Insights into the origins of configurational stability of axially chiral biaryl amines with an intramolecular N-H-N hydrogen bond

Article abstract of DOI:10.1021/jo100586b

(Figure presented) Configurationally stable chiral biaryl amines with an intramolecular N-H-N hydrogen bond have been developed. The barriers for racemization are in the range of 19.3-28.2 kcal/mol, which corresponds to the half-lives of racemization of the enantiomers in the range of 7 s to 2 years at 20 °C. Enantiomers of some of these compounds were separable by HPLC with chiral stationary phases. The biaryl amines are supposed to have a conformation similar to that of a binaphthyl skeleton, which was indicated by an X-ray crystal analysis of a biaryl amine. The N-H appears at 11.1-13.3 ppm in their ¹H NMR spectrum in CDCl₃, indicating strong hydrogen bonding. Biaryl amines with an extremely strong intramolecular N-H-N hydrogen bond (δ_NH ～13 ppm) were assumed to undergo racemization without cleavage of an N-H-N hydrogen bond, while those with a mediumly strong N-H-N hydrogen bond (δ_NH ～11 ppm) are assumed to undergo racemization via cleavage of an N-H-N hydrogen bond. Hydrogen/deuterium exchange of a chiral biaryl amine was found to proceed without any trace of racemization.

Full text of DOI:10.1021/jo100586b

pubs.acs.org/joc
Insights into the Origins of Configurational Stability of Axially Chiral
Biaryl Amines with an Intramolecular N-H-N Hydrogen Bond
Kazuhiro Hayashi, Nobuyuki Matubayasi, Changsheng Jiang, Tomoyuki Yoshimura,
Swapan Majumdar, Takahiro Sasamori, Norihiro Tokitoh, and Takeo Kawabata*
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
kawabata@scl.kyoto-u.ac.jp
Received April 1, 2010
Configurationally stable chiral biaryl amines with an intramolecular N-H-N hydrogen bond have been
developed. The barriers for racemization are in the range of 19.3-28.2 kcal/mol, which corresponds to the
half-lives of racemization of the enantiomers in the range of 7 s to 2 years at 20 °C. Enantiomers of some of
these compounds were separable by HPLC with chiral stationary phases. The biaryl amines are supposed
to have a conformation similar to that of a binaphthyl skeleton, which was indicated by an X-ray crystal
analysis of a biaryl amine. The N-H appears at 11.1-13.3 ppm in their 1H NMR spectrum in CDCl3,
indicating strong hydrogen bonding. Biaryl amines with an extremely strong intramolecular N-H-N
hydrogen bond (δNH ∼13 ppm) were assumed to undergo racemization without cleavage of an N-H-N
hydrogen bond, while those with a mediumly strong N-H-N hydrogen bond (δNH ∼11 ppm) are
assumed to undergo racemization via cleavage of an N-H-N hydrogen bond. Hydrogen/deuterium
exchange of a chiral biaryl amine was found to proceed without any trace of racemization.
Introduction
which corresponds to a half-life of racemization of 24 months at
20 °C.4 An extremely strong hydrogen bond was assumed to
be the key to maintain the enantiomeric stability of the biaryl
amines. We describe here the properties of axially chiral biaryl
amines with an intramolecular N-H-N hydrogen bond and
the possible origins of their exceptional tolerance against
racemization.5-7
Chiral binaphthyls have been extensively used in asymmetric
synthesis. In particular, metal complexes of 2,20-disubstitu-
ted 1,10-binaphthyls (1) have been shown to be extremely effec-
tive catalysts for a variety of asymmetric transformations
(Figure 1).1-3 While the catalytically active metal center (M)
in 1 is separated from the chiral axis (C(1)-C(10)) by three
bonds, it is quite effective for asymmetric induction in many
cases. The ultimate structure to minimize the distance between
the catalytically active metal center and the chiral axis is shown
as 2, where the central metal is directly connected to the chiral
C(10)-X axis. Rational precursors for 2 are shown as 3.
A crucial question about 3 was whether enantiomers of
3 with axial chirality could exist without rapid racemization
at ambient temperature. We have reported that several chiral
biaryl amines with an intramolecular N-H-N hydrogen bond
such as 3 are tolerant against racemization at ambient tem-
perature and have racemization barriers up to 28.2 kcal/mol,
(4) Kawabata, T.; Jiang, C.; Hayashi, K.; Tsubaki, K.; Yoshimura, T.;
Majumdar, S.; Sasamori, T.; Tokitoh, N. J. Am. Chem. Soc. 2009, 131, 54–55.
