Nickel-catalyzed reductive cyclization of unactivated 1,6-enynes in the presence of organozinc reagents

Article abstract of DOI:10.1002/anie.200704452

(Chemical Equation Presented) Pyrrolidine and tetrahydrofuran derivatives were synthesized in a highly stereoselective manner through the Ni-catalyzed reduction of the title compounds under mild conditions (see scheme). The product of cyclization is initi

Full text of DOI:10.1002/anie.200704452

Angewandte
Chemie
DOI: 10.1002/anie.200704452
Synthetic Methods
Nickel-Catalyzed Reductive Cyclization of Unactivated 1,6-Enynes in
the Presence of Organozinc Reagents**
Mao Chen, Yue Weng, Mian Guo, Hua Zhang, and Aiwen Lei*
The transition-metal-catalyzed cyclization of 1,6-enynes is
one of the most convenient and efficient methods for the
synthesis of a variety of carbocyclic and heterocyclic com-
pounds.[1–4] By this approach, enynes can be transformed into
cyclic skeletons in a one-pot fashion with impressive regio-
and stereoselectivity.[3,5,6] The readily available and inexpen-
sive metal nickel stands out for its remarkable power in
catalyzing cycloisomerization and cycloaddition reactions of
enynes.[7–9] Important examples include a Ni-catalyzed [4+2]
cycloaddition developed by Wender and co-workers[10,11] and
a series of cyclization reactions of activated 1,6-enynes
described by Montgomery and co-workers [Scheme 1,
electronically unactivated enynes has been explored
[Scheme 1, Eq. (3)]. Such unactivated enynes have histori-
cally been used in combination with catalytic systems based
on Pd,[16–19] Au,[20] Ru,[21] and Rh.[19,22–24] We and others have
described highly enantioselective Rh-mediated cycloisomeri-
zation reactions of 1,6-enynes [Scheme 1, Eq. (3),
path A].[25–29] To further explore this cyclization chemistry,
we have now investigated a Ni-based system with the aim of
uncovering new reactivity and selectivity in a Ni-mediated
Pauson–Khand-type cyclization under a reductive atmo-
sphere, such as CO gas.[30–34]
Unlike NiII species, most Ni0 complexes are extremely air-
sensitive and are thus rather difficult to manipulate.[35]
Consequently, many known processes have resorted to the
generation of these compounds in situ from air-stable NiII
precursors in the presence of an appropriate reducing
reagent, such as diisobutylaluminum hydride or a dialkyl
zinc reagent.[7,36] We initially set out to probe the feasibility of
the Pauson–Khand reaction (PKR) of enyne 1a in the
presence of [Ni(PPh3)2Cl2] (5 mol%) and iPr2Zn (30 mol%)
under a CO atmosphere (balloon pressure).[36,37] Despite
extensive experimentation, this system failed to deliver any of
the desired PKR product. However, a new compound was
detected by serendipity when 3.0 equivalents of iPr2Zn were
used. The compound was isolated and identified as 2a, that is,
a compound into which a molecule of dihydrogen has
formally been incorporated following cyclization, rather
than a molecule of CO as intended (Scheme 2).
Scheme 1. Ni-mediated cyclization of enynes. binap=2,2’-bis(diphenyl-
phosphanyl)-1,1’-binaphthyl.
Eq. (1,2)].[7,12–15] These strategies have established new
approaches for the highly stereoselective formation of ring
systems decorated with exocyclic trisubstituted or tetrasub-
=
stituted C C bonds. Viable substrates for these processes,
however, usually bear electron-withdrawing substituents. To
our knowledge, very few studies have been described to date
in which the potential of Ni catalysis in direct cyclizations of
Scheme 2. Ni-catalyzed cyclization of the 1,6-enyne 1a.
