Catalytic asymmetric benzidine rearrangement

Article abstract of DOI:10.1002/anie.201304039

A chiral Br?nsted acid catalyzes the asymmetric benzidine rearrangement of N,N′-dinaphthylhydrazines. Different electronically and structurally diverse axially chiral 2,2′-binaphthyl diamine (BINAM) derivatives are obtained with high enantioselectivity. Copyright

Full text of DOI:10.1002/anie.201304039

Angewandte
Chemie
Communications
Organocatalysis
C. K. De, F. Pesciaioli,
B. List*
&&&& — &&&&
Catalytic Asymmetric Benzidine
Rearrangement
A chiral Brønsted acid catalyzes the
asymmetric benzidine rearrangement of
N,N’-dinaphthylhydrazines. Different
electronically and structurally diverse
axially chiral 2,2’-binaphthyl diamine
(BINAM) derivatives are obtained with
high enantioselectivity.
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DOI: 10.1002/anie.201304039
Organocatalysis
Catalytic Asymmetric Benzidine Rearrangement**
Chandra Kanta De, Fabio Pesciaioli, and Benjamin List*
The [3,3]-diaza Cope rearrangement is a powerful synthetic
We envisioned that a catalytic enantioselective benzidine
rearrangement of N,N’-dinaphthylhydrazines could poten-
tially be a powerful and general approach towards BINAM
derivatives. Previously, only one example of an asymmetric
benzidine rearrangement was reported by Sannicolꢀ, using
three equivalents of camphor sulfonic acid to obtain the
product with poor enantioselectivity.[9,10]
À
principle that can be utilized to generate a C C bond at the
À
expense of an N N bond. It forms the basis of important and
fundamental acid-catalyzed transformations such as the
Fischer indolization and the benzidine rearrangement
(Scheme 1).[1–3] Recently, our group has established the first
We started our studies by reacting hydrazine 1a in CHCl3
with different chiral Brønsted acid catalysts.[11,12] Spirocyclic
phosphoric acid catalysts (S)-3a and (S)-3b, which provided
excellent results in our asymmetric Fischer indolization gave
product 2a in 52% and 27% yield, respectively. However, the
reaction did not lead to full conversion and the enantiose-
lectivity was poor in both cases (Table 1, entries 1 and 2).
Table 1: Reaction development.[a]
Entry
Catalyst
Solvent
T [8C], t [h]
Yield [%]
e.r.
Scheme 1. The diaza Cope rearrangement and its synthetic utilization.
1[b]
(S)-3a
(S)-3b
(R)-4a
(S)-4b
(S)-4c
(S)-4d
(R)-4e
(S)-5
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
(R)-4a
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
PhMe
CHCl3
PhMe
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
RT, 22
RT, 48
RT, 22
RT, 48
RT, 48
RT, 22
RT, 48
RT, 48
RT, 24
52
27
67
51
63
51
21
38
62
54
67
57
65
69
76
67
77
60:40
2[b]
60.1:39.9
17.5:82.5
65.3:34.7
60:40
catalytic asymmetric variant of the Fischer indolization.[4] Two
years ago, in light of the mechanistic similarities between the
two reactions, we set up a program towards developing an
asymmetric benzidine rearrangement. Such a transformation
may find utility in the synthesis of highly useful chiral biaryls
such as 1,1’-binaphthyl-2,2’-diamine (BINAM). Herein we
report the successful realization of this idea with a benzidine
rearrangement of N,N’-dinaphthylhydrazines catalyzed by
a chiral phosphoric acid, furnishing the corresponding
BINAM derivatives with high enantioselectivity.
Although several well-established BINAM-based cata-
lysts have been developed for asymmetric catalysis,[5,6]
BINAM is rather expensive and its current synthetic route
relies on a classical resolution.[7] Only few synthetic attempts
towards enantiopure BINAM derivatives exist. These involve
a moderately enantioselective oxidative homocoupling of 2-
naphthylamines.[8]
3
4
5
6[b]
70:30
7[b]
23.7:76.3
44.3:55.7
17:83
15.5:84.5
9.5:90.5
14.8:85.2
5.2:94.8
4.5:95.5
4:96
8[b]
9
10
11
RT, 24
À15, 48
À15, 48
À50, 66
À50, 66
À50, 55
À50, 66
À50, 48
12[b]
13[b]
14[b,c]
15[d]
16[b,d,e]
17[d,e,f]
4:96
3.5:96.5
[a] Reactions were run on a 0.05 mmol scale and the e.r. value was
determined by using HPLC. [b] Reactions were incomplete. [c] Reactions
were run at a concentration of 0.05m. [d] Reactions were run at
a concentration of 0.025m. [e] Reactions were run with 5 mol% catalyst
loading. [f] Reaction was run with 50 mg of CG-50 resin.
