Direct Amination of Isohexides via Borrowing Hydrogen Methodology: Regio- and Stereoselective Issues

Article abstract of DOI:10.1002/ejoc.201901661

The regio and diastereoselective direct mono or diamination of bio-based isohexides (isosorbide and isomannide) has been developed through borrowing hydrogen (BH) methodology using a cooperative catalysis between an iridium complex and a Br?nsted acid. The access to chiral amino-alcohol (NH₂-OH) and diamine (NH₂-NH₂), interesting optically pure bio-based monomers, was also proposed using BH strategy as a sustainable route for their obtention.

Full text of DOI:10.1002/ejoc.201901661

A Journal of
Accepted Article
Title: Direct amination of isohexides via borrowing hydrogen
methodology: regio- and stereoselective issues
Authors: Florian Bahé, Lucie Grand, Elise Cartier, Maiwenn Jacolot,
Sylvie Moebs-Sanchez, Daniel Portinha, Etienne Fleury, and
Florence Popowycz
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901661
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10.1002/ejoc.201901661
European Journal of Organic Chemistry
FULL PAPER
Direct amination of isohexides via borrowing hydrogen
methodology: regio- and stereoselective issues
Florian Bahé,[a][b] Lucie Grand,[a] Elise Cartier,[a] Maïwenn Jacolot,*[a] Sylvie Moebs-Sanchez,[a] Daniel
Portinha,[b] Etienne Fleury[b] and Florence Popowycz*[a]
Abstract: The regio and diastereoselective direct mono or diamination of bio-based isohexides (isosorbide and isomannide) has been
developed through borrowing hydrogen (BH) methodology using a cooperative catalysis between an iridium complex and a Brønsted
acid. The access to chiral amino-alcohol (NH2-OH) and diamine (NH2-NH2), interesting optically pure bio-based monomers, was also
proposed using BH strategy as a sustainable route for their obtention.
Introduction
Having a survey of the literature, a large number of applications
Isosorbide 1 is a major product of the starch industry,1 produced
by Roquette at a twenty thousand tons per year (Figure 1).
Belonging to the same isohexide family, isomannide 2 can also
be produced, but to a less extent from renewable resources such
as starch and cellulose.2 In a context of the advent of sustainable
chemistry, guided by economical and energetic goals, the
development of biorefinery has emerged and a robust bio-based
industry can, from now, supply these bio-based platforms in a
satisfying tonnage. Since then, the valorization of isohexides as
chiral diols industrially produced form renewable resources has
been exploited in a wide range of applications (pharmaceuticals,
materials, surfactants, solvents).3 In the polymer field, the rigid
skeleton of isosorbide contributed to enhance the glass transition
temperature of the materials.4
could also be easily found for the corresponding mono and
diamino congeners for the synthesis of polyamines5 and
polyurethanes6 or as ligands and organocatalysts in the field of
asymmetric induction7 for the molecular design of fine chemicals.
The promotions of the amino-derivatives can be exploited from
isosorbide and isomannide that are commercially available, using
classical methodologies. Their synthetic process was described
using a two or three-step sequence: activation of the alcohol,
substitution with inversion of the configuration and final
hydrogenolysis to release the corresponding primary amine.8
Although effective, this strategy has a low atom efficiency and
generates high amount of waste. The advent of green chemistry
has promoted innovative methodologies such as borrowing
hydrogen (BH) transformations.
A first step of catalytic
dehydrogenation converts an unreactive alcohol into the
corresponding carbonyl compound. Subsequent reaction with an
amine leads to the imine in situ, which upon hydrogenation affords
the desired product and water as sole by-product.9
Recently we have been interested to use this methodology to
functionalize bio-based alcohols of interest in a more direct way,
with a step economy, allowing also a lean in terms of procedure,
time and waste (Scheme 1). In 2018, our group reported the
direct amination of monobenzylated isohexides through a
borrowing hydrogen methodology using a cooperative catalysis
between an iridium catalyst and a Brønsted acid.10 The amination
Figure 1 structure of isohexides
[a]
F. Bahé, L. Grand, E. Cartier, Dr. M. Jacolot, Dr. S. Moebs-Sanchez,
Prof. F. Popowycz
Univ Lyon, INSA Lyon, Université Lyon 1, CNRS, CPE Lyon, UMR
5246, ICBMS
could
be
achieved
with
good
yields
and
high
diastereoselectivities using various primary amines. We also
highlighted the better reactivity of the hydroxyl group in endo
position allowing the direct transformation of isosorbide into a
chiral amino-alcohol. This selectivity, in accordance with the DFT
calculations reported by Kroutil et al., can be explained by the
higher energy required to oxidize the alcohol in exo position due
to the higher steric hindrance of the hydride to be removed.11
1 rue Victor Grignard, F-69621 Villeurbanne Cedex
E-mail: Florence.popowycz@insa-lyon.fr, maiwenn.jacolot@insa-lyon.fr
Homepage: http://www.icbms.fr/cob
F. Bahé, Dr. D. Portinha, Prof. E. Fleury
Univ Lyon, INSA Lyon, Ingénierie des Matériaux Polymères, IMP-UMR
CNRS 5223
[b]
F 69621, Villeurbanne, France
Supporting information for this article is given via a link at the end of the
document
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10.1002/ejoc.201901661
European Journal of Organic Chemistry
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Scheme 1 Strategies for the direct amination of isohexide derivatives
breakthrough lays on finding the appropriate combination in the
reaction conditions to secure an optimal conversion with excellent
regio- and diastereoselectivities. Considering the borrowing
hydrogen mechanism, the expected by-products during the
monitoring reaction have been identified as following: the diamine
4a raising from the over-reaction (double amination), the
monoamine 5a and epimerized isohexides (isomannide 2 and
isoidide 6) (Table 1).13
Taking advantage of our previous studies on the
diastereoselective amination of the exo-monobenzylated
isosorbide, we started investigations with (S, S)-[Ir] (5 mol%),
diphenylphosphate (5 mol%) in anhydrous toluene at 120 °C
during 24 hours in the presence of 3Å molecular sieves (entry 1)
in a sealed tube. The conversion of isosorbide reached 98% and
the expected amino-alcohol 3a was formed with an excellent
diastereoselectivity and a selectivity of 84%. Diamine 4a, amino-
alcohol 5a and isoidide 6 were observed respectively in 3, 5 and
8%. Interestingly, switching from diphenylphosphate to boric acid
provided the same result both in terms of conversion and
selectivity (entry 2). In order to promote the formation of the
amino-alcohol 3a, we increased the loading of phosphoric acid to
10 and 40 mol% but it was detrimental to the conversion (entries
3 and 4). Increasing the loading of catalyst to 7.5 mol% led to a
full conversion of isosorbide but to a lower selectivity: 15% of
diaminated product 4a was formed (entry 5). In order to prevent
the oxidation of the exo-hydroxyl group, reaction was performed
at a lower temperature of 100 °C (entry 6). Gratifyingly, 3a was
obtained with an excellent selectivity of 93% and a good isolated
yield of 71%. Decreasing the catalyst loading to 5 mol% led to a
lower yield of 60% (entry 7). Other conditions were screened such
as changing the solvent to greener cyclopentylmethylether
(CPME), switching to an achiral iridacycle complex, or using
microwave activation without significant improvement. The overall
conditions tested are reported in the supporting information. As,
the nature of the configuration of the ligand has poor influence
both on the conversion and diastereoselectivity of the reaction,
the (S,S)-iridium catalyst was selected for the rest of the study
with a 7.5 mol% loading.
The sole example reported in our previous publication used
hexylamine affording the corresponding amino-alcohol in 65%
isolated yield. Encouraged by this preliminary result, we
envisioned to explore the direct and regioselective amination of
isosorbide using the borrowing hydrogen (BH) methodology. A
second aspect of our contribution was devoted to the direct
diamination of isomannide where both hydroxyl groups in endo
position could react leading to diamino-derivatives. Finally, the
access to chiral amino-alcohols (HO/NH2) and diamines
(NH2/NH2) was proposed using the BH principle, which represents
a sustainable route for their obtention as an alternative to the
standard procedures already reported in literature.
Results and Discussion
We first envisioned the direct and regioselective amination of
isosorbide with benzylamine as a model substrate for optimization
and evaluation of the region- and diastereoselective issues.
Although, the oxidation of the endo position is favored, Beller et
al. have also shown that diamination of isosorbide could be
achieved with ammonia using a ruthenium catalyst under high
temperature leading to 96% yield of a mixture of the three
diastereomers related to the C3/C6 positions.12 The challenging
Table 1. Optimization towards the regioselective amination of isosorbide with benzylamine
Entry
T (°C)
Solvent
Cat (mol %)
Acid (mol %)
Conva (%)
Ratioa 3a:4a:5a:6
Yieldb 3a
1
2
3
4
5
6
7
120
120
120
120
120
100
100
toluene
toluene
toluene
toluene
toluene
toluene
toluene
5
5
5
5c
98
98
84:3:5:8
82:7:8:3
66:8:26:0
90:10:0:0
80:15:3:2
93:3:2:2
78:4:9:9
52%
62%
nd
5
10
40
7.5
7.5
5
84
5
48
nd
7.5
7.5
5
> 99
97
64%
71%
60%
93
Reaction conditions: 1 (1 eq.), benzylamine (1 eq.), (S,S)-[Ir], diphenylphosphate, solvent [2M], 24 h. a) conversion and ratio were determined by 1H NMR b) isolated yields c) B(OH)3 was used. nd : not determined
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10.1002/ejoc.201901661
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Scheme 2. Scope of the regioselective amination of isosorbide
With optimized conditions in hand (7.5 mol% of both
organometallic and acidic catalysts in toluene in the presence of
3Å molecular sieves during 24 h), the scope of the reaction was
studied using various substituted benzylamines and aliphatic
amines (Scheme 2). As noticed previously, the temperature has
a strong influence on both the conversion and the selectivity.
