Zn-alkynylide additions to acyl iminiums

Article abstract of DOI:10.1021/ol049578u

A new addition reaction of zinc-alkynylides to M-acyl and N-phosphinoyl iminiums is reported. These can be prepared in situ from imines with acid halides in the presence of a Zn-acetylide. The reaction is general with regard to imine, alkyne, and acid hal

Full text of DOI:10.1021/ol049578u

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1497-1499
Zn-Alkynylide Additions to Acyl
Iminiums
Christian Fischer and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Ho¨nggerberg,
CH-8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received March 7, 2004
ABSTRACT
A new addition reaction of zinc-alkynylides to N-acyl and N-phosphinoyl iminiums is reported. These can be prepared in situ from imines with
acid halides in the presence of a Zn-acetylide. The reaction is general with regard to imine, alkyne, and acid halides, allowing access to a large
number of differentially protected propargylic amines.
Propargylic amines, like the corresponding propargylic
alcohols, can serve as high-value added intermediates and
building blocks for organic synthesis.1,2 However, while
propargylic alcohols can be conveniently prepared using a
variety of synthetic transformations,3-5 in general, methods
that provide reliable and convenient access to propargylic
amines are far fewer.6-8 Recently, we9 and others10 have
reported the addition reaction of terminal alkynes to imines
catalytic in transition metal. Our continuing interest in the
chemistry of zinc-alkynylides11 prepared directly from
terminal alkynes and zinc salts with trialkylamine bases have
led us to the discovery that imines activated in situ with a
range of acid halides serve as reactive electrophiles toward
addition by zinc-alkynylides.
There have been numerous reports on the addition reaction
of 1-alkynes and imines proceeding via Zn-acetylides,
generated from terminal acetylenes under the novel condi-
tions we reported (Zn(OTf)2, R3N, 23 °C). In general, these
(6) For addition of alkynilides to imines, see: (a) Enders, D.; Schankat,
J. HelV. Chim. Acta 1995, 78, 970. (b) Harwood, L. M.; Vines, K. J.; Drew,
M. G. B. Synlett 1996, 1051. (c) Brasseur, D.; Marek, I.; Normant, J.-F.
Tetrahedron 1996, 52, 7235. (d) Sato, Y.; Nishimata, T.; Mori, M.
Heterocycles 1997, 44, 443. (e) Cossy, J.; Poitevin, C.; Pardo, D. G.; Peglion,
J.-L.; Dessinges, A. Synlett 1998, 3, 251. (f) Courtois, G.; Desre, V.;
Miginiac, L. J. Organomet. Chem. 1998, 570, 279. (g) Florio, S.; Troisi,
L.; Capriati, V.; Suppa, G. Eur. J. Org. Chem. 2000, 65, 3793. (h) Wipf,
P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2001, 123, 5122.
(7) For Cu-mediated addition of acetylene gas to N-alkyl imines at
elevated temperatures, see: Rohm + Haas Co. U.S. Patent 2 665 311, 1950.
(8) For representative additions of other carbanions to imines, see: (a)
Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998,
120, 4548. (b) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121,
268. (c) Hamada, T.; Mizojiri, R.; Urabe, H.; Sato, F. J. Am. Chem. Soc.
2000, 122, 7138. (d) Knudsen, K.; Risgaard, T.; Nishiwaki, N.; Gothelf,
K. V.; Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843. (e) Porter, J.
R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc.
2001, 123, 984.
(1) (a) Porco, J. A., Jr.; Schoenen, F. J.; Stout, T. J.; Clardy, J.; Schreiber,
S. L. J. Am. Chem. Soc. 1990, 112, 7410.
(2) For selected examples of the use of optically active propargylic
alcohols in synthesis, see: (a) Trost, B. M.; Hipskind, P. A.; Chung, J. Y.
L.; Chan, C. Angew. Chem., Int. Ed. Engl. 1989, 28, 1502. (b) Marshall, J.
A.; Wang, X. J. J. Org. Chem. 1992, 57, 1242. (c) Roush, W. R.; Sciotti,
R. J. J. Am. Chem. Soc. 1994, 116, 6457. (d) Myers, A. G.; Zheng, B. J.
Am. Chem. Soc. 1996, 118, 4492.
