Organocatalytic aryl-aryl bond formation: An atroposelective [3,3]-rearrangement approach to BINAM derivatives

Article abstract of DOI:10.1021/ja401709k

Herein we disclose an organocatalytic aryl-aryl bond-forming process for the regio- and atroposelective synthesis of 2,2′-diamino-1,1′- binaphthalenes (BINAMs). In the presence of catalytic amounts of axially chiral phosphoric acids, achiral N,N′-binaphthyl hydrazines undergo a facile [3,3]-sigmatropic rearrangement to afford enantiomerically enriched BINAM derivatives in good to excellent yield. This transformation represents the first example of a metal-free, catalytic C(sp²)-C(sp²) bond formation between two aromatic rings with concomitant de novo atroposelective installation of an axis of chirality. Density functional calculations reveal that, in the transition state for C-C bond formation, the phosphoric acid proton of the catalyst is fully transferred to one of the N-atoms of the substrate, and the resulting phosphate acts as a chiral counterion.

Full text of DOI:10.1021/ja401709k

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Communication
Organocatalytic Aryl-Aryl Bond-Formation: An Atroposelective
[3,3]-Rearrangement Approach to BINAM Derivatives
Gong-Qiang Li, HONGYIN GAO, Craig Keene, Michael Devonas, Daniel Halsell Ess, and László Kürti
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja401709k • Publication Date (Web): 05 May 2013
Downloaded from http://pubs.acs.org on May 6, 2013
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Organocatalytic Aryl-Aryl Bond-Formation: An Atroposelec-
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Gong-Qiang Li†, Hongyin Gao†, Craig Keene†, Michael Devonas ‡, Daniel H. Ess‡ and László Kürti†*
†Division of Chemistry, Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas TX
75390.
‡Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602
Supporting Information Placeholder
catalytic atroposelective biaryl synthesis using N,N’-diaryl hydra-
zines as substrates (Figure 1, B).7
ABSTRACT: Herein we disclose an organocatalytic aryl-aryl
bond-forming process for the regio- and atroposelective synthesis
of 2,2’-diamino-1,1’-binaphthalenes (BINAMs). In the presence
of catalytic amounts of axially chiral phosphoric acids, achiral
N,N’-binaphthyl hydrazines undergo a facile [3,3]-sigmatropic
rearrangement to afford enantiomerically enriched BINAM deriv-
atives in good to excellent yield. This transformation represents
the first example of a metal-free, catalytic C(sp2)-C(sp2) bond-
formation between two aromatic rings with concomitant de novo
atroposelective installation of an axis of chirality. Density func-
tional calculations reveal that in the transition state for C-C bond
formation, the phosphoric acid proton of the catalyst is fully trans-
ferred to one of the nitrogen atoms of the substrate and the result-
ing phosphate acts as a chiral counterion.
During the past 20 years axially chiral biaryl compounds1 have
played a key role as ligands in the development of many catalytic
enantioselective transformations, including transition metal cata-
lyzed cross-coupling reactions.2 Without exaggeration it can be
stated that axially chiral non-racemic biaryls (e.g., BINAP,
BINOL and their derivatives) have become the most successful
class of ligands in history with a wide range of catalytic enanti-
oselective processes, including several on an industrial scale.3,2b
Axial chirality is also widespread in nature. More than 1000 axial-
ly chiral natural products have so far been isolated and many of
them exhibit remarkable biological activities (e.g., vancomycin,
streptonigrin, michellamines, etc.) and it is not uncommon that
opposite enantiomers display completely different biological pro-
files (e.g., gossypol).1c Recently it was recognized that the phe-
nomenon of atropisomerism has enormous implications in the
development of pharmaceuticals.4 Given the abundance of axially
chiral biaryl compounds in nature as well as their importance in
asymmetric catalysis and materials science, it is surprising that
relatively few methods are available for their atroposelective syn-
thesis.5,1c Current strategies6 for the synthesis of axially chiral
nonracemic biaryls include resolution of racemic biaryls, desym-
metrization of preformed prohiral biaryls, dynamic kinetic resolu-
tion of rapidly racemizing preformed chiral biaryls6c,6g, transition
metal-catalyzed aryl-aryl coupling5b,6d, de novo construction of an
aromatic ring6b and traceless central-to-axial chirality exchange6f
(Figure 1).
