Stereoselective Synthesis of 1,2-trans-Diamines Using the Three-Component Borono-Mannich Condensation – Reaction Scope and Mechanistic Insights

Article abstract of DOI:10.1002/ejoc.201700089

The Petasis borono-Mannich (PBM) process with easily accessible N-protected α-amino aldehydes produces 1,2-trans-diamines diastereoselectively with an enantiomeric excess up to 98 %. The protecting group on the nitrogen atom had a decisive influence on bo

Full text of DOI:10.1002/ejoc.201700089

A Journal of
Accepted Article
Title: Stereoselective Synthesis of 1,2-trans-Diamines using the Three-
Component Borono-Mannich Condensation: Reaction Scope and
Mechanistic Insights
Authors: Jean-Marie Beau, Stéphanie Norsikian, Margaux Beretta,
Alexandre Cannillo, Marie Auvray, Amélie Martin, Pascal
Retailleau, and Bogdan I Iorga
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10.1002/ejoc.201700089
European Journal of Organic Chemistry
FULL PAPER
Stereoselective Synthesis of 1,2-trans-Diamines using the Three-
Component Borono-Mannich Condensation: Reaction Scope and
Mechanistic Insights.
Stéphanie Norsikian,*[a] Margaux Beretta,[a] Alexandre Cannillo,[a] Marie Auvray,[a] Amélie Martin,[a] Pascal
Retailleau,[a] Bogdan I. Iorga[a] and Jean-Marie Beau*[a,b]
Dedication ((optional))
[12,13]
Abstract: The Petasis borono-Mannich (PBM) process with easily
accessible N-protected α-amino aldehydes produces
complex natural products.
The cornerstone of this reaction
is the presence of the directing α-hydroxyl group proximate to
the reacting carbonyl group. This allows the activation of the
boronic acid as an ‘‘ate’’ complex and results in the transfer of a
vinyl or aryl group on the transient iminium species.
Examples of the activation of the boronic acid by a nitrogen
diastereoselectively 1,2-trans-diamines with an enantiomeric excess
up to 98 %. The protecting group on the nitrogen atom had a
decisive influence on both the yield and the enantiomeric purity of
the condensation products and the best results were obtained with
sulfonamide derivatives (Ns, Ts, Ms). In order to get a better
understanding of the influence of the protecting groups, we
investigated the mechanism of the borono-Mannich reaction using
DFT calculations.
[ 14 ]
[
15 ]
atom are rare and only 2-pyridinecarbaldehyde,
2-
sulfamidobenzaldehyde [16] and aziridine aldehyde dimer [17] have
been reported to react successfully in the PBM reaction. In the
latter case, aziridine-containing vicinal diamines were produced
in a high syn-selective fashion. Herein, we report the details of
an efficient trans-selective synthesis of enantioenriched vicinal
diamines using the PBM reaction of N-protected α-amino-
aldehydes. These substrates are easily accessible but known for
their susceptibility to racemization. [18,19, 20,21]
Introduction
1,2-Diamines are compounds that are found in a wide range of
natural products and in various pharmacologically active
derivatives. [1] They are also employed in organic syntheses as
building blocks, chiral auxiliaries, ligands and catalysts. [2] Much
effort has been made for the development of efficient and
stereocontrolled routes to optically active vicinal diamines.
Among the known strategies for their synthesis are 1,2-
Results and Discussion
1- Reaction optimization
Initial experiments to examine this possibility were conducted by
coupling the commercially available (E)-phenyl vinyl boronic acid
1, N,N-diallylamine 2, and the N-tosylated aminoaldehyde 7a
(Tables 1 and 2). The latter was derived from L-phenylalanine
methyl ester hydrochloride after tosylation, reduction of the ester
[1g, 3]
[4 ]
diamination of olefines,
amination of enecarbamates,
aziridine ring opening by nitrogen nucleophiles, [5] nucleophilic
[6]
addition to α-amino imines
and Mannich type reactions of
glycine ester Schiff bases or nitro compounds with imines (aza-
Henry reaction). [1e,7,8]
As an alternative to these approaches, we became interested in
the use of α-protected aminoaldehydes in the Petasis borono-
Mannich (PBM) reaction [9] to access these compounds. From α
-hydroxyaldehydes, amines, and vinyl- or arylboronic acids, the
and TEMPO-mediated oxidation of the corresponding primary
[22]
alcohol 3a.
The resulting α-tosylated amino aldehyde 7a was
then used directly after the oxidation workup in the next Petasis
condensation. At this stage, the enantiomeric purity and the
configurational stability of the amino aldehyde 7a were checked
after addition of sodium borohydride in MeOH leading to the
aminoalcool 3a in 98 % ee and we found that 7a could be stored
at -18 °C for one month with minimal racemization (97 % ee).
On the basis of our previous work with α-hydroxyaldehydes,
[13,23] the first reactions were carried out with 2 equiv. of 2 and
7a in CH2Cl2 at 120 °C for 30 min under microwave radiation or
at 50 °C for 36 h by conventional heating (Table 2, entries 1
and 2). In both cases, the reaction produced the desired
PBM reaction is known to furnish β-amino alcohols with an
[10 , 11 ]
exclusive anti-diastereoselectivity
and this methodology
was applied to the synthesis of many elaborated molecules and
[a]
[b]
Dr. S. Norsikian, M. Beretta, Dr. A. Cannillo, M. Auvray, A. Martin,
Dr. P. Retailleau, Dr. B. I. Iorga, Prof. J.-M. Beau
Institut de Chimie des Substances Naturelles, CNRS UPR2301,
Univ. Paris-Sud, Université Paris-Saclay
1 av. de la Terrasse, F‐91198 Gif‐sur‐Yvette, France.
E-mail: stephanie.norsikian@cnrs.fr, jean-marie.beau@u-psud.fr
http://www.icsn.cnrs-gif.fr/spip.php?article718#
Prof. J.-M. Beau
compound 11 in 85 and 52 % yields respectively but in low ees
(30 to 42 %). [19,24] X-ray crystal diffraction
analysis of 11
[19,25]
confirmed that the reaction occurred with a high degree of
diastereocontrol leading exclusively to the anti adduct. The use
[ 26 , 27 ]
of HFIP
as an additive polar solvent accelerated the
Laboratoire de Synthèse de Biomolécules, Institut de Chimie
Moléculaire et des Matériaux d’Orsay, Univ. Paris-Sud and CNRS,
Université Paris-Saclay,
reaction but had a detrimental effect on the enantiomeric purity
producing the compound 11 in very low ees (0 to 8 %) even at
0 °C (entries 3 and 5). This solvent of high ionizing power
probably favored the formation of the transient iminium species
F-91405 Orsay, France.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700089
European Journal of Organic Chemistry
FULL PAPER
but also favored the erosion of the enantiomeric purity. The less
acidic TFE (pKa(TFE)H2O = 12.4 versus pKa(HFIP)H2O = 9.3)
using THF, chloroform, acetonitrile, methyl tert-butylether
whereas higher ee values (86 to 97 %) resulted with aromatic
solvents (toluene, mesitylene, trifluorotoluene, see Figure 1).
[27c]
as an additive gave the same effect but to a lesser extent (entry
4, 29 % versus 8 % ee at 50 °C). Since the reaction in CH2Cl2
was very slow at room temperature (entry 6, 19 % yield after 36
h), the reaction was attempted in the presence of the ionic liquid
1-butyl-3-methylimidazolium tetrafluoroborate [bmim]BF4 but no
improvement was observed (entry 7). [28] The reaction was then
carried out in the presence of 4Å molecular sieves that are also
Table 2. Optimization of the Petasis reaction with boronic acid 1, N,N-
diallylamine 2 and the N-tosylated aminoaldehyde 7a in CH2Cl2.
B(OH)2
O
Ph
N
Conditions
Ph
1
H
Ph
Table 1. Synthesis of α-amino-aldehydes 7-10.
