Using N-nitrosodichloroacetamides to conveniently convert linear primary amines into alcohols

Article abstract of DOI:10.1080/00397911.2015.1061672

The reported rearrangement of N-nitrosodichloroacetamides provides a practicalmethod for converting primary amines into primary alcohols. The reaction sequence is operationally simple, requires only a single purification, and is compatible with a number of common functional groups. Mechanistic studies of the nitrosylation and rearrangement reactions illustrate the increased utility of dichloroacetamides compared to various other amides for this transformation.

Full text of DOI:10.1080/00397911.2015.1061672

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Using N-Nitrosodichloroacetamides to Conveniently
Convert Linear Primary Amines into Alcohols
Nicholas S. MacArthura, Linshu Wanga, Blaine G. McCarthya & Charles E. Jakobschea
a Clark University Carlson School of Chemistry & Biochemistry, Worcester, MA, USA
Accepted author version posted online: 16 Jun 2015.
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To cite this article: Nicholas S. MacArthur, Linshu Wang, Blaine G. McCarthy & Charles E. Jakobsche (2015): Using N-
Nitrosodichloroacetamides to Conveniently Convert Linear Primary Amines into Alcohols, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1061672
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Using N-nitrosodichloroacetamides to conveniently convert linear primary amines
into alcohols
Nicholas S. MacArthur1, Linshu Wang1, Blaine G. McCarthy1, Charles E. Jakobsche1
1Clark University Carlson School of Chemistry & Biochemistry, Worcester, MA, USA
Corresponding Author E-mail: cjakobsche@clarku.edu
Abstract
The reported rearrangement of N-nitrosodichloroacetamides provides a practical method
for converting primary amines into primary alcohols. The reaction sequence is
operationally simple, only requires a single purification, and is compatible with a number
of common functional groups. Mechanistic studies of the nitrosylation and rearrangement
reactions illustrate the increased utility of dichloroacetamides compared to various other
amides for this transformation.
KEYWORDS: nitrosoamide, rearrangement, nitrosylation, dichloroacetamide, alcohol
INTRODUCTION
Primary alcohols are highly versatile functional groups in organic synthesis as they can
be easily converted into numerous other functional groups and can enable a variety of
options for forming carbon–carbon bonds and increasing structural complexity. By
comparison, there are fewer reactions available for utilizing primary amines in this
manner; therefore, synthetic strategies that can convert amines into alcohols can greatly
1

increase the synthetic utility of amines in organic synthesis. Although some amines,
especially those in -amino acids, can be directly converted into alcohols by treatment
with sodium nitrite,[1] this transformation is rather ineffective on isolated amines that do
not benefit from a neighboring carbonyl group. Pioneering work has identified the
thermal rearrangement of N-nitrosoamides (Scheme 1) as an option for amide-to-ester
conversion,[2,3,4] yet this transformation has only found minimal use in target-oriented
organic synthesis.[5,6] Variations in the structure of the amide (R in Scheme 1) affect the
ease and effectiveness of the nitrosylation and rearrangement reactions,[7] and herein we
show that using dichloroacetamides for this transformation enables a simple, mild, and
effective synthetic sequence to transform linear primary amines into alcohols.
RESULTS AND DISCUSSION
Optimized Procedure
N-nitrosodichloroacetamides enable a mild and operationally simple 4-step procedure to
convert linear primary amines into primary alcohols. The four steps can be performed
sequentially with only aqueous workups as purification of the intermediates and one
simple chromatographic purification of the final product.
Amine 1 (Scheme 2) is an example substrate that is non-volatile and whose reactivity is
not modified by adjacent functional groups or the absence of -hydrogen atoms. To form
dichloroacetamide 2, amine 1 can be treated with methyl dichloroacetate at ambient
temperature. Simply removing volatiles yields dichloroacetamide 2 with full conversion
and 99% mass recovery. Next, the dichloroacetamide functionality is nitrosylated using
2