Figure 1. Organocatalytic atroposelective aryl-aryl bond-
formation utilizing a facile [3,3]-sigmatropic rearrangement.
The thermal or acid-mediated [3,3]-rearrangement of N,N'-
diaryl hydrazines, a process known for nearly 110 years, leads to
the formation of a new C(sp2)-C(sp2) bond between two aromatic
rings.8 This remarkable transformation does not require the use of
transition metals, halogen atoms or other replaceable substituents:
the two reacting C(sp2)-H bonds are not activated in any way and
reactive intermediates (e.g., carbenes, carbon-centered radicals,
carbanions or carbocations) are not involved in the process.
A thorough literature search yielded a single report in 1985 by
Sannicolo9 in which an attempted non-catalytic enantioselective
rearrangement of 2,2'-hydrazonapthalene (1a) to BINAM (2a),
requiring a large excess (3-6 equivalents) of (+)-camphor-10-
sulfonic acid (CSA), is described (Scheme 1). The observed enan-
tiomeric ratio (er) for 2a was very low (57.5:42.5).10 No further
studies to render this transformation, or any other closely related
transformation that furnish biaryls, catalytic and/or highly enanti-
oselective have been reported.11
We surmised that via the careful screening of catalysts, solvents
and temperature, a set of ideal conditions could be identified that
would facilitate the catalytic and highly atroposelective rear-
rangement of N,N'-biaryl hydrazines to biaryl amines. We chose
1a as our preferred substrate over other N,N’-biaryl hydrazines
since its substitution pattern allows the formation of only two
While the methods outlined in Figure 1 are influential, they all
have limited scope; therefore new and powerful synthetic strate-
gies are needed to complement existing methods. Recently, we
became intrigued by the possibility of achieving the first organo-
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possible regioisomeric [3,3]-rearrangement products (2a and 3,
and (R)-H8-8g) as substituents led to faster rearrangement; the
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3
4
5
6
7
Scheme 1); the [5,5]- and [3,5]-pathways were not expected to
presence of CF3 groups (catalysts 8g and H8-8g) led to the highest
observed er (84.5:15.5 and 90.5:9.5) in the shortest amount of
time (entries 13 and 16). Use of the vaulted type catalyst 9 (entry
17) nearly doubled the er values when compared to catalysts 8c
and 8d, although the reaction rate did not improve (72 h).
compete.12
Scheme 1. Regiochemical Considerations and the Initial
Model for the Hypothetical Transitions State
Table 1. Catalyst Screen for the Atroposelective Synthesis
of 2a from 1a.
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In addition, density functional calculations at the M06-2X/6-
31G(d,p)13 level of theory with CPCM toluene solvent confirmed
that for the uncatalyzed-concerted rearrangement of 1a, the lowest
energy transition state (TS-1, Figure 2) provides the expected
[3,3] peri- and regioselectivity as well as the potential exclusive
formation of 2a over 3. The free energy barrier (ꢀG‡) for 1a→2a
via TS-1 is 34.2 kcal/mol and for 1a→3 via TS-2 is 48.9
kcal/mol. The dearomatized intermediate along the pathway for
1a→2a is endergonic with ꢀG = 11.9 kcal/mol. The overall rear-
rangement 1a→2a is exergonic by 30.5 kcal/mol.
Figure 2. M06-2X transition states for the thermal (i.e., uncata-
lyzed) rearrangement of 1a. Distances reported in Å.
