Formate ester synthesis via reaction of 2-bromoethylamines with dimethylformamide

Article abstract of DOI:10.1016/j.tetlet.2008.01.002

2-Bromoethylamines are converted to the corresponding formate esters in the presence of DMF. Both primary and secondary bromides are smoothly transformed to the esters in satisfactory yields. The reaction mechanism involves the formation of an aziridinium ion, which upon reaction with DMF forms a Vilsmeier-type intermediate that is further hydrolyzed to the corresponding formates. Participation of the β-amino group appears to control not only the regioselectivity but also the stereoselectivity of the reaction. Application of the reaction conditions to chiral substrates indicated that non-rearranged products are formed with retention of configuration at the reacting center.

Full text of DOI:10.1016/j.tetlet.2008.01.002

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1648–1651
Formate ester synthesis via reaction of 2-bromoethylamines
with dimethylformamide
Marianna Dakanali a, George K. Tsikalas a, Harald Krautscheid b,
Haralambos E. Katerinopoulos a,*
a Division of Organic Chemistry, Department of Chemistry, University of Crete, Heraklion 71 003, Crete, Greece
b Fakulta¨t fu¨r Chemie und Mineralogie, Institut fu¨r Anorganische Chemie, Universita¨t Leipzig, 04103 Leipzig, Germany
Received 25 September 2007; revised 14 December 2007; accepted 3 January 2008
Available online 8 January 2008
Abstract
2-Bromoethylamines are converted to the corresponding formate esters in the presence of DMF. Both primary and secondary
bromides are smoothly transformed to the esters in satisfactory yields. The reaction mechanism involves the formation of an aziridinium
ion, which upon reaction with DMF forms a Vilsmeier-type intermediate that is further hydrolyzed to the corresponding formates. Par-
ticipation of the b-amino group appears to control not only the regioselectivity but also the stereoselectivity of the reaction. Application
of the reaction conditions to chiral substrates indicated that non-rearranged products are formed with retention of configuration at the
reacting center.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 2-Bromoethylamines; Formate esters; Aziridinium ion; Vilsmeier-intermediate
As a part of an ongoing project aimed at the synthesis of
zinc chelating sensors,1 we attempted the alkylation of aro-
matic amines with 2-[(2-bromoethyl)(cyanomethyl)amino]-
acetonitrile (1) using DMF as a reaction solvent. To our
surprise the alkylated amines were isolated as the minor
products of the reactions, the major product being the
corresponding formate ester 2. Reproduction of the experi-
mental conditions in the absence of nucleophile gave 2 in
66% yield (Scheme 1). Under the same experimental condi-
tions the bis-t-butyl ester analog, namely tert-butyl
2-((2-bromoethyl)(2-tert-butoxy-2-oxoethyl)amino)acetate
(3) gave the corresponding formate in 76% yield.
to the corresponding formate esters in methylene chloride,
using 2,4,6-trichloro-1,3,5-triazine and DMF in the pres-
ence of lithium fluoride.2 Similarly, O-tert-butyldimethyl-
silyl or O-triethylsilyl alcohols were converted to their
DIPEA
O
DMF
Br
CN
CN
C
O
CN
CN
H
N
80 °C, 18 h
N
66%
1
2
To the best of our knowledge there is no previous report
of such a transformation. The preparation of 2-aminoethyl-
formates has been mentioned in the literature as a result of
applications of general methods such as the conversion of
primary alcohols or their O-tert-butyldimethylsilyl ethers
O
t-Bu
DIPEA
DMF
O
t-Bu
O
Br
C
O
O
O
O
O
N
80 °C, 18 h H
N
76%
3
4
Ot-Bu
Ot-Bu
*
Scheme 1. Conversion of 2-bromoamines to the corresponding formate
esters.
Corresponding author. Tel.: +30 2810 545 026; fax: +30 2810 545 001.
E-mail address: kater@chemistry.uoc.gr (H. E. Katerinopoulos).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.002

