Skeletal editing through direct nitrogen deletion of secondary amines

Article abstract of DOI:10.1038/s41586-021-03448-9

Synthetic chemistry aims to build up molecular complexity from simple feedstocks¹. However, the ability to exert precise changes that manipulate the connectivity of the molecular skeleton itself remains limited, despite possessing substantial potential to expand the accessible chemical space^2,3. Here we report a reaction that ‘deletes’ nitrogen from organic molecules. We show that N-pivaloyloxy-N-alkoxyamides, a subclass of anomeric amides, promote the intermolecular activation of secondary aliphatic amines to yield intramolecular carbon–carbon coupling products. Mechanistic experiments indicate that the reactions proceed via isodiazene intermediates that extrude the nitrogen atom as dinitrogen, producing short-lived diradicals that rapidly couple to form the new carbon–carbon bond. The reaction shows broad functional-group tolerance, which enables the translation of routine amine synthesis protocols into a strategy for carbon–carbon bond constructions and ring syntheses. This is highlighted by the use of this reaction in the syntheses and skeletal editing of bioactive compounds.

Full text of DOI:10.1038/s41586-021-03448-9

Article
Skeletal editing through direct nitrogen
deletion of secondary amines
1
Sean H. Kennedy1, Balu D. Dherange1,2, Kathleen J. Berger1,2 & Mark D. Levin
ꢀ✉
https://doi.org/10.1038/s41586-021-03448-9
Received: 2 November 2020
Accepted: 11 March 2021
Synthetic chemistry aims to build up molecular complexity from simple feedstocks1.
However, the ability to exert precise changes that manipulate the connectivity of the
molecular skeleton itself remains limited, despite possessing substantial potential to
expand the accessible chemical space2,3. Here we report a reaction that ‘deletes’
nitrogen from organic molecules. We show that N-pivaloyloxy-N-alkoxyamides, a
subclass of anomeric amides, promote the intermolecular activation of secondary
aliphatic amines to yield intramolecular carbon–carbon coupling products.
Mechanistic experiments indicate that the reactions proceed via isodiazene
intermediates that extrude the nitrogen atom as dinitrogen, producing short-lived
diradicals that rapidly couple to form the new carbon–carbon bond. The reaction
shows broad functional-group tolerance, which enables the translation of routine
amine synthesis protocols into a strategy for carbon–carbon bond constructions and
ring syntheses. This is highlighted by the use of this reaction in the syntheses and
skeletal editing of bioactive compounds.
Published online: 12 May 2021
Check for updates
Retrosynthetic analysis is the cornerstone of synthesis. As chemical
Our approach was based on the mechanistic hypothesis outlined in
transformations are discovered, they can be evaluated in terms of the Fig. 1b. This hypothesis was in turn supported by precedented chemis-
retrosynthetic disconnections that they enable, and the forward pro- try of anomeric amides, which—in analogy to the anomeric centres of
gress of synthesis—broadly speaking—can be assessed by inspection carbohydrates—bear two oxygen substituents on the amide nitrogen15
.
of the total set of available disconnections. Accordingly, the identifi- Bis-heteroatom-substituted amides have been studied in detail and
cation and realization of synthetically attractive transformations that display unusual pyramidalization at nitrogen as well as notable electro-
represent inaccessible or otherwise underused molecular changes is philic reactivity16. In particular, N-methylaniline was observed to form
paramount to the continued advancement of the chemical sciences, a tetrazene product upon reaction with reagent 1a, which is strongly
and as such the advancement of all allied fields that design and deploy suggestive of an isodiazene intermediate15 (Fig. 1c). These latter species
purpose-built molecules. Molecular editing and late-stage function- piqued our interest owing to their known N2-extrusion reactivity, pro-
alization have emerged as appealing strategies for the identification viding diradical species that undergo rapid, intramolecular C-C bond
of such ‘missing’ transformations4–7, and represent the ideals of mod- formation17–19. Classical routes to such intermediates involve multistep
ern synthesis—including the ability to build and tolerate complexity. protocols that use hazardous reagents—one frequently used synthesis
However, their intellectual deployment has so far largely focused on involves a sequence of N-nitrosation (requiring isolation of carcino-
C–H functionalization chemistry (peripheral editing). Conversely, genic N-nitrosamine compounds), reduction to the 1,1-hydrazine and
modification of the underlying molecular skeleton (skeletal editing) has oxidation with stoichiometric mercuric oxide or lead tetraacetate20. We
not achieved the same level of refinement, despite receiving increasing reasoned that the combination of anomeric amide reagents with suit-
interest from many laboratories8–12
.
