A room temperature copper catalyzed N-selective arylation of β-amino alcohols with iodoanilines and aryl iodides

Article abstract of DOI:10.1016/j.tet.2013.04.128

An efficient method is described for the synthesis of N-(2-aminophenyl)-2- hydroxyethylamines via a copper catalyzed N-selective arylation of β-amino alcohols with iodoanilines. The corresponding coupling products are useful intermediates for the synthesis of a variety of N-2-hydroxyethyl-substituted benzimidazoles, benzimidazolones, and iminobenzimidazoles. We found that 2-iodoaniline only arylates certain amino alcohols but not amines lacking a hydroxyl group. We also demonstrate the arylation of sterically demanding β-amino alcohols, such as ephedrine and prolinol with aryl iodides at room temperature.

Full text of DOI:10.1016/j.tet.2013.04.128

Tetrahedron 69 (2013) 7646e7652
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A room temperature copper catalyzed N-selective arylation of
b-amino alcohols with iodoanilines and aryl iodides
*
Priyabrata Das, Jef K. De Brabander
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 March 2013
Received in revised form 23 April 2013
Accepted 26 April 2013
Available online 2 May 2013
An efficient method is described for the synthesis of N-(2-aminophenyl)-2-hydroxyethylamines via
a copper catalyzed N-selective arylation of
b-amino alcohols with iodoanilines. The corresponding
coupling products are useful intermediates for the synthesis of a variety of N-2-hydroxyethyl-substituted
benzimidazoles, benzimidazolones, and iminobenzimidazoles. We found that 2-iodoaniline only arylates
certain amino alcohols but not amines lacking a hydroxyl group. We also demonstrate the arylation of
sterically demanding
temperature.
b
-amino alcohols, such as ephedrine and prolinol with aryl iodides at room
Keywords:
Cross-coupling
Copper catalysis
Arylation
Ó 2013 Elsevier Ltd. All rights reserved.
Amino Alcohol
Iodoaniline
Benzimidazole
1. Introduction
N3 alkylation, the latter approach is limited to symmetrical benz-
imidazoles. Moreover, reaction with internal epoxides or more
hindered stereogenic 2-bromoalkylketones is problematic, thereby
2-(1,2-Dihydro-2-iminobenzo[d]imidazol-3-yl)ethanol (1), 1-
(2-hydroxyethyl)-1H-benzo[d]imidazol-2(3H)-one (2), and 2-(1H-
benzo[d]imidazol-1-yl)ethanol (3) are important scaffolds for me-
dicinal chemistry and/or asymmetric catalysis (Fig. 1; 4e12).1e10
Our interest in these N-2-hydroxyalkyl decorated heterocycles
stems from a recent High Throughput screening campaign aimed at
identifying orexin receptor agonists of potential use for the treat-
ment of narcolepsy, during which we identified compounds related
to structures included in Fig. 1.6 Known synthetic protocols toward
these important heterocycles primarily exploit SNAr-type reactivity
to produce intermediate 15 from 2-fluoro nitrobenzene (13) and
amino alcohol 14,2,8 followed by a subsequent reduction (nitro to
amino) and cyclization of intermediate amino alcohol 15 with the
relevant electrophilic partner to produce benzimidazoles 3 (from
reaction with aldehydes, carboxylic acids or carboxylic acid equiv-
alents),3,4,11 benzimidazolones 16 (from reaction with carbonyl
diimidazole),8 or iminobenzimidazoles 17 (from capping with cy-
anogen bromide).2,6 Alternatively, the latter can also be obtained
from direct alkylation of iminobenzimidazole 18 with primary ep-
oxides or bromomethylketones followed by ketone reduction.6,12
Given the difficulty in controlling chemoselectivity for N1 versus
precluding introduction of an
a-stereogenic aminoethanol frag-
ment (R0).
In the context of our above mentioned medicinal chemistry
program regarding orexin receptor agonists, we sought to explore
methodology for the direct synthesis of N-2-aminoaryl substituted
amino alcohols, such as 21 via a N-selective copper catalyzed ary-
lation of unprotected amino alcohols 20 with iodoanilines 19 (Eq.
1). Such an approach would alleviate problems associated with the
direct alkylation of iminobenzimidazole 18, and allows the in-
troduction of
a-stereogenic amino alcohols, of which many are
commercially available. Compared to the SNAr route depicted in
Fig. 2, this route would be one-step shorter, and potentially occur
under milder conditions (lower temperatures, no reducing agents).
Furthermore, the number of commercially available 2-iodo/bromo-
anilines exceeds that of the corresponding 2-fluoronitroarenes
(Aldrich), thus enabling the expansion of chemical diversity in
the corresponding 2-amino-aniline products.
ð1Þ
* Corresponding author. Tel.: þ1 214 648 7808; fax: þ1 214 648 0320; e-mail
address: jef.debrabander@utsouthwestern.edu (J.K. De Brabander).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.128

P. Das, J.K. De Brabander / Tetrahedron 69 (2013) 7646e7652
7647
a secondary amine is only tolerated separately, not together. Im-
portant for our intended purpose (Eq. 1), this report remains to the
best of our knowledge the only one describing a singular example
documenting a cross-coupling of 2-iodoaniline with a b-amino al-
cohol (2-amino-1-phenylethanol).15 In what follows, we describe
a room temperature copper catalyzed N-selective arylation of
a variety of
demonstrate the effectiveness of our conditions for the N-selective
arylation of -amino alcohols containing a secondary amine, in-
cluding those with -branching, with a variety of aryl iodides.
