α-Arylamino Diazoketones: Diazomethane-Loading Controlled Synthesis, Spectroscopic Investigations, and Structural X-ray Analysis

Article abstract of DOI:10.1021/acs.joc.7b03134

Primary and secondary α-halomethyl diazoketones generated via Arndt-Eistert chemistry with minimum loading of diazomethane efficiently alkylate aromatic amines in the presence of calcium oxide to furnish the corresponding α-arylamino diazoketones under full chemocontrol. Such a simple inorganic acid scavenger fully neutralizes the hydrohalic acid formed during the nucleophilic displacement which otherwise would immediately react to produce the corresponding α-haloketone. The methodology can be further exploited in analogous acylation-type processes on secondary arylamino diazoketones. In depth spectroscopic (¹H, ¹³C, and ¹⁵N NMR) and crystallographic analyses document interesting structural features of these previously unknown diazo derivatives.

Full text of DOI:10.1021/acs.joc.7b03134

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#-Arylamino Diazoketones: Diazomethane-Loading Controlled
Synthesis, Spectroscopic Investigations and Structural X-ray Analysis
Laura Castoldi, Laura Ielo, Wolfgang Holzer, Gerald Giester, Alexander Roller, and Vittorio Pace
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03134 • Publication Date (Web): 16 Mar 2018
Downloaded from http://pubs.acs.org on March 16, 2018
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α-Arylamino Diazoketones: Diazomethane-Loading Controlled Synthesis, Spectroscopic Investigations
and Structural X-ray Analysis
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Laura Castoldi,a Laura Ielo,a,b Wolfgang Holzer,a Gerald Giester,c Alexander Roller,d Vittorio Pacea *
a Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
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b
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale
Annunziata, 98168 Messina, Italy
c Department of Mineralogy and Crystallography, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
d X-Ray Structure Analysis Center, University of Vienna, Waehringerstrasse 42, A-1090 Vienna, Austria.
e-mail: vittorio.pace@univie.ac.at
Abstract
Primary and secondary α-halomethyl diazoketones generated via Arndt-Eistert chemistry with minimum
loading of diazomethane efficiently alkylate aromatic amines in the presence of calcium oxide to furnish the
corresponding α-arylamino diazoketones under full chemocontrol. Such a simple inorganic acid scavenger
fully neutralizes the hydrohalic acid formed during the nucleophilic displacement which otherwise would
immediately react to produce the corresponding α-haloketone. The methodology can be further exploited
in analogous acylation-type processes on secondary arylamino diazoketones. In depth spectroscopic (1H, 13
C
and 15N-NMR) and crystallographic analyses document interesting structural features of these previously
unknown diazo derivatives.
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Introduction
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α-Diazoketones represent a versatile class of organic compounds given the plethora of transformations that
the reactive diazo moiety can undergo.1 In particular, it could act as precursor of β-lactams,2 β-amino acid
derivatives3 and in general β-peptides via the Wolff rearrangement4 or as placeholder for transition-metal-
catalyzed reactions (e.g. carbenoid chemistry, cyclopropanation, ylide-mediated processes).5 Effectively,
the contemporaneous presence of an amino group renders the corresponding α-amino diazoketones very
interesting from a synthetic medicinal chemistry perspective (Figure 1).6 In this regard, because of the
synthetic equivalence of diazo compounds to carbocations, this motif has been often employed for the
preparation of α-haloketones through the reaction with hydrohalic acids5a,7 in alternative to lithium
carbenoids8 or sulfur-ylides9 based strategies on different acyl donors. In fact, they represent valuable
scaffolds for the preparation of HIV inhibitors10 such as saquinavir11 (I), nelfinavir12 (II) or palinavir13 (III), in
which the diazo moiety (IV) acts as precursor of the α-haloketone (V) which, upon stereoselective
reduction-ring closure sequence to the epoxide6,10 (VI), provides the core of such important drugs.
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Figure 1. Importance of the α-amino diazoketone motif in medicinal chemistry. Examples of drugs prepared via an
intermediate diazo ketone (top). General synthetic sequence to convert an α-amino diazoketone into an HIV protease
inhibitor (down).
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So far, the most common access to α-amino diazoketones is constituted by the Arndt-Eistert type
diazotization1c,14 of an activated carboxylic functionality (VII, Scheme 1) such as a chloride15 or a (mixed)
anhydride with diazomethane (CH2N2).6,16 However, a series of widely known drawbacks limits the
applicability of these procedures: a) the approach is evidently non attractive from a synthetic perspective
because the activation and the diazotization steps need to be repeated in parallel for the full series of
amino acids; b) as a consequence of the hazardous and safety issues of using an explosive (bp -23 °C) and a
carcinogenic and skin irritant as diazomethane is,17 it does not represent an ideal process for suitable
industrial applications;18 c) the success of the method strongly depends on the nature of the substituents
on the aminic nitrogen which could lead to substantial decomposition of the products;19 d) from a
chemoselective perspective the resulting α-amino diazoketones are contaminated by variable amounts of
the corresponding methyl esters20 or α-halomethyl ketones (Nierenstein process)21 generated through side
reactions dependent on the conditions employed for the activation; e) the direct diazotization of an
optically active acid chloride leads to considerable racemization and thus, the employment of synthetically
non-economical activation as mixed anhydride still remains the preferred method to overcome this
issue.3,16b For example, Siciliano and Liguori reported an effective one-pot preparation of N-Fmoc protected
diazoketones highlighting the dual role of Fmoc-Cl as both protecting group source and carboxilyc moiety
activator agent for the diazotization.19 Notwithstanding, the innate potential of C1 homologations22 realized
with diazomethane still continues to attract interest within the synthetic community1b,1c and, the advent of
microfluidic techniques allowed to design safe reliable processes for methyl esters production,23 synthesis
of pyrazoles or β-amino acids,23b,24 as well as, Pd-catalyzed cyclopropanations,23b inter alia.25 Remarkably,
Kappe documented the direct synthesis of α-halo ketones23b,26 from N-protected amino acids via Arndt-
Eistert chemistry without isolating the intermediate α-diazoketones.
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A conceptually distinct approach to α-amino diazoketones (X) would involve the use of a preformed α-halo
diazoketone (IX) to alkylate the nitrogen atom of amines (Scheme 1). Although this strategy has been
employed for the functionalization of different nucleophiles such as alcohols27 and thiols,28 analogous
reactions in the case of amines are limited to aliphatic ones, thus leaving unexplored the full synthetic
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potential.29 An excess was required for ensuring good chemical yields and significantly, as far as we know,
more challenging aromatic amines have not been employed in these processes.29a
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As part of our research program aimed at the identification and development of homologation
strategies,8c,30 we have been seeking approaches for the preparation of α-diazoketones by using only
minimal loadings (1 equiv, i.e. stoichiometric) of diazomethane21b introducing the beneficial effect
displayed by a cheap and simple earth-alkaline metal oxide (i.e. CaO) as an effective hydrohalic acid
scavenger for the acylation of diazomethane. The formation of innocuous by-products as calcium halide
(CaX2) and water, together with excellent chemoselectivities, makes the method versatile and considerably
more convenient than previously employed techniques. In fact, the addition of amines could trigger ketene
formation events on acid halides featuring acidic α-protons,31 while realizing chemistry with big excesses of
CH2N2 (2-6 equiv, i.e. 200-600 mol %) poses serious questions on the real practicability of using such an
hazardous reagent.18a The reliability of the method was further documented in the synthesis of enantiopure
diazoketones, as reported in recent works by Deska32 and Gaich.33 Additionally, we also extended its use to
the chemoselective acylation of different nucleophiles such as amines and alcohols34 in the biomass-
derived solvent 2-methyltetrahydrofuran (2-MeTHF).35
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Cognizant of the substantial improvement introduced in acylation processes by running reaction in the
presence of CaO, we deemed similar alkylation procedures could benefit as well. In fact, considering that
also in the latter case the deleterious (for the diazo group) by-product was the liberated hydrohalic acid
(HX), its simple removal via CaO-mediated chemosorption appeared worth of investigations and herein, we
present our results on a straightforward route to α-arylamino diazoketones. We anticipate the role of CaO
consists in the formation - upon reaction with HX – of the innocuous CaX2 salt which can be easily
eliminated via filtration. Notably, only one diazotization procedure was accomplished and the full series of
compounds was simply obtained by a simple nucleophilic displacement.
