Nickel-catalyzed regio- and stereoselective reductive coupling of Oxa- and azabicyclic alkenes with enones and electron-rich alkynes

Article abstract of DOI:10.1002/adsc.201300910

A nickel-catalyzed regio- and stereoselective reductive coupling of oxa- and azabicyclic alkenes with activated alkenes and electron-rich alkynes is described. Thus, 7-oxabenzonorbornadienes underwent reductive coupling with various vinyl ketones such as ethyl, methyl, propyl and α-methyl- substituted vinyl ketones, in the presence of a nickel(II) iodide (NiI ₂), zinc (Zn), and water catalyst system in acetonitrile at 50 °C for 14 h to afford 2-alkylnaphthalenes in good to excellent yields. Under similar reaction conditions, 7-azabenzonorbornadiene derivatives provided cis-2-alkyl-1,2-dihydronaphthalene derivatives in high yields. On the other hand, the nickel(II) iodide, tris(4-fluorophenyl)phoshine [P(4-FC ₆H₄)₃] and zinc catalyst system successfully catalyzed the reductive coupling reaction of electron-rich alkynes, with 7-aza- and 7-oxabenzonorbornadienes to give cis-2-alkenyl-1,2-dihydronaphthalene derivatives in good to excellent yields. In the reaction, a mild reducing agent (zinc) and simple hydrogen source (water) were used.

Full text of DOI:10.1002/adsc.201300910

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DOI: 10.1002/adsc.201300910
Nickel-Catalyzed Regio- and Stereoselective Reductive Coupling
of Oxa- and Azabicyclic Alkenes with Enones and Electron-Rich
Alkynes
Subramaniyan Mannathana and Chien-Hong Chenga,*
a
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
Fax : (+886)-3572-4698; e-mail: chcheng@mx.nthu.edu.tw
Received: October 11, 2013; Revised: December 8, 2013; Published online: March 11, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300910.
Abstract: A nickel-catalyzed regio- and stereoselec- naphthalene derivatives in high yields. On the other
tive reductive coupling of oxa- and azabicyclic al- hand, the nickel(II) iodide, tris(4-fluorophenyl)-
kenes with activated alkenes and electron-rich al- phoshine [PACHTNUGTRNE(UNG 4-FC6H4)3] and zinc catalyst system suc-
kynes is described. Thus, 7-oxabenzonorbornadienes cessfully catalyzed the reductive coupling reaction of
underwent reductive coupling with various vinyl ke- electron-rich alkynes, with 7-aza- and 7-oxabenzo-
tones such as ethyl, methyl, propyl and a-methyl- norbornadienes to give cis-2-alkenyl-1,2-dihydro-
substituted vinyl ketones, in the presence of a naphthalene derivatives in good to excellent yields.
nickel(II) iodide (NiI2), zinc (Zn), and water catalyst In the reaction, a mild reducing agent (zinc) and
system in acetonitrile at 508C for 14 h to afford 2-al- simple hydrogen source (water) were used.
kylnaphthalenes in good to excellent yields. Under
similar reaction conditions, 7-azabenzonorborna- Keywords: alkynes; bicyclic alkenes; nickel; nickel-
diene derivatives provided cis-2-alkyl-1,2-dihydro- acyclopentene; reductive coupling
Introduction
alkynes by the use of a cationic rhodium/(R)-BINAP
catalyst.[6] Recently, Tenaglia et al. disclosed a rutheni-
The transition metal-catalyzed ring opening addition um-catalyzed coupling of oxabenzonorbornadienes
reaction of oxa- and azabicyclic alkenes is an efficient with alkynes bearing oxygen atoms at the propargylic
method for the synthesis of cyclic compounds with position to synthesize benzonorcaradienes.[7] Despite
multiple stereocenters in a highly stereocontrolled these advances, the reductive ring opening addition
manner.[1] Addition of carbon and heteroatom nucleo- reaction of oxa- and azabicyclic alkenes with alkenes
philes, organometallic reagents, and electrophilic aryl has hardly been exploited. Specifically, only the ho-
and alkyl halides, in the presence of metal complexes mocyclodimerization of oxabenzonorbornadienes to
as the catalyst, was the most commonly employed give naphtho
ACHTUNGTRENUN[NG 1,2-b]furan ring systems using a rhodium
method.[2] Conversely, such ring-opening addition re- complex as the catalyst was reported.[5c,6]
actions using p-components have been scarcely stud-
Our ongoing interest in the regioselective reductive
ied.[3–7] Notably, few reports have been published on coupling reaction of different p-components[8] and bi-
the use of an alkyne as the p component. In 2001, we cyclic chemistry[1b,9] prompted us to extend the reduc-
found an efficient nickel-catalyzed reductive cycliza- tive coupling reaction of bicyclic alkenes with alkenes.