Thus, when reactions were performed at 100 °C with substituted
benzylamines with methoxy group in para and meta position, a
significant drop of the conversion was monitored: respectively 63
and 50 %. At 120 °C, despite full conversions, selectivities
decreased to 70% due to the formation of epimerized isoidide and
diaminated isohexide. Thus, reactions were conducted at 110 °C
(86 to 90 % conversion and 93 to 95% selectivity) affording the
isolated compounds 3b-3c respectively in 54% and 59% yield. No
conversion was observed with ortho-methoxybenzylamine, which
could be explained by the formation of an intramolecular
Hydrogen bond between the methoxy and the amino groups
leading to a loss of reactivity of the amine. The nature of halide
substituent did not bring significant impacts in terms of yields,
neither the methyl substituent. A similar reactivity was observe d
for para- and ortho- substituted methylbenzylamine affording the
corresponding amine 3g and 3h respectively in 64 and 55%
yields. But, surprisingly, when ortho-fluorobenzylamine was
subjected to the reaction, a drop of conversion was observed
compared with para-fluorobenzylamine and the amine 3f was
obtained in only 43% NMR yield. Switching to aliphatic amines, a
significant decrease of the conversion (around 80%) was
observed and compelled us to adjust the reaction conditions to
120 °C which allowed complete conversions and selectivities
higher than 90% in favor of the desired amino alcohol. n-
Hexylamine,
n-decylamine,
3-phenylpropanamine
and
isoamylamine were subjected to the reaction at 120 °C and
afforded the corresponding amino alcohols 3i, 3j, 3l and 3m with
excellent selectivities and good yields from 56 to 70%. It should
also emphasized that this methodology could afford
straightforwardly novel biobased surfactants. As an example,
using a fatty amine: hexadecylamine, the desired amino-alcohol
3k could be isolated in 64%yield. More hindered cyclohexylamine
appeared to be less efficient, in addition to a moderate conversion
of isosorbide of 84%, 3n was obtained in a mixture with isoidide
in ratio 86:14. Amino-alcohol 3n was thus isolated after
purification in a lower yield of 36%. When aniline and p-anisidine
were subjected into the reaction, conversions only reached 15 to
25% (data not shown), affording the corresponding mono-amines
along with isoidide and unidentified side-products. Given the lack
of reactivity of the less nucleophilic anilines, regioselective
amination of 4-aminobenzylamine was envisioned. Gratifyingly,
the desired amine 3o was formed regioselectively, but the product
was obtained along with isoidide and remaining isosorbide in a
ratio of 30:34:36. The drop of conversion and selectivity toward
the formation of the desired amines was also noticed when N,N-
dimethylethylenediamine and 4-dimethylaminobenzylamine were
subjected into the reaction. Moderate conversions and
selectivities were observed and amines 3p and 3q were isolated
respectively in 34 and 11% yields.
Beside the access to various chiral amino-alcohols and diamines
which could be used as bio-based surfactants, new
organocatalysts or ligands for asymmetric synthesis, the
borrowing hydrogen strategy may allow the access to the optically
pure bio-based monomer 7 that was never described by classical
strategies. The synthesis of chiral amino-alcohols from isohexides
has already been described using multi-step strategies and
affording amino-alcohols in 12-13% yield over 4 steps (Scheme
3).8c,14 But, this strategy has only been used for the synthesis of
endo-endo and exo-exo amino-alcohols. Indeed, according to
reported strategies, endo-exo amino-alcohol, could only be
prepared from isoidide which is not commercially available. It
could be emphasized that Rose et al. reported the first mono-
amination of isosorbide using Ru/C in aqueous ammonia under
H2 pressure at 170 °C within 50 to 60% conversion (GC). Due to
a lack of diastereoselectivity, a mixture of the two amino-alcohols
was obtained.15 More recently, Barta et al. also reported the
mono-amination of isosorbide using a supported-Ni catalyst and
aqueous ammonia within 32 to 51% GC yield but without
information concerning the stereochemistry.16 We thus developed
the first synthesis of this pure chiral amino-alcohol 7 in 54% over
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2 steps from isosorbide with an excellent optical purity (Scheme
3). The effective mass yield (EMY) is an additional parameter of
the sustainable characteristic of the reaction, as carbon efficiency
and atom economy were almost optimal in the direct borrowing
hydrogen methodology. This metric takes into account atom
economy, chemical yield and stoichiometry and appeared a
relevant criterion to compare both strategies. The EMY for the
synthesis of the common intermediate 3a was evaluated to 51%
in our approach and would be lower than 5% using classical
organic methods.
2 equivalents of benzylamine, 5 mol% of iridium catalyst and
5 mol% of diphenylphosphate in toluene at 120 °C for 24 h, we
observed a full conversion of isomannide with a good selectivity
of 83% toward the formation of the desired diamine 4a with endo-
endo configuration (entry 1). Surprisingly, the sole by-product
1
observed after analyzing the crude mixture by H NMR was the
amino-alcohol 3a obtained via the mono-amination of isomannide
followed by the epimerization of the second hydroxyl group; no
epimerized isohexides (isosorbide or isoidide) were detected.
Switching to the achiral iridium complex or to (R,R)-[Ir] provided
4a with similar selectivities (entries 2 - 3). As reported with
isosorbide, the reduction of the imine also led to a sole
stereoisomer with the amino group in endo configuration. Based
on our observations and on the mechanistic study of Sunoj
explaining the cooperative action of an [Ir]-catalyst and a
phosphoric acid for the stereocontrolled amination of alcohols
through borrowing hydrogen methodology,17 we could explain our
unique stereoselectivity by the approach of the iridium hydride on
the less hindered si face of the imine. Whatever the solvent used
Scheme 3 : Synthesis of chiral amino-alcohols
t
(toluene, amyl alcohol, anisole or CPME), the conversion was
complete, but the best result in term of selectivities was obtained
in toluene. In tamyl alcohol and anisole (entries 4 - 5), structurally
unidentified side-products (between 5 and 10%) were also
detected, leading to the desired diamine in slightly lower yields
(56 and 50%). As previously mentioned, temperature is a key
parameter to tune both optimal conversion and selectivity. At
100 °C, epimerization leading to 3a was thus avoided but with
decreased conversion rate and mono amine 5a was formed as a
major product (entry 7). At 110 °C, despite a full conversion of
isomannide, diamine 4a was obtained along with 2a and 5a
(entry 8). Best results were thus obtained at 120 °C in toluene.
Finally, when running the reaction with 7.5% of the catalytic
system (entry 9) at 120 °C, the desired diamine 4a was obtained
within 91% selectivity and 65% isolated yield.
We also envisioned the direct diamination of isomannide bearing
two hydroxyl groups in endo position, which are more sensitive to
oxidation.11 Benzylamine was also chosen as a model substrate
to optimize the reaction (Table 2). Based on the reaction
mechanism and on our previous results observed on isosorbide,
desired diamine 4a could be obtained along with amino-alcohol
5a, epimerized amino-alcohol 3a and epimerized isohexides
(isosorbide and isoidide). After
a
first screening using
Table 2. Optimization of the reaction conditions for the diamination of isomannide with benzylamine
Entry
T (°C)
Solvent
Cat (mol %)
Acid (mol %)
Conva (%)
Ratiob 4a:3a:5a
Yieldb 4a
61%c
58%
nd
5
5
5c
5
1
2d
3e
4f
5f
6
120
120
120
120
120
120
100
110
120
toluene
toluene
>99
>99
>99
>99
>99
> 99
85
83:17:0
81:19:0
79:21:0
80:20:0
71:15:14
57:30:13
34:0:66
65:22:13
91:9:0
5
5
toluene
tamyl alcohol
5
5
56%
50%
nd
5
5
anisole
5
5
CPME
5
5
7
toluene
nd
5
5
8
toluene
> 99
> 99
nd
7.5
7.5
9
toluene
65%
Reaction conditions: 1 (80 mg, 1 eq.), benzylamine (2 eq.), (S,S)-[Ir], diphenylphosphate, solvent [2M], 24 h. a) conversion and ratio were determined by 1H NMR b) isolated yields c) when
reaction performed on 200 mg of isomannide, the yield reached 69% d) use of the achiral Iridacycle e) use of (R, R)-[Ir] f) structurally unidentified side-products also detected
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10.1002/ejoc.201901661
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final hydrogenolysis. In this synthesis, the nucleophilic
displacement was performed with sodium azide. The seminal
work of Beller in 2011 described the first direct amination of
isosorbide with ammonia. The use of [Ru(CO)ClH(PPh3)3] with
The reaction was investigated with various substituted
benzylamines (Scheme 4). The nature of the substituent
(methoxy, methyl or halogen) did not bring significant impacts on
conversions (>99%) and selectivities (80-86%). Desired diamines
4b-4h were thus obtained in 50 to 62% isolated yields. The same
conditions were used with 4-phenylbenzylamine but after 24 h,
the conversion of isomannide only reached 77%. A full conversion
was observed after 48 h, leading to the diamine 4i with a
moderate selectivity of 66% and 35% isolated yield. The scope
was then studied with aliphatic amines. When n-hexylamine was
tested using the previously optimized conditions, despite a full
conversion of isomannide, the desired diamine 4j was obtained
along with endo/endo and endo/exo amino-alcohols. Satisfyingly,
when a slight excess of hexylamine was used, a better selectivity
of 90% was observed and diamine 4j was isolated in 79% yield.