(5) Conformationally stable atropisomers of biaryl ethers have been repor-
ted; see: (a) Fuji, K.; Oka, T.; Kawabata, T.; Kinoshita, T. Tetrahedron Lett.
1998, 39, 1373–1376. (b) Betson, M. S.; Clayden, J.; Worrall, C. P.; Peace, S.
Angew. Chem., Int. Ed. 2006, 45, 5803–5807. (c) Clayden, J.; Worrall, C. P.;
Moran, W. J.; Helliwell, M. Angew. Chem., Int. Ed. 2008, 47, 3234–3237.
(6) For an example of conformational studies of alkyl aryl amines, see:
Casarini, D.; Lunazzi, L.; Placucci, G. J. Org. Chem. 1987, 52, 4721–4726.
(7) For asymmetric synthesis of atropisomeric aromatic amine derivatives,
see: (a) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc.
1994, 116, 3131–3132. (b) Hughes, A. D.; Simpkins, N. S. Synlett1998, 967–968.
(c) Ates, A.; Curran, D. P. J. Am. Chem. Soc. 2001, 123, 5130–5131. (d) Clayden,
J.; Mitjans, D.; Youssef, L. H. J. Am. Chem. Soc. 2002, 124, 5266–5267.
(e) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.; Morita, T.; Takahashi,
M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc. 2006, 128, 12923–12931.
(f) Brandes, S.; Bella, M.; Kjarsgaard, A.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2006, 45, 1147–1151. (g)Leusse, S.B.;Counceller, C. M.;Wilt,J. C.;Perkins,
B. R.; Johnston, J. N. Org. Lett. 2008, 10, 2445–2447.
(1) Mei, L.; Xuan, L. X. Asian J. Chem. 2006, 18, 2089–2106.
(2) Brunel, J. M. Chem. Rev. 2005, 105, 857–897.
(3) Kocovsky, P.; Vyskocil, S.; Smrcina, M. Chem. Rev. 2003, 103, 3213–3245.
DOI: 10.1021/jo100586b
r
Published on Web 06/29/2010
J. Org. Chem. 2010, 75, 5031–5036 5031
2010 American Chemical Society

Hayashi et al.
JOCArticle
the range of δ 13.01-13.33 ppm, which indicates the ex-
tremely strong hydrogen bonding. This observation is con-
sistent with the hypothesis that strong hydrogen bonding is
critical for configurationally stable axial chirality. Substitu-
ent effects at N(3) were investigated with compounds 9-12
(entries 5-8). The half-life of racemization increased with an
increase in the donating ability of the substituents among these
compounds. The contribution of the electron-withdrawing
group (NO2) to the configurational stability of axial chirality
is obvious when the half-life of racemization of 10 with 6,8-
dinitro substituents (4.3 months) is compared with that of 8
with 6,8-dimethyl substituents (2.4 days) (entries 4 vs 6). The
larger rotational barrier of 10 compared to that of 8 does not
seem to be due to steric effects because the steric bulkiness of
a nitro group (A value = ∼1.2) is estimated to be similar or
even smaller than that of a methyl group (A value = ∼1.7).
On the other hand, steric effects on the naphthalene ring are
obvious when the half-life of racemization of 6 (2.3 h) is
compared with that of 12 (24 months), which has an addi-
tional 80-methyl substituent (entries 2 vs 8). Among these
compounds, compound 12 with an electron-donating iso-
propyl group at N(3), electron-withdrawing nitro groups at
C(6) and C(8), and sterically demanding methyl groups at
C(20) and C(80) has the largest rotational barrier and the
longest half-life of racemization (entry 8). The observation is
consistent with the hypothesis for the design of axially chiral
biaryl amines with high configurational stability shown in
Scheme 1.
FIGURE 1. Central metal (M) is directly connected to the chiral
C(10)-X axis in binaphthyl surrogates 2, while M in 1 is separated
from the chiral axis (C(1)-C(10)) by three bonds. Biaryl amines 3 are
possible precursors to 2.
SCHEME 1. Hypothetical Scheme for Configurationally
Stable Axially Chiral Biaryl Amines with an Intramolecular
N-H-N Hydrogen Bond
Results and Discussion
A hypothetical scheme for the design of configurationally
stable axially chiral biaryl amines 4 is shown in Scheme 1.
