Construction of Nitrated Benzo[3.3.1]bicyclic Acetal/Ketal Core via Nitration of o-Carbonyl Allylbenzenes

Article abstract of DOI:10.1021/acs.orglett.7b00245

Intramolecular annulation of o-carbonyl allylbenzenes was achieved to construct novel nitrated [6,6,6]tricycles having an acetal or ketal motif in good yields. The expeditious one-step nitration route provides 4 or 5 new bond formations, including 2 or 3 C-N bonds and 2 C-O bonds. The structural framework of benzobicycle [3.3.1] is confirmed by X-ray crystallographic analysis. A plausible mechanism is proposed.

Full text of DOI:10.1021/acs.orglett.7b00245

Letter
pubs.acs.org/OrgLett
Construction of Nitrated Benzo[3.3.1]bicyclic Acetal/Ketal Core via
Nitration of o‑Carbonyl Allylbenzenes
Chieh-Kai Chan, Yu-Lin Tsai, and Meng-Yang Chang*
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung
807, Taiwan
*
S Supporting Information
ABSTRACT: Intramolecular annulation of o-carbonyl allylbenzenes
was achieved to construct novel nitrated [6,6,6]tricycles having an
acetal or ketal motif in good yields. The expeditious one-step nitration
route provides 4 or 5 new bond formations, including 2 or 3 C−N
bonds and 2 C−O bonds. The structural framework of benzobicycle
[
3.3.1] is confirmed by X-ray crystallographic analysis. A plausible mechanism is proposed.
omino/tandem/cascade reactions to construct complex
molecules from simple building blocks have been
lytic homolytic cleavage of an endo-peroxide bond followed by
annulation of a diradical species, (iv) low-valent titanium-
5
D
indentified as attractive synthetic routes because they combine
mediated pinacol-type cross-coupling of o-phthalaldehydes and
6a
1
o-hydroxybenzaldehydes, (v) oxone-promoted oxidation of the
benzofuran ring leading to transient o-quinone methides and its
rapid and efficient transformations in a single reaction vessel.
This single-step or one-pot process can reduce human effort,
avoid chemical waste, involve multiple sequences of reactions,
and economize cost and reaction time. In accordance with this
powerful tool, much effort has been devoted to the benzofused
dioxabicyclo[3.3.1]nonane core 1. Naturally occurring products
having this core as the central framework include peniciketals A−
6b
subsequent intramolecular [4 + 2] cycloaddition, and (vi)
Pd(II)/Cu(II)-catalyzed Wacker-type oxidative cyclization of
7
diol. Although different promoters were used to form a
benzo[3.3.1]bicyclic ring system (Z = C), such as metal ions
or acids/Lewis acids, it remained challenging to develop a novel
reaction system for constructing this core structure (Z = N).
Scheme 2 shows part of our synthetic chemistry of o-carbonyl
allylbenzenes (2, o-allylbenzaldehydes): a one-pot nitronium ion
2
a
2b
2c
C, integrastatins A and B, epicoccolide A, and epicoconi-
2
d
grone A. Recently, synthetic routes toward core structure 1
have been thoroughly investigated (Scheme 1).
3
−9
The approaches included (i) a novel cis-selective Ramberg-
Scheme 2. Our Synthetic Route to 1
Backlund reaction followed by an unusual Sn(II)-catalyzed ring
3
closure, (ii) BF ·OEt or H SO -mediated intramolecular
3
2
2
4
4
rearrangement of benzofused bicyclo[4.2.0]octane, (iii) photo-
Scheme 1. Routes of Benzofused Dioxabicyclo[3.3.1] Cores
(+
NO )-mediated synthetic route of core 1 with a ketal motif via
2
intramolecular annulation of 2. The o-allyl functional group of 2
plays an important role in enabling different C−C bond
formations for useful substituents during the tandem sequence.
