Mechanistic studies of the copper-catalyzed electrophilic amination of diorganozinc reagents and development of a zinc-free protocol

Article abstract of DOI:10.1021/ol0702829

Equation Presented An S_N2 mechanism for the copper-catalyzed amination of diorganozinc reagents by O-benzoyl-N,N-dialkylhydroxyamines is supported by following stereochemically defined organometallics through the reaction and by employing the endocyclic restriction test. A copper-catalyzed electrophilic amination of organomagnesium compounds is also described in which the use of zinc halides has been eliminated.

Full text of DOI:10.1021/ol0702829

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1521-1524
Mechanistic Studies of the
Copper-Catalyzed Electrophilic
Amination of Diorganozinc Reagents
and Development of a Zinc-Free
Protocol
Matthew J. Campbell and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
jsj@unc.edu
Received February 4, 2007
ABSTRACT
An SN2 mechanism for the copper-catalyzed amination of diorganozinc reagents by O-benzoyl-N,N-dialkylhydroxylamines is supported by
following stereochemically defined organometallics through the reaction and by employing the endocyclic restriction test. A copper-catalyzed
electrophilic amination of organomagnesium compounds is also described in which the use of zinc halides has been eliminated.
The electrophilic amination of nonstabilized carbanions is a
well-studied but underutilized method in synthetic chemistry.1
Such aminations are classically conducted under relatively
harsh conditions with variable yields, but a number of studies
have provided improved protocols for the oxidative amination
of myriad organometallics.2 These reactions provide a
valuable complement to the Buchwald-Hartwig coupling,3
currently the state of the art in nucleophilic amination.
To better understand the Cu-catalyzed amination of
diorganozinc reagents with O-acyl-N,N-dialkylhydroxyl-
amines 1,2d-f we wished to conduct experiments to elucidate
the mechanism. This particular reaction lies at the crossroads
of two well-understood scenarios. Various aminations of
organolithium reagents have been reported to proceed
through a substitution mechanism;4,5 oxidative addition/
reductive elimination is not possible for lithium. Conversely,
it has been inferred that Cu mediates C-N bond formation
by reductive elimination,6 but several mechanisms can be
invoked that lead to the formation of the necessary copper-
amido bond.7 In the reaction of interest, a copper complex
could (i) diplace the benzoate leaving group through an SN2
reaction, (ii) oxidatively add across the N-O bond in a non-
SN2 process, or (iii) add though a radical process (Figure
1).
We first sought to determine whether copper alone can
effect the amination or if a synergistic effect with zinc is
involved. The results of the amination of 1a with stoichio-
metrically generated phenylcuprates are listed in Table 1.
(1) Reviews: (a) Dembech, P.; Seconi, G.; Ricci, A. Chem. Eur. J. 2000,
6, 1281-1286. (b) Erdik, E.; Ay, M. Chem. ReV. 1989, 89, 1947-1980.
(c) Greck, C.; Gene`t, J. P. Synlett 1997, 741-748.
Figure 1. Possible mechanistic scenarios.
10.1021/ol0702829 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/16/2007

Grignard reagents 3-endo8 and 4 were chosen to conduct
the study (Scheme 1). Though conveniently prepared, the
Table 1. Amination of 4-(Benzoyloxy)piperidine with
Phenylcupratesa
Scheme 1. Amination of Stereodefined Grignard Reagents
with O-Benzoyl-N,N-dibenzylhydroxylamine
entry
Cu source
CuBr‚SMe2
CuBr‚SMe2
CuBr‚SMe2
CuBr‚SMe2
Li2CuCl3
Li2CuCl3
Li2CuCl3
0.05 equiv of CuCl ZnPh
M
equiv of PhM % yieldd
1b
2b
3b
4b
5c
6c
7c
8
Li
Li
1
55
68
56
68
72
68
78
88
2
1
2
2
MgBr
ZnBre
Li
MgBr
ZnBre
1
2
1.1
a Conditions: 1 equiv of “Cu”, 1 equiv of R2NOC(O)Ph, 0.25 M THF.
b Cuprate reacted at 0 °C for 30 min. c Cuprate reacted at -15 °C for 1 h.
d Isolated yields (average of at least two experiments). Yield is based on
the starting R2NOC(O)Ph. e Prepared from Rieke zinc and bromobenzene.
b
a See footnote 13. Determined by GLC.
