Synthesis of N1-tritylethane-1,1,2,2-d4-1,2-diamine: A novel mono-protected C-deuterated ethylenediamine synthon

Article abstract of DOI:10.1002/jlcr.2977

A convenient and high-yield synthesis for N¹-tritylethane-1,1,2, 2-d₄-1,2-diamine, a novel mono-protected ethylenediamine-C-d ₄, is reported. N¹-tritylethane-1,1,2,2-d ₄-1,2-diamine was prepared in three steps from ethylene oxide-d ₄ in a combined yield in the range 68-76%. Also reported is a synthesis of ethylenediamine-C-d₄ in two steps from 1,2-dibromoethane-d₄ in a combined yield in the range 61-65%. Published 2012. This article is a US Government work and is in the public domain in the USA.

Full text of DOI:10.1002/jlcr.2977

Research Article
Received 22 August 2012,
Revised 20 September 2012,
Accepted 27 September 2012
Published online 25 October 2012 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.2977
Synthesis of N1-tritylethane-1,1,2,2-d4-1,
2-diamine: a novel mono-protected
C-deuterated ethylenediamine synthon
*
Jun Yang, Kunlun Hong, and Peter V. Bonnesen
A convenient and high-yield synthesis for N1-tritylethane-1,1,2,2-d4-1,2-diamine, a novel mono-protected ethylenediamine-
C-d4, is reported. N1-tritylethane-1,1,2,2-d4-1,2-diamine was prepared in three steps from ethylene oxide-d4 in a combined
yield in the range 68–76%. Also reported is a synthesis of ethylenediamine-C-d4 in two steps from 1,2-dibromoethane-d4
in a combined yield in the range 61–65%.
Keywords: deuterated ethylenediamine; ethylenediamine-C-d4; trityl-protected ethylenediamine-C-d4; en-C-d4, Mitsunobu reaction
equivalent of di-tert-butyldicarbonate, followed by neutralization.
This methodology could be applied to en-C-d4, but overall yields
from a deuterated starting material such as 1,2-dibromoethane-d4
could still be <30%.
Introduction
Ethylenediamine is a key building block in the polyamido(amine)
(PAMAM) class of dendrimers.1,2 With regard to the use of
neutron scattering methods to gain more insight into the solution
To increase the yield of a mono-protected en-C-d4 reagent
structure and conformations of PAMAM dendrimers, particularly of
and to conserve deuterium, we sought a means to introduce a
the higher (G4 and G5) generations, preparing deuterated analogs
single protecting group to one of the amine groups through
of PAMAM dendrimers is of great interest. Toward the preparation
of PAMAM dendrimers in which ethylenediamine linkages are
C-deuterated (>NCD2CD2N<), we were interested in methods
of preparing ethylenediamine-C-d4 by a convenient and efficient
synthetic route in which one of the amine groups possessed a
stable but easily cleavable protecting group.
an en-C-d4 precursor molecule. We were particularly interested
in the triphenylmethyl (trityl) moiety as the protecting group,
as it is easily cleavable using 1N HCl, conditions that many other
functionalities can tolerate. Here, we report the preparation of
N1-tritylethane-1,1,2,2-d4-1,2-diamine in three steps from ethylene
oxide-d4, in isolated yields in the range 68–76%. We also report the
two-step synthesis of en-C-d4 from 1,2-dibromoethane-d4 by using
the Gabriel synthesis in isolated yields in the range 61–65%.
Although ethylenediamine-C-d4 (and derivatives such as N,
N0-dibenzylethylene-C-d4-diamine and ethylenediamine-C-d4
dihydrochloride) and ethylenediamine-d8 are commercially
available, they are generally quite expensive, at hundreds to
thousands of dollars per gram, depending on the compound.