Introduction of an o-allyl substituent is expected to shorten the
synthetic step of targets by utilizing a simple tandem design. The
expeditious one-step transition-metal-free route sets up a novel
framework having the linkage of 4 or 5 newly formed bonds,
including 2 or 3 C−N bonds and 2 C−O bonds under open
vessel conditions. The required starting materials for 2 were
easily prepared from substituted benzaldehydes 3 in moderate
10
overall yields according to reported procedures. To examine
the nitration of o-carbonyl allylbenzenes, we employed 2a
Received: January 23, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00245
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
prepared from 3-hydroxylbenzaldehyde (3a) via a three-step
Letter
(
combination of fuming HNO and H SO provided optimal
reaction conditions (80 °C and 24 h) for one-pot cyclization.
A plausible mechanism for the formation of 1a is illustrated in
3
2
4
protocol of O-allylation, Claisen rearrangement, O-methyla-
1
0
+
tion) as the model substrate to screen the NO -mediated
2
+
reaction conditions. On the basis of the considered synthetic
operation and use of cheaper reagent, the common combination
of fuming HNO (97%, 0.5 mL) and H SO (98%, 2 mL) was
Scheme 3. By the initial in situ formed NO
2
(generated from the
Scheme 3. Plausible Mechanism
3
2
4
11
first examined under open vessel conditions (Table 1).
a
Table 1. Optimal Nitration Conditions
b
entry reagent (mL/equiv)
solvent
H SO
temp (°C) time (h) 1a (%)
mixture of fuming HNO and H SO ), olefinic nitration of 2a
3
2
4
1
2
3
4
5
6
7
8
9
0
1
2
3
4
HNO (0.5 mL)
25
25
80
80
150
80
80
80
80
80
80
80
80
80
12
24
12
24
12
24
24
24
24
24
24
24
24
24
13
22
80
85
51
c
3
2
4
4
4
4
4
gives I, with a secondary carbocation and one nitro substituent
via the first C−N bond formation. Through subsequent
carbonyl-promoted intramolecular annulation, II with an
oxonium ion is formed via the first C−O bond formation.
Following the involvement of the nitro group, III with a
HNO (0.5 mL)
H SO
2
3
HNO (0.5 mL)
H SO
2
3
HNO (0.5 mL)
H SO
2
3
HNO (0.5 mL)
H SO
2
3
NaNO (5 equiv)
AcOH
H SO
3
[3.3.1]bicyclic skeleton is afforded via the second C−O bond
NaNO (5 equiv)
35
c
3
2
4
formation. Tautomerization of III leads to IV. By intermolecular
α-nitration, a nitro group is installed to produce V via the second
C−N bond formation. After a cascade route for tautomerization
of V, VI is yielded. Finally, dehydration of VI produces 1a.
With optimal conditions established (Table 1, entry 4) and a
plausible mechanism proposed (Scheme 3), we examined
HNO /H SO -mediated nitration of 2a−e (Scheme 4). For
AgNO (5 equiv)
AcOH
3
d
d
d
AgNO (5 equiv)
H SO
2
18
13
11
3
4
1
1
1
1
1
Cu(NO ) (5 equiv)
H SO
3
3
2
4
4
4
4
Fe(NO ) (5 equiv)
H SO
2
3
3
d
Bi(NO ) (5 equiv)
H SO
2
5
3
3
AgNO (5 equiv)
H SO
2
26
2
3
2
4
tBuONO (5 equiv)
MeNO2
c
a
Reactions were performed at a 1.0 mmol scale with 2a, reagents (10
b
c
d
Scheme 4. Synthesis of 1a−e
equiv), solvent (2 mL). Isolated yields. No reaction. Complex
mixture was isolated as major products.
Unfortunately, by controlling the reaction temperature and
time as 25 °C and 12 h (entry 1), the yield was low (13%).
