Synthesis of Donor/Acceptor-Substituted Diazo Compounds in Flow and Their Application in Enantioselective Dirhodium-Catalyzed Cyclopropanation and C-H Functionalization

Article abstract of DOI:10.1021/acs.orglett.7b01073

A tandem reaction system has been developed for the preparation of donor/acceptor-substituted diazo compounds in continuous flow coupled to dirhodium-catalyzed C-H functionalization or cyclopropanation. Hydrazones were oxidized in flow by solid-supported N-iodo-p-toluenesulfonamide potassium salt (PS-SO₂NIK) to generate the diazo compounds, which were then purified by passing through a column of molecular sieves/sodium thiosulfate.

Full text of DOI:10.1021/acs.orglett.7b01073

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Letter
pubs.acs.org/OrgLett
Synthesis of Donor/Acceptor-Substituted Diazo Compounds in Flow
and Their Application in Enantioselective Dirhodium-Catalyzed
Cyclopropanation and C−H Functionalization
Daniel Rackl,†,§ Chun-Jae Yoo,‡,§ Christopher W. Jones,*,‡ and Huw M. L. Davies*,†
†Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
‡School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Drive NW, Atlanta, Georgia 30332,
United States
S
* Supporting Information
ABSTRACT: A tandem reaction system has been developed
for the preparation of donor/acceptor-substituted diazo
compounds in continuous flow coupled to dirhodium-
catalyzed C−H functionalization or cyclopropanation. Hydra-
zones were oxidized in flow by solid-supported N-iodo-p-
toluenesulfonamide potassium salt (PS-SO2NIK) to generate
the diazo compounds, which were then purified by passing
through a column of molecular sieves/sodium thiosulfate.
Scheme 1. Diazo Compound Synthesis in Flow
−H Functionalization has become an exciting new
Csynthetic strategy that has brought significant innovation
into total synthesis and new methodologies for drug develop-
ment.1 One particularly useful C−H functionalization proce-
dure has been the C−H insertion chemistry of transient metal
carbenes, typically generated from diazo compounds.2 In recent
years, rhodium-stabilized donor/acceptor carbenes have proven
to be effective in a wide range of intermolecular C−H
functionalization reactions, in which the site selectivity and
stereoselectivity are dominated by catalyst control.3 However, a
drawback of the use of diazo compounds as carbene precursors
is the issue of safe handling of large quantities of these high-
energy compounds.4 Even though there are reports of metal-
catalyzed reactions of donor/acceptor diazo compounds
conducted on kilogram or larger scale,5 the broad utilization
of metal carbene chemistry would be greatly facilitated if the
diazo compounds were generated under flow conditions and
directly used in subsequent reactions.
We have begun applying flow conditions and immobilized
catalysts to intermolecular enantioselective C−H functionaliza-
tion and cyclopropanation reactions of donor/acceptor
carbenes.6 We previously developed an immobilized form of
an early-generation catalyst, Rh2(S-DOSP)4, and showed that it
can be incorporated into fibers and used for cyclopropanation
reactions.6b In this paper we describe the development of
suitable flow conditions for the generation of donor/acceptor-
substituted diazo compounds that then can be used in batch
reactions for Rh2(S-p-BrTPCP)4- and Rh2(R-3,5-di(p-tBuPh)-
TPCP)4-catalyzed cyclopropanations and challenging C−H
functionalization reactions (Scheme 1).3
pounds, several groups have explored methods specifically
focused on the synthesis of this type of diazo compound.7a−c
The standard diazo transfer reaction using a sulfonyl azide has
been employed but has the disadvantage of requiring an in-line
purification procedure to remove the sulfonamide byproduct.7a
More attractive is the oxidation of a hydrazone to the diazo
7b
compound using either MnO2 or solid-supported N-iodo-p-
toluenesulfonamide potassium salt (PS-SO2NIK)7c as the
oxidant. In all of these reactions, the subsequent reactions
were conducted with very reactive trapping agents, such as
heteroatoms that would readily form ylide intermediates or
styrenes. For these approaches to be effective in our chemistry,
it would need to be applied to diazo compounds with
The preparation of diazo compounds in flow has generated
considerable interest in recent years.7 Considering the breadth
of the chemistry of donor/acceptor-substituted diazo com-
Received: April 9, 2017
Published: June 5, 2017
© 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b01073
Org. Lett. 2017, 19, 3055−3058

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Organic Letters
Letter
trichloroethyl (TCE) esters,3b,c and further C−H functionaliza-
tion reactions with much less reactive substrates than anything
previously reported would need to be accommodated. On the
basis of the prior literature precedent, we concluded that PS-
SO2NIK resin7c would likely be the most effective because the
oxidation reaction is fast under ambient temperature and no
interfering byproducts would be formed.