able secondary amine nucleophiles would enable a single-step protocol
In our own assessment, such skeletal transformations represent a for nitrogen deletion directly from secondary amines. Crucially, this
large untapped pool of potentially transformative chemical reactions, would facilitate the examination of skeletal edits by circumventing the
should they be realized (Fig. 1a). Among these, single-atom insertions laborious and undesirable features of existing protocols21,22
.
and deletions are particularly attractive from the standpoint of ret-
From a retrosynthetic perspective, this strategy would enable
rosynthetic simplicity, in contrast to many known skeletal rearrange- aliphatic C–N bond-forming reactions to serve formally as C–C
ments for which complex patterns of reactivity require substantial bond-forming surrogates. This is advantageous in part because of
skill and insight to recognize as disconnections. Indeed, many classic the reliability and broad scope of iminium-based transformations
reactions—especially in the context of carbonyl chemistry—enable that feature prominently among the medicinal chemistry toolbox.
the insertion or deletion of carbon, nitrogen or oxygen into molecular For example, reductive amination consistently ranks in the top ten
skeletons (for example the Wolff, Favorskii and Bayer–Villiger rear- most-used reactions in drug discovery, and iminium-based cycliza-
rangements)13,14. Nonetheless, broadly speaking, accessible single-step tion methods are broadly applied for the synthesis of cyclic amines23
.
skeletal transformations remain limited. Here we report a reaction These methods have led to the proliferation of amines as feedstock
that excises nitrogen atoms from secondary amines, liberating N2 and chemicals, and thousands of derivatives are now commercially
forging a new C–C bond between the remaining molecular fragments. available24,25
.
1
2
✉
Department of Chemistry, University of Chicago, Chicago, IL, USA. These authors contributed equally: Balu D. Dherange, Kathleen J. Berger. e-mail: marklevin@uchicago.edu
Nature | Vol 593 | 13 May 2021 | 223

Article
a
Oxygen
insertion
Me
Me
Nitrogen
deletion
Me
NH
NH
Peripheral
editing
Skeletal
editing
(this work)
Me
e.g. C–H
functionalization
(well developed)
Single-atom
‘elementary’ edits
(limited precedent)
CF3
O
N
CF3
C-to-N
Me
CF3
Hypothetical ‘lead’ structure
replacement
O
b
c
Ph
1a
Bn
Bn
Ph
Me
Ph
Ph
N
N
Me
Ph
AcO
N
N
H
N
H
Ref. 15
Me
N
N
OBn
Ph
Secondary
amine
Anomeric
amide
(1a)
HgO
or Pb(OAc)4
Ref. 17
Ph
In-cage
radical
coupling
Ph
N
Ph
Ph
Nucleophilic
–AcOH
NH2
substitution
via
O
R
R
R
R
H
H
R = Bn
Homolytic
extrusion
+
N
N
N
N
R = Me, Ph
Dimerization
N
N
–
Bn
Bn
–PhCO2Bn
Ph
N
Ph
N
N
–
Ph
Homolytic
extrusion
Reductive
elimination
Bn
OBn
N
Isodiazene
reactivity controlled by radical stability
Bn
H
H
Fig. 1 | Background. a, Conceptual overview of skeletal editing and peripheral
editing techniques as used in molecular optimization campaigns.
amide reagents. c, Precedent for isodiazene generation from anomeric amides,
and for nitrogen extrusion from isodiazenes.
b, Mechanistic hypothesis for direct nitrogen deletion enabled by anomeric
Our investigation began with the N-benzyloxy-N-acetoxybenzamide furnishes 28 g of material in 78% overall yield with no chromatographic
1a (ref. 15) (Fig. 2a). Reaction with the model substrate 2a in tetrahy- purification.
