A New, Short, and Stereocontrolled Synthesis of C2-Symmetric 1,2-Diamines

Article abstract of DOI:10.1021/acs.orglett.7b01768

The previously unknown 5-spirocyclohexylisoimidazole has been made efficiently and simply by reaction of ammonia, glyoxal hydrate, and cyclohexanone. It is a very useful precursor for the diastereocontrolled synthesis of many C₂-symmetric 1,2-diamines, a class which is important for the generation of a variety of C₂-symmetric reagents and catalysts for enantioselective synthesis.

Full text of DOI:10.1021/acs.orglett.7b01768

Letter
pubs.acs.org/OrgLett
A New, Short, and Stereocontrolled Synthesis of C2‑Symmetric 1,2-
Diamines
Rajender Vemula, Nathan C. Wilde, Rajendar Goreti, and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S
* Supporting Information
ABSTRACT: The previously unknown 5-spirocyclohexylisoi-
midazole has been made efficiently and simply by reaction of
ammonia, glyoxal hydrate, and cyclohexanone. It is a very
useful precursor for the diastereocontrolled synthesis of many
C2-symmetric 1,2-diamines, a class which is important for the
generation of a variety of C2-symmetric reagents and catalysts
for enantioselective synthesis.
e describe herein a new, stereocontrolled, short, and
Scheme 1. Projected Route to the Decafluoro Diamine 1
W
widely applicable synthesis of C2-symmetric 1,2-
diamines. This diamine class represents one of the most
important structural subunits for numerous reagents and
catalysts that have advanced synthetic carbomolecular chem-
istry over the past three decades.1,2 Since racemic C2-symmetric
amines are usually easily resolved as the salts with (+)- or
(−)-tartaric acid, our objective was to develop a method for the
synthesis of the racemic 1,2-diamines, free of contamination by
the meso diastereomers. This approach is time saving since
both enantiomers of the 1,2-diamine result from this process
and are available for applications after resolution.
formed in 90% yield simply by reaction of glyoxal trimer·2H2O,
cyclohexanone (3 equiv), and ammonium acetate (4 equiv) in
THF−anhydrous ammonia at 23 °C for 8 h, followed by
removal of solvents, extractive workup, and distillation (52 °C,
0.8 barr) as reported in detail in the Supporting Information.
Pure 2 is stable indefinitely when stored in a sealed container in
a−20 °C freezer. The conversion of the bis-imine 2 to the
fluorinated 1,2-diamine 3 was accomplished in 88% yield by the
following sequence of operations: (1) deprotonation of
pentafluoroethane in ether below −78 °C by slow addition of
precooled n-butyllithium to form the perfluoroethyllithium;5,6
(2) gradual addition of the cold solution of C2F5Li via cannula
to a stirred solution of 2 and BF3·Et2O (2 equiv) in ether at
−78 °C; (3) gradual increase in the temperature of the reaction
mixture to −50 °C for 12 h; (4) addition of aqueous NaHCO3
solution, extractive isolation with ether, and flash chromatog-
raphy. The C2-symmetric ( )-1,2-diamine 3 was formed with
The most widely used chiral C2-symmetric 1,2-diamines are
1,2-diphenyl-1,2-diaminoethane (DPEN)3 and trans 1,2-dia-
minocyclohexane (DAC),4 which have proven to be immensely
useful for enantioselective synthesis. The versatility of DPEN is
clear from its application to many enantioselective reactions,
including Diels−Alder,3a 1,2-dihydroxylation of olefins,3b syn-
or anti-aldol,3c carbonyl allylation,3d Ireland−Claisen rearran-
gement,3e−g Darzens reaction,3h β-lactam and β-amino acid
synthesis,3i prostanoid synthesis,3j,k Jacobsen olefin epoxida-
tion,3l Noyori carbonyl reduction.3m and Fu C−C coupling.3n,o
trans-1,2-Diaminocyclohexane has been especially useful for
enantioselective Horner−Wadsworth−Emmons reactions,4a,b
Jacobsen olefin epoxidation,4d and Pd-catalyzed allyl coupling
reactions via the Trost bisphosphine ligand.4f
One motivation for this research came from an initial interest
in synthesizing C2-symmetric 1,2-diamine derivatives in which
the electron density at nitrogen is greatly diminished. Such
compounds offer new possibilities as ligands for enantiose-
lective catalysis because of greatly attenuated electron density at
nitrogen. One of our objectives was a simple synthesis of
( )-1,2-pentafluoroethyl-1,2-diaminoethane (PFEEN) (1). As
described below, that goal was readily achieved by the addition
of perfluoroethyllithium to the previously unknown cyclic bis-
imine 2, as shown in Scheme 1.
