A 'sulfonyl-azide-free' (SAFE) aqueous-phase diazo transfer reaction for parallel and diversity-oriented synthesis

Article abstract of DOI:10.1039/c9cc02042j

Diazo transfer reactions are notoriously associated with the use of potentially explosive sulfonyl azides. The first 'sulfonyl-azide-free' (SAFE) protocol for producing diazo compounds from their active-methylene precursors via the Regitz diazo transfer reaction was developed and has displayed a remarkable substrate scope. It can be applied to generating arrays of diazo compounds for further evolution via combinatorial chemistry and a range of scaffold-generating transformations.

Full text of DOI:10.1039/c9cc02042j

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
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DOI: 10.1039/C9CC02042J
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‘Sulfonyl-Azide-Free’ (SAFE) Aqueous-Phase Diazo Transfer
Reaction for Parallel and Diversity-Oriented Synthesis
Received 00th January 20xx,
Accepted 00th January 20xx
Dmitry Dar’in, Grigory Kantin, and Mikhail Krasavin*
DOI: 10.1039/x0xx00000x
Diazo transfer reactions are notoriously associated with the use of In principle, the risks associated with diazo transfer reagents
potentially explosive sulfonyl azides. The first ‘sulfonyl-azide-free’ can be avoided by preparing them in situ. Such an approach
(SAFE) protocol for producing diazo compounds from their active- has not been realized for diazo transfer reactions to-date
methylene precursors via the Regitz diazo transfer reaction was except for one isolated example reported by Hoveyda11 and
developed and has displayed a remarkable substrate scope. It can the recently reported noteworthy examples of generating
be applied to generating arrays of diazo compounds for further diazo compounds in a flow reactor described by Maguire and
evolution via combinatorial chemistry and a range of scaffold- Collins.12 Considering this methodology void, we became
generating transformations.
interested in exploring diazo transfer reaction without a need
to prepare, isolate and handle the hazardous reagent which
could be instead generated in situ.
Diazo compounds are distinctly versatile reactive building
blocks which can be activated, with the loss of a nitrogen
molecule, to give rise to carbene or metal carbenoid
intermediates.1 Besides their appeal in synthetic organic
chemistry, diazo compounds display a growing significance as
tools for chemical biology.2 Perhaps the most popular method
of preparing diazo compounds is currently the Regitz diazo
transfer from a sulfonyl azide to an active methylene
substrate.3 Although this process is generally clean and high-
yielding, potential explosion hazards4 associated with diazo
transfer reagents precludes their use on the industrial scale
and may even be hindering active exploration of the diazo
chemical space. In particular, there have been no examples of
diazo compound synthesis in an array format, which would
ultimately enable combinatorial library generation based on
the vast diazo chemistry.
Continued search for safer alternatives to tosyl azide (the most
commonly used diazo transfer reagent5) has delivered such
promising reagents as p-acetamidobenzenesulfonyl azide,6 p-
dodecylbenzenesulfonyl azide,7 imidazole-1-sulfonyl azide
hydrogen sulfate8 as well as polymer-supported9 and ionic
liquid sulfonyl azides.10 However, all these reagents are
nonetheless prone to exothermal decomposition and,
therefore, should be handled with care.
Any in situ protocol is potentially associated with increased by-
product formation. It is especially the case with diazo transfer
reagents where a large molecular entity (the sulfonyl portion)
is already destined to become a by-product and needs to be
effectively removed upon completion of the reaction. Our
attention was drawn by m-carboxybenzenesulfonyl azide
which has been successfully employed as a diazo transfer
reagent in organic solvents13a-f and in water.13g Although its
preparation has never been attempted in aqueous medium,
we saw it as a suitable lead for the development of a ‘sulfonyl-
azide-free’ (SAFE) protocol for the preparation of diazo
compounds in water.