One of the critical preconditions for 4 is the formation of an
extremely strong hydrogen bond, since the non-hydrogen-
bonded form of 4 must adopt an s-trans conformation around
the C(4)-C(10) bond and it should be achiral due to rapid
bond rotation around the C(10)-N(1) axis. To generate a
stronger hydrogen bond, donor substituents D on N(3) and
electron-withdrawing substituents W on the upper pseudo-
naphthalene ring are assumed to be preferable. Sterically
demanding substituents Y on the lower naphthalene ring are
expected to be effective in increasing the rotational barrier
around the C(10)-N(1) axis.
An X-ray structure of a single crystal of 11 is shown in
Figure 3.4 A ring consisting of nine atoms of N(1)-C(9)-
C(8)-C(7)-C(6)-C(5)-C(10)-C(4)-N(3) is almost com-
pletely planar (Figure 3, a and b), which suggests the formation
of a pseudonaphthalene ring involving the N-H-N hydro-
gen bond. The dihedral angle between the pseudonaphtha-
lene ring and the naphthalene ring is 128° (Figure 3, b).
The CD spectra of the separated enantiomers of 11 clearly
indicate the enantiomeric relationship.4 All of the experimen-
tal evidence indicates the biaryl amine 11 has a conformation
similar to that of binaphthyl skeletons. The observed distance
˚
(2.67 A) between N(3) and N(1) of 11 indicates the strong
hydrogen bonding, which is comparable to the reported
Several biaryl amines 5-11 were prepared via Buchwald
cross-coupling reactions8 between substituted 1-aminonaph-
thalenes and substituted phenyl bromides (Figure 2). Chiral
properties of these amines were investigated (Table 1).4 The
rotational barrier of the N(1)-C(10) bond of 5 was deter-
mined to be 19.3 kcal/mol (92 °C) by variable-temperature
˚
distance (2.69 A) of the intramolecular N-H-N hydrogen
bond of the related anilido aldimine derivative9 and is much
10
˚
shorter than the intermolecular counterpart (2.92 A).
We next investigated the mechanistic aspects on racemiza-
tion of these chiral biaryl amines. We had anticipated that an
intramolecular N-H-N hydrogen bond is critical for the
configurational stability of the axially chiral biaryl amines,
since the non-hydrogen-bonded form of 4 must adopt an s-trans
conformation around the C(4)-C(10) bond and it should be
readily racemized due to rapid bond rotation around the
C(10)-N(1) axis. This assumption was confirmed by the pro-
perties of compound 13, the corresponding N-methyl deri-
vative of 5 (Figure 4). The NOESY spectrum of 13 indicates
its s-trans conformation around the C(4)-C(10) bond. The
rotational barrier of the N(1)-C(10) bond was determined to
be 15.6 kcal/mol (54 °C) by variable-temperature NMR mea-
surements in toluene-d8 (400 MHz NMR, ΔνAB =123.8 Hz,
NMR measurements in toluene-d8 (400 MHz NMR, ΔνAB
=
9.9 Hz, Tcoales =365 K, entry 1). The half-life of racemization
of 5 at 20 °C was estimated to be ca. 7 s based on the acti-
vation entropy (-5.0 eu, vide infra). Enantiomers of 6-12
could be separated at ambient temperature by HPLC with
chiral stationary phases. The processes for time-dependent
racemization of the separated enantiomers were monitored
by HPLC analysis at 22 °C for 6-8 and at 80 °C for 9-12,
and their racemization barriers are shown in entries 2-8 in
Table 1. The half-lives of racemization of 9-12 at 20 °C were
roughly estimated on the assumption that ΔSq of the res-
1
tricted C-N bond rotation is nearly zero. The H NMR
chemical shifts of N-H of compounds 9-12 in CDCl3 are in
(9) Lee, B. Y.; Kwon, H. Y.; Lee, S. Y.; Na, S. J.; Han, S-i.; Yun, H.; Lee,
H.; Park, Y.-W. J. Am. Chem. Soc. 2005, 127, 3031–3037.
(10) Brennan, C. J.; McKee, V. Acta Crystallogr. 1999, C55, 1492–1494.
(8) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
7215–7216.
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Hayashi et al.
JOCArticle
FIGURE 2. Preparation and structures of biaryl amines 5-12.
