Synthesis of Cyclic Guanidines Bearing N-Arylsulfonyl and N-Cyano Protecting Groups via Pd-Catalyzed Alkene Carboamination Reactions

Article abstract of DOI:10.1021/acs.orglett.7b00946

Palladium-catalyzed carboamination reactions of N-allylguanidines bearing cleavable N-cyano or N-arylsulfonyl protecting groups are described. The reactions afford cyclic guanidine products in good yield, and transformations of substrates bearing internal alkenes proceed with high diastereoselectivity. Deuterium labeling studies indicate these transformations proceed via anti-aminopalladation pathways.

Full text of DOI:10.1021/acs.orglett.7b00946

Letter
pubs.acs.org/OrgLett
Synthesis of Cyclic Guanidines Bearing N‑Arylsulfonyl and N‑Cyano
Protecting Groups via Pd-Catalyzed Alkene Carboamination
Reactions
Luke J. Peterson, Jingyi Luo, and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States
S
* Supporting Information
ABSTRACT: Palladium-catalyzed carboamination reactions of N-
allylguanidines bearing cleavable N-cyano or N-arylsulfonyl protecting
groups are described. The reactions afford cyclic guanidine products in
good yield, and transformations of substrates bearing internal alkenes
proceed with high diastereoselectivity. Deuterium labeling studies
indicate these transformations proceed via anti-aminopalladation
pathways.
he synthesis of cyclic guanidines has attracted consid-
erable attention due to the presence of cyclic guanidine
However, the conditions that provided high yields in reactions
of N-propargylguanidines did not work with analogous N-
allylguanidines; efforts to couple 5 with 4-methoxyphenyl
triflate afforded little or none of the desired product. In this
letter we describe a significant expansion in the scope of this
method that allows for transformation of substrates bearing
cleavable N-arylsulfonyl or N-cyano groups.
In order to develop Pd-catalyzed carboamination reactions of
N-allylguanidines bearing cleavable protecting groups, we
elected to explore the reactivity of two different substrates, 6a
and 7a, which contain benzyl groups on two nitrogen atoms
and either a cyano or tosyl group on the third. Our prior studies
had indicated it should be possible to cleave the N-tosyl group
from the products, and N-cyano groups can be cleaved from
guanidines via treatment with strong acids. Moreover, the N-
cyanoguanidines appeared to be particularly attractive products
to target, as many N-cyanoguanidines have interesting bio-
logical activities.7
T
subunits in a variety of biologically active natural products.1,2
Many recent approaches to the construction of these motifs
have focused on the use of metal catalysts to effect formation of
carbon−nitrogen bonds.3,4 However, aside from our prior
studies in the area,5,6 no existing methods effect formation of a
C−N bond, a C−C bond, and the ring in a single
transformation.
Our group previously described a new approach to the
preparation of cyclic guanidines via Pd-catalyzed alkene
carboamination reactions between PMP-protected N-allylgua-
nidines 1 and aryl bromides (eq 1).5 These transformations
Our initial optimization studies were focused on the coupling
of 6a and 7a with bromobenzene. As shown in Table 1, the
coupling of 6a afforded good yields of 8a using a number of
different phosphine ligands under conditions that have
provided good results in many other alkene carboamination
reactions.8 Optimal yields were obtained with the biaryl
phosphine XPhos (entry 4). However, efforts to employ
these conditions for the coupling of 7a with bromobenzene
were not successful, as the desired product 9a was generated in
low yield (25%) along with a complex mixture of side products
(entry 5). Fortunately, simply employing reaction conditions
that previously provided optimal results with N-tosyl N-
propargyl guanidine 3 (aryl triflate in place of aryl bromide,
Pd(OAc)2 as a palladium source, LiOtBu as a base, and PhCF3
as a solvent) afforded the desired product 9a in 92% yield
(entry 7).