1
complete exclusion of the meso isomer as shown by H and 13C
NMR analysis. As expected, the hydrolysis of the cyclo-
hexylidine diamine 3 required vigorous conditions: heating to
boiling with 6 N HCl and removal of a cyclohexanone−aq HCl
mixture by distillation. ( )-1,2-Perfluoroethyl-1,2-diamino-
ethane (PFEEN) was isolated by basification of the aqueous
acid, extraction with ether, and flash chromatography on neutral
alumina (86% yield). The stereochemistry of 1 was
demonstrated by conversion to the cyclic C2-symmetric aminal
with benzaldehyde (either with or without HOAc as catalyst)
A practical synthesis of the previously unknown precursor 2
for this synthetic approach to vic-diamines could be developed
from inexpensive starting materials. The bis-imine 2 was
Received: June 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01768
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Organic Letters
Letter
and separation of the resulting enantiomers by HPLC using a
chiral OD-H column and 95% hexanes in 2-propanol as the
eluent.7,8 Further studies with this novel, very weakly basic
diamine are in progress.
corresponding trans-4,5-disubstituted imidazolidines 12, 13,
and 14, as summarized in Scheme 4. The addition of 2-lithiated
furan and 4,5-benzofuran to 2 was also successful and provided
the trans-4,5-imidazolidines 15 and 16 (Scheme 4).
We were able to demonstrate the general utility of the cyclic
bis-imine 2 as a key starting material for the completely
diastereoselective synthesis of many racemic 1,2-diamines using
the approach described above for the synthesis of the
fluorinated diamine 1. A series of cyclohexylidine derivatives
of 1,2-diaryl-1,2-diaminoethanes was readily obtained by slow
addition of the corresponding aryllithium reagents to a solution
of BF3·Et2O and the bis-imine 2 in a ratio of 2:1. Aryl Grignard
reagents could also be used. In each case, only the trans-cyclic
amine was formed. These racemic cyclic diaryldiamines are
shown in Scheme 2 together with the yields of isolated product.
Scheme 4. Unsaturated and Heteroaromatic 1,2-Diamines
Scheme 2. Arylation Products Derived from 2
The cyclic bis-imine 2 is a valuable intermediate for further
elaboration into a variety of interesting nitrogen-containing
compounds, most obvious of which in the context of the
synthesis of 3−16 is the synthesis of monosubstituted 1,2-
diamines. Thus, the reaction of 2 with BF3·Et2O and 1 equiv of
C2F5Li in ether at −78 °C provided the cyclic monoamine 17
(90%), which was converted via the 4-substituted imidazolidine
18 to pentafluoroethylethylene diamine 19 (88% as the
hydrochloride) as indicated in Scheme 5.
Scheme 5. Synthesis of Monosubstituted 1,2-
Ethylenediamines
The conversion of the cyclic diamines 4−8 to the
corresponding rac-1,2-diaryl-1,2-diaminoethanes was accom-
plished in high yields by heating with 6 equiv of 2 N aqueous
HCl at 60 °C for 6 h followed by extractive isolation. Both
cyclic diamine 4 and the corresponding hydrolysis product
(DPEN) matched authentic samples, further confirming the
trans-selectivity of these reactions with bis-imine 2.
The attachment of two sp3 carbon centered groups to the key
cyclic intermediate 2 was also demonstrated as an effective
stereocontrolled route to trans-4,5-disubstituted imidazolidines
using n-butyllithium, tert-butyllithium, and cyclohexylmagne-
sium bromide, with ether as solvent in each case, to form the
racemic C2-symmetric products 9−11 shown in Scheme 3.
