Amine-free approach toward N-toluenesulfonyl amidine construction: A phosphite-mediated beckmann-like coupling of oximes and p-toluenesulfonyl azide

Article abstract of DOI:10.1002/anie.201305141

Atom hopping: A chlorophosphite-mediated Beckmann ligation of oximes and p-toluenesulfonyl azide gives access to N-sulfonyl phosphoramidines in good to excellent yields. The reaction proceeds under exceptionally mild conditions and constitutes a bioorthogonal approach toward amidines by avoiding the use of amines and transition-metal catalysts. dmp-ol=3,3-dimethylpropanediol. Copyright

Full text of DOI:10.1002/anie.201305141

Angewandte
Chemie
DOI: 10.1002/anie.201305141
Synthetic Methods
Amine-Free Approach toward N-Toluenesulfonyl Amidine
Construction: A Phosphite-Mediated Beckmann-Like Coupling of
Oximes and p-Toluenesulfonyl Azide**
Lauren M. Fleury, Erin E. Wilson, Monika Vogt, Tiffany J. Fan, Allen G. Oliver, and
Brandon L. Ashfeld*
Amidines constitute one of the most prolific and versatile
functional groups in organic synthesis. In recent years they
have become a common synthetic building block in hetero-
palladium(II)-catalyzed sulfonyl ynamide rearrangement in
the presence of an amine to provide N-sulfonyl amidines
[
8]
(Scheme 1b). In contrast, we sought to develop a mild and
diversifiable route which avoids the direct use of amines and
transition-metal catalysts while providing the corresponding
N-sulfonyl amidines without the need for chromatographic
purification.
[1]
cycle construction and the synthesis of biologically active
[
2]
natural products. They also have emerged as a key func-
[3]
tional group in pharmaceutical drug design. Despite their
[
4]
growing biological significance, the use of amidines as
[
5]
bioorthogonal chemical reporters is notably absent. This is
likely attributable to the central tenet in reaction design for
amidine synthesis as it involves addition of an amine to an
Despite the fact that the Beckmann rearrangement is
[9]
highly useful for constructing amides,
the analogous
approach toward amidines by trapping the intermediate
nitrilium with a primary amine was found to proceed at best
[
6]
activated acyl equivalent. For example, a recent report by
Chang and co-workers describes a triazole decomposition
strategy resulting in an innovative three-component coupling
[
10]
in poor yield.
Given our recent work on phosphorus-
[
11]
mediated CÀN bond construction, we envisioned a solution
[7]
of an alkyne, sulfonyl azide, and an amine (Scheme 1a).
to this challenge in amidine construction which involves the
Additionally, Hsung and co-workers employed a remarkable
coupling of the oxime 1 and TsN to yield the amidine 3 via
iminophosphorane 2 (Scheme 1c). The strong driving force
of P=O bond formation and preorganization of each compo-
3
[
12]
nent in 2 results in a mild, chemoselective Beckmann-like
[
13]
ligation event. This amine-free approach toward amidine
synthesis effectively exploits the bioorthogonal reactivity of
[
14]
azides.
To evaluate our approach toward amidine construction we
began with the treatment of oxime 1a and TsN with ClPPh
3
2
and Et N (Scheme 2). However, these reaction conditions
3
Scheme 1. Construction of N-toluenesulfonyl amidines. THF=tetra-
hydrofuran, Ts=4-toluenesulfonyl.
[
+]
[+]
Scheme 2. Phosphinamide versus amidine formation.
[
*] L. M. Fleury, E. E. Wilson, M. Vogt, T. J. Fan, A. G. Oliver,
Prof. Dr. B. L. Ashfeld
Department of Chemistry and Biochemistry
University of Notre Dame
failed to provide the desired amidine leading only to the
formation of phosphinamide 4a, presumably resulting from
rearrangement of the intermediate phosphinite, in 66% yield
251 Nieuwland Science Hall, Notre Dame, IN 46556 (USA)
E-mail: bashfeld@nd.edu
+
[
] These authors contributed equally to this work.