tion reaction of oxanorbornadienes with propiolates Herein, we report a nickel(II)-catalyzed regio- and
(electron-deficient alkynes) to synthesize benzocou- stereoselective reductive coupling of oxa- and azanor-
marins.[3] Subsequently, we also demonstrated a new bornadienes with enones to give functionalized 2-
method to synthesize cis-2-alkenyl-1,2-dihyronaphtha- alkyl-1,2-dihydro- and 2-alkylnaphthalene derivatives.
lene derivatives.[4] In the meantime, Tam and Burton In addition, we also demonstrated a nickel-catalyzed
reported an Ru(II)-catalyzed cyclization of azabenzo- reductive coupling of bicyclic alkenes with electron-
norbornadienes with alkynes for the formation of the rich alkynes to prepare cis-2-alkenyl-1,2-dihydronaph-
dihydrobenz[g]indole framework.[5a,b] Later, Hayashi thalenes in high regio- and stereoselectivity.[10] The re-
and co-workers reported an asymmetric ring opening action is highly step and atom-economical, an impor-
of oxa- and azabicyclic alkenes with electron-deficient tant consideration for modern synthetic chemistry.[11]
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Subramaniyan Mannathan and Chien-Hong Cheng
It is noteworthy that the 2-alkyl- and dihydronaptha-
lene skeletons have been found in a wide range of
naturally occurring compounds that exhibit diverse
biological activities (Figure 1).[12]
Results and Discussion
Our initial investigation began by treating 7-azaben-
zonorbornadiene (1a) with ethyl vinyl ketone (2a) in
the presence of NiACHTNUTRGNE(UGN dppe)Br2/Zn/H2O system using
acetonitrile (CH3CN) as the solvent at 808C (Table 1,
entry 1).[4] The reaction did not give the expected
product 3a, but afforded only the reductive ring open-
ing product 4a in high yield. Similarly, NiACTHNURGTNEUNG(phen)Br2
(phen=1,10-phenanthroline) also failed to provide
product 3a (entry 2). We then examined the reaction
with simple nickel(II) salts under similar reaction con-
ditions (entries 3–5). Surprisingly, all nickel salts such
as NiCl2, NiBr2, and NiI2 were active affording 3a in
51, 60 and 64% yields, respectively, (entries 3–5). In
all these reactions, 4a was observed in 24–36% yield.
To suppress the formation of 4a and to increase the
product yield of 3a, the reaction was carried out at
Figure 1. Representative structures involving 1,2-dihydro-
and 2-alkylnaphthalenes.
Table 1. Optimization studies[a]
Entry
Catalyst
Temperature [8C]
Solvent
Yield [%][b]
4a
3a
1
2
3
4
5
6
7
Ni
Ni
NiBr2
NiCl2
NiI2
NiI2
NiI2
NiI2
NiBr2
NiCl2
NiI2/PPh3
NiI2/dppe
none
NiI2
NiI2
NiI2
NiI2
N
80
80
80
80
80
50
rt
50
50
50
50
50
50
50
50
50
50
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
–
–
90
85
35
36
24
trace
–
–
–
–
–
35
–
–
–
–
60
51
64
75
–
93
90
91
–
–
–
–
–
8[c]
9[c]
10[d]
11
12
13
14
15
16
17
DCM
1,4-dioxane
toluene
–
–
–
[a]
All reactions were carried out using azabenzonorbornadiene (1a) (1.00 mmol), ethyl vinyl ketone (2a) (1.50 mmol), cata-
lyst (0.050 mmol), Zn (1.50 mmol) and H2O (2.00 mmol) for 14 h.