Reactions with aliphatic amines were thus performed using
7.5 mol% of (S,S)-[Ir] and 7.5% of diphenylphosphate with 2.5
equivalents of amine. Reactions with n-decylamine, 3-
t
additional Xantphos ligands at 170 °C in amyl-alcohol for 20 h
afforded the diamine as a mixture of the 3 diastereomers within
Signet non défini.
96% GC yield.Erreur !
Later, the amination of
isomannide with ammonia was also described by Vogt using a
PNP-pincer-coordinated Ru-catalyst at 170 °C in tamyl-alcohol for
21 h yielding to the diamines endo/endo, endo/exo, exo/exo in
ratio 38:47:15 within 96% GC yield.19 Our procedure allows the
production of a sole compound with an excellent optical purity in
2 steps and a global yield of 59% (Scheme 5). The EMY was not
calculated on the borrowing hydrogen reaction as the generated
intermediates in both syntheses (diazide vs diamine) are not the
same.
Scheme 5. Synthesis of chiral diamines
phenylpropanamine
and
isoamylamine
afforded
the
corresponding diamines 4k, 4l and 4m with excellent selectivities
(87-90%) and good yields from 64 to 75%. The use of the slightly
more hindered cyclohexylamine led to the corresponding diamine
4n in 47% isolated yield due to a lower conversion and a lack of
selectivity.
Scheme 4. Scope of the diamination of isomannide
Conclusion
The use of borrowing hydrogen methodology to the isohexide
chemistry, renowned for its complexity raising any selectivity
issues was gratifyingly developed. Both regioselective and
diastereoselective concerns were faced in a sample of 17 amines
with isosorbide (monoamination) and 14 amines with isomannide
(diamination). As an extension of the scope, we obtained
successfully the non-protected amino alcohol 7 and the diamine
8 and evaluated our strategy regarding the standard reactions run
for their usual access. In terms of efficiency, taking into account
the number of steps and global yield of our synthesis, this strategy
undoubtedly will increase the availability of these molecules in
higher quantity or an easy-to-run methodology, which should
open their potential especially in the field of polymers synthesis.
Our procedure offers a good compromise between the isolation of
a unique diamine with controlled stereochemistry in a 59% global
isolated yield obtained in 2 steps, avoiding also the handling of
undesired azide derivatives addressing safety issues.
The synthesis of the primary diamine 8 is quite challenging
according to literature reporting multi-step synthesis in 5 steps
and a global yield of 18%, which limited its use for direct
application (Scheme 5).18 The 5 steps include the preparation of
isoidide (2 steps) and the classical previously described
sequence of hydroxyl activation / nucleophilic displacement and
Experimental Section
General note: Reagents and solvents were supplied by Aldrich,
Acros, Lancaster, Alfa Aesar, Fluka or TCI and purchased at the
highest commercial quality to be used without further purification.
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NMR spectra were recorded on a Brüker 300 (1H: 300 MHz; 13C:
75 MHz), Bruker 400 (1H: 400 MHz; 13C: 100 MHz) spectrometers
at 298 K, using CDCl3, CD3OD or D2O as solvents. The chemical
shifts (δ, ppm) are referenced to the residual solvent peak and
coupling constants (J) are reported in the standard fashion. The
following abbreviations are used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, quint = quintet, hept. =
heptuplet, m = multiplet, br = broad, app. = apparent. NMR peak
assignments were performed for each compound using classical
1D and 2D NMR (COSY, HSQC and HMBC). For better clarity, a
mean of close measured coupling constants for correlated
protons are displayed in NMR assignments. Electrospray
ionization (ESI) mass spectrometry (MS) experiments were
4.32 (m, 1H, H3), 4.45 (d, J = 3.9, 1H, H3a), 4.66 (app. t, J = 3.9,
1H, H6a), 6.86 (d, J = 8.7, 2H, Hc), 7.26 (d, J = 8.7, 2H, Hb); 13C
NMR (CDCl3, 100 MHz) δ 51.9 (C1’), 55.4 (OMe), 62.0 (C6), 71.6
(C5), 75.7 (C2), 77.4 (C3), 79.9 (C6a), 88.6 (C3a), 114.0 (2 Cc),
129.5 (2 Cb), 132.2 (Ca), 158.9 (Cd); IR (ATR) ν 3276, 2940, 2865,
1609, 1511, 1247, 1075, 1032, 817 cm-1; [휶]푫ퟐퟏ = +71.3° (c 1.01
CHCl3); HRMS (ESI) [M+Na]+: calcd for C14H19NNaO4: 288.1206;
found 288.1199; [M+H]+: calcd for C14H20NO4: 266.1387 ; found
266.1380.
(3S,3aR,6R,6aR)-6-[(3-Methoxybenzyl)amino]hexahydrofuro
[3,2-b]furan-3-ol 3c: 1H NMR (CDCl3, 400 MHz) δ 3.25 (dd, J =
8.2 and 9.9, 1H, H5), 3.33-3.38 (m, 1H, H6), 3.76 (d, J = 13.0, 1H,
H1’), 3.80 (s, 3H, OMe), 3.84-3.91 (m, 3H, H2 and H1’), 4.00 (app.
t, J = 8.2, 1H, H5), 4.29-4.30 (m, 1H, H3), 4.45 (d, J = 3.9, 1H, H3a),
4.65 (app. t, J = 3.9, 1H, H6a), 6.79-6.81 (m, 1H, Hd), 6.91-6.93
(m, 2H, Hb and Hf), 7.24 (app. t, J = 7.9, 1H, He); 13C NMR (CDCl3,
100 MHz) δ 52.5 (C1’), 55.4 (OMe), 62.1 (C6), 71.6 (C5), 75.7 (C2),
77.4 (C3), 80.0 (C6a), 88.7 (C3a), 112.8 (Cd), 113.8 (Cb), 120.6 (Cf),
129.6 (Ce), 141.8 (Ca), 160.0 (Cc); IR (ATR) ν 3352, 2940, 2867,
performed on
a Thermo Finnigan LCQ Advantage mass
spectrometer. High-resolution mass spectra (HRMS) were
recorded on a Finnigan Mat 95xL mass spectrometer using either
the electrospray (ESI) or atmospheric pressure chemical
ionization (APCI) technique. Analytical thin-layer chromatography
was carried out on silica gel Merck 60 D254 (0.25 mm). Flash
chromatography was performed on Merck Si 60 silica gel (40–63
μm). Infra-red (IR) spectra were recorded with an IRAffinity-1
Shimadzu spectrometer using attenuated total reflectance
(ATRMiracle), and the wavenumbers were expressed in cm–1.
Optical rotations (concentration c expressed in g/100 mL) were
measured with a Perkin–Elmer 241 polarimeter using a 10 cm cell
for compound 8 and with a Bellingham + Stanley ADP 450 using
a 5 cm cell for other compounds. Melting points were measured
using Büchi apparatus B-540.
1596, 1489, 1456, 1262, 1156, 1071, 1036, 778 cm-1; [휶]푫ퟐퟏ
=
+70.6° (c 1.02 CHCl3); HRMS (ESI) [M+Na]+: calcd for
C14H19NNaO4: 288.1206; found 288.1200; [M+H]+: calcd for
C14H20NO4: 266.1387 ; found 266.1381.
(3S,3aR,6R,6aR)-6-[(4-Chlorobenzyl)amino]hexahydrofuro
1
[3,2-b]furan-3-ol 3d: Mp = 67 °C; H NMR (CDCl3, 400 MHz) δ
3.24 (dd, J = 10.0 and 8.0, 1H, H5), 3.31-3.38 (m, 1H, H6), 3.74
(d, J = 13.1, 1H, H1’), 3.84-3.91 (m, 3H, H2 and H1’), 3.99 (app. t,
J = 8.0, 1H, H5), 4.31-4.32 (m, 1H, H3), 4.46 (d, J = 3.9, 1H, H3a),
4.65 (app. t, J = 3.9, 1H, H6a), 7.28-7.30 (m, 4H, Hb and Hc);
13C NMR (CDCl3, 100 MHz) δ 51.8 (C1’), 62.1 (C6), 71.5 (C5), 75.7
(C2), 77.4 (C3), 79.9 (C6a), 88.7 (C3a), 128.7 (2 Cc), 129.6 (2 Cb),
133.0 (Cd), 138.7 (Ca); IR (ATR) ν 3294, 2937, 2858, 1490, 1075,
806 cm-1; [휶]ퟐ푫ퟏ = +72.0° (c 1.00 CHCl3); HRMS (ESI) [M+Na]+:
calcd for C13H16ClNNaO3: 292.0711; found 292.0710; [M+H]+:
calcd for C13H17ClNO3: 270.0891 ; found 270.0888.