[15]
even at temperatures as low as À508C. Speculating that
electron-withdrawing ligands on phosphorus would decrease
the rate of O-to-N migration, we chose to examine the use of
[
**] We thank the NSF (CHE-1056242) and the University of Notre
Dame for financial support, including the purchase of a copper
microfocus source used in this research.
[16]
a chlorophosphite in place of chlorophosphine.
Gratify-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305141.
ingly, the addition of 3,3-dimethylpropanediol chlorophos-
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[
a]
phite [ClP(dmp-ol)] gave the amidine 3a in 35% yield while
concurrently suppressing conversion into the corresponding
phosphoramidate 4a. To the best of our knowledge, this
constitutes the first approach toward acyclic amidine CÀN
Table 2: Oxime structural variability.
bond construction, which avoids the direct use of nucleophilic
amines.
[
b]
Entry
1
Oxime 1
Amidine 3
Yield [%]
Anticipating that an oxime with electron-rich aryl sub-
stituents would undergo a more facile rearrangement, we
began a systematic evaluation of the reaction conditions in an
attempt to optimize the yield of amidine 3b (Table 1).
95
[
a]
2
3
99
Table 1: Optimization of reaction conditions.
98
26
[
c]
4
Entry
ClPL2
Solvent
3b
yield [%]
4b
yield [%]
[
b]
[c]
5
6
7
99
71
64
1
2
3
4
5
6
7
8
9
ClP(dmp-ol)
ClP(dmp-ol)
ClP(dmp-ol)
ClP(dmp-ol)
ClP(dmp-ol)
ClP(dmp-ol)
ClP(pin)
PhH
PhMe
PhCl
51
98
76
77
64
0
25
0
0
0
0
0
0
0
[d]
Et O
2
1,4-dioxane
DMF
PhMe
PhMe
PhMe
0
55
86
>95
ClP(cat)
ClP(OEt)2
[
a] Reaction conditions: 0.3 mmol of 1b, 0.3 mmol of Et N, 0.3 mmol of
3
8
72
ClPL , and 0.3 mmol of TsN at 0.2m. [b] Yield of isolated product.
2
3
[c] Quantitative recovery of 1b observed. DMF=N,N’-dimethylform-
amide.
[a] Reaction conditions: 0.3 mmol of 1, 0.3 mmol of ClP(dmp-ol),
0
.3 mmol of Et N, and 0.3 mmol of TsN in PhMe (0.2m). [b] Yield of
3
3
isolated product. [c] Reaction performed at 1008C in 1,4-dioxane for 2 h.
[d] Reaction performed using iPr NEt in PhCl at 608C for 30 min.
Performing the reaction in PhH provided 3b in 51% yield,
2
whose structure was verified by single-crystal X-ray diffrac-
[
17]
tion, while PhMe and PhCl gave 3b in 98% and 76% yield,
respectively (entries 1–3). Although ethereal solvents were
effective, they proved inferior to PhMe (Table 1, entries 4 and
In general, good to excellent yields of the amidine 3 were
obtained upon ligation of oxime 1 and TsN with ClP(dmp-ol)
3
5
). Interestingly, performing the reaction in DMF led only to
and Et N in PhMe at 08C (Table 2). The conversion of the aryl
3
recovered 1b (Table 1, entry 6). In addition, the efficiency of
the ligation was highly dependent on the chlorophosphite
reagent employed. Although ClP(dmp-ol) minimized the
rearrangement of 1b into phosphinite 4b, in contrast to
oximes 1a, 1c, and 1d proceeded smoothly to give the
corresponding amidines in 95–99% yield (Table 2, entries 1–
3). The electron-deficient aryl oxime 1e gave 3e in lower yield
than its electron-rich counterparts (Table 2, entry 4). The
diminished yield for this substrate is likely a consequence of
undesired side-product formation due to the elevated temper-
atures required for full oxime conversion. The a,b-unsatu-
rated oximes 1 f and 1g gave enamines 3 f and 3g, respec-
tively, which resulted from vinyl migration, in excellent yields
(Table 2, entries 5 and 6). Secondary alkyl groups also
underwent facile ligation to afford N-sulfonyl amidines, as
illustrated by the conversion of 1h into amidine 3h in 64%
yield (Table 2, entry 7). Additionally, the cyclic oxime 1i
underwent ring expansion to give the phosphazepanylidene 3i
in 72% yield (Table 2, entry 8). While more reactive electron-
ClPPh , pinacol chlorophosphite [ClP(pin)] yielded a 1:2.2
2
mixture of 3b and 4b (Table 1, entry 7). Employing the
catechol-derived chlorophosphite [ClP(cat)] or ClP(OEt)2
gave exclusively the undesired 4b (Table 1, entries 8 and 9).
