A tuned bicyclic proazaphosphatrane for catalytically enhanced n-arylation reactions with aryl chlorides

Article abstract of DOI:10.1002/ejoc.201403428

The N-arylation of various amines with aryl chlorides proceeded in good-to-excellent yields in the presence of P[N{(p-NMe₂)C₆H₄CH₂}CH₂CH₂]₃N (1e, a new electron-rich proazaphosphatrane ligand) and small amounts of Pd₂(dba)₃ (dba = dibenzylideneacetone). This catalytic system was also very effective for the synthesis of carbazoles. An efficient palladium-catalyzed N-arylation reaction of amines under mild conditions with a tuned bicyclic proazaphosphatrane has been developed.

Full text of DOI:10.1002/ejoc.201403428

FULL PAPER
DOI: 10.1002/ejoc.201403428
A Tuned Bicyclic Proazaphosphatrane for Catalytically Enhanced N-Arylation
Reactions with Aryl Chlorides
So Han Kim,[a] Min Kim,*[a] John G. Verkade,*[b] and Youngjo Kim*[a]
Keywords: Synthetic methods / N-Arylation / Ligand design / P ligands / Palladium
The N-arylation of various amines with aryl chlorides
proceeded in good-to-excellent yields in the presence of
P[N{(p-NMe2)C6H4CH2}CH2CH2]3N (1e, a new electron-rich
proazaphosphatrane ligand) and small amounts of Pd2(dba)3
(dba = dibenzylideneacetone). This catalytic system was also
very effective for the synthesis of carbazoles.
low activity for the coupling of primary amines and aryl
bromides.[4a] In contrast, a Pd2(dba)3/BINAP [BINAP =
2,2Ј-bis(diphenylphosphanyl)-1,1Ј-binaphthyl] catalytic sys-
tem showed improved catalytic activity for the cross-cou-
pling of primary amines with both electron-rich and elec-
tron-poor aryl bromides.[4a] Also, the (DPPF)PdCl2 [DPPF
= 1,1Ј-bis(diphenylphosphanyl)ferrocene] catalytic system
showed high activity for the cross-coupling of primary
amines with both electron-donating and -withdrawing aryl
halides.[4a] The Buchwald group also developed a highly
efficient C–N bond-formation methodology that utilizes
cheap and normally unreactive aryl chlorides with primary
and secondary amines in the presence of Pd(OAc)2/DBPF
[DBPF = 1,1Ј-bis(di-tert-butylphosphanyl)ferrocene][4b] and
Pd(dba)2/P(tBu)3.[8] Recently, the Pd2(dba)3/Ph5FcP(tBu)2
(Fc = ferrocenyl) and Pd(OAc)2/Ph5FcP(tBu)2 catalytic sys-
tems were found to improve the reactivity of various aryl
chlorides with primary and secondary amines at 70–100 °C;
4-chlorobenzonitrile was reactive at 45 °C.[9a] Although a
variety of amines tend to be facile for general palladium-
catalyzed N-arylation reactions of aryl bromides and iod-
ides under mild conditions, aryl chlorides readily underwent
this transformation only with relatively large quantities of
catalyst or under harsh conditions.[8,9]
The synthesis of a growing family of bicyclic proazaphos-
phatranes has led to the investigation of their catalytic
properties as ligands in a variety of organic transformations
(e.g., Suzuki,[10] Stille,[11] α-arylation,[12] Morita–Baylis–
Hillman,[13] and Hiyama[14] reactions). Proazaphos-
phatranes lend themselves to electronic tuning of the phos-
phorus atom by variation of the organic substituent at each
PN3 nitrogen atom. Several years ago, the Verkade group
investigated the palladium-catalyzed N-arylation reactions
of primary and secondary amines with aryl halides in the
presence of Pd(OAc)2/1a or Pd2(dba)3/1a.[15] However, the
palladium-catalyzed N-arylation with aryl chlorides showed
high activity only with a relatively large quantities of cata-
Introduction
Amination reactions involving the formation of a carb-
on–nitrogen bond such as reductive amination, electrophilic
amination, and Buchwald–Hartwig N-arylation are funda-
mentally important organic transformations.[1] Especially
important is the Buchwald–Hartwig N-arylation, a valuable
reaction for carbon–nitrogen bond formation through the
palladium-catalyzed cross-coupling of various amines
with aryl halides.[2] In 1983, Migita and co-workers devel-
oped this N-arylation methodology for the coupling of
Bu3SnNEt2 with aryl bromides in the presence of
PdCl2[P(oTol)3]2 (oTol = o-tolyl).[3] Significantly improved
catalytic systems for N-arylation reactions have sub-
sequently been developed by Buchwald,[4] Hartwig,[5] and
others.[6] Organotin-free palladium-catalyzed N-arylation
reactions of various amines with aryl halides in the presence
of bulky bases such as tBuOK[5a] and lithium hexamethyl-
disilazide (LiHMDS)[7] were introduced by the Buchwald
and Hartwig groups. These results constitute the first gener-
ation of Buchwald–Hartwig catalytic systems containing
phosphine ligands.
