Catalytic (3+2) Palladium-Aminoallyl Cycloaddition with Conjugated Dienes

Article abstract of DOI:10.1002/anie.201900693

We describe the design and application of tailored aminoallyl precursors for catalytic (3+2) cycloaddition with conjugated dienes via a Pd-aminoallyl intermediate. The new cycloaddition reactions override the conventional (4+3) selectivity of aminoallyl cation cycloaddition through a sequence of Pd-allyl transfer and ring closure. A variety of highly substituted or fused pyrrolidine rings were synthesized using the cycloaddition, and can further undergo [1,3] N-to-C rearrangement to five-membered carbocycles with a different palladium catalyst. The utility of the (3+2) cycloaddition is also demonstrated by the preparation of various derivatives from the bicyclic pyrrolidine products.

Full text of DOI:10.1002/anie.201900693

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International Edition: DOI: 10.1002/anie.201900693
German Edition: DOI: 10.1002/ange.201900693
Homogeneous Catalysis
Catalytic (3+2) Palladium-Aminoallyl Cycloaddition with Conjugated
Dienes
Barry M. Trost* and Zhongxing Huang
Abstract: We describe the design and application of tailored
aminoallyl precursors for catalytic (3+2) cycloaddition with
conjugated dienes via a Pd-aminoallyl intermediate. The new
cycloaddition reactions override the conventional (4+3) selec-
tivity of aminoallyl cation cycloaddition through a sequence of
Pd-allyl transfer and ring closure. A variety of highly
substituted or fused pyrrolidine rings were synthesized using
the cycloaddition, and can further undergo [1,3] N-to-C
rearrangement to five-membered carbocycles with a different
palladium catalyst. The utility of the (3+2) cycloaddition is
also demonstrated by the preparation of various derivatives
from the bicyclic pyrrolidine products.
H
eteroallyl cations are important classes of zwitterion
intermediates of cycloaddition reactions to construct fused-
and bridged-ring systems.[1] In particular, (4+3) cycloaddition
reactions of oxyallyl and aminoallyl cations with conjugated
dienes have enabled the synthesis of a wide array of complex
and bioactive molecules via chemoselective seven-membered
ring formation (Scheme 1A).[2] In contrast, the (3+2) cyclo-
addition of heteroallyl cations with 2p acceptors to afford
synthetically useful five-membered rings, such as tetrahydro-
furan, pyrrolidine, and cyclopentanone, has been relatively
elusive.[3] A major obstacle to the (3+2) cycloaddition is the
unmatched frontier molecular orbitals of the oxy-/aminoallyl
cation and the 2p partner that prohibit the concerted pathway.
Only a limited number of methods based on stepwise
mechanisms have been developed to enable the thermally
forbidden five-membered ring formation, and these reactions
often require stoichiometric amounts of metal-based
reagents, such as low valent iron carbonyl complexes[4] and
aluminum-based Lewis acids.[5]
Scheme 1. Oxyallyl and aminoallyl cycloadditions.
In 2018, we demonstrated that tailored oxyallyl precursors
with an electron-withdrawing group could participate in the
Pd-catalyzed (3+2) cycloaddition with conjugated dienes to
afford various fused or highly substituted tetrahydrofuran
rings (Scheme 1B, Eq. 1) via a Pd-oxyallyl intermediate (1).[6]
The cycloaddition is proposed to override the conventional
(4+3) chemoselectivity of oxyallyl cations through a Pd-allyl
transfer/ring closure sequence, and the pendant electron-
withdrawing group proved indispensable for inhibiting the
formation of a four-membered palladacycle that leads to the
(2+1) cyclopropanation product.[7,8] We envision that the
extension of the new (3+2) cycloaddition paradigm to the
analogous Pd-aminoallyl intermediate (e.g., 4) would be
highly desirable, since nitrogen-containing five-membered
hetero- and carbocycles, such as pyrrolidines and cyclopentyl-
amines, are versatile building blocks and prevalent in
bioactive compounds. We also hypothesize that cyclic carba-
mate 2,[8] which has an electron-withdrawing group, would be
a suitable precursor for the proposed (3+2) Pd-aminoallyl
cycloaddition. Once exposed to a Pd0 catalyst, the precursor is
proposed to be ionized to zwitterion 3, which after sponta-
neous decarboxylation, gives Pd-aminoallyl 4. Subsequently,
the addition of 4 to the conjugated diene would generate
a new Pd-allyl species 5,[9] and this Pd-allyl transfer process
[*] Prof. B. M. Trost, Z. Huang
Department of Chemistry, Stanford University
333 Campus Drive, Stanford, CA 94305 (USA)
E-mail: bmtrost@stanford.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201900693.