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Classical approach:
Drawbacks:
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- Needing to prepare several activated
carboxylic derivatives;
- The Arndt-Eistert procedure (i.e. repeated use of CH2N2)
must be realized on each one of the substrates;
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PG
X
PG
CH2N2
N
R
N
R
N2
O
O
- Chemoselective issues: effect of the PG on the transformation
and formation of undesired contaminant compounds:
VII
VIII
PG
R = H, alkyl
PG = acyl type
X = Cl, F, OCOR
PG
OMe
N
R
Hal
N
R
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O
O
This work:
R
R
ArNHR'
Ar
N
Advantages:
X
N2
N2
CaO
(KF-Celite)
R1
O
X
O
- The common diazo precursors are easily
obtained in high yields;
IX
X = Cl, Br
R = H, alkyl
R1 = H, alkyl, benzensulfonyl
(if R1 = H)
R2OCOCl
CaO
- The use of diazomethane is limited
to the preparation of the alkylating agents;
- High yields and full control of chemoselectivity
R
O
Ar
R2
N
N2
O
XI
CaO beneficial effect in CH2N2 acylation (2010)
- low chemoselectivity (i.e. ketenes by-products)
- hazard risk of CH2N2 in excess (4-6 equiv)
XHNEt3 or CH3X (+N2)
Base (e.g. NEt3)
Excess CH2N2
O
O
O
immediate
spontaneous
CH2N2
+
N2
+
HX
X
R
X
R
R
Nierenstein
X = Cl, Br
CaO
CaO (only 1 equiv CH2N2)
innocous by-products
easily removable
CaX2 + H2O
chemoselective, exclusive product
wide scope (not limited by R nature)
Scheme 1. Preparation of α-amino diazoketones: classical approach vs. this study (top). Concept of CaO-mediated
diazomethane acylation (down).
Results and Discussion
Using N-ethylaniline 1 and α-chlorodiazoacetone 2a21b as the model substrates, we explored the
nucleophilic displacement under different conditions (Table 1). Interestingly, when the reaction was run in
the absence of any base under stoichiometric conditions, we could isolate the corresponding α-
chloroketone 4 in 54% yield together with only 16% of the desired diazo ketone 3 (entry 1). It appeared
clear that eliminating the so-called Nierenstein reaction21a between the incipient α-diazoketone and the HCl
liberated during the nucleophilic substitution was critical to achieve full chemoselectivity. Accordingly,
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when the loading of 1 was progressively increased to 4 equiv a substantial improvement of the yield of the
target compound up to 49% (entries 2-3) was observed. These preliminary results suggest that the excess
of amine neutralizes the HCl by-product formed during the reaction. The addition of an external base (2
equiv.) such as DIPEA and TEA or inorganic ones (K2CO3, KHCO3, Na2CO3) confirms this trend but,
unfortunately the concomitant formation of the α-chloroketone could not be suppressed at all (entries 4-
8). Pleasingly, by using a simple acid scavenger (under stoichiometric conditions) such as CaO we could
obtain exclusively the desired diazoketone in a satisfactory 61% yield (entry 9). A brief screening of other
metal oxides such as MgO, ZnO and Al2O3 revealed the better performance of CaO (entries 10-12).
Interestingly, by employing earth-alkaline metal bases (i.e. CaCO3 and MgCO3, entries 13-14) an analogous
result to the above seen potassium and sodium (bi)-carbonates was observed, albeit the formation of α-
chloroketone was somewhat reduced. The solvent effect was remarkable in order to maximize the yield of
3, though the chemoselectivity was not affected : DMSO proved to be the best solvent to accomplish the
reaction (entries 15 and 24) compared to other media such as dichloromethane, 1,2-dichloroethane, DMF,
THF, 2-MeTHF and acetonitrile (entries 16-21 and 25). Temperature was crucial to optimize the reaction: at
rt reaction reached to completion within 12 h (entry 15), while attempts to increase up to 60 °C resulted in
obtaining low yields of the desired diazoketone 3 jointly with complex decomposition products (entries 22-
23). Finally, the use of the corresponding α-bromodiazoacetone 2b allowed to shortening reaction time to 8
h thus, obtaining the desired diazoketone 3 in a very good 86% yield (entry 24).
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Table 1. Reaction optimization.a
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Entry
1 (equiv.)
Base or acidic
sponge (equiv) Temperature (° C)
Solvent /
Reaction
time (h)
Yield of 3
Yield of 4a
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(%)a
(%)a
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23
24b
25b
1.0
2.5
4.0
4.0
3.0
3.0
3.0
3.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
-
-
-
Et2O / rt
Et2O / rt
Et2O / rt
Et2O / rt
Et2O / rt
Et2O / rt
Et2O / rt
Et2O / rt
Et2O / rt
Et2O / rt
Et2O / rt
Et2O / rt
Et2O / rt
Et2O / rt
DMSO / rt
DCM / rt
DCE / rt
24
24
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
24
12
8
16
34
49
55
58
57
53
55
61
55
51
46
54
51
81
54
64
57
49
38
72
46
32
86
80
54
31
18
16
21
13
17
15
-
8
14
8
13
15
-
-
-
-
-
-
-
-
-
DIPEA (2.0)
TEA (2.0)
K2CO3 (2.0)
KHCO3 (2.0)
Na2CO3 (2.0)
CaO (2.0)
MgO (2.0)
ZnO (2.0)
Al2O3 (2.0)
CaCO3 (2.0)
MgCO3 (2.0)
CaO (2.0)
CaO (2.0)
CaO (2.0)
CaO (2.0)
CaO (2.0)
CaO (2.0)
CaO (2.0)
CaO (2.0)
CaO (2.0)
CaO (2.0)
CaO (2.0)
DMF / rt
THF / rt
2-MeTHF / rt
DMF / rt
MeCN / 40
MeCN / 60
DMSO / rt
MeCN / rt
6
8
12
-
-
a Isolated yield. b 2b was employed as the alkylating agent.
Once the optimal conditions have been established, we next turned our attention to the scope of the
reaction. As shown in Scheme 2, various secondary aromatic amines react smoothly to afford the desired
diazo compounds (6a-e): the presence of steric hindrance on the aromatic ring (6d) or, the use of less
nucleophilic anilines (6a-b) do not influence the effectiveness - although a substantial increase of the
reaction time was noticed compared to more nucleophilic ones (6c, 6e). Analogously, the protocol is
applicable to primary aromatic amines which showed a similar trend based on the nucleophilicity of the
amines (6f-j). When N-sulfonamido-type protected anilines were employed, only traces of diazoketones
were recovered after prolonged reaction times; however, by adding a proper base such as KF-Celite (2
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equiv) in acetonitrile36 prior to the addition of 2b permitted a successful outcome thus, giving diazo ketones
6k and 6l in very good yields. Remarkably the fluoride base chemoselectively deprotonates the sulfonamide
anilines, thus simply increasing the nucleophilicity of the conjugate base. No concomitant proton
abstraction at the alkali-sensitive C-H bond37 of the diazo moiety was noticed. Interestingly, the procedure
could be efficiently applied also for the alkylation of aniline derivatives with a secondary bromide (2c) thus,
providing α-arylamino-α’-diazoketones 6m and 6n in high yields after 24 h.
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Scheme 2. Scope of the reaction.a
a Isolated yields. b Reaction run in MeCN; KF-Celite 2.0 equiv was added to the suspension of N-benzensulfoyl-type aniline. Ns = 4-
nitrobenzensulfonyl.
Calcium oxide was also effective in preserving the highly sensitive diazo moiety to the acidic environment
generated through the release of HCl during the acylation of diazoketones 6f and 6m with chloroformates.
As showed in Table 2, in its absence exclusively chloroketone 10 was formed within only 10 min thus,
further showcasing its capability to act as an innocuous acid scavenger to completely impede deleterious
Nierenstein-type phenomena. Thus, upon the addition of CaO (2 equiv), we could obtain the desired acyl-
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type protected diazoketones 7-9 in a fully chemoselective fashion, without observing any collateral
4
5
chloroketone.
