5), 6.15 (dd, J = 4.0, 2.8 Hz, 1 H, H-4), 4.30 (q,
J = 7.2 Hz, 2 H, O-CH2), 3.65 (t, J = 5.6 Hz, 2 H, SiO-CH2), 2.46–2.41 (m,
2 H, CC-CH2), 1.72–1.64 (m, 4 H, CH2CH2), 1.34 (t, J = 7.2 Hz, 3 H,
OCH2-CH3), 0.88 (s, 9 H, Si-tBu), 0.04 (s, 6 H, Si-CH3).
13C NMR (100 MHz, CDCl3): δ = 159.6, 131.5, 125.5, 117.6, 109.8, 72.6,
69.2, 62.6, 60.2, 31.9, 25.9, 25.1, 18.3, 18.1, 14.3, –5.3.
tert-Butyl 1-[(Triisopropylsilyl)ethynyl]-1H-pyrrole-2-carboxylate
(4a)
Clear oil (66.8 mg, 96%).
IR: 2942, 2185, 1718, 1546, 1457, 1268, 1172, 1099, 1073, 882, 730
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.00 (dd, J = 2.4, 1.2 Hz, 1 H, H-3), 6.81
(dd, J = 4.0, 2.0 Hz, 1 H, H-5), 6.14 (dd, J = 4.0, 3.2 Hz, 1 H, H-4), 1.55 (s,
9 H, O-tBu), 1.13 (m, 21 H, Si-iPr).
HRMS (CI): m/z [M + H]+ calcd for C19H32NO3Si: 350.2151; found:
350.2145.
13C NMR (100 MHz, CDCl3): δ = 158.4, 131.3, 127.5, 117.3, 110.0, 94.9,
81.0, 68.1, 28.2, 18.6, 11.3.
HRMS (ESI): m/z [M + Na]+ calcd for C20H33NO2SiNa: 370.2173; found:
370.2184.
Ethyl 1-[(Triisopropylsilyl)ethynyl]-1H-pyrrole-2-carboxylate (3b)
Pale yellow oil (64.0 mg, 99%).
IR: 2942, 2187, 1724, 1457, 1255, 1099, 1074, 996, 882, 731, 675 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

G
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
2-(Trimethylsilyl)ethyl 1-[(Triisopropylsilyl)ethynyl]-1H-pyrrole-
2-carboxylate (4b)
1H NMR (400 MHz, CDCl3): δ = 9.87 (s, 1 H, CHO), 7.13 (dd, J = 2.8, 1.2
Hz, 1 H, H-5), 7.03–6.99 (m, 1 H, H-3), 6.34–6.29 (m, 1 H, H-4), 1.17–
1.10 (m, 21 H, Si-iPr).
13C NMR (100 MHz, CDCl3): δ = 178.7, 134.5, 131.9, 118.6, 111.7, 92.6,
70.2, 18.5, 11.2.
Clear oil (66.2 mg, 85%).
IR: 2944, 2187, 1721, 1458, 1420, 1252, 1096, 1073, 836, 731 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.04 (dd, J = 3.2, 2.0 Hz, 1 H, H-3), 6.91
(dd, J = 3.2, 1.2 Hz, 1 H, H-5), 6.17 (dd, J = 3.6, 2.4 Hz, 1 H, H-4), 4.39–
4.33 (m, 2 H, O-CH2), 1.16–1.12 (m, 21 H, Si-iPr), 1.12–1.06 (m, 2 H, Si-
CH2), 0.06 (s, 9 H, Si-CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C16H25NOSiNa: 298.1598; found:
298.1602.
N,N-Diethyl-1-[(triisopropylsilyl)ethynyl]-1H-pyrrole-2-carbox-
amide (4g)
13C NMR (100 MHz, CDCl3): δ = 159.4, 131.8, 126.3, 118.0, 110.2, 94.6,
68.2, 62.5, 18.6, 17.5, 11.3, –1.5.
Pale yellow oil (67.8 mg, 98%).
HRMS (ESI): m/z [M + Na]+ calcd for C21H37NO2Si2Na: 414.2255;
IR: 2941, 2865, 2183, 1632, 1461, 1272, 1092, 1067, 995, 882, 791,
found: 414.2273.
735 cm–1
.
Ethyl 5-Methyl-1-[(triisopropylsilyl)ethynyl]-1H-pyrrole-2-car-
boxylate (4c)
1H NMR (400 MHz, CDCl3): δ = 6.87 (dd, J = 3.2, 1.6 Hz, 1 H, H-5), 6.23
(dd, J = 3.6, 1.2 Hz, 1 H, H-3), 6.10 (dd, J = 3.6, 2.8 Hz, 1 H, H-4), 3.41
(br s, 4 H, N-CH2), 1.16 (t, J = 7.2 Hz, 6 H, NCH2-CH3), 1.07 (s, 21 H, Si-
iPr).