À
would be followed by C N reductive elimination to give the
(3+2) cycloaddition product.
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To test our hypothesis, the carbamate precursor 8 was
prepared from commercially available ethyl propiolate 6 and
arylsulfonyl isocyanate 7 in one step through initial addition
of the propargyl alcohol to the isocyanate and subsequent
aza-Michael addition to close the ring.[10] It is worth mention-
ing that compared with the case of Pd-oxyallyl, both the
synthesis of the aminoallyl precursor and generation of the
Pd-aminoallyl intermediate have a higher atom economy
through generating significantly less byproduct.
We were pleased to find that the tailored aminoallyl
precursor could indeed participate in the (3+2) cycloaddition
with 1,3-cyclohexadiene to chemoselectively give the fused
pyrrolidine product 9a (Scheme 2, Eq. 2) without the gen-
eration of (4+3) cycloaddition (10 and 11),[11] (2+1) cyclo-
propanation (12),[8] and (3+2) carbocycle (13) products.
Similar to the Pd-oxyallyl cycloaddition,[6] triarylphosphine
ligands with weakly coordinating ortho substituents [e.g.,
methoxy (L1–L3) and ester (L5)] that can offer secondary but
reversible coordination to the palladium were also preferred
for the aminoallyl cycloaddition.[12] However, a brief compar-
ison between ligand effects for Pd-oxyallyl and -aminoallyl
cycloadditions demonstrates that while a higher number of
ortho-methoxy motifs in the phosphine ligand leads to
a higher yield for the Pd-oxyallyl cycloaddition, the efficiency
of the Pd-aminoallyl cycloaddition reaches a maximum with
phenylbis(o-methoxyphenyl)phosphine (L1) as the ligand,
and tris(o-methoxyphenyl)phosphine (L2) diminished the
yield significantly. This phenomenon can be explained by
the larger size of the aminoallyl motif compared with oxyallyl,
which would disfavor the coordination of sterically hindered
ligand (i.e., L2) to the palladium intermediate. It is also
possible that the less electronegative nature of the nitrogen
atom leads to more electronic stabilization from the amino-
allyl zwitterion to the palladium center. As a result, excess
stabilization from the coordination of the ortho-methoxy
group becomes less important.
Next, the substrate scope of the Pd-aminoallyl cyclo-
addition was explored (Scheme 3). Besides the ethyl ester
Scheme 3. Scope of the (3+2) Pd-aminoallyl cycloaddition. Unless
noted otherwise, the (3+2) cycloaddition reactions were run with
10 mol% CpPd(cinnamyl), 40 mol% L1, 0.1 mol of aminoallyl precur-
sors, and 200–300 mol% of dienes in toluene at 908C or 1108C for
12 hours (See the SI for detailed procedures). The data are reported as
yields of isolated product.
Scheme 2. (3+2) Pd-aminoallyl cycloaddition.
2
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(9a), aminoallyl precursors with a large range of ester groups,
aminoallyl precursor, the cycloaddition overrode the previous
including benzyl (9b), methyl (9c), phenyl (9d), and 9-
fluorenylmethyl (9e) esters, can all give the (3+2) cyclo-
addition products. Aromatic sulfonyl groups were found
suitable as the protecting group for the cyclic carbamate
precursor, since their corresponding isocyanates are readily
available and pyrrolidine products are generated in good
yields (9 f and 9g). However, aminoallyl precursors with
a phenyl (14) or benzoyl (15) group on the nitrogen showed
no reactivities for the cycloaddition. In addition, we also
demonstrated that the electron-withdrawing ester motif is
indispensable, since aminoallyl precursor 16 failed to give the
cycloaddition product.