Table 2. Effect of Drying Agents for Cyclopropanations
The first stage of the project was to develop an effective
protocol for the synthesis of the 2,2,2-trichloroethyl aryldia-
zoacetates. The required hydrazones were generated in two
steps: first, the 2-oxo-2-arylacetates were synthesized through
Friedel−Crafts acylation to form 2. Subsequent condensation
with hydrazine monohydrate gave chromatographically separa-
ble mixtures of Z and E hydrazones 3. (Table 1). Both isomers
yields (%)
entry
drying column
none
5c
6c
combined
1
2
3
4
5
6
7
72
69
77
70
75
73
89
24
13
12
11
10
8
96
82
89
81
85
81
93
Na2SO4
MgSO4
flash silica gel
<50 μM 3 Å MS
120−320 μm 4 Å MS
<50 μM 4 Å MS
Table 1. Aryldiazoacetate Synthesis in Flow from
Presynthesized Hydrazones
5
Scheme 2. Cyclopropanations with Aryldiazoacetates
Synthesized in Flow
yield of 2
(%)
yield of 4
purity of 4
a
b
cmpd
R
yield of 3 (%)
(%)
(%)
a
b
c
H
68
66 (Z), 6 (E)
46 (Z), 6 (E)
58 (Z), 7 (E)
59 (Z), 5 (E)
97
99
97
98
97
F
77
85
89
87
Br
tBu
97
d
e
100
OMe 58 (p) +
43 (p/Z),
21 (o/Z)
90 (p),
90 (o)
98 (p),
97 (o)
29 (o)
a
b
From (Z)-hydrazone. Determined by Q-NMR.
of the hydrazones were cleanly oxidized by the PS-SO2NIK
resin7c to give the aryldiazoacetates 4 in high yield and purity
(Table 1). Excess PS-SO2NIK resin7c (5 equiv) was used to
ensure full conversion of the hydrazones to the corresponding
diazo compounds because any unreacted hydrazone in the
product stream would likely poison the dirhodium catalyst in
the downstream reaction.
The initial studies to directly utilize the as-generated stream
of donor/acceptor-substituted diazo species for subsequent
dirhodium-catalyzed reactions were not very successful (Table
2). When Rh2(S-p-BrTPCP)4-catalyzed cyclopropanation with
4c and styrene to form 5 was attempted, alcohol 6, derived
from O−H insertion into water, was a significant byproduct
(Table 2, entry 1). Prolonged drying of the PS-SO2NIK resin
(and all other materials) in vacuo over potassium hydroxide did
not improve the situation. Therefore, to remove trace water
from the diazo product stream, we examined various drying
agents such as sulfate salts and silica for their drying capability
under the conditions employed, but none were very effective
(Table 2, entries 2−4). Better results were obtained using
molecular sieves (Table 2, entries 5−7), with fine powdered 4
Å molecular sieves giving the best recovery and drying capacity
(Table 2, entry 7).
additional separation steps after the aryldiazoacetate synthesis
are not required. Cyclopropanes 5a−e were synthesized in
good yields (77−88%) with high levels of enantioselectivity
(91−99% ee). However, cyclopropane 5f, stemming from o-
methoxyphenyldiazoacetate, afforded only moderate enantiose-
lectivity (67% ee). The 4-chloro- and 4-methoxy-substituted
styrenes afforded cyclopropanes 5g and 5h in similar yields
(88% and 87%, respectively) and enantioselectivity (90% ee
and 91% ee, respectively). For a direct comparison in terms of
the employed reaction conditions, the concentration (0.2 M)
and flow rate (3 mL/min) of the aryldiazoacetates in DCM
were matched with the conventional batch reaction conditions.