Published synthetic routes to ethylenediamine-C-d4 (en-C-d4) have
Experimental
included the synthesis of the dihydrobromide (en-C-d4ꢀ2HBr) in
General
excellent yields (80–90%) by direct reaction of anhydrous
ammonia with 1,2-dibromoethane-d4 in a sealed tube at 55 ꢁC.3
All chemicals were reagent grade and used as received without further
purification unless noted otherwise. The deuterated starting materials
However, the reported yield on the free amine from the hydrobro-
1,2-dibromoethane-d4 (99 atom %D) and ethylene oxide-d4 (99.5 atom
%D) were obtained from Cambridge Isotope Laboratories, Inc., Andover,
MA, USA. The ethylene oxide-d4 was received in a lecture bottle and can
be used as received without further purification to make 2-(tritylamino)
mide salt was low (29%). Although the Gabriel synthesis4 was
mentioned3 as a possible route, we have not located a published
procedure for en-C-d4 using phthalimide chemistry.
Selective protection of one amine group of en-C-d4 (such as with
the tert-butyl carbamate or ‘t-Boc’ group5,6) from direct reaction of
the protecting reagent with en-C-d4 using stoichiometric control
invariably leads to mixtures containing unreacted diamine,
mono-substituted diamine, and di-substituted diamine, and
hence, yields of the desired mono-substituted product (e.g.,
ethan-1,1,2,2-d4-ol (2). However, because we had available in our
laboratory ampoules containing ethylene oxide-d4 that we had purified
for the purpose of synthesizing deuterated poly(ethylene oxide), for
convenience, we used the purified material. As a point of interest, this
t-BocNHCD2CD2NH2) are often low (≤30%;5,6 t-BocNHCD2CD2NH2 Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak
Ridge, TN 37831-6494, USA
is commercially available from for example C/D/N Isotopes Inc.).
It has been reported that significantly higher yields (87%) of
t-BocNHCH2CH2NH2 can be achieved by treating ethylenedia-
*Correspondence to: Peter V. Bonnesen, Center for Nanophase Materials Sciences,
Oak Ridge National Laboratory, Oak Ridge, TN 37831–6494, USA.
7
mine sequentially with one equivalent of HCl and then one E-mail: bonnesenpv@ornl.gov
Published 2012. This article is a US Government work
and is in the public domain in the USA.
J. Label Compd. Radiopharm 2012, 55 463–466

J. Yang et al.
purification involved condensing the ethylene oxide-d4 into a round
bottom flask containing calcium hydride that had been cooled to
ꢂ78 ꢁC, degassing, stirring at ꢂ10 ꢁC for 30 min, and then distilling to
a second flask containing sodium metal. After again degassing and
stirring at ꢂ10 ꢁC for 30 min, the material was distilled to a third flask
containing n-BuLi, and the purified ethylene oxide-d4 was finally
distilled into graduated ampoules.
Proton and proton-decoupled carbon (without nuclear Overhauser
effect enhancement) NMR spectra were obtained on a Varian VNMRS
500 NMR spectrometer (Palo Alto), operating at 499.72 MHz for proton.
Spectra were recorded at 23 ꢁC in either CDCl3 or D2O/TSP (TSP = sodium
3-(trimethylsilyl)propionate-2,2,3,3-d4). Spectra recorded in CDCl3 were
referenced to the residual CHCl3 at 7.24 ppm for proton spectra and to
the center CDCl3 peak at 77.23 ppm for carbon spectra; spectra recorded
in D2O/TSP were referenced to 0 ppm for TSP for both proton and car-
bon spectra. Elemental analysis was performed by Columbia Analytical
Services, Tucson, AZ, USA.
2-(2-(tritylamino)ethyl)isoindoline-1,3-dione (3H)
The non-deuterated analog 3H was prepared in an analogous manner to 3.