13C NMR (100 MHz, CDCl3): δ = 162.1, 130.7, 126.3, 110.2, 109.4, 94.3,
67.5, 18.5, 11.2.
Clear oil (49.6 mg, 74%).
IR: 2942, 2865, 2183, 1719, 1492, 1259, 1133, 1026, 882, 795, 752
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.86 (d, J = 3.6 Hz, 1 H, H-3), 5.95 (dd,
J = 3.6, 0.8 Hz, 1 H, H-4), 4.31 (q, J = 7.2 Hz, 2 H, O-CH2), 2.34 (s, 3 H,
C5-CH3), 1.32 (t, J = 7.2 Hz, 3 H, OCH2-CH3), 1.18–1.12 (m, 21 H, Si-iPr).
HRMS (ESI): m/z [M + Na]+ calcd for C20H34N2OSiNa: 369.2333; found:
369.2350.
13C NMR (100 MHz, CDCl3): δ = 159.3, 140.1, 125.1, 118.2, 108.6, 93.0,
72.3, 60.0, 18.6, 14.4, 12.9, 11.3.
1-[(Triisopropylsilyl)ethynyl]-1H-pyrrole-2-carbonitrile (4h)
Pale yellow oil (58.8 mg, 99%).
IR: 2943, 2865, 2227, 2185, 1455, 1146, 1071, 882, 782 cm–1
HRMS (ESI): m/z [M + Na]+ calcd for C19H31NO2SiNa: 356.2016; found:
356.2016.
.
1H NMR (400 MHz, CDCl3): δ = 7.05 (dd, J = 3.2, 1.2 Hz, 1 H, H-5), 6.81
(dd, J = 3.6, 1.2 Hz, 1 H, H-3), 6.22 (dd, J = 4.0, 2.8 Hz, 1 H, H-4), 1.18–
1.11 (m, 21 H, Si-iPr).
Methyl 1-[(Triisopropylsilyl)ethynyl]-1H-pyrrole-3-carboxylate
(4d)
13C NMR (100 MHz, CDCl3): δ = 129.3, 121.0, 111.8, 110.8, 108.8, 91.9,
Clear oil (22.8 mg, 37%).
70.9, 18.4, 11.1.
IR: 2944, 2865, 2189, 1721, 1556, 1495, 1246, 1201, 1119, 1068, 982,
882, 755 cm–1
.
HRMS (CI): m/z [M + H]+ calcd for C16H25N2Si: 273.1787; found:
1H NMR (400 MHz, CDCl3): δ = 7.49 (t, J = 2.0 Hz, 1 H, H-2), 6.82 (dd,
J = 2.4, 1.6 Hz, 1 H, H-5), 6.57 (dd, J = 3.2, 1.6 Hz, 1 H, H-4), 3.81 (s, 3 H,
O-CH3), 1.14–1.06 (m, 21 H, Si-iPr).
273.1786.
1-{1-[(Triisopropylsilyl)ethynyl]-1H-pyrrol-2-yl}ethan-1-one (4i)
Light orange oil (54.8 mg, 95%).
13C NMR (100 MHz, CDCl3): δ = 164.0, 129.6, 125.5, 117.6, 110.9, 95.1,
66.5, 51.3, 18.5, 11.1.
HRMS (ESI): m/z [M + H]+ calcd for C17H28NO2Si: 306.1884; found:
IR: 2942, 2864, 2184, 1673, 1454, 1253, 1076, 940, 881, 783, 734, 659
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.08 (dd, J = 2.8, 1.6 Hz, 1 H, H-5), 6.89
(dd, J = 4.0, 2.0 Hz, 1 H, H-3), 6.20 (dd, J = 4.0, 2.8 Hz, 1 H, H-4), 2.45 (s,
3 H, CO-CH3), 1.14 (s, 21 H, Si-iPr).
306.1888.
Methyl 2-Methyl-1-[(triisopropylsilyl)ethynyl]-1H-pyrrole-3-car-
boxylate (4e)
13C NMR (100 MHz, CDCl3): δ = 186.4, 133.9, 133.0, 118.8, 110.4, 95.0,
Clear oil (15.3 mg, 24%).
68.1, 26.8, 18.6, 11.3.
HRMS (CI): m/z [M + H]+ calcd for C17H28NOSi: 290.1940; found:
290.1941.
IR: 2943, 2865, 2187, 1713, 1577, 1438, 1304, 1243, 1080, 915, 882,
783, 711 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.73 (d, J = 2.8 Hz, 1 H, H-5), 6.49 (d, J =
2.8 Hz, 1 H, H-4), 3.80 (s, 3 H, O-CH3), 2.59 (s, 3 H, C2-CH3), 1.14–1.09
(m, 21 H, Si-iPr).