afforded the desired cyclic guanidines (e.g., 2) in good chemical
yield. However, efforts to cleave the PMP-protecting groups
were unsuccessful. We have also reported a related series of Pd-
catalyzed alkyne carboamination reactions of tosyl-protected N-
propargyl guanidines 3, which also proceed in good yield under
appropriate conditions to afford 2-aminoimidazoles such as 4
(eq 2), and the N-tosyl group proved to be readily cleavable.6
Received: March 29, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00946
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Letter
a
a
Table 1. Optimization Studies
Table 2. Carboamination of N-Protected Guanidines
b
entry
substrate
ligand
yield (%)
1
2
3
4
5
6
7
6a
6a
6a
6a
7a
7a
7a
Xantphos
Dpe-Phos
CPhos
73
89
92
XPhos
>99
25
XPhos
CPhos
33
c
CPhos
92
a
Conditions: 1.0 equiv of substrate 6a or 7a, 1.5 equiv of PhBr, 2.0
equiv of NaOtBu, 2 mol % Pd2(dba)3, 8 mol % ligand, toluene (0.1 M),
90 °C, 1 h. Reactions were conducted on a 0.2 mmol scale. NMR
b
c
yield using phenanthrene as internal standard. The reaction was
conducted using PhOTf in place of PhBr, LiOtBu in place of NaOtBu,
Pd(OAc)2 in place of Pd2(dba)3, and PhCF3 (0.2 M) in place of
toluene, and a reaction temperature of 100 °C.
We then explored the scope of the Pd-catalyzed carboami-
nation reactions of N-cyano and N-tosylguanidine substrates.
As shown in Table 2, the transformations are effective with a
range of different aryl halide coupling partners, including
electron-rich, and -poor derivatives. The reaction of 7a with o-
methylphenyl triflate also proceeded in good yield, but ca. 10%
of an inseparable impurity resulting from competing Heck
arylation of the alkene was also generated (entry 7). In most
instances comparable yields were obtained when either 6 or 7
were coupled with the same aryl bromide/triflate (entries 1−2,
3−4, 8−9, 11−12, and 15−16). The reactions were amenable
to the construction of both five- and six-membered cyclic
guanidines, and substrates 6b and 7b bearing a methyl group at
the internal alkene carbon were also efficiently converted to the
desired products.
Surprisingly, the diastereoselectivity obtained in reactions of
substrates bearing a substituent adjacent to the N atom was
quite low (Scheme 1, 8k−m and 9h−j, 1.5:1 to 3:1 dr).9 This is
in stark contrast to results obtained in analogous reactions of
N-allylureas10 and N-allylsulfamides,11 which typically proceed
with ca. 8:1 to >20:1 dr. In addition, although we were gratified
to find that substrates bearing an internal alkene were
transformed to 8n and 9k−l, which result from net anti-
addition to the alkene, with good to excellent diastereose-
lectivity,12 the stereochemistry of 8n was rather surprising. Our
prior studies on reactions of sulfamides, ureas, and PMP-
protected guanidines13 suggested that use of an aryl bromide in
these guanidine carboamination reactions would lead to syn-
addition to the double bond, whereas use of an aryl triflate was
expected to favor anti-addition (as observed).11
a
Conditions A (P = CN): 1.0 equiv of 6, 1.5 equiv of R1−Br, 2.0 equiv
of NaOtBu, 1 mol % Pd2(dba)3, 4 mol % XPhos, toluene (0.1 M), 90
°C, 1 h. Conditions B (P = Ts): 1.0 equiv of 7, 1.5 equiv of Ar−OTf,
2.0 equiv of LiOtBu, 2 mol % Pd(OAc)2, 4 mol % CPhos, PhCF3 (0.2
M), 100 °C, 2 h. Reactions were conducted on a 0.2−0.3 mmol scale.
b
c
Isolated yield. This material contained ca. 10% of an inseparable side
d
product resulting from Heck arylation of the alkene. The reaction was
conducted at 0.1 M concentration. The reaction was conducted using
e
f
CPhos as ligand. The reaction was conducted on a 1 mmol scale.
g
The reaction was conducted for 2 h at 90 °C.
