Copper-catalyzed electrophilic amination of organozinc nucleophiles: Documentation of O-benzoyl hydroxylamines as broadly useful R2N(+) and RHN(+) synthons

Article abstract of DOI:10.1021/jo051999h

This paper details new copper-catalyzed electrophilic amination reactions of diorganozinc reagents using O-benzoyl hydroxylamines as electrophilic nitrogen sources that may be accessed in one step. Simple and functionalized aryl, heteroaryl-, benzyl, n-alkyl, sec-alkyl, and tert-alkyl nucleophiles couple with R₂NOC(O)Ph and RHNOC(O)Ph reagents in the presence of catalytic quantities of copper salts to provide tertiary and secondary amines, respectively, in generally good yields. In many cases, the product may be isolated analytically pure after a simple extractive workup. The amination process is shown to tolerate a significant degree of steric demand. The amination of nominally unreactive C_aryl-H bonds via a sequential directed ortho metalation/transmetalation/catalytic amination reaction sequence is detailed. The direct Cu-catalyzed amination of Grignard reagents using cocatalysis by ZnCl₂ is described.

Full text of DOI:10.1021/jo051999h

Copper-Catalyzed Electrophilic Amination of Organozinc
Nucleophiles: Documentation of O-Benzoyl Hydroxylamines as
Broadly Useful R N(+) and RHN(+) Synthons
2
Ashley M. Berman and Jeffrey S. Johnson*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
jsj@unc.edu
ReceiVed September 23, 2005
This paper details new copper-catalyzed electrophilic amination reactions of diorganozinc reagents using
O-benzoyl hydroxylamines as electrophilic nitrogen sources that may be accessed in one step. Simple
and functionalized aryl, heteroaryl-, benzyl, n-alkyl, sec-alkyl, and tert-alkyl nucleophiles couple with
2
R NOC(O)Ph and RHNOC(O)Ph reagents in the presence of catalytic quantities of copper salts to provide
tertiary and secondary amines, respectively, in generally good yields. In many cases, the product may be
isolated analytically pure after a simple extractive workup. The amination process is shown to tolerate
a significant degree of steric demand. The amination of nominally unreactive Caryl-H bonds via a sequential
directed ortho metalation/transmetalation/catalytic amination reaction sequence is detailed. The direct
2
Cu-catalyzed amination of Grignard reagents using cocatalysis by ZnCl is described.
Introduction
Because of the central role of amine synthesis in organic
chemistry, the electrophilic amination problem continues to
The investigation of umpolung strategies in organic synthesis
often produces reactions that are complementary to counterparts
following normal polarity pathways. In the context of amine
10-14
attract considerable interest.
Hydroxylamine derivatives
occupy a prominent position in the development of umpolung
C-N bond constructions, with key advances relying on the use
of appropriate activating groups to facilitate the amination. The
1
synthesis, the effective application of the umpolung concept
relies on the identification of useful electrophilic nitrogen
synthons and reaction conditions that are sufficiently mild so
as to tolerate functionality that might be required for subsequent
manipulation. A large number of R2N(+) synthons have been
15
16,17
use of sulfonyl and phosphinyl
activation is representative,
(8) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling
Reactions; De Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
2
developed for reactions with nucleophiles, and recent advances
2
004; Vol. 2, pp 699-760.
9) Hartwig, J. F. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-i., Ed.; Wiley: New York, 2002; Vol. 1, pp
from Erdik3 and Narasaka
,4
5,6,7
have demonstrated that transition-
(
metal catalysts can potentiate the reactivity of Grignard reagents
or zincates with oxime derivatives; however, in most instances
electrophilic amination approaches are not currently competitive
with catalytic nucleophilic amination strategies discovered and
1
051-1096.
(
10) Erdik, E. Tetrahedron 2004, 60, 8747-8782.
(11) Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J. Org. Chem. 2004,
1377-1385.
8,9
(12) Dembech, P.; Seconi, G.; Ricci, A. Chem. Eur. J. 2000, 6, 1281-
286.
developed by Buchwald and Hartwig.