The [Pd2(dba)3]/P(oTol)3 (dba = dibenzylideneacetone)
catalytic system is limited to the cross-coupling of second-
ary amines with aryl bromides containing para electron-
withdrawing substituents and ortho substituents.[5a] How-
ever, a [Pd2(dba)3]/P(oTol)3 catalytic system displayed only
[a] Department of Chemistry and BK21+ Program Research
Team, Chungbuk National University,
Cheongju, Chungbuk, 361-763, Republic of Korea
E-mail: ykim@chungbuk.ac.kr
minkim@chungbuk.ac.kr
http://omlab2005.chungbuk.ac.kr
https://sites.google.com/site/minkimchem/
[b] Department of Chemistry, Iowa State University,
Ames, Iowa 50011, USA
E-mail: jverkade@iastate.edu
http://www.chem.iastate.edu/faculty/John_Verkade
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403428.
1954
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 1954–1960

N-Arylation Reactions with Aryl Chlorides
Results and Discussion
We initially focused on the cross-coupling of 4-methyl-
chlorobenzene (2a) with N-Boc-piperazine (3a; Boc = tert-
butyloxycarbonyl) as a model reaction for the optimization
of the catalyst (Table 1). Previously, the Verkade group in-
vestigated the Pd2(dba)3/1a catalyzed cross-coupling of aryl
chlorides with N-Boc-piperazine in the presence of tBuONa
at 100 °C for 24 h.[15c] Although these results showed effec-
tive cross-coupling of aryl chlorides in high yields, the reac-
tion conditions were harsh compared with those of other
catalytic systems.[8,9] To optimize our catalytic system, we
performed the reaction in Table 1 at 40 °C for 72 h and at
80 °C for 24 h in the presence of tBuONa. As shown in
Table 1, ligand 1e is considerably more efficient than 1a–1d
under both sets of reaction conditions (Table 1, Entries 1–
10). Therefore, we selected proazaphosphatrane 1e as the
lyst or under harsh conditions.[15b,15c,15d] In the present ligand of choice for further studies. Apparently, the catalytic
study, benzyl- and isobutyl-substituted bicyclic proazaphos- activities of 1a–1e decrease as the electron richness of the
phatrane ligands (1a, 1b, and 1c) were synthesized accord- phosphorus atom decreases as isobutyl groups are substi-
ing to previously reported procedures,[16] and 1d and 1e tuted with benzyl substituents. The catalytic activity also
were prepared in a manner analogous to the procedure for increases as the benzyl groups are substituted by the more
the known compounds (see Scheme 1). Herein, we also electron-rich para-dimethylaminophenyl substituents.
compare the catalytic activity of a series of bicyclic proaza-
Next, we performed the coupling of the secondary cyclic
phosphatrane ligands 1a–1e in the palladium-catalyzed N- amine 3a with various aryl chlorides (Table 2). The opti-
arylation of a variety of amines with a broad range of aryl mized reaction conditions were 0.25 mol-% of Pd2(dba)3
chlorides.
and 0.05 mol-% of ligand 1e with tBuONa at 80 °C for 24 h.