Yields were measured from the crude products by the H NMR integration method using mesitylene as an internal stan-
[b]
1
dard.
[c]
[d]
10 mol% nickel salt was used.
20 mol% NiCl2 was used.
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Nickel-Catalyzed Regio- and Stereoselective Reductive Coupling
a lower temperature. As expected, the reaction of 1a
A possible reaction mechanism for the present
and 2a at 508C in the presence of NiI2 afforded 3a in nickel-catalyzed reductive coupling reaction is pro-
75% yield with 4a in low yield (entry 6). However, on posed in Scheme 1. The catalytic reaction is likely ini-
further lowering the reaction temperature, we did not tiated by the reduction of Ni(II) species to Ni(0) by
observe any coupling product (entry 7). Finally, in- zinc dust.[3,4] Highly chemoselective coordination of
creasing the catalytic loading of nickel salts furnished an azabenzonorbornadiene (1a) and ethyl vinyl
3a in high yields (entries 8–10). Addition of any ketone (2a) to the Ni(0) center followed by regiose-
monoACHTUNGTRENNUNGdentate and bidentate phosphine ligands com- lective oxidative cyclometallation yields nickelacyclo-
pletely retarded the present catalytic reaction (en- pentane intermediate 9.[4,13] Subsequent b-heteroatom
tries 11 and 12). The choice of solvent is also crucial elimination and protonation afforded product 3a and
to obtain product 3a in high yield. Acetonitrile ap- the Ni(II) species. Later, the Ni(II) species, is reduced
peared to give the highest yield, while other solvents to the active Ni(0) species by Zn.
including THF, DCM, toluene and 1,4-dioxane are to-
After successfully achieving the reductive coupling
tally inactive (entries 13–17). This catalytic reaction is reaction of oxa- and azabicyclic alkenes with enones,
highly regio- and stereoselective where the ethyl vinyl we then extended our methodology for the coupling
ketone (2a) is added to 1a exclusively at the face cis of electron-rich alkynes (6) with bicyclic alkenes (1).
À
to the nitrogen atom and the C C bond formation In our previously reported reductive coupling of oxa-
occurs specifically at the methylene carbon of vinyl and azabicyclic alkenes with alkynes, the reactions
ketone. Control experiments revealed that the reac- were limited to propiolates.[4] The reaction of elec-
tion did not proceed in the absence of either NiI2 or tron-rich alkynes with oxa- and azabicyclic alkenes
Zn and water.
under the NiACTHUNGTERNU(NG dppe)Br2/Zn/H2O system in CH3CN at
To explore the scope of the reaction, various types 808C always provided the reductive ring opening
of aza- and oxabenzonorbornadienes 1 with ethyl product of bicyclic alkene 4 and therefore the cou-
vinyl ketone (2a) under the standard reaction condi- pling reaction of 1 with electron-rich alkynes remains
tions were investigated (Table 2, entries 1–9). Thus, very challenging.
azabenzonorbornadienes, 1b–f, reacted smoothly with
2a under optimized reaction conditions to give the clic alkenes with electron-rich alkynes, we began our
corresponding cis-1-aza-2-alkyldihydronaphthalene optimization studies by treating oxabicyclic alkene
derivatives 3b–f in 77–93% yields (entries 2–6). 7- (1g) with 1-phenyl-1-propyne (6a) under the NiI2/Zn/
Oxabenzonorbornadiene derivatives (1g–i) also under- H2O system in CH3CN at 458C for 14 h. To our de-
To achieve the reductive coupling reaction of bicy-
ACHTUNGTRENNUNG
went reductive coupling reaction but afforded 2-alkyl- light, the reductive coupling product 7a was obtained
substituted naphthalene derivatives 5 instead of the in 25% yield, along with 1,2-dihydronaphthol and
normal ring opening product, cis-2-alkyl-1,2-dihydro- naphthalene as the side products. The reaction is re-
naphthols 3. This was probably due to the fact that markably high regio- and stereoselective in which 1-
cis-2-alkyl-1,2-dihydronaphthols formed during the re- phenyl-1-propyne (6a) was added to 1g exclusively at
À
action readily underwent dehydration (aromatization) the face cis to the oxygen atom and the C C bond
to afford the 2-alkyl-substituted naphthalene deriva- formation occurs specifically at the alkyne carbon at-
tives 5.[15] Thus, the reaction of oxabicyclic alkene 1g tached to the methyl substituent. Moreover, the
with 2a provided 2-alkylnaphthalene 5a in 93% yield phenyl and methyl groups of 6a in the product are cis
(entry 7). Similarly, other oxabenzonorbornadienes, to each other. To improve the yield of 6a, the reaction
1h and 1i, also afforded 5b and 5c in excellent yields was examined with various monodentate and biden-
(entries 8 and 9).
