Rhodium-Catalyzed Asymmetric Intramolecular Hydroamination of Allenes

Article abstract of DOI:10.1002/anie.201904833

The rhodium-catalyzed asymmetric intramolecular hydroamination of sulfonyl amides with terminal allenes is reported. It provides selective access to 5- and 6-membered N-heterocycles, scaffolds found in a large range of different bioactive compounds. Moreover, gram scale reactions, as well as the application of suitable product transformations to natural products and key intermediates thereof are demonstrated.

Full text of DOI:10.1002/anie.201904833

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Accepted Article
Title: Rhodium-Catalyzed Asymmetric Intramolecular Hydroamination
of Allenes
Authors: Bernhard Breit, Dino Berthold, Arne Geissler, and Sabrina
Giofré
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904833
Angew. Chem. 10.1002/ange.201904833
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10.1002/anie.201904833
Angewandte Chemie International Edition
COMMUNICATION
Rhodium-Catalyzed Asymmetric Intramolecular Hydroamination
of Allenes
Dino Berthold, Arne G. A. Geissler, Sabrina Giofré and Bernhard Breit*
Abstract: The rhodium-catalyzed asymmetric intramolecular
hydroamination of sulfonyl amides with terminal allenes is reported.
It provides selective access to 5- and 6-membered N-heterocycles,
scaffolds found in a large range of different bioactive compounds.
Moreover, gram scale reactions, as well as the application of
suitable product transformations to natural products and key
intermediates thereof are demonstrated.
Widenhoefer and Liu utilized chiral AuI-complexes and chiral
Brønstedt acids for the asymmetric addition of amides and
amines to internal allenes. Unfortunately, these reactions are
limited to rather special substrate classes.[7,8]
Throughout the last years, we reported on a series of
rhodium-catalyzed chemo-, regio- and enantioselective coupling
10]
reactions involving allenes[9,
and alkynes[11] with various
pronucleophiles, thus establishing an atom efficient alternative to
the classic allylic substitution. Especially in light of our previously
reported diastereoselective addition of tosylated carbamates[10a]
and tosylated amides[10e], we envisioned that a suitable chiral
catalyst might be able to realize an intramolecular,
enantioselective hydroamination of alkynes or allenes (Scheme
2).
Nitrogen-containing heterocycles are core scaffolds in many
bioactive and functional molecules. In particular, pyrrolidines and
piperidines bearing an α-chiral carbon center are important
structural motives in natural products (Peripentadenine and
Peripentonines), pharmaceuticals (Tacrolimus) and as chiral
ligands (Sparteine) (Scheme 1).[1]
Previous work:
H
N
a) Yamamoto[6]
OH
O
O
MeO
HO
R
H
Pd, dppf, AcOH
N
O
R
N
N
•
R
n
H
R = Ts, Bn, Tf
n = 1-2
n
H
N
O
O
racemic
O
Peripentadenine
Peripentonine B, C
O
b) Toste, Widenhoefer and others[7]
R2 R2
R1
N
OMe
H
N
O
N
Au, BIPHEP ligands, AgX
H
R1HN
R3
n
R3
HO
•
R1 = Ts, Cbz, Mes; R2 = H, Me, Ph;
R3 ≠ H; X = ClO4-, BF4-, (BINOL)PO2
n = 1-2
R2
R2
n
OMe
H
R3
-
R3
c) our previous work[10a, 10e]
Tacrolimus
(-)-Sparteine
Scheme 1. Bioactive and functional compounds possessing an α-chiral N-
heterocyclic scaffold.
syn: Rh, dppf, acid
anti: Pd, dppf, acid
Rh, DPEphos, acid
syn or anti selective
O
O
Y
X
NHTs
•
O
NTs
NTs
X = O, Y = C(O)
R = Ar, aliphatic
X = CH2, Y = CO
R = Ar, aliphatic
R
R
R
For this reason, several asymmetric methods, like allylic
This work:
R1
N
R2
substitution,[2]
allylic
oxidation[3]
and
nucleophilic
Rh, L*, TFA/PPTS
R1 = Ts, Ns, Mbs;
R2
H
R1
N
Y
R3
•
R3
substitution/addition[4] have been disclosed for the preparation of
these branched, α-chiral N-heterocyclic compounds. However,
these approaches come along with limitations with regard to the
requirement of stoichiometric amounts of a leaving group or an
oxidant, thus rendering these synthesis economically
unattractive. Thus, a more atom efficient[5] pathway involving a
X
S
O2
X
n
Y
n
R3
enantioselective
R3
X = CH2, CO, etc.; Y = O, NPMP, etc.;
R2 = H, Me; R3 = H, Me
n = 1-2
Scheme 2. Strategies for the synthesis of chiral, α-vinylated N-heterocycles.