Scheme 1. Synthetic routes for 1d and 1e.
Eur. J. Org. Chem. 2015, 1954–1960
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1955

S. H. Kim, M. Kim, J. G. Verkade, Y. Kim
FULL PAPER
Table 1. Survey of Buchwald–Hartwig N-arylation reactions of N-Boc-piperazine with 1-chloro-4-methylbenzene in the presence of 1a–
1e.[a]
Entry
Ligand
Temperature [°C]
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
40
40
40
40
40
80
80
80
80
80
72
72
72
72
72
24
24
24
24
24
48
37
5
57
87
61
53
15
69
92
10
[a] Reaction conditions: 1-chloro-4-methylbenzene (1 mmol), 1-Boc-piperazine (1.2 mmol), Pd2(dba)3 (0.25 mol-%), 1a–1e (0.5 mol-%),
tBuONa (1.4 mmol), toluene (3.0 mL). [b] Isolated yields after silica gel column chromatography.
Under these reaction conditions, aryl chlorides of the elec- Table 3. Pd2(dba)3/1e-catalyzed N-arylation of various primary and
secondary amines with 1-chloro-4-methylbenzene (2a).[a]
tron-neutral, -donating, -withdrawing, and heteroaryl types
gave the expected products in excellent isolated yields (90–
99%) within 24 h at 80 °C (Table 2, Entries 1–4). These re-
sults with small amounts of Pd2(dba)3 and 1e as well as a
moderate reaction temperature contrast with the harsher
ones we reported previously for the Pd2(dba)3/1a catalytic
system.[15b,15c]
Table 2. Pd2(dba)3/1e-catalyzed N-arylation of 1-Boc-piperazine
with various aryl chlorides.[a]
[a] Reaction conditions: aryl chloride (1 mmol), 1-Boc-piperazine
(1.2 mmol), Pd2(dba)3 (0.25 mol-%), 1e (0.5 mol-%), tBuONa
(1.4 mmol), toluene (3.0 mL), 80 °C, 24 h. [b] Isolated yields after
[a] Reaction conditions: 1-chloro-4-methylbenzene (1 mmol),
amine (1.2 mmol), Pd2(dba)3 (0.25 mol-%), 1e (0.5 mol-%),
tBuONa (1.4 mmol), toluene (3.0 mL), 80 °C, 24 h. [b] Isolated
silica gel column chromatography.
yields after silica gel column chromatography.
We then assessed the reactivity of various amines includ-
ing cyclic secondary amines (3b and 3c), noncyclic second-
Our next category of amine substrates for investigation
ary amines (3d, 3e, and 3f), and primary amines (3g and included secondary amines containing alkyl or aryl substit-
3h) with the electron-neutral aryl chloride 2a in the presence uents for reactions with electron-neutral, -donating, and
of Pd2(dba)3 and 1e (Table 3). All of the amine substrates -withdrawing aryl chlorides and also a heteroaryl chloride
provided good-to-excellent yields of N-arylated products.
in the presence of Pd2(dba)3 and 1e.
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Eur. J. Org. Chem. 2015, 1954–1960

N-Arylation Reactions with Aryl Chlorides
The reactions of all the chlorides with the secondary anil- ary aliphatic amines are also summarized in Table 4 (4bd,
ine N-methylaniline (3e) to give diarylamines are depicted 4cd, 4cc, 4cd, 4da, 4db, 4dd, 4eh, 4em, and 4hd, 80–89%).
