Synthesis of (E)-3-alkylidene-l-pyrrolines by the rhodiumcatalyzed cyclization of terminal alkynes with homopropargylic amines

Article abstract of DOI:10.1002/adsc.200900439

The cyclization of terminal alkynes with homopropargylic amines in the presence of a rhodium complex as catalyst leads to the formation of (E)-3-alkylidene-l-pyrrolines. The reaction tolerates a wide range of functional groups on the terminal alkynes. The

Full text of DOI:10.1002/adsc.200900439

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DOI: 10.1002/adsc.200900439
Synthesis of (E)-3-Alkylidene-1-pyrrolines by the Rhodium-
Catalyzed Cyclization of Terminal Alkynes with Homopropargylic
Amines
Yoshiya Fukumoto,a,* Takuya Kawahara,a Yukinori Kanazawa,a
and Naoto Chatania
a
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Fax : (+81)-6-6879-7396; e-mail: fukumoto@chem.eng.osaka-u.ac.jp
Received: June 25, 2009; Revised: August 6, 2009; Published online: October 1, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900439.
Abstract: The cyclization of terminal alkynes with
homopropargylic amines in the presence of a rhodi-
um complex as catalyst leads to the formation of
(E)-3-alkylidene-1-pyrrolines. The reaction tolerates
a wide range of functional groups on the terminal
alkynes. The formation of a vinylidene-rhodium
complex, followed by the intermolecular nucleo-
philic attack of a homopropargylic amine nitrogen
on the a-carbon atom of the vinylidene-rhodium
complex, is proposed as a key step in the catalytic
reaction.
place of PPSE.[8] While these reactions are efficient,
there are certain restrictions, in that the substituents
on the alkene carbon are required to form more
stable benzylic or tertiary carbocation intermediates.[9]
Snider applied an intramolecular aza-Wittig reac-
tion[10,11] of 3-(2-azidoehtyl)-3-eicocen-2-one with po-
lymer-bound PPh3 in the synthesis of lanopylin B1.[12]
We wish to report herein a novel approach to the syn-
thesis of (E)-3-alkylidene-1-pyrrolines by the rhodi-
um-catalyzed cyclization of terminal alkynes with ho-
mopropargylic amines (Scheme 1).
The cyclization of 1-octyne (1a) with oct-3-ynyl-
Keywords: homopropargylic amines; N-heterocy-
cles; rhodium catalysis; terminal alkynes; vinylidene
intermediates
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
NH4BF4-catalyzed reaction of terminal alkynes with
allylic amines,[13] except that a reaction temperature
of 508C was used. Under these conditions, product
3aa was obtained in 40% yield as a single stereoiso-
mer, along with some by-products that included
The 3-alkylidene-1-pyrroline framework is stable and dimers and trimers of 1a, and the cyclization product
is frequently found in natural products such as lano- of 2a itself (Table 1, entry 1). An NOE experiment
pylines[1] and lokysterolamines,[2] in synthetic biologi- confirmed the stereochemistry of 3aa as being an E-
cally active molecules,[3] and in photoisomerization isomer. Whereas the addition of NH4BF4 to the reac-
molecules.[4] This unique structure can be prepared by tion mixture was required to afford 3aa when
the condensation of 1-pyrrolines with aldehydes[5] or RhCl
enamines[6] in the absence or presence of an acid cata-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
lyst. In most cases, however, product yields are low. absence of the ammonium salt (entry 3). These results
Gawley reported that such compounds can be pre- indicate that a cationic rhodium complex can serve as
pared by treating 4-alkenyl hydroximes with P2O5 or an active catalytic species.[14]
trimethylsilyl polyphosphate (PPSE). The reaction in-
volves the formation of a nitrilium ion intermediate,
followed by intramolecular cyclization.[7a–c] The same
authors subsequently reported that nitrilium ions
could also be generated from N-(3-alkenyl)amides
under the same reaction conditions to give 3-alkyli-
dene-1-pyrrolines,[7d,e] although the same type of
transformation has been achieved by using POCl3 in Scheme 1.
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Yoshiya Fukumoto et al.
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Table 1. Effect of catalyst, phosphine, and ammonium salt.[a]
Table 2. Substrate scope.[a]
Entry
R1
R2
Yield [%][b]
1
2
C6H13 (1a)
C6H13 (1a)
C6H13 (1a)
C6H13 (1a)
CyCH2 (1b)
Cy (1c)
Bu (2a)
Me (2b)
i-Pr (2c)
Ph (2d)
Me (2b)
Me (2b)
Me (2b)
Me (2b)
Me (2b)
Me (2b)
Me (2b)
Me (2b)
73 (3ab)
76 (3ab)
67 (3ac)
68 (3ad)
72 (3bb)
55 (3cb)
0
68 (3eb)
65 (3fb)
67 (3gb)
77 (3hb)
67 (3ib)
Entry Catalyst
PR3
NH4X
Yield
[%][b]
3
4[c]
5
1
2
RhCl
RhCl
N
–
–
NH4BF4 40
none
none
NH4BF4
N
0
30
0
3
4
5
6
[Rh
[RhCl
[RhCl
[RhCl
[RhCl
[RhCl
[RhCl
[RhCl
G
6