After relatively brief experimentation involving variations of
reagent ratios, solvent volume and reaction time, we realized
that a wealth of active-methylene substrates 1-49 can be
conveniently transformed into their diazo counterparts 1ʹ-49ʹ
in good to excellent yields via a simple ‘mix-all’ protocol,
mostly on 1.5 mmol scale, using m-carboxybenzenesulfonyl
chloride (commercially available or conveniently prepared in
>50 g batches – see ESI) and sodium azide in basic aqueous
solution (Scheme 1). As it is evident from the substrate scope
displayed by the new SAFE method, diazo group can be
transferred from sodium azide to give a wide variety of known
as well as hitherto unreported (5ʹ, 13ʹ, 20ʹ, 23ʹ-24ʹ, 30ʹ, 33ʹ-37ʹ,
39ʹ, 40ʹ, 42ʹ, 45ʹ, 49ʹ) diazo compounds. Only certain substrates
required longer reaction time for the diazo transfer; otherwise
the reaction was complete in 1-2 h. In addition to the R2 group
being most commonly represented by another carbonyl group,
it can include other carbanion-stabilizing moieties such as
vinylogous (9) and phenylogous (10, 41-42) carbonyls (or
a. Institute of Chemistry, Saint Petersburg State University
b. Saint Petersburg 199034 Russian Federation
c. E-mail: m.krasavin@spbu.ru
Electronic Supplementary Information (ESI) available: Experimental details, full
characterization data, crystallographic information, copies of 13C and 1H NMR
spectra. See DOI: 10.1039/x0xx00000x
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variants thereof, cf. 27-28), cyano (21-26), sulfone (33-38), applicable to the variants of the Danheiser deacylative diazo
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phosphonate (31-32) or electron-deficient aromatic (29-30) transfer14 successfully producing hitherto undescribed diazo
DOI: 10.1039/C9CC02042J
groups. Some substrates (25-28) displayed incomplete compounds 52ʹ-53ʹ with the loss of acetyl and methoxalyl
conversion and suboptimal product yield under standard groups, respectively (Scheme 2). Altogether, except for a
reaction conditions; both of these aspects were improved by handful of examples (13ʹ, 27ʹ-28ʹ, 42ʹ), the crude diazo
doubling the amount of NaN3, the base and the sulfonyl compounds produced in the course of the initial scope
1
chloride.
investigation had a purity of at least 95% as determined by H
NMR. Moreover, the reaction displayed comparable yield on
3.0-9.0 mmol scale.
The SAFE protocol:
NaN3 (2.0 equiv.)
m-HO2CC6H4SO2Cl
(1.3 equiv.)
N2
R1
R1
R2
1 49
R2
N2
O
Me
CO2Me
B
B
HO
OH
O
N2
O
O
O
A
K2CO3 (2.6 equiv.)
H2O, r. t., 1-2 h
CO2Me
1' 49'
-
-
MeO2C
MeO2C
N2
N2
52'
, 71%
N2
50
52
C(O)CO2Me
N2
N2
S
N2
50'
, 45%
O
O
O
O
N2
O
O
O
O
O
O
O
N
N
O
O
N
N
O
Me Me
Me OEt
Me
Me
N2 N2
Me
Me
O
O
A
Me Me
4'
O
O
O
(MeCN)
2'
, 79%
5'
3'
, 82%
, 81%
1'
, 91%
OMe O
51
Reaction conditions:
OMe
, 88%
OMe O
OMe
F
N2
N2
N2
N2
F
N2
51', 85%
53
53'
, 83%
O
O
O
O
O
O
O
O
CO2Me
N
O
OEt OEt
OMe
NaN3 (4.0 (A) or 2.0 (B) equiv.), m-HO2CC6H4SO2Cl (2.6 (A) or 1.3 (B) equiv.), K2CO3 (5.2 (A) or
2.6 (B) equiv.), H2O, r. t., 1-2 h
Me
Ph Me
Me Me
[c]
9', 68%[a]
[a]
[a][b][e]
6'
, 96%
7'
, 86%
8'
, 92%
10'
, 86%
Scheme 2. Double and decylative SAFE diazo transfer.
N2
N2
N2
O
N2
O
O
O
O
Me
p-TolSO2
O
O
N
O
N2
[a]
Having established the efficiency of the newly developed SAFE
protocol, we sought to apply it to simultaneous generation of
different diazo compounds from their active-methylene
precursors in an array format. To test this possibility, we
prepared aqueous solution of sodium azide, m-
carboxybenzenesulfonyl chloride and potassium carbonate
and added it in proportionate aliquots to an array of 20
reaction vessels containing different substrates (54-73)
followed by the addition of 50% v/v of MeCN. After 2 h of
stirring at r.t., parallel extraction with chloroform gave, after
drying and evaporation of the solvent, diazo compounds 54ʹ-
73ʹ all of which were judged to be at least 95% pure by 1H NMR
(Scheme 3). Thus, the SAFE method was found suitable for
producing structurally diverse sets of diazo compounds in
N
N
O
Me OBu-t
O
OEt
Ph
Ph
Ph
, 88%
[e]
[a][c]
14'
, 84%
[a]
11'
, 92%
12'
, 92%
[a][g]
15'
13'
, 66%
N2
O
N2
N2
N2
O
O
O
O
t-Bu
O
N
O
N2
Ph OEt
O
OEt
Ph Ph
O
OEt
O
[a][c]
[a][b]
20'
, 89%
18'
, 86%
16'
, 81%
19'
[a]
, 92%
17'
, 86%
O
N2
CN
N2
O
N2
CN
N2
O
t-BuO
N2
t-Bu
CN
Ph
N
MeO
CN
O
O
[e]
25', 71%[f]
N2
24'
, 96%
23'
, 68%
22'
, 78%
21'
, 63%
O
N2
O
N2
N2
N2
O
Me
EtO
O
CN
[f]
O
OMe
[a][e]
O2N
[f][g]
[f][g]
27'
, 64%
28'
, 41%
O2
N
Me
30', 84%[a]
29'
, 61%
26'
, 44%
(from -naphthol)
(from -naphthol)
O
O
N2
O
P
N2
O
O
S
O
O
S
N2
O
N2
O
S
N2
O
parallel fashion.
