Synthesis of pyrrolidines and pyrroles by tandem amination/cyanation/alkylation and amination/oxidation sequences

Article abstract of DOI:10.1002/ejoc.201402748

Copper-catalyzed three-component tandem amination/cyanation/alkylation of the primary-amine-tethered alkynes 1 gave α-CN-substituted pyrrolidines 6 in good yields and regioselectivities. In addition, silver-mediated tandem amination/oxidation of the secon

Full text of DOI:10.1002/ejoc.201402748

FULL PAPER
DOI: 10.1002/ejoc.201402748
Synthesis of Pyrrolidines and Pyrroles by Tandem Amination/Cyanation/
Alkylation and Amination/Oxidation Sequences
Junbin Han,[a] Zhichao Lu,[a] Gerald B. Hammond,*[a] and Bo Xu*[a]
Keywords: Synthetic methods / Tandem reactions / Reaction mechanisms / Nitrogen heterocycles / Amination
Copper-catalyzed three-component tandem amination/cyan- ation/oxidation of the secondary-amine-tethered alkynes 7
ation/alkylation of the primary-amine-tethered alkynes 1
gave α-CN-substituted pyrrolidines 6 in good yields and re-
gioselectivities. In addition, silver-mediated tandem amin-
produced functionalized pyrroles 8 in good yields. All reac-
tions were conducted in one pot without any protection/de-
protection steps.
there is demand for a more concise and efficient synthesis
of structurally more complex N heterocycles. The need to
map new chemical spaces through tandem or cascade reac-
tions[3] in an atom-economic fashion has inspired us to de-
velop a strategy to access heterocycles of different ring sizes
with different substitution patterns through cyclization-
triggered tandem reactions (Scheme 1). We have applied
this strategy successfully to tandem amination/alkyn-
Introduction
N-Heterocycles of different ring sizes and different sub-
stitution patterns are among the most common synthetic
intermediates and the most important structural classes in
medicinal chemistry.[1] Although N heterocycles have been
synthesized for over a century and a variety of well-estab-
lished methods are available for their synthesis, such as the
cyclization of amine-tethered C–C unsaturated systems,[2]
ylation,[4]
amination/cyanation,[5]
amination/trifluoro-
methylation,[5] and amination/phosphorylation sequences[6]
(Scheme 1, a).
Results and Discussion
We report herein an extension of our tandem strategy to
primary amines tethered to alkynes and a new amination/
oxidation sequence (Scheme 1, b). This extension has al-
lowed a three-component synthesis of α-CN-substituted
pyrrolidines and a versatile synthesis of functionalized pyr-
roles. All the reactions were carried out in one pot without
the need for protection/deprotection steps.
In our earlier work (Scheme 1, a), the starting material
was a secondary-amine-tethered alkyne, which underwent
cyclization via an enamine intermediate. When we started
with a primary-amine-tethered alkyne, such as 1a, the tan-
dem amination/cyanation sequence gave only 46% yield of
the desired product 4a under our published conditions[5]
Scheme 1. Synthesis of N heterocycles by cyclization-triggered tan- (Table 1, entry 1) and imine 3a was obtained as a major
dem reactions.
byproduct. Increasing the amount of trimethylsilyl cyanide
and changing the temperature did not improve the yield
[a] Department of Chemistry, University of Louisville,
significantly (Table 1, entries 2–5). We also found that 4a
Louisville, Kentucky 40292, USA
was unstable towards silica gel chromatography. We ex-
plained this result by invoking a thermodynamic equilib-
rium between 3a and 4a that prevented its complete conver-
sion to 4a.
E-mail: gb.hammond@louisville.edu
bo.xu@louisville.edu
http://louisville.edu/research/hammondgroup
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402748.
5786
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5786–5792

Synthesis of Pyrrolidines and Pyrroles
Table 1. Tandem amination/cyanation of primary-amine-tethered tries 1–4, conditions A). In general, the use of Sc(OTf)3 as
co-catalyst was helpful if the reaction was sluggish[7]
alkyne 1a as starting material.
