Molybdenum(0)-promoted carbonylative cyclization of o-haloaryland β-haloalkenylimine derivatives by oxidative addition of a carbon(sp 2)-halogen bond: Preparation of two types of γ-lactams

Full text of DOI:10.1002/anie.200902884

Communications
DOI: 10.1002/anie.200902884
Synthetic Methods
Molybdenum(0)-Promoted Carbonylative Cyclization of o-Haloaryl-
and b-Haloalkenylimine Derivatives by Oxidative Addition of a
2
À
Carbon(sp ) Halogen Bond: Preparation of Two Types of g-Lactams**
Jun Takaya, Kenichiro Sangu, and Nobuharu Iwasawa*
In contrast to the widespread use of late-transition-metal
catalysts for the activation and transformation of a carbon-
2
(sp ) halogen bond by oxidative addition,[1] related reactions
À
promoted by early-transition-metal complexes have scarcely
been reported owing to their low activity to oxidative addition
and difficulty in regenerating the catalytic species.[2–4] Never-
theless, it is highly desirable to develop such reactions as the
À
carbon metal bond of early-transition-metals formed by the
oxidative addition is expected to show characteristic reac-
tivity resulting from the high polarity of this bond. Our
research group has recently reported a reaction involving the
Scheme 1. Carbonylative cyclization promoted by a Group 6 metal
carbonyl species.
stoichiometric intermolecular addition to alkenes of acylmo-
lybdenum species generated by oxidative addition of aryl- or
alkenylhalides to a molybdenum(0) carbonyl complex.[5]
Herein, we report that by utilizing chelation-assisted oxida-
tive addition of o-haloaryl- and b-haloalkenylimines to
[Mo(CO)6], two types of synthetically useful g-lactam deriv-
atives can be obtained selectively by the appropriate choice of
reaction conditions.
yield as a mixture of diastereomers and was accompanied by
11% yield of a monomeric isoindolinone 3a (Scheme 2).[9]
1
The structure of the dimer 2a was determined by H and
We chose a Group 6 metal carbonyl species to promote
the carbonylative cyclization reaction of aryl- or alkenylha-
lides bearing an aldimine moiety at a neighboring position,
with the expectation that coordination of the imine nitrogen
atom to the metal would assist oxidative addition of the
2
À
carbon(sp ) halogen bond to initiate the reaction
(Scheme 1).[6] The focus of this study involves the investiga-
tion of reaction pathways that follow this oxidative addition
step, also the usefulness of Group 6 metal carbonyl species
will be compared to the well-known palladium-catalyzed
reactions.[7,8]
Scheme 2. Formation of bis(isoindolinone) 2a by the carbonylative
cyclization of 1a with [Mo(CO)6] in the presence of the proton sponge.
Conditions A: X=100, 1008C, 1.5h. Conditions B: X=30, proton
sponge (200 mol%), 1208C, 10h. DMF=N,N-dimethylformamide.
Based on these considerations, we examined the reaction
of (N-tert-butyl)-o-iodobenzylideneamine 1a as a model
substrate. After extensive screening of reaction conditions,
it was found that when the aldimine 1a was treated with a
stoichiometric amount of [Mo(CO)6] in DMF at 1008C in a
CO atmosphere, bis(isoindolinone) 2a was obtained in 83%
13C NMR spectroscopy, high-resolution mass spectrometry,
elemental analysis, and X-ray analysis of its analogue.[10]
Further investigation of various additives disclosed that the
addition of 1,8-bis(dimethylamino)naphthalene (the proton
sponge) realized a semi-catalytic version of this carbonylative
cyclization with perfect selectivity of products. Thus, treat-
ment of 1a with 30 mol% of [Mo(CO)6] and 200 mol% of
proton sponge in DMFat 1208C in a CO atmosphere afforded
2a as the exclusive product in 93% yield. Among the Group 6
metals examined, only [Mo(CO)6] showed activity while
Cr(CO)6 or W(CO)6 did not afford the products.
[*] Dr. J. Takaya, K. Sangu, Prof. Dr. N. Iwasawa
Department of Chemistry
Tokyo Institute of Technology
O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
Fax: (+81)3-5734-2931
A proposed reaction mechanism is depicted in Scheme 3.
First, (N-tert-butyl)-aldimine-assisted oxidative addition of
aryl iodide to coordinatively unsaturated Mo(CO)n, which is
generated by the dissociation of carbonyl ligands under the
reaction conditions, occurs to afford an arylmolybdenum(II)
intermediate A.[11] The successive insertion of a carbonyl
E-mail: niwasawa@chem.titech.ac.jp
[**] This research was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902884.
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conditions described above (30 mol% of [Mo(CO)6]). Aryl
iodides 1b and 1c with an electron-donating substituent on
their aromatic rings smoothly reacted to afford the corre-
sponding bis(isoindolinone) derivatives 2b and 2c in good
yields (Table 1, entries 1 and 2). A chloride atom on the
benzene ring was also tolerated and selective activation of the
À
carbon iodine bond was realized (Table 1, entry 3). Further-
more, not only aryl halides but also alkenyl halides containing
cyclic (1 f, 1g: Table 1, entries 5 and 6) or acyclic backbones
(1h, 1i: Table 1, entries 7 and 8) smoothly underwent this
carbonylative cyclization with and gave bis(g-lactam) deriv-
atives in good to high yields: although the production of
monomeric lactams increased slightly. The successful appli-
cation of this methodology to less reactive aryl- or alkenyl-
bromides disclosed the high activity of Mo(CO)n toward
oxidative addition (Table 1, entries 4–6). Thus, this protocol is
general and provides easy access to bis(g-lactam) derivatives,
which are difficult to synthesize by previously reported
processes catalyzed by late-transition-metals. This dimeric
skeleton is observed in the structure of b-isoindigo derivatives
and is also potentially useful as a precursor to diimine-type
bidentate ligands.
Based on the observation that monomeric lactam 3 was
formed by protonation of intermediate C even with a trace
amount of water present in DMF, we developed a general
protonation protocol leading to monomeric lactam 3 in the
presence of a proton donor. After examination of the reaction
of 1h, it was found that the addition of 3 equivalents of water
dramatically changed the course of the reaction and only
monomeric g-lactam 3 f was obtained in 90% yield using a
stoichiometric amount of [Mo(CO)6] at 1608C (Scheme 4).[16]
This ease of protonation is thought to result from the high
nucleophilicity of alkylmolybdenum intermediate D and has
rarely been observed in related palladium-promoted reac-
tions.[17]
Scheme 3. Proposed reaction mechanism.
ligand generates an acyl molybdenum complex B and
=
insertion of the C N bond occurs to afford an alkyl
molybdenum intermediate C. Finally, transmetalation and
reductive elimination of intermediate C gives the dimeric
isoindolinone 2a, whereas protonation of intermediate C by
the water present in DMF affords the monomer 3a as a minor
product. The generated MoII species is reduced to the
catalytically active Mo0 by the proton sponge.[12,13] These
two reaction pathways (of alkylmolybdenum intermediate C)
are characteristic of the molybdenum-mediated reaction and
are in striking contrast to palladium-promoted carbonylative
cyclization of similar haloimines: in which alkylpalladium
intermediates corresponding to C react with nucleophiles to
give coupling products instead of undergoing dimerization or
protonation.[14,15] This behavior strongly reflects the nucleo-
philic character of alkylmolybdenum species, which favor
transmetalation and protonation. Although the efficiency of
the current catalytic reaction is still inadequate compared to
the well-developed palladium-catalyzed reactions, this reac-
tion is a rare example of a carbon–carbon bond-forming
reaction (including oxidative addition of an carbon(sp )
halogen bond) catalyzed by a Group 6 metal.
Table 1 shows the generality of our [Mo(CO)6]-catalyzed
synthesis of bis(g-lactam) derivatives under the reaction
2
À
This protonation protocol also showed generality as
summarized in Table 2. Other alkenyl- or arylhalides bearing
various substituents were also applicable to this protocol and
Table 1: General scope of the [Mo(CO)6]-catalyzed synthesis of bis(g-lactam) derivatives.
Entry
Aldimine
Products
Yield of bis(g-lactam) [%] (d.r.)
Ratio of 2/3
Yield of g-lactam [%]
3b trace
1
2
1b R=CH3, X=I
1c R=OMe, X=I
1d R=Cl, X=I
1e R=H, X=Br
2b 86 (61:39)
2c 72 (53:47)
2d 55 (58:42)
2a 75 (69:31)
>95:<5
>95:<5
>95:<5
>95:<5
3c trace
3d 2
3a trace
3
4[a]
5
6
7
8
1 f R1 =R2 =CH2CH2CH2, X=Br
1g R1 =R2 =CH2(CH2)2CH2, X=Br
1h R1 =Ph, R2 =H, X=I
2 f 90 (83:17)
2g 91 (79:21)
2h 58 (95:5)
2i 60 (77:23)
3 f trace
3g trace
3h 21
>95:<5
>95:<5
73:27
1i R1 =Ph, R2 =CH3, X=I
3i 13
82:18
[a] Reaction temperature at 1608C.
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Table 3: Selective protonation over b-hydride elimination.
Scheme 4. Selective formation of g-lactam 3 by protonation of inter-
mediate D.
Entry
Ketimine
Yield of 5 + 6 [%]
Ratio of 5/6
1
2
3
4
5
4a R1 =H
73
59
52
79
81
5a/6a=92:8
4b R1 =Cl
5b/6b=92:8
5c/6c=>95:<5
5d/6d=71:29
5e/6e=86:14
4c R1 =CF3
4d R1 =Me
4e R1 =OMe
selectively afforded monomeric g-lactams by the appropriate
choice of the proton source (water or PPTS) and the
substituent on the nitrogen center (tBu or PMP; Table 2).
Furthermore, the uniqueness of the alkylmolybdenum inter-
mediate is highlighted by the reaction of ketimine derivatives,
in which similar alkyl transition-metal intermediates bearing
a b hydrogen are known to undergo rapid b-hydride elimi-
nation to afford enamine derivatives.[18] Various ketimines
derived from acetophenones bearing an electron-donating or
-accepting substituent gave protonation products 5 with high
selectivity under slightly modified reaction conditions
(100 mol% of nBu4NCl and 3 equiv of water as additives;
Table 3). Interestingly, no formation of dimerized bis(isoin-
dolinone) derivatives was observed, probably owing to strong
steric repulsion between tert-alkylmolybdenum intermediates
in the transmetalation step. Even though this protonation
protocol needs a stoichiometric amount of molybdenum at
present, it is a facile method for the construction of syntheti-
cally useful g-lactam and isoindolinone derivatives.
Experimental Section
General procedure for [Mo(CO)6]-promoted carbonylative cycliza-
tion of (N-tert-butyl)-2-iodobenzylideneamine 1a in the presence of
the proton sponge: A mixture of aldimine 1a (41 mg, 0.14 mmol),
[Mo(CO)6] (11 mg, 0.042 mmol), and proton sponge (60 mg,
0.28 mmol) in DMF (5.6 mL) was heated at 1208C for 10 h in a CO
atmosphere. After 1a was completely consumed (as evident by TLC)
the reaction was quenched at room temperature with 1m HCl
solution, and then the mixture was neutralized with a phosphate
buffer at pH 7. The mixture was extracted four times with diethyl
ether and the combined organic extracts were washed with brine and
dried over MgSO4. The solvent was removed under reduced pressure
and the residue was purified by preparative TLC (silica gel, eluent:
1:1 hexanes:ethyl acetate) to afford the bis(isoindolinone) 2a
(24.1 mg, 0.064 mmol, 91% yield).
Received: May 29, 2009
In conclusion, we have established a unique molybdenum-
promoted carbonylative cyclization of o-haloaryl- and b-
haloalkenylimines leading to g-lactam derivatives. By utiliz-
ing the characteristic property of the molybdenum complex,
two kinds of products (both of which have rarely been
obtained by reactions catalyzed by late-transition-metals)
were obtained selectively simply by changing the reaction
conditions.
Published online: August 24, 2009
Keywords: carbonylation · lactams · molybdenum ·
.
oxidative addition · synthetic methods
[1] a) Metal-Catalyzed Cross-Coupling Reactions (Eds.: A. de Mei-
jere, F. Diederich), Wiley-VCH, Weinheim, 2004; b) Handbook
Table 2: General scope of protonation protocol.
Entry
Aldimine
Yield of 2 + 3 [%]
Ratio of 2/3
1[a]
2[b]
3[b]
1 f R1 =R2 =CH2CH2CH2, X=Br
1g R1 =R2 =CH2(CH2)2CH2, X=Br
1i R1 =Ph, R2 =CH3, X=I
68
86
94
2 f/3 f=32:68
2g/3g=2:98
2i/3i=<5:>95
4[c]
5[c]
6[c]
7[c]
1j R3 =H, R4 =PMP
1k R3 =CH3, R4 =PMP
1l R3 =OMe, R4 =PMP
1d R3 =Cl, R4 =tBu
82
76
65
61
2j/3j=20:80
2k/3k=21:79
2l/3l=15:85
2d/3d=20:80
[a] 200 mol% PPTS. [b] 300 mol% H2O. [c] 500 mol% PPTS. PMP=p-methoxyphenyl, PPTS=pyridinium p-toluenesulfonate.
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[9] The reaction with a stoichiometric amount of [Mo(CO)6] in a
nitrogen atmosphere afforded the products in slightly lower
yield (by ꢀ 10%).
[3] Richmond and co-workers established that a bidentate or
À
tridentate chelating lignd assisted oxidative addition of Ar X
[10] The structures of both stereoisomers of 2d, derived from (N-tert-
butyl)-2-iodo-4-chloro-benzylideneamine 1d, were confirmed by
X-ray analysis (see the Supporting Information).
to tungsten or molybdenum carbonyl complexes to give air-
stable, seven coordinate WII or MoII complexes. However, the
high stability of the resulting complexes and specificity of
substrates limited their application to synthetic chemistry, see:
a) T. G. Richmond, M. A. King, E. P. Kelson, A. M. Arif,
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[11] The fact that the N-tosyl analogue, in which coordinating ability
of its imino nitrogen atom is decreased because of the strong
electron-withdrawing nature of the tosyl group, failed to afford
any carbonylation products. This result strongly supports the
crucial role of the (N-tert-butyl)-aldimine moiety as a directing
group (see the Supporting Information).
[4] a) H. Guo, F. Kong, K.-i. Kanno, J. He, K. Nakajima, T.
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236.
[12] The role of the proton sponge as a reductant is confirmed by the
observation of N,N,N’-trimethylnaphthalene-1,8-diamine after
work-up.
[13] The complete suppression of the formation of 3a in the presence
of the proton sponge can be explained by considering the role of
the proton sponge as a proton scavenger.
[5] K. Sangu, T. Watanabe, J. Takaya, N. Iwasawa, Synlett 2007, 929.
[14] The formation of dimer as a minor product has been observed in
a palladium-catalyzed reaction of a similar haloimine, see
Ref. [7a].
[15] Recently, Li and co-workers reported nickel-promoted carbon-
ylative cyclization and dimerization of o-halophenylimines to
give bis(isoindolinone)in low yields, see Ref. [7g].
[6] Palladium-catalyzed
carbonylative
cyclization
utilizing
[Mo(CO)6] as a carbonyl source has been reported: a) X. Wu,
A. K. Mahalingam, Y. Wan, M. Alterman, Tetrahedron Lett.
2004, 45, 4635; b) X. Wu, P. Nilsson, M. Larhed, J. Org. Chem.
2005, 70, 346.
[7] For catalytic carbonylative cyclization reactions of o-halophe-
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H. S. Lee, S.-D. Cho, J. Heterocycl. Chem. 1997, 34, 1371; b) C. S.
Cho, D. Y. Chu, D. Y. Lee, S. C. Shim, T. J. Kim, W. T. Lim, N. H.
Heo, Synth. Commun. 1997, 27, 4141; c) C. S. Cho, H. S. Shim,
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[16] The reaction of 1i in the presence of 3.0 equivalents of D2O
afforded 3i with 81% incorporation of deuterium at the g-
position, thus supporting the concept of protonation of the
alkylmolybdenum intermediate by added water (see the Sup-
porting Information).
[17] a) During the preparation of this manuscript, Cho and Ren
reported the palladium-catalyzed synthesis of isoindolinone
through the hydrogenolysis of an alkylpalladium intermediate
generated by carbonylative cyclization of o-halophenylimines.
The hydrogenolysis was proposed to proceed with H2 generated
by the reaction of DMF and/or CO with H2O, see: C. S. Cho,
W. X. Ren, Tetrahedron Lett. 2009, 50, 2097; b) See Ref. [8e].
[18] See Ref. [7c, 8a, 8b].
[8] For carbonylative cyclization reactions of o-halobenzaldehyde,
o-halophenylketones, or related compounds, see: a) I. Shi-
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