Ph
NHTs
7a
N
NHTs
2
H
11
O2N
SO2Cl
Yield
Entry
T (°C) [a]
t (h)
Additive
ee ( %)[c]
OH
O
( %)[b]
NO2
BH3.THF
Ph
R
HO
Ph
O
NH2
NaHCO3
NHBoc
1
2
3
4
5
6
7
8
120 (MW)
0.5
36
12
12
48
36
36
36
-
85
30
42
8
O
cat.TEMPO
NaOCl,KBr
OH
50
50
50
0
-
52
1°) Protection
R
R
MeO
H
HFIP[d]
70
2°) LiAlH4 or LiBH4
or DMP
NH3
Cl
NHPG
7a-j, 8a-b,
9, 10
NHPG
3a-j, 4a-b
5, 6
TFE[d]
42
29
0
NaBH4, MeOH
HFIP[d]/4Å MS
-
70
Alcohol
Aldehyde
R
PG
(yield( %))[a,b]
3a (97)
3b (81)
3c (87)
3d (58)
3e (51)
3f (50)
3g (45)
3h (72)
3i (93)
(yield( %))[c]
7a (98)
7b (95)
7c (67)
7d (99)
7e (99)
7f (99)
7g (68)
7h (99)
7i (21)
r.t.
r.t.
r.t.
19
50
48
37-84
[d]
[bmim]BF4
25
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
iPr
iPr
Ts
4Å MS
46-85
Ns
Ms
DNs
Mtr
Ses
Tf
[a] Reaction conditions: 1 (1 equiv.), 2 (2 equiv.), 7a (2 equiv.), CH2Cl2. [b]
Isolated yield after chromatography, based on boronic acid. [c] ee determined
by chiral HPLC. [d] mixture CH2Cl2/HFIP, CH2Cl2/TFE or CH2Cl2/[bmim]BF4 :
9/1.
Boc
Ac
TFA
Ts
3j (72)
7j (62)
4a (95)
4b (58)
5 (78)
8a (93)
8b (94)
9 (90)
Ns
Figure 1. Effect of the solvent on the Petasis reaction with 1, 2 and 7a [a]
Reaction conditions: 1 (1 equiv.), 2 (2 equiv.), 7a (2 equiv). [b] Isolated yield
after chromatography, based on boronic acid. [c] ee determined by chiral
HPLC.
iPrCH2
Ns
TBSOCH2
Ns
6 (65)
10 (97)
[a] Calculated yield for two steps. [b] Isolated yield after chromatography. [c]
Yield of the crude aldehyde. For the details of reagents and conditions, see
ESI or ref 19.
When the reaction was performed with environmentally friendly
trifluorotoluene, [11a,30] 11 was obtained in a 50-53 % yield and
95-98 % ee. PhCF3 was then chosen as the standard solvent to
further explore the reaction conditions. It is also worth to note
that only traces of the expected compound 11 were observed
when EtOH was used as solvent. We also examined the
known to accelerate the PBM reactions and proved to be
effective for both the yield and the enantiomeric purity with ees
increasing to 84 % (entry 8). [29] However, with the volatile CH2Cl2,
the results were non reproducible and reactions with other
solvents were carried out. Low to moderate ees were obtained
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10.1002/ejoc.201700089
European Journal of Organic Chemistry
FULL PAPER
[ 31 ]
influence of the reactants’ stoichiometry and we found that the
after sulfonylation of L-2-amino-3-phenyl-1-propanol
and
amount of both aldehyde and amine could be reduced (1.3 equiv. classical oxidation to the corresponding aldehyde. In the case of
of 7a and 1.25 equiv. of 2) providing 11 in a similar yield with a
minimal decrease of the ee (92.5 %). Stoichiometric amounts of
all the reactants or an excess of the boronic acid or amine had a
negative effect on the enantiomeric purity (ees between 74-
86 %). In contrast, with an excess of boronic acid (2 equiv. of 1),
the yield of 11 was improved to 67 % (versus 53 % yield with 1
equiv.).
the aldehyde 7g with the triflate protecting group, oxidation was
carried out with the Dess-Martin periodinane, [32] which gave a
cleaner reaction than that with TEMPO-NaOCl. The
enantiomeric purity and the configurational stability of this amino
aldehyde was also checked after the DMP oxidation by addition
of sodium borohydride that furnished the aminoalcohol 3g in
99 % ee.
2- Substrate Scope and Limitation
a- Substrate scope based on the protecting group of the α-
amino aldehyde derived from L-phenylalanine. In order to
study the influence of the protecting group of the α-amino
aldehyde, compounds 12-20 were synthesized from 7b-j (Table
3).
Table 3. Influence of the protecting group of the α-aminoaldehyde 7 in the
Petasis reaction with boronic acid 1 and N,N-diallylamine 2.
O
N
PhCF3, 4Å MS
+
+
2
1
H
Ph
Ph
Ph
RT
NHPG
NHPG
7b-j
12-20
N
N
N
Figure 2. Enantiomeric purity and chemical yield of the diamine products as a
function of the calculated pKa (aqueous medium) of N-protected aldehydes 7
derived from L-phenylalanine and condensed with 1 and 2.
Ph
Ph
Ph
Ph
Ph
Ph
NHMs
NHDNs
NHNs
12, 71 % yield, 94 %
13, 62 % yield, 93 %
ee
14, 51 % yield, 94 % ee
ee (99.5 ) [d]
All these substrates were then tested in the PBM reaction using
diallylamine 2 and phenyl vinylboronic acid 1. We found that the
protecting group of the amino aldehyde had a decisive influence
on both the yield and the enantiomeric purity of the
condensation products and the results could be partially
correlated to the pKa of the corresponding NH-groups. With the
exception for the N-trifluoroacetylated compound 7j, the higher
the ees of the diamine products, the lower the pKa of the
corresponding NH-groups (Table 3 and Fig. 2). Thus, acetamide
7i (pKa 15) [33,34,35] and tert-butyl carbamate 7h (pKa 11.4) gave
ineffective results (diamines 19, 3 % ee and 18, 15 % ee,
respectively) while the N-sulfonylated (Ts, Ms, Ns, DNs, Tf)
compounds with pKa between 9.5 and 4.8 provided good
solutions in terms of ees (diamines 11, 12, 13, 14, and 17, 93-
96 % ee). The N-nosylated group was the best option since the
yield of the diamine product decreased for the NHDNs and NHTf
derivatives with the lowest pKas (72 % for 12 versus 51 % for 14
and 41 % for 17). The other sulfonamide derivatives 4-methoxy-
N
N
N
Ph
Ph
NHSES
Ph
Ph
Ph
Ph
NHMtr
NHTf
15, 28 % yield,[c] 20 %
16, 30 % yield,[c] 67 %
17, 41 % yield,
ee
ee
96 % ee
N
N
N
Ph
Ph
Ph
Ph
NHBoc
Ph
Ph
NHAc
NHTFA
18, 21 % yield,[c] 15 %
19, 23 % yield,[c]
20, 42 % yield,
ee
3 % ee
4 % ee
[a] Reaction conditions: boronic acid (1 equiv.), aminoaldehyde 7 (1.3 equiv.),
amine (1.25 equiv.), PhCF3, 4Å MS, 48 h at r.t., unless otherwise stated. [b]
Isolated yield after chromatography, based on boronic acid, ee determined by
chiral HPLC. [c] aminoaldehyde (2 equiv.) and amine (2 equiv.) were used. [d]
ee after recrystallization.
2,3,6-trimethylphenylsulfonamide
(Mtr)
7e
and
2-
Generally, the aminoaldehydes were easily prepared in three
steps from L-phenylalanine methyl ester hydrochloride after
appropriate protection, reduction of the ester (LiAlH4 or LiBH4)
and TEMPO-mediated oxidation (Table 1). The Boc derivative
7h was prepared directly from the commercially available N-
(tert-butoxycarbonyl)-L-phenylalanine after reduction of the acid
with BH3.THF and oxidation of 3h with TEMPO-NaOCl. The 2,4-
dinitrophenylsulfonamide (DNs) compound 7d was prepared
(trimethylsilyl)ethanesulfonamide (SES) 7f with pKa around 10
gave unsatisfactory results in terms of yields and ees. These
results suggest that the protecting group on nitrogen is important
in modulating the coordination to boron as well as in preventing
the racemization of the asymmetric center. With the Ns-
protected aldehyde 7b, the reaction was carried out on higher
scale (0.25 g of boronic acid 1) and provided 0.63 g of the
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10.1002/ejoc.201700089
European Journal of Organic Chemistry
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diamine 12 in 72 % yield and 91 % ee that could be increased to
with 4Å MS and the yields were not optimized. With the N-
tosylated or N-nosylated aminoaldehydes 7a or 7b and the
boronic acid 1, the reaction could be performed with other
secondary amines. With N-allyl-N-benzyl amine 25 or N,N-
dibenzyl amine 26, the diamines 29, 30 and 31 were obtained in
56, 64 and 72 % yields respectively, with good enantiomeric
purity (91 to 98 % ee). With N-methyl-N-benzyl amine 27, the
reaction was less efficient affording 32 in 48 % yield and a lower
71 % ee and with the primary N-benzylamine 28, the reaction
did not provide any condensation adduct.