b- and other amino alcohols with iodoaniline. We also
b
a
2. Results and discussion
Our investigations began with exploring conditions for the
arylation of 2-amino-1-phenylethanol with 2-iodoaniline (Table 1),
a combination reported singularly by Job and Buchwald.15 Using
2.5% of CuI and 2 equiv of NaOH in isopropanol at 90 ꢀC, they ob-
tained N-(2-aminophenyl)-2-amino-1-phenylethanol 15a in 63%
yield.15 We decided to frame our exploratory ligand screening to
reaction conditions at room temperature, with mild base (Cs2CO3)
and 10% CuI as the catalyst. As shown in Table 1 (entry 1), under
these milder conditions, omission of an external ligand resulted in
low conversion (w11% isolated yield after 14 h), indicating the in-
effectiveness of the amino alcohol starting material for ligand ac-
celeration. Proline (L1), a ligand described by Ma and co-workers
for copper catalyzed N-arylation of amines including glycinol
(>80 ꢀC),16d yielded 45% of product 21a (entry 2). Picolinic acid (L2)
did not fare better than ligandless conditions, providing low yields
of the N-arylated product (w15%, entry 3). Interestingly, this ligand
was reported to yield selective O-arylation of 3-aminophenol.17b
Next, we examined isobutyrylcyclohexanone (L3), a catalyst de-
scribed by Buchwald for the N-selective copper catalyzed arylation
of amino alcohols under mild conditions (5% CuI, Cs2CO3, room
temperature).16c Although the N- versus O-selectivity and yield was
Fig. 1. N-2-Hydroxyalkyl-substituted iminobenzimidazole, benzimidazole, and benzi-
midazolone scaffolds and representative examples.
modest for the only b-amino alcohol (glycinol) included in that
report, this ligand provided the first breakthrough for our screen,
yielding product 21a in 60% isolated yield (entry 4). Gratifyingly,
evaluation of other b-diketone ligands led us to identifying tetra-
methylheptane-3,5-dione (L4) as an efficient ligand for this trans-
formation (88% yield, entry 5). This catalyst was originally
described by Merck for the Ullman-type coupling of phenols,19 and
Table 1
Ligand screening for the Cu-catalyzed arylation of amino alcohol 20a with iodoa-
niline (19) at room temperature
Fig. 2. Synthetic routes N-2-hydroxyalkyl-substituted benzimidazole, iminobenzimi-
dazole, and benzimidazolone heterocycles.
Over the past two decades or so, palladium and copper cata-
lyzed carbonenitrogen bond formation for the synthesis of N-
arylamines has gained a lot of attention.13,14 Of these, the copper
catalyzed variant remains attractive for industrial applications due
to lower catalyst costs and enhanced stability toward air and
moisture, resulting in a significant increase in research on ligand-
assisted carbonenitrogen bond formation under milder reaction
conditions.14 Despite these advances, there remain relatively few
reports on the N-selective arylation of b
-amino alcohols,15 and most
,
b
Entry
Ligand
Yield %
Entry
Ligand
Yield %a
include only glycinol.16e18 The Buchwald group has been particu-
larly active in this area, and disclosed a ligand-free copper catalyzed
1
2
3
4
None
L1
L2
11
45
15
60
5
6
7
8
L4
L5
L6
L7
88
84
81
87
arylation of
first and only examples of
glycinol, there remain some limitations including the use of higher
temperatures and/or strong base. Furthermore, -branching or
b
-amino alcohols.15 Although this report describes the
L3
b
-amino alcohols more complex than
a
Isolated yields reported as the average of three experiments.
b
a
NMR spectroscopic data for 21a are in agreement with those reported in Ref. 15.

7648
P. Das, J.K. De Brabander / Tetrahedron 69 (2013) 7646e7652
Table 3
Arylation of
amino-3-iodopyridine
later utilized by Buchwald for the room temperature copper cata-
lyzed arylation of amines.17a In the latter report, this more sterically
b-amino alcohols with 2-iodoaniline, N-Boc-2-iodoaniline and 2-
hindered
anone (L3).17a In an attempt to increase steric bulk, we prepared
mixed adamantyl/tert-butyl -diketone L5, which however did not
b-diketone L4 was less effective than butyrylcyclohex-
Entry
1
Amino alcohol
Product
Yield % (L4/L6)a
b
further improve the yield (84%, entry 6). Finally, we found pyrrole-
2-carboxylic acid L7 and indole-2-carboxylic acid L6 to be equally
80/78
effective as
We selected
b
-diketones L4 and L5 (81e87%, entries 7e8).20,21
b-diketone L4 and indolecarboxylic acid L6 for
further evaluation as they are both commercially available at more
viable prices than pyrrolecarboxylic acid L7. As shown in Table 2,
lowering the catalyst and ligand loading by half (5% CuI, 10% ligand)
provided results similar to our initial conditions (entry 3), whereas
further reduction in catalyst and ligand loading were less satis-
factory (entry 1), as was reduction of only ligand loading (entry 2).
Further experiments were thus continued with the use of 5 mol %
CuI and 10 mol % ligand. A solvent screen indicated that DMSO was
superior to all other solvents examined (entries 4e9), with dime-
thylacetamide (DMA) as a viable runner-up (entry 6). Comparing
entry 3 to the last two entries demonstrate that the milder car-
bonate base Cs2CO3 was more effective than sodium or potassium
carbonate.
2
3
77/77
90/89
4
5
6
78/79
72/70
68/68
Table 2
Optimization of reaction conditions for the reaction depicted in Table 1 with ligands
L4 and L6
Entry
Mol % CuI
Mol %
ligand
Base
Solvent
Yield %a
(L4/L6)
1
2
3
4
5
6
7
8
2.5
5
5
10
5
5
5
5
5
5
5
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMF
51/47
60/58
87/86
81/75
67/66
75/73
70/69
46/40
56/50
51/50
60/59
10
10
10
10
10
10
10
10
10
DMA
7
8
a
50/40
Dioxane
Toluene
DCM
DMSO
DMSO
NTb/81c
9
10
11
5
a
Isolated yields reported as the average of three experiments.
NT¼Not Tested.
Isolated yields reported as the average of three experiments.
b
c
Yield based on single experiment.