in Table 4. The expected products were obtained in good- The coupling of aryl chlorides with aliphatic amines had
to-excellent isolated yields (4be, 4ce, 4ee, and 4ie, 86–97%). previously required a relatively large amount of the palla-
The products of the reactions of the chlorides with di- dium complex and ligand 1a to produce low yields of prod-
phenylamine (a secondary amine) are also given in Table 4 ucts.[15b] Again, we found the expected products in excellent
(4bf, 4ef, and 4if). Previously, the coupling of diphenyl- isolated yields with our low-catalyst-loading system. For ex-
amine with aryl chlorides required high catalyst loading, ample, although the product of the reaction of 3-methoxy-
higher than that for dialkylamines and alkyl arylamines.[15b] chlorobenzene with n-hexylamine was obtained in 43%
Gratifyingly, we found that our protocol gave similar out- yield with 1a,[15b] the analogous reaction with 1e proceeds
comes for dibutylamine (3d) and N-methylaniline (3e), for in much better yield (4em, 83%).
which the expected products were formed in excellent iso-
By our methodology reported herein, a one-step synthe-
lated yields (4bd, 4cd, 4dd, 4hd, 4be, 4ce, 4ee, and 4ie, 88– sis of carbazoles was readily achieved under mild conditions
97%). Notably, the Pd2(dba)3/1e catalytic system is useful with good-to-excellent yields (Table 5). Various primary
for N-arylation reactions despite steric congestion of the amines were successively reacted with 2,2-dichlorobiphenyl.
substrates.
Under our conditions, a broad range of primary amines,
As seen with 4bi, 4bj, 4cm, 4ei, 4ej, 4eh, 4em, and 4hk in including electron-neutral, electron-rich, and electron-poor
Table 4, the reactions of aryl chlorides with primary amines amines, were easily coupled to produce the expected prod-
proceed in high yields (85–97%). Substituted aryl anilines ucts in good-to-excellent isolated yields (Table 5, Entries 1–
are notably more reactive than aniline itself. Thus, although 14; 83–98%). Additional observations of note are that our
the reaction of ortho-substituted anilines resulted in 91– palladium loading (0.25 mol-%) is one-half that previously
94% product yields (4fl, 4gk, and 4gl), the analogous reac- reported for Pd2(dba)3-catalyzed carbazole synthesis, and
tions with aniline proceeded in only 86 or 85% yield (4bi the reaction temperature is lower.[17] Furthermore, unreac-
and 4ei, respectively). The results of the reactions of aryl tive primary amines, including electron-poor 3u and ali-
chlorides with primary aliphatic amines as well as second- phatic 3v and 3w, gave rise to unexpectedly higher yields of
Table 4. Pd2(dba)3/1e-catalyzed N-arylation of various primary and secondary amines with a variety of aryl chlorides.[a,b]
[a] Aryl chloride (1 mmol), amine (1.2 mmol), Pd2(dba)3 (0.25 mol-%), 1e (0.5 mol-%), tBuONa (1.4 mmol), toluene (3.0 mL), 80 °C,
24 h. [b] Isolated yields after silica gel column chromatography.
Eur. J. Org. Chem. 2015, 1954–1960
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1957

S. H. Kim, M. Kim, J. G. Verkade, Y. Kim
FULL PAPER
Table 5. Pd/1e-catalyzed N-substituted carbazole synthesis from various primary amines and 2,2Ј-dichlorobiphenyl.[a,b]
[a] Reaction conditions: 2,2Ј-dichlorobiphenyl (0.5 mmol), aniline (0.6 mmol), Pd2(dba)3 (0.25 mol-%), 1e (1 mol-%), tBuONa (1.5 mmol),
toluene (3.0 mL). [b] Isolated yields after silica gel column chromatography. [c] 2.5 mol-% of Pd2(dba)3 was employed. [d] 1.5 mmol of
2,2Ј-dichlorobiphenyl and 4.5 mmol of tBuONa were employed.
