Highly diastereoselective zinc-catalyzed propargylation of tert-butanesulfinyl lmines

Article abstract of DOI:10.1021/ol9028258

(Chemical Equetion Presentation) A zinc-catalyzed diastereoselective propargylation of t-butanesulfinyl imines is presented. The methodology provided both aliphatic and aryl homopropargylic amines in up to 98:2 and 99.8:0.2 dr, respectively. The utility of the homopropargylic amines was demonstrated by the application to the synthesis of a cis-substituted pyrido-indole through a diastereoselective Pictet-Spengler cyclization.

Full text of DOI:10.1021/ol9028258

ORGANIC
LETTERS
2010
Vol. 12, No. 4
748-751
Highly Diastereoselective Zinc-Catalyzed
Propargylation of tert-Butanesulfinyl
Imines
Daniel R. Fandrick,* Courtney S. Johnson, Keith R. Fandrick, Jonathan
T. Reeves, Zhulin Tan, Heewon Lee, Jinhua J. Song, Nathan K. Yee, and Chris
H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals, Inc.,
900 Old Ridgebury Road/P.O. Box 368, Ridgefield, Connecticut 06877-0368
daniel.fandrick@boehringer-ingelheim.com
Received December 8, 2009
ABSTRACT
A zinc-catalyzed diastereoselective propargylation of t-butanesulfinyl imines is presented. The methodology provided both aliphatic and aryl
homopropargylic amines in up to 98:2 and 99.8:0.2 dr, respectively. The utility of the homopropargylic amines was demonstrated by the
application to the synthesis of a cis-substituted pyrido-indole through a diastereoselective Pictet-Spengler cyclization.
The prevalence of chiral R-branched amines in natural
products, active biological molecules, and ligands under-
scores the importance for general asymmetric methods for
their efficient construction.1 Nucleophilic additions to enan-
tiomerically pure sulfinyl imines have quickly emerged as a
practical and highly diastereoselective approach for the
synthesis of this functional group.2 The alkynyl functionality
within homopropargylic amines derived from a propargyla-
tion of imines provides a synthetic handle for couplings or
further derivation.3 The diastereoselective propargylation of
chiral t-butanesulfinyl imines has been reported by the
addition with a stoichiometrically pregenerated Grignard4
or allenylzinc3,5 reagent. Recently, we reported the zinc-
catalyzed propargylation of aldehydes with propargyl boro-
lanes wherein a catalytic cycle was achieved through a B/Zn
exchange between an alkoxide-zinc intermediate and the
borolane reagent.6 A complementary catalytic cycle can also
be achieved if the sulfinyl imido zinc product 4 from the
propargylation of a sulfinyl imine with an allenylzinc species
can also participate in a B/Zn exchange with the borolane
reagent 1 (Scheme 1). Herein, we report this diastereose-
(3) For selected examples of synthetic application of chiral amines
derived from the propargylation of sulfinyl imines, see: (a) Voituriez, A.;
Ferreira, F.; Perez-Luna, A.; Chemla, F. Org. Lett. 2007, 9, 4705–4708.
(b) Voituriez, A.; Ferreira, F.; Chemla, F. J. Org. Chem. 2007, 72, 5358–
5361. (c) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. J. Org. Chem.
2009, 74, 2238–2241.
(4) Hashmi, A. S. K.; Schafer, S.; Bats, J. W.; Frey, W.; Rominger, F.
Eur. J. Org. Chem. 2008, 489, 1–4899.
(1) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kesseler, M.;
Stuermer, R.; Zelinski, T. Angew. Chem., Int. Ed. Engl. 2004, 43, 788–
824.
(5) (a) Chemla, F.; Ferreira, F. J. Org. Chem. 2004, 69, 8244–8250. (b)
Ferreira, F.; Audouin, M.; Chemla, F. Chem.sEur. J. 2005, 11, 5269–
5278. (c) Chemla, F.; Ferreira, F. Synlett 2006, 2613–2616. (d) Chemla,
F.; Ferreira, F.; Gaucher, X.; Palasi, L. Synthesis 2007, 1235–1241. (e)
Seguin, C.; Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. J. Org.
Chem. 2009, 74, 6986–6992. (f) Voilturiez, A.; Perez-Luna, A.; Ferreira,
F.; Botuha, C.; Chemla, F. Org. Lett. 2009, 11, 931–934.
(2) For recent reviews, see: (a) Ellman, J. A.; Owens, T. D.; Tang, T. P.
Acc. Chem. Res. 2002, 35, 984–995. (b) Zhou, P.; Chen, B.-C.; Davis, F. A.
Tetrahedron 2004, 60, 8003–8030. (c) Senanayake, C. H.; Krishnamurthy,
D.; Lu, Z.-H.; Han, Z.; Gallou, I. Aldrichimica Acta 2005, 38, 93–104. (d)
Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869–8905. (e) Ferreira,
F.; Botuha, C.; Chemla, F.; Perez-Luna, A. Chem. Soc. ReV. 2009, 38, 1162–
1186.
(6) Fandrick, D. R.; Fandrick, K. R.; Reeves, J. T.; Tan, Z.; Johnson,
C. S.; Lee, H.; Song, J. J.; Yee, N. K.; Senanayake, C. H. Org. Lett. 2010,
12, 88–91.
10.1021/ol9028258  2010 American Chemical Society
Published on Web 01/25/2010