(Table 3, entries 5–9, conditions B); its use significantly in-
creased the rate of reactions and improved the chemical
yields. Compounds 6f, 6g, and 6h were formed as mixtures
of two diastereoisomers in ratios of approximately 1:1.
We also studied the reactions of primary amines 1d and
1e with no geminal groups. Neither amine gave the desired
product under conditions A given in Table 3 [Equations (1)
and (2)], only complex mixtures were obtained. Use of a
more powerful hydroamination catalyst, IPrAuOTf, and
alkyl mesylate instead of CuBr did not improve the reaction
outcomes [Equations (3) and (4)].
(1)
[a] Determined by NMR spectroscopy.
We speculated that if the nitrogen in 4a could be further
substituted, the resulting tertiary amine would be more
stable. This strategy proved successful with chloroaceto-
(2)
nitrile (5a) as the alkylating reagent (Table 2, entry 1). We
also found that acetonitrile is a better solvent for this trans-
formation (Table 2, entry 2). Reducing the amount of 5a led
to a slightly increased yield (Table 2, entry 3) and the use
of conventional heating instead of microwave heating was
also effective (Table 2, entry 4), although longer reaction
times were needed. However, the reaction of the internal
alkyne-tethered amine 1c under the same optimized condi-
tions was sluggish (Table 2, entry 5), probably because the
imine intermediate was less reactive. We solved this problem
by adding Sc(OTf)3 as a Lewis acid co-catalyst, which is
known to activate imines towards nucleophilic attack.[7]
The scope of our new three-component tandem reaction
(3)
(4)
Our proposed mechanism for the formation of 6 is shown
is shown in Table 3. A variety of alkylating reagents are in Scheme 2. The alkylation step could occur as the first
compatible with our tandem reaction sequence (Table 3, en- (pathway A) or last step of the reaction (pathway B). We
Table 2. Optimization of the tandem amination/cyanation sequence using a primary amine.
Eur. J. Org. Chem. 2014, 5786–5792
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5787

J. Han, Z. Lu, G. B. Hammond, B. Xu
FULL PAPER
favor pathway B because, as shown in Scheme 3, 1a is cessful reactions of primary amines with no geminal groups
known to cyclize to imine 3a easily in the presence of a (1d, 1e) can also be rationalized by pathway B. The cycliza-
copper catalyst due to the Thorpe–Ingold or gem-dimethyl tion of 1d or 1e is much slower and less selective than the
effect.[8] Also, isolated 3a reacts with TMSCN. Our unsuc- cyclization of 1a. Indeed, the cyclization of 1d gave a com-
Table 3. Scope of the three-component tandem amination/cyanation/alkylation reaction.
[a] Conditions A: amino-alkyne 1 (0.25 mmol), TMSCN (1 mmol), alkylating reagent (0.5 mmol), water (1.0 equiv.), CuBr (5 mol-%),
acetonitrile (1 mL), microwave/90 °C, 40 min. Conditions B: same as for A but with the use of co-catalyst Sc(OTf)3 (2%). [b] Reaction
was conducted in DCE. [c] 40 equiv. of 1-pentyl chloride was used.
5788
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5786–5792

Synthesis of Pyrrolidines and Pyrroles
ited scope (only two substrates reported).[9] Because we had
already reported that hydroamination was a reversible pro-
cess and the migration of the triple bond was plausible,[5]
we were confident that homopropargylamines were not the
only starting materials that could be employed in our proto-
col. Thus, we chose dec-5-ynamine 7a, in which the N atom
is separated from the alkyne carbon by four carbon atoms.