M.p. 201–202 ꢁC. 1H NMR (CDCl3, d ppm): 7.86 (m, 2H, Phthal), 7.71 (m, 2H,
Phthal), 7.37 (d, J= 7.5Hz, 6H, TritArH2,6), 7.16 (t, J = 7.5 Hz, 6H, TritArH3,5),
7.11 (t, J = 7.5 Hz, 3H, TritArH4), 3.79 (t, J = 6.0 Hz, 2H, PhthalCH2–), 2.45
(t, J = 6.0Hz, 2H, TritNHCH2–), 1.77 (br s, 1H, –NH). 13C {1H} NMR (CDCl3,
d ppm): 168.7 (C= O), 145.9 (TritAr1), 134.2 (PhthalAr4,5), 132.4 (PhthalAr1,2),
128.6 (TritAr3,5), 128.0 (TritAr2,6), 126.5 (TritAr4), 123.4 (PhthalAr3,6), 70.9
(Ph3C), 42.8 (TritNHCH2–), 38.7 (PhthalCH2–).
N1-tritylethane-1,1,2,2-d4-1,2-diamine (4)
To a 250-mL round bottom flask were added 3 (10.0 g, pooled from
several syntheses, 22.9 mmol), toluene (40 mL), absolute ethanol (80 mL),
and a stir bar. The mixture was heated to reflux, and hydrazine monohy-
drate (6.68 mL, 138 mmol) was added into the solution using a syringe.
The solution became clear, and after 30 min, a white precipitate formed.
The mixture was refluxed overnight. The solution was cooled to room
temperature, and the white precipitate was filtered off and washed with
absolute ethanol (10 mL ꢃ 3). The solvent was removed from the combined
filtrate and washings by rotary evaporation, and the product dried
under vacuum. The product was obtained as white solid (6.93 g, 99%).
M.p. >90 ꢁC (decomposed). 1H NMR (CDCl3, d ppm): 7.50 (d, J = 7.5 Hz,
6H, ArH2,6), 7.27 (t, J = 7.5 Hz, 6H, ArH3,5), 7.18 (t, J = 7.5 Hz, 3H, ArH4)
1.58 (br s, 3H, –NH and –NH2). 13C {1H} NMR (CDCl3, d ppm): 146.3
(Ar1), 128.8 (Ar3,5), 127.9 (Ar2,6), 126.4 (Ar4), 70.8 (Ph3C), 45.7 (p, JCD = 20
Hz, –NHCD2–), 42.0 (p, JCD = 20 Hz, –CD2NH2).
2-(tritylamino)ethan-1,1,2,2-d4-ol (2)
The following is a typical reaction. A 350-mL heavy wall glass pressure
vessel was charged with trityl amine (20.0 g, 77.0 mmol), methanol
(120 mL), and a stir bar. The stirred suspension was cooled to 0 ꢁC in an
ice bath. An ampoule containing ethylene oxide-d4 (1, 4.5 mL, 83 mmol)
also cooled to 0 ꢁC was opened, and the contents were quickly
transferred to the vessel. The vessel was sealed with a solid Teflon bushing
with a Viton O-ring back seal, and the reaction mixture heated slowly to
80 ꢁC in an oil bath (caution: this operation should be performed behind a
shield). The mixture was stirred at this temperature for 12 h, during which
time the mixture became clear and yellow. The solution was allowed to cool
to room temperature, and the bushing was carefully opened behind a
shield. The solution was transferred to a 500-mL round bottom flask, the
solvent removed by rotary evaporation, and the crude product purified
by column chromatography using a mixture of ethyl acetate and hexanes
in a 1:2 volume ratio. The product was obtained as a white solid (20.88 g,
88%). M.p. 92–95 ꢁC. 1H NMR (CDCl3, d ppm): 7.55 (d, J = 7.5 Hz, 6H,
ArH2,6), 7.33 (t, J = 7.5Hz, 6H, ArH3,5), 7.24 (t, J= 7.5 Hz, 3H, ArH4), 2.24 (br s,
2H, –NH and –OH). 13C {1H} NMR (CDCl3, d ppm): 146.0 (Ar1), 128.7 (Ar3,5),
128.0 (Ar2,6), 126.5 (Ar4), 70.7 (Ph3C), 61.8 (p, JCD = 21 Hz, –CD2OH), 44.9
(p, JCD = 20 Hz, –NHCD2–).