The Rh2(S-p-BrTPCP)4-catalyzed synthesis of cyclopropane 5c
through flow synthesis showed a very similar yield (89% vs 91%
in batch) and level of enantioselectvity (93% ee vs 95% ee in
batch) as the conventional batch reaction.
The optimized flow synthesis and drying conditions were
then applied to the enantioselective synthesis of a series of
cyclopropanes 5a−h (Scheme 2).8 The in-flow-synthesized
aryldiazoacetates 4 were directly consumed downstream upon
reaction with appropriate coupling agents in the presence of
dirhodium catalysts. The advantage of this system is that
While the optimized process for drying the diazo stream was
effective for cyclopropanation reactions, the application of the
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DOI: 10.1021/acs.orglett.7b01073
Org. Lett. 2017, 19, 3055−3058

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Organic Letters
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same protocol to the more challenging C−H functionalization
reactions was unsuccessful. The dichloromethane wash of the
PS-SO2NIK resin had a faint violet color, suggesting that iodine
was leaching from the resin. Control studies were conducted to
determine the influence of iodine and the reducing agent
sodium thiosulfate. The iodine color dissipated upon exposure
to solid sodium thiosulfate, and the diazo compound was stable
in the presence of sodium thiosulfate (see the Supporting
Information for details). In batch reactions between aryldia-
zoacetate 4c and p-cymene (7), the standard reaction
proceeded in high yield and enantioselectvity, but when 5
mol % iodine was added, carbene dimer became the dominant
product and virtually no C−H insertion product 8c was
obtained. Carbene dimerization was blocked when a 20 mol %
loading of the commercial pentahydrate form of sodium
thiosulfate was added, but O−H insertion into water was the
major product. A large amount of O−H insertion was obtained
with sodium thiosulfate pentahydrate in the absence of iodine,
but the efficiency of the reaction was fully recovered when 20
mol % anhydrous sodium thiosulfate was used instead (Table 3,
entry 5).
in a batch reaction (Table 3, entry 1). Similarly, the Rh2(S-p-
BrTPCP)4-catalyzed reaction of the unsubstituted aryldiazoa-
cetate 3a generated in flow gave the C−H functionalization
product 8a in high yield (91%), regioselectivity (>20:1), and
enantioselectivity (95% ee).
The applicability of the developed tandem protocol was
further exemplified though the Rh2(S-p-BrTPCP)4-catalyzed
C−H insertion with p-bromodiazoacetate 4c and methyl tert-
butyl ether (9) (Scheme 4).3b From the batch reaction,
Scheme 4. Methyl Ether C−H Insertions with
Aryldiazoacetates Synthesized in Flow
compound 10 was obtained in 69% yield with 66%
enantioselectivity. A similar yield (70%) and enantioselectivity
(63%) of compound 10 were again achieved through flow
synthesis.
Table 3. Effect of Sodium Thiosulfate and Iodine on
Benzylic C−H Functionalization
In order to challenge the effectiveness of the in-line
purification of the diazo compound, we studied the C−H
functionalization of a completely unfunctionalized and thus
highly challenging substrate, pentane (Scheme 5). We recently
a
entry
additive(s)
none
yield (%)
85
ee (%)
Scheme 5. Pentane C−H Insertion with Aryldiazoacetate
Synthesized in Flow
1
2
3
4
5
96
b
I2
1
n.d.
n.d.
n.d.
c
I2 + Na2S2O3·5H2O
Na2S2O3·5H2O
Na2S2O3
25
c
19
88
96
a
b
c
Isolated yields. Major amounts of dimerization product. No
dimerization, major amounts of O−H insertion products.
On the basis of these control experiments, the diazo drying
protocol was modified to include addition of anhydrous sodium
thiosulfate to the bottom of the molecular sieves cartridge. With
this adjustment, benzylic C−H functionalization was success-
fully conducted using aryldiazoacetates generated in flow.