6
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8
Table 2. Chemoselective CaO-mediated acylation of a secondary α-aminodiazoketone with chloroformates.
9
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Entry
Diazoketone Chloroformate Acid scavenger
(equiv)
Reaction
time
(min)
Acyl-
diazoketone
(%)a
Acyl-
chloroketone
(%)a
1
2
3
4
6f
6f
6f
6m
MeOCOCl
MeOCOCl
EtOCOCl
-
10
60
60
60
-
(10) 84
CaO (2.0)
CaO (2.0)
CaO (2.0)
(7) 95
(8) 88
(9) 91
-
-
-
MeOCOCl
a Isolated yield.
X-ray Analysis
The diazo group (C=N=N) in 6k_ortho (Figure 2) is nearly coplanar with the carbonyl group (C=O) (a torsion
angle O3-C15-C16-H16 of -176.4° and the torsion angle O3-C15-C16-N2 of 3.5°; Z orientation). The
diazomethylene group deviates from planarity by approx. 20° (H16-C16-N2-N3 of -163°, C15-C16-N2-N3 of 17°).
These values suggest that conjugation is possible between the carbonyl and the azomethylene groups in
6k_ortho. In addition, the C14-C15-C16-N2 angle of -172.3° and C14-C15-C16-H16 of -7.8° indicate that all six
substituents around carbonyl lie in one plane. The C16-N2 bond length of 1.322 Å is intermediate between
an average sp3 C-N (1.477-1.493 Å) and an average sp2 C=N bond (~ 1.28 Å). The C16-N2 bond length is
comparable with the analogous bond in dibenzoyl diazomethane (1.338 Å). The N2-N3 bond length in 6k
(1.123 Å) is slightly longer than an average sp2 N=N bond (1.101 Å). In addition, the C15-C16 bond length of
1.422 Å is slightly shorter than an average sp3 C-C bond (1.542 Å). All results discussed for 6k_ortho
strongly match to 6k_mono.
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Figure 2. Compound 6k crystalizes in two different conformations. Asymmetric units of 6k_ortho (left, light
orange) and 6k_mono (right, blue), drawn with 50% displacement ellipsoid.
The three independent molecules have almost the same geometric data. In 6k_mono the solvent area was
removed. It was not possible to proof the correct positions of the solvent. The volume of 194.8 Å3 was
removed. The according number of electrons cut is 45.1. This implies a too big volume in ratio to the
available number of electrons and, therefore a very high degree of flexibility in this area for small possible
solvent molecules such as water, methanol and ethanol. In 6k_ortho the probability of an inversion twin
could be detected with TWIN LAW (-1.0, 0.0, 0.0, 0.0, -1.0, 0.0, 0.0, 0.0, -1.0) and BASF [0.57(11)]. Also a
pseudo centre of symmetry (green) located at centre of mass for the asymmetric unit is visualized. Outside
the asymmetric unit this pseudo centre is not valid.
NMR Spectroscopic Investigations
The NMR data of selected diazoketones prepared are summarized in Tables 3 (1H-NMR data), 4 (13C-NMR
data) and 5 (15N-NMR data). Characteristic features observed in all types of spectra recorded at ambient
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temperature are somewhat broadened lines for the nuclei belonging to the CH2-CO-CHN2 system (see SI).
This phenomenon can be attributed to hindered rotation around the central OC-CN2 bond caused by the
resonance contribution of the enolate form e (Scheme 4b) somewhat decelerating the interconversion
between the s-cis (Z) and the s-trans form (E) with regard to the NMR timescale (Scheme 3a).38 It has been
shown that at lower temperatures with slower interconversion rates separate signals for both rotamers can
be detected.38 Moreover, it has been ruled out that this dynamic behavior arises from an intermolecular
process such as a possible keto-enol tautomerism as indicated in Scheme 3b.38a
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Scheme 3. Plausible physical phenomena existing in substituted α-aminodiazo ketones.
1
In the H NMR spectra of compound 3, 6a-n, 7-9 the methinic protons appear in the range of 5.44-6.24
ppm, whereas the CH2 resonances are located between 3.75-4.78 ppm, the latter being expectedly
somewhat influenced by the electronic properties of the substituents attached to the aminic nitrogen
atom. Thus, compounds carrying an electron withdrawing N-substituent (Tos, Moc, COOEt) exhibit larger
chemical shifts for the concerning methylene protons.
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Table 3. 1H NMR Data of 3-Aminodiazoketones presented in this study.a
4
5
6
7
8
9
No. H of R1
H of R2
CH(R)
CH=N2
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11
12
13
14
15
16
17
18
19
20
21
22
23
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37
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49
50
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53
54
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60
3
7.26 (Ph H-3,5), 6.78 (Ph H-4), 6.68 (Ph H-2,6)
3.47 (q, J = 7.1 Hz,
CH2), 1.21 (t, J = 7.1
Hz, CH3)
3.93 (s, CH2) 5.58
6a
6b
6c
6d
7.18 (Ph H-3,5), 6.58 (Ph H-2,6)
3.03 (s, CH3)
3.02 (s, CH3)
2.99 (s, CH3)
2.76 (s, CH3)
3.94 (s, CH2) 5.44
3.91 (s, CH2) 5.53
3.88 (s, CH2) 5.59
3.75 (s, CH2) 6.10
6.96 (Ph H-3,5), 6.61 (Ph H-2,6)
6.85 (Ph H-3,5), 6.65 (Ph H-2,6), 3.76 (Ph-4-OCH3)
6.84 (Ph H-3,5), 2.33 (Ph-2,6-CH3), 2.33 (Ph-2,6-CH3),
2.25 (Ph-4-CH3)
6e
6.82 (Ph H-3,5), 6.70 (Ph H-2,6), 3.75 (Ph-4-OCH3)
4.56 (s, CH2), 7.33 (Ph 3.97 (s, CH2) 5.59
H-3,5), 7.27 (Ph H-4),
7.22 (Ph H-2,6)
6f
6fb
7.21 (Ph H-3,5), 6.78 (Ph H-4), 6.60 (Ph H-2,6)
7.09 (Ph H-3,5), 6.59 (Ph H-4), 6.55 (Ph H-2,6)
4.47 (s, NH)
6.18 (t, J = 5.6 Hz,
NH)
3.89 (s, CH2) 5.63
3.81 (d, J =
6.06
5.6 Hz, CH2)
6g
6h
6i
7.30 (Ph H-3,5), 6.50 (Ph H-2,6)
4.52 (NH)
4.48 (NH)
4.73 (NH)
3.90 (s, CH2) 5.58
3.85 (s, CH2) 5.59
3.93 (s, CH2) 5.55
5.92 (Ph H-4), 5.76 (Ph H-2,6), 3.74 (Ph-3,5-OCH3)
7.29 (Ph H-5), 6.99 (Ph H-4), 6.78 (Ph H-2), 6.74 (Ph H-
6)
6j
7.10 (Ph H-5), 6.33 (Ph H-4), 6.21 (Ph H-6), 6.14 (Ph H-
2), 3.74 (Ph 3-OCH3)
4.46 (NH)
3.87 (s, CH2) 5.59
4.25 (s, CH2) 5.92
6k
7.28 (Ph H-3,4,5), 7.09 (Ph H-2,6)
7.42 (Ph H-2,6), 7.23
(Ph H-3,5), 2.40 (Ph-
4-CH3)
6lb
7.35 (Ph H-3,5), 7.34 (Ph H-4), 7.20 (Ph H-2,6)
8.37 (Ph H-3,5), 7.86
(Ph H-2,6)
4.52 (s, CH2) 6.24
6m 7.19 (Ph H-3,5), 6.77 (Ph H-4), 6.58 (Ph H-2,6)
4.05(s, NH)
3.91 (q, J =
7.0 Hz, CH),
1.46 (d, J =
7.0 Hz, CH3)
4.25 (q, J =
6.9 Hz, CH),
1.44 (d, J =
6.9 Hz, CH3)
5.71
6n
7.25 (Ph H-3,5), 6.79 (Ph H-4), 6.76 (Ph H-2,6)
3.27-3.40 (m, CH2),
1.21 (t, J = 7.0 Hz,
CH3)
5.56
7
8
7.23-7.44 (Ph H)
3.74 (s, OCH3)
4.15 (q, J = 7.1 Hz,
OCH2), 1.19 (t, J = 7.1
Hz, CH3)
4.37 (s, CH2) 5.46
4.31 (s, CH2) 5.44
7.30 (Ph H-3,5), 7.26 (Ph H-2,6), 7.19 (Ph H-4)
9
7.23 (Ph H-2,6), 7.30 (Ph H-4), 7.36 (Ph H-3,5)
3.68 (OCH3)
4.78 (q, J =
7.2 Hz, CH),
1.21 (d, J =
7.2 Hz, CH3)
5.62
a Except otherwise stated spectra were recorded in CDCl3. b Recorded in DMSO-d6.