our optimized procedure; the amide is solvated in a 1:1 mixture of acetic anhydride and
dichloroacetic acid, cooled in an ice bath under dry conditions, treated with 2 equivalents
of solid sodium nitrite, stirred for 2 hours, treated with another 2 equivalents of sodium
nitrite, and stirred for another 4 hours to give full nitrosylation. After aqueous workup,
N-nitrosodichloroacetamide 3 is warmed directly in the ethyl acetate extraction solvent to
40 C for 24 h, which causes complete reaction of the N-nitrosoacetamide. The
rearrangement yields a 7:1 mixture of desired dichloroacetate ester 4 and an undesired
elimination byproduct (4a in the supporting information) in 98% overall mass recovery.
Dichloroacetate ester 4 can be fully and selectively hydrolyzed under mild conditions by
treating it with 2 equivalents of triethylamine in methanol for 2 hours at ambient
temperature. Alcohol 5 is isolated by short column chromatography with an overall yield
of 66% for the full 4-step sequence.
Conditions: (a) 1 M in EtOAc, 1.5 equiv methyl dichloroacetate, 25 ºC, 21 h, full
conversion observed by 1H NMR, 99% mass recovery. (b) 0.3 M in 1:1 dichloroacetic
acid / acetic anhydride, dry, 0 ºC, 2 equiv NaNO2, 2 h, additional 2 equiv NaNO2,
additional 4 h, full conversion observed by 1H NMR, used directly for next step. (c) 0.1
M in EtOAc, 40 ºC, 24 h, starting material consumed by 1H NMR, 7:1 rearrangement /
elimination, 98% mass recovery. (d) 0.2 M in MeOH, 2 equiv TEA, 2 h, full conversion
observed by 1H NMR, silica gel chromatography, 66% isolated yield from amine 1.
To evaluate the breadth of this amine-to-alcohol conversion strategy, we performed our
optimized procedure on the amine substrates shown in Scheme 3. The reaction sequence
3

is compatible with a variety of common functional groups including ethers, methyl and
benzyl esters, tertiary amides, electron-neutral and electron-poor aromatic groups,
aromatic nitro groups and silyl-protected alcohols. The reaction also tolerates steric bulk
created by a branch point at the -carbon (amine 18). Based on NMR analysis of the
crude reaction products, benzyl ethers and azides do not appear to be stable to the
nitrosylation conditions. Based on these results overall, we believe that the rearrangement
of N-nitrosodichloroacetamides will be a useful addition to the synthetic chemist's
toolbox of reactions.
MECHANISM
In order to identify the types of amides that are most effective for this rearrangement
sequence, we initially compared a number of different amides in both the nitrosylation
and rearrangement steps. The results help illustrate how the identity of the amide can
facilitate an effective overall synthetic transformation. Compared to other amides,
dichloroacetamides benefit from their branched shape and the mild electron-withdrawing
nature of their dichloromethyl groups.
Comparing the rearrangements of different N-nitrosoamides (varying R in Scheme 4)
shows two major trends (Supporting Tables S1 and S2 and prior data).[Error! Bookmark not
defined.,Error! Bookmark not defined.,8] First, electron-deficient N-nitrosamides rearrange at lower
temperatures than electron-neutral ones; for example N-nitrosoacetamides must be heated
to approximately 85 C for several hours whereas N-nitrosotrifluoroacetamides rearrange
spontaneously below ambient temperature. And second, branched amides and
4

benzamides rearrange at somewhat lower temperatures than linear ones or acetamides.
Mechanistically, the rearrangements in non-polar solvents of N-nitrosoamides derived
from linear primary amines are believed to proceed through the steps outlined in Scheme
4. Insightful experiments by Streitwieser & Schaeffer[9] and by White & Aufdermarch[10]
support the idea that these N-nitrosoamides first go through a rate-determining cyclic
substitution reaction to form transient diazoesters (21), then proceed through a
disassociation process to form diazoalkanes (22), and finally recombine with the
carboxylic acid fragment to form esters (23) and release nitrogen gas. Huisgen & Krause
proposed that the faster rates observed for -branched N-nitrosoamides (with a branched
R group in 20) may result from their steric bulk assisting the amide bond to rotate out of
plane and position the nucleophilic oxygen near the carbonyl's * to accelerate the
formation of diazoester 21.[Error! Bookmark not defined.] The faster rates for electron deficient
amides can be explained by their increased electrophilicity accelerating attack at the
carbonyl.
This rearrangement proceeds cleanly in a variety of nonpolar solvents (including
heptane, toluene, ethyl acetate, and carbontetrachloride) with the only notable byproduct
being approximately 10–20% of the terminal alkene produced by a formal elimination of
the N-nitrosoamide group (Supporting Tables S1 and S2). Fortunately, this alkene
product can be easily separated from the final alcohol product by column
chromatography. With toluene as the solvent the rearrangement-to-elimination ratio is not
substantially affected by changing the amide's R group or by adding a mild acid or base
to the reaction mixture (Supporting Tables S1 and S2).
5

