Palladium-catalyzed intermolecular aerobic oxidative amination of terminal alkenes: Efficient synthesis of linear allylamine derivatives

Article abstract of DOI:10.1002/anie.200801009

(Chemical Equation Presented) O₂-coupledallylic C-H amination: A first general palladium-mediated intermolecular aerobic oxidative allylic amination was developed to synthesize linear (E)-allylimides with high regioselectivity (see scheme; MA = maleic anhydride). The proposed mechanism involves an allylic C-H activation with subsequent nitrogen nucleophile substitution. The catalytic system allows efficient dioxygen-coupled turnover without additional cocatalysts.

Full text of DOI:10.1002/anie.200801009

Angewandte
Chemie
DOI: 10.1002/anie.200801009
Aerobic Oxidation
Palladium-Catalyzed Intermolecular Aerobic Oxidative Amination of
Terminal Alkenes: Efficient Synthesis of Linear Allylamine
Derivatives**
Guosheng Liu,* Guoyin Yin, and Liang Wu
Dedicated to Professor Xiyan Lu on the occasion of his 80th birthday
À
The rich variety of nitrogen-containing molecules that occur
as natural and synthetic products has inspired considerable
interest in the development of new methods for their
syntheses.[1] Among the strategies involving the direct ami-
proceed by allylic C H activation and subsequent nucleo-
philic attack at the C1 position of an intermediate p-
allylpalladium species.
We initiated the search for allylic amination reactions by
examining the reaction of 1-undecene (1a) with nitrogen
nucleophiles having an acidic NH group.[11] Dimethylacet-
amide (DMA) was selected as the solvent because it was
shown to be the most effective solvent for aerobic allylic
acetoxylation of alkenes.[7c] Treatment of phthalimide and 1a
with Pd(OAc)2 under a dioxygen atmosphere (6 atm) in the
presence or absence of the basic resin D301 (OH)[12] afforded
oxidative amination products exclusively associated with aza-
Wacker-type reactivity; the products were enimide 3 and
various alkene isomers (Scheme 2). No allylic amination
products were observed. The reaction of tosylamide and N-
methyl tosylamide did not form any amination product. The
use of saccharin as the nucleophile, however, resulted in
highly regioselective linear (E)-allylic amination products (2)
and the corresponding alkene isomers (Scheme 2). Optimal
results were obtained when the reaction was performed in the
nation of olefins by C N bond formation,[2–3] the synthesis of
À
amine derivatives by intermolecular dioxygen-coupled oxi-
dative amination of olefins is particularly attractive.[4–6]
Palladium-catalyzed methods for intermolecular aerobic
oxidative amination of unactivated olefins, known as aza-
Wacker reactions, have been recently reported to yield
enamide derivatives (Scheme 1, left arrow).[2e,4,6] These reac-
tions are proposed to proceed by Markovnikov aminopalla-
Scheme 1. Possible pathways for Pd-mediated intermolecular oxidative
anation of akenes.
dation of the alkene with subsequent b-
hydride elimination, resulting in the func-
tionalization of the olefin at the C2posi-
tion. Herein we describe a new method for
intermolecular dioxygen-coupled oxida-
tive amination of unactivated olefins
under cocatalyst free reaction conditions,
which affords linear allylic amine deriva-
tives with high regioselectivity (Scheme 1,
Scheme 2. Pd-catalyzed the aerobic oxidative amination of 1-undecene (1a) with phthali-
mide and saccharin.
right arrow).[7–10] These reactions appear to
[*] Prof. Dr. G. Liu, G. Yin, L. Wu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences
presence of maleic anhydride (MA) and 4 Š molecular sieves
(see the Supporting Information Table-S1 for details), which
led to a 95% yield of the oxidative allylic amination product
with respect to saccharin. Only linear amination products (C1
amination) were obtained; neither the enimide (C2amina-
tion) nor the branched allylimide (C3 amination) was
detected. The yield decreased to 78% under 1 atmosphere
of dioxygen, and the use of N-methylpyrrolidinone (NMP) or
N,N-dimethylformamide (DMF) instead of DMA, gave a
slightly lower yield. A very low product yield (ca. 10%) was
obtained with dimethylsulfoxide (DMSO) as the solvent.