99.5 % after recrystallization. [36]
Table 4. Substrate scope for the Petasis borono-Mannich process with N-
protected α-amino aldehydes[a,b]
Boronic acids
1
Amines
2
Aldehydes
O
B
B
B
7a,7b, 8a, 8b
9,10
Bn
.
N
H
O
O
N
25
O
22
21
Regarding the boronic acid component, the reaction was carried
out with (E)-(2-cyclohexylvinyl)boronic acid 21, 2,4,6-
trivinylcyclotriboroxane pyridine complex 22 and 4-anisylboronic
acid 23. In combination with N,N-diallylamine 2 and the N-
nosylated aminoaldehyde 7b, the reaction furnished the
expected products 33, 34 and 35 in 48, 51 and 38 % yields,
respectively, with some erosion of the enantiomeric purity (82,
86 % and 82.5 % ee). 2-Furanboronic acid 24 proved to be a
good reaction partner with N,N-dibenzyl amine 26 and aldehyde
7b, leading to the corresponding adduct 36 in 63 % yield and
93 % ee.
Bn
Me
B(OH)2
B(OH)2
H
Ph
Me
Bn
N
Bn
N
H
NsN
B(OH)2
H
26
27
Bn
7k
23
NH2
24
O
MeO
28
Bn
Bn
Bn
Bn
N
N
N
Ph
Ph
Ph
Ph
NHNs
Ph
Ph
NHNs
NHTs
7a+1+25" 29
56 % yield, 91 % ee
7b+1+25" 30
64 % yield, 98 % ee
7b+1+26" 31
72 % yield, 96 % ee
A short survey of the aldehyde component was performed with
N-tosylated aminoaldehyde 8a and N-nosylated aminoaldehydes
8b, 9 and 10 derived from L-valine, L-leucine and protected L-
serine. These aldehydes were all prepared from the
corresponding aminoacid methyl ester hydrochloride using the
same procedure as that for phenylalanine (Table 1). Their
condensation with 1 and 2 or 26 afforded the desired products
37, 38, 39 and 40 in moderate to good yields (46 to 63 %) with
ees from 82 to 93 %. It is also worth noting that no reaction
occurred with the N-methyl N-tosylaminoaldehyde 7k, which
highlights the importance of the boron coordination to the
nitrogen so that the reaction could take place.
Me
Bn
N
N
N
Ph
Ph
NHNs
Ph
Ph
NHNs
NHNs
7b+1+27" 32
48 % yield, 71 % ee
7b+21+2" 33
48 % yield, 82 % ee
7b+22+2" 34
51 % yield,[d] 86 % ee
Bn
O
Bn
N
N
Ph
NHNs
N
Ph
NHNs
Ph
MeO
For synthetic purposes, orthogonal removal of the N-protecting
groups was also carried out on compound 12 (Scheme 1).
Treatment with thiophenol in the presence of K2CO3 in DMF at
50 °C for 5 h selectively deprotected the nosyl group, leading to
the monoprotected diamine 41 in 74 % yield. Using N,N-
dimethylbarbituric acid and a catalytic amount of Pd(0) could
afford the other monoprotected diamine 42 by allyl protecting
groups removal. [37] Finally, the fully deprotected diamine 43 was
obtained from 42 after treatment with PhSH/K2CO3.
NHTs
7b+23+2" 35
7b+24+26" 36
63 % yield, 93 % ee
8a+1+2" 37
46 % yield, 93 % ee
38 % yield, [e] 82.5 % ee
Bn
Bn
N
OTBS
N
Ph
N
Ph
NHNs
NsHN
Ph
NHNs
PhSH, K2CO3
DMF, 50 °C, 5h
N
N
8b+1+2" 38
53 % yield, 87 % ee
9+1+2" 39
51 % yield, 83 % ee
(96) [c]
10+1+26"40
63 % yield, 82 %
ee (86) [c]
41, 74%
Ph
Ph
Ph
Ph
NHNs
NH2
Ph
12
NH2
NH2
NH2
PhSH, K2CO3
DMF, 50 °C, 5h
[a] Reaction conditions: boronic acid (1 equiv.), aminoaldehyde (1.3 equiv.),
amine (1.25 equiv.), PhCF3, 4 Å MS, 48 h at r.t., unless otherwise stated. [b]
Isolated yield after chromatography, based on boronic acid, ee determined by
chiral HPLC. [c] ee after recrystallization. [d] Boronic acid (1 equiv.),
aminoaldehyde (1.3 equiv.) and amine (1 equiv.) were used, yield based on
amine.
Pd(PPh3)4
Ph
Ph
NHNs
Ph
DMBA, DCM
35 °C, 4h
42, 98%
43, 64%
Scheme 1. Orthogonal deprotection of 12. DMBA = N,N’-dimethylbarbituric
acid.
b- Substrate scope based on the α-amino aldehydes,
amines and boronic acids. A variety of reaction partners were
then surveyed in the three-component borono-Mannich reaction
as shown in Table 4. Typically, the results were obtained using
1.3 equiv. of aldehyde and 1.25 equiv. of amine at r.t. in PhCF3
3- Mechanistic considerations using DFT calculations
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10.1002/ejoc.201700089
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For a better understanding of the influence of the protecting
group on the nitrogen, we also investigated the mechanism of
the borono-Mannich reaction using DFT calculations. The
transformation is the result of complex equilibria between the
three components and their intermediates, which provides
In pathway 1, the first step is the nucleophilic addition of the
N,N-dimethylamine B on the carbonyl compounds A (Scheme 2,
see Scheme 1 in ESI for more structural details). This reaction
proceeds with a simultaneous hydrogen transfer through a four
membered ring transition state TS1 (see Figure S1 in ESI) and
leads to the formation of the hemiaminals C. For all of the
starting compounds, the energy barrier of this step is about the
stereoselectively the di-amine product via an irreversible C-C
[9b,c]
bond formation.
For practical reasons, all the calculations
were realized with the simplified structures A, B and E, which
same (between 26.6 and 27.3 kcal.mol-1). This in agreement
[14d]
contained only the atoms that are pertinent to the considered
with earlier reported calculations
and the high activation
[38]
reactions (Scheme 2).
The geometries of all these structures
energy barrier is probably due to a significant tension of the four-
membered ring formed in the transition state. However, with the
assistance of a second molecule of N,N-dimethylamine B, the
energy barrier of this step (TS1’) can be significantly reduced
(between 10.7 and 12.1 kcal.mol-1) and give the much more
stable C.B adduct (Figure 3). [42]
In the second step, water is eliminated through a five membered
ring transition state TS2, originating from a probable hydrogen
bond as shown in C (Scheme 2, Figure 3). The reaction is
endothermic in all cases and the calculations lead to a partially
were optimized by using DFT calculations, starting from the
aminoaldehydes protected as NH-Ms (A-Ms), NH-Ns (A-Ns),
NH-Tf (A-Tf), NH-CO2Me (A-CO2Me) and NH-Ac (A-Ac). For our
study, we examined two different pathways for the overall
transformation ending by an intramolecular delivery of the
nucleophile (Scheme 2). In pathway 1, which has been already
considered for the borono-Mannich process with other
[14d,9c]
substrates,
the following steps were calculated: 1) the
nucleophilic addition of the amine B to the aldehyde A to form
an hemiaminal C; 2) its dehydration leading to iminium species
D.H2O; 3) from intermediate F, the production of the tetra-
coordinated borate intermediate G; 4) the C—C bond formation
after the intramolecular transfer of the vinyl group leading to H
and 5) the hydrolysis of H to give the final adduct I. [39] Pathway 2
started by a plausible initial formation of a boronate complex
between A and E. [40,41] It consisted in the following steps: 1)
activation of the carbonyl compound A by complexation with the
boronic acid E; 2) nucleophilic addition of the amine B leading to
J; 2) formation of the hemiaminal K by water elimination and 3)
rearrangement of K to the iminium F. The steps of boron
coordination, vinyl transfer and hydrolysis remained the same as
in pathway 1.
open zwitterionic iminium species D.H2O stabilized by
a
hydrogen bond between the amide anion or one oxygen of the
sulfonamide and a molecule of water. The asymmetric carbon
(C2) next to the iminium carbon is not tetrahedral with an
C1-C2-N2 angle between 93.4 and 100.7°. The C1-N2 bond length
is between 2.14 and 2.27 Å and C1-N1 bond length of 1.30-1.31
Å. For TS2, the calculated energy barrier is lower for the
sulfonamide compounds having Tf, Ns and Ms group (13.8, 16.9
and 20.2 kcal.mol-1, respectively) while higher values are
obtained for the carbamate (26.6 Kcalmol-1) or the acetamide
(24.3 Kcalmol-1) adduct.