1
(
13) Greck, C.; Gen eˆ t, J. P. Synlett 1997, 741-748.
(
(
(
1) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239-258.
(14) For recent examples of electrophilic amination reactions, see: (a)
2) Erdik, E.; Ay, M. Chem. ReV. 1989, 89, 1947-1980.
Berman, A. M.; Johnson, J. S. Synlett 2005, 1799-1801. (b) Sapountzis,
I.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 897-900. (c) Kitamura,
M.; Suga, T.; Chiba, S.; Narasaka, K. Org. Lett. 2004, 6, 4619-4621. (d)
Saaby, S.; Bella, M.; Jorgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120-
8121. (e) Smulik, J. A.; Vedejs, E. Org. Lett. 2003, 5, 4187-4190. (f)
Kitamura, M.; Chiba, S.; Narasaka, K. Bull. Chem. Soc. Jpn. 2003, 76,
1063-1070. (g) Sapountzis, I.; Knochel, P. J. Am. Chem. Soc. 2002, 124,
9390-9391. (h) Niwa, Y.; Takayama, K.; Shimizu, M. Bull. Chem. Soc.
Jpn. 2002, 75, 1819-1825.
3) Erdik, E.; Ay, M. Synth. React. Inorg. Met.-Org. Chem. 1989, 19,
6
3
63-668.
(
4) Erdik, E.; Daskapan, T. J. Chem. Soc., Perkin Trans. 1 1999, 3139-
142.
(
5) Tsutsui, H.; Hayashi, Y.; Narasaka, K. Chem. Lett. 1997, 317-318.
(6) Tsutsui, H.; Ichikawa, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1999,
7
2, 1869-1878.
7) Narasaka, K. Pure App. Chem. 2002, 74, 143-149.
(
1
0.1021/jo051999h CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/02/2005
J. Org. Chem. 2006, 71, 219-224
219

Berman and Johnson
TABLE 1. Preparation of O-Benzoyl Hydroxylaminesa
but surprisingly little had been done in the field employing acyl
activation of the hydroxylamine moiety.18
In an effort to address the technology gap between nucleo-
philic and electrophilic catalytic amination, we initiated a search
for a useful electrophilic amination protocol that would employ
readily accessible R2N(+) synthons and enjoy broad functional
group compatibility. In this paper, we document the scope and
limitations of a new copper-catalyzed C-N bond construction
that couples O-benzoyl hydroxylamine derivatives and in situ
generated diorganozinc reagents (eq 1). Salient features of the
protocol that will be detailed in this article include the
following: (i) remarkable tolerance of both steric hindrance at
the reaction site and reactive functionality elsewhere in the
molecules undergoing coupling; (ii) mild reaction conditions
(
rt, <1 h) and ease of product isolation/purification (acid-base
3
extractive workup); (iii) broad scope with respect to the sp -
and sp -hybridized nucleophiles; (iv) capacity of the reaction
2
to facilitate direct amination of Caryl-H bonds using directed
ortho-metalation; and (v) direct amination of Grignard reagents
using catalysis by Cu(II) and cocatalysis by Zn(II).1
9
Results and Discussion
Preparation of O-Benzoyl Hydroxylamines. The O-benzoyl
hydroxylamines utilized in our earlier studies were prepared via
the oxidation of secondary amines with benzoyl peroxide and
an exogenous inorganic base in ethereal solvent, as originally
reported by Ganem.20 In the Ganem report, extended reaction
times (>12 h) and refluxing conditions are necessary. While
this method results in acceptable yields of desired product,
competitive N-acylation of the amine was noted as a problematic
side reaction. We discovered that these same oxidations, when
conducted in a polar aprotic solvent, proceed to completion at
room temperature with competitive N-acylation greatly sup-
pressed. Utilizing this modified procedure, we were able to
prepare a variety of O-benzoyl hydroxylamines, both from
primary and secondary amines, in uniformly high yields (Table
a
b
1
.2 equiv of the amine and 1.5 equiv of K2HPO4 were employed. 2.5
c
equiv of the amine and 1.5 equiv of K2HPO4 were employed. Isolated
yield of product of purity g95% based on H NMR spectroscopy (average
of at least two experiments). Yield is based on the starting benzoyl peroxide.