Ns = p-NO2-C6H4-SO2; Mbs = p-MeO-C6H4-SO2.
transition
metal
catalyzed,
intramolecular
hydroamination/cyclization of C–C multiple bonds is of greater
interest. In this respect, various groups contributed to the field of
hydroamination of alkynes and allenes. Beginning in 1998,
Yamamoto and co-workers introduced sulfonyl amides as
suitable pronucleophiles for the Pd-catalyzed intramolecular
addition to alkynes and allenes.[6] More recently, Toste,
We herein disclose the development of a rhodium-catalyzed
intramolecular and enantioselective hydroamination of allenyl
sulfonyl amides, providing the desired N-heterocyclic products
without structural limitations.[12]
Initial reactivity assays were carried out using N-(hexa-4,5-
dien-1-yl)tosylamide (1a) in the presence of [{Rh(cod)Cl}2] (2.0
mol%), dppf (L1) (5.0 mol%) and PPTS (10 mol%) in DCE at
60 °C (Table 1, entry 1). To our delight, we already obtained the
allylated pyrrolidine 2a in a promising yield of 58%. This result
encouraged us to screen numerous chiral bidentate ligands.[13]
We were pleased to find that JosPOphos ligand J688-1 (L2)
furnished the desired product in a low yield (28%) but in a
promising enantioselectivity (77% ee) (entry 2).
[*]
D. Berthold, A. G. A. Geissler, S. Giofré and B. Breit
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg
Albertstr. 21, 79104 Freiburg im Breisgau (Germany)
Email: bernhard.breit@chemie.uni-freiburg.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201904833
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COMMUNICATION
Table 1. Rhodium-catalyzed intramolecular, enantioselective addition of
structure analysis of Ns-substituted pyrrolidine 2c. Next, we
were interested if substitutions on the alkyl chain or allene affect
the outcome of the reaction. For this, two geminal disubstituted
substrates were tested, both of them gave the desired products
2e and 2f in high yield and ee. Employing an already chiral
substrate we were pleased to see that by employing ligand L5 or
ent-L5 both diastereomers 2g and 2h were obtained in high
yield and diastereoselectivity. Next, we examined the suitability
of higher substituted allenes, which are prone for facile
isomerization to the corresponding diene, as reaction partners.
In this respect, both 3,3-disubstituted pyrrolidine 2i and 1,1-
disubstituted pyrrolidine 2j were obtained in moderate to very
good yields and high enantioselectivities.[16] As expected, an
amide also reacted smoothly to the γ-lactam 2k. Finally, we
were interested in ring-closing reactions of Ph-substituted
allenes and internal alkynes, since the latter ones were already
exploited in the past.[13] Remarkably, isoindoline 2l was obtained
for both substrates in great enantioselectivity, albeit the yield for
tosylamides to allenes.[a]
O
P(tBu)2
[{Rh(cod)Cl}2] (2.0 mol%)
ligand (5.0 mol%)
additive (10 mol%)
P
H
Fe
R
Ts
N
TsHN
•
n
solvent (0.4 M), 60 °C, 18 h
n
R = Ph: J688-1 (L2)
R = 3,5-DiMe-Ph: L3
R = 4-CF3-Ph: L4
R = 4-MeO-Ph: L5
n = 1: 1a
n = 2: 1b
n = 1: 2a
n = 2: 2b
Yield
Entry
n
Ligand
Additive
Solvent
ee [%][c]
[%][b]
1
2
1
1
1
1
1
1
1
2
2
L1
L2
L3
L4
L5
L5
L5
L5
L5
PPTS
PPTS
PPTS
PPTS
PPTS
TFA
DCE
DCE
58%
28%
27%
35%
47%
63%
91%
42%
89%
rac
77%
78%
77%
88%
91%
94%
79%
90%
3
DCE
4
DCE
the internal alkyne derived product was only 56%
– in
comparison to 89% for the allene – owing to the low reaction
temperature of 60 °C.[17]
5
DCE
6[d]
7[e]
8[e]
9[f]
DCE
[{Rh(cod)Cl}2] (2.0 mol%)
NHR1
TFA
CH2Cl2
CH2Cl2
DCE
p-MeO-J688-1 (L5) (5.0 mol%)
R2
NR1 R3
additive (10 mol%)
TFA
R3
R3
solvent (0.2 M), T, 12 h
•
R2
R3
PPTS
1a-q
2a-q
5-membered rings[a]
[a] Reactions were performed in 0.4 mmol scales. [b] Yield of isolated product.