[*] M. Chen, Y. Weng, M. Guo, H. Zhang, Prof. A. Lei
College of Chemistry and Molecular Sciences
Wuhan University
Wuhan, Hubei, 430072 (China)
Fax: (+86)27-68754067
E-mail: aiwenlei@whu.edu.cn
Homepage: http://www.chem.whu.edu.cn/GCI_WebSite/
main.htm
Compound 3a was established to be a superior substrate
to 1a upon subsequent optimization of the reaction and was
therefore chosen as the substrate for the further screening of
catalyst systems. The reactions were carried out at 408C for
18 h at a concentration of 0.1m in THF. It was found that a
combination of [Ni(acac)2] (10 mol%) and iPr2Zn (3.0 equiv)
furnished the product of reductive cyclization 4a in 95% yield
with exclusive formation of the Z alkene (Table 1, entry 3). A
decrease in the temperature, the catalyst loading, or the
[**] This research was supported by the National Natural Science
Foundation of China (20502020) and a startup fund from Wuhan
University.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Ni-catalyzed reductive cyclization of 3a under different con-
Table 2: Ni-catalyzed reductive cyclization reactions of compounds 3 to
ditions.[a]
give pyrrolidine derivatives.[a]
Entry
3
4
Yield [%][b] Z/E[c]
1
2
3
4
5
6
3a R1 =Ph
4a
4b
4c
4d
95
89
56
36
65
62
>99:1
>99:1
>99:1
>99:1
74:26
Entry Catalyst (mol%)
Ligand (mol%) iPr2Zn [equiv] Yield [%]
3b R1 =Ph-4-OMe
3c R1 =Ph-3-OMe
3d R1 =Ph-2-OMe
1[b]
2
3
4
5
6
7
8
9
[Ni(acac)2] (10)
[Ni(acac)2] (5)
[Ni(acac)2] (10)
[Ni(acac)2] (10)
[Ni(acac)2] (10)
[Ni(PPh3)2Cl2] (10)
[Ni(PPh3)4] (10)
[Ni(acac)2] (10)
[Ni(acac)2] (10)
[Ni(acac)2] (10)
–
3.0
3.0
3.0
2.0
1.0
3.0
3.0
3.0
3.0
3.0
64
–
–
–
69[c]
95[c]
64
3e R1 =Ph-4-COOEt 4e
3 f R1 =C5H11
4 f
>99:1
–
–
–
40
94[c]
45
7
3g
4g
66
24
72
>99:1
PPh3 (10)
PPh3 (20)
PPh3 (40)
94
90
85
10
[a] All reactions were carried out at a substrate concentration of 0.1m for
18 h. The yields and the selectivities were determined by GC. [b] The
reaction was carried out at 288C. [c] Yield of the isolated product. acac=
acetylacetonate, Ts=p-toluenesulfonyl.
8
9
3h
3i
4h
4i
>99:1
>99:1
66
[a] All reactions were carried out with [Ni(acac)2] (10 mol%) and iPr2Zn
(3.0 equiv) in THF at 408C for 18 h. [b] Yield of the isolated product.
[c] The Z/E ratio was determined by GC. Boc=tert-butoxycarbonyl,
Cbz=carbobenzyloxy.
amount of iPr2Zn used resulted in a lower yield of 4a (Table 1,
entries 1, 2, 4, and 5). When [Ni(PPh3)4] was used as the
catalyst, the product was formed in 45% yield. However, an
almost identical result was observed with [Ni(PPh3)2Cl2]
(Table 1, entry 6) to that with [Ni(acac)2]. Further experi-
ments revealed that the presence of PPh3 as a ligand in a 1:1
ratio with [Ni(acac)2] did not effect the outcome of the
reaction; at higher ratios of 2:1 or 4:1, PPh3 inhibited the
reaction to a certain extent (Table 1, entries 8–10).[12,13,38]
A variety of N-tethered enynes were tested as substrates
under the optimized reaction conditions (Table 2). In most
cases, the desired cyclized product was generated with
exceedingly high selectivity for the Z-configured alkene,[39]
as confirmed unambiguously by an NOE experiment. The
steric and electronic properties of the substituent on the aryl
group attached to the alkyne affected the reaction. Com-
pound 3b with a p-MeO group was transformed into the
desired product in 89% yield with high selectivity for the
Z alkene, whereas lower yields were observed for the
reactions of 3c and 3d; the position of the methoxy
substituent did not have an influence on the stereoselectivity
(Table 2, entries 2–4). When an electron-withdrawing ester
substituent was present, the product was obtained in 65%
yield, and the selectivity dropped to Z/E 74:24 (Table 2,
entry 5).[40] When the aromatic substituent on the alkyne was
exchanged for an alkyl group, the product was furnished in
moderate yield but with a selectivity of greater than 99:1
(Table 2, entry 6). A substrate with an internal alkene in the
side chain was transformed into 4g in 66% yield. Compound
4j was also obtained in 24% yield, and no cyclic product with
an isomerized alkene side chain was detected (Table 2,
entry 7). When the protecting group on the N tether was
changed from a tosyl group to Boc (3h) or Cbz (3i), the
catalyst system still afforded the cyclized products in satis-
factory yields with high selectivity.