Even though the most favored cyclization path for 7a is the
6-exo-dig pathway,[5] we did not observe the formation of a
six-membered ring, rather, the pyrrole product 8a was ob-
tained in the presence of catalytic amounts of AgF (Table 4,
entry 1), albeit in very low yield (6%). A stoichiometric
amount of silver was needed to increase the yield (Table 4,
entry 2). In addition, the reaction was cleaner if it was con-
ducted at room temperature (Table 4, entry 3). We also in-
vestigated the effect of different silver salts. Silver acetate
exhibited the highest activity; other silver salts, such as sil-
ver nitrate, only generated trace amounts of product
(Table 4, entries 4, 9, and 10). The screening of various sol-
Scheme 2. Proposed mechanism for the formation of 6.
Table 4. Optimization of the synthesis of pyrrole 8a by a tandem
amination/oxidation sequence.
Scheme 3. Investigation of the mechanism for the formation of 6.
plex mixture [Equation (5)]. Because the corresponding im-
ine cannot be formed selectively, according to pathway B,
the tandem cyanation/alkylation product can be obtained.
(5)
When 3a and 4a were allowed to react under the condi-
tions of Table 3 in the presence of DCE, we obtained 6d as
the final product in good yield (Scheme 3).
We then turned our attention to the tandem amination/
oxidation sequence. Agarwal and Knölker reported a sil-
ver(I)-promoted oxidative cyclization of homoproparg-
ylamines to yield pyrroles, but their method has only lim- [a] Determined by NMR spectroscopy. [b] Isolated yield.
Scheme 4. Proposed mechanism for the formation of 8.
Eur. J. Org. Chem. 2014, 5786–5792
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5789

J. Han, Z. Lu, G. B. Hammond, B. Xu
FULL PAPER
vents demonstrated DCM to be the most appropriate for
the reaction (Table 4, entry 5). In general, 2 equiv. of silver
acetate and longer reaction times gave better yields (Table 4,
entries 7 and 8). Our attempt to reduce the amount of silver
salt by using a catalytic amount of silver acetate in combi-
nation with an oxidant was unsuccessful (Table 4, entry 13).
The scope of our pyrrole synthesis is shown in Table 5.
The reaction worked well for both aliphatic and aromatic
amines tethered to the alkyne starting material 7 when the
carbon chain between the amine and alkyne moieties con-
tained between two and four carbons. Typically, silver fluor-
ide furnished better yields when the starting material was a
substituted aniline.
Conclusions
Our copper-catalyzed three-component tandem amin-
ation/cyanation/alkylation sequence gives α-CN-substituted
pyrrolidines 6 in good yields and regioselectivities. In ad-
dition, silver-mediated tandem amination/oxidation of sec-
ondary-amine-tethered alkynes 7 produces functionalized
pyrroles 8 in good yields.
Experimental Section
General: Compounds 1a–c were synthesized according to a litera-
ture method[10] and amino-alkynes 7 were synthesized following
our previously published procedure.[5]
Table 5. Scope of the synthesis of pyrroles 8 by a tandem amin-
General Procedure for the Synthesis of 6: Amino-alkyne 1a (43 mg,
0.25 mmol), trimethylsilyl cyanide (99 mg, 1.0 mmol), dioxane
(1 mL), and water (4.5 mg, 1.0 equiv.) were placed in a microwave
tube reactor and CuBr (1.8 mg, 5% equiv.) was added to the mix-
ture whilst stirring. After all the starting materials had dissolved,
the microwave tube reactor was flushed with argon and the reaction
mixture was heated at 100 °C under microwave irradiation for
0.5 h. The resulting reaction mixture was directly concentrated in
a rotary evaporator and purified by silica gel flash chromatography
(4:1 hexane/diethyl ether) to give 6a (48 mg, 93%) as a yellow li-
quid.
ation/oxidation sequence.[a]
5-Methyl-3,3-diphenyl-3,4-dihydro-2H-pyrrole (3a): Yellow solid. IR
(KBr disk): ν = 3289, 3065, 2949, 2865, 1644, 1602, 1495, 1448,
˜
1378, 1304, 1033, 754, 698 cm–1. 1H NMR (400 MHz, CDCl3): δ =
2.08 (s, 3 H), 3.20 (s, 2 H), 4.45 (s, 2 H), 7.08–7.33 (m, 10 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 20.2, 52.6, 56.3, 73.1, 126.2,
127.0, 128.4, 147.9, 174.4 ppm. HRMS (ESI+): calcd. for C17H17N
[M + H]+ 236.1434; found 236.1431.