The suitability of organolithium and -magnesium compounds
in this reaction as precursors to the cuprate (entries 1-3, 5,
6) establishes that the Zn metal center is not integral for the
C-N bond-forming event. Li2CuCl3 was used in addition
to the CuBr‚SMe2 complex because its high solubility in THF
rendered formation of the cuprate (especially monophenyl-
copper) more facile. Its use resulted in more consistent results
and marginally higher yields (cf. entries 3 and 6). Under no
set of conditions was the yield obtained in the Cu-catalyzed
amination of Ph2Zn matched (entry 8). In some reactions, a
small amount of piperidine (<5%) was produced. In these
reactions, we also observed the production of biphenyl;
presumably, the N-O bond can serve as an oxidant that
promotes biaryl coupling.
use of 3-endo is not completely unbiased, as the reaction of
interest must proceed through diastereomeric transition states.
This limitation has been overcome through the pioneering
work of Hoffmann, who has developed the unbiased chiral
Grignard reagent 4 and successfully used it to investigate
various oxidations,9 including electrophilic amination.10
Transmetalation of an equilibrium mixture of 3 to zinc
and further reaction with an excess of 1b yielded a 65:35
endo:exo mixture of amine 5 in 55% yield (Scheme 1). This
is similar to published ratios obtained for carbonation,8a
mercuration,8a and amination.11 After establishing that both
isomers react similarly, we examined the resolved isomer.
The use of 3-endo provided amine 5-endo (>95:5), sup-
porting retention of configuration during the amination. Both
isomers of 5 were assigned using NOESY spectroscopy.
We next examined the fate of a stereodefined R*2Zn
reagent when subjected to the amination conditions. The
(2) (a) Brown, H. C.; Hedkamp, W. R.; Breuer, E.; Murphy, W. S. J.
Am. Chem. Soc. 1964, 86, 3565-3566. (b) Brown, H. C.; Kim, K. W.;
Srebnik, M.; Singaram, B. Tetrahedron 1987, 43, 4071-4078. (c) Brown,
H. C.; Kim, K. W.; Cole, T. E.; Singaram, B. J. Am. Chem. Soc. 1986,
108, 6761-6764. (d) Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc.
2004, 126, 5680-5681. (e) Berman, A. M.; Johnson, J. S. J. Org. Chem.
2005, 70, 364-366. (f) Berman, A. M.; Johnson, J. S. J. Org. Chem. 2006,
71, 219-224. (g) Tsutsui, H.; Ichikawa, T.; Narasaka, K. Bull. Chem. Soc.
Jpn. 1999, 72, 1869-1878. (h) Kitamura, M.; Chiba, S.; Narasaka, K. Bull.
Chem. Soc. Jpn. 2003, 76, 1063-1070. (i) Kitamura, M.; Suga, T.; Chiba,
S.; Narasaka, K. Org. Lett. 2004, 6, 4619-4621. (j) Sapountzis, I.; Knochel,
P. J. Am. Chem. Soc. 2002, 124, 9390-9391. (k) Sapountzis, I.; Knochel,
P. Angew. Chem., Int. Ed. 2004, 43, 897-900. (l) Carpino, L. A.; Terry, P.
H.; Crowley, P. J. J. Org. Chem. 1961, 26, 4336-4340. (m) Velarde-Ortiz,
R.; Guijarro, A.; Rieke, R. D. Tetrahedron Lett. 1998, 39, 9157-9160. (n)
Niwa, Y.; Takayama, K.; Shimizu, M. Bull. Chem. Soc. Jpn. 2002, 75,
1819-1825.
Transmetalation of 4 (∼84% ee) to zinc followed by
amination with 1b formed the corresponding tertiary amine.