(3) Stoichiometric reductions: (a) Midland, M. M.; Tramontano, A.;
Zderic, S. A. J. Am. Chem. Soc. 1977, 99, 5211. (b) Yamaguchi, S.; Mosher,
H. S.; Pohland, A. J. Am. Chem. Soc. 1972, 94, 9254. (c) Nishizawa, M.;
Yamada, M.; Noyori, R. Tetrahedron Lett. 1981, 22, 247. (d) Brown, H.
C.; Ramachandran, P. V. Acc. Chem. Res. 1992, 25, 16.
(4) Catalytic methods: (a) Helal, C. J.; Magriotis, P. A.; Corey, E. J. J.
Am. Chem. Soc. 1996, 118, 10938. (b) Matsumura, K.; Hashiguchi, S.;
Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738.
(5) For the addition of lithium and magnesium acetylides to trifluoro-
methyl aryl ketones, see: (a) Tan, L.; Chen, C.-Y.; Tillyer, R. D.;
Grabowski, E. J. J.; Reider, P. Angew. Chem., Int. Ed. 1999, 38, 711. (b)
For a recent report on the addition of aromatic aldehydes with alkynylzinc
reagents generated in situ from terminal acetylenes and dimethylzinc, see;
Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele, L.; Reider, P. J. Synthesis
1999, 1453. (c) For a recent study of chelation-controlled stannylacetylene
additions to aldehydes, see: Evans, D. A.; Halstead, D. P.; Allison, B. D.
Tetrahedron Lett. 1999, 40, 4461.
(9) Fischer, C.; Carreira, E. M. Org. Lett. 2001, 3, 4319.
(10) (a) Li, C.-J.; Wei, C. Chem. Commun. 2002, 268. (b) Wei, C.; Li,
C.-J. J. Am. Chem. Soc. 2002, 124, 5638. (c) Wei, C.; Li, Z.; Li, C.-J. Org.
Lett. 2003, 5, 4473. (d) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125,
9584. (e) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed.
2002, 41, 2535. (f) Koradin, C.; Gommermann, N.; Polborn, K.; Knochel,
P. Chem. Eur. J. 2003, 9, 2797. (g) Gommermann, N.; Koradin, C.; Polborn,
K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763.
10.1021/ol049578u CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/07/2004

reports tend to include a rather limited number of imine and
alkyne substrates, most typically aromatic aldimines and
phenyl acetylene.12 Moreover, examples involving additions
to acyl imminiums to give amide products are, to date, wholly
unprecedented.
Mechanistic observations suggest that the species gener-
ated under the conditions we have described give rise to
organozinc reagents that are unique, displaying quite different
characteristics relative to the more traditional dialkyl or
dialkynylzinc reagents previously documented. We have been
interested in exploring the reactivity and behavior of these
systems with a wide range of electrophiles. Prospecting
studies in our group revealed that zinc-alkynylides prepared
from terminal alkynes, Zn(OTf)2, and triethylamine do not
undergo addition to simple unactivated imines under a variety
of conditions. However, in the presence of Lewis acid
promoters such as BF3‚OEt2, imine additions could be
observed, albeit long reaction times (days) were necessary,
and, depending on the imine, extensive decomposition of
the aldimine was observed.
5), and propargyl trimethylsilane (entry 6). Isoquinoline
(entry 12) can be utilized in the addition reaction.
As indicated in Table 1, a number of acyl halides were
examined as activating agents from which acetyl chloride,
acetyl bromide, benzoyl chloride, and trichloroacetyl chloride
were particularly useful. The product propargyl amides were
obtained in high yields for any combination of the three
components in the reaction.