Furthermore, the addition of allyl, 3-butenyl, and propargyl
Grignard reagents in ether to 2 produced smoothly the
Another aspect of the versatility of the new approach to the
diastereoselective synthesis of 1,2-diamines that is disclosed
herein involves the use of functionalized substituents. For
example, catalytic olefin metathesis on the bis-olefinic diamines
12 and 13 (or N-protected derivatives) obviously could lead to
6- or 8-membered cyclic trans-1,2-diamines (or N-protected
derivatives).8 In addition, the facile synthesis of the useful C2-
symmetric bicyclic diamine9 23 by the route that is depicted in
Scheme 6 provides a quite different example of the synthetic
opportunities that our methodology enables. The key
intermediate 20 was readily obtained from the addition of 3-
(benzyloxy)propyllithium to 2, as detailed in Scheme 6, and
then converted to the bis-trifluoroacetyl bicyclic amide 22. The
free bicyclic diamine 23 was then obtained simply by hydrolysis
with base. The usefulness of 23 in catalysis has previously been
demonstrated.10
Scheme 3. Stereocontrolled Dialkylation of Bis-imine 2
B
DOI: 10.1021/acs.orglett.7b01768
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Letter
The N,N′-bistrifluoromethane sulfonamide derivative, mp 86−
88 °C,7 is actually a stronger acid than acetic acid with a
measured pKa of 3.57 in 1:9 ethanol−water at 23 °C. The
applications of these unusual compounds as chiral subunits for
enantioselective reactions (cf. ref 3) are now being studied.
Reaction of 1 with benzaldehyde in CH2Cl2 at ambient
temperature provided the corresponding aminal 28, which was
easily separated into the pure enantiomers by HPLC using
Chiral Technologies Chiralcel OD-H column with 95:5
hexanes−isopropyl alcohol for elution (peak 1, tR = 4.09 min,
and peak 2, tR = 6.00 min, on analytical scale, and tR = 3.87 and
5.43 min on a multigram preparative scale).7,8 Peaks 1 and 2
Scheme 6. Synthesis of C2-Symmetric Diamine 23
23
were shown to be S,S-28 ([α]D −17.2, c 1, CHCl3) and R,R-
23
28 ([α]D +17.5 c 1, CHCl3), respectively, by the results
described below. Hydrogenation of R,R-28 using H2, Pd−C
23
afforded the R,R-enantiomer of 1, [α]D −8.0 (c 1, CHCl3).
We have also been able to access the C2-symmetric 2,2′-
bisisoindoline 27 by an approach analogous to that used for the
synthesis of 23, as outlined in Scheme 7.
Scheme 7. Synthesis of C2-Symmetric Diamine 27
Three recrystallizations of the of ( )-1 with S,S-di-p-
toluoyltartaric acid and 9:1 1,2-dichloroethane−ethyl acetate
afforded an 85:15 mixture of the R,R- and S,S-diamine 1 salts,
indicating that resolution of ( )-1 by this particular salt is less
practical than the chromatographic separation described above.
Studies of other methods for direct resolution of 1 are
underway.
We have also synthesized R,R-1 using as a starting point the
bis-imine from glyoxal and S-α-methylbenzylamine (29) as
shown in Scheme 8. This method was first used in our
Scheme 8. Synthetic Route to R,R-(+)-1
The key intermediate 24 was obtained by reaction of the bis-
imine 2 with 2-[[(triisopropylsilyl)oxy]methyl]phenyllithium
(from 2-[[(triisopropylsilyl)oxy]methyl]iodobenzene and n-
BuLi in ether at −78 °C for 1 h) in the presence of 1 equiv
of BF3·Et2O in ether at −78 to −50 °C for 24 h. Acidic cleavage
of the TIPS ether and cyclohexylidine group in 24 was
accomplished using 2 N methanolic HCl at 23 °C for 16 h.
Trifluoroacetylation of the resulting dihydroxy diamine with
trifluoroacetic anhydride−pyridine provided the dihydroxy bis-
amide 25. Mitsunobu cyclization of 25 furnished bis-amide 26
(26% overall yield from 2), which by base treatment, afforded
the desired C2-symmetric diamine 27.