It is well known that diazo carbon atoms (CN2) are extremely shielded compared to ‘normal’ sp2-hybridized
C-atoms: for instance, the carbon atom in diazomethane appears at δ 23.1 ppm.39 This extraordinarily small
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chemical shift can be attributed to the contribution of resonance forms with a negative charge located at
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5
the diazo C-atom (forms b and c in Scheme 4a). In the series of α-diazoketones studied herein we found 13
C
6
7
8
9
chemical shifts for the regarding C-atom of approximately 53 ppm, which resembles those of ω-
diazoacetophenone (δ 54.2 ppm)32 and ethyl diazoacetate (δ 46.3 ppm)32. The larger chemical shift
compared to the corresponding C-atom in diazomethane may be (partly) attributed to the delocalization of
the negative charge into the carbonyl moiety (form e, Scheme 4b). The one-bond 13C,1H spin coupling
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1
constant J(CHN2) for the diazoketones presented was found to be within a narrow range (199-204 Hz,
1
Table 4) and corresponds well to those found with related compounds (ω-diazoacetophenone: J = 199.2
Hz; ethyl diazoacetate: 1J = 202.6 Hz).40
Scheme 4. Resonance forms of diazomethane (a) and 3-aminodiazoketones (b)
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Table 4. 13C-NMR Data of 3-Aminodiazoketones presented in this study.a
4
5
6
7
8
9
10
11
12
13
14
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No.
C of aryl
C-4
C of R3
C of R2
CHR
C=O
195.6
194.3
195.0
195.7
196.4
195.3
CHN2
(1JCH)
50.0
(203.4)
53.2
C-1
C-2
C-3
C-5
C-6
3
147.3
112.3
129.4
129.1
115.8
114.8
129.9
114.8
117.5
122.5
156.0
152.4
135.3
152.6
129.4
112.3
--
46.1 (CH2), 11.9
(CH3)
59.1
(CH2)
6a
6b
6c
6d
6e
147.1
145.4
143.3
146.4
142.5
113.4
113.4
114.0
136.1
114.7
129.1
115.8
114.8
129.9
114.8
113.4
133.4
114.0
136.1
114.7
--
--
39.8 (CH3)
61.5
(CH2)
(201.9)
53.2
40.2 (CH3)
40.3 (CH3)
62.2
(CH2)
55.7 (OCH3)
62.6
(CH2)
65.1
(CH2)
59.9
(CH2)
53.1
(201.1)
53.1
(200.9)
53.4
20.6 (4-CH3), 19.5 41.3 (CH3)
(2,6-CH3)
55.6 (OCH3)
56.4 (CH2),
137.8 (Ph-1),
128.7 (Ph-3,5),
127.3 (Ph-4),
127.1 (Ph-2,6)
--
(201.7)
6f
146.8
147.9
145.8
148.8
147.0
112.8
112.1
114.4
91.7
129.4
129.0
132.1
161.8
118.4
116.6
110.1
90.5
129.4
129.0
132.1
161.8
129.8
112.8
112.1
114.4
91.7
--
52.0
(CH2)
51.3
(CH2)
51.7
(CH2)
51.8
(CH2)
51.2
(CH2)
193.7
195.2
192.2
193.2
191.5
53.3
6fb
6g
6h
6i
--
--
--
--
--
52.6
(204.1)
53.5
(200.4)
53.4
(202.6)
53.6
(201.4)
--
55.2 (3,5-OCH3)
109.0
(q, J =
4.0 Hz)
131.1
(q, J =
114.8
(q, J =
115.9
124.1 (CF3)
(q, J = 272.4 Hz)
31.9 Hz)
4.0 Hz)
6j
148.2
139.4
99.0
160.8
129.2
103.4
128.1
130.2
129.2
105.7
127.7
55.1 (OCH3)
--
--
51.9
(CH2)
58.1
(CH2)
193.4
190.5
53.3
(200.8)
54.7
6k
127.7
144.1 (Ph-4),
133.9 (Ph-1),
129.5 (Ph-3,5),
127.7 (Ph-2,6),
21.5 (CH3)
(202.0)
6lb
6m
6n
138.9
146.3
147.0
128.2
113.0
114.2
129.3
129.3
129.3
128.3
118.5
117.9
129.3
129.3
129.3
128.2
113.0
114.2
--
--
--
150.0 (Ph-4),
143.2 (Ph-1),
129.0 (Ph-2,6),
124.5 (Ph-3,5)
--
57.6
(CH2)
189.6
198.5
197.2
54.2
52.2
53.1
53.5
57.7
(CH),
19.3
(CH3)
63.3
(CH),
13.8
(CH3)
42.3 (CH2), 13.8
(CH3)
7
8
142.0
142.0
126.4
126.1
129.1
128.8
126.9
126.4
129.1
128.8
126.4
126.1
--
--
156.0 (CO), 53.3 57.7
(OCH3)
190.3
190.4
(CH2)
57.4
(CH2)
155.3 (CO),
62.1 (OCH2),
14.3 (CH3)
53.2
(199.2)
9
138.8
128.8
128.9
127.7
128.9
128.8
--
156.2 (CO), 53.2 60.2
(OCH3)
193.5
53.8
(202.1)
(CH),
14.9
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(CH3)
a Except otherwise stated spectra were recorded in CDCl3. b Recorded in DMSO-d6.
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To the best of our knowledge, 15N-NMR studies on diazo compounds are rather limited.40-41 The difficulties
associated with the unambiguous and correct assignment of the two diazo nitrogen atoms resonances has
been solved by Albright and Freeman employing selective enrichment with 15N.40 According to these
experiments the terminal nitrogen atom, in general, is more deshielded and, thus presents a larger
chemical shift than the central one. As summarized in Table 4, this principle was also applied for the
distinction between the diazo nitrogen atoms in our series of aminodiazoketones. Whereas the central
diazo N-atom resonates between -119.3 and -112.6 ppm (referencing against external nitromethane), the
shifts of the terminal N-atom are located between -11.5 and -8.5 ppm. Obviously, these shifts are only little
influenced by the residual part of the molecule. There is a fairly good agreement with shifts of related
compounds such as, for instance, ethyl diazoacetate (-112.6 and 3.7 ppm)40,33 or ω-diazoacetophenone
(-112.6 and -6.4 ppm).40,33 The 15N NMR chemical shifts of the aminic nitrogen atom are mostly dependent
from the nature of substituent R2 (Table 5). The presence of an electron withdrawing group (Ts, Ns,
COOMe) at this nitrogen atom causes a considerable increase of the chemical shift, as observed in the cases
of compounds 6k, 6l and 9. An interesting phenomenon can be observed in the case of N-methyl
substituted compounds (R2 = CH3) 6a-d: while in 6a (R1 = 4-chlorophenyl) and 6c (R1 = 4-methoxyphenyl) the
shifts of the amine-nitrogen atoms are closely together (δ -332.5 and δ -337.4 ppm), the corresponding
signal in 6d (R1 = 2,4,6-trimethlyphenyl) is distinctly shifted upfield (δ -355.0 ppm). This can be explained by
the lack of conjugation between phenyl ring and the nitrogen’s lone pair owing to sterical reasons
(distorsion of the aromatic system).
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Table 5. 15N NMR data of selected compounds.a
4
5
6
7
8
9
No.