Using our optimized reaction conditions, we explored the scope
of the arylation of various -amino alcohols with 2-iodoaniline, 2-
b
material, entry 4). Primary or secondary amines that do not contain
a free hydroxy-group were completely inert to the reaction con-
ditions, as shown by the attempted arylation of benzylamine and
morpholine (entries 5 and 6). From the latter two examples, it
appears that a hydroxy-functionality is crucial for the successful
arylation with iodoaniline. The poor conversion under ligandless
conditions (Table 1, entry 1), in combination with the successful
arylation of 6-aminohexanol and 4-hydroxypiperidine (Table 4,
entries 2 and 3) appear to preclude a simple model where the
amino alcohol acts as a bidentate ligand for copper. Perhaps hy-
drogen bonding involving the alcohol is important. At this point, we
do not have sufficient data to provide a reasonable hypothesis.
The requirement for an alcohol group is specific for the arylation
with 2-iodoaniline. Indeed, the room temperature copper catalyzed
arylation of a wide range of amines with aryl halides other than
iodoaniline has been documented in the literature.13,14,16,17 A no-
tably mild procedure was reported by Buchwald with iso-
butyrylcyclohexanone (L3).17a Using their conditions (5 mol % CuI,
20 mol % L3, 2 equiv Cs2CO3, room temperature), arylation of
benzylamine with 3,4-dimethyl-1-phenyliodide provided 96% of
product. We were therefore not surprised that our conditions
(5 mol % CuI, 10 mol % L4, 2 equiv Cs2CO3, DMSO, room tempera-
ture) provided similar results (91% isolated yield). As noted in the
Introduction, although a room temperature copper catalyzed N-
amino-3-iodopyridine, and Boc-protected 2-iodoaniline. As shown
in Table 3, we found that 2-amino-3-iodopyridine was an excellent
donor for the arylation of 2-hydroxyphenethylamine 20a, yielding
N-arylated product 21b in 78e80% yield (entry 1). Secondary
amines flanked by a stereogenic hydroxy-substituent (20b) per-
formed equally well, providing product 21c with iodoaniline in 77%
and Boc-protected product 21d after coupling with N-Boc-2-
iodoaniline (w90%, entries 2e3). Next, a series of
b-amino alco-
hols derived from -amino acids were examined. All substrates
a
(20cef) were arylated in good to moderate yield with iodoaniline
(entries 4e7). There is a clear trend toward lower reactivity with
t
increased steric hindrance; with the sterically demanding butyl-
glycinol 20f affording the lowest yield (w50%, entry 7).22 However,
using Boc-protected iodoaniline drastically improved the yield of
the corresponding arylation product 21i to 81% (entry 8).
Next, amino alcohols other than
b-amino alcohols and non-
hydroxylated amines were investigated. As shown in Table 4, lon-
ger chain amino alcohols 4-aminobutanol (20g) and 6-
aminohexanol (20h) also reacted smoothly with 2-iodoaniline at
room temperature, although the yields appear to diminish with
increasing chain length (entries 1e2). Interestingly, 4-
hydroxypiperidine (20i) was readily arylated (55e60%, entry 3),
whereas 3-hydroxymethylpiperidine was unresponsive to the
copper catalyzed arylation with iodoaniline (recovered starting
selective arylation of amino alcohols other than b-amino alcohols

P. Das, J.K. De Brabander / Tetrahedron 69 (2013) 7646e7652
7649
Table 4
Table 5
Arylation of amines with 2-iodoaniline
Arylation of secondary amines with aryl iodides
Entry
Amine
Product
Yield % (L4/L6)a
1
63/60
Entry
1
Product
Yield % (L4/L6)a
79/69
75/70
74/70
2
3
65/57
60/55
2
3
4
5
NRb
NRb
NRb
4
5
78/71
78/73
82/77
6
a
Isolated yields reported as the average of three experiments.
NR¼No Reaction. Starting materials were recovered.
6
b
and glycinol (mainly longer chain
achieved previously, to the best of our knowledge, there are no
examples with sterically demanding -amino alcohols under sim-
ilarly mild conditions. In Table 5, we tabulate data indicating that
our conditions are particularly efficient for -amino alcohols con-
taining a secondary amine, including those with -branching. Thus,
u-amino alcohols) has been
a
Isolated yields reported as the average of three experiments.
b
and iminobenzimidazoles as important scaffolds for medicinal
chemistry efforts.
b
a
ephedrine was efficiently arylated with a range of methyl, dimethyl,
or methoxy-substituted phenyliodides in yields >70e75% at room
temperature (entries 1e5). The final entry shows the arylation of
the secondary amino alcohol prolinol with phenyliodide in 77e82%
isolated yield.
4. Experimental section
Unless otherwise noted, commercially available materials were
used without further purification. All solvents were of HPLC or ACS
grade. Anhydrous solvents were purchased from commercial
sources. Reactions were performed under an atmosphere of argon
with magnetic stirring unless noted otherwise. Flash chromatog-
raphy (FC) was performed using E Merck silica gel 60 (240e400
mesh). Thin layer chromatography was performed using pre-coated
plates purchased from E. Merck (silica gel 60 PF254, 0.25 mm) that
were visualized using a KMnO4 or Ce(IV) stain. Nuclear magnetic
resonance (NMR) spectra were recorded on a Varian Inova-400,
Varian Inova-500 spectrometer at operating frequencies of 400/
3. Conclusion
In this manuscript, we disclosed an efficient copper catalyzed N-
selective arylation of
b-amino alcohols with 2,2,6,6-
tetramethylheptane-3,5-dione or indole-2-carboxylic acid as effi-
cient supporting ligands for this process. Although indole-2-
carboxylic acid is very rarely included as a ligand for copper cata-
lyzed N- or O-arylation processes, we found it performing as an ex-
cellent supporting and accelerating ligand for this copper catalyzed
N-arylation of amino alcohols. To the best of our knowledge, this
represents the first example of such a cross-coupling at room tem-
500 MHz (1H NMR) or 125/100 MHz (13C NMR). Chemical shifts (
d)
are given in parts per million relative to residual solvent and cou-
pling constants (J) in Hertz. Multiplicity is tabulated as s for singlet,
d for doublet, t for triplet, q for quadruplet, and m for multiplet.