General procedure for the direct amination of isosorbide: Into
a 2 mL vial equipped with a magnetic stirrer was added isosorbide
(1 eq), diphenylphosphate (0.075 eq) and iridium catalyst
(0.075 eq). After 3 vacuum-nitrogen cycles, anhydrous toluene
(2M), 3 Å molecular sieves and benzylamine (1 eq) were added.
The vial was sealed, and the reaction mixture was stirred under
heating at the desired temperature (100 to120 °C) for 24 h. After
cooling down to rt, the mixture was filtered through a pad of
Celite with dichloromethane, and the solvent was evaporated
under reduced pressure. The crude mixture was further purified
by flash column chromatography on silica gel.
(3S,3aR,6R,6aR)-6-[(4-Fluorobenzyl)amino]hexahydrofuro
[3,2-b]furan-3-ol 3e: 1H NMR (CDCl3, 400 MHz) δ 3.24 (dd, J =
10.0 and 8.3, 1H, H5), 3.33-3.38 (m, 1H, H6), 3.74 (d, J = 12.9, 1H,
H1’), 3.85-3.92 (m, 3H, H2 and H1’), 4.00 (app. t, J = 7.8, 1H, H5),
4.31-4.33 (m, 1H, H3), 4.46 (d, J = 3.9, 1H, H3a), 4.66 (app. t, J =
3.9, 1H, H6a), 7.01 (app. t, J = 8.7, 2H, Hc), 7.31 (dd, J = 8.7 and
5.4, 2H, Hb); 13C NMR (CDCl3, 100 MHz) δ 51.8 (C1’), 62.1 (C6),
71.5 (C5), 75.7 (C2), 77.4 (C3), 79.9 (C6a), 88.7 (C3a), 115.4 (d, J =
21.2, Cc), 129.9 (d, J = 8.0, Cb), 135.8 (d, J = 3.1, Ca), 162.2 (d,
J = 245.0, Cd); IR (ATR) ν 3342, 2942, 2867, 1602, 1509, 1219,
1071, 824 cm-1; [휶]푫ퟐퟏ = +66.3° (c 1.02 CHCl3); HRMS (ESI)
[M+Na]+: calcd for C13H16FNNaO3: 276.1006; found 276.1007;
[M+H]+: calcd for C13H17FNO3: 254.1187; found 254.1186.
3S,3aR,6R,6aR)-6-(Benzylamino)hexahydrofuro[3,2-b]furan-
3-ol 3a: Mp 97 °C; 1H NMR (CDCl3, 400 MHz) δ 3.25 (dd, J = 10.0
and 8.1, 1H, H5), 3.34-3.40 (m, 1H, H6), 3.78 (d, J = 12.9, 1H, H1’),
3.84-3.89 (m, 2H, H2), 3.93 (d, J = 12.9, 1H, H1’), 3.99 (app. t, J =
8.1, 1H, H5), 4.29-4.33 (m, 1H, H3), 4.45 (d, J = 3.8, 1H, H3a), 4.66
(app. t, J = 3.8, 1H, H6a), 7.37 – 7.24 (m, 5H, HAr); 13C NMR
(CDCl3, 100 MHz), 52.5 (C1’), 62.1 (C6), 71.6 (C5), 75.7 (C2), 77.4
(C3), 79.9 (C6a), 88.7 (C3a), 127.3 (Cd), 128.3 (2 Cb), 128.6 (2 Cc),
140.0 (Ca); IR (ATR) ν 3342, 2974, 2881, 1381, 1045; [휶]ퟐ푫ퟏ = 71.8
(c 1.03 CHCl3); HRMS (ESI) [M+Na]+: calcd for C13H17NNaO3:
258.1101; found 258.1102; [M+H]+: calcd for C13H18NO3:
236.1281; found 236.1281.
(3S,3aR,6R,6aR)-6-((4-methylbenzyl)amino)hexahydro
1
furo[3,2-b]furan-3-ol 3g: H NMR (CDCl3, 400 MHz) δ 2.33 (s,
3H, Me), 3.24 (dd, J = 10.0 and 8.0, H5), 3.33-3.38 (m, 1H, H6),
3.74 (d, J = 12.7, 1H, H1’), 3.83-3.91 (m, 3H, H2 and H1’), 3.99
(app. t, J = 8.0, 1H, H5), 4.29-4.30 (m, 1H, H3), 4.44 (d, J = 3.9,
1H, H3a), 4.65 (app. t, J = 3.9, 1H, H6a), 7.13 (d, J = 7.9, 2H, Hc),
7.23 (d, J = 7.9, 2H, Hb); 13C NMR (CDCl3, 100 MHz) δ 21.2 (Me),
(3S,3aR,6R,6aR)-6-[(4-Methoxybenzyl)amino]hexahydrofuro
[3,2-b] furan-3-ol 3b: Mp = 62 °C; 1H NMR (CDCl3, 400 MHz) δ
3.23 (dd, J = 10.0 and 8.1, 1H, H5), 3.33-3.38 (m, 1H, H6), 3.72
(d, J = 12.6, 1H, H1’), 3.80 (s, 3H, OMe), 3.86 (d, J = 12.6, 1H,
H1’), 3.84-3.91 (m, 2H, H2), 3.99 (app. t, J = 8.1, 1H, H5), 4.31-
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10.1002/ejoc.201901661
European Journal of Organic Chemistry
FULL PAPER
52.2 (C1’), 62.0 (C6), 71.6 (C5), 75.7 (C2), 77.4 (C3), 80.0 (C6a),
88.7 (C3a), 128.3 (Cb), 129.3 (Cc), 136.9 (Ca), 137.0 (Cd); IR (ATR)
ν 3426, 2943, 2854, 1457, 1088, 1062, 808 cm-1; [휶]푫ퟐퟏ = +72.0°
(c 1.00 CHCl3); HRMS (ESI) [M+Na]+: calcd for C14H19NNaO3:
272.1257; found 272.1260; [M+H]+: calcd for C14H20NO3:
250.1438; found 250.1438.
4.31 (m, 1H, H3), 4.47 (dd, J = 3.9 and 1.2, 1H, H3a), 4.66 (app. t,
J = 3.9, 1H, H6a); 13C NMR (CDCl3, 100 MHz) δ 14.3 (Me), 22.8
(CH2), 27.5 (CH2), 29.5 (CH2), 29.67 (CH2), 29.73 (CH2), 29.76
(CH2), 29.80 (CH2), 29.81 (CH2), 29.84 (4 CH2), 30.6 (CH2), 32.0
(CH2), 48.8 (C1’), 63.0 (C6), 71.5 (C5), 75.7 (C2), 77.3 (C5), 80.0
(C6a), 88.7 (C3a); IR (ATR) ν 3113, 3063, 2953, 2819, 1080 cm-1;
[휶]ퟐ푫ퟏ = 39.5 (c 0.91 CHCl3); HRMS (ESI) [M+Na]+: calcd for
C22H43NNaO3: 392.3135; found 392.3136; [M+H]+: calcd for
C22H44NO3: 370.3316; found 370.3316.
(3S,3aR,6R,6aR)-6-[(2-Methylbenzyl)amino]hexahydro
1
furo[3,2-b]furan-3-ol 3h : Mp = 115 °C; H NMR (CDCl3, 400
MHz) δ 2.36 (s, 3H, Me), 3.25 (dd, J = 10.0 and 8.2, 1H, H5), 3.38-
3.43 (m, 1H, H6), 3.75 (d, J = 12.9, 1H, H1’), 3.84-3.94 (m, 3H, H2
and H1’), 4.02 (app. t, J = 8.2, 1H, H5), 4.31-4.32 (m, 1H, H3), 4.47
(d, J = 4.0, 1H, H3a), 4.68 (app. t, J = 4.0, 1H, H6a), 7.15-7.18 (m,
3H, Hc, Hd, Hf), 7.32 (app. t J = 3.6, 1H, He); 13C NMR (CDCl3, 100
MHz) δ 19.1 (Me), 50.2 (C1’), 62.5 (C6), 71.6 (C5), 75.7 (C2), 77.4
(C3), 79.9 (C6a), 88.7 (C3a), 126.1 (Cd), 127.3 (Ce), 128.6 (Cf),
130.5 (Cc), 136.6 (Cb), 138.0 (Ca); IR (ATR) ν 3277, 2945, 2882,
1490, 1073, 749 cm-1; [휶]푫ퟐퟏ = +69.4° (c 0.98 CHCl3); HRMS (ESI)
[M+Na]+: calcd for C14H19NNaO3: 272.1257; found 272.1256;
[M+H]+: calcd for C14H20NO3: 250.1438; found 250.1436.
