Highly enantioselective catalytic cross-dehydrogenative coupling of n -carbamoyl tetrahydroisoquinolines and terminal alkynes

Article abstract of DOI:10.1021/acs.orglett.5b00447

The first catalytic asymmetric cross-dehydrogenative coupling of cyclic carbamates and terminal alkynes has been established. The reaction features high enantiocontrol and excellent functional group tolerance and displays a wide range of structurally and electronically diverse carbamates as well as terminal alkynes. N-Acyl hemiaminals were identified as the reactive intermediates through preliminary control experiments. Employing readily removable carbamates as substrates rather than traditionally adopted N-aryl amines allows applications in complex molecule synthesis and therefore advances the C-H functionalization strategy to a synthetically useful level.

Full text of DOI:10.1021/acs.orglett.5b00447

Letter
pubs.acs.org/OrgLett
Highly Enantioselective Catalytic Cross-Dehydrogenative Coupling
of N‑Carbamoyl Tetrahydroisoquinolines and Terminal Alkynes
Shutao Sun,†,‡ Chengkun Li,†,‡ Paul E. Floreancig,§ Hongxiang Lou,† and Lei Liu*,†
†Key Lab of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, P. R.
China
§Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: The first catalytic asymmetric cross-dehydro-
genative coupling of cyclic carbamates and terminal alkynes
has been established. The reaction features high enantiocontrol
and excellent functional group tolerance and displays a wide
range of structurally and electronically diverse carbamates as
well as terminal alkynes. N-Acyl hemiaminals were identified as
the reactive intermediates through preliminary control experi-
ments. Employing readily removable carbamates as substrates
rather than traditionally adopted N-aryl amines allows applications in complex molecule synthesis and therefore advances the C−
H functionalization strategy to a synthetically useful level.
he catalytic enantioselective cross-dehydrogenative cou-
pling (CDC) reactions of readily accessible substrates
represent a straightforward and effective strategy for the
synthesis of numerous complex chiral molecules whereby the
only loss is H2 formally.1 While impressive progress has recently
been achieved for nitrogen-containing components, the scope is
only limited to highly reactive N-aryl amines (Scheme 1, eq 1).2
dicarbonyl compounds are always required for high enantiose-
lectivity probably due to the poor electrophilicity of the stabilized
iminium intermediate.2,3b Li and co-workers reported their
efforts on the employment of relatively weak nucleophiles such as
the arylacetylene.2h,i However, limited scope of both compo-
nents was observed with modest enantiocontrol (36%−74% ee).
The direct C−H functionalization of carbamates rather than
aryl amines provides an attractive solution for enhancing the
scope and utility of the strategy through generating a more
reactive acyliminium intermediate that can react with a broader
range of nucleophiles and affords products that can be readily
cleaved under mild conditions. While some progress in the
racemic CDC of carbamates has been achieved, the existing
methods usually required relative harsh conditions probably due
to reduced substrate reactivities and stabilities of resulting N-
acyliminium ions.4 The art seriously hampers the design of
catalytic enantioselective variants. So far, only one example of the
catalytic enantioselective C−H functionalization of carbamates
has been reported by Sodeoka (Scheme 1, eq 2).5 Good
enantiocontrol (up to 86% ee) was achieved by using a fastidious
procedure for the oxidant addition over 10 h to avoid the
decomposition of unstable acyliminium ions. However, the scope
is still restricted to dimethoxy substituted electron-rich
carbamates even when nucleophilic malonates are employed,
leaving electron-neutral and -deficient ones intact. Herein, we
report our recent efforts on the catalytic asymmetric CDC of
electronically varied cyclic carbamates with weakly nucleophilic
terminal alkynes and the applications in complex molecule
synthesis (Scheme 1, eq 3).6
T
Scheme 1. Catalytic Enantioselective CDC of N-Heterocycles
The aryl group linked to the nitrogen weakens the target C−H
bond and stabilizes the resulting iminium intermediate, allowing
the initial C−H cleavage and subsequent nucleophilic addition to
occur at ambient conditions. Despite excellent enantioselectivity,
removal of the aryl moiety in the presence of other functional
groups proves to be difficult and thus limits the synthetic utility.3a
Moreover, relatively strong nucleophiles such as enamines or 1,3-
Received: February 11, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00447
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Initially, the racemic CDC of benzyl carbamate 1a with
phenylacetylene 2a in the presence of CuCl was selected as the
model reaction for optimization (Scheme 2). Oxidants including
Table 1. Reaction Condition Optimization
Scheme 2. Strategy for CDC of Electron-Neutral Carbamate
1a and Terminal Alkyne 2a
TBHP, DDQ, 2,2,6,6-tetramethylpiperidine N-oxide salt
(T+BF4 ), and Ph3CBF4 did not promote the coupling, with all
−
the 1a recovery. The observation might be ascribed to the low
reactivity of 1a and poor stability of the resulting acyliminium A,
making the C−H oxidation of 1a thermodynamically unfavor-
able. Therefore, the low concentrations of the acyliminium ion A
and copper acetylide would be insufficient to drive the coupling
to the product. We envision that a protic additive that reacts
quickly and thermodynamically favorably with A would drive the
C−H oxidation to retain the oxidation state of the acyliminium
ion in the form of N-acyl hemiaminal 4. A suitable acid would
promote the conversion of 4 to acyliminium B with a better
counterion Y− than X− in A to stabilize the cation, and the
coupling might be viable.