N(3), probably due to the increase in the strength of the
hydrogen bond (Table 1, entries 5-8). On the basis of this
data, two hypothetical mechanisms for the racemization of
the biary amines are shown in Scheme 2. The first one in-
volves direct bond rotation of the N(1)-C(10) chiral axis
without cleavage of an N-H-N hydrogen bond (a). The
second one involves s-cis/s-trans isomerization through the
C(10)-C(4) bond rotation with concomitant cleavage of an
N-H-N hydrogen bond (b). We envisaged relatively small
solvent effects for the racemization process via the former
mechanism. The racemization barrier is expected to be less
solvent-dependent, and the entropy term is to be less signi-
ficant. Actually, activation entropies in the range of -5.2 to
-9.9 eu for the racemization process of 1,10-binaphthyl deri-
vatives have been reported.11 On the other hand, relatively
large solvent effects on the racemization barrier and the large
negative activation entropy are expected for the racemiza-
tion process via the latter mechanism because the NH-free
intermediate with an s-trans configuration is expected to
undergo solvation more significantly than the corresponding
s-cis congener. Polar solvents may be expected to decrease the
racemization barrier due to stabilization of this intermediate.
The barriers and the activation entropies for the racemiza-
tion process of 5 in various solvents were determined
(Table 2). The 1H NMR spectrum of 5 at 20 °C showed two
diastereotopic isopropyl methyl peaks, indicating restricted
bond rotation along the C(10)-N(1) axis. The rotational
barriers of the N(1)-C(10) bond (the racemization barriers of
the biaryl amines) at the coalescence temperature in each
solvent were shown in entries 1-7. The activation entropies
(ΔSq) for the racemization process were determined from
temperature dependence of the racemization barriers, which
TABLE 1. Behavior toward Racemization of Biaryl Amines with an
Intramolecular N-H-N Hydrogen Bond
b
t
1/2 (racemization)
(20 °C)
δNH
(ppm)
entry
compd
ΔGqa (kcal/mol)
1
2
3
4
5
6
7
8
5
6
7
8
9
10
11
12
19.3 (92 °C)c
23.2 (22 °C)e
23.6 (22 °C)e
24.9 (22 °C)e
27.0 (80 °C)g
27.2 (80 °C)g
27.4 (80 °C)g
28.2 (80 °C)g
7 sd
11.07
13.47
12.02
11.44
13.01
13.33
13.24
13.30
2.3 hf
5.0 hf
2.4 daysf
3.0 monthsh
4.3 monthsh
6.0 monthsh
24 monthsh
aRotational barrier of the chiral axis at the temperature indicated in
parentheses. b1H NMR (400 MHz) chemical shift (ppm) of N-H
measured in CDCl3 at 21 °C. cDetermined by VNMR. dDetermined
on the basis of ΔSq = -5.0 eu (see Table 2, entry 1). eDetermined by time-
dependent racemization of an isolated enantiomer at 22 °C by HPLC
analysis. fHalf-life or racemization at 22 °C determined by time-depen-
dent racemization of an isolated enantiomer by HPLC analysis. gDeter-
mined by time-dependent racemization of an isolated enantiomer at
80 °C (benzene reflux) by HPLC analysis. hHalf-life of racemization at
20 °C roughly estimated on the assumption that ΔSq of the restricted
C-N bond rotation is nearly zero.
Tcoales = 327 K), which was much smaller than that of 5
(19.3 kcal/mol). The larger rotational barrier of 5 than 13 would
be attributed to the difference in the preferred conformation
of 5 from that of 13 (i.e., s-cis conformation for 5 and s-trans
conformation for 13) because 5 should have a smaller rota-
tional barrier than 13 due to the fewer substituents on N(1) if
both of them could adopt the s-trans conformation (Figure 4).
The strength of the intramolecular N-H-N hydrogen
bond of the biaryl amines appears to be critically related to
the racemization barriers of the biaryl amines. An increase in
the strength of the hydrogen bond by the electron-withdrawing
NO2 groups at C(6) and C(8) in 10 is assumed to be the origin
of its larger racemization barrier (27.2 kcal/mol) than that of
8 (24.9 kcal/mol) possessing the corresponding methyl groups.
The racemization barriers of compounds 9-12 increased
with an increase in the donating ability of the substituents at
1
were obtained by line shape analyses of H NMR signals
of the isopropyl methyl peaks (see the Supporting Information).
(11) (a) Badar, Y.; Cooke, A. S.; Harris, M. M. J. Chem. Soc. 1965, 1412–
1418. (b) Colter, A. K.; Clemens, L. M. J. Am. Chem. Soc. 1965, 87, 847–852.
J. Org. Chem. Vol. 75, No. 15, 2010 5033

Hayashi et al.
JOCArticle
FIGURE 3. X-ray structure of 11: (a) top view; (b) side view. Displacement ellipsoids were drawn at the 50% probability level. Hydrogens
except N-H were omitted for clarity.