[c] The ee was determined by HPLC analysis using a chiral stationary phase.
[d] 10 mol% of TFA were used. [e] Concentration was 0.2 M. [f] Reaction was
performed with 10 mol% of PPTS at a concentration of 0.2 M at 80 °C.
Ts
N
Ns
N
Mbs
N
2a
2c
2d
X-ray
91%, 94% ee
75%, 91% ee
97%, 93% ee
Ts
N
Ts
N
Ts
N
Ts
N
Evaluation of different members of the JosPOphos ligand
family, which we recently introduced for the rhodium-catalyzed
allylation of triazoles,[14c] we found that neither more sterically
demanding ligand L3 nor electron-poor ligand L4 resulted in
higher yields and enantioselectivities (entry 3 and 4). However,
the electron-rich ligand L5 provided the desired product 2a in
significantly higher yield (47%) together with an improved
enantioselectivity (entry 5). We were pleased to observe that by
using TFA (10 mol%) instead of PPTS (10 mol%) as an additive
the yield and enantioselectivity increased even further (63%,
91% ee) (entry 6). Finally, by changing the solvent to CH2Cl2
and lowering the concentration to 0.2 M we obtained the desired
5-membered product 2a in excellent yield and enantioselectivity
(91%, 94% ee) (entry 7). Regrettably, these optimized conditions
were not suitable for the conversion of N-(hepta-5,6-dien-1-
yl)tosylamide (1b) to piperidine 2b, since the latter was obtained
in only 42% yield and with 79% ee. However, we were pleased
to observe that our initial conditions (entry 5) at a slightly higher
temperature of 80 °C proved satisfactory (89%, 90% ee) (entry
9).[15]
2e
2f
2g
2h
90%, dr = 13:1[b]
85%, 91% ee
91%, 93% ee
92%, dr = 13:1
Ts
N
Ts
N
Ts
N
O
NTs
Me
2l
2i
2j
2k
89%, 94% ee
56%, 92% ee[c]
86%, 97% ee
95%, 94% ee
52%, 91% ee
6-membered rings[b]
Ts
N
Ts
N
NTs
2b
2m
2n
89%, 90% ee
69%, 93% ee
87%, 92% ee
O
O
Ts
N
O
NTs
PMPN
NTs
O
2o
2p
83%, 85% ee
2q
71%, 86% ee
71 %, 81% ee
Scheme 3. Scope of intramolecular hydroamination of allenes. [a]
[{Rh(cod)Cl}2] (2.0 mol%), L5 (5.0 mol%), TFA (10 mol%), CH2Cl2 (0.2 M),
60 °C, 12 h; [b] [{Rh(cod)Cl}2] (2.0 mol%), L5 (5.0 mol%), PPTS (10 mol%),
DCE (0.2 M), 80 °C, 12 h. Ns = p-NO2-C6H4-SO2; Mbs = p-MeO-C6H4-SO2.