drofuran solution at 45ꢀ°C resulted in a 35% yield of nitrogen deletion
product 3a. However, acetamide 4a was observed as a major side limitations of this process in terms of both the functional-group com-
product, which probably formed through competitive substitution patibility and the structural diversity. To address the former, we evalu
With reagent 1c in hand, we endeavoured to explore the scope and
-
at the acyl carbon. To ameliorate this, we synthesized the N-pivaloxy ated a series of substituted dibenzylamines and their heteroaromatic
derivative 1b. When used under identical conditions, none of the analogues, all of which were prepared through reductive amination and
corresponding pivalamide side product 4b could be detected and bore various medicinally relevant functionality. As shown in Fig. 3, the
3a was produced in an improved yield of 57%. Further evaluation of functional-group tolerance of this methodology is high, and includes
substituent effects revealed that para-trifluoromethyl-substituted both basic nitrogen heterocycles (3j–3m), unprotected protic function-
reagent 1c reacted more rapidly, leading to complete conversion of 2a ality (3h, 3i), and reducing or Lewis basic functionality (3c, 3f, 3g, 3l).
within 5 h, in comparison to the 18-h reaction time required for 1b. This This is particularly notable considering the presence of several highly
was representative of a general trend: a competition Hammett study reactive intermediates in our proposed mechanism, and highlights the
revealed a slope of 0.60 (corresponding to the reaction constant ρ) chemoselectivity of the anomeric amide reagents.
when rate data were plotted against the electrophilic substituent
With respect to structural variation, cyclic amines offer a unique
constant (σ+)26 (Fig. 2b). However, the preparation of reagents that opportunity to promote ring contractions that give access to new
are more electron-poor than 1c failed using our standard procedure. molecular skeletons. Although atom deletion might ostensibly be
Anomeric amide 1c is straightforward to prepare on a multigram considered to be a simplifying transformation, ring contractions high-
scale: a three-step sequence from commercially available reagents light the power of these transformations to instead build molecular
a
b
O
1
Ar
N
Ar
Ar
Ar
N
Ar
Ar
THF
45 °C
H
N
O
R
OBn
PivO
2a
3a
O
4a (R = Me)
4b (R = tBu)
X
0.6
0.4
O
O
O
U = 0.60
2 = 0.94
3
Ph
N
Ph
N
N
R
0.2
=
OBn
OBn
OBn
O
O
O
O
0
F3C
O
–0.2
–0.4
–0.6
4
Me
Me
Me
Me
Me
Me Me
• Decagram scale
• 78% over 3 steps
• No chromatography
1a
1b
1c
–0.9
–0.5
–0.1
V+
0.3
0.7
2:1 3a/4a
>20:1 3a/4b
57%a
>20:1 3a/4b
74%b (69%)
35%a
Fig. 2 | Development of an anomeric amide reagent. a, Optimization of the
reagent structure for direct nitrogen deletion. The yields stated are NMR
yields, with isolated yields given in parentheses. a18 h, b5 h. Ar, p-bromophenyl;
THF, tetrahydrofuran. b, Hammett plot (s.d., n = 3) indicating the electronic
origin of the increased rate of reaction with reagent 1c. kX/kH, the ratio of the
rate of reaction with different substituents at X to the rate when X = H in a
one-pot direct competition experiment. Piv, pivaloyl.