M. Dakanali et al. / Tetrahedron Letters 49 (2008) 1648–1651
1649
Table 1
panamides and acetamides also gave the corresponding
formate esters as side-products in base promoted cyclo-
coupling reactions with DMF.7 Besides these reports, there
is no evidence that alkyl bromides are regularly converted
to formyl esters via reaction with dimethyl formamide.
Although limited, these initial results indicate that the
reaction proceeds via initial neighboring group partici-
pation of the nitrogen atom, most likely leading to the
formation of an aziridinium intermediate (Scheme 2).
Reaction of the aziridinium ion with DMF produces an
alkoxymethaniminium salt (a Vilsmeier-type intermediate)
which, either in the presence of traces of water or during
work-up, is hydrolyzed to the corresponding formate ester.
In a parallel example, N,N-bis-(2-chloroethyl)amides of ali-
phatic acids were reported to rearrange to the correspond-
ing esters via an intermediate oxazolinium ion.4
To test the validity of this hypothesis, we used substrates
that contained bromoethylamino-analogs with the amino
group at a secondary center. As mentioned in the literature,
diprotected 2-aminoalcohols with the amino group at a sec-
ondary center lead to the exclusive formation of rearranged
bromoamines with complete stereochemical inversion at
the secondary centers via translocation through aziridi-
nium salt intermediates.8
Dependence of the formate ester yield on the type of substrate, the
reaction time and the presence of base
DMF, 80 °C
Br
O
H
R
R
O
R
Compound Reaction time (h) Product yield (%)
NC
1
20
66
N
NC
t
t
-BuO2C
-BuO2C
N
3
20
76
O
5
20
44
N
O
6
6
6
6
20
71
97
68
74
Bn
Bn
40
N
20a
40a
7
7
7
8
20
40
60
20
24
61
80
7
Bn
Bn
N CH2
Following a published procedure,8 we synthesized N,N-
dibenzyl-2-bromo-3-phenyl-1-propanamine (10, Scheme 3A)
and subjected this compound to the formylation reaction
conditions. The result verified our initial hypothesis: since
the reaction proceeds via a substituted aziridinium interme-
diate, reaction with DMF took place predominantly in the
same fashion as in the bromination step, yielding the
unrearranged formate 11 as the major product. The minor
product 12, identified by GC/MS as the rearranged
formate, is apparently the result of the reaction of DMF
with the methylene carbon of the aziridinium system.
The study was extended by the conversion of 1-di-
benzylamino-2-propanol (13) to the corresponding second-
ary bromide,8 which was in turn treated with DMF to
PhCH2Br
a
DIPEA was used as base in the reaction.
corresponding formates under Vilsmeier–Haack conditions
(POCl3/DMF).3
To explore the mechanism as well as the scope of the
reaction we repeated the experiment using N-(2-bromo-
ethyl)phthalimide (5) where the nitrogen is part of a conju-
gated system. The yield of the corresponding formate was
reduced to 44%, presumably due to the reduced availability
of the electron pair on the nitrogen (Table 1). A similar
explanation was given for the lack of potency of N,N-bis-
(2-chloroethyl)nitroanilines as nitrogen mustards.4 The
two-carbon distance between the nitrogen and bromine
atoms appears crucial for the outcome of the reaction:
while N,N-dibenzyl-N-(2-bromoethyl)amine (6) gave the
desired formate in 97% yield after 40 h of heating, its
homologue N,N-dibenzyl-N-(3-bromopropyl)amine (7)
reacted much slower under the same conditions. The nitro-
gen base, used in the initial reaction, was not necessary,
since it did not accelerate the conversion of bromide 6 to
the desired product.
When benzyl bromide (8) was used as the substrate,
benzyl formate was isolated in only 7% yield after 20 h.
This compound was reported as a side-product in mixed
carbonate preparations involving treatment of benzyl
bromide with alcohols in the presence of K2CO3 and
Bu4NI, under a CO2 atmosphere, using DMF as a solvent.5
Formate esters were also formed as side-products upon the
reaction of bromomethyl substituted 2-isoxazolines with
AgNO3 when DMF was used as a solvent.6 2-Bromopro-
CN
CN
CN
CN
N:
N
Br
Br
H3C
H3C
O
N C
H
CN
CN
N
H3C
H3C
O
N C
Br
H
H
O
C
H3C
CN
CN
CN
CN
hydrolysis
N C
N:
N:
H3C
Br
H
O
O
Scheme 2. Proposed mechanism for the conversion of 2-bromoamines
into formate esters.