The substrate scope was examined utilizing the optimized
reaction conditions for the synthesis of pyrrolidines and
piperidines. Starting with the scope of 5-membered rings we
were delighted to see that efficient and enantioselective coupling
reactions did not only occur with Tosyl substituted amines but
also with Nosyl and Mbs substitution. At this point the absolute
configuration could be determined by means of a X-ray crystal
With these results in hand, we sought to examine the scope
of 6-membered N-heterocycles. Beside piperidine 2b, we also
obtained the tetrahydroisoquinoline 2m and tetrahydroquinoline
2n in good yields and very good enantioselectivities. Both
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10.1002/anie.201904833
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COMMUNICATION
H2
N
substrates might serve as valuable building blocks for natural
product synthesis.[18] As an example for substitution of the alkyl
chain by a heteroatom, 1,4-benzoxazine 2o was prepared in
good yields and a slightly lower enantioselectivity. Finally, we
obtained the synthetically valuable carbamate 2p and urethane
2q in very good yields along with high enantioselectivities.[19,20]
Cl
H
N
.
(+)-coniine HCl
(80%, 3 steps)
Cl
.
(+)-coniceine HCl
(54%, 3 steps)
b)
d)
R
N
H
N
Ts
N
Inspired by these synthetic possibilities, this new
intramolecular allylation was applied to the syntheses of different
natural products and key intermediates. By using both
substrates for pyrrolidine 1a and piperidine 1b in the previously
described rhodium-catalyzed coupling, we could synthesize ent-
2a and 2b in gram quantities in a straightforward fashion.
c)
OH
d)
OH
R = Ts: 2b
4
(-)-pipecolinol
(93%, 2 steps)
a)
R = Boc: 3
Ts
N
Ts
N
5
e)
OH
Ts-(-)-homoproline
60% (2 steps)
O
ent-2a
Ts
N
a)
TsHN
Scheme 5. Various functionalizations of allylated N-heterocycles ent-2a and
2b. Reagents and conditions: a) 1. Mg powder (5.0 eq), ultrasonification,
MeOH/THF (2.5:1, 0.1 M), rt, 3 h; 2. Boc2O (1.2 eq), K2CO3 (2.0 eq), CH2Cl2
(0.3 M), rt, 12 h, 79% (2 steps). b) 1. Grubbs II (10 mol%), 2-butene (167 eq),
neat, 40 °C, 24 h, 89%, 91% ee; 2. Pd/C (10 w.%, 10 mol%), H2 (1 atm),
MeOH (0.2 M), rt, 92%; 3. Na (6.0 eq), naphthalene (5.0 eq), THF (0.1 M), –
78 °C, 2 h, 98%. c) 1. O3, CH2Cl2/MeOH (1:1, 0.1 M), –78 °C; then NaBH4 (3.0
eq), –78 °C - rt, 2 h, 96%, 91% ee; 2. Na (6.0 eq), naphthalene (5.0 eq), THF
(0.1 M), –78 °C, 2 h, 92%. d) 1. [Rh(CO)2acac] (0.50 mol%), 6-DPPon (5.0
mol%), L6 (5.0 mol%), CO/H2 (1:1, 20 bar), toluene (0.25 M), 80 °C, 72 h, 84%,
91% ee; 2. Na (6.0 eq), naphthalene (5.0 eq), THF (0.1 M), –78 °C, 2 h, then I2
(3.0 eq), PPh3 (3.0 eq), imidazole (3.0 eq), CH2Cl2 (0.05 M), 0 °C - rt, 6 h, 59%.
e) 1. 9-BBN (1.1 eq), THF (0.5 M), 0 °C - rt, 4 h; then NaOH sol. (2.0 M), H2O2,
0 °C - rt, 2 h, 85%, 90% ee; 2. CrO3 (2.2 eq), H2SO4 (4.2 eq), acetone/H2O
(2:1, 0.15 M), 0 °C - rt, 2 h, 91%. 6-DPPon = 6-diphenylphosphinopyridin-2-
(1H)-one.
•
1a
1.25 g,
5.00 mmol
ent-2a
81%, 90% ee
Ts
N
b)
•
TsHN
1b
1.33 g,
5.00 mmol
2b
71%, 91% ee
Scheme 4. Gram-scale catalysis. Reagents and conditions: a) [{Rh(cod)Cl}2]
(2.0 mol%), ent-L5 (5.0 mol%), TFA (10 mol%), CH2Cl2 (0.2 M), 60 °C, 18 h;
81%, 90% ee. b) [{Rh(cod)Cl}2] (2.0 mol%), L5 (5.0 mol%), PPTS (10 mol%),
DCE (0.2 M), 80 °C, 18 h; 71%, 91% ee.