a
−
Reaction condition: 1a (0.1 mmol), 2a (0.2 mmol), T+BF4 (0.1
mmol), ligand (0.015 mmol), metal (0.015 mmol), EtOH (0.1 mmol),
acid (0.12 mmol), and base (0.19 mmol) in CH2Cl2 (1.0 mL) at rt for
b
c
48 h, unless otherwise specified. Isolated yield. Determined by chiral
HPLC analysis. Lewis acids including Yb(OTf)3, Sc(OTf)3, In-
d
e
To test the hypothesis, one equivalent of ethanol was
introduced. After all the carbamate 1a was consumed, a variety
of acids were explored. Delightedly, several Lewis acids bearing a
triflate anion promoted the coupling when using T+BF4− as the
oxidant (Table 1, entry 1, and Table S1 in the Supporting
Information (SI)). Despite observed reactivity, racemic 3a was
always obtained in the presence of chiral ligand L1 (Table 1,
entry 2). After extensive studies of a series of additives,
enantioselectivity was observed when KOH was used (Table 1,
entry 3, and Table S2 in the SI). A systematic exploration of chiral
ligands and copper salts identified L3 with CuBr as the ideal
combination (Table 1, entries 3−7, and Table S3 in the SI). The
investigation on the Lewis acid effect on the enantioselectivity
revealed that Yb(OTf)3 proved to be the unique choice for the
asymmetric reaction (Table 1, entries 7 and 8). The further study
on the additive effect indicated that EtOH (1 equiv) together
with H2O (2 equiv) were beneficial to increasing the selectivity
(Table 1, entries 7 and 9, and Table S4 in the SI). Extensive
optimization of the solvent, carbamate, and oxidant identified a
(OTf)3, and Ga(OTf)3. Lewis acid in footnote d except Yb(OTf)3.
f
g
H2O (0.2 mmol). CH2Cl2/toluene (v/v, 1:4). LA = Lewis acid. n.d.
= not determined.
a
Scheme 3. Scope of the Terminal Alkynes
−
mixture of CH2Cl2/toluene (v/v, 1:4), Cbz moiety, and T+BF4
to be optimal (Table 1, entries 9 and 10, and Tables S5 and S6 in
the SI).
a
−
Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), T+BF4 (0.1
mmol), L3 (0.015 mmol), CuBr (0.015 mmol), EtOH (0.1 mmol),
Yb(OTf)3 (0.12 mmol), KOH (0.19 mmol), and H2O (0.2 mmol) in
1.0 mL of CH2Cl2/toluene (v/v, 1:4) at rt for 48 h.
Under the optimized conditions, a variety of electronically
varied aryl acetylenes with different substituent patterns were
tolerated with the catalytic enantioselective CDC with carbamate
1a efficiently (Scheme 3). Good to excellent enantioselectivities
were observed for aryl acetylenes bearing both electron-
withdrawing and -donating functionalities (3a−3n). Heteroaryl
acetylenes like thiophen-2-yl ethyne (3o) and alkenyl acetylenes
(3p) proved to be suitable substrates. Alkyl acetylene 2q and
methyl propiolate 2r afforded desired products with compro-
mised yields and ee, which might be ascribed to the reduced
reactivity of alkynes.
