Tetrasubstituted pyrrolidines via a tandem aza-Payne/hydroamination reaction

Article abstract of DOI:10.1021/ja068077w

A facile tandem aza-Payne/hydroamination reaction of aziridinol is reported, which yields highly functionalized pyrrolidines. Addition of alkynyl Grignards to 2,3-aziridinals yields, in most cases, high syn to anti ratios of the aziridinol. Treatment of the syn-aziridinol with base leads initially to an aza-Payne rearrangement, which juxtaposes the amine and the alkyne in favorable orientation to complete the hydroamination. The anti-aziridinol undergoes the aza-Payne rearrangement, but cannot proceed further with the hydroamination. Copyright

Full text of DOI:10.1021/ja068077w

Published on Web 03/10/2007
Tetrasubstituted Pyrrolidines via a Tandem Aza-Payne/Hydroamination
Reaction
Jennifer M. Schomaker, Andrea R. Geiser, Rui Huang, and Babak Borhan*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
Received November 18, 2006; E-mail: babak@chemistry.msu.edu
Scheme 1
Hydroamination reactions of alkenes and alkynes have received
considerable attention in the recent literature.1 While the hydroami-
nation of alkynes is facile compared to that of the corresponding
alkenes, many alkyne hydroamination protocols require the use of
metal catalysts or rigorously anhydrous or anaerobic conditions.
Functional group tolerance often poses a particular problem in
expanding hydroamination protocols to the preparation of syntheti-
cally useful building blocks. Hydroamination methods that do not
involve the use of transition metals are not as well developed, but
strong bases or bases containing electropositive metals have been
reported to give alkyne hydroamination, especially when the
nucleophilic nitrogen is in the form of an amide or sulfonamide.1d,e,2
Table 1. Preparation of Aziridinol Substratesa
However, the use of highly functionalized precursors has tradition-
ally been avoided, as the strongly basic conditions can often lead
to unwanted side reactions.
We report a mild tandem aza-Payne/hydroamination reaction of
aziridinols mediated by dimethylsulfoxonium methylide that yields
highly functionalized pyrrolidine ring systems in one pot at room
temperature (Scheme 1). The resulting strained enamide products
are potentially useful synthons for the rapid construction of densely
substituted pyrrolidines and pyrrolidinones for use in natural product
synthesis.3
The aziridinol substrates were synthesized from the correspond-
ing aziridine aldehydes according to a previous report describing a
chelation-controlled addition of Grignard reagents to Boc-protected
aziridine aldehydes.4 Addition of Grignard or organolithium reagents
to a series of N-tosylated aziridine aldehydes gave the desired
alcohols in good yields. The presence of an R group syn to the
carbonyl eroded the diastereoselectivity (1a and 1o, Table 1), while
the use of a trans disubstituted aziridine aldehyde gave only
moderate dr (1b and 1c). However, the use of 2,2,3-trisubstituted
aziridine aldehydes gave the syn-aziridinols as the sole detectable
product (Table 1, 1d-1m). Also of note was the excellent diaster-
eoselectivity obtained in the generation of quaternary hydroxyl
centers from aziridine ketones (1j and 1k). The presumed chelation-
a A 0.028 M solution of the aldehyde in dichloromethane was cooled to
-78 °C and treated with 5 equiv of the Grignard reagent. b Lithium acetylide
controlled process with tosyl-protected aziridines is in doubt with
the excellent dr’s obtained with the 2,2,3-trisubstituted aziridines;
this is the subject of ongoing studies (addition of excess TMEDA
as a chelating agent had no effect on the dr of the reaction). The
syn relationship between the aziridine and the alcohol was verified
by X-ray crystallography of 2d and 2h (see Supporting Information).
The high diastereoselectivity obtained in the addition of Grignard
reagents to the aziridine aldehydes was crucial to the success of
the hydroamination. As shown in Scheme 2, only the syn diaster-
eomer underwent hydroamination, as the aza-Payne rearrangement5
orients the anionic nitrogen and the alkyne on the same side of the
epoxide. The anti diastereomer undergoes the aza-Payne rearrange-
ment, but cannot cyclize to the pyrrolidine.
was used to prepare the alcohol.
pyrrolidine 5d (Table 2) was obtained in 99% yield. However, we
found dimethylsulfoxonium methylide to be an effective base for
the aza-Payne rearrangement, and thus, a one-pot conversion of
aziridinols to tetrasubstituted pyrrolidines was developed (Table
2).6 The substrates were treated with an excess of ylide (2-4 equiv)
and stirred at rt to yield the desired pyrrolidines in moderate to
good yields. For 2a and 2c, the desired syn-aziridinol substrate could
not be cleanly separated from the anti byproduct. Thus, prior
treatment of 2a and 2c with NaH in THF gave mixtures of the
epoxy amines, which were separated by column chromatography,
and the desired diastereomer was subjected to hydroamination
conditions. Alternatively, the hydroamination could be run on the
mixture of syn/anti compounds, and the epoxy amine (resulting
The hydroamination reaction was initially performed by treating
the epoxy amine 4d with 8.0 equiv of dimethylsulfoxonium
methylide and heating the reaction to 80 °C overnight. The product