2-(2-aminoethyl)isoindoline-1,3-dione hydrochloride (5HꢀHCl)
To a 100-mL round bottom flask were added 3H (0.60g, 1.4 mmol), hydro-
chloric acid (1N, 25 mL), and a stir bar. The mixture was heated to 80 ꢁC with
stirring for 4 h, during which time triphenyl methanol precipitated out. After
the mixture was cooled to room temperature, the precipitate was filtered
and washed with H2O (5mL ꢃ 3). The water was removed from the
combined filtrate and washings by rotary evaporation, leaving a white solid,
which was further dried under high vacuum (0.26g, 82%). The purity as
determined by 1H NMR was about 95%, with the remaining 5% consisting
of a 1:1 mixture of phthalic acid and enthylenediamine dihydrochloride,
produced through acid hydrolysis of the product. 1H NMR (D2O/TSP,
d ppm): 7.84 (m, 4H, Phthal), 4.02 (t, J = 5.8 Hz, PhthalCH2-), 3.36
(t, J = 5.8 Hz, –CH2ND3Cl). 13C {1H} NMR (D2O/TSP, d ppm): 173.0 (C = O),
137.9 (PhthalAr4,5), 134.0 (PhthalAr1,2), 126.5 (PhthalAr3,6), 41.4
(ꢂCH2ND3Cl), 38.2 (PhthalCH2–).
2-(2-(tritylamino)ethyl-1,1,2,2-d4)isoindoline-1,3-dione (3)
To a 250-mL round bottom flask were added 2-(tritylamino)ethan-
1,1,2,2-d4-ol (2, 5.13 g, 16.7 mmol), triphenyl phosphine (5.25 g,
20.0 mmol), phthalimide (2.95 g, 20.0 mmol), dry THF (150 mL), and a
stir bar. The mixture was cooled to 0 ꢁC with stirring, and diethyl
azodicarboxylate (DEAD, 9.12 mL of a 40 wt.% solution in toluene,
20.0 mmol) was added dropwise to the mixture. At the end of the
addition, the mixture was allowed to warm to ambient temperature,
and stirring continued overnight. The solvent was removed by rotary
evaporation, and the crude product was diluted with 150 mL CHCl3
and allowed to stand at room temperature for 4 h, during which time
most of the diethyl hydrazine-1,2-dicarboxylate byproduct precipitated
out. The solution was filtered, and the solvent evaporated from the
filtrate to leave a residue that contained both the product and triphe-
nylphosphine oxide. Final purification was achieved by column
2,20-(ethane-1,1,2,2-d4-1,2-diyl)diisoindoline-1,3-dione (6)
To a 500-mL round bottom flask were added potassium phthalimide (53.09 g,
287 mmol), 1,2-dibromoethane-d4 (25.0 g, 130 mmol), dimethylformamide
(400mL), and a stir bar. The mixture was stirred at 95 ꢁC overnight. The
mixture was cooled to room temperature and poured into 1-L water, preci-
pitating a white solid. This suspension was stirred for 30min, filtered, and
the precipitate washed with water (25 mL ꢃ 3). The precipitate was dried
under vacuum to afford the product as a white solid (39.15 g, 93%). M.p.
235.5–236.0 ꢁC. 1H NMR (CDCl3, d ppm): 7.80 (m, 4H, Phthal), 7.70 (m. 4H,
Phthal). 13C {1H} NMR (CDCl3, d ppm): 168.2 (C = O), 134.0 (PhthalAr4,5),
131.9 (PhthalAr1,2), 123.4 (PhthalAr3,6), 36.2 (m, JCD = 22 Hz, –CD2 CD2–).
