Copper-Catalyzed Asymmetric Propargylation of Cyclic Aldimines

Article abstract of DOI:10.1021/acs.orglett.6b03253

The copper-catalyzed asymmetric propargylation of cyclic aldimines is reported. The influence of the imine trimer to inhibit the reaction was identified, and equilibrium constants between the monomer and trimer were determined for general classes of imines. Asymmetric propargylation of a diverse series of N-alkyl and N-aryl aldimines was achieved with good to high asymmetric induction. The utility was demonstrated by a titanium catalyzed hydroamination and reduction to generate the chiral indolizidines (-)-crispine A and (-)-harmicine.

Full text of DOI:10.1021/acs.orglett.6b03253

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Asymmetric Propargylation of Cyclic Aldimines
,
†
‡
†
†
†
Daniel R. Fandrick,* Christine A. Hart, Ifeanyi S. Okafor, Michael A. Mercadante, Sanjit Sanyal,
†
†
†
‡
†
James T. Masters, Max Sarvestani, Keith R. Fandrick, Jennifer L. Stockdill, Nelu Grinberg,
†
†
†
Nina Gonnella, Heewon Lee, and Chris H. Senanayake
†Chemical Development and Material and Analytical Sciences, Boehringer-Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury
Road/P.O. Box 368, Ridgefield, Connecticut 06877-0368, United States
‡
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States
*
S Supporting Information
ABSTRACT: The copper-catalyzed asymmetric propargylation of cyclic aldimines is reported. The influence of the imine trimer
to inhibit the reaction was identified, and equilibrium constants between the monomer and trimer were determined for general
classes of imines. Asymmetric propargylation of a diverse series of N-alkyl and N-aryl aldimines was achieved with good to high
asymmetric induction. The utility was demonstrated by a titanium catalyzed hydroamination and reduction to generate the chiral
indolizidines (−)-crispine A and (−)-harmicine.
symmetric additions to carbonyl and imine species can be
regarded as seminal advances necessary for the sustainable1
the parent dihydroisoquinoline 1a was more pronounced and
proceeded at ambient temperature with high selectivity for the
allenyl product 4a (Figure 1). The selectivity was reversed to
strongly favor the propargylation pathway by the addition of
catalytic diethyl zinc and lowering the reaction temperature to
allow the catalytic reaction to effectively compete with the
background process. Furthermore, the boron−metal exchange
mechanism generates an N-boropinacol complex, thereby
protecting the amine from metal coordination until liberation
A
synthesis of bioactive natural products and pharmaceuticals.
Stereoselective propargylations are strategically advantageous
reactions because they enable the concomitant formation of a
chiral center and installation of a synthetically versatile alkyne
2
functional group. Recently, significant advances in catalytic
asymmetric propargylations have been achieved for the addition
2
,3
2,4
5
to aldehydes, ketones 3 and protected imines. The latter
d
6
studies used hydrazones, phosphinoyl imines, or sulfonyl
imines, because these functional groups share attributes
7
necessary for an effective catalytic cycle. The imine protecting8
group stabilizes the imine by preventing oligomerization,
provides chemoselectivity between the electrophile and
9
10
reagents, and activates the substrate for the addition.
However, unprotected N-alkyl and N-aryl imines encompass a
plethora of structural diversity, and only limited examples for the
asymmetric allylation and stoichiometric propargylation are
2
,11
reported.
Recognizing this potential utility, we report the
copper-catalyzed asymmetric propargylation of cyclic aldimines.
Figure 1. Catalyst influence on the site selectivity for the addition of
propargyl borolane 2 to imine 1a. Site selectivity determined by HPLC
and isolated yield for the major isomer.