(2+1) chemoselectivity[8] and proceeded exclusively at the
internal olefin, with the exo adduct as the major product (9x).
While the pyrrolidine product was formed exclusively
through the (3+2) cycloaddition, we were delighted to find
that the heterocycle adducts can be readily isomerized to
thermodynamically more stable carbocycles through palla-
dium-catalyzed [1,3] N-to-C rearrangement (Scheme 4A).[13]
1,3-Cyclohexadiene derivatives proved to be an outstand-
ing class of substrates for the (3+2) cycloaddition, since they
are easily accessible and the locked s-cis conformation of the
double bonds can facilitate the generation of the p-allyl
palladium intermediates (5, Scheme 1C; see above) with
lowered entropy of activation. In particular, terminally
substituted cyclohexadienes were shown to afford bicyclic
pyrrolidines in a chemo- and regioselective manner, with
initial addition of the Pd-aminoallyl intermediate to the less
hindered terminus. In addition, the diversity of functional
groups that can be tolerated for the cycloaddition, such as
methyl (9h), phenyl (9i), methoxy (9j), and ester (9k) groups,
enabled the synthesis of fused ring systems containing
structurally distinct olefins bearing both electron-donating
and electron-withdrawing substituents. Beside the 5-6 bicyclic
product, the 5-5 fused pyrrolidine product (9l) can also be
obtained with a cyclopentadiene substrate that exists as
a dynamic mixture of two isomers (17a and 17b), and the
cycloaddition takes place exclusively at the least hindered
olefin.
Linear dienes with a terminal aromatic ring are demon-
strated to be another prominent class of substrates for the
(3+2) cycloaddition, and the aryl substitution is proposed to
provide extra stabilization for the p-allyl palladium inter-
mediate generated after the migratory insertion of diene (5,
Scheme 1C; see above). Dienes containing functional groups
that have distinct electronic properties can all participate in
the reaction to give 2-alkylidene-5-vinyl-pyrrolidines (9m–
9s). Nevertheless, while the reaction of an oxyallyl precursor
with linear dienes was able to proceed at 908C,[6] the Pd-
aminoallyl cycloaddition requires an elevated temperature
(1108C). In addition to linear dienes with substituted phenyl
rings, dienes with other aromatic motifs, such as dibenzofuran
(9t) and naphthalene (9u), can also be accommodated in the
(3+2) cycloaddition. A linear alkyl diene with a benzyl ether
was also shown to cyclize with the aminoallyl precursor in
good yield (9v), and the protected alcohol motif could serve
as a handle for further derivatization of the adduct. Interest-
ingly, the Pd-aminoallyl cycloaddition with benzyl 2,4-penta-
dienoate, an electron-deficient diene with an ester substitu-
ent, proceeded smoothly to give the pyrrolidine product
bearing an electron-deficient vinyl group (9w). It is worth
noting that diene substrates for 9v and 9w were both inferior
for the previous Pd-oxyallyl cycloaddition, giving a low yield
of the cycloaddition product and no cycloaddition product,
respectively. When 1-vinylnorbornene was reacted with the
Scheme 4. Derivatization of pyrrolidine adducts.
The bidentate dppe ligand was found to be superior for the
isomerization reaction, presumably because it facilitates the
À
oxidative addition of the allylic C N bond in the heterocycle
(18) through a bent and less stable L2Pd(0) intermediate
compared with monodentate ligands. In addition, the
increased steric hinderance of the chelating ligand would
À
also accelerate the subsequent and irreversible C C reductive
elimination to the carbocycle 19. It was also discovered that
the exo imine double bonds of the five-membered rings
migrated during the isomerization to give cyclic and unsatu-
rated b-aminoesters (19a–c) as the final products.