1
where the free hydroxylamine is readily available (e.g., Et2-
NOH is commercially available), benzoylation represents a
simple alternate route to these compounds. In the case of Et2N-
OC(O)Ph (2e), acylation of the commercially available parent
hydroxylamine resulted in clean formation of product (98%
isolated yield), representing an alternative route to these
compounds. While the reaction works uniformly well for
N-alkylamines, heteroaromatic amines (e.g., imidazole) failed
to undergo oxidation under the present reaction conditions.
Attempted oxidation of methyl prolinate was likewise unsuc-
cessful.
Electrophilic Amination of Diorganozinc Reagents: Prepa-
ration of Secondary and Tertiary Amines. Our studies into
the transition-metal-catalyzed electrophilic amination of weak
carbon donors began with the discovery that copper salts
catalyze the amination of R2Zn reagents with O-benzoyl
hydroxylamines under mild reaction conditions (rt, <1 h). With
a convenient means of preparing our aminating reagents (vida
supra), we next set out to test the generality of this newly
discovered amination protocol. The reaction scope is quite broad,
allowing for the facile preparation of a wide variety of both
secondary and tertiary amines (Table 2). Aryl coupling proceeds
in good to excellent yield for various N-monoalkyl- and N,N-
dialkyl-O-benzoyl hydroxylamines (entries 1-3, 6-14, and 18-
2
1
1
). The reactions are typically run on a 50 mmol scale of the
limiting reagent (benzoyl peroxide), and the products are easily
purified by column chromatography. A number of these
compounds are crystalline solids, and all show good stability
(they can be stored indefinitely in the freezer without decom-
position or loss of reactivity). Reaction times varied from 1 h
for sterically unhindered primary and secondary amines (entries
1
, 2, and 9) to 24 h for the most sterically demanding primary
and secondary amines tested (entries 3, 6, and 7). In instances
(
15) Boche, G.; Mayer, N.; Bernheim, M.; Wagner, K. Angew. Chem.,
Int. Ed. Engl. 1978, 17, 687-688.
16) Colvin, E. W.; Kirby, G. W.; Wilson, A. C. Tetrahedron Lett. 1982,
3, 3835-3836.
17) Boche, G.; Bernheim, M.; Schrott, W. Tetrahedron Lett. 1982, 23,
399-5402.
18) Oguri, T.; Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1975, 23,
67-172.
19) A portion of this work has been previously communicated: (a)
Berman, A. M.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680-5681.
(
2
5
1
(
(
(
(
b) Berman, A. M.; Johnson, J. S. J. Org. Chem. 2005, 70, 364-366.
(
20) Biloski, A. J.; Ganem, B. Synthesis 1983, 537-538.
2
0), allowing for the preparation of diverse aniline derivatives.
Heteroaryl coupling is also realized in good yield (entry 4).
These results offer a complement to existing transition-metal-
(21) (a) White, E. H.; Reefer, J.; Erickson, R. H.; Dzadzic, P. M. J. Org.
Chem. 1984, 49, 4872-4876. (b) Zinner, G. Arch. Pharm. (Weinheim, Ger.)
1
963, 296, 57-60.
220 J. Org. Chem., Vol. 71, No. 1, 2006

Cu-Catalyzed Electrophilic Amination of Organozinc Nucleophiles
TABLE 2. Scope of the Copper-Catalyzed Electrophilic Amination
of Diorganozinc Reagentsa
SCHEME 1. Strategy for the Preparation of Functionalized
Arylamines
OC(O)Ph with both di(o-tolyl)- and di(mesityl)zinc reagents
(entries 9 and 10). Sterically hindered secondary alkylamines
are also accessible using this methodology. The synthesis of
N,N-tert-octyl-tert-butylamine (3u), an immediate precursor to
t
t
22
the useful lithio amide base LiN( Oct) Bu, is exemplary; entry
1 reports the isolated yield (by distillation) for the preparation
2
of 3u on a 10 mmol scale. Although moderate compared to
other entries in Table 2, the simplicity of the two-step process
represents an attractive route to this useful secondary amine.