354 Fenglin Road, Shanghai, 200032 (China)
Fax: (+86)21-64166128
E-mail: gliu@mail.sioc.ac.cn
[**] We are grateful for financial support from the Chinese Academy of
Sciences, the National Nature Science Foundation of China (No.
20842002) and the Science and Technology Commission of the
Shanghai Municipality (Grant No. 07JC14063). G. Liu thanks Prof.
Shannon S. Stahl and Prof. Xiyan Lu for helpful discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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These results highlight the ability to achieve selective
terminal functionalization of alkenes.
We next explored the scope and the utility of this method
with other unactivated alkenes. As summarized in Table 2,
these reactions are operationally simple and tolerant of a wide
Reactions of saccharin with various terminal alkenes
worked well (see the Supporting Information Table-S2for
additional examples), however, the difficulty of converting
saccharin into useful amine analogs prompted us to inves-
tigate other nitrogen sources. Under mild reaction conditions,
slightly modified from those identified with saccharin, 1-
undecene (1a, 6 equiv) reacted with O-methyl-N-tosylcarba-
mate (4a, 1 equiv) to afford linear allylimide 5a and its
isomers[13] in 92% yield (Table 1, entry 1). A similar yield
Table 2: Pd-catalyzed oxidative allylic amination of alkenes.[a]
Entry
Product
Yield [%][b]
1
5a R’=Me
5a
5b R’=tBu69 (76:24)
87 (70:30)
65 (71:29)
2[c]
3
Table 1: Reaction optimization for the palladium-catalyzed aerobic allylic
amination of 1-undecene 1a.[a]
4
5c R’=Bn
5c
63 (66:34)
61 (74:26)
5[c]
6
7
6
7
75 (69:31)
74 (57:43)
63 (84:16)[e]
81 (91:9)[e]
Entry
Catalyst
Imide 4
1a:4
5
Yield [%][b]
8
8
9[c,d]
10
9
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
4a R=OMe
6:1
3:1
1:1.2
1:1.2
3:1
5a
92 (69:31)
88 (64:36)
52 (65:35)
73 (72:28)
57 (17:83)
52 (56:44)
74(73:27)[e]
67(65:35)[e]
32(62:38)[e] <5[e]
<5[e]
3[c]
4[c,d]
5
10
78 (92:8)[e]
61
11
12
13[c]
14
15
16
17
11a R’=Me
11b R’=tBu83
11b
12a R’=Me
12b R’=tBu65
13a R’=Me
13b R’=tBu62
6
7
8
9
10
11
12
3:1
80
62
4b R=OtBu3:1
4c R=OBn
4d R=CH2CF3
4e R=CH3
4 f R=Bn
5b
5c
5d
5e
5 f
5g
3:1
3:1
3:1
3:1
3:1
70
<5[e]
4g[f]
15[e]
18
14
75
71
[a] The reaction was conducted on a 0.1 mmol scale in 0.5 mL of DMA.
[b] Yield determined by GC methods in which diphenyl ether was used as
the internal standard. The data in parentheses is the ratio of allylimide
and nonallylimide isomers. [c] NaOAc 50 mol%. [d] 20 mol% Pd(OAc)2.
[e] Yield determined by 1H NMR spectroscopy methods in which 1,3,5-
trimethoxybenzene was used as the internal standard. [f] 4g=
CF3CH2OSO2NHCOOMe. Ts=p-toluenesulfonyl.
19
20
15a R’=Me
15b R’=tBu67
15c R’=Bn
15c
21
80
64
22[c]
23[c]
16
53
[a] The reaction was conducted on a 0.2 mmol scale in 0.8 mL of DMA.
