Enantioselective Hydroaminomethylation of Olefins Enabled by Rh/Br?nsted Acid Relay Catalysis

Article abstract of DOI:10.1021/acs.orglett.7b00100

Herein, by employing a rhodium catalyst with a commercial ligand and a phosphoric acid catalyst, highly chemo-, regio-, and enantioselective hydroaminomethylation of olefins is realized through a relay catalytic hydroformylation/dynamic kinetic reductive amination process. The method features mild conditions (1 bar of syngas, room temperature in most cases), high yields (up to 99%), and high enantioselectivities (up to >99.5:0.5 er). Besides styrenes, acrylamides also provided the products with high yields and enantioselectivities. Aliphatic alkenes and vinyl esters are also applicable for the current method, albeit lower yields and enantioselectivities were obtained.

Full text of DOI:10.1021/acs.orglett.7b00100

Letter
pubs.acs.org/OrgLett
Enantioselective Hydroaminomethylation of Olefins Enabled by Rh/
Brønsted Acid Relay Catalysis
§
§
Jing Meng, Xing-Han Li, and Zhi-Yong Han*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
*
S Supporting Information
ABSTRACT: Herein, by employing a rhodium catalyst with a
commercial ligand and a phosphoric acid catalyst, highly chemo-,
regio-, and enantioselective hydroaminomethylation of olefins is
realized through a relay catalytic hydroformylation/dynamic kinetic
reductive amination process. The method features mild conditions
(
1 bar of syngas, room temperature in most cases), high yields (up
to 99%), and high enantioselectivities (up to >99.5:0.5 er). Besides styrenes, acrylamides also provided the products with high
yields and enantioselectivities. Aliphatic alkenes and vinyl esters are also applicable for the current method, albeit lower yields and
enantioselectivities were obtained.
ydroaminomethylation (HAM), a triple sequential reac-
tion consisting of hydroformylation of an alkene,
Rhodium complexes are able to catalyze both hydro-
H
formylation and hydrogenation reactions and are thus often
6
condensation of the generated aldehyde with an amine, and the
reduction of the resulting imine or enamine, provides a highly
efficient and atom-economical method to synthesize amines from
used for HAM. In a recent publication from Urrutigoit
̈
y, Maron,
and Kalck, a series of chiral diphosphine ligands were tested in the
rhodium-catalyzed HAM of styrene and found to be completely
unable to introduce any enantioselectivity, though excellent
1
alkenes,carbonmonoxide, andhydrogengas. Sincethediscovery
2
of HAM in the 1940s by Reppe, tremendous efforts have been
chemo- and regio-selectivities were often obtained (Scheme
devotedtoimprovethechemo-andregio-selectivity, aswellasthe
4a
2
a). Zhang and co-workers very recently developed a rhodium-
3
overall efficiency of the reaction. However, the development of
catalyzed asymmetric intramolecular interrupted hydroamino-
asymmetric HAM of olefins remained uncharted territory for a
long time, despite the significant impact such reactions would
Scheme 2. Asymmetric Hydroaminomethylation of Alkenes
have on academic research and the fine chemicals industry
4
(
Scheme 1a). Asymmetric HAM of alkenes may also provide
unique and straightforward approaches to access a large number
of bioactive compounds, drugs, and natural products, as
5
exemplified in Scheme 1b.
Scheme1. AsymmetricHydroaminomethylationandPotential
Synthetic Applications
Received: January 11, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00100
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
7
a
methylation using allylamine substrates. While transition metal-
catalyzed direct asymmetric HAM encountered difficulties, a
metal/organo relay catalytic strategy could provide an alternative
way (Scheme 2b). This pathway consists of several consecutive
processes: (1) rhodium-catalyzed selective hydroformylation of
alkenes to generate α-branched aldehydes; (2) formation of
imines; (3) chiral Brønsted acid-catalyzed dynamic kinetic
Table 1. Optimization of Catalysts and Reaction Conditions
8
−10
reduction of imines to produce the chiral amines.
Very
recently, during the course of our current research project, Xiao
and co-workers applied this strategy for the asymmetric HAM of
1
1
styrenes. However, the transformation required harsh con-
ditions (11 bar syngas) and showed unsatisfying enantioselectiv-
ities (most examples <95:5 er) and limited olefin scope (styrenes
only).