[*] Dr. C. K. De, Dr. F. Pesciaioli, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: list@kofo.mpg.de
[**] We gratefully acknowledge generous financial support from the
Max-Planck-Society and the Alexander von Humboldt Foundation
(fellowship for C.K.D).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304039.
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While most investigated binaphthyl-based phosphoric
acids gave only moderate results, catalyst (R)-4a gave product
2a in promising yield and enantioselectivity (Table 1,
entries 3–7). Interestingly, the chiral Brønsted acid catalyst
(S)-5, which is based on a stronger acidic disulfonimide, gave
poor conversion as well as a poor e.r. value (entry 8). We
therefore selected catalyst (R)-4a for further optimizations.
The evaluation of different solvents (entries 9 and 10) showed
that toluene was a comparably effective solvent. However,
when performing the reactions at lower temperature
(À158C), CHCl3 was found to be superior (entries 11 and
12). Lowering the reaction temperature to À508C signifi-
cantly increased the e.r. value to 5.2:94.8 and gave the product
in 65% yield with an incomplete consumption of 1a after 66 h
(entry 13). Interestingly, when the reactions were conducted
at that same temperature but with a lower concentration,
a beneficial effect on the conversion with virtually no effect
on the e.r. value was found (entries 14 and 15). Finally,
addition of weakly acidic CG-50 resin as an additive, allowed
us to perform the reaction at even lower catalyst loading with
full consumption of hydrazine 1a (entries 16 and 17).
reaction proceeds through a monocationic pathway, involving
a structure such as A, or through a dicationic, potentially
radical-cation-involving pathway via structures B or C
(Figure 1). We hypothesized that a study on the nonlinear
effects in the asymmetric catalysis could give an indication,
With the optimized conditions established, the scope of
the reaction was explored next (Scheme 2). A number of
naphthyl hydrazines with electronically diverse substituents
at different ring positions yielded the desired products,
typically with good yields and enantioselectivities of e.r. >
95:5. Both substrates with substituents at their 6- or 7-
position, irrespective of their electronic nature gave the
corresponding BINAM derivatives with good yields and high
enantioselectivity.
Until today, no generally accepted mechanism of the
benzidine rearrangement has been established. There is
considerable debate concerning the question, whether the
Figure 1. Observed nonlinear effects in the asymmetric catalysis of the
rearrangement of 1a to 2a, and potential ion pair intermediates.
which of the suggested pathways is operative.[13] If the
reaction indeed would proceed via a dicationic intermediate,
nonlinear effects may be anticipated, since two catalyst anions
would be involved in the presumably enantioselectivity-
determining rearrangement step. Remarkably, in the rear-
rangement of substrate 1a, we did indeed see a significant
negative nonlinear effect. While there may be various
alternative explanations for this observation, including the
involvement of a catalyst dimer, our results are consistent
with a dicationic mechanism.
In summary, we have developed a catalytic asymmetric
benzidine rearrangement using a chiral phosphoric acid
catalyst. With this methodology, electronically and structur-
ally diverse axially chiral 2,2’-binaphthyldiamine (BINAM)
derivatives were synthesized with a high level of enantiose-
lectivity.[14] Current work aims at a further expansion of the
asymmetric catalysis of reactions involving a diaza Cope
rearrangement and at a deeper understanding of their
mechanistic details.
Received: May 10, 2013
Published online: && &&, &&&&
Scheme 2. Scope of the asymmetric benzidine rearrangement. Reac-
tions were run on a 0.1 mmol scale and the e.r. value was determined
by using HPLC. [a] Reaction was run at À308C with 10 mol% catalyst
loading. [b] Reaction was run at À458C with 10 mol% catalyst loading.
Keywords: asymmetric catalysis · benzidine rearrangement ·
.
hydrazines · organocatalysis · phosphoric acids
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