224 | Nature | Vol 593 | 13 May 2021

1c
N
N
N
THF, 45 °C
H
2
3
Functional group compatibility
MeO2C
O
P(OEt)2
(EtO)2P
O
N
Ts
CO2Me
3b
64%
3c
67%
3d
68%
3e
49%
H
N
MeS
Me2N
O
CF3
CF3
Me
OH
Cl
3f
52%
3g
50%
3h
63%
3i
43%
CF3
O
O
N
S
N
Me
N
OCF3
N
CF3
N
N
CF3
3j
58%
3k
57%
3l
55%
3m
54%
Skeletal diversity
Br
MeO2C
Cl
Me
Me
Ph
Ph
Ph
Ph
O
O
NMe
Ph
NMe
Ph
Ar
Ph
(Ar = p-biphenyl)
NC
3n
72%a
3o
81%a
3p
62%b
3q
54%b
3r
44%c
3s
25%b,d
3t
86%
3u
47%b
3v
49%b
3w
34%c
Nitrogen linchpin cyclobutane synthesis
Pharmaceutical synthesis
O
O
H
N
S
O
tBu
N
N
[3+2] cycloaddition
NH
RHN
(1) Pd(PPh3)4, THF;
HCl, Et2O
e
H
CO2R′
N
TMS
OAc
HN
S
R′O2C
5
(2) 1c, THF, 45 °C
3z
H3 receptor
modulator
NC
6 (R = R′ = H)
Pemetrexed (Alimta)
chemotherapeutic
f
Nitrogen deletion
(R = CPh3, R′ = Et)
3x
57%
3y
71%
66%b
NC
Natural product synthesis
Skeletal editing of bioactive compounds
Cl
OMe
OH
F
O
OH
O
NH
N
Br
OMe
Br
NH
Br
Br
HO
HO
MeO
MeO
g
S
O
O
S
Me
N
N
O
3ab
42%b
3ac + 3ac′h
41%b
from anatabine
nicotinic alkaloid
3ad
53%b
7
3aa
53%
Polysiphenol
marine metabolite
from lapatinib (Tykerb)
tyrosine kinase inhibitor
from tenilsetam
AGE inhibitor
Fig. 3 | Scope of the nitrogen-deletion reaction promoted by reagent 1c.
Conditions: 2 (1.0 equivalent), 1c (1.5 equivalents), THF (0.2 M). The yields
stated are isolated yields for nitrogen deletion. a3n and 3o formed
stereospecifically, trans-3n from trans-2n and cis-3o from cis-2o. b2 equivalents
trimethylamine were added. c2 equivalents 1c. dReaction conducted at 25ꢀ°C.
e3y, 9-borabicyclo(3.3.1)nonane, NaBO3 (3:1 diastereomeric ratio);
4-toluenesulfonyl chloride, pyridine; pyrrolidine, K2CO3, 42% yield over 3 steps.
fAcOH, H2O; 1 M NaOH, THF/H2O, 56% yield over 2 steps. gPhI(OCOCF3)2,
F3B-OEt2; BBr3, see ref. 32
.
h1.7:1 mixture of cyclopentene and vinylcyclopropane
isomers were isolated. TMS, trimethylsilyl; Ts, tosyl.
complexity, wherein the nitrogen atom can serve as a traceless linch- amines are typically inert to the present conditions27. Notably, conju-
pin for the initial ring synthesis, yielding the (n − 1) carbon framework gated radicals are not a strict requirement on both substituents for
after nitrogen deletion. Contractions of azetidines to cyclopropanes, efficient reactivity, as demonstrated by 2p, 2s, 2v, 2w, 2ab and 2ad,
pyrrolidines to cyclobutanes, piperidines to cyclopentanes, azepanes for which benzylic substitution is present on only one of the two react-
to cyclohexanes, and azocanes to cycloheptanes—as well as their het- ing aliphatic substituents; in acyclic systems a single benzylic centre
erocyclic analogues—can all be achieved using reagent 1c. It should be is sufficient, whereas for cyclic systems, two stabilizing elements are
noted that steric effects can preclude reactivity altogether: whereas 2n necessary for productive C–C bond formation, either one on each
and 2o react smoothly, acyclic bis(α-secondary)amines and α-tertiary terminus or both on the same reactive centre. In cases in which the
Nature | Vol 593 | 13 May 2021 | 225

Article
a
b
1c
N
Ar
N
H
Ar
N
N
via
Ar
N
THF
8, 61%
2ae
Ar = 2,6-dimethoxyphenyl
No additive
=
93:4:3 (3af/9/10)
Ph
Ar
Ph
+ 1 equiv. TEMPO = 100:0:0 (3af/9/10)
Ph
9
Ar
1c
Me
Ar
N
Ph
+
Ar
H
Me
3af
THF
R = Ph, Ar
10
2af
N
TEMPO adducts
observed
Intramolecular
product
Intermolecular
products
R
O
Ar = p-chlorophenyl
Me Me
c
H
H
1c
Ar
N
H
Ar
Ar
THF
2ag
3ag
30%
11
R
Ar = p-bromophenyl
Not observed
R = H
(kr = 108 s–1
R = Ph
(kr = 1011 s–1
) )
1c
Ar
Ar
N
H
Ar
Ph
Ph
THF
Ph
3ah
20%
12
19%
2ah
Ar = p-biphenyl
R
H
Fig. 4 | Mechanistic experiments. a, Evidence for the isodiazene intermediate
via competitive rearrangement to a 1,2-diazene. b, Product ratios in a trapping
experiment with TEMPO demonstrate the scavenging of intermolecular
products, suggesting largely in-cage C–C bond formation. c, A radical clock
experiment also suggests largely in-cage radical recombination.