The present catalytic reaction was also successfully tion). After, extensive screening, we found that elec-
extended to various types of enones (2b–d) (Table 2, tron-deficient ligands such as P(2-furyl)3, P(OMe)3,
(4-FC6H4)3 were effective affording the
tate phosphine ligands (see the Supporting Informa-
A
ACHTUNGTRENNUNG
entries 10–14).[14] The reaction of methyl vinyl ketone
PACTHNGUERTNNU(G OBu)3 and PACHTGNUTRENNUNG
(2b) with the respective oxa- and azabicyclic alkenes product in 31, 50, 85 and 92% yields, respectively.[16]
1g and 1c afforded coupling products 5d and 3g in Similar to the reductive coupling of bicyclic alkenes
high yields (entries 10 and 11). In a similar manner, n- with enones, the use of CH3CN as the solvent is also
propyl vinyl ketone 2c also underwent coupling to crucial to obtain high product yield. Based on the
provide 3h and 5e in good yields (entries 12 and 13). above studies, we chose 5 mol% NiI2, 10 mol% PACHTUNGTRENNUNG(4-
A substituted vinyl ketone also worked well in the re- FC6H4)3, Zn, and H2O in CH3CN at 458C for 14 h as
action. Thus, treatment of a-substituted vinyl ketone the standard reaction conditions for the reactions in
2d with 1g afforded 5f in 70% yield (entry 14). How- Table 3.
ever, b-substituted vinyl ketone and cyclic enones
Under the standard reaction conditions, the reac-
failed to give the respective reductive coupling prod- tions of various alkynes (6b–g) with 1g were exam-
ucts 3 or 5.
ined. Treatment of 1-phenyl-1-butyne (6b) with 1g
gave 7b in 68% yield. Functionalized alkyne, 6c, un-
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Table 2. Results of the reductive coupling of oxa- and azabenzonorbornadiene 1 with alkenes 2.[a]
Entry
1
1
2
Product
Yield [%][b]
90
3a
3b
2
3
2a
2a
81
80
3c
4
5
2a
2a
3d
3e
77
93
6
7
2a
2a
3f
90
93
5a
8
9
2a
2a
5b
5c
80
77
10
11
1g
1c
5d
3g
92
87
2b
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Table 2. (Continued)
Entry
1
2
Product
Yield [%][b]
85
12
1a
3h
5e
5f
13
1g
1g
2c
88
14
70[c]
[a]
Unless otherwise mentioned, all reactions were carried out with oxa- or azabenzonorbornadienes 1 (1.00 mmol), enones 2
(1.50 mmol), NiI2 (10.0 mol%), Zn (1.50 mmol), H2O (2.00 mmol) and CH3CN (1.50 mL) at 508C for 14 h under N2.
[b]
[c]
Isolated yield; the stereochemistry of product 3 is a relative configuration and not absolute.
20.0 mol% of ZnI2 was
used.
derwent reductive coupling with 1g to give the expect- phenylacetylenes furnished single regioisomeric prod-
ed product 7c in 82% yield. Terminal alkynes were ucts 7e and 7f in good to excellent yields.[9a] Gratify-
also compatible for the present reaction.[8b] Thus, ingly, an aliphatic alkyne, 1,4-dimethoxybutyne (6g)
phenyl acetylene (6d) gave 7d in high yield. Similarly, also gave 7g in 78% yield. It should be noted that the
para-methoxy- (6e) and para-methyl- (6f) substituted reaction of diphenylacetylene (6h) with 1g provided
the reductive coupling product 7m only in low yield
whereas 4-octyne (6i) did not afford any reductive
coupling product (Scheme 2).