TABLE 2. Activation Parameters for the Racemization Process of 5 in
Various Solvents
FIGURE 4. s-cis- and s-trans-conformers of 5, s-trans-conformer
of 13, and the rotational barrier around the N(1)-C(10) bond of 13.
entry
solvent
εa
ΔGqb,c (kcal/mol)
ΔSqd (eu)
1
2
3
4
5
6
7
toluene-d8
(CDCl2)2
pyridine-d5
isopropanol-d8
ethanol-d6
DMF-d7
2.6
8.2
19.3 (92 °C), [9.9]
18.9 (86 °C), [10.7]
18.4 (81 °C), [14.8]
18.3 (74 °C), [9.2]
17.9 (66 °C), [9.0]
17.8 (64 °C), [7.8]
18.0 (67 °C), [9.0]
-5.0
-15
e
-15
-18
-25
-18
SCHEME 2. Possible Mechanisms for Racemization of Biaryl
Amines (a) via Direct Rotation of the Chiral N(1)-C(10) Axis and
(b) via s-cis/s-trans Isomerization through the C(10)-C(4) Bond
Rotation
12.3
18.3
24.6
36.7
37.5
acetonitrile-d3
aDielectric constant of the undeuterated solvents quoted from Lange’s
Handbook of Chemistry, 13thed;Dean, J. A., Ed.;McGrawHill:NewYork,
1972. bRotational barrier of the chiral axis at the temperature indicated in
parentheses. cDetermined from Δν (Hz) indicated in brackets and the coale-
scence temperature obtained by V NMR. dDetermined from temperature
dependency of the racemization barriers; see the Supporting Information.
eNot determined.
for the racemization process were much smaller in magnitude
(entry 1, -5.0 eu).
We next examined the racemization processes of 8 and 11.
Racemization barriers of 8 were determined by time-dependent
racemization of the isolated enantiomer in various solvents
at 20 °C and are shown in entries 1-4 of Table 3. The barriers
in benzene, toluene, ethanol, and DMF are 24.9, 25.2, 23.7,
and 23.8 kcal/mol, respectively. The activation entropy for the
racemization process of 8 in DMF was determined to be 20 eu
from racemization barriers of 8 at -6 °C (23.1 kcal/mol), 9 °C
(23.4 kcal/mol), 17 °C (23.6 kcal/mol), 31 °C (23.8 kcal/mol),
and 42 °C (24.0 kcal/mol), which were also determined by
time-dependent racemization of the isolated enantiomer of 8
at the indicated temperature (see the Supporting Informa-
tion). The racemization barriers of 8 were solvent-dependent
and were smaller in more polar solvents. A large negative acti-
vation entropy (-20 eu) was observed for the racemization
process of 8 in DMF (entry 4). The observation also indicates
that racemization of 8 might proceed through the mechanism
via s-cis/s-trans isomerization as shown in Scheme 2 (b).
Similarly, racemization barriers of 11 were determined by
time-dependent racemization of the isolated enantiomer in
various solvents at 78-83 °C and are shown in entries 5-8 of
In more polar solvents such as ethanol-d6, DMF-d7, and aceto-
nitrile-d3, smaller racemization barriers (17.8-18.0 kcal/mol)
were observed (entries 5-7), while larger racemization barri-
ers (18.9-19.3 kcal/mol) were observed in less polar solvents
such as toluene-d8 and (CDCl2)2 (entries 1 and 2). Large
negative activation entropies (-18 to -25 eu) were observed
for the racemization process especially in polar solvents
(entries 5-7). The observation indicates that racemization
of 5 might proceed, especially in polar solvents, through
the mechanism via s-cis/s-trans isomerization as shown in
Scheme 2 (b). However, it is totally unclear whether race-
mization of 5 in less polar solvents such as toluene-d8
proceeds via the same mechanism because activation entropies
5034 J. Org. Chem. Vol. 75, No. 15, 2010

Hayashi et al.
JOCArticle
TABLE 3. Activation Parameters for the Racemization Processes of
8 and 11 in Various Solvents
calculations.12 We were interested in the deuterium isotope
effect on the racemization behavior of the chiral biaryl
1
amines. The NH signal of 5 appeared at δ 11.3 ppm in H
NMR in DMF-d7 disappeared immediately after the addition
1% D2O, indicating the formation of 5d (Figure 5). The
rotational barrier around the N(1)-C(10) axis of 5d was
determined by variable-temperature NMR to be 17.7 kcal/mol
at 62 °C. Essentially no deuterium effect on the rotational
barrier of 5 was observed. Next, the racemization barrier of 11d
was measured by time-dependent racemization of enantio-
enriched 11d in ethanol-d6 at 78 °C.13 Enantioenriched 11d
was prepared by hydrogen/deuterium exchange of 11 (84%
ee) without loss of eanatiomeric purity (vide infra). Racemi-
zation barrier of 11d (27.6 kcal/mol) was comparable to that
of 11. The observation indicates that deuterium effects on the
rotational barriers of these biaryl amines were not signifi-
cant, irrespective of the mechanism of the racemization.