A few of the diamines discussed above have been resolved by
the traditional method using chiral 1:1 tartaric acid−diamine
salts and simple recrystallization from ethanol, as described in
detail in the Supporting Information for the diamines derived
from 7 and 10.
laboratories in 1988 for the synthesis of the R,R- and S,S-
enantiomers of 1,2-di-tert-butylethylenediamine11 and devel-
oped independently by Neumann et al.12 Reaction of 29 with
perfluoroethyllithium and BF3·Et2O at −78 °C afforded the bis-
adduct 30 with 92:8 diastereoselectivity. The product could be
purified by recrystallization from pentane or by conversion to
the crystalline triflate.
23
The structure of 30, mp 57 °C and [α]D −87.6 (c 2,
CHCl3), was confirmed by X-ray crystallographic analysis (see
Figure 1).7 Cleavage of the N-α-phenethyl groups under
strongly acidic conditions provided pure R,R-(+)-bis-penta-
fluoroethyl-1,2-diaminoethane in good yield.
As expected, the basicity of 1,2-pentafluoroethyl-1,2-diamino-
ethane (1, PFEEN) is greatly attenuated, with a measured pKa
of 2.45 in 10% ethanol and 90% water at 23 °C. Thus, PFEEN
is the least basic 1,2-disubstituted ethylenediamine now known.
In summary, the readily available cyclic bis-imine 2 serves as
a useful starting point for the completely diastereoselective and
very direct access to a wide variety of C2-symmetric 1,2-
C
DOI: 10.1021/acs.orglett.7b01768
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Organic Letters
Letter
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Figure 1. X-ray crystallographic structure of 30.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01768.
■
chenko, N. E.; Nenajdenko, V. G.; Roschenthaler, G.-V. J. Fluorine
̈
S
Chem. 2008, 129, 390−396. (b) Kazabova, O.; Roschenthaler, G.-V. In
̈
Efficient Preparation of Fluorine Compounds; Roesky, H. W., Ed.; J.
Wiley, 2013; pp 205−209.
(6) The formation of C2F5Li from C2F5H (commercial refrigerant
HFC-125) and n-BuLi is strongly exothermic, which necessitates that
n-BuLi be precooled and added slowly with good stirring and a bath
temperature of −80 to −90 °C (liquid N2−hexanes). Once formed,
C2F5Li is stable for at least 2 h at −78 °C; see the experimental
procedure in the Supporting Information for further details.
(7) See the Supporting Information for detailed HPLC information
for compound 28.
(8) For precedent, see: (a) Alvaro, G.; Grilli, S.; Martelli, G.; Savoia,
D. Eur. J. Org. Chem. 1999, 7, 1523−1526. (b) Grilli, S.; Martelli, G.;
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(9) (a) Ferguson, R. R.; Boojamra, C. G.; Brown, S. H.; Crabtree, R.
H. Heterocycles 1989, 28, 121−124. (b) Alexakis, A.; Tomassini, A.;
Chouillet, C.; Roland, S.; Mangeney, P.; Bernardinelli, G. Angew.
Chem., Int. Ed. 2000, 39, 4093−4095. (c) Denmark, S. L.; Fu, J.;
Lawler, M. J. Org. Synth. 2006, 83, 121−130.
(10) Chen, M. S.; White, M. C. Science 2007, 318, 783−787.
(11) Yuen, P.-W. Corey Group Research Report; Harvard University,
June 1988. See also: Lou, Y.; Remarchuk, T. P.; Corey, E. J. J. Am.
Chem. Soc. 2005, 127, 14223−14230.
(12) (a) Neumann, W. L.; Rogic, M. M.; Dunn, J. Tetrahedron Lett.
1991, 32, 5865−5868. (b) See also: Roland, S.; Mangeney, P.;
Alexakis, A. Synthesis 1999, 1999, 228−230.
Experimental methods and HPLC data for compound 28
(PDF)
1H and 13C NMR spectra for new compounds (PDF)
Crystallographic data for compound 30 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: corey@chemistry.harvard.edu.
ORCID
Rajender Vemula: 0000-0002-7214-1094
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Pfizer, Gilead, and Bristol-Myers Squibb for
research grants, Chiral Technologies for preparative-scale
HPLC separation of ( )-28, and DuPont/Chemours for a
gift of pentafluoroethane. The X-ray crystallographic analysis
was performed in the Harvard X-ray facility by Dr. Shao-Liang
Zheng.
REFERENCES
■
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DOI: 10.1021/acs.orglett.7b01768
Org. Lett. XXXX, XXX, XXX−XXX