When p-bromodiazoacetate 4c reacted with 7 as a C−H
insertion partner in a flow reaction (Scheme 3),3b compound
8c was obtained in good yield (85%), regioselectivity (>20:1),
and enantioselectivity (96% ee). This matched the result of the
standard reaction of the preformed diazo compound generated
reported a new rhodium catalyst, Rh2(R-3,5-di(p-tBuPh)-
TPCP)4, which showed highly site-selective, diastereoselective,
and enantioselective C−H functionalization of n-alkanes.3c
Comparison of the reactivities of pentane under batch and flow
reaction conditions with this catalyst (11 Batch and Flow)
showed that very similar results were obtained (regioisomeric
ratio (rr), 20:1 vs 22:1; diastereomeric ratio (dr), 8.3:1 vs 9.2:1;
yield, 90% vs 89%; ee, 93% vs 95%), showcasing that even for a
very challenging reaction, the flow-generated diazo compound
was equally effective.
In conclusion, we have developed a tandem reaction system
for rhodium-catalyzed cyclopropanation and C−H functional-
ization in which the aryldiazoacetates are generated in flow and
used immediately in the subsequent carbenoid transformation.
A critical requirement for ensuring an effective carbene
transformation with relatively unreactive substrates is in-flow
drying and reduction of any iodine impurities. When these
precautions were made, the aryldiazoacetates generated in flow
performed equally well as material generated under standard
batch conditions. This process eliminates the need to
presynthesize and store potentially hazardous diazo compounds
and expands the range of carbene reactions of flow-generated
Scheme 3. Benzylic C−H Insertions with Aryldiazoacetates
Synthesized in Flow
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DOI: 10.1021/acs.orglett.7b01073
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N.; Battilocchio, C.; Labes, R.; Ingham, R. J.; Hawkins, J. M.; Ley, S. V.
Org. Biomol. Chem. 2015, 13, 2550. (c) Nicolle, S. M.; Hayes, C. J.;
diazo compounds to enantioselective cyclopropanation and C−
H functionalization. The approach offers a safer way to carry
out rhodium-catalyzed reactions of diazo compounds, especially
in the context of large-scale and industrial applications.
Moody, C. J. Chem. - Eur. J. 2015, 21, 4576. (d) Muller, S. T. R.;
̈
Wirth, T. ChemSusChem 2015, 8, 245. (e) Poh, J. S.; Tran, D. N.;
Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Angew. Chem., Int. Ed. 2015,
54, 7920. (f) Tran, D. N.; Battilocchio, C.; Lou, S.-B.; Hawkins, J. M.;
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01073.
́
■
Ley, S. V. Chem. Sci. 2015, 6, 1120. (g) Lev
́
esque, E.; Laporte, S. T.;
S
Charette, A. B. Angew. Chem., Int. Ed. 2017, 56, 837. (h) Poh, J.-S.;
Makai, S.; von Keutz, T.; Tran, D. N.; Battilocchio, C.; Pasau, P.; Ley,
S. V. Angew. Chem., Int. Ed. 2017, 56, 1864. (i) Deadman, B. J.;
O’Mahony, R. M.; Lynch, D.; Crowley, D. C.; Collins, S. G.; Maguire,
A. R. Org. Biomol. Chem. 2016, 14, 3423. (j) Audubert, C.; Gamboa
Marin, O. J.; Lebel, H. Angew. Chem., Int. Ed. 2017, 56, 6294.
(k) Mccaw, P. G.; Buckley, N. M.; Eccles, K. S.; Lawrence, S. E.;
Maguire, A. R.; Collins, S. G. J. Org. Chem. 2017, 82, 3666.
(l) Lehmann, H. Green Chem. 2017, 19, 1449.
Full experimental data for the compounds described in
the paper (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(8) Negretti, S.; Cohen, C. M.; Chang, J. J.; Guptill, D. M.; Davies, H.
M. L. Tetrahedron 2015, 71, 7415.
*E-mail: cjones@chbe.gatech.edu.
*E-mail: hmdavie@emory.edu.
ORCID
Christopher W. Jones: 0000-0003-3255-5791
Huw M. L. Davies: 0000-0001-6254-9398
Author Contributions
§D.R. and C.-J.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support was provided by NSF under the CCI Center
for Selective C−H Functionalization (CHE-1205646).
■
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DOI: 10.1021/acs.orglett.7b01073
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