Electrospray ionization mass spectra (ESI-MS) were obtained with
an Agilent Technologies 6130 Quadrupole LC/MS.
perature with b-amino alcohols more complex than glycinol, in-
cluding examples with secondary amines flanked with
a stereocenter, such as ephedrine. We also found that the oxidative
coupling partner 2-iodoaniline uniquely engages with amino alco-
hols, but not amines that do not possess a hydroxy-substituent. 4-
4.1. General experimental procedure
Piperidinol,
b
- and some longer chain
u
-amino alcohols were read-
Into a flame dried Schlenk tube containing a magnetic stir bar
was added aryliodide (1.0 mmol), amino alcohol (1.1 mmol), Cs2CO3
(652 mg, 2.0 mmol; or 977 mg, 3.0 mmol for entries 1e5 in Table 5,
which employ ephedrine hydrochloride salt) and CuI (9.5 mg,
0.05 mmol). Under an atmosphere of argon, DMSO (2 mL) and
ily arylated with 2-iodoaniline, whereas 3-hydroxymethylpiperidine
was resistant. Finally, this straightforward synthesis of N-(2-
aminoaphenyl)-substituted
N-2-hydroxyethyl substituted benzimidazoles, benzimidazolones,
b-amino alcohols streamlines access to

7650
P. Das, J.K. De Brabander / Tetrahedron 69 (2013) 7646e7652
2,2,6,6-tetramethylheptane-3,5-dione (21.0
m
L, 0.1 mmol) or in-
C20H27N2O3: 343.1, found: 343.0; HRMS m/z (ESI) calcd for
dole-2-carboxylic acid (0.1 mmol) were added and the reaction
mixture was stirred at room temperature for 14 h. After addition of
ethyl acetate (15 mL) and brine (5 mL), the organic layer was sep-
arated and the aqueous layer extracted with ethyl acetate
(3ꢁ20 mL). The combined organic layer was dried over anhydrous
Na2SO4 before passing it through a short pad of silica gel. The fil-
trate was concentrated and purified via flash column chromatog-
raphy to afford the corresponding arylated product.
C20H26N2O3K [(MþK)þ]: 381.1575, found: 381.1561.
4.6. (R)-2-(2-Aminophenylamino)pentan-1-ol (21e)
Using the general procedure, title compound 21e was obtained
as a dark red semi-solid with yields ranging from 78 to 80% (three
repetitions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione
(L4) or 77e79% (three repetitions, same scale) with indole-2-
carboxylic acid (L6). 1H NMR (500 MHz, CDCl3):
d 0.96 (t,
4.2. 2-(2-Aminophenylamino)-1-phenylethanol (21a)15
J¼7.3 Hz, 3H), 1.43 (dt, J¼11.0, 5.8 Hz, 2H), 1.56 (m, 2H), 3.20 (br s,
4H), 3.51 (m, 2H), 3.78 (dd, J¼10.9, 3.6 Hz, 1H), 6.73 (m, 3H), 6.84
(m, 1H); 13C NMR (125 MHz, CDCl3):
d 14.5, 19.7, 34.4, 54.9, 64.2,
Using the general procedure, title compound 21a was obtained
as a dark red semi-solid with yields ranging from 86 to 89% (three
repetitions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione
(L4) or 85e87% (three repetitions, same scale) with indole-2-
113.6, 117.6, 119.2, 121.2, 134.7, 137.2; ESI-MS (MþH)þ calcd for
C11H19N2O: 195.1, found: 195.1; HRMS m/z (ESI) calcd for C11H19N2O
[(MþH)þ]: 195.1492, found: 195.1489.
carboxylic acid (L6). 1H NMR (500 MHz, CDCl3):
d 3.24 (dd,
4.7. (R)-2-(2-Aminophenylamino)-4-methylpentan-1-ol (21f)
J¼12.5, 9.1 Hz, 1H), 3.37 (dd, J¼12.5, 3.3 Hz, 1H), 3.54 (br s, 4H), 4.90
(dd, J¼9.1, 3.3 Hz, 1H), 6.72 (m, 3H), 6.85 (m, 1H), 7.36 (m, 5H); 13C
Using the general procedure, title compound 21f was obtained
as a dark red semi-solid with yields ranging from 70 to 73% (three
repetitions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione
(L4) or 68e72% (three repetitions, same scale) with indole-2-
NMR (125 MHz, CDCl3):
d 52.2, 72.5, 112.8, 117.1, 119.6, 121.0, 126.2,
128.2, 128.8, 134.8, 137.2, 142.4; ESI-MS (MþH)þ calcd for
C14H17N2O: 229.1, found: 229.0; HRMS m/z (ESI) calcd for
C14H17N2O [(MþH)þ]: 229.1335, found: 229.1324.
carboxylic acid (L6). 1H NMR (500 MHz, CDCl3):
d 0.91 (d,
J¼6.5 Hz, 3H), 0.96 (d, J¼6.6 Hz, 3H), 1.40 (m, 1H), 1.50 (m, 1H), 1.74
(m, 1H), 3.04 (br s, 4H), 3.48 (dd, J¼10.8, 5.2 Hz, 1H), 3.55 (m, 1H),
3.77 (dd, J¼10.8, 3.4 Hz, 1H), 6.68 (m, 3H), 6.82 (t, J¼7.5 Hz, 1H); 13C
4.3. 2-(2-Aminopyridin-3-ylamino)-1-phenylethanol (21b)
Using the general procedure, title compound 21b was obtained
as a dark red semi-solid with yields ranging from 78 to 82% (three
repetitions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione
(L4) or 76e79% (three repetitions, same scale) with indole-2-
NMR (125 MHz, CDCl3):
d 23.1, 25.2, 41.7, 53.1, 64.5, 113.4, 117.7,
119.2, 121.3, 134.6, 137.2; ESI-MS (MþH)þ calcd for C12H21N2O:
209.1, found: 209.1; HRMS m/z (ESI) calcd for C12H21N2O [(MþH)þ]:
209.1648, found: 209.1638.