Herein, as a continuation of our research in asymmetric metal/
12,13
organo combined catalysis,
we report a highly enantiose-
lective HAM of olefins employing a rhodium catalyst with a
commercial ligand and a phosphoric acid catalyst. The trans-
formation shows a broad substrate scope toward diversely
substituted chiral amines with up to 99% yields and up to
b
c
entry
L
CPA
5a
temp (°C) time (h) yield (%)
er
1
L1
50
50
50
50
50
50
50
50
40
25
25
25
25
16
16
16
16
16
16
16
72
72
72
72
72
72
50
34
30
61
trace
24
18
65
66
60
95.5:4.5
95:5
9
9.5:0.5 er under mild conditions (Scheme 2c).
2
L1
5b
ent-5b
5c
Ourinvestigation initiatedwith styrene1aandp-anisidine2aas
3
L1
7:93
t
the model substrates, Bu-HEH 4a as the hydrogen source (Table
4
L1
94.5:5.5
1). Rhodium complexes were chosen as the hydroformylation
5
L1
5d
5a
catalysts because of their excellent performance in alkene
hydroformylations. The hydroformylation step should be highly
branch-selective to avoid the formation of linear amines. Also,
highly active hydroformylation catalyst is needed because the
subsequent asymmetric hydrogen transfer process often requires
much milder conditions. Among numerous ligands for rhodium
catalyzed hydroformylation, commercially available (R,R)-Ph-
BPE L1 was selected due to its high activity, excellent branch-
6
L2
95:5
7
L3
5a
94.5:5.5
96:4
8
L1
5a
9
L1
5a
96.5:3.5
97:3
10
L1
5a
d
f
11
L1
5a
89 (81 )
96.5:3.5
96.5:3.5
96.5:3.5
d
,
,
e
e
f
12
13
L1
5a
--(83 )
d
f
ent-L1
5a
--(82 )
14
a
selectivity, and easy accessibility. Racemic L1 was not employed
Unless indicated otherwise, the reaction was carried out under CO/
H (1:1, 2 bar) atmosphere in the scale of 1a (0.3 mmol), 2a (0.2
(0.004 mmol), ligand (0.0048
mmol), chiral phosphoric acid (0.01 mmol), and 5 Å molecular sieve
200 mg) in toluene (2.0 mL). NMR yield with trimethylbenzene-
,3,5-tricarboxylate as the internal standard. Determined by chiral
HPLC. Toluene (1.0 mL). CO/H (1 bar, 1:1). Isolated yield.
directly because it is not commercially available. In addition,
2
(S,S)-L1 almost provided identical results as shown later. In the
mmol), 4a (0.3 mmol), Rh(acac)(CO)
2
beginning, aseriesofchiralphosphoricacidswereexaminedinthe
presence of Rh/L1 at 50 °C (entries 1−5). Compound 5a was
identified as the optimal chiral acid catalyst in regard to the
enantioselectivity (entry 1). Notably, ent-5b provided ent-3a as
the major enantiomer, indicating that the enantioselectivity of the
reaction is controlled by chiral phosphoric acid. Other ligands, L2
and L3, which have been previously used in the hydroformylation
of alkenes, gave significantly inferior yields under identical
conditions (entries 6−7). A prolonged reaction time facilitated
the reaction to 65% NMR yield and 96:4 er (entries 7−8).
Lowering the reaction temperature (entries 9−10) to room
temperature could slightly increase the enantioselectivity without
considerable loss of yield (entry 10). Performing the reaction at a
higher concentration greatly increased the NMR yield to 89%
with 81% isolated yield (entry 11). By lowering the pressure of
syngas from 2 to 1 bar, a slightly higher isolated yield could be
obtained (entry 12). As mentioned previously, (S,S)-Ph-BPE
provided almost identical results, supporting the speculation that
the in situ generated α-branched aldehyde could undergo a fast
racemization in the presence of the amine and acid catalyst via an
imine/enamine tautomerization (entry 13).
b
(
1
c
d
e
f
2
worthy, ortho-substituted styrenes, which gave lower yields in a
1
1
previous report, were also well tolerated, providing the
corresponding chiral amines in 73%−99% yields and excellent
enantioselectivities (3ba−3da). Interestingly, styrenes bearing
strong electron-withdrawing groups, 2,3,4,5,6-pentafluorostyr-
ene and 3,5-bis(trifluoromethyl)styrene, are also suitable
substrates for this method (3ja and 3ka). Heteroaromatic
systems (e.g., 3na) could be employed as well. As for the amine
component, while the enantiomeric ratios remain high, electron-
rich anilines resulted in the best yields (3md, 3me) but electron-
deficient anilines only gave low yields (3mb, 3mc). This is likely
because of inefficient condensation between electron-deficient
anilines and in situ generated aldehyde.