Besides [1,3] N-to-C rearrangement to carbocycles, the
Pd-aminoallyl cycloaddition adducts can also be readily
converted using a variety of transformations to other
derivatives (Scheme 4B). For example, the internal olefin in
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b) J. Rigby, F. Pigge, in Organic Reactions, Vol. 51 (Eds.: L. A.
Paquette), Wiley, Hoboken, 1997, pp. 351; Selected and recent
examples of (4+3) cycloaddition of oxyallyl cation: c) J. He, Z.
Chen, W. li, K. H. Low, P. Chiu, Angew. Chem. Int. Ed. 2018, 57,
5253; Angew. Chem. 2018, 130, 5351; d) B. Lo, P. Chiu, Org. Lett.
2011, 13, 864. For examples of (4 + 3) cycloaddition of aminoallyl
cation, see Ref. [11].
9 f can be dihydroxylated (22) and hydrogenated (23) chemo-
selectively in the presence of the exo double bond. On the
other hand, the ethyl ester group can be reduced by DIBAL
to give bicyclic product 20 with an allylic alcohol motif. In
addition, treatment of the adduct with LDA was shown to
À
deprotonate the C H bond adjacent to the exo olefin and
generate an extended enolate 24,[14] which was chemoselec-
tively alkylated with 1-iodohexane to give tetrahydroindole
25 with the double bond migrated inside the heterocycle.
In summary, we have demonstrated that the use of
tailored cyclic carbamates as the aminoallyl precursor ena-
bled a catalytic and expeditious synthesis of highly-function-
alized pyrrolidines via a Pd-aminoallyl intermediate. The
(3+2) cycloaddition with conjugated dienes represents
a sharp contrast in chemoselectivity to the conventional
(4+3) cycloaddition of aminoallyl cations. Subsequent palla-
dium-catalyzed isomerization of the pyrrolidine products to
cyclic and unsaturated b-aminoesters was also developed,
along with several chemo- and diastereoselective transforma-
tions of the bicyclic pyrrolidine products. Collectively, these
new methods are expected to provide new and efficient access
to nitrogen-containing five-membered rings, which are prev-
alent in bioactive molecules.
[3] A recent review of (3+2) cycloaddition: H. Li, J. Wu, Synthesis
2015, 47, 22.
[4] Selected examples: a) R. Noyori, Y. Hayakawa, M. Funakura, H.
Takaya, S. Murai, R. Kobayashi, S. Tsutsumi, J. Am. Chem. Soc.
1972, 94, 7202; b) Y. Hayakawa, K. Yokoyama, R. Noyori, J. Am.
Chem. Soc. 1978, 100, 1791; c) R. Noyori, Acc. Chem. Res. 1979,
12, 61; d) M. C. Dipoto, R. P. Hughes, J. Wu, J. Am. Chem. Soc.
2015, 137, 14861; e) E. H. Krenske, S. He, J. Huang, Y. Du, K. N.
Houk, R. P. Hsung, J. Am. Chem. Soc. 2013, 135, 5242; f) H. Li,
R. P. Hughes, J. Wu, J. Am. Chem. Soc. 2014, 136, 6288.
[5] For a selected example using aluminium-based Lewis Acids, see:
K. Masuya, K. Domon, K. Tanino, I. Kuwajima, J. Am. Chem.
Soc. 1998, 120, 1724.
[6] B. M. Trost, Z. Huang, G. M. Murhade, Science 2018, 362, 564.
[7] Early studies of (2+1) Pd-oxyallyl cycloaddition: a) B. M. Trost,
S. Schneider, J. Am. Chem. Soc. 1989, 111, 4430; b) B. M. Trost,
H. Urabe, Tetrahedron Lett. 1990, 31, 615; c) I. Ikeda, A.
Ohsuka, K. Tani, T. Hirao, H. Kurosawa, J. Org. Chem. 1996, 61,
4971.
[8] An early study of (2+1) Pd-aminoallyl cycloaddition: K. Ohe, T.
Ishihara, N. Chatani, S. Murai, J. Am. Chem. Soc. 1990, 112, 9646.