OH
B
O
H
OH
B
PGN
H
HO OH
B
N
Pathway 1
HO
O
H
OH
N
NHPG
H
HO
PGN
PGN
E
H
N
B
OH
B
PGN
O
TS1
TS2
TS3
TS4
O H
PGN
2
1
N
O
H
A.B
N
N
H2O
H
PG = Ms, Ns, Ac,
CO2Me, Tf
PGN
D.H2O
H
C
G
N
OH
+ H2O
TS5
F
B
HO
E
H
O
B
NHPG
Pathway 2
TS6
HO OH
B
OH
HO
TS8
PGN
H2O
B
PGHN
NHPG
NHPG
H3C
CH3
OH
B
OH
N
N
O
H
O
O
OH
TS4
B
CH3
I
TS7
N
H
H
N
N
OH
OH
A.B.E
J
K
Scheme 2. Proposed mechanisms for the PBM reaction with aldehyde A, amine B and boronic acid E used in the DFT calculations.
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10.1002/ejoc.201700089
European Journal of Organic Chemistry
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Relative energy (kcal/mol)
30
H
N
H
H
O
PGHN
TS2 (+B) PGN
O
N
H
N
26.6
24.3
25
H
H
PGHN
H
O
A.B.B
20.2
20
N
H
H
N
TS1'
17.3
15.1
16.9
13.8
15
10
5
TS1'
H
PGN
12.1
11.2
10.7
11.0 11.0
O
H
H
N
6.8
5.0
N
Ns
Ms
C.B
0.9
0.3
-1.8
-2.6
0.0
-0
-1.7
-2.2
D.H O
(+ B)
2
A.B.B
O
CO2Me
Tf
C (+ B)
H
-5
H
-5.9
-6.5
-6.9
N
-7.0
-8.0
PGN
H
N
H
PGHN
PGN
N
O
O
H
-10
-15
C.B
H
H
Ac
H
N
PGN
O
H
H
N
N
Figure 3. Energy diagrams for step 1 and 2 of pathway 1 of scheme 2 and formation of the hemiaminal C.B with the assistance of a second molecule of amine B.
These results agree with the fact that water elimination is
disfavored for the less acidic amide/carbamate substituent
(highest pKa, Figure 2) and with our experimental results
showing that the reaction was very slow in the absence of
molecular sieves (Table 2, entries 6 and 8). Therefore, the use
of MS seems to be mandatory in order to shift the equilibrium
towards the formation of iminium D.
boron atom to the nitrogen atom to form the tetra-coordinated
intermediates G (Scheme 2, Figure 4).
The reactants F can be as an aziridine form (F-Ms, F-Ns, F-Ac),
as a partially open iminium species (F-CO2Me) or fully open
iminium species (F-Tf). As noted above, for F-CO2Me the carbon
atom next to the iminium carbon is not tetrahedral (with C1-C2-N2
angle of 91.2°), C1-N2 bond length of 2.10 Å and C1-N1 bond
length of 1.31 Å. For F-Tf, the C1-C2-N2 angle is of 110° with
C1-N2 bond length of 2.44 Å and C1-N1 bond length of 1.29 Å. All
The next step was then calculated in the presence of boronic
acid E without water and consists in the coordination of the
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10.1002/ejoc.201700089
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TS4
H
O
Relative energy (kcal/mol)
27.2
HO
24.3PGN
O
B
B
N
H
PGN
OH
20.1
20
15
10
5
TS3
N
19.2 19.2
17.4
TS4-Ns
13.1
8.0
12.5
5.3
8.4
6.6
4.3
G
OH
N
0.0
0
HO
B
F
PGN
OH
H
O
-5
O
B
B
H
O
H
or PGN
PGN
-10
-15
-20
-25
-30
-35
N
N
Ns
Ms
-20.9
-25.5
HO
CO2Me
Tf
B
OH
PGN
-31.0
-32.2 -32.1
N
Ac
H
Figure 4. Energy diagrams for step 3 and 4 of pathway 1 of scheme 2 and optimized geometry of transition state TS4-Ns leading to the stereoselective vinyl
transfer.
the structures are stabilized through a hydrogen bond with the
boronic acid. In agreement with our experimental results, the
protecting group on nitrogen has a significant influence on the
coordination to boron. Indeed, for TS3 the value of the energy
barrier is the lowest for the Ns and Ms group (5.3 and 8.4
kcal.mol-1 respectively), whereas with the methylcarbamate and
acetamide derivatives, it increases to 12.5 and 17.4 kcal.mol-1
other sulfonamide derivatives (27.2 kcal.mol-1) and could explain
why the reaction was less efficient in term of yield with this
protecting group.
We also examined an alternative route for the PBM reaction
(Pathway 2, Scheme 2) in which the boronic acid E first
activates the carbonyl compound A before the nucleophilic
[41]
respectively. When the intermediates
G
are formed, the
addition of the amine B (Figure 5).
This step leads to an
intramolecular transfer of the vinyl group from the boron center
to the carbon atom of the iminium can take place via transition
states TS4 (Scheme 2, Figure 4), which provide the products H
with the anti configuration. This step is irreversible and strongly
exothermic with energy barriers between 11.2 and 15.0 kcal.mol-
1. Compared to the previous step, the energy barrier is the
smallest for the acetamide compound and the highest for the
para-nitrophenylsulfonamide derivative.
For the triflate derivative, we were not able to locate a transition
state TS3 for intermediate G formation. Only the transition state
for the vinyl transfer TS4 could be calculated and the IRC
calculation led directly to the intermediate imimium F-Tf. The
energy barrier of this step is therefore higher than that of the
adduct J with energy barriers for TS6 below 12.9 kcal.mol-1. In
the next step, the C-N bond is formed accompanied by the
departure of one hydroxyl of the tetra-coordinated borate via a
six membered ring transition state TS7. For all compounds, this
step has low energy barrier (between 6.1 and 9.0 kcal.mol-1) and
leads to the hemiaminals K.H2O. In the third step of this pathway,
the boronic acid E is eliminated through a five membered ring
transition state TS8 (Scheme 2, Figure 5). The reaction leads
from hemiaminals K to the corresponding neutral anti aziridine
F-Ns and F-Ac. In the other cases, the calculations lead to a
partially open zwitterionic iminium species F-Ms, F-Tf and F-
CO2Me similar to those obtained in pathway 1, with similar
geometries including C1-C2-N2 angles between 91.7 and 97.3°.
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10.1002/ejoc.201700089
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For TS8, the calculated energy barrier is lower for the
sulfonamide protected compounds K-Ns, K-Tf and K-Ms
(between 14.7 and 17.3 kcal.mol-1) while higher values are
obtained for carbamate K-CO2Me (25.0 kcal.mol-1) or acetamide
K-Ac (24.9 kcal.mol-1) adduct.
These data reveal that both pathways are possible, although
pathway 2 is more favorable energetically than pathway 1
(difference of 1.1 to 5.9 kcal.mol-1 for the rate-determining step).
In both pathways, the rate-determining step (rds) seems to be
the formation of the intermediate compounds F (TS2 or TS8 with
the highest activation barriers), except for the triflate derivative
for which the rds is the vinyl transfer (TS4). Also, the reaction is
less favorable with the aminoaldehydes protected as carbamate
and acetamide, in particular for the steps forming F. All of these
results are not only in agreement with the experimental data
was allowed to stand alone in CH2Cl2, in PhCF3, in a 9/1 mixture
of PhCF3/HFIP or in the presence of the boronic acid 1 in PhCF3.