2,2-Dimethyl-1-{1-[(triisopropylsilyl)ethynyl]-1H-pyrrol-2-
yl}propan-1-one (4j)
13C NMR (100 MHz, CDCl3): δ = 164.9, 139.9, 122.7, 112.8, 110.7, 93.6,
Pale yellow oil (66.1 mg, 99%).
70.3, 51.0, 18.5, 11.7, 11.2.
HRMS (ESI): m/z [M + H]+ calcd for C18H30NO2Si: 320.2040; found:
IR: 2942, 2865, 2182, 1661, 1448, 1409, 1325, 1182, 928, 881, 784,
732 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.02 (dd, J = 2.8, 1.2 Hz, 1 H, H-5), 6.84
(dd, J = 4.0, 1.2 Hz, 1 H, H-3), 6.16 (dd, J = 4.0, 3.2 Hz, 1 H, H-4), 1.33 (s,
9 H, O-tBu), 1.17–1.11 (m, 21 H, Si-iPr).
320.2043.
1-[(Triisopropylsilyl)ethynyl]-1H-pyrrole-2-carbaldehyde (4f)
13C NMR (100 MHz, CDCl3): δ = 195.4, 132.2, 131.5, 116.8, 109.6, 95.6,
Pale yellow oil (37.3 mg, 68%).
IR: 2944, 2866, 2189, 1682, 1543, 1462, 1417, 1385, 883, 763 cm–1
.
67.3, 43.5, 28.1, 18.6, 11.3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

H
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C20H34NOSi: 332.2404; found:
13C NMR (100 MHz, CDCl3): δ = 178.2, 163.8, 146.5, 132.7, 120.5,
332.2413.
114.8, 90.0, 76.2, 51.5, 18.5, 12.1, 11.2.
HRMS (ESI): m/z [M + Na]+ calcd for C19H29NO3SiNa: 370.1809; found:
370.1815.
1-[(Triisopropylsilyl)ethynyl]-1H-pyrrole (4k)
Clear oil (28.0 mg, 57%).
IR: 2942, 2865, 2185, 1480, 1313, 958, 882, 762, 721, 674 cm–1
1H NMR (400 MHz, CDCl3): δ = 6.88 (t, J = 2.0 Hz, 2 H, H-2/5), 6.17 (t,
J = 2.0 Hz, 2 H, H-3/4), 1.12 (s, 21 H, Si-iPr).
.
Methyl 5-{[(tert-Butyldimethylsilyl)oxy]methyl}-2-methyl-1-[(tri-
isopropylsilyl)ethynyl]-1H-pyrrole-3-carboxylate (4p)
Clear oil (17.9 mg, 19%).
IR: 2944, 2864, 2185, 1714, 1593, 1544, 1462, 1224, 1070, 882, 835,
13C NMR (100 MHz, CDCl3): δ = 124.7, 110.0, 96.7, 64.4, 18.5, 11.2.
HRMS (ESI): m/z [M + H]+ calcd for C15H26NSi: 248.1829; found:
774, 676 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.40 (s, 1 H, H-4), 4.66 (s, 2 H, O-CH2),
3.79 (s, 3 H, O-CH3), 2.59 (s, 3 H, C2-CH3), 1.15–1.09 (m, 21 H, Si-iPr),
0.88 (s, 9 H, Si-tBu), 0.04 (s, 6 H, Si-CH3).
13C NMR (100 MHz, CDCl3): δ = 165.0, 140.0, 134.1, 112.3, 109.2, 91.7,
73.6, 57.2, 51.0, 25.8, 18.6, 18.3, 12.0, 11.2, –5.2.
248.1831.
2,5-Dimethyl-1-[(triisopropylsilyl)ethynyl]-1H-pyrrole (4l)
Clear oil (2.6 mg, 5%).
IR: 2941, 2865, 2169, 1693, 1541, 1463, 1397, 1195, 882, 794, 764,
HRMS (ESI): m/z [M + Na]+ calcd for C25H45NO3Si2Na: 486.2830;
found: 486.2827.
675 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 5.73 (s, 2 H, H-3/4), 2.27 (s, 6 H, CH3),
1.11 (s, 21 H, Si-iPr).
Pyrrolo[2,1-c][1,4]oxazin-1-ones 5; General Procedure
13C NMR (100 MHz, CDCl3): δ = 131.2, 106.5, 94.1, 70.6, 18.6, 12.5,
11.3.
HRMS (CI): m/z [M]+ calcd for C17H29NSi: 275.2069; found: 275.2068.