In contrast, performing the rearrangement in polar solvents, especially acetic acid, causes
the rearrangement to produce multiple additional byproducts that include rearranged
esters, rearranged alkenes, and products derived from reaction with the solvent
(Supporting Table S2 and prior data).[4],[8] These byproducts are especially problematic
for highly electron-deficient N-nitrosoacetamides because they react spontaneously in the
acetic acid solvent used for the nitrosylation reaction. Indeed, a trifluoroacetamide
precursor forms only 15% of the desired rearrangement product with the major product
resulting from reaction with the solvent (Supporting Table S2). From a mechanistic
perspective, if other carboxylic acids – such as the solvent – are present in the reaction
mixture then diazoalkane intermediate 22 may produce byproducts by combining with
these acids rather than with those generated from the starting N-nitrosoamide. In these
competitions, reactions with poorly nucleophilic carboxylates, such as trifluoroacetate,
will be disfavored. Other data suggest that N-nitrosoamides derived from branched
amines likely rearrange through slightly different pathways that may involve secondary
carbocations and tight ion pairs.[11,12,13] Related pathways for N-nitrosoamides derived
from linear amines may explain the occasional formation of rearranged ester and
rearranged elimination products when highly polar solvents, especially acetic acid, are
used. N-nitrosodichloroacetamides, which are not as electron deficient as the trifluoro-
analogues, avoid these problems by being stable to the conditions of the nitrosylation step
and being able to be extracted from the acetic acid solvent into a nonpolar solvent that
enables a cleaner rearrangement. As a side note, thermal denitrosylation of
N-nitrosoacetamides to form amides has been described,[14] but typically this pathway is
6

favored by acidic or basic aqueous solvents; we did not observe substantial
denitrosylation in any of our experiments (<2% produced by 1H NMR analysis).
For the nitrosylation reaction, comparing the reactivities of various amides (R in
Scheme 5A) shows that it is more difficult to nitrosylate amides that are highly electron
deficient, especially trifluoroacetamides (Supporting Table S3), which highlights a
second benefit of using the mildly electron-deficient dichloroacetamides. Nitrosylation
reactions with sodium nitrite typically utilize acetic acid as a co-solvent. The acid
protonates the nitrite anion and generates equilibrium concentrations of the nitrosonium
cation, which can react as an electrophile with nucleophilic nitrogen atoms. Acetic
anhydride is also typically used as a co-solvent.[15] We find that omitting the anhydride
co-solvent prevents any reaction. We hypothesize that the starting amide reacts with the
anhydride solvent to generate imidoyl acetate 25 (Scheme 5A), and that this intermediate
is the nucleophilic nitrogen species rather than the original amide. We support this
hypothesis by showing that when the co-solvent is switched from acetic anhydride to
trifluoroacetic anhydride, benzamide 27 cleanly forms imidoyl trifluoroacetate 28 rather
than the expected N-nitrosoamide (Scheme 5B). Notably, Nagubandi & Fodor have also
observed similar imidoyl trifluoroacetates while studying Bischler–Napieralski
cyclodehydrations.[16] We speculate that although imidoyl acetates are nucleophilic
enough to react with the nitrosonium cation and form N-nitrosamides, for the trifluoro-
analogues the electron withdrawing nature of the trifluoromethyl group reduces the
nucleophilicity of this intermediate and causes it to not react any further. This
mechanistic hypothesis and the difference in nucleophilicity of intermediate 25
7

depending on its R group can also explain the reduced reactivity of the highly electron
deficient trifluoroacetamides (R = CF3 in Scheme 5A) compared to dichloroacetamides or
other non-halogenated acetamides.
Conditions: (a) 0.3 M in 5:1:1 EtOAc / TFA / TFAA, dry, 0 ºC, 2 equiv NaNO2, 2 h,
additional 2 equiv NaNO2, additional 4 h, full conversion. Abbreviations: TFA =
trifluoroacetic acid, TFAA = trifluoroacetic anhydride.
CONCLUSIONS
Despite some exciting initial reports about the rearrangements of N-nitrosoamides and a
few creative extensions of the methodology17,18 this transformation seems to remain
underutilized in target-oriented organic synthesis. Herein we expand the practicality of
this transformation by identifying the dichloroacetamide functional group as an ideal
substrate for conversion of linear primary amines into primary alcohols. Compared to
other acetamides, the branching and mild electron deficiency of dichloroacetamides allow
their N-nitroso derivatives to rearrange at temperatures just above ambient. Not only are
these conditions mild, but they also enable cleaner reactions versus more reactive
N-nitrosoamides that rearrange spontaneously under the nitrosylation conditions.
Additionally, nitrosylation of dichloroacetamides can be done under milder conditions
than those required for trifluoroacetamides. Finally, compared to non-halogenated
analogues, dichloroacetamides have the additional benefits of (1) being able to be formed
under exceptionally simple conditions and (2) having rearrangement products
(dichloroacetate esters) that can be selectively hydrolyzed under mild conditions in the
8