We proceeded to address the question of whether other
activating agents could be employed for the activation of
imines, allowing access to differentially protected propargylic
amines. A protecting group that is often used in imine
addition reactions is the diphenylphosphinoyl moiety.15 This
masking group has an important advantage, as it is con-
veniently cleaved from the product amides with Brønsted
acids.16 Because phosphinoyl chlorides are more tame as
In further investigations, we noted that the reaction of
imines with acyl halides leads to the formation of a putative
acyl iminium, which undergoes additions by zinc-alkynylides
in good yields over 1 h (eq 1).13 In the experiment, when a
solution of the imine and acid chloride (toluene, 0 °C) was
added to a solution of Zn-acetylide (terminal acetylene, Zn-
(OTf)2, Et3N, and N,N,N′,N′-tetramethylpropylene diamine,
TMPDA14) rapid formation of propagyl amide was observed
(eq 1, Table 1).
Table 1. Zinc-Alkynylide Additions to N-Acyl Iminiumsa
The addition reaction displays broad scope (Table 1):
imines derived from aromatic and aliphatic aldehydes furnish
adducts in good yields. Aldimines with protecting groups
such as N-allyl, N-benzyl, or N-(p-methoxy-phenyl) react
with zinc-alkynylides derived from phenylacetylene, silyl-
acetylenes (entries 1 and 2), alkyl-substituted alkynes such
as 4-phenylbutyne (entry 8), bulky 2,2-dimethylbutyne (entry
(11) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
1999, 121, 11245. (b) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am.
Chem. Soc. 2000, 122, 1806. (c) Boyall, D.; Lopez, F.; Sasaki, H.; Carreira,
E. M. Org. Lett. 2000, 2, 4233. (d) Sasaki, H.; Boyall, D.; Carreira, E. M.
HelV. Chim. Acta 2001, 84, 964. (e) El-Sayed, E.; Anand, N. K.; Carreira,
E. M. Org. Lett. 2001, 3, 3017. (f) Anand, N. K.; Carreira, E. M. J. Am.
Chem. Soc. 2001, 123, 9687. (g) Boyall, D.; Frantz, D. E.; Carreira, E. M.
Org. Lett. 2002, 4, 2605. (h) Diez, R. S.; Adger, B.; Carreira, E. M.
Tetrahedron 2002, 58, 8341. (i) Fa¨ssler, R.; Frantz, D. E.; O¨ tiker, J.; Carreira,
E. M. Angew. Chem., Int. Ed. 2002, 41, 3054. (j) Reber, S.; Kno¨pfel, T. F.;
Carreira, E. M. Tetrahedron 2003, 59, 6813.
(12) (a) Jiang, B.; Si, Y.-G. Tetrahedron Lett. 2003, 44, 6767. (b) Jiang,
B.; Si, Y.-G. Angew. Chem., Int. Ed. 2004, 43, 216.
(13) Use of acylating reagents to facilitate nucleophilic additions to imines
is most commonly employed in additions to heteroaromatic compounds such
as quinolines. For selected examples, see: (a) Mori, S.; Iwakura, H.;
Takechi, S. Tetrahedron Lett. 1988, 29, 5391. (b) Shair, M. D.; Yoon, T.;
Chou, T.-C.; Danishefsky, S. J. Angew. Chem. 1994, 106, 2578. (c) Elbaum,
D.; Porco, J. A., Jr.; Stout, T. J.; Clardy, J.; Schreiber, S. L. J. Am. Chem.
Soc. 1995, 117, 211. (d) Brana, M. F.; Moran, M.; De Vega, M. J. P.;
Pita-Romero, I. J. Org. Chem. 1996, 61, 1369. (e) Nicolaou, K. C.; Gross,
J. L.; Kerr, M. A. J. Heterocycl. Chem. 1996, 33, 735. (f) Unno, R.;
Michishita, H.; Inagaki, H.; Baba, Y.; Jomori, T.; Nishikawa, T.; Isobe, M.
Chem. Pharm. Bull. 1997, 45, 125. (g) Magnus, P.; Eisenbeis, S. A.;
Fairhurst, R. A.; Iliadis, T.; Magnus, N. A.; Parry, D. J. Am. Chem. Soc.
1997, 119, 5591. (h) Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S.