The ynpyrroles were synthesized following the previously outlined
procedure. Following the synthesis and isolation of the appropriate
ynpyrrole, the compounds were taken up in DMF (~0.5 M) and cooled
to 0 °C. Once cooled, a 1 M solution of TBAF in THF was added drop-
wise (1.25 equiv TBAF per silyl protecting group) and the solution al-
lowed to warm to r.t. After 2 h, the solution was diluted with sat.
NH4Cl (~10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined
organics were washed with brine and dried over Na2SO4. The solvent
was then removed and the residue purified by column chromatogra-
phy (yields are reported over 2 steps).
2-Phenyl-1-[(triisopropylsilyl)ethynyl]-1H-pyrrole (4m)
Clear oil (8.1 mg, 13%).
IR: 2923, 2864, 2177, 1727, 1469, 1323, 1247, 1180, 1072, 978, 882,
782, 753 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.74–7.69 (m, 2 H, o-Ar-H), 7.40–7.33
(m, 2 H, m-Ar-H), 7.33–7.27 (m, 1 H, p-Ar-H), 6.97 (dd, J = 3.2, 1.6 Hz,
1 H, H-5), 6.30 (dd, J = 3.6, 1.6 Hz, 1 H, H-3), 6.22 (dd, J = 3.6, 2.8 Hz, 1
H, H-4), 1.09–1.03 (m, 21 H, Si-iPr).
13C NMR (100 MHz, CDCl3): δ = 136.6, 131.3, 128.1, 127.6, 127.2,
126.7, 110.3, 108.9, 96.0, 68.1, 18.5, 11.3.
1H-Pyrrolo[2,1-c][1,4]oxazin-1-one (5a)
The product was prepared from pyrrole 4b.
White solid (15.7 mg, 58%); mp 102–103 °C.
IR: 3125, 3112, 1746, 1718, 1532, 1474, 1379, 1300, 1205, 1076,
HRMS (ESI): m/z [M + H]+ calcd for C21H30NSi: 324.2142; found:
324.2133.
1024, 1001, 886, 730 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.24 (d, J = 4.8 Hz, 1 H, H-3), 7.11 (dd,
J = 2.4, 1.6 Hz, 1 H, H-6), 7.03 (d, J = 4.8 Hz, 1 H, H-4), 6.81 (d, J = 4.4
Hz, 1 H, H-8), 6.55 (dd, J = 4.4, 2.4 Hz, 1 H, H-7).
13C NMR (100 MHz, CDCl3): δ = 154.9, 131.7, 121.1, 117.7, 115.9,
113.1, 109.0.
3-Phenyl-1-[(triisopropylsilyl)ethynyl]-1H-pyrrole (4n)
Clear oil (34.9 mg, 54%).
IR: 2943, 2865, 2183, 1727, 1462, 1367, 1265, 1157, 1069, 988, 881,
736 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C7H5NO2Na: 158.0212; found:
158.0213.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.49 (m, 2 H, o-Ar-H), 7.39–7.33
(m, 2 H, m-Ar-H), 7.23 (tt, J = 7.2, 1.2 Hz, 1 H, p-Ar-H), 7.17 (t, J = 2.0
Hz, 1 H, H-5), 6.93 (dd, J = 2.8, 2.0 Hz, 1 H, H-2), 6.49 (dd, J = 2.8, 1.6
Hz, 1 H, H-3), 1.15 (s, 21 H, Si-iPr).
13C NMR (100 MHz, CDCl3): δ = 134.1, 128.6, 126.3, 126.3, 125.8,
125.4, 120.7, 108.6, 96.6, 65.1, 18.6, 11.3.
2-(Trimethylsilyl)ethyl-5-methyl-1-[(triisopropylsilyl)ethynyl]-
1H-pyrrole-2-carboxylate (5b′)
IR: 2944, 2865, 2184, 1718, 1493, 1259, 1134, 837, 752, 676 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.84 (d, J = 4.0 Hz, 1 H, H-3), 5.94 (dd,
J = 4.0, 0.8 Hz, 1 H, H-4), 4.39–4.31 (m, 2 H, O-CH2), 2.34 (d, J = 0.8 Hz,
3 H, C5-CH3), 1.17–1.14 (m, 21 H, Si-iPr), 1.11–1.06 (m, 2 H, Si-CH2),
0.06 (s, 9 H, Si-CH3).
13C NMR (100 MHz, CDCl3): δ = 159.4, 140.0, 125.3, 118.1, 108.6, 93.0,
72.3, 62.2, 18.6, 17.5, 12.9, 11.3, –1.4.
HRMS (ESI): m/z [M + H]+ calcd for C21H30NSi: 324.2142; found:
324.2130.
Methyl 5-Formyl-2-methyl-1-[(triisopropylsilyl)ethynyl]-1H-pyr-
role-3-carboxylate (4o)
Clear oil (19.8 mg, 28%).