To broaden the scope of the present catalytic reac-
tion, various oxa- and azabicyclic alkenes with 6a
were investigated (Table 3). Thus, 7-oxanorborna-
dienes, 1h and 1i, effectively participated in the reduc-
tive coupling reaction to give the corresponding prod-
ucts 7h and 7i in good yields. In a similar manner,
azabicyclic alkenes 1a–c also furnished the respective
1,2-dihydronaphthalene derivatives 7j–l in excellent
yields.
The mechanism for the reductive en-yne coupling is
appealing in view of the observed novel regio- and
stereoselectivity. On the basis of the above results and
known nickel chemistry, the key pathways are pro-
posed as shown in Scheme 3. The catalysis is initiated
by the reduction of Ni(II) to Ni(0) by zinc powder.
exo Coordination of 7-oxabenzonorbornadiene 1g and
alkyne 6a to the Ni(0) center followed by the regiose-
lective oxidative coupling of the bicyclic alkene and
Scheme 1. Proposed mechanism for reductive coupling of
azabicyclic alkene (1a) with ethyl vinyl ketone (2a).
Scheme 2. Nickel-catalyzed reductive coupling of 6h and 6i with 1g.
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Table 3. Results of the reductive coupling of oxa- and azabenzonorbornadiene 1 with alkynes 6.[a,b]
[a]
Unless otherwise mentioned, all reactions were carried out with oxa- or azabenzonorbornadiene 1 (1.00 mmol), alkynes 6
(1.50 mmol), Nil2 (5.0 mol%), P(4-FC6H4)3 (10.0 mol%), Zn (2.75 mmol), H2O (2.00 mmol) and CH3CN (1.5 mL) at 458C
for 14 h under N2.
AHCTUNGTRENNUNG
[b]
Isolated yields reported; the stereochemistry of product 7 is a relative configuration and not absolute.
alkyne leads to the formation of nickelacyclopentene
intermediate 13.[3–6] Subsequent b-oxy elimination of
13 followed by protonation affords the final product
7a and Ni(II) species. The latter is then reduced by
Zn to regenerate the Ni(0) species. It is noteworthy
that in the absence of water, intermediate 13 affords
[2+2]cycloadduct 15 in 66% yield under the similar
reaction conditions. This result clearly reveals that the
reaction proceeds via nickelacyclopentene intermedi-
ate 13. In addition, an isotope-labeling experiment
was carried using D2O instead of H2O (Scheme 4).
The reaction proceeded well at 608C and afforded the
product 7a-d1 in 85% yield with 72% deuterium incor-
poration at the styrene double bond; which strongly
supports the requirement of water for the protonation
Scheme 3. Proposed mechanism for the reductive coupling
of oxabicyclic alkene (1g) with 1-phenyl-1-propyne (6a).
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Nickel-Catalyzed Regio- and Stereoselective Reductive Coupling
distilled CH3CN (1.50 mL) was added and the reaction mix-
ture was stirred for 2 min. Then, alkyne 6 (1.50 mmol) and
H2O (2.00 mmol) were added sequentially via syringe. The
reaction mixture was stirred at 458C for 14 h and was dilut-
ed with dichloromethane and stirred in the air for 10 min.
The mixture was filtered through a Celite and silica gel pad
and washed with dichloromethane. The filtrate was concen-
trated and the residue was purified on a silica gel column
using hexane/ethyl acetate as eluent to afford the desired
product 7
Scheme 4. Deuterium labeling experiment.
of 14 in the reaction. The isotope abundance was de-
1
termined by the H NMR integration method.
Acknowledgements
We thank the National Science Council of Republic of China
(NSC-102-2628M-007-005) for support of this research.
Conclusions
In conclusion, we have demonstrated a new nickel-
catalyzed reductive coupling reaction of oxa- and aza-
bicyclic alkenes with enones to prepare 2-alkylnaph-
thalene and cis-2-alkyl-1,2-dihydronaphthalenes in
good to excellent yields. In addition, we have also suc-
cessfully developed suitable reaction conditions for
the reductive coupling of oxa- and azabicyclic alkenes
with electron-rich alkynes. These reactions are highly
regio- and stereoselective, and could be an excellent
complement to the ring opening addition reaction- of
oxa- and azabicyclic alkenes. Further extension of the
reaction with other p components and its related
asymmetric version are underway.