requisite stabilizing elements are lacking, side reactions can predomi- reductive elimination of the benzoate ester to afford an isodiazene
nate, including rearrangement of the isodiazene to a hydrazone. For a intermediate36,37; N2 loss to generate a geminate radical pair; and C–C
more detailed analysis of limitations, see Supplementary Fig. 2 and its bond-forming radical recombination. However, because we are using
associated analysis in the Supporting Information.
more-electron-rich amine nucleophiles and have modified several
As noted above, connecting this methodology to existing amine features of the anomeric amide, this expected pathway might not be
syntheses enables fundamentally new retrosynthetic logic: [3+2] operative. Nonetheless, we have garnered preliminary evidence for
cycloaddition can be used to construct pyrrolidines 2x and 2y, and this proposed mechanism.
subsequent nitrogen deletion affords cyclobutanes 3x and 3y28. 3y
With respect to the first step, a minimal solvent effect was observed.
can be further elaborated to the histamine H3 receptor modulator 5 Initial rates were only slightly perturbed across solvents whose Reich-
through stepwise, formal hydroamination, highlighting the potential ardt polarity index ENT ranged from 0.309 (dichloromethane) to 0.099
for this method to benefit medicinal chemistry29,30. This method also (toluene); this suggests that the initial nucleophilic substitution is
enables the synthesis of the folate antimetabolite pemetrexed (6, via probably SN2-like, in line with the ρ value measured in the Hammett
the protected precursor 3z), which is used as a chemotherapeutic in the study discussed above. A crossover experiment using reagents with
treatment of lung cancer31. In this synthesis, reductive amination unites distinct benzoyl and alkoxy substituents (Supplementary Fig. 12) led
the two functional-group-laden halves of the molecule, and nitrogen to the exclusive formation of benzoate esters corresponding to intra-
deletion subsequently forges the central C–C bond, again highlighting molecular C–O bond formation, and no crossover products were
the functional-group compatibility of this method. We have further detected. This indicates that the second step of the transformation is
used our method to provide an accelerated synthesis of the atropoi- an intramolecular process. Although we cannot conclusively rule out
someric marine metabolite polysiphenol, 7, intercepting the known an ionic mechanism that involves fast intramolecular recombination,
synthetic intermediate 3aa32. The previously reported preparation of previous computational studies have demonstrated concerted, formal
3aa relies on hydrogenation of a stilbene, the preparation of which—via reductive elimination to be an accessible pathway in N-alkoxyhydrazine
olefination—requires diverging a common aldehyde intermediate to thermolyses36,37. The involvement of an isodiazene intermediate is
prepare the corresponding ylide over 3 steps. By contrast, our synthe- supported by the formation of the rearranged 1,2-diazine product 8
sis enables conversion of the aldehyde to the bibenzyl dimer (via an from allylamine 2ae, arising from [2,3]-sigmatropic rearrangement of
amine linchpin) without the need to divert half of the material through the intermediate isodiazene38 (Fig. 4a).