Ethylenediamine-C-d4 (7)
chromatography, and the product was eluted using a mixture of ethyl To a 500-mL round bottom flask were added 6 (39.15 g, 121 mmol),
acetate and hexanes in a 1:2 volume ratio. The product was obtained methanol (250 mL), and a stir bar. The mixture was stirred and heated
as white solid (6.11 g, 84%). M.p. 203–205 ꢁC. 1H NMR (CDCl3, d ppm): to reflux. Hydrazine monohydrate (12.9 mL, 266 mmol) was added to
7.88 (m, 2H, Phthal), 7.72 (m, 2H, Phthal), 7.41 (d, J = 7.5 Hz, 6H, the solution. The solution was refluxed overnight during which time a
TritArH2,6), 7.19 (t, J = 7.5 Hz, 6H, TritArH3,5), 7.13 (t, J = 7.5 Hz, 3H, white precipitate formed. After the mixture was cooled to room tempera-
TritArH4), 1.82 (br s, 1H, –NH). 13C {1H} NMR (CDCl3, d ppm): 168.6 ture, the precipitate was filtered off and washed with methanol (10 mL ꢃ 3).
(C = O), 145.9 (TritAr1), 134.1 (PhthalAr4,5), 132.3 (PhthalAr1,2), 128.5 The combined filtrate and washings were refluxed for 1 h over 6.5 g of CaH2
(TritAr3,5), 128.0 (TritAr2,6), 126.4 (TritAr4), 123.2 (PhthalAr3,6), 70.7 to remove water. After filtering, the solution was fractionally distilled
(Ph3C), 41.8 (p, JCD = 20 Hz, TritNHCD2–), 37.8 (p, JCD = 21 Hz, at atmospheric pressure, and the colorless liquid distilling at 109ꢁC was
PhthalCD2–). Anal. Calc. for C29H20D4N2O4 (%): C, 79.79; H + D, 6.46; collected, yielding 5.57 g (91.6% w/w in methanol; 66% overall yield).
N, 6.42; Found: C, 79.89; H + D, 6.07; N, 6.40.
13C {1H} NMR (CDCl3, d ppm): 43.2 (p, JCD = 20Hz, –CD2CD2–).
www.jlcr.org
Published 2012. This article is a US Government work
and is in the public domain in the USA.
J. Label Compd. Radiopharm 2012, 55 463–466

J. Yang et al.
1
been reported in the literature, the H NMR spectrum is very
Results and discussion
Synthesis of N1-tritylethane-1,1,2,2-d4-1,2-diamine
similar to that of 3, except of course for the presence of the
two triplet resonances at 3.79 and 2.45 ppm, respectively, for
the PhthalCH2– and TritNHCH2– protons. In the 13C NMR, the
PhthalCH2– and TritNHCH2– are singlets and are shifted slightly
(~1 ppm unit) downfield relative to deuterated 3 at, respectively,
38.7 and 42.8 ppm.
Because 3 is ethylenediamine-C-d4 bearing dissimilar protecting
groups at the two amine termini, in principle, either the phthal-
imide group or the trityl group can be cleaved to afford the trityl–
or phthalimide– mono-protected ethylenediamine-C-d4. Cleaving
the phthalimide group by heating 3 with excess hydrazine mono-
hydrate in a 2:1 vol/vol mixture of ethanol and toluene affords the
title compound N1-tritylethane-1,1,2,2-d4-1,2-diamine (4) as a
white solid in high purity at nearly quantitative yield (typically
99%). Similar to 2 and 3, the 13C NMR showed two pentet signals
for the two –CD2– groups; however, for this compound, the JCD
was 20 Hz in both cases, with the pentets centered at 45.7 ppm
(TritNHCD2–) and 42.0ppm (ꢂCD2NH2). The combined yield for
the three steps for preparing N1-tritylethane-1,1,2,2-d4-1,2-diamine
from ethylene oxide-d4 is in the 68–76% range.
For our purposes, 4 was the desired synthon; however, if the
phthalimide-protected ethylenediamine-C-d4 is desired instead,
3 could be treated with 1N HCl to cleave the trityl group to afford
2-(2-aminoethyl-1,1,2,2-d4)isoindoline-1,3-dione (5) as the stable
hydrochloride 5ꢀHCl. To test this option, we performed the reac-
tion on the hydrogen version 3H (Scheme 2) by heating a
solution of 3H in 1N aqueous HCl at 80 ꢁC for 4 h. After cooling,
the solution was filtered to remove the insoluble triphenyl methan-
ol that precipitated. Removal of the water from the aqueous
filtrate afforded 2-(2-aminoethyl)isoindoline-1,3-dione hydrochlor-
ide, 5HꢀHCl, at a purity of 95%, in 82% yield. Acid hydrolysis of the
phthalimide group is a competing side reaction, and the remaining
5% of the product was a 1:1 mixture of phthalic acid and ethylene-
diamine dihydrochloride. Hence, this reaction would need to
be monitored carefully to avoid excessive hydrolysis of the
phthalimide group.