catalyst loading. However, the use of a highly coordinating
solvent such as DMF reduced the selectivity.
The structure of the chiral auxiliary showed a more
pronounced effect on the diastereoselectivity (Table 2).
Scheme 1
.
Proposed Catalytic Cycle for the Zinc-Catalyzed
Propargylation of Sulfinyl Imines
Table 2. Effect of Sulfinyl Substituent on Diastereoselectivitya
lective zinc-catalyzed propargylation of t-butanesulfinyl
imines with propargyl borolanes.
No reaction was observed between the propargyl borolane
1 and t-butanesulfinyl imine 6b at ambient temperature
(Table 1). The addition of catalytic diethyl zinc (10 mol %)
Table 1. Optimization of the Zinc-Catalyzed Propargylation of
tert-Butanesulfinyl Iminesa
a Reaction performed with 1.5 equiv of borolane 1. b Isolated yield.
c
dr determined by H NMR or HPLC.7 d 91% HPLC assay yield. e 18 h
1
reaction.
Utilizing the p-toluene sulfinyl auxiliary afforded an 85:15
diastereomeric ratio. The more sterically demanding 2,4,6-
triisopropylphenyl substituent8 also lowered the diastereo-
selectivity compared to the parent t-butyl group. This reaction
with the more hindered substituent was also significantly
slower than the parent system and furnished a lower yield.
After establishing the optimal conditions with the parent
t-butanesulfinyl auxiliary, the substrate scope was examined
(Table 3). High diastereoselectivities were achieved for both
aryl (>98:2) and alkyl substrates (>94:6). A positive cor-
relation between the diastereoselectivity and the steric
influence at the R-position of the substrate was apparent. For
example, a 99.4:0.6 dr (entry 1) was obtained with the phenyl
substrate, and a 99.8:0.2 dr (entry 10) was observed with
the R-naphthyl imine. A similar increase was exhibited
between the primary and secondary aliphatic imines (entries
entry Et2Zn
temp
solvent timeb yieldc
drd
1
2
3
4
5
6
7
8
9
none
10%
20%
40%
80%
20%
20%
20%
20%
20%
20%
20%
20 °C THF
20 °C THF
20 °C THF
20 °C THF
20 °C THF
40 °C THF
0 °C THF
-20 °C THF
20 °C CH2Cl2
20 °C EtOAc
20 °C MTBE
20 °C DMF
30 he
18 h
3 h
0%
90%
91%f
80%
77%
86%
88%
86%
91%
91%
92%
89%
-
99.3:0.7
99.4:0.6
99.6:0.4
99.6:0.4
99.5:0.5
99.5:0.5
99.4:0.6
99.5:0.5
99.7:0.3
99.7:0.3
92:8
1 h
1 h
1 h
21 h
72 h
16 h
16 h
16 h
1 h
10
11
12
a Reactions performed with 1.5 equiv of borolane 1. b Time until
complete conversion. c HPLC assay yield. d dr determined by HPLC.7 e At
30 h, < 5% conversion. f 83% Isolated yield.
(7) Diastereoselectivity determined by HPLC analysis compared to
diastereomer mixture standards prepared acoording to: Brak, K.; Barrett,
K. T.; Ellman, J. A. J. Org. Chem. 2009, 74, 3606–3608.
(8) (a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Pflum,
D. A.; Senanayake, C. H. Tetrahedron Lett. 2003, 44, 4195–4197. (b)
Schenkel, L. B.; Ellman, J. A. J. Org. Chem. 2004, 69, 1800–1802. (c)
Savile, C. K.; Magloire, V. P.; Kazlauskas, R. J. J. Am. Chem. Soc. 2005,
127, 2104–2113. (d) Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413–
2416. (e) Davis, F. A.; Chai, J. ARKIVOC 2008, 190–203.
promoted the propargylation reaction to afford the homopro-
pargylic amine 7b in 90% yield with high diastereoselectivity
(>99:1) (entry 2). Increasing the catalyst loading to 20 mol
% enabled complete conversion within 3 h while maintaining
the high yield. Interestingly, the diastereoselectivity (>99:1
dr) was generally insensitive to temperature, solvent, and
Org. Lett., Vol. 12, No. 4, 2010
749