Therefore, it was repeated at 24 h (entry 2), and 1a was formed in
only a 22% yield. The reaction at increased temperatures (25 →
8
3
0 °C) was completed in 12 h, furnishing 1a in 80% yield (entry
the R group of 2a−e (R = OMe, OiPr, OnBu, OcC H , OBn),
5
9
). The results prompted us to optimize the reaction to improve
primary and secondary alkyl substituents provided the desired
the yield of 1a. Furthermore, after the reaction time was
increased from 12 to 24 h, a better yield (85%) of 1a was
observed (entry 4) under at 80 °C. However, when the reaction
temperature continued to increase to 150 °C (entry 5), the yield
1
a−e in good yields (73−85%). No obvious yield changes were
observed. This nitration was found to not be limited to a
monomethoxybenzene ring as the substrate, and 2f−i (prepared
from isovanillin (3b) via a three-step protocol of O-allylation,
(
51%) of 1a decreased for 12 h. With these results (80 °C, 24 h),
10
Claisen rearrangement, O-methylation) with a dimethoxyben-
we treated 2a with five commercially available metal nitrates
zene ring also delivered 1f−i (R = OMe, OiPr, OnBu, OcC H )
1
2
13
14
15
16
5
9
(
NaNO , AgNO , Cu(NO ) , Fe(NO ) , Bi(NO ) ) in
2 3 3 2 3 3 3 3
in high yields (75−86%; Scheme 5). One extra nitro group was
installed at the para position of the methoxy substituent on the
benzene ring to form benzo[3.3.1]bicycle. With the p-methoxy
substituent, a third C−N bond formation was generated. One-
step nitration of 2f−i provides 5 new bond formations, including
AcOH or H SO (2 mL) as the medium at 80 °C for 24 h.
However, none of them provided higher yields of 1a than HNO3.
With AcOH, no reactions were observed for NaNO and AgNO3
2
4
3
(entries 6 and 8). Changing the solvent from AcOH to H SO4
2
generated only low (18, 13, 11%) or trace (5%) yields of 1a by
metal-nitrate-mediated nitration of 2a (entries 7, 9−12). From
the phenomenon, we understand that metal nitrates are
inappropriate nitrating reagents for the formation of 1a.
Furthermore, metal nitrite was also examined; however, the
3
C−N bonds and 2 C−O bonds. The structures of 1h,i were
Scheme 5. Synthesis of 1f−i
isolated yield of 1a only increased slightly to 26% via AgNO -
2
17
18
mediated nitration of 2a (entry 13). Organic nitrite tBuONO
was studied, but no 1a was isolated (entry 14). The structure of
a was determined by single-crystal X-ray crystallography. On
19
1
the basis of these observations, we concluded that the
B
DOI: 10.1021/acs.orglett.7b00245
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
19
determined by single-crystal X-ray crystallography. Compared
to 2a−e, the additional methoxy group of 2f−i could make the
electron density of the π-system more likely to participate in an
additional nitration at the para position of the R group under the
electrophilic substitution process.
Scheme 9. Synthesis of 4a−e
Next, nitration of biphenyls was explored. According to
previous works, 2j−m were synthesized from 2-aryl-5-hydroxy-4-
methoxybenzaldehyde (3c, prepared from 3b by NBS-mediated
bromination and Suzuki−Miyaura cross-coupling) via a three-
step protocol of O-allylation, Claisen rearrangement, and O-
1
0
methylation. Different aryl groups of 2j−m (Ar = Ph, 2-
MeC H , 2-MeOC H , 4-CF C H ) produced the desired 1j−m
6
4
6
4
3
6
4
(Scheme 6) in moderate yields (60−72%) under the above
Scheme 6. Synthesis of 1j−m
no isolation of 4e was observed. The electron-withdrawing group
is inappropriate for the formation of 4. A proposed mechansim
conditions. For the electronic nature of aryl substituents, not
only electron-neutral but also electron-withdrawing and
electron-donating groups were achieved.