3
R1
R2
R
NR1R2
-318.8
-332.5
-335.3
-337.4
-355.0
-326.6
-325.6
-321.3
-269.7
-271.3
-309.8
-273.3
CH=N=N
-117.9
-118.7
-118.5
-117.9
-116.3
-118.1
-118.1
-112.6
-119.3
-115.2
-116.0
-117.9
CH=N=N
-11.2
-11.6
-11.4
-11.0
-8.5
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Ph
Et
H
6a
6b
6c
6d
6e
6f
4-chlorophenyl
CH3
CH3
CH3
CH3
CH2Ph
H
H
4-fluorophenyl
H
4-methoxyphenyl
H
2,4,6-trimethylphenyl
H
4-methoxyphenyl
H
-10.6
n.f.c
Ph
Ph
Ph
Ph
Ph
Ph
H
6fb
6g
6jb
6n
9
H
H
-10.3
-11.4
-11.5
n.f.c
Ts
H
Nsd
Et
H
CH3
CH3
COOCH3
n.f.c
a Otherwise stated spectra were recorded in CDCl3. b Recorded in DMSO-d6. c n.f. = not found.
d -13.1 (NO2).
Conclusions.
A straightforward synthesis of α-arylamino diazoketones via nucleophilic displacement of widely
substituted anilines on primary and secondary α-halodiazoketones has been developed. Crucial for the
chemoselectivity of the process is the action of innocuous and inexpensive calcium oxide (CaO) as acid
scavenger. In fact, the deleterious Nierenstein-type side reaction of immediate conversion of the
intermediate diazoketones to the corresponding α-haloketones was completely suppressed. The protocol is
quite convenient in terms of versatility and practical applicability: only a unique Arndt-Eistert diazotization
– again, under minimal diazomethane loadings – is required for furnishing the key alkylating diazo
compound to be employed in the whole process. In-depth NMR and X-ray analyses contribute to
understand key characteristics of such densely functionalized synthons.
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Experimental Section.
Materials and methods.
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α-halodiazoketones 2a-b21b and 2c42 were prepared according to our previously reported method.21b All 1H
NMR and 13C NMR spectra were recorded on Bruker Avance spectrometers operating at 200, 400 or 500
MHz and at 50, 100 or 125 MHz, respectively, at 25 °C. The (residual) solvent peak was used as an internal
standard which was related to TMS with δ 7.26 ppm (1H, CDCl3) and δ 2.49 ppm (1H, DMSO-d6), δ 77.0 ppm
(13C, CDCl3) and 39.5 (13C, DMSO-d6). The 19F NMR experiments were conducted on a Bruker Avance 400
spectrometer (377 MHz), here absolute referencing via the Ξ ratio was used. The 15N NMR spectra (gs-
HSQC, gs-HMBC, or ‘direct’ detection via inverse gated decoupling) were recorded on a Bruker Avance 500
or a Bruker Avance 400 machine (50 and 40 MHz, respectively) and were referenced against external
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1
nitromethane. Spin-spin coupling constants (J) are given in Hz. Full and unambiguous assignment of all H,
1
13C, 15N and 19F-NMR resonances was achieved by combining standard NMR techniques, such as fully H-
coupled 13C-NMR spectra, APT, DEPT, HSQC, HMBC, and NOESY experiments. In some cases 15N NMR
chemical shifts were determined via the inverse gated decoupling technique in long term experiments
(4000 scans, relaxation delay 15s). HRMS were measured on a Bruker maXis 4G instrument (ESI-TOF).
The X-ray intensity data were measured on Enraf Nonius KappaCCD diffractometer equipped with graphite
monochromator and monocapillary optics, Mo K/a Siemens KFF Mo sealed tube and Oxford Cryosystems
Cryostream 600 cooling device. The structures were solved by direct methods and refined by full-matrix
least-squares techniques. Non-hydrogen atoms were refined with anisotropic displacement parameters.
Hydrogen atoms were inserted at calculated positions and refined with riding model and as rotating groups.
All calculations were performed using Enraf Nonius software and the SHELX9743 program package.
Additionally OLEX244 was used for refinement, molecular diagrams and graphical user-interface. Platon45 was
employed for symmetry check. Experimental data and CCDC-Codes can be found in the Supporting
Information.
General procedure for the synthesis of α-arylamino diazoketones (GP1).
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To a suspension of CaO (2.0 equiv) in dry DMSO (8 mL) at rt was added a solution of α-halodiazoketones
(1.0 equiv) (2a-c) in DMSO (1 mL) followed by the addition of the proper amine (1.0 equiv). The resulting
mixture was stirred for the appropriate time (Tables 1 and 2) and then, filtered under vacuum, washed
successively with Et2O, NaHCO3 (sat. aq.) and NaCl (sat. aq., 5 times). After liquid chromatographic (LC)
purification on silica gel, pure samples of diazoketones 3, 6a-n were obtained.
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1-diazo-3-(ethyl(phenyl)amino)propan-2-one. (3)
By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and N-
ethylaniline (121 mg, 1.0 mmol, 1.0 equiv), compound 3 was obtained in 86% yield (175 mg) as a yellow oil
after LC (eluent: hexanes / AcOEt 10%). 1H NMR (400 MHz, CDCl3) δ: 7.26 (m, 2H, Ph H-3,5), 6.78 (m, 1H, Ph
H-4), 6.68 ( m, 2H, Ph H-2,6), 5.58 (s, 1H, CHN2), 3.93(s, 2H, NCH2CO), 3.47 (q, J = 7.1 Hz, 2H, NCH2CH3),
1.21 (t, J = 7.1 Hz, 3H, NCH2CH3). 13C NMR (100 MHz, CDCl3) δ: 195.6 (C=O), 147.3 (Ph C-1), 129.4 (Ph C-3,5),
117.5 (Ph C-4), 112.3 (Ph C-2,6), 65.1 (CH2), 59.1 (CH2CO), 50.0 (CHN2), 46.1 (NCH2CH3), 11.9 (NCH2CH3). 15
N
NMR (40 MHz, CDCl3) δ: -318.8 (amine), -117.9 (CH=N=N), -11.2 (CH=N=N). Elemental Analysis (%) for
C11H13N3O. Calcd: C, 65.01; H, 6.45; N, 20.68. Found: C, 65.07; H, 6.47; N, 20.73.
1-chloro-3-[ethyl(phenyl)amino]acetone. (4)
By following GP1, starting from 2b (163 mg, 1.0 mmol, 1.0 equiv) and N-ethylaniline (121 mg, 1.0 mmol,
1.0 equiv) in diethyl ether (entry 1 – Table 1 in Results and Discussion), compound 4 was obtained in 54%
yield (114 mg) as a yellow oil after LC (eluent: hexanes / AcOEt 10%). 1H NMR (300 MHz, CDCl3) δ 7.31-7.23
(m, 2H), 6.83-6.76 (m, 1H), 6.67-6.62 (m, 2H), 4.22 (s, 2H), 4.20 (s, 2H), 3.51 (q, J = 7.1 Hz, 2H), 1.22 (t, J =
7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 203.0, 147.7, 130.1, 118.2, 112.8, 59.2, 47.2, 47.1, 12.5. IR (KBr, cm-
1) 3084, 1745. Elemental Analysis (%) for C11H14ClNO. Calcd.: C, 62.41; H, 6.67; N, 6.62. Found: C, 62.49; H,
6.72; N, 6.66.
1-((4-chlorophenyl)(methyl)amino)-3-diazopropan-2-one. (6a)
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By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and 4-
chloro-N-methylaniline (141 mg, 1.0 mmol, 1.0 equiv), compound 6a was obtained in 86% yield (192 mg) as
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a yellow oil after LC (eluent: hexanes / AcOEt 5%). H NMR (400 MHz, CDCl3) δ: 7.18 (d, J = 9.0 Hz 2H, Ph H-
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13C NMR (100 MHz,
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CDCl3) δ: 194.3 (C=O), 147.1 (Ph C-1), 129.1 (Ph C-3,5), 133.4 (Ph C-4), 113.4 (Ph C-2,6), 61.5 (CH2), 53.2
(CHN2), 39.8 (CH3). 15N NMR (40 MHz, CDCl3) δ: -332.5 (amine), -118.7 (CH=N=N), -11.6 (CH=N=N).