Table 3. Substrate Scope for the Zinc-Catalyzed Propargylation
Scheme 2
.
Conversion to Homoallylic Sulfinylamine and
Determination of Configuration
of Sulfinyl Iminesa
to the known homoallylic amine 11 (Scheme 2). Standard
trimethylsilyl deprotection and hydrozirconation provided
olefin 11 in good yield. The relative configuration of
homoallylic amine 11 derived from the propargylation
reaction was readily established by spectral comparison to
both previously characterized diastereomers of amine 11.9
The relative stereochemical assignments of the propargylation
products 9a-i were assigned by analogy.
The utility of the homopropargylic amines was demon-
strated by the application to the synthesis of the pyrido-indole
17 through a diastereoselective Pictet-Spengler cyclization10
(Scheme 3). Sonogashira coupling of the homopropargylic
amine 10 to the o-iodoaniline 12 furnished the indole
precursor 13 in good yield. The subsequent TBAF-promoted
cyclization11 also proceeded with BOC migration and sulfinyl
deprotection to provide the BOC-protected aminoindole 14
in high yield. To probe whether TBAF can directly deprotect
sulfinyl auxiliaries, the t-butanesulfinyl homopropargylic
amine 10 was subjected to the TBAF cyclization conditions
and showed minimal deprotection after 15 h. Accordingly,
the sulfinyl deprotection observed during the TBAF-
promoted cyclization of alkyne 13 reasonably occurred after
acyl migration.12 The aminoindole 14 showed some instabil-
ity to strong acids. Therefore, BOC deprotection was
performed with TBSOTf13 to cleanly provide amine 15. The
Pictet-Spengler reaction between amine 15 and 3-bro-
mobenzaldehyde readily proceeded at ambient temperature
with good diastereoselectivity (>10:1 dr) by simple treatment
with MgSO4 to afford the cis-substituted pyrido-indole 17
in reasonable yield after acylation.
The catalytic activity observed with zinc for the propar-
gylation of sulfinyl imines can be reasonably rationalized
by a zinc-mediated propargylation and a subsequent B/Zn
exchange between the imidozinc adduct 4 and the propargyl
borolane reagent 1 (Scheme 1). Previously, the rapid conver-
sion of propargyl borolane 1 to ethyl borolane 2 with diethyl
(9) Sun, X.-W.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2006, 8, 4979–4982.
(10) For related Pictet-Splenger reactions, see: (a) Molina, P.; Alcantara,
J.; Lopez-Leonardo, C. Tetrahedron Lett. 1996, 36, 953–956. (b) Bailey,
P. D.; Morgan, K. M. J. Chem. Soc., Perkin Trans. 1 2000, 3578–3583.
(11) Xiong, X.; Pirrung, M. C. Org. Lett. 2008, 10, 1151–1154.
(12) Proposed mechanism for the acyl migration and sulfinyl deprotection
observed during the preparation of indole 14:
a Reaction performed with 1.5 equiv of borolane 1. b Isolated yield.
c Diastereoselectivity determined by HPLC.7 d Diastereoselectivity deter-
1
mined by H NMR, and the minor diastereomer was not detected.
5-7). The methodology tolerated numerous functional
groups including halides, esters, primary amides, and car-
bamates.
The stereochemical outcome of the zinc-catalyzed prop-
argylation of sulfinyl imines was determined by conversion
(13) Trost, B. M.; Fandrick, D. R. Org. Lett. 2005, 7, 823–826.
Org. Lett., Vol. 12, No. 4, 2010
750