The faster rate of 4b formation with ClP(pin) and ClP(cat) is
likely due to a more facile oxidative rearrangement at
phosphorus with the smaller strained ring, and greater lone-
pair accessibility, in contrast to ClP(dmp-ol). With our
optimized reaction conditions identified, we turned our
attention toward evaluating various structural elements of
the oxime component.
2
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[
a]
deficient azides (e.g., MsN , CbzN ) were also effective at
Table 3: Oxime and azide chemoselectivity.
3
3
providing the corresponding amidines, yields were generally
lower (ca. 20%) than that observed with TsN . Not surpris-
3
ingly, non-stabilized azides (e.g., BnN ) led to exclusive
3
isolation of rearranged phosphinite as a result of the higher
temperatures required for phosphazene generation. The
formation of the amidines 3 depicted in Table 2 is consistent
with a Beckmann-like ligation in which the anti-periplanar
oxime substituent migrates preferentially.
To gain insight into the stereochemical outcome of the
migration event, we chose to evaluate our phosphite-medi-
ated ligation approach using the a-chiral menthone-derived
[
c]
Entry Additive
5
3b
yield [%]
3b/5
[
b]
[
c]
1
H
O
2
49
4:1
oxime 1j [Eq. (1)]. Exposure of 1j and TsN to ClP(dmp-ol)
3
[d]
2
3
PhSO NH
85
40
>99:1
2
2
[
c]
5a
3:1
[a] Reaction conditions: 0.3 mmol of 1b, 0.3 mmol of ClP(dmp-ol),
0
.3 mmol of Et N, 0.3 mmol of TsN , and 0.3 mmol of additive in PhMe
3
3
1
(0.2m). [b] Yield of isolated product. [c] Ratio determined by H NMR
(600 MHz) spectroscopy. [d] Ratio determined by HPLC.
and Et N in PhMe at 08C yielded the N-sulfonyl phosphor-
3
[
18]
amidine 3j in 58% yield as a single regio- and stereoisomer.
nucleophile (Table 3). Treatment of 1b and TsN with ClP-
3
It is important to note that under the reaction conditions,
a epimerization of the chiral oxime is not observed, and the
retention of absolute configuration at the site of migration is
consistent with a concerted [1,2] shift.
(dmp-ol), Et N, and H O (1 equiv) led to the formation of 3b
3
2
and 5 in a ratio of 4:1 (Table 3, entry 1). It is unlikely that 5 is
generated by in situ amidine hydrolysis as independent
treatment of 3b under the reaction conditions led solely to
While our results point to a distinct steric influence on the
migratory preference of oxime substituents, the relative
reactivity of electron-rich and electron-deficient aryl oximes
suggest that electronic factors may also impact the rate of
rearrangement. Speculating that we could exploit this dispa-
rate reactivity to kinetically resolve a mixture of oxime
isomers bearing electronically dissimilar, yet sterically con-
gruent substituents, we examined the oxime 1k as a 1:1 E/Z
mixture of isomers in our azide ligation approach toward
amidines. Exposure to our optimized reaction conditions led
exclusively to migration of the more electron-rich anti-
periplanar aryl ring to give the amidine 3k in 30% yield
recovered amidine. The presence of H O also resulted in
a less efficient ligation, thus giving 3b in only 49% yield.