This amine was transformed via hydrogenolysis and subse-
quent acetylation to the acetamide (S)-6 (75% ee, GLC). In
a reaction of relevance reported by Hoffmann, sequential
transmetalation of 4 to zinc and copper followed by conjugate
addition to mesityl oxide resulted in 6% racemization.12 The
9% racemization that we observe is comparable, and we
conclude that this amination transfers chirality to the same
extent as the conjugate addition of cuprates to enones. Taken
(3) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067. (b)
Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res.
1998, 31, 805-818. (c) Schlummer, B.; Scholz, U. AdV. Synth. Catal. 2004,
346, 1599-1626.
(4) (a) Boche, G.; Wagner, H. U. Chem. Commun. 1984, 1591-1592.
(b) McKee, M. L. J. Am. Chem. Soc. 1985, 107, 859-864. (c) Armstrong,
D. R.; Snaith, R.; Walker, G. T. Chem. Commun. 1985, 789-791.
(5) (a) Beak, P.; Basha, A.; Kokko, B.; Loo, D. J. Am. Chem. Soc. 1986,
108, 6016-6023. (b) Beak, P.; Selling, G. W. J. Org. Chem. 1989, 54,
5574-5580. (c) Beak, P.; Li, J. J. Am. Chem. Soc. 1991, 113, 2796-2797.
(6) Yamamoto, H.; Maruoka, K. J. Org. Chem. 1980, 45, 2739-2740.
(7) (a) Barton, D. H. R.; Doris, E. Tetrahedron Lett. 1996, 37, 3295-
3298. (b) Lindley, J. Tetrahedron 1984, 40, 1433-1456.
(8) (a) Jensen, F. R.; Nakamaye, K. L. J. Am. Chem. Soc. 1966, 88,
3437-3438. (b) Morrison, J. D.; Lambert, G. J. Org. Chem. 1972, 37,
1034-1037. (c) San Filippo, J.; Nicoletti, J. W. J. Org. Chem. 1977, 42,
1940-1944.
(9) (a) Hoffmann, R. W.; Nell, P. G.; Leo, R.; Harms, K. Chem. Eur. J.
2000, 6, 3359-3365. (b) Hoffmann, R. W.; Ho¨lzer, B.; Knopff, O.; Harms,
K. Angew. Chem., Int. Ed. 2000, 39, 3072-3074.
(10) Hoffmann, R. W.; Ho¨lzer, B.; Knopff, O. Org. Lett. 2001, 3, 1945-
1948.
(11) Pearson, W. H. Ph.D. Thesis, University of Wisconsin, Madison,
WI, 1982.
(12) Hoffmann, R. W.; Ho¨lzer, B. J. Am. Chem. Soc. 2002, 124, 4204-
4205.
1522
Org. Lett., Vol. 9, No. 8, 2007

together with the retention observed in the norbornyl system,
we conclude that a polar mechanism is at least dominant, if
not exclusive. A radical mechanism can be eliminated, since
considerable racemization would accompany such an inter-
mediate.
We used the endocyclic restriction test5,14 to differentiate
between an SN2 displacement at nitrogen and non-SN2
oxidative addition/reductive elimination of the N-O/C-N
bond. This test allows one to obtain a general picture of the
transition state geometry. When the system is a six-membered
ring, an intramolecular SN2 process is forbidden because the
6-endo-tet transition structure 8 is prohibitively strained
(Scheme 2). A non-SN2 oxidative addition process into the
lyzing the intermediate diorganozinc with no detectable
amination prior to the addition of CuCl2.
Analysis of the products by MS revealed a near statistical
mixture of the four isotopomers, meaning the amination is
occurring intermolecularly. This supports a transition state
that has a large Cu-N-OBz bond angle (e.g., ∼180°).
We then reinitiated our previous efforts toward devising
a procedure that would reduce or eliminate completely the
need for pregenerating the diorganozinc.2f Eliminating stoi-
chiometric amounts of an anhydrous zinc salt would be
beneficial for large-scale reactions.
The dominant side reaction when Grignard reagents react
with O-acylhydroxylamines is C-acylation to form ketones.