Elemental Analysis (%) for C10H10ClN3O. Calcd: C, 53.70; H, 4.51; N, 18.79. Found: C, 53.77; H, 4.56; N,
18.90.
1-((4-fluorophenyl)(methyl)amino)-3-diazopropan-2-one. (6b)
By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and 4-
fluoro-N-methylaniline (125 mg, 1.0 mmol, 1.0 equiv), compound 6b was obtained in 85% yield (176 mg) as
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a yellow oil after LC (eluent: DCM). H NMR (400 MHz, CDCl3) δ: 6.96 (m, 2H, Ph H-3,5), 6.61 (d, m, 2H, Ph
H-2,6), 5.53 (s, 1H, CH=N2), 3.91 (s, 2H, CH2), 3.03 (s, 3H, NCH3). 13C NMR (100 MHz, CDCl3) δ: 195.0 (C=O),
156.0 (d, J = 237.1 Hz, Ph C-4), 145.3 (Ph C-1), 115.8 (d, J = 22.2 Hz, Ph C-3,5), 113.4 (d, J = 7.4 Hz, Ph C-2,6),
62.6 (CH2), 53.2 (CHN2), 40.2 (CH3). 15N NMR (40 MHz, CDCl3) δ: -335.3 (amine), -118.5 (CH=N=N), -11.4
(CH=N=N). 19F NMR (376 MHz, CDCl3): δ -127.6 (Ph F-4). HRMS (ESI), m/z: calcd. for C10H10FN3NaO230.0701
[M+Na]+; found 230.0700.
1-diazo-3-((4-methoxyphenyl)(methyl)amino)propan-2-one. (6c)
By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and 4-
methoxy-N-methylaniline (137 mg, 1.0 mmol, 1.0 equiv), compound 6c was obtained in 88% yield (193 mg)
as a yellow oil after LC (eluent: hexanes / AcOEt 10%).1H NMR (400 MHz, CDCl3) δ: 6.85 (m, 2H, Ph H-3,5),
6.65 (m, 2H, Ph H-2,6), 5.59 (s, 1H, CH=N2), 3.88 ( s, 2H, CH2), 3.76 (s, 3H, Ph 3-OCH3), 2.99 (s, 3H, NCH3). 13
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NMR (100 MHz, CDCl3) δ: 193.7 (C=O), 152.4 (Ph C-4), 143.3 (Ph C-1), 114.8 (Ph C-3,5), 114.0 (Ph C-2,6),
62.6 (CH2), 55.7 (OCH3), 53.1 (CHN2), 40.3 (CH3). 15N NMR (40 MHz, CDCl3) δ: -337.4 (amine), -117.9
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(CH=N=N), -11.0 (CH=N=N). Elemental Analysis (%) for C11H13N3O2. Calcd: C, 60.26; H, 5.98; N, 19.17. Found:
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1-diazo-3-(mesityl(methyl)amino)propan-2-one. (6d)
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By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and N-
2,4,6-tetramethyl-N-methylaniline (149 mg, 1.0 mmol, 1.0 equiv), compound 6d was obtained in 68% yield
(157 mg) as a yellow oil after LC (eluent: hexanes / AcOEt 20%). 1H NMR (400 MHz, CDCl3) δ: 6.84 (s, 2H, Ph
H-3,5), 6.10 (s, 1H, CH=N2), 3.75 ( s, 2H, CH2), 2.76 (s, 3H, CH3), 2.33 (s, 6H, Ph-2,6-CH3), 2.25 (s, 3H, Ph-4-
CH3). 13C NMR (100 MHz, CDCl3) δ: 196.4 (C=O), 146.4 (Ph C-1), 136.1 (Ph C-2,6), 135.3 (Ph C-4), 129.9 (Ph C-
3,5), 65.1 (CH2), 53.1 (CHN2), 41.3 (CH3), 20.6 (Ph 4-CH3), 19.5 (Ph 2,6-CH3). 15N NMR (40 MHz, CDCl3) δ: -
355.0 (amine), -116.3 (CH=N=N), -8.5 (CH=N=N). Elemental Analysis (%) for C13H17N3O. Calcd: C, 67.51; H,
7.41; N, 18.17. Found: C, 67.44; H, 7.33; N, 18.09. HRMS (ESI), m/z: calcd. for C13H18N3O: 232.1444 [M+H]+;
found 232.1448.
1-(benzyl(4-methoxyphenyl)amino)-3-diazopropan-2-one. (6e)
By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and N-
(4-methoxyphenyl)-benzylaniline (213 mg, 1.0 mmol, 1.0 equiv), compound 6e was obtained in 91% yield
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(269 mg) as a yellow oil after LC (eluent: hexanes / AcOEt 5%). H NMR (400 MHz, CDCl3) δ: 7.33 (m, 2H,
CH2Ph H-3,5), 7.27 (m, 1H, CH2Ph H-4), 7.22 (m, 2H, CH2Ph H-2,6), 6.82 (m, 2H, NPh H-3,5), 6.70 ( m, 2H,
NPh H-2,6), 5.59 (s, 1H, CHN2), 4.56 (s, 2H, NCH2), 3.97 (s, 2H, NCH2CO), 3.75 (NPh-4-OCH3). 13C NMR (100
MHz, CDCl3) δ: 195.3 (C=O), 152.6 (NPh C-4), 142.5 (NPh C-4), 137.8 (CH2Ph-1), 128.7 (CH2Ph-3,5), 127.3
(CH2Ph-4), 127.1 (CH2Ph-2,6), 114.8 (NPh C-3,5), 114.7 (NPh C-2,6), 59.9 (CH2CO), 56.4 (NCH2Ph), 55.6
(OCH3), 53.4 (CHN2). 15N NMR (40 MHz, CDCl3) δ: -326.6 (amine), -118.1 (CH=N=N), -10.6 (CH=N=N).
Elemental Analysis (%) for C17H17N3O2. Calcd: C, 69.14; H, 5.80; N, 14.23. Found: C, 69.25; H, 5.86; N, 14.31.
1-diazo-3-(phenylamino)propan-2-one. (6f)
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By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and
aniline (93 mg, 1.0 mmol, 1.0 equiv), compound 6f was obtained in 90% yield (158 mg) as a yellow oil after
LC (eluent: hexanes / AcOEt 15%). 1H NMR (400 MHz, DMSO-d6) δ: 7.09 (m, 2H, Ph H-3,5), 6.59 (m, 1H, Ph
H-4), 6.55 (m, 2H, Ph H-2,6), 6.06 (br s, 1H, CH=N2), 6.18 (t, J = 5.6 Hz, 1H, NH), 3.81 (d, J = 5.6 Hz, 2H, CH2).
13C NMR (100 MHz, DMSO-d6) δ: 195.2 (C=O), 147.9 (Ph C-1), 129.0 (Ph C-3,5), 116.6 (Ph C-4), 112.1 (Ph C-
2,6), 52.6 (CHN2), 51.3 (CH2). 15N NMR (40 MHz, DMSO-d6) δ: -321.3 (amine), -112.6 (CH=N=N), -10.3
(CH=N=N). Elemental Analysis (%) for C9H9N3O. Calcd: C, 61.70; H, 5.18; N, 23.99. Found: C, 61.79; H, 5.22;
N, 24.08.
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1-(4-bromophenylamino)-3-diazopropan-2-one. (6g)
By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and 4-
bromo-aniline (172 mg, 1.0 mmol, 1.0 equiv), compound 6g was obtained in 77% yield (196 mg) as a yellow
oil after LC (eluent: hexanes / AcOEt 20%). 1H NMR (400 MHz, CDCl3) δ: 7.30 (m, 2H, Ph H-3,5), 6.50 (m, 1H,
Ph H-2,6), 5.58 (br s, 1H, CH=N2), 4.52 (br s, 1H, NH), 3.90 (br s, 2H, CH2). 13C NMR (100 MHz, CDCl3) δ: 192.2
(C=O), 145.8 (Ph C-1), 132.1 (Ph C-3,5), 114.4 (Ph C-2,6), 110.1 (Ph C-4), 53.5 (CHN2), 51.7 (CH2). 15N NMR
(40 MHz, CDCl3) δ: -325.6 (amine). Elemental Analysis (%) for C9H8BrN3O. Calcd: C, 42.54; H, 3.17; N, 16.54.