We finally examined whether racemization of 11 takes place
on hydrogen/deuterium exchange process of the N-H-N
group (Scheme 3). After formation of 11d by treatment of 11
(95% ee) with 1% D2O in DMF-d7 at 20 °C for 1 h, 11d was
treated with brine to give 11 back, whose ee was found to be
95% ee. No racemization took place during the hydrogen/
deuterium exchange process. This might indicate that hydro-
gen/deuterium exchange proceeds via an ammonium inter-
mediate without an N-H(D)-N bond cleavage. The observed
property of 11 may be beneficial when enantiomerically
enriched organometallic species such as 2 are to be prepared
from enantiomerically enriched precursor 3 because the
hydrogen/metal exchange process may proceed in the similar
way to the hydrogen-deuterium exchange process depend-
ing on the nature of metal sources.14
entry
R
compd
solvent
ΔGqa (kcal/mol)
ΔSqb (eu)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
NO2
NO2
NO2
NO2
8
8
8
benzene
toluene
ethanol
DMF
benzene
toluene
ethanol
DMF
24.9 (20 °C)
25.2 (20 °C)
23.7 (20 °C)
23.8 (20 °C)
27.4 (80 °C)
27.5 (83 °C)
27.9 (78 °C)
28.1 (80 °C)
c
c
c
-20
c
c
c
8
11
11
11
11
-2.0
aDetermined by time-dependent racemization of the isolated enantio-
mer at the temperature indicated in parentheses. bDetermined from
temperature-dependent racemization barriers; see the Supporting Infor-
mation. cNot determined.
Conclusions
We have developed chiral biaryl amines with an intramole-
cular N-H-N hydrogen bond which possess configuration-
ally stable axial chirality at ambient temperature. The half-lives
of racemization of the chiral biaryl amines are up to 2 years at
20 °C. These biaryl amines are supposed to have a conforma-
tion similar to that of 1,10-binaphthyl derivatives, which was
indicated by an X-ray crystal analysis of 11. Biaryl amines with
an extremely strong intramolecular N-H-N hydrogen bond
such as 9-12 were assumed to undergo racemization with-
out cleavage of an N-H-N hydrogen bond, while those with a
mediumly strong N-H-N hydrogen bond such as 5 and 8
are assumed to undergo racemization mostly via cleavage of
an N-H-N hydrogen bond. Hydrogen/deuterium exchange
of 11 was found to proceed without any trace of racemization.
FIGURE 5. Comparison of the racemization barriers of 5 and 11
with those of their deuterated derivatives 5d and 11d, respectively.
Table 3. Contrary to the cases of 5 and 8, solvent dependency
of the racemization barriers of 11 was less significant, and the
barrier in DMF was slightly larger than that in benzene.
Activation entropy for the racemazation process in DMF
was close to zero (-2.0 eu, entry 8). The observation indi-
cates that racemization of 11 might proceed through the
mechanism via direct rotation of the N(1)-C(10) chiral axis
without cleavage of an N-H-N hydrogen bond as shown in
Scheme 2 (a). On the basis of these results, it would be
assumed that biaryl amines with an extremely strong intra-
molecular N-H-N hydrogen bond such as 9-12 undergo
racemization without cleavage of an N-H-N hydrogen
bond and, thus, are tolerant against racemization. On the
other hand, biaryl amines with a mediumly strong N-H-N
hydrogen bond such as 5 and 8 are assumed to undergo
racemization via cleavage of an N-H-N hydrogen bond.
We then investigated the deuterium isotope effect on the
Experimental Section
Compounds 5-12. Preparation and spectroscopic data of
compounds 5-12 were reported in the Supporting Information
of our previous publication: see ref 4.
(13) Compound 11d was prepared by addition of D2O to a DMF-d7
solution of 11, and its formation was confirmed by disappearance of the NH
signal at δ 13.6 ppm in the 1H NMR in DMF-d7. After removal of the
solvents under vacuum at ambient temperature, the residue was dissolved in
ethanol-d6 for measurement of the racemization barrier.