In these conditions, we calculated the energy barriers TS9 for
the α-deprotonation of all the protected aldehydes A in the
presence of B forming the corresponding enol L.B (Figure 6).
The results showed that all the starting aldehydes could
racemize at room temperature, with similar barriers of energies
(between 19.9 and 21.2 kcal.mol-1). [43]
Therefore, the difference in behavior between sulfonylated
derivatives (Ms, Ns) on the one hand and the aminoaldehydes
protected as carbamate and acetamide on the other, can be
explained by the relative rate of the PBM reaction compared to
the epimerization. Indeed, the PBM reaction is favored for Ms
and Ns derivatives, with a barrier of energy of 16.9-17.3
kcal.mol-1 (TS8) in the rds of pathway 2, which is lower
compared to TS9 (20.7-21.2 kcal.mol-1). In contrast, the TS9 of
the carbamate and acetamide derivatives (20.2-20.5 kcal.mol-1)
was lower than TS8 (24.9-25.0 kcal.mol-1), which makes the
racemization more favorable than the PBM reaction. Taken
together, these data thoroughly explain the experimental results
(see also Table S1 in the ESI). The agreement is not complete
in the case of pathway 1 where the energy barrier for the rds
(TS2) of the Ms derivative is 22.8 kcal.mol-1, a value higher than
for TS9 (20.7 kcal.mol-1). Under these conditions, an important
racemization should be observed for this compound, which is
not the case experimentally making the occurrence of pathway 1
less likely.
H
HO
Relative energy (kcal/mol)
B
O
PGHN
PGHN
O
HO
H
O
N
B
15
10
5
H
TS6
TS7
N
12.9
12.4
12.4
11.7
OH
H
7.0
6.4
6.4
4.7
4.4
3.6
2.7
2.7
2.6
2.6
H
0.0
-0
-5
H
O
-1.7
A.B.E
PGN
-3.5
-3.7
O
B
H
-5.0
-5.3
-4.0
H
O
J
N
PGHN
K.H2O
HO
PGHN
O
H
B
O
B
H
N
OH
Relative energy (kcal/mol)
N
OH
O
H
Relative energy (kcal/mol)
25
H
H
TS9
B
O
OH
N
21.2
20.7
20.2
PGN
Ns
20.5
19.9
NHGP
H
O
TS8
N
H
20
15
10
5
Ns
Ms
25.0
24.9
Ms
25
H
18.2
17.0
H
CO2Me
Ac
20
A.B
17.3
16.9
CO2Me
Tf
TS9
15
14.7
Tf
10.6
10.0
HN
O
Ac
10
5
PGHN
H
0.0
0.5
HO
3.4
-0
-5
H
H
B
B
-1.2
-1.9
H
PGN
H
O
-1.4
-3.1
O
H
F
O
L.B
A.B
PG
0.0
-0
O
PGN
N
B
K
L.B
N
N
or
N
OH
Figure 6. Energy diagrams for isomerization of aldehydes A in the presence of
amine B.
Figure 5. Energy diagrams for steps 1, 2 and 3 of pathway 2 in Scheme 2.
Conclusions
obtained regarding the yield but with the epimerization as well:
the acetamide and carbamate derivatives showed low yields and
a high degree of epimerization whereas Ns and Ms compounds
showed the opposite trend, with high yields and almost no
epimerization. However, this is in apparent contradiction with the
fact that the α-tosylated amino aldehyde 7a could epimerize at
room temperature in the presence of a base and in the absence
of the boronic acid. Indeed, when 7a reacted with 30 mol-% of
diallylamine 2 for 24 h in PhCF3 at r.t., it led, after sodium
borohydride reduction, to the aminoalcool 3a in 45 % ee. On the
contrary, no racemization was noticed without base, when 7a
In summary, we demonstrated here that the borono-Mannich
reaction can be applied for producing enantioenriched 1,2-trans
diamines, starting from α-protected aminoaldehydes. The
protecting group on the nitrogen atom has a decisive influence
on both the yield and the enantiomeric purity of the
condensation products. The best results were obtained with
sulfonamide derivatives (Ns, Ts and Ms substituents at the
nitrogen). DFT calculations confirmed the experimental results
and evidenced a novel pathway for the borono-Mannich reaction
starting with the electrophilic activation of the aminoaldehydic
carbonyl group. Competition between the PBM reaction and the
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10.1002/ejoc.201700089
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racemization of the starting aldehyde[43] is responsible for low
yields and ees obtained with the aminoaldehydes protected as
carbamate and acetamide. These calculations explain well for
some of the practical details of this reaction and could be
beneficial in optimizing further the experimental conditions. This
reaction may represent a valuable methodology to design
ligands for transition metals [44] or to synthesize building blocks of
biologically active molecules. [1a,b,g]
temperature. Water (0.4 mL) was added dropwise, then 15 % aqueous
NaOH (0.8 mL) and water (0.8 mL) were added and the mixture was
stirred at 20°C for 30 min and filtered on Celite. The Celite pad was
washed with hot ethanol (5 x 50 mL) and the filtrate was concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel (AcOEt/heptane 4:6) to afford the
corresponding alcohol 3c (1.85 g, 8.06 mmol, 91 %) as white powder
(NMR data consistent with those reported in the literature [46 ]). The
General Procedure (A) was followed using the alcohol 3c (217 mg, 0.94
mmol), TEMPO (7 mg, 0.047 mmol), KBr (113 mg, 0.94 mmol), NaOCl
(2.8 mL, 0.5M, 1.4 mmol) and saturated aqueous NaHCO3 (6 mL) in
CH2Cl2 (12 mL). The crude α-amino aldehyde 7c (145 mg, 0.63 mmol,
67 %) was obtained as a pale yellow solid and was used without
purification in the next step. 1H NMR (300 MHz, CDCl3) δ 9.73 (s, 1H,
CHO), 7.48-7.08 (m, 5H, HAr), 4.99-4.79 (m, 1H, NH), 4.48-4.35 (m, 1H,
CHNH), 3.24 (dd, J = 6.0, 14.0 Hz, 1H, CH2Ph), 3.04 (dd, J = 7.5, 14.0
Hz, 1H, CH2Ph), 2.70 (s, 3H, SO2CH3).
Experimental Details
General
Reactions were monitored with analytical thin-layer chromatography
(TLC) on silica gel 60 F254 plates and visualized under UV (254 nm)
and/or by staining with KMnO4. Silica gel SDS 60 ACC 35-70 mm was
used for column chromatography. Preparative TLC was done using
Merck 60 F254 0.5 mm. NMR spectra were recorded with AM 300,
AVANCE 300 and AVANCE 500 Brüker spectrometers. Chemical shifts
are given in parts per million, referenced to the solvent peak of CDCl3,
defined at 77.23 ppm (13C NMR) and 7.26 ppm (1H NMR). Microwave
reactions were carried out with an Anton Paar Monowave 300 instrument.
Melting points (uncorrected) were determined with the aid of a Büchi B-
540 apparatus. IR spectra were recorded on a Perkin-Elmer Spectrum
BX instrument with an FT-IR system. Optical rotations were measured on
an Anton Paar MCP300 polarimeter using a cell of 1 dm-length path. All
the reagent grade chemicals obtained from commercial sources were
used as received excepted for (E)-phenyl vinyl boronic acid 1, which was
purchased from the Aldrich Chemical Company. It was diluted with Et2O,
the ethereal phase was washed with water and dried with Na2SO4. After
evaporation of the solvent, the solid was washed with pentane. For the
oxidation reaction with TEMPO, CH2Cl2 stabilized with ethanol was used.