presence of other typical ester groups. In total, these collected benefits allow
N-nitrosodichloroacetamides to provide a useful synthetic sequence to convert linear
amines into primary alcohols.
EXPERIMENTAL
General Procedures: Column chromatography was performed with 60 Å 40–63 m
silia–P flash silica gel. Solvents for reactions (DMF, DCM, THF, and toluene) were dried
using a LC Technology Solutions purification system. Other solvents were used as
received unless noted otherwise. Chemicals were purchased from Fisher, VWR, or
Sigma–Aldrich and used as received unless noted otherwise. NMR Spectra were
measured in CDCl3 at ambient temperature unless otherwise noted. 1H NMR spectra were
recorded on either a 600 or 200 MHz Varian spectrometer. Chemical shifts are reported
in ppm ( ) relative to tetramethylsilane using the solvent as a reference (CDCl3 = 7.26
ppm). 13C NMR spectra were recorded on a 600 or 200 MHz (150 or 50 MHz) Varian
spectrometer with complete proton decoupling. Chemical shifts are reported in ppm ( )
relative to tetramethylsilane using the solvent as a reference (CDCl3 = 77.0 ppm). IR
spectra were recorded on a Perkin Elmer Spectrum 100 FT–IR spectrometer with Perkin
Elmer Spectrum software. Spectra are partially reported ( max, cm-1). HRMS were
obtained at The University of Illinois Urbana–Champagne. TLC was performed on 60 Å
F254 pre-coated silica gel plates. Samples were visualized by either ultraviolet irradiation,
potassium permanganate staining, or cerium ammonium molybdenate staining.
9

Standard dichloroacetylation procedure Into a flask were added the starting free amine
(1 equiv), distilled EtOAc (1 M), and methyl dichloroacetate (1.5 equiv). The mixture
was stirred at ambient temperature overnight. Volatiles were removed under reduced
pressure to yield the dichloroacetamide, which was used directly for the subsequent
reaction.
Standard nitrosylation procedure The crude dichloroacetamide was dissolved in the
required solvent mixture (typically 0.3 M in 1:1 acetic anhydride / dichloroacetic acid).
The flask was capped with a rubber septum and stirred in an ice bath (0 ºC, 30 min). To
the mixture was added solid sodium nitrite (2 equiv, creating a blue solution and slowly
evolving brown gas). The flask was capped with a rubber septum and vented with a
syringe packed with anhydrous calcium sulfate, and stirred (2 h). To the mixture was
added additional sodium nitrite (2 equiv). The mixture was stirred (additional 4 h),
diluted with EtOAc (0.1 M), washed with cold water (equal volume) and then cold
sodium carbonate (10% aqueous, 3 x equal volume), diluted with cold sodium carbonate
(10% aqueous, equal volume), and stirred rapidly (30 min, to quench any remaining
anhydride). The organic phase was isolated, washed with potassium phosphate
monobasic (1 M aqueous, pH 5, equal volume), dried with sodium sulfate, and used
directly for the subsequent transformation without removing the solvent.
Standard rearrangement procedure The solution of the crude N-nitrosoamide was
warmed in an oil bath (40 ºC, 24 h). Volatiles were removed under reduced pressure to
10

yield the crude dichloroacetate ester, which was used directly for the subsequent
transformation.
Standard hydrolysis procedure The crude dichloroacetate ester was dissolved in MeOH
(0.2 M), and TEA (2 equiv) was added. The mixture was stirred (2 h), diluted with
potassium phosphate monobasic (1 M aqueous, pH 5, 0.5 M), stirred (10 min), further
diluted with water, extracted with EtOAc, and dried with sodium sulfate. Volatiles were
removed under reduced pressure to yield a crude alcohol, which was purified by silica gel
chromatography.
SUPPORTING INFORMATION
Tabulated comparisons of the reactivities of different substrates in the rearrangement and
nitrosylation reactions, full experimental details, analytical data, and NMR spectra for
this article can be accessed on the publisher’s website.
FUNDING & ACKNOWLEDGEMENTS
Funding for this work was provided by Clark University's faculty startup funds. CEJ and
NSM acknowledge a LEEP Fellowship provided by The Clark University LEEP Center.
NSM acknowledges a PCI Synthesis Inc. Partial Summer Fellowship. BGM
acknowledges a Steinbrecher Fellowship and a Frederick M. & Alice Murdock Research
Fellowship, both provided by Clark University.
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Scheme 1. Overview of the rearrangement of N-nitrosoamides.
13

Scheme 2. Conversion of example amine 1 into alcohol 5.
14

Scheme 3. Substrate scope using the standard amine-to-alcohol 4-step sequence
15

Scheme 4. Mechanism of rearrangement.
16

Scheme 5. Nitrosylation mechanism and data.
17