HRMS (ESI): m/z [M + Na]+ calcd for C22H39NO2Si2Na: 428.2412;
found: 428.2429.
IR: 2944, 2865, 2186, 1718, 1682, 1568, 1502, 1440, 1234, 1134,
1072, 881, 773, 676 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.77 (s, 1 H, CHO), 7.31 (s, 1 H, H-4),
6-Methyl-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (5b)
3.84 (s, 3 H, O-CH3), 2.68 (s, 3 H, C2-CH3), 1.18–1.11 (m, 21 H, Si-iPr).
White solid (16.8 mg, 56%); mp 106–107 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

I
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
IR: 3129, 3105, 2925, 1739, 1705, 1488, 1430, 1365, 1320, 1230,
1077, 1043, 977, 726 cm–1
2-(Trimethylsilyl)ethyl-1-[5-(benzyloxy)pent-1-yn-1-yl]-1H-pyr-
role-2-carboxylate (5e′)
.
1H NMR (400 MHz, CDCl3): δ = 7.17 (d, J = 4.4 Hz, 1 H, H-3), 6.92 (dd,
J = 4.4, 0.8 Hz, 1 H, H-8), 6.82 (d, J = 4.4 Hz, 1 H, H-4), 6.31 (dd, J = 4.0,
0.8 Hz, 1 H, H-7), 2.38 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 155.0, 131.5, 130.2, 116.8, 115.7,
112.5, 106.1, 11.3.
IR: 2952, 2852, 2272, 1715, 1542, 1464, 1421, 1257, 1100, 1028, 934,
857, 836, 733, 696 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.24 (m, 5 H, Ar-H), 6.96 (dd, J =
4.0, 2.0 Hz, 1 H, H-3), 6.89 (dd, J = 4.0, 2.0 Hz, 1 H, H-5), 6.15 (dd, J =
4.0, 3.2 Hz, 1 H, H-4), 4.54 (s, 2 H, Ph-CH2), 4.40–4.30 (m, 2 H, CO2-
CH2), 3.65 (t, J = 6.0 Hz, 2 H, O-CH2), 2.55 (t, J = 7.2 Hz, 2 H, CC-CH2),
1.98–1.88 (m, 2 H, CH2), 1.12–1.06 (m, 2 H, Si-CH2), 0.07 (s, 9 H, Si-
CH3).
HRMS (ESI): m/z [M + H]+ calcd for C8H8NO2: 150.0550; found:
150.0547.
13C NMR (100 MHz, CDCl3): δ = 159.7, 138.4, 131.4, 128.2, 127.5,
127.4, 125.6, 117.4, 109.7, 72.8, 72.7, 68.7, 68.6, 62.4, 28.7, 17.3, 15.2,
–1.5.
HRMS (ESI): m/z [M + Na]+ calcd for C22H29NO3SiNa: 406.1809; found:
406.1826.
2-(Trimethylsilyl)ethyl-1-{5-[(tert-butyldimethylsilyl)oxy]pent-1-
yn-1-yl}-1H-pyrrole-2-carboxylate (5c′)
Characterized with impurity.
IR: 2953, 2856, 1719, 1542, 1465, 1421, 1256, 1100, 938, 857, 833,
755, 731 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.99 (dd, J = 2.8, 1.6 Hz, 1 H, H-5), 6.87
(dd, J = 4.0, 1.6 Hz, 1 H, H-3), 6.14 (dd, J = 4.0, 2.8 Hz, 1 H, H-4), 4.37–
4.31 (m, 2 H, CO2-CH2), 3.75 (t, J = 6.0 Hz, 2 H, SiO-CH2), 2.49 (t, J = 6.8
Hz, 2 H, CC-CH2-CH2), 1.85–1.77 (m, 2 H, CH2), 1.11–1.05 (m, 2 H, Si-
CH2), 0.89 (s, 9 H, Si-tBu), 0.06 (s, 15 H, Si-CH3).
3-[3-(Benzyloxy)propyl]-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (5e)
Clear oil (31.1 mg, 55%).
IR: 3116, 3030, 2926, 2856, 1723, 1689, 1532, 1478, 1454, 1361,
1215, 1074, 1033, 970, 892, 732, 697 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.26 (m, 5 H, Ar-H), 7.21–7.17
(m, 1 H, H-6), 6.99 (dd, J = 2.4, 1.6 Hz, 1 H, H-8), 6.69 (d, J = 0.8 Hz, 1 H,
H-4), 6.50 (dd, J = 4.0, 2.4 Hz, 1 H, H-7), 4.50 (s, 2 H, Ph-CH2), 3.52 (t,
J = 6.0 Hz, 2 H, O-CH2), 2.52 (t, J = 7.2 Hz, 2 H, CH2), 2.01–1.91 (m, 2 H,
CH2).