Synthesis
of
(S)-2,4-dinitro-N-(1-oxo-3-phenylpropan-2-
yl)benzenesulfonamide 7d. (S)-To a solution of phenylalaninol (350 mg,
2.3 mmol, 1 equiv) in dry THF (4.5 mL), Na2CO3 (0.49 g, 4.6 mmol, 2
equiv) and a solution of 2,4-dinitrobenzenesulfonyl chloride (0.61 g, 2.3
mmol, 1 equiv) in dry THF (3 mL) were added at 0-5 °C. The reaction
mixture was stirred at 0 °C for 4 hours before being acidified by dropwise
addition of acetic acid (0.6 mL) in dry THF (1.5 mL). The solvent was
evaporated, the residue was distributed between MTBE (15 mL) and
water (5 mL), the combined organic layers were washed with NaHCO3
(10 mL), brine (10 mL), and dried over Na2SO4. Concentration of the
solvent led to precipitation of pure 3d, which was collected by filtration
(378 mg, 43 %). (NMR data consistent with those reported in the
literature [31]). The General Procedure (A) was followed using the alcohol
3d (184 mg, 0.48 mmol), TEMPO (4 mg, 0.024 mmol), KBr (57 mg, 0.48
mmol), NaOCl (2 mL, 0.5M, 0.96 mmol) and saturated aqueous NaHCO3
(5 mL) in CH2Cl2 (10 mL). The crude α-amino aldehyde 7d (181 mg, 0.48
mmol, 99 %) was obtained as a pale yellow solid and was used without
purification in the next step. 1H NMR (300 MHz, CDCl3) δ 9.68 (s, 1H,
CHO), 8.64 (d, J = 2.0 Hz, 1H, HAr), 8.44 (dd, J = 2.0 and 8.5 Hz, 1H, HAr),
8.09 (d, J = 8.5 Hz, 1H, HAr), 7.22-7.06 (m, 5H, HAr), 6.12-6.00 (m, 1H,
NH), 4.50-4.34 (m, 1H, CHNH), 3.27 (dd, J = 5.5 and 14.0 Hz, 1H,
CH2Ph), 2.99 (dd, J = 8.5, 14.0 Hz, 1H, CH2Ph).
Synthesis of the α-aminoaldehydes
General Procedure (A) for the oxidation to α-amino aldehyde.To a
stirred solution of alcohol (1.0 equiv) in CH2Cl2 (0.035 m, V mL) at -5 °C
was added saturated aqueous NaHCO3 (0.5 x V CH2Cl2 mL), KBr (1.0
equiv) and TEMPO (0.05 equiv). NaOCl (0.5 m, 2.0 equiv) was then
added with a syringe pump over 30 min. Saturated aqueous Na2S2O3 (V
Na2S2O3 = V NaHCO3) was added, the phases were separated and the
aqueous layer was extracted with CH2Cl2 (3 x). The combined organic
layers were dried over Na2SO4, filtered and concentrated under reduced
pressure to afford the corresponding crude α-amino aldehyde, which was
used directly in the next step.
Synthesis
of
(S)-1,1,1-trifluoro-N-(1-hydroxy-3-phenylpropan-2-
yl)methanesulfonamide 3g. To a solution of L-phenylalanine methyl
ester hydrochloride (0.9 g, 4.2 mmol, 1 equiv) in dichloromethane (20
mL) was added triethylamine (2.3 mL, 16.7 mmol, 4.0 equiv) at -78 °C
under nitrogen. After stirring for 5 min at -78 °C, trifluoromethanesulfonic
anhydride (0.5 mL, 3.1 mmol, 0.75 equiv) was added dropwise and then
the mixture was stirred for 12 h at that temperature before being
quenched by ice water (20 mL). The organic layer was separated and the
aqueous layer was extracted with dichloromethane (2 x 20 mL). The
combined organic phase was washed with brine (15 mL), and then dried
over Na2SO4. Evaporation and column chromatography on silica gel
(heptane/ethyl acetate : 8/2 to 5/5) afforded corresponding
trifluoromethanesulfonamide ester as yellow pale oil (1g, 77 %). (NMR
data consistent with those reported in the literature [47]). To a stirred
solution of the ester (440 mg, 1.41 mmol, 1 eq) in dry THF (14 mL) at 0°C
under argon atmosphere was added LiAlH4 (161 mg, 4.23 mmol, 3 eq).
The resulting mixture was stirred for 3 h at room temperature. Water (0.1
mL) was added dropwise, then 15 % aqueous NaOH (0.2 mL) and water
(0.1 mL) were added and the mixture was stirred at 20°C for 30 min and
filtered on Celite. The Celite pad was washed with hot ethanol (5 x 15
mL) and the filtrate was concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (heptane/ethyl
acetate : 8/2 to 5/5) to afford the corresponding alcohol 3g (304 mg,
Synthesis
of
N-[(2S)-1-oxo-3-phenylpropan-2-
yl]methanesulfonamide 7c. To a stirred solution of L-phenylalanine
methyl ester hydrochloride (2.0 g, 9.27 mmol, 1.0 equiv) in dry CH2Cl2
(50 mL) under argon atmosphere at 0 °C was added Na2CO3 (2.95 g,
27.8 mmol, 3.0 equiv) then methanesulfonyl chloride (0.93 mL, 12.1
mmol, 1.3 equiv). The resulting mixture was stirred for 12 h allowing the
temperature to raise 20°C then filtered. The filtrate was concentrated
under reduced pressure and the residue was purified by flash
chromatography on silica gel (AcOEt/heptane 3:7) to afford product the
corresponding ester (2.3 g, 8.94 mmol, 96 %) as a white powder (NMR
data consistent with those reported in the literature [45]). To a stirred
solution of the ester (2.28 g, 8.86 mmol, 1.0 equiv) in dry THF (85 mL) at
0°C under argon atmosphere was added portionwise LiAlH4 (673 mg,
17.7 mmol, 2.0 equiv). The resulting mixture was stirred for 2 h at room
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10.1002/ejoc.201700089
European Journal of Organic Chemistry
FULL PAPER
76 %) as a yellow powder. [α]D25 −40.9 (c 0.8, EtOH). IR 3386, 3114,
2922, 1488, 1368, 1231, 1180, 1035 cm-1.1H NMR (300 MHz, CDCl3) δ
7.31-7.09 (m, 5H, HAr), 5.39 (d, J = 9.0 Hz, 1H, NH), 3.83-3.68 (m, 1H,
CHNH), 3.63 (dd, J = 11.0 and 3.5 Hz, 1H, CH2OH), 3.55 (dd, J = 11.0
and 3.5 Hz, 1H, CH2OH), 2.95-2.88 (m, 2H, CH2Ph). 13C NMR (75 MHz,
CDCl3) δ 136.0 (CqAr), 129.4 (CAr), 129.3 (CAr), 128.9 (CAr), 127.3 (CAr),
121.6 (CqAr), 117.3 (CF3), 62.8 (CH2OH), 57.8 (CHNH), 38.3 (CH2Ph).
ESIHRMS m/z = 282.0399 [M-H]+. C10H11F3NO3S requires 282.0412.
boronic acid (1.0 equiv), PhCF3 ([boronic acid] = 0,15M) and amine (1.25
equiv). The resultant mixture was stirred for 48 h at room temperature.
Solvent was removed under reduced pressure and the residue was
purified by preparative TLC to afford corresponding amine.
Synthesis of N-((2S,3R,E)-3-(diallylamino)-1,5-diphenylpent-4-en-2-
yl)methanesulfonamide 13 . The General Procedure (B) was followed
using α-amino aldehyde 7c (60 mg, 0.26 mmol) diallylamine 2 (31 µL,
0.25 mmol), boronic acid 1 (30 mg, 0.20 mmol) and molecular sieve 4Å
(120 mg) in PhCF3 (1.3 mL). After purification by preparative TLC
(AcOEt/Heptane 3:7), 13 (52 mg, 0.127 mmol, 62 %) was obtained as a
yellow oil, ee = 93 % determined by chiral HPLC (Chiralpak IC column,
eluent: heptane+0.1 % Et3N/ethanol+ 0.1 % Et3N 90:10, rate = 1.0
mL/min, 254 nm, tminor = 12.56 min, tmajor = 6.23 min). [α]D25 + 0.7 (c 0.6,
CHCl3). IR 3262, 2977, 1303, 1148, 1077 cm-1. 1H NMR (300 MHz,
CDCl3) δ 7.42-7.22 (m, 10H, HAr), 6.43 (d, J = 16.0 Hz, 1H, PhCH=CH),
6.26 (dd, J= 10.0 and 16.0 Hz, 1H, PhCH=CH), 5.90-5.82 (m, 2H), 5.28-
5.14 (m, 4H, CH=CH2), 5.90-5.82 (m, 1H, CH=CH2), 4.56-4.24 (bs, 1H,
NH), 3.87-6.73 (m, 1H; CHNH), 3.45 (ddt, J = 14.5, 5.0 and 1.5 Hz, 2H,
NCH2), 3.39 (dd, J = 14.0 and 4.0 Hz, 1H, CH2Ph), 3.27 (dd, J = 9.5 and
8.5 Hz, 1H, CHNAll2), 3.00 (dd, J= 14.5 and 7.5 Hz, 2H, NCH2), 2.59 (dd,
J= 14.0 and 9.5 Hz, 1H, CH2Ph), 2.23 (s, 3H, CH3). 13C NMR (75 MHz,
CDCl3) δ 138.8 (CqAr), 136.6 (CqAr), 136.3 (CH=CH2), 135.6 (PhCH=CH),
129.9 (CAr), 128.7 (CAr), 128.6 (CAr), 127.8 (CAr), 126.7 (CAr), 126.5 (CAr),
125.1 (PhCH=CH), 117.4 (CH=CH2), 66.2 (CHNAll2), 58.6 (CHNH), 53.8
(NCH2), 41.6 (CH3), 39.3 (CH2Ph). ESIHRMS m/z = 411.2108 [M+H]+.