To further explore the scope of application of this method,
we tested the use of O-tethered enynes as substrates
(Table 3). Good selectivity for the Z isomer and moderate
yields were observed when substrates with an aryl or an alkyl
group attached to the alkyne were used. Again, only when a
p-COOEt group was present on the aromatic ring did the
yield and selectivity drop (to 39% and 75:25; Table 3,
entry 3). This result is similar to that observed with 3e. Poor
diastereoselectivity was observed for the reaction of 1a, with
a methyl substituent at the 5-position, but the Z/E ratio of the
product was still greater than 99:1 (Table 3, entry 5).
Table 3: Ni-catalyzed reductive cyclization reactions of compounds 1 to
give tetrahydrofuran derivatives 2.[a]
Entry
1
2
Yield [%][b]
Z/E[c]
1
2
1b
1c
1d
1e
R1 =Ph
2b
2b
2b
2b
66(84)
65(77)
39
>99:1
>99:1
75:25
R1 =Ph-4-OMe
R1 =Ph-4-COOEt
R1 =C5H11
3[d]
4
65
>99:1
5
1a
72
>99:1
[a] Reactions were carried out in the presence of iPr2Zn (3.0 equiv) and
[Ni(acac)2] (10 mol%) at 408C for 12 h. [b] Yield of the isolated product.
Yields determined by GC are reported in parentheses. [c] The Z/E ratio
was determined by GC. [d] Reaction time: 18 h.
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Angewandte
Chemie
A speculative catalytic cycle is shown in Scheme 3.
Oxidative cyclization of the enyne to Ni0, derived from
[Ni(acac)2] through reduction by iPr2Zn,[41] would afford a
nickel metallocyclopentene intermediate I,[42–44] which could
undergo transmetalation with iPr2Zn through two possible
pathways to form intermediate II or III. Subsequent b-H
elimination and reductive elimination would generate VI and
Scheme 4. Confirmation of the proposed mechanism by a quenching
experiment with CD3COOD.
highly stereoselective manner in moderate to high yields. Our
proposed mechanism was confirmed through a quenching
experiment with CD3COOD. Studies into the scope of the
reaction and mechanistic studies are under way.
Experimental Section
Typical procedure: iPr2Zn (6 mL, 0.5m in THF) was added to a
solution of 3b (355 mg, 1.0 mmol) and [Ni(acac)2] (25.6 mg,
0.1 mmol) in anhydrous THF (4 mL) at À788C. The reaction mixture
was stirred at 408C for 18 h under N2, and then 2m HCl (25 mL) was
added to quench the reaction. The mixture was extracted with
dichloromethane, and the combined organic layers were washed with
saturated NaHCO3 and brine, dried (Na2SO4), and then concentrated
in vacuo. The residue was purified by column chromatography over
silica gel (ethyl acetate/petroleum 1:20, v/v) to give 4b (318 mg, 89%)
as a colorless oil. 1H NMR (300 MHz, CDCl3): d = 7.63 (d, J = 8.1 Hz,
2H), 7.20 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.78 (d, J =
8.7 Hz, 2H), 6.06 (s, 1H), 4.12 (d, J = 14.7 Hz, 1H), 3.93 (d, J =
14.4 Hz, 1H), 3.70 (s, 3H), 3.44 (t, J = 7.8 Hz, 1H), 2.76 (m, 1H),
2.62 (t, J = 8.4 Hz, 1H), 2.30 (s, 3H), 1.05 ppm (d, J = 6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3): d = 158.7, 143.8, 139.6, 133.0, 129.9,
129.7, 129.5, 127.9, 121.6, 114.1, 55.4, 54.1, 51.0, 39.1, 21.7, 17.1 ppm;
HRMS (APCI): calcd for C20H23NO3S: 357.1399 [M]+; found:
357.1404.
Scheme 3. Proposed mechanism for the reductive cyclization pro-
moted by [Ni(acac)2].
VII, respectively, both of which would be converted into the
product of reductive cyclization upon hydrolysis. Montgom-
ery et al. suggested the formation of five- or seven-membered
nickel metallacycle intermediates through the oxidative
cyclization of an alkynal or an alkynone to a Ni0 species and
subsequent generation of ring-opened intermediates by trans-
metallation between the nickel metallacycle and an organo-
zinc reagent, in direct analogy to the formation of II and III in
Scheme 3.[7] Furthermore, Knochel and co-workers have
demonstrated such an exchange between organonickel inter-
mediates and Et2Zn.[45–49] The palladium-catalyzed reductive
cyclization of carbon-tethered 1,6-enynes in the presence of a
silicon hydride and HOAc provided similar products, but the
mechanism was different from our hypothesis.[50]
Received: September 27, 2007
Revised: December 21, 2007
Published online: February 8, 2008
Keywords: cyclization · enynes · nickel · organozinc reagents ·
.
synthetic methods
To gain more information about the reaction mechanism,
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