The triphenylmethyl (trityl) group is a useful protecting group for
primary amines8,9 that can be easily and quantitatively removed
using 1N–6N aqueous HCl and as such was suitable for our
research needs. A search of the literature revealed no reports of
N1-tritylethane-1,1,2,2-d4-1,2-diamine, but the di-deuterated ana-
log 2-(tritylamino)ethan-1,1-d2-ol has been previously reported.10
That material was synthesized in two steps by the reaction of trityl
chloride with ethyl glycine ester hydrochloride, followed by reduc-
tion of the ester carbonyl with lithium aluminum deuteride. In our
case, to obtain the –CD2CD2– linkage, we used the ring opening
reaction of trityl amine with commercially available ethylene
oxide-d4 to obtain 2-(tritylamino)ethan-1,1,2,2-d4-ol (2) (Scheme 1),
knowing that we could convert the pendant hydroxyl functionality
to an amine using Mitsunobu chemistry11 in combination with the
Gabriel reaction.4
For the synthesis of 2, the reaction was performed in a sealed
heavy-walled vessel capable of handling up to 80 PSI, because
the reaction temperature of 80 ꢁC needed for the nucleophilic
ring opening of the epoxide12 is well above the 9 ꢁC boiling point
of ethylene oxide-d4. Following purification by column chroma-
tography, 2 can be obtained as a white solid with a 92–95ꢁC melt-
ing point, with isolated yields typically in the 88–92% range
(reported in the Experimental Section is the largest scale reaction
performed, which provided 2 in 88% yield). The 1H NMR of 2
showed resonances associated with the phenyl protons of the trityl
group, plus a broad singlet at 2.24 ppm that represented both
the –NH– and –OH resonances. The 13C NMR featured the two
deuterated carbons as pentets, with C-D coupling constants of
21 Hz for –CD2OH (centered at 61.8ppm) and 20 Hz for –NHCD2–
(centered at 44.9 ppm); these coupling constants are similar to
those reported for other molecules containing the NCD2CD2N
group.13
Alcohol 2 was converted to amine 4 in two steps using the
Mitsunobu and Gabriel reactions. For the preparation of the
phthalimide intermediate 3, a 20% excess of triphenylphosphine,
phthalimide, and diethyl azodicarboxylate (DEAD) were used to
drive the conversion of 2 to 3. After purification by column
chromatography, product 3 is obtained as a white solid with
a 203–205 ꢁC melting point, with isolated yields typically in the
78–84% range. The 13C NMR again featured the deuterated
carbons as pentets with C-D coupling constants of 20 Hz for
the carbon (centered at 41.8 ppm) on the side attached to the
trityl group, and 21 Hz for the carbon (centered at 37.8 ppm)
on the side possessing the phthalimide group. For the non-
deuterated analog 2-(2-(tritylamino)ethyl)isoindoline-1,3-dione
(3H), which to the best of our knowledge has not previously
Synthesis of ethylenediamine-C-d4
Although the Gabriel synthesis4 had been mentioned3 as a possi-
ble route to en-C-d4, it appears that no detailed procedure for pre-
paring en-C-d4 using phthalimide chemistry has been reported in
the literature. We did find the Gabriel synthesis to be a useful route
for preparing en-C-d4 in two steps from commercially available 1,2-
dibromoethane-d4. Reaction of 1,2-dibromoethane-d4 with a 10%
excess of potassium phthalimide in dimethylformamide at 95ꢁC
overnight, followed by pouring the cooled solution into a large
volume of water, afforded the intermediate 2,20-(ethane-
1,1,2,2-d4-1,2-diyl)diisoindoline-1,3-dione (6) as a white precipitate
in high (93–99%) yields (Scheme 3). The product 6 is a shelf-stable
white solid with a melting point in the range 235.5–236.0 ꢁC, which
can be used to generate en-C-d4 (7) as needed.