1-(Cyanomethyl)-2-methyl-4,4-diphenylpyrrolidine-2-carbonitrile
(6a): Yellow oil (70.1 mg, 93% yield). IR (neat): ν = 3457, 3027,
˜
1
2970, 2810, 2215, 1739, 1446, 1366, 1217, 734, 695 cm–1. H NMR
(400 MHz, CDCl3): δ = 1.56 (s, 3 H), 2.69 (d, J = 11.2 Hz, 1 H),
3.35 (d, J = 7.6 Hz, 1 H), 3.44 (d, J = 11.2 Hz, 1 H), 3.55 (d, J =
13.6 Hz, 1 H), 3.79 (d, J = 13.6 Hz, 1 H), 4.12 (d, J = 7.6 Hz, 1
H), 7.17–7.41 (m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
24.5, 37.3, 51.7, 52.4, 60.6, 64.4, 115.7, 119.2, 126.5, 126.6, 126.9,
127.0, 128.6, 128.7, 145.3, 150.0 ppm. HRMS (ESI+): calcd. for
C25H24N2 [M – CN]+ 326.1908; found 326.1906.
2-(2-Cyano-2-methyl-4,4-diphenylpyrrolidin-1-yl)acetamide (6b):
Brown solid (73.5 mg, 92% yield), m.p. 151.2–154.7 °C. IR (neat):
ν = 3446, 3210, 3170, 2960, 2920, 2875, 2234, 1679, 1648, 1451,
˜
1
1218, 1114, 705 cm–1. H NMR (400 MHz, CDCl3): δ = 1.57 (s, 3
[a] Reagents and conditions: amino-alkyne (0.25 mmol), silver acet-
ate (0.375 mmol), DCM (1 mL), room temp., 40 h. [b] Silver fluor-
ide (0.375 mmol) was used. [c] Isolated yields.
H), 2.94 (d, J = 14.4 Hz, 1 H), 3.18 (d, J = 16.8 Hz, 1 H), 3.24 (d,
J = 14.4 Hz, 1 H), 3.37 (d, J = 10 Hz, 1 H), 3.45 (d, J = 17.2 Hz,
1 H), 3.83 (d, J = 10 Hz, 1 H), 5.98 (s, 1 H), 6.24 (d, 1 H), 7.14–
7.32 (m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.4, 51.1,
52.5, 52.6, 60.8, 64.6, 120.4, 126.4, 126.7, 126.8, 126.8, 128.7, 145.8,
147.4, 172.6 ppm. HRMS (ESI+): calcd. for C20H21N3O [M –
CN]+ 293.1654; found 293.1652.
A reasonable mechanism for the formation of pyrrole 8a
is illustrated in Scheme 4. Hydroamination of dec-5-ynam-
ine 7a produces the six-membered enamine 9 by 6-exo-dig
cyclization[5] and subsequent migration of the double bond
in enamine 9 yields 10. Hydroamination in the presence of
a metal catalyst is a reversible process[5] and retro-hydro-
amination of 10 delivers alkyne 11, which undergoes a sec-
ond hydroamination/migration sequence to give 13, simi-
larly to the reaction of 7 to yield 10. Oxidation or dehydro-
genation of 13 with the silver oxidant furnishes the final
pyrrole product 8a.[9]
1-Benzyl-2-methyl-4,4-diphenylpyrrolidine-2-carbonitrile (6c): Yel-
low oil (66.8 mg, 79% yield). IR (neat): ν = 3061, 3033, 2832, 2222,
˜
1714, 1597, 1495, 1448, 1210, 1145, 1038, 907, 758, 698 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.60 (s, 3 H), 2.54 (d, J = 14 Hz, 1
H), 3.02 (d, J = 10.8 Hz, 1 H), 3.43 (d, J = 14 Hz, 1 H), 3.49 (d, J
= 13.2 Hz, 1 H), 3.71 (d, J = 10 Hz, 1 H), 4.10 (d, J = 13.6 Hz, 1
H), 7.11–7.39 (m, 15 H) ppm. HRMS (ESI+): calcd. for C20H19N3
[M – CN]+ 275.1548; found 275.1553.