β-hydride elimination processes that occur after the amino-
palladation step.14 To address this question we examined the
reactivity of substrate 12 and discovered its coupling with
bromobenzene proceeds in 16:1 dr. Since the intermediate
alkylpalladium complex derived from 12 cannot undergo β-
hydride elimination, this result suggests that much of the minor
diastereomer formed in the reaction of 10 is generated via β-
hydride elimination side reactions.
The results of these experiments suggest the mechanism of
the carboamination reactions proceeds as shown in Scheme 2.
Oxidative addition of the aryl halide or triflate to the Pd(0)
catalyst affords 16. Coordination of the pendant alkene to the
metal (17) followed by anti-aminopalladation and deprotona-
tion then generates alkylpalladium complex 18. Reductive
Given the surprising results of these experiments, we further
explored syn- vs anti-addition pathways in transformations of
deuterated substrates 10−11. As shown in eq 4, the coupling of
10 with bromobenzene afforded anti-addition product 13 in
58% yield and 9:1 dr. The reaction of 11 with phenyl triflate to
yield 14 also proceeded via anti-addition to the double bond,
but with >20:1 dr. In principle the lower selectivity obtained
with 10 could result either from competing anti- vs syn-
aminopalladation pathways in the catalytic cycle11a or from
partial epimerization of the benzylic stereocenter via reversible
B
DOI: 10.1021/acs.orglett.7b00946
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a
Scheme 1. Diastereoselectivity Studies
Scheme 2. Mechanism
the transition state for anti-heteropalladation is less organized
than that for a syn-heteropalladation process.15
To further demonstrate the utility of this method we briefly
explored the cleavage of the N-cyano or N-tosyl protecting
groups from the guanidine products. As shown in eq 7,
treatment of 7f with concentrated HCl led to clean
deprotection of the N-cyano group to afford a 95% yield of
19. However, efforts to cleave the N-tosyl group from 9f with
either acids or reducing agents did not provide satisfactory
results. The detosylated product was obtained in low yield due
to competing cleavage of one or both N-benzyl groups (eq 8).
Prior studies have shown that electron-rich arylsulfonyl
groups are more readily cleaved from guanidines than tosyl
groups.16 As such we prepared Mtr-protected guanidine
substrate 20 (Mtr = 4-methoxy-2,3,6-trimethylbenzenesulfonyl)
and subjected it to our standard reaction conditions to afford
guanidine 21 in 95% yield (Scheme 3). Treatment of 21 with
a
Conditions A (P = CN): 1.0 equiv of substrate 6, 1.5 equiv of R1−Br,
2.0 equiv of NaOtBu, 1 mol % Pd2(dba)3, 4 mol % XPhos, toluene (0.1
M), 90 °C, 1 h. Reactions were conducted on a 0.15−0.2 mmol scale.
b
Conditions B (P = Ts): 1.0 equiv of substrate 7, 1.5 equiv of Ar−
OTf, 2.0 equiv of LiOtBu, 2 mol % Pd(OAc)2, 4 mol % CPhos, PhCF3
(0.2 M), 100 °C, 2 h. Reactions were conducted on a 0.3 mmol scale.
All yields are isolated yields. The reaction was conducted using CPhos
c
as ligand.
Scheme 3. Synthesis/Deprotection of N-Mtr Guanidine 20
methanesulfonic acid and trifluoroacetic acid in the presence of
thioanisole led to cleavage of the N-Mtr group and one N-
benzyl group to afford 22 in 47% yield.
Due to our difficulties with cleanly removing only the N-
arylsulfonyl group from cyclic guanidines bearing N-benzyl
groups, we examined the preparation and deprotection of a
cyclic N-tosyl guanidine bearing methyl groups on the other
two nitrogen atoms. As shown in Scheme 4, the Pd-catalyzed
elimination of 18 affords the observed major stereoisomer 13
or 14. The minor stereoisomer is formed from competing β-
hydride elimination side reactions of 18.14 The anti-
heteropalladation mechanism is likely responsible for the
modest diastereoselectivities observed for 8k−m and 9h−j, as
C
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(e) Bhonde, V. R.; Looper, R. E. J. Am. Chem. Soc. 2011, 133,
20172−20174. (f) Gibbons, J. B.; Gligorich, K. M.; Welm, B. E.;
Looper, R. E. Org. Lett. 2012, 14, 4734−4737. (g) Giles, R. L.;
Sullivan, J. D.; Steiner, A. M.; Looper, R. E. Angew. Chem., Int. Ed.