C24H31N2O2S requires 411.2106.
Synthesis
of
(S)-1,1,1-trifluoro-N-(1-oxo-3-phenylpropan-2-
yl)methanesulfonamide 7g. The Dess–Martin periodinane (240 mg,
0.59 mmol, 2.1 equiv.) was added to a solution of 3g (80 mg, 0.282 mmol,
1 equiv.) in water-saturated dichloromethane (1.6 mL). The resulting
suspension was stirred at r.t. for 2 h. The reaction mixture was filtrated,
diluted with ether (10mL), and a solution of sodium thiosulfate/NaHCO3
(1:1, 10 mL) was added. The layers were separated and the aqueous
layer was extracted with ether (20 mL). The combined organic layers
were washed sequentially with saturated aqueous sodium bicarbonate
solution (15 mL), water (2 x15 mL), and brine (2x15 mL), then dried over
sodium sulfate. The crude α-amino aldehyde 7g (72 mg, 0.59 mmol,
99 %) was obtained as a pale yellow solid and was used without
purification in the next step. 1H NMR (300 MHz, CDCl3) δ 9.65 (s, 1H,
CHO), 7.53-7.10 (m, 5H, HAr), 5.69-5.43 (m, 1H, NH), 4.67-4.46 (m, 1H,
CHNH), 3.33 (dd, J =14.5 and 5.5 Hz, 1H, CH2Ph), 2.98 (dd, J =14.5 and
7.5 Hz, 1H, CH2Ph).
Synthesis
of
4-methyl-N-[(2S)-3-methyl-1-oxobutan-2-
yl]benzenesulfonamide 8a. To a stirred solution of L-valine methyl
ester hydrochloride (690 mg, 4.12 mmol, 1.0 equiv) in dry CH2Cl2 (10 mL)
under argon atmosphere at 0 °C was added triethylamine (1.3 mL, 9.06
mmol, 2.2 equiv) then para-toluenesulfonyl chloride (864 mg, 4.53 mmol,
1.1 equiv). The resulting mixture was stirred for 12 h allowing the
temperature to raise 20°C. Solvent was then removed under reduced
pressure and the residue was diluted with AcOEt (10 mL). The organic
phase was washed with saturated aqueous NaHCO3 (10 mL), dried over
Na2SO4, filtered and concentrated under reduced pressure to afford the
clean ester (1.22 g, 4.12 mmol, 99 %) as a white powder (NMR data
consistent with those reported in the literature [48]). To a stirred solution of
the methyl ester (1.2 g, 4.20 mmol, 1 equiv.) in dry THF (40 mL) at 0°C
under argon atmosphere was added LiAlH4 ((320 mg, 8.41 mmol, 2 eq).
The resulting mixture was stirred for 3 h at room temperature. Water (0.2
mL) was added dropwise, then 15 % aqueous NaOH (0.4 mL) and water
(0.2 mL) were added and the mixture was stirred at 20°C for 30 min and
filtered on Celite. The Celite pad was washed with hot ethanol (5 x 20
mL) and the filtrate was concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (heptane/ethyl
acetate 3:7 to 4:6) to afford the corresponding alcohol 4a (1.04 g, 4.04
mmol, 96 %) as a white powder powder (NMR data consistent with those
reported in the literature [ 49 ]). The General Procedure (A) was then
followed using the alcohol 4a (250 mg, 0.971 mmol), TEMPO (8 mg,
0.049 mmol), KBr (116 mg, 0.971 mmol), NaOCl (4 mL, 0.5M, 2 mmol)
and saturated aqueous NaHCO3 (10 mL) in CH2Cl2 (20 mL). The crude
α-amino aldehyde 8a (230 mg, 0.90 mmol, 93 %) was obtained as a pale
yellow solid and was used without purification in the next step. 1H NMR
(300 MHz, CDCl3) δ 9.46 (s, 1H, CHO), 7.77 (d, J = 8.0 Hz, 2H, HAr),
7.35-7.25 (m, 3H, HAr), 5.27 (d, J =7.5 Hz, 1H, NH), 3.83 (dd, J =7.5 and
4.0 Hz, 1H, CHNH), 2.43 (s, 3H, CH3), 2.34-2.17 (m, 1H, CHi-Pr), 1.04 (d,
J =7.0 Hz, 3H, CH3), 0.92 (d, J =7.0 Hz, 3H, CH3).
Synthesis of N-((2S,3R,E)-3-(diallylamino)-1,5-diphenylpent-4-en-2-
yl)-2,4-dinitrobenzenesulfonamide 14. The General Procedure (B) was
followed using 7d (60 mg, 0.158 mmol), diallylamine 2 (19 µL, 0.152
mmol), boronic acid 1 (19 mg, 0.122 mmol) and molecular sieve 4Å (100
mg) in PhCF3 (0.8 mL). After purification by preparative TLC
(AcOEt/Heptane 2:8), 14 (35 mg, 0.062 mmol, 51 %) was obtained as a
yellow solid, ee = 94 % determined by chiral HPLC (Chiralpak IC column,
eluent: heptane+0.1 % Et3N/ethanol+ 0.1 % Et3N 95:5, rate = 1.0 mL/min,
254 nm, tminor = 16.65 min, tmajor = 18.75 min). [α]D25 -2.7 (c 0.3, CHCl3).
IR 3334, 3098, 2921, 1535, 1340, 1165, 976 cm-1.1H NMR (300 MHz,
CDCl3) δ 8.17-8.10 (m, 1H, HAr), 7.85 (d, (d, J = 9.0 Hz, 1H, HAr), 7.26-
7.04 (m, 11H, HAr), 6.29 (d, J = 16.0 Hz, 1H, PhCH=CH), 5.95-5.76 (m,
3H, PhCH=CH, CH=CH2), 5.30-5.16 (m, 4H, CH=CH2), 4.09-3.97 (m, 1H,
CHNH), 3.52 (dd, J = 14.0, 3.0 Hz, 1H, CH2Ph), 3.43 (td, J = 14.0 and 2.0
Hz, 2H, NCH2), 3.22 (t, J = 10.0 Hz, 1H, CHNAll2), 2.94 (dd, J = 14.0 and
8.0 Hz, 2H, NCH2), 2.68 (dd, J = 14.0 and 8 Hz, 1H, CH2Ph). 13C NMR
(75 MHz, CDCl3) δ 137.6 (CqAr), 136.1 (CH=CH2), 136.0 (PhCH=CH),
130.7 (CAr), 129.8 (CAr), 128.5 (CAr), 128.3 (CAr), 127.1 (CAr), 126.6 (CAr),
126.2 (CAr), 124.5 (PhCH=CH), 120.4 (CAr), 117.6 (CH=CH2), 66.1
(CHNAll2), 59.9 (CHNH), 53.6 (NCH2), 39.4 (CH2Ph). ESIHRMS m/z =
563.1963 [M+H]+. C29H31N4O6S requires 563.1964.