The scope of carbamates was next explored (Scheme 4). As
expected, the CDC of carbamates with electron-donating
B
DOI: 10.1021/acs.orglett.5b00447
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
logical activities.4e The asymmetric CDC of carbamates with aryl
acetylenes provides a straightforward approach to synthesize
such scaffold, as demonstrated by the synthesis of homoproto-
berberine 8 through asymmetric CDC of 1b with 2s followed by
a hydrogenation and cyclization (Scheme 6). The synthesis also
helps to assign the absolute configuration of products in this
work.7a
a
Scheme 4. Scope of Trityl Ion-Mediated CDC Reactions
Scheme 6. Synthetic Applications
a
−
Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), T+BF4 (0.1
mmol), L3 (0.015 mmol), CuBr (0.015 mmol), EtOH (0.1 mmol),
Yb(OTf)3 (0.12 mmol), KOH (0.19 mmol), and H2O (0.2 mmol) in
b
1.0 mL of CH2Cl2/toluene at rt for 48 h. NaOMe was used instead of
EtOH.
substituents proceeded smoothly with high enantiocontrol (5b−
5d). Notably, substrates bearing electron-withdrawing substitu-
ents such as chlorines and bromines were tolerated with excellent
ee for further diversifications (5e-5g), albeit reduced yields
probably due to reduced reactivities of the carbamate and
stabilities of corresponding acyliminium intermediate.
In Scheme 2, N-acyl hemiaminal 4 was presumed as the
precursor for subsequent alkynylation. Moreover, the CDC
reaction required both EtOH and H2O as the additives. To verify
the identity of the intermediate for the asymmetric CDC
reaction, N-acyl hemiaminal 4a and 4b were prepared and
subjected respectively to the standard condition omitting
T+BF4 and base (Scheme 5). In the presence of H2O,
−
Scheme 5. N-Acyl Hemiaminals as Substrates
In the majority of catalytic asymmetric reactions involving
terminal alkynes, aryl acetylenes typically display better
enantioselectivities than alkyl ones. Therefore, we designed a
concise three-step sequence to enhance synthetic utilities of
these methods by manipulating aryl acetylenes (Scheme 6). Aryl
alkyne 9 generated through the asymmetric CDC of carbamate
1b with 2k was smoothly converted to aldehyde 10 through
hydration, Baeyer−Villiger oxidation, and reduction with the ee
highly conserved. Compound 11 was the intermediate for the
total synthesis of biologically active natural product emetine
(12), where 10 steps were conducted to prepare enantiopure
11.7b The two examples demonstrate the method outlined herein
has practicability in synthesizing structurally diverse complex
molecules.
In conclusion, the first catalytic asymmetric CDC reaction of
cyclic carbamates and terminal alkynes has been described. The
reaction features high enantiocontrol and excellent functional
group tolerance and displays a wide range of structurally and
electronically diverse carbamates as well as terminal alkynes.
Preliminary control experiments identified N-acyl hemiaminals
as the reactive intermediates. Employing readily prepared and
removable carbamates as substrates rather than traditionally
adopted N-aryl amines allows applications in complex molecule
synthesis and therefore advances the CDC reaction to a
synthetically useful level. We envision that the strategy described
comparable enantioselectivities were observed for both sub-
strates 4a and 4b as that of the CDC process. However,
compromised enantiocontrol was observed for either 4a or 4b in
the absence of H2O. These experiments together with the
observation that a considerable amount of 4a and a small
quantity of 4b were detected on the TLC during the course of the
reaction suggested that both N-acyl hemiaminals 4a and 4b
should be the intermediates for the alkynylation process, though
the exact role of H2O remains unclear.
One of the greatest advantages for the C−H functionalization
of carbamates over N-aryl amines is that the former can be readily
cleavaged or functionalized, which would advance the strategy to
complex molecule synthesis. 1-Arylethyl substituted tetrahy-
droisoquinolines (THIQs) represent ubiquitous structural
motifs in numerous alkaloids exhibiting a range of pharmaco-
C
DOI: 10.1021/acs.orglett.5b00447
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Seidel, T. M.; Suzuki, S.; Hashizume, D.; Sodeoka, M. J. Org. Chem.
2008, 73, 5859.
herein would serve as a guide for future efforts in the catalytic
asymmetric C−H functionalization of substrates in low
reactivities with a broad range of nucleophiles.
(6) (a) Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143.
(b) Hashimoto, T.; Omote, M.; Maruoka, K. Angew. Chem., Int. Ed.
2011, 50, 8952. (c) Lin, W.; Cao, T.; Fan, W.; Han, Y.; Kuang, J.; Luo,
H.; Miao, B.; Tang, X.; Yu, Q.; Yuan, W.; Zhang, J.; Zhu, C.; Ma, S.
Angew. Chem., Int. Ed. 2014, 53, 277. (d) Sun, Z.; Yu, S.; Ding, Z.; Ma, D.
J. Am. Chem. Soc. 2007, 129, 9300. (e) Black, D. A.; Beveridge, R. E.;
Arndtsen, B. A. J. Org. Chem. 2008, 73, 1906. (f) Maity, P.; Srinivas, H.