2009, 48, 3116−3120. (h) Kwon, K.-H.; Serrano, C. M.; Koch, M.;
Barrows, L. R.; Looper, R. E. Org. Lett. 2014, 16, 6048. (i) Garlets, Z.
J.; Silvi, M.; Wolfe, J. P. Org. Lett. 2016, 18, 2331−2334. Ring
expansion of aziridines: (j) Butler, D. C. D.; Inman, G. A.; Alper, H. J.
Scheme 4. Synthesis/Deprotection of N-Ts Guanidine 24
Org. Chem. 2000, 65, 5887−5890. Allylic alkylation: (k) Buchi, G.;
̈
Rodriguez, A. D.; Yakushijin, K. J. Org. Chem. 1989, 54, 4494−4496.
Carbenylative amination: (l) Kitamura, M.; Yuasa, R.; Van Vranken, D.
L. Tetrahedron Lett. 2015, 56, 3027.
(4) For other recent approaches to the synthesis of saturated cyclic
guanidines that do not utilize metal catalysts, see: (a) Mailyan, A. K.;
Young, K.; Chen, J. L.; Reid, B. T.; Zakarian, A. Org. Lett. 2016, 18,
5532. (b) Fedoseev, P.; Sharma, N.; Khunt, R.; Ermolat’ev, D. S.; Van
der Eycken, E. V. RSC Adv. 2016, 6, 75202. (c) Daniel, M.; Blanchard,
F.; Nocquet-Thibault, S.; Cariou, K.; Dodd, R. H. J. Org. Chem. 2015,
80, 10624.
coupling of 23 with 4-bromobenzophenone afforded cyclic
guanidine 24 in 69% yield. We were gratified to find that
cleavage of the N-tosyl group from 24 proceeded smoothly to
provide a 70% yield of 25.
In conclusion, we have developed a new approach to the
synthesis of five- and six-membered cyclic guanidines bearing
cleavable N-sulfonyl or N-cyano protecting groups. The Pd-
catalyzed carboamination reactions proceed in generally good
chemical yields and provide products resulting from anti-
addition to the alkene. Future studies will be directed toward
improving diastereoselectivities in these reactions.
(5) Zavesky, B. P.; Babij, N. R.; Fritz, J. A.; Wolfe, J. P. Org. Lett.
2013, 15, 5420.
(6) Zavesky, B. P.; Babij, N. R.; Wolfe, J. P. Org. Lett. 2014, 16, 4952.
(7) (a) Wenzel, M.; Light, M. E.; Davis, A. P.; Gale, P. A. Chem.
Commun. 2011, 47, 7641. (b) Perez-Medrano, A.; Brune, M. E.;
Buckner, S. A.; Coghlan, J. J.; Fey, T. A.; Gopalakrishnan, M.; Gregg,
R. J.; Kort, M. E.; Scott, V. E.; Sullivan, J. P.; Whiteaker, K. L.; Carroll,
W. A. J. Med. Chem. 2007, 50, 6265. (c) Durant, G. J.; Emmett, J. C.;
Ganellin, C. R.; Miles, P. D.; Parsons, M. E.; Prain, H. D.; White, G. R.
J. Med. Chem. 1977, 20, 901.
(8) For reviews, see: (a) Garlets, Z. J.; White, D. R.; Wolfe, J. P.
Asian. J. Org. Chem. 2017, in press, doi: 10.1002/ajoc.201600577.
(b) Wolfe, J. P. Top. Heterocycl. Chem. 2013, 32, 1. (c) Schultz, D. M.;
Wolfe, J. P. Synthesis 2012, 44, 351.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00946.