carboxylic acid (L6). 1H NMR (500 MHz, CDCl3):
d 2.15 (br s, 4H),
3.22 (m, 2H), 4.91 (m, 1H), 6.66 (m, 1H), 6.76 (d, J¼7.7 Hz, 1H), 7.19
4.8. 2-(2-Aminophenylamino)-3-methylbutan-1-ol (21g)
(m, 1H), 7.34 (m, 4H), 7.51 (d, J¼4.9 Hz, 1H); 13C NMR (125 MHz,
CDCl3): d 51.7, 72.6,115.9,118.3,126.1,128.4,129.0,131.8,137.1,142.2,
Using the general procedure, title compound 21g was obtained
as a dark red semi-solid with yields ranging from 67 to 69% (three
repetitions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione
(L4) or 67e69% (three repetitions, same scale) with indole-2-
149.5; ESI-MS (MþH)þ calcd for C13H16N3O: 230.1, found: 230.1;
HRMS m/z (ESI) calcd for C13H16N3O [(MþH)þ]: 230.1288, found:
230.1279.
carboxylic acid (L6). 1H NMR (500 MHz, CDCl3):
d 0.96 (d,
4.4. (1R,2S)-2-(2-Aminophenylamino)-1-phenylpropan-1-ol
(21c)
J¼7.1 Hz, 3H),1.03 (d, J¼7.2 Hz, 3H),1.97 (m,1H), 3.06 (br s,1H), 3.29
(m, 1H), 3.41 (br s, 3H), 3.51 (m, 1H), 3.76 (d, J¼8.6 Hz, 1H), 6.71 (m,
3H), 6.85 (m, 1H); 13C NMR (125 MHz, CDCl3):
d 19.1, 19.7, 29.8, 60.6,
62.0, 113.3, 117.9, 118.7, 121.4, 134.2, 137.9; ESI-MS (MþH)þ calcd for
C11H19N2O: 195.1, found: 195.1; HRMS m/z (ESI) calcd for C11H19N2O
[(MþH)þ]: 195.1492, found: 195.1482.
Using the general procedure, title compound 21c was obtained
as a dark red semi-solid with yields ranging from 76 to 78% (three
repetitions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione
(L4) or 75e79% (three repetitions, same scale) with indole-2-
carboxylic acid (L6). 1H NMR (500 MHz, CDCl3):
d 1.06 (d,
4.9. (S)-2-(2-Aminophenylamino)-3,3-dimethylbutan-1-ol
(21h)
J¼6.5 Hz, 3H), 3.31 (br s, 4H), 3.75 (d, J¼6.3 Hz, 1H), 4.97 (d,
J¼3.0 Hz, 1H), 6.74 (m, 2H), 6.85 (m, 2H), 7.34 (m, 1H), 7.40 (m, 4H);
13C NMR (125 MHz, CDCl3):
d 14.3, 54.6, 74.1,114.2,117.5,119.7,121.1,
Using the general procedure, title compound 21h was obtained
as a dark red semi-solid with yields ranging from 48 to 52% (three
repetitions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione
(L4) or 38e42% (three repetitions, same scale) with indole-2-
126.2, 127.6, 128.5, 135.2, 136.3, 141.8; ESI-MS (MþH)þ calcd for
C15H19N2O: 243.1, found: 243.1.
4.5. tert-Butyl 2-((1R,2S)-1-hydroxy-1-phenylpropan-2-
carboxylic acid (L6). 1H NMR (500 MHz, CDCl3):
d 1.00 (s, 9H),
ylamino)phenylcarbamate (21d)
3.36 (dd, J¼8.1, 4.0 Hz, 1H), 3.40 (br s, 4H), 3.54 (dd, J¼11.0, 8.0 Hz,
1H), 3.87 (dd, J¼11.0, 3.9 Hz, 1H), 6.67 (d, J¼7.7 Hz, 1H), 6.80 (m,
Using the general procedure, title compound 21d was obtained
as a brown solid with yields ranging from 87 to 93% (three repe-
titions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione (L4)
or 87e90% (three repetitions, same scale) with indole-2-carboxylic
3H); 13C NMR (125 MHz, CDCl3):
d 27.1, 34.8, 62.2, 63.7, 112.9, 118.2,
118.4, 121.6, 133.0, 139.4; ESI-MS (MþH)þ calcd for C12H21N2O:
209.1, found: 209.1; HRMS m/z (ESI) calcd for C12H21N2O [(MþH)þ]:
209.1648, found: 209.1638.
acid (L6). 1H NMR (500 MHz, CDCl3):
d
1.01 (d, J¼6.4 Hz, 3H), 1.53 (s,
9H), 3.49 (br s, 1H), 3.78 (d, J¼6.5 Hz, 1H), 4.02 (br s, 1H), 5.03 (s,
1H), 6.26 (br s, 1H), 6.75 (t, J¼7.6 Hz, 1H), 6.92 (d, J¼8.0 Hz, 1H), 7.17
(t, J¼7.8 Hz, 2H), 7.26 (m, 1H), 7.37 (m, 4H); 13C NMR (125 MHz,
4.10. (S)-tert-Butyl (2-((1-hydroxy-3,3-dimethylbutan-2-yl)
amino)phenyl)carbamate (21i)
CDCl3):
d
13.5, 28.6, 54.7, 72.5, 81.4, 114.5, 118.4, 124.4, 126.0, 126.8,
Using the general procedure, title compound 21i was obtained
in 81% yield (single experiment) with 2,2,6,6-tetramethylheptane-
127.2, 127.8, 128.4, 141.8, 142.1, 154.9; ESI-MS (MþH)þ calcd for

P. Das, J.K. De Brabander / Tetrahedron 69 (2013) 7646e7652
7651
3,5-dione (L4). 1H NMR (500 MHz, CDCl3):
d
0.97 (s, 9H),1.49 (s, 9H),
repetitions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione
3.31 (m, 2H), 3.47 (m, 1H), 3.85 (m, 2H), 6.17 (br s, 1H), 6.61 (td,
(L4) or 68e72% (three repetitions, same scale) with indole-2-
J¼7.5, 1.3 Hz, 1H), 6.79 (dd, J¼8.3, 1.2 Hz, 1H), 7.00 (dd, J¼7.8, 1.5 Hz,
carboxylic acid (L6). 1H NMR (500 MHz, CDCl3):
d 1.20 (d,
1H), 7.09 (td, J¼7.5, 1.3 Hz, 1H); 13C NMR (125 MHz, CDCl3):
d
27.1,
J¼6.8 Hz, 3H), 2.28 (s, 3H), 2.29 (br s, 1H), 2.76 (s, 3H), 4.02 (dd,
28.2, 34.3, 62.6, 64.2, 81.0, 113.1, 116.7, 122.1, 127.2, 128.2, 145.2,
154.7; ESI-MS (MþH)þ calcd for C17H29N2O3: 309.2, found: 309.2;
HRMS m/z (ESI) calcd for C17H29N2O3 [(MþH)þ]: 309.2173, found:
309.2161.
