Palladium(II)-catalyzed intramolecular hydroamination of 1,3-dienes to give homoallylic amines

Article abstract of DOI:10.1002/anie.201305766

A pincer for high selectivity: A mild palladium-catalyzed hydroamination of protected amino-1,3-dienes is possible. This highly regioselective reaction employs a tridentate PNP pincer ligand and leads to cyclic and homoallylic protected amines in high yields. Substrates with a wide array of amine protecting groups and diene substitution patterns were cyclized to form five- and six-membered heterocycles. PG=protecting group.

Full text of DOI:10.1002/anie.201305766

Angewandte
Chemie
DOI: 10.1002/anie.201305766
Homoallylic Amines
Palladium(II)-Catalyzed Intramolecular Hydroamination of 1,3-Dienes
to Give Homoallylic Amines**
Justin M. Pierson, Erica L. Ingalls, Richard D. Vo, and Forrest E. Michael*
Nitrogen heterocycles are key features of many natural
products and industrially relevant pharmaceuticals.[1] As
a result, many methods for the construction of these core
structures have been developed. In particular, the hydro-
amination of unsaturated hydrocarbons has arisen as a general
and useful method for generating new carbon–nitrogen bonds
in heterocycles because of its atom-economic nature and mild
reaction conditions.[2] Numerous transition-metal and
Brønsted acid hydroamination catalysts have been discov-
ered.
lidine, piperidine, and piperazine scaffolds (Scheme 1a).[9] We
hypothesized that the same Pd catalyst should also catalyze
the hydroamination of dienes by a similar mechanism, and, by
The hydroamination of 1,3-dienes is a useful transforma-
tion, because the resulting aminoalkenes possess a handle for
further functionalization. A major challenge for diene hydro-
amination catalysts is the controlled formation of one of the
several possible regioisomeric products. In practice, the vast
majority of reported diene hydroamination reactions are
selective for the formation of allylic amines.[3] In particular,
known hydroamination reactions catalyzed by nickel or
palladium give exclusively allylic amines, owing to the
intermediacy of an h3-allyl complex.[4] Similarly, Brønsted
acid catalyzed hydroamination reactions also generate allylic
amines, as predicted by the stability of the intermediate allyl
cation.[5] In contrast, the formation of homoallylic amines in
hydroamination reactions is a more challenging task. A few
hydroamination catalysts have been reported to give mixtures
of allylic and homoallylic amines,[6] but only two reports on
hydroamination catalysts that selectively give homoallylic
amines have been published. Marks et al. described a Th
catalyst that gives high selectivity for two substrates lacking
substitution on the diene, but with a trisubstituted diene
substrate, the selectivity was poor.[7] Yamamoto and co-
workers discovered a carbaboranyl–Hg catalyst that exclu-
sively afforded homoallylic amines from a range of sulfona-
midodiene substrates.[8] In this case, the conversion of
substrates with substituents on the diene moiety was not
reported. Herein, we report a Pd catalyst for the hydro-
amination of dienes that exclusively gives homoallylic amines
in excellent yields for a variety of diene substitution patterns.
We previously reported a mild Pd-catalyzed intramolec-
ular hydroamination of aminoalkenes that generated pyrro-
Scheme 1. Pd-catalyzed intramolecular hydroamination reactions.
virtue of the increased reactivity of dienes, tolerate a greater
range of substitution patterns. Initial studies began by
subjecting protected aminodiene 4a to the previously
reported hydroamination conditions (Scheme 1b). Encourag-
ingly, this afforded a single isomer of the cyclization product
in excellent yield. This isomer was identified as the homo-
allylic amine product 5a, which arises from a 5-exo 1,2-
addition. Exposure of a substrate without geminal backbone
substitution to these conditions gave the product in equally
high yields and regioselectivity (Table 1, entry 1), which
established that this hydroamination catalyst is even active
for substrates that do not benefit from Thorpe–Ingold effects.
This reaction can be applied to substrates with a wide
array of amine protecting groups (Table 1). Importantly, the
Table 1: Variation of the protecting group.
Entry
Protecting group[a]
Product
Yield [%]
1
2
3
4
5
6
7
Cbz (6a)
Boc (6b)
p-toluoyl (6c)
Ac (6d)
Ts (6e)
4-Ns (6 f)
SES (6g)
7a
7b
7c
7d
7e
7 f
7g
>99 (95%)[b]
76
86
>99
73
97
[*] J. M. Pierson,[+] E. L. Ingalls,[+] R. D. Vo, Prof. Dr. F. E. Michael
Department of Chemistry, University of Washington
Seattle, Box 351700, WA 98195-1700 (USA)
E-mail: michael@chem.washington.edu
[+] These authors contributed equally to this work.
73
[**] We thank the University of Washington and the National Science
Foundation for financial support of this project.
[a] For the E/Z ratios, see the Supporting Information. [b] 1.8 mmol
scale. Boc=tert-butoxycarbonyl, Cbz=benzyloxycarbonyl, 4-Ns=4-
nitrobenzenesulfonyl, PG=protecting group, SES=2-(trimethylsilyl)-
ethanesulfonyl, Ts=p-toluenesulfonyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305766.
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13311