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10.1021/ja068077w CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
Scheme 3
epoxide by the aza-Payne rearrangement (Scheme 2). An unfunc-
tionalized amino alkyne (8) was subjected to hydroamination
conditions (Scheme 3), but no pyrrolidine product was obtained
under several different conditions, implying a decrease in activation
entropy of the cyclization is the underlying reason for the favorable
hydroamination reaction.7
In conclusion, we have demonstrated a mild, base-mediated
tandem aza-Payne/hydroamination reaction that yields a highly
functionalized pyrrolidine ring system in the form of a strained
enamide. Further studies are underway to expand the scope and
mechanism of this hydroamination. Elaboration of the products into
useful synthons for natural product synthesis is also currently under
examination.
Table 2. One-Pot Conversion of Aziridinols to Pyrrolidinesa
Acknowledgment. Generous support was provided for J.M.S.
by a Michigan State University Distinguished Fellowship and a
Division of Organic Chemistry Graduate Fellowship sponsored by
Eli Lilly. We thank Professors Mitch Smith and Ned Jackson for
illuminating discussions.
Supporting Information Available: Experimental procedures and
spectral information is available for compounds 1a-o, 2a-o, and
5a-o, as well as coordinates for the X-ray crystal structures of 2d and
2h. This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) For selected examples, see: (a) Takemiya, A.; Hartwig, J. J. Am. Chem.
Soc. 2006, 128, 6042-6043. (b) Anderson, L. L.; Arnold, J.; Bergman,
R. G. J. Am. Chem. Soc. 2005, 127, 14542-14543. (c) Michael, F. E.;
Cochran, B. M. J. Am. Chem. Soc. 2006, 128, 4246-4247. For selected
recent reviews, see: (d) Pohlki, F.; Doye, S. Chem. Soc. ReV. 2003, 32,
104-114. (e) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. AdV.
Synth. Catal. 2002, 344, 795-813. (f) Hong, S.; Marks, T. J. Acc. Chem.
Res. 2004, 37, 673-686. (g) Odom, A. L. Dalton Trans. 2005, 2, 225-
233. (h) Hazari, N.; Mountford, P. Acc. Chem. Res. 2005, 38, 839-849.
(i) Muller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675. (j) Li, Y.; Marks,
T. J. Organometallics 1996, 15, 3770-3772.
(2) For selected examples, see: (a) Tzalis, D.; Koradin, C.; Knochel, P.
Tetrahedron Lett. 1999, 40, 6193-6195. (b) Kruse, C. W.; Kleinschmidt,
R. F. J. Am. Chem. Soc. 1961, 83, 216-220 and references therein. (c)
Koseki, Y.; Kusano, S.; Ichi, D.; Yoshida, K; Nagasaka, T. Tetrahedron
2000, 56, 8855-8865.
a The aziridinols (0.1 M in DMSO) were treated with 4.0 equiv of
dimethylsulfoxonium methylide (prepared from Me3SOI and NaH in
DMSO) and stirred at rt. b Yield starting from the epoxy amine.
from reaction of the anti diastereomer) was separated from the
desired pyrrolidine (2o). The remaining substrates (2b, 2d-2n)
contained only the syn-aziridinol, and the majority underwent
hydroamination smoothly. The exceptions were alkynes substituted
with alkyl or silyl groups (Table 2, 2h, 2l, and 2m). It may be
necessary for terminally substituted alkynes to contain a group
capable of stabilizing a developing negative charge on the carbon
adjacent to the newly forming C-N bond. The TMS-substituted
alkyne 2l did deliver the desilylated product 5d, presumably as a
result of initial deprotection of the TMS group. The Z-stereochem-
istry of the enamides obtained from aryl-substituted alkynes (2i
and 2k) may result from prior coordination of the sulfoxonium to
the opposite face of the alkyne, thus leading to rapid proton transfer
and the observed stereochemistry.
The hydroamination reaction can be run catalytically in ylide,
but the aza-Payne rearrangement requires an excess (2-4 equiv)
of ylide to proceed with good conversion. A 64% yield of 5d was
obtained from the epoxy amine 4d using 0.2 equiv of ylide. Further
studies are ongoing to find conditions that allow the aza-Payne
rearrangement to proceed using only a catalytic amount of base.
We suspected this facile hydroamination was aided by the pre-
orientation of the nitrogen and the alkyne on the same side of the
(3) For selected examples of natural products with given skeleton see: (a)
Wang, L.-W.; Su, H.-J.; Yang, S.-Z.; Won, S.-J.; Lin, C.-N. J. Nat. Prod.
2004, 67, 1182-1185. (b) Lam, Y. K. T.; Hensens, O. D.; Ransom, R.;
Giacobbe, R. A.; Polishook, J.; Zink, D. Tetrahedron 1996, 52, 1481-
1486. (c) Humphrey, A. J.; O’Hagan, D. Nat. Prod. Rep. 2001, 18, 494-
502.
(4) Righi, G.; Piertrantonio, S.; Bonini, C. Tetrahedron 2001, 57, 10039-
10046.
(5) For selected examples, see: (a) Ibuka, T.; Nakai, K.; Habashita, H.; Hotta,
Y.; Otaka, A.; Tamamura, H.; Fujii, N.; Mimura, N.; Miwa, Y.; Taga, T.;
Chounan, Y.; Yamamoto, Y. J. Org. Chem. 1995, 60, 2044-2058. (b)
Ibuka, T.; Nakai, K.; Akaji, M.; Tamamura, H.; Fujii, N. Tetrahedron
1996, 52, 11739-11752. (c) Ibuka, T. Chem. Soc. ReV. 1998, 27, 145-
154.
(6) The use of other bases, such as NaH in THF or DMSO, or Grignards was
unsuccessful in yielding the pyrrolidine products, and instead delivered
the aza-Payne rearranged epoxy amines. Presumably, the protonated ylide
(ylide used as the base) functions as a proton source during the
hydroamination of the alkyne.
(7) (a) Winnik, M. A. Chem. ReV. 1981, 81, 491-525. (b) Page, M. I.; Jencks,
W. P. Proc. Nat. Acad. Sci. U.S.A. 1971, 68, 1678-1683.
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