1
2
We introduced the propargyl borolane 2 to effect
1
3
3b,4b
propargylations through B/Zn and B/Cu
exchange
processes that demonstrated a suppressed background reaction
between the reagent and carbonyl electrophile over typical allyl
or allenyl borolane reagents. The background reaction between
Received: October 30, 2016
9b
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03253
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
by an aqueous workup. Utilization of this boron−metal exchange
strategy allowed entry into the copper catalyzed process wherein
diverse classes of chiral ligands can be screened for asymmetric
induction (Table 1). Several ligands, JOSIPHOS, BPE, and
Table 2. Monomer−Trimer Solution Equilibrium Constants
a
for Respective Classes of Aldimines
Table 1. Initial Optimization for the Asymmetric
a
Propargylation of Aldimines
b
c
entry
ligand
BINAP
solvent
conv (%)
[er]
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
toluene
75
80
79
84
77
67
75
72
82
76
77
68:32
64:36
56:44
85:15
85:15
63:37
74:26
51:49
84:16
63:37
85:15
95:5
DIOP
BIPI 69 H
JOSIPHOS
BPE
iPr-DuPHOS
DUANPHOS
NorPHOS
MONOPHOS
Me-BIBOP
Ph-BIBOP
MeO-BIBOP
MeO-BIBOP
MeO-BIBOP
10
11
12
13
14
d
95
aConcentrations determined by 1H NMR spectroscopy with an
e
72
96:4
f
g
internal standard at 18−20 °C. Less than represents limit of detection.
>95
98:2
b
Average of two values for K > 1 at different concentrations. Average
for four measurements with 6 h to 3 d of solution aging. Not
determined due to limited solubility.
a
Catalyst preformed in THF and subjected to the substrate under the
c
b
indicated conditions. Relative conversion by HPLC at 205 nm.
c
d
Absolute enantiomeric ratio determined by chiral HPLC. 78:22 3a
e
f
to 4a and 75% yield for 3a. 68:32 3a to 4a and 45% yield for 3a. 9
1
8a,c
such as Δ -piperidine. Dihydroisoquinoline 1a was isolated as
mol % Cu catalyst utilized and reaction conducted for 36 h at −15 °C.
g
an oil, which slowly crystallized as the trimer (Figure 2), whereas
8
4:16 3a to 4a and 84% yield for 3a.
Figure 2. Crystallization driven trimerization of imine 1a. ORTEP
diagram for a single crystal X-ray of crystalline trimer of 1a.
MONOPHOS, provided moderate enantiomeric ratios, but the
MeOBIBOP ligand furnished a high 95:5 er. Changing the
solvent to toluene and lowering the reaction temperature to −15
in solution or as a melted oil, this compound displays a strong
equilibrium preference toward the monomer. This property of
the parent imine demonstrated a profound influence on the
optimized copper-catalyzed conditions. While the asymmetric
reaction proceeded smoothly by subjecting the imine oil or
solution to the catalyst solution, no reaction was observed if the
crystalline trimer was charged to the catalyst. Trace conversion
°
C improved chemoselectivity over the background reaction and
increased the er to 98:2 (entry 14).
One challenge with N-aliphatic aldimines was the propensity
8
to trimerize. In previous reports, inconsistencies were apparent
in the nature of the equilibrium and within the characterization
complicating methodologies associated with their use. NMR
1
was also observed with Δ -piperidine, which has a strong
1
8a,c,e
analysis of the classical Δ -piperidine
revealed a rapid
preference for the trimer in solution, to further support the
inhibitory effect of the trimer on the catalyst. Therefore, the
substrate scope focused on imine classes that demonstrated an
equilibrium favoring the imine monomer.
concentration dependent equilibrium between the monomer
and trimer. Systematic variation of the concentration (Table 2)
8
e,14
allowed the solution equilibrium constants
for representative
1
imine classes to be determined. Δ -Piperidine demonstrated a
strong preference for the trimer, while the dihydroisoquinoline,
β-alkalidene, and N-aryl imines strongly favored the monomer.
