Umpolung amination: Nickel-catalyzed coupling reactions of N,N-dialkyl-N-chloroamines with diorganozinc reagents

Article abstract of DOI:10.1021/ja907038b

(Chemical Equation Presented) N,N-Dialkyl-N-chloroamines are an effective source of electrophilic nitrogen for nickel-catalyzed coupling with diarylzinc reagents. A variety of N-chloroamines as well as organozinc reagents react smoothly under the reaction conditions. A one-pot procedure that circumvents the need to isolate the N-chloroamines is described.

Full text of DOI:10.1021/ja907038b

Published on Web 10/13/2009
Umpolung Amination: Nickel-Catalyzed Coupling Reactions of
N,N-Dialkyl-N-chloroamines with Diorganozinc Reagents
Timothy J. Barker and Elizabeth R. Jarvo*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
Received August 19, 2009; E-mail: erjarvo@uci.edu
Table 1. Amination of Diorganozinc Reagents
Nitrogen-carbon bond-forming reactions are important for their
use in the synthesis of natural products and medicinal chemistry
targets, as demonstrated by the breadth of research interest in this
area in recent years.1 The Buchwald-Hartwig amination, cross-
coupling of aryl halides with amines, is an efficient method for
this bond construction.1b-d An umpolung strategy, reaction of an
electrophilic nitrogen source with a nucleophilic organometallic
reagent, would provide a complementary method for the formation
of anilines under nonbasic conditions. We report the use of N,N-
dialkyl-N-chloroamines as electrophilic nitrogen sources for the
amination of diarylzinc reagents in the presence of a Ni catalyst
(eq 1). A one-pot procedure for chlorination and coupling of the
amine with diarylzinc is also presented.
Umpolung amination reactions have received significant attention
recently because of the utility an electrophilic amination provides
in forming N-C bonds.2 Johnson and co-workers have reported
Cu- and Ni-catalyzed amination of organozinc reagents using N,N-
dialkyl-O-acyl hydroxylamine derivatives.3,4 Lei and co-workers
recently published a Cu-catalyzed arylation of N-chloroamides with
phenylboronic acid derivatives to form secondary amides.5,6
The coupling of N-chloroamines would be a significant advance
in umpolung amination because these substrates are straightforward
to prepare and isolate by treatment of the corresponding amines
with bleach followed by extraction.7 Prior investigations into
coupling of N-chloroamines with organometallic reagents provided
the desired anilines in low yields (10-20%).3a,5 We hypothesized,
however, that under the appropriate reaction conditions, oxidative
addition of Ni(0) with the chloroamine would occur, allowing for
cross-coupling to form the requisite C-N bond.8,9 Gratifyingly,
we found that the reaction of N,N-dibutyl-N-chloroamine (1a) with
phenylzinc chloride, using a bipyridine-ligated Ni catalyst, afforded
the desired product in modest yield (Table 1, entry 1).
a Isolated yield after column chromatography. b Reaction conditions:
PhZnCl (2.5 equiv), DMA/THF (1:2), rt, 16 h. c Reaction conditions:
PhZnBr (1.6 equiv), DMA/THF (1:2.4),
0 °C, 8
h. d Reaction
conditions: Ph2Zn (1 equiv), DMA/THF (1:1.6), 0 °C, 6 h. e Using 3
equiv of Ph2Zn.
With an optimized catalyst system in hand, a number of arylations
of N,N-dialkyl-N-chloroamines were examined. Acyclic as well as
cyclic N-chloroamines proved to be effective in this reaction. Boc-
protected nitrogens were well-tolerated in this reaction (entry 7).
The diminished yield with N-methyl-N-chlorobenzylamine (1g) was
attributed to the formation of benzaldehyde during the course of
the reaction.14 Electron-poor N-chloroamines such as N-chloroa-
mides and N-chlorosuccinimide (NCS) did not undergo coupling
under the current reaction conditions.15
The reaction conditions were optimized for the coupling of 1a.