a phosphonium synthesis. Finally, we performed skeletal editing on
Evidence for the subsequent extrusion process comes from an analy-
several bioactive compounds, including the tyrosine kinase inhibi- sis of product distributions in asymmetric substrates (Fig. 4b). The
tor lapatinib33, the nicotinic alkaloid anatabine34, and the advanced formally intramolecular products (3) for non-symmetric substrates are
glycation end product inhibitor tenilsetam35. The chemoselective favoured in all cases—well above the statistically anticipated 1:2:1 ratio
nitrogen deletion of lapatinib in particular exemplifies the merits of that would arise from a free-radical process, as was recently observed
a skeletal-editing approach, as preparation of derivative 3ab would for a Ni-catalysed deamination of benzylic ammonium salts—which sug-
otherwise require repetition of the entire synthetic sequence for the gests a largely in-cage recombination process39. The variable amounts
preparation of lapatinib from the beginning, starting from a des-amino (1–10% yield depending on the substrate used) of the corresponding
analogue of the sidearm.
symmetric (‘intermolecular’) products (9, 10) are effectively scavenged
Mechanistically, we anticipated that this transformation would by the addition of 2,2,6,6-tetramethylpiperidin-1-yl-oxyl (TEMPO),
follow the pattern outlined in Fig. 1b, namely: bimolecular nucleo- whereas the intramolecular coupling product shows minimal pertur-
philic substitution of the pivaloxy group of 1c by the amine; formal bation by such scavengers.
226 | Nature | Vol 593 | 13 May 2021

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Radical clock experiments were conducted using (cyclopropyl)
methyl-substituted amines to gain further insight into the radical
recombination process (Fig. 4c). The parent compound (2ag) under-
goes nitrogen deletion without detectable rearrangement, whereas
a phenyl-substituted analogue (2ah) yields products both with and
without rearrangement of the cyclopropane. Despite the poor mass
balance in these reactions (see Supplementary Fig. 17 for identified side
products), the results are nonetheless consistent with predominantly
in-cage recombination (rate of rearrangement, kr, is around 108 s−1 for
the cyclopropyl methyl radical)40, with partial rearrangement of 2ah
suggesting that the in-cage C–C bond-forming mechanism involves
radical species. Although estimates of cage-escape rates differ, the
rate of rearrangement of the intermediate cyclopropylmethyl radical
derived from substrate 2ah (kr ≈ 1011 s−1) is roughly similar to that of such
processes41. However, we cannot categorically exclude a competitive
non-radical pathway for the formation of 3ah. Given the high-energy
species involved in this reaction, it is likely that dynamic effects strongly
influence the partitioning of the isodiazene intermediate. This is further
evidenced by the exclusive formation of cis-3o from cis-2o, in contrast
to the trans product diastereomer that is predicted by a Woodward–
Hoffman analysis of the putative ortho-quinodimethane intermediate,
which suggests that the initially formed diradical intermediate never
relaxes to a fully planar conformation42
.
In summary, we have developed an anomeric amide reagent that ena-
bles straightforward nitrogen deletion of secondary amine substrates.
The reaction relies on the facile in situ generation of an isodiazene
intermediate, which extrudes N2 and forms a new C–C bond. We have
demonstrated the high functional-group tolerance of this method and
its application to ring contractions of cyclic amines. This transforma-
tion should serve as a valuable tool for structural optimization in a
variety of contexts, adding to the growing catalogue of skeletal-editing
technologies.
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butions and competing interests; and statements of data and code avail-
ability are available at https://doi.org/10.1038/s41586-021-03448-9.
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Article
Competing interests Reagent 1c is under development for commercialization with
Sigma-Aldrich (product number 919799), but the authors have retained no financial interest
and no patents have been filed.
Data availability
All data are available from the corresponding author upon reasonable
request.
Additional information
Supplementary information The online version contains supplementary material available at
https://doi.org/10.1038/s41586-021-03448-9.
Correspondence and requests for materials should be addressed to M.D.L.
Peer review information Nature thanks the anonymous reviewers for their contribution to the
peer review of this work.
Acknowledgements We thank D. Nagib, F. D. Toste, M. Johnson and Z. Wickens for discussions.
Financial support for this work was provided by start-up funding from the University of Chicago.
Author contributions S.H.K., K.J.B. and B.D.D. designed and conducted experiments, and
collected and analysed the data. M.D.L. supervised the research, conceived of the project and
wrote the manuscript with input from all authors.
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