Surprisingly, 3,4-dihydro-β-carboline 1d showed a moderate
equilibrium with the trimer. In addition to the solution behavior
of imines, some imines are known to crystallize as the trimer,
The copper catalyzed asymmetric propargylation utilizing the
MeOBIBOP ligand demonstrated a broad substrate scope for
both N-aliphatic and N-aryl aldimines (Table 3). Dihydro-
isoquinolines (1a−c), dibenzo-oxazepines (1f and 1g), β-
alkalidene imine (1e), and phenathridine systems (1h−1j)
were tolerated to provide reasonable to high asymmetric
B
DOI: 10.1021/acs.orglett.6b03253
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Substrate Scope for the Asymmetric Propargylation
of Aldimines
requiring a 20% catalyst loading to achieve high conversion. This
poor reactivity may be due to the unprotected indole N-H or its
equilibrium with the trimer in contrast to the other substrates
a
(
Table 2). Overall, a broad diversity of aldimine scaffolds was
15
tolerated, including several complex heterocyclic systems.
The asymmetric propargylation provides ideal substrates for
an intramolecular reductive hydroamination to generate
16
indolizidine alkaloids. However, related attempts with catalytic
17
silver led to oxidative products with loss of the chiral center.
Therefore, titanium based systems were examined with the TMS-
deprotected alkynes 5a, 5b, and 5d. While the Ackermann et al.
1
8
system (TiCl and tBuNH ) furnished poor yields, the Schafer
4
2
1
9
et al. catalyst provided high yields and complete stereointegrity
after reduction (Figure 3). The reductive hydroamination
sequence with the dimethoxy (5b) and indole (5d) substrates
20
allowed rapid access to both (−)-crispine A and (−)-harmi-
21
cine.
Figure 3. Reductive hydroamination toward indolizidine alkaloids.
a
Enantiomeric ratios determined by chiral HPLC. 20% Titanium
catalyst with 40% ligand 7 employed.
In conclusion, the copper catalyzed asymmetric propargyla-
tion of N-aliphatic and N-aryl aldimines was developed. The
reactions generally proceeded in high yield with synthetically
useful enantiomeric ratios and excellent selectivity for the
propargylation pathway. The imine substrate demonstrated a
propensity for dynamic trimerization, an equilibrium that was
dependent on the imine structure, solvent, and state of matter.
Tabulating this property allowed predictable substrate selection
and reproducibility for the methodology while simultaneously
rectifying the inconsistency in the literature as to the nature of
these trimerization equilibria. The structural breadth of the
aldimine substrates combined with the installation of the
synthetically versatile alkyne boosts the potential impact of this
propargylation chemistry, which will facilitate the continued
development of novel medicines and materials.
a
See Supporting Information for reaction and isolation conditions for
b
c
every example. Isolated yields. Enantiomeric ratio determined by
chiral HPLC with reference to racemic standards. Absolute stereo-
chemistry assigned by analogy to the determined configuration of 3b
and 3d. 5 mol % catalyst with 7 mol % ligand. 7 mol % catalyst with
9
d
e
f
g
mol % ligand. 9 mol % catalyst with 11 mol % ligand. 20 mol %
ASSOCIATED CONTENT
h i j k
■
catalyst with 28 mol % ligand. 0 °C. −10 °C. −15 °C. −25 °C.
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03253.
induction. These diverse structures also allowed the incorpo-
ration of valuable heterocycles such as a quinoline (1g),
pyrazoloquinoline (1i), and benzonapthyridine (1j) into the
substrates. Due to the diverse scope, the reaction conditions were
optimized for each substrate with most systems proceeding with
good conversion and high selectivity with 5−9 mol % catalyst
loadings and at −25 to 0 °C. The 3,4-dihydro-β-carboline (1d)
proved to be a challenging substrate for the methodology,
Complete optimization studies, experimental procedures,
characterization data, equilibrium constants determina-
tion, X-ray data, copies of chiral HPLC chromatograms,
1
13
H and C NMR spectra for all products (PDF, PDF,
PDF)
Crystallographic data (CIF)
C
DOI: 10.1021/acs.orglett.6b03253
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
Jpn. 1983, 56, 3199. (e) For the neat oil equilibrium constant of Δ -
pyrrolidine, see: Wiberg, K. B.; Nakaji, D. Y.; Morgan, K. M. J. Am. Chem.