.
Angewandte
Communications
synthetically useful substrates that bear the carbamate
protecting groups Cbz (6a) or Boc (6b) were successfully
converted into the corresponding hydroamination products,
which makes this the only catalytic system that gives
homoallylic amines with these protecting groups. Amides
also cyclized in good to excellent yields (6c and 6d). Even
sulfonamide-protected amines (6e–6g) underwent hydroami-
nation under standard conditions, which is somewhat surpris-
ing given the previous failure of catalyst 1 to react with
sulfonamidoalkenes.[9]
The effect of the diene substitution pattern on the
regioselectivity of an intramolecular hydroamination had
not been extensively explored, so we prepared the substituted
dienes 10a, 12a, and 14a with substituents at the 4, 3, and
1 positions of the diene, respectively. All three substrates
cleanly underwent hydroamination, affording the allylpyrro-
lidine products in high yields (11a, 13a, 15a; Scheme 2). The
excellent yield of 15a shows that this method can be used to
construct sterically hindered tetrasubstituted carbon centers.
Other backbone substitution patterns and lengths were also
tolerated, as isoindoline, piperidine, and morpholine hetero-
cycles were isolated in > 95% yield (19a, 21a, 23a, 25a).
Excellent regioselectivities (> 20:1) were obtained in all
cases.
Although it is clear from Scheme 2 that both E and Z
alkenes are capable of undergoing hydroamination, we tested
whether the initial stereochemistry had any influence on the
hydroamination reactivity. Hydroamination of (E)-6a and
(Z)-6a gave the same products in identical yields (98%),
illustrating that alkene stereochemistry has little effect on the
outcome of hydroamination (Scheme 3).
Understanding the high selectivity for formation of the
homoallylic amines in this system requires consideration of
the key Pd–alkyl intermediate that arises from aminopalla-
dation of the diene.[9c] To investigate this intermediate,
a stoichiometric reaction of the Pd complex with substrate
8d was performed in the presence of various bases. N,N-
Dimethylaniline proved to be an appropriately strong and
bulky base to allow the allyl intermediate 26 to be isolated as
a yellow solid in 66% yield (Scheme 4). NMR spectroscopy
confirmed that the allyl group was bound to the metal center
in an h1 fashion, and that palladium was bound to the distal
terminus of the former diene moiety. Similar pincer-ligated
Pd–allyl complexes have been shown to be preferentially of
h1 hapticity.[10] When complex 26 was treated with a Brønsted
acid, hydroamination product 9d was obtained, which is
consistent with the intermediacy of this complex in the
catalytic reaction. It appears that the regioselectivity
observed in this hydroamination reaction arises from 1) initial
1,4 aminopalladation to form the less-substituted h1-allyl
complex 26, followed by 2) regioselective SE2’ protonation of
the Pd–allyl complex.[11]
Scheme 2. Substrate scope of the hydroamination. [a] 1 (5 mol%),
AgBF4 (10 mol%), MgSO4 (1 equiv), CH2Cl2, RT, 18 h. [b] For the E/Z
ratios, see the Supporting Information. [c] The same yield was
obtained on both a 0.2 and a 2.0 mmol scale.
Scheme 3. Hydroaminations of E and Z dienes. [a] 1 (5 mol%), AgBF4
(10 mol%), MgSO4 (1 equiv), CH2Cl2, RT, 18 h.
In conclusion, a palladium-catalyzed hydroamination of
amino-1,3-dienes at room temperature has been developed
that results in the formation of useful olefinic nitrogen
heterocycles. Homoallylic amines were formed in high yields
and with high selectivity. A wide variety of amine protecting
groups could be employed, and various diene substitution
patterns were tolerated. Finally, an h1-allyl–palladium com-
Scheme 4. Formation of the h1-allyl–Pd complex and protonolysis.