References
[1] Reviews: a) M. Lautens, K. Fagnou, S. Hiebert, Acc.
Chem. Res. 2003, 36, 48; b) D. K. Rayabarapu, C.-H.
Cheng, Acc. Chem. Res. 2007, 40, 971.
[2] Selected recent references: a) J. Zhu, G. C. Tsui, M.
Lautens, Angew. Chem. 2012, 124, 12519; Angew.
Chem. Int. Ed. 2012, 51, 12353; b) G. C. Tsui, M. Laut-
ens, Angew. Chem. 2012, 124, 5496; Angew. Chem. Int.
Ed. 2012, 51, 5400; c) G. C. Tsui, N. M. Ninnemann, A.
Hosotani, M. Lautens, Org. Lett. 2013, 15, 1064; d) R.
Webster, A. Boyer, M. J. Fleming, M. Lautens, Org.
Lett. 2010, 12, 5418; e) Y. Sawama, Y. Ogata, K. Kawa-
moto, H. Satake, K. Shibata, Y. Monguchi, H. Sajiki, Y.
Kita, Adv. Synth. Catal. 2013, 355, 517; f) J. Hu, Q.
Yang, J. Xu, C. Huang, B. Fan, J. Wang, C. Lin, Z.
Bian, A. S. C. Chan, Org. Biomol. Chem. 2013, 11, 814;
g) H. Cheng, D. Yang, J. Org. Chem. 2012, 77, 9756;
h) S. Fang, X. Liang, Y.-H. Long, X. Li, D. Yang, S.
Wang, C. Li, Organometallics 2012, 31, 3113, and refer-
ences cited therein.
[3] D. K. Rayabarapu, T. Sambaiah, C.-H. Cheng, Angew.
Chem. 2001, 113, 1326; Angew. Chem. Int. Ed. 2001, 40,
1286.
[4] D. K. Rayabarapu, C.-H. Cheng, Chem. Eur. J. 2003, 9,
3164.
[5] a) R. R. Burton, W. Tam, Org. Lett. 2007, 9, 3287; b) A.
Tenaglia, S. Marc, J. Org. Chem. 2008, 73, 1397; c) A.
Allen, P. Le Marquand, R. Burton, K. Villeneuve, W.
Tam, J. Org. Chem. 2007, 72, 7849.
[6] T. Nishimura, T. Kawamoto, K. Sasaki, E. Tsurumaki,
T. Hayashi, J. Am. Chem. Soc. 2007, 129, 1492.
[7] A. Tenaglia, S. Marc, L. Giordano, I. De Riggi, Angew.
Chem. 2011, 123, 9228; Angew. Chem. Int. Ed. 2011, 50,
9062.
Experimental Section
General Procedure for Nickel-Catalyzed Reductive
Coupling of Oxa- and Azabicyclic Alkenes (1) with
Enones (2)
A
sealed tube (20 mL) containing NiI2 (0.100 mmol,
10.0 mol%), bicyclic alkene 1 (1.0 mmol), and zinc powder
(2.75 mmol) was evacuated and purged with nitrogen gas
three times. Freshly distilled CH3CN (1.50 mL) was added
and the reaction mixture was stirred for 2 min. Then, alkene
2 (1.50 mmol) and H2O (2.0 mmol) were added sequentially
via syringe. The reaction mixture was stirred at 508C for
12 h and was diluted with dichloromethane and stirred in
the air for 10 min. The mixture was filtered through a Celite
and silica gel pad and washed with dichloromethane. The fil-
trate was concentrated and the residue was purified on
a silica gel column using hexane/ethyl acetate as eluent to
afford the desired product 3 or 5.
[8] a) M. Jeganmohan, C.-H. Cheng, Chem. Eur. J. 2008,
14, 10876; b) S. Mannathan, C.-H. Cheng, Chem. Eur. J.
2012, 18, 11771.
[9] a) D. K. Rayabarapu, C.-F. Chiou, C.-H. Cheng, Org.
Lett. 2002, 4, 1679; b) S. Mannathan, C.-H. Cheng,
Chem. Commun. 2013, 49, 1557.
General Procedure for Nickel-Catalyzed Reductive
Coupling of Oxa- and Azabicyclic Alkenes (1) with
Alkynes (6)
A
sealed tube (20 mL) containing NiI2 (0.0500 mmol,
5 mol%), P(4-FC6H4)3 (0.2000 mmol, 20 mol%), bicyclic
ACHTUNGTRENNUNG
alkene 1 (1.00 mmol), and zinc powder (2.75 mmol) was
evacuated and purged with nitrogen gas three times. Freshly
[10] For metal-catalyzed/mediated reductive coupling of
alkACTHNGUTERNyUNG nes with alkene; Ni: a) W. Li, A. Herath, J. Mont-
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Subramaniyan Mannathan and Chien-Hong Cheng
gomery, J. Am. Chem. Soc. 2009, 131, 17024; b) S. K.
Chowdhury, K. K. D. Amarasinghe, M. J. Heeg, J.
Montgomery, J. Am. Chem. Soc. 2000, 122, 6775; c) A.
Herath, W. Li, J. Montgomery, J. Am. Chem. Soc. 2008,
130, 469; d) A. Herath, J. Montgomery, J. Am. Chem.
Soc. 2008, 130, 8132; Rh: e) H. Y. Jang, M. J. Krische, J.
Am. Chem. Soc. 2004, 126, 7875; Ti: f) H. A. Reichard,
G. C. Micalizio, Angew. Chem. 2007, 119, 1462; Angew.
Chem. Int. Ed. 2007, 46, 1440.
3359; d) K. Kim, Y. Guo, G. A. Sulikowski, J. Org.
Chem. 1995, 60, 6866; e) R. Perrone, F. Berardi, N. A.
Colabufo, M. Leopoldo, V. Tortorella, F. Fiorentini, V.
Olgiati, A. Ghiglieri, S. Govoni, J. Med. Chem. 1995,
38, 942.
[13] a) Z. Qiu, Z. Xie, J. Am. Chem. Soc. 2009, 131, 2084;
b) R. J. McKinney, D. L. Thorn, R. Hoffmann, A.
Stockis, J. Am. Chem. Soc. 1981, 103, 2595; c) M. J.
Doyle, J. McMeeking, P. Binger, J. Chem. Soc. Chem.
Commun. 1976, 376.
[14] Activated alkenes such as acrylates, acrylonitrile, vinyl
sulfone, and acrylamides are not suitable substrates for
the present reductive coupling reactions under the stan-
dard reaction conditions.
[11] a) B. M. Trost, Science 1991, 254, 1471; b) B. M. Trost,
Angew. Chem. 1995, 107, 285; Angew. Chem. Int. Ed.
Engl. 1995, 34, 259; c) B. M. Trost, Acc. Chem. Res.
2002, 35, 695; d) J. Montgomery, Acc. Chem. Res. 2000,
33, 467; e) S. Ikeda, Acc. Chem. Res. 2000, 33, 511; f) S.
Ikeda, Angew. Chem. 2003, 115, 5276; Angew. Chem.
Int. Ed. 2003, 42, 5120; g) J. Montgomery, Angew.
Chem. 2004, 116, 3980; Angew. Chem. Int. Ed. 2004, 43,
3890.
[15] NiI2 could act as Lewis acid and possibly can facilitate
the dehydration of cis-2-alkyl-1,2-dihydronaphthols.
[16] We did not observe dehydration product of 7a in the
reaction. This is probably due to the presence of PACHTUNGTRENNUNG(4-
[12] a) B. M. Johnson, P. T. L. Chang, Anal. Profiles Drug
Subst. Excipients 1996, 24, 443; b) S. E. Snyder, F. A.
Aviles-Garay, R. Chakraborti, D. E. Nichols, V. J.
Watts, R. B. Mailman, J. Med. Chem. 1995, 38, 2395;
c) A. Kamal, L. Gayatri, Tetrahedron Lett. 1996, 37,
FC6H4)3 ligand which has lowered the acidity of NiI2
and thus 7 is sustained. This was verified by treating 7a
in the absence of ligand under the standard reaction
conditions (Table 3) which afforded the dehydration
product of 7a in 88% yield.
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