J¼6.9, 5.4 Hz, 1H), 4.87 (d, J¼5.1 Hz, 1H), 6.73 (m, 2H), 7.05 (d,
J¼8.3 Hz, 2H), 7.32 (m, 5H); 13C NMR (125 MHz, CDCl3):
d 12.0, 20.3,
33.1, 60.5, 75.9, 114.4, 126.1, 126.7, 127.4, 128.2, 129.6, 142.7, 148.2;
ESI-MS (MþH)þ calcd for C17H22NO: 256.1, found: 256.0; HRMS m/z
(ESI) calcd for C17H22NO [(MþH)þ]: 256.1696, found: 256.1681.
4.11. 4-(2-Aminophenylamino)butan-1-ol (21j)
4.16. (1S,2R)-2-(N-(4-Methoxyphenyl)-N-methylamino)-1-
Using the general procedure, title compound 21j was obtained
as a dark red semi-solid with yields ranging from 62 to 64% (three
repetitions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione
(L4) or 59e61% (three repetitions, same scale) with indole-2-
phenylpropan-1-ol (24c)
Using the general procedure, title compound 24c was obtained
as a colorless oil with yields ranging from 72 to 76% (three repeti-
tions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione (L4)
or 69e71% (three repetitions, same scale) with indole-2-carboxylic
carboxylic acid (L6). 1H NMR (500 MHz, CDCl3):
d 1.73 (m, 4H),
3.14 (t, J¼6.6 Hz, 2H), 3.30 (br s, 4H), 3.68 (t, J¼6.1 Hz, 2H), 6.69 (m,
3H), 6.84 (t, J¼7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3):
d
26.5, 30.8,
acid (L6). 1H NMR (500 MHz, CDCl3): 1H NMR (500 MHz, CDCl3):
d
44.4, 62.8, 112.2, 116.8, 119.0, 121.0, 134.4, 138.0; ESI-MS (MþH)þ
calcd for C10H17N2O: 181.1, found: 181.1; HRMS m/z (ESI) calcd for
C10H17N2O [(MþH)þ]: 181.1335, found: 181.1328.
d
0.79 (dd, J¼6.8, 1.6 Hz, 3H), 1.53 (br s, 1H), 2.74 (s, 3H), 3.52 (dd,
J¼9.4, 6.2 Hz,1H), 3.77 (s, 3H), 4.47 (d, J¼9.3 Hz,1H), 6.85 (dd, J¼8.8,
1.7 Hz, 2H), 7.01 (m, 2H), 7.30 (m, 4H), 7.43 (m, 1H); 13C NMR
(125 MHz, CDCl3):
d 10.3, 55.6, 66.3, 75.1, 77.2, 114.4, 119.5, 127.3,
4.12. 6-(2-Aminophenylamino)hexan-1-ol (21k)
127.9, 128.3, 129.0, 129.7, 141.3; ESI-MS (MþH)þ calcd for
C17H22NO2: 272.1, found: 272.0; HRMS m/z (ESI) calcd for
C17H22NO2 [(MþH)þ]: 272.1645, found: 272.1645.
Using the general procedure, title compound 21k was obtained
as a semi-solid with yields ranging from 63 to 67% (three repeti-
tions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione (L4)
or 55e58% (three repetitions, same scale) with indole-2-carboxylic
4.17. (1S,2R)-2-(N-Methyl-N-m-tolylamino)-1-phenylpropan-
1-ol (24d)
acid (L6). 1H NMR (500 MHz, CDCl3):
d 1.45 (m, 4H), 1.58 (m, 2H),
1.67 (m, 2H), 2.93 (br s, 4H), 3.12 (t, J¼7.1 Hz, 2H), 3.65 (t, J¼6.5 Hz,
Using the general procedure, title compound 24d was obtained
as a colorless oil with yields ranging from 76 to 80% (three repeti-
tions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione (L4)
or 69e73% (three repetitions, same scale) with indole-2-carboxylic
2H), 6.70 (m, 3H), 6.84 (t, J¼7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3):
d
25.9, 27.3, 29.9, 32.9, 44.4, 63.0, 111.9, 116.8, 118.6, 121.0, 134.2,
138.4; ESI-MS (MþH)þ calcd for C12H21N2O: 209.1, found: 209.1.