[9] An example of Pd-allyl transfer: R. Hughes, J. Powell, J. Am.
Chem. Soc. 1972, 94, 7723.
Acknowledgements
[10] T. Yoshinao, K. Masanari, T. Shuji, K. Sigeru, Y. Zen-ichi, Bull.
Chem. Soc. Jpn. 1994, 67, 2838.
The authors thank Mr. C. Kalnmals and Dr. G. M. Murhade
for providing several synthetic intermediates.
[11] Examples of (4+3) cycloaddition of aminoallyl cation: a) J. Oh,
J. Lee, S. J. Jin, J. K. Cha, Tetrahedron Lett. 1994, 35, 3449; b) J.
Lee, J. Oh, S. J. Jin, J.-R. Choi, J. L. Atwood, J. K. Cha, J. Org.
Chem. 1994, 59, 6955; c) H. Kim, C. Ziani-Cherif, J. Oh, J. K.
Cha, J. Org. Chem. 1995, 60, 792; d) A. S. Kende, H. Huang,
Tetrahedron Lett. 1997, 38, 3353; e) G. Priꢀ, N. Prꢀvost, H. Twin,
S. A. Fernandes, J. F. Hayes, M. Shipman, Angew. Chem. Int. Ed.
2004, 43, 6517; Angew. Chem. 2004, 116, 6679.
Conflict of interest
The authors declare no conflict of interest.
[12] A recent example where an ortho methoxy group in the
phosphine ligand provides a weak coordination during palla-
dium catalysis: B. P. Fors, D. A. Watson, M. R. Biscoe, S. L.
Buchwald, J. Am. Chem. Soc. 2008, 130, 13552.
Keywords: (3+2) cycloaddition · aminoallyl · dienes ·
palladium · pyrrolidines
[13] Precedents for palladium-catalyzed [1,3] heteroatom-to-carbon
rearrangement: a) B. M. Trost, T. A. Runge, J. Am. Chem. Soc.
1981, 103, 7550; b) J. C. R. Brioche, T. A. Barker, D. J. Whatrup,
M. D. Barker, J. P. A. Harrity, Org. Lett. 2010, 12, 4832; c) S.
Murahashi, Y. Makabe, K. Kunita, J. Org. Chem. 1988, 53, 4489.
[14] An example of the generation of extended enolate in a similar
molecule: P. Langer, E. Bellur, J. Org. Chem. 2003, 68, 9742.
[1] Selected reviews of oxyallyl and aminoallyl cations: a) J. Mann,
Tetrahedron 1986, 42, 4611; b) M. Harmata, Chem. Commun.
2010, 46, 8886; c) H. M. R. Hoffmann, Angew. Chem. Int. Ed.
Engl. 1984, 23, 1; Angew. Chem. 1984, 96, 29; d) R. Noyori, Y.
Hayakawa, Org. React. 1983, 29, 163; e) M. Harmata, Tetrahe-
dron 2003, 59, 2371.
[2] Selected reviews of (4+3) cycloaddition: a) A. Hosomi, Y.
Tominaga, in Comprehensive Organic Synthesis, Vol. 5 (Eds.:
B. M. Trost, I. Fleming), Pergamon Press, Oxford, 1991, pp. 593;
Manuscript received: January 17, 2019
Version of record online: && &&, &&&&
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Communications
Homogeneous Catalysis
B. M. Trost,* Z. Huang
&&&& — &&&&
Catalytic (3+2) Palladium-Aminoallyl
Cycloaddition with Conjugated Dienes
New tailored precursors are shown to
enable the catalytic synthesis of fused or
highly substituted pyrrolidine rings
through a (3+2) Pd-aminoallyl cycload-
dition with conjugated dienes that over-
rides the conventional (4+3) chemose-
lectivity of aminoallyl cations. Rearrange-
ment of the pyrrolidine rings to carbo-
cycles is also demonstrated using a dif-
ferent palladium catalyst.
Angew. Chem. Int. Ed. 2019, 58, 1 – 5
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