Our initial hypothesis was that the ideal catalyst would activate
1a by engaging both nitrogen atoms (Scheme 1). To maximize the
hydrogen bonding between 1a and the catalyst, toluene was cho-
sen as the solvent and a catalyst loading of 20% was used (Table
1). First, we evaluated BINOL (4a) and thiourea 5; these catalysts
did not promote the rearrangement (1a→2a) even after two days
(entries 1 & 3). However, the 3,3'-di-CF3 derivative of BINOL
(4b), gave rise to 2a in good yield but with very low enantioselec-
tivity (51.5:48.5 er). Presumably, the greater acidity of catalyst 4b
relative to 4a, is why 4b is able to catalyze the rearrangement as
opposed to 4a.14 Next, we chose tartaric acid derivatives and (+)-
CSA (entries 4-6) as catalysts; formation of 2a was fast and the
yield was high, but the enantioselectivity remained low. At this
point we reasoned that it was unlikely that the rearrangement
could be catalyzed by hydrogen bond donors, but rather would
require full proton transfer from the catalyst to one of the nitrogen
atoms of 1a. If so, enantioselectivity could still be induced via a
chiral counterion strategy. Thus we turned our attention to
BINOL-derived chiral phosphoric acids as catalysts.3d,15 Indeed,
catalyst 8a led to rapid product formation with 56.5:43.5 er. This
result encouraged us to continue the evaluation of axially chiral
Brønsted acids for the rearrangement of 1a. Variation of the steric
bulk and electronic properties of substituents at the 3- and 3'-
positions (catalysts 8b-i) resulted in dramatic changes both in the
reaction rate and the level of asymmetric induction. For example,
catalyst 8b and 8e (entries 8 and 11) afforded 2a in 54:46 er and
80.5:19.5 er, respectively, however the reaction was very slow (6
days) in both cases. Catalysts bearing fused aromatic rings (8c and
8d) or aromatic rings with electron-withdrawing groups (8f, 8g
Next, we investigated the effect of solvent using catalyst (R)-8g
(Table 2). Among non-polar solvents (entries 1-7), benzene was
the most effective at 25 °C (entry 6). Polar solvents containing
highly electronegative heteroatoms (i.e., O and N, entries 8-11)
generally furnished 2a in lower isolated yields and in significantly
diminished er; presumably the heteroatoms disrupted the proton
transfer from the catalyst to 1a. Based on these findings, it was
reasonable to assume that traces of water will likely erode the er;
indeed, addition of molecular sieves (3Å, 4Å or 5Å MS) resulted
in a slight improvement of the er (85.5:14.5→87.5:12.5). In ben-
zene, using 4Å MS and lowering of the temperature (25→7 °C)
improved the enantioselectivity (87.5:12.5→90.5:9.5 er). Howev-
er, due to the high freezing point of benzene (+5.5 °C), we had to
switch back to toluene that has a much lower freezing point (−95
°C). The highest er (93:7) and excellent yield (89%) of 2a was
achieved in toluene at −20 °C in the presence of 4Å MS. Surpris-
ingly, further lowering of the temperature (−20→−40 °C) in tolu-
ene decreased both the yield (89→80%) and er (93:7→90:10).
Table 2. Solvent Screen for the Atroposelective Synthesis
of 2a.
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R2
R2
R1
R1
R1
Method A
1
2
NH2
NH2
R2
NH
NH
R2
or
R1
Method B
3
4
5
6
7
8
9
10
11
12
13
1a-h
2a-h
Yieldd (%), ere
Yieldd (%), ere
Entrya
Product
Entrya
Product
A
B
A
B
OMe
MeO
5 ( )-2e
MeO
89
86
85
51
:
49
[2]
83
52
:
48
[4]
93:7a 92:8a
NH2
NH2
NH2
NH2
1
2
( )-2a
88
90
93:7b 92:8c
(S)
[86]
(S)
[84]
OMe
Me
85
85
:
82
72.5
:
70
90
MeO
NH2
NH2
87.5 91.5
:
NH2
NH2
(+)-2b
6 ( )-2f
MeO
:
15
[70]
27.5
[45]
12.5
[75]
8.5
[83]
Scheme 2. Practical Atroposelective Synthesis of (S)-2a on
a 0.5-2.8 g Scale Using Catalysts (R)-8g and (R)-H8-8g.
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Me
OMe
i-Pr
87
82
:
18
[64]
81
81.5
:
18.5
[63]
69
67
85.5 54.5
:
14.5 45.5
[71]
NH2
NH2
NH2
NH2
7
8
( )-2g
3
( )-2c
:
[9]
i-Pr
OMe
OMe
89
NH2 50
86
50
:
50
[0]
83
80
NH2
NH2
65.5 51.5
2h
The practicality of this powerful catalytic atroposelective meth-
od could also be convincingly demonstrated (Scheme 2). The
optimized procedure performed well on a 2-10 mmol (up to 2.8 g)
scale, affording 88-90% isolated yield of 2a with up to 93:7 er.16
Remarkably, the catalysts could be recovered in nearly quantita-
tive yield (99%) after flash chromatography and, a single recrys-
tallization of the enantiomerically enriched 2a from toluene yield-
ed optically pure (>99.5:0.5 er) material.