(3S,3aR,6R,6aR)-6-[(3-Phenylpropyl)amino]hexahydro
furo[3,2-b]furan-3-ol 3l: 1H NMR (CDCl3, 400 MHz) δ 1.79-1.87
(m, 2H, H2’), 2.56-2.63 (m, 1H, H1’), 2.65-2.69 (m, 2H, H3’), 2.76-
2.82 (m, 1H, H1’), 3.22 (dd, J = 10.1 and 7.9, 1H, H5), 3.29-3.34
(m, 1H, H6), 3.84-3.90 (m, 2H, H2), 4.01 (app. t, J = 7.9, 1H, H5),
4.30-4.31 (m, 1H, H3), 4.46 (d, J = 3.9, 1H, H3a), 4.64 (app. t, J =
3.9, 1H, H6a), 7.16-7.20 (m, 3H, 2 Hc and Hd), 7.26-7.29 (m, 2H, 2
Hb); 13C NMR (CDCl3, 100 MHz) δ 32.2 (C2’), 33.7 (C3’), 48.2 (C1’),
62.9 (C6), 71.5 (C5), 75.7 (C2), 77.3 (C3), 80.1 (C6a), 88.7 (C3a),
125.9 (Cd), 128.48, 128.51 (2 Cb, 2 Cc), 142.1 (Ca); IR (ATR) ν
3337, 2938, 2860, 1453, 1078, 1042, 747 cm-1; [휶]푫ퟐퟏ = 56.0° (c
1.03 CHCl3); HRMS (ESI) [M+Na]+: calcd for C15H21NNaO3:
286.1414 ; found 286.1413; [M+H]+: calcd for C15H22NO3:
264.1594; found 264.1594.
(3S,3aR,6R,6aR)-6-(Hexylamino)hexahydrofuro[3,2-b]furan-
1
3-ol 3i: H NMR (400 MHz, CDCl3) δ 0.86 (t, J = 6.8, 3H, Me),
1.19-1.34 (m, 6H, H3’, H4’ and H5’), 1.40-1.57 (m, 2H, H2’), 2.54
(ddd, J = 6.7, 8.2 and 11.1, 1H, H1’), 2.71 (ddd, J = 6.7, 8.2 and
11.1, 1H, H1’), 3.21 (dd, J = 7.8 and 10.1, 1H, H5), 3.24-3.37 (m,
1H, H6), 3.79-3.91 (m, 2H, H2), 4.01 (app. t, J = 7.8, 1H, H5), 4.18-
4.33 (m, 1H, H3), 4.44 (d, J = 3.8, 1H, H3a), 4.64 (app. t, J = 3.8,
1H, H6a); 13C NMR (CDCl3, 100 MHz) δ 14.0 (Me), 22.5 (C4’ or
C5’), 26.9 (C3’), 30.3 (C2’), 31.7 (C4’ or C5’), 48.6 (C1’), 62.7 (C6),
71.2 (C5), 75.5 (C2), 76.9 (C3), 79.8 (C6a), 88.6 (C3a); IR (ATR) ν
3362, 3285, 2953, 2926, 2857, 1458, 1078, 1049, 775, 735 cm-1;
[휶]ퟐ푫ퟏ = +37.3° (c 0.96 CHCl3) [litt. : + 48.9° (c 0.94 CHCl3)]1;
HRMS (ESI) [M+Na]+: calcd for C12H23NNaO3: 252.1570; found
252.1574; [M+H]+: calcd for C12H24NO3: 230.1751; found
230.1743.
(3S,3aR,6R,6aR)-6-[(3-Methylbuty)amino]hexahydrofuro[3,2-
1
b]furan-3-ol 3m: H NMR (CDCl3, 400 MHz) δ 0.89 (d, J = 6.6,
6H, 2 Me), 1.39 (app. q, J = 7.3, 2H, H2’), 1.56-1.69 (m, 1H, H3’),
2.57 (dt, J = 11.0 and 7.6, 1H, H1’), 2.76 (dt, J = 11.0 and 7.6, 1H,
H1’), 3.22 (dd, J = 10.1 and 8.0, 1H, H5), 3.31-3.36 (m, 1H, H6),
3.84-3.91 (m, 2H, H2), 4.03 (app. t, J = 8.0, 1H, H5), 4.31-4.32 (m,
1H, H3), 4.48 (d, J = 3.9, 1H, H3a), 4.67 (app. t, J = 3.9, 1H, H6a);
13C NMR (CDCl3, 100 MHz) δ 22.6 (Me), 23.0 (Me), 26.3 (C3’),
39.6 (C2’), 46.9 (C1’), 63.1 (C6), 71.6 (C5), 75.7 (C2), 77.4 (C3), 80.0
(C6a), 88.7 (C3a); IR (ATR) ν 3356, 2954, 2869, 1653, 1465, 1078,
1045 cm-1; [휶]푫ퟐퟏ = + 64.3° (c 0.99 CHCl3) ; HRMS (ESI) [M+Na]+:
calcd for C11H21NNaO3: 238.1414; found 238.1425; [M+H]+: calcd
for C11H22NO3: 216.1594 ; found 216.1602.
(3S,3aR,6S,6aR)-6-(Decylamino)hexahydrofuro[3,2-b]furan-
1
3-ol 3j: H NMR (CDCl3, 400 MHz) δ 0.87 (t, J = 6.7, 3H, Me),
1.17-1.37 (m, 14H, H3’, H4’, H5’, H6’, H7’, H8’ and H9’), 1.42-1.55 (m,
2H, H2’), 2.51-2. 59 (m, 1H, H1’), 2.69-2.78 (m, 1H, H1’), 3.22 (dd,
J = 10.1 and 7.8, 1H, H5), 3.29-3.37 (m, 1H, H6), 3.83-3.91 (m,
2H, H2), 4.03 (app. t, J = 7.8, 1H, H5), 4.31-4.32 (m, 1H, H3), 4.48
(d, J = 3.8, 1H, H3a), 4.66 (app. t, J = 3.8, 1H, H6a); 13C NMR
(CDCl3, 100 MHz) δ 14.3 (Me), 22.8 (C8’ or C9’), 27.5, 29.5, 29.67,
29.71, 29.73 (C3’, C4’, C5’, C6’, C7’), 30.7 (C2’), 32.0 (C8’ or C9’), 48.8
(C1’), 63.0 (C6), 71.6 (C5), 75.7 (C2), 77.4 (C3), 80.0 (C6a), 88.7
(C3a); IR (ATR) ν 3346, 2923, 2853, 1465, 1079, 1047 cm-1;
[휶]ퟐ푫ퟏ = +43.1° (c 1.02 CHCl3); HRMS (ESI) [M+Na]+: calcd for
C16H31NNaO3: 308.2196; found 308.2199; [M+H]+: calcd for
C16H32NO3: 286.2376 ; found 286.2378.
(3S,3aR,6R,6aR)-6-(Cyclohexylamino)hexahydrofuro[3,2-b]
furan-3-ol 3n : Mp = 87 °C; H NMR (CDCl3, 400 MHz) δ 0.99-
1
1.32 (m, 5H, CH2-cyclohexyl), 1.58-1.62 (m, 1H, CH2-cyclohexyl),
1.70-1.77 (m, 2H, CH2-cyclohexyl), 1.82-1.90 (m, 2H, CH2-
cyclohexyl), 2.46-2.56 (m, 1H, CH-cyclohexyl), 3.20 (dd, J = 10.2
and 8.1, 1H, H5), 3.42-3.49 (m, 1H, H6), 3.82-3.90 (m, 2H, H2),
4.01 (app. t, J = 8.1, 1H, H5), 4.29-4.30 (m, 1H, H3), 4.47 (d, J =
3.9, 1H, H3a), 4.61 (app. t, J = 3.9, 1H, H6a); 13C NMR (CDCl3, 100
MHz) δ 25.0, 25.2, 26.1, 33.7, 34.3 (CH2-cyclohexyl), 55.5 (CH-
cyclohexyl), 59.7 (C6), 71.9 (C5), 75.7 (C2), 77.4 (C3), 80.5 (C6a),
88.6 (C3a); IR (ATR) ν 3270, 2922, 2853, 1456, 1081 cm-1; [휶]푫ퟐퟏ
=
+80.4° (c 0.97 CHCl3); HRMS (ESI) [M+Na]+: calcd for
C12H21NNaO3: 250.1414; found 250.1410; [M+H]+: calcd for
C12H22NO3: 228.1594 ; found 228.1590.
(3S,3aR,6R,6aR)-6-(Hexadecylamino)hexahydrofuro[3,2-b]
furan-3-ol 3k: Mp = 37 °C; 1H NMR (CDCl3, 400 MHz) δ 0.87 (t,
J = 6.8, 3H, Me), 1.25-1.29 (m, 26 H, H3’, H4’, H5’, H6’, H7’, H8’, H9’,
H10’, H11’, H12’, H13’, H14’, H15’), 1.46-1.51 (m, 2H, H2’), 2.55 (ddd, J
= 11.1, 8.3 and 6.2, 1H, H1’), 2.73 (ddd, J = 11.1, 8.3 and 6.2, 1H,
H1’), 3.22 (dd, J = 10.1 and 8.1, 1H, H5), 3.30-3.35 (m, 1H, H6),
3.84-3.90 (m, 2H, H2), 4.03 (dd, J = 8.1 and 7.3, 1H, H5), 4.30-
(3S,3aR,6R,6aR)-6-((4-(Dimethylamino)benzyl)amino)hexa
hydrofuro[3,2-b]furan-3-ol 3p: Mp = 92 °C ; 1H NMR (CDCl3,
400 MHz) δ 2.93 (s, 6H, 2 Me), 3.23 (dd, J = 10.0 and 8.1, 1H,
H5), 3.33-3.39 (m, 1H, H6), 3.69 (d, J = 12.5, 1H, H1’), 3.81-3.91
(m, 3H, H2 and H1’), 3.99 (app. t, J = 8.1, 1H, H5), 4. 30-4.31 (m,
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10.1002/ejoc.201901661
European Journal of Organic Chemistry
FULL PAPER
1H, H3), 4.45 (d, J = 3.9, 1H, H3a), 4.66 (app. t, J = 3.9, 1H, H6a),
6.71 (d, J = 8.7, 2H, Hc), 7.21 (d, J = 8.7, 2H, Hb); 13C NMR
(CDCl3, 100 MHz) δ 40.9 (2 Me), 52.0 (C1’), 61.9 (C6), 71.6 (C5),
75.7 (C2), 77.4 (C3), 80.0 (C6a), 88.6 (C3a), 112.9 (2 Cc), 128.0
(Ca), 129.3 (2 Cb), 150.1 (Cd); IR (ATR) ν 3281, 2932, 2862, 1524,
1070, 1054, 763 cm-1; [휶]푫ퟐퟏ = +62.0° (c 1.00 CHCl3) ; HRMS (ESI)
[M+Na]+: calcd for C15H22N2NaO3: 301.1523; found 301.1518;
[M+H]+: calcd for C15H23N2O3: 279.1703 ; found 279.1699.