Soc. 1993, 115, 3527.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: daniel.fandrick@boehringer-ingelheim.com.
ORCID
(9) For a review on allylation of imines, see: (a) Ramadhar, T. R.;
Batey, R. A. Synthesis 2011, 1321. For an example of a propargyl
borolane addition to N-alkyl imines, see: (b) Nikam, S. S.; Wang, K. K. J.
Org. Chem. 1985, 50, 2193.
(10) For examples of the influence of the imine protecting group on an
addition, see: (a) Kondo, M.; Nishi, T.; Hatanaka, T.; Funahashi, Y.;
Nakamura, S. Angew. Chem., Int. Ed. 2015, 54, 8198. (b) He, Q.; Wu, L.;
Kou, X.; Butt, N.; Yang, G.; Zhang, W. Org. Lett. 2016, 18, 288.
(11) For selected examples, see: (a) Okamoto, S.; Teng, X.; Fujii, S.;
Takayama, Y.; Sato, F. J. Am. Chem. Soc. 2001, 123, 3462. (b) Song, Y.;
Okamoto, S.; Sato, F. Tetrahedron Lett. 2002, 43, 8635. (c) Wu, T. R.;
Chong, J. M. J. Am. Chem. Soc. 2006, 128, 9646. (d) Itoh, T.; Miyazaki,
M.; Fukuoka, H.; Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8, 1295.
Daniel R. Fandrick: 0000-0002-4522-0643
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was influenced and inspired by the Non-Precious
Metal Catalysis Alliance between Abbvie, Boehringer-Ingelheim,
and Pfizer.
(
(
e) Gonzalez, A. Z.; Soderquist, J. A. Org. Lett. 2007, 9, 1081.
f) Miyazaki, M.; Ando, N.; Sugai, K.; Seito, Y.; Fukuoka, H.; Kanemitsu,
REFERENCES
■
(
1) (a) Asymmetric Catalysis on Industrial Scale: Challenges, Approaches
T.; Nagata, K.; Odanaka, Y.; Nakamura, K. T.; Itoh, T. J. Org. Chem.
2
D.-D.; Suh, Y.-G. Org. Biomol. Chem. 2012, 10, 5202. (h) Yeung, K.;
Ruscoe, R. E.; Rae, J.; Pulis, A. P.; Procter, D. J. Angew. Chem., Int. Ed.
and Solutions, 2nd ed.; Blaser, H.-U., Federsel, H.-J., Eds.; Whiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, 2010. (b) Classics in
Stereoselective Synthesis; Carreira, E. M., Kvaerno, L., Eds.; Whiley-
VCH Verlag GmbH & Co. KGaA: Weinheim, 2009.
2) For recent reviews, see: (a) Ding, C.-H.; Hou, X.-L. Chem. Rev.
011, 111, 1914. (b) Yus, M.; Gonzales-Gomez, J. C.; Foubelo, F. Chem.
Rev. 2011, 111, 7774. (c) Wisniewska, H. M.; Jarvo, E. R. J. Org. Chem.
013, 78, 11629.
3) For recent examples, see: (a) Liu, S.; Kim, J. T.; Dong, C.-G.; Kishi,
Y. Org. Lett. 2009, 11, 4520. (b) Fandrick, D. R.; Fandrick, K. R.; Reeves,
J. T.; Tan, Z.; Tang, W.; Capacci, A. G.; Rodriguez, S.; Song, J. J.; Lee, H.;
Yee, N. K.; Senanayake, C. H. J. Am. Chem. Soc. 2010, 132, 7600.
c) Usanov, D. L.; Yamamoto, H. Angew. Chem., Int. Ed. 2010, 49, 8169.
d) Chen, J.; Captain, B.; Takenaka, N. Org. Lett. 2011, 13, 1654.
e) Chen, M.; Roush, W. R. J. Am. Chem. Soc. 2012, 134, 10947. (f) Jain,
P.; Wang, H.; Houk, K. N.; Antilla, J. C. Angew. Chem., Int. Ed. 2012, 51,
391. (g) Reddy, L. R. Org. Lett. 2012, 14, 1142. (h) Woo, S. K.; Geary,
L. M.; Krische, M. J. Angew. Chem., Int. Ed. 2012, 51, 7830. (i) Geary, L.
M.; Woo, S. K.; Leung, J. C.; Krische, M. J. Angew. Chem., Int. Ed. 2012,
1, 2972. (j) Meng, F.; Haeffner, F.; Hoveyda, A. H. J. Am. Chem. Soc.