13C NMR (100 MHz, CDCl3): δ = 159.7, 131.4, 125.6, 117.4, 109.8, 79.9,
72.5, 68.9, 62.4, 61.6, 61.3, 37.6, 31.6, 31.2, 25.9, 25.8, 18.3, 18.2, 17.3,
16.0, 14.8, –1.3, –1.4, –5.3, –5.4.
HRMS (ESI): m/z [M + Na]+ calcd for C21H37NO3Si2Na: 430.2204;
found: 430.2223.
13C NMR (100 MHz, CDCl3): δ = 155.4, 143.7, 138.2, 128.3, 127.7,
127.6, 120.6, 116.5, 115.1, 112.7, 104.9, 72.8, 68.3, 27.5, 26.6.
HRMS (ESI): m/z [M + Na]+ calcd for C17H17NO3Na: 306.1101; found:
306.1108.
3-(3-Hydroxypropyl)-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (5c)
Clear oil (16.8 mg, 43%).
IR: 3407, 3116, 2928, 2874, 1717, 1683, 1532, 1478, 1388, 1363,
1215, 1035, 970, 892, 734 cm–1
.
2-(Trimethylsilyl)ethyl-1-[3-(benzyloxy)-3-methylbut-1-yn-1-yl]-
1H-pyrrole-2-carboxylate (5f′)
1H NMR (400 MHz, CDCl3): δ = 7.22–7.17 (m, 1 H, H-6), 7.04 (dd, J =
2.8, 1.6 Hz, 1 H, H-8), 6.85 (d, J = 0.8 Hz, 1 H, H-4), 6.50 (dd, J = 4.0, 2.4
Hz, 1 H, H-7), 3.71 (t, J = 6.4 Hz, 2 H, O-CH2), 2.54 (t, J = 7.6 Hz, 2 H,
CH2), 1.96–1.87 (m, 2 H, CH2), 1.84 (br s, 1 H, OH).
13C NMR (100 MHz, CDCl3): δ = 155.5, 143.8, 120.8, 116.5, 115.2,
112.9, 105.0, 61.2, 29.4, 27.1.
IR: 2953, 2920, 2851, 2268, 1716, 1544, 1470, 1421, 1260, 1207,
1155, 1098, 1057, 944, 857, 836, 732. 695 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.23 (m, 5 H, Ar-H), 7.00 (dd, J =
2.4, 1.2 Hz, 1 H, H-3), 6.93 (dd, J = 4.0, 1.6 Hz, 1 H, H-5), 6.20 (dd, J =
4.0, 2.8 Hz, 1 H, H-4), 4.74 (s, 2 H, Ph-CH2), 4.40–4.34 (m, 2 H, CO2-
CH2), 1.66 (s, 6 H, CH3), 1.14–1.06 (m, 2 H, Si-CH2), 0.07 (s, 9 H, Si-
CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C10H11NO3Na: 216.0631; found:
216.0627.
13C NMR (100 MHz, CDCl3): δ = 159.5, 139.1, 131.2, 128.2, 127.7,
127.2, 126.1, 118.1, 110.3, 71.1, 70.9, 66.6, 62.6, 28.9, 17.4, –1.4.
3-(3-Chloropropyl)-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (5d)
To a mixture of 5c (10.0 mg, 0.05 mmol) and CCl4 (44 μL, 0.45 mmol)
in CH2Cl2 (0.1 mL) was added PPh3 (25 mg, 0.15 mmol) in CH2Cl2 (0.1
mL) dropwise at r.t. The mixture was allowed to stir for 6 h, after
which the solvent was removed and the residue purified by column
chromatography (hexanes/EtOAc).
HRMS (ESI): m/z [M + Na]+ calcd for C22H29NO3SiNa: 406.1809; found:
406.1826.
3-[2-(Benzyloxy)propan-2-yl]-1H-pyrrolo[2,1-c][1,4]oxazin-1-one
(5f)
Clear oil (7.7 mg, 70%).
White solid (45.8 mg, 81%); mp 89–90 °C.
IR: 3118, 2959, 2922, 2850, 1747, 1723, 1688, 1532, 1478, 1364,
IR: 3122, 2983, 2926, 1725, 1535, 1478, 1390, 1352, 1260, 1194,
1290, 1215, 1078, 1035, 972, 734 cm–1
.