:
4 ( )-2d
NH2
:
:
50
[0]
34.5 48.5
[31] [3]
OMe
Method A: Catalyst (R)-8g (20 mol%), 4Å MS, -20 °C, 24 h (0.025 M solution);
Method B: Catalyst (R)-H8-8g (5 mol%), 4Å MS, 0 °C, 24 h (0.025 M solution);
aReactions were performed on 0.05 mmol scale (0.025 M solution) unless indicated
otherwise. bPerformed on a 2.8 g scale; cPerformed on a 0.5 g scale; dIsolated
yield. eThe er was determined using Chiralpak IA column. [ee] values are in %.
To understand the role of the chiral phosphoric acid catalyst
and stereoselectivity, we have used M06-2X/6-31G(d,p) density
functional calculations in CPCM-toluene solvent to model the
rearrangement 1a→2a catalyzed by (R)-H8-8g. Figure 3 shows
TS-3S and TS-3R, which are the lowest energy enantiomeric C-C
bond forming transition states leading to the dearomatized inter-
mediate from 1a. TS-3S has a ꢀG‡ of 20.0 kcal/mol and TS-3R
has a ꢀG‡ of 22.2 kcal/mol at 253 K relative to free catalyst and
substrate. These ꢀG‡ values are ~14 kcal/mol lower than for un-
catalyzed TS-1. TS-3S and TS-3R feature the phosphoric acid
proton fully transferred from the catalyst to one of the N atoms of
1a and the phosphate acts as a chiral counterion.17 This protona-
tion lowers the barrier by charge polarization to create a more
asynchronous, but still concerted, transition state. Transition
states without proton transfer were found to be several kcal/mol
higher in energy. After proton transfer the phosphate counterion
interacts with protonated 1H+ in a bidentate fashion involving two
hydrogen bonding interactions. However, the hydrogen bonding
interactions are not equivalent. In TS-3S/3R the phosphate oxy-
gen atom that was involved in proton transfer has a short hydro-
gen bonding distance of ~1.6Å due to the enhanced electrostatic
attraction while the second hydrogen bonding interaction has a
distance of 2.4-2.7Å.
The free energy difference between TS-3S and TS-3R is
2.2kcal/mol at 253 K. We have also modeled the similar (R)-8g
catalyst. The ꢀꢀG‡ for (R)-8g transition states is 1.4 kcal/mol. We
have confirmed the in silico predicted preferential formation of
the (S)-enantiomer using chiral HPLC (see SI). The C-C bond
forming step in 1a→2a is likely stereo-determining because re-
aromatization via phosphate anion deprotonation and proton shut-
tling to set the axial chirality occurs via amino groups twisting
past each other while avoiding naphthyl groups twisting past each
other. See the SI for further explanation. Stereoselectivity in the
Figure 3. Enantiomeric C-C bond forming transition states.
Table 3. Exploration of the Substrate Scope for 1→2
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C-C bond forming transition states is the result of both steric and
this work and M.D. thanks the Department of Chemistry and
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electronic effects. The chiral counterion creates a spatial chiral
pocket to house 1H+. In addition, the electron deficient CF3
groups of catalyst (R)-H8-8g (and (R)-8g) induce significant C-H
bond- and π-π-aryl interactions that favor TS-3S over TS-3R.
Indeed, modeling of the C-C bond forming transition states with
catalyst 8a and 8g with aryl CH3 groups rather than aryl CF3
groups showed the expected decrease in stereoselectivity.
Biochemistry for an undergraduate research award.
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tuted in their 3,3'-, 5,5'-, 6,6'- and 7,7'-positions.18,8b Both cata-
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the case of 3,3’-disubstituted hydrazines the observed er values
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values (entries 4 & 5) while 5,5’- and 7,7’-di-methoxy hydrazines
afforded the corresponding biaryls with good er values (entries 2
& 3). It is noteworthy that the rearrangement of unsymmetrical
hydrazine 2h did not result in any enantioselectivity, which is in
agreement with the predicted TS.
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In conclusion, we have successfully developed the first organo-
catalytic atroposelective synthesis of biaryl amines, exploiting a
facile [3,3]-rearrangement. BINOL-derived axially chiral phos-
phoric acid catalysts (R)-8g and (R)-H8-8g, featuring electron-
deficient CF3 groups, were found to be optimal in achieving high
product yields and good enantioselectivity. Using density func-
tional calculations of the C-C bond forming step, we can predict
the absolute configuration of the axially chiral biaryl products.