All reactions were complete within 15-60 min at room
temperature, and simple acid-base extractive workup was
sufficient to obtain analytically pure product in most instances.
Both Cu(I) and Cu(II) salts catalyze the reaction with equal
facility. Additives and/or supporting ligands for the metal are
unnecessary. The aminations were generally performed on a
<
1 mmol scale. Upon scale up (25 mmol), we observed a slight
decrease in yield (entry 1, 91%, 0.5 mmol scale; compared with
2%, 25 mmol scale). This may be attributed to a deleterious
7
exotherm which becomes manifest on larger scale; the exotherm
is easily managed by conducting the larger scale aminations at
2
3
0
°C.
The use of 0.6 equiv of the diorganozinc reagent engenders
a higher level of efficiency to the process. When 2b was treated
with 0.6 equiv of (o-MePh)2Zn in the presence of 2.5 mol % of
CuCl2, N-o-tolylpiperidine was isolated in 86% yield.
Preparation of Functionalized Arylamines. Knochel’s
recently described I/Mg exchange reaction offers a useful route
1
4
to functionalized aryl Grignard reagents. Treatment of an
i
electron-deficient aryl iodide with RMgX (typically PrMgBr)
at low temperatures results in rapid I/Mg exchange. Electron-
rich aryl iodides can also be accommodated when elevated
reaction temperatures (room temperature) are employed. We
envisioned utilizing such reagents in electrophilic amination
processes, via an I/Mg exchange/transmetalation sequence, as
a simple route to functionalized arylamines (Scheme 1).
The Grignard reagents derived from I/Mg exchange readily
undergo transmetalation with 0.5 equiv of ZnCl2, giving access
to functionalized diarylzinc reagents that can be used without
prior isolation and/or purification. We were successful in
employing such reagents in our copper catalyzed electrophilic
amination protocol, giving access to a wide array of function-
alized arylamine products, which are readily purified in many
cases by simple acid-base extractive workup (Table 3). The
amination reaction shows broad functional group tolerance in
a
1
.1 equiv of diorganozinc was employed. With the exception of Et2Zn
(
commercial solution), R2Zn reagents were prepared via transmetalation of
the corresponding RMgX or RLi reagent with 0.5 equiv of ZnCl2. 2.5
mol % of CuCl2 was employed. Isolated yield of product of purity g95%
based on H NMR spectroscopy and GLC analysis (average of at least two
b
c
1
experiments). Yield is based on the starting R2NOC(O)Ph.
catalyzed methods for the arylation of amines. The preparation
of tertiary benzylamines is also possible using this methodology
entry 5). Likewise, alkyl coupling proceeds in good to excellent
(
yield for primary, secondary, and tertiary dialkylzincs (entries
1
5-17 and 21).
(
(
22) Corey, E. J.; Gross, A. W. Org. Synth. 1987, 65, 166-172.
23) Berman, A. M.; Johnson, J. S. Org. Synth., in press. See the
A high level of steric tolerance is apparent in these reactions,
i
as evidenced by the facile coupling of sterically hindered Pr2N-
Supporting Information for details.
J. Org. Chem, Vol. 71, No. 1, 2006 221

Berman and Johnson
TABLE 3. Copper-Catalyzed Electrophilic Amination of
Functionalized Diarylzinc Reagentsa
SCHEME 2. Strategy for the Directed Ortho Metalation/
Amination Sequence
the obtention of 3v (74%), 3y (74%), 3ab (83%), and 3c (71%)
in yields comparable to those reported in Table 3.