acid (L6). 1H NMR (500 MHz, CDCl3):
d
1.22 (d, J¼6.7 Hz, 3H), 2.10 (br
4.13. 1-(2-Aminophenyl)piperidin-4-ol (21l)
s, 1H), 2.30 (s, 3H), 2.77 (s, 3H), 4.08 (dd, J¼7.0, 5.4 Hz, 1H), 4.88 (d,
J¼5.2 Hz, 1H), 6.57 (q, J¼7.7 Hz, 3H), 7.10 (t, J¼7.8 Hz, 1H), 7.31 (m,
Using the general procedure, title compound 21l was obtained as
a brown solid with yields ranging from 58 to 62% (three repetitions,
same scale) with 2,2,6,6-tetramethylheptane-3,5-dione (L4) or
53e57% (three repetitions, same scale) with indole-2-carboxylic acid
1H), 7.33 (m, 4H); 13C NMR (125 MHz, CDCl3):
d 12.1, 21.9, 32.7, 59.7,
76.1, 110.7, 114.3, 118.0, 126.0, 127.5, 128.3, 128.9, 138.7, 142.6, 150.2;
ESI-MS (MþH)þ calcd for C17H22NO: 256.1 found: 256.0; HRMS m/z
(ESI) calcd for C17H22NO [(MþH)þ]: 256.1696, found: 256.1682.
(L6). 1H NMR (500 MHz, CDCl3):
d 1.76 (m, 3H), 2.05 (m, 2H), 2.74 (m,
2H), 3.14 (dt, J¼10.2, 4.4 Hz, 2H), 3.86(br s,1H), 4.00 (br s, 2H), 6.76 (m,
4.18. (1S,2R)-2-(N-Methyl-N-(3,5-dimethylphenyl)amino)-1-
phenylpropan-1-ol (24e)
2H), 6.96 (t, J¼7.6 Hz, 1H), 7.03 (d, J¼7.8 Hz, 1H); 13C NMR (125 MHz,
CDCl3): d 35.7, 49.5, 68.2,115.4,118.8,120.1,124.8,139.9,141.7; ESI-MS
(MþH)þ calcd for C11H17N2O: 193.1, found: 193.0; HRMS m/z (ESI)
Using the general procedure, title compound 24e was obtained
as a colorless oil with yields ranging from 77 to 79% (three repeti-
tions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione (L4)
or 72e74% (three repetitions, same scale) with indole-2-carboxylic
calcd for C11H17N2O [(MþH)þ]: 193.1335, found: 193.1329.
4.14. (1S,2R)-2-(N-Methyl-N-phenylamino)-1-phenylpropan-
1-ol (24a)23
acid (L6). 1H NMR (500 MHz, CDCl3):
d
1.26 (d, J¼6.8 Hz, 3H), 2.34 (s,
6H), 2.40 (br s, 1H), 2.81 (s, 3H), 4.12 (qd, J¼6.7, 4.9 Hz, 1H), 4.89 (d,
Using the general procedure, title compound 24a was obtained
as a colorless oil with yields ranging from 77 to 81% (three repeti-
tions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione (L4)
or 67e70% (three repetitions, same scale) with indole-2-carboxylic
J¼5.1 Hz, 1H), 6.47 (s, 3H), 7.26 (m, 1H), 7.40 (m, 4H); 13C NMR
(125 MHz, CDCl3):
d 12.4, 22.1, 33.1, 56.0, 76.4, 112.0, 119.4, 126.3,
127.7,128.6,138.9,142.9,150.7; ESI-MS (MþH)þ calcd for C18H24NO:
270.2, found: 270.1.
acid (L6). 1H NMR (500 MHz, CDCl3):
d
0.79 (d, J¼6.4 Hz, 3H), 2.73 (s,
3H), 3.65 (s, 1H), 3.73 (m, 1H), 4.48 (m, 1H), 6.81 (t, J¼6.8 Hz, 1H),
4.19. ((S)-1-Phenylpyrrolidin-2-yl)methanol (24f)
6.96 (dd, J¼8.6, 4.5 Hz, 2H), 7.26 (m, 5H), 7.39 (t, J¼6.2 Hz, 2H); 13C
NMR (125 MHz, CDCl3):
d
11.6, 31.1, 64.6, 75.6, 116.8, 119.8, 127.6,
Using the general procedure, title compound 24f was obtained
as a colorless oil with yields ranging from 81 to 83% (three repeti-
tions, same scale) with 2,2,6,6-tetramethylheptane-3,5-dione (L4)
or 75e79% (three repetitions, same scale) with indole-2-carboxylic
128.3, 128.7, 129.4, 141.5, 151.6; ESI-MS (MþH)þ calcd for C16H20NO:
242.2, found: 242.1.
4.15. (1S,2R)-2-(N-Methyl-N-p-tolylamino)-1-phenylpropan-
1-ol (24b)
acid (L6). 1H NMR (500 MHz, CDCl3):
d
1.65 (t, J¼4.9 Hz, 1H), 2.05
(m, 4H), 3.18 (td, J¼9.4, 6.1 Hz, 1H), 3.54 (t, J¼8.2 Hz, 1H), 3.70 (d,
J¼5.1 Hz, 2H), 3.90 (m, 1H), 6.74 (d, J¼8.1 Hz, 3H), 7.26 (m, 2H); 13C
Using the general procedure, title compound 24b was obtained
as a colorless oil with yields ranging from 73 to 76% (three
NMR (125 MHz, CDCl3): d 24.1, 29.1, 49.8, 60.4, 64.1, 112.6, 116.7,
129.5, 148.3; ESI-MS (MþH)þ calcd for C11H16NO: 178.1 found:

7652
P. Das, J.K. De Brabander / Tetrahedron 69 (2013) 7646e7652
178.0; HRMS m/z (ESI) calcd for C11H16NO [(MþH)þ]: 178.1226,
5. East, S. P.; Whittaker, M.; Ichihara, O.; Kotey, A. K.; Bamford, J. S. WO 2010/
067067, 2010.
6. Yanagisawa, M. US 2010/0150840, 2010.
found: 178.1228.