Found: C, 42.62; H, 3.22; N, 16.62.
1-diazo-3-((3,5-dimethoxyphenyl)amino)propan-2-one. (6h)
By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and 3,
5-dimethoxy-aniline (153 mg, 1.0 mmol, 1.0 equiv), compound 6h was obtained in 93% yield (219 mg) as a
yellow oil after LC (eluent: hexanes / AcOEt 5%). 1H NMR (500 MHz, CDCl3) δ: 5.92 (t, J = 2.1 Hz, 1H, Ph H-4),
5.76 (d, J = 2.1 Hz, 2H, Ph H-2,6), 5.59 (s, 1H, CHN2), 4.48 (s, 1H, NH), 3.85 (s, 2H, CH2), 3.74 (s, 6H, Ph-3,5-
OCH3). 13C NMR (126 MHz, CDCl3) δ: 193.2 (C=O), 161.8 (Ph C-3,5), 148.8 (Ph C-1), 91.7 (Ph C2), 90.5 (Ph C-
4), 55.2 (Ph-3,5-OCH3), 53.4 (CHN2), 51.8 (CH2). Elemental Analysis (%) for C11H13N3O3. Calcd: C, 56.16; H,
5.57; N, 17.86. Found: C, 56.27; H, 5.61; N, 17.95.
1-diazo-3-(3-(trifluoromethyl)phenylamino)propan-2-one. (6i)
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By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and 3-
(trifluoromethyl)-aniline (161 mg, 1.0 mmol, 1.0 equiv), compound 6i was obtained in 74% yield (180 mg) as
a yellow oil after LC (eluent: hexanes / AcOEt 10%). 1H NMR (400 MHz, CDCl3) δ: 7.29 (m, 1H, Ph H-5), 6.99
(m, 1H, Ph H-4), 6.78 (m, 1H, Ph H-2), 6.44 (m, 1H, Ph H-6), 5.55 (s, 1H, CH=N2), 4.73 (s, 1H, NH), 3.93 (s, 2H,
NHCH2CO). 13C NMR (100 MHz, CDCl3) δ: 191.5 (C=O), 147.0 (Ph C-1), 131.1 (q, J = 31.9 Hz, Ph C-3), 129.8
(Ph C-5), 124.1 (1J = 272.4 Hz, CF3), 115.9 (Ph C-6), 114.8 (q, J = 4.0 Hz, Ph C-4), 109.0 (q, J = 4.0 Hz, Ph C-2),
53.6 (CHN2), 51.2 (CH2). 15N NMR (40 MHz, CDCl3) δ: -324.4 (amine). 19F (376 MHz, CDCl3) δ:-62.8 (CF3).
Elemental Analysis (%) for C10H8F3N3O. Calcd: C, 49.39; H, 3.32; N, 17.28. Found: C, 49.50; H, 3.39; N, 17.41.
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1-diazo-3-(3-methoxyphenylamino)propan-2-one. (6j)
By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and 3-
methoxy-aniline (123 mg, 1.0 mmol, 1.0 equiv), compound 6j was obtained in 89% yield (183 mg) as a
yellow oil after LC (eluent: hexanes / AcOEt 10%). 1H NMR (400 MHz, CDCl3) δ: 7.10 (“t”, J = 8.1 Hz, 1H, Ph
H-3), 6.33 (ddd, J = 8.2, 2.3, 0.7 Hz, 1H, Ph H-4), 6.21 (ddd, J = 8.2, 2.3, 0.7 Hz, 1H, Ph H-6), 6.14 (“t”, J = 8.1
Hz, 1H, Ph H-2), 5.61 (br s, 1H, CH=N2), 4.46 (br s, 1H, NH), 3.87 (br s, 2H, CH2), 3.76 (s, 3H, Ph 3-OCH3). 13
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NMR (100 MHz, CDCl3) δ: 193.4 (C=O), 160.8 (Ph C-3), 148.2 (Ph C-1), 130.2 (Ph C-5), 105.7 (Ph C-6), 103.4
(Ph C-4), 99.0 (Ph C-2), 55.1 (OCH3), 53.3 (CHN2), 51.9 (CH2). 15N NMR (40 MHz, CDCl3) δ: -324.6 (amine).
Elemental Analysis (%) for C10H11N3O2. Calcd: C, 58.53; H, 5.40; N, 20.48. Found: C, 58.64; H, 5.48; N, 20.61.
General procedure for the synthesis of N-aryl-N-benzensulfonamido diazoketones (6k, 6l) (GP2).
To a suspension of CaO (2.0 equiv) and KF-Celite (2.0 equiv) in dry MeCN (8 mL) at rt was added a solution
of α-bromodiazoketone (2b, 1.0 equiv) in MeCN (1 mL) followed by the addition of the proper N-
benzenulfonamido-type aniline (1.0 equiv). The resulting mixture was stirred for the appropriate time
(Table 2) and then, filtered under vacuum, washed successively with Et2O, NaHCO3 (sat. aq.) and NaCl (sat.
aq.). After liquid chromatographic (LC) purification on silica gel, pure samples of diazoketones 6k and 6l
were obtained.
N-(3-diazo-2-oxopropyl)-4-methyl-N-phenylbenzenesulfonamide. (6k)
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By following GP2, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), KF-Celite (50% w/w, 232 mg, 2.0 mmol,
1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and N-tosylaniline (247 mg, 1.0 mmol, 1.0 equiv) in dry MeCN
(8 mL) compound 6k was obtained in 83% yield (273 mg) as a white solid (mp 179 °C – recrystallized from 2-
butanone) after LC (eluent: hexanes / AcOEt 20%). 1H NMR (400 MHz, CDCl3) δ: 7.42 (m, 2H, SO2Ph H-2,6),
7.28 (m, 3H, NPh H-3,4,5), 7.23 (m, 2H, SO2Ph H-3,5), 7.09 (m, 2H, NPh H-2,6), 5.92 (s, 1H, CHN2), 4.25 (s,
2H, NCH2CO), 2.40 (SO2Ph-4-CH3). 13C NMR (100 MHz, CDCl3) δ: 190.5 (C=O), 144.1 (SO2Ph C-4), 139.4 (NPh
C-1), 133.9 (SO2Ph-1), 129.5 (SO2Ph-3,5), 129.2 (NPh-3,5), 128.1 (NPh-4), 127.7 (NPh C-2,6), 127.7 (SO2Ph C-
2,6), 58.1 (CH2), 54.2 (CHN2). 15N NMR (40 MHz, CDCl3) δ: -269.7 (amine), -119.3 (CH=N=N), -11.4 (CH=N=N).
Elemental Analysis (%) for C16H15N3O3S. Calcd: C, 58.34; H, 4.59; N, 12.76. Found: C, 58.45; H, 4.64; N,
12.88.
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N-(3-diazo-2-oxopropyl)-4-nitro-N-phenylbenzenesulfonamide. (6l)
By following GP2, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), KF-Celite (50% w/w, 232 mg, 2.0 mmol,
1.0 equiv), 2b (163 mg, 1.0 mmol, 1.0 equiv) and N-(4-nosyl)aniline (278 mg, 1.0 mmol, 1.0 equiv) in dry
MeCN (8 mL) compound 6l was obtained in 77% yield (277 mg) as a yellow solid (mp 199 °C - recrystallized
from ethanol) after LC (eluent: hexanes / AcOEt 5%). 1H NMR (400 MHz, DMSO-d6) δ: 8.37 (m, 2H, SO2Ph H-
3,5), 7.86 (m, 2H, SO2Ph H-2,6), 7.35 (m, 2H, NPh H-3,5), 7.34 (m, 1H, NPh H-4), 7.20 (m, 2H, NPh H-2,6),
6.24 (s, 1H, CHN2), 4.52 (s, 2H, NCH2CO). 13C NMR (100 MHz, DMSO-d6) δ: 189.6 (C=O), 150.0 (SO2Ph C-4),
143.2 (SO2Ph C-1), 138.9 (NPh-1), 129.3 (NPh-3,5), 129.0 (SO2Ph-2,6) , 128.3 (NPh-4), 128.2 (NPh C-2,6),
124.5 (SO2Ph C-3,5), 57.6 (CH2), 54.2 (CHN2). 15N NMR (40 MHz, DMSO-d6) δ: -271.3 (amine), -115.2
(CH=N=N), -13.1 (nitro), -11.5 (CH=N=N). Elemental Analysis (%) for C15H12N4O5S. Calcd: C, 50.00; H, 3.36; N,