Directed Ortho Lithiation/Amination Sequence. Directed
ortho lithiation has been utilized extensively as a reliable tool
for the functionalization of poorly reactive Caryl-H bonds.24
Most work in this area has focused on the utility of this
methodology toward the construction of new C-C bonds.25
Fewer studies have addressed the aspects of C-N bond
construction. Seminal examples by Snieckus illustrate the
potential utility of this methodology for the formation of new
2
6,27
C-N bonds.
We envisaged employing a directed ortho
lithiation/transmetalation sequence to obtain Ar2Zn reagents in
situ. These reagents could then be used (without isolation and/
or purification) in the title copper-catalyzed electrophilic ami-
nation protocol, allowing for the facile, selective oxidation of
Caryl-H bonds (Scheme 2).
We tested this hypothesis with four arenes, employing the
most commonly used directing groups in similar directed ortho
lithiation protocols (Table 4). The reaction works well for both
N,N-dialkylamide and methoxymethyl ether directing groups
(entries 1 and 3). Somewhat less effective are the commonly
employed O-aryl carbamate and oxazoline directing groups
under the current reaction conditions (entries 2 and 4). A
noticeable reduction in reaction rate is apparent for all substrates
tested, presumably a result of the enhanced coordination in the
derived diorganozinc reagents. The directed ortho metalation/
amination sequence allows for the preparation of diverse amine
products not readily accessible using previous methodology.
Double-Metal-Catalyzed Electrophilic Amination. The
organozinc reagents employed in these studies were generally
prepared from the corresponding RMgX or RLi reagent via
transmetalation with 0.5 equiv of ZnCl2. The resultant R2Zn
solution was subsequently added to the remaining reaction
components and amination allowed to proceed under normal
reaction conditions. Recent reports in the literature suggest that
in situ generation of organozinc reagents from RMgX is also
a
1
.1 equiv of diarylzinc was employed. Ar2Zn reagents were prepared
i
from the corresponding ArI as follows: (1) PrMgBr, -35 °C, 1 h; (2)
b
ZnCl2, -35 °C, 10 min. Ar2Zn prepared from the corresponding ArI as
i
c
follows: (1) PrMgBr, rt, 1 h; (2) ZnCl2, rt, 10 min. Ar2Zn prepared from
the corresponding ArI as follows: (1) PhMgBr, -35 °C, 10 min; (2) ZnCl2,
35 °C, 10 min. Isolated yield of product of g95% purity as judged by
H NMR spectroscopy and GLC analysis (average of at least two
experiments). Yield is based on the starting R2NOC(O)Ph.
d
-
1
28
possible using a catalytic quantities of a Zn(II) salt. This
method obviates the use of large quantities of anhydrous zinc
salts, which could present processing concerns on scale. We
tested the feasibility of this protocol for our electrophilic
amination reaction.
the nucleophilic component. Diverse functional groups, includ-
ing nitrile, ester, halide, triflate, and nitro, are all tolerated under
the reaction conditions. Those functional groups requiring prior
protection were a phenol (as the derived acetate ester, entry 6)
and ketone (as the derived ketal, entry 9). Interestingly, the
reaction proceeds equally well for both electron-deficient (entry
) and electron-rich (entry 8) Ar2Zn reagents.
As was true for the unfunctionalized diorganozinc reagents,
the use of 0.6 equiv of Ar2Zn is feasible as demonstrated by
(
24) Snieckus, V. Chem. ReV. 1990, 90, 879-933.
(25) Anctil, E. J. G.; Snieckus, V. J. Organomet. Chem. 2002, 653, 150-
160.
26) Reed, J. N.; Snieckus, V. Tetrahedron Lett. 1983, 24, 3795-3798.
27) Iwao, M.; Reed, J. N.; Snieckus, V. J. Am. Chem. Soc. 1982, 104,
(
5
(
5
531-5533.
(28) Miller, J.; Farrell, R. P. Tetrahedron Lett. 1998, 39, 7275-7278.