2
However, the addition of PhSO NH yielded exclusively the
2
2
azide ligation product 3b in 85% yield (Table 3, entry 2).
Performing the reaction in the presence of p-methoxybenzoic
acid did not lead to sulfonyl imide formation consistent with
our recently reported chlorophosphite-mediated Staudinger-
[
11b]
like ligation (Table 3, entry 3).
However, 3b and 5a, likely
arising from carboxylic acid addition to a nitrilium cation
intermediate and subsequent hydrolysis, were obtained in
a 3:1 ratio. Our observation that the addition of a radical
inhibitor did not hinder the formation of 3b would indicate
[17]
(
Scheme 3). The corresponding Z-oxime isomer proceeded
a non-radical mechanism. While these results demonstrate
a distinct preference for azide ligation indicative of an
intermediate iminophosphorane (2), CÀN bond formation
no further than azide reduction to give the iminophosphorane
[
19]
(Z)-2k in 36% yield.
[
20]
In an effort to evaluate azide chemoselectivity we
likely occurs through a polar intermolecular process.
examined the ligation event in the presence of an added
To verify the intermediacy of 2 we again exploited the
tempered reactivity of the electron-deficient aryl oxime 1l in
the isolation of phosphazene 2l (Scheme 4). Treatment of 1l
with ClP(dmp-ol), Et N, and TsN at room temperature for
3
3
3
0 minutes gave 2l in 85% yield as a free-flowing solid whose
structure was unequivocally ascertained by single-crystal X-
[
17]
ray diffraction.
Monitoring of the reaction over time
showed the appearance and subsequent disappearance of 2l
en route to 3l in 40% overall yield. This observation provides
compelling evidence that 2l is a chemically and kinetically
[
17]
viable intermediate under the reaction conditions.
Based on these composite results, our working mecha-
nistic hypothesis involves initial phosphinylation of the oxime
1
and subsequent Staudinger-like reduction of TsN to give
3
Scheme 3. Kinetic resolution of oxime isomers.
iminophosphorane 2 (Scheme 5). A stereo- and regioselective
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In summary, we have developed a phosphite-mediated
Beckmann-like approach toward N-toluenesulfonyl amidine
construction and that avoids the direct use of amines, harsh
reaction conditions, and the need for a metal catalyst. The
ligation is mechanistically related to the Beckmann rear-
rangement in that oxime geometry dictates migratory apti-
tude and proceeds with retention of absolute configuration.
This procedure constitutes a new approach toward amidine
construction, and is applicable to the assembly of biologically
active natural products and pharmaceutical drug targets.
Further mechanistic studies and use of this reaction in total
synthesis is underway, and will be reported in due course.
Scheme 4. Evidence for the iminophosphorane 2. Thermal ellipsoids
shown at 50% probability.
Received: June 14, 2013
Published online: && &&, &&&&
Keywords: amidines · azides · Beckmann rearrangement ·
.
rearrangement · oximes
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Angewandte
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Communications
Synthetic Methods
L. M. Fleury, E. E. Wilson, M. Vogt,
T. J. Fan, A. G. Oliver,
B. L. Ashfeld*
&&&& — &&&&
Amine-Free Approach toward N-
Toluenesulfonyl Amidine Construction: A
Phosphite-Mediated Beckmann-Like
Coupling of Oximes and p-
Atom hopping: A chlorophosphite-medi-
ated Beckmann ligation of oximes and p-
toluenesulfonyl azide gives access to N-
sulfonyl phosphoramidines in good to
excellent yields. The reaction proceeds
under exceptionally mild conditions and
constitutes a bioorthogonal approach
toward amidines by avoiding the use of
amines and transition-metal catalysts.
dmp-ol=3,3-dimethylpropanediol.
Toluenesulfonyl Azide
6
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