(
for 2s, R = OiPr) is shown in Scheme 9. Complexation of an
+
olefin motif having one NO provided A. Subsequent carbonyl-
2
1
n,o (Ar = 2-MeC H , 4-FC H ; Scheme 7) were obtained in
6 4 6 4
promoted intramolecular annulation afforded B. Involvement of
+
7
9 and 84% yields, respectively, via HNO /H SO -mediated
3 2 4
another NO caused the para-methoxy group to promote an
2
intramolecular electrophilic cyclization of B to give C via a C−N
bond formation. After the nitro-group-mediated aromatization,
D was formed. Water was installed to D so that transformation
from E to F was achieved via a six-membered ring opening. After
a cascade route for tautomerization of F and dehydration of the
resulting G occurred, H was yielded. The structure of H was
determined by single-crystal X-ray crystallography. Although
the isolated yield of H (R = OiPr) is low (8%), generation of H
can explain the reaction pathway properly. With the release of
Scheme 7. Synthesis of 1n,o
19
benzannulation of benzoketones 2n,o (prepared from a two-step
route of Grignard addition of 2f and sequential PCC-mediated
oxidation of the resulting secondary alcohols). The structures of
formic acid and involvement of H O, H led to I. Finally,
2
hydrolysis of I produced 4b. From the reaction pathway, we
observed that different positions of dioxygenated substituents on
the benzaldehyde skeleton are a key factor affecting nitration
products. Compared with the R of a 3,4-dioxygenated group
19
1m,o were determined by single-crystal X-ray crystallography.
Compared to Scheme 5, no further p-nitration on the benzene
ring was observed due to the steric hindrance of the aryl group.
Nitration of the simplest o-allylbenzaldehyde (2p, R = H,
prepared by Suzuki−Miyaura cross-coupling of o-formylphenyl
boronic acid and allyl bromide) yielded 1p (82% yield; Scheme
(
Scheme 5, near the ring junction), R on the 4,5-dioxygenated
group possessed less steric hindrance such that it could trigger
the ring opening of C followed by sequential aromatization.
Furthermore, after the o-side chain changed from an allyl and
crotyl group to a styryl group, an unexpected result was observed.
Treatment of 2w with HNO /H SO provided 5a via intra-
8). When R was changed to a fluoro group (for 2q), we found
3
2
4
Scheme 8. Synthesis of 1p,q
molecular dehydrogenative aromatization followed by o-position
nitration (Scheme 10).
To explore the synthetic applications of nitrated [6,6,6]-
tricycles, we examined oxidation of 1o (Scheme 11). When 1o
was treated with the combination of SeO (5 equiv)/30% H O
2
2
2
(
5 mL), 6a was obtained in a 51% yield via a domino process,
including allylic oxidation of 1o, ring opening of nitrated
that a complex mixture replaced the desired 1q, showing that an
electron-withdrawing group is an inappropriate substituent for
HNO /H SO -mediated annulation.
[6,6,6]tricycles, S Ar reaction of H O and further oxidation of
N
2
3
2
4
Scheme 10. Synthesis of 5a
Different results were observed when the dioxygenated group
was adjusted from a 3,4- to a 4,5-position on benzaldehyde
skeleton 3 (Scheme 9). Treatment of 2r−u (prepared from the
three-step route of O-allylation, double Claisen rearrangement,
1
0
and O-methylation) with HNO /H SO provided 4a−d in
3
2
4
moderate yields (67−75%). When R was a nitro group (for 2v),
C
DOI: 10.1021/acs.orglett.7b00245
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Tetrahedron Lett. 2002, 43, 2351. For epicoccolide A, see: (c) Talontsi,
F. M.; Dittrich, B.; Schuffler, A.; Sun, H.; Laatsch, H. Eur. J. Org. Chem.
Scheme 11. Synthesis of 6a
2
013, 2013, 3174. For epicoconigrone A, see: (d) El Amrani, M.; Lai,
D.; Debbab, A.; Aly, A. H.; Siems, K.; Seidel, C.; Schnekenburger, M.;
Gaigneaux, A.; Diederich, M.; Feger, D.; Lin, W.; Proksch, P. J. Nat. Prod.
2
(
4
014, 77, 49.
3) (a) Foot, J. S.; Giblin, C. M. P.; Taylor, R. J. K. Org. Lett. 2003, 5,
441. (b) Foot, J. S.; Giblin, G. M. P.; Whitwood, A. C.; Taylor, R. J. K.
Org. Biomol. Chem. 2005, 3, 756. (c) Cayley, A. N.; Gallagher, K. A.;
Menard-Moyon, C.; Schmidt, J. P.; Diorazio, L. J.; Taylor, R. J. K.
Synthesis 2008, 2008, 3846.
(
4) Mal, J.; Nath, A.; Venkateswaran, R. V. J. Org. Chem. 1996, 61,
164.