15.55. Found: C, 49.89; H, 3.32; N, 15.44.
1-diazo-3-(phenylamino)butan-2-one. (6m)
By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2c (177 mg, 1.0 mmol, 1.0 equiv) and
aniline (93 mg, 1.0 mmol, 1.0 equiv), compound 6m was obtained in 87% yield (165 mg) as a yellow oil after
LC (eluent: hexanes / AcOEt 10%). 1H NMR (400 MHz, CDCl3) δ: 7.19 (m, 2H, Ph H-3,5), 6.77 (m, 1H, Ph H-4), 6.58
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(m, 2H, Ph H-2,6), 5.71 (s, 1H, CHN2), 4.05 (s, 1H, NH), 3.91 (q, 1H, J = 7.0 Hz, CH), 1.46 (d, 3H, J = 7.0 Hz, CH3).
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57.7 (CH), 52.2 (CHN2), 19.3 (CH3). Elemental Analysis (%) for C10H11N3O. Calcd.: C, 63.48; H, 5.86; N, 22.21.
Found: C, 63.59; H, 5.83; N, 22.30.
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1-diazo-3-(ethyl(phenyl)amino)butan-2-one. (6n)
By following GP1, starting from CaO (112 mg, 2.0 mmol, 1.0 equiv), 2c (177 mg, 1.0 mmol, 1.0 equiv) and N-
ethyl-aniline (121 mg, 1.0 mmol, 1.0 equiv), compound 6n was obtained in 83% yield (180 mg) as a yellow
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oil after LC (eluent: hexanes / AcOEt 15%). H NMR (500 MHz, CDCl3) δ: 7.16 – 7.03 (m, 2H), 6.62 (dd, J =
20.8, 7.7 Hz, 3H), 5.40 (s, 1H), 4.09 (d, J = 7.2 Hz, 1H), 3.32 – 3.04 (m, 2H), 1.28 (d, J = 7.0 Hz, 3H), 1.04 (t, J =
7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 197.2, 147.0, 129.3, 118.0, 114.3, 63.3, 53.1, 42.3, 13.8. Elemental
Analysis (%) for C12H15N3O. Calcd: C, 66.34; H, 6.96; N, 19.34. Found: C, 66.46; H, 7.02; N, 19.43.
General procedure for the synthesis of α-arylamino diazoketones (GP3).
To a suspension of CaO (2.0 equiv) in dry Et2O (8 mL) at 0 °C was added a solution of α-
arylaminodiazoketone (1.0 equiv) (6f, 6m) in Et2O (1 mL) followed by the addition of the proper
chloroformate (1.0 equiv). The resulting mixture was stirred for the 1h and then, filtered under vacuum,
washed successively with Et2O, NaHCO3 (sat. aq.) and NaCl (sat. aq.). Pure samples of diazoketones 7-9
were obtained after removal of the solvent under reduced pressure.
Methyl (3-chloro-2-oxopropyl)phenylcarbamate. (10)8a
By following GP3, starting from diazoketone 6f (175 mg, 1.0 mmol, 1.0 equiv) and methyl chloroformate (95
mg, 1.0 mmol, 1.0 equiv) – (Entry 1 – Table 2 in Results and Discussion), compound 10 was obtained as a
colorless oil in 84% yield (203 mg). 1H NMR (300 MHz, CDCl3) δ 3.69 (s, 3H), 4.16 (s, 2H), 4.61 (s, 2H), 7.25-
7.28 (m, 3H), 7.33-7.37 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 46.3, 53.3, 57.8, 126.8, 127.2, 129.1, 141.6
(detectable only via HMBC), 155.9 (detectable only via HMBC), 197.9. IR (KBr, cm-1) 3084, 1754, 1731, 1708,
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905, 703. Elemental Analysis (%) for C11H12ClNO3. Calcd.: C, 54.67; H, 5.00; N, 5.80. Found: C, 54.78; H, 5.12;
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Methyl (3-diazo-2-oxopropyl)(phenyl)carbamate. (7)
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By following GP3, starting from CaO (112 mg, 2.0 mmol, 2.0 equiv), diazoketone 6f (175 mg, 1.0 mmol, 1.0
equiv) and methyl chloroformate (95 mg, 1.0 mmol, 1.0 equiv), compound 7 was obtained as a yellow oil in
95% yield (222 mg). 1H NMR (200 MHz, CDCl3) δ: 7.54 – 7.13 (m, 5H), 5.47 (s, 1H), 4.38 (s, 2H), 3.76 (s, 3H).
13C NMR (50 MHz, CDCl3) δ: 190.5, 156.2, 142.2, 129.2, 127.1, 126.6, 57.8, 53.6, 53.5, 53.5, 29.8. Elemental
Analysis (%) for C11H11N3O3. Calcd: C, 56.65; H, 4.75; N, 18.02;. Found: C, 56.51; H, 4.68; N, 17.90.
Ethyl 3-diazo-2-oxopropyl(phenyl)carbamate. (8)
By following GP3, starting from CaO (112 mg, 2.0 mmol, 2.0 equiv), diazoketone 6f (175 mg, 1.0 mmol, 1.0
equiv) and ethyl chloroformate (109 mg, 1.0 mmol, 1.0 equiv), compound 8 was obtained as a yellow oil in
1
88% yield (218 mg). H NMR (400 MHz, CDCl3) δ: 7.30 (m, 2H, Ph H-3,5), 7.26 ( m, 2H, Ph H-2,6), 7.19 (m,
1H, Ph H-4), 5.44 (br s, 1H, CHN2), 4.31 (br s, 2H, NCH2CO), 4.15 (q, J = 7.1 Hz, 2H, CH2CH3), 1.19 (t, J = 7.1
Hz, 2H, CH2CH3). 13C NMR (100 MHz, CDCl3) δ: 190.4 (C=O), 155.3 (COO), 142.0 (Ph -1), 128.8 (Ph-3,5), 126.4
(Ph-4), 126.1 (Ph-2,6), 62.1 (COOCH2), 57.4 (CH2CO), 53.2 (CHN2), 14.3 (CH2CH3). 15N NMR (40 MHz, CDCl3)
δ: -284.8 (amine). Elemental Analysis (%) for C12H13N3O3. Calcd: C, 58.29; H, 5.30; N, 16.99. Found: C, 58.40;
H, 5.38; N, 17.11.
Methyl (4-diazo-3-oxobutan-2-yl)(phenyl)carbamate. (9)
By following GP3, starting from CaO (112 mg, 2.0 mmol, 2.0 equiv), diazoketone 6m (189 mg, 1.0 mmol, 1.0
equiv) and methyl chloroformate (95 mg, 1.0 mmol, 1.0 equiv), compound 9 was obtained as a yellow oil in
1
91% yield (225 mg). H NMR (500 MHz, CDCl3) δ 7.40 – 7.28 (m, 3H), 7.25 – 7.21 (m, 2H), 5.62 (s, 1H), 4.78
(d, J = 7.4 Hz, 1H), 3.68 (s, 3H), 1.22 (d, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 193.5, 156.3, 128.9,
127.7, 53.8, 53.2, 15.0. Elemental Analysis (%) for C12H13N3O3. Calcd: C, 58.29; H, 5.30; N, 17.00. Found: C,
58.41; H, 5.36; N, 17.11.
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Acknowledgments
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The Authors thank the University of Vienna for generous financial support. L. C. thanks the Austrian
Academy of Sciences for a postdoctoral L’Oréal grant.
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We dedicate this work to Professor Massimo Curini in the occasion of his 70th birthday.
Associated Content
Supporting Information: Copies of 1H and 13C NMR spectra for all the compounds. X-ray crystallographic
information for 6k. This material is available free of charge via the Internet at http://pubs.acs.org.
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