407.1938; [M+H]+: calcd for C22H29N2O4: 385.2122; found
385.2116.
(3R,3aR,6R,6aR)-N,N’-Bis(3-
methoxybenzyl)hexahydrofuro[3,2-b]furan-3,6-diamine 4c:
1H NMR (MeOD, 400 MHz) δ 3.34-3.41 (m, 4H, H2, H5 and H3,
H6), 3.70 (d, J = 12.8, 2H, H1’), 3.78 (s, 6H, OMe), 3.82 (d, J =
12.8, 2H, H1’), 3.98-4.07 (m, 2H, H2, H5), 4.54 (d, J = 1.7, 2H, H3a,
H6a), 6.82 (ddd, J = 8.1, 2.6 and 0.8, 2H, Hd), 6.89-6.95 (m, 4H,
Hb, Hf), 7.23 (app. t, J = 8.1, 2H, He); 13C NMR (MeOD, 100 MHz)
δ 53.0 (2 C1’), 55.6 (2 OMe), 63.5 (C3/C6), 73.1 (C2/C5), 82.2
(C3a/C6a), 113.9 (2 Cd), 115.0 (2 Cb), 121.7 (2 Cf), 130.5 (2 Ce),
142.2 (2 Ca), 161.3 (2 Cc); IR (ATR) ν 1707, 1362, 1222, 978 cm-
1; [휶]ퟐ푫ퟏ = +100.0° (c 1.06 CHCl3); HRMS (ESI) [M+H]+: calcd for
C22H29N2O4: 385.2122; found 385.2113.
(3S,3aR,6R,6aR)-6-((2-(Dimethylamino)ethyl)amino)hexa
hydrofuro[3,2-b]furan-3-ol 3q: 1H NMR (CDCl3, 400 MHz) δ
2.22 (s, 6H, 2 Me), 2.30-2.37 (m, 1H, H2’), 2.47-2.53 (m, 1H, H2’),
2.59-2.65 (m, 1H, H1’), 2.86-2.90 (m, 1H, H1’), 3.24 (dd, J = 10.2
and 7.9, 1H, H5), 3.31-3.36 (m, 1H, H6), 3.83-3.89 (m, 2H, H2),
4.02 (app. t, J = 7.9, 1H, H5), 4.28-4.29 (m, 1H, H3), 4.47 (d, J =
3.8, 1H, H3a), 4.66 (app. t, J = 3.8, 1H, H6a); 13C NMR (CDCl3, 100
MHz) δ 45.6 (2 Me), 45.9 (C2’), 59.6 (C1’), 63.1 (C6), 71.4 (C5),
75.7 (C2), 77.4 (C3), 79.8 (C6a), 88.8 (C3a); IR (ATR) ν 3310, 2948,
2866, 1654, 1458, 1081, 1039 cm-1; [휶]푫ퟐퟏ = +53.9° (c 0.44 CHCl3);
HRMS (ESI) [M+Na]+: calcd for C10H20N2NaO3: 239.1366; found
239.1369; [M+H]+: calcd for C10H21N2O3: 217.1547; found
217.1547.
(3R,3aR,6R,6aR)-N,N’-bis(4-chlorobenzyl)hexahydrofuro[3,2-
b]furan-3,6-diamine 4d: 1H NMR (MeOD, 400 MHz) δ 3.34-3.38
(m, 4H, H2, H5, H3, H6), 3.70 (d, J = 13.0, 2H, H1’), 3.81 (d, J =
13.0, 2H, H1’), 3.96-4.07 (m, 2H, H2, H5), 4.53 (dd, J = 2.7 and 1.2,
2H,
H3a,
H6a),
7.27-7.37
(m,
8H,
Hb,
Hc);
13C NMR (MeOD, 100 MHz) δ 52.2 (2 C1’), 63.5 (C3/C6), 73.1
(C2/C5), 82.2 (C3a/C6a), 129.5 (4 Cc), 131.1 (4 Cb), 134.0 (2 Cd),
140.0 (2 Ca); IR (ATR) ν 2743, 1120, 1015, 822 cm-1; [휶]푫ퟐퟏ
=
General procedure for the diamination of isoamannide: Into a
2 mL vial equipped with a magnetic stirrer were added isomannide
(1.0 eq), diphenylphosphate (0.075 eq) and the iridium catalyst
(0.075 eq). After 3 vacuum-nitrogen cycles, anhydrous toluene
(2M), 3 Å molecular sieves and the amine (2.2 to 2.5 eq) were
added. The vial was sealed, and the reaction mixture was stirred
at 120 °C for 24 hours. After cooling down to room temperature,
+112.1° (c 0.66 CHCl3); HRMS (ESI) [M+Na]+: calcd for
C20H22Cl2N2NaO2: 415.0951; found 415.0953; [M+H]+ calcd for
C20H23Cl2N2O2: 393.1131; found 393.1130.
(3R,3aR,6R,6aR)-N,N’-Bis(4-fluorobenzyl)hexahydrofuro[3,2-
b]furan-3,6-diamine 4e: 1H NMR (MeOD, 400 MHz) δ 3.33-3.40
(m, 4H, H2, H5, H3, H6), 3.71 (d, J = 12.8, 2H, H1’), 3.83 (d, J =
12.8, 2H, H1’), 3.99-4.06 (m, 2H, H2, H5), 4.54-4.57 (m, 2H, H3a,
H6a), 7.01-7.07 (m, 4H, Hb), 7.34-7.39 (m, 4H, Hc); 13C NMR
(MeOD, 100 MHz) δ 52.2 (2 C1’), 63.5 (C3/C6), 73.1 (C2/C5), 82.2
(C3a/C6a), 116.1 (d, J = 21.5, 4 Cc), 131.4 (d, J = 3.2, 4 Cb), 136.8
(d, J = 3.2, 2 Ca), 163.5 (d, J = 243.9, 2 Cd); IR (ATR) ν 2900,
1508, 1219, 1074, 825 cm-1; [휶]푫ퟐퟏ = +112.5° (c 0.96 CHCl3);
HRMS (ESI) [M+Na]+: calcd for C20H22F2N2NaO2: 383.1542 ;
found 383.1538; [M+H]+: calcd for C20H23F2N2O2: 361.1722; found
361.1717.
the mixture was filtered through
a
pad of Celite with
dichloromethane, and the solvent was evaporated under reduced
pressure. The crude was further purified by flash column
chromatography on silica gel.
(3R,3aR,6R,6aR)-N,N’-Dibenzylhexahydrofuro[3,2-b]furan-
3,6-diamine 4a: 1H NMR (CDCl3, 400 MHz) δ 3.29 (dd, J = 10.0
and 8.0, 2H, H2, H5), 3.36-3.46 (m, 2H, H3, H6), 3.77 (d, J = 13.0,
2H, H1’), 3.89 (d, J = 13.0, 2H, H1’), 4.08 (app. t, J = 8.0, 2H, H2,
H5), 4.52 (dt, J = 3.9 and 2.0, 2H, H3a, H6a), 7.22-7.28 (m, 2H, Hd),
7.29-7.37 (m, 8H, Hb, Hc); 13C NMR (CDCl3, 100 MHz) δ 52.5 (2
C1’), 62.9 (C3/C6), 72.8 (C2/C5), 80.4 (C3a/C6a), 127.2 (2 Cd), 128.3
(4 Cb), 128.6 (4 Cc), 140.2 (2 Ca); IR (ATR) ν 3028, 2932, 2857,
1452, 1080, 737 cm-1; [휶]푫ퟐퟏ = +106.3° (c 0.64 CHCl3); HRMS
(ESI) [M+Na]+: calcd for C20H24N2NaO2: 347.1730; found
347.1728; [M+H]+: calcd for C20H25N2O2: 325.1911; found
325.1907.