5) Guney, M.; Coskun, A.; Topal, F.; Dastan, A.; Gulcin, I.; Supuran,
C. T. Bioorg. Med. Chem. 2014, 22, 3537.
6) (a) Ramana, C. V.; Reddy, C. N.; Gonnade, R. G. Chem. Commun.
008, 3151. (b) More, A. A.; Ramana, C. V. Org. Lett. 2016, 18, 612.
7) Tadross, P. M.; Bugga, P.; Stoltz, B. M. Org. Biomol. Chem. 2011, 9,
354.
8) Synthesis routes of other benzofused [3.3.1]-dioxabicycles:
(a) Green, J. C.; Brown, E. R.; Pettus, T. R. R. Org. Lett. 2012, 14,
2929. (b) Kim, I.; Kim, S. G.; Choi, J.; Lee, G. H. Tetrahedron 2008, 64,
664. (c) Ullah, E.; Rotzoll, S.; Schmidt, A.; Michalik, D.; Langer, P.
Tetrahedron Lett. 2005, 46, 8997. (d) Srinivas, V.; Koketsu, M. J. Org.
Chem. 2013, 78, 11612. (e) Yin, G.; Ren, T.; Rao, Y.; Zhou, Y.; Li, Z.;
Shu, W.; Wu, A. J. Org. Chem. 2013, 78, 3132. (f) Gueney, M.; Dastan,
A.; Balci, M. Helv. Chim. Acta 2005, 88, 830.
9
(
(
2
(
5
aldehyde, and Friedel−Crafts ring closure. The intriguing
conversion is novel for the formation of an oxygenated
20
anthraquinone skeleton. The structure of 6a was determined
19
by single-crystal X-ray crystallography.
In summary, we developed HNO /H SO -mediated synthesis
(
3
2
4
of nitrated [6,6,6]tricycles having an acetal or ketal motif in good
yields via intramolecular annulation of o-carbonyl allylbenzenes.
The expeditious one-step nitration route provides 4 or 5 new
bond formations, including 2 or 3 C−N bonds and 2 C−O
bonds. The key products were confirmed by X-ray crystallog-
raphy.
(
9) Synthesis routes of the central [3.3.1]-dioxabicyclic core:
(
a) Aiguade, J.; Hao, J.; Forsyth, C. J. Org. Lett. 2001, 3, 979.
ASSOCIATED CONTENT
Supporting Information
■
(b) Cho, Y. S.; Kim, H. Y.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Choi, J. H.;
Chang, M. H. Org. Lett. 2002, 4, 2025. (c) Francisco, C. G.; Freire, R.;
Herrera, A. J.; Perez-Martin, I.; Suarez, E. Org. Lett. 2002, 4, 1959.
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00245.
(
3
d) Oikawa, M.; Uehara, T.; Iwayama, T.; Sasaki, M. Org. Lett. 2006, 8,
943.
10) Synthetic applications on the o-carbonyl allylbenzenes:
a) Chang, M.-Y.; Wu, M.-H.; Chen, Y.-L. Org. Lett. 2013, 15, 2822.
X-ray data of 1a (CIF), 1h (CIF), 1i (CIF), 1m (CIF), 1o
(
(
CIF), 4a (CIF), H (CIF), 5a (CIF), and 6a (CIF)
(
Detailed experimental procedures and spectroscopic data
for all new compounds (PDF)
(b) Chan, C.-K.; Chan, Y.-L.; Chang, M.-Y. Tetrahedron 2016, 72, 547.
(c) Chan, C.-K.; Tsai, Y.-L.; Chan, Y.-L.; Chang, M.-Y. J. Org. Chem.
2
(
016, 81, 9836.
11) For HNO : (a) Chentsova, A.; Ushakov, D. B.; Seeberger, P. H.;
3
AUTHOR INFORMATION
Corresponding Author
■
*
Gilmore, K. J. Org. Chem. 2016, 81, 9415. (b) Ogurtsov, V. A.; Shastin, A.
V.; Zlotin, S. G.; Rakitin, O. A. Tetrahedron Lett. 2016, 57, 4027.