Ph
Ph
Ph
Ph
D
D
O
H
N
80 o
88 - 92%
C
PPh3, phthalimide
D
D
Ph
+
NH2
Ph
Ph
OH
DEAD
78-84%
D
D
D
D
O
H
1
2
Ph
O
H
H
H
H
Ph
N
1 N HCl
Ph
Ph
N
N
O
D
D
H
N
Ph
Ph
NH2 HCl
Ph
D
D
H
4 h, 80 oC, 82%
H
H
N
Ph
N
H H
O
NH2NH2 H2O
reflux, 99%
O
NH2
D
D
3H
5H•HCl
D
D
O
3
4
Scheme 2. Conversion of 3H to 2-(2-aminoethyl)isoindoline-1,3-dione hydrochloride
(5HꢀHCl).
Scheme 1. Synthesis of N1-tritylethane-1,1,2,2-d4-1,2-diamine (4).
J. Label Compd. Radiopharm 2012, 55 463–466
Published 2012. This article is a US Government work
and is in the public domain in the USA.
www.jlcr.org

J. Yang et al.
O
D
Acknowledgements
O
O
D
D
D
DMF
Br
N
+
KN
Br
N
95 oC, 93-99%
This research was conducted at the Center for Nanophase
Materials Sciences, which is sponsored at the Oak Ridge National
Laboratory by the Scientific User Facilities Division, Office of Basic
Energy Sciences, US Department of Energy. This manuscript has
been authored by UT-Battelle, LLC, under Contract No. DE-AC05-
00OR22725 with the US Department of Energy. The publisher, by
accepting the article for publication, acknowledges that the United
States Government retains a non-exclusive, paid-up, irrevocable,
world-wide license to publish or reproduce the published form
of this manuscript, or allow others to do so, for United States
Government purposes.
D
D
O
D D
O
O
6
D
D
NH2NH2 H2O
reflux, 66%
H2N
NH2
D
D
7
Scheme 3. Synthesis of ethylenediamine-C-d4 (7).
Removal of the phthalimide groups to convert 6 to 7 was per-
formed using hydrazine monohydrate in a manner similar to that
described for converting 3 to 4, except that the stoichiometric
amount (two equivalents) of hydrazine monohydrate required
was used rather than an excess, and the reaction was performed
in pure methanol rather than the 2:1 ethanol : toluene mixture, to
Conflict of Interest
The authors did not report any conflict of interest.
facilitate the isolation of 7 via fractional distillation. Nevertheless, References
it is difficult to obtain 7 completely methanol-free without sacri-
[1] D. A. Tomalia, H. Baker, J. Dewald, M. Hall, G. Kallos, S. Martin,
ficing yield, and typically, the ethylenediamine-C-d4 is obtained
as a ~9:1 mixture with methanol, in 66% product yield, giving a
combined yield from 1,2-dibromoethane-d4 of 61–65%. Fully
deuterated ethylenediamine-d8 can be obtained from ethylene-
diamine-C-d4 following the method reported for converting
ethylenediamine to ethylenediamine-N-d4 via exchange with
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Summary
A procedure for preparing N1-tritylethane-1,1,2,2-d4-1,2-diamine,
4, a novel mono-protected ethylenediamine-C-d4, in three steps
from ethylene oxide-d4 in a combined yield in the range 68–76%,
has been successfully developed. This compound can be a useful
way for introducing the en-C-d4 moiety, where subsequent mild
deprotection conditions (e.g., 1N HCl) are needed. Also described
is a synthesis of en-C-d4 in two steps from 1,2-dibromoethane-d4
in combined yields in the range 61–65%.
www.jlcr.org
Published 2012. This article is a US Government work
and is in the public domain in the USA.
J. Label Compd. Radiopharm 2012, 55 463–466