P
EtO
EtO
R1
CO2Me
[a][e]
COPh
[a][e]
N
O
OEt Me
OEt OEt
R2
Me
35', 69%[a]
N2
33'
, 87%
34'
, 89%
[e]
31'
, 91%
R1
32'
, 81%
O
SAFE protocol
R2
O
O
N2
N2
O
O
O
O
S
54-73
(0.75 mmol)
array of 20 parallel
reactions
O
O
S
Me
N2
O
O
N
S
N2
O
N
54' 73'
N
-
N2
O
N
O
Me
O
Ph
, 84%
[a]
[e]
38'
, 58%
39'
N2
O
36'
, 81%
37'
, 83%
40', 68%[a]
O
O
N2
N2
N2
N2
N2
N2
S
N2
O
N2
O
O
O
O
O
O
O
O
N2
O
O
N
N
O
OEt
p-FC6H4
O
c-Hex
Hex-c
N
NH
NMe2
[e]
OMe OMe
C6H4OMe-p
Me
57'
OMe
O
O
Me
[a]
p-FC6H4
45'
O
O
O
, 74%
54'
O
, 97%
58'
56'
, 86%
, 95%
55'
, 83%
43'
, 62%
44'
, 93%
[e][h]
[a]
42'
, 83%
, 96%
41'
, 90%
N2
O
N2
N2
N2
MeO
O
BnO
N2
O
O
N2
N2
p-Tol
HN
p-FC6H4
O
O
COMe
CO2Me
O
N2
CN
O
O
Me
F
O
p-Tol
O
C6H4F-p
p-FC6H4
O
S
S
S
O
OMe
[a]
N2
S
O
[a]
[a]
Ph OMe
O O
NC
[a]
O
Ph
, 97%
46'
, 93%
47'
, 91%
48'
, 92%
49'
, 92%
60'
, 60%
62'
61'
, 76%
63'
, 87%
Scheme 1. Scope of the SAFE diazo transfer reaction. Yields of the isolated products.
59'
, 75%
N2
[a]Acetonitrile (1-2 mL) was added to aid in the formation of a fine suspension or
N2
O
N2
O
O
O
O
N2
O
O
emulsion; [b]3.0 mmol scale; [c]6.0 mmol scale; [d]9.0 mmol scale; increased reaction
O
[e]
N2
O
N
N
N
N
2
time (see ESI for details); [f]double amount of NaN3 and m-HO2CC6H4SO2Cl was used;
N
Ph
Cl
O
O
[g]purified by chromatography; [h]purified by crystallization.
68'
, 90%
66'
, 88%
64'
67', 93%
, 93%
65'
, 78%
N2
N2
N2
O
O
O
O
O
O
O
O
N2
N2
O
Naturally, increasing the amount of these reagents twofold
was also needed to achieve double diazo transfer onto
substrates 50-51 to produce respective bis-diazo compounds
50ʹ-51ʹ. Interestingly, the SAFE reaction conditions were found
OEt
Ph
69'
MeO
Ph
O
Me OPr-i
72'
MeO
EtO
70'
, 93%
73'
, 98%
71'
, 85%
, 87%
, 84%
Scheme 3. SAFE array synthesis of diazo compounds 54ʹ-73ʹ.
2 | J. Name., 2012, 00, 1-3
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The established amenability of the SAFE protocol for array RhII-catalyzed X-H insertion chemistry. Considering the
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diazo compound synthesis motivated us to explore the versatility of diazo compounds in generaDtiOnIg: 1d0i.v10e3r9s/eCm9CoCl0e2c0u4l2aJr
possibility of modifying compounds 1ʹ-73ʹ in combinatorial skeletons,16 we aimed to confirm that 11ʹ (an exemplary
fashion, so as to obtain the products of subsequent diazo compound prepared, without purification, on a 9 mmol scale,
chemistry directly from their active-methylene precursors, vide supra) can be considered a starting point for generating
without a need to purify the SAFE diazo transfer products in skeletally diverse compounds thereby validating the SAFE
the interim. Such a possibility was indeed realized for a small protocol for the future use in diversity-oriented synthesis. This
set of substrates (7-8, 12, 35 and 52) which were prepared in compound was split into six 1.38 mmol batches which were
parallel fashion and used directly in reactions involving individually subjected to a range of reactions hallmark for
Rh2(esp)2-catalyzed decomposition15 and Rh carbene insertion diazo compounds. In particular, microwave-assisted Wolff
into an O-H or N-H bond of a carboxylic acid, an alcohol or a rearrangement17 of compound 11ʹ generated the respective
carboxamide (Scheme 4).