Several solvents were surveyed, and a DMA/THF solvent mixture
was found to be optimal.10 A variety of ligands were examined,
with bipyridine producing the highest yield.11 Phosphines were
ineffective as ligands for this reaction.12 Either phenylzinc bromide
or diphenylzinc could be utilized as a coupling partner (entries 2
and 3). The amount of diphenylzinc could be reduced to 1 equiv
with increased reaction time (entry 4); use of less diphenylzinc
resulted in a lower yield because of competitive formation of
biphenyl as a byproduct under the reaction conditions. Control
experiments revealed that the bipyridine-ligated Ni catalyst was
necessary for the reaction to proceed.13
The functional-group tolerance of this reaction is highlighted in
entries 12 and 13. Substrates with a terminal alkene, such as 1i,
were tolerated in this reaction. Coupling of the N-chloroamine
occurred, and no cyclization with the olefin was observed. This
result contrasts with previous work by Go¨ttlich and co-workers,
who reported that under transition metal-catalyzed conditions,
N-chloroamines were found to cyclize onto terminal olefins and
rearrange to form substituted piperidines.16,17 Substrate 1j with a
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15598 J. AM. CHEM. SOC. 2009, 131, 15598–15599
10.1021/ja907038b CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Amination of Diorganozinc Reagents
strategy for aniline synthesis employs a readily available catalyst and
ligand and provides a mild and convenient complement to amination
reactions of aryl halides. Either isolated N-chloroamines or a one-pot
procedure starting from the corresponding amine and NCS can be
utilized, increasing the versatility of the method. Further work in our
laboratories will focus on expanding the scope of this reaction to
include primary and aryl N-chloroamines as well as studying the
mechanism of this transformation.
Acknowledgment. We thank Pfizer for financial support and
Dr. John Greaves for mass spectrometric analyses.
Supporting Information Available: Experimental details and
spectroscopic and analytical data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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S. L. Acc. Chem. Res. 1998, 31, 805. (c) Hartwig, J. F. Angew. Chem., Int.
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1947. Also see: (d) Smulik, J. A.; Vedejs, E. Org. Lett. 2003, 5, 4187. (e)
Greck, C.; Bischoff, L.; Ferreira, F.; Geneˆt, J. P. J. Org. Chem. 1995, 60,
7010. (f) Bernardi, P.; Dembech, P.; Fabbri, G.; Ricci, A.; Seconi, G. J.
Org. Chem. 1999, 64, 641. (g) Sapountzis, I.; Knochel, P. Angew. Chem.,
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a Isolated yield after column chromatography. b Yield determined by
1H NMR spectroscopy by comparison to an internal standard.
Scheme 1. One-Pot Chlorination and Arylation of Amines
(3) For Cu-catalyzed amination using hydroxylamines, see: (a) Berman, A. M.;
Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680. (b) Berman, A. M.;
Johnson, J. S. J. Org. Chem. 2005, 70, 364. (c) Berman, A. M.; Johnson,
J. S. J. Org. Chem. 2006, 71, 219. (d) Campbell, M. J.; Johnson, J. S. Org.
Lett. 2007, 9, 1521.
(4) For Ni-catalyzed amination using hydroxylamines, see: Berman, A. M.;
Johnson, J. S. Synlett 2005, 1799.
(5) He, C.; Chen, C.; Cheng, J.; Liu, C.; Liu, W.; Li, Q.; Lei, A. Angew. Chem.,
Int. Ed. 2008, 47, 6414. This method was not effective with 1a (11% yield).
(6) N-Arylsuccinimide has been observed as a minor byproduct (8% yield) in
NCS-mediated, Pd-catalyzed oxidative functionalization of C-H bonds.
See: Whitfield, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 15142.
(7) N-Chloroamines can be prepared by treating the corresponding amines with
bleach. See: Zhong, Y.-L.; Zhou, H.; Gauthier, D. R.; Lee, J.; Askin, D.;
Dolling, U. H.; Volante, R. P. Tetrahedron Lett. 2005, 46, 1099.