(3R,3aR,6R,6aR)-N,N’-Bis(2-fluorobenzyl)hexahydrofuro[3,2-
b]furan-3,6-diamine 4f: 1H NMR (MeOD, 400 MHz) δ 3.33-3.44
(m, 4H, H2, H5, H3, H6), 3.82 (d, J = 13.4, 2H, H1’), 3.90 (d, J =
13.4, 2H, H1’), 4.03 (app. t, J = 7.1, 2H, H2, H5), 4.52 (dd, J = 1.3
and 2.9, 2H, H3a, H6a), 7.07 (ddd, J = 10.2, 8.2 and 1.2, 2H, Hc),
7.14 (td, J = 7.5 and 1.2, 2H, He), 7.26-7.32 (m, 2H, Hd), 7.42 (td,
J = 7.5, 7.3 and 1.2, 2H, Hf); 13C NMR (MeOD, 100 MHz)
δ 46.3 (d, J = 3.4, 2 C1’), 63.8 (C3/C6), 72.2 (C2/C5), 82.4 (C3a/C6a),
116.2 (d, J = 22.1, 2 Cc), 125.4 (d, J = 3.6, 2 Ce), 127.8 (d, J =
15.1, 2 Ca), 130.3 (d, J = 8.3, 2 Cd), 131.8 (d, J = 4.5, 2 Cf), 162.6
(d, J = 244.62, Cb); IR (ATR) ν 2480, 2070, 1120, 974, 737 cm-1;
[휶]ퟐ푫ퟏ = +80.0° (c 1.15 CHCl3); HRMS (ESI) HRMS (ESI) [M+Na]+:
calcd for C20H22F2N2NaO2 : 383.1542; found 383.1542; [M+H]+:
calcd for C20H23F2N2O2: 361.1722; found 361.1717.
(3R,3aR,6R,6aR)-N,N’-Bis(4-methoxybenzyl)hexahydro
1
furo[3,2-b]furan-3,6-diamine 4b: H NMR (MeOD, 400 MHz) δ
3.34-3.40 (m, 4H, H2, H5, H3, H6), 3.66 (d, J = 12.6, 2H, H1’), 3.76
(s, 6H, OMe), 3.78 (d, J = 12.6, 2H, H1’), 3.95-4.07 (m, 2H, H2,
H5), 4.52 (d, J = 1.5, 2H, H3a, H6a), 6.87 (d, J = 8.7, 4H, Hc), 7.25
(d, J = 8.7, 4H, Hb); 13C NMR (MeOD, 100 MHz) δ 52.4 (2 C1’),
55.6 (2 OMe), 63.2 (C3/C6), 73.1 (C2/C5), 82.2 (C3a/C6a), 114.9 (4
Cc), 130.8 (4 Cb), 132.4 (2 Ca), 160.5 (2 Cd); IR (ATR) ν 2747,
1514, 1250, 1121, 1036, 735 cm-1; [휶]푫ퟐퟏ = +101.1° (c 0.95 CHCl3);
HRMS (ESI) [M+Na]+: calcd for C22H28N2NaO2: 407.1941; found
(3R,3aR,6R,6aR)-N,N’-Bis(4-methylbenzyl)hexahydrofuro
[3,2-b]furan-3,6-diamine 4g: 1H NMR (MeOD, 400 MHz) δ 2.31
(s, 6H, Me), 3.32-3.46 (m, 4H, H2, H5, H3, H6), 3.68 (d, J = 12.6,
2H, H1’), 3.80 (d, J = 12.6, 2H, H1’), 3.98-4.05 (m, 2H, H2, H5),
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10.1002/ejoc.201901661
European Journal of Organic Chemistry
FULL PAPER
4.53-4.55 (m, 2H, H3a, H6a), 7.13 (d, J = 8.0, 4H, Hc), 7.22 (d, J =
8.0, 4H, Hb); 13C NMR (MeOD, 100 MHz) δ 21.2 (2 Me), 52.7 (2
C1’), 63.3 (C3/C6), 73.1 (C2/C5), 82.2 (C3a/C6a), 129.6 (4 Cb), 130.2
(4 Cc), 137.4 (2 Ca), 138.1 (2 Cd); IR (ATR) ν 2944, 2859, 2547,
1120, 978, 806 cm-1; [휶]푫ퟐퟏ = +106.9° (c 1.01 CHCl3); HRMS (ESI)
[M+Na]+: calcd for C22H28N2NaO2: 375.2043; found 375.2043;
[M+H]+: calcd for C22H29N2O2: 353.2224, found 353.2222.
1; [휶]ퟐ푫ퟏ = +62.5° (c 0.96 CHCl3); HRMS (ESI) [M+Na]+: calcd for
C26H52N2NaO2: 447.3921; found 447.3922; [M+H]+: calcd for
C26H53N2O2: 425.4102; found 425.4100.
(3R,3aR,6R,6aR)-N,N’-Bis(3-phenylpropyl)hexahydrofuro
1
[3,2-b]furan-3,6-diamine 4l: H NMR (MeOD, 400 MHz) δ 1.82
(app. quint, J = 7.3, 4H, H2’), 2.53-2.80 (m, 8H, H1’, H3’), 3.30-3.37
(m, 4H, H3, H6, H2, H5), 4.00-4.10 (m, 2H, H2,H5), 4.54-4.56 (m,
2H, H3a, H6a), 7.12-7.28 (m, 10 H, HAr). 13C NMR (MeOD, 100
MHz) δ 32.7 (2 C2’), 34.5 (3 C3’), 48.7 (2 C1’), 64.1 (C3/C6), 73.0
(C2/C5), 82.3 (C3a/C6a), 126.9 (2 Cd), 129.39 (4 Cb), 129.41 (4 Cc),
143.2 (2 Ca); IR (ATR) ν 3024, 2934, 2857, 1454, 1086, 746 cm-
1; [휶]ퟐ푫ퟏ = +81.6° (c 0.52 CHCl3); HRMS (ESI) [M+Na]+ calcd for
C24H32N2NaO2 403.2356, found 403.2351; [M+H]+ calcd for
C24H33N2O2 381.2537, found 381.2529.
(3R,3aR,6R,6aR)-N,N’-Bis(2-methylbenzyl)hexahydrofuro
[3,2-b]furan-3,6-diamine 4h: 1H NMR (MeOD, 400 MHz) δ 2.36
(s, 6H, Me), 3.36 (dd, J = 10.1 and 8.0, 2H, H2, H5), 3.44-3.49 (m,
2H, H3, H6), 3.73 (d, J = 12.8, 2H, H1’), 3.89 (d, J = 12.8, 2H, H1’),
4.07 (app. t, J = 8.0, 2H, H2, H5), 4.60 (dd, J = 4.1 and 2.0, 2H,
H3a, H6a), 7.12-7.16 (m, 6H, 6 HAr), 7.26-7.31 (m, 2H, 2 Hf); 13C
NMR (MeOD, 100 MHz) δ 19.1 (2 Me), 50.6 (2 C1’), 64.0 (C3/C6),
73.1 (C2/C5), 82.3 (C3a/C6a), 127.0 (2 Cc), 128.4 (2 Ce), 130.0 (2
Cf), 131.3 (2 Cd), 137.6 (2 Ca), 138.6 (2 Cb); IR (ATR) ν 2900,
1462, 1072, 743 cm-1; [휶]푫ퟐퟏ = +113.7° (c 0.95 CHCl3); HRMS
(ESI) [M+Na]+: calcd for C22H28N2NaO2: 375.2043, found
375.2045; [M+H]+: calcd for C22H29N2O2 353.2224; found
353.2223.
(3R,3aR,6R,6aR)-N,N’-(3-Methylbutyl)hexahydrofuro[3,2-
b]furan-3,6-diamine 4m: 1H NMR (MeOD, 400 MHz) δ 0.93 (d, J
= 6.6, 12H, 4 Me), 1.38-1.45 (m, 4H, H2’), 1.56-1.70 (m, 2H, H3’),
2.57 (dt, J = 11.2 and 7.7, 2H, H1’), 2.73 (dt, J = 11.2 and 7.7, 2H,
H1’), 3.30-3.41 (m, 4H, H2, H5, H3, H6), 4.08 (t, J = 5.9, 2H, H2, H5),
4.59-4.61 (m, 2H, H3a, H6a); 13C NMR (MeOD, 100 MHz) δ 22.9 (2
C4’), 23.2 (2 C4’), 27.4 (2 C3’), 40.0 (2 C2’), 47.4 (2 C1’), 64.2
(C3/C6), 73.1 (C2/C5), 82.2 (C3a/C6a); IR (ATR) ν 2951, 2866, 1466,
1366, 1160, 748 cm-1; [휶]푫ퟐퟏ = +91.4° (c 1.05 CHCl3);
HRMS (ESI) [M+Na]+: calcd for C16H32N2NaO2 307.2356; found
335.2663; [M+H]+: calcd for C16H33N2O2 285.2537; found
285.2535.
(3R,3aR,6R,6aR)-N,N’-Bis[(1,1'-biphenyl)-4-ylmethyl]hexa
hydrofuro[3,2-b]furan-3,6-diamine
4i:
1H NMR
(CDCl3, 400 MHz) δ 3.33 (dd, J = 10.1 and 8.1, 2H, H2, H5), 3.42-
3.49 (m, 2H, H3, H6), 3.82 (d, J = 13.0, 2H, H1’), 3.94 (d, J = 13.0,
2H, H1’), 4.12 (t, J = 8.1, 2H, H2, H5), 4.57 (dd, J = 3.1 and 1.4,
2H, H3a, H6a), 7.32-7.3 (m, 2H, HAr), 7.41-7.45 (m, 8H, HAr), 7.55-
7.60 (m, 8H, HAr); 13C NMR (CDCl3, 100 MHz) δ 52.2 (2 C1’), 62.9
(C3/C6), 72.9 (C2/C5), 81.0 (C3a/C6a), 127.2 (4 CHAr), 127.3 (6
CHAr), 128.7 (4 CHAr), 128.9 (4 CHAr), 139.3 (2 CqAr), 140.2 (2
CqAr), 141.1 (2 CqAr); IR (ATR) ν 2500, 1487, 1078, 762 cm-1;
[휶]ퟐ푫ퟏ = +102.3° (c 0.43 CHCl3); HRMS (ESI) [M+Na]+: calcd for
C32H32N2NaO2: 499.2356; found 499.2358, [M+H]+: calcd for
C32H33N2O2: 477.2537; found 477.2535.