Scheme 3
.
Application toward Indole Synthesis and a
Scheme 4. Mechanism Proposal for Stereocontrol
Diastereoselective Intramolecular Pictet-Spengler Reaction
transition state previously proposed for the zinc-mediated
allylation9 of chiral sulfinyl imines also predicts the stere-
ochemical outcome observed for the zinc-catalyzed propar-
gylation (Scheme 4). By analogy to the B/Zn exchange
described between an alkoxyzinc species and an allyl16 or
propargyl borolane,6 a similar exchange can be proffered
between the imidozinc adduct 4 and the propargyl borolane
reagent 1. Accordingly, this exchange readily regenerates the
allenyl zinc reagent and establishes a catalytic cycle to require
substoichiometric amounts of zinc to effect a propargylation
of sulfinyl imines.
zinc was demonstrated.6 The selective formation of the
propargyl product over the allenyl adduct is consistent with
a zinc-mediated propargylation.5,14 Alternatively, the direct
reaction of the propargyl borolane with the electrophile
commonly proceeds through an inversion mechanism to favor
the allenyl isomer.15 Employing the chelated six-membered
In conclusion, we demonstrated the highly diastereose-
lective zinc-catalyzed propargylation of t-butanesulfinyl
imines. This process wherein the propargylation of sulfinyl
imines is achieved by charging catalytic diethyl zinc to a
solution of propargyl borolane and substrate at ambient
temperature provides an operationally simple method for the
synthesis of synthetically useful chiral homopropargylic
amines.
(14) For selected examples, see: (a) Tamaru, Y.; Goto, S.; Tanaka, A.;
Shimizu, M.; Kimura, M. Angew. Chem., Int. Engl. Ed. 1996, 35, 878–
880. (b) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1998, 63, 3812–
3813. (c) Marshall, J. A.; Adams, N. D. Org. Lett. 2000, 2, 2897–2900. (d)
Marshall, J. A.; Yanik, M. M. J. Org. Chem. 2001, 66, 1373–1379. (e)
Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C.
J. Am. Chem. Soc. 2002, 124, 1664–1668. (f) Bahadoor, A. B.; Flyer, A.;
Micalizio, G. C. J. Am. Chem. Soc. 2005, 127, 3694–3695. (g) Marshall,
Acknowledgment. We thank Dr. Nina Gonnella at Boe-
hringer Ingelheim Pharmaceuticals Inc. for the NMR struc-
tural determination of pyrido-indole 17.
J. A. J. Org. Chem. 2007, 72, 8153–8166
.
(15) For selected exampes of propargylations and allenylations with
boron reagents, see: (a) Brown, H. C.; Khire, U. R.; Narla, G. J. Org. Chem.
1995, 60, 8130–8131. (b) Ikeda, N.; Arai, I.; Yamamoto, H. J. Am. Chem.
Soc. 1986, 108, 483–486. (c) Corey, E. J.; Yu, C.-M.; Lee, D.-H. J. Am.
Chem. Soc. 1990, 112, 878–879. (d) Hernandez, E.; Burgos, C. H.; Alicea,
E.; Soderquist, J. A. Org. Lett. 2006, 8, 4089–4091.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C for
all products and unknown substrates. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Fujita, M.; Nagano, T.; Schneider, U.; Hamada, T.; Ogawa, C.;
Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 2914–2915.
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