This approach also allows us to engage in the rational design of
more effective catalysts and explore related rearrangements. We
are in the process of expanding the scope of this powerful atro-
poselective method to unsymmetrical biaryl hydrazines. The axi-
ally chiral and structurally diverse biaryl products are expected to
find broad utility in asymmetric catalysis, drug discovery and
materials science.
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ASSOCIATED CONTENT
Supporting Information
Complete experimental procedures and charactetization data in-
1
cluding H and 13C NMR spectra and chiral HPLC traces. Full
reference 13b. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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S455/451-S455/460.
Corresponding Author
laszlo.kurti@utsouthwestern.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(9) Sannicolo, F. Tetrahedron Lett 1985, 26, 119-120.
L.K. gratefully acknowledges the generous financial support
of the UT Southwestern Endowed Scholars in Biomedical Re-
search Program (W.W. Caruth, Jr, Endowed Scholarship in Bio-
medical Research), the Robert A. Welch Foundation (Grant I-
1764), the ACS Petroleum Research Fund (Doctoral New Investi-
gator Grant 51707-DNI1) and the American Cancer Society &
Simmons Cancer Center Institutional Research Grant (New Inves-
tigator Award in Cancer Research, ACS-IRG 02-196). A donation
of a 1220 Infinity LC by Agilent Technologies and a Chiralpak IE
column from Chiral Technologies Inc. (Daicel group) is also
greatly appreciated. We thank Dr. Ramakrishna Edupuganti for
the preparation of the initial batch 2-aminonaphthalene. D.H.E.
thanks BYU and the Fulton Supercomputing Lab for support of
(10) One likely explanation for the observed low enantioselectivity
(57.5:42.5 or 1.35:1 er) is that a simple optical resolution occurred due to
the presence of large quantities of (+)-CSA. The 57.5:42.5 er corresponds
to 15% ee, which was the value reported by Sannicolo (ref. 9).
(11) List et al. recently reported a SPINOL-phosphoric acid-catalyzed
asymmetric Fisher indolization reaction, see: Muller, S.; Webber, M. J.;
List, B. J. Am. Chem. Soc. 2011, 133, 18534.
(12) Upon rearrangement, N,N'-biaryl hydrazines that contain only
substituted benzene rings can give rise to a mixture of regioisomeric
biaryl products featuring 2,2', 2,4' and 4,4'-biaryl linkages. These biaryls
arise via [3,3], [3,5] and [5,5]-sigmatropic pathways, respectively. The
number of possible regioisomers is greatly reduced when the biaryl
hydrazines substrates are derived from fused aromatic systems, such as 2-
substituted naphthalenes. In these cases, the formation of only 1,1' and
1,3'-linked biaryls are expected via a [3,3]-pathway.
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(13) (a) Calculations were carried out using Gaussian 09. Transition-
2011, 75, 589. (d) Simón, L.; Goodman, J. M. J. Am. Chem. Soc. 2009,
131, 4070. (e) Simón, L.; Goodman, J. M. J. Am. Chem. Soc. 2008, 130,
8741.
(18) These substrates are prepared via the reduction of the corresponding
symmetrical azo compounds (Ref. 8b). We found that the solubility of
6,6'-disubstituted azo compounds is generally very poor compared to azo
compounds that bear substituents in any other position. This limited
solubility hinders their reduction to the corresponding N,N'-biaryl
hydrazines.
state structures were confirmed to be first-order saddle points by
vibrational normal mode analysis. (b) Frisch, M. J.; et al. Gaussian 09,
revision B.01; Gaussian, Inc.: Wallingford, CT, 2009. For M06-2X
references see: (c) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120,
215. (d) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.
(14) We found that regular, non-deactivated, silica gel is able to catalyze
the rearrangement of 1a to 2a in nearly quantitative yield.
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(15) (a) Kampen, D.; Reisinger, C. M.; List, B. Top Curr Chem 2010,
291, 395-456. (b) Terada, M. Synthesis 2010, 1929-1982.
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(16) In this reaction, 8% of 7H-dibenzo[c,g]carbazole was also formed
which could be easily separated from 2a.
(17) (a) Grayson, M. N.; Pellegrinet, S. C.; Goodman, J. M. J. Am.
Chem. Soc. 2012, 134, 2716. (b) Simón, L.; Goodman, J. M. J. Org.
Chem. 2011, 76, 1775. (c) Simón, L.; Goodman, J. M. J. Org. Chem.
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