5790
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5786–5792

Synthesis of Pyrrolidines and Pyrroles
1-(2-Chloroethyl)-2-methyl-4,4-diphenylpyrrolidine-2-carbonitrile (s, 2 H), 5.88 (s, 1 H), 6.05 (t, J = 2.4 Hz, 1 H), 6.53–6.55 (m, 1 H),
(6d): Yellow oil (80.4 mg, 99% yield). IR (neat): ν = 3024, 2988,
6.86–6.96 (m, 2 H), 7.11–7.27 (m, 3 H) ppm. 13C NMR (100 MHz,
˜
2768, 2107, 1685, 1395, 1039, 785 cm–1 1H NMR (400 MHz, CDCl3): δ = 14.1, 22.6, 26.2, 28.8, 29.1, 31.6, 50.2, 105.8, 107.0,
.
CDCl3): δ = 1.44 (s, 3 H), 2.46 (d, J = 14 Hz, 2 H), 2.73–2.88 (m, 120.7, 126.3, 127.3, 128.6, 133.7, 138,6 ppm. HRMS (ESI+): calcd.
1 H), 3.02–3.11 (m, 2 H), 3.31 (d, J = 13.6 Hz, 1 H), 3.59–3.64 (m, for C17H23N [M + H]+ 242.1903; found 242.1905.
2 H), 3.95 (d, J = 10 Hz, 1 H), 7.05–7.38 (m, 10 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 24.8, 42.5, 51.5, 51.8, 52.5, 61.8, 64.9,
120.3, 126.1, 126.6, 126.9, 127.3, 128.2, 128.6, 145.9, 149.7 ppm.
HRMS (ESI+): calcd. for C20H21ClN2 [M – CN]+ 298.1362; found
298.1359.
2-Hexyl-1-phenyl-1H-pyrrole (8b): Yellow oil (40.4 mg, 71% yield).
IR (neat): ν = 2963, 2930, 2860, 1709, 1667, 1457, 1294, 1168, 1075,
˜
1033, 693 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.83 (t, J =
6.8 Hz, 3 H), 1.14–1.30 (m, 6 H), 1.44–1.55 (m, 2 H), 2.51 (t, J =
8 Hz, 2 H), 6.05 (s, 1 H), 6.20 (s, 1 H), 6.73 (d, J = 1.2 Hz, 1 H),
7.18–7.43 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0,
22.5, 26.7, 29.0, 29.1, 31.5, 106.6, 107.8, 121.4, 126.1, 127.0, 129.0,
134.3, 140.5 ppm. HRMS (ESI+): calcd. for C16H21N [M + H]+
228.1747; found 228.1745.