Synthesis of N-((2S,3R,E)-3-(diallylamino)-1,5-diphenylpent-4-en-2-
yl)-1,1,1-trifluoromethanesulfonamide 17. The General Procedure (B)
was followed using α-amino aldehyde 7g (80 mg, 0.284 mmol)
diallylamine 2 (34 µL, 0.27 mmol), boronic acid 1 (32 mg, 0.22 mmol) and
molecular sieve 4Å (300 mg) in PhCF3 (1.5 mL). After purification by
preparative TLC (AcOEt/Heptane 2:8), the diamine 17 (35 mg, 0.075
mmol, 41 %) was obtained as a yellow solid, ee = 96 % determined by
chiral HPLC (Chiralpak IB column, eluent: heptane+0.1 % Et3N/ethanol+
0.1 % Et3N 98:2, rate = 1.0 mL/min, 254 nm, tminor = 5.38 min, tmajor = 6.54
min). [α]D25 +46.6 (c 0.5, CHCl3). IR 3311, 2979, 2925, 2818, 1708,
1373, 1225, 1143 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.46-7.18 (m, 10H,
HAr), 6.41 (d, J = 15.5 Hz, 1H, PhCH=CH), 6.16 (dd, J = 15.5 and 10.0 Hz,
1H, PhCH=CH), 5.99-5.76 (m, 2H, CH=CH2), 5.32-5.13 (m, 4H, CH=CH2),
3.99-3.87 (m, 1H, CHNH), 3.35 (dd, J =14.5 and 4.5 Hz, 2H, NCH2), 3.21
Petasis reaction
General Procedure (B) for the Petasis reaction.To a stirred solution of
crude α-amino aldehyde (1.3 equiv) was added sequentially freshly
activated molecular sieves 4Å (mass = 1.5-2 x mass of all the reactants),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700089
European Journal of Organic Chemistry
FULL PAPER
(t, J = 9.0 Hz, 1H, CHNAll2), 3.13-3.00 (m, 2H, CH2Ph), 2.94 (dd, J =14.5
and 8.0 Hz, 2H, NCH2). 13C NMR (75 MHz, CDCl3) δ 136.7 (PhCH=CH),
135.5 (CH=CH2), 130.0 (CAr), 128.7 (CAr), 128.6 (CAr), 128.1 (CAr), 127.0
(CAr), 126.5 (CAr), 123.3 (PhCH=CH), 118.2 (CH=CH2), 65.5 (CHNAll2),
58.6 (CHNH), 53.9 (NCH2), 37.8 (CH2Ph). ESIHRMS m/z = 465.1825
[M+H]+. C24H28F3N2O2S requires 465.1824.
effects were introduced using single-point PCM calculations on gas-
phase optimized geometries at the B3LYP/6-311++G(d,p) level in 1,2-
dichloroethane (ε = 10.13), which is supported by the program and has a
[ 51 ]
dielectric constant similar to that of trifluorotoluene (ε = 9.18).
CACTVS Chemoinformatics Toolkit (http://www.xemistry.com/) was used
for generating the PDF3D representations of structures included in this
study.
Synthesis of N-((2S,3R,E)-3-(allyl(benzyl)amino)-1,5-diphenylpent-4-
en-2-yl)-4-methylbenzenesulfonamide 29. The General Procedure (B)
was followed using α-amino aldehyde 7a (67 mg, 0.22 mmol) amine 25
(33 µL, 0.13 mmol), boronic acid 1 (25 mg, 0.17 mmol) and molecular
sieve 4Å (200 mg) in PhCF3 (1.05 mL). After purification by preparative
TLC (AcOEt/Heptane 25:75), 29 (51 mg, 0.042 mmol, 39 %) was
obtained as an yellow oil, ee = 91 % determined by chiral HPLC
(Chiralpak IC column, eluent: heptane+0.1 % Et3N/ethanol+ 0.1 % Et3N
97:3, rate = 1.0 mL/min, 254 nm, tminor = 15.09 min, tmajor = 18.13 min).
[α]D25 −34.3 (c 0.8, CHCl3). IR 3277, 2923, 1736, 1494, 1452, 1330,
1154, 1091 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J= 8.0 Hz, 2H,
HAr), 7.29-7.04 (m, 13H, HAr), 6.96 (d, J= 8.0 Hz, 2H, HAr), 6.90 (dd, J=
6.0 and 3.5 Hz, 2H, HAr), 6.21 (d, J = 16.0 Hz, 1H, PhCH=CH), 5.83 (dd,
J = 16.0 and 10.0 Hz, 1H, PhCH=CH), 5.78-5.62 (m, 2H, CH=CH2), 5.07-
4.97 (m, 4H, CH=CH2), 4.35 (d, J = 7.5 Hz, 1H, NH), 3.81-3.68 (m, 2H,
CH2Ph), 3.28 (d, J = 14.0 Hz, 1H, CH2Ph), 3.16 (dd, J = 14.5 and 5.5 Hz,
1H, NCH2), 3.04 (dd, J = 9.5 and 8.5 Hz, 2H, CHNAll2), 2.97-2.80 (m, 3H,
CH2Ph), 2.27 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3) δ 142.9 (CqAr),
139.4 (CqAr), 138.0 (CqAr), 137.1 (CqAr), 136.4 (CqAr), 136.0, 135.7
(CH=CH2, PhCH=CH), 130.1 (CAr), 129.5 (CAr), 128.9 (CAr), 128.5 (CAr),
128.0 (CAr), 127.8 (CAr), 127.0 (CAr), 126.9 (CAr), 126.3 (CAr), 125.0
(PhCH=CH), 117.7 (CH=CH2), 64.8 (CHNAll2), 56.0 (CHNH), 54.5
(NCH2), 53.6 (NCH2Ph), 37.9 (CH2Ph). ESIHRMS m/z = 537.2568
[M+H]+. C34H37N2O2S requires 537.2576.
Electronic supplementary information (ESI): HPLC, 1H and 13C NMR
spectra for novel compounds, theoretical data for all the structures
involved in the reaction mechanism and PDF3D representations of all
structures.
Acknowledgements
We thank the ICSN-CNRS for
a PhD grant (A.C.), the
CHARMMMAT Labex program (ANR-11-LABX-39) for financial
support for this study (M.B.), the LERMIT Labex program (ANR-
10-LABX-33, B.I.I.) and the Institut Universitaire de France (IUF).
Keywords: Boron chemistry * diamines * amino-aldehydes *
Petasis reaction * DFT calculations
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1323, 1156, 1093 cm-1. 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J= 8.0 Hz,
2H), 7.26-7.04 (m, 5H, HAr), 6.93 (d, J= 8.0 Hz, 2H, HAr), 6.15 (d, J= 16.0
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10.0 Hz, 1H, PhCH=CH), 5.10-4.99 (m, 4H, CH=CH2), 4.06 (d, J= 9.5 Hz,
1H, NH), 3.43 (t, J = 9.5 Hz, 1H, CHNH), 3.19 (ddt, J = 14.0, 4.0 and 1.5
Hz, 2H, NCH2), 3.04 (t, J= 9.5 Hz, 1H, CHNAll2), 2.67 (dd, J= 14.0 and
8.5 Hz, 2H, NCH2), 2.35-2.24 (m, 1H, CH(CH3)2), 2.21 (s, 3H, PhCH3),
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136.6 (CqAr), 135.3 (PhCH=CH), 129.4 (CAr), 128.4 (CAr), 127.5 (CAr),
126.8 (CAr), 126.6 (CAr), 125.5 (PhCH=CH), 117.2 (CH=CH2), 63.8
(CHNAll2), 60.2 (CHNH), 53.2 (NCH2), 27.8 (CH(CH3)2), 21.5 (PhCH3),
20.6 (CH(CH3)2), 15.3 (CH(CH3)2). ESIHRMS m/z = 439.2417 [M+H]+.
C26H35N2O2S requires 439.2419.
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700089
European Journal of Organic Chemistry
FULL PAPER
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10.1002/ejoc.201700089
European Journal of Organic Chemistry
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10.1002/ejoc.201700089
European Journal of Organic Chemistry
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Diamine Synthesis
N-Nosylated α-amino aldehydes
generate diastereoselectively 1,2-
trans-diamines with an enantiomeric
excess of up to 98 % using the
Petasis borono-Mannich three-
component condensation.
Stéphanie Norsikian,* Margaux Beretta,
Alexandre Cannillo, Marie Auvray,
Amélie Martin, Pascal Retailleau,
Bogdan I. Iorga and Jean-Marie Beau*
Page No. – Page No.
Stereoselective Synthesis of 1,2-
trans-Diamines using the Three-
Component Borono-Mannich
Condensation: Reaction Scope and
Mechanistic Insights.
This article is protected by copyright. All rights reserved.