1157, 1035, 958, 732, 696 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.23–7.21 (m, 1 H, H-6), 7.06 (dd, J =
2.8, 1.6 Hz, 1 H, H-8), 6.89–6.87 (m, 1 H, H-4), 6.53 (dd, J = 4.4, 2.8 Hz,
1 H, H-7), 3.60 (t, J = 6.0 Hz, 2 H, Cl-CH2), 2.62 (t, J = 7.6 Hz, 2 H, CH2),
2.20–2.10 (m, 2 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 155.2, 142.5, 120.8, 116.6, 115.5,
113.0, 105.5, 43.6, 29.0, 27.9.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.32 (m, 4 H, o-,m-Ar-H), 7.30–
7.24 (m, 1 H, p-Ar-H), 7.24–7.20 (m, 1 H, H-6), 7.13 (d, J = 0.8 Hz, 1 H,
H-4), 7.09 (dd, J = 2.8, 1.6 Hz, 1 H, H-8), 6.54 (dd, J = 4.0, 2.8 Hz, 1 H, H-
7), 4.50 (s, 2 H, Ph-CH2), 1.61 (s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 154.9, 146.6, 138.4, 128.3, 127.4,
127.2, 121.3, 116.5, 115.3, 113.2, 104.9, 74.8, 65.1, 24.9.
HRMS (ESI): m/z [M + Na]+ calcd for C10H10ClNO2Na: 234.0292; found:
234.0292.
HRMS (ESI): m/z [M + H]+ calcd for C17H18NO3: 284.1281; found:
284.1280.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

J
B. J. Reinus, S. M. Kerwin
Paper
Synthesis
2-(Trimethylsilyl)ethyl 1-{[(8R,9S,13S,14S,17S)-3,17-dimethoxy-
13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopen-
ta[a]phenanthren-17-yl]ethynyl}-1H-pyrrole-2-carboxylate (5g′)
(3) For ynamine reviews, see: (a) Zificsak, C. A.; Mulder, J. A.;
Hsung, R. P.; Rameshkumar, C.; Wei, L. L. Tetrahedron 2001, 57,
7575. (b) Ficini, J. Tetrahedron 1976, 32, 1449.
(4) For reviews of ynamide chemistry, see: (a) Evano, G.; Blanchard,
N.; Compain, G.; Coste, A.; Demmer, C. S.; Gati, W.; Guissart, C.;
Heimburger, J.; Henry, N.; Jouvin, K.; Karthikeyan, G.; Laouiti,
A.; Lecomte, N. A.; Theuniseen, C.; Thibaudeau, S.; Wang, J. J.;
Zarca, M.; Zhang, C. Y. Chem. Lett. 2016, 45, 574. (b) Evano, G.;
Theunissen, C.; Lecomte, M. Aldrichimica Acta 2015, 48, 59.
(c) Cook, A. M.; Wolf, C. Tetrahedron Lett. 2015, 56, 2377.
(d) Wang, X.; Yeom, H.; Fang, L.; He, S.; Ma, Z.; Kdedrowski, B.;
Hsung, R. P. Acc. Chem. Res. 2014, 47, 560. (e) Evano, G.; Coste,
A.; Jouvin, K. Angew. Chem. Int. Ed. 2010, 49, 2840. (f) Dekorver,
K.; Li, H.; Lohse, A.; Kayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R.
Chem. Rev. 2010, 110, 5064.
(5) (a) Klapars, A.; Huang, X.; Buchwald, S. J. Am. Chem. Soc. 2002,
124, 7421. (b) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S.
J. Am. Chem. Soc. 2001, 123, 7727.
(6) (a) Jouvin, K.; Couty, F.; Evano, G. Org. Lett. 2010, 12, 3272.
(b) Hamada, T.; Ye, X.; Stahl, S. J. Am. Chem. Soc. 2008, 130, 833.
(7) Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, 727.
(8) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R.; Kurtz, K.;
Oppenheimer, J.; Peterson, M.; Sagamanova, I.; Shen, L.; Tracey,
M. J. Org. Chem. 2006, 71, 4170.
(9) (a) Hamada, T.; Ye, X.; Stahl, S. J. Am. Chem. Soc. 2008, 130, 833.
(b) Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000.
(10) Zhang, Y.; Hsung, R.; Tracey, M.; Kurtz, K.; Vera, E. Org. Lett.
2004, 6, 1151.
(11) Yao, B.; Liang, Z.; Niu, T.; Zhang, Y. J. Org. Chem. 2009, 74, 4630.
(12) Frederick, M.; Mulder, J.; Tracey, M.; Hsung, R.; Huang, J.; Kurtz,
K.; Shen, L.; Douglas, C. J. Am. Chem. Soc. 2003, 125, 2368.
(13) Sueda, T.; Oshima, A.; Teno, N. Org. Lett. 2011, 13, 3996.
(14) Laouiti, A.; Rammah, M. M.; Rammah, M. B.; Marrot, J.; Couty,
F.; Evano, G. Org. Lett. 2012, 14, 6.
[α]D –36.1 (c 1.0, CH2Cl2); mp 106–108 °C.