ꢀ
N-H-N hydrogen bonding. Scheiner and Cuma reported
that deuterium bonding between D2O (DO-D OD2)
3 3 3
was estimated to be stronger than hydrogen bonding bet-
ween H2O (HO-H OH2) by ∼0.5 kcal/mol by ab initio
(14) Recently, we have prepared an anilidoaldimine aluminum complex
from 5 and found that the racemization barrier of the aluminum complex was
higher by ca. 4 kcal mol than the corresponding biaryl amine precursor with
3 3 3
3
an N-H-N hydrogen bond; see: Hayashi, K.; Nakajima, Y.; Ozawa, F.;
Kawabata, K. Chem. Lett. 2010, 39, 643–645.
ꢀ
(12) Scheiner, S.; Cuma, M J. Am. Chem. Soc. 1996, 118, 1511–1521.
J. Org. Chem. Vol. 75, No. 15, 2010 5035

Hayashi et al.
JOCArticle
SCHEME 3. Hydrogen/Deuterium Exchange of 11 without Racemization
(E)-N-(2-((Isopropylimino)methyl)phenyl)-N,2-dimethylnaph-
thalen-1-amine (13). Iodomethane (3.0 mL, 48.2 mmol) was
added to a stirred suspension of 2-methylnaphthalen-1-amine
(7.45 g, 47.4 mmol) and K2CO3 (13.0 g, 94.3 mmol) in acetone
(189 mL) at 0 °C. The mixture was heated under reflux of ace-
tone for 10 h. After the mixture was cooled to room temperature,
the solvent was removed in vacuo. The residue was purified by
column chromatography (SiO2, ethyl acetate/hexane = 1:8) to
give 2-methyl-1-methylaminonaphthalene (3.22 g, 40% yield) as
an oil: 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=8.2 Hz, 1H),
7.81 (d, J=7.8 Hz, 1H), 7.53-7.38 (m, 3H), 7.31 (d, J=8.3 Hz,
1H), 3.32 (br s, 1H), 2.96 (s, 3H), 2.48 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 143.9, 133.5, 129.3, 128.4, 128.3, 125.3, 125.2,
124.8, 122.7, 122.5, 36.9, 18.0; IR (neat) 2945, 1572, 1510, 1468,
1372, 806 cm-1; MS m/z (rel intensity) 171 (Mþ, 100), 156 (80),
128(20), 115 (17), 58 (18); HRMS calcd for C12H13N 171, 1048,
found 171.1053. Anal. Calcd for C12H13N: C, 84.17; H, 7.65; N,
8.18. Found: C, 84.07; H, 7.78; N, 8.21.
AmixtureofPd2(dba)3-CHCl3 (10 mg, 0.0175 mmol), P(t-Bu)3-
HBF4 (3.7 mg, 0.0125 mmol), sodium tert-butoxide (358 mg,
3.75 mmol), 1-bromo-2-(diethoxymethyl)benzene (774 mg, 2.99
mmol), 2-methyl-1-methylaminonaphthalene (514 mg, 3.0 mmol),
and toluene (11.2 mL) was prepared in a round-bottom flask
placed in a glovebox. After the septum-sealed flask was taken
out of the glovebox, the mixture was stirred at 80 °C for 12 h.
After being cooled to room tempeature, the mixture was diluted
with ethyl acetate and washed with saturated aq NaHCO3 and
brine, dried over anhydrous Na2SO4, filtered, and evaporated
in vacuo. The residue was purified by column chromatography
(SiO2, ethyl acetate/hexane=1:10) to give the mixture of N-(2-(di-
ethoxymethyl)phenyl)-N,2-dimethylnaphthalen-1-amine and
2-(methyl(2-methylnaphthalen-1-yl)amino)benzaldehyde. The mix-
ture was dissolved in 5% aq HCl (21 mL) and THF (21 mL).
After the mixture was heated under THF reflux for 5 h, satu-
rated aq NaHCO3 solution was added to the mixture until pH 8.