7. Drasner, K.; Weber, K. T.; WO 03/105779, 2003.
4.20. (S)-3,3-Dimethyl-2-(2-phenyl-1H-benzo[d]imidazol-1-
yl)butan-1-ol
8. Zhang, P.; Terefenko, E. A.; Bray, J.; Deecher, D.; Fensome, A.; Harrison, J.;
Kim, C.; Koury, E.; Mark, L.; McComes, C. C.; Mugford, C. A.; Trybulski, E. J.;
Vu, A. T.; Whiteside, G. T.; Mahaney, P. E. J. Med. Chem. 2009, 52,
5703e5711.
Into a flame dried round bottom flask containing a magnetic stir
bar was added (S)-2-(2-aminophenylamino)-3,3-dimethylbutan-
1-ol (21h) (4.0 mg, 0.019 mmol), ammonium bromide (9.4 mg,
9. Hu, W.; Hofstetter, W.; Wei, X.; Guo, W.; Zhou, Y.; Pataer, A.; Li, H.; Fang, B.;
Swisher, S. G. J. Pharmacol. Exp. Ther. 2009, 328, 866e872.
ꢀ
10. Rix, D.; Labat, S.; Toupet, L.; Crevisy, C.; Mauduit, M. Eur. J. Inorg. Chem. 2009, 13,
1989e1999.
0.096 mmol), and benzaldehyde (2.3
mL, 0.023 mmol). MeOH
11. Raju, B. C.; Theja, N. D.; Kumar, J. A. Synth. Commun. 2009, 39, 175e188.
12. Christodoulou, M. S.; Colombo, F.; Passarella, D.; Ieronimo, G.; Zuco, V.; De
Cesare, M.; Zunino, F. Bioorg. Med. Chem. 2011, 19, 1649e1657.
13. For selected reviews with palladium, see: (a) Surry, D. S.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2008, 47, 6338e6361; (b) Surry, D. S.; Buchwald, S. L. Chem. Sci.
2011, 2, 27e50; (c) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805e818; (d) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37,
2046e2067; (e) Hartwig, J. F. Pure Appl. Chem. 1999, 71, 1417e1423.
14. For selected reviews with copper: (a) Surry, D. S.; Buchwald, S. L. Chem. Sci.
2010, 1, 13e31; (b) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47,
3096e3099; (c) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428e2439; (d)
Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400e5499; (e) Ma, D.;
Cai, Q. Acc. Chem. Res. 2008, 41, 1450e1460; (f) Evano, G.; Blanchard, N.; Toumi,
M. Chem. Rev. 2008, 108, 3054e3131.
(0.5 mL) was added into the reaction mixture and the slurry was
stirred at room temperature for 18 h. The solvent was removed at
this point and ethyl acetate (4 mL) and brine (1 mL) was added. The
organic layer was separated and the aqueous layer was extracted
with ethyl acetate (3ꢁ4 mL). Combined organic layer was dried
over anhydrous Na2SO4 before passing it through a pad of silica gel.
The filtrate was concentrated and purified via flash column chro-
matography (40% Hex in EA) to afford the product as an off white
solid (3.9 mg, 70%). 1H NMR (500 MHz, CD3OD):
d 0.92 (s, 9H), 4.28
(m, 1H), 4.79 (m, 2H), 7.46 (m, 1H), 7.65 (m, 2H), 7.80 (m, 5H), 8.19
(d, J¼8.1 Hz, 1H); 13C NMR (125 MHz, CD3OD):
d 25.8, 34.0, 55.7,
15. Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 3703e3706.
16. For selected examples that include glycinol, see: Ref. 14 and (a) Zhang, Y.; Yang,
X.; Yao, Q.; Ma, D. Org. Lett. 2012, 14, 3056e3059; (b) Yang, C.-T.; Fu, Y.; Huang,
Y.-B.; Yi, J.; Guo, Q.-X.; Liu, L. Angew. Chem., Int. Ed. 2009, 48, 7398e7401; (c)
Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3490e3491;
(d) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164e5173; (e) Lu, Z.; Twieg,
R. J. Tetrahedron Lett. 2005, 46, 2997e3001.
17. For selected examples that include other amino alcohols and aminophenols,
see Ref. 14a, c, e and (a) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128,
8742e8743; (b) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131,
17423e17429; (c) Yang, K.; Qiu, Y.; Li, Z.; Wang, Z.; Jiang, S. J. Org. Chem. 2011, 76,
3151e3159.
18. For two alternative mechanistic interpretations to explain N/O-arylation
selectivities, see: (a) Jones, G. O.; Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am. Chem.
Soc. 2010, 132, 6205e6213; (b) Yu, H.-Z.; Jiang, Y.-Y.; Liu, L. J. Am. Chem. Soc.
2010, 132, 18078e18091.
19. Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org.
Lett. 2002, 4, 1623e1626.
69.4, 113.1, 114.8, 124.0, 124.6, 127.2, 127.7, 128.9, 129.1, 130.2, 131.2;
ESI-MS (MþH)þ calcd for C19H23N2O: 295.2, found: 295.2; HRMS m/
z (ESI) calcd for C19H23N2O [(MþH)þ]: 295.1805, found: 295.1790.
Acknowledgements
Financial support was provided by the National Institutes of
Health through grant RC1 NS068963. J.K.D.B. thanks the Robert A.
Welch Foundation for support (grant I-1422) and holds the Julie
and Louis Beecherl, Jr., Chair in Medical Science.
References and notes
20. Pyrrole-2-carboxylic acid was moderately selective for N-arylation of
2-aminophenol, see Ref. 17b.
21. Indole-2-carboxylic acid is usually not included in ligand screens for copper-
catalyzed arylation. It was included in a screen for the arylation of anilines
where it provided poor yields, see Altman, R. A.; Anderson, K. W.; Buchwald, S.
L. J. Org. Chem. 2008, 73, 5167e5169.
22. N-Arylation with this sterically demanding amino alcohol was ascertained via
transformation of 21h into the corresponding 2-phenylbenzimidazole
derivative according to Ref. 11; see Experimental section 4.20 for experimental
details.
23. Mulvihill, M. J.; Cesario, C.; Smith, V.; Beck, P.; Nigro, A. J. Org. Chem. 2004, 69,
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