D.; Watson, M. P. J. Am. Chem. Soc. 2011, 133, 17142.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and spectral data for new compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
(7) (a) Brossi, A.; Teitel, S. Helv. Chim. Acta 1969, 52, 1228. (b) Tietze,
L. F.; Rackelmann, N.; Muller, I. Chem.Eur. J. 2004, 10, 2722.
̈
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: leiliu@sdu.edu.cn
Author Contributions
‡These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Science Foundation of
China (21202093, 21472112), the Program for New Century
Excellent Talents in University (NCET-13-0346), and the
Shandong Science Fund for Distinguished Young Scholars
(JQ201404).
REFERENCES
■
(1) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (b) Girard, S. A.;
Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74. (c) Yeung, C.
S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (d) Rohlmann, R.; García
Mancheno, O. Synlett 2013, 6. (e) Liu, C.; Zhang, H.; Shi, W.; Lei, A.
̃
Chem. Rev. 2011, 111, 1780. (f) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int.
Ed. 2008, 47, 7497. (g) Boess, E.; Sureshkumar, D.; Sud, A.; Wirtz, C.;
̀
Fares, C.; Klussmann, M. J. Am. Chem. Soc. 2011, 133, 8106.
(h) Murahashi, S. I.; Komiya, N.; Terai, H.; Nakae, T.; Komiya, N. J.
Am. Chem. Soc. 2003, 125, 15312.
(2) (a) Guo, C.; Song, J.; Luo, S.-W.; Gong, L.-Z. Angew. Chem., Int. Ed.
2010, 49, 5558. (b) Zhang, G.; Zhang, Y.; Wang, R. Angew. Chem., Int.
Ed. 2011, 50, 10429. (c) Zhang, J.; Tiwari, B.; Xing, C.; Chen, X.; Chi, Y.
R. Angew. Chem., Int. Ed. 2012, 51, 3649. (d) Zhang, G.; Ma, Y.; Wang,
S.; Zhang, Y.; Wang, R. J. Am. Chem. Soc. 2012, 134, 12334. (e) Zhang,
G.; Ma, Y.; Wang, S.; Kong, W.; Wang, R. Chem. Sci. 2013, 4, 2645.
(f) Neel, A. J.; Hehn, J. P.; Tripet, P. F.; Toste, F. D. J. Am. Chem. Soc.
2013, 135, 14044. (g) Bergonzini, G.; Schindler, C. S.; Wallentin, C.-J.;
Jacobsen, E. N.; Stephenson, C. R. J. Chem. Sci. 2014, 5, 112. (h) Li, Z.;
Li, C.-J. Org. Lett. 2004, 6, 4997. (i) Li, Z.; MacLeod, P. D.; Li, C.-J.
Tetrahedron: Asymmetry 2006, 17, 590. (j) Wei, X.-H.; Wang, G.-W.;
Yang, S.-D. Chem. Commun. 2015, 51, 832. (k) Liu, X.; Meng, Z.; Li, C.;
Lou, H.; Liu, L. Angew. Chem., Int. Ed. 2015, DOI: 10.1002/
anie.201500703. (l) Meng, Z.; Sun, S.; Yuan, H.; Lou, H.; Liu, L.
Angew. Chem., Int. Ed. 2014, 53, 543.
(3) (a) Mengozzi, L.; Gualandi, A.; Cozzi, P. G. Chem. Sci. 2014, 5,
3915. (b) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
(4) (a) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.; Schnurch,
̈
M. Chem. Commun. 2010, 46, 8836. (b) Richter, H.; García Mancheno,
̃
O. Eur. J. Org. Chem. 2010, 4460. (c) Liu, X.; Sun, B.; Xie, Z.; Qin, X.;
Liu, L.; Lou, H. J. Org. Chem. 2013, 78, 3104. (d) Richter, H.; Frohlich,
̈
R.; Daniliuc, C.-G.; García Mancheno, O. Angew. Chem., Int. Ed. 2012,
̃
51, 8656. (e) Xie, Z.; Liu, L.; Chen, W.; Zheng, H.; Xu, Q.; Yuan, H.;
Lou, H. Angew. Chem., Int. Ed. 2014, 53, 3904. (f) Schweitzer-Chaput,
́
B.; Sud, A.; Pinter, A.; Dehn, S.; Schulze, P.; Klussmann, M. Angew.
́
Chem., Int. Ed. 2013, 52, 13228.
(5) (a) Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka, M. J. Am.
Chem. Soc. 2006, 128, 14010. (b) Christian, D.; Yoshitaka, H.; Naoki, S.;
D
DOI: 10.1021/acs.orglett.5b00447
Org. Lett. XXXX, XXX, XXX−XXX