[b] Yield of isolated product; the data in parentheses is the ratio of the
allylimide and the nonallylimide isomers. [c] Alkene was used as the
limiting reagent: 1 (0.2 mmol, 1 equiv), 4 (0.25 mmol, 1.25 equiv),
Pd(OAc)2 (20 mol%), MA (40 mol%), NaOAc (50 mol%), 4 Š M.S.
(50 mg), DMA (0.8 mL). [d] phthN=Phthalimidyl. [e] The nonallylic
isomer is the homoallylic imide. Bn=benzyl; Bz=benzoyl.
(88%) was obtained, even when the amount of 1a was
reduced to 3 equivalents (Table 1, entry 2). Allylimide 5a was
the predominant product isomer in all cases, except when
PdCl2 was used as the catalyst, in which case a complex
mixture of alkene isomers resulted. The same products were
obtained when alkene 1a was used as the limiting reagent,
albeit in somewhat reduced yield (52%, Table 1, entry 3). A
higher chemical yield (73%) could be obtained with alkene
1a as the limiting reagent if the Pd(OAc)2 loading was
increased to 20 mol% (Table 1, entry 4). Pd(OAc)2 was a
more effective catalyst than Pd(O2CCF3)2 or PdCl2 (Table 1,
entries 5–6). Different nitrogen nucleophiles were examined
under the optimized conditions, and both 4b and 4c showed
good reactivity towards the formation of linear amination
products 5b and 5c, respectively (Table 1, entries 7–8). The
use of nucleophiles 4d and 4g resulted in lower yields
(Table 1, entries 9 and 12), and 4e and 4 f exhibited almost no
reactivity (Table 1, entries 10–11).
range of functionalities. Terminal olefins featuring benzyl
ether, methyl aryl ether, ester, phthalimidyl, and ketal
functional groups underwent direct oxidative amination at
the C1 position to generate the corresponding linear (E)-
allylamine derivatives in preparatively useful yields. Olefins
with long alkyl chains usually yielded a mixture of the linear
allylimide and the corresponding alkene isomers (Table 2,
entries 1–10). When homoallylic alcohol derivatives and
allylarenes were employed, linear (E)-allylic imides were
formed. Nonlinear (Z)-allylic imides were observed (Table 2,
entries 11–22). We also examined the possibility of using
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crude mixture was purified by column chromatography to afford
allylic amination products.
alkenes as the limiting reagent; when alkenes 1 (1 equiv) and
nitrogen sources 4 (1.25 equiv) were treated with Pd(OAc)2
(20 mol%) and NaOAc (50 mol%), the reactions afforded
modest to good yields (Table 2, entries 2, 5, 9, 13, and 22–23).
The present oxidative amination procedure provides an
effective route to anti-Markovnikov hydroamination products
if the allylic (and isomeric) terminal amination products are
reduced under standard alkene hydrogenation conditions (H2,
Pd/C; see the Supporting Infomation for details). The tosyl
protecting groups of 5–16 are easily removed to provide linear
allylcarbamates by treatment with magnesium in methanol
under sonication.[14]
Received: March 2, 2008
Published online: May 16, 2008
Keywords: alkenes · allylic compounds · amination · oxidation ·
.
palladium
[1] a) J. P. Michael in The Alkaloids, Vol. 55 (Ed.: G. A. Cordell),
Academic Press, San Diego, 2001, pp. 91 – 258; b) H. Yoda, Curr.
Org. Chem. 2002, 6, 223 – 243; c) R. Bloch, Chem. Rev. 1998, 98,
1407 – 1438; d) G. Casiraghi, F. Zanardi, G. Rassu, P. Spanu,
Chem. Rev. 1995, 95, 1677 – 1716.
[2] For reviews, see: a) T. E. Müller, M. Beller, Chem. Rev. 1998, 98,
675 – 703; b) J. J. Brunet, D. Neibecker, Catalytic Heterofunc-
tionalization (Eds.: A. Togni, H. Grützmacher), Wiley-VCH,
New York, 2001, pp. 91 – 141; c) S. Hong, T. J. Marks, Acc. Chem.