Besides styrenes, we also employed other alkenes using current
method (Table 2). Alkyl alkenes, 1o and 1p, although with lower
yields and enantiomeric ratios, can also be employed in the relay
catalytic reaction. Interestingly, acrylamides, 1q and 1r, under-
went the reactions smoothly, giving β-amino amides 3pa and 3qa
in high yields with high enantiomeric ratio. Vinyl ester 1s was also
tolerated, providing chiral 2-amino alcohol 3sa with moderate
yield and enantiomeric ratio.
With the established optimal reaction conditions (Table 1,
entry 12), we continued to explore the substrate scope of the
method (Scheme 3 and Table 2). Because the p-methoxyphenyl
groupcouldberemovedconvenientlybyoxidation, p-anisidine2a
was generally employed as the amine component. In general, high
yields and with excellent enantioselectivities could be obtained
with a broad series of styrene derivatives (3aa−3na). Note-
An example for the synthetic utility of chiral amine 3aa was
shown below (eq 1). Through a protection, oxidation, and
B
DOI: 10.1021/acs.orglett.7b00100
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope of Styrene Derivatives and
Aromatic Amine
Table 2. Asymmetric HAM of Nonaromatic Alkenes
a
a
Reaction conditions: reaction of 1 (0.3 mmol), 2 (0.2 mmol), 5a
t
(0.01 mmol), (R,R)-Ph-BPE (0.0048 mmol), Bu-HEH (0.3 mmol),
Rh(acac)(CO) (0.004 mmol) 5 Å MS (200 mg), CO/H (1 bar,1:1)
2
2
were carried out in toluene (1 mL).
the expansion of the substrate scope and development of related
transformations are underway and will be reported in due course.
ASSOCIATED CONTENT
Supporting Information
■
*
S
a
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b00100.
Reaction conditions: reaction of 1 (0.3 mmol), 2 (0.2 mmol), 5a
t
(
0.01 mmol), (R,R)-Ph-BPE (0.0048 mmol), Bu-HEH (0.3 mmol),
Rh(acac)(CO) (0.004 mmol) 5 Å MS (200 mg), CO/H (1 bar,1:1)
were carried out in toluene (1 mL) at 25 °C for 72 h.
2
2
Complete description of methods and additional results;
spectroscopic data for all new compounds 3 and 4 (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: hanzy2014@ustc.edu.cn.
ORCID
Zhi-Yong Han: 0000-0002-9225-5064
deprotection sequence, compound 4 could be obtained with no
enantiomeric loss. Optically pure primary amine 4, which was
prepared by chiral resolution therein, has been employed as a key
intermediate in the development of a large number of bioactive
Author Contributions
§
These authors contributed equally.
Notes
5a,15
compounds and pharmaceuticals.
The authors declare no competing financial interest.
In summary, we have developed a highly enantioselective
hydroaminomethylation of olefins by employing a rhodium
catalyst with a commercial ligand and a phosphoric acid catalyst.
The relay catalytic reaction consists of a rhodium-catalyzed
hydroformylation step and Brønsted acid catalyzed subsequent
dynamic kinetic reductive amination process. The salient features
of this reaction include mild conditions (1 atm of syngas, room
temperature in most cases), high yields (up to 99%), and high
enantioselectivities (up to >99.5:0.5 er). Besides styrenes, other
olefins, including aliphatic alkenes, acrylamides, and vinyl esters
can also undergo this transformation. Further studies regarding
ACKNOWLEDGMENTS
We are grateful for financial support from the NSFC (21502183).