7
8
9
10
11
12
R
R
E
E
G
N
A
G
G
E
t-Bu (1d)
NH4BF4 38
Ph
MeO2C
NC(CH2)3 (1g)
t-BuMe2SiO(CH2)3 (1h)
THPO(CH2)3 (1i)
T
NH4BF4
NH4BF4
3
ACHTUNGTRENNUNG
7
A
ACHTUNGTRENNUNG
8[c]
9[d]
10
A
AHCTUNGTRENNUNG
A
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG(cod)2]2 PCy3
0
[a]
Reaction conditions: 1-octyne (0.5 mmol), oct-3-ynyl-
ACHTUNGTRENNUNGamine (1 mmol), Rh catalyst (0.05 mmol in entries 1–3 or
13
Me (2b)
66[d] (3jb)
0.025 mmol in entries 4–9), PR3 (0.15 mmol), NH4X
(0.06 mmol) in THF (1 mL), 508C, 6 h.
Yields determined by GC with 1-undecane as an internal
standard.
THF (2 mL) for 30 h.
THF (2 mL) for 24 h. Isolated yield was 69%.
[a]
[b]
Reaction conditions: terminal alkyne (0.5 mmol), homo-
propargylic amine (1 mmol), [RhCl(cod)]2 (0.025 mmol),
P(4-Et2NC6H4)3 (0.15 mmol), NH4NO3 (0.06 mmol) in
THF (2 mL) at 508C for 24 h.
Yields determined by GC with 1-undecane as an internal
standard.
AHCTUNGTRENNUNG
[c]
[d]
[b]
[c]
[d]
At 708C for 30 h.
Isolated yield.
To examine the efficiency of phosphines, which are
essential for the present reaction to proceed, as
shown in Table 1, entries 4 and 5, [RhCl
ACHTUNGTERNN(UNG cod)]2 to-
gether with NH4BF4 was used as a catalyst precursor.
A small amount of 3aa was formed when a phosphine only primary but also secondary alkyl-substituted al-
containing an electron-withdrawing group at the para- kynes reacted to give 3bb and 3cb in preparatively
position was used (entry 6). In contrast, the yield was useful yields. On the other hand, the use of tert-butyl-
improved when electron-rich arylphosphines, e.g.,
ACHTUNGTRENaNUNG cetylene 1d gave a small amount of dimerization
tris(4-methoxyphenyl)phosphine (entry 7) and tris(4- product, along with unreacted 1d. The reaction was
diethylaminophenyl)phosphine (entry 8) were used. compatible with functional groups such as ester (1f),
The addition of NH4NO3 in place of NH4BF4 gave the nitrile (1g), siloxy (1h), THP (1i), and imide (1j). The
best result of 73% yield (entry 9).[15] No reaction oc- reaction of 1a with homopropargylic amine 2e under
curred when PCy3 was used (entry 10).
the same reaction conditions gave trisubstituted N-
With the optimized reaction conditions in hand, the heterocycle 3ae in 68% yield [Eq. (1)]. However, the
scope of the reactions of terminal alkynes with homo-
propargylic amines was investigated (Table 2). Some
homopropargylic amines were tested in reactions with
1-octyne (1a). The reactions of methyl- and isopropyl-
substituted homopropargylic amines afforded 3ab and
3ac in 76% and 67% yields, respectively (Table 2, en-
tries 2 and 3). Although no reaction occurred in the
case of the phenyl-substituted substrate 2d under
these reaction conditions, increasing the reaction tem-
perature to 708C led to the formation of 3ad in 68%
yield.
The scope of this cyclization with regard to various
terminal alkynes with 2b was further examined. Not
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Synthesis of (E)-3-Alkylidene-1-pyrrolines by the Rhodium-Catalyzed Cyclization
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Experimental Section
General Procedure for Rhodium-Catalyzed
Cyclization of Terminal Alkynes with
Homopropargylic Amines
A 10-mL reaction flask equipped with a reflux condenser
was flame-dried under an N2 atmosphere and then cooled to
room temperature, after which, [RhClACHTUNTGRNEUNG(cod)2]2 (12.3 mg,
0.025 mmol), NH4NO3 (4.8 mg, 0.06 mmol), P(4-Et2NC6H4)3
(71.3 mg, 0.15 mmol), THF (2 mL), homopropargylic amine
(1 mmol), and terminal alkyne (0.5 mmol) were sequentially
added. The reaction mixture was heated at 508C for 24 h.
After cooling to room temperature, the volatiles were re-
moved under vacuum and the product was isolated by silica-
gel column chromatography.
Acknowledgements
Scheme 2. A plausible reaction mechanism.
This work was partially supported by the Otsuka Pharma-
ceutical Company Award in Synthetic Organic Chemistry,
Japan and the Kurata Memorial Hitachi Science and Tech-
nology Foundation. Thanks are also given to the Instrumental
Analysis Center, Faculty of Engineering, Osaka University,
for assistance in NOE, HR-MS and elemental analyses.
use of non-4-ynylamine, leading to the formation of 6-
membered ring, resulted in no cyclization product.
A proposed reaction mechanism is shown in
Scheme 2 although the details are obscure at this
time. A terminal alkyne reacts with a cationic rhodi-
um complex to form the vinylidene complex I,[16]
which undergoes nucleophilic attack by a homopro-
pargylic amine at the a-carbon atom of I to afford an
a-aminocarbene-rhodium complex II.[16,17] Deprotona-
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