Experimental procedures, characterization data, and
copies of 1H and 13C NMR spectra for all new
compounds (PDF)
(9) The relative stereochemistry of products illustrated in Scheme 1
and eqs 4−6 was assigned by H NMR NOE experiments. See the
Supporting Information for complete details.
1
(10) (a) Fritz, J. A.; Wolfe, J. P. Tetrahedron 2008, 64, 6838.
(b) Fritz, J. A.; Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2006, 8, 2531.
(11) (a) Fornwald, R. M.; Fritz, J. A.; Wolfe, J. P. Chem. - Eur. J.
2014, 20, 8782. (b) Babij, N. R.; McKenna, G. M.; Fornwald, R. M.;
Wolfe, J. P. Org. Lett. 2014, 16, 3412.
(12) The low yield of 8n is due to competing base-mediated
hydroamination of the starting material. This hydroamination side
reaction was not observed with the less nucleophilic N-tosyl guanidine
substrates.
(13) In our prior studies on Pd-catalyzed carboamination reactions of
PMP-protected guanidines with aryl bromides (ref 1) we observed the
stereochemistry of a product closely related to 8n resulted from syn-
addition to a Z-alkene. This assignment was originally based on
analogy to the outcome of reactions of related ureas, and has since
been confirmed via NOE studies.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jpwolfe@umich.edu.
ORCID
John P. Wolfe: 0000-0002-7538-6273
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the NIH (GM 071650) for financial support
of this work.
■
(14) For a detailed discussion of epimerization via β-hydride
elimination pathways that occur after alkene heteropalladation in the
conversion of 4-penten-1-ol derivatives to substituted tetrahydrofur-
ans, see: Hay, M. B.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 16468.
(15) Syn-heteropalladation reactions are believed to proceed via
organized chair-like transition states that result from a need for an
eclipsed orientation between the Pd−N bond and the alkene. In
general, reactions that proceed via syn-heteropalladation provide
products similar to 8k and 9h with much higher selectivities than in
analogous transformations that involve anti-heteropalladation. For
further discussion, see: Peterson, L. J.; Wolfe, J. P. Adv. Synth. Catal.
2015, 357, 2339.
REFERENCES
■
(1) For recent reviews on guanidine-containing natural products, see:
(a) Berlinck, R. G. S.; Romminger, S. Nat. Prod. Rep. 2016, 33, 456.
(b) Berlinck, R. G. S.; Trindade-Silva, A. E.; Santos, M. F. C. Nat. Prod.
Rep. 2012, 29, 1382−1406. (c) Berlinck, R. G. S.; Burtoloso, A. C. B.;
Trindade-Silva, A. E.; Romminger, S.; Morais, R. P.; Bandeira, K.;
Mizuno, C. M. Nat. Prod. Rep. 2010, 27, 1871−1907.
(2) For reviews on the synthesis of natural products that contain
cyclic guanidines, see: (a) Ma, Y.; De, S.; Chen, C. Tetrahedron 2015,
71, 1145. (b) Aron, Z. D.; Overman, L. E. Chem. Commun. 2004, 253.
(c) Heys, L.; Moore, C. G.; Murphy, P. J. Chem. Soc. Rev. 2000, 29, 57.
(3) Alkene diamination: (a) Hovelmann, C. H.; Streuff, J.; Brelot, L.;
Muniz, K. Chem. Commun. 2008, 2334−2336. (b) Zhao, B.; Du, H.;
Shi, Y. Org. Lett. 2008, 10, 1087−1090. C−H functionalization:
(c) Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Org. Lett. 2006,
8, 1073−1076. Oxidative amination: (d) Mulcahy, J. V.; Du Bois, J. J.
Am. Chem. Soc. 2008, 130, 12630−12631. Hydroamination:
(16) (a) Fujino, M.; Wakimasu, M.; Kitada, C. Chem. Pharm. Bull.
1981, 29, 2825. (b) Wakimasu, M.; Kitada, C.; Fujino, M. Chem.
Pharm. Bull. 1982, 30, 2766.
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DOI: 10.1021/acs.orglett.7b00946
Org. Lett. XXXX, XXX, XXX−XXX