N-substituted carbazoles than we obtained previously un-
Experimental Section
der mild conditions.[17]
General Information: All reactions of air- and moisture-sensitive
materials were performed under dinitrogen with standard Schlenk-
type glassware on a dual-manifold Schlenk line in a glovebox. Di-
nitrogen was deoxygenated with activated Cu catalyst and dried
Conclusions
with Drierite. All reagents were purchased from Aldrich and used
as supplied unless otherwise indicated. All solvents were dried by
We have developed an efficient Pd2(dba)3/1e-catalyzed N-
arylation protocol for a wide range of amines with a variety
distillation from sodium diphenyl ketyl under dinitrogen and stored
of aryl chlorides. Good-to-excellent yields of secondary and
over activated 3-Å molecular sieves. NMR solvents such as CDCl3
tertiary amine derivatives (38 products in 80–99% isolated
and C6D6 were dried with activated 4-Å molecular sieves and used
yields) were achieved in single N-arylations. Similar isolated
yields (83–98%) of 14 carbazoles were obtained for double
N-arylations with the same catalytic system.
after vacuum transfer to a Schlenk tube equipped with a Young
1
valve. H, 13C, and 31P NMR spectra were recorded with samples
in CDCl3 [internal standard at δ = 7.24 ppm (CDCl3) and at δ
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Eur. J. Org. Chem. 2015, 1954–1960

N-Arylation Reactions with Aryl Chlorides
= 7.15 ppm (C6D6) for 1H spectra; at δ = 77.0 ppm (CDCl3) and
128.0 ppm (C6D6) for 13C spectra; and at δ = 0.00 ppm for 85%
phosphoric acid added as an external standard for 31P spectra] with
phase was dried with Na2SO4, and then the solution was filtered
and evaporated under reduced pressure with a rotary evaporator to
give the desired product 1e·heptamine (37 g, 96.5%) as a yellow-
a 400 MHz NMR spectrometer. HRMS data were recorded with a orange oil. 1H NMR (CDCl3, 400.13 MHz): δ = 7.11 (d, J =
Shimadzu LCMS 2010 instrument. Column chromatography was
performed by flash column techniques with 300–400 mesh silica
gel.
8.0 Hz, 6 H, Ph), 6.64 (d, J = 8.0 Hz, 6 H, Ph), 3.63 (s, 6 H,
NCH2C6H4NMe2), 2.89 (s, 18 H, NMe2), 2.61 (t, J = 6.0 Hz, 6 H,
NCH2CH2NH), 2.52 (t, J = 6. 0 Hz, 6 H, NCH2CH2NH) ppm.
13C NMR (100.63 MHz, CDCl3): δ = 149.6, 129.0, 128.3, 128.3,
112.6, 54.32, 53.35, 46.93, 40.66 ppm. HRMS: calcd. for C33H52N7
[M + H]+ 546.4284; found 546.4280. In a manner analogous to the
procedure for 1d·HCl, the desired precursor 1e·HCl was prepared
from a dichloromethane solution of PCl(NMe2)2 (3.44 mmol) and
1e·heptamine (1.88 g, 3.44 mmol) in 96.3% yield (2.02 g) as a yel-
low powder. 1H NMR (CDCl3, 400.13 MHz): δ = 6.94 (d, J =
8.60 Hz, 6 H, Ph), 6.59 (d, J = 8.56 Hz, 6 H, Ph), 6.36 (s, 0.5 H),
5.14 (s, 0.5 H), 3.96 (d, J = 16.95 Hz, 6 H, NCH2C6H4NMe2), 3.36
(m, 6 H, NCH2CH2NP), 2.93 (m, 6 H, NCH2CH2NP), 2.87 (s, 9
H, NMe2) ppm. 13C NMR (100.63 MHz, CDCl3): δ = 150.1, 128.5,
124.4 (d), 112.6, 50.75 (d), 46.83 (d), 40.47, 38.89 (d) ppm. 31P