■
REFERENCES
■
(
1)(a)Bondzi
̌
c,
́
B.P.J. Mol.Catal.A:Chem. 2015,408,310.(b)Petricci,
E.; Cini, E. In Hydroformylation for Organic Synthesis; Taddei, M., Mann,
A., Eds.; Springer Berlin Heidelberg: Berlin, Heidelberg, 2013; p 117.
c) Crozet, D.; Urrutigoïty, M.; Kalck, P. ChemCatChem 2011, 3, 1102.
(d) Alper, H.; Vasylyev, M. Synthesis 2010, 2010, 2893. (e) Eilbracht, P.;
Schmidt, A. M. In Catalytic Carbonylation Reactions; Beller, M., Ed.;
(
C
DOI: 10.1021/acs.orglett.7b00100
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Springer Berlin Heidelberg: Berlin, Heidelberg, 2006; p 65. (f) Eilbracht,
Zanotti-Gerosa, A.; Abboud, K. A. Angew. Chem., Int. Ed. 2005, 44, 5834.
(c) Pilkington, C. J.; Zanotti-Gerosa, A. Org. Lett. 2003, 5, 1273.
(15) (a) Heitman, L. H.; Ijzerman, A. P. Med. Res. Rev. 2008, 28, 975.
(b) Miller, W. D.; Fray, A. H.; Quatroche, J. T.; Sturgill, C. D. Org. Process
Res. Dev. 2007, 11, 359.
P.; Bar
Kranemann, C. L.; Rische, T.; Roggenbuck, R.; Schmidt, A. Chem. Rev.
999, 99, 3329.
̈
facker, L.; Buss, C.; Hollmann, C.; Kitsos-Rzychon, B. E.;
1
(
2) Reppe, W. Experientia 1949, 5, 93.
(
3) (a) Sacher, J. R.; Weinreb, S. M. Org. Lett. 2012, 14, 2172. (b) Liu,
G.;Huang, K.;Cao,B.;Chang, M.;Li,S.;Yu, S.;Zhou, L.;Wu, W.;Zhang,
X. Org. Lett. 2012, 14, 102. (c) Okuro, K.; Alper, H. Tetrahedron Lett.
2
010,51,4959. (d)Ahmed, M.;Bronger, R.P.;Jackstell, R.;Kamer, P.C.;
vanLeeuwen, P. W.;Beller, M. Chem. -Eur. J. 2006,12,8979. (e)Briggs, J.
R.; Klosin, J.; Whiteker, G. T. Org. Lett. 2005, 7, 4795. (f) Ahmed, M.;
Seayad, A. M.; Jackstell, R.; Beller, M. J. Am. Chem. Soc. 2003, 125, 10311.
(
g) Seayad, A.; Ahmed, M.; Klein, H.; Jackstell, R.; Gross, T.; Beller, M.
Science 2002, 297, 1676. (h) Lin, Y.-S.; Ali, B. E.; Alper, H. J. Am. Chem.
Soc. 2001, 123, 7719. (i) Zimmermann, B.; Herwig, J.; Beller, M. Angew.
Chem., Int. Ed. 1999, 38, 2372. (j) Rische, T.; Bar
Eur. J. Org. Chem. 1999, 1999, 653. (k) Eilbracht, P.; Kranemann, C. L.;
Barfacker, L. Eur. J. Org. Chem. 1999, 1999, 1907. (l) Breit, B. Tetrahedron
Lett. 1998, 39, 5163.
4) (a) Crozet, D.; Kefalidis, C. E.; Urrutigoïty, M.; Maron, L.; Kalck, P.
ACS Catal. 2014, 4, 435. (b) Noonan, G. M.; Newton, D.; Cobley, C. J.;
Suarez, A.; Pizzano, A.; Clarke, M. L. Adv. Synth. Catal. 2010, 352, 1047.
5)(a)Bocchinfuso, R.;Robinson, J. B. Eur. J. Med.Chem. 1999,34,293.
b) Regnier, G.; Canevari, R.; Le Douarec, J.; Holstorp, S.; Daussy, J. J.
̈
facker, L.; Eilbracht, P.
̈
(
́
(
(
Med. Chem. 1972, 15, 295. (c) Sun, J.-Z.; Jiang, C.-S.; Chen, X.-Q.; Chen,
K.-S.;Zhen, X.-C.;vanSoest, R. W. M.;Guo, Y.-W. Tetrahedron 2014, 70,
3
(
(
166.