ketene which was subsequently trapped with an aniline (to
give 79), enol ether (to give 80)18 or underwent a [2+2]
Staudinger cycloaddition with an imine19 to produce -lactam
81 whose structure was confirmed by single-crystal X-ray
analysis (ESI). Reactions with the Lawesson’s reagent20 and
phenyl hydrazine21 delivered 1,2,3-thiadiazole 82 and 1,2,3-
triazole 83, respectively. Finally, the RhII carbene insertion into
C-H bond of the tert-butyl moiety22 produced -lactone 84
which was, without isolation, subjected to the deacetylative
SAFE diazo transfer (realized in a two-phase format by adding
the alkaline aqueous diazo transfer cocktail to the crude DCM
solution of 84). However, instead of diazo compound 85, we
obtained -hydroxy -lactone 86 formed, presumably, via the
metal carbene insertion into HO-H bond catalyzed by the
leftover Rh2(esp)2 present in the biphasic mixture (Scheme 5).
N2
X
XH
R1
SAFE protocol
R1
R1
R2
R2
R2
1 mol%
Rh2(esp)2
r. t., 18 h
O
O
O
5 parallel reactions
Solution in DCE
74-78
0.75 mmol
F
O
O
O
O
NHCO2Et
O
S
OMe
O
O
O
Ph
Ts
O
O
N
O
MeO2C
O
Me
O
Me
Me
EtO2C
CO2Et
CO2Me
76
77
78
50% (from
75
31% (from
74
12
)
35
)
34% (from
52% (from
52
)
8
)
7
)
52% (from
Scheme 4. Combinatorial format for the SAFE diazo transfer and subsequent Rh
carbene X-H insertion reactions.
The latter finding demonstrated that the purity of diazo
compounds obtained via the SAFE protocol was adequate for
N
N
N
N
S
N
PhHN
CO2tBu
CO2tBu
Me
82
Me
, 45%
83
, 31%
Lawesson's
reagent
PhNHNH2.HCl
MeOH, r. t.
PhH

Me
O
O
O
N2
SAFE
protocol
p-Tol-NH2
Rh2(esp)2
0.5 mol %
N2
Ac
HO
O
O
DCE
O
NH
O
O
O
W, 140 o
C
DCM, r. t.
18 h
Me
O
Me
Me
1 h
Me
Me
85
Me
Me
11'
Me
CO2tBu
84
79
, 71%
86
, 38%
DCE
over 3 steps
(one-pot)
Ph
DCE
W, 140 o
C
W, 140 oC, 1 h
N
O
PMP
1 h
O
Ph
O
N
H
CO2tBu
tBuO2C
Me
81
PMP
Me
, 42%
O
, 57%
80
Scheme 5. Diversity-oriented synthetic exploration of 11ʹ.
To conclude, we developed the first ‘sulfonyl-azide-free’ (SAFE) applied to the evolution of the diazo compound scaffold can
protocol for diazo transfer in aqueous medium.23 It has been be expanded so as to enable diversity-oriented synthesis of
found workable for 73 structurally diverse, active-methylene skeletally unique compounds. Efforts are underway in our
substrates and produced the respective diazo compounds (22 laboratories to adapt the SAFE protocol to a continuous flow
of them new) in high product yields and purities.§ The SAFE format. The results of these studies will be reported in due
method was found to be applicable to producing diazo course.
compounds in an array format and the products thus obtained We are grateful to the Russian Foundation for Basic Research
can be conveniently used in subsequent chemistry conducted for financial support (grant #19-03-00775). We thank the
in combinatorial fashion. Moreover, the range of chemistries Research Centre for Magnetic Resonance, the Center for
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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23 The aqueous-phase waste should be disposed oVfieawccAortircdleinOgnline
Chemical Analysis and Materials Research, and the Centre for
X-ray Diffraction Methods of Saint Petersburg State University
Research Park for obtaining the analytical data.
to the general guidelines for aqueous solutions containing
DOI: 10.1039/C9CC02042J
inorganic azides: Bretherick’s Handbook of Reactive
Chemical Hazards 6th Ed., P.G. Urben (Ed.), Oxford,
Butterworth-Heinemann, 1999.
Conflicts of interest
The authors declare no conflict of interest.
Notes and references
§
All diazo compounds reported in this Communication are now
available from ABCR GmbH.
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DOI: 10.1039/C9CC02042J