1-(Cyanomethyl)-2,4-dimethyl-4-phenylpyrrolidine-2-carbonitrile
(6f): Yellow oil (54.4 mg, 91% yield). Carbonitrile 6f was obtained
as a mixture of two diastereoisomers in a ratio of 1:1. IR (neat): ν
˜
= 3047, 2963, 2879, 2119, 1602, 1495, 1448, 1257, 1029, 907, 763,
1
735 cm–1. H NMR (400 MHz, CDCl3): δ = 1.54 (s, 3 H), 1.56 (s,
2-Hexyl-1-(4-methoxyphenyl)-1H-pyrrole (8c): Yellow oil (39.3 mg,
3 H), 2.34 (d, J = 13.6 Hz, 1 H), 2.55 (d, J = 13.6 Hz, 1 H), 2.93
(d, J = 9.2 Hz, 1 H), 3.50 (d, J = 16.8 Hz, 1 H), 3.67 (d, J = 9.6 Hz,
1 H), 3.74 (d, J = 16.8 Hz, 1 H), 7.16–7.28 (m, 5 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 23.9, 28.5, 37.2, 42.5, 55.3, 60.6,
66.5, 117.6, 119.4, 125.2, 126.4, 128.6, 144.3 ppm. HRMS (ESI+):
calcd. for C15H17N3 [M – CN]+ 213.1392; found 213.1389.
62% yield). IR (neat): ν = 2930, 2857, 1688, 1514, 1463, 1302, 1247,
˜
1
1040, 838, 709, 607 cm–1. H NMR (400 MHz, CDCl3): δ = 0.768
(t, J = 6.6 Hz, 3 H), 1.12–1.23 (m, 6 H), 1.33–1.47 (m, 2 H), 2.39
(t, J = 7.6 Hz, 2 H), 3.77 (d, J = 1.2 Hz, 3 H), 5.95 (s, 1 H), 6.11
(s, 1 H), 6.61 (d, J = 1.2 Hz, 1 H), 6.84–6.88 (m, 2 H), 7.10–7.18
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0, 22.5, 26.6,
29.0, 29.1, 31.6, 55.5, 106.1, 107.4, 114.1, 121.6, 127.4, 133.8, 134.6,
158.5 ppm. HRMS (ESI+): calcd. for C17H23NO [M + H]+
258.1852; found 228.1855.
1-Benzyl-2,4-dimethyl-4-phenylpyrrolidine-2-carbonitrile (6g): Yel-
low oil (64.6 mg, 89% yield). IR (neat): ν = 3061, 2972, 2800, 2154,
˜
1665, 1606, 1499, 1443, 1373, 1127, 1033, 762, 698, 549 cm–1. Car-
bonitrile 6g was obtained as a mixture of two diastereoisomers in
ratio of 1:1. H NMR (400 MHz, CDCl3): δ = 1.50 (s, 3 H), 1.61
(s, 3 H), 2.16 (J = 13.6 Hz, 1 H), 2.55 (d, J = 13.2 Hz, 1 H), 2.84
(d, J = 9.6 Hz, 1 H), 3.02 (d, J = 9.6 Hz, 1 H), 3.49 (d, J = 13.6 Hz,
1 H), 4.09 (d, J = 13.2 Hz, 1 H), 7.31–7.43 (m, 5 H) ppm. HRMS
(ESI+): calcd. for C20H22N2 [M – CN]+ 264.1572; found 264.1569.
1-Benzyl-2-butyl-1H-pyrrole (8e): Yellow oil (46.3 mg, 80% yield).
1
IR (neat): ν = 2961, 2924, 2855, 1698, 1603, 1497, 1322, 1078, 755,
˜
1
695 cm–1. H NMR (400 MHz, CDCl3): δ = 0.884 (t, J = 7.6 Hz,
3 H), 1.24–1.40 (m, 2 H), 1.49–1.61 (m, 2 H), 2.50 (t, J = 8 Hz, 2
H), 5.04 (s, 2 H), 5.97 (s, 1 H), 6.14 (t, J = 2.4 Hz, 1 H), 6.62 (s, 1
H), 7.00 (m, 2 H), 7.22–7.36 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 13.9, 22.5, 25.9, 31.0, 50.2, 105.8, 107.0, 120.7, 126.3,
127.3, 128.7, 133.7, 138.6 ppm. HRMS (ESI+): calcd. for C15H19N
[M + H]+ 214.1590; found 213.1591.