The resulting mixture was extracted with ethyl acetate, and the
organic phase was washed with brine, dried over anhydrous Na2SO4,
filtered, and evaporated in vacuo. The residue was purified by
column chromatography (SiO2, ethyl acetate/hexane=1:10) to
give 2-(methyl(2-methylnaphthalen-1-yl)amino)benzaldehyde
(807 mg, 98% for 2 steps) as yellow needles: mp (hexane) 89-90 °C;
1H NMR (400 MHz, DMSO-d6, 20 °C): δ 9.16 (br s, 1H), 7.98-
7.39 (m, 9H), 6.88 (t, J = 7.6 Hz, 2H), 3.34 (s, 3H), 2.09 (br s,
3H); 13C NMR (100 MHz, DMSO-d6, 20 °C) δ 189.2, 151.8,
144.9, 134.7, 133.4, 131.8, 130.1, 129.7, 128.8, 128.5, 127.3, 127.2,
125.6, 123.7, 122.6, 118.2, 115.8, 40.1, 17.9; 1H NMR (400 MHz,
DMSO-d6, 100 °C) d 9.50 (br s, 1H), 7.94-7.85 (m, 2H), 7.80
(d, J=8.8 Hz, 1H), 7.53-7.38 (m, 5H), 6.95-6.82 (m, 2H), 3.37
(s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, DMSO-d6, 100 °C): δ
188.7, 151.0, 142.7, 133.8, 133.1, 132.2, 129.9, 129.8, 129.1, 128.0,
126.7, 126.6, 125.0, 123.6, 122.1, 117.4, 115.6, 41.4, 17.2; IR
(KBr) 2855, 1675, 1597, 1481, 1189, 816 cm-1; MS m/z (rel inten-
sity) 275 (Mþ, 100), 258 (42), 230 (30), 223 (25), 105 (40), 58 (61);
HRMS calcd for C19H17NO 275.1310, found 275.1311. Anal.
Calcd for C19H17NO: C, 82.88; H, 6.22; N, 5.09. Found: C, 83.07;
H, 6.33; N, 5.04.
Isopropylamine (31 μL, 0.40 mmol) was added to a solution
of 2-(methyl(2-methylnaphthalen-1-yl)amino)benzaldehyde (50 mg,
0.182 mmol) in toluene (5.0 mL). The mixture was heated under
toluene reflux for 10 h. After the mixture was cooled to room
temperature, the solvent was removed in vacuo to give 13 (57.5 mg,
100% yield) as a colorless oil: 1H NMR (400 MHz, toluene-d8,
20 °C) δ 8.02 (d, J=8.3 Hz, 1H), 7.95 (d, J=7.3 Hz, 1H), 7.74
(br s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H),
7.35-7.31 (m, 1H), 7.26-7.18 (m, 2H), 6.94 (d, J=8.3 Hz, 1H),
6.82 (t, J=7.3 Hz, 2H), 2.94 (s, 3H), 2.36 (br s, 1H), 1.80 (s, 3H),
0.81 (br s, 3H), 0.63 (br s, 3H); 13C NMR (100 MHz, toluene-d8,
20 °C): δ 156.2, 150.2, 144.9, 134.2, 132.8, 132.0, 130.8, 130.2,
130.1, 128.6, 127.0, 126.5, 126.3, 125.4, 123.9, 119.6, 115.1, 61.2,
40.1, 24.0, 18.9; 1H NMR (400 MHz, toluene-d8, 90 °C) δ 7.99
(d, J=8.2 Hz, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H), 7.77 (s, 1H),
7.60 (d, J=8.2 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.31-7.24 (m,
1H), 7.23-7.11 (m, 2H), 6.98 (d, J=8.7 Hz, 1H), 6.82 (d, J=8.2
Hz, 1H), 6.77 (t, J=7.8 Hz, 1H), 3.04 (s, 3H), 2.49 (sept, J=6.0
Hz, 1H), 1.89 (s, 3H), 0.72 (d, J =6.0 Hz, 6H); 13C NMR (100
MHz, toluene-d8, 100 °C): δ 156.5, 150.3, 145.1, 134.7, 133.3,
132.5, 130.8, 130.7, 130.2, 128.8, 127.0, 126.94, 126.85, 125.6,
124.3, 119.8, 115.7, 60.8, 41.0, 23.9, 18.8; IR (neat) 2964, 1635,
1597, 1476, 1382, 753 cm-1; MS (FAB) m/z (rel intensity) 339
(MNaþ, 2), 317 (MHþ, 100); HRMS (FABþ) calcd for
C22H24N2 317.2018, found 317.2018.
Acknowledgment. We are grateful to Prof. Masaharu
Nakamura, Kyoto University, for generous discussions on
DFT calculations. This work was supported by a Grant-in-
Aid for Exploratory Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan, and
by a Grant-in-Aid for JSPS Fellows to K.H.
Supporting Information Available: 1H NMR and 13C NMR
spectra. Determination of the activation parameters for the
racemization processes. This material is available free of charge
via the Internet at http://pubs.acs.org.
5036 J. Org. Chem. Vol. 75, No. 15, 2010