Res. 2004, 37, 673 – 686; d) J. F. Hartwig, Pure Appl. Chem. 2004,
76, 507 – 516; e) V. Kotov, C. C. Scarborough, S. S. Stahl, Inorg.
Chem. 2007, 46, 1910 – 1923.
[3] For other examples of catalytic amination of unactivated olefins,
see: a) J.-S. Ryu, G. Y. Li, T. J. Marks, J. Am. Chem. Soc. 2003,
125, 12584 – 12605; b) J. Zhang, C.-G. Yang, C. He, J. Am. Chem.
Soc. 2006, 128, 1798 – 1799; c) H. Du, W. Yuan, B. Zhao, Y. Shi, J.
Am. Chem. Soc. 2007, 129, 7496 – 7497.
[4] For reviews that describe aerobic oxidative amination reactions,
see: a) E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocor-
nola, Chem. Rev. 2007, 107, 5318 – 5365; b) S. S. Stahl, Angew.
Chem. 2004, 116, 3480 – 3501; Angew. Chem. Int. Ed. 2004, 43,
3400 – 3420.
The products of these reactions are consistent with a
À
mechanism in which allylic C H activation proceeds with
subsequent attack of the nitrogen nucleophile at the terminal
position of the p-allyl intermediate. The alternate possibility,
anti-Markovnikov aminopalladation and then b-hydride
elimination, seems less likely because intermolecular aza-
Wacker reactions of terminal alkenes (Scheme 1) exhibit
Markovnikov regioselectivity[6b,d] unless the alkene bears an
electron-withdrawing group (e.g., styrenes[6a,c] or acrylates[5]).
À
Experimental support for an allylic C H activation mecha-
nism was obtained by preparing p-allylpalladium complex
17[15] and investigating its reactivity with imide 4a. When the
reaction was performed in the presence of MA (4 equiv) and a
base (Bu4NOAc, 3 equiv), linear allylimide 5a was formed in
66% yield [Eq. (1)]. In the absence of MA, no reaction was
observed. These results are consistent with a mechanism
involving p-allylpalladium intermediates and suggest that
maleic anhydride facilitates nucleophilic attack on the p-
allylpalladium species.[16]
[5] For intermolecular aerobic oxidative amination of electron-
deficient olefins, see: a) T. Hosokawa, M. Takano, Y. Kuroki, S.-
I. Murahashi, Tetrahedron Lett. 1992, 33, 6643 – 6646; b) F.
Ragaini, T. Longo, S. Cenini, J. Mol. Catal. A. 1996, 110, L171 –
L175.
[6] For intermolecular aerobic oxidative amination, see: a) V. I.
Timokhin, N. R. Anastasi, S. S. Stahl, J. Am. Chem. Soc. 2003,
125, 12996 – 12997; b) J. L. Brice, J. E. Harang, V. I. Timokhin,
N. R. Anastasi, S. S. Stahl, J. Am. Chem. Soc. 2005, 127, 2868 –
2869; c) V. I. Timokhin, S. S. Stahl, J. Am. Chem. Soc. 2005, 127,
17888 – 17893; d) M. M. Rogers, V. Kotov, J. Chatwichien, S. S.
Stahl, Org. Lett. 2007, 9, 4331 – 4334.
[7] For Pd-catalyzed allylic acetoxylation of terminal alkenes, see:
a) M. S. Chen, M. C. White, J. Am. Chem. Soc. 2004, 126, 1346 –
1347; b) M. S. Chen, N. Prabagaran, N. A. Labenz, M. C. White,
J. Am. Chem. Soc. 2005, 127, 6970 – 6971; c) T. Mitsudome, T.
Umetani, N. Nosaka, K. Mori, T. Mizugaki, K. Ebitani, K.
Kaneda, Angew. Chem. 2006, 118, 495 – 499; Angew. Chem. Int.
Ed. 2006, 45, 481 – 485.
[8] For an example of Pd-catalyzed oxidative allylic amination of
unactivated alkenes this is limited to an intramolecular case and
requires quinone as the stoichiometric oxidant, see: a) K. J.