NMR (161.79 MHz, CDCl3): δ = –7.98 ppm. In a manner analo-
gous to the procedure for 1d, product 1e was prepared from a THF
solution of 1e·HCl (2.3 g, 3.77 mmol) and tBuOK (1.27 g,
11.3 mmol) in 72.1% yield (1.56 g) as a yellow sticky oil. 1H NMR
(CDCl3, 400.13 MHz): δ = 7.44 (d, J = 8.56 Hz, 6 H, Ph), 6.67 (d,
Compound 1d: A mixture of diisobutyltren [6.46 g, 32.0 mmol; tren
= tris(2-aminoethyl)amine] and 4-(dimethylamino)benzaldehyde
(5.22 g, 35.0 mmol) in methanol (100 mL) was stirred overnight at
room temp. To the stirring reaction mixture was slowly added
NaBH4 (1.82 g, 48.0 mmol), and stirring was continued for 2 h. The
desired product 1d·pentamine was obtained in 83.7% (10.5 g) yield
as
a
colorless oil after purification. 1H NMR (CDCl3,
400.13 MHz): δ = 7.14 (d, J = 11 Hz, 2 H), 6.66 (d, J = 11 Hz, 2
H), 3.67 (s, 2 H), 2.90 (s, 6 H), 2.53 (m, 12 H), 2.35 (d, J = 8.9 Hz,
4 H), 1.64 (m, 2 H), 1.40 (br s, 3 H), 0.85 (d, J = 8.8 Hz, 12 H)
ppm. 13C NMR (CDCl3, 100.63 MHz): δ = 149.7, 129.0, 128.5,
112.7, 58.20, 54.61, 54.47, 53.56, 47.93, 47.10, 40.75, 28.38, 20.70
ppm. HRMS: calcd. for C23H45N5 [M + H]+ 392.3753, found
392.3751. To a solution of PCl(NMe2)2 in 30 mL of CH2Cl2 gener-
ated in situ from PCl3 (0.24 mL, 2.75 mmol) and P(NMe2)3
(1.00 mL, 5.50 mmol) was added dropwise
a solution of
1d·pentamine (3.23 g, 8.25 mmol) in CH2Cl2 (30 mL) at 0 °C. The
reaction mixture was maintained at room temp. overnight, and then
all volatiles were removed under reduced pressure. The residue was
washed three times with Et2O and dried under reduced pressure to
give the desired product 1d·HCl (3.25 g, 86.4%) as a yellow powder.
1H NMR (CDCl3, 400.13 MHz): δ = 6.93 (d, J = 11 Hz, 2 H), 6.62
(d, J = 11 Hz, 2 H), 6.15 (s, 0.5 H), 4.49 (s, 0.5 H), 3.88 (d, J =
22 Hz, 2 H), 3.44 (m, 6 H), 3.06 (m, 4 H), 2.58 (m, 12 H), 1.74 (m,
2 H), 0.84 (d, J = 3.0 Hz, 6 H), 0.82 (d, J = 2.7 Hz, 6 H) ppm. 13C
NMR (100.63 MHz, CDCl3): δ = 149.8, 127.9 (d), 123.9 (d), 112.3,
55.23 (d), 50.48 (d), 46.65 (d), 40.16, 39.26 (d), 38.35 (d), 34.31,
26.57 (d), 19.67 ppm. 31P NMR (CDCl3, 161.79 MHz): δ =
–7.87 ppm. HRMS: calcd. for C23H43N5P [M – Cl]+ 420.3256;
found 420.3260. A solution of 1d·HCl (1.21 g, 2.65 mmol) and
tBuOK (0.89 g, 7.95 mmol) in tetrahydrofuran (THF, 30 mL) was
stirred for 1 h at room temp., and then the volatile compounds were
removed under reduced pressure. Compound 1d was extracted with
n-hexane, and then all volatiles were removed under vacuum to give
the desired monomeric 1d (0.83 g, 74.5%) as a yellow gel. 1H NMR
(C6D6, 400.13 MHz): δ = 7.35 (d, J = 11 Hz, 2 H), 6.65 (d, J =
11 Hz, 2 H), 4.16 (d, J = 12 Hz, 2 H), 2.72 (m, 16 H), 2.53 (s, 6
H), 1.80 (m, 2 H), 0.99 (d, J = 2.9 Hz, 6 H), 0.96 (d, J = 3.0 Hz, 6
H) ppm. 13C NMR (C6D6, 100.63 MHz): δ = 150.1, 129.8 (d), 129.3
(d), 113.1, 58.12 (d), 53.13 (d), 51.64, 51.53 (d), 46.74 (d), 45.21
(d), 40.49, 28.77 (d), 20.90 (d), 20.86 (d) ppm. 31P NMR (C6D6,
161.79 MHz): δ = 129.7 ppm. HRMS: calcd. for C23H43N5P [M+
H]+ 420.3256; found 420.3254.