222 J. Org. Chem., Vol. 71, No. 1, 2006

Cu-Catalyzed Electrophilic Amination of Organozinc Nucleophiles
TABLE 4. Directed Ortho Metalation/Amination Reactionsa
Conclusion
In conclusion, we have developed a mild and broadly
applicable method for the preparation of a wide variety of
secondary and tertiary amines via the copper-catalyzed elec-
trophilic amination of R2Zn reagents. The O-benzoyl hydroxyl-
amine aminating reagents employed are easily prepared in one
step from the corresponding primary or secondary amine and
show good stability. The R2Zn reagents are generated from the
corresponding RMgX or RLi, and are used without prior
isolation and/or purification. Isolation of analytically pure
material is possible in most instances via a simple acid/base
extractive workup, thus making these reactions operationally
convenient. The reaction shows good substrate scope, both in
terms of the functional groups tolerated on the nucleophilic
component and the sterics of the coupling partners. Work is
continuing in our laboratory on the development of new methods
of R2N(+) delivery and results from these studies will be
reported in future publications.
Experimental Section
4-Benzoyloxymorpholine (2a). Representive Oxidation. A 500-
mL, one-necked, round-bottomed flask equipped with a Teflon-
coated magnetic stirbar was charged with benzoyl peroxide (12.11
g, 50 mmol), dipotassium hydrogen phosphate (13.06 g, 75 mmol),
and N,N-dimethylformamide (125 mL). The suspension was stirred,
and morpholine (5.20 mL, 60 mmol) was added via syringe in one
portion. The suspension was stirred at ambient temperature for 1
h. Deionized water (200 mL) was added, and the contents were
stirred vigorously for several minutes until all solids dissolved. The
reaction mixture was transferred to a 1-L separatory funnel and
extracted with 150 mL of ethyl acetate. The organic phase was
collected and washed with two 100-mL portions of saturated aq
a
1
.1 equiv of diarylzinc was employed. Ar2Zn reagents were prepared
s
from the corresponding arene as follows: (1) BuLi, TMEDA, -78 °C, 30
b
min; (2) ZnCl2, -78 °C to rt, 30 min. Ar2Zn prepared from the
t
corresponding arene as follows: (1) BuLi, 0 °C, 1 h; (2) ZnCl2, 0 °C to rt,
c
1
3
0 min. Isolated yield of product of g95% purity as judged by H NMR
spectroscopy and GLC analysis (average of at least two experiments). Yield
is based on the starting R2NOC(O)Ph.
3
NaHCO solution. All of the aqueous fractions were combined and
extracted with three 100-mL portions of ethyl acetate. All of the
organic fractions were combined and washed with three 100-mL
portions of deionized water and 100 mL of brine, dried over MgSO4,
and concentrated by rotary evaporation. The resulting crude product
mixture was purified by flash column chromatography, eluting with
Studies early in this project illustrated the apparent incompat-
ibility of R2NO-C(O)Ph reagents with RMgX nucleophiles:
rapid acylation (ketone formation) of the Grignard reagent under
standard reaction conditions was the predominant reaction
pathway. Thus, for the proposed “catalytic-in-zinc” protocol to
be successful, the projected transmetalation/amination must be
faster than direct acylation. Gratifyingly, this is the case, and
we observed good yields of the desired amination product when
catalytic quantities of ZnCl2 were employed (eq 2). An
analogous experiment using morpholine-derived 2a, 2.5 mol %
of CuCl2, and 10 mol % of ZnCl2 gave N-phenylmorpholine
5
0% EtOAc/hexanes to afford the title compound (7.71 g, 37 mmol,
1
74%) of g95% purity as judged by H NMR spectroscopy. The
product was stored at subambient temperature under anhydrous
conditions. Analytical data 2a: mp (uncorrected) 82-84 °C; IR
-
1
1
(
Nujol, cm ) 2924, 2852, 1730, 1599, 1456; H NMR (400 MHz,
CDCl
3
) δ 8.00-7.98 (m, 2H), 7.58-7.53 (m, 1H), 7.45-7.41 (m,
2H), 3.96 (br d, J ) 10.7 Hz, 2H), 3.85 (br t, J ) 11.2 Hz, 2H),
3.43 (br d, 9.3 Hz, 2H), 3.03 (br t, 9.4 Hz, 2H); C NMR (100
13
(3a) in 69% isolated yield.