To explore the synthetic utility of allylated 5- and 6-
membered N-heterocycles, we subjected ent-2a and 2b to
various transformations. On one hand, we demonstrated the
utility of the tosyl group as an activating protection group of the
amine by cleaving it under reductive conditions and introducing
a Boc protection group. Piperidine 3 represents, for instance, a
key intermediate for the total synthesis of aloperine.[21] On the
other hand, the olefin moiety could be functionalized by
metathesis and subsequent hydrogenation and deprotection to
yield (+)-coniine•HCl in an overall yield of 80%. Moreover, C1
cleavage by ozonolysis of 2b and cleavage of the tosyl group
provided (–)-pipecolinol, a common starting material in alkaloid
syntheses.[22] Tandem hydroformylation/hydrogenation of the
terminal alkene, using our supramolecular catalyst system,[23]
furnished alcohol 4 in high yield (84%) and with an excellent
linear/branched selectivity (95:5). After deprotection of the tosyl
group and ring closure under Mukaiyama redox condensation
conditions (+)-coniceine•HCl was obtained as a colourless solid.
Finally, by hydroboration and subsequent oxidation we obtained
tosylated (–)-homoproline (5), which is, for instance, a valuable
intermediate in glycoheterocylic chemistry.[24]
In summary, we have accomplished an enantioselective,
intramolecular addition of sulfonyl amides to allenes in an atom
efficient manner by using a rhodium/JosPOphos catalyst system.
α-Chiral α-vinyl-substituted pyrrolidines and piperidines were
obtained in high yields and high stereoselectivities tolerating a
broad range of sulfonyl amides and differently substituted
allenes. Moreover, several N-heterocycles including a lactam
were accessed in high yields alongside with high
enantioselectivities. Furthermore, we presented synthetic
possibilities for either deprotection and introduction of an
orthogonal protection group, or, alternatively, the elaboration of
the allylic moiety enabling the straightforward synthesis of
alkaloid natural products and intermediates thereof. Further
studies on extending this strategic approach of intramolecular
allylation of allenes and alkynes with different pronucleophiles,
as well as their application in target-oriented synthesis, are
ongoing in our laboratories.
Acknowledgements
This work was supported by the DFG. Moritz Benka is
acknowledged for extended preliminary studies. Monika
Lutterbeck is thanked for her technical support during ligand
synthesis. We thank Dr. Daniel Kratzert for X-ray crystal
structure analysis and Dr. Manfred Keller for NMR analysis
concerning the reaction mechanism.
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10.1002/anie.201904833
Angewandte Chemie International Edition
COMMUNICATION
23, 6531 - 6534; d) Y. Zhou, B. Breit, Chem. Eur. J. 2017, 23, 18156 -
18160; e) J. P. Schmidt, B. Breit Chem. Sci. 2019, 10, 3074 - 3079.
[11] For a recent review, see: A. Haydl, B. Breit, T. Liang, M. J. Krische,
Angew. Chem. 2017, 129, 11466 - 11480; Angew. Chem. Int. Ed. 2017,
56, 11312 - 11325.
Keywords: allenes • heterocycles • allylic products • asymmetric
catalysis • rhodium
[1]
a) J. P. Michael, The Alkaloids: Chemistry and Biology 2016, 75, 1 -
498; b) P. L. Katavic, D. A. Venables, G. P. Guymer, P. I. Forster, A. R.
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[12] For the screening of different protecting groups and the free amine
under racemic conditions, see supporting information.
[13] For ligand screening, see supporting information.
[14] a) Q.-A. Chen, Z. Chen, V. M. Dong, J. Am. Chem. Soc. 2015, 137,
8392 - 8395; b) A. M. Haydl, L. J. Hilpert, B. Breit, Chem. Eur. J. 2016,
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Chem. 2016, 55, 8440 - 8443; e) T. M. Beck, B. Breit, Eur. J. Org.
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Chem. 2017, 129, 8542 - 8545; Angew. Chem. Int. Ed. 2017, 56, 8422 -
8425.
[2]
For examples of asymmetric allylic substitution, see: Ru-catalyzed: K.
Miyata, H. Kutsuna, S. Kawakami, M. Kitamura, Angew. Chem. Int. Ed.