014, 136, 11304. (k) Wei, X.-F.; Shimizu, Y.; Kanai, M. ACS Cent. Sci.
016, 2, 21. For examples of related asymmetric propargylations
utilizing alcohols, see: (l) Liang, T.; Woo, S. K.; Krische, M. J. Angew.
Chem., Int. Ed. 2016, 55, 9207. (m) Nguyen, K. D.; Herkommer, D.;
Krische, M. J. J. Am. Chem. Soc. 2016, 138, 5238.
011, 76, 534. (g) Jang, J.; Jung, J.-W.; Ahn, J.; Sim, J.; Chang, D.-J.; Kim,
2
016, 55, 11912. (i) Jiang, L.; Cao, P.; Wang, M.; Chen, B.; Wang, B.;
Liao, J. Angew. Chem., Int. Ed. 2016, 55, 13854.
12) Fandrick, D. R.; Roschangar, F.; Kim, C.; Hahm, B. J.; Cha, M. H.;
(
2
(
Kim, H. Y.; Yoo, G.; Kim, T.; Reeves, J. T.; Song, J. J.; Tan, Z.; Qu, B.;
Haddad, N.; Shen, S.; Grinberg, N.; Lee, H.; Yee, N.; Senanayake, C. H.
Org. Process Res. Dev. 2012, 16, 1131.
2
(
(
13) Fandrick, D. R.; Fandrick, K. R.; Reeves, J. R.; Tan, Z.; Johnson, C.
S.; Lee, H.; Song, J. J.; Yee, N. K.; Senanayake, C. H. Org. Lett. 2010, 12,
8.
14) For examples of equilibria for formaldehyde based imines, see:
Kallen, R. G.; Jencks, W. P. J. Biol. Chem. 1966, 241, 5864.
15) For examples of asymmetric additions to phenanthridine systems,
8
(
(
(
(
(
see: (a) Frisch, K.; Landa, A.; Saaby, S.; Jorgensen, K. A. Angew. Chem.,
Int. Ed. 2005, 44, 6058. (b) Janody, S.; Hermange, P.; Retailleau, P.;
Thierry, J.; Dodd, R. H. J. Org. Chem. 2014, 79, 5673.
1
(16) For reviews on hydroamination, see: (a) Alonso, F.; Beletskaya, I.
5
2
2
P.; Yus, M. Chem. Rev. 2004, 104, 3079. (b) Muller, T. E.; Hultzsch, K.
C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795.
(
c) Huang, L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J. Chem.
Rev. 2015, 115, 2596.
17) (a) Knolker, H.-J.; Agarwal, S. Tetrahedron Lett. 2005, 46, 1173.
b) Agarwal, S.; Kataeva, O.; Schmidt, U.; Knolker, H.-J. RSC Adv. 2013,
, 1089.
(
(
3
(
4) For recent examples, see: (a) Shi, S.-L.; Xu, L.-W.; Oisaki, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 6638. (b) Fandrick,
K. R.; Fandrick, D. R.; Reeves, J. T.; Gao, J.; Ma, S.; Li, W.; Lee, H.;
Grinberg, N.; Lu, B.; Senanayake, C. H. J. Am. Chem. Soc. 2011, 133,
0332. (c) Trost, B. M.; Ngai, M.-Y.; Dong, G. Org. Lett. 2011, 13, 1900.
d) Harper, K. C.; Sigman, M. S. Science 2011, 333, 1875. (e) Barnett, D.