(3R,3aR,6R,6aR)-N,N’-Dicyclohexylhexahydrofuro[3,2-
b]furan-3,6-diamine 4n: 1H NMR (MeOD, 400 MHz) δ 1.03-1.16
(m, 4H, CH2-cyclohexyl), 1.18-1.36 (m, 6H, CH2-cyclohexyl) 1.64-
1.68 (m, 2H, CH2-cyclohexyl), 1.74-1.79 (m, 4H, CH2-cyclohexyl),
1.88-1.91 (m, 2H, CH2-cyclohexyl), 1.94-1.97 (m, 2H, CH2-
cyclohexyl), 2.56 (tt, J = 10.8 and 3.8, 2H, CH-cyclohexyl), 3.31–
3.36 (m, 2H, H2, H5) 3.54-3.59 (m, 2H, H3, H6), 4.07 (app. t, J =
8.0, 2H, H2, H5), 4.57-4.58 (m, H3a, H6a); 13C NMR (MeOD, 100
MHz) δ 26.0 (2 CH2-cyclohexyl), 26.1 (2 CH2-cyclohexyl), 27.0 (2
CH2-cyclohexyl), 33.7 (2 CH2-cyclohexyl), 34.3 (2 CH2-
cyclohexyl), 56.4 (2 CH-cyclohexyl), 60.6 (C3/ C6), 73.3 (C2/C5),
(3R,3aR,6R,6aR)-N,N’-Dihexylhexahydrofuro[3,2-b]furan-3,6-
1
diamine 4j: H NMR (MeOD, 400 MHz) δ 0.90-0.93 (t, J = 6.8,
6H, 2 Me), 1.28-1.39 (m, 12H, H3’, H4’, H5’), 1.47-1.56 (m, 4H, H2’),
2.56 (ddd, J = 11.3, 8.5 and 6.4, 2H, H1’), 2.70 (ddd, J = 11.3, 8.5
and 6.4, 2H, H1’), 3.34-3.40 (m, 4H, H2, H5, H3, H6), 4.08 (app. t, J
= 6.1, 2H, H2, H5), 4.59-4.61 (m, 2 H, H3a, H6a); 13C NMR (MeOD,
100 MHz) δ 14.4 (2 Me), 23.7 (2 C5’), 28.1 (2 C3’), 30.9 (2 C2’),
32.9 (2 C4’), 49.2 (2 C1’), 64.1 (C3/C6), 73.1 (C2/C5), 82.3 (C3a/C6a);
IR (ATR) ν 2928, 2857, 1464, 1200, 1028, 744, 733 cm-1;
[휶]ퟐ푫ퟏ = +85.3° (c 0.68 CHCl3); HRMS (ESI) [M+Na]+: calcd for
C18H36N2NaO2 335.2669: found 335.2663; [M+H]+: calcd for
C18H37N2O2: 313.2850; found 313.2846.
82.6 (C3a/C6a); IR (ATR) ν 2926, 2856, 1450, 1090 cm-1; [휶]푫ퟐퟏ
=
+78.3° (c 0.69 CHCl3); HRMS (ESI) [M+Na]+: calcd for
C18H32N2NaO2: 331.2356; found 331.2352; [M+H]+: calcd for
C18H33N2O2: 309.2537; found 309.2532.
(3S,3aR,6R,6aR)-6-Aminohexahydrofuro[3,2-b]furan-3-ol 7
In a 25 mL flask, Pd/C (10%) (79 mg, 0.5 mass. eq) was added to
a solution of compound 3a (157 mg, 0.68 mmol, 1 eq) in
anhydrous methanol (7.5 mL) under argon. After 3 vacuum-argon
cycles and 3 vacuum-hydrogen cycles, the suspension was
stirred at room temperature under H2 (1 atm) for 30 hours. After
completion, the reaction mixture was filtered through a Celite® bed
and then washed several times with methanol. The crude product
was purified on column chromatography on silica gel using
dichloromethane/MeOH/NEt3 95:5:1 as eluent affording 7 as a
(3R,3aR,6R,6aR)-N,N’-Didecylhexahydrofuro[3,2-b]furan-3,6-
diamine 4k: 1H NMR (MeOD, 400 MHz) δ 0.90 (m, 6H, 2Me),
1.25-1.41 (m, 28H, H3’, H4’, H5’, H6’, H7’, H8’, H9’), 1.49 - 1.54 (m,
4H, H2’), 2.55 (ddd, J = 11.3, 8.5 and 6.4, 2H, H1’), 2.70 (ddd, J =
11.3, 8.5, 6.4, 2H, H1’), 3.32 - 3.37 (m, 4H, H2, H5, H3, H6), 4.07
(app. t, J = 6.2, 2H, H2, H5), 4.58-4.61 (d, J = 2.1, 2H, H3a, H6a);
13C NMR (MeOD, 100 MHz) δ 14.5 (2 Me), 23.8 (2 C9’), 28.4 (2
C3’), 30.7 (2 C2’), 30.5, 30.6, 30.7 and 31.0 (2 C7’, 2 C6’, 2 C5’, 2
C4’), 33.1 (2 C8’), 49.4 (2 C1’), 64.2 (C3/C6), 73.1 (C2/C5), 82.2
(C3a/C6a); IR (ATR) ν 2924, 2853, 1466, 1265, 1084, 737 cm-
1
pale yellow solid (74 mg, 76% yield).Mp = 62-65 °C; H NMR
(MeOD, 400 MHz) δ 3.24 (dd, J = 9.9 and 8.1, 1H, H5), 3.47-3.41
(ddd, J = 9.9, 8.1 and 4.1, 1H, H6), 3.83-3.86 (m 2H, H2), 3.93
(app. t, J = 8.1, 1H, H5), 4.17-4.19 (m, 1H, H3), 4.42 (dd, J = 4.1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901661
European Journal of Organic Chemistry
FULL PAPER
and 1.1, 1H, H3a), 4.48 (app. t, J = 4.1, 1H, H6a); 13C NMR (MeOD,
100 MHz) δ 56.6 (C6), 73.0 (C5), 76.5 (C2), 77.9 (C3), 83.6
(C6a), 89.8 (C3a); [휶]ퟐ푫ퟏ = +44.2 (c 1.13, MeOH); HRMS (ESI)
[M+Na]+: calcd for C6H11NNaO3:168.0631; found 168.0637;
[M+H]+: calcd for C6H12NO3:146.0817; found 146.0810.
Mp = 60-63 °C; 1H NMR (CD3OD, 300 MHz) δ 3.27 (dd, J = 10.0
and 8.2, 2H, H2, H5), 3.42-3.49 (m, 2H, H3, H6), 4.01 (app. t, J =
8.2, 2H, H2, H5), 4.37-4.41 (m, 2H, H3a,H6a); 13C NMR (CD3OD, 75
MHz) δ 57.4 (C3/C6), 74.7 (C2/C5), 84.7 (C3a/C6a); IR (ATR) ν 3354,
3294, 2945, 2868, 1661, 1593, 1524, 1028, 1007, 966, 930 cm-1;
[휶]ퟐ푫ퟓ +119.4° (c 0.47, MeOH); HRMS (ESI) [M+H]+: calcd for
C6H13N2O2: 145.0972; found 145.0974.
(3R,3aR,6R,6aR)-hexahydrofuro[3,2-b]furan-3,6-diamine 8
In a flask, Pd/C (10%) (290 mg, 0.75 mass. eq) was added to a
solution of compound 4a (387 mg, 1.19 mmol, 1 eq) in anhydrous
methanol (25 mL) under Argon. After 3 vacuum-argon cycles and Acknowledgments
3 vacuum-hydrogen cycles, the suspension was stirred at room
temperature under H2 (1 atm) for 48 hours. After completion, the
reaction mixture was filtered through a Celite® bed and then
washed several times with methanol. The filtrate was
concentrated to give compound 8 as a white solid (157 mg, 92%
yield).
The authors are grateful for the access to the MS analysis at the
CCSM and NMR facilities at the Université Lyon 1. The French
Ministry of Research and INSA Lyon (Projet BQR2018 ICBMS)
are acknowledged for F.B.’s Ph.D. grant and E.C.’s Master grant,
respectively.
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Keywords: isohexide • borrowing hydrogen • iridium catalysis • regioselectivity • diastereoselectivity
Keytopic: bio-based chemistry
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901661
European Journal of Organic Chemistry
FULL PAPER
TOC Text: Isohexides, chiral bio-based diols, were directly functionalized to provide novel amines using the borrowing hydrogen
methodology. The efficient regio- and diastereo-controlled synthesis of chiral mono- and di-amines was thus achieved using cooperative
catalysis between an iridium complex and a Brønsted acid.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901661
European Journal of Organic Chemistry
FULL PAPER
This article is protected by copyright. All rights reserved.