With the hope that acylation could be slowed enough to
permit amination, several analogs of 12 were prepared that
contain either electron-rich or sterically bulky substituents
on the acyl moiety. Table 2 displays the relevant experiments
Scheme 2. Endocyclic Restriction Test
Table 2. Amination of O-Acyl-N,N-diethylhydroxylamines
with Phenylmagnesium Bromide Catalyzed by ZnCl2 and CuCl2
a
equiv of
PhMgBr
equiv of
ZnCl2
entry
R
% yieldb
1
2
3
4
5
6
7
8
Ph (12a)
2.2
2.2
2.2
2.2
2.2
2.2
1.1
2.2
2.2
2.2
2.2
2.2
2.2
0.1
0.1
0.1
0.1
0.1
84
62
81
74
75
87
89
79
79
89
82
83
27
4-MeOPh (12b)
4-Me2NPh (12c)
2-MePh (12d)
2,4,6-Me3Ph (12e)
Ph (12a)
pendent N-O bond would proceed to give an oxametala-
cyclopentane. This intermediate is geometrically attainable
because the precursor σ-bond complex 9 is not strained; the
intramolecular cross-coupling is therefore feasible via this
mechanism.
Ph (12a)
4-MeOPh (12b)
4-Me2NPh (12c)
2-MePh (12d)
2,4,6-Me3Ph (12e)
tBu (12f)
9
10
11
12
13
We selected iodide 10 as the organocopper precursor. The
deuterated analog 10-d14 is easily prepared from benzene-
d6.15 This system provides 11-d0 and 11-d14 as non-crossover
products and 11-d4 and 11-d10 as crossover products,
analyzed easily by mass spectrometry (MS). Low-tempera-
ture iodine/magnesium exchange16 of an equivalent mixture
of 10 and 10-d14 provided the functionalized Grignard
reagents that were converted to the corresponding diorga-
nozincs. The addition of catalytic CuCl2 and warming to
room temperature provided amino acids that were converted
to the methyl esters 11 using TMSCHN2.17 Deiodi-
nated starting material could be recovered by hydro-
EtO (12g)
a Conditions: PhMgBr added via syringe pump (0.15 mmol/min), 1 equiv
of R2NOC(O)Ph, 0.03 equiv of CuCl2, 0.16 M 12 in THF. b Yields
determined by GLC vs internal standard. Yield is based on the starting
Et2NOC(O)R.
that were conducted using 3 mol % CuCl2 with or without
catalytic ZnCl2. PhMgBr was added by syringe pump over
7 min to ensure reproducibility. Higher yields were realized
when ZnCl2 was omitted altogether. The use of 2.2 equiv of
the Grignard was not necessary (entry 7). All analogs except
carbonate 12g were equally capable of providing amine 13
(entry 13).
(13) We established this value by preparing known alcohol 7 (from ref
9) in 84% ee, which is slightly lower than that published (ca. 91% ee).
The Mg f Cu transmetalation and resulting amination
evidently occurs much faster than C-acylation regardless of
the relative reactivity of the carbonyl toward nucleophilic
attack (ktransmetalation‚kamination . kacylation). This observation
parallels the copper-catalyzed conjugate addition of Grignard
reagents to R,â-unsaturated ketones. To gauge the relative
reactivity of the two electrophilic sites, aminations were then
examined in the absence of CuCl2 (Table 3).
(14) Beak, P. Acc. Chem. Res. 1992, 25, 215-222.
(15) See Supporting Information for preparation of 10 and 10-d14.
(16) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003, 42,
4302-4320.
(17) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981,
29, 1475-1478.