S.; Schaus, S. E. Org. Lett. 2011, 13, 4020. (f) Kohn, B. L.; Ichiishi, N.;
Jarvo, E. R. Angew. Chem., Int. Ed. 2013, 52, 4414. (g) Yamashita, Y.; Cui,
Y.; Xie, P.; Kobayashi, S. Org. Lett. 2015, 17, 6042. (h) Yang, Y.; Perry, I.
B.; Lu, G.; Liu, P.; Buchwald, S. L. Science 2016, 353, 144.
5) For the related propargylation of N,O-aminals, see: Huang, Y.-H.;
Chakrabarti, A.; Morita, N.; Schneider, U.; Kobayashi, S. Angew. Chem.,
(18) Ackermann, L.; Kaspar, L. T. J. Org. Chem. 2007, 72, 6149.
(19) Yim, J.C-H.; Bexrud, J. A.; Ayinla, R. O.; Leitch, D. C.; Schafer, L.
L. J. Org. Chem. 2014, 79, 2015.
20) For the isolation of crispine A, see: (a) Zhang, Q.; Tu, G.; Zhao,
Y.; Cheng, T. Tetrahedron 2002, 58, 6795. For recent examples of
asymmetric syntheses, see: (b) Lin, W.; Ma, S. Org. Chem. Front. 2014, 1,
3
2
1
(
(
38. (c) Heath, R. S.; Pontini, M.; Bechi, B.; Turner, N. J. ChemCatChem
014, 6, 996. (d) Mons, E.; Wanner, M. J.; Ingemann, S.; van
Maarseveen, J. H.; Hiemstra, H. J. Org. Chem. 2014, 79, 7380.
21) For the isolation of harmicine, see: (a) Kam, T.-S.; Sim, K.-W.
Phytochemistry 1998, 47, 145. For reviews of synthetic efforts, see:
b) Chakraborty, I.; Jana, S. Synthesis 2013, 45, 3325. (c) Lood, C. S.;
Koskinen, A. M. P. Chem. Heterocycl. Compd. (N. Y., NY, U. S.) 2015, 50,
367. For recent examples of asymmetric syntheses, see: (d) Mondal,
(
(
Int. Ed. 2011, 50, 11121.
6) (a) Vieira, E. M.; Haeffner, F.; Snapper, M. L.; Hoveyda, A. H.
(
(
Angew. Chem., Int. Ed. 2012, 51, 6618. (b) Wu, H.; Haeffner, F.;
Hoveyda, A. H. J. Am. Chem. Soc. 2014, 136, 3780. For the related
allenylation, see: (c) Mszar, N. W.; Haeffner, F.; Hoveyda, A. H. J. Am.
Chem. Soc. 2014, 136, 3362.
7) (a) Kagoshima, H.; Uzawa, H.; Akiyama, T. Chem. Lett. 2002, 31,
98. (b) Wisniewska, H. M.; Jarvo, E. R. Chem. Sci. 2011, 2, 807.
c) Osborne, C. A.; Endean, T. B. D.; Jarvo, E. R. Org. Lett. 2015, 17,
340.
8) (a) Schopf, C.; Arm, H.; Krimm, H. Chem. Ber. 1951, 84, 690.
b) Fuhlhage, D. W.; VanderWerf, C. A. J. Am. Chem. Soc. 1958, 80,
1
P.; Argade, N. P. Synthesis 2014, 46, 2591. (e) Lood, C. S.; Koskinen, A.
M. P. Eur. J. Org. Chem. 2014, 2014, 2357. (f) Reddy, N. S. S.; Babu, R.
A.; Reddy, B. V. S. Synthesis 2016, 48, 1079.
(
2
(
5
(
(
6249. (c) Claxton, G. P.; Allen, L.; Grisar, J. M. Org. Synth. 1977, 56, 118.
(
d) Nomura, Y.; Bando, T.; Takeuchi, Y.; Tomoda, S. Bull. Chem. Soc.
D
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Org. Lett. XXXX, XXX, XXX−XXX