1650
M. Dakanali et al. / Tetrahedron Letters 49 (2008) 1648–1651
Ph
Br
A
Ph
Ph
SOBr2
NBn2
Br
OH
C4
DMF, rt
Bn2N
C10
C8
C5
Bn N
C2
C3
+
2
10
9
DMF, 80 °C
C9
N
C1
Ph
C11
Ph
Ph
NBn2
C6
+
C7
OCHO
OHCO
Bn2N
Bn2N
C12
C17
+
92%
11
2%
12
C13
___________________________________________________
C14
C15
B
OH
13
SOBr2
Br
C16
Bn2N
Bn2N
DMF, rt
14
Fig. 1. X-ray structure of (R)-14 (35% probability ellipsoids).
DMF, 80 °C, 8 h
OCHO
NBn2
+
aziridinium intermediate with retention of configuration
(Scheme 4).
Bn2N
OHCO
99%
1%
These results are in agreement with recently reported
data describing aziridinium ion formation from b-amino-
trifluoroacetates and subsequent attack of the liberated
trifluoroacetate anion onto the more substituted carbon
of the aziridinium ion with the same stereospecificity
described above.11 Similarly, N,N-dibenzyl-O-methylsulf-
onyl serine methyl ester reacted with a variety of hetero-
nucleophiles to yield, via an aziridinium intermediate, the
corresponding b-amino esters.12
16
15
Scheme 3. Conversion of secondary 2-bromoamines into formate esters.
yield, as expected, the secondary as well as the primary
formate esters in 99% and 1% yields, respectively. In this
case, the bromide was completely converted to products
within 8 h due to the reduced steric hindrance of the com-
pound (Scheme 3B).
It should be noted that the tendency of the formation of
the aziridinium system is so great that it is practically
impossible to convert such substrates to the corresponding
aminoethyl halides or sulfonate esters in satisfactory yields.
When primary alcohol 9 was treated with tosyl chloride in
the presence of 4-dimethylaminopyridine, the sole product
isolated was the secondary chloride. The conversion of
alcohols to the corresponding chlorides under these condi-
tions is a known process and its mechanism has been
described earlier.9 The result may be explained by a similar
mechanism involving initial conversion to the primary
tosylate, the formation of the aziridinium intermediate
and its subsequent attack by the chloride anion in a similar
fashion to that described in Scheme 3A.
In conclusion, we have investigated the conversion of
2-bromoethylamines to the corresponding formate esters
in the presence of DMF. Both primary and secondary
bromides were esterified smoothly in satisfactory yields.13
The reaction mechanism involves the formation of an azirid-
inium ion which, upon reaction with DMF, forms a Vilsme-
ier-type intermediate that is further hydrolyzed to the
corresponding formate esters. Participation of the b-amino
group appears to control not only the regioselectivity but
also the stereoselectivity of the reaction. The reaction
presented facilitates the stereocontrolled formation of
protected b-amino alcohols (vicinal amino alcohols), a
A strong indication that participation by the b-amino
group may not only promote the regioselectivity but also
the stereoselectivity of the reaction sprang from the follow-
ing simple experiment. (R)-13 was transformed to (R)-15
OH
OCHO
HCOOH
Bn2N
Bn2N
(R
)-15
-13
(R)
α 20
20
[ ] D 33.0 ( 1.0, EtOH)
c
½aꢀD 33.0 (c 1.0, EtOH) via direct esterification with formic
CBr4
PPh3
acid. The enantiomeric purity of the product was verified
1
by H NMR studies using Eu(hfc)3. Reaction of (R)-13
20
with CBr4/PPh3, yielded (R)-14 ½aꢀD 12.7 (c 1.0, EtOH).
Br
DMF, RT, 72 h
The absolute stereochemistry of (R)-14 was verified by
X-ray structure analysis10 (Fig. 1, 35% probability ellip-
soids). When (R)-14 was treated with DMF at room
temperature the bromide was converted in 72 h to (R)-15
with identical optical rotation to that of the esterification
product, indicating that both reactions proceed via an
Bn2N
(
R
)-14
α 20
[ ] D 12.7 ( 1.0, EtOH)
c
Scheme 4. Conversion of chiral 2-bromoamines into chiral formate esters.