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Sasaki, K. Namba, H. Imagawa, M. Nishizawa, Chem. Lett. 2010,
39, 830 – 831.
plex was isolated and shown to be a viable intermediate,
which gave insight into the reaction mechanism.
[4] a) R. W. Armbruster, M. M. Morgan, J. L. Schmidt, C. M. Lau,
R. M. Riley, D. L. Zabrowski, H. A. Dieck, Organometallics
1986, 5, 234 – 237; b) O. Lçber, M. Kawatsura, J. F. Hartwig, J.
Am. Chem. Soc. 2001, 123, 4366 – 4367; c) T. Minami, H.
Okamoto, S. Ikeda, R. Tanaka, F. Ozawa, M. Yoshifuji, Angew.
Chem. 2001, 113, 4633 – 4635; Angew. Chem. Int. Ed. 2001, 40,
4501 – 4503; d) J. Pawlas, Y. Nakao, M. Kawatsura, J. F. Hartwig,
J. Am. Chem. Soc. 2002, 124, 3669 – 3679; e) A. M. Johns, M.
Utsunomiya, C. D. Incarvito, J. F. Hartwig, J. Am. Chem. Soc.
2006, 128, 1828 – 1839; f) N. Sakai, A. Ridder, J. F. Hartwig, J.
Am. Chem. Soc. 2006, 128, 8134 – 8135; g) A. M. Johns, Z. Liu,
J. F. Hartwig, Angew. Chem. 2007, 119, 7397 – 7399; Angew.
Chem. Int. Ed. 2007, 46, 7259 – 7261.
[5] a) O. Kanno, W. Kuriyama, J. Z. Wang, D. F. Toste, Angew.
Chem. 2011, 123, 10093 – 10096; Angew. Chem. Int. Ed. 2011, 50,
9919 – 9922; b) C. Brinkmann, A. G. M. Barrett, M. S. Hill, P. A.
Procopiou, J. Am. Chem. Soc. 2012, 134, 2193 – 2207.
[6] a) Z. Li, J. Zhang, C. Brouwer, C. G. Yang, N. W. Reich, C. He,
Org. Lett. 2006, 8, 4175 – 4178; b) N. D. Shapiro, V. Rauniyar,
G. L. Hamilton, J. Wu, F. D. Toste, Nature 2011, 470, 245 – 250.
[7] a) S. Hong, T. J. Marks, J. Am. Chem. Soc. 2002, 124, 7886 – 7887;
b) B. D. Stubbert, T. J. Marks, J. Am. Chem. Soc. 2007, 129,
4253 – 4271.
[8] H. Yamamoto, I. Sasaki, S. Shiomi, N. Yamasaki, H. Imagawa,
Org. Lett. 2012, 14, 2266 – 2269.
[9] a) F. E. Michael, B. M. Cochran, J. Am. Chem. Soc. 2006, 128,
4246 – 4247; b) B. M. Cochran, F. E. Michael, Org. Lett. 2008, 10,
329 – 332; c) B. M. Cochran, F. E. Michael, J. Am. Chem. Soc.
2008, 130, 2786 – 2792.
[10] L. Barloy, S. Ramdeehul, J. A. Osborn, C. Carlotti, F. Taulelle, A.
De Cian, J. Fisher, Eur. J. Inorg. Chem. 2000, 2523 – 2532.
[11] As the two regioisomeric h1-allyl complexes are known to
interconvert rapidly at room temperature (see Ref. [10]), we
cannot rule out SE2 protonation of the unobserved allyl isomer.
Experimental Section
General hydroamination conditions for the reaction with 5a: In
a glove box, 2,6-bis(diphenylphosphinomethyl)pyridine dichloropal-
ladium (1; 3.27 mg, 0.05 mmol), AgBF4 (1.97 mg, 0.01 mmol), and
MgSO4 (12 mg, 0.1 mmol) were added to a round-bottomed flask. The
flask was capped with a septum and removed from the glove box. The
reaction mixture was placed under an atmosphere of nitrogen, and
CH2Cl2 (0.5 mL) was added. A solution of the substrate (27.3 mg,
0.1 mmol) in CH2Cl2 (0.5 mL) was added by syringe to the stirring
mixture. The reaction was stirred overnight; then the mixture was
filtered through a plug of celite. Purification by column chromatog-
raphy (CH2Cl2) on silica gel afforded the pure product (26.0 mg, 95%
yield).
Received: July 3, 2013
Revised: August 27, 2013
Published online: October 24, 2013
Keywords: 1,3-dienes · homoallylic amines · hydroamination ·
.
nitrogen heterocycles · palladium catalysis
[1] a) D. OꢀHagan, Nat. Prod. Rep. 2000, 17, 435 – 446; b) J. R.
Liddell, Nat. Prod. Rep. 2002, 19, 773 – 781.
[2] T. E. Mꢁller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem.
Rev. 2008, 108, 3795 – 3892.
[3] a) X. Giner, C. Nꢂjera, Org. Lett. 2008, 10, 2919 – 2922; b) C.
Brouwer, C. He, Angew. Chem. 2006, 118, 1776 – 1779; Angew.
Chem. Int. Ed. 2006, 45, 1744 – 1747; c) N. T. Patil, L. M. Lutete,
H. Wu, N. K. Pahadi, I. D. Gridnew, Y. Yamamoto, J. Org. Chem.
2006, 71, 4270 – 4279; d) H. Yamamoto, S. Shiomi, D. Odate, I.
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