IR: 2940, 2263, 1715, 1609, 1499, 1463, 1421, 1251, 1097, 1040, 908,
858, 836, 731 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.22 (d, J = 4.8 Hz, 1 H, H-1), 7.07 (dd,
J = 2.8, 1.6 Hz, 1 H, pyrrole H-5), 6.93 (dd, J = 4.0, 2.0 Hz, 1 H, pyrrole
H-3), 6.71 (dd, J = 4.8, 2.8 Hz, 1 H, H-2), 6.63 (d, J = 2.8 Hz, 1 H, H-4),
6.21 (dd, J = 4.0, 2.8 Hz, 1 H, pyrrole H-4), 4.40–4.33 (m, 2 H, O-CH2),
3.78 (s, 3 H, O3-CH3), 3.50 (s, 3 H, O17-CH3), 2.94–2.78 (m, 2 H, C6-
H2), 2.46–2.24 (m, 3 H, C9-H, C15-H, C16-H), 2.24–2.18 (m, 2 H, C11-
H, C7-H), 1.96–1.80 (m, 4 H), 1.58–1.34 (m, 4 H), 1.13–1.05 (m, 2 H,
Si-CH2), 0.93 (s, 3 H, C13-CH3), 0.06 (s, 9 H, Si-CH3).
13C NMR (100 MHz, CDCl3): δ = 159.4, 157.3, 137.9, 132.7, 131.3,
126.3, 126.2, 117.9, 113.7, 111.4, 110.2, 86.1, 79.9, 69.8, 62.5, 55.1,
53.4, 49.4, 48.0, 43.3, 39.2, 36.5, 34.2, 29.8, 27.2, 26.6, 22.8, 17.5, 12.8.
–1.4.
HRMS (CI): m/z [M + H]+ calcd for C32H44NO4Si: 534.3040; found:
534.3023.
3-[(8R,9S,13S,14S,17S)-3,17-dimethoxy-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenan-
thren-17-yl]-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (5g)
White solid (65.4 mg, 75%); mp 186–192 °C; [α]D 37.1 (c 0.35, CH2Cl2).
IR: 2930, 1727, 1609, 1534, 1499, 1475, 1386, 1354, 1255, 1035, 869,
737 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25 (m, 1 H, pyrrolooxazine H-6), 7.15
(dd, J = 2.4, 1.2 Hz, 1 H, pyrrolooxazine H-8), 7.12 (d, J = 8.8 Hz, 1 H, H-
1), 7.04 (s, 1 H, pyrrolooxazine H-4), 6.67 (dd, J = 8.4, 2.4 Hz, 1 H, H-2),
6.63–6.56 (m, 2 H, H-4, pyrrolooxazine H-7), 3.76 (s, 3 H), 3.24 (s, 3
H), 2.92–2.78 (m, 2 H, C6-H2), 2.30–2.18 (m, 2 H), 2.16–2.02 (m, 2 H),
2.00–1.86 (m, 2 H), 1.85–1.76 (m, 1 H), 1.62–1.16 (m, 6 H), 0.99 (s, 3
H, C13-CH3).
13C NMR (100 MHz, CDCl3): δ = 157.4, 154.8, 144.4, 137.8, 132.5,
126.1, 121.0, 116.6, 115.1, 113.7, 113.3, 111.3, 108.2, 89.6, 55.1, 52.8,
48.7, 48.4, 43.3, 39.2, 33.9, 29.8, 29.7, 27.4, 26.3, 23.4, 14.6.
(15) Chen, X. Y.; Wang, L.; Frings, M.; Bolm, C. Org. Lett. 2014, 16,
3796.
(16) Laroche, C.; Li, J.; Freyer, M.; Kerwin, S. J. Org. Chem. 2008, 73,
6462.
(17) Burley, G.; Davies, D.; Griffith, G.; Lee, M.; Singh, K. J. Org. Chem.
2010, 75, 980.
(18) Ziegler, D.; Choi, J.; Munoz-Molina, J.; Bissember, A.; Peters, J.;
Fu, G. J. Am. Chem. Soc. 2013, 135, 13107.
HRMS (CI): m/z [M + H]+ calcd for C27H32NO4: 434.2331; found:
434.2312.
(19) (a) See ref. 16. (b) Laroche, C.; Li, J.; Kerwin, S. M. Tetrahedron
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(20) For a review of N-alkynyl heterocycle chemistry, see: Katritzky,
A. R.; Jiang, R.; Singh, S. K. Heterocycles 2004, 63, 1455.
(21) For previous uses of ynpyrroles, see: (a) Paley, M.; Frazier, D.;
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Acknowledgment
We thank the Welch Foundation (AI-1298), The William and Ella
Owens Medical Research Foundation, and Texas State University (REP
Award) for generous support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588736.
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