M. Dakanali et al. / Tetrahedron Letters 49 (2008) 1648–1651
1651
moiety widely used in modern pharmacopoeia.14 The use of
vicinal amino alcohols in the synthesis of natural or synthetic
biologically active compounds has been reviewed15 and
studies on asymmetric aminohydroxylation have revealed
the importance of methodologies introducing chirality in
this system.16 Studies aimed at the exploitation of this reac-
tion in the synthesis of amino acid derivatives are in progress
in our laboratory.
group P21 (No. 4), a = 9.7188(9), b = 7.2139(6), c = 12.3783(11),
b = 111.624(10)°, V = 806.8(1) ꢂ 106 pm3, Z = 2, T = 213(2) K,
q
ber = 1.310 g cmꢁ3
,
l = 2.535 mmꢁ1
,
k = 71.073 pm (Mo-Ka),
numerical absorption correction, Tmin = 0.582, Tmax = 0.419, 5233
measured, 2927 independent reflections, Rint = 0.0285, 2264 with
I > 2r(I), 173 parameters,
H atoms in idealized positions, R1
(observed reflections)=0.032, wR2 (all data) = 0.069, Flack parameter
x = ꢁ0.001(10), max./min. residual electron density peaks 0.28/
ꢁ0.17 eꢁ/106 pm3. Programs for structure solution and refinement:
SHELXS-97 (Sheldrick, 1990) and SHELXL-97 (Sheldrick, 1997); Graph-
ical presentation: Diamond2 (Brandenburg, 1999).
Acknowledgment
11. For a related mechanism, see: Metro, T.-X.; Appenzeller, J.; Pardo,
D. G.; Cossy, J. Org. Lett. 2006, 8, 3509 and references cited
therein.
12. Couturier, C.; Blanchet, J.; Schlama, T.; Zhu, J. Org. Lett. 2006, 8,
2183. In this case, the diprotected 2-aminoalcohols, with the amino
group at a secondary center, lead to the exclusive formation of the
corresponding rearranged b-amino esters with complete stereochem-
ical inversion at the secondary centers.
This work was supported by an EPEAEK grant from
the Greek Ministry of Education.
Supplementary data
13. Representative experimental procedure for the conversion of
2-bromoethylamines to the corresponding formate esters: The
2-bromoethylamine (1 mmol) was dissolved in 4 ml of DMF. The
mixture was continuously stirred and heated at 80 °C, unless
otherwise stated, under an argon atmosphere. A typical reaction
was complete within 8 h as determined by thin layer chromatographic
analysis. Longer reaction times up to 60 h were used as necessary until
complete reaction of starting material was obtained. The reaction
mixture was diluted with dichloromethane (30 ml) and washed with
water (3 ꢂ 50 ml) and brine (1 ꢂ 50 ml). The organic layer was dried
over anhydrous Na2SO4, filtered and concentrated in vacuo. Products
were purified by flash chromatography using 10% ethyl acetate in
petroleum ether. The identity and the purity of the reaction products
were established by their spectral (1H, 13C NMR, IR and MS) data.
Crystallographic data (excluding structure factors) for (R)-14 have
been deposited with the Cambridge Crystallographic Data Centre as
Supplementary Publication Number CCDC 661281. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0) 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk].
A general procedure for the conversion of 2-bromoethyl-
1
amines to the corresponding formate esters, H NMR, 13
C
NMR, and mass spectra of compounds 1–15, DEPT-135
1
NMR spectra of compounds 11 and 15, and H NMR
spectra of 15 in the presence of Eu(hfc)3 are available.
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2008.01.002.
References and notes
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10. (R)-14
(C17H20BrN):
STOE
IPDS
diffractometer,
Mm =
318.25 g molꢁ1, crystal size 0.35 ꢂ 0.10 ꢂ 0.05 mm, monoclinic, space