(8) Our working hypothesis was based on a cross-coupling mechanism for the
transformation that would be initiated by oxidative addition of the Ni
catalyst into the N-Cl bond by a single-electron-transfer (SET) mechanism.
For studies of oxidative addition of alkyl halides by an SET mechanism,
see: (a) Stille, J. K.; Cowell, A. B. J. Organomet. Chem. 1977, 124, 253.
(b) Jones, G. D.; Martin, J. L.; McFarland, C.; Allen, O. R.; Hall, R. E.;
Haley, A. D.; Brancond, R. J.; Konovalova, T.; Desrochers, P. J.; Pulay,
P.; Vicic, D. A. J. Am. Chem. Soc. 2006, 128, 13175. For the reaction of
NBS with Ni(0) complexes, see: (c) Weston, C. W.; Verstuyft, A. W.;
Nelson, J. H.; Jonassen, H. B. Inorg. Chem. 1977, 16, 1313. For reductive
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Organometallics 1995, 14, 4421.
free amide was also a competent substrate, affording the tertiary
amine in good yield.18
An array of diarylzinc reagents were found to be effective under
the reaction conditions (Table 2). Electron-donating substituents
(entries 1, 2, and 4) as well as electron-withdrawing substituents
(entries 3 and 5) were tolerated, providing coupling products in
good yields. A meta-substituted diarylzinc reagent (entry 5) and a
heterocyclic organozinc (entry 6) also reacted to afford the
corresponding tertiary amines in good yield.
Development of a one-pot chlorination and arylation reaction would
be attractive for certain applications, as isolation of the N-chloroamines
would no longer be necessary. In preliminary studies, we observed
that NCS did not undergo the Ni-catalyzed coupling reaction. On the
basis of this observation, we hypothesized that NCS could oxidize
the amine to the N-chloroamine and that the byproduct, succinimide,
would be a spectator in the subsequent coupling reaction. To test this
hypothesis, dibutylamine was reacted with NCS for 25 min, after which
catalyst and a solution of diphenylzinc in THF were added (Scheme
1). The desired aniline 3a was isolated in 79% yield. The one-pot
procedure was also applied in coupling of morpholine and piperidine,
yielding the corresponding anilines in 78 and 81% yields, respectively.
Therefore, the reaction is adaptable, allowing amination of diarylzinc
reagents to be accomplished using either amines or N-chloroamines
as starting materials.
(9) A viable alternative mechanism involves SN2 attack of an arylnickel complex
on the N-chloroamine (see ref 3d).
(10) DMA appears to play a key role in the reaction.
(11) See the Supporting Information for details of the ligand screen.
(12) N-Chloroamines are known to oxidize phosphines. See: Sopchik, A. E.;
Bentrude, W. G. Tetrahedron Lett. 1980, 21, 4679.
(13) In the absence of Ni(cod)2 and/or bipyridine, reaction of 1a with diphenylzinc
under the standard reaction conditions afforded <5% yield of 3a.
(14) 1H NMR spectroscopy of the unpurified reaction mixture revealed that
benzaldehyde was formed in 23% yield in this reaction. Its formation is
tentatively attributed to ꢀ-hydride elimination from a Ni amido complex
to form N-methylbenzaldimine, which was hydrolyzed upon aqueous
workup.
(15) Electron-withdrawing substituents on N substantially slow the reductive
elimination from arylpalladium amido complexes. See: Yamashita, M.;
Cuevas Vicario, J. V.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 16347.
(16) (a) Helaja, J.; Go¨ttlich, R. Chem. Commun. 2002, 720. (b) Go¨ttlich, R.
Synthesis 2000, 1561. (c) Heuger, G.; Kalsow, S.; Go¨ttlich, R. Eur. J. Org.
Chem. 2002, 1848.
(17) Cyclization of these substrates frequently proceeds by a radical mechanism
(see ref 16c).
(18) Preparation of 1j takes advantage of the chemoselectivity of the N-
chlorination reaction toward the more nucleophilic nitrogen.
The Ni-catalyzed amination of N-chloroamines with diorganozincs
provides a system for the formation of tertiary anilines. This umpolung
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