Org. Lett., Vol. 9, No. 8, 2007
1523

Table 3. Uncatalyzed Amination of O-Acyl-N,N-
diethylhydroxylamines with Phenylmagnesium Bromidea
Table 4. Copper-Catalyzed Amination of
O-Acyl-N,N-dialkylhydroxylamines with Grignard Reagentsa
entry
R
PhM (equiv)
temp
% yieldb
1
2
3
4
5
6
7
8
Ph (12a)
PhMgBr (1.1)
PhMgBr (1.1)
PhMgBr (1.1)
PhMgBr (1.1)
rt
rt
rt
rt
rt
9
17
21
18
85
36
50
46
54
37
57
14
4-MeOPh (12b)
4-Me2NPh (12c)
2-MePh (12d)
2,4,6-Me3Ph (12e) PhMgBr (1.1)
2,4,6-Me3Ph (12e) PhLi (2.2)
2,4,6-Me3Ph (12e) PhLi (2.2)
2,4,6-Me3Ph (12e) PhLi (2.2)
tBu (12f)
tBu (12f)
tBu (12f)
EtO (12g)
rt
-30 °C
0 °C
rt
0 °C
44 °C
rt
9
PhMgBr (2.2)
PhMgBr (2.2)
PhMgBr (2.2)
PhMgBr (2.2)
10
11
12
a Conditions: 1 equiv of R2NOC(O)Ph, 0.16 M 12 in THF. b Yields
determined by GLC vs internal standard. Yield is based on the starting
Et2NOC(O)R.
In the absence of Cu, the predominant products were
benzophenone, benzhydrol, and triphenylmethanol. Electron-
rich and moderately sterically encumbered substrates pro-
vided a slight improvement over 12a (entries 2-4, compare
to 1); however, it was not until large acyl groups were used
that 13 became the major product (entries 5, 9). Attempts to
increase the yield using 12f by varying the temperature were
unsuccessful. PhLi reacts with 12e to give modest yields that
increased as the temperature was decreased (entries 6-8).
The use of other O-2,4,6-trimethylbenzoyl hydroxylamines
was not extensively evaluated because they are not as easily
accessed as the demethylated derivatives. Instead, we
investigated the scope of the copper-catalyzed amination of
organomagnesium compounds (Table 4). The yields for
tertiary amines 14a-q were moderate to excellent for the
majority of cases investigated. For a number of cases, it was
necessary to increase the catalyst loading to achieve syntheti-
cally useful yields. The benefit of this increase was substrate-
dependent (compare entries 5 and 6 to entries 11 and 12),
and high catalyst loadings were ultimately detrimental
(entries 17-20). Secondary amines were not sucessfully
prepared. Instead, deprotonation to the Mg-amide occurred
(entry 22). As predicted by an SN2 pathway, 1g18 was unable
to provide N-phenylindole by this methodology (entry 23).19
In summary, we can support an SN2 pathway for the Cu-
catalyzed amination of dialkylzinc reagents by (i) demon-
strating that zinc is not essential in the C-N bond-forming
step, (ii) showing that the configuration at the reacting carbon
is retained through the reaction, and (iii) employing the
a Conditions: RMgX added via syringe pump (0.15 mmol/min), 1 equiv
of R2NOC(O)Ph. b Isolated yields of product of purity g95% based on 1H
NMR spectroscopy (average of at least two experiments) unless noted.c Yield
determined by 1H NMR spectroscopy vs internal standard. d Yield deter-
mined by GLC vs internal standard. Yield is based on the starting
R2NOC(O)Ph.
endocyclic restriction test. We were able to develop a Cu-
catalyzed amination of Grignard reagents after realizing the
relative rates of O-acylation, transmetalation, and C-N bond
formation were favorable. This reaction does not possess the
scope of our previous protocol employing diorganozinc
compounds but in some cases can be operationally superior
as a result of the absence of anhydrous zinc salts.
Acknowledgment. Funding for this work was provided
by a Focused Giving Award from Johnson and Johnson.
Research support from Eli Lilly, Amgen, and GSK is
gratefully acknowledged. J.S.J. an Alfred P. Sloan Fellow
and a Camille Dreyfus Teacher-Scholar.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Acheson, R. M.; Benn, M. H.; Jacyno, J.; Wallis, J. D. J. Chem.
Soc., Perkins Trans. 2 1983, 497-500.
(19) The copper-catalyzed amination ofdiphenylzinc with 1g was also
unsuccessfull.
OL0702829
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Org. Lett., Vol. 9, No. 8, 2007