J
= 8.60 Hz, 6 H, Ph), 4.32 (d, J = 9.04 Hz, 6 H,
NCH2C6H4NMe2), 2.88 (m, 6 H, NCH2CH2NP), 2.69 (m, 6 H,
NCH2CH2NP), 2.55 (s, 18 H, NMe2) ppm. 13C NMR
(100.63 MHz, CDCl3): δ = 150.1, 129.9 (d), 128.4 (d), 113.1 (d),
54.13 (d), 52.80 (d), 45.27 (d), 40.52 ppm. 31P NMR (161.79 MHz,
CDCl3): δ = 127.4 ppm. HRMS: calcd. for C33H49N7P [M+ H]+
574.3787; found 574.3785.
Although 1d and 1e are quite stable to atmospheric oxidation, they
and their hydrochloride salts are somewhat sensitive to moisture.
It may be assumed that ligands 1d and 1e (even as their correspond-
ing oxides) are less toxic than O=P(NMe2)3, which is more vola-
tile.[18]
Representative Procedure for N-Arylation Reactions with Aryl
Chloride: An oven-dried 10 mL vial equipped with a magnetic stir-
ring bar and a septum was charged with ligand (0.5 mol-%) inside
a nitrogen-filled drybox. After the removal of the vial from the
drybox, toluene (3 mL) was added. To an oven-dried 10 mL round-
bottomed flask equipped with a magnetic stirring bar and a septum
inside a nitrogen-filled drybox was added Pd2(dba)3 (0.25 mol-%)
and NaOtBu (1.4 mmol). After the removal of the flask from
the drybox, the ligand/toluene (3 mL) solution, aryl chloride
(1.0 mmol), and amine (1.2 mmol) were added, and stirring was
continued under the specified reaction conditions. The reaction
mixture was then cooled to room temp., adsorbed onto silica gel,
and then purified by column chromatography (ethyl acetate/hex-
anes as eluent). Isolated yields are the average of two runs.
Compound 1e: To a 250 mL round-bottomed flask containing a
magnetic stirring bar and a septum was added tren (10.3 g,
70.2 mmol) followed by methanol (80 mL). Another 250 mL
round-bottomed flask containing a magnetic stirring bar and a sep-
tum was charged with 4-(dimethylamino)benzaldehyde (34.5 g,
231.7 mmol) to which was added methanol (150 mL). The solution
of 4-(dimethylamino)benzaldehyde was added dropwise to the solu-
tion of tren at room temp. overnight. To this reaction mixture in a
water bath at room temp. was slowly added NaBH4 (3.99 g,
105.3 mmol), and then the reaction mixture was stirred for 2 h at
room temp. To the reaction mixture was added distilled water
(40 mL), and the mixture was stirred for 3 h at room temp. The
reaction mixture was extracted with dichloromethane, the organic
Supporting Information (see footnote on the first page of this arti-
cle): 1H, 13C, and 31P NMR and mass spectra of all of the products.
Acknowledgments
This work was financially supported by the Korean Ministry of
Education (MOE) and the National Research Foundation of Korea
(NRF) through the Creative Human Resource Training Project for
Regional Innovation (grant number 2014H1C1A1066874).
[1] a) J. P. Wolfe, S. Wagaw, J.-F. Marcoux, S. L. Buchwald, Acc.
Chem. Res. 1998, 31, 805–818; b) J. F. Hartwig, Acc. Chem.
Eur. J. Org. Chem. 2015, 1954–1960
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S. H. Kim, M. Kim, J. G. Verkade, Y. Kim
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Received: November 3, 2014
Published Online: February 9, 2015
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