B.; Madar, D. J. J. Am. Chem. Soc. 1997, 119, 6072.
a In a typical reaction, Zn(OTf)2 (0.6 mmol), NEt3 (0.66 mmol), TMPDA
(0.66 mmol), and alkyne (0.66 mmol) along with imine (0.5 mmol) and
the acyl halide (0.5 mmol) were used. Yields refer to isolated yields after
chromatography. TMPDA ) N,N,N′,N′-tetramethyl propane diamine. PMP
) p-methoxy phenyl. For details, see Supporting Information
(14) We have found that the addition of TMPDA leads to a homogeneous
solution of the acetylide in toluene and overall faster, cleaner reactions.
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Org. Lett., Vol. 6, No. 9, 2004

reagents than their carboxylic acid chloride counterparts, we
examined the possibility of conducting the reaction using a
simplified reaction protocol, wherein imine activation (imine
+ phosphinoyl halide) and acetylene metalation (acetylene
+ Zn(II) + amine base) are effected in one reaction vessel.
Successful implementation of this protocol would require
differential reactivity, or chemoselective reaction, of the
phosphinoyl chloride and the Zn-acetylide versus imine.
In the experiment, we observed that both aromatic and
aliphatic aldimines react with zinc-alkynylides directly in the
presence of diphenylphosphinic chloride to give the corre-
sponding diphenylphosphinic acid-derived propargyl amides
(Scheme 1). Given the fact that in control experiments Zn-
absence of acid chloride activator, the results strongly suggest
that imine preferentially reacts with the phosphinoyl chloride
to give an activated phosphinoyl iminium that then undergoes
addition by the acetylide.
In an effort to provide some detailed insight into the
reaction process involving activation by carboxylic acid
1
halides, we have carried out some H NMR spectroscopic
experiments. When a solution of benzyl-benzylidene-amine
is treated with benzoyl chloride in toluene-d8 at room
temperature, formation of a precipitate is observed, which
we believe to be the N-acyl iminium salt. The monitoring
of the reaction by 1H NMR allowed us to determine that the
imine is quantitatively consumed upon addition of the acyl
halide within 1 h as determined by the disappearance of the
singlet at δ 4.52 ppm, corresponding to the benzylic protons.
When the carboxylic acid halide is added directly to a
solution of zinc-alkynylide and imine, no propargylic amide
is formed and decomposition ensues. We surmise that the
alkynylide adds to the acid chloride to afford the corre-
sponding ynone that then subsequently participates in a
number of further reactions.
Scheme 1
We have documented a new process for the synthesis of
fully differentially protected propargylic amines via a zinc-
alkynylide addition to N-acyl iminiums prepared in situ from
aldimines and acid halides. Additionally, we have shown the
feasibility of direct activation by phosphinic chlorides and
alkynylation of an acyl imine without recourse to activation.
The development of asymmetric and catalytic zinc-alkynylide
addition reactions to N-acyl imines and iminiums is ongoing
and will be reported in due course.
acetylides were shown to be unreactive toward imines in the
(15) For selected recent examples, see: (a) Yamamoto, Y.; Kubota, Y.;
Honda, Y.; Fukui, H.; Asao, N.; Nemoto, H. J. Am. Chem. Soc. 1994, 116,
3161. (b) Cantrill, A. A.; Hall, L. D.; Jarvis, A. N.; Osborn, H. M. I.; Raphy,
J.; Sweeney, J. B. J. Chem. Soc., Chem. Commun. 1996, 2631. (c) Gaul,
C.; Schaerer, K.; Seebach, D. J. Org. Chem. 2001, 66, 3059. (d) Pinho, P.;
Andersson, P. G. Tetrahedron 2001, 57, 1615. (e) Wipf, P.; Kendall, C.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2001, 123, 5122. (f) Boezio, A. A.;
Charette, A. B. J. Am. Chem. Soc. 2003, 125, 1692. (g) Matsunaga, S.;
Kumagai, N.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 4712.
(16) For a recent example, see: Wipf, P.; Kendall, C.; Stephenson, C.
R. J. J. Am. Chem. Soc. 2003, 125, 761.
Acknowledgment. We are grateful for the support of this
research by Sumika, Ltd., Japan.
Supporting Information Available: Experimental pro-
cedures and spectral data for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL049578U
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