E-mail: mychang@kmu.edu.tw.
ORCID
(12) NaNO
Org. Lett. 2016, 18, 4190.
13) AgNO : Li, C.; Deng, H.; Li, C.; Jia, X.; Li, J. Org. Lett. 2015, 17,
: Dighe, S. U.; Mukhopadhyay, S.; Priyanka, K.; Batra, S.
3
(
3
Meng-Yang Chang: 0000-0002-1983-8570
Notes
5718.
(14) Cu(NO ) : Gao, M.; Xu, B. Org. Lett. 2016, 18, 4746.
3 2
(15) Fe(NO ) : Sadhu, P.; Alla, S. K.; Punniyamurthy, T. J. Org. Chem.
3
3
The authors declare no competing financial interest.
2
015, 80, 8245.
(
16) Bi(NO ) : Manna, S.; Maity, S.; Rana, S.; Agasti, S.; Maiti, D. Org.
3
3
ACKNOWLEDGMENTS
We thank the Ministry of Science and Technology of the
Republic of China for financial support (MOST 105-2113-M-
37-001).
■
Lett. 2012, 14, 1736.
(17) AgNO : Pawar, G. G.; Brahmanandan, A.; Kapur, M. Org. Lett.
2016, 18, 448.
18) Nonmetal reagent-mediated nitration for tBuONO: (a) Lin, Y.;
2
(
0
Kong, W.; Song, Q. Org. Lett. 2016, 18, 3702. (b) Zhang, W.; Ren, S.;
Zhang, J.; Liu, Y. J. Org. Chem. 2015, 80, 5973. For NO BF :
REFERENCES
2
4
■
(
8
c) Natarajan, P.; Chaudhary, R.; Venugopalan, P. J. Org. Chem. 2015,
0, 10498.
19) CCDC 1525439 (1a), 1525440 (1h), 1525441 (1i), 1535310
1m), 1525442 (1o), 1525443 (4a), 1532864 (H), 1525444 (5a), and
(
1) (a) Tietze, L. F.; Gordon, B.; Kersten, G. M. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006. (b) Tietze, L. F.;
Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967. (c) Hussain, M. M.;
Walsh, P. J. Acc. Chem. Res. 2008, 41, 883. (d) Li, Z.; Brouwer, C.; He, C.
Chem. Rev. 2008, 108, 3239. (e) Grondal, C.; Jeanty, M.; Enders, D. Nat.
Chem. 2010, 2, 167. (f) Moyano, A.; Rios, R. Chem. Rev. 2011, 111, 4703.
g) Pellissier, H. Adv. Synth. Catal. 2012, 354, 237. (h) Lu, L.-Q.; Chen,
J.-R.; Xiao, W.-J. Acc. Chem. Res. 2012, 45, 1278.
2) Natural products with the benzodioxabicyclo[3.3.1]nonane core;
for peniciketals A−C, see: (a) Liu, W.-Z.; Ma, L.-Y.; Liu, D.-S.; Huang,
Y.-L.; Wang, C.-H.; Shi, S.-S.; Pan, X.-H.; Song, X.-D.; Zhu, R.-X. Org.
Lett. 2014, 16, 90. For integrastatins A,B, see: (b) Singh, S. B.; Zink, D.
L.; Quamina, D. S.; Pelaez, F.; Teran, A.; Felock, P.; Hazuda, D. J.
(
(
1
532720 (6a) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge via www.ccdc.cam.ac.
uk/conts/retrieving.html (or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: 44-1223-336033; e-mail: deposit@
ccdc.cam.ac.uk).
(
(
(20) Selected examples on synthesis of oxygenated anthraquinones:
(a) Punner, F.; Schieven, J.; Hilt, G. Org. Lett. 2013, 15, 4888.
(b) Podlesny, E. E.; Kozlowski, M. C. Org. Lett. 2012, 14, 1408. (c) Xu,
W.; Paira, R.; Yoshikai, N. Org. Lett. 2015, 17, 4192.
D
DOI: 10.1021/acs.orglett.7b00245
Org. Lett. XXXX, XXX, XXX−XXX