2011, 50, 4649
- 4653; Pd-catalyzed: a) L. E. Overman, T. P.
Remarchuk, J. Am. Chem. Soc. 2002, 124, 12 - 13; b) O. Hara, T.
Koshizawa, K. Makino, I. Kunimune, A. Nimini, Y. Hamada,
Tetrahedron 2007, 63, 6170 - 6181; c) B. Olzsewska, B. Kryczka, A.
Zawis, Tetrahedron 2013, 69, 9551 - 9556; Ir-catalyzed: a) C. Welter, O.
Koch, G. Lipowsky, G. Helmchen. Chem. Commun. 2004, 896 - 897; b)
C. Welter, A. Dahnz, B. Brunner, S. Streiff, P. Dübon, G. Helmchen,
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Taquet, G. Helmchen, Angew. Chem. Int. Ed. 2008, 47, 7652; d) J. F.
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Carreira, Org. Lett. 2017, 19, 3235 - 3238.
[15] For reaction optimization, see supporting information.
[16] Hydroamination of 1,3-disubstituted internal allenes were not
successful under these reaction conditions, since the products were
only obtained in poor yield and enantioselectivity.
[17] Hydroamination of other internal alkynes were not successful under
these reaction conditions, since the products were only obtained in low
yield and enantioselectivity.
[18] G. D. Muñoz, G. B. Dudley, Org. Prep. Proced. Int. 2015, 47, 179 - 206.
[19] Intramolecular hydroamination of substrates leading either to 4- or 7-
membered heterocyles were not successful, except for the 7-
membered product 2r, which was obtained in 38% and 84% ee
applying the conditions for the piperidene cyclizations.
[3]
[4]
R. I. McDonald, P. B. White, A. B. Weinstein, C. P. Tam, S. S. Stahl,
Org. Lett. 2011, 13, 2830 - 2833.
a) Y. Kuroda, S. Harada, A. Oonishi, Y. Yamaoka, K. i. Yamada, K.
Takasu, Angew. Chem. 2015, 127, 8381 - 8384; Angew. Chem. Int. Ed.
2015, 54, 8263 - 8266; b) T. Azuma, A. Murata, Y. Kobayashi, T.
Inokuma, Y. Takemoto, Org. Lett. 2014, 16, 4256 - 4259.
[{Rh(cod)Cl}2] (2.0 mol%)
Ts
NHTs
O
L5 (5.0 mol%)
PPTS (10 mol%)
N
[5]
[6]
B. M. Trost, Science 1991, 254, 1471 - 1477.
a) M. Meguro, Y. Yamamoto, Tetrahedron Lett. 1998, 39, 5421 - 5424;
b) L. M. Luete, I. Kadota, Y. Yamamoto, J. Am. Chem. Soc. 2004, 126,
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2754.
•
DCE (0.2 M), 80 °C, 12 h
O
2r
38%, 84% ee
1r
[20] For deuterium labelling experiments, in-situ NMR-monitoring and
general mechanistic details, see supporting information.
[7]
For gold-catalyzed intramolecular hydroamination of special classes of
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In this work the ligand L6 was used:
H
N
HN
P(p-MeO-C6H4)2
N
H
H2N
O
L6
[8]
[9]
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10.1002/anie.201904833
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Dino Berthold, Arne G. A. Geissler,
Sabrina Giofré and Bernhard Breit*
O
O
R1
NHTs
RhI
O
S
O
R1
S
NH
R2
O
P
•
N
P(tBu)2
H
Fe
R2
•
Page No. – Page No.
MeO
R2
R2
Rhodium-Catalyzed Asymmetric
Intramolecular Hydroamination of
Allenes
Aliphatic, Aromatic, Heterocyclic
R1 = C6H4Me, C6H4NO2, C6H4OMe
R2 = H, Me
5- and 6-membered Rings
up to 97% yield
up to 94% ee
The rhodium-catalyzed asymmetric intramolecular hydroamination of sulfonyl
amides with terminal allenes is described furnishing enantioselective access to 5-
and 6-membered N-heterocycles, scaffolds found in a wide variety of bioactive
molecules. Moreover, gram scale reactions, as well as the application of suitable
product transformation to natural products or key intermediates thereof are
demonstrated.
This article is protected by copyright. All rights reserved.