6) (a) Jia, X.; Wang, Z.; Xia, C.; Ding, K. Youji Huaxue 2013, 33, 1369.
b) Etayo, P.; Vidal-Ferran, A. Chem. Soc. Rev. 2013, 42, 728. (c) Chi, Y.;
Tang, W.; Zhang, X. In Modern Rhodium-Catalyzed Organic Reactions;
Wiley-VCH Verlag GmbH & Co. KGaA: 2005; p 1.
(
7)Chen, C. Y.;Jin,S.C.;Zhang, Z. F.;Wei,B.;Wang,H.;Zhang, K.;Lv,
H.; Dong, X. Q.; Zhang, X. M. J. Am. Chem. Soc. 2016, 138, 9017.
8) Hoffmann, S.; Nicoletti, M.; List, B. J. Am. Chem. Soc. 2006, 128,
3074.
9) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int.
Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004,
26, 5356. (c) Akiyama, T. Chem. Rev. 2007, 107, 5744. (d) Doyle, A. G.;
Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (e) Terada, M. Synthesis
(
1
(
1
2
010, 2010, 1929. (f) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44,
1
156. (g) Lv, F.; Liu, S.; Hu, W. Asian J. Org. Chem. 2013, 2, 824.
(
h) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114,
047. (i) Akiyama, T.; Mori, K. Chem. Rev. 2015, 115, 9277.
10) (a) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2006, 128, 84. (b) You, S.-L. Chem. - Asian J. 2007, 2, 820.
9
(
(
(
c) Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753.
d) Wakchaure, V. N.; Zhou, J.; Hoffmann, S.; List, B. Angew. Chem., Int.
Ed. 2010, 49, 4612. (e) Chen, Q.-A.; Chen, M.-W.; Yu, C.-B.; Shi, L.;
Wang, D.-S.; Yang, Y.; Zhou, Y.-G. J. Am. Chem. Soc. 2011, 133, 16432.
(
2
f) Henseler, A.; Kato, M.; Mori, K.; Akiyama, T. Angew. Chem., Int. Ed.
011, 50, 8180. (g) Zhou, S.; Fleischer, S.; Junge, K.; Beller, M. Angew.
Chem., Int. Ed. 2011, 50, 5120. (h) Chen, Q.-A.; Gao, K.; Duan, Y.; Ye, Z.-
S.; Shi, L.; Yang, Y.; Zhou, Y.-G. J. Am. Chem. Soc. 2012, 134, 2442.
(
i) Zheng, C.; You, S.-L. Chem. Soc. Rev. 2012, 41, 2498. (j) Wang, C.;
Xiao, J.; Li, W.; Zhang, X. Top. Curr. Chem. 2013, 343, 261.
(
11) Villa-Marcos, B.; Xiao, J. Chin. J. Catal. 2015, 36, 106.
(
12) (a) Zhao, F.; Li, N.; Zhu, Y. F.; Han, Z. Y. Org. Lett. 2016, 18, 1506.
(
b)Lian, X.-L.;Meng, J.;Han, Z.-Y. Org. Lett. 2016, 18, 4270. (c)Han, Z.-
Y.;Chen, D.-F.; Wang, Y.-Y.; Guo, R.;Wang, P.-S.; Wang, C.; Gong, L.-Z.
J. Am. Chem. Soc. 2012, 134, 6532. (d) Han, Z.-Y.; Xiao, H.; Chen, X.-H.;
Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 9182.
(
13) (a) Inamdar, S. M.; Shinde, V. S.; Patil, N. T. Org. Biomol. Chem.
2
015, 13, 8116. (b) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3,
6
33. (c) Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2010, 2999. (d) Shao,
Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (e) Wasilke, J.-C.; Obrey, S.
J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001. (f) Chen, D. F.;
Han, Z. Y.; Zhou, X. L.; Gong, L. Z. Acc. Chem. Res. 2014, 47, 2365.
(
14) (a) Yu, Z.; Eno, M. S.; Annis, A. H.; Morken, J. P. Org. Lett. 2015,
1
7, 3264. (b) Axtell, A. T.; Cobley, C. J.; Klosin, J.; Whiteker, G. T.;
D
DOI: 10.1021/acs.orglett.7b00100
Org. Lett. XXXX, XXX, XXX−XXX