3
MHz, CDCl ) δ 164.6, 133.1, 129.4, 129.2, 128.4, 65.8, 57.0. Anal.
Calcd for C11
H, 6.40; N, 6.67.
-Phenylmorpholine (3a). Representative Amination. An
3
H13NO : C, 63.76; H, 6.32; N, 6.76. Found: C, 63.96;
4
oven-dried 10-mL, one-necked, round-bottomed flask equipped with
a Teflon-coated magnetic stirbar was maintained under an inert
atmosphere of argon and charged with zinc chloride (0.075 g, 0.55
mmol) and anhydrous tetrahydrofuran (2.0 mL). The solution was
stirred at ambient temperature, and an ethereal solution of PhMgBr
(1.1 mL, 1.1 mmol, 1.0 M) was added via cannula in one portion.
The resulting solution was stirred for 20 min at ambient temperature
prior to use (vida infra). An oven-dried 25-mL, one-necked, round-
bottomed flask equipped with a Teflon-coated magnetic stirbar was
maintained under an inert atmosphere of argon and charged with
Our studies suggest that the rate of addition of the Grignard
reagent is important, with both rapid (<1 min) and exceedingly
slow (>60 min) additions resulting in lower product yield.
Dropwise addition over the course of 5 min results in optimal
yields. Reaction temperature is likewise crucial, with subambient
temperatures resulting in diminished yields and/or incomplete
reaction.
2a (0.103 g, 0.50 mmol), the copper(I) trifluoromethanesulfonate
benzene complex ([CuOTf] ‚C , 0.003 g, 0.0056 mmol), and
2
6 6
H
anhydrous tetrahydrofuran (5.0 mL). The solution was stirred, and
the previously generated diphenylzinc solution (vida supra) was
added via cannula in one portion. The resulting solution was stirred
J. Org. Chem, Vol. 71, No. 1, 2006 223

Berman and Johnson
3.84 (m, 4H), 3.16-3.13 (m, 4H); 13C NMR (100 MHz, CDCl
) δ
3
at ambient temperature for 1 h. Diethyl ether (10 mL) was added,
and the reaction mixture was transferred to a 125-mL separatory
funnel. The reaction mixture was washed with three 10-mL portions
151.3, 129.2, 120.0, 115.7, 66.9, 49.4. Anal. Calcd for C10H13NO:
C, 73.59; H, 8.03; N, 8.58. Found: C, 73.71; H, 8.03; N, 8.52.
3
of saturated aq NaHCO solution and extracted with three 10-mL
Acknowledgment. Funding for this work was provided by
a Focused Giving Award from Johnson and Johnson, Research
Corporation, and a UNC Junior Faculty Development Award.
Research support from Amgen, Eli Lilly, and 3M is gratefully
acknowledged. A.M.B. acknowledges a Burroughs-Wellcome
Fellowship.
portions of 10% aq HCl solution. The aqueous extracts were basified
with 10% aq NaOH solution and extracted with three 10-mL
portions of dichloromethane. The organic fraction was washed with
10 mL of brine, dried over Na
2 4
SO , and concentrated by rotary
evaporation to afford the title compound as a white solid (0.080 g,
1
0
.49 mmol, 98%) of g95% purity as judged by H NMR
spectroscopy. This yield is for a specific experiment and differs
slightly from that in Table 2, which is an average of multiple
experiments. Analytical data for 3a: mp (uncorrected) 53-55 °C;
Supporting Information Available: Experimental procedures
and analytical data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
-
1
1
IR (Nujol, cm ) 2922, 2854, 1601, 1458, 1377; H NMR (400
MHz, CDCl ) δ 7.30-7.24 (m, 2H), 6.92-6.85 (m, 3H), 3.86-
3
JO051999H
224 J. Org. Chem., Vol. 71, No. 1, 2006