1-(2-Chloroethyl)-2,4-dimethyl-4-phenylpyrrolidine-2-carbonitrile
(6h): Yellow oil (61.1 mg, 93% yield). IR (neat): ν = 3033, 2983,
˜
2835, 2100, 1665, 1443, 1273, 1225, 1033, 762, 736, 570 cm–1. Car-
bonitrile 6h was obtained as a mixture of two diastereoisomers in
ratio of 1:1. H NMR (400 MHz, CDCl3): δ = 1.51 (s, 3 H), 1.57
2-Butyl-1-phenyl-1H-pyrrole (8f): Yellow oil (73% yield). The spec-
1
troscopic data is consistent with literature data.[11]
(s, 3 H), 2.09 (d, J = 14.0 Hz, 1 H), 2.47 (d, J = 14.0 Hz, 1 H),
2.74 (d, J = 9.6 Hz, 1 H), 2.79–2.84 (m, 1 H), 3.07–3.18 (m, 1 H),
3.26 (d, J = 7.2 Hz, 1 H), 3.57–3.66 (m, 2 H), 7.21–7.47 (m, 5
H) ppm. HRMS (ESI+): calcd. for C15H19ClN2 [M – CN]+
236.1206; found 236.1201.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra for compounds 6 and 8.
Acknowledgments
1-(Cyanomethyl)-2-ethyl-4,4-diphenylpyrrolidine-2-carbonitrile (6i):
The authors are grateful to the National Institute of Health (NIH)
for financial support (grant number NIGMS-1R15GM101604-01).
The support provided by the CREAM Mass Spectrometry Facility,
University of Louisville that is funded by the National Science
Foundation (NSF)/EPSCoR (grant number EPS-0447479) is ac-
knowledged.
Yellow oil (63.8 mg, 81% yield). IR (neat): ν = 3069, 2963, 2874,
˜
2229, 1681, 1446, 1220, 1145, 987, 725, 697 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.93 (t, J = 6 Hz, 3 H), 1.26–1.55 (m, 2
H), 2.64 (d, J = 14 Hz, 1 H), 3.26 (d, J = 10.4 Hz, 1 H), 3.32 (d, J
= 13.6 Hz, 1 H), 3.49 (d, J = 17.6 Hz, 1 H), 3.76 (d, J = 16.8 Hz,
1 H), 4.13 (d, J = 10 Hz, 1 H), 7.13–7.33 (m, 10 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 14.0, 18.1, 37.5, 39.3, 50.2, 51.6, 64.4, 65.2,
115.7, 118.6, 126.4, 126.6, 126.8, 127.0, 1285, 128.7, 145.3,
148.1 ppm. HRMS (ESI+): calcd. for C21H21N3 [M – CN]+
289.1705; found 289.1711.
[1] a) C. Zhang, C. K. De, R. Mal, D. Seidel, J. Am. Chem. Soc.
2008, 130, 416–417; b) B. M. Trost, N. Maulide, R. C. Living-
ston, J. Am. Chem. Soc. 2008, 16502–16503; c) S. Fustero, J.
Moscardo, D. Jimenez, M. D. Perez-Carrion, M. Sanchez-Ro-
sello, C. Del Pozo, Chem. Eur. J. 2008, 14, 9868–9872; d) J. L.
Vicario, D. Badia, L. Carrillo, New methods for the asymmetric
synthesis of nitrogen heterocycles 2005, Research Signpost, Ker-
ala, India, 2005; e) E. S. H. El Ashry, A. El-Nemr, Synthesis
of naturally occurring nitrogen heterocycles from carbohydrates,
Blackwell, Oxford, UK, Ames, Iowa, 2005; f) T. Liu, H. Fu,
Synthesis 2012, 44, 2805–2824; g) X.-G. Hu, L. Hunter,
Beilstein J. Org. Chem. 2013, 9, 2696–2708; h) Q. Ding, X. Fan,
J. Wu, Curr. Org. Chem. 2014, 18, 700–718; i) G. Cravotto, S.
Tagliapietra, M. Caporaso, D. Garella, E. Borretto, A. Di Stilo,
Chem. Heterocycl. Compd. 2013, 49, 811–826.
General Procedure for the Synthesis of 8: Amino-alkyne 7a (61 mg,
0.25 mmol), silver acetate (63 mg, 0.375 mmol), and DCM (1 mL)
were added to a glass vial. The mixture was stirred for 40 h at room
temperature and then concentrated in a rotary evaporator and puri-
fied by silica gel flash chromatography (5:1 hexane/diethyl ether)
to give 8a (45 mg, 74%) as a yellow liquid.
1-Benzyl-2-hexyl-1H-pyrrole (8a): Yellow oil (44.6 mg, 74% yield).
IR (neat): ν = 2930, 2851, 1658, 1518, 1248, 1033, 837, 698 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ = 0.78 (t, J = 7.2 Hz, 3 H), 1.05–
1.28 (m, 6 H), 1.41–1.53 (m, 2 H), 2.36 (d, J = 8.0 Hz, 2 H), 4.95
Eur. J. Org. Chem. 2014, 5786–5792
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5791

J. Han, Z. Lu, G. B. Hammond, B. Xu
FULL PAPER
[2]
[5] J. Han, B. Xu, G. B. Hammond, Org. Lett. 2011, 13, 3450–
3453.
a) N. T. Patil, Y. Yamamoto, Chem. Rev. 2008, 108, 3395–3442;
b) S. F. Kirsch, Synthesis 2008, 3183–3204.
[6] J. Han, R. S. Paton, B. Xu, G. B. Hammond, Synthesis 2013,
[3] a) X.-Y. Liu, C.-M. Che, Angew. Chem. Int. Ed. 2008, 47, 3805–
3810; Angew. Chem. 2008, 120, 3865; b) X.-Y. Liu, C.-M. Che,
Angew. Chem. Int. Ed. 2009, 48, 2367–2371; Angew. Chem.
2009, 121, 2403; c) L. Zhou, H.-f. Jiang, C.-J. Li, Adv. Synth.
Catal. 2008, 350, 2226–2230; d) D. Yang, D. Zhao, L. Mao, L.
Wang, R. Wang, J. Org. Chem. 2011, 76, 6426–6431; e) E.
Haak, I. Bytschkov, S. Doye, Eur. J. Org. Chem. 2002, 457–463;
f) A. V. Lee, L. L. Schafer, Synlett 2006, 2973–2976; g) X. Zeng,
G. D. Frey, R. Kinjo, B. Donnadieu, G. Bertrand, J. Am.
Chem. Soc. 2009, 131, 8690–8696; h) X. Wang, Z. Yao, S.
Dong, F. Wei, H. Wang, Z. Xu, Org. Lett. 2013, 15, 2234–2237.
[4] J. Han, B. Xu, G. B. Hammond, J. Am. Chem. Soc. 2010, 132,
916–917.
45, 463–470.
[7] S. Kobayashi, M. Sugiura, H. Kitagawa, W. W. L. Lam, Chem.
Rev. 2002, 102, 2227–2302.
[8] R. M. Beesley, C. K. Ingold, J. F. Thorpe, J. Chem. Soc. 1915,
107, 1080–1106.
[9] S. Agarwal, H.-J. Knölker, Org. Biomol. Chem. 2004, 2, 3060–
3062.
[10] E. M. Broderick, N. P. Gutzwiller, P. L. Diaconescu, Organo-
metallics 2010, 29, 3242–3251.
[11] Y. N. Romashin, A. Nadim, O. G. Kulinkovich, Chem. Hetero-
cycl. Compd. 1990, 26, 1110–1111.
Received: June 12, 2014
Published Online: August 1, 2014
5792
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5786–5792