Fraunhoffer, M. C. White, J. Am. Chem. Soc. 2007, 129, 7274 –
In conclusion, we have developed a novel method for the
highly regioselective synthesis of linear (E)-allylimide from
palladium-catalyzed oxidative amination of unactivated alkyl
olefins, and the catalytic system allows an efficient dioxygen-
coupled turnover without additional redox-active cocatalysts.
Investigation of the reaction mechanism is in progress.
À
Experimental Section
7276; For single examples of catalytic allylic C H amination,
see: b) R. C. Larock, T. R. Hightower, L. A. Hasvold, K. P.
Peterson, J. Org. Chem. 1996, 61, 3584 – 3585.
Representative procedure: Alkene 1 (0.6 mmol), imide 4 (0.2mmol),
Pd(OAc)2 (0.02mmol), maleic anhydride (0.08 mmol), NaOAc
(0.05 mmol), and 4 Š molecular sieves (50 mg) were combined in a
glass tube containing 0.8 mL of DMA. The reaction tubes, each with
different alkene substrates, were placed into a nine-well parallel
reactor mounted in a 300 mL Parr bomb and sealed. The whole
system was purged with molecular oxygen ca. 10 times. Then the
oxygen pressure was increased to 6 atm and the reactor was warmed
to 358C. The reactions were stirred for 36 h. After the reactions were
stopped, the reaction mixtures were concentrated in vacuo and the
[9] A related Pd-catalyzed method for allylic amination of alkenes
by using a chromium cocatalyst and benzoquinone as the oxidant
appeared just prior to submission of this manuscript; see: S. A.
Reed, M. C. White, J. Am. Chem. Soc. 2008, 130, 3316 – 3318.
[10] For other metal-catalyzed intermolecular oxidative allylic ami-
nation of unactivated olefins, see: a) R. S. Srivastava, K. M.
Nicholas, J. Am. Chem. Soc. 1997, 119, 3302– 3310; b) S. Cenini,
F. Ragaini, S. Tollari, D. Paone, J. Am. Chem. Soc. 1996, 118,
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Communications
11964 – 11965; c) M. Johannsen, K. A. Jørgenson, J. Org. Chem.
1994, 59, 214 – 216, and references therein.
[14] B. Nyasse, L. Grehn, U. Ragnarsson, Chem. Commun. 1997,
1017 – 1018.
[15] B. M. Trost, P. J. Metzner, J. Am. Chem. Soc. 1980, 102, 3572–
3577.
[11] The pKa values of the nitrogen sources in dimethyl sulfoxide are
listed below: saccharin (4.0), TsNHBoc (8.5), phthalimide (13.4),
and PhSO2NH2 (16.1); see: a) I. Koppel, J. Koppel, F. Deger-
beck, L. Grehn, U. Ragnarsson, J. Org. Chem. 1991, 56, 7172–
7174; b) F. G. Bordwell, Acc. Chem. Res. 1988, 21, 456 – 463.
[12] D301 (OH) is a basic resin with a structure that is similar to
Amberlite IRA93/94. For more information, see http://
www.kingresin.com.
[16] The role of MA is analogous to that of benzoquinone in other
Pd-mediated oxidation reactions that involve nucleophilic attack
on p-allylpalladium species. See references [7a and b] and: a) J.-
E. Bꢀckvall, S. E. Bystrꢁm, R. E. Nordberg, J. Org. Chem. 1984,
49, 4619 – 4631; b) J.-E. Bꢀckvall, A. Gogoll, Tetrahedron Lett.
1988, 29, 2243 – 2246; c) J.-E. Bꢀckvall, R. E. Nordberg, E. E.
Bjꢁrkman, C. Moberg, J. Chem. Soc. Chem. Commun. 1980,
943 – 944; d) J.-E. Bꢀckvall, R. E. Nordberg, J. Am. Chem. Soc.
1981, 103, 4959 – 4960.
[13] The nonallylic isomers